JP2004083567A - Tricyclic condensed heterocyclic compound, its production method and use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new tricyclic condensed heterocyclic compound and its production method and use. <P>SOLUTION: A pharmaceutical composition comprises a compound represented by formula (1), its optical isomer and its conjugate, or their pharmaceutically permissible salts (in formula (1), X is CH, CH<SB>2</SB>, CHR or CRR'; Y is CH, CH<SB>2</SB>or C=O; Z is selected from O, S, S=O and SO<SB>2</SB>; U is C or N; R<SB>1</SB>-R<SB>4</SB>are each independently a hydrogen atom, OR, SR, an aromatic ring, a substituted aromatic ring or a heterocyclic ring; at least one of R<SB>5</SB>-R<SB>8</SB>is, for example, OH and the others are each independently a hydrogen atom or OH; and R and R' are each a lower alkyl group or a substituted lower alkyl group). These compounds have a wide range of the following pharmacological effects: an excellent effect on relaxant of the tracheae smooth muscle, effects on suppressing airway hypersensitivity and on suppressing invasion of inflammatory cells into the airway, and they also have a high safety. <P>COPYRIGHT: (C)2004,JPO

Description

【００２５】
［式中
Ｘ、Ｙは、
Ｘ―Ｙの結合が単結合である場合は、Ｘ、Ｙそれぞれ独立に（同一又は異なって）、ＣＷ_１Ｗ_２（Ｗ_１、Ｗ_２はそれぞれ独立に（同一又は異なって）、水素原子、ハロゲン、水酸基、低級アルキル基、置換低級アルキル基、低級アルコキシ基、シクロアルキル基、シクロアルケニル基のいずれかである）、Ｃ＝Ｏ、Ｃ＝ＮＯＷ_３（Ｗ_３は水素原子又は低級アルキル基）から選ばれる任意のものであり、
Ｘ―Ｙの結合が二重結合の場合は、Ｘ、Ｙそれぞれ独立に（同一又は異なって）ＣＷ_４（Ｗ_４は水素原子、ハロゲン、水酸基、低級アルキル基、置換低級アルキル基、低級アルコキシ基、アシルオキシ基のいずれかである）であり、
ＺはＯ，Ｓ，Ｓ＝Ｏ，ＳＯ_２から選ばれる任意のものであり、
ＵはＣまたはＮであり、
Ｒ_１ないしＲ_４はそれぞれ独立に（同一又は異なって）、水素原子、低級アルキル基、置換低級アルキル基、シクロアルキル基、置換シクロアルキル基、低級アルケニル基、置換低級アルケニル基、低級アルキニル基、置換低級アルキニル基、ハロゲン基、低級アルキルカルボニル基、置換低級アルキルカルボニル基、トリハロメチル基、Ｖ_１Ｗ_５（Ｖ_１はＯ，Ｓ、Ｓ＝Ｏ、ＳＯ_２から選ばれる任意のものであり、Ｗ_５は水素原子、低級アルキル基、置換低級アルキル基、低級アルキルカルボニル基、置換低級アルキルカルボニル基、アシルオキシ基、トリハロメチル基から選ばれる任意のものである。）、ニトロ基、アミノ基、置換アミノ基、シアノ基、アシル基、アシルアミノ基、置換アシル基、置換アシルアミノ基、芳香環、置換芳香環、複素環、置換複素環から選ばれる任意のものであり（ＵがＮの場合、Ｒ_４は存在しない場合もある）、
Ｒ_５ないしＲ_８はそれぞれ独立に（同一又は異なって）、水素原子、低級アルキル基、置換低級アルキル基、低級アルケニル基、置換低級アルケニル基、低級アルキニル基、置換低級アルキニル基、ハロゲン基、低級アルキルカルボニル基、置換低級アルキルカルボニル基、トリハロメチル基、Ｖ_２Ｗ_７（Ｖ_２はＯ，Ｓ、Ｓ＝Ｏ、ＳＯ_２から選ばれる任意のものであり、Ｗ_７は水素原子、低級アルキル基、置換低級アルキル基、低級アルキルカルボニル基、置換低級アルキルカルボニル基、トリハロメチル基から選ばれる任意のものである。）、ニトロ基、アミノ基、置換アミノ基、アシルアミノ基、芳香環、置換芳香環、複素環、置換複素環から選ばれる任意のものである。
但し、ＸがＣＨＷ_０、ＣＷ_０Ｗ_０またはＣＷ_０（式中、Ｗ_０は低級アルキル基、置換低級アルキル基から選ばれる任意のものである）の場合は、Ｒ_５ないしＲ_８のうち少なくとも一つが水酸基であり（但し、Ｘ−ＹがＣＨ（Ｃ_２Ｈ_５）ＣＯのときはＲ_６が単独で水酸基ではない）、ＸがＣＨＷ_０、ＣＷ_０Ｗ_０またはＣＷ_０（式中、Ｗ_０は低級アルキル基、置換低級アルキル基から選ばれる任意のものである）以外の場合は、Ｒ_５ないしＲ_８のうち少なくとも１つは水酸基であり、またそれ以外のＲ_５ないしＲ_８のうち少なくとも１つの基はＯＲ基（式中、Ｒは水素原子、低級アルキル基、置換低級アルキル基、低級アルキルカルボニル基および置換低級アルキルシリルから選ばれる任意のものである）である。
さらに、Ｘ−ＹがＣＨ_２ＣＨ_２、ＣＨＢｒＣＨ_２、ＣＨ_２ＣＯ、ＣＯＣＨ_２、ＣＨＢｒＣＯ、ＣＨ＝ＣＨ、ＣＨ＝ＣＯＣＯＣＨ_３、ＣＨ＝ＣＯＣＨ_３の場合は
Ｒ_１ないしＲ_４の少なくとも一つが芳香環、置換芳香環、複素環、置換複素環であるか（但し、Ｒ_６およびＲ_７の両方が水酸基の場合はＲ_１ないしＲ_４のいずれもフェニル基ではない）、
Ｒ_１ないしＲ_４の少なくとも一つがＳＷ_８（Ｗ_８は低級アルキル基または置換低級アルキル基）または、Ｓ（Ｏ）Ｗ_９（Ｗ_９は低級アルキル基または置換低級アルキル基）のいずれかであるか（但し、ＺがＯのときはＲ_７は水素原子でない）、
Ｒ_２が低級アルキル基、または置換低級アルキル基のいずれかであり、かつ、Ｒ_８は水酸基であるか（但し、ＺがＯのときは低級アルキル基の炭素数は３以上である）、
Ｒ_１ないしＲ_４の少なくとも一つが低級アルキルカルボニル　（但し、低級アルキル基の炭素数は３以上である）、シクロアルキルカルボニルまたはシクロアルケニルカルボニルであり、かつＲ_８が水酸基であるか、
Ｒ_１ないしＲ_４の少なくとも一つが−Ｃ（＝ＮＯＲ）ＣＨ_３（Ｒは水素原子または低級アルキル基である）
のいずれかである。］
で表される化合物、その光学異性体、その抱合体またはそれらの薬剤学的に許容される塩。
（２）Ｒ_６が水酸基である前記（１）記載の化合物。
（３）Ｒ_６およびＲ_７が水酸基である前記（１）記載の化合物。
（４）Ｒ_６およびＲ_８が水酸基である前記（１）記載の化合物。
（５）Ｒ_５およびＲ_６が水酸基である前記（１）記載の化合物。
（６）Ｘ−Ｙが単結合で、ＸがＣＷ_１Ｗ_２（Ｗ_１、Ｗ_２の少なくとも一方が低級アルキル基、置換低級アルキル基、シクロアルキル基、シクロアルケニル基から選ばれる任意のものである）であるか、Ｘ−Ｙが二重結合で、ＸがＣＷ_３（Ｗ_３は低級アルキル基又は置換低級アルキル基から選ばれる任意のものである）である前記（１）ないし（５）のいずれか１項記載の化合物。
（７）ＹがＣＯである前記（１）ないし（６）のいずれか１項記載の化合物。
（８）低級アルキル基がメチル基、エチル基、ｎ−プロピル基、ｉ−プロピル基、ｎ−ブチル基、ｓ−ブチル基、ｉ−ブチル基、ｔ−ブチル基のいずれかである前記（６）または（７）記載の化合物。
（９）Ｒ_２またはＲ_３が複素環、置換複素環、芳香環、置換芳香環のいずれかであるである前記（１）ないし（５）のいずれか１項記載の化合物。
（１０）複素環が芳香性の複素環である前記（１）ないし（５）のいずれか１項記載の化合物。
（１１）Ｒ_２またはＲ_３がＳＷ_８（Ｗ_８は低級アルキル基または置換低級アルキル基）または、Ｓ（Ｏ）Ｗ_９（Ｗ_９は低級アルキル基または置換アルキル基）である前記（１）ないし（５）のいずれか１項記載の化合物。
（１２）低級アルキル基がメチル基、エチル基、ｎ−プロピル基、ｉ−プロピル基、ｎ−ブチル基、ｓ−ブチル基、ｉ−ブチル基、ｔ−ブチル基のいずれかである前記（１１）記載の化合物。
（１３）ＺがＳである前記（１）ないし（１２）のいずれか１項記載の化合物。（１４）７，８−ジヒドロキシ−１１−エチル−１０，１１−シヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オンである前記（１）記載の化合物。
（１５）１１−ジエチル−７，８−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オンである前記（１）記載の化合物。
（１６）７，９−ジヒドロキシ−２−メチルチオ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オンである前記（１）記載の化合物。
（１７）下記▲１▼、▲２▼の反応工程
▲１▼ウルマン反応によりＡ環とＣ環を結合させる（式２）。
▲２▼フリーデル−クラフツ反応、または、光反応によりＡ環とＣ環を結合させる（式３）。
【００２６】
【化７】

【００２７】
［式２、３中、Ｑ、Ｓ、Ｗは任意の置換基を表し、ＵはＣ又はＮであり、Ｘ、Ｙのうち一方は脱離基を、他方は求核基を表し、ＺはＯ、Ｓ、ＳＯ、ＳＯ_２のいずれかを表す。］
を任意の順序で含むことを特徴とする、
式１
【００２８】
【化８】

【００２９】
［式中
Ｘ、Ｙは、
Ｘ―Ｙの結合が単結合である場合は、Ｘ、Ｙそれぞれ独立に（同一又は異なって）、ＣＷ_１Ｗ_２（Ｗ_１、Ｗ_２はそれぞれ独立に（同一又は異なって）、水素原子、ハロゲン、水酸基、低級アルキル基、置換低級アルキル基、低級アルコキシ基、シクロアルキル基、シクロアルケニル基のいずれかである）、Ｃ＝Ｏ、Ｃ＝ＮＯＷ_３（Ｗ_３は水素原子又は低級アルキル基）から選ばれる任意のものであり、
Ｘ―Ｙの結合が二重結合の場合は、Ｘ、Ｙそれぞれ独立に（同一又は異なって）ＣＷ_４（Ｗ_４は水素原子、ハロゲン、水酸基、低級アルキル基、置換低級アルキル基、低級アルコキシ基、アシルオキシ基のいずれかである）であり、
ＺはＯ，Ｓ，Ｓ＝Ｏ，ＳＯ_２から選ばれる任意のものであり、
ＵはＣまたはＮであり、
Ｒ_１ないしＲ_４はそれぞれ独立に（同一又は異なって）、水素原子、低級アルキル基、置換低級アルキル基、シクロアルキル基、置換シクロアルキル基、低級アルケニル基、置換低級アルケニル基、低級アルキニル基、置換低級アルキニル基、ハロゲン基、低級アルキルカルボニル基、置換低級アルキルカルボニル基、トリハロメチル基、Ｖ_１Ｗ_５（Ｖ_１はＯ，Ｓ、Ｓ＝Ｏ、ＳＯ_２から選ばれる任意のものであり、Ｗ_５は水素原子、低級アルキル基、置換低級アルキル基、低級アルキルカルボニル基、置換低級アルキルカルボニル基、アシルオキシ基、トリハロメチル基から選ばれる任意のものである。）、ニトロ基、アミノ基、置換アミノ基、シアノ基、アシル基、アシルアミノ基、置換アシル基、置換アシルアミノ基、芳香環、置換芳香環、複素環、置換複素環から選ばれる任意のものであり（ＵがＮの場合、Ｒ_４は存在しない場合もある）、
Ｒ_５ないしＲ_８はそれぞれ独立に（同一又は異なって）、水素原子、低級アルキル基、置換低級アルキル基、低級アルケニル基、置換低級アルケニル基、低級アルキニル基、置換低級アルキニル基、ハロゲン基、低級アルキルカルボニル基、置換低級アルキルカルボニル基、トリハロメチル基、Ｖ_２Ｗ_７（Ｖ_２はＯ，Ｓ、Ｓ＝Ｏ、ＳＯ_２から選ばれる任意のものであり、Ｗ_７は水素原子、低級アルキル基、置換低級アルキル基、低級アルキルカルボニル基、置換低級アルキルカルボニル基、トリハロメチル基から選ばれる任意のものである。）、ニトロ基、アミノ基、置換アミノ基、アシルアミノ基、芳香環、置換芳香環、複素環、置換複素環から選ばれる任意のものである。
但し、ＸがＣＨＷ_０、ＣＷ_０Ｗ_０またはＣＷ_０（式中、Ｗ_０は低級アルキル基、置換低級アルキル基から選ばれる任意のものである）の場合は、Ｒ_５ないしＲ_８のうち少なくとも一つが水酸基であり（但し、Ｘ−ＹがＣＨ（Ｃ_２Ｈ_５）ＣＯのときはＲ_６が単独で水酸基ではない）、ＸがＣＨＷ_０、ＣＷ_０Ｗ_０またはＣＷ_０（式中、Ｗ_０は低級アルキル基、置換低級アルキル基から選ばれる任意のものである）以外の場合は、Ｒ_５ないしＲ_８のうち少なくとも１つは水酸基であり、またそれ以外のＲ_５ないしＲ_８のうち少なくとも１つの基はＯＲ基（式中、Ｒは水素原子、低級アルキル基、置換低級アルキル基、低級アルキルカルボニル基および置換低級アルキルシリルから選ばれる任意のものである）である。
さらに、Ｘ−ＹがＣＨ_２ＣＨ_２、ＣＨＢｒＣＨ_２、ＣＨ_２ＣＯ、ＣＯＣＨ_２、ＣＨＢｒＣＯ、ＣＨ＝ＣＨ、ＣＨ＝ＣＯＣＯＣＨ_３、ＣＨ＝ＣＯＣＨ_３の場合は
Ｒ_１ないしＲ_４の少なくとも一つが芳香環、置換芳香環、複素環、置換複素環であるか（但し、Ｒ_６およびＲ_７の両方が水酸基の場合はＲ_１ないしＲ_４のいずれもフェニル基ではない）、
Ｒ_１ないしＲ_４の少なくとも一つがＳＷ_８（Ｗ_８は低級アルキル基または置換低級アルキル基）または、Ｓ（Ｏ）Ｗ_９（Ｗ_９は低級アルキル基または置換低級アルキル基）のいずれかであるか（但し、ＺがＯのときはＲ_７は水素原子でない）、
Ｒ_２が低級アルキル基、または置換低級アルキル基のいずれかであり、かつ、Ｒ_８は水酸基であるか（但し、ＺがＯのときは低級アルキル基の炭素数は３以上である）、
Ｒ_１ないしＲ_４の少なくとも一つが低級アルキルカルボニル　（但し、低級アルキル基の炭素数は３以上である）、シクロアルキルカルボニルまたはシクロアルケニルカルボニルであり、かつＲ_８が水酸基であるか、
Ｒ_１ないしＲ_４の少なくとも一つが−Ｃ（＝ＮＯＲ）ＣＨ_３（Ｒは水素原子または低級アルキル基である）
のいずれかである。］
で表される化合物、その光学異性体、その抱合体またはそれらの薬剤学的に許容される塩の製造方法。
（１８）さらに、炭素増加反応工程、置換基の変換反応工程、置換基の導入反応工程、置換基の脱保護反応を行う工程、塩を形成する工程および光学分割を行う工程のうちいずれか１以上の工程を含む（１７）記載の製造方法。なお、本発明において、上記各工程、▲１▼の反応工程および▲２▼の反応工程の順序に特に制限はなく、目的化合物の構造を初めとする種々の条件を勘案して当業者が任意に設定することができる。
（１９）有効量の（１）ないし（１６）のいずれか１項に記載された化合物及び薬剤学的に許容される担体又は希釈剤を含む薬剤組成物。
（２０）気管平滑筋弛緩作用を利用する（１９）記載の薬剤組成物。
（２１）気道過敏性抑制作用を利用する（１９）記載の薬剤組成物。
（２２）炎症性細胞の浸潤抑制作用を利用する（１９）記載の薬剤組成物。
（２３）抗喘息薬として使用する（１９）記載の薬剤組成物。
（２４）下式
【００３０】
【化９】

【００３１】
［式中、Ｑは低級アルキル基である。］
で表される化合物、その光学異性体またはその塩。
（２５）下式
【００３２】
【化１０】

【００３３】
［式中、Ｑは低級アルキル基であり、Ｑ_１ないしＱ_５はそれぞれ独立に（同一に又は異なって）水素原子、低級アルコキシ基および水酸基から選ばれる任意のものである。］
で表される化合物、その光学異性体またはその塩。
【００３４】
なお、前記（１）に記載の化合物またはその塩が構造中に不斉炭素を含有する場合、光学活性化合物およびラセミ体化合物も本発明の範囲に含まれる。さらに、前記（１）に記載の化合物またはその塩は水和物あるいは非水和物のいずれであってもよく、また、溶媒和物であってもよい。
【００３５】
【発明の実施の形態】
本願明細書中で用いられる用語「ハロゲン基」とは、フッ素、塩素、臭素、ヨウ素のいずれかの基を意味する。また、本願明細書中で用いられる用語「トリハロメチル基」とは、メチル基の３個の水素原子がハロゲン原子によって置換された形の基を意味し、この３個のハロゲン原子はすべて同一であっても、２個以上の異なるハロゲン原子から構成されていてもよい。
【００３６】
本願明細書中で用いられる用語「低級アルキル基」とは、例えば、直鎖状もしくは分枝状のＣ_１−６アルキル基を意味する。Ｃ_１−６アルキル基としては、例えば、メチル、エチル、ｎ−プロピル、ｉ−プロピル、ｎ−ブチル、ｉ−ブチル、ｔ−ブチル、ｎ−ペンチル又はｎ−ヘキシルなどが用いられる。該「低級アルキル基」が有していてもよい置換基としては、例えば、ヒドロキシ、アミノ、カルボキシル、ニトロ、アリール基、置換アリール基、モノ−またはジ−低級アルキルアミノ（例えば、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、ジエチルアミノなどのモノ−またはジ−Ｃ_１−６アルキルアミノなど）、低級アルコキシ（例えば、メトキシ、エトキシ、プロポキシ、ヘキシルオキシなどのＣ_１−６アルコキシなど）、低級アルキルカルボニルオキシ（例えば、アセトキシ、エチルカルボニルオキシなどのＣ_１−６アルキル−カルボニルオキシなど）またはハロゲン原子などから選ばれた１個もしくは２個以上が用いられる。なお、本願明細書中において、「低級アルコキシ基」における、低級アルキル部分は上記「低級アルキル基」について記載された意味を有する。
【００３７】
本願明細書中で用いられる用語「シクロアルキル基」とは、例えば、Ｃ_３−８の環状アルキル基を意味する。Ｃ_３−８シクロアルキル基としては、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロオクチル基などが用いられる。該「シクロアルキル基」が有していてもよい置換基としては、例えば、ヒドロキシ、アミノ、カルボキシル、ニトロ、モノ−またはジ−低級アルキルアミノ（例えば、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、ジエチルアミノなどのモノ−またはジ−Ｃ_１−６アルキルアミノなど）、低級アルコキシ（例えば、メトキシ、エトキシ、プロポキシ、ヘキシルオキシなどのＣ_１−６アルコキシなど）、低級アルキルカルボニルオキシ（例えば、アセトキシ、エチルカルボニルオキシなどのＣ_１−６アルキル−カルボニルオキシなど）またはハロゲン原子などから選ばれた１個もしくは２個以上が用いられる。
【００３８】
本願明細書中で用いられる用語「シクロアルケニル基」とは、シクロアルキル基の環状部分に二重結合が一つ以上存在するものを意味する。
【００３９】
本願明細書中で用いられる用語「低級アルケニル基」とは、例えば、直鎖状もしくは分枝状のＣ_２−６アルケニル基を意味する。Ｃ_２−６アルケニル基としては、例えば、ビニル、アリル、２−メチルアリル、ｉ−プロペニル、２−ブテニル、３−ブテニル、２−ペンテニル、３−ペンテニル、２−ヘキセニル、３−ヘキセニルなどが用いられる。該「低級アルケニル基」が有していてもよい置換基としては、例えば、ヒドロキシ、アミノ、カルボキシル、ニトロ、モノ−またはジ−低級アルキルアミノ（例えば、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、ジエチルアミノなどのモノ−またはジ−Ｃ_１−６アルキルアミノなど）、低級アルコキシ（例えば、メトキシ、エトキシ、プロポキシ、ヘキシルオキシなどのＣ_１−６アルコキシなど）、低級アルキルカルボニルオキシ（例えば、アセトキシ、エチルカルボニルオキシなどのＣ_１−６アルキル−カルボニルオキシなど）またはハロゲン原子などから選ばれた１個もしくは２個以上が用いられる。
【００４０】
本願明細書中で用いられる用語「低級アルキニル基」とは、例えば、直鎖状もしくは分枝状のＣ_２−６アルキニル基を意味する。Ｃ_２−６アルキニル基としては、例えば、エチニル、２−プロピニル、２−ブチニル、３−ブチニル、２−ペンチニル、３−ペンチニル、２−ヘキシニル、３−ヘキシニルなどが用いられる。該「低級アルキニル基」が有していてもよい置換基としては、例えば、ヒドロキシ、アミノ、カルボキシル、ニトロ、モノ−またはジ−低級アルキルアミノ（例えば、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、ジエチルアミノなどのモノ−またはジ−Ｃ_１−６アルキルアミノなど）、低級アルコキシ（例えば、メトキシ、エトキシ、プロポキシ、ヘキシルオキシなどのＣ_１−６アルコキシなど）、低級アルキルカルボニルオキシ（例えば、アセトキシ、エチルカルボニルオキシなどのＣ_１−６アルキル−カルボニルオキシなど）またはハロゲン原子などから選ばれた１個もしくは２個以上が用いられる。
【００４１】
本願明細書中で用いられる用語「低級アルキルカルボニル基」における低級アルキル部分は上記「低級アルキル基」について記載された意味を有する。
【００４２】
本願明細書中で用いられる用語「置換アミノ基」における置換基としては、例えば、ヒドロキシ、カルボキシル、モノ−またはジ−低級アルキル（例えば、メチル、エチル、ｎ−プロピル、ｉ−プロピル、ジメチル、ジエチルなどのモノ−またはジ−Ｃ_１−６アルキル）、低級アルコキシ（例えば、メトキシ、エトキシ、プロポキシ、ヘキシルオキシなどのＣ_１−６アルコキシなど）、低級アルキルカルボニルオキシ（例えば、アセトキシ、エチルカルボニルオキシなどのＣ_１−６アルキル−カルボニルオキシなど）またはハロゲン原子などから選ばれた１個もしくは２個が用いられる。
【００４３】
本願明細書中で用いられる用語「アシル基」とは−ＣＯＲ（Ｒは、水素原子、低級アルキル基、低級アルケニル基、低級アルキニル基、炭素数３〜８のシクロアルキル基、単環もしくは多環の芳香環または複素環等のいずれかを意味する）で表される基を意味する。本願明細書中で用いられる用語「アシルオキシ基」および「アシルアミノ基」におけるアシル部分も上記アシル基と同じ意味を表す。該「アシル基」および「アシルアミノ基」が有していてもよい置換基とはＲ上における置換基を意味し、例えば、ヒドロキシ、アミノ、カルボキシル、ニトロ、モノ−またはジ−低級アルキルアミノ（例えば、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、ジエチルアミノなどのモノ−またはジ−Ｃ_１−６アルキルアミノなど）、低級アルコキシ（例えば、メトキシ、エトキシ、プロポキシ、ヘキシルオキシなどのＣ_１−６アルコキシなど）、低級アルキルカルボニルオキシ（例えば、アセトキシ、エチルカルボニルオキシなどのＣ_１−６アルキル−カルボニルオキシなど）またはハロゲン原子などから選ばれた１個もしくは２個以上が用いられる。
【００４４】
本願明細書中で用いられる用語「芳香環」とは芳香族炭化水素から水素原子１個を除いた残りの原子団、すなわち、アリール基を意味する。特に、Ｃ_６−１４のアリール基が好ましい。Ｃ_６−１４アリール基としては、例えば、フェニル、ナフチル、トリル、キシリル、ビフェニル、１−ナフチル、２−ナフチル、１−アントリル、２−アントリル、９−アントリル、１−フェナントリル、２−フェナントリル、３−フェナントリル、４−フェナントリル、９−フェナントリル、１−アズレニル、２−アズレニル、４−アズレニル、５−アズレニル、６−アズレニルなどが用いられる。該「芳香環」が有していてもよい置換基としては、例えば、低級アルキル、ヒドロキシ、アミノ、カルボキシル、ニトロ、モノ−またはジ−低級アルキルアミノ（例えば、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、ジエチルアミノなどのモノ−またはジ−Ｃ_１−６アルキルアミノなど）、低級アルコキシ（例えば、メトキシ、エトキシ、プロポキシ、ヘキシルオキシなどのＣ_１−６アルコキシなど）、低級アルキルカルボニルオキシ（例えば、アセトキシ、エチルカルボニルオキシなどのＣ_１−６アルキル−カルボニルオキシなど）、トリハロメタン、トリハロメトキシ、ハロゲン原子またはフェニルなどのアリールなどから選ばれた１個もしくは２個以上が用いられる。
【００４５】
本願明細書中で用いられる用語「複素環」とは、例えば、炭素原子以外に、窒素原子、酸素原子、硫黄原子などから選ばれた１ないし４個のヘテロ原子を含んでいてもよい３ないし７員の複素環から水素原子１個を除いた残りの原子団を意味する。複素環は縮合していてもよい。複素環の具体例としては、例えば、オキセタン、テトラヒドロフラン、テトラヒドロチオフェン、テトラヒドロピラン、ピロール、アゼチジン、ピロリジン、ピペリジン、ピペラジン、チオフェン、ホモピペリジン、モルホリン、フラン、ピリジン、ベンゾフランあるいはベンゾチオフェンなどが挙げられる。該「複素環」が有していてもよい置換基としては、例えば、ヒドロキシ、アミノ、カルボキシル、ニトロ、モノ−またはジ−低級アルキルアミノ（例えば、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、ジエチルアミノなどのモノ−またはジ−Ｃ_１−６アルキルアミノなど）、低級アルコキシ（例えば、メトキシ、エトキシ、プロポキシ、ヘキシルオキシなどのＣ_１−６アルコキシなど）、低級アルキルカルボニルオキシ（例えば、アセトキシ、エチルカルボニルオキシなどのＣ_１−６アルキル−カルボニルオキシなど）またはハロゲン原子などから選ばれた１個もしくは２個以上が用いられる。
【００４６】
なお、本発明において特に好ましい化合物の例としては、次の化合物又はその光学異性体、抱合体又は塩が挙げられる。
１）Ｃ環（Ｒ_５〜Ｒ_８）に２個の水酸基が存在し、１１位（Ｘの位置）に低級アルキル基が存在する化合物、具体的には、７，８−ジヒドロキシ−１１−エチル−１０，１１−シヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オン、１１−ジエチル−７，８−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オン、１１−メチル−７，８−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オンなどが例示される。
２）Ｃ環（Ｒ_５〜Ｒ_８）に２個の水酸基が存在し、Ａ環（Ｒ_１〜Ｒ_４）にチオ低級アルキル基が存在する化合物、具体的には、７，９−ジヒドロキシ−２−メチルチオ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オン、８−メチルチオ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１，３−ジオールなどが例示される。
３）Ｃ環（Ｒ_５〜Ｒ_８）に２個の水酸基が存在し、Ａ環（Ｒ_１〜Ｒ_４）に複素環が結合する化合物、具体的には、７，９−ジヒドロキシ−３−（２−フリル）−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オン、７−（２−チエニル）−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１，３−ジオール、７−（２−フリル）−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１，３−ジオールなどが例示される。
【００４７】
本発明化合物の塩としては、とりわけ医薬上あるいは生理学的に許容される酸付加塩が好ましい。この様な塩としては、例えば無機酸（例えば、塩酸、リン酸、臭化水素酸、硫酸）との塩、有機酸（例えば、酢酸、ギ酸、プロピオン酸、フマル酸、マレイン酸、コハク酸、酒石酸、乳酸、クエン酸、リンゴ酸、蓚酸、安息香酸、メタンスルホン酸、ｐ−トルエンスルホン酸、ベンゼンスルホン酸）との塩、あるいはアルカリ（例えば、ナトリウム、カリウム、マグネシウム、カルシウム、アンモニウム、ピリジン、トリエチルアミン）との塩などが用いられる。
【００４８】
本発明化合物の抱合体とは、式１で表される化合物、その光学異性体、その塩のグルクロン酸抱合体、硫酸抱合体などである。
【００４９】
次に、本発明化合物またはその塩の製造法を述べる。
本発明化合物の三環性縮合複素環化合物は、下記（式４）に示すように、Ａ、Ｂ、Ｃ３つの環からなる６−７−６三環性化合物である。
【００５０】
【化１１】

【００５１】
この化合物の骨格は、ウルマン反応によるＡ環とＣ環の結合およびフリーデル−クラフツ反応または光反応によるＡ環とＣ環の結合を組み合わせることにより製造できる。原料や目的化合物によっては炭素増加反応を加える必要がある。さらに必要であれば、置換基導入反応、置換基変換反応を行うことによって目的化合物を得ることができる。
【００５２】
例えば、第１工程として、ウルマン反応によってＡ環とＣ環とを結合させる。次いで、第２工程として、Ｂ環を７員環にするために、Ｗの炭素数を増加させる（炭素増加反応）。さらに、第３工程として、フリーデル−クラフツ反応によりＢ環を形成する。第４工程として、このようにして形成された三環性化合物にハロゲン基、低級アルキル基等の必要な置換基を導入する（置換基導入反応）。
【００５３】
置換基導入は、第１工程の原料に導入しておくことも、第２工程の増炭反応途中に導入することも可能であり、目的とする化合物の種類等を考慮して必要に応じて選択することができる。さらに、必要に応じて、１０位のカルボニル基を還元したり、置換基であるＯＲ（例えば、ＯＣＨ_３等）を脱保護反応によりＯＨに変換する。
【００５４】
以下に各工程の反応スキームの１例を示す。
【００５５】
【化１２】

【００５６】
上記各工程の反応スキームについて以下に説明する。
▲１▼ウルマン反応
必要な官能基を有するＡ環およびＣ環に相当する置換ベンゼンをウルマン反応によりカップリング体とする。ウルマン反応の脱離基としては、例えば、ハロゲン（例えば、塩素、臭素、ヨウ素など）、炭素数６から１０のアリールスルホニルオキシ（例えば、ベンゼンスルホニルオキシ、ｐ−トルエンスルホニルオキシなど）、炭素数１から４のアルキルスルホニルオキシ（例えば、メタンスルホニルオキシなど）などが用いられ、なかでもハロゲン（例えば、塩素、臭素、ヨウ素など）などが好ましい。求核側としては、例えば、酸素、イオウを含む官能基を有する前駆体を用いることができ、なかでも置換フェノール、置換チオフェノール、置換ジスルフィドなどが好ましい。
▲２▼フリーデル−クラフツ反応または光反応
さらにＡ環とＣ環を結合させる反応は、フリーデル−クラフツ反応として一般に行われている方法を用いることができる。例えば、“Ｃｏｍｐｒｅｈｅｎｓｉｖｅ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ：　Ｔｈｅ　Ｉｎｔｒａｍｏｌｅｃｕｌａｒ　Ａｒｏｍａｔｉｃ　Ｆｒｉｅｄｅｌ−Ｃｒａｆｔｓ　Ｒｅａｃｔｉｏｎ，”　Ｖｏｌ．　２，ｐｐ．　７５３　（１９９１），　Ｊ．　Ｏｒｇ．　Ｃｈｅｍ．，　５２，　８４９　（１９８７），　Ｓｙｎｔｈｅｓｉｓ，　１２５７　（１９９５）の方法またはそれに準じた方法などを用いることができる。また、特開平１０−２０４０７９に示される光環化反応の方法またはそれに準じた方法などを用いることにより、直接、置換アセトフェノン体から環化体に導くこともできる。また、ウルマン反応とこれらの反応は順序を入れ替えることも可能である。
▲３▼炭素増加反応
ウルマン反応において、置換フェニル酢酸誘導体を用いた場合は、直接環化体に導くことができるが、置換安息香酸誘導体の場合はＢ環に相当する部分の炭素増加反応を行う。その際、置換安息香酸誘導体からは置換ベンジルアルコール体、置換ベンジルハロゲン体、置換ベンジルニトリル体を経て置換フェニル酢酸に導くことができる。また、置換ベンジルハロゲン体からは二酸化炭素で、直接、置換フェニル酢酸に導くこともできる。置換アセトフェノン体からはウィルゲロット反応により置換モルホリン体とした後、置換フェニル酢酸に導くことができる。
▲４▼ハロゲン基の他の官能基への変換反応
複素環、置換フェニル環、低級アルキル基の導入反応は、パラジウムを用いて、例えば、Ｃｈｅｍ．　Ｒｅｖ．，　９５，　２４５７　（１９９５），“Ｏｒｇａｎｉｃ　Ｒｅａｃｔｉｏｎｓ，”　Ｖｏｌ．　５０，　（１９９７）　の方法またはそれに準じた方法などを用いることができる。
▲５▼アルキル基、アルキルカルボニル基の導入反応
エチル基等のアルキル基の導入は、環化体に対して塩基存在下、無水溶媒中ハロゲン化アルキル剤あるいはアルカリ存在下、相関移動触媒とハロゲン化アルキル剤を用いることにより行うことができる。また、アルキル基は、閉環前の炭素増加反応中間体あるいはウルマン反応を行う前の原料にも導入しておくことができる。アルキルカルボニル基の導入はフリーデル−クラフツ反応を用いて行うことができる。
▲６▼１０位変換反応
環化体は、カルボニル基をアルコール体に還元した後、脱水反応でオレフィン体とし、接触還元により脱カルボニル体に導くことができる。また、アルコール体について▲７▼の脱保護反応を行うことにより、オレフィン体とし、還元により脱カルボニル体に導くことができる。あるいは、環化体を直接ヴォル−キッシュナ還元により脱カルボニル体に導くこともできる。
▲７▼　脱保護反応は、ピリジン塩酸塩あるいはハロゲン化ホウ素により行うことができる。
【００５７】
本発明化合物の製造は溶媒中で行うのが好ましく、この様な溶媒としては、例えば、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン、ジオキサン等のエーテル類、ジメチルホルムアミド、ジメチルアセトアミド等のアミド類、ジメチルスルホキシド等のスルホキシド類、アセトニトリル等のニトリル類、Ｎ−メチル−２−ピロリドンなど、およびこれらの無水溶媒が用いられる。反応温度は−７８℃ないし２００℃、反応時間は、３０分ないし数日間、反応は窒素、アルゴン気流下で行なうのが有利である。反応生成物は、公知の手段、たとえば溶媒抽出、液性変換、転溶、塩析、晶出、再結晶、クロマトグラフィーなどによって単離精製することができる。
【００５８】
本発明の方法では、置換基がアミノ基の場合には、アミノ基を保護することが好ましく、保護基としてはペプチド化学等の分野で一般に用いられる保護基を用いることができ、例えばホルミル、アセチル、ベンゾイルなどアミドを形成するタイプの保護基；例えばｔｅｒｔ−ブトキシカルボニル、ベンジルオキシカルボニルなどのカルバメートを形成するタイプの保護基；ジメチルアミノメチレン、ベンジリデン、ｐ−メトキシベンジリデン、ジフェニルメチレンなどのイミノタイプの保護基が用いられる。好ましい保護基としては例えばホルミル、アセチルあるいはジメチルアミノメチレン等が用られる。なお、上記反応において得られた生成物が保護基を有する場合には、常法に基づいて保護基を除去することができ、例えば酸あるいは塩基による加水分解あるいは接触還元等の脱保護操作により保護基を除去することができる。
【００５９】
なお、得られた本発明化合物が不斉炭素を有する場合、従来公知の種々の光学分割法、例えば光学異性体分離カラム等を用いることにより光学異性体を得ることができる。
【００６０】
さらに、本発明化合物またはその医薬上あるいは生理学的に許容される塩は、優れた気管平滑筋弛緩作用、気道過敏性の抑制作用及び気道内への炎症性細胞の浸潤抑制作用といった幅広い薬理作用を有しており、哺乳動物（ヒト、マウス、イヌ、ラット、ウシ等）に対して安全な抗喘息薬等として使用できる。具体的には人に対して抗喘息剤として使用する場合、その投与量は、年令、体重、症状、投与経路、投与回数等により異なるが、１日当り０．１ないし１００ｍｇ／ｋｇ、好ましくは１ないし５０ｍｇ／ｋｇを１日１回又は２回に分割して投与するのが好ましい。投与経路は経口、非経口のいずれでもよい。
【００６１】
本発明化合物またはその塩は原末のままでもよいが、通常製剤用担体と共に調製された形で投与される。その具体例としては、錠剤、カプセル剤、顆粒剤、細粒剤、散剤、シロップ剤、注射剤、吸入剤等が用いられる。これらの製剤は常法に従って調製される。経口用製剤担体としては、デンプン、マンニット、結晶セルロース、カルボキシメチルセルロースナトリウム等の製剤分野において常用されている物質が用いられる。注射用担体としては、蒸留水、生理食塩水、グルコース溶液、輸液剤等が用いられる。その他製剤一般に用いられる添加剤を適宜添加することもできる。
【００６２】
参考例
以下に、本発明の原料物質の製造方法、および前述した各反応の具体例を参考例として説明するが、本発明はこれらにより限定されるものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。参考例のカラムクロマトグラフィーにおける溶出は、特に言及しない限り、ＴＬＣ（薄層クロマトグラフィー）による観察下に行われた。ＴＬＣ観察においては、ＴＬＣプレートとしてメルク社製の６０Ｆ２５４を用い、展開溶媒としてはカラムクロマトグラフィーで溶出溶媒として用いられた溶媒を用いた。また、検出にはＵＶ検出器を採用した。カラムクロマトグラフィー用のシリカゲルとしては、メルク社製のシリカゲル６０（７０−２３０メッシュ）あるいはアサヒガラス社製マイクロスフェアーゲルＤ７５−６０Ａを用いた。室温とは通常約１０℃ないし約３５℃を意味する。
【００６３】
参考例１：４−ブロモ−２−クロロ安息香酸（３）の製造方法
【００６４】
【化１３】

