JP2007084526A - Composition for amyloid-associated disease diagnosis - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound simultaneously having high binding specificity to amyloid β-protein, high capability of permeating through the blood-brain barrier and a high rate of disappearance from regions other than intracerebral senile plaque. <P>SOLUTION: A composition for amyloid-associated disease diagnosis is provided, containing a compound of the general formula(III)( wherein, R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>and R<SP>4</SP>are each H or the like; and R<SP>8</SP>is an aryl group or the like ) or a pharmaceutically acceptable salt thereof. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

本発明は、アルツハイマー病などのアミロイド関連疾患の診断のために用いられる組成物、前記組成物を利用したアミロイド関連疾患の治療薬又は予防薬のスクリーニング方法、前記組成物を利用したアミロイド関連疾患の治療薬又は予防薬の評価方法に関する。   The present invention relates to a composition used for diagnosis of amyloid-related diseases such as Alzheimer's disease, a method for screening a therapeutic or preventive agent for amyloid-related diseases using the composition, and an amyloid-related disease using the composition. The present invention relates to a method for evaluating a therapeutic agent or a preventive agent.

近年の急速な高齢化に伴い、アルツハイマー病(AD)をはじめとする痴呆性疾患の増加が大きな社会問題のひとつになっている。現在、ADの臨床診断法には、長谷川式、ADAS、MMSEがあり、いずれもADが疑われる個体の認知機能の低下を定量的に評価する方法が一般的に用いられる。この他画像診断法（MRI, CT等）が補助的に用いられるが、これらの診断法ではADを確定診断するには不十分であり、確定診断には生前における脳の生検、死後脳の病理組織学的検査において、老人斑と神経原繊維の出現を確認することが必要である。したがって、現在の診断方法では、広範な脳障害が生じる前の早期段階でADを診断するのは困難である。これまでにADの生物学的診断マーカーとしていくつかの報告があるが、臨床上実用的なものはいまだ開発されていない。このような状況下、ADの早期診断に対する社会的要求は高く、その早急な開発が強く望まれている。   With the recent rapid aging of society, an increase in dementia diseases such as Alzheimer's disease (AD) has become one of the major social problems. Currently, there are Hasegawa's method, ADAS, and MMSE as clinical diagnostic methods for AD, and all of them generally use a method for quantitatively evaluating the decline in cognitive function of an individual suspected of having AD. Other diagnostic imaging methods (MRI, CT, etc.) are used supplementarily, but these diagnostic methods are not sufficient for definitive diagnosis of AD. For definitive diagnosis, biopsy of the brain before birth, postmortem brain In histopathological examination, it is necessary to confirm the appearance of senile plaques and neurofibrils. Therefore, with current diagnostic methods, it is difficult to diagnose AD at an early stage before extensive brain damage occurs. To date, there have been several reports as biological diagnostic markers for AD, but clinically practical ones have not yet been developed. Under such circumstances, there is a high social demand for early diagnosis of AD, and its rapid development is strongly desired.

老人斑はADの最も特徴的な脳病変であり、その主構成成分はβシート構造をとったアミロイドβ蛋白である。体外からの老人斑の画像化はADの有効な診断法の確立につながると考えられるが、画像化には、アミロイドβ蛋白と特異的に結合するプローブ化合物が必要である。これまでに、プローブ化合物としてコンゴーレッドおよびチオフラビンTを母体構造とする誘導体が、いくつか報告されているが（特許文献１、特許文献２、非特許文献１）、アミロイドβ蛋白に対する結合特異性が低いこと、血液脳関門の透過性が低いこと、脳内での非特異的結合によりクリアランスが遅いことなど問題が少なくない。それゆえ、報告されたこれらの化合物は未だアミロイドが蓄積する疾患の診断において実用化されていないのが現状である。   Senile plaque is the most characteristic brain lesion of AD, and its main component is amyloid β protein with β sheet structure. Although imaging of senile plaques from outside the body is thought to lead to the establishment of an effective diagnostic method for AD, a probe compound that specifically binds to amyloid β protein is necessary for imaging. So far, several derivatives having a parent structure of Congo red and thioflavin T as probe compounds have been reported (Patent Document 1, Patent Document 2, Non-Patent Document 1), but have binding specificity to amyloid β protein. There are many problems such as lowness, low permeability of the blood-brain barrier, and low clearance due to nonspecific binding in the brain. Therefore, at present, these reported compounds have not been put into practical use in the diagnosis of diseases in which amyloid accumulates.

特開2004-250407号公報JP 2004-250407 A 特開2004-250411号公報JP 2004-250411 A W.E.Klunk et al., Annals of Neurology Vol55 No.3 March 2004 306-319W.E.Klunk et al., Annals of Neurology Vol55 No.3 March 2004 306-319

本発明は、以上のような技術的背景のもとになされたものであり、アミロイドβ蛋白に対する高い結合特異性、高い血液脳関門の透過性、脳内老人斑以外の部位からの速やかな消失性を併せ持つ化合物を提供することを目的とする。   The present invention has been made based on the technical background as described above, and has high binding specificity for amyloid β protein, high blood-brain barrier permeability, and rapid disappearance from sites other than brain senile plaques. An object is to provide a compound having both properties.

本発明者は、上記課題を解決するため鋭意検討を重ねた結果、コンゴーレッドやチオフラビンTとは全く構造が異なるフラボンの誘導体、カルコンの誘導体、スチリルクロモンの誘導体、及びクマリンの誘導体が、アミロイドβ蛋白を画像化するためのプローブ化合物としてきわめて優れた性質を持つことを見出し、この知見から本発明を完成するに至った。
即ち、本発明は、以下の（１）〜（２０）を提供するものである。 As a result of intensive studies to solve the above problems, the present inventor has found that flavone derivatives, chalcone derivatives, styryl chromone derivatives, and coumarin derivatives having completely different structures from Congo Red and Thioflavin T are amyloid β The present inventors have found that it has extremely excellent properties as a probe compound for imaging a protein, and from this finding, the present invention has been completed.
That is, the present invention provides the following (1) to (20).

（１）一般式（Ｉ）
〔式中、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は、互いに独立して、水素原子、ハロゲン原子、水酸基、カルボキシル基、スルホン基、ジメチルアミノ基、メチルアミノ基、アミノ基、ニトロ基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、２−フルオロエトキシ基、３−フルオロプロポキシ基、４−フルオロブトキシ基、又は５−フルオロペントキシ基を示し、Ｒ^５は下記置換基群Ａから選ばれた１若しくは２以上の置換基によって置換されていてもよいアリール基、下記置換基群Ａから選ばれた１若しくは２以上の置換基によって置換されていてもよい芳香族複素環基、又は式：-ＣＨ＝ＣＨ−Ｒ^６で表される基（式中、Ｒ^６は下記置換基群Ａから選ばれた１若しくは２以上の置換基によって置換されていてもよいアリール基、下記置換基群Ａから選ばれた１若しくは２以上の置換基によって置換されていてもよい芳香族複素環基を示す。）を示し、置換基群Ａは、ハロゲン原子、水酸基、カルボキシル基、スルホン基、ジメチルアミノ基、メチルアミノ基、アミノ基、ニトロ基、炭素数１〜４のアルキル基、及び炭素数１〜４のアルコキシ基からなる群である。〕
で表される化合物又はその医薬上許容される塩を含有するアミロイド関連疾患診断用組成物。 (1) General formula (I)
[Wherein R ¹ , R ² , R ³ , and R ⁴ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a sulfone group, a dimethylamino group, a methylamino group, an amino group, or a nitro group. , An alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a 2-fluoroethoxy group, a 3-fluoropropoxy group, a 4-fluorobutoxy group, or a 5-fluoropentoxy group, and R ⁵ is An aryl group which may be substituted with one or more substituents selected from the following substituent group A, and an fragrance which may be substituted with one or more substituents selected from the following substituent group A group heterocyclic group, or the formula: group (wherein represented by ^{-CH = CH-R 6, R} 6 may be substituted by one or more substituents selected from the following substituent group a Aryl Represents an aromatic heterocyclic group which may be substituted with one or more substituents selected from the following substituent group A.), and substituent group A includes a halogen atom, a hydroxyl group, a carboxyl group, It is a group consisting of a sulfone group, a dimethylamino group, a methylamino group, an amino group, a nitro group, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms. ]
A composition for diagnosing amyloid-related diseases, which comprises a compound represented by the formula: or a pharmaceutically acceptable salt thereof.