【００６５】
４−アミノ−２−クロロ安息香酸（２）の合成
２−クロロ−４−ニトロ安息香酸（１）　１００ｇ　（Ｆ．Ｗ．　２０１．５７，　４９６　ｍｍｏｌ）、エタノール　（２５０ｍＬ）にとかしアルゴン置換をしたのち１０％パラジウム炭素触媒　（４．０＋１．５ｇ）　を加えた。水素置換をしたのち室温で７２時間撹拌した。生成した結晶をアセトンで溶解後濾過し触媒を除去した。溶媒を減圧留去し、目的とする４−アミノ−２−クロロ安息香酸（２）　８８ｇを定量的に得た。
融点２１５〜２１７　℃
【００６６】
４−ブロモ−２−クロロ安息香酸（３）の合成
４−アミノ−２−クロロ安息香酸（２）　８８ｇ　（Ｆ．Ｗ．　１７１．５８，　５１３ｍｍｏｌ）、４８％臭化水素酸（３０４ｍＬ）、水　（３０４ｍＬ）を１２０℃、１時間加熱して溶解し臭化水素酸塩とした。撹拌下冷却（氷−食塩）し亜硝酸ナトリウム４４．４ｇ　（Ｆ．Ｗ．　６９．００，　６４３ｍｍｏｌ）水溶液（水，　２５０ｍＬ）を５℃以下に保ちながら溶液中に加えた。
臭化銅　１２０．８ｇ　（Ｆ．Ｗ．　８０．７９，　２．８３ｍｏｌ）の４８％臭化水素酸（３３１ｍＬ）液をビーカー中で０℃とし撹拌下、調製したジアゾニウム塩溶液を泡立たないようにゆっくり加えた。加え終わったら湯浴上で窒素の発生がなくなるまで加熱した。放冷後、酢酸エチルで抽出した。常法に従って処理し目的とする４−ブロモ−２−クロロ安息香酸（３）　８８．３ｇ（７３％）を得た。
融点１５２〜１６０℃．　ＩＲ　（ＫＢｒ）νｍａｘ　３０９０，　１６８２，　１５７８　ｃｍ^−１．　^１Ｈ　ＮＭＲ　（ＣＤＣｌ_３，　４００　ＭＨｚ）δ　７．５０　（１Ｈ，　ｄｄ，　Ｊ　＝　８．５，　２Ｈｚ，　Ａｒ−Ｈ），　７．６９　（１Ｈ，　Ｊ　＝　２Ｈｚ，　Ａｒ−Ｈ），　７．８９（１Ｈ，　Ｊ　＝　８．５Ｈｚ，　Ａｒ−Ｈ）．
【００６７】
参考例２：ジ−（３，５−ジメトキシフェニル）ジスルフィド（９）の製造方法
【００６８】
【化１４】

【００６９】
３，５−ジメトキシアニリン（４）２５．０ｇ　（Ｆ．Ｗ．　１５３．１８，　１６３．２ｍｍｏｌ）の水　５００ｍｌ懸濁液に濃塩酸４０．８ｍｌ　（４８９．６ｍｍｏｌ）を加え、撹拌および加熱により塩酸塩を完全に溶解させた。ここに水　４００ｍｌを加えた後、氷冷した。反応温度（内温）を５℃以下に保ち、激しく撹拌しながら、亜硝酸ナトリウム　１１．８ｇ　（Ｆ．Ｗ．　６９．００，　１７１．４ｍｍｏｌ）の水　４０ｍｌ　溶液を液中へ注意深く加えた。この溶液を同温度で約３０分撹拌し、ジアゾニウム塩溶液を調製した。
【００７０】
キサントゲン酸カリウム（６）６８０．５ｇ　（Ｆ．Ｗ．　１６０．３０，　４２４３．２ｍｍｏｌ）の水　５５０ｍｌ懸濁液を６５〜７０℃まで昇温し、完全に溶解し、キサントゲン酸カリウム溶液とした。
６５〜７０℃に保ったこの溶液中に５℃以下に保ったジアゾニウム塩溶液３０分間で徐々に滴下した。この操作を４回繰り返した。
６５〜７０℃で約１時間撹拌した後、室温まで放冷した。酢酸エチルを加え３回抽出した。これを１Ｎ水酸化ナトリウム、水、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を除去し、粗生成物（７）を得た。カラムクロマトグラフィー（ヘキサン：酢酸エチル＝７：１）により生成物（７）（および（９）の混合物）１２２．３１ｇ　を得た。
【００７１】
粗生成物（７）（および（９）の混合物）８５．７ｇ　をエタノール　４５０ｍｌに溶解した後、水　５０ｍｌ、水酸化カリウム　２００．０ｇ　（Ｆ．Ｗ．　５６．１１，　４８９６．０ｍｍｏｌ）を加えた。反応溶液を還流下１０分間撹拌した。ＴＬＣ　により化合物（７）が存在しないことを確認後、放冷し、３Ｎ塩酸で中和した。減圧下エタノールを除去後、酢酸エチルで３回抽出し、飽和食塩水で洗浄した。有機層に酸化銅（ＩＩ）（粉末）２５．０ｇ　（Ｆ．Ｗ．　７９．５４，　３１４．３ｍｍｏｌ）　を加え、空気（または酸素）を通気しながら室温でチオール（８）が消失するまで、撹拌した。濾過により不溶物を除去した後、水を加え、酢酸エチルで３回抽出し、１Ｎ塩酸、水、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を除去し、粗生成物（９）５３．６５ｇを得た。この粗生成物（９）をカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１９：１）で精製し、ジスルフィド（９）３４．８７ｇ　（ｐｕｒｅ）　（Ｆ．Ｗ．　３３８．４４，　１０３．０ｍｍｏｌ），　１１．０５ｇ
（ｃｒｕｄｅ）を収率　４１％で得た。
融点１５２〜１６０℃．　ＩＲ（ＫＢｒ）　νｍａｘ　３０９０，　１６８２，　１５７８　ｃｍ^−１．　^１Ｈ　ＮＭＲ　（ＣＤＣｌ　_３，　４００ＭＨｚ）δ７．５０　（１Ｈ，　ｄｄ，　Ｊ＝８．５，　２Ｈｚ，　Ａｒ−Ｈ），　７．６９　（１Ｈ，　Ｊ＝２Ｈｚ，　Ａｒ−Ｈ），　７．８９　（１Ｈ，Ｊ＝８．５Ｈｚ，　Ａｒ−Ｈ）．
【００７２】
参考例３：ジ−（３，４−ジメトキシフェニル）ジスルフィド（１１）の製造方法
【００７３】
【化１５】

【００７４】
ベラトロール（１０）　１００　ｇに無水塩化メチレン　５００　ｍｌを加え０℃で撹拌した。これにクロロスルホン酸　２３５　ｍｌを１時間で加え５０℃で３０分撹拌した。この溶液を０℃のメタノール　１．５　ｌに４０分かけて滴下し、これに塩酸　２９０　ｍｌ、塩化第一スズ　５７０　ｇを加え室温で２時間撹拌した。半分量まで減圧濃縮後、トルエンで抽出し、有機層を１２％塩酸、水及び飽和塩化ナトリウム溶液で洗浄後、無水硫酸マグネシウムにて乾燥し溶媒を減圧留去した。残さを酢酸エチルに溶解し、酸化第二銅　２０　ｇを加え空気をバブリングしながら撹拌した。触媒をろ過し、酢酸エチルで洗浄後、酢酸エチル−ヘキサンで再結晶を行い目的物（１１）とした。（総収率２１％）
ＥＩ−ＭＳ；　３３８　（Ｍ＋），　１６９　（Ｂａｓｅ）．　ＮＭＲ　（ＣＤＣｌ_３）；　３．８３　（６Ｈ，　ｓ），　３．８７　（６Ｈ，　ｓ），　６．７９　（２Ｈ，　ｄ，　Ｊ　＝　８．３　Ｈｚ），　７．０１　（２Ｈ，　ｄ，　Ｊ　＝　２．１　Ｈｚ），　７．０５（　２Ｈ，　ｄｄ，　Ｊ　＝　２．１，８．３　Ｈｚ）
【００７５】
参考例４：８−ブロモ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１，３−ジオール（２１）の製造方法
【００７６】
【化１６】

【００７７】
カルボン酸（１４）の合成
５−ブロモ−２−クロロ安息香酸（１２）３０．０ｇ　（Ｆ．Ｗ．　２３５．４６，　１２７ｍｍｏｌ）、３，５−ジメトキシフェノール（１３）２１．６ｇ　（Ｆ．Ｗ．　１５４．１６５，　１４０ｍｍｏｌ）、炭酸カリウム　３５．３ｇ　（Ｆ．Ｗ．　１３８．２１，　３２５．６ｍｍｏｌ）、Ｎ−メチル−２−ピロリドン　１８０ｍｌの混合物にベンゼン（１００ｍｌ）を加えディーン−スターク水分離器で３時間乾燥後（１４０−１７０℃）、銅（粉末）　１．５９ｇ　（Ｆ．Ｗ．　６３．５５，　２５．０ｍｍｏｌ）、ヨウ化銅（Ｉ）　６．０５ｇ　（Ｆ．Ｗ．１９０．４５，　２５．０ｍｍｏｌ）を加え、１２０℃で１．５時間撹拌した。この反応混合物を放冷し、氷水および酢酸エチルを加えた後、濃塩酸で　ｐＨ２とし濾過した。有機層を分離後よく水洗し飽和食塩水で塩析した。無水硫酸マグネシウムで乾燥、濃縮、ベンゼンから再結晶化し、カルボン酸（１４）２５．４７ｇを得た。母液をカラムクロマトグラフィー（シリカゲル，　含６％水；　２５０ｇ，　酢酸エチル：ヘキサン＝１：２）で精製し結晶４．５８ｇを得た。合計収率：　３０．０５ｇ（６７％）　＋　母液９．２３ｇ　（ｐｕｒｉｔｙ，　４０％）（ＴＬＣ；酢酸エチル：ヘキサン＝１：２　ｏｒ　１：１）ＭＳ　（ＥＩ）：　３５４，　３５２，　２６９．ＮＭＲ（ＣＤＣｌ_３）：　３．７６
（２Ｈ，　ｓ，　ＣＨ_２），　３．７７　（６Ｈ，　ｓ，　ＣＨ_３Ｘ２），　６．２２　（２Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　６．３３　（１Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　６．８５　（１Ｈ，　ｄ，　Ｊ＝８．５Ｈｚ，　Ａｒ−Ｈ），　７．５７　（１Ｈ，　ｄｄ，　Ｊ＝８．５，　２．２Ｈｚ，　Ａｒ−Ｈ），　８．２６　（１Ｈ，　ｄ，　Ｊ＝２．２Ｈｚ，　Ａｒ−Ｈ）．
【００７８】
アルコール（１５）の合成
カルボン酸（１４）２１．５ｇ　（Ｆ．Ｗ．　３５３．１６８，　６０．９ｍｍｏｌ）のテトラヒドロフラン　７５ｍｌ　溶液に水素化ホウ素ナトリウム２．６５ｇ　（Ｆ．Ｗ．　３７．８３，　７０．０５ｍｍｏｌ）　を室温で少しずつ加えた後、フッ化ホウ素エーテル錯体　９．４９ｍｌ　（Ｆ．Ｗ．　１４１．９３，　ｄ＝１．１５４，　７７．１６ｍｍｏｌ）　を滴下した。室温で１時間撹拌した。この反応溶液に氷水　２００ｍｌを徐々に加えた。酢酸エチルで抽出し、飽和食塩水で３回洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去した。ベンゼン−ジイソプロピルエーテルで再結晶をしアルコール（１５）１９．０４ｇ　（９８％）を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：４）
ＭＳ　（ＥＩ）：　３４０，　３３８，　２９１，　２８９．ＮＭＲ（ＣＤＣｌ_３）：　３．７５　（６Ｈ，　ｓ，　ＣＨ_３Ｘ２），　４．７０　（２Ｈ，　ｓ，　ＣＨ_２），　６．０２　（２Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　６．０７　（１Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　６．８５　（１Ｈ，　ｄ，　Ｊ＝８．５Ｈｚ　，Ａｒ−Ｈ），　７．３９　（１Ｈ，　ｄｄ，　Ｊ＝８．５，　２．２Ｈｚ，　Ａｒ−Ｈ），　７．６４　（１Ｈ，　ｄ，　Ｊ＝２．２Ｈｚ，　Ａｒ−Ｈ）．
【００７９】
塩化物（１６）の合成
アルコール（１５）２０．０ｇ　（Ｆ．Ｗ．　３３９．１８５，　６２．６ｍｍｏｌ）をベンゼンとともに共沸して乾燥しベンゼン４０ｍｌ、塩化メチレン１０ｍｌに塩化チオニル　５．６３ｍｌ　（Ｆ．Ｗ．　１１８．９７，　ｄ＝１．６３１，　７６．７ｍｍｏｌ）および塩化メチレン５．６ｍｌを０℃で加え、同温度で３０分間撹拌した。さらに室温で一晩撹拌した。氷水を反応混合物に加え、酢酸エチルで抽出し、水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去した。残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１：４）にて精製し塩化物（１６）１４．０３ｇ　（６５％）　を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：４）ＮＭＲ（ＣＤＣｌ_３）：　３．７５　（６Ｈ，　ｓ，　ＣＨ_３Ｘ２），　４．４９　（２Ｈ，　ｓ，　ＣＨ_２），　６．１６　（２Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　６．２５　（１Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　６．７８　（１Ｈ，　ｄ，　Ｊ＝８．７Ｈｚ，　Ａｒ−Ｈ），　７．３５　（１Ｈ，　ｄｄ，　Ｊ＝８．７，　２．４Ｈｚ，　Ａｒ−Ｈ），　７．５７　（１Ｈ，　ｄ，　Ｊ＝２．４Ｈｚ，　Ａｒ−Ｈ）．
【００８０】
シアノ化物（１７）の合成
塩化物（１６）２７．９ｇ　（Ｆ．Ｗ．　３５７．６３１，　７８．０ｍｍｏｌ）をジメチルスルホキシド　３０ｍｌ　に溶解する。この溶液にシアン化ナトリウムを　５．４９ｇ　（Ｆ．Ｗ．　４９．０１，　１１２．０ｍｍｏｌ）加え、８０℃で１時間撹拌した。氷冷下、水を加えた後、酢酸エチルで３回抽出した。これを水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去した。塩化メチレン−ヘキサンで再結晶し、シアノ化物（１７）１６．９１ｇ　（６５％）　を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：４）ＭＳ　（ＥＩ）：　３４９，　３４７．ＮＭＲ（ＣＤＣｌ_３）：　３．７０　（２Ｈ，　ｓ，　ＣＨ_２），　３．７４　（３Ｈ，　ｓ，　ＣＨ_３），　３．７５　（３Ｈ，　ｓ，　ＣＨ_３），　６．１１　（２Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　６．２６　（１Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　６．８１　（１Ｈ，　ｄ，　Ｊ＝８．５Ｈｚ，　Ａｒ−Ｈ），　７．４０　（１Ｈ，　ｄｄ，　Ｊ＝８．５，　２．２Ｈｚ，　Ａｒ−Ｈ），　７．６２　（１Ｈ，　ｄ，　Ｊ＝２．２Ｈｚ，　Ａｒ−Ｈ）．
【００８１】
フェニル酢酸（１８）の合成
シアノ体（１７）１４．００ｇ　（Ｆ．Ｗ．　３４８．１９６，　４０．０ｍｍｏｌ）　をエタノール　３３．６ｍｌ、６Ｎ水酸化ナトリウム水溶液　３３．６ｍｌ（水酸化ナトリウム８．０６ｇ（Ｆ．Ｗ．　４０．００，　２０１．５ｍｍｏｌ）を水に溶解）を加え、１１０℃で１晩撹拌した。反応溶液に氷を加え、濃塩酸でｐＨ２にした。酢酸エチルで抽出し、水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を完全に除去しベンゼン−ヘキサンから結晶化しフェニル酢酸（１８）１３．３３ｇ　（９０％）　を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：２ｏｒ　１：１）
ＮＭＲ（ＣＤＣｌ_３）：　３．７０　（３Ｈ，　ｓ，　ＣＨ_３），　３．９０　（３Ｈ，　ｓ，　ＣＨ_３），　３．９５　（１Ｈ，　ｓ，　ＣＨ_２），　６．２６　（１Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　６．４６　（１Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　７．０８　（１Ｈ，　ｄ，　Ｊ＝８．５Ｈｚ，　Ａｒ−Ｈ），　７．３３　（１Ｈ，　ｄｄ，　Ｊ＝８．５，　２．３Ｈｚ，　Ａｒ−Ｈ），　７．４１　（１Ｈ，　ｄ，　Ｊ＝２．３Ｈｚ，　Ａｒ−Ｈ），　１２．９１　（１Ｈ，　ｓ，　ＯＨ）
【００８２】
環化体（１９）の合成
カルボン酸（１８）１１．７５ｇ（Ｆ．Ｗ．　３６７．１９５，　３２．０ｍｍｏｌ）にメタンスルホン酸　６０ｍｌ　を加え、溶解した。この溶液を４０℃で３日間撹拌した。反応溶液に氷水３００ｍｌを加え環化体を析出させた。析出した環化体を濾別し酢酸エチルで抽出し常法に従って処理し粗生成物をえた。ヘキサン−塩化メチレンで再結晶し、環化体（１９）６．０ｇ　（５４％）を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：２）
ＭＳ　（ＥＩ）：　３４９，　３４７，　２６９．　ＮＭＲ（ＣＤＣｌ_３）：　３．８４（３Ｈ，　ｓ，　ＣＨ_３），　３．９０（３Ｈ，　ｓ，　ＣＨ_３），　３．９５　（１Ｈ，　ｓ，　ＣＨ_２），　６．２６　（１Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　６．４６　（１Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　７．０８　（１Ｈ，　ｄ，　Ｊ＝８．５Ｈｚ，　Ａｒ−Ｈ），　７．３３　（１Ｈ，　ｄｄ，　Ｊ＝８．５，　２．３Ｈｚ，　Ａｒ−Ｈ），　７．４１　（１Ｈ，　ｄ，　Ｊ＝２．３Ｈｚ，　Ａｒ−Ｈ），　１２．９１　（１Ｈ，　ｓ，　ＯＨ）
【００８３】
２−ブロモ−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１０−オン（２０）の合成
ジメトキシ化合物（１９）　３９５ｍｇ　（Ｆ．Ｗ．　３４９．１８，　１．１３ｍｍｏｌ）にピリジン塩酸塩２．０ｇ　を加え、１９５℃で１．５時間、加熱撹拌後、氷水を徐々に加えた。酢酸エチルで抽出し、１Ｎ塩酸、水、飽和食塩水で順次洗浄した。無水硫酸マグネシウムで乾燥後、濃縮した。残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１：２）にて精製した。さらに、ジイソプロピルエーテル−ヘキサンで再結晶することにより標記化合物　２２３ｍｇ　（６１％）を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：２）
融点１９４〜１９５℃；　ＭＳ　（ＥＩ）：　３２２，　３２０，　２４１．　ＮＭＲ（ＣＤＣｌ_３）　４．０３（２Ｈ，　ｓ，　ＣＨ_２），５．８８（１Ｈ，　ｓ，　ＯＨ），　６．１７　（１Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　６．３５　（１Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　７．１０　（１Ｈ，　ｄ，　Ｊ＝８．５Ｈｚ，　Ａｒ−Ｈ），　７．３６　（１Ｈ，　ｄｄ，　Ｊ＝８．５，　２．３Ｈｚ，　Ａｒ−Ｈ），　７．４３　（１Ｈ，ｄ，　Ｊ＝２．３Ｈｚ，　Ａｒ−Ｈ），　１２．９１　（１Ｈ，　ｓ，　ＯＨ）
【００８４】
８−ブロモ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１，３−ジオール（２１）の合成
ジメトキシ化合物（１９）２．００ｇ　（Ｆ．Ｗ．　３２１．１２６，　６．２３ｍｍｏｌ）にメタノール５０ｍｌを加え撹拌した。懸濁状態のまま溶液を０℃に冷却した。そこに水素化ホウ素ナトリウム５００ｍｇを数回に分け加えた。反応液を室温に戻し１時間撹拌した。反応液に希塩酸を加え反応を停止し、メタノールを減圧留去した。酢酸エチルを加え分配した。有機層を水洗及び飽和塩化ナトリウム溶液で洗浄後、無水硫酸マグネシウムにて乾燥し溶媒を減圧留去し得られた油状物にピリジン塩酸塩１０ｇを加え２００℃で２時間加熱撹拌した。反応終了後、反応液を酢酸エチル、希塩酸にて分配した。有機層を水洗及び飽和塩化ナトリウム溶液で洗浄後、無水硫酸マグネシウムにて乾燥し溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝１：１）にて精製した。得られた油状物を酢酸エチル２０ｍｌに溶解した。酸化白金（ＩＶ）１００ｍｇを加え室温で３日間接触還元を行った。反応終了後反応液を濾過、濃縮し、残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝２：１）にて精製した。クロロホルム−ヘキサンで再結晶し、標記化合物（９０１．０ｍｇ，　５１．２％）をうすオレンジ色の板状晶として得た。融点１７３．８〜１７５．８℃，
ＮＭＲ　（ＤＭＳＯ−ｄ_６）；　２．７４　（２Ｈ，　ｔ，　Ｊ＝６．３Ｈｚ，　ＣＨ_２），　２．９９　（２Ｈ，　ｔ，　Ｊ＝６．３Ｈｚ，　ＣＨ_２），　６．０５　（１Ｈ，　ｄ，　Ｊ＝２．３Ｈｚ，　Ａｒ−Ｈ），　６．１０　（１Ｈ，　ｄ，　Ｊ＝２．３Ｈｚ，　Ａｒ−Ｈ），　７．０４　（１Ｈ，　ｄ，　Ｊ＝８．５Ｈｚ，　Ａｒ−Ｈ），　７．３２　（１Ｈ，　ｄｄ，　Ｊ＝８．５，　２．５Ｈｚ，　Ａｒ−Ｈ），　７．４２　（１Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ）　９．１９　（１Ｈ，　ｓ，　Ｐｈ−ＯＨ）　９．３９　（１Ｈ，　ｓ，　Ｐｈ−ＯＨ）
【００８５】
参考例５：７−ブロモ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１，３−ジオール（２９）の製造方法
【００８６】
【化１７】

【００８７】
４ −ブロモ− ２ − （３，５ −ジメトキシフェノキシ ） 安息香酸（２２）の合成
４−ブロモ−２−クロロ安息香酸（３）、８８．３ｇ　（Ｆ．Ｗ．　２３５．４６，　３７５ｍｍｏｌ）、３，５−ジメトキシフェノール（１３）　５７．８ｇ　（Ｆ．Ｗ．　１５４．１６５，　３７５ｍｍｏｌ）、炭酸カリウム　９３．２ｇ　（Ｆ．Ｗ．　１３８．２１，　６７０ｍｍｏｌ）、Ｎ−メチル−２−ピロリドン　４００ｍＬの混合物にベンゼン　（２００ｍＬ）を加えディーン−スターク水分離器で３時間乾燥後（１４０→１７０℃）、銅（粉末）　６．０ｇ　（Ｆ．Ｗ．　６３．５５，　９３．７ｍｍｏｌ）、ヨウ化銅　（Ｉ）　１７．８ｇ　（Ｆ．Ｗ．　１９０．４５，　９３．７ｍｍｏｌ）を加え、１２０℃で３０分撹拌した。この反応混合物を放冷し、氷水および酢酸エチルを加えた後、濃塩酸で　ｐＨ２にし濾過した。有機層を分離後よく水洗し飽和食塩水で塩析した。無水硫酸マグネシウムで乾燥、濃縮後、シリカゲル・カラムクロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１：３）で精製し酢酸エチル−ヘキサンにて再結晶を行い目的物（２０）７５．４ｇ　（５７％）を得た。
（ＴＬＣ；酢酸エチル：ヘキサン＝１：２ｏｒ　１：１）融点１１２〜１１７℃；　ＵＶ　（ＥｔＯＨ）　λｍａｘ　（ε）　２９２　（２０００）　ｎｍ．　ＩＲ　（ＫＢｒ）νｍａｘ　３４１１，　１６９９，　１６０５　ｃｍ^−１．　^１Ｈ　ＮＭＲ　（ＣＤＣｌ_３，　４００　ＭＨｚ）　δ　３．７５　（２Ｈ，　ｓ，　ＣＨ_２），　３．７７　（６Ｈ，　ｓ，　ＣＨ_３ｘ　２）　６．２３　（１Ｈ，　ｄ，　Ｊ　＝　２．１Ｈｚ，　Ａｒ−Ｈ），　６．３４　（１Ｈ，　ｄ，　Ｊ　＝　２．１Ｈｚ，　Ａｒ−Ｈ），　７．０９　（２Ｈ，　ｍ，　Ａｒ−Ｈ），　７．３２　（１Ｈ，　ｍ，　Ａｒ−Ｈ），　７．９８　（１Ｈ，　ｍ，　Ａｒ−Ｈ）．　ＭＳ　（ＥＩ）　ｍ／ｚ　３５４，　３５２，　３０９，　３０７．
【００８８】
４ −ブロモ− ２ − （３，５ −ジメトキシフェノキシ ） ベンジルアルコール（２３）の合成
４−ブロモ−２−（３，５−ジメトキシフェノキシ）安息香酸（２２）７５．４ｇ　（Ｆ．Ｗ．　３５３．１６８，　２１３ｍｍｏｌ）　のテトラヒドロフラン　３００ｍＬ溶液に水素化ホウ素ナトリウム８．９ｇ　（Ｆ．Ｗ．　３７．８３，　２３５ｍｍｏｌ）を室温で少しずつ加えた後、フッ化ホウ素エーテル錯体　３１ｍＬ　（Ｆ．Ｗ．　１４１．９３，　ｄ＝１．１５４，　２５２ｍｍｏｌ）　を滴下した。室温で１時間撹拌した。この反応溶液に氷水　２００ｍＬを徐々に加えた。酢酸エチルで抽出し、飽和食塩水で３回洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去した。ベンゼン−ジイソプロピルエーテルで再結晶しアルコール体（２３）４６．６ｇ　（６４％）を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：４）ＭＳ　（ＥＩ）　ｍ／ｚ　３４０，　３３８．
【００８９】
４ −ブロモ− ２ − （３，５ −ジメトキシフェノキシ ） ベンジルブロマイド（２４）の合成
アルゴン雰囲気下、アルコール（２３）４６ｇ　（Ｆ．Ｗ．　３３９．１９，　１３５ｍｍｏｌ）の塩化メチレン　１００ｍＬ溶液に０℃で三臭化リン　４．７ｍＬ　（Ｆ．Ｗ．　２７０．７０，　ｄ＝２．８５０，　４９．５ｍｍｏｌ）　を加えた。室温で３０分間撹拌後した。この反応溶液を氷中に加えた。さらに室温で３０分間撹拌した。氷水を反応混合物に加え、酢酸エチルで抽出し、水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、濃縮した。残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１：５）にて精製し臭化物（２４）４４．６ｇ　（８４％）　を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：４）
【００９０】
４ −ブロモ− ２ − （３，５ −ジメトキシフェノキシ ） ベンジルニトリル（２５）の合成
臭化物（２４）４４．６ｇ　（Ｆ．Ｗ．　３５７．６３１，　１１１ｍｍｏｌ）　をジメチルスルホキシド　５０ｍＬ　に溶解する。この溶液にシアン化ナトリウムを　８．１５ｇ　（Ｆ．Ｗ．　４９．０１，　１６６ｍｍｏｌ）加え、８０℃で１時間撹拌した。氷冷下、水を加えた後、酢酸エチルで３回抽出した。これを水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去した。残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１：４）にて精製しニトリル体（２５）３４．５ｇ　（８９％）　を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：４）
^１Ｈ　ＮＭＲ　（ＣＤＣｌ_３，　４００　ＭＨｚ）　δ　３．７０　（２Ｈ，　ｓ，　ＣＨ_２），　３．７７　（６Ｈ，　ｓ，　ＣＨ_３ｘ　２）　６．１４（１Ｈ，　ｄ，　Ｊ　＝　２．１Ｈｚ，　Ａｒ−Ｈ），　６．２８　（１Ｈ，　ｄ，　Ｊ　＝　２．１Ｈｚ，　Ａｒ−Ｈ），　７．０２　（１Ｈ，　ｍ，　Ａｒ−Ｈ），　７．１５　（１Ｈ，　ｍ，　Ａｒ−Ｈ），　７．２１　（１Ｈ，　ｍ，　Ａ　ｒ−Ｈ）．　ＭＳ　（ＥＩ）　ｍ／ｚ　３４９，　３４７，　２６９．
【００９１】
４−ブロモ−２− （ ３，５−ジメトキシフェノキシ ） フェニル酢酸（２６）の合成ニトリル体（２５）３４．５ｇ　（Ｆ．Ｗ．　３４８．１９６，　９９．１ｍｍｏｌ）をエタノール　８３ｍＬ　、６Ｎ水酸化ナトリウム水溶液　８３ｍＬ　（水酸化ナトリウム　１９．９ｇ　（Ｆ．Ｗ．　４０．００，　４９７ｍｍｏｌ）を水に溶解）を加え、１１０℃で１晩撹拌した。反応溶液に氷を加え、濃塩酸でｐＨ２にした。酢酸エチルで抽出し、水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を完全に除去し、残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝２：３）にて精製し酢酸エチル−ヘキサンから結晶化しカルボン酸（２６）２７．３ｇ　（７５％）　を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：２　ｏｒ　１：１）
融点１２１．９〜１２３．６　℃；　ＵＶ　（ＥｔＯＨ）　λｍａｘ　（ε）　２７２　（２２００）　ｎｍ．　ＩＲ　（ＫＢｒ）νｍａｘ　２９５４，　１７０５，　１６０６，　１５７６　ｃｍ^−１．　^１Ｈ　ＮＭＲ　（ＣＤＣｌ_３，　４００　ＭＨｚ）　δ　３．６０　（２Ｈ，　ｓ，　ＣＨ_２），　３．６０　（６Ｈ，　ｓ，　ＣＨ_３ｘ　２），　６．１３　（１Ｈ，　ｄ，　Ｊ　＝　２．１Ｈｚ，　Ａｒ−Ｈ），　６．２５　（１Ｈ，　ｄ，　Ｊ　＝　２．１Ｈｚ，　Ａｒ−Ｈ），　７．０２　（１Ｈ，　ｍ，　Ａｒ−Ｈ），　７．１５　（１Ｈ，　ｍ，　Ａｒ−Ｈ），　７．２１　（１Ｈ，　ｍ，　Ａｒ−Ｈ）．　ＭＳ　（ＥＩ）　ｍ／ｚ　３６８，　３６６．
【００９２】
３−ブロモ−７ ， ９−ジメトキシ−１０ ， １１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１０−オン（２７）の合成
カルボン酸（２６）２７．３ｇ　（Ｆ．Ｗ．　３６７．１９５，　７４．３ｍｍｏｌ）にメタンスルホン酸　１４０ｍＬを加え、溶解した。この溶液を４０℃で３日間撹拌した。反応溶液に氷水３００ｍＬを加え環化体を析出させた。析出した環化体を濾別し酢酸エチルで抽出し常法に従って処理し粗生成物をえた。シリカゲル・カラムクロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１：２）にて精製し、ヘキサン−酢酸エチルで再結晶し、環化体（２７）　１７．１ｇ　（６６％）を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：２）融点９５〜１０３℃；　ＵＶ　（ＥｔＯＨ）　λｍａｘ　（ε）　２７２　（２８００）　ｎｍ．　ＩＲ　（ＫＢｒ）νｍａｘ　２９７７，　１６７９，　１６０４　ｃｍ^−１．　^１Ｈ　ＮＭＲ　（ＣＤＣｌ_３，　４００　ＭＨｚ）　δ　３．８４　（３Ｈ，　ｓ，　ＣＨ_３），　３．８８　（３Ｈ，　ｓ，　ＣＨ_３），　３．９５　（２Ｈ，　ｓ，　ＣＨ_２），　６．２７　（１Ｈ，　ｄ，　Ｊ　＝　２．１Ｈｚ，　Ａｒ−Ｈ），　６．４７　（１Ｈ，　ｄ，　Ｊ　＝　２．１Ｈｚ，　Ａｒ−Ｈ），　７．１５　（１Ｈ，　ｍ，　Ａｒ−Ｈ），　７．３０　（１Ｈ，　ｍ，　Ａｒ−Ｈ），　７．４０　（１Ｈ，　ｍ，　Ａｒ−Ｈ）．　ＭＳ　（ＥＩ）　ｍ／ｚ　３５０，　３４８．
【００９３】
３−ブロモ−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１０−オン 　（ ２８ ） の合成
ジメトキシ体（２７）　３９５ｍｇ　（Ｆ．Ｗ．　３４９．１８，　１５．７５ｍｍｏｌ）　にピリジン塩酸塩　２．０ｇ　を加え、１９５℃で１．５時間撹拌した後、氷水を徐々に加えた。酢酸エチルで抽出し、１Ｎ塩酸、水、飽和食塩水で順次洗浄した。無水硫酸マグネシウムで乾燥後、濃縮した。残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１：２）にて精製した。さらに、ジオキサンおよびジオキサンとヘキサンで再結晶し標記化合物　２２３ｍｇ　（６１％）を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：２）
融点１９４〜１９５℃；　^１Ｈ　ＮＭＲ　（ＣＤＣｌ_３，　４００　ＭＨｚ）δ　４．０３　（２Ｈ，　ｓ，　ＣＨ_２），　６．０９　（１Ｈ，　ｄ，　Ｊ　＝　２．１Ｈｚ，　Ａｒ−Ｈ），　６．３９　（１Ｈ，　ｄ，　Ｊ　＝　２．１Ｈｚ，　Ａｒ−Ｈ），　７．４３　（２Ｈ　，ｍ，　Ａｒ−Ｈ），　７．６４　（１Ｈ，　ｍ，　Ａｒ−Ｈ），　１１．０７　（１Ｈ，　ｓ，　ＯＨ），　１２．９５　（１Ｈ，　ｓ，　ＯＨ）　．　ＭＳ　（ＥＩ）　ｍ／ｚ　３２２，　３２０．
【００９４】
７−ブロモ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１，３−ジオール （ ２９ ） の合成
ジメトキシ体（２７）　５．５ｇ　（Ｆ．Ｗ．　３４９．１８，　１５．７５　ｍｍｏｌ）　にメタノール８０ｍＬを加え撹拌した。懸濁状態のまま溶液を０℃に冷却した。そこに水素化ホウ素ナトリウム８９０ｍｇを数回に分け加えた。反応液を室温に戻し１時間撹拌した。反応液に希塩酸を加え反応を停止し、メタノールを減圧留去した。酢酸エチルを加え分配した。有機層を水洗及び飽和塩化ナトリウム溶液で洗浄後、無水硫酸マグネシウムにて乾燥し溶媒を減圧留去し得られた油状物にピリジン　２０ｍＬ，トシルクロライド３．６ｇを加え９０℃で１晩撹拌した。反応液を酢酸エチル、希塩酸にて分配した。有機層を水洗及び飽和塩化ナトリウム溶液で洗浄後、無水硫酸マグネシウムにて乾燥し溶媒を減圧留去した。残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝５：１）にて精製した（４．９６ｇ，　収率９５％）。得られた油状物を酢酸エチル５０ｍＬに溶解し、酸化白金（ＩＶ）１５０ｍｇを加え室温で１日間接触還元を行った。反応終了後、反応液を濾過、濃縮し、残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝１０：１）にて精製した（４．２１ｇ，　収率８４％：融点６０．０−６６．２℃）。得られた結晶のうち１５０ｍｇ　（Ｆ．Ｗ．　３３５．２０，　０．４５ｍｍｏｌ）にピリジン−塩酸２ｇを加え２００℃で２時間加熱撹拌した。反応終了後、反応液を酢酸エチル、希塩酸にて分配した。有機層を水洗及び飽和塩化ナトリウム溶液で洗浄後、無水硫酸マグネシウムにて乾燥し溶媒を減圧留去した。残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝１：１）にて精製した。クロロホルム−ヘキサンで再結晶し、標記化合物　８０ｍｇ　（５８％）　をうすピンク色の板状晶として得た。
融点１７７．５−１７９．５℃；　^１Ｈ　ＮＭＲ　（ＤＭＳＯ−ｄ_６，　９０　ＭＨｚ）　δ２．７−２．９　（２Ｈ，　ｍ，　ＣＨ_２），　２．９−３．１　（２Ｈ，　ｍ，　ＣＨ_２），　６．０−６．２　（２Ｈ，　ｍ，　Ａｒ−Ｈ），　７．１−７．４　（３Ｈ，　ｍ，　Ａｒ−Ｈ），　９．２２　（１Ｈ，　ｓ，　ＯＨ），　９．４１　（１Ｈ，　ｓ，　ＯＨ）．　ＭＳ　（ＥＩ）　ｍ／ｚ　３０８，　３０６，　２２７．
【００９５】
参考例６：１−クロロ−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１０−オン（３８）の製造方法
【００９６】
【化１８】