（２）一般式（Ｉ）におけるＲ^１、Ｒ^２、Ｒ^３、Ｒ^４のいずれかが、ハロゲン原子である（１）記載のアミロイド関連疾患診断用組成物。
（３）一般式（Ｉ）におけるＲ^１、Ｒ^２、Ｒ^３、Ｒ^４のいずれかが、ヨウ素原子である（１）記載のアミロイド関連疾患診断用組成物。
（４）一般式（Ｉ）におけるＲ^５が、置換基群Ａから選ばれた１若しくは２以上の置換基によって置換されていてもよいフェニル基である（１）乃至（３）のいずれか記載のアミロイド関連疾患診断用組成物。
（５）一般式（Ｉ）におけるＲ^５が、４−ジメチルアミノフェニル基、４−メチルアミノフェニル基、４−メトキシフェニル基、又は４−ヒドロキシフェニル基である（１）乃至（３）のいずれか記載のアミロイド関連疾患診断用組成物。 (2) The composition for diagnosing amyloid-related diseases according to (1), wherein any of R ¹ , R ² , R ³ and R ^{4 in} the general formula (I) is a halogen atom.
(3) The composition for diagnosing amyloid-related diseases according to (1), wherein any of R ¹ , R ² , R ³ and R ^{4 in} the general formula (I) is an iodine atom.
(4) Any one of (1) to (3), wherein R ⁵ in formula (I) is a phenyl group which may be substituted with one or more substituents selected from substituent group A A composition for diagnosing amyloid-related diseases.
(5) Any one of (1) to (3), wherein R ⁵ in formula (I) is a 4-dimethylaminophenyl group, a 4-methylaminophenyl group, a 4-methoxyphenyl group, or a 4-hydroxyphenyl group Or a composition for diagnosing amyloid-related diseases.

（６）一般式（Ｉ）におけるＲ^５が、式：-ＣＨ＝ＣＨ−Ｒ^６で表される基（式中、Ｒ^６は置換基群Ａから選ばれた１若しくは２以上の置換基によって置換されていてもよいフェニル基を示す。）である（１）乃至（３）のいずれか記載のアミロイド関連疾患診断用組成物。
（７）一般式（Ｉ）におけるＲ^５が、４−アミノスチリル基、４−メチルアミノスチリル基、又は４−ジメチルアミノスチリル基である（１）乃至（３）のいずれか記載のアミロイド関連疾患診断用組成物。 (6) ^{R 5} in the general formula (I), wherein: group (wherein represented by ^{-CH = CH-R 6, R} 6 is by one or more substituents selected from substituent group A (A phenyl group which may be substituted.) The composition for diagnosing amyloid-related diseases according to any one of (1) to (3).
(7) The amyloid-related disease according to any one of (1) to (3), wherein R ⁵ in the general formula (I) is a 4-aminostyryl group, a 4-methylaminostyryl group, or a 4-dimethylaminostyryl group Diagnostic composition.

（８）一般式（II）
〔式中、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は、互いに独立して、水素原子、ハロゲン原子、水酸基、カルボキシル基、スルホン基、ジメチルアミノ基、メチルアミノ基、アミノ基、ニトロ基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、２−フルオロエトキシ基、３−フルオロプロポキシ基、４−フルオロブトキシ基、又は５−フルオロペントキシ基を示し、Ｒ^７は下記置換基群Ａから選ばれた１若しくは２以上の置換基によって置換されていてもよいアリール基、又は下記置換基群Ａから選ばれた１若しくは２以上の置換基によって置換されていてもよい芳香族複素環基を示し、置換基群Ａは、ハロゲン原子、水酸基、カルボキシル基、スルホン基、ジメチルアミノ基、メチルアミノ基、アミノ基、ニトロ基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、２−フルオロエトキシ基、３−フルオロプロポキシ基、４−フルオロブトキシ基、又は５−フルオロペントキシ基からなる群である。〕
で表される化合物又はその医薬上許容される塩を含有するアミロイド関連疾患診断用組成物。 (8) General formula (II)
[Wherein R ¹ , R ² , R ³ , and R ⁴ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a sulfone group, a dimethylamino group, a methylamino group, an amino group, or a nitro group. , An alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a 2-fluoroethoxy group, a 3-fluoropropoxy group, a 4-fluorobutoxy group, or a 5-fluoropentoxy group, and R ⁷ is An aryl group which may be substituted by one or more substituents selected from the following substituent group A, or an aryl group which may be substituted by one or more substituents selected from the following substituent group A Represents an aromatic heterocyclic group, and the substituent group A includes a halogen atom, a hydroxyl group, a carboxyl group, a sulfone group, a dimethylamino group, a methylamino group, an amino group, a nitro group, Alkyl group, an alkoxy group having 1 to 4 carbon atoms, a group consisting of 2-fluoroethoxy group, 3-fluoro-propoxy group, 4-fluoro-butoxy group, or 5-fluoro-pentoxy group. ]
A composition for diagnosing amyloid-related diseases, which comprises a compound represented by the formula: or a pharmaceutically acceptable salt thereof.

（９）一般式（II）におけるＲ^１、Ｒ^２、Ｒ^３、Ｒ^４のいずれかが、ハロゲン原子である（８）記載のアミロイド関連疾患診断用組成物。
（１０）一般式（II）におけるＲ^１、Ｒ^２、Ｒ^３、Ｒ^４のいずれかが、ヨウ素原子である（８）記載のアミロイド関連疾患診断用組成物。
（１１）一般式（II）におけるＲ^７が、４−ヒドロキシ−３−メトキシフェニル基、又は４−ジメチルアミノフェニル基である（８）乃至（１０）のいずれか記載のアミロイド関連疾患診断用組成物。 (9) The composition for diagnosing amyloid-related diseases according to (8), wherein any of R ¹ , R ² , R ³ and R ^{4 in} the general formula (II) is a halogen atom.
(10) The composition for diagnosing amyloid-related diseases according to (8), wherein any of R ¹ , R ² , R ³ and R ^{4 in} the general formula (II) is an iodine atom.
(11) The composition for diagnosing amyloid-related disease according to any one of (8) to (10), wherein R ⁷ in formula (II) is a 4-hydroxy-3-methoxyphenyl group or a 4-dimethylaminophenyl group object.

（１２）一般式（III）
〔式中、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は、互いに独立して、水素原子、ハロゲン原子、水酸基、カルボキシル基、スルホン基、ジメチルアミノ基、メチルアミノ基、アミノ基、ニトロ基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、２−フルオロエトキシ基、３−フルオロプロポキシ基、４−フルオロブトキシ基、又は５−フルオロペントキシ基を示し、Ｒ^８は下記置換基群Ａから選ばれた１若しくは２以上の置換基によって置換されていてもよいアリール基、又は下記置換基群Ａから選ばれた１若しくは２以上の置換基によって置換されていてもよい芳香族複素環基を示し、置換基群Ａは、ハロゲン原子、水酸基、カルボキシル基、スルホン基、ジメチルアミノ基、メチルアミノ基、アミノ基、ニトロ基、炭素数１〜４のアルキル基、及び炭素数１〜４のアルコキシ基からなる群である。〕
で表される化合物又はその医薬上許容される塩を含有するアミロイド関連疾患診断用組成物。 (12) General formula (III)
[Wherein R ¹ , R ² , R ³ , and R ⁴ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a sulfone group, a dimethylamino group, a methylamino group, an amino group, or a nitro group. , An alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a 2-fluoroethoxy group, a 3-fluoropropoxy group, a 4-fluorobutoxy group, or a 5-fluoropentoxy group, and R ⁸ is An aryl group which may be substituted by one or more substituents selected from the following substituent group A, or an aryl group which may be substituted by one or more substituents selected from the following substituent group A Represents an aromatic heterocyclic group, and the substituent group A includes a halogen atom, a hydroxyl group, a carboxyl group, a sulfone group, a dimethylamino group, a methylamino group, an amino group, a nitro group, Alkyl group, and a group consisting of alkoxy group having 1 to 4 carbon atoms. ]
A composition for diagnosing amyloid-related diseases, which comprises a compound represented by the formula: or a pharmaceutically acceptable salt thereof.

（１３）一般式（III）におけるＲ^１、Ｒ^２、Ｒ^３、Ｒ^４のいずれかが、ハロゲン原子である（１２）記載のアミロイド関連疾患診断用組成物。
（１４）一般式（III）におけるＲ^１、Ｒ^２、Ｒ^３、Ｒ^４のいずれかが、ヨウ素原子である（１２）記載のアミロイド関連疾患診断用組成物。
（１５）一般式（Ｉ）、一般式（II）、又は一般式（III）で表される化合物が、放射性核種で標識されている化合物である（１）乃至（１４）のいずれか記載のアミロイド関連疾患診断用組成物。 (13) The composition for diagnosing amyloid-related diseases according to (12), wherein any of R ¹ , R ² , R ³ , and R ^{4 in} the general formula (III) is a halogen atom.
(14) The composition for diagnosing amyloid-related diseases according to (12), wherein any of R ¹ , R ² , R ³ and R ^{4 in} the general formula (III) is an iodine atom.
(15) The compound represented by any one of (1) to (14), wherein the compound represented by the general formula (I), the general formula (II), or the general formula (III) is a compound labeled with a radionuclide. A composition for diagnosing amyloid-related diseases.