【００９７】
カルボン酸（３１）の合成
２，６−ジクロロ安息香酸（３０）９．３２ｇ　（Ｆ．Ｗ．　１９１．０１，　４８．８ｍｍｏｌ）、３，５−ジメトキシフェノール（１３）６．６０ｇ　（Ｆ．Ｗ．　１５４．１６５，　４．２９ｍｍｏｌ）、炭酸カリウム　９．３２ｇ　（Ｆ．Ｗ．　１３８．２１，　６７．４ｍｍｏｌ）、Ｎ−メチル−２−ピロリドン　５６ｍｌ　の混合物にベンゼン（４０ｍｌ）を加えディーン−スターク水分離器で３時間乾燥後（１４０−１７０℃）、銅（粉末）　６１４ｍｇ　（Ｆ．Ｗ．　６３．５５，　９．６７ｍｍｏｌ）、ヨウ化銅（Ｉ）　２．３０ｇ　（Ｆ．Ｗ．　１９０．４５，１２．１ｍｍｏｌ）を加え、１４０℃で１時間撹拌した。この反応混合物を放冷し、氷水および酢酸エチルを加えた後、濃塩酸で　ｐＨ２とし濾過した。有機層を分離後よく水洗し飽和食塩水で塩析した。無水硫酸マグネシウムで乾燥、濃縮した。残さ（１７ｇ）をカラムクロマトグラフィー（シリカゲル，　含６％水；　３４０ｇ，　酢酸エチル：ヘキサン＝１：２）で精製し（３１）の結晶５．０５ｇ（３８％）を得た。
【００９８】
エステル体（３２）の合成
カルボン酸（３１）２．５ｇ　（Ｆ．Ｗ．　３５３．１６８，　８．１０ｍｍｏｌ）　のジクロロメタン　１０ｍｌ、メタノール　１０ｍｌの混合溶液に溶かしジアゾメタンのエーテル溶液を黄色い色が消えなくなるまで加えた。反応液を濃縮しシリカゲル・カラムクロマトグラフィー（シリカゲル；　９０ｇ，　酢酸エチル：ヘキサン＝１：４）で精製しエステル体（３２）　２．５０７ｇ　（９８％）を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：４）
【００９９】
アルコール体（３３）の合成
水素化リチウムアルミニウム２５０ｍｇ　（Ｆ．Ｗ．　３７．８３，　６．６０ｍｍｏｌ），　ジエチルエーテル　１０ｍｌの混合物に０℃で撹拌下、エステル（３２）２．５１ｇ　（Ｆ．Ｗ．　３２２．７４４，　７．７６ｍｍｏｌ）のエーテル溶液（５＋３ｍｌ）を少しずつ加えた。室温で３時間撹拌後、この反応溶液に９０％メタノール溶液、飽和塩化アンモニウム水を加えた。有機層を分離し、飽和食塩水で３回洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去した。反応液を濃縮しシリカゲル・カラムクロマトグラフィー（シリカゲル，　；１５０ｇ，　酢酸エチル：ヘキサン＝３：７）で精製しアルコール（３３）１．５３ｇ　（６４％）を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：４）
【０１００】
臭化物（３４）の合成
アルコール（３３）２．２４ｇ　（Ｆ．Ｗ．　３０８．７６１，　７．２８ｍｍｏｌ）をベンゼンとともに共沸して乾燥し、塩化メチレン５ｍｌに三臭化リン　０．２５４ｍｌ　（Ｆ．Ｗ．　２７０．７０，　ｄ＝２．８５，　２．６７ｍｍｏｌ）および塩化メチレン５．６ｍｌを０℃で加え、室温で２時間撹拌した。氷水を反応混合物に加え、酢酸エチルで抽出し、水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去した。残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１：４）にて精製し臭化物（３４）　２．５８ｇ　（９９％）　を結晶として得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：４）
【０１０１】
シアノ化物（３５）の合成
臭化物（３４）２．５８ｇ　（Ｆ．Ｗ．　３５７．６３１，　７．２１ｍｍｏｌ）をジメチルスルホキシド　５ｍｌに溶解した。この溶液にシアン化ナトリウムを　５３０ｍｇ　（Ｆ．Ｗ．　４９．０１，　１０．８２ｍｍｏｌ）加え、８０℃で３０分間撹拌した。氷冷下、水を加えた後、酢酸エチルで３回抽出した。これを水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去した。残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１：４）にて精製しシアノ化物（３５）１．９５ｇ　（８９％）　を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：４）
【０１０２】
フェニル酢酸（３６）の合成
シアノ体（３５）１．９３ｇ　（Ｆ．Ｗ．　３０３．７４５，　６．３５ｍｍｏｌ）にエタノール　４．５６ｍｌ、６Ｎ水酸化ナトリウム水溶液　４．５６ｍｌ（水酸化ナトリウム１．１３ｇ（Ｆ．Ｗ．　４０．００，　２８．３ｍｍｏｌ）　を水に溶解）を加え、１１０℃で１晩撹拌した。反応溶液に氷を加え、濃塩酸でｐＨ２にした。酢酸エチルで抽出し、水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を完全に除去しベンゼン−ヘキサンから結晶化しフェニル酢酸（３６）１．３６ｇ　（６６％）　を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：２ｏｒ
１：１）
【０１０３】
環化体（３７）の合成
カルボン酸（３６）１．３０ｇ　（Ｆ．Ｗ．　３２２．７４４，　４．０３ｍｍｏｌ）をトルエン６ｍＬに溶かし、これにポリリン酸（リン酸１０ｍＬ，　五酸化リン７ｇを１５０℃にて加熱）を加え、濃縮した。この溶液を１００℃で１．５時間撹拌した。反応溶液に氷水を加え酢酸エチルで抽出し常法に従って処理し粗生成物をえた。ヘキサン−塩化メチレンで再結晶し、環化体（３７）１．１７ｇ　（８５％）を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：２）
【０１０４】
１−クロロ−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１０−オン（３８）の合成
ジメトキシ化合物（３７）１５０ｍｇ　（Ｆ．Ｗ．　３０４．７２９，　０．４９２ｍｍｏｌ）、ベンゼン０．１５ｍＬにピリジン塩酸塩　２．０ｇ　を加え、１９５℃で１．５時間、加熱撹拌後、氷水を徐々に加えた。酢酸エチルで抽出し、１Ｎ塩酸、水、飽和食塩水で順次洗浄した。無水硫酸マグネシウムで乾燥後、濃縮した。残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１：２）にて精製した。さらに、ジクロロメタン−ヘキサンで再結晶し標記化合物　１０４ｍｇ　（７７％）を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：２）
【０１０５】
参考例７：９−クロロ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１，３−ジオール（４０）の製造方法
【０１０６】
【化１９】

【０１０７】
Ｂ環ケトンの還元
Ｂ環−ケトン化合物（３７）４７５ｍｇ　（Ｆ．Ｗ．　３０４．７２９，　１．５６ｍｍｏｌ）をエチレングリコール２０ｍＬにとかし、ヒドラジン一水和物　２．２５ｍＬ　（Ｆ．Ｗ．　５０．０６，　ｄ＝１．０３２，　４６．５ｍｍｏｌ）　と水酸化カリウム　３．０５ｇ　（Ｆ．Ｗ．　５６．１１，　５４．３ｍｍｏｌ）　を加え、７０℃で４．５時間撹拌した。１４０℃まで昇温した後、さらに２時間撹拌した。、氷冷下、反応溶液に４Ｎ塩酸を加え中和した。酢酸エチルで抽出し、水、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を除去し粗生成物を得た。残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝１９：１）にて精製し、還元体（３９）　３４７ｍｇ　（Ｆ．Ｗ．　２９０．７４６，　１．１９ｍｍｏｌ，　７６％）を得た。
【０１０８】
脱保護
ジメトキシ体（３９）　３４７ｍｇ　（Ｆ．Ｗ．　２９０．７４６，　１．１９ｍｍｏｌ）、にピリジン塩酸塩３．５ｇを加え、２００℃で２時間、加熱撹拌後、氷水を徐々に加えた。酢酸エチルで抽出し、１Ｎ塩酸、水、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥後、濃縮した。残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝３：１）にて精製し、さらに、クロロホルム−ヘキサンで再結晶し標記化合物２２５ｍｇ　（Ｆ．Ｗ．　２６２．６９２，　０．８６ｍｍｏｌ，　７２％）　を得た。
【０１０９】
【実施例】
以下に、実施例に基づいて本発明をより詳細に説明するが、本発明は実施例等により限定されるものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。実施例のカラムクロマトグラフィーにおける溶出は、特に言及しない限り、ＴＬＣ（薄層クロマトグラフィー）による観察下に行われた。ＴＬＣ観察においては、ＴＬＣプレートとしてメルク社製の６０Ｆ２５４を用い、展開溶媒としてはカラムクロマトグラフィーで溶出溶媒として用いられた溶媒を用いた。また、検出にはＵＶ検出器を採用した。カラムクロマトグラフィー用のシリカゲルとしては、メルク社製のシリカゲル６０（７０−２３０メッシュ）あるいはアサヒガラス社製マイクロスフェアーゲルＤ７５−６０Ａを用いた。室温とは通常約１０℃ないし約３５℃を意味する。
【０１１０】
実施例１：２−メチルチオ−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オン（実施例１の化合物）の製造方法
【０１１１】
【化２０】

【０１１２】
カルボン酸（４２）の合成
５−チオメチル−２−クロロ安息香酸（４１）　６０．８ｇ　（Ｆ．Ｗ．　２０２．６６，　０．３０ｍｏｌ）、３，５−ジメトキシジスルフィド（９）２１．０ｇ　（Ｆ．Ｗ．　３３８．４４８，　０．１５ｍｏｌ）、炭酸カリウム　２１．０ｇ　（Ｆ．Ｗ．　１３８．２１，　０．１５ｍｏｌ）、Ｎ−メチル−２−ピロリドン　３００ｍｌの混合物にベンゼン（１００ｍｌＸ３）を加えディーン−スターク水分離機で共沸乾燥後、１３５℃で加熱した。銅（粉末）　９．５３ｇ　（Ｆ．Ｗ．　６３．５５，　０．１５ｍｏｌ）、ヨウ化銅（Ｉ）　２８．５７ｇ（Ｆ．Ｗ．　１９０．４５，　０．１５ｍｏｌ）を加え、１３５℃で５．５時間撹拌した。この反応混合物を放冷し、氷水および酢酸エチルを加えた後、濃塩酸で　ｐＨ２とし濾過した。有機層を分離後よく水洗し飽和食塩水で塩析した。無水硫酸マグネシウムで乾燥、濃縮後、２−ブタノン−イソプロピルエーテルから再結晶化し、カルボン酸（４２）６５．０８ｇを得た。合計収率：　６５．０８ｇ（６５％）　＋　母液１１．０３ｇ　（ｐｕｒｉｔｙ，　４０％）（ＴＬＣ；酢酸エチル：ヘキサン＝１：２ｏｒ　１：１）
ＭＳ　（ＥＩ）：　３３６，　３１８，　３０３，　２４４．　ＮＭＲ（ＣＤＣｌ_３）：　２．４８　（３Ｈ，　ｓ，　ＣＨ_３），　３．７８　（６Ｈ，　ｓ，ＣＨ_３Ｘ２），　６．５０　（１Ｈ，　ｄ，　Ｊ＝２．２Ｈｚ，　Ａｒ−Ｈ），　６．６９　（１Ｈ，　ｄ，　Ｊ＝　２．２Ｈｚ，　Ａｒ−Ｈ），　６．９１（１Ｈ，　ｄ，　Ｊ＝８．５Ｈｚ，　Ａｒ−Ｈ），　７．２２　（１Ｈ，　ｄｄ，　Ｊ＝８．５，　２．２Ｈｚ，　Ａｒ−Ｈ），　７．９７　（１Ｈ，　ｄ，
Ｊ＝２．２Ｈｚ，　Ａｒ−Ｈ）．
【０１１３】
アルコール（４３）の合成
カルボン酸（４２）５０．４５ｇ　（Ｆ．Ｗ．　３３６．４３２，　１５０ｍｍｏｌ）のテトラヒドロフラン　２００ｍｌ溶液に水素化ホウ素ナトリウム６．２４ｇ　（Ｆ．Ｗ．　３７．８３，　１６５．０ｍｍｏｌ）　を室温で少しずつ加えた後、フッ化ホウ素エーテル錯体　２０．２９ｍｌ　（Ｆ．Ｗ．　１４１．９３，　ｄ＝１．１５４，　１６５．０ｍｍｏｌ）を滴下した。室温で１時間撹拌した。この反応液に氷水を徐々に加えた。酢酸エチルで抽出し、飽和食塩水で３回洗浄した。硫酸マグネシウムで乾燥後、減圧下溶媒を除去した。ジイソプロピルエーテルで結晶化しアルコール（４３）４６．２３ｇを得た。酢酸エチル−ヘキサンで再結晶し４３．６１ｇ（７７％）を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：２）
ＭＳ　（ＥＩ）：　３２２，　３０３，　２８９，　２７３．　ＮＭＲ（ＣＤＣｌ_３）：　２．５１　（３Ｈ，　ｓ，　ＣＨ_３），　３．７１　（６Ｈ，　ｓ，ＣＨ_３Ｘ２），　４．７４　（２Ｈ，　ｄ，　Ｊ＝６．３Ｈｚ，　ＣＨ_２），　６．２６　（３Ｈ，　ｓ，　Ａｒ−Ｈ），　６．８５　（１Ｈ，　ｄｄ，　Ｊ＝８．５，　２．２Ｈｚ，　Ａｒ−Ｈ），　７．４０　（１Ｈ，　ｄ，　Ｊ＝２．２Ｈｚ，　Ａｒ−Ｈ），　７．４２　（１Ｈ，　ｄ，　Ｊ＝８．５Ｈｚ，　Ａｒ−Ｈ）．
【０１１４】
臭化物（４４）の合成
アルコール（４３）５９．０６ｇ　（Ｆ．Ｗ．　３２２．４４９，　１７５．５ｍｍｏｌ）の塩化メチレン（１２７ｍｌ）　溶液に三臭化燐　６．４ｍｌ　（Ｆ．Ｗ．　１１８．９７，　ｄ＝１．６３１，　６４．４ｍｍｏｌ）を０℃で加え、同温度で３０分間撹拌した。さらに室温で１５分間撹拌した。氷水を反応混合物に加え、酢酸エチルで抽出し、水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去した。残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１：５）にて精製後、酢酸エチル−ヘキサンで再結晶し臭化物（４４）５７．７４ｇ　（８２％）　を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：４）
ＭＳ　（ＥＩ）：　３８６，　３８４．　ＮＭＲ（ＣＤＣｌ_３）：　２．５０　（３Ｈ，　ｓ，　ＣＨ_３），　３．７３　（６Ｈ，　ｓ，　ＣＨ_３Ｘ２），　４．６４　（２Ｈ，　ｓ，　ＣＨ_２），　６．２８　（１Ｈ，　ｄ，　Ｊ＝２．２Ｈｚ，　Ａｒ−Ｈ），　６．３３　（２Ｈ，　ｄ，　Ｊ＝２．２Ｈｚ，　Ａｒ−Ｈ），　７．１２　（１Ｈ，　ｄｄ，　Ｊ＝８．２，　２．４Ｈｚ，　Ａｒ−Ｈ），　７．３３　（１Ｈ，ｄ，　Ｊ＝８．２Ｈｚ，　Ａｒ−Ｈ），　７．３５　（１Ｈ，　ｄ，　Ｊ＝２．４Ｈｚ，　Ａｒ−Ｈ）．
【０１１５】
ニトリル体（４５）の合成
臭化物（４４）５７．７４ｇ　（Ｆ．Ｗ．　３８５．３４６，　１４９．８ｍｍｏｌ）をジメチルスルホキシド　１２７ｍｌに溶解した。この溶液にシアン化ナトリウムを　１１．０２ｇ　（Ｆ．Ｗ．　４９．０１，　２２４．８ｍｍｏｌ）　加え、８０℃で４５分間撹拌した。氷冷下、水を加えた後、酢酸エチルで３回抽出した。これを水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去した。酢酸エチル−ヘキサンで再結晶し、ニトリル体（４５）３４．８３ｇ　（７０％）　を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：４）ＭＳ　（ＥＩ）：　３３１．　ＮＭＲ（ＣＤＣｌ_３）：　２．５３　（３Ｈ，　ｓ，　ＣＨ_３），　３．７２　（６Ｈ，　ｓ，　ＣＨ_３），　３．８５　（３Ｈ，　ｓ，　ＣＨ_３），　６．２０　（２Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　６．２７　（１Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　７．１９　（１Ｈ，　ｄｄ，　Ｊ＝８．５，　２．３Ｈｚ，　Ａｒ−Ｈ），　７．４４　（１Ｈ，　ｄ，　Ｊ＝２．３Ｈｚ，　Ａｒ−Ｈ），　７．４５　（１Ｈ，　ｄ，　Ｊ＝８．５Ｈｚ，　Ａｒ−Ｈ）．
【０１１６】
フェニル酢酸（４６）の合成
ニトリル体（４５）３０．０７ｇ　（Ｆ．Ｗ．　３３１．４６，　９０．８ｍｍｏｌ）をエタノール　７５ｍｌ、６Ｎ水酸化ナトリウム水溶液　７５ｍｌ（水酸化ナトリウム１８．０６ｇ（Ｆ．Ｗ．　４０．００，　４５０ｍｍｏｌ）　を水に溶解）を加え、１１０℃で１晩撹拌した。反応液に氷を加え、濃塩酸でｐＨ２にした。酢酸エチルで抽出し、水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を完全に除去しベンゼン−ヘキサンから結晶化しフェニル酢酸（４６）２８．８６ｇ　（９１％）　を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：２ｏｒ　１：１）ＭＳ　（ＥＩ）：　３５０，　２７３．　ＮＭＲ（ＣＤＣｌ_３）：　２．４９　（３Ｈ，　ｓ，　ＣＨ_３），　３．７０　（６Ｈ，　ｓ，　ＣＨ_３），　３．８４　（１Ｈ，　ｓ，　ＣＨ_２），　６．２５　（３Ｈ，　ｍ，　Ａｒ−Ｈ），　７．１５　（１Ｈ，　ｄｄ，　Ｊ＝８．５，　２．３Ｈｚ，　Ａｒ−Ｈ），　７．２１　（１Ｈ，　ｄ，　Ｊ＝２．３Ｈｚ，　Ａｒ−Ｈ），　７．４２　（１Ｈ，　ｄ，　Ｊ＝８．５Ｈｚ，　Ａｒ−Ｈ），　１２．９１　（１Ｈ，
ｓ，　ＯＨ）．
【０１１７】
環化体（４７）の合成
カルボン酸（４６）２７．８９ｇ（Ｆ．Ｗ．　３５０．４５９，　３２．０ｍｍｏｌ）にメタンスルホン酸　１４０ｍＬを加え、溶解した。この溶液を４０℃で１日間撹拌した。反応液に氷水を加え環化体を析出させた。析出した環化体を濾別し酢酸エチルで抽出し常法に従って処理し粗生成物をえた。ヘキサン−塩化メチレンで再結晶し、環化体（４７）　１５．２２ｇ　（５８％）を得た。（ＴＬＣ；酢酸エチル：ヘキサン＝１：２）ＭＳ　（ＥＩ）：３３２，　３４７，　２６９．ＮＭＲ（ＣＤＣｌ_３）：２．４９　（３Ｈ，　ｓ，　ＣＨ_３），　３．８１　（３Ｈ，　ｓ，　ＣＨ_３），　３．８５　（３Ｈ，　ｓ，　ＣＨ_３），４．１９　（１Ｈ，　ｓ，　ＣＨ_２），　６．３６　（１Ｈ，　ｄ，　Ｊ＝２．５Ｈｚ，　Ａｒ−Ｈ），　６．６６　（１Ｈ，　ｄ，　Ｊ＝２．３Ｈｚ，　Ａｒ−Ｈ），　７．０４　（１Ｈ，　ｄｄ，　Ｊ＝８．５，　２．２Ｈｚ，　Ａｒ−Ｈ），　７．２２　（１Ｈ，　ｄ，　Ｊ＝２．２Ｈｚ，　Ａｒ−Ｈ），　７．４６　（１Ｈ，　ｄ，　Ｊ＝８．５Ｈｚ，　Ａｒ−Ｈ）．
【０１１８】
７−メチルチオ−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１０−オン（実施例１の化合物）の合成
ジメトキシ化合物（４７）２７．８８ｇ　（Ｆ．Ｗ．　３３２．４４，　１．１３ｍｍｏｌ）にピリジン塩酸塩１２０ｇ　を加え、１９５℃で１．５時間、加熱撹拌後、氷水を徐々に加えた。酢酸エチルで抽出し、１Ｎ塩酸、水、飽和食塩水で順次洗浄した。無水硫酸マグネシウムで乾燥後、濃縮した。残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１：２）にて精製した。さらに、イソプロピルアルコール−２−ブタノンで再結晶することにより標記化合物　１９．４０ｇ　（６４％）　を得た。
【０１１９】
実施例２：８−メチルチオ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１，３−ジオール（実施例２の化合物）の製造方法
【０１２０】
【化２１】

【０１２１】
環化体（４７）６６５ｍｇ　（Ｆ．Ｗ．　３３２．４３，　２．０ｍｍｏｌ）をエチレングリコール５０ｍＬに溶かし、ヒドラジン一水和物　２．９ｍＬ　（Ｆ．Ｗ．　５０．０６，　ｄ＝１．０３２，　６０．０ｍｍｏｌ）と水酸化カリウム　４．０４ｇ　（Ｆ．Ｗ．　５６．１１，　７２．０ｍｍｏｌ）　を加え、８０℃で１．５時間撹拌した。１４０℃まで昇温した後、さらに５時間撹拌した。氷冷下、反応液に１Ｎ塩酸を加え中和した。酢酸エチルで抽出し、水、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を完全に除去し粗生成物を得た。残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝１９：１）で精製し、還元体（４８）　２３８．５ｍｇ　（３７．５％）を得た。
【０１２２】
還元体（４８）　２３８．５ｍｇ　（Ｆ．Ｗ．　３１８．４５，　０．７５ｍｍｏｌ）、にピリジン塩酸塩３．０ｇを加え、２００℃で６時間、加熱撹拌後、氷水を徐々に加えた。酢酸エチルで抽出し、１Ｎ塩酸、水、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥後、濃縮した。残渣をシリカゲル・カラムクロマトグラフィー（展開溶媒；酢酸エチル：ヘキサン＝１９：１）で精製し、さらに、ヘキサン−酢酸エチルで再結晶し標記化合物１３２．７ｍｇ　（６１．０％）　を得た。
【０１２３】
実施例３：１１−ジエチル−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オン（実施例３の化合物）の製造方法
【０１２４】
【化２２】

【０１２５】
水素化ナトリウム１．９２ｇ　（６０％含有，　Ｆ．Ｗ．　２４．００，　４８．０ｍｍｏｌ）　とテトラヒドロフラン５０ｍＬの懸濁液に、化合物（４９）　５．７２ｇ　（Ｆ．Ｗ．　２８６．３４，　２０．０ｍｍｏｌ）をテトラヒドロフラン２００ｍＬにとかした溶液を滴下した。この懸濁液を室温で３０分撹拌した後、ヨウ化エチル３．８４ｍＬ　（Ｆ．Ｗ．　１５５．９７，　ｄ＝１．９４，　４８．０ｍｍｏｌ）加え、さらに室温で２日間撹拌した。氷冷下、反応溶液に塩化アンモニウムを加え、減圧下テトラヒドロフランを完全に除去した後、酢酸エチルと水で分配し、水、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を完全に除去し粗生成物９．４３ｇを得た。残渣をシリカゲルカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝９：１〜３：１）にて精製し、化合物（５０）と（５１）の混合物３．６２ｇおよび化合物（５２）２．６２ｇ　（Ｆ．Ｗ．　３４２．４５，　７．６５ｍｍｏｌ，　３８．２％）を得た。副生成物である化合物（５２）はエタノール−濃塩酸で酸処理して化合物（５１）に変換した。化合物（５１）は上記反応を再度行い、化合物（５０）に導いた。
【０１２６】
粗生成物（５０）を合わせてシリカゲルカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝９：１〜５：１）にて精製し、化合物（５０）３．７３ｇ　（Ｆ．Ｗ．３４２．４５，　１０．８９ｍｍｏｌ，　５４．５％）　を得た。脱メチル反応は実施例１の方法に従って行い、標記化合物を得た。
【０１２７】
実施例４：１１−エチル−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オン（実施例４の化合物）の製造方法
【０１２８】
【化２３】

【０１２９】
ｔ−ブトキシカリウム　（１２．３　ｇ，　１１０　ｍｍｏｌ）　とテトラヒドロフラン５００　ｍＬの懸濁液に、化合物（４９）３０　ｇ　（Ｆ．Ｗ．　２８６．３４，　１０５　ｍｍｏｌ）のテトラヒドロフラン５００ｍＬ溶液を０℃で滴下した。この懸濁液を室温で２時間撹拌した後、０℃まで冷却しヨウ化エチル１６．８　ｍＬ　（Ｆ．Ｗ．　１５５．９７，　ｄ＝１．９４，　２１０　ｍｍｏｌ）を加え、室温で２０時間撹拌した。氷冷下、反応溶液に塩酸を加え、減圧下テトラヒドロフランを完全に除去した後、酢酸エチルと水で分配し、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去し、残渣をシリカゲルカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝４：１）にて精製し、メタノールにて再結晶後、（５１）を１８．７　ｇ（収率５７％）得た。
化合物（５１）の脱メチル反応は実施例１の方法に従って行い、標記化合物を１４．８ｇ得た。
【０１３０】
実施例５：３−（２−チオフェン）−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１０−オン（実施例５の化合物）の製造方法
【０１３１】
【化２４】

【０１３２】
３−ブロモ−７，９−ジメトキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１０−オン（２７）　（５００ｍｇ，　１．４ｍｍｏｌ）、２−（トリブチルスタニル）−チオフェン　（０．９　ｍＬ，　２．８ｍｍｏｌ）およびテトラキス（トリフェニルフォスフォニウム）パラジウム　（８２．５ｍｇ，　０．０７ｍｍｏｌ）にヘキサメチルホスオリックトリアミド　５ｍＬを加え１００℃で１時間撹拌した。反応終了後、ジエチルエーテル、水で分配し、有機層を水洗および飽和食塩水で洗浄を行い、無水硫酸マグネシウムにて乾燥し溶媒を減圧留去した。残さをシリカゲルカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝１：１）にて精製を行い、３−（２−チオフェン）−７，９−ジメトキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１０−オン　５３８ｍｇ　（収率８９％）を得た。脱メチル反応は実施例１の方法に従って行い、標記化合物を得た。
【０１３３】
実施例６：３−フェニル−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１０−オン（実施例６の化合物）の製造方法
【０１３４】
【化２５】

【０１３５】
３−ヨード−７，９−ジメトキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１０−オン（５２）　（４０３ｍｇ，　１．０ｍｍｏｌ）、フェニルボロン酸　（１８６ｍｇ，　１．５ｍｍｏｌ）、２Ｍ炭酸カリウム水溶液　（０．６ｍＬ，　１．２ｍｍｏｌ）およびテトラキス（トリフェニルフォスフォニウム）パラジウム　（１１８ｍｇ，　０．１０ｍｍｏｌ）にトルエン５ｍＬを加え１２５℃で１９時間撹拌した。反応終了後、希塩酸にて中和し酢酸エチルで抽出した。有機層を水洗および飽和食塩水で洗浄を行い、無水硫酸マグネシウムにて乾燥し溶媒を減圧留去した。残さをシリカゲルカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝２：１）にて精製を行い、３−フェニル−７，９−ジメトキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１０−オン　１０８ｍｇ　（収率３１％）を得た。脱メチル反応は実施例１の方法に従って行い、標記化合物を得た。
【０１３６】
実施例７：７−フェニル−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１，３−ジオール（実施例７の化合物）の製造方法
【０１３７】
【化２６】

【０１３８】
先の化合物（２７）の１０位カルボニル基を還元して得られた１，３−ジメトキシ−７−ブロモ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン（５３）　（９７０ｍｇ，２．９ｍｍｏｌ）、フェニルボロン酸　（３８０ｍｇ，　３．１ｍｍｏｌ）、炭酸カリウム　（１．９８ｍｇ，　１４．３ｍｍｏｌ）、酢酸パラジウム（２０ｍｇ，　０．０９ｍｍｏｌ）およびテトラ−ｎ−ブチルアンモニウムブロマイド　（９２０ｍｇ，　２．９ｍｍｏｌ）に水５ｍＬを加え７０℃で１時間撹拌した。反応終了後、希塩酸にて中和し酢酸エチルで抽出した。有機層を水洗および飽和食塩水で洗浄を行い、無水硫酸マグネシウムにて乾燥し溶媒を減圧留去した。残さをシリカゲルカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝１０：１）にて精製を行い、１，３−ジメトキシ−７−フェニル−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン１．０５ｇを定量的に得た。脱メチル反応は実施例１の方法に従って行い、標記化合物を得た。
【０１３９】
実施例８：３−ヨード−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オン（実施例８の化合物）の製造方法
【０１４０】
【化２７】

【０１４１】
カルボン酸（５５）の合成
２−クロロ−３−ヨード安息香酸（５４）　１４．１ｇ　（Ｆ．Ｗ．　２８２．４６，　５０．０ｍｍｏｌ）、ジスルフィド（９）　８．４６ｇ　（Ｆ．Ｗ．　３３８．４４，　２５．０ｍｍｏｌ）、銅（粉末）　１．５８ｇ　（Ｆ．Ｗ．　６３．５５，　２５．０ｍｍｏｌ）、ヨウ化銅（Ｉ）　４．７６ｇ　（Ｆ．Ｗ．　１９０．４５，　２５．０ｍｍｏｌ）、炭酸カリウム　１２．４ｇ　（Ｆ．Ｗ．　１３８．２１，　９０．０ｍｍｏｌ）、Ｎ−メチル−２−ピロリドン　１００ｍｌの混合物を１２０℃で１．５時間撹拌した。この反応溶液を放冷し、４Ｎ　塩酸で　ｐＨ２にした。酢酸エチルで抽出し、水、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を除去して得られた粗カルボン酸を酢酸エチルで再結晶し、カルボン酸（５５）　４．２１ｇ　（Ｆ．Ｗ．　４１６．２３，　１０．１ｍｍｏｌ）を得た。再結晶後の濾液からさらに結晶化（酢酸エチル）し、カルボン酸（５５）　３．４５ｇ　（Ｆ．Ｗ．　４１６．２３，　８．３ｍｍｏｌ）　を得た。収率は　３６．８％であった。
【０１４２】
アルコール（５６）の合成
カルボン酸（５５）７．６６ｇ　（Ｆ．Ｗ．　４１６．２３，　１８．４ｍｍｏｌ）　のテトラヒドロフラン　２０ｍｌ　溶液に水素化ホウ素ナトリウム７２２ｍｇ　を加えた後、フッ化ホウ素エーテル錯体　２．７４ｍｌ　を滴下した。室温で４５分間撹拌した。この反応溶液に氷水を徐々に加えた。酢酸エチルで抽出し、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去した。この粗生成物をカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝４：１）で精製し、アルコール（５６）７．５９ｇ（Ｆ．Ｗ．　４０２．２５）を定量的に得た。
【０１４３】
臭化物（５７）の合成
粗アルコール（５６）７．４９ｇ　（Ｆ．Ｗ．　４０２．２５）　の塩化メチレン　２０ｍｌ　溶液に０℃で三臭化リン　０．６２ｍｌ　を加え、室温で３０分間撹拌した。この反応溶液に氷水を徐々に加えた。さらに室温で３０分間撹拌した後、塩化メチレンで抽出し、水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去した。粗生成物を得た。この粗生成物をカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝４：１）で精製し、臭化物（５７）５．１４ｇ　（Ｆ．Ｗ．　４６５．１４，　１１．０５ｍｍｏｌ）を得た。収率は２段階で　６１．４％であった。
【０１４４】
シアノ化物（５８）の合成
臭化物（５７）５．００ｇ　（Ｆ．Ｗ．　４６５．１４，　１０．７５ｍｍｏｌ）をジメチルスルホシド　２０ｍｌ　に溶解する。この溶液にシアン化ナトリウムを　６３０ｍｇ加え、８０℃で１時間撹拌した。氷冷下、水を加えた後、酢酸エチルで抽出し、水、飽和食塩水で順次洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去し、得られた粗生成物をカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝３：１）で精製し、シアノ化物（５８）２．３０ｇ　（Ｆ．Ｗ．　４１１．２６，　５．５９ｍｍｏｌ）　と粗シアノ化物（５８）２．０６ｇ　（Ｆ．Ｗ．　４１１．２６）　を得た。
【０１４５】
カルボン酸（５９）の合成
シアノ化合物（５８）２．２７ｇ　（Ｆ．Ｗ．　４１１．２６，　５．５ｍｍｏｌ）をエタノール　３０ｍｌ　に加え、１１０℃まで昇温し完全に溶解した。この溶液に１Ｎ水酸化ナトリウム水溶液　２．３５ｍｌ　を加えた。さらに１１０℃で１晩撹拌した。反応溶液に氷を加え、１Ｎ塩酸で中和した。酢酸エチルで抽出し、水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を完全に除去し粗カルボン酸（５９）２．３６ｇ　（Ｆ．Ｗ．　４３０．２６）　を得た。
【０１４６】
環化体（６０）の合成
粗カルボン酸（５９）４．４０ｇ　（Ｆ．Ｗ．　４３０．２６ｍｏｌ）にメタンスルホン酸　６０ｍｌ　を加え、溶解した。この溶液を室温で１晩撹拌した。反応溶液に氷冷下水を加え後、酢酸エチルで抽出し、水、飽和食塩水で順次洗浄した。無水硫酸マグネシウムで乾燥後、溶媒を完全に除去し得られた粗生成物をカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝４：１）、ヘキサンと塩化メチレン、ヘキサンと酢酸エチルで再結晶を繰り返し、環化体（６０）１．８２ｇ　（Ｆ．Ｗ．　４１２．２４，　４．４ｍｍｏｌ）を得た。収率は３段階で　４１．１％であった。
【０１４７】
３−ヨード−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オン（実施例８の化合物）の合成
環化体（６０）４１２．２ｍｇ　（Ｆ．Ｗ．　４１２．２４，　１．０ｍｍｏｌ）にピリジン塩酸塩２．０ｇ加え、２００℃まで昇温した。この溶液を２００℃で２時間撹拌した後、氷水を徐々に加えた。テトラヒドロフランを少量加えた酢酸エチルで抽出し、１Ｎ塩酸、水、飽和食塩水で順次洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を完全に除去し粗生成物　２８９．１ｍｇを得た。シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１〜４：１）で精製した。さらに、クロロホルムで再結晶することにより標記化合物　１５０．１ｍｇ　（Ｆ．Ｗ．　３８４．１９，　３９．１ｍｍｏｌ）を得た。収率　３９．１％であった。
【０１４８】
実施例９：３−ブロモ−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オン（実施例９の化合物）の製造方法
【０１４９】
【化２８】