（１６）放射性核種が、陽電子放出核種である（１５）記載のアミロイド関連疾患診断用組成物。
（１７）放射性核種が、γ線放出核種である（１５）記載記載のアミロイド関連疾患診断用組成物。
（１８）アミロイド関連疾患が、アルツハイマー病である（１）乃至（１７）のいずれか記載のアミロイド関連疾患診断用組成物。 (16) The composition for diagnosing amyloid-related diseases according to (15), wherein the radionuclide is a positron emitting nuclide.
(17) The composition for diagnosing amyloid-related diseases according to (15), wherein the radionuclide is a γ-ray-emitting nuclide.
(18) The composition for diagnosing amyloid-related disease according to any one of (1) to (17), wherein the amyloid-related disease is Alzheimer's disease.

（１９）アミロイド関連疾患のモデル動物に被験物質を投与する工程、前記モデル動物に（１）乃至（１８）のいずれか記載のアミロイド関連疾患診断用組成物を投与する工程、及び前記モデル動物の脳中に含まれる一般式（Ｉ）、一般式（II）、又は一般式（III）で表される化合物の分布又は量を調べる工程を含むアミロイド関連疾患の治療薬又は予防薬のスクリーニング方法。 (19) A step of administering a test substance to a model animal of amyloid-related disease, a step of administering to the model animal the composition for diagnosing amyloid-related disease according to any one of (1) to (18), and A screening method for a therapeutic or prophylactic agent for amyloid-related diseases, which comprises the step of examining the distribution or amount of a compound represented by general formula (I), general formula (II), or general formula (III) contained in the brain.

（２０）アミロイド関連疾患のモデル動物に前記疾患の治療薬又は予防薬を投与する工程、前記モデル動物に（１）乃至（１８）のいずれか記載のアミロイド関連疾患診断用組成物を投与する工程、及び前記モデル動物の脳中に含まれる一般式（Ｉ）、一般式（II）、又は一般式（III）で表される化合物の分布又は量を調べる工程を含むアミロイド関連疾患の治療薬又は予防薬の評価方法。 (20) A step of administering a therapeutic or prophylactic agent for the disease to a model animal of amyloid-related disease, and a step of administering the amyloid-related disease diagnostic composition according to any one of (1) to (18) to the model animal And a therapeutic drug for amyloid-related diseases, comprising a step of examining the distribution or amount of the compound represented by the general formula (I), the general formula (II), or the general formula (III) contained in the brain of the model animal, or How to evaluate prophylactic drugs.

一般式（Ｉ）、一般式（II）、及び一般式（III）で表される化合物（以下、「一般式（Ｉ）等で表される化合物」という）は、アミロイドβ蛋白に対し高い結合特異性を持ち、また、血液脳関門の透過性も高く、更に、脳内老人斑以外の部位からの速やかに消失する性質を持つので、アルツハイマー病の診断に有用である。   Compounds represented by general formula (I), general formula (II), and general formula (III) (hereinafter referred to as “compounds represented by general formula (I) etc.”) are highly bound to amyloid β protein. It has specificity, has high permeability of the blood brain barrier, and further has a property of rapidly disappearing from sites other than cerebral senile plaques, which is useful for diagnosis of Alzheimer's disease.

以下、本発明を詳細に説明する。
本発明において、「ハロゲン原子」とは、例えば、フッ素原子、塩素原子、臭素原子、ヨウ素原子である。
本発明において、「炭素数１〜４のアルキル基」とは、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、sec-ブチル基、tert-ブチル基である。 Hereinafter, the present invention will be described in detail.
In the present invention, the “halogen atom” is, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
In the present invention, the “alkyl group having 1 to 4 carbon atoms” is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group.

本発明において、「炭素数１〜４のアルコキシ基」とは、例えば、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、sec-ブトキシ基、tert-ブトキシ基である。
本発明において、「アリール基」とは、例えば、フェニル基、１−ナフチル基、２−ナフチル基などである。 In the present invention, the “C 1-4 alkoxy group” is, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxy group.
In the present invention, the “aryl group” includes, for example, a phenyl group, 1-naphthyl group, 2-naphthyl group and the like.

本発明において、「芳香族複素環基」とは、例えば、チオフェン−２−イル基、チオフェン−３−イル基、フラン−２−イル基、フラン−３−イル基、ピリジン−２−イル基、ピリジン−３−イル基、ピリジン−４−イル基、ピリミジン−２−イル基、ピリミジン−４−イル基、ピリミジン−５−イル基などである。   In the present invention, the “aromatic heterocyclic group” is, for example, a thiophen-2-yl group, a thiophen-3-yl group, a furan-2-yl group, a furan-3-yl group, or a pyridin-2-yl group. , Pyridin-3-yl group, pyridin-4-yl group, pyrimidin-2-yl group, pyrimidin-4-yl group, pyrimidin-5-yl group and the like.

本発明において、「置換基群Ａから選ばれた置換基によって置換されていてもよいアリール基」とは、例えば、２−ジメチルアミノフェニル基、２−メチルアミノフェニル基、２−メトキシフェニル基、２−ヒドロキシフェニル基、３−ジメチルアミノフェニル基、３−メチルアミノフェニル基、３−メトキシフェニル基、３−ヒドロキシフェニル基、４−ジメチルアミノフェニル基、４−メチルアミノフェニル基、４−メトキシフェニル基、４−ヒドロキシフェニル基、３−ヒドロキシ−４−ジメチルアミノフェニル基、３−ヒドロキシ−４−メチルアミノフェニル基、３−ヒドロキシ−４−メトキシフェニル基、３，５−ジヒドロキシ−４−ジメチルアミノフェニル基、３，５−ジヒドロキシ−４−メチルアミノフェニル基、３，５−ジヒドロキシ−４−メトキシフェニル基などである。   In the present invention, the “aryl group optionally substituted by a substituent selected from substituent group A” includes, for example, a 2-dimethylaminophenyl group, a 2-methylaminophenyl group, a 2-methoxyphenyl group, 2-hydroxyphenyl group, 3-dimethylaminophenyl group, 3-methylaminophenyl group, 3-methoxyphenyl group, 3-hydroxyphenyl group, 4-dimethylaminophenyl group, 4-methylaminophenyl group, 4-methoxyphenyl Group, 4-hydroxyphenyl group, 3-hydroxy-4-dimethylaminophenyl group, 3-hydroxy-4-methylaminophenyl group, 3-hydroxy-4-methoxyphenyl group, 3,5-dihydroxy-4-dimethylamino Phenyl group, 3,5-dihydroxy-4-methylaminophenyl group, 3,5-di Dorokishi-4-methoxyphenyl group and the like.

本発明において、「置換基群Ａから選ばれた置換基によって置換されていてもよい芳香族複素環基」とは、例えば、５−ジメチルアミノピリジン−２−イル基、５−メチルアミノピリジン−２−イル基、５−メトキシピリジン−２−イル基、６−ジメチルアミノピリジン−３−イル基、６−メチルアミノピリジン−３−イル基、６−メトキシピリジン−３−イル基などである。   In the present invention, the “aromatic heterocyclic group optionally substituted by a substituent selected from substituent group A” includes, for example, 5-dimethylaminopyridin-2-yl group, 5-methylaminopyridine- And 2-yl group, 5-methoxypyridin-2-yl group, 6-dimethylaminopyridin-3-yl group, 6-methylaminopyridin-3-yl group, and 6-methoxypyridin-3-yl group.

一般式（Ｉ）、一般式（II）、及び一般式（III）において、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４は、好適には、いずれかがハロゲン原子であり、より好適には、いずれかがヨウ素原子である。 In general formula (I), general formula (II), and general formula (III), any one of R ¹ , R ² , R ³ , and R ⁴ is preferably a halogen atom, and more preferably, Either is an iodine atom.

一般式（Ｉ）において、Ｒ^５は、好適には、ハロゲン原子、水酸基、カルボキシル基、スルホン基、ジメチルアミノ基、メチルアミノ基、アミノ基、ニトロ基、炭素数１〜４のアルキル基、及び炭素数１〜４のアルコキシ基からなる群から選ばれた１若しくは２以上の置換基によって置換されていてもよいフェニル基、又は式：-ＣＨ＝ＣＨ−Ｒ^６で表される基（式中、Ｒ^６はハロゲン原子、水酸基、カルボキシル基、スルホン基、ジメチルアミノ基、メチルアミノ基、アミノ基、ニトロ基、炭素数１〜４のアルキル基、及び炭素数１〜４のアルコキシ基からなる群から選ばれた１若しくは２以上の置換基によって置換されていてもよいフェニル基を示す。）であり、より好適には、４−ジメチルアミノフェニル基、４−メチルアミノフェニル基、４−メトキシフェニル基、４−ヒドロキシフェニル基、４−アミノスチリル基、４−メチルアミノスチリル基、又は４−ジメチルアミノスチリル基である。なお、Ｒ^５のクロモン上の位置は２位、３位のいずれであってもよい。 In the general formula (I), R ⁵ is preferably a halogen atom, a hydroxyl group, a carboxyl group, a sulfone group, a dimethylamino group, a methylamino group, an amino group, a nitro group, an alkyl group having 1 to 4 carbon atoms, and A phenyl group optionally substituted by one or more substituents selected from the group consisting of alkoxy groups having 1 to 4 carbon atoms, or a group represented by the formula: —CH═CH—R ⁶ (in the formula, And R ⁶ is a group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a sulfone group, a dimethylamino group, a methylamino group, an amino group, a nitro group, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms. And a phenyl group which may be substituted with one or more substituents selected from the group consisting of 4-dimethylaminophenyl group and 4-methylaminopheny group. Group, 4-methoxyphenyl group, 4-hydroxyphenyl group, 4-aminostyryl group, 4-methylaminostyryl group, or 4-dimethylaminostyryl group. The position of R ^{5 on} the chromone may be either the second position or the third position.

一般式（II）において、Ｒ^７は、好適には、ハロゲン原子、水酸基、カルボキシル基、スルホン基、ジメチルアミノ基、メチルアミノ基、アミノ基、ニトロ基、炭素数１〜４のアルキル基、及び炭素数１〜４のアルコキシ基からなる群から選ばれた１若しくは２以上の置換基によって置換されていてもよいフェニル基であり、より好適には、４−ヒドロキシ−３−メトキシフェニル基、又は４−ジメチルアミノフェニル基である。 In the general formula (II), R ⁷ is preferably a halogen atom, a hydroxyl group, a carboxyl group, a sulfone group, a dimethylamino group, a methylamino group, an amino group, a nitro group, an alkyl group having 1 to 4 carbon atoms, and A phenyl group which may be substituted by one or more substituents selected from the group consisting of alkoxy groups having 1 to 4 carbon atoms, more preferably a 4-hydroxy-3-methoxyphenyl group, or 4-dimethylaminophenyl group.

一般式（III）において、Ｒ^８は、好適には、ハロゲン原子、水酸基、カルボキシル基、スルホン基、ジメチルアミノ基、メチルアミノ基、アミノ基、ニトロ基、炭素数１〜４のアルキル基、及び炭素数１〜４のアルコキシ基からなる群から選ばれた１若しくは２以上の置換基によって置換されていてもよいフェニル基であり、より好適には、４−メチルアミノフェニル基、又は４−ジメチルアミノフェニル基である。 In the general formula (III), R ⁸ is preferably a halogen atom, a hydroxyl group, a carboxyl group, a sulfone group, a dimethylamino group, a methylamino group, an amino group, a nitro group, an alkyl group having 1 to 4 carbon atoms, and A phenyl group which may be substituted with one or more substituents selected from the group consisting of alkoxy groups having 1 to 4 carbon atoms, more preferably a 4-methylaminophenyl group or 4-dimethyl An aminophenyl group.

一般式（Ｉ）で表される化合物のうち代表的なものを表１〜表９に示す。
なお、以下の表において、「Me」はメチル基を、「Phe」はフェニル基を、「X1」は２−フルオロエトキシ基を、「X2」は３−フルオロプロポキシ基、「X3」は４−フルオロブトキシ基、「X4」は５−フルオロペントキシ基を表す。 Tables 1 to 9 show typical compounds represented by the general formula (I).
In the following table, “Me” represents a methyl group, “Phe” represents a phenyl group, “X1” represents a 2-fluoroethoxy group, “X2” represents a 3-fluoropropoxy group, and “X3” represents 4- A fluorobutoxy group, “X4” represents a 5-fluoropentoxy group.

上記化合物のうちで、好ましいものとしては、I-1の化合物（化合物１１）、I-2の化合物（化合物１０）、I-3の化合物（化合物１９）、I-28（化合物４７）、I-29（化合物４８）、I-46（化合物２０）、I-59（化合物４６）を挙げることができる。 Among the above compounds, preferred are the compound of I-1 (Compound 11), the compound of I-2 (Compound 10), the compound of I-3 (Compound 19), I-28 (Compound 47), I -29 (Compound 48), I-46 (Compound 20), I-59 (Compound 46).

一般式（II）で表される化合物のうち代表的なものを表１０〜表２０に示す。
Tables 10 to 20 show typical compounds represented by the general formula (II).

上記化合物のうちで、好ましいものとしては、II-7の化合物（化合物３１）、II-2の化合物（化合物３６）を挙げることができる。 Among the above compounds, preferred examples include II-7 compound (Compound 31) and II-2 compound (Compound 36).

一般式（III）で表される化合物のうち代表的なものを表２１〜表２８に示す。
Representative compounds among the compounds represented by the general formula (III) are shown in Tables 21 to 28.

上記化合物のうちで、好ましいものとしては、III-1の化合物（化合物６５）、III-2の化合物（化合物６６）、III-3の化合物（化合物６７）を挙げることができる。 Among the above compounds, preferred are the compound III-1 (compound 65), the compound III-2 (compound 66), and the compound III-3 (compound 67).

一般式（Ｉ）等で表される化合物は、後述する実施例の記載、及びMarder M et al, Biochemical and Biophysical Research Communications, 223, 384-389, 1996, Marder M et al, Bioorganic &Medicinal Chemistry Letters, 7, 2003-2008, 1997などの記載に従って合成することができる。   The compounds represented by the general formula (I) and the like are described in Examples described later, and Marder M et al, Biochemical and Biophysical Research Communications, 223, 384-389, 1996, Marder M et al, Bioorganic & Medicinal Chemistry Letters, 7, 2003-2008, 1997 and the like.

一般式（Ｉ）等で表される化合物は、標識物質によって標識されていることが好ましい。標識物質としては、蛍光物質、アフィニティー物質などを使用してもよいが、放射性核種を使用するのが好ましい。標識に用いる放射性核種の種類は特に限定されず、使用の態様によって適宜決めることができる。例えば、一般式（Ｉ）等で表される化合物をコンピューター断層撮影法（SPECT）による診断に使用する場合、放射性核種は^９９ｍＴｃ、^１１１Ｉｎ、^６７Ｇａ、^２０１Ｔｌ、^１２３Ｉ、^１３３Ｘｅ（好適には、^９９ｍＴｃ、^１２３Ｉ）などのγ線放出核種を使用することができる。また、陽電子断層撮影法（PET）による診断に使用する場合には、^１１Ｃ、^１３Ｎ、^１５Ｏ、^１８Ｆ、^６２Ｃｕ、^６８Ｇａ、^７６Ｂｒ（好適には、^１１Ｃ、^１３Ｎ、^１５Ｏ、^１８Ｆ）などの陽電子放出核種を使用することができる。また、一般式（Ｉ）等で表される化合物をヒト以外の動物に投与する場合には、より半減期の長い放射性核種、例えば、^１２５Ｉなどを使用してもよい。放射性核種は、一般式（Ｉ）等で表される化合物の分子中に含まれる形でもよく、また、一般式（Ｉ）等で表される化合物に結合する形であってもよい。 The compound represented by the general formula (I) or the like is preferably labeled with a labeling substance. As the labeling substance, a fluorescent substance, an affinity substance or the like may be used, but it is preferable to use a radionuclide. The kind of radionuclide used for labeling is not particularly limited, and can be appropriately determined depending on the mode of use. For example, when a compound represented by the general formula (I) or the like is used for diagnosis by computer tomography (SPECT), the radionuclide is ^99m Tc, ¹¹¹ In, ⁶⁷ Ga, ²⁰¹ Tl, ¹²³ I, ¹³³ Xe (preferable). Γ-ray emitting nuclides such as ^99m Tc, ¹²³ I) can be used. When used for diagnosis by positron emission tomography (PET), ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F, ⁶² Cu, ⁶⁸ Ga, ⁷⁶ Br (preferably ¹¹ C, ¹³ N, ¹⁵ Positron emitting nuclides such as O, ¹⁸ F) can be used. In addition, when a compound represented by the general formula (I) or the like is administered to an animal other than a human, a radionuclide having a longer half-life, for example, ¹²⁵ I may be used. The radionuclide may be included in the molecule of the compound represented by the general formula (I) or the like, or may be bonded to the compound represented by the general formula (I) or the like.