【０１５０】
カルボン酸（６１）の合成
３−ブロモ−２−クロロ安息香酸（３）　５８．８７ｍｇ　（Ｆ．Ｗ．　２３５．４７，　０．２５ｍｍｏｌ）、ジスルフィド（８０％）　（９）４２．３１ｍｇ　（Ｆ．Ｗ．　３３８．４４，　０．１０ｍｍｏｌ）、銅（粉末）　７．９４ｍｇ　（Ｆ．Ｗ．　６３．５５，　０．１２５ｍｍｏｌ）、ヨウ化銅（Ｉ）　２３．８１ｍｇ　（Ｆ．Ｗ．　１９０．４５，　０．１２５ｍｍｏｌ）、炭酸カリウム　４１．４６ｍｇ　（Ｆ．Ｗ．　１３８．２１，　０．３０ｍｍｏｌ）、Ｎ−メチル−２−ピロリドン　３ｍｌの混合液を１５０℃で２．５時間撹拌した。この反応溶液を放冷し、１Ｎ　塩酸で　ｐＨ２にした。酢酸エチルで抽出し、水、飽和食塩水で順次洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を除去して粗カルボン酸（６１）　（Ｆ．Ｗ．　３６９．２３）を得た。収率はＨＰＬＣより　６４．５％であった。
カルボン酸の合成以降は実施例８に従い合成し標記化合物を得た。
【０１５１】
実施例１０：８−プロピオニル−１０、１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１，３−ジオール（実施例１０の化合物）の製造方法
【０１５２】
【化２９】

【０１５３】
塩化アルミニウム　（１ｇ，　７．５　ｍｍｏｌ）の無水塩化メチレン　（３ｍＬ）けん濁液に塩化プロピオニル　（６６８μＬ，　７．７ｍｍｏｌ）を加え室温で１時間撹拌した。これを１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１，３−ジオールジアセテート（６２）　（３００ｍｇ，　０．９６ｍｍｏｌ）の塩化メチレン　（５ｍＬ）溶液に０℃で滴下し、室温で１時間撹拌した。反応液にメタノール　（１０ｍＬ）を滴下し、２０％水酸化ナトリウム水溶液　（３ｍＬ）を加え室温で３０分撹拌した。反応終了後、塩酸氷水に注ぎ酢酸エチルで抽出し、有機層を水洗および飽和食塩水で洗浄を行い、無水硫酸マグネシウムにて乾燥し溶媒を減圧留去した。残さをシリカゲルカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝２：１）にて精製を行い、酢酸エチル、ヘキサンにて再結晶を行いはだ色針状晶の標記化合物　１９０ｍｇ（収率７０％）を得た。
【０１５４】
実施例１１：８−（１−ヒドロキシイミノエチル）−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１，３−ジオール（実施例１１の化合物）の製造方法
【０１５５】
【化３０】

【０１５６】
８−アセチル−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１，３−ジオール（６３）１８０ｍｇをエタノールに溶解し、これにヒドロキシアミン塩酸塩４９ｍｇ，酢酸ナトリウム　１００ｍｇを水１ｍＬに溶解した水溶液を加えた。混合液を１２０℃で３時間撹拌し、減圧濃縮後、酢酸エチルで抽出した。有機層を水洗および飽和食塩水で洗浄を行い、無水硫酸マグネシウムにて乾燥し溶媒を減圧留去した。残さをシリカゲルカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝１：１）にて精製し、酢酸エチル−ヘキサンにて再結晶を行い、はだ色不定形の標記化合物　１２０ｍｇ（収率６３％）を得た。融点２１５．４−２１７．５℃
【０１５７】
実施例１２：８−ヘキシル−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１，３−ジオール（実施例１２の化合物）の製造方法
【０１５８】
【化３１】

【０１５９】
２−ブロモ−７，９−ジメトキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］オキセピン−１０−オン（６４）２００ｍｇ、パラジウム錯体３２ｍｇ、トリフェニルホスフィン３４ｍｇさらにヨウ化銅１１．８ｍｇを耐圧反応容器に入れ、アセトニトリル（脱水）３ｍｌを加え撹拌した。この溶液にＮ，Ｏ−ビス（トリメチルシリル）アセタミド（以降ＢＳＡ）を加え室温で５分間撹拌しシリル化した。シリル化後１−ヘキシン１１０μｌとＮ，Ｎ−ジイソプロピルエチルアミン２５０μｌを加え封管し、１２０℃で１７時間加熱撹拌した。反応終了後、反応液を酢酸エチル、希塩酸にて分配した。有機層を水洗及び飽和塩化ナトリウム溶液で洗浄後、無水硫酸マグネシウムにて乾燥し溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝３：１）にて精製した。得られた油状物を酢酸エチル５ｍｌに溶解し、パラジウム−炭素２０ｍｇを加え室温で一晩水素添加を行った。反応終了後反応液を濾過、濃縮し、残渣をシリカゲルカラムクロマトグラフィー（展開溶媒；ヘキサン：酢酸エチル＝７：１）にて精製した。クロロホルム−ヘキサンで再結晶し標記化合物の無色板状晶を４９．３ｍｇ得た（収率２４．３％）。
【０１６０】
上記各実施例と同様にして種々の本願発明化合物を合成した。実施例１〜１２において合成した化合物も含め、合成した全１７８個の化合物および以下の試験例において用いた実施例の化合物の構造式を下記に一括して示す。これらの化合物は、参考例、実施例の製造方法と同様な方法で、詳細な説明中で述べたように▲１▼ウルマン反応、▲２▼−１フリーデル−クラフツ反応または▲２▼−２光反応、▲３▼炭素増加反応、▲４▼ハロゲンの他の官能基への変換反応、▲５▼アルキル基、アルキルカルボニル基の導入反応、▲６▼１０位変換反応および▲７▼脱保護反応を組み合わせることによって製造できるが、表１に各化合物の製造工程を説明する。
また、これらの化合物の物性データの一覧表を表２〜表１８に示す。
【０１６１】
【表１】

【０１６２】
【化３２】

【０１６３】
【化３３】

【０１６４】
【化３４】

【０１６５】
【化３５】

【０１６６】
【化３６】

【０１６７】
【化３７】

【０１６８】
【化３８】

【０１６９】
【化３９】

【０１７０】
【化４０】

【０１７１】
【化４１】

【０１７２】
【化４２】

【０１７３】
【化４３】

【０１７４】
【化４４】

【０１７５】
【化４５】

【０１７６】
【化４６】

【０１７７】
【化４７】

【０１７８】
【化４８】

【０１７９】
【化４９】

【０１８０】
【化５０】

【０１８１】
【表２】

【０１８２】

【０１８３】
【表３】

【０１８４】

【０１８５】
【表４】

【０１８６】

【０１８７】
【表５】

【０１８８】

【０１８９】
【表６】

【０１９０】

【０１９１】
【表７】

【０１９２】

【０１９３】
【表８】

【０１９４】

【０１９５】
【表９】

【０１９６】

【０１９７】
【表１０】

【０１９８】

【０１９９】
【表１１】

【０２００】

【０２０１】
【表１２】

【０２０２】

【０２０３】
【表１３】

【０２０４】

【０２０５】
【表１４】

【０２０６】

【０２０７】
【表１５】

【０２０８】

【０２０９】
【表１６】

【０２１０】

【０２１１】
【表１７】

【０２１２】

【０２１３】
【表１８】

【０２１４】
実施例１６４：１１−エチル−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オン（実施例４の化合物）の製造方法
【０２１５】
【化５１】

【０２１６】
カルボン酸（６７）の合成
チオサリチル酸（６５）３９．３ｇ（Ｆ．Ｗ．　１５４．１９，　２５５ｍｍｏｌ）、４−ブロモベラトロール（６６）５５．４ｇ（Ｆ．Ｗ．　２１７．０６，　２５５ｍｍｏｌ）、銅（粉末）１．９０ｇ（Ｆ．Ｗ．　６３．５５，　３０．０ｍｍｏｌ）、ヨウ化銅（Ｉ）５．７ｇ（Ｆ．Ｗ．　１９０．４５，　３０．０ｍｍｏｌ）、炭酸カリウム　４５．０ｇ（Ｆ．Ｗ．　１３８．２１，　３２６ｍｍｏｌ）、Ｎ−メチル−２−ピロリドン　１２０ｍＬの混合物を１５０℃で４時間撹拌した。反応後７０〜８０℃まで放冷し、氷水を加えた後、６Ｎ　塩酸でｐＨ２にした。析出した粗結晶を濾取し、水、ジイソプロピルエーテル、ヘキサンで洗浄し、乾燥後粗生成物　７４．４ｇを得た。１，４−ジオキサンで再結晶し、カルボン酸（６７）５５．０ｇを得た。母液を減圧下濃縮して得られた粗カルボン酸に酢酸エチルを加え、濾過後、酢酸エチルで洗浄し、カルボン酸（６７）６．１ｇ（合計収率８３％）を得た。
【０２１７】
アルコール（６８）の合成
カルボン酸（６７）７５．２ｇ（Ｆ．Ｗ．　２９０．３４，　２５９ｍｍｏｌ）のテトラヒドロフラン　２００ｍＬ溶液に０℃で水素化ホウ素ナトリウム１０．４ｇ（Ｆ．Ｗ．　３７．８３，　２７４ｍｍｏｌ）を加えた後、フッ化ホウ素エーテル錯体　３７．０ｍＬ（Ｆ．Ｗ．　１４１．９３，　ｄ＝１．１５４，　３０１ｍｍｏｌ）を同温で滴下し、室温で１時間撹拌した。この反応液に氷水を徐々に加え、酢酸エチルで抽出し、水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去し、粗アルコール（６８）７３．４ｇを得た。
【０２１８】
臭化物（６９）の合成
粗アルコール（６８）７３．４ｇ（Ｆ．Ｗ．　２７６．３６）の塩化メチレン１００ｍＬ　溶液に０℃で三臭化リン　８．５ｍＬ（Ｆ．Ｗ．　２７０．７０，　ｄ＝２．８５０，　８９．０ｍｍｏｌ）を加えた。室温で３０分間撹拌後、この反応溶液を粉砕した氷に加えた。さらに室温で３０分間撹拌した後、水を加え、塩化メチレンで抽出し、水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去した。粗生成物８３．４ｇを得た。粗臭化物を　塩化メチレン−ヘキサンで再結晶し臭化物（６９）７５．２ｇを得た。収率は２段階で８６％であった。
【０２１９】
ニトリル体（７０）の合成
シアン化ナトリウム１．７６ｇ（Ｆ．Ｗ．　４９．０１，　３６．０ｍｍｏｌ）を水　１５ｍＬに溶解した後、エタノール２０ｍＬを加えた。この溶液中に臭化物（６９）１０．２ｇ（Ｆ．Ｗ．　３３９．２５，　３０．０ｍｍｏｌ）を室温でゆっくり加えた。この混合液を８０℃に加熱し、同温で３０分撹拌した。この反応液を激しく撹拌しながら室温まで放冷した。減圧下エタノールを除去し、水を加えた。析出した粗結晶を濾取し、水で洗浄した。乾燥後、粗ニトリル体８．１３ｇを得た。この粗結晶を酢酸エチル−ヘキサンで再結晶し、ニトリル体（７０）７．３０ｇ（収率８５．３％）を得た。
【０２２０】
エチル体（７１）の合成
ニトリル体（７０）２２．８ｇ（Ｆ．Ｗ．　２８５．３７，　８０．０ｍｍｏｌ）の塩化メチレン　５０ｍＬ溶液にヨウ化エチル　６．７２ｍＬ（Ｆ．Ｗ．　１５５．９７，　ｄ＝１．９４，　８４．０ｍｍｏｌ）を加え、撹拌した。さらに硫酸水素テトラブチルアンモニウム２７．２ｇ（Ｆ．Ｗ．　３３９．５４，　８０．０ｍｍｏｌ）を加え、完全に溶かした。この溶液に２０％水酸化ナトリウム水溶液（８０．０ｇ）を滴下した後、室温で１時間撹拌した。氷冷下、反応溶液に４Ｎ塩酸を加え中和した後、塩化メチレンで抽出し、有機層を水、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を除去し、オイル状の生成物を得た。残渣にヘキサン：酢酸エチル＝３：１を加え、析出するヨウ化テトラブチルアンモニウムを濾過により除去した。濾液について減圧下溶媒を除去し、粗エチル体（７１）２７．０ｇを得た。
【０２２１】
フェニル酢酸（７２）の合成
粗エチル体（７１）２７．０ｇ（Ｆ．Ｗ．　３１３．４１，　７７．２ｍｍｏｌ）とエチレングリコール　６６ｍＬの混合物に３０％水酸化ナトリウム水溶液（４２．７ｇ）を加えた。この溶液を１５０℃で１晩撹拌した。反応溶液に氷を加え、４Ｎ塩酸で中和した。酢酸エチルで抽出し、水、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を完全に除去し粗フェニル酢酸　２９．０ｇを得た。酢酸エチル−ヘキサンで再結晶し、フェニル酢酸（７２）２３．０ｇを得た。収率は２段階で８７％であった。
【０２２２】
環化体（５１）の合成
乾燥したフェニル酢酸（７２）１０．０ｇ（Ｆ．Ｗ．　３３２．４１，　３０．１ｍｍｏｌ）にメタンスルホン酸　５０ｍＬを加え溶解した後、室温で１晩撹拌した。反応液に氷冷下、水を加えた後、酢酸エチルと水で分配し、有機層を水、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を除去し粗生成物　９．５２ｇを得た。粗生成物に少量の酢酸エチルを加え濾取後、少量の酢酸エチルで洗浄し、環化体（５２）８．８４ｇ（収率９３．４％）を得た。
環化体（５１）２５．０ｇ（Ｆ．Ｗ３１４．４０，　８０．０ｍｍｏｌ）にピリジン塩酸塩１５０ｇを加え、２００℃で２時間撹拌した。反応混合物に希塩酸および酢酸エチルを加え抽出し、有機層を水、飽和食塩水で洗浄し無水硫酸マグネシウムで乾燥した。濃縮残渣を酢酸エチル８００ｍＬに溶解し、シリカゲル５０ｇ　およびフロリジル２５ｇで極性物質を吸着後、濾過した。酢酸エチルを濃縮した後、酢酸エチル−ヘキサンより再結晶し標記化合物１９．９ｇ（収率８７％）を得た。
【０２２３】
実施例１６５：１１−エチル−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オン（実施例４の化合物）の製造方法
【０２２４】
【化５２】

【０２２５】
エチル体（７４）の合成
ニトリル体（７３）　３０．０ｇ（Ｆ．Ｗ．　１９６．０５，　１５３ｍｍｏｌ）とヨウ化エチル　１３．６ｍＬ（Ｆ．Ｗ．　１５５．９７，　ｄ＝１．９４，　１６９ｍｍｏｌ）のトルエン５０ｍＬ溶液に氷浴下、硫酸水素テトラブチルアンモニウム　５１．８ｇ（Ｆ．Ｗ．　３３９．５４，　１５３ｍｍｏｌ）と２０％水酸化ナトリウム水溶液（３００ｇ）の懸濁液をすみやかに加え、室温で２時間撹拌した。生じたヨウ化テトラブチルアンモニウムの結晶を濾別し、結晶をトルエン２００ｍＬで洗浄した。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を除去し、エチル体（７４）３４．４ｇ　を得た。
【０２２６】
カルボン酸（７５）の合成
エチル体（７４）３４．４ｇ（Ｆ．Ｗ．　２２４．１０）に６Ｎ水酸化ナトリウム水溶液（７５．０ｍＬ）　とエタノール　７５．０ｍＬを加え、１００℃で２日間撹拌した。減圧下エタノールを除去した後、トルエンを加え分配した。水層に濃塩酸を加えｐＨ３にした。酢酸エチルで抽出し、水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下溶媒を除去し粗生成物約３８ｇを得た。ヘキサンで再結晶し、カルボン酸（７５）３３．５ｇを得た。収率は２段階で９０％であった。
【０２２７】
フェニル酢酸（７２）の合成
カルボン酸（７５）２６．７ｇ（Ｆ．Ｗ．　２４３．１０，　１１０ｍｍｏｌ）、３，４−ジメトキシチオフェノール（７６）１８．７ｇ（Ｆ．Ｗ．　１７０．２３，　１１０ｍｍｏｌ）、銅（粉末）３．５０ｇ（Ｆ．Ｗ．　６３．５５，　５５．０ｍｍｏｌ）、ヨウ化銅（Ｉ）１０．５ｇ（Ｆ．Ｗ．　１９０．４５，　５５．０ｍｍｏｌ）、炭酸カリウム１８．２ｇ（Ｆ．Ｗ．　１３８．２１，　１３２ｍｍｏｌ）、Ｎ−メチル−２−ピロリドン１４０ｍＬの混合物を１４０℃で３．５時間撹拌した。反応液に氷を加え、氷冷下濃塩酸でｐＨ７〜６にした。トルエンと水を加え生成物を溶解し、不溶物を濾別した。濾液に２０％水酸化ナトリウム水溶液を加え分配した。有機層を分離し、さらに２％水酸化ナトリウム水溶液で抽出した後、水層を合わせ、氷冷下濃塩酸でｐＨ２〜３にした。酢酸エチルで抽出し、有機層を水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧下溶媒を除去し粗生成物３５．１ｇ　を得た。少量のジイソプロピルエーテルで洗浄した後、乾燥させ、フェニル酢酸（７２）２８．７ｇ（収率７８．６％）を得た。
【０２２８】
環化体（５１）の合成
乾燥したフェニル酢酸（７２）２８．６ｇ（Ｆ．Ｗ．　３３２．４１，　８６．０ｍｍｏｌ）にメタンスルホン酸１４０ｍＬを加え、室温で１晩撹拌した。反応液を氷水中に滴下し、析出物を濾取した後、水で洗浄した。乾燥後、環化体（５１）２６．９ｇ（収率９９．４％）を得た。
環化体（５１）１８．９ｇ（Ｆ．Ｗ３１４．４０，　６０．０ｍｍｏｌ）にピリジン塩酸５６．６ｇを加え、１８５℃で６時間撹拌した。反応混合物を完全に室温まで冷却してから氷水および酢酸エチルを加え抽出した。有機層を水、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を除去し粗生成物１６．２ｇ　を得た。６０％含水イソプロピルアルコールより再結晶し、標記化合物１５．９ｇ（収率９２．４％）を得た。
【０２２９】
実施例１６６：（＋）−１１−エチル−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オン（実施例４の化合物の（＋）光学異性体）の製造方法
実施例４の化合物を下記の条件でカラムにより光学分割し、前のピークを得た。この化合物の比旋光度［α］_Ｄ（２０℃）は＋１６．７であった。
カラム：ＣＨＩＲＡＬＰＡＫ　　ＡＤ
移動相：ｎ−へキサン／エタノール／酢酸＝４０／６０／０．１（ｖｏｌ／ｖｏｌ）
【０２３０】
実施例１６７：（−）−１１−エチル−７，９−ジヒドロキシ−１０，１１−ジヒドロジベンゾ［ｂ，ｆ］チエピン−１０−オン（実施例４の化合物の（−）光学異性体）の製造方法
実施例４の化合物を下記の条件でカラムにより光学分割し、後のピークを得た。この化合物の比旋光度［α］_Ｄ（２０℃）は−１６．７であった。
カラム：ＣＨＩＲＡＬＰＡＫ　　ＡＤ
移動相：ｎ−へキサン／エタノール／酢酸＝４０／６０／０．１（ｖｏｌ／ｖｏｌ）
【０２３１】
実施例１７８：α−エチル−２−ブロモフェニル酢酸（７５）の製造方法
実施例１６５の第２段階までに記載された通りの方法により得られた標題の化合物は下記の物性を有することを確認した。
性状：無色板状晶。
融点：３７−３９℃（冷ヘキサン）
^１Ｈ−ＮＭＲ　（４００　ＭＨｚ，　ＣＤＣｌ_３）δ：０．９４　（３Ｈ，　ｄｄ，　Ｊ　＝　７．４，　７．４　Ｈｚ），　１．８３　（１Ｈ，　ｄｄｑ，　Ｊ　＝　１４．９，　７．４，　７．４　Ｈｚ），２．１０　（１Ｈ，　ｄｄｑ，　Ｊ　＝　１４．９，　７．４，　７．４　Ｈｚ），　４．１４　（１Ｈ，　ｄｄ，　Ｊ　＝　７．４，　７．４　Ｈｚ），　７．１２　（１Ｈ，　ｄｄｄ，　Ｊ　＝　８．０，　７．５，　１．６　Ｈｚ），　７．２９　（１Ｈ，　ｄｄｄ，　Ｊ　＝　７．８，　７．５，　１．２　Ｈｚ），　６．９４　（１Ｈ，　ｄｄ，　Ｊ　＝　７．８，　１．２　Ｈｚ），　７．３８　（１Ｈ，　ｄｄ，　Ｊ　＝　８．０，　１．６　Ｈｚ）
ＥＩＭＳ　ｍ／ｚ：２４４，　２４２　（Ｍ^＋），　１９９，　１９７，　１７１，　１６９，　１６３
ＩＲ　（ＫＢｒ）　ｃｍ^−１：１７０５
ＵＶ　λ_ｍａｘ　（ＥｔＯＨ）　ｎｍ　（ε）：２７４　（４０），　２６４　（３００）
【０２３２】
実施例１７９：α−エチル−２−［（３、４−ジメトキシフェニル）チオ］フェニル酢酸（７２）の製造方法
実施例１６４の第６段階および実施例１６５の第３段階までに記載された通りの方法により得られた標題の化合物は下記の物性を有することを確認した。
性状：薄茶色不定形。
融点：１１５．２−１１７．０℃　（Ｄｅｃ．）
^１Ｈ−ＮＭＲ　（４００　ＭＨｚ，　ＣＤＣｌ_３）δ：０．９２　（３Ｈ，　ｄｄ，　Ｊ　＝　７．４，　７．４　Ｈｚ），　１．７９　（１Ｈ，　ｄｄｑ，　Ｊ　＝　１４．８，　７．４，　７．４　Ｈｚ），　２．１２　（１Ｈ，　ｄｄｑ，　Ｊ　＝　１４．８，　７．４，　７．４　Ｈｚ），　３．７９　（３Ｈ，　ｓ），　３．８７　（３Ｈ，　ｓ），　４．３３　（１Ｈ，　ｄｄ，　Ｊ　＝　７．４，　７．４　Ｈｚ），　６．８０　（１Ｈ，　ｄ，　Ｊ　＝　８．３　Ｈｚ），　６．８８　（１Ｈ，　ｄ，　Ｊ　＝　１．９　Ｈｚ），　６．９４　（１Ｈ，　ｄｄ，　Ｊ　＝　８．３，　１．９　Ｈｚ），　７．１４−７．２６　（３Ｈ，　ｍ），　７．３７　（１Ｈ，　ｄ，　Ｊ　＝　１．８　Ｈｚ）ＥＩＭＳ　ｍ／ｚ：３３２　（Ｍ^＋，　Ｂａｓｅ）
ＩＲ　（ＫＢｒ）　ｃｍ^−１：１７０５，　１５８５，　１５０４，　１４４２
ＵＶ　λ_ｍａｘ　（ＥｔＯＨ）　ｎｍ　（ε）：２５０　（１５２００），　２８３　（８０００）
【０２３３】
実施例１８０
実施例化合物４　１．００ｇ　（Ｆ．Ｗ．　２８６．３７，　３．５０　ｍｍｏｌ）　１Ｎ−ＮａＯＨ　（４　ｍＬ）の混合物に、アセトブロモグルクロン酸メチルエステル　１．４０ｇ　（Ｆ．Ｗ．　３９７．２，　３．５０　ｍｍｏｌ）　をアセトン６　ｍＬに溶解したものをすこしづつ０℃で加え、１Ｎ−ＮａＯＨ　でｐＨを６付近に調節しながら室温で６時間撹拌した。濃縮後、２０％ＮａＯＨ（１１．２ｍＬ）　を加えて室温で３０分撹拌した。冷却後、濃塩酸５ｍＬを注意深く加え、１Ｎ−塩酸でｐＨ２〜３としＨＰ−２０を充填したカラムで脱塩した。カラムをよく水で洗浄後、１００％ＭｅＯＨで目的物を溶離した。得られた粗生物２．５７ｇをシリカゲル８ｇに吸着したものをシリカゲル・クロマトグラフィー（溶出液は３３％　酢酸エチル：ヘキサン→２０％エタノール：酢酸エチル）にて原料を除去した。濃縮後、得られた粗生成物をさらにＨＰＬＣ（Ｄｅｔｅｃｔｉｏｎ，　２８０　ｎｍ；　ｍｏｂｉｌｅ　ｐｈａｓｅ，　５０％　ＭｅＣＮ−Ｈ２Ｏ　ｃｏｎｔａｉｎｉｎｇ　０．２％　ｏｆ　ＡｃＯＨ）　で精製した。濃縮した油状物をジオキサンに溶かし凍結乾燥し、標記化合物４６３ｍｇ　（収率３６％）を得た。
【０２３４】
【試験例】
以下に試験例を挙げて本発明化合物が優れた薬理活性を有することを示す。
試験例１：気管平滑筋収縮に対する拡張作用
ブタ気管平滑筋を用いて本発明化合物の気管平滑筋収縮に対する作用を検討した。方法は平滑筋マニュアル（文永堂出版（株）発行）１２５頁−１３７頁を参考にした。ブタ気管より気管軟骨粘膜及び粘膜下組織を除去し、長径約１０ｍｍ、短径約１．５ｍｍの気管平滑筋標本を作成した。この標本を酸素９５％及び炭酸ガス５％の混合ガスを通気した３７℃の栄養液の入ったマグヌス管中に懸垂し、この標本に０．８　ｇの負荷を加え、標本の張力が安定した後、栄養液を高濃度Ｋ^＋液（７２．７　ｍＭ）に交換してＫ^＋収縮を惹起させた。高濃度Ｋ^＋による収縮力が一定となるまでマグヌス管内の液を栄養液に交換して洗浄し、再度、高濃度Ｋ^＋液で収縮を惹起する操作を繰り返した。Ｋ^＋収縮の張力が一定になったとき、被験物質として、表１９に記載の化合物（比較例の構造式は前記実施例１８０の化合物の右側に記載されている）を高濃度Ｋ^＋液に添加して張力変化を測定した。被験物質は、ジメチルスルホキシドに所要濃度になるように溶解し、最終濃度１０μＭ　となるように添加した。なお、添加の際、ジメチルスルホキシドの最終濃度は０．３　％以下となるようにした。張力変化はＦＤピックアップトランスデユーサー（ＴＢ−６１１Ｔ，日本光電工業製）を介してひずみ圧力用アンプ（ＡＰ−６２１Ｇ，日本光電工業製）に導き、記録計（Ｒ−６４Ｖ，理化電機製）上に記録した。高濃度Ｋ^＋液に交換前の張力を０％とし、高濃度Ｋ^＋液に交換後に発生する張力のうち、被験物質添加前の張力を１００　％としたとき、被験物質を添加して２　時間後の気管平滑筋収縮力を相対百分率で表した。なお、このとき、高濃度Ｋ^＋液による収縮は、張力が安定した後、少なくとも２時間は、ほぼ一定であった。その結果を表１９に示した。
【０２３５】
【表１９】

【０２３６】
試験例２：モルモット即時型喘息反応、遅発型喘息反応及び気道管腔内への炎症性細胞浸潤に対する抑制作用
喘息患者に抗原を吸入させると、吸入１５−３０　分後をピークとする即時性の気道収縮反応（ＩＡＲ）　が惹起され、この反応は、２時間以内に回復するが、喘息患者のうち６０％　には、抗原吸入４−１２　時間後に遅発性の気道収縮反応（ＬＡＲ）　が出現することが報告されている（Ｐｅｐｙｓ，　Ｊ．　ａｎｄ　Ｈｕｔｃｈｃｒｏｆｔ，　Ｂ．　Ｊ．：　Ｂｒｏｎｃｈｉａｌ　ｐｒｏｖｏｃａｔｉｏｎ　ｔｅｓｔｓ　ｉｎ　ｅｔｉｏｌｏｇｉｃ　ｄｉａｇｎｏｓｉｓ　ａｎｄ　ａｎａｌｙｓｉｓ　ｏｆ　ａｓｔｈｍａ．　Ａｍ．　Ｒｅｖ．　Ｒｅｓｐｉｒ．　Ｄｉｓ．，　１１２，　８２９−８５９　（１９７５））。ＬＡＲ　は持続時間が長く、自然発作の喘息、特に難治性の喘息発作に類似しており、その病態を解明することは気管支喘息の治療上極めて重要であると思われる。一方、抗原により能動感作されたモルモットに、再度抗原を吸入させると２相性の気道収縮反応を示すことが知られている。したがって、前述した喘息患者で認められるＩＡＲ　及びＬＡＲ　の動物モデル系としてモルモットを用いた喘息モデルが喘息薬の評価等に広く使われている。一方、このモルモットＩＡＲ　及びＬＡＲモデルにおいて、感作モルモットに抗原を暴露すると、２　相性の気道収縮とともに、気道管腔内への炎症性細胞の浸潤が起こり、これにより気道組織への種々の炎症性の障害が生じることが知られており、これは遅発型の気道収縮反応及び気道過敏性の発症につながると考えられている。そこで、気道管腔内への炎症性細胞の浸潤に対する指標として気管支肺胞洗浄液中の炎症性細胞数が広く用いられている。モルモットＩＡＲ　及びＬＡＲモデルにおける上記の各作用について本発明化合物の作用を調べた。
【０２３７】
［実験方法］
（１）感作
超音波ネブライザー（ＮＥ−Ｕ１２，　Ｏｍｒｏｎ，　Ｊａｐａｎ）を用い、モルモットに１％ｏｖａｌｂｕｍｉｎ　（ＯＶＡ，　Ｓｉｇｍａ−Ａｌｄｒｉｃｈ　Ｃｏ．，　Ｕ．Ｓ．Ａ．）　生理食塩溶液を１日に１０分間、連続８日間吸入させた。
（２）惹起
最終感作１週間後、超音波ネブライザーを用い、２％　ＯＶＡ生理食塩溶液を５分間吸入させた。惹起２４時間前及び１時間前にｍｅｔｙｒａｐｏｎｅ　（１０　ｍｇ／ｋｇ，　Ｓｉｇｍａ−ＡｌｄｒｉｃｈＣｏ．，　Ｕ．Ｓ．Ａ．）　を静脈内に、惹起３０分前にｐｙｒｉｌａｍｉｎｅ　（１０　ｍｇ／ｋｇ，　Ｓｉｇｍａ−Ａｌｄｒｉｃｈ　Ｃｏ．，　Ｕ．Ｓ．Ａ．）　を腹腔内に投与した。
（３）被験物質の調製及び投与方法
被験物質（実施例１及び４　の化合物）は、０．５％カルボキシメチルセルロースナトリウム（ＣＭＣ−Ｎａ）　水溶液で２　ｍｇ／ｍｌの濃度に各々懸濁調製した。被験物質の懸濁液を、惹起１　時間前に１０　ｍｇ／ｋｇ　になるようにモルモットに経口投与した。対照群には、媒体（０．５％　ＣＭＣ−Ｎａ　水溶液）を用いた。
（４）気道抵抗の測定
気道抵抗測定装置（Ｐｕｌｍｏｓ−Ｉ，　Ｍ．Ｉ．Ｐ．Ｓ．，　Ｊａｐａｎ）を用い、惹起１，　１０　及び３０　分後、更に１，　２，　３，　４，　５，　６，　７，　８，　及び２４時間後にそれぞれ１　回ずつ、１　分間の気道抵抗　（ｓｐｅｃｉｆｉｃ　ａｉｒｗａｙ　ｒｅｓｉｓｔａｎｃｅ：　ｓＲａｗ）　を測定した。
（５）気管支肺胞洗浄液中炎症性細胞数の測定
抗原惹起２３−２４　時間後、モルモットをネンブタール　（５０　ｍｇ／ｋｇ）　腹腔内麻酔下で腹大動脈を切って脱血し、開胸した。気管内にチューブを挿入固定し、これを介して生理食塩水５　ｍｌ　（３７　℃）を注入、吸引する操作を２回繰り返し（全１０　ｍｌ）　、その回収液を気管支肺胞洗浄液　（Ｂｒｏｎｃｈｏａｌｖｅｏｌａｒ　ｌａｖａｇｅ　ｆｌｕｉｄ，　ＢＡＬＦ）　とした。ＢＡＬＦ　を１１００　ｒｐｍ，　４　°Ｃ，　１０　分間遠心し、沈澱物　（ペレット）　を得た。ペレットを１　ｍｌ　の生理食塩水に懸濁し、チルク液を加えて、血球計数板にて１μｌ　当たりの白血球数をカウントした。再度上記条件で遠心し、そのペレットにウサギ血清を加え、塗沫標本を作製した。乾燥後、メイグリンワルド・ギムザ染色を行った。顕微鏡にて白血球を数え、好中球、好酸球、マクロファージ及びリンパ球の全細胞数に対する比率を求め、この比率に基づき１μｌ　当たりの細胞数を算出した。
（６）統計学的解析処理方法
得られた試験成績は、平均値及び標準誤差で表し、Ｓｔｕｄｅｎｔ’ｓ　ｔ−ｔｅｓｔ　を行った。有意水準は、５％　以下とした。各試験群の使用動物数は６匹で実施した。
【０２３８】
［結果］
（１）抗原誘発即時型及び遅発型喘息反応
図１　に示すように、能動感作されたモルモットでは、　ＯＶＡ　吸入により気道抵抗は速やかに上昇し、１分後には惹起前の平均４７５％　に増加した。その後、速やかに減少し、３　時間後には５２％　まで低下した。さらに、気道抵抗は再び上昇し、６時間後には１５６％　に達した。４時間から８時間までのＡＵＣ　（ａｒｅａ　ｕｎｄｅｒ　ｔｈｅ　ｒｅｓｐｏｎｓｅ　ｃｕｒｖｅ）は、４６６％・ｈｒ　であった。このことから、ＯＶＡ吸入による惹起後３０分以内に生じる即時型喘息反応（ＩＡＲ）と惹起後数時間以降に起こる遅発型喘息反応（ＬＡＲ）　の２相性の反応が認められた。
ここで、実施例１及び実施例４の化合物を１０　ｍｇ／ｋｇ　の用量でＯＶＡ惹起１時間前に経口投与した場合、対照群に比較して各々ＩＡＲ　（％　ｃｈａｎｇｅ　ｉｎ　ｓＲａｗ）　が７０、７３％抑制され、ＬＡＲ　（ＡＵＣ）　が７７、８６％　抑制された（図２）。
（２）気管支肺胞洗浄液中細胞数
結果を図３　に示す。　ＯＶＡ　吸入により能動感作されたモルモットにおいて、抗原惹起２４　時間後の気管支肺胞洗浄液中の総細胞数は平均６６６７　個／μｌ、マクロファージ、好中球、好酸球及びリンパ球の細胞数は、それぞれ平均２４９９，　２４８７，　１６２２　及び５９　個／μｌ　であった。
実施例１　の化合物を１０　ｍｇ／ｋｇ　の用量でＯＶＡ惹起１　時間前に経口投与した場合、総細胞数は平均３７７５個／μｌ、マクロファージ、好中球、好酸球及びリンパ球の細胞数は、それぞれ平均１８７２，　１０７２，　８１０　及び２１　個／μｌ　となり、対照群と比べて総細胞数の有意な減少ならびに好酸球、好中球及びリンパ球数の減少傾向が認められた。一方、実施例４　の化合物を１０　ｍｇ／ｋｇ　の用量でＯＶＡ惹起１時間前に経口投与した場合、総細胞数は平均４３０４個／μｌ、マクロファージ、好中球、好酸球及びリンパ球の細胞数は、それぞれ平均２４７８，　１０６２，　７００　及び６４　個／μｌ　となり、対照群と比べて総細胞数及び好酸球数の有意な減少ならびに好中球数の減少傾向が認められた。
以上の結果から、実施例１及び４　の化合物は、いずれもモルモット即時及び遅発型喘息反応、さらには気管支肺胞洗浄液中の炎症性細胞数の増加に対して抑制作用を示し、臨床における喘息治療薬として有望な薬物になりえる可能性が示唆された。
【０２３９】
試験例３：感作モルモットでの抗原誘発による気道過敏性に対する作用
気管支喘息は、気管支収縮、気道過敏性及び気道内への炎症性細胞の浸潤を特徴とする疾患である。気道過敏性は、さまざまな軽微な刺激に対して気道が敏感に収縮反応を生ずる状態であり、とくにアレルギー性気管支喘息患者に共通の特徴であると考えられている。感作モルモットを用いた本系は、気道過敏モデルとして有用な系である。
（１）感作
超音波ネブライザー（ＮＥ−Ｕ１２，　Ｏｍｒｏｎ，　Ｊａｐａｎ）を用い、モルモットに１％　ＯＶＡ（Ｓｉｇｍａ−Ａｌｄｒｉｃｈ　Ｃｏ．，　Ｕ．Ｓ．Ａ．）　生理食塩溶液を１日に１０分間、連続８日間吸入させた。
（２）惹起
最終感作１週間後、超音波ネブライザーを用い、２％　ＯＶＡ生理食塩溶液を５分間吸入させた。惹起２４　時間前及び１　時間前にｍｅｔｙｒａｐｏｎｅ　（１０　ｍｇ／ｋｇ，　Ｓｉｇｍａ−Ａｌｄｒｉｃｈ　Ｃｏ．，　Ｕ．Ｓ．Ａ．）　を静脈内に、惹起３０分前にｐｙｒｉｌａｍｉｎｅ　（１０　ｍｇ／ｋｇ，　Ｓｉｇｍａ−Ａｌｄｒｉｃｈ　Ｃｏ．，　Ｕ．Ｓ．Ａ．）　を腹腔内に投与した。
（３）被験物質の調製及び投与方法
被験物質（実施４の化合物）は、０．５％ＣＭＣ−Ｎａ　水溶液で各濃度で懸濁調製した。被験物質の懸濁液を、惹起１　時間前に１０及び３０　ｍｇ／ｋｇ　になるようにモルモットに経口投与した２　群と惹起１６及び２　時間前に３０　ｍｇ／ｋｇ　になるようにモルモットに経口投与した１群を設定した。デキサメタゾン　は、０．５％ＣＭＣ−Ｎａ水溶液で懸濁調製し１０　ｍｇ／ｋｇ　の濃度で抗原惹起１６及び２時間前の２　回の投与を行った。対照群には、媒体（０．５％ＣＭＣ−Ｎａ水溶液）を用いた。投与容量は、すべて５　ｍｌ／ｋｇ　とした。
（４）気道抵抗の測定
気道抵抗測定装置（Ｐｕｌｍｏｓ−Ｉ，　Ｍ．Ｉ．Ｐ．Ｓ．，　Ｊａｐａｎ）を用い、ｄｏｕｂｌｅ　ｆｌｏｗ　ｐｌｅｔｈｙｓｍｏｇｒａｐｈ法にて覚醒モルモットの気道抵抗　（ｓｐｅｃｉｆｉｃ　ａｉｒｗａｙ　ｒｅｓｉｓｔａｎｃｅ：　ｓＲａｗ）　を測定した。
（５）気道反応性の測定
抗原惹起２２−２６　時間後、モルモットをａｎｉｍａｌ　ｃｈａｍｂｅｒ　に入れ、生理食塩水及びアセチルコリン（ＡＣｈ）　の０．０６２５、０．１２５、０．２５、０．５、１　及び２　ｍｇ／ｍｌ　溶液を順次各１分ずつ吸入させ、ｓＲａｗ　がｂａｓｅｌｉｎｅ　ｓＲａｗ　（生理食塩水吸入後のｓＲａｗ）　の２倍以上になるまで続けた。ＡＣｈ　濃度とｓＲａｗ　の濃度ー抵抗曲線かｓＲａｗ　がｂａｓｅｌｉｎｅ　ｓＲａｗ　から１００％　上昇するのに必要なＡＣｈ　の濃度（　ＰＣ_１００ＡＣｈ）　を求めた。（６）統計学的解析処理方法
得られた試験成績は、平均値及び標準誤差で表し、Ｓｔｕｄｅｎｔ’ｓ　ｔ−ｔｅｓｔ　を行った。有意水準は、５％以下とした。各試験群の使用動物数は６　匹で実施した。
【０２４０】
［結果］
結果を図４に示す。ＯＶＡ　吸入により能動感作されたモルモットにおいて、抗原抗体反応惹起２２−２６　時間後にＡＣｈ　対する気道反応性を測定した。媒体対照群のＰＣ_１００ＡＣｈ　は、０．１５　ｍｇ／ｍｌ　であった。同様の系における報告（Ｆｕｃｈｉｋａｍｉ，　Ｊ−Ｉ，　ｅｔａｌ：　Ｐｈａｒｍａｃｏｌｏｇｉｃａｌ　ｓｔｕｄｙ　ｏｎ　ａｎｔｉｇｅｎ　ｉｎｄｕｃｅｄ　ｉｍｍｅｄｉａｔｅ　ａｎｄ　ｌａｔｅ　ａｓｔｈｍａｔｉｃ　ｒｅｓｐｏｎｓｅｓ　ｉｎ　ａｃｔｉｖｅｌｙ　ｓｅｎｓｉｔｉｚｅｄ　ｇｕｉｎｅａ−ｐｉｇｓ．　　Ｊａｐ．　Ｊ．　Ｐｈａｒｍａｃｏｌ．，　７１，　１９６Ｐ　（１９９６））では、ＯＶＡ　吸入により能動感作されたモルモットにおける生理食塩水によりチャレンジしたモルモットのＰＣ_１００ＡＣｈ　は、平均１．２０　ｍｇ／ｍｌ　であったことから、本試験の対照群では、抗原誘発による気道過敏性が明確に認められた。また、ポジテイブコントロールとして使用したＤｅｘａｍｅｔｈａｓｏｎｅ　は、１０　ｍｇ／ｋｇの用量でＯＶＡ惹起１６　及び２時間前に経口投与した場合、　ＰＣ_１００ＡＣｈ　は、１．１４　ｍｇ／ｍｌ　であり、対照群と比較して有意に気道過敏性を抑制した。一方、実施例４の化合物を１０　及び３０　ｍｇ／ｋｇ　の用量でＯＶＡ惹起１　時間前に経口投与した場合、　ＰＣ_１００ＡＣｈ　は、それぞれ０．５９　及び１．６３　ｍｇ／ｍｌ　であり、用量依存的な抑制を示した。また、実施例４の化合物を３０　ｍｇ／ｋｇ　の用量でＯＶＡ惹起１６　及び２時間前に経口投与した場合、　ＰＣ_１００ＡＣｈ　は、１．２４　ｍｇ／ｍｌ　であり、対照群と比較して有意に気道過敏性を抑制した。
以上の結果から、実施例４の化合物は、感作モルモットにおける気道過敏性に対して強力な抑制作用をもつことが明らかとなり、臨床においても有効な抗喘息薬となる可能性が示唆された。
【０２４１】
試験例４：ラットを用いた２週間反復経口投与毒性試験
化合物の反復投与による毒性を検討するため、化合物０，　１２５，　５００ｍｇ／ｋｇ／日（０．５ｗ／ｖ％ＣＭＣ−Ｎａ水溶液）を１群雄各３匹のＳｐｒａｇｕｅ−Ｄａｗｌｅｙ系ＳＰＦラットに２週間反復経口投与した。結果を下記表２０に示す。
【０２４２】
【表２０】