一般式（Ｉ）等で表される化合物の代わりに、医薬上許容される塩を使用することも可能である。医薬上許容される塩としては、アルカリ金属塩（ナトリウム塩、カリウム塩、リチウム塩）、アルカリ土類金属塩（カルシウム塩、マグネシウム塩）、硫酸塩、塩酸塩、硝酸塩、リン酸塩などを例示できる。   Instead of the compound represented by the general formula (I) or the like, a pharmaceutically acceptable salt can be used. Examples of pharmaceutically acceptable salts include alkali metal salts (sodium salt, potassium salt, lithium salt), alkaline earth metal salts (calcium salt, magnesium salt), sulfate, hydrochloride, nitrate, phosphate, etc. it can.

本発明の組成物はアミロイド関連疾患の診断に用いられる。ここで、「アミロイド関連疾患」とは、アミロイドβ蛋白の蓄積によって起きる疾患をいい、主にアルツハイマー病を意味するが、ダウン症候群、オランダ型アミロイドーシスを伴う遺伝性脳出血症（hereditary cerebral hemorrhage with amyloidosis─Dutch type: HCHWA-D）などの疾患も含まれる。また、一般には「疾患」と認識されない疾患の前駆症状も、本発明における「アミロイド関連疾患」に含まれる。このような疾患の前駆症状としては、アルツハイマー病の発症前にみられる軽度認知障害（MCI）などを例示できる。   The composition of the present invention is used for diagnosis of amyloid-related diseases. Here, “amyloid-related disease” refers to a disease caused by accumulation of amyloid β protein, which mainly means Alzheimer's disease, but hereditary cerebral hemorrhage with amyloidosis─ Diseases such as Dutch type: HCHWA-D) are also included. In addition, precursor symptoms of diseases that are generally not recognized as “diseases” are also included in “amyloid-related diseases” in the present invention. Examples of prodromal symptoms of such diseases include mild cognitive impairment (MCI) seen before the onset of Alzheimer's disease.

本発明の組成物によるアミロイド関連疾患の診断は、通常、本発明の組成物を診断対象者又は実験動物などに投与し、その後、脳の画像を撮影し、画像における一般式（Ｉ）等で表される化合物の状態（量、分布等）に基づいて行う。本発明の組成物の投与方法は特に限定されず、化合物の種類、標識物質の種類などに応じて適宜決めることができるが、通常は、皮内、腹腔内、静脈、動脈、又は脊髄液への注射又は点滴等によって投与する。本発明の組成物の投与量は特に限定されず、化合物の種類、標識物質の種類などに応じて適宜決めることができるが、成人の場合、一般式（Ｉ）等で表される化合物を１日当たり10^-10〜10^-3mg投与するのが好ましく、10^-8〜10^-5 mg投与するのが更に好ましい。 Diagnosis of an amyloid-related disease with the composition of the present invention is usually performed by administering the composition of the present invention to a subject to be diagnosed or a laboratory animal, and then taking a brain image, using the general formula (I) or the like in the image. Based on the state (amount, distribution, etc.) of the compound represented. The administration method of the composition of the present invention is not particularly limited and can be appropriately determined according to the type of compound, the type of labeling substance, etc., but is usually intradermal, intraperitoneal, intravenous, arterial, or spinal fluid. It is administered by injection or infusion. The dose of the composition of the present invention is not particularly limited, and can be appropriately determined according to the type of compound, the type of labeling substance, etc. In the case of an adult, the compound represented by the general formula (I) or the like is 1 The dose is preferably 10 ⁻¹⁰ to 10 ⁻³ mg per day, more preferably 10 ⁻⁸ to 10 ⁻⁵ mg.

上記のように本発明の組成物は、通常、注射又は点滴によって投与するので、注射液や点滴液に通常含まれる成分を含んでいてもよい。このような成分としては、液体担体（例えば、リン酸カリウム緩衝液、生理食塩水、リンゲル液、蒸留水、ポリエチレングリコール、植物性油脂、エタノール、グリセリン、ジメチルスルホキサイド、プロピレングリコールなど）、抗菌剤、局所麻酔剤（例えば、塩酸プロカイン、塩酸ジブカインなど）、緩衝液（例えば、トリス−塩酸緩衝液、ヘペス緩衝液など）、浸透圧調節剤（例えば、グルコース、ソルビトール、塩化ナトリウムなど）を例示できる。   As described above, since the composition of the present invention is usually administered by injection or infusion, it may contain components usually contained in injection solutions or infusion solutions. Such components include liquid carriers (for example, potassium phosphate buffer, physiological saline, Ringer's solution, distilled water, polyethylene glycol, vegetable oils, ethanol, glycerin, dimethyl sulfoxide, propylene glycol, etc.), antibacterial agents Local anesthetics (eg, procaine hydrochloride, dibucaine hydrochloride, etc.), buffers (eg, tris-hydrochloric acid buffer, hepes buffer, etc.), osmotic pressure regulators (eg, glucose, sorbitol, sodium chloride, etc.) .

本発明のアミロイド関連疾患診断用組成物は、アミロイド関連疾患の治療薬や予防薬のスクリーニングにも利用できる。例えば、アルツハイマー病などの「疾患」のモデル動物に被験物質を投与した後、前記モデル動物に本発明のアミロイド関連疾患診断用組成物を投与し、その後、前記モデル動物の脳中に含まれる一般式（Ｉ）等で表される化合物の分布又は量を調べ、その結果、コントロール（被験物質を投与していないモデル動物）との間に有意な差異（例えば、分布部位の縮小、量の減少など）が検出されれば、被験物質はアミロイド関連疾患の治療薬の候補となり得る。また、軽度認知障害などの「疾患の前駆症状」のモデル動物に被験物質を投与した後、前記モデル動物に本発明のアミロイド関連疾患診断用組成物を投与し、その後、前記モデル動物の脳中に含まれる一般式（Ｉ）等で表される化合物の分布又は量を調べ、その結果、コントロールとの間に有意な差異（例えば、分布部位の縮小又は拡大の鈍化、量の減少又は増大の鈍化など）が検出されれば、被験物質はアミロイド関連疾患の予防薬の候補となり得る。   The composition for diagnosing amyloid-related diseases of the present invention can also be used for screening for therapeutic or prophylactic agents for amyloid-related diseases. For example, after administering a test substance to a model animal of “disease” such as Alzheimer's disease, the composition for amyloid-related disease diagnosis of the present invention is administered to the model animal, and then contained in the brain of the model animal. The distribution or amount of the compound represented by the formula (I) or the like is examined, and as a result, a significant difference from the control (model animal not administered with the test substance) (for example, reduction of the distribution site, reduction of the amount) Etc.) is detected, the test substance can be a candidate for a therapeutic drug for amyloid-related diseases. Further, after administering a test substance to a model animal of “disease symptoms” such as mild cognitive impairment, the composition for amyloid-related disease diagnosis of the present invention is administered to the model animal, and then the brain of the model animal The distribution or amount of the compound represented by the general formula (I) and the like contained in the above is examined, and as a result, there is a significant difference from the control (for example, the reduction or expansion of the distribution site, the decrease in the amount or the increase in the amount). If blunting is detected, the test substance can be a candidate for a prophylactic agent for amyloid-related diseases.

また、本発明のアミロイド関連疾患診断用組成物は、既に効果が確認されているアミロイド関連疾患の治療薬や予防薬の評価にも利用できる。即ち、アミロイド関連疾患のモデル動物に前記疾患の治療薬又は予防薬を投与した後、前記モデル動物に本発明のアミロイド関連疾患診断用組成物を投与し、その後、前記モデル動物の脳中に含まれる一般式（Ｉ）等で表される化合物の分布又は量を調べ、これにより、前記治療薬や予防薬の評価（具体的には、有効な投与量、有効な投与方法など）を行う。   In addition, the composition for diagnosing amyloid-related diseases of the present invention can also be used for the evaluation of therapeutic or preventive drugs for amyloid-related diseases whose effects have already been confirmed. That is, after the therapeutic or prophylactic agent for the disease is administered to a model animal for amyloid-related disease, the composition for diagnosing amyloid-related disease of the present invention is administered to the model animal, and then contained in the brain of the model animal. The distribution or amount of the compound represented by the general formula (I) or the like is examined, and thereby, evaluation of the therapeutic agent or prophylactic agent (specifically, effective dose, effective administration method, etc.) is performed.