【０２４３】
【発明の効果】
本発明化合物は優れた気管平滑筋弛緩作用、気道過敏性の抑制作用及び気道内への炎症性細胞の浸潤抑制作用といった幅広い薬理作用を有し安全性も高いので、医薬品として極めて有用である。
【図面の簡単な説明】
【図１】図１は、能動感作モルモットにおける即時型及び遅発型喘息反応に対する本発明化合物の抑制作用を示すグラフである。
【図２】図２は、能動感作モルモットにおける即時型及び遅発型喘息反応における本発明化合物の抑制率を示すグラフである。
【図３】図３は、能動感作モルモットにおける抗原惹起２４時間後の気管支肺胞洗浄液中の炎症性細胞数に対する本発明化合物の抑制作用を示すグラフである。
【図４】図４は、能動感作モルモットにおける抗原惹起２２−２６時間後におけるアセチルコリンに対する気道反応性に対する本発明化合物の抑制作用を示すグラフである。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a novel tricyclic fused heterocyclic compound, a method for producing the same, and a use thereof. The tricyclic fused heterocyclic compound of the present invention has a wide range of pharmacological effects such as a relaxing effect on tracheal smooth muscle, a suppressing effect on airway hyperreactivity, and a suppressing effect on infiltration of inflammatory cells into the airways, and is useful as a drug for asthma and the like. is there.
[0002]
[Prior art]
Until now, various cyclic compounds have been proposed as compounds useful for asthma and the like. For example, xanthine derivatives such as theophylline and β such as salbutamol₂Agonists, steroids, antiallergic agents and the like are known.
[0003]
In addition, various tricyclic fused heterocyclic compounds have been proposed.
For example, it is as follows.
[0004]
Pharmaceutical Journal Vol. 87, No. 2, pp. 198-201 (1967) discloses three dihydrodibenzo [b, f] oxepin derivatives as intermediates of natural products. However, there is no description of the pharmacological action of the compound.
[0005]
U.S. Pat. No. 4,104,280 discloses that a compound containing oxygen or sulfur as a heterocyclic atom and having a benzene ring containing --CHRCOOH or --CHRCOOCH₃It is described that a tricyclic fused heterocyclic compound having a substituent (R is a hydrogen atom or a methyl group) is useful as an anti-inflammatory agent and a relaxing agent.
[0006]
EP-A-0 011 067 discloses that a compound containing sulfur as a heterocyclic atom and having-(CH) as one of substituents on a benzene ring._nIt is taught that a tricyclic fused heterocyclic compound having -A (n = 0 to 4, A is a heterocyclic residue) is effective for asthma, allergy and the like.
[0007]
British Patent No. 2,016,466 discloses that a compound containing oxygen or sulfur as a heterocyclic atom and having --CH as a substituent on a benzene ring.₂COR (R is OH, NH₂, An alkyl group having 1 to 5 carbon atoms) are described as being useful as anti-inflammatory agents.
[0008]
German Patent No. 3203065 discloses that certain tricyclic fused heterocyclic compounds containing oxygen as a heterocyclic atom and having various substituents on the benzene ring have pharmacological actions such as analgesic, sedative, antidepressant and antispasmodic. Is disclosed.
[0009]
EP-A-0 003 893 discloses that a compound containing oxygen or sulfur as a heterocyclic atom and having --CHR as one of the substituents on the benzene ring.₂COOR₃(R₂Is a hydrogen atom, a methyl group, R₃Is a hydrogen atom, -CH₂CH₂OCH₂CH₂It is taught that tricyclic fused heterocyclic compounds having OH) have pharmacological actions such as anti-inflammatory, analgesic, and antipyretic.
[0010]
German Patent 1,302,590 describes tricyclic fused heterocyclic compounds containing sulfur as a heterocyclic atom and having various substituents on the benzene ring.
[0011]
U.S. Pat. No. 4,104,280 teaches that 3-hydroxymethyldibenzo [b, f] thiepin and its derivatives containing sulfur as a heterocyclic atom can be used in the treatment of allergic diseases such as allergic asthma. ing.
[0012]
Br. {J. {Pharmac.82, 389-395 (1984), describe that 3-hydroxymethyl-dibenzo [b, f] thiepin-5,5-dioxide is an antagonist of contractile prostanoids on lung smooth muscle.
[0013]
Japanese Pharmacology Magazine,94, 299-307 (1989) states that 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid contains cardiovascular and autonomic compounds only when used in relatively large amounts. It has only a modest effect on the nervous system, suggesting that it has the potential to be a clinically useful drug as an anti-inflammatory, analgesic and antipyretic.
[0014]
WO 96/10021 describes an antioxidant tricyclic fused heterocyclic compound containing oxygen or sulfur as a heterocyclic atom and having various substituents on a benzene ring.
[0015]
WO 96/25927 describes a glutamate receptor blocker and a brain function improving agent containing oxygen or sulfur as a heterocyclic atom and having various substituents on a benzene ring.
[0016]
WO 97/25985 describes a tracheal smooth muscle relaxant containing, as an active ingredient, a tricyclic fused heterocyclic compound containing oxygen or sulfur as a heterocyclic atom and having various substituents on a benzene ring.
[0017]
J. {Org. {Chem.61, {5818-5822} (1996) and Collection {Czechoslov. {Chem. {Commun.43, {309} (1978) describe a method for synthesizing dibenzooxepin and dibenzothiepine.
[0018]
Tetrahedron,40, {4245-4252} (1984) and Phytochemistry, {31, {(3)} 1068-1070} (1992) describe a dibenzooxepin derivative derived from a natural product.
[0019]
Chem. {Pharm. {Bull.23, {(10)} 2232-2231} (1975) and Chem. {Pharm. {Bull.26, (10) {3058-3070} (1978) describe a method for synthesizing dibenzothiepine derivatives and the antiemetic effect of these compounds.
[0020]
J. {Chem. {Soc. {Perkin} Trans. {1. {3291-3294} (1991) and J.M. {Med. {Chem.26, 1131-1137} (1983) describe a method for synthesizing dibenzoxepin and dibenzothiepine derivatives and their use as antiestrogens.
[0021]
[Problems to be solved by the invention]
As described above, various tricyclic fused heterocyclic compounds have been disclosed, and these compounds are used for bronchial asthma, acute chronic bronchitis, emphysema, pulmonary emphysema, upper esophagitis, etc. As a therapeutic drug for allergic diseases, chronic inflammation, etc., it cannot be said that the therapeutic effect, sustainability, safety (side effects) and the like are sufficient. Therefore, it has a wide range of pharmacological actions such as a tracheal smooth muscle relaxation action, an airway hypersensitivity inhibitory action, and an inflammatory cell infiltration inhibitory action in the airway, which are superior to known compounds, and is highly safe (with few side effects). ) Development of new compounds is required.
[0022]
[Means for Solving the Problems]
An object of the present invention is to provide a novel compound having a wide range of pharmacological actions such as a clinically useful action of relaxing tracheal smooth muscle, an action of suppressing airway hyperreactivity and an action of suppressing infiltration of inflammatory cells into the airway, in view of the above-mentioned current situation. Is to provide.
[0023]
The present inventors have conducted intensive studies on the tricyclic fused heterocyclic compound, and as a result, have found that the benzene ring has an OH group or an OH group and an OR group (R is a hydrogen atom or a lower alkyl group) as a substituent. Various tricyclic fused heterocyclic compounds have a wide range of pharmacological effects such as excellent tracheal smooth muscle relaxation, airway hyperreactivity, and inhibition of inflammatory cell infiltration into the airway, as well as excellent durability and safety. And have completed the present invention based on these findings. That is, the present invention relates to the compounds described in the following (1) to (25), their production methods, applications, and intermediates.
(1) Equation 1
[0024]
Embedded image

[0025]
[In the formula
X and Y are
When the bond XY is a single bond, X and Y are each independently (same or different), CW₁W₂(W₁, W₂Each independently (same or different) is any one of a hydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkoxy group, a cycloalkyl group and a cycloalkenyl group), C ＝ O, C = NOW₃(W₃Is a hydrogen atom or a lower alkyl group),
When the XY bond is a double bond, X and Y are each independently (same or different) CW₄(W₄Is a hydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkoxy group, or an acyloxy group)
Z is O, S, S = O, SO₂Is any one selected from
U is C or N;
R₁Or R₄Each independently (same or different), a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, a substituted lower alkynyl group, Halogen group, lower alkylcarbonyl group, substituted lower alkylcarbonyl group, trihalomethyl group, V₁W₅(V₁Are O, S, S = O, SO₂Any one selected from₅Is any selected from a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkylcarbonyl group, a substituted lower alkylcarbonyl group, an acyloxy group, and a trihalomethyl group. ), Nitro group, amino group, substituted amino group, cyano group, acyl group, acylamino group, substituted acyl group, substituted acylamino group, aromatic ring, substituted aromatic ring, heterocyclic ring, substituted heterocyclic ring. (If U is N, R₄May not exist),
R₅Or R₈Each independently (same or different) is a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, a substituted lower alkynyl group, a halogen group, a lower alkylcarbonyl group, Lower alkylcarbonyl group, trihalomethyl group, V₂W₇(V₂Are O, S, S = O, SO₂Any one selected from₇Is any selected from a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkylcarbonyl group, a substituted lower alkylcarbonyl group, and a trihalomethyl group. ), A nitro group, an amino group, a substituted amino group, an acylamino group, an aromatic ring, a substituted aromatic ring, a heterocyclic ring, and a substituted heterocyclic ring.
Where X is CHW₀, CW₀W₀Or CW₀(Where W₀Is an arbitrary one selected from a lower alkyl group and a substituted lower alkyl group).₅Or R₈At least one is a hydroxyl group (provided that XY is CH (C₂H₅) R for CO₆Is not a hydroxyl group by itself), and X is CHW₀, CW₀W₀Or CW₀(Where W₀Is an arbitrary one selected from a lower alkyl group and a substituted lower alkyl group).₅Or R₈At least one is a hydroxyl group, and the other R₅Or R₈At least one group is an OR group (wherein, R is any one selected from a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkylcarbonyl group and a substituted lower alkylsilyl).
Further, XY is CH₂CH₂, CHBrCH₂, CH₂CO, COCH₂, CHBrCO, CH = CH, CH = COCOCH₃, CH = COCH₃In the case of
R₁Or R₄Is at least one of an aromatic ring, a substituted aromatic ring, a heterocyclic ring and a substituted heterocyclic ring (provided that R₆And R₇When both are hydroxyl groups,₁Or R₄Are not phenyl groups),
R₁Or R₄At least one of the SW₈(W₈Is a lower alkyl group or a substituted lower alkyl group) or S (O) W₉(W₉Is a lower alkyl group or a substituted lower alkyl group) (provided that when Z is O, R₇Is not a hydrogen atom),
R₂Is either a lower alkyl group or a substituted lower alkyl group, and R₈Is a hydroxyl group (however, when Z is O, the lower alkyl group has 3 or more carbon atoms);
R₁Or R₄At least one is a lower alkylcarbonyl (provided that the lower alkyl group has 3 or more carbon atoms), cycloalkylcarbonyl or cycloalkenylcarbonyl, and R₈Is a hydroxyl group,
R₁Or R₄At least one of -C (= NOR) CH₃(R is a hydrogen atom or a lower alkyl group)
Is one of ]
Or a conjugate thereof or a pharmaceutically acceptable salt thereof.
(2) R₆Is a hydroxyl group.
(3) R₆And R₇Is a hydroxyl group.
(4) R₆And R₈Is a hydroxyl group.
(5) R₅And R₆Is a hydroxyl group.
(6) XY is a single bond and X is CW₁W₂(W₁, W₂Is any one selected from a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group and a cycloalkenyl group), or XY is a double bond and X is CW₃(W₃Is an arbitrary one selected from a lower alkyl group or a substituted lower alkyl group.) The compound according to any one of the above (1) to (5).
(7) The compound according to any one of the above (1) to (6), wherein Y is CO.
(8) The above (6), wherein the lower alkyl group is any one of a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group, an i-butyl group and a t-butyl group. ) Or (7).
(9) R₂Or R₃Is a heterocyclic ring, a substituted heterocyclic ring, an aromatic ring or a substituted aromatic ring, the compound according to any one of the above (1) to (5).
(10) The compound according to any one of (1) to (5), wherein the heterocycle is an aromatic heterocycle.
(11) R₂Or R₃Is SW₈(W₈Is a lower alkyl group or a substituted lower alkyl group) or S (O) W₉(W₉Is a lower alkyl group or a substituted alkyl group). The compound according to any one of the above (1) to (5).
(12) The above (11) wherein the lower alkyl group is any one of a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group, an i-butyl group, and a t-butyl group. ).
(13) The compound according to any one of the above (1) to (12), wherein Z is S. (14) The compound according to the above (1), which is 7,8-dihydroxy-11-ethyl-10,11-sihydrodibenzo [b, f] thiepin-10-one.
(15) The compound according to (1), which is 11-diethyl-7,8-dihydroxy-10,11-dihydrodibenzo [b, f] thiepin-10-one.
(16) The compound according to (1), which is 7,9-dihydroxy-2-methylthio-10,11-dihydrodibenzo [b, f] thiepin-10-one.
(17) The following steps (1) and (2)
{Circle around (1)} Ring A and ring C are bonded by the Ullmann reaction (Formula 2).
(2) Ring A and ring C are bonded by Friedel-Crafts reaction or photoreaction (Formula 3).
[0026]
Embedded image

[0027]
[In formulas 2 and 3, Q, S, and W represent arbitrary substituents, U is C or N, one of X and Y represents a leaving group, the other represents a nucleophilic group, and Z represents O, S, SO, SO₂Represents any of ]
, In any order,
Equation 1
[0028]
Embedded image

[0029]
[In the formula
X and Y are
When the bond XY is a single bond, X and Y are each independently (same or different), CW₁W₂(W₁, W₂Each independently (same or different) is any one of a hydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkoxy group, a cycloalkyl group and a cycloalkenyl group), C ＝ O, C = NOW₃(W₃Is a hydrogen atom or a lower alkyl group),
When the XY bond is a double bond, X and Y are each independently (same or different) CW₄(W₄Is a hydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkoxy group, or an acyloxy group)
Z is O, S, S = O, SO₂Is any one selected from
U is C or N;
R₁Or R₄Each independently (same or different), a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, a substituted lower alkynyl group, Halogen group, lower alkylcarbonyl group, substituted lower alkylcarbonyl group, trihalomethyl group, V₁W₅(V₁Are O, S, S = O, SO₂Any one selected from₅Is any selected from a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkylcarbonyl group, a substituted lower alkylcarbonyl group, an acyloxy group, and a trihalomethyl group. ), Nitro group, amino group, substituted amino group, cyano group, acyl group, acylamino group, substituted acyl group, substituted acylamino group, aromatic ring, substituted aromatic ring, heterocyclic ring, substituted heterocyclic ring. (If U is N, R₄May not exist),
R₅Or R₈Each independently (same or different) is a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, a substituted lower alkynyl group, a halogen group, a lower alkylcarbonyl group, Lower alkylcarbonyl group, trihalomethyl group, V₂W₇(V₂Are O, S, S = O, SO₂Any one selected from₇Is any selected from a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkylcarbonyl group, a substituted lower alkylcarbonyl group, and a trihalomethyl group. ), A nitro group, an amino group, a substituted amino group, an acylamino group, an aromatic ring, a substituted aromatic ring, a heterocyclic ring, and a substituted heterocyclic ring.
Where X is CHW₀, CW₀W₀Or CW₀(Where W₀Is an arbitrary one selected from a lower alkyl group and a substituted lower alkyl group).₅Or R₈At least one is a hydroxyl group (provided that XY is CH (C₂H₅) R for CO₆Is not a hydroxyl group by itself), and X is CHW₀, CW₀W₀Or CW₀(Where W₀Is an arbitrary one selected from a lower alkyl group and a substituted lower alkyl group).₅Or R₈At least one is a hydroxyl group, and the other R₅Or R₈At least one group is an OR group (wherein, R is any one selected from a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkylcarbonyl group and a substituted lower alkylsilyl).
Further, XY is CH₂CH₂, CHBrCH₂, CH₂CO, COCH₂, CHBrCO, CH = CH, CH = COCOCH₃, CH = COCH₃In the case of
R₁Or R₄Is at least one of an aromatic ring, a substituted aromatic ring, a heterocyclic ring and a substituted heterocyclic ring (provided that R₆And R₇When both are hydroxyl groups,₁Or R₄Are not phenyl groups),
R₁Or R₄At least one of the SW₈(W₈Is a lower alkyl group or a substituted lower alkyl group) or S (O) W₉(W₉Is a lower alkyl group or a substituted lower alkyl group) (provided that when Z is O, R₇Is not a hydrogen atom),
R₂Is either a lower alkyl group or a substituted lower alkyl group, and R₈Is a hydroxyl group (however, when Z is O, the lower alkyl group has 3 or more carbon atoms);
R₁Or R₄At least one is a lower alkylcarbonyl (provided that the lower alkyl group has 3 or more carbon atoms), cycloalkylcarbonyl or cycloalkenylcarbonyl, and R₈Is a hydroxyl group,
R₁Or R₄At least one of -C (= NOR) CH₃(R is a hydrogen atom or a lower alkyl group)
Is one of ]
A process for producing a compound represented by the formula (I), an optical isomer thereof, a conjugate thereof or a pharmaceutically acceptable salt thereof.
(18) Further, any one of a carbon increase reaction step, a substituent conversion reaction step, a substituent introduction reaction step, a substituent deprotection reaction step, a salt formation step, and an optical resolution step The manufacturing method according to (17), including the above steps. In the present invention, the order of the above-mentioned steps, the reaction step (1) and the reaction step (2) is not particularly limited, and a person skilled in the art can freely consider various conditions including the structure of the target compound. Can be set to
(19) A pharmaceutical composition comprising an effective amount of the compound according to any one of (1) to (16) and a pharmaceutically acceptable carrier or diluent.
(20) The pharmaceutical composition according to (19), which utilizes a relaxing effect on tracheal smooth muscle.
(21) The pharmaceutical composition according to (19), which utilizes an airway hypersensitivity inhibitory action.
(22) The pharmaceutical composition according to (19), which utilizes the action of suppressing infiltration of inflammatory cells.
(23) The pharmaceutical composition according to (19), which is used as an anti-asthma drug.
(24) Lower formula
[0030]
Embedded image

[0031]
Wherein Q is a lower alkyl group. ]
Or an optical isomer or a salt thereof.
(25) Lower formula
[0032]
Embedded image

[0033]
Wherein Q is a lower alkyl group;₁Or Q₅Are each independently (same or different) selected from a hydrogen atom, a lower alkoxy group and a hydroxyl group. ]
Or an optical isomer or a salt thereof.
[0034]
When the compound or a salt thereof described in the above (1) contains an asymmetric carbon in the structure, an optically active compound and a racemic compound are also included in the scope of the present invention. Further, the compound or a salt thereof described in the above (1) may be a hydrate or a non-hydrate, or may be a solvate.
[0035]
BEST MODE FOR CARRYING OUT THE INVENTION
As used herein, the term “halogen group” refers to any group of fluorine, chlorine, bromine, and iodine. The term “trihalomethyl group” used in the specification of the present application means a group in which three hydrogen atoms of a methyl group are replaced by halogen atoms, and all three halogen atoms are the same. Or it may be composed of two or more different halogen atoms.
[0036]
As used herein, the term "lower alkyl" refers to, for example, a linear or branched C_1-6It means an alkyl group. C_1-6Examples of the alkyl group include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl and n-hexyl. Examples of the substituent which the “lower alkyl group” may have include, for example, hydroxy, amino, carboxyl, nitro, aryl group, substituted aryl group, mono- or di-lower alkylamino (eg, methylamino, ethyl Mono- or di-C such as amino, propylamino, dimethylamino, diethylamino, etc._1-6Alkylamino and the like, lower alkoxy (for example, methoxy, ethoxy, propoxy, hexyloxy, etc._1-6Lower alkoxycarbonyloxy (eg, acetoxy, ethylcarbonyloxy, etc._1-6Alkyl or carbonyloxy) or a halogen atom or the like. In the specification of the present application, the lower alkyl moiety in the “lower alkoxy group” has the meaning described for the “lower alkyl group”.
[0037]
The term “cycloalkyl group” as used herein refers to, for example, C_3-8Means a cyclic alkyl group. C_3-8Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group. Examples of the substituent which the “cycloalkyl group” may have include, for example, hydroxy, amino, carboxyl, nitro, mono- or di-lower alkylamino (eg, methylamino, ethylamino, propylamino, dimethylamino Mono- or di-C such as diethylamino_1-6Alkylamino and the like, lower alkoxy (for example, methoxy, ethoxy, propoxy, hexyloxy, etc._1-6Lower alkoxycarbonyloxy (eg, acetoxy, ethylcarbonyloxy, etc._1-6Alkyl or carbonyloxy) or a halogen atom or the like.
[0038]
As used herein, the term "cycloalkenyl group" means a cycloalkyl group having one or more double bonds in the cyclic portion.
[0039]
As used herein, the term “lower alkenyl group” refers to, for example, a straight-chain or branched C_2-6It means an alkenyl group. C_2-6Examples of the alkenyl group include vinyl, allyl, 2-methylallyl, i-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl and the like. Examples of the substituent which the “lower alkenyl group” may have include, for example, hydroxy, amino, carboxyl, nitro, mono- or di-lower alkylamino (eg, methylamino, ethylamino, propylamino, dimethylamino Mono- or di-C such as diethylamino_1-6Alkylamino and the like, lower alkoxy (for example, methoxy, ethoxy, propoxy, hexyloxy, etc._1-6Lower alkoxycarbonyloxy (eg, acetoxy, ethylcarbonyloxy, etc._1-6Alkyl or carbonyloxy) or a halogen atom or the like.
[0040]
As used herein, the term “lower alkynyl group” refers to, for example, a straight-chain or branched C_2-6It means an alkynyl group. C_2-6As the alkynyl group, for example, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like are used. Examples of the substituent which the “lower alkynyl group” may have include, for example, hydroxy, amino, carboxyl, nitro, mono- or di-lower alkylamino (eg, methylamino, ethylamino, propylamino, dimethylamino Mono- or di-C such as diethylamino_1-6Alkylamino and the like, lower alkoxy (for example, methoxy, ethoxy, propoxy, hexyloxy, etc._1-6Lower alkoxycarbonyloxy (eg, acetoxy, ethylcarbonyloxy, etc._1-6Alkyl or carbonyloxy) or a halogen atom or the like.
[0041]
The lower alkyl moiety in the term “lower alkylcarbonyl group” used herein has the meaning described for the above “lower alkyl group”.
[0042]
As the substituent in the term “substituted amino group” as used herein, for example, hydroxy, carboxyl, mono- or di-lower alkyl (eg, methyl, ethyl, n-propyl, i-propyl, dimethyl, diethyl Mono- or di-C such as_1-6Alkyl), lower alkoxy (for example, C such as methoxy, ethoxy, propoxy, hexyloxy, etc.)_1-6Lower alkoxycarbonyloxy (eg, acetoxy, ethylcarbonyloxy, etc._1-6Alkyl or carbonyloxy) or a halogen atom.
[0043]
As used herein, the term “acyl group” refers to —COR (R represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group having 3 to 8 carbon atoms, a monocyclic or polycyclic ring, Which means any of an aromatic ring, a heterocyclic ring, etc.). The acyl moiety in the terms “acyloxy group” and “acylamino group” used in the present specification has the same meaning as the above acyl group. The substituents that the “acyl group” and “acylamino group” may have mean a substituent on R, for example, hydroxy, amino, carboxyl, nitro, mono- or di-lower alkylamino (for example, Mono- or di-C such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc._1-6Alkylamino and the like, lower alkoxy (for example, methoxy, ethoxy, propoxy, hexyloxy, etc._1-6Lower alkoxycarbonyloxy (eg, acetoxy, ethylcarbonyloxy, etc._1-6Alkyl or carbonyloxy) or a halogen atom or the like.
[0044]
As used herein, the term “aromatic ring” means an atomic group obtained by removing one hydrogen atom from an aromatic hydrocarbon, that is, an aryl group. In particular, C_6-14Are preferred. C_6-14Examples of the aryl group include phenyl, naphthyl, tolyl, xylyl, biphenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4 -Phenanthryl, 9-phenanthryl, 1-azulenyl, 2-azulenyl, 4-azulenyl, 5-azulenyl, 6-azulenyl and the like are used. Examples of the substituent which the “aromatic ring” may have include, for example, lower alkyl, hydroxy, amino, carboxyl, nitro, mono- or di-lower alkylamino (for example, methylamino, ethylamino, propylamino, Mono- or di-C such as dimethylamino and diethylamino_1-6Alkylamino and the like, lower alkoxy (for example, methoxy, ethoxy, propoxy, hexyloxy, etc._1-6Lower alkoxycarbonyloxy (eg, acetoxy, ethylcarbonyloxy, etc._1-6Alkyl or carbonyloxy), trihalomethane, trihalomethoxy, halogen atom or aryl such as phenyl.
[0045]
As used herein, the term “heterocycle” refers to, for example, 3 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like in addition to a carbon atom. It means the remaining atomic group obtained by removing one hydrogen atom from a 7-membered heterocyclic ring. Heterocycles may be fused. Specific examples of the heterocycle include oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, pyrrole, azetidine, pyrrolidine, piperidine, piperazine, thiophene, homopiperidine, morpholine, furan, pyridine, benzofuran, and benzothiophene. Examples of the substituent which the “heterocycle” may have include, for example, hydroxy, amino, carboxyl, nitro, mono- or di-lower alkylamino (for example, methylamino, ethylamino, propylamino, dimethylamino, Mono- or di-C such as diethylamino_1-6Alkylamino and the like, lower alkoxy (for example, methoxy, ethoxy, propoxy, hexyloxy, etc._1-6Lower alkoxycarbonyloxy (eg, acetoxy, ethylcarbonyloxy, etc._1-6Alkyl or carbonyloxy) or a halogen atom or the like.
[0046]
Examples of particularly preferable compounds in the present invention include the following compounds or optical isomers, conjugates or salts thereof.
1) Ring C (R₅~ R₈) Has two hydroxyl groups and a lower alkyl group at the 11 position (position of X), specifically, 7,8-dihydroxy-11-ethyl-10,11-cyhydrodibenzo [b , F] thiepin-10-one, 11-diethyl-7,8-dihydroxy-10,11-dihydrodibenzo [b, f] thiepin-10-one, 11-methyl-7,8-dihydroxy-10,11- Examples thereof include dihydrodibenzo [b, f] thiepin-10-one.
2) Ring C (R₅~ R₈) Has two hydroxyl groups and the ring A (R₁~ R₄)), In which a thio-lower alkyl group is present, specifically, 7,9-dihydroxy-2-methylthio-10,11-dihydrodibenzo [b, f] thiepin-10-one, 8-methylthio-10,11 -Dihydrodibenzo [b, f] thiepin-1,3-diol and the like.
3) Ring C (R₅~ R₈) Has two hydroxyl groups and the ring A (R₁~ R₄) To which a heterocyclic ring is bonded, specifically, 7,9-dihydroxy-3- (2-furyl) -10,11-dihydrodibenzo [b, f] thiepin-10-one, 7- (2- Thienyl) -10,11-dihydrodibenzo [b, f] thiepin-1,3-diol, 7- (2-furyl) -10,11-dihydrodibenzo [b, f] thiepin-1,3-diol and the like. Is exemplified.
[0047]
As the salt of the compound of the present invention, a pharmaceutically or physiologically acceptable acid addition salt is particularly preferable. Examples of such salts include salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid), and organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, Salts with tartaric acid, lactic acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid) or alkalis (eg, sodium, potassium, magnesium, calcium, ammonium, pyridine, Triethylamine) and the like.
[0048]
The conjugate of the compound of the present invention includes a compound represented by the formula 1, an optical isomer thereof, a glucuronide conjugate of a salt thereof, a sulfate conjugate and the like.
[0049]
Next, a method for producing the compound of the present invention or a salt thereof will be described.
The tricyclic fused heterocyclic compound of the compound of the present invention is a 6-7-6 tricyclic compound composed of three rings A, B and C as shown in the following (Formula 4).
[0050]
Embedded image

[0051]
The skeleton of this compound can be produced by combining the bond between the rings A and C by the Ullmann reaction and the bond between the rings A and C by the Friedel-Crafts reaction or photoreaction. It is necessary to add a carbon increasing reaction depending on a raw material and a target compound. If necessary, the desired compound can be obtained by performing a substituent introduction reaction or a substituent conversion reaction.
[0052]
For example, as the first step, the A ring and the C ring are bonded by the Ullmann reaction. Next, as a second step, the number of carbon atoms of W is increased to make the ring B a 7-membered ring (carbon increase reaction). Further, as a third step, a B ring is formed by a Friedel-Crafts reaction. In the fourth step, necessary substituents such as a halogen group and a lower alkyl group are introduced into the thus formed tricyclic compound (substituent introduction reaction).
[0053]
The substituent may be introduced into the raw material of the first step or may be introduced in the middle of the carbon increase reaction in the second step. You can choose. Further, if necessary, the carbonyl group at the 10-position may be reduced or the substituent OR (for example, OCH₃Is converted to OH by a deprotection reaction.
[0054]
An example of a reaction scheme for each step is shown below.
[0055]
Embedded image

[0056]
The reaction scheme of each of the above steps will be described below.
(1) Ullmann reaction
Substituted benzenes corresponding to the rings A and C having the necessary functional groups are converted into a coupling product by Ullmann reaction. Examples of the leaving group in the Ullmann reaction include halogen (eg, chlorine, bromine, iodine, etc.), arylsulfonyloxy having 6 to 10 carbon atoms (eg, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.), and carbon atom 1 To 4 alkylsulfonyloxy (eg, methanesulfonyloxy) and the like, and among them, halogen (eg, chlorine, bromine, iodine, etc.) is preferable. As the nucleophilic side, for example, a precursor having a functional group containing oxygen and sulfur can be used, and among them, a substituted phenol, a substituted thiophenol, a substituted disulfide and the like are preferable.
(2) Friedel-Crafts reaction or photoreaction
Further, for the reaction for bonding the A ring and the C ring, a method generally performed as a Friedel-Crafts reaction can be used. For example, “Comprehensive Organic Synthesis: The Intramolecular Aromatic Friedel-Crafts Reaction,” Vol. {2, pp. {753} (1991), {J. {Org. {Chem. , {52, {849} (1987), {Synthesis, {1257} (1995) or a method similar thereto. In addition, by using the method of the photocyclization reaction described in JP-A-10-204079 or a method analogous thereto, the cyclized product can be directly obtained from the substituted acetophenone compound. In addition, the order of the Ullmann reaction and these reactions can be changed.
(3) Carbon increase reaction
In the Ullmann reaction, when a substituted phenylacetic acid derivative is used, it can lead directly to a cyclized product, but in the case of a substituted benzoic acid derivative, a carbon increase reaction of a portion corresponding to the B ring is performed. At that time, the substituted benzoic acid derivative can be led to a substituted phenylacetic acid via a substituted benzyl alcohol compound, a substituted benzyl halogen compound, and a substituted benzyl nitrile compound. In addition, a substituted benzyl halide can be directly converted to a substituted phenylacetic acid with carbon dioxide. The substituted acetophenone form can be converted to a substituted phenylacetic acid after being converted into a substituted morpholine form by a Wilgerott reaction.
(4) Conversion reaction of halogen groups to other functional groups
The introduction reaction of a heterocyclic ring, a substituted phenyl ring and a lower alkyl group can be performed by using palladium, for example, as described in Chem. Rev. , {95, {2457} (1995), "Organic Reactions," Vol. The method of {50, {(1997)} or a method similar thereto can be used.
(5) Introduction reaction of alkyl group and alkylcarbonyl group
An alkyl group such as an ethyl group can be introduced into the cyclized product by using a phase transfer catalyst and an alkyl halide in the presence of a base in an anhydrous solvent or an alkali in the presence of a base. In addition, the alkyl group can be introduced into a carbon increase reaction intermediate before ring closure or a raw material before performing the Ullmann reaction. Introduction of an alkylcarbonyl group can be performed using a Friedel-Crafts reaction.
(6) 10-position conversion reaction
The cyclized form can be converted to an olefin form by a dehydration reaction after reducing the carbonyl group to an alcohol form, and can be led to a decarbonyl form by catalytic reduction. Further, by performing the deprotection reaction (7) on the alcohol form, it can be converted to an olefin form and reduced to a decarbonyl form by reduction. Alternatively, the cyclized product can be directly converted to a decarbonylated product by Vol-Kishna reduction.
{7} The deprotection reaction can be performed with pyridine hydrochloride or boron halide.
[0057]
The production of the compound of the present invention is preferably carried out in a solvent.Examples of such a solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane, dimethylformamide, Amides such as dimethylacetamide, sulfoxides such as dimethylsulfoxide, nitriles such as acetonitrile, N-methyl-2-pyrrolidone and the like, and anhydrous solvents thereof are used. The reaction temperature is preferably -78 ° C to 200 ° C, the reaction time is 30 minutes to several days, and the reaction is advantageously carried out under a stream of nitrogen and argon. The reaction product can be isolated and purified by known means, for example, solvent extraction, liquid conversion, phase transfer, salting out, crystallization, recrystallization, chromatography and the like.
[0058]
In the method of the present invention, when the substituent is an amino group, it is preferable to protect the amino group, and as the protecting group, a protecting group generally used in the field of peptide chemistry and the like can be used, for example, formyl, acetyl And protecting groups of the type forming amides such as benzoyl; benzoyl; protecting groups of the type forming carbamates such as tert-butoxycarbonyl and benzyloxycarbonyl; and protecting groups of the type imino such as dimethylaminomethylene, benzylidene, p-methoxybenzylidene and diphenylmethylene. Protecting groups are used. Preferred protective groups include, for example, formyl, acetyl and dimethylaminomethylene. When the product obtained in the above reaction has a protecting group, the protecting group can be removed according to a conventional method, for example, protection by a deprotection operation such as hydrolysis with an acid or a base or catalytic reduction. The group can be removed.
[0059]
When the obtained compound of the present invention has an asymmetric carbon, an optical isomer can be obtained by using various conventionally known optical resolution methods, for example, an optical isomer separation column or the like.
[0060]
Furthermore, the compound of the present invention or a pharmaceutically or physiologically acceptable salt thereof has a wide range of pharmacological actions such as an excellent action of relaxing tracheal smooth muscle, an action of suppressing airway hyperreactivity, and an action of suppressing infiltration of inflammatory cells into the airways. And can be used as a safe anti-asthmatic drug or the like for mammals (human, mouse, dog, rat, cow, etc.). Specifically, when used as an anti-asthmatic agent for humans, the dosage varies depending on age, body weight, symptoms, administration route, number of administrations, etc., but is 0.1 to 100 mg / kg per day, preferably It is preferable to administer 1 to 50 mg / kg once or twice daily. The administration route may be oral or parenteral.
[0061]
The compound of the present invention or a salt thereof may be used in the neat form, but is usually administered in a form prepared with a carrier for pharmaceutical preparation. Specific examples thereof include tablets, capsules, granules, fine granules, powders, syrups, injections, and inhalants. These preparations are prepared according to a conventional method. As the carrier for oral preparations, substances commonly used in the field of preparations such as starch, mannitol, crystalline cellulose and sodium carboxymethylcellulose are used. As the carrier for injection, distilled water, physiological saline, glucose solution, infusion agent and the like are used. Other additives generally used in preparations can also be appropriately added.
[0062]
Reference example
Hereinafter, the method for producing the raw material of the present invention, and specific examples of each of the above-described reactions will be described as reference examples.However, the present invention is not limited thereto, and is not departed from the scope of the present invention. It may be changed. Elution in column chromatography of the reference example was performed under observation by TLC (thin layer chromatography) unless otherwise specified. In TLC observation, 60F254 manufactured by Merck was used as a TLC plate, and a solvent used as an elution solvent in column chromatography was used as a developing solvent. A UV detector was used for detection. As silica gel for column chromatography, silica gel 60 (70-230 mesh) manufactured by Merck or Microsphere Gel D75-60A manufactured by Asahi Glass was used. Room temperature usually means about 10 ° C to about 35 ° C.
[0063]
Reference Example 1: Method for producing 4-bromo-2-chlorobenzoic acid (3)
[0064]
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[0065]
Synthesis of 4-amino-2-chlorobenzoic acid (2)
After dissolving 2-chloro-4-nitrobenzoic acid (1) {100 g} (FW {201.57, {496} mmol) and ethanol (250 mL) and replacing with argon, a 10% palladium carbon catalyst (4.0 + 1.5 g) was added. added. After hydrogen replacement, the mixture was stirred at room temperature for 72 hours. The resulting crystals were dissolved in acetone and filtered to remove the catalyst. The solvent was distilled off under reduced pressure to quantitatively obtain 88 g of the desired 4-amino-2-chlorobenzoic acid (2).
215-217 ° C
[0066]
Synthesis of 4-bromo-2-chlorobenzoic acid (3)
4-Amino-2-chlorobenzoic acid (2) {88 g} (FW {171.58, 513 mmol), 48% hydrobromic acid (304 mL), and water (304 mL) were heated at 120 ° C. for 1 hour to dissolve. It was hydrobromide. The mixture was cooled (ice-salt) with stirring, and an aqueous solution (water, 250 mL) of 44.4 g of sodium nitrite (FW 69.00, 643 mmol) was added to the solution while keeping the temperature at 5 ° C or lower.
A 48% hydrobromic acid (331 mL) solution of copper bromide (120.8 g) (FW 80.79, 2.83 mol) was set to 0 ° C. in a beaker, and the prepared diazonium salt solution was not foamed with stirring. Added slowly. After the addition, the mixture was heated on a hot water bath until the generation of nitrogen disappeared. After cooling, the mixture was extracted with ethyl acetate. This was treated according to a conventional method to obtain 88.3 g (73%) of the desired 4-bromo-2-chlorobenzoic acid (3).
152-160 ° C. IR (KBr) νmax 3090, 1682, 1578 cm^-1.¹H NMR (CDCl₃, {400} MHz) δ {7.50} (1H, dd, J = 8.5, 2 Hz, Ar-H), 7.69 (1H, J = 2 Hz, Ar-H), 7.89 (1H, J = 8). .5 Hz, @ Ar-H).
[0067]
Reference Example 2: Method for producing di- (3,5-dimethoxyphenyl) disulfide (9)
[0068]
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[0069]
40.8 ml of concentrated hydrochloric acid (489.6 mmol) was added to a suspension of 25.0 g of 3,5-dimethoxyaniline (4) in 500 ml of water (FW {153.18, 163.2 mmol), and the mixture was stirred and heated to give hydrochloric acid. The salt was completely dissolved. After adding 400 ml of water thereto, the mixture was ice-cooled. While maintaining the reaction temperature (internal temperature) at 5 ° C. or lower, while stirring vigorously, a solution of sodium nitrite {11.8 g} (FW {69.00, {171.4 mmol}) in water {40 ml} was carefully added into the solution. This solution was stirred at the same temperature for about 30 minutes to prepare a diazonium salt solution.
[0070]
A suspension of 680.5 g of potassium xanthate (6) (FW 160.30, 4243.2 mmol) in 550 ml of water was heated to 65 to 70 ° C. and completely dissolved to obtain a potassium xanthate solution.
The diazonium salt solution kept at 5 ° C or lower was gradually dropped into this solution kept at 65 to 70 ° C over 30 minutes. This operation was repeated four times.
After stirring at 65 to 70 ° C. for about 1 hour, the mixture was allowed to cool to room temperature. Ethyl acetate was added and extracted three times. This was washed with 1N sodium hydroxide, water, and saturated saline. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain a crude product (7). By column chromatography (hexane: ethyl acetate = 7: 1), 122.31 g of the product (7) (and a mixture of (9)) was obtained.
[0071]
After dissolving 85.7 g of the crude product (7) (and the mixture of (9)) in 450 ml of ethanol, 50 ml of water and 200.0 g of potassium hydroxide (56.11, 4896.0 mmol) of potassium hydroxide were added. . The reaction solution was stirred under reflux for 10 minutes. After confirming the absence of compound (7) by TLC, the mixture was allowed to cool and neutralized with 3N hydrochloric acid. After removing ethanol under reduced pressure, the mixture was extracted three times with ethyl acetate and washed with saturated saline. 25.0 g of copper (II) oxide (powder) {(FW. {79.54, {314.3 mmol)}} is added to the organic layer, and air (or oxygen) is passed through at room temperature until thiol (8) disappears at room temperature. Stirred. After removing insoluble matters by filtration, water was added, and the mixture was extracted three times with ethyl acetate, and washed with 1N hydrochloric acid, water, and saturated saline in this order. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain 53.65 g of a crude product (9). The crude product (9) was purified by column chromatography (hexane: ethyl acetate = 19: 1), and 34.87 g of disulfide (9) (pure) (FW {338.44, 103.0 mmol), 11 .05g
(Crude) was obtained in a yield of about 41%.
152-160 ° C. IR (KBr) νmax 3090, 1682, 1578 cm^-1.¹H NMR (CDCl)₃, {400 MHz) δ 7.50} (1H, dd, J = 8.5, 2 Hz, Ar-H), 7.69 (1H, J = 2 Hz, Ar-H), 7.89 (1H, J = 8.5 Hz) , {Ar-H).
[0072]
Reference Example 3: Method for producing di- (3,4-dimethoxyphenyl) disulfide (11)
[0073]
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[0074]
To 500 g of veratrol (10) was added 500 ml of anhydrous methylene chloride, and the mixture was stirred at 0 ° C. Chlorosulfonic acid {235} ml was added thereto over 1 hour, and the mixture was stirred at 50 ° C. for 30 minutes. This solution was added dropwise to methanol 1.5 ° l at 0 ° C over 40 minutes, and hydrochloric acid {290} ml and stannous chloride {570} g were added thereto, followed by stirring at room temperature for 2 hours. After concentration under reduced pressure to half the volume, extraction was performed with toluene. The organic layer was washed with 12% hydrochloric acid, water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, {20} g of cupric oxide was added, and the mixture was stirred while bubbling air. The catalyst was filtered, washed with ethyl acetate, and recrystallized from ethyl acetate-hexane to obtain the desired product (11). (Total yield 21%)
EI-MS; {338} (M +), {169} (Base). << NMR >> (CDCl₃); {3.83} (6H, s), {3.87} (6H, s), 6.79 (2H, d, JＨ = 8.3 Hz), 7.01 (2H, d, J = 2.1 Hz). ), {7.05 ({2H, dd, J} = 2.1, 8.3 Hz)
[0075]
Reference example 4: Method for producing 8-bromo-10,11-dihydrodibenzo [b, f] oxepin-1,3-diol (21)
[0076]
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[0077]
Synthesis of carboxylic acid (14)
3-bromo-2-chlorobenzoic acid (12) 30.0 g {FW.235.46, 127 mmol), 3,5-dimethoxyphenol (13) 21.6 g} (FW.154.165, 140 mmol) , Potassium carbonate {35.3 g} (FW {138.21, {325.6 mmol}), N-methyl-2-pyrrolidone} (180 ml), benzene (100 ml) was added, and the mixture was dried for 3 hours with a Dean-Stark water separator (140). (−170 ° C.), copper (powder) 1.59 g (FW 63.55, 25.0 mmol), copper (I) iodide 6.05 g (190.45, 25.0 mmol). And stirred at 120 ° C. for 1.5 hours. The reaction mixture was allowed to cool, ice water and ethyl acetate were added, and the mixture was adjusted to pH 2 with concentrated hydrochloric acid and filtered. The organic layer was separated, washed well with water and salted out with a saturated saline solution. Drying over anhydrous magnesium sulfate, concentration and recrystallization from benzene gave 25.47 g of carboxylic acid (14). The mother liquor was purified by column chromatography (silica gel, 6% water containing; 250 g, ethyl acetate: hexane = 1: 2) to obtain 4.58 g of crystals. Total yield: {30.05 g (67%)} + {9.23 g of mother liquor} (purity, {40%) (TLC; ethyl acetate: hexane = 1: 2 or 1: 1) MS} (EI): {354, 352, {269. NMR (CDCl₃): $ 3.76
(2H, s, CH₂), {3.77} (6H, s, CH₃X2), {6.22} (2H, d, ＝ J = 2.5 Hz, Ar-H), 6.33 (1H, d, J = 2.5 Hz, Ar-H), 6.85 (1H, d, J = 8.5 Hz, Ar-H), 7.57 (1H, dd, J = 8.5, 2.2 Hz, Ar-H), 8.26 (1H, d, J = 2.2 Hz, Ar-H) ).
[0078]
Synthesis of alcohol (15)
To a solution of 21.5 g of carboxylic acid (14) {(FW. 353.168, 60.9 mmol) in 75 ml of tetrahydrofuran, 2.65 g of sodium borohydride (FW {37.83, {70.05 mmol)} was added slightly at room temperature. After addition, the boron fluoride ether complex {9.49 ml} (FW {141.93, {d = 1.154, {77.16 mmol)}} was added dropwise. Stirred at room temperature for 1 hour. 200 ml of ice water was gradually added to the reaction solution. The mixture was extracted with ethyl acetate and washed three times with a saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. Recrystallization from benzene-diisopropyl ether gave 19.04 g of alcohol (15) (98%). (TLC; ethyl acetate: hexane = 1: 4)
MS (EI): $ 340, $ 338, $ 291, $ 289. NMR (CDCl₃): {3.75} (6H, Δs, ΔCH₃X2), {4.70} (2H, Δs, ΔCH₂), {6.02} (2H, d, J = 2.5 Hz, Ar-H), 6.07 (1H, d, J = 2.5 Hz, Ar-H), 6.85 (1H, d, J = 8.5 Hz, Ar-H), 7.39 (1H, dd, J = 8.5, 2.2 Hz, Ar-H), 7.64 (1H, d, J = 2.2 Hz, Ar-H) .
[0079]
Synthesis of chloride (16)
20.0 g of alcohol (15) (FW 339.185, 62.6 mmol) was azeotropically dried with benzene, dried and dried in 40 ml of benzene and 10 ml of methylene chloride in 5.63 ml of thionyl chloride {FW. 118.97, d = 1.631, (76.7 mmol) and methylene chloride (5.6 ml) were added at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. The mixture was further stirred at room temperature overnight. Ice water was added to the reaction mixture, extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 4) to obtain 14.03 g (65%) of chloride (16). (TLC; ethyl acetate: hexane = 1: 4) NMR (CDCl₃): {3.75} (6H, Δs, ΔCH₃X2), {4.49} (2H, s, CH₂), {6.16} (2H, Δd, ΔJ = 2.5 Hz, ΔAr-H), {6.25} (1H, Δd, ΔJ = 2.5 Hz, ΔAr-H), {6.78} (1H, Δd, ΔJ = 8.7 Hz, Ar-H), 7.35 (1H, dd, J = 8.7, 2.4 Hz, Ar-H), 7.57 (1H, d, J = 2.4 Hz, Ar-H) .
[0080]
Synthesis of cyanide (17)
Dissolve 27.9 g of chloride (16) (FW {357.631, {78.0 mmol)) in dimethyl sulfoxide (30 ml). To this solution was added sodium cyanide {5.49 g} (FW {49.01, {112.0 mmol)), and the mixture was stirred at 80 ° C for 1 hour. After adding water under ice cooling, the mixture was extracted three times with ethyl acetate. This was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The crystals were recrystallized from methylene chloride-hexane to obtain 16.91 g of the cyanide (17) {(65%)}. (TLC; ethyl acetate: hexane = 1: 4) MS (EI): 349, 347. NMR (CDCl₃): {3.70} (2H, Δs, ΔCH₂), {3.74} (3H, s, CH₃), {3.75} (3H, Δs, ΔCH₃), {6.11} (2H, d, J = 2.5 Hz, Ar-H), 6.26 (1H, d, J = 2.5 Hz, Ar-H), 6.81 (1H, d, J = 8.5 Hz, Ar-H), 7.40 (1H, dd, J = 8.5, 2.2 Hz, Ar-H), 7.62 (1H, d, J = 2.2 Hz, Ar-H) .
[0081]
Synthesis of phenylacetic acid (18)
14.00 g of the cyano compound (17) {(FW. {348.196, {40.0 mmol)}} was dissolved in ethanol (33.6 ml) and a 6N aqueous sodium hydroxide solution (33.6 ml) (sodium hydroxide 8.06 g (FW # 40.00 mmol). , (201.5 mmol) dissolved in water) and stirred at 110 ° C. overnight. Ice was added to the reaction solution, and the solution was adjusted to pH 2 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was completely removed under reduced pressure, and the residue was crystallized from benzene-hexane to obtain 13.33 g (90%) of phenylacetic acid (18). (TLC; ethyl acetate: hexane = 1: 2 or 1: 1)
NMR (CDCl₃): {3.70} (3H, Δs, ΔCH₃), {3.90} (3H, Δs, ΔCH₃), {3.95} (1H, s, CH₂), {6.26} (1H, Δd, ΔJ = 2.5 Hz, ΔAr-H), {6.46} (1H, Δd, ΔJ = 2.5 Hz, ΔAr-H), {7.08} (1H, Δd, ΔJ = 8.5 Hz, Ar-H), 7.33 (1H, dd, J = 8.5, 2.3 Hz, Ar-H), 7.41 (1H, d, J = 2.3 Hz, Ar-H) , {12.91} (1H, $ s, $ OH)
[0082]
Synthesis of cyclized form (19)
Methanesulfonic acid {60 ml} was added to and dissolved in 11.75 g (FW {369.195, {32.0 mmol}) of carboxylic acid (18). The solution was stirred at 40 ° C. for 3 days. 300 ml of ice water was added to the reaction solution to precipitate a cyclized product. The precipitated cyclized product was separated by filtration, extracted with ethyl acetate, and treated according to a conventional method to obtain a crude product. The crystals were recrystallized from hexane-methylene chloride to obtain 6.0 g of the cyclized compound (19) (54%). (TLC; ethyl acetate: hexane = 1: 2)
MS (EI): $ 349, $ 347, $ 269. NMR (CDCl₃): $ 3.84 (3H, $ s, $ CH₃), $ 3.90 (3H, $ s, $ CH₃), {3.95} (1H, s, CH₂), {6.26} (1H, Δd, ΔJ = 2.5 Hz, ΔAr-H), {6.46} (1H, Δd, ΔJ = 2.5 Hz, ΔAr-H), {7.08} (1H, Δd, ΔJ = 8.5 Hz, Ar-H), 7.33 (1H, dd, J = 8.5, 2.3 Hz, Ar-H), 7.41 (1H, d, J = 2.3 Hz, Ar-H) , {12.91} (1H, $ s, $ OH)
[0083]
Synthesis of 2-bromo-7,9-dihydroxy-10,11-dihydrodibenzo [b, f] oxepin-10-one (20)
Pyridine hydrochloride (2.0 g) was added to the dimethoxy compound (19) {395 mg} (FW {349.18, {1.13 mmol)), and the mixture was heated with stirring at 195 ° C. for 1.5 hours, and ice water was gradually added. The mixture was extracted with ethyl acetate and washed sequentially with 1N hydrochloric acid, water, and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 2). The solid was recrystallized from diisopropyl ether-hexane to obtain the title compound {223 mg} (61%). (TLC; ethyl acetate: hexane = 1: 2)
Melting point 194-195 ° C; {MS} (EI): {322, 320, 241. NMR (CDCl₃) 4.03 (2H, s, CH)₂), 5.88 (1H, s, OH), 6.17Ｈ (1H, d, J = 2.5 Hz, Ar-H), 6.35 (1H, d, J = 2.5 Hz, Ar-H). , {7.10} (1H, d, ＝ J = 8.5 Hz, Ar-H), 7.36 (1H, dd, J = 8.5, 2.3 Hz, Ar-H), 7.43 (1H, d , J = 2.3 Hz, Ar-H), 12.91 (1H, s, OH)
[0084]
Synthesis of 8-bromo-10,11-dihydrodibenzo [b, f] oxepin-1,3-diol (21)
50 ml of methanol was added to 2.00 g of the dimethoxy compound (19) (FW 321.126, 6.23 mmol), and the mixture was stirred. The solution was cooled to 0 ° C. while still in suspension. Thereto, 500 mg of sodium borohydride was added in several portions. The reaction solution was returned to room temperature and stirred for 1 hour. Dilute hydrochloric acid was added to the reaction solution to stop the reaction, and methanol was distilled off under reduced pressure. Ethyl acetate was added and partitioned. The organic layer was washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 10 g of pyridine hydrochloride was added to the obtained oil, and the mixture was heated with stirring at 200 ° C. for 2 hours. After completion of the reaction, the reaction solution was partitioned between ethyl acetate and dilute hydrochloric acid. The organic layer was washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 1). The obtained oil was dissolved in 20 ml of ethyl acetate. 100 mg of platinum (IV) oxide was added, and catalytic reduction was performed at room temperature for 3 days. After completion of the reaction, the reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 2: 1). The crystals were recrystallized from chloroform-hexane to give the title compound (901.0 mg, @ 51.2%) as light orange plate-like crystals. 173.8-175.8 ° C,
NMR (DMSO-d₆); {2.74} (2H, Δt, ΔJ = 6.3 Hz, ΔCH₂), {2.99} (2H, Δt, ΔJ = 6.3 Hz, ΔCH₂), {6.05} (1H, d, J = 2.3 Hz, Ar-H), 6.10 (1H, d, J = 2.3 Hz, Ar-H), 7.04 (1H, d, J = 8.5 Hz, Ar-H), 7.32 (1H, dd, J = 8.5, 2.5 Hz, Ar-H), 7.42 (1H, d, J = 2.5 Hz, Ar-H) 9.19 (1H, s, Ph-OH) 9.39 (1H, s, Ph-OH)
[0085]
Reference example 5: Method for producing 7-bromo-10,11-dihydrodibenzo [b, f] oxepin-1,3-diol (29)
[0086]
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[0087]
4 -Bromo- 2 − (3,5 -Dimethoxyphenoxy ) Synthesis of benzoic acid (22)
4-bromo-2-chlorobenzoic acid (3), 88.3 g (FW 233.56, 375 mmol), 3,5-dimethoxyphenol (13) 57.8 g (FW 154.165, 375 mmol) ), Potassium carbonate {93.2 g} (FW {138.21, {670 mmol)), N-methyl-2-pyrrolidone {400 mL}, benzene (200 mL) was added, and the mixture was dried for 3 hours with a Dean-Stark water separator (140 → 170 ° C.), copper (powder) {6.0 g} (FW {63.55, {93.7 mmol), copper iodide (I) {17.8 g} (FW {190.45, {93.7 mmol), The mixture was stirred at 120 ° C. for 30 minutes. The reaction mixture was allowed to cool, ice water and ethyl acetate were added, and the mixture was adjusted to pH 2 with concentrated hydrochloric acid and filtered. The organic layer was separated, washed well with water and salted out with a saturated saline solution. After drying over anhydrous magnesium sulfate and concentration, the product was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 3) and recrystallized from ethyl acetate-hexane to give 75.4 g of the desired product (20) (57%). %).
(TLC; ethyl acetate: hexane = 1: 2 or 1: 1) Melting point 112-117 ° C .; {UV} (EtOH) {λmax} (ε) {292} (2000)} nm. IR (KBr) νmax 3411, 1699, 1605 cm^-1.¹H NMR (CDCl₃, 400 MHz) δ 3.75 (2H, s, CH₂), {3.77} (6H, s, CH₃x 2) 6.23 (1H, d, J = 2.1 Hz, Ar-H), 6.34 (1H, d, J = 2.1 Hz, Ar-H), 7.09− (2H, m, Ar -H), {7.32} (1H, @m, @ Ar-H), {7.98} (1H, @m, @ Ar-H). {MS} (EI) m / z 354, 352, 309, 307.
[0088]
4 -Bromo- 2 − (3,5 -Dimethoxyphenoxy ) Synthesis of benzyl alcohol (23)
8.9 g of sodium borohydride in a solution of 75.4 g of 4-bromo-2- (3,5-dimethoxyphenoxy) benzoic acid (22) {(FW. {353.168, {213 mmol)}) in 300 mL of tetrahydrofuran (FW. After adding 37.83, {235 mmol) little by little at room temperature, boron fluoride ether complex {31 mL} (FW {141.93, {d = 1.154, {252 mmol)}) was added dropwise. Stirred at room temperature for 1 hour. 200 mL of ice water was gradually added to the reaction solution. The mixture was extracted with ethyl acetate and washed three times with a saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. Recrystallization from benzene-diisopropyl ether gave 46.6 g (64%) of the alcohol (23). (TLC; ethyl acetate: hexane = 1: 4) MS (EI) m / z 340, 338.
[0089]
4 -Bromo- 2 − (3,5 -Dimethoxyphenoxy ) Synthesis of benzyl bromide (24)
Under an argon atmosphere, a solution of 46 g of alcohol (23) {(339.19, 135 mmol) in methylene chloride} in 100 mL of methylene chloride at 0 ° C was added with 4.7 mL of phosphorous tribromide {4.7 mL} (FW = 270.70, d = 2.850). , {49.5 mmol)}. After stirring at room temperature for 30 minutes. This reaction solution was added to ice. The mixture was further stirred at room temperature for 30 minutes. Ice water was added to the reaction mixture, extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 5) to obtain 44.6 g (84%) of bromide (24). (TLC; ethyl acetate: hexane = 1: 4)
[0090]
4 -Bromo- 2 − (3,5 -Dimethoxyphenoxy ) Synthesis of benzyl nitrile (25)
44.6 g of the bromide (24) {(FW. {357.631, {111 mmol)}} is dissolved in dimethylsulfoxide {50 mL}. To this solution was added sodium cyanide (8.15 g) (FW $ 49.01, $ 166 mmol), and the mixture was stirred at 80 ° C for 1 hour. After adding water under ice cooling, the mixture was extracted three times with ethyl acetate. This was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 4) to obtain 34.5 g (89%) of a nitrile compound (25). (TLC; ethyl acetate: hexane = 1: 4)
¹H NMR (CDCl₃, 400 MHz) δ 3.70 (2H, s, CH₂), {3.77} (6H, s, CH₃x 2) 6.14 (1H, d, J = 2.1 Hz, Ar-H), 6.28 (1H, d, J = 2.1 Hz, Ar-H), 7.02 (1H, m, Ar) -H), {7.15} (1H, m, −Ar-H), {7.21} (1H, m, A r-H). {MS} (EI) m / z 349, 347, 269.
[0091]
4-bromo-2- ( 3,5-dimethoxyphenoxy ) Synthesis of phenylacetic acid (26)34.5 g of the nitrile compound (25) (FW. 348.196, 99.1 mmol) was added to 83 mL of ethanol and 83 mL of 6N aqueous sodium hydroxide solution (19.9 g of sodium hydroxide, 49.9, 497 mmol of sodium hydroxide). (Dissolved in water) and stirred at 110 ° C. overnight. Ice was added to the reaction solution, and the solution was adjusted to pH 2 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was completely removed under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 2: 3) and crystallized from ethyl acetate-hexane to form a carboxylic acid ( 26) 27.3 g {(75%)} were obtained. (TLC; ethyl acetate: hexane = 1: 2 or 1: 1)
121.9-123.6 ° C; UV (EtOH) λmaxｍ () 272 (2200) nm. IR (KBr) νmax 2954, 1705, 1606, 1576 cm^-1.¹H NMR (CDCl₃, 400 MHz) δ 3.60 (2H, s, CH₂), {3.60} (6H, Δs, ΔCH₃x 2), {6.13} (1H, d, J = 2.1 Hz, Ar-H), 6.25 (1H, d, J = 2.1 Hz, Ar-H), {7.02} (1H, m, Ar-H), {7.15} (1H, m, Ar-H), {7.21} (1H, m, Ar-H). {MS} (EI) m / z 368, 366.
[0092]
3-bromo-7 , 9-dimethoxy-10 , Synthesis of 11-dihydrodibenzo [b, f] oxepin-10-one (27)
140 mL of methanesulfonic acid was added to 27.3 g of the carboxylic acid (26) (FW. 365.195, 74.3 mmol) and dissolved. The solution was stirred at 40 ° C. for 3 days. 300 mL of ice water was added to the reaction solution to precipitate a cyclized product. The precipitated cyclized product was separated by filtration, extracted with ethyl acetate, and treated according to a conventional method to obtain a crude product. The product was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 2) and recrystallized from hexane-ethyl acetate to obtain a cyclized form (27) {17.1 g} (66%). (TLC; ethyl acetate: hexane = 1: 2) Melting point 95-103 ° C .; {UV} (EtOH) {λmax} (ε) {272} (2800)} nm. IR (KBr) νmax 2977, 1679, 1604 cm^-1.¹H NMR (CDCl₃, {400} MHz) δ 3.84 (3H, s, CH₃), {3.88} (3H, Δs, ΔCH₃), {3.95} (2H, s, CH₂), {6.27} (1H, d, J = 2.1 Hz, Ar-H), 6.47 (1H, d, J = 2.1 Hz, Ar-H), 7.15 (1H, m, Ar- H), {7.30} (1H, @m, @ Ar-H), {7.40} (1H, @m, @ Ar-H). {MS} (EI) m / z 350, 348.
[0093]
3-bromo-7,9-dihydroxy-10,11-dihydrodibenzo [b, f] oxepin-10-one ( 28 ) Synthesis of
Pyridine hydrochloride {2.0 g} was added to the dimethoxy compound (27) {395 mg} (FW {349.18, {15.75 mmol)}, and the mixture was stirred at 195 ° C for 1.5 hours, and ice water was gradually added. The mixture was extracted with ethyl acetate and washed sequentially with 1N hydrochloric acid, water, and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 2). The crystals were recrystallized from dioxane and dioxane and hexane to give the title compound {223 mg} (61%). (TLC; ethyl acetate: hexane = 1: 2)
Melting point 194-195 ° C;¹H NMR (CDCl₃, {400} MHz) δ {4.03} (2H, s, CH₂), {6.09} (1H, d, J = 2.1 Hz, Ar-H), 6.39 (1H, d, J = 2.1 Hz, Ar-H), 7.43 (2H, m, Ar−). H), {7.64} (1H, m, Ar-H), {11.07} (1H, s, OH), {12.95} (1H, s, OH). {MS} (EI) {m / z} 322, {320.
[0094]
7-bromo-10,11-dihydrodibenzo [b, f] oxepin-1,3-diol ( 29 ) Synthesis of
80 mL of methanol was added to the dimethoxy compound (27) {5.5 g} (FW {349.18, {15.75} mmol)}, and the mixture was stirred. The solution was cooled to 0 ° C. while still in suspension. Thereto was added 890 mg of sodium borohydride in several portions. The reaction solution was returned to room temperature and stirred for 1 hour. Dilute hydrochloric acid was added to the reaction solution to stop the reaction, and methanol was distilled off under reduced pressure. Ethyl acetate was added and partitioned. The organic layer was washed with water and washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained oily product, pyridine (20 mL) and tosyl chloride (3.6 g) were added, and the mixture was stirred at 90 ° C. overnight. The reaction solution was partitioned between ethyl acetate and dilute hydrochloric acid. The organic layer was washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 5: 1) (4.96 g, 95% yield). The obtained oil was dissolved in 50 mL of ethyl acetate, 150 mg of platinum (IV) oxide was added, and the mixture was subjected to catalytic reduction at room temperature for 1 day. After completion of the reaction, the reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 10: 1) (4.21 g, yield: 84%, melting point: 60.0). -66.2 ° C). 2 g of pyridine-hydrochloric acid was added to 150 mg of the obtained crystals (FW: 335.20, 0.45 mmol), and the mixture was heated and stirred at 200 ° C. for 2 hours. After completion of the reaction, the reaction solution was partitioned between ethyl acetate and dilute hydrochloric acid. The organic layer was washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 1). Recrystallization from chloroform-hexane gave the title compound {80 mg} (58%) as pale pink plate crystals.
Melting point 177.5-179.5 ° C;¹H NMR (DMSO-d₆, {90} MHz) δ2.7-2.9} (2H, m, CH₂), {2.9-3.1} (2H, m, CH₂), {6.0-6.2} (2H, m, Ar-H), {7.1-7.4} (3H, m, Ar-H), {9.22} (1H, s, OH), 9.41. (1H, $ s, $ OH). {MS} (EI) {m / z} 308, {306, {227.
[0095]
Reference Example 6: Method for producing 1-chloro-7,9-dihydroxy-10,11-dihydrodibenzo [b, f] oxepin-10-one (38)
[0096]
Embedded image