以下、実施例により本発明を更に詳細に説明する。
〔実験方法〕
試薬・機器
放射性ヨウ素-125 (¹²⁵I) はアマシャムバイオサイエンス株式会社製IODINE-125 (74 MBq)を用いた。逆相HPLCはナカライテスク社製Cosmosil 5C₁₈-ARカラム(4.6 x 150 mm)を用いて、超純水 (A)とアセトニトリル(B)をA:B = 40:60を溶出溶媒とし、流速1.0 mL/minで分析した。¹H-NMRは、Varian Gemini 300を用い、テトラメチルシランを内部標準物質として測定した。質量分析は、JEOL IMS-DX300を用いて測定した。Amyloid βProtein (Human, 1-40) [HCl form]及びAmyloid βProtein (Human, 1-42) [TFA form]はペプチド研究所より購入し、その他の試薬は特級試薬を用いた。 Hereinafter, the present invention will be described in more detail with reference to examples.
〔experimental method〕
As reagent / equipment radioactive iodine-125 ( ¹²⁵ I), IODINE-125 (74 MBq) manufactured by Amersham Bioscience Co., Ltd. was used. Reversed-phase HPLC was performed using a Cosmosil 5C _18- AR column (4.6 x 150 mm) manufactured by Nacalai Tesque, with ultrapure water (A) and acetonitrile (B) as the elution solvent at A: B = 40:60, and a flow rate of 1.0. Analyzed at mL / min. ¹ H-NMR was measured using Varian Gemini 300 and tetramethylsilane as an internal standard substance. Mass spectrometry was measured using JEOL IMS-DX300. Amyloid βProtein (Human, 1-40) [HCl form] and Amyloid βProtein (Human, 1-42) [TFA form] were purchased from Peptide Institute, and other reagents used special grade reagents.

（１）フラボン誘導体の合成
4-ニトロ安息香酸 2-アセチル-4-ブロモフェニルエステルの合成
氷浴中、4-塩化ニトロベンゾイル(1.00 g, 4.65 mmol)のピリジン溶液(20 mL)に5’-ブロモ-2’-ヒドロキシアセトフェノン（化合物１）(863 mg, 4.65 mmol)を加えた。室温で30分間反応させた後、氷冷下1 N塩酸へ注ぎ、激しく攪拌させた。析出した沈澱を濾取し、精製水で洗浄後、目的物である4-ニトロ安息香酸 2-アセチル-4-ブロモフェニルエステル（化合物２）を得た。収量1.57 g（収率：92.7%）¹H NMR (300 MHz, CDCl₃) δ 8.37 (s, 4H), 8.00 (s, 1H), 7.76-7.72 (m, 1H), 7.16 (d, J = 8.7 Hz, 1H), 2.55 (s, 3H). MS m/z 365 (MH⁺). (1) Synthesis of flavone derivatives
Synthesis of 4-nitrobenzoic acid 2-acetyl-4-bromophenyl ester 5'-Bromo-2'-hydroxyacetophenone in pyridine solution (20 mL) of 4-nitrobenzoyl chloride (1.00 g, 4.65 mmol) in an ice bath (Compound 1) (863 mg, 4.65 mmol) was added. After reacting at room temperature for 30 minutes, the mixture was poured into 1 N hydrochloric acid under ice cooling and stirred vigorously. The deposited precipitate was collected by filtration and washed with purified water to give the desired product, 4-nitrobenzoic acid 2-acetyl-4-bromophenyl ester (Compound 2). Yield 1.57 g (Yield: 92.7%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.37 (s, 4H), 8.00 (s, 1H), 7.76-7.72 (m, 1H), 7.16 (d, J = 8.7 Hz, 1H), 2.55 (s, 3H). MS m / z 365 (MH ⁺ ).

1-(5-ブロモ-2-ヒドロキシフェニル)-3-(4-ニトロフェニル)プロパン-1,3-ジオンの合成
化合物２（2.31 g, 6.34 mmol）をピリジン(40 mL)に溶解し、50℃まで加熱した。粉砕した水酸化カリウム(530 mg, 9.45 mmol)を加え、15分間撹拌後、氷冷し、10%酢酸溶液を加えた。析出した淡黄色の沈澱を濾取し、目的物である1-(5-ブロモ-2-ヒドロキシフェニル)-3-(4-ニトロフェニル)プロパン-1,3-ジオン（化合物３）を得た。収量2.01 g（収率：87.1%）¹H NMR（300 MHz, CDCl₃）δ11.85 (s, 1H), 8.36 (d, J = 9.0 Hz, 2H), 8.13 (d, J = 9.0 Hz, 2H), 7.88 (s, 1H), 7.57 (d, J = 9.0 Hz, 1H), 6.95 (d, J = 9.0 Hz, 1H), 6.83 (s, 2H). MS m/z 365 (MH⁺). Synthesis of 1- (5-bromo-2-hydroxyphenyl) -3- (4-nitrophenyl) propane-1,3-dione Compound 2 (2.31 g, 6.34 mmol) was dissolved in pyridine (40 mL). Heated to ° C. Crushed potassium hydroxide (530 mg, 9.45 mmol) was added, and the mixture was stirred for 15 minutes, cooled on ice, and 10% acetic acid solution was added. The precipitated pale yellow precipitate was collected by filtration to obtain 1- (5-bromo-2-hydroxyphenyl) -3- (4-nitrophenyl) propane-1,3-dione (compound 3) as the target product. . Yield 2.01 g (Yield: 87.1%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 11.85 (s, 1H), 8.36 (d, J = 9.0 Hz, 2H), 8.13 (d, J = 9.0 Hz, 2H), 7.88 (s, 1H), 7.57 (d, J = 9.0 Hz, 1H), 6.95 (d, J = 9.0 Hz, 1H), 6.83 (s, 2H) .MS m / z 365 (MH ⁺ ) .

6-ブロモ-4’-ニトロフラボンの合成
化合物３（2.00 g, 5.49 mmol）、濃硫酸(0.5 mL)、酢酸(40 mL)の混液を1時間加熱還流した。室温に戻した後、氷片を反応溶液に加え、析出した結晶を濾取し、目的物である6-ブロモ-4’-ニトロフラボン（化合物４）を得た。収量1.79 g（収率：94.2%）MS m/z 347 (MH⁺). A mixture of 6-bromo-4′-nitroflavone synthesis compound 3 (2.00 g, 5.49 mmol), concentrated sulfuric acid (0.5 mL), and acetic acid (40 mL) was heated to reflux for 1 hour. After returning to room temperature, ice pieces were added to the reaction solution, and the precipitated crystals were collected by filtration to obtain the desired 6-bromo-4′-nitroflavone (Compound 4). Yield 1.79 g (Yield: 94.2%) MS m / z 347 (MH ⁺ ).

6-ブロモ-4’-アミノフラボンの合成
化合物４（100 mg, 0.289 mmol）のエタノール（7 mL）溶液に、撹拌しながら塩化スズ(II)（275 mg, 1.45 mmol）をゆっくり加え、1時間加熱還流した。反応終了後、反応溶液に1 N水酸化ナトリウム水溶液(50 mL)を加え、酢酸エチル 50 mL (25 mL x 2)で抽出した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、目的物である6-ブロモ-4’-アミノフラボン（化合物５）を黄色結晶として得た。収量 77 mg（収率：84.3%）¹H NMR（300 MHz, CDCl₃）δ8.36 (s, 1H), 7.72-7.76 (m, 3H), 7.44 (d, J = 9.0 Hz, 1H), 6.72 (d, J = 8.7 Hz, 2H), 6.70 (s, 1H), 4.15 (s, 2H). MS m/z 317 (MH⁺). Synthesis of 6-bromo-4'- aminoflavone Compound 4 (100 mg, 0.289 mmol) in ethanol (7 mL) was slowly added with tin (II) chloride (275 mg, 1.45 mmol) with stirring for 1 hour. Heated to reflux. After completion of the reaction, 1N aqueous sodium hydroxide solution (50 mL) was added to the reaction solution, and the mixture was extracted with 50 mL (25 mL × 2) of ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 6-bromo-4′-aminoflavone (Compound 5) as the target product as yellow crystals. Yield 77 mg (Yield: 84.3%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.36 (s, 1H), 7.72-7.76 (m, 3H), 7.44 (d, J = 9.0 Hz, 1H), 6.72 (d, J = 8.7 Hz, 2H), 6.70 (s, 1H), 4.15 (s, 2H). MS m / z 317 (MH ⁺ ).

6-ブロモ-4’-メチルアミノフラボンの合成
化合物５（300 mg, 0.949 mmol）とパラホルムアルデヒド（154 mg, 5.13 mmol）のメタノール溶液（15 mL）に撹拌しながらナトリウムメチラートメタノール溶液（0.27 mL）をゆっくり滴下した。1時間加熱還流後、水素化ホウ素ナトリウム（180 mg, 4.75 mmol）を固体のまま少しずつ加えて、さらに2時間加熱還流した。反応溶媒を減圧留去し、残渣を酢酸エチル/ヘキサン( 3 / 5 )を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物である6-ブロモ-4’-メチルアミノフラボン（化合物６）を得た。収量 121 mg（収率：38.6%）¹H NMR（300 MHz, CDCl₃）δ8.31 (s, 1H), 7.69-7.75 (m, 3H), 7.39 (d, J = 8.7 Hz, 1H), 6.62-6.66 (m, 3H), 4.18 (s, 1H). 2.91 (s, 3H). Synthesis of 6-bromo-4'-methylaminoflavone Compound 5 (300 mg, 0.949 mmol) and paraformaldehyde (154 mg, 5.13 mmol) in methanol (15 mL) with stirring, sodium methylate methanol solution (0.27 mL) ) Was slowly added dropwise. After heating under reflux for 1 hour, sodium borohydride (180 mg, 4.75 mmol) was added little by little as a solid, and the mixture was further heated under reflux for 2 hours. The reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (3/5) as an elution solvent to obtain 6-bromo-4′-methylaminoflavone (Compound 6) as the target product. Obtained. Yield 121 mg (Yield: 38.6%) ¹ H NMR (300 MHz, CDCl ₃ ) δ8.31 (s, 1H), 7.69-7.75 (m, 3H), 7.39 (d, J = 8.7 Hz, 1H), 6.62-6.66 (m, 3H), 4.18 (s, 1H) .2.91 (s, 3H).

6-ブロモ-4’-ジメチルアミノフラボンの合成
化合物５（75 mg, 0.237 mmol）とパラホルムアルデヒド（71.1 mg, 2.37 mmol）の酢酸溶液（10 mL）に水素化シアノホウ素ナトリウム（74.5 mg, 1.19 mmol）を撹拌しながらゆっくり加え、室温で 3時間撹拌した。反応終了後、反応溶液に1 N水酸化ナトリウム水溶液50 mLを加え、クロロホルム50 mL (25 mL x 2)で抽出した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、目的物である6-ブロモ-4’-ジメチルアミノフラボン（化合物７）を黄色結晶として得た。収量 70 mg（収率：85.7%）¹H NMR（300 MHz, CDCl₃）δ8.34 (s, 1H), 7.72-7.82 (m, 3H), 7.43 (d, J = 9.0 Hz, 1H), 6.70-6.77 (m, 3H), 3.08 (s, 6H). MS m/z 345 (M⁺). Synthesis of 6-bromo-4'-dimethylaminoflavone Compound 5 (75 mg, 0.237 mmol) and paraformaldehyde (71.1 mg, 2.37 mmol) in acetic acid solution (10 mL) and sodium cyanoborohydride (74.5 mg, 1.19 mmol) ) Was slowly added with stirring, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 50 mL of 1N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with 50 mL (25 mL x 2) of chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 6-bromo-4′-dimethylaminoflavone (Compound 7) as the target product as yellow crystals. Yield 70 mg (Yield: 85.7%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 7.72-7.82 (m, 3H), 7.43 (d, J = 9.0 Hz, 1H), 6.70-6.77 (m, 3H), 3.08 (s, 6H) .MS m / z 345 (M ⁺ ).

6-(トリブチルスタニル)-4’-メチルアミノフラボンの合成
化合物6（286 mg, 0.866 mmol）のジオキサン溶液(21 mL)に、ビス（トリブチルスズ） (0.55 mL)、テトラキストリフェニルホスフィンパラジウム(41 mg, 0.035mmol)、トリエチルアミン（7 mL）を加え、90℃で6時間加熱した。反応溶媒を減圧留去し、残渣を酢酸エチル/ヘキサン( 1 / 4 )を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物である6-(トリブチルスタニル)-4’-メチルアミノフラボン（化合物８）を得た。収量 174 mg（収率：37.2%）¹H NMR（300 MHz, CDCl₃）δ8.30 (s, 1H), 7.65-7.78 (m, 3H), 7.46 (d, J = 9.0 Hz, 1H), 4.14(s, 1H), 2.92 (s, 3H), 0.86-1.35 (m, 27H). MS m/z 541 (MH⁺). Synthesis of 6- (tributylstannyl) -4'-methylaminoflavone Compound 6 (286 mg, 0.866 mmol) in dioxane (21 mL) was mixed with bis (tributyltin) (0.55 mL), tetrakistriphenylphosphine palladium (41 mg, 0.035 mmol) and triethylamine (7 mL) were added, and the mixture was heated at 90 ° C. for 6 hours. The reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/4) as an elution solvent to obtain 6- (tributylstannyl) -4′-methylaminoflavone (the target product). Compound 8) was obtained. Yield 174 mg (Yield: 37.2%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.30 (s, 1H), 7.65-7.78 (m, 3H), 7.46 (d, J = 9.0 Hz, 1H), 4.14 (s, 1H), 2.92 (s, 3H), 0.86-1.35 (m, 27H). MS m / z 541 (MH ⁺ ).

6-(トリブチルスタニル)-4’-ジメチルアミノフラボンの合成
化合物７（200 mg, 0.58 mmol）のジオキサン溶液(20 mL)に、ビス（トリブチルスズ） (0.5 mL)、テトラキストリフェニルホスフィンパラジウム(45 mg)、トリエチルアミン（6 mL）を加え、90℃で6時間加熱した。反応溶媒を減圧留去し、残渣を酢酸エチル／ヘキサン(1/2)を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物である6-(トリブチルスタニル)-4’-ジメチルアミノフラボン（化合物９）を得た。収量54 mg（収率：16.8%）¹H NMR（300 MHz, CDCl₃）δ8.30 (s, 1H), 7.82 (d, J = 9.0 Hz, 2H), 7.71-7.75 (m, 1H), 7.49 (d, J = 9.0 Hz, 1H), 6.72-6.77 (m, 3H), 0.86-1.56 (m, 27H). MS m/z 555 (MH⁺). Synthesis of 6- (tributylstannyl) -4'-dimethylaminoflavone Compound 7 (200 mg, 0.58 mmol) in dioxane (20 mL) was added to bis (tributyltin) (0.5 mL), tetrakistriphenylphosphine palladium (45 mL). mg) and triethylamine (6 mL) were added, and the mixture was heated at 90 ° C. for 6 hours. The reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/2) as an elution solvent to obtain 6- (tributylstannyl) -4′-dimethylaminoflavone (the target product). Compound 9) was obtained. Yield 54 mg (Yield: 16.8%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.30 (s, 1H), 7.82 (d, J = 9.0 Hz, 2H), 7.71-7.75 (m, 1H), 7.49 (d, J = 9.0 Hz, 1H), 6.72-6.77 (m, 3H), 0.86-1.56 (m, 27H). MS m / z 555 (MH ⁺ ).

6-ヨード-4’-メチルアミノフラボンの合成
化合物８（100 mg, 0.185 mmol）のクロロホルム溶液(20 mL)に、ヨウ素のクロロホルム溶液(1.5 mL, 1 M)を室温で加えた。室温で10分間反応した後、飽和亜硫酸水素ナトリウム水溶液(15 mL)を加え、反応を終了させた。クロロホルム層を分液し、硫酸ナトリウムで乾燥、溶媒を減圧留去後、残渣を酢酸エチル/ヘキサン( 1 / 2 )を溶出溶媒とするシリカゲルクロマトグラフィに付し、目的物である6-ヨード-4’-メチルアミノフラボン（化合物１０）を得た。収量20 mg（収率：28.7%）¹H NMR（300 MHz, CDCl₃）δ8.53 (s, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 10.8 Hz, 1H), 6.64-6.69 (m, 3H), 4.15 (s, 1H), 2.93 (s, 3H). MS m/z 377 (M⁺). Synthesis of 6-iodo-4′-methylaminoflavone Compound 8 (100 mg, 0.185 mmol) in chloroform (20 mL) was added iodine in chloroform (1.5 mL, 1 M) at room temperature. After reacting at room temperature for 10 minutes, saturated aqueous sodium hydrogensulfite solution (15 mL) was added to terminate the reaction. The chloroform layer was separated, dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography using ethyl acetate / hexane (1/2) as an elution solvent to obtain the desired product, 6-iodo-4. '-Methylaminoflavone (Compound 10) was obtained. Yield 20 mg (Yield: 28.7%) ¹ H NMR (300 MHz, CDCl ₃ ) δ8.53 (s, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 10.8 Hz, 1H), 6.64-6.69 (m, 3H), 4.15 (s, 1H), 2.93 (s, 3H). MS m / z 377 (M ⁺ ).