[0097]
Synthesis of carboxylic acid (31)
9.32 g of 2,6-dichlorobenzoic acid (30) (FW = 191.01, 48.8 mmol), 6.60 g of 3,5-dimethoxyphenol (13) (FW = 154.165, {4. Benzene (40 ml) was added to a mixture of potassium carbonate {9.32 g} (FW {138.21, {67.4 mmol}) and N-methyl-2-pyrrolidone {56 ml}, followed by drying with a Dean-Stark water separator for 3 hours. (140-170 ° C.), copper (powder) {614 mg} (FW 63.55, 9.67 mmol), copper (I) iodide 2.30 g (FW 190.45, 12.1 mmol). And stirred at 140 ° C. for 1 hour. The reaction mixture was allowed to cool, ice water and ethyl acetate were added, and the mixture was adjusted to pH 2 with concentrated hydrochloric acid and filtered. The organic layer was separated, washed well with water and salted out with a saturated saline solution. The extract was dried over anhydrous magnesium sulfate and concentrated. The residue (17 g) was purified by column chromatography (silica gel, 6% water containing; 340 g, ethyl acetate: hexane = 1: 2) to obtain 5.05 g (38%) of the crystal of (31).
[0098]
Synthesis of ester (32)
The carboxylic acid (31) was dissolved in a mixed solution of 2.5 g of {(FW. {353.168, {8.10 mmol)}} in 10 ml of dichloromethane and 10 ml of methanol, and an ether solution of diazomethane was added until the yellow color did not disappear. The reaction mixture was concentrated and purified by silica gel column chromatography (silica gel; {90 g, ethyl acetate: hexane = 1: 4) to obtain the ester (32) {2.507 g} (98%). (TLC; ethyl acetate: hexane = 1: 4)
[0099]
Synthesis of alcohol (33)
2.51 g of ester (32) in a mixture of lithium aluminum hydride 250 mg (FW 37.83, 6.60 mmol) and diethyl ether 10 ml at 0 ° C. with stirring (FW 322.444, 7.76 mmol). )) (5 + 3 ml) was added portionwise. After stirring at room temperature for 3 hours, a 90% methanol solution and a saturated aqueous ammonium chloride solution were added to the reaction solution. The organic layer was separated and washed three times with a saturated saline solution. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The reaction mixture was concentrated and purified by silica gel column chromatography (silica gel,; 150 g, {ethyl acetate: hexane = 3: 7) to obtain 1.53 g of alcohol (33) (64%). (TLC; ethyl acetate: hexane = 1: 4)
[0100]
Synthesis of bromide (34)
2.24 g of alcohol (33) (FW@308.761, 7.28 mmol) was azeotroped with benzene and dried, and phosphorus tribromide {0.254 ml} in 5 ml of methylene chloride (FW {270.70, d = 2.85, 2.67 mmol) and methylene chloride 5.6 ml were added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. Ice water was added to the reaction mixture, extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 4) to obtain bromide (34) {2.58 g (99%)} as crystals. (TLC; ethyl acetate: hexane = 1: 4)
[0101]
Synthesis of cyanide (35)
2.58 g of bromide (34) (FW {357.631, {7.21 mmol)) was dissolved in 5 ml of dimethyl sulfoxide. To this solution was added sodium cyanide (530 mg) (FW 49.01, 10.82 mmol), and the mixture was stirred at 80 ° C for 30 minutes. After adding water under ice cooling, the mixture was extracted three times with ethyl acetate. This was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 4) to obtain 1.95 g (89%) of the cyanide (35). (TLC; ethyl acetate: hexane = 1: 4)
[0102]
Synthesis of phenylacetic acid (36)
To 1.93 g of the cyano compound (35) (FW: 303.745, 6.35 mmol), 4.56 ml of ethanol and 4.56 ml of a 6N aqueous solution of sodium hydroxide (1.13 g of sodium hydroxide, 4.13 ml (FW 40.00) , {28.3 mmol)} in water) and stirred at 110 ° C overnight. Ice was added to the reaction solution, and the solution was adjusted to pH 2 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was completely removed under reduced pressure, and the residue was crystallized from benzene-hexane to obtain 1.36 g (66%) of phenylacetic acid (36). (TLC; ethyl acetate: hexane = 1: 2 or
1: 1)
[0103]
Synthesis of cyclized form (37)
1.30 g of carboxylic acid (36) (FW @ 322.744, 4.03 mmol) was dissolved in 6 mL of toluene, and polyphosphoric acid (10 mL of phosphoric acid, 7 g of phosphorus pentoxide heated at 150 ° C.) was added thereto. Concentrated. The solution was stirred at 100 ° C. for 1.5 hours. Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate and treated according to a conventional method to obtain a crude product. Recrystallization from hexane-methylene chloride gave 1.17 g (85%) of the cyclized compound (37). (TLC; ethyl acetate: hexane = 1: 2)
[0104]
Synthesis of 1-chloro-7,9-dihydroxy-10,11-dihydrodibenzo [b, f] oxepin-10-one (38)
Pyridine hydrochloride {2.0 g} was added to 150 mg of dimethoxy compound (37) (FW {304.729, 0.492 mmol) and 0.15 mL of benzene, and the mixture was heated and stirred at 195 ° C. for 1.5 hours. added. The mixture was extracted with ethyl acetate and washed sequentially with 1N hydrochloric acid, water, and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 2). The solid was recrystallized from dichloromethane-hexane to obtain the title compound {104 mg} (77%). (TLC; ethyl acetate: hexane = 1: 2)
[0105]
Reference Example 7: Method for producing 9-chloro-10,11-dihydrodibenzo [b, f] oxepin-1,3-diol (40)
[0106]
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[0107]
Reduction of B-ring ketone
Ring B-ketone compound (37) (475 mg) (FW {304.729, 1.56 mmol) was dissolved in 20 mL of ethylene glycol, and hydrazine monohydrate {2.25 mL} (FW {50.06, {d = 1. 032, {46.5 mmol)} and potassium hydroxide {3.05 g} (FW {56.11, {54.3 mmol)} were added, and the mixture was stirred at 70 ° C for 4.5 hours. After the temperature was raised to 140 ° C., the mixture was further stirred for 2 hours. The reaction solution was neutralized by adding 4N hydrochloric acid under ice-cooling. The mixture was extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain a crude product. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 19: 1) to obtain a reduced form (39) (347 mg) (FW 290.746, 1.19 mmol, 76%). .
[0108]
Deprotection
3.5 g of pyridine hydrochloride was added to the dimethoxy compound (39) {347 mg} (FW {290.746, 1.19 mmol), and the mixture was heated with stirring at 200 ° C. for 2 hours, and ice water was gradually added. The mixture was extracted with ethyl acetate and washed sequentially with 1N hydrochloric acid, water, and saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: hexane = 3: 1), and further recrystallized from chloroform-hexane to give 225 mg of the title compound (FW 266.292, 0.86 mmol, 72%).
[0109]
【Example】
Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to the examples and the like, and may be changed without departing from the scope of the present invention. Elution in column chromatography in Examples was performed under observation by TLC (thin layer chromatography), unless otherwise specified. In TLC observation, 60F254 manufactured by Merck was used as a TLC plate, and a solvent used as an elution solvent in column chromatography was used as a developing solvent. A UV detector was used for detection. As silica gel for column chromatography, silica gel 60 (70-230 mesh) manufactured by Merck or Microsphere Gel D75-60A manufactured by Asahi Glass was used. Room temperature usually means about 10 ° C to about 35 ° C.
[0110]
Example 1: Method for producing 2-methylthio-7,9-dihydroxy-10,11-dihydrodibenzo [b, f] thiepin-10-one (compound of Example 1)
[0111]
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[0112]
Synthesis of carboxylic acid (42)
5-thiomethyl-2-chlorobenzoic acid (41) {60.8 g} (FW {202.66, {0.30 mol), 3,5-dimethoxydisulfide (9) 21.0 g} (FW {338.448, 0.15 mol), potassium carbonate {21.0 g} (FW {138.21, 0.15 mol), N-methyl-2-pyrrolidone} 300 ml, benzene (100 ml × 3) was added, and the mixture was azeotroped with a Dean-Stark water separator. After drying, it was heated at 135 ° C. Copper (powder) {9.53 g} (FW 63.55, 0.15 mol), copper (I) iodide 28.57 g (FW 190.45, 0.15 mol) were added, and the mixture was heated at 135 ° C for 5 hours. Stirred for .5 hours. The reaction mixture was allowed to cool, ice water and ethyl acetate were added, and the mixture was adjusted to pH 2 with concentrated hydrochloric acid and filtered. The organic layer was separated, washed well with water and salted out with a saturated saline solution. After drying over anhydrous magnesium sulfate and concentration, recrystallization from 2-butanone-isopropyl ether gave 65.08 g of carboxylic acid (42). Total yield: {65.08 g (65%)} + {1.003 g mother liquor} (purity, 40%) (TLC; ethyl acetate: hexane = 1: 2 or 1: 1)
MS (EI): $ 336, $ 318, $ 303, $ 244. NMR (CDCl₃): {2.48} (3H, Δs, ΔCH₃), {3.78} (6H, {s, CH₃X2), {6.50} (1H, d, J = 2.2 Hz, Ar-H), 6.69 (1H, d, J = 2.2 Hz, Ar-H), 6.91 (1H, d, J). = 8.5 Hz, Ar-H), 7.22 (1H, dd, ＝ J = 8.5, 2.2 Hz, Ar-H), 7.97 (1H, d,
J = 2.2 Hz, {Ar-H).
[0113]
Synthesis of alcohol (43)
To a solution of 50.45 g of carboxylic acid (42) {(FW. {336.432, {150 mmol)} in tetrahydrofuran (200 ml), slowly add 6.24 g of sodium borohydride (FW {37.83, {165.0 mmol)} at room temperature. Then, boron fluoride ether complex {20.29 ml} (FW {141.93, {d = 1.154,} 165.0 mmol) was added dropwise. Stirred at room temperature for 1 hour. Ice water was gradually added to the reaction solution. The mixture was extracted with ethyl acetate and washed three times with a saturated saline solution. After drying over magnesium sulfate, the solvent was removed under reduced pressure. Crystallization from diisopropyl ether gave 46.23 g of alcohol (43). Recrystallization from ethyl acetate-hexane gave 43.61 g (77%). (TLC; ethyl acetate: hexane = 1: 2)
MS (EI): $ 322, $ 303, $ 289, $ 273. NMR (CDCl₃): {2.51} (3H, s, CH₃), {3.71} (6H, {s, CH₃X2), {4.74} (2H, Δd, ΔJ = 6.3 Hz, ΔCH₂), {6.26} (3H, s, Ar-H), 6.85Ｈ (1H, dd, J = 8.5, 2.2 Hz, Ar-H), 7.40 (1H, d, J = 2. 2 Hz, Ar-H), 7.42 (1H, d, J = 8.5 Hz, Ar-H).
[0114]
Synthesis of bromide (44)
In a solution of 59.06 g of alcohol (43) {(FW. {322.449, {175.5 mmol)) in methylene chloride (127 ml)}, phosphorus tribromide {6.4 ml} (FW {118.97, {d = 1.631, 64.4 mmol) at 0 ° C. and stirred at the same temperature for 30 minutes. The mixture was further stirred at room temperature for 15 minutes. Ice water was added to the reaction mixture, extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 5), and recrystallized from ethyl acetate-hexane to obtain 57.74 g (82%) of bromide (44). (TLC; ethyl acetate: hexane = 1: 4)
MS (EI): $ 386, $ 384. NMR (CDCl₃): {2.50} (3H, Δs, ΔCH₃), {3.73} (6H, s, CH₃X2), {4.64} (2H, s, CH₂), {6.28} (1H, Δd, ΔJ = 2.2 Hz, ΔAr-H), {6.33} (2H, Δd, ΔJ = 2.2 Hz, ΔAr-H), {7.12} (1H, Δdd, ΔJ = 8.2, 2.4 Hz,） Ar-H), 7.33 (1H, d, J = 8.2 Hz, Ar-H), 7.35 (1H, d, J = 2.4 Hz, Ar-H) .
[0115]
Synthesis of nitrile form (45)
57.74 g of bromide (44) (FW. 385.346, 149.8 mmol) was dissolved in 127 ml of dimethyl sulfoxide. To this solution was added sodium cyanide {11.02 g} (FW {49.01, {224.8 mmol)}, and the mixture was stirred at 80 ° C for 45 minutes. After adding water under ice cooling, the mixture was extracted three times with ethyl acetate. This was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. Recrystallization from ethyl acetate-hexane gave 34.83 g of {(70%)} nitrile. (TLC; ethyl acetate: hexane = 1: 4) MS (EI): 331. NMR (CDCl₃): {2.53} (3H, s, CH₃), {3.72} (6H, s, CH₃), {3.85} (3H, Δs, ΔCH₃), {6.20} (2H, Δd, ΔJ = 2.5 Hz, ΔAr-H), {6.27} (1H, Δd, ΔJ = 2.5 Hz, ΔAr-H), {7.19} (1H, Δdd, ΔJ = 8.5, 2.3 Hz, Ar-H, 7.44 (1H, d, J = 2.3 Hz, Ar-H), 7.45 (1H, d, J = 8.5 Hz, Ar-H) .
[0116]
Synthesis of phenylacetic acid (46)
30.07 g of nitrile compound (45) (FW {331.46, {90.8 mmol)) was added to 75 ml of ethanol and 75 ml of 6N aqueous sodium hydroxide solution (75 ml of sodium hydroxide 18.80 g (FW 40.00, {450 mmol)). (Dissolved in water) and stirred at 110 ° C. overnight. Ice was added to the reaction solution, and the mixture was adjusted to pH 2 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was completely removed under reduced pressure and crystallized from benzene-hexane to obtain 28.86 g of phenylacetic acid (46) (91%). (TLC; ethyl acetate: hexane = 1: 2 or 1: 1) MS (EI): 350, 273. NMR (CDCl₃): {2.49} (3H, Δs, ΔCH₃), {3.70} (6H, Δs, ΔCH₃), {3.84} (1H, s, CH₂), {6.25} (3H, m, Ar-H), 7.15Ｈ (1H, dd, J = 8.5, 2.3 Hz, Ar-H), 7.21 (1H, d, J = 2. 3 Hz, {Ar-H), {7.42} (1H, d, J = 8.5 Hz, Ar-H), {12.91} (1H,
s, @OH).
[0117]
Synthesis of cyclized form (47)
140 mL of methanesulfonic acid was added to 27.89 g of carboxylic acid (46) (FW 350.459, 32.0 mmol) and dissolved. The solution was stirred at 40 ° C. for 1 day. Ice water was added to the reaction solution to precipitate a cyclized product. The precipitated cyclized product was separated by filtration, extracted with ethyl acetate, and treated according to a conventional method to obtain a crude product. Recrystallization from hexane-methylene chloride gave the cyclized compound (47) {15.22 g} (58%). (TLC; ethyl acetate: hexane = 1: 2) MS (EI): 332, 347, 269. NMR (CDCl₃): 2.49 (3H, s, CH₃), {3.81} (3H, Δs, ΔCH₃), {3.85} (3H, Δs, ΔCH₃), 4.19} (1H, s, CH₂), {6.36} (1H, Δd, ΔJ = 2.5 Hz, ΔAr−H), {6.66} (1H, Δd, ΔJ = 2.3 Hz, ΔAr-H), {7.04} (1H, Δdd, ΔJ = 8.5, 2.2 Hz, −Ar-H), 7.22 (1H, d, J = 2.2 Hz, Ar-H), 7.46 (1H, d, J = 8.5 Hz, Ar-H) .
[0118]
Synthesis of 7-methylthio-7,9-dihydroxy-10,11-dihydrodibenzo [b, f] oxepin-10-one (compound of Example 1)
Pyridine hydrochloride (120 g) was added to 27.88 g of the dimethoxy compound (47) (FW {332.44, {1.13 mmol)), and the mixture was heated with stirring at 195 ° C. for 1.5 hours, and ice water was gradually added. The mixture was extracted with ethyl acetate and washed sequentially with 1N hydrochloric acid, water, and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 1: 2). Further, recrystallization from isopropyl alcohol-2-butanone gave the title compound {19.40 g} (64%).
[0119]
Example 2: Method for producing 8-methylthio-10,11-dihydrodibenzo [b, f] thiepin-1,3-diol (compound of Example 2)
[0120]
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[0121]
665 mg of the cyclized compound (47) (FW@332.43, 2.0 mmol) was dissolved in 50 mL of ethylene glycol, and hydrazine monohydrate {2.9 mL} (FW = 50.06, d = 1.032, 60.0 mmol) and potassium hydroxide {4.04 g} (FW {56.11, {72.0 mmol)} were added, and the mixture was stirred at 80 ° C for 1.5 hours. After the temperature was raised to 140 ° C., the mixture was further stirred for 5 hours. The reaction solution was neutralized by adding 1N hydrochloric acid under ice-cooling. The mixture was extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was completely removed under reduced pressure to obtain a crude product. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 19: 1) to give a reduced form (48) {238.5 mg} (37.5%).
[0122]
To the reduced form (48) {238.5 mg} (FW {318.45, 0.75 mmol), 3.0 g of pyridine hydrochloride was added, and after heating and stirring at 200 ° C for 6 hours, ice water was gradually added. The mixture was extracted with ethyl acetate and washed sequentially with 1N hydrochloric acid, water, and saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated. The residue was purified by silica gel column chromatography (developing solvent; ethyl acetate: hexane = 19: 1), and further recrystallized from hexane-ethyl acetate to obtain 132.7 mg of the title compound (61.0%).
[0123]
Example 3Method for producing 11-diethyl-7,9-dihydroxy-10,11-dihydrodibenzo [b, f] thiepin-10-one (compound of Example 3)
[0124]
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[0125]
In a suspension of 1.92 g of sodium hydride {containing 60%, {FW. {24.00, {48.0 mmol)}} and 50 mL of tetrahydrofuran, compound (49) {5.72 g} (FW {286.34, {20. 0 mmol) in 200 mL of tetrahydrofuran was added dropwise. After the suspension was stirred at room temperature for 30 minutes, 3.84 mL of ethyl iodide (FW 155.97, d = 1.94, 48.0 mmol) was added, and the mixture was further stirred at room temperature for 2 days. Under ice-cooling, ammonium chloride was added to the reaction solution, and tetrahydrofuran was completely removed under reduced pressure. The mixture was partitioned between ethyl acetate and water, and washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was completely removed under reduced pressure to obtain 9.43 g of a crude product. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 9: 1 to 3: 1), and 3.62 g of a mixture of compound (50) and (51) and 2.62 g of compound (52) ( FW (342.45, 7.65 mmol, 38.2%). Compound (52) as a by-product was converted to compound (51) by acid treatment with ethanol-concentrated hydrochloric acid. Compound (51) was subjected to the above reaction again to obtain compound (50).
[0126]
The crude product (50) was combined and purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 9: 1-5: 1) to give 3.73 g of compound (50) (FW 342.45). , {10.89 mmol, {54.5%)}. Demethylation was carried out according to the method of Example 1 to obtain the title compound.
[0127]
Example 4Method for producing 11-ethyl-7,9-dihydroxy-10,11-dihydrodibenzo [b, f] thiepin-10-one (compound of Example 4)
[0128]
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[0129]
To a suspension of potassium t-butoxide {(12.3 mg, {110} mmol)} and 500 ml of tetrahydrofuran, a solution of 30 mg of compound (49) (FW {286.34, {105} mmol) in 500 ml of tetrahydrofuran was added dropwise at 0 ° C. did. The suspension was stirred at room temperature for 2 hours, cooled to 0 ° C., added with 16.8 mL of ethyl iodide (FW {155.97, {d = 1.94, {210} mmol), and added at room temperature for 20 hours. Stirred. Hydrochloric acid was added to the reaction solution under ice-cooling, tetrahydrofuran was completely removed under reduced pressure, and the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 4: 1), and recrystallized with methanol. 0.7 g (57% yield) was obtained.
The demethylation reaction of the compound (51) was carried out according to the method of Example 1 to obtain 14.8 g of the title compound.
[0130]
Example 5: Method for producing 3- (2-thiophene) -7,9-dihydroxy-10,11-dihydrodibenzo [b, f] oxepin-10-one (compound of Example 5)
[0131]
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[0132]
3-bromo-7,9-dimethoxy-10,11-dihydrodibenzo [b, f] oxepin-10-one (27) {(500 mg, {1.4 mmol), 2- (tributylstannyl) -thiophene} (0.9 mL, {2.8 mmol) and tetrakis (triphenylphosphonium) palladium} (82.5 mg, 0.07 mmol) were added with 5 mL of hexamethylphosphoric triamide, and the mixture was stirred at 100 ° C for 1 hour. After completion of the reaction, the reaction mixture was partitioned with diethyl ether and water, and the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 1) to give 3- (2-thiophene) -7,9-dimethoxy-10,11-dihydrodibenzo [b, f]. Oxepin-10-one {538 mg} (89% yield) was obtained. Demethylation was carried out according to the method of Example 1 to obtain the title compound.
[0133]
Example 6: Method for producing 3-phenyl-7,9-dihydroxy-10,11-dihydrodibenzo [b, f] oxepin-10-one (compound of Example 6)
[0134]
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[0135]
3-iodo-7,9-dimethoxy-10,11-dihydrodibenzo [b, f] oxepin-10-one (52) (403 mg, 1.0 mmol), phenylboronic acid (186 mg, 1.5 mmol), 2M carbonic acid 5 mL of toluene was added to an aqueous potassium solution (0.6 mL, 1.2 mmol) and tetrakis (triphenylphosphonium) palladium (118 mg, 0.10 mmol), and the mixture was stirred at 125 ° C. for 19 hours. After completion of the reaction, the mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 2: 1) to give 3-phenyl-7,9-dimethoxy-10,11-dihydrodibenzo [b, f] oxepin-10-. On {108 mg} (31% yield) was obtained. Demethylation was carried out according to the method of Example 1 to obtain the title compound.
[0136]
Example 7: Method for producing 7-phenyl-10,11-dihydrodibenzo [b, f] oxepin-1,3-diol (compound of Example 7)
[0137]
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[0138]
1,3-dimethoxy-7-bromo-10,11-dihydrodibenzo [b, f] oxepin (53) obtained by reducing the carbonyl group at the 10-position of compound (27) above (970 mg, 2.9 mmol) Phenylboronic acid (380 mg, 3.1 mmol), potassium carbonate (1.98 mg, 14.3 mmol), palladium acetate (20 mg, 0.09 mmol) and tetra-n-butylammonium bromide (920 mg, 2.9 mmol) in water. 5 mL was added and the mixture was stirred at 70 ° C. for 1 hour. After completion of the reaction, the mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 10: 1), and 1.03 g of 1,3-dimethoxy-7-phenyl-10,11-dihydrodibenzo [b, f] oxepin was obtained. Was quantitatively obtained. Demethylation was carried out according to the method of Example 1 to obtain the title compound.
[0139]
Example 8: Method for producing 3-iodo-7,9-dihydroxy-10,11-dihydrodibenzo [b, f] thiepin-10-one (compound of Example 8)
[0140]
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[0141]
Synthesis of carboxylic acid (55)
2-chloro-3-iodobenzoic acid (54) {14.1 g} (FW. 282.46, 50.0 mmol), disulfide (9) 8.46 g} (FW. 338.44, 25.0 mmol), Copper (powder) {1.58 g} (FW {63.55, {25.0 mmol), copper (I) iodide {4.76 g} (FW {190.45, {25.0 mmol), potassium carbonate {12.4 g} ( FW (138.21, 90.0 mmol) and N-methyl-2-pyrrolidone 100 ml were stirred at 120 ° C for 1.5 hours. The reaction solution was allowed to cool and was adjusted to pH 2 with 4N hydrochloric acid. The mixture was extracted with ethyl acetate and washed sequentially with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude carboxylic acid obtained was recrystallized from ethyl acetate to give carboxylic acid (55) {4.21 g} (FW {416.23, {10.1 mmol)). Obtained. The filtrate after recrystallization was further crystallized (ethyl acetate) to obtain carboxylic acid (55) {3.45 g} (FW {416.23, {8.3 mmol)}. The yield was $ 36.8%.
[0142]
Synthesis of alcohol (56)
To a solution of 7.66 g of carboxylic acid (55) {(FW. {416.23, {18.4 mmol)}} in tetrahydrofuran (20 ml) was added sodium borohydride (722 mg), and boron fluoride ether complex (2.74 ml) was added dropwise. Stir at room temperature for 45 minutes. Ice water was gradually added to the reaction solution. Extracted with ethyl acetate and washed with saturated saline. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. This crude product was purified by column chromatography (developing solvent; hexane: ethyl acetate = 4: 1) to quantitatively obtain 7.59 g of alcohol (56) (FW @ 402.25).
[0143]
Synthesis of bromide (57)
To a solution of 7.49 g of crude alcohol (56) {(FW {402.25)} in methylene chloride (20 ml) was added phosphorus tribromide (0.62 ml) at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. Ice water was gradually added to the reaction solution. After further stirring at room temperature for 30 minutes, the mixture was extracted with methylene chloride and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. A crude product was obtained. The crude product was purified by column chromatography (developing solvent; hexane: ethyl acetate = 4: 1) to obtain 5.14 g of bromide (57) (FW: 465.14, 11.05 mmol). The yield was $ 61.4% in two steps.
[0144]
Synthesis of cyanide (58)
Dissolve 5.00 g of bromide (57) (FW {465.14, {10.75 mmol)) in dimethylsulfoside {20 ml}. To this solution, $ 630 mg of sodium cyanide was added, and the mixture was stirred at 80 ° C for 1 hour. After adding water under ice-cooling, the mixture was extracted with ethyl acetate, and washed sequentially with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the resulting crude product was purified by column chromatography (developing solvent; hexane: ethyl acetate = 3: 1) to obtain 2.30 g of the cyanide (58) ( FW {411.26, {5.59 mmol)} and 2.06 g of crude cyanide (58) {(FW {411.26)}.
[0145]
Synthesis of carboxylic acid (59)
2.27 g of the cyano compound (58) (FW {411.26, 5.5 mmol) was added to 30 ml of ethanol, and the mixture was heated to 110 ° C. and completely dissolved. To this solution was added a 1N aqueous solution of sodium hydroxide {2.35 ml}. The mixture was further stirred at 110 ° C. overnight. Ice was added to the reaction solution and neutralized with 1N hydrochloric acid. The mixture was extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was completely removed under reduced pressure to obtain 2.36 g of a crude carboxylic acid (59) {(FW {430.26)}.
[0146]
Synthesis of Cyclized Form (60)
Methanesulfonic acid {60 ml} was added to 4.40 g of the crude carboxylic acid (59) (FW {430.26 mol) and dissolved. The solution was stirred overnight at room temperature. Water was added to the reaction solution under ice-cooling, followed by extraction with ethyl acetate, and washing with water and saturated saline in this order. After drying over anhydrous magnesium sulfate, the solvent was completely removed, and the resulting crude product was recrystallized from column chromatography (developing solvent; hexane: ethyl acetate = 4: 1), using hexane and methylene chloride, hexane and ethyl acetate. By repeating this, 1.82 g of the cyclized compound (60) (FW = 412.24, {4.4 mmol) was obtained. The yield was $ 41.1% in three steps.
[0147]
Synthesis of 3-iodo-7,9-dihydroxy-10,11-dihydrodibenzo [b, f] thiepin-10-one (compound of Example 8)
2.0 g of pyridine hydrochloride was added to 412.2 mg of the cyclized compound (60) (FW {412.24, 1.0 mmol), and the temperature was raised to 200 ° C. After the solution was stirred at 200 ° C. for 2 hours, ice water was gradually added. The mixture was extracted with ethyl acetate to which a small amount of tetrahydrofuran was added, and washed sequentially with 1N hydrochloric acid, water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was completely removed under reduced pressure to obtain a crude product # 289.1 mg. Purification was performed by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 4: 1). Further, the residue was recrystallized from chloroform to obtain the title compound {150.1 mg} (FW 384.19, 39.1 mmol). The yield was 39.1%.
[0148]
Example 9: Method for producing 3-bromo-7,9-dihydroxy-10,11-dihydrodibenzo [b, f] thiepin-10-one (compound of Example 9)
[0149]
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[0150]
Synthesis of carboxylic acid (61)
3-bromo-2-chlorobenzoic acid (3) {58.87 mg} (FW. 235.47, 0.25 mmol), disulfide (80%) 42.31 mg of (9) (FW 338.44, 0) .10 mmol), copper (powder) 7.94 mg (FW 63.55, 0.125 mmol), copper (I) iodide 23.81 mg (FW 190.45, 0.125 mmol), potassium carbonate A mixed solution of 41.46 mg (FW {138.21, 0.30 mmol) and 3 ml of N-methyl-2-pyrrolidone} was stirred at 150 ° C for 2.5 hours. The reaction solution was allowed to cool and was adjusted to pH 2 with 1N hydrochloric acid. The mixture was extracted with ethyl acetate and washed sequentially with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain crude carboxylic acid (61) (FW@369.23). The yield was $ 64.5% by HPLC.
After the synthesis of the carboxylic acid, the compound was synthesized according to Example 8 to obtain the title compound.
[0151]
Example 10: Method for producing 8-propionyl-10,11-dihydrodibenzo [b, f] oxepin-1,3-diol (compound of Example 10)
[0152]
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[0153]
Propionyl chloride (668 μL, 7.7 mmol) was added to a suspension of aluminum chloride {(1 g, {7.5} mmol) in anhydrous methylene chloride (3 mL), and the mixture was stirred at room temperature for 1 hour. This was added dropwise at 0 ° C. to a solution of 10,11-dihydrodibenzo [b, f] oxepin-1,3-diol diacetate (62) {(300 mg, {0.96 mmol) in methylene chloride} (5 mL) at 0 ° C. for 1 hour at room temperature. Stirred. Methanol (10 mL) was added dropwise to the reaction solution, a 20% aqueous sodium hydroxide solution (3 mL) was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was poured into hydrochloric acid ice water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 2: 1) and recrystallized from ethyl acetate and hexane to give the title compound as a yellow needle (190 mg, 70% yield). ) Got.
[0154]
Example 11: Method for producing 8- (1-hydroxyiminoethyl) -10,11-dihydrodibenzo [b, f] thiepin-1,3-diol (compound of Example 11)
[0155]
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[0156]
An aqueous solution in which 180 mg of 8-acetyl-10,11-dihydrodibenzo [b, f] thiepin-1,3-diol (63) is dissolved in ethanol, and 49 mg of hydroxyamine hydrochloride and 100 mg of sodium acetate are dissolved in 1 mL of water. Was added. The mixture was stirred at 120 ° C. for 3 hours, concentrated under reduced pressure, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 1) and recrystallized from ethyl acetate-hexane to give the amorphous amorphous title compound (120 mg, 63% yield). Got. 215.4-217.5 ° C
[0157]
Example 12: Method for producing 8-hexyl-10,11-dihydrodibenzo [b, f] oxepin-1,3-diol (compound of Example 12)
[0158]
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[0159]
200 mg of 2-bromo-7,9-dimethoxy-10,11-dihydrodibenzo [b, f] oxepin-10-one (64), 32 mg of palladium complex, 34 mg of triphenylphosphine and 11.8 mg of copper iodide were added to a pressure-resistant reaction vessel. And 3 ml of acetonitrile (dehydrated) was added and stirred. N, O-bis (trimethylsilyl) acetamide (hereinafter BSA) was added to the solution, and the mixture was stirred at room temperature for 5 minutes to silylate. After silylation, 110 μl of 1-hexyne and 250 μl of N, N-diisopropylethylamine were added, the tube was sealed, and the mixture was heated with stirring at 120 ° C. for 17 hours. After completion of the reaction, the reaction solution was partitioned between ethyl acetate and dilute hydrochloric acid. The organic layer was washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 3: 1). The obtained oil was dissolved in 5 ml of ethyl acetate, 20 mg of palladium-carbon was added, and hydrogenation was performed at room temperature overnight. After completion of the reaction, the reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 7: 1). Recrystallization from chloroform-hexane gave 49.3 mg of colorless plate crystals of the title compound (yield 24.3%).
[0160]
Various compounds of the present invention were synthesized in the same manner as in the above Examples. The structural formulas of all 178 compounds synthesized, including the compounds synthesized in Examples 1 to 12, and the compounds of Examples used in the following Test Examples are collectively shown below. These compounds are prepared in the same manner as in the production methods of Reference Examples and Examples, as described in the detailed description, such as (1) Ullmann reaction, (2) -1 Friedel-Crafts reaction or (2) -2. Photoreaction, (3) carbon increase reaction, (4) conversion reaction of halogen to another functional group, (5) introduction reaction of alkyl group and alkylcarbonyl group, (6) 10-position conversion reaction and (7) deprotection The compound can be produced by combining the reactions. Table 1 describes the production steps of each compound.
Tables 2 to 18 list physical property data of these compounds.
[0161]
[Table 1]

[0162]
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[0163]
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[0164]
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[0165]
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[0166]
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[0167]
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[0168]
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[0169]
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[0170]
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[0171]
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[0172]
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[0173]
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[0174]
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[0175]
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[0176]
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[0177]
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[0178]
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[0179]
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[0180]
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[0181]
[Table 2]

[0182]

[0183]
[Table 3]

[0184]

[0185]
[Table 4]

[0186]

[0187]
[Table 5]

[0188]

[0189]
[Table 6]

[0190]

[0191]
[Table 7]

[0192]

[0193]
[Table 8]

[0194]

[0195]
[Table 9]

[0196]

[0197]
[Table 10]

[0198]

[0199]
[Table 11]

[0200]

[0201]
[Table 12]

[0202]

[0203]
[Table 13]

[0204]

[0205]
[Table 14]

[0206]

[0207]
[Table 15]

[0208]

[0209]
[Table 16]

[0210]

[0211]
[Table 17]

[0212]

[0213]
[Table 18]

[0214]
Example 164Method for producing 11-ethyl-7,9-dihydroxy-10,11-dihydrodibenzo [b, f] thiepin-10-one (compound of Example 4)
[0215]
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[0216]
Synthesis of carboxylic acid (67)
Thiosalicylic acid (65) 39.3 g (FW 154.19, 255 mmol), 4-bromoveratrol (66) 55.4 g (FW 217.06, 255 mmol), copper (powder) 1.90 g (FW 63.55, 30.0 mmol), copper (I) iodide 5.7 g (FW 190.45, 30.0 mmol), potassium carbonate 45.0 g (FW 138.21) , {326 mmol) and 120 mL of N-methyl-2-pyrrolidone were stirred at 150 ° C. for 4 hours. After the reaction, the reaction solution was allowed to cool to 70 to 80 ° C., added with ice water, and adjusted to pH 2 with 6N hydrochloric acid. The precipitated crude crystals were collected by filtration, washed with water, diisopropyl ether and hexane, and dried to obtain 74.4 g of a crude product. Recrystallization from 1,4-dioxane gave 55.0 g of carboxylic acid (67). Ethyl acetate was added to the crude carboxylic acid obtained by concentrating the mother liquor under reduced pressure, followed by filtration and washing with ethyl acetate to obtain 6.1 g of carboxylic acid (67) (total yield: 83%).
[0219]
Synthesis of alcohol (68)
To a solution of 75.2 g (FW 290.34, 259 mmol) of carboxylic acid (67) in 200 mL of tetrahydrofuran at 0 ° C. was added 10.4 g of sodium borohydride (FW 37.83, 274 mmol). Boron fluoride ether complex 37.0 mL (FW 141.93, d = 1.154, 301 mmol) was added dropwise at the same temperature, and the mixture was stirred at room temperature for 1 hour. Ice water was gradually added to the reaction solution, extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to obtain 73.4 g of a crude alcohol (68).
[0218]
Synthesis of bromide (69)
Phosphorus tribromide (8.5 mL, FW = 270.70, d = 2.850, {89.) was added to a solution of 73.4 g (FW {276.36) of crude alcohol (68) in 100 mL of methylene chloride at 0 ° C. 0 mmol) was added. After stirring at room temperature for 30 minutes, the reaction solution was added to crushed ice. After further stirring at room temperature for 30 minutes, water was added, extracted with methylene chloride, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. 83.4 g of crude product were obtained. The crude bromide was recrystallized from methylene chloride-hexane to obtain 75.2 g of a bromide (69). The yield was 86% in two steps.
[0219]
Synthesis of nitrile form (70)
After dissolving 1.76 g (FW # 49.01, # 36.0 mmol) of sodium cyanide in 15 mL of water, 20 mL of ethanol was added. To this solution, 10.2 g of bromide (69) (FW 339.25, 30.0 mmol) was slowly added at room temperature. This mixture was heated to 80 ° C. and stirred at the same temperature for 30 minutes. The reaction was allowed to cool to room temperature with vigorous stirring. The ethanol was removed under reduced pressure and water was added. The precipitated crude crystals were collected by filtration and washed with water. After drying, 8.13 g of a crude nitrile body was obtained. The crude crystals were recrystallized from ethyl acetate-hexane to obtain 7.30 g (yield: 85.3%) of the nitrile (70).
[0220]
Synthesis of ethyl form (71)
In a methylene chloride (50 mL) solution of the nitrile compound (70) (22.8 g, FW # 285.37, 80.0 mmol), ethyl iodide ト リ 6.72 mL (FW 155.97, d = 1.94, 84. 0 mmol) and stirred. Further, 27.2 g of tetrabutylammonium hydrogensulfate (FW 339.54, 80.0 mmol) was added and completely dissolved. After a 20% aqueous sodium hydroxide solution (80.0 g) was added dropwise to this solution, the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized by adding 4N hydrochloric acid under ice-cooling, extracted with methylene chloride, and the organic layer was washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain an oily product. Hexane: ethyl acetate = 3: 1 was added to the residue, and the precipitated tetrabutylammonium iodide was removed by filtration. The solvent was removed from the filtrate under reduced pressure to obtain 27.0 g of a crude ethyl compound (71).
[0221]
Synthesis of phenylacetic acid (72)
A 30% aqueous solution of sodium hydroxide (42.7 g) was added to a mixture of 27.0 g (FW 313.41; 77.2 mmol) of the crude ethyl compound (71) and 66 mL of ethylene glycol. The solution was stirred at 150 ° C. overnight. Ice was added to the reaction solution and neutralized with 4N hydrochloric acid. The mixture was extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was completely removed under reduced pressure to obtain 29.0 g of crude phenylacetic acid. Recrystallization with ethyl acetate-hexane gave 23.0 g of phenylacetic acid (72). The yield was 87% in two steps.
[0222]
Synthesis of cyclized form (51)
50 mL of methanesulfonic acid was added to and dissolved in 10.0 g of dried phenylacetic acid (72) (FW @ 332.41, @ 30.1 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution under ice cooling, and the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain 9.52 g of a crude product. A small amount of ethyl acetate was added to the crude product, which was collected by filtration and washed with a small amount of ethyl acetate to obtain 8.84 g of the cyclized compound (52) (yield 93.4%).
150 g of pyridine hydrochloride was added to 25.0 g (FW314.40, 80.0 mmol) of the cyclized compound (51), and the mixture was stirred at 200 ° C. for 2 hours. Dilute hydrochloric acid and ethyl acetate were added to the reaction mixture for extraction, and the organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The concentrated residue was dissolved in 800 mL of ethyl acetate, and a polar substance was adsorbed with 50 g of silica gel and 25 g of Florisil, followed by filtration. After concentrating the ethyl acetate, recrystallization from ethyl acetate-hexane gave 19.9 g (yield 87%) of the title compound.
[0223]
Example 165Method for producing 11-ethyl-7,9-dihydroxy-10,11-dihydrodibenzo [b, f] thiepin-10-one (compound of Example 4)
[0224]
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[0225]
Synthesis of ethyl form (74)
An ice bath is applied to a 50 mL toluene solution of nitrile compound (73) 30.0 g (FW 196.05, 153 mmol) and ethyl iodide 13.6 mL (FW 155.97, d = 1.94, 169 mmol). A suspension of tetrabutylammonium hydrogensulfate (51.8 g, FW@339.54, @ 153 mmol) and a 20% aqueous sodium hydroxide solution (300 g) was immediately added, and the mixture was stirred at room temperature for 2 hours. The resulting crystals of tetrabutylammonium iodide were separated by filtration, and the crystals were washed with 200 mL of toluene. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 34.4 g of an ethyl compound (74).
[0226]
Synthesis of carboxylic acid (75)
6N sodium hydroxide aqueous solution (75.0 mL) and ethanol {75.0 mL were added to 34.4 g (FW {224.10) of the ethyl form (74), and the mixture was stirred at 100 ° C for 2 days. After removing the ethanol under reduced pressure, toluene was added and partitioned. The aqueous layer was adjusted to pH 3 by adding concentrated hydrochloric acid. The mixture was extracted with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to obtain about 38 g of a crude product. Recrystallization from hexane gave 33.5 g of carboxylic acid (75). The yield was 90% in two steps.
[0227]
Synthesis of phenylacetic acid (72)
Carboxylic acid (75) 26.7 g (FW 243.10, 110 mmol), 3,4-dimethoxythiophenol (76) 18.7 g (FW 170.23, 110 mmol), copper (powder) 3 .50 g (FW 63.55, 55.0 mmol), copper (I) iodide 10.5 g (FW 190.45, 55.0 mmol), potassium carbonate 18.2 g (FW 138) .21, @ 132 mmol) and 140 mL of N-methyl-2-pyrrolidone were stirred at 140 ° C. for 3.5 hours. Ice was added to the reaction solution, and the pH was adjusted to 7 to 6 with concentrated hydrochloric acid under ice cooling. Toluene and water were added to dissolve the product, and insolubles were removed by filtration. A 20% aqueous sodium hydroxide solution was added to the filtrate and partitioned. The organic layer was separated and extracted with a 2% aqueous sodium hydroxide solution. The aqueous layers were combined and adjusted to pH 2-3 with concentrated hydrochloric acid under ice-cooling. The mixture was extracted with ethyl acetate, and the organic layer was washed with water. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain 35.1 g of a crude product. After washing with a small amount of diisopropyl ether, it was dried to obtain 28.7 g (yield: 78.6%) of phenylacetic acid (72).
[0228]
Synthesis of cyclized form (51)
140 mL of methanesulfonic acid was added to 28.6 g (FW # 332.41, # 86.0 mmol) of dried phenylacetic acid (72), and the mixture was stirred at room temperature overnight. The reaction solution was dropped into ice water, and the precipitate was collected by filtration and washed with water. After drying, 26.9 g (yield 99.4%) of the cyclized compound (51) was obtained.
To 18.9 g of the cyclized compound (51) (FW314.40, @ 60.0 mmol) was added 56.6 g of pyridine hydrochloride, and the mixture was stirred at 185 ° C for 6 hours. After the reaction mixture was completely cooled to room temperature, ice water and ethyl acetate were added for extraction. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 16.2 g of a crude product. Recrystallization from 60% aqueous isopropyl alcohol gave 15.9 g (yield 92.4%) of the title compound.
[0229]
Example 166: Method for producing (+)-11-ethyl-7,9-dihydroxy-10,11-dihydrodibenzo [b, f] thiepin-10-one ((+) optical isomer of the compound of Example 4)
The compound of Example 4 was optically resolved by a column under the following conditions, and the previous peak was obtained. Specific rotation [α] of this compound_D(20 ° C.) was +16.7.
Column: CHIRALPAK @ AD
Mobile phase: n-hexane / ethanol / acetic acid = 40/60 / 0.1 (vol / vol)
[0230]
Example 167: Method for producing (−)-11-ethyl-7,9-dihydroxy-10,11-dihydrodibenzo [b, f] thiepin-10-one ((−) optical isomer of the compound of Example 4)
The compound of Example 4 was optically resolved by a column under the following conditions, and the subsequent peak was obtained. Specific rotation [α] of this compound_D(20 ° C) was -16.7.
Column: CHIRALPAK @ AD
Mobile phase: n-hexane / ethanol / acetic acid = 40/60 / 0.1 (vol / vol)
[0231]
Example 178: Method for producing α-ethyl-2-bromophenylacetic acid (75)
The title compound obtained by the method described in the second step of Example 165 was confirmed to have the following physical properties.
Properties: colorless plate crystals.
Melting point: 37-39 ° C (cold hexane)
¹H-NMR (400 MHz, CDCl₃) Δ: 0.94 (3H, dd, J = 7.4, 7.4 Hz), 1.83 (1H, ddq, J = 14.9, 7.4, 7.4 Hz), 2.10 (1H, ddq, J = ９14.9, 7.4, 7.4 Hz), 4.14 (1H, dd, J = 7.4, 7.4 Hz), 7.12 (1H, dd, J) = {8.0, {7.5, {1.6} Hz), {7.29} (1H, dd, J) = 7.8, 7.5, 1.2 Hz), 6.94 (1H, dd, J = 7) .8, {1.2} Hz), {7.38} (1H, {dd, {J} = {8.0, {1.6} Hz)
EIMS {m / z: 244, 242} (M⁺), $ 199, $ 197, $ 171, $ 169, $ 163
IR (KBr) cm^-1: 1705
UV λ_max{(EtOH)} nm} (ε): 274 {(40), {264} (300)
[0232]
Example 179: Method for producing α-ethyl-2-[(3,4-dimethoxyphenyl) thio] phenylacetic acid (72)
It was confirmed that the title compound obtained by the method described in the sixth step of Example 164 and the third step of Example 165 had the following physical properties.
Properties: light brown amorphous.
Melting point: 115.2-117.0 ° C (Dec.)
¹H-NMR (400 MHz, CDCl₃) Δ: 0.92 (3H, dd, J = 7.4, 7.4 Hz), 1.79 (1H, ddq, J = 14.8, 7.4, 7.4 Hz), 2.12 (1H, ddq, J = 14.8, 7.4, 7.4 Hz), 3.79 (3H, s), 3.87 (3H, s), 4.33 (1H, dd, J = 7). .4, {7.4} Hz), {6.80} (1H, d, J = 8.3 Hz), 6.88 (1H, d, J = 1.9 Hz), 6.94 (1H, dd, J) = {8.3, {1.9} Hz), {7.14-7.26} (3H, {m), {7.37} (1H, {d, {J} = {1.8} Hz) EIMS {m / z: 332} (M⁺, @Base)
IR (KBr) cm^-1: 1705, $ 1585, $ 1504, $ 1442
UV λ_max{(EtOH)} nm} (ε): 250 (15200), {283} (8000)
[0233]
Example 180
Example Compound 4 To a mixture of {1.00 g} (FW {286.37, {3.50 mmol}) {1N-NaOH} (4 mL), acetobromoglucuronic acid methyl ester 1.40 g {FW. 397.2, (3.50 mmol)} in 6 mL of acetone was added little by little at 0 ° C, and the mixture was stirred at room temperature for 6 hours while adjusting the pH to about 6 with 1N-NaOH. After concentration, 20% NaOH (11.2 mL) was added, and the mixture was stirred at room temperature for 30 minutes. After cooling, 5 mL of concentrated hydrochloric acid was carefully added, the pH was adjusted to 2 to 3 with 1 N hydrochloric acid, and the mixture was desalted with a column packed with HP-20. After the column was washed well with water, the desired product was eluted with 100% MeOH. A material obtained by adsorbing 2.57 g of the obtained crude product on 8 g of silica gel was subjected to silica gel chromatography (eluent: 33% ethyl acetate: hexane → 20% ethanol: ethyl acetate) to remove the raw material. After concentration, the resulting crude product was further purified by HPLC (Detection, {280} nm; mobile phase, 50% MeCN-H2O containing 0.2% of AcOH). The concentrated oil was dissolved in dioxane and freeze-dried to obtain 463 mg of the title compound (36% yield).
[0234]
[Test example]
Test Examples are shown below to show that the compound of the present invention has excellent pharmacological activity.
Test example 1: Dilation effect on tracheal smooth muscle contraction
The effect of the compound of the present invention on tracheal smooth muscle contraction was examined using porcine tracheal smooth muscle. The method was referred to the smooth muscle manual (published by Buneido Shuppan Co., Ltd.) pages 125-137. Tracheal cartilage mucosa and submucosal tissue were removed from the porcine trachea, and a tracheal smooth muscle specimen having a major axis of about 10 mm and a minor axis of about 1.5 mm was prepared. The specimen was suspended in a Magnus tube containing a nutrient solution at 37 ° C., which was aerated with a mixed gas of 95% oxygen and 5% carbon dioxide, and a 0.8 g load was applied to the specimen to stabilize the tension of the specimen. After that, the nutrient solution is concentrated K⁺Liquid (72.7 mM)⁺A contraction was induced. High concentration K⁺The solution in the Magnus tube is exchanged for a nutrient solution and washed until the contraction force of the solution becomes constant.⁺The operation of inducing contraction with the liquid was repeated. K⁺When the contraction tension became constant, a compound shown in Table 19 (the structural formula of the comparative example is described on the right side of the compound of Example 180) was used as a test substance at a high concentration K.⁺It was added to the solution and the change in tension was measured. The test substance was dissolved in dimethylsulfoxide to a required concentration and added to a final concentration of 10 μM. At the time of addition, the final concentration of dimethyl sulfoxide was adjusted to 0.3% or less. The change in the tension is guided to an amplifier for strain pressure (AP-621G, manufactured by Nippon Koden Kogyo) via an FD pickup transducer (TB-611T, manufactured by Nippon Koden Kogyo), and recorded on a recorder (R-64V, manufactured by Rika Denki). Recorded. High concentration K⁺The tension before replacing the liquid is 0%,⁺Assuming that the tension before the addition of the test substance was 100% of the tension generated after the exchange with the liquid, the tracheal smooth muscle contraction force 2 hours after the addition of the test substance was expressed as a relative percentage. At this time, the high concentration K⁺The contraction by the liquid was almost constant for at least 2 hours after the tension was stabilized. The results are shown in Table 19.
[0235]
[Table 19]

[0236]
Test example 2: Inhibitory effect on guinea pig immediate asthmatic response, delayed asthmatic response and inflammatory cell infiltration into airway lumen
Inhalation of antigen by asthmatics elicits an immediate airway constriction response (IAR), which peaks 15-30 minutes after inhalation, and this response recovers within 2 hours, but 60% of asthmatics Reported that a late airway constriction reaction (LAR) appeared 4-12 hours after inhalation of the antigen (Pepys, {J. and J. Hutchcroft, B. J .: Bronchial Provation Tests in Etiological Diagnosis>. of Asthma. Am. Rev. Respir. Dis., 112, 829-859 (1975)). LAR has a long duration and resembles spontaneous asthma, especially refractory asthma attacks, and elucidation of its pathology appears to be extremely important in the treatment of bronchial asthma. On the other hand, it is known that when a guinea pig actively sensitized with an antigen is inhaled again, the antigen exhibits a biphasic airway contraction reaction. Therefore, an asthma model using guinea pigs as an animal model system of IAR and LAR found in asthma patients described above is widely used for evaluation of asthma drugs and the like. On the other hand, in the guinea pig IAR and LAR models, when an antigen is exposed to a sensitized guinea pig, 2 -phase airway constriction and infiltration of inflammatory cells into the airway lumen occur, thereby causing various inflammatory tissues in airway tissues. Is known to occur, which is thought to lead to the development of late-onset airway contractile response and airway hyperresponsiveness. Therefore, the number of inflammatory cells in bronchoalveolar lavage fluid is widely used as an index for infiltration of inflammatory cells into the airway lumen. The effects of the compounds of the present invention were examined for the above effects in the guinea pig IAR and LAR models.
[0237]
[experimental method]
(1) sensitization
Using a supersonic nebulizer (NE-U12, Omron, Japan), 1% ovalbumin (OVA, Sigma-Aldrich Co., USA) physiological saline solution was inhaled in guinea pigs for 10 minutes a day for 8 consecutive days. I let it.
(2) Initiation
One week after the final sensitization, a 2% OVA physiological saline solution was inhaled for 5 minutes using an ultrasonic nebulizer. 24 hours and 1 hour before the induction, metyrapone {(10 mg / kg, Sigma-Aldrich Co., USA)} was intravenously injected, and 30 minutes before the induction, pyrylamine (10 mg / kg, Sigma-Aldrich Co., Ltd.). , {USA}) was administered intraperitoneally.
(3) Preparation and administration method of test substance
Test substances (compounds of Examples 1 and 4) were each prepared by suspension in a 0.5% sodium carboxymethylcellulose (CMC-Na) aqueous solution to a concentration of 2 mg / ml. The suspension of the test substance was orally administered to guinea pigs at a concentration of 10 mg / kg 1 hour before the induction. For the control group, a medium (0.5% {CMC-Na} aqueous solution) was used.
(4) Measurement of airway resistance
Using an airway resistance measurement device (Pulmos-I, MIPS, Japan), 1, {10} and 30 minutes after the induction, and further 1, 2, 3, 4, 5, 5, 6, 7, 8, and Twenty-four hours later, the airway resistance {(specific airway resistance: {sRaw}}) was measured once for each 1 minute.
(5) Measurement of the number of inflammatory cells in bronchoalveolar lavage fluid
23-24 hours after antigen induction, guinea pigs were excised from the abdominal aorta under Nembutal {(50 mg / kg)} intraperitoneal anesthesia, bleeding, and thoracotomy. The operation of inserting and fixing a tube into the trachea, injecting 5 ml of physiological saline (37 ° C.) through the tube and aspirating it twice is repeated twice (10 ml in total), and collecting the collected bronchoalveolar lavage fluid (Bronchoalveolar lavage fluid). , {BALF)}. BALF was centrifuged at 1100 rpm at 4 ° C. for 10 minutes to obtain a precipitate {(pellet)}. The pellet was suspended in 1 ml of physiological saline, a chill solution was added, and the number of leukocytes per 1 μl was counted using a hemocytometer. After centrifugation again under the above conditions, rabbit serum was added to the pellet to prepare a smear. After drying, Maygrinwald-Giemsa staining was performed. Leukocytes were counted under a microscope, and the ratio of neutrophils, eosinophils, macrophages and lymphocytes to the total number of cells was determined, and the number of cells per μl was calculated based on this ratio.
(6) Statistical analysis processing method
The obtained test results were represented by an average value and a standard error, and Student's {t-test} was performed. The significance level was 5% 、 ５ or less. The number of animals used in each test group was six.
[0238]
[result]
(1) Antigen-induced immediate and late asthmatic reactions
As shown in FIG. 1, in the sensitized guinea pig, the airway resistance increased rapidly by OVA inhalation, and increased to an average of 475% before the challenge 1 minute later. After that, it rapidly decreased, and after 3 hours, dropped to 52%. In addition, airway resistance rose again, reaching 156% after 6 hours. The AUC (area {under} the response {curve) from 4 hours to 8 hours was 466% .hr. From this, a biphasic reaction was observed, which was an immediate asthmatic response (IAR) occurring within 30 minutes after the induction by OVA inhalation and a delayed asthmatic response (LAR) 時間 occurring several hours after the induction.
Here, when the compounds of Example 1 and Example 4 were orally administered at a dose of 10 mg / kg 1 hour before OVA induction, the IAR (% change in s Raw) was 70 and 73%, respectively, as compared with the control group. LAR {(AUC)} was reduced by 77, 86% (FIG. 2).
(2) Number of cells in bronchoalveolar lavage fluid
The results are shown in FIG. In guinea pigs actively sensitized by OVA inhalation, the total number of cells in bronchoalveolar lavage fluid 24 hours after antigen challenge was on average 6667 / μl, and the number of cells of macrophages, neutrophils, eosinophils and lymphocytes was: The average was 2499, {2487, {1622} and 59} / μl, respectively.
When the compound of Example 1 was orally administered at a dose of 10 mg / kg 1 hour before OVA induction, the total number of cells was 3775 cells / μl on average, and the number of cells of macrophages, neutrophils, eosinophils and lymphocytes was The average was 1872, {1072, {810} and 21} cells / μl, respectively, indicating a significant decrease in the total cell number and a decrease in the number of eosinophils, neutrophils and lymphocytes as compared to the control group. On the other hand, when the compound of Example 4 was orally administered at a dose of 10 mg / kg 1 hour before OVA induction, the total number of cells was 4304 cells / μl on average, and cells of macrophages, neutrophils, eosinophils and lymphocytes were averaged. The numbers averaged 2478, {1062, {700} and 64} / μl, respectively, indicating a significant decrease in the total cell count and eosinophil count and a decrease in neutrophil count compared to the control group.
From the above results, all of the compounds of Examples 1 and 4 showed an inhibitory effect on the guinea pig immediate and late asthmatic reactions and an increase in the number of inflammatory cells in bronchoalveolar lavage fluid, and showed clinical asthma. It was suggested that it could be a promising therapeutic drug.
[0239]
Test example 3: Effects on antigen-induced airway hyperreactivity in sensitized guinea pigs
Bronchial asthma is a disease characterized by bronchoconstriction, airway hyperresponsiveness and infiltration of inflammatory cells into the airways. Bronchial hyperreactivity is a condition in which the airway is sensitive to various minor stimuli and produces a contractile response, and is considered to be a common feature of patients with allergic bronchial asthma. This system using sensitized guinea pigs is a useful system as a model for airway hyperresponsiveness.
(1) sensitization
Using an ultrasonic nebulizer (NE-U12, Omron, Japan), guinea pigs were inhaled with 1% OVA (Sigma-Aldrich Co., USA) physiological saline solution for 10 minutes a day for 8 consecutive days. .
(2) Initiation
One week after the final sensitization, a 2% OVA physiological saline solution was inhaled for 5 minutes using an ultrasonic nebulizer. 24 hours and 1 hour before challenge, metyrapone (10 mg / kg, Sigma-Aldrich Co., USA) was intravenously injected, and 30 minutes before challenge, pyriramine (10 mg / kg, Sigma-Aldrich Co). , {USA}) was administered intraperitoneally.
(3) Preparation and administration method of test substance
A test substance (compound of Example 4) was prepared by suspending at each concentration with a 0.5% CMC-Na aqueous solution. The test substance suspension was orally administered to guinea pigs at a dose of 10 and 30 mg / kg at 1 hour prior to challenge, and administered to guinea pigs at 30 mg / kg at 16 and 2 hours prior to challenge. One group was set up. Dexamethasone was suspended in a 0.5% CMC-Na aqueous solution and administered at a concentration of 10 mg / kg twice, 16 times and 2 hours before antigen induction. The vehicle (0.5% CMC-Na aqueous solution) was used for the control group. All dose volumes were 5 ml / kg.
(4) Measurement of airway resistance
Using an airway resistance measurement apparatus (Pulmos-I, MIPS, Japan), the airway resistance of awake guinea pigs was measured by the double flow plethysmograph method (specific airway resistance (sraw)).
(5) Measurement of airway reactivity
After 22-26 hours of antigen induction, guinea pigs were placed in animal {chamber}, and 0.0625, 0.125, 0.25, 0.5, 1% and 2 mg / ml solutions of physiological saline and acetylcholine (ACh) were sequentially added to each. The inhalation was continued for one minute, and continued until sRaw became twice or more of baseline {sRaw} (sRaw after inhalation of physiological saline). The concentration-resistance curve of ACh concentration and sRaw or the concentration of ACh (に PC₁₀₀ACh) was determined. (6) Statistical analysis processing method
The obtained test results were represented by an average value and a standard error, and Student's {t-test} was performed. The significance level was 5% or less. The number of animals used in each test group was 6.
[0240]
[result]
FIG. 4 shows the results. In guinea pigs actively sensitized by OVA inhalation, airway reactivity to ACh was measured 22 to 26 hours after the induction of the antigen-antibody reaction. Vehicle control group PC₁₀₀ACh was 0.15 mg / ml. In a similar system (Fuchikami, J-I, etal: ｃｏPharmalogical study on antigen induced immediate and late asthmatic responses in active.seng. Guinea pig PC challenged with saline in active sensitized guinea pigs₁₀₀Since ACh averaged 1.20 mg / ml, the control group of this test clearly showed antigen-induced airway hyperresponsiveness. Dexamethasone used as a positive control was 10 mg / kg, when administered orally 2 hours before OVA induction and at 2 hours prior to OPC.₁₀₀ACh was 1.14 mg / ml, which significantly suppressed airway hyperresponsiveness as compared to the control group. On the other hand, when the compound of Example 4 was orally administered at doses of 10 mg and 30 mg / kg 1 hour before OVA induction,₁₀₀ACh was 0.59 and 1.63 mg / ml, respectively, indicating a dose-dependent suppression. In addition, when the compound of Example 4 was orally administered at a dose of 30 mg / kg at the time of OVA induction 16 days and 2 hours before, the PC₁₀₀ACh was 1.24 mg / ml, which significantly suppressed airway hyperresponsiveness as compared to the control group.
From the above results, it was clarified that the compound of Example 4 had a strong inhibitory effect on airway hyperreactivity in sensitized guinea pigs, suggesting that it may be an effective anti-asthmatic drug in clinical practice.
[0241]
Test example 4: 2-week repeated oral toxicity study in rats
To examine the toxicity due to repeated administration of the compound, the compound 0, $ 125, $ 500 mg / kg / day (0.5 w / v% CMC-Na aqueous solution) was repeatedly administered to three male Sprague-Dawley SPF rats for one week for each group. It was administered orally. The results are shown in Table 20 below.
[0242]
[Table 20]

[0243]
【The invention's effect】
The compound of the present invention has a wide range of pharmacological actions such as an excellent action of relaxing tracheal smooth muscle, an action of suppressing airway hyperreactivity, and an action of suppressing infiltration of inflammatory cells into the airway, and is highly safe.
[Brief description of the drawings]
FIG. 1 is a graph showing the inhibitory effect of the compounds of the present invention on the immediate and delayed asthmatic responses in active sensitized guinea pigs.
FIG. 2 is a graph showing the inhibition rate of the compound of the present invention in the immediate and delayed asthmatic reactions in active sensitized guinea pigs.
FIG. 3 is a graph showing the inhibitory effect of the compound of the present invention on the number of inflammatory cells in bronchoalveolar lavage fluid 24 hours after antigen induction in actively sensitized guinea pigs.
FIG. 4 is a graph showing the inhibitory effect of the compounds of the present invention on airway reactivity to acetylcholine 22 to 26 hours after antigen induction in active sensitized guinea pigs.

Claims (25)

formula

[Where X and Y are
When the bond XY is a single bond, X and Y are each independently (identical or different), CW ₁ W ₂ (W ₁ and W ₂ are each independently (identical or different), a hydrogen atom, A halogen, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkoxy group, a cycloalkyl group, or a cycloalkenyl group), CＯO, CＮＯNOW ₃ (W ₃ is a hydrogen atom or a lower alkyl group) Is any one selected from
When the XY bond is a double bond, X and Y are each independently (identical or different) CW ₄ (W ₄ is a hydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkoxy group) , An acyloxy group)
Z is an arbitrary one selected from O, S, S = O and SO ₂ ;
U is C or N;
R ₁ to R ₄ are each independently (identical or different), a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, A substituted lower alkynyl group, a halogen group, a lower alkylcarbonyl group, a substituted lower alkylcarbonyl group, a trihalomethyl group, V ₁ W ₅ (V ₁ is any one selected from O, S, SＳO, and SO ₂ ; W ₅ is any selected from a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkylcarbonyl group, a substituted lower alkylcarbonyl group, an acyloxy group and a trihalomethyl group.), A nitro group, an amino group, a substituted Amino group, cyano group, acyl group, acylamino group, substituted acyl group, substituted acylamino group, aromatic ring, Aromatic, heterocyclic, and any of those selected from substituted heterocycle (when U is N, there is a case where R ₄ is absent),
R ₅ to R ₈ are each independently (same or different) hydrogen atom, lower alkyl group, substituted lower alkyl group, lower alkenyl group, substituted lower alkenyl group, lower alkynyl group, substituted lower alkynyl group, halogen group, lower group. Alkylcarbonyl group, substituted lower alkylcarbonyl group, trihalomethyl group, V ₂ W ₇ (V ₂ is any selected from O, S, S ＝ O and SO ₂ , W ₇ is a hydrogen atom, a lower alkyl group , A substituted lower alkyl group, a lower alkylcarbonyl group, a substituted lower alkylcarbonyl group, and a trihalomethyl group.), A nitro group, an amino group, a substituted amino group, an acylamino group, an aromatic ring, and a substituted aromatic ring , A heterocyclic ring, or a substituted heterocyclic ring.
However, when X is CHW ₀ , CW ₀ W ₀ or CW ₀ (where W ₀ is any selected from a lower alkyl group and a substituted lower alkyl group), at least one of R ₅ to R ₈ One is a hydroxyl group (however, when XY is CH (C ₂ H ₅ ) CO, R ₆ is not a hydroxyl group alone), and X is CHW ₀ , CW ₀ W ₀ or CW ₀ (where W is ₀ is any one selected from a lower alkyl group and a substituted lower alkyl group), at least one of R ₅ to R ₈ is a hydroxyl group, and other R ₅ to R ₈ At least one group is an OR group, wherein R is any selected from a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkyl carbonyl group, and a substituted lower alkyl silyl.
Furthermore, X-Y is _{CH 2 CH 2, CHBrCH 2,} CH 2 CO, COCH 2, CHBrCO, CH = CH, CH = COCOCH 3, CH = in the case of COCH _3, at least one aromatic ring of from _{R 1 R 4} A substituted aromatic ring, a heterocyclic ring or a substituted heterocyclic ring (however, when both R ₆ and R ₇ are hydroxyl groups, none of R ₁ to R ₄ is a phenyl group);
At least one of R ₁ to R ₄ is either SW ₈ (W ₈ is a lower alkyl group or a substituted lower alkyl group) or S (O) W ₉ (W ₉ is a lower alkyl group or a substituted lower alkyl group) Or (however, when Z is O, R ₇ is not a hydrogen atom),
R ₂ is a lower alkyl group or a substituted lower alkyl group, and R ₈ is a hydroxyl group (provided that when Z is O, the lower alkyl group has 3 or more carbon atoms);
At least one of R ₁ to R ₄ is a lower alkylcarbonyl (provided that the lower alkyl group has 3 or more carbon atoms), cycloalkylcarbonyl or cycloalkenylcarbonyl, and R ₈ is a hydroxyl group;
At least one of R ₁ to R ₄ is —C (＝ NOR) CH ₃ (R is a hydrogen atom or a lower alkyl group)
Is one of ]
Or a conjugate thereof or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein R ₆ is a hydroxyl group. The compound according to claim 1, wherein R ₆ and R ₇ are hydroxyl groups. The compound according to claim 1, wherein R ₆ and R ₈ are hydroxyl groups. The compound according to claim 1, wherein R ₅ and R ₆ are hydroxyl groups. XY is a single bond, and X is CW ₁ W ₂ (at least one of W ₁ and W ₂ is any selected from a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group, and a cycloalkenyl group). Or XY is a double bond and X is CW (W is any one selected from a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group and a cycloalkenyl group). The compound according to any one of the above. The compound according to any one of claims 1 to 6, wherein Y is CO. The lower alkyl group is any one of a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group, an i-butyl group, and a t-butyl group. 7. The compound according to 7. The compound according to any one of claims 1 to 5, wherein R ₂ or R ₃ is any one of a heterocycle, a substituted heterocycle, an aromatic ring, and a substituted aromatic ring. The compound according to any one of claims 1 to 5, wherein the heterocycle is an aromatic heterocycle. 6. The method according to claim _{1, wherein} R ₂ or R ₃ is SW ₈ (W ₈ is a lower alkyl group or a substituted lower alkyl group) or S (O) W ₉ (W ₉ is a lower alkyl group or a substituted alkyl group). Or the compound of claim 1. The compound according to claim 11, wherein the lower alkyl group is any one of a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an s-butyl group, an i-butyl group, and a t-butyl group. . The compound according to any one of claims 1 to 12, wherein Z is S. The compound according to claim 1, which is 7,8-dihydroxy-11-ethyl-10,11-sihydrodibenzo [b, f] thiepin-10-one. The compound according to claim 1, which is 11-diethyl-7,8-dihydroxy-10,11-dihydrodibenzo [b, f] thiepin-10-one. The compound according to claim 1, which is 7,9-dihydroxy-2-methylthio-10,11-dihydrodibenzo [b, f] thiepin-10-one. The following reaction steps (1) and (2): (1) Ring A and ring C are bonded by the Ullmann reaction (Formula 2).
(2) Ring A and ring C are bonded by Friedel-Crafts reaction or photoreaction (Formula 3).

[In formulas 2 and 3, Q, S, and W represent arbitrary substituents, U is C or N, one of X and Y represents a leaving group, the other represents a nucleophilic group, and Z represents O, S, SO, either the SO ₂ represents. ]
In any order,
Equation 1

[Where X and Y are
When the bond XY is a single bond, X and Y are each independently (identical or different), CW ₁ W ₂ (W ₁ and W ₂ are each independently (identical or different), a hydrogen atom, A halogen, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkoxy group, a cycloalkyl group, or a cycloalkenyl group), CＯO, CＮＯNOW ₃ (W ₃ is a hydrogen atom or a lower alkyl group) Is any one selected from
When the XY bond is a double bond, X and Y are each independently (identical or different) CW ₄ (W ₄ is a hydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkoxy group) , An acyloxy group)
Z is an arbitrary one selected from O, S, S = O and SO ₂ ;
U is C or N;
R ₁ to R ₄ are each independently (identical or different), a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a cycloalkyl group, a substituted cycloalkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, A substituted lower alkynyl group, a halogen group, a lower alkylcarbonyl group, a substituted lower alkylcarbonyl group, a trihalomethyl group, V ₁ W ₅ (V ₁ is any one selected from O, S, SＳO, and SO ₂ ; W ₅ is any selected from a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkylcarbonyl group, a substituted lower alkylcarbonyl group, an acyloxy group and a trihalomethyl group.), A nitro group, an amino group, a substituted Amino group, cyano group, acyl group, acylamino group, substituted acyl group, substituted acylamino group, aromatic ring, Aromatic, heterocyclic, and any of those selected from substituted heterocycle (when U is N, there is a case where R ₄ is absent),
R ₅ to R ₈ are each independently (same or different) hydrogen atom, lower alkyl group, substituted lower alkyl group, lower alkenyl group, substituted lower alkenyl group, lower alkynyl group, substituted lower alkynyl group, halogen group, lower group. Alkylcarbonyl group, substituted lower alkylcarbonyl group, trihalomethyl group, V ₂ W ₇ (V ₂ is any selected from O, S, S ＝ O and SO ₂ , W ₇ is a hydrogen atom, a lower alkyl group , A substituted lower alkyl group, a lower alkylcarbonyl group, a substituted lower alkylcarbonyl group, and a trihalomethyl group.), A nitro group, an amino group, a substituted amino group, an acylamino group, an aromatic ring, and a substituted aromatic ring , A heterocyclic ring, or a substituted heterocyclic ring.
However, when X is CHW ₀ , CW ₀ W ₀ or CW ₀ (where W ₀ is any selected from a lower alkyl group and a substituted lower alkyl group), at least one of R ₅ to R ₈ One is a hydroxyl group (however, when XY is CH (C ₂ H ₅ ) CO, R ₆ is not a hydroxyl group alone), and X is CHW ₀ , CW ₀ W ₀ or CW ₀ (where W is ₀ is any one selected from a lower alkyl group and a substituted lower alkyl group), at least one of R ₅ to R ₈ is a hydroxyl group, and other R ₅ to R ₈ At least one group is an OR group, wherein R is any selected from a hydrogen atom, a lower alkyl group, a substituted lower alkyl group, a lower alkyl carbonyl group, and a substituted lower alkyl silyl.
Furthermore, X-Y is _{CH 2 CH 2, CHBrCH 2,} CH 2 CO, COCH 2, CHBrCO, CH = CH, CH = COCOCH 3, CH = in the case of COCH _3, at least one aromatic ring of from _{R 1 R 4} A substituted aromatic ring, a heterocyclic ring or a substituted heterocyclic ring (however, when both R ₆ and R ₇ are hydroxyl groups, none of R ₁ to R ₄ is a phenyl group);
At least one of R ₁ to R ₄ is either SW ₈ (W ₈ is a lower alkyl group or a substituted lower alkyl group) or S (O) W ₉ (W ₉ is a lower alkyl group or a substituted lower alkyl group) Or (however, when Z is O, R ₇ is not a hydrogen atom),
R ₂ is a lower alkyl group or a substituted lower alkyl group, and R ₈ is a hydroxyl group (provided that when Z is O, the lower alkyl group has 3 or more carbon atoms);
At least one of R ₁ to R ₄ is a lower alkylcarbonyl (provided that the lower alkyl group has 3 or more carbon atoms), cycloalkylcarbonyl or cycloalkenylcarbonyl, and R ₈ is a hydroxyl group;
At least one of R ₁ to R ₄ is —C (＝ NOR) CH ₃ (R is a hydrogen atom or a lower alkyl group)
Is one of ]
A method for producing a compound represented by the formula, an optical isomer thereof, a conjugate thereof or a pharmaceutically acceptable salt thereof. Further, at least one of a carbon increase reaction step, a substituent conversion reaction step, a substituent introduction reaction step, a substituent deprotection reaction step, a salt formation step, and an optical resolution step The production method according to claim 17, comprising: A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier or diluent. 20. The pharmaceutical composition according to claim 19, which utilizes a tracheal smooth muscle relaxing action. 20. The pharmaceutical composition according to claim 19, which utilizes an effect of suppressing airway hyperreactivity. 20. The pharmaceutical composition according to claim 19, which utilizes the action of inhibiting infiltration of inflammatory cells. The pharmaceutical composition according to claim 19, which is used as an anti-asthmatic drug. Lower formula

Wherein Q is a lower alkyl group. ]
Or an optical isomer or a salt thereof. Lower formula

[Wherein Q is a lower alkyl group, and Q ₁ to Q ₅ are each independently (identical or different) selected from a hydrogen atom, a lower alkoxy group and a hydroxyl group (however, Q ₁ to at least one of Q ₅ is other than hydrogen atom). ]
Or an optical isomer or a salt thereof.

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