6-ヨード-4’-ジメチルアミノフラボンの合成
化合物９（30 mg, 0.054 mmol）のクロロホルム溶液(5 mL)に、ヨウ素のクロロホルム溶液(1 mL, 1 M)を室温で加えた。室温で30分間反応した後、飽和亜硫酸水素ナトリウム水溶液(5 mL)を加え、反応を終了させた。クロロホルム層を分液し、硫酸ナトリウムで乾燥、溶媒を減圧留去後、残渣を酢酸エチル／ヘキサン(1 / 9)を溶出溶媒とするシリカゲルクロマトグラフィに付し、目的物である6-ヨード-4’-ジメチルアミノフラボン（化合物１１）を得た。収量 10 mg（収率：47.3%）¹H NMR（300 MHz, CDCl₃）δ8.54 (s, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 1H), 6.71-6.80 (m, 3H), 3.09 (s, 6H). MS m/z 392 (MH⁺). Synthesis of 6-iodo-4′-dimethylaminoflavone To a chloroform solution (5 mL) of Compound 9 (30 mg, 0.054 mmol), a chloroform solution of iodine (1 mL, 1 M) was added at room temperature. After reacting at room temperature for 30 minutes, a saturated aqueous sodium hydrogen sulfite solution (5 mL) was added to terminate the reaction. The chloroform layer was separated, dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography using ethyl acetate / hexane (1/9) as an elution solvent to obtain 6-iodo-4 '-Dimethylaminoflavone (Compound 11) was obtained. Yield 10 mg (Yield: 47.3%) ¹ H NMR (300 MHz, CDCl ₃ ) δ8.54 (s, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 1H), 6.71-6.80 (m, 3H), 3.09 (s, 6H) .MS m / z 392 (MH ⁺ ).

4-メトキシ安息香酸 2-アセチル-4-ブロモフェニルエステルの合成
氷浴中、4-塩化メトキシベンゾイル(2.01 g, 9.35 mmol)のピリジン溶液(40 mL)に5’-ブロモ-2’-ヒドロキシアセトフェノン（化合物１２）(1.80 g, 10.6 mmol)を加えた。室温で 30分間反応させた後、氷冷下1 N塩酸へ注ぎ、激しく攪拌させた。析出した沈澱を濾取し、精製水で洗浄後、目的物である4-メトキシ安息香酸 2-アセチル-4-ブロモフェニルエステル（化合物１３）を得た。収量3.15 g（収率：96.5%）¹H NMR (300 MHz, CDCl₃) δ 7.72 (d, J = 7.5 Hz, 1H), 8.06 (d, J = 7.2 Hz, 1H), 8.86 (s, 1H), 10.13 (s, 1H). Synthesis of 4-methoxybenzoic acid 2-acetyl-4-bromophenyl ester 5'-Bromo-2'-hydroxyacetophenone in pyridine solution (40 mL) of 4-methoxybenzoyl chloride (2.01 g, 9.35 mmol) in an ice bath (Compound 12) (1.80 g, 10.6 mmol) was added. After reacting at room temperature for 30 minutes, the mixture was poured into 1 N hydrochloric acid under ice cooling and stirred vigorously. The deposited precipitate was collected by filtration and washed with purified water to obtain the desired product, 4-methoxybenzoic acid 2-acetyl-4-bromophenyl ester (Compound 13). Yield 3.15 g (Yield: 96.5%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.72 (d, J = 7.5 Hz, 1H), 8.06 (d, J = 7.2 Hz, 1H), 8.86 (s, 1H ), 10.13 (s, 1H).

1-(5-ブロモ-2-ヒドロキシフェニル)-3-(4-メトキシフェニル)プロパン-1,3-ジオンの合成
化合物１３（1.63 g, 4.67 mmol）をピリジン(50 mL)に溶解し、50℃まで加熱した。粉砕した水酸化カリウム(524 mg, 9.33 mmol)を加え、15分間撹拌後、氷冷し、10%酢酸溶液を加えた。析出した淡黄色の沈澱を濾取し、目的物である1-(5-ブロモ-2-ヒドロキシフェニル)-3-(4-メトキシフェニル)プロパン-1,3-ジオン（化合物１４）を得た。収量 1.42 g（収率：85.2%）¹H NMR（300 MHz, CDCl₃）δ12.01 (s, 1H), 7.94 (d, J = 9.3 Hz, 2H), 7.83 (s, 1H), 7.53 (d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.3 Hz, 2H), 6.90 (d, J = 8.7 Hz, 1H), 6.68 (s, 2H). 3.90 (s, 3H). Synthesis of 1- (5-bromo-2-hydroxyphenyl) -3- (4-methoxyphenyl) propane-1,3-dione Compound 13 (1.63 g, 4.67 mmol) was dissolved in pyridine (50 mL). Heated to ° C. Crushed potassium hydroxide (524 mg, 9.33 mmol) was added, and the mixture was stirred for 15 minutes, cooled on ice, and 10% acetic acid solution was added. The precipitated pale yellow precipitate was collected by filtration to obtain 1- (5-bromo-2-hydroxyphenyl) -3- (4-methoxyphenyl) propane-1,3-dione (Compound 14) as the target product. . Yield 1.42 g (Yield: 85.2%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 12.01 (s, 1H), 7.94 (d, J = 9.3 Hz, 2H), 7.83 (s, 1H), 7.53 ( d, J = 9.0 Hz, 1H), 7.00 (d, J = 9.3 Hz, 2H), 6.90 (d, J = 8.7 Hz, 1H), 6.68 (s, 2H). 3.90 (s, 3H).

6-ブロモ-4’-メトキシフラボンの合成
化合物１４（2.67 g, 7.65 mmol）、濃硫酸(0.78 mL)、酢酸(40 mL)の混液を1時間加熱還流した。室温に戻した後、氷片を反応溶液に加え、析出した結晶を濾取し、目的物である6-ブロモ-4’-メトキシフラボン（化合物１５）を得た。収量2.01 g（収率：79.4%）¹H NMR（300 MHz, CDCl₃）δ8.35 (s, 1H), 7.87 (d, J = 9.0 Hz, 2H), 7.77 (d, J = 9.0 Hz, 1H), 7.45 (d, J = 9.3 Hz, 1H), 7.03 (d, J = 9.0 Hz, 2H), 6.75 (s, 1H), 3.90 (s, 3H). A mixture of 6-bromo-4′-methoxyflavone compound 14 (2.67 g, 7.65 mmol), concentrated sulfuric acid (0.78 mL), and acetic acid (40 mL) was heated to reflux for 1 hour. After returning to room temperature, ice pieces were added to the reaction solution, and the precipitated crystals were collected by filtration to obtain the desired 6-bromo-4′-methoxyflavone (Compound 15). Yield 2.01 g (Yield: 79.4%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 7.87 (d, J = 9.0 Hz, 2H), 7.77 (d, J = 9.0 Hz, 1H), 7.45 (d, J = 9.3 Hz, 1H), 7.03 (d, J = 9.0 Hz, 2H), 6.75 (s, 1H), 3.90 (s, 3H).

6-ブロモ-4’-ヒドロキシフラボンの合成
化合物１５（400 mg, 1.21 mmol）のジクロロメタン（215 mL）溶液に、氷冷下、撹拌しながら三臭化ホウ素のジクロロメタン溶液（12 mL）をゆっくり加え、時間反応を行った。反応終了後、反応溶液に精製水(100 mL)を加え、ジクロロメタン層を抽出した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、残渣を酢酸エチル／ヘキサン( 2 / 5 )を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物である6-ブロモ-4’-ヒドロキシフラボン（化合物１６）を得た。収量 50 mg（収率：13.1%）¹H NMR（300 MHz, CDCl₃）δ10.38 (s, 1H), 8.09 (s, 1H), 7.97-8.00 (m, 3H), 7.76 (d, J = 9.0 Hz, 1H), 6.93-6.96 (m, 3H). Synthesis of 6-bromo-4'-hydroxyflavone Compound 15 (400 mg, 1.21 mmol) in dichloromethane (215 mL) was slowly added with boron tribromide in dichloromethane (12 mL) with stirring under ice-cooling. Time reaction. After completion of the reaction, purified water (100 mL) was added to the reaction solution, and the dichloromethane layer was extracted. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (2/5) as an elution solvent to obtain the desired 6-bromo-4'-hydroxyflavone. (Compound 16) was obtained. Yield 50 mg (Yield: 13.1%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.38 (s, 1H), 8.09 (s, 1H), 7.97-8.00 (m, 3H), 7.76 (d, J = 9.0 Hz, 1H), 6.93-6.96 (m, 3H).

6-(トリブチルスタニル)-4’-メトキシフラボンの合成
化合物１５（500 mg, 1.51 mmol）のジオキサン溶液(36 mL)に、ビス（トリブチルスズ） (0.95 mL)、テトラキストリフェニルホスフィンパラジウム(72 mg, 0.0623 mmol)、トリエチルアミン（12 mL）を加え、90℃で10時間加熱した。反応溶媒を減圧留去し、残渣を酢酸エチル／ヘキサン( 1 / 10 )を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物である6-(トリブチル)-4’-メトキシフラボン（化合物１７）を得た。収量 562 mg（収率：68.8%）¹H NMR（300 MHz, CDCl₃）δ8.31 (s, 1H), 7.88-7.92 (m, 2H), 7.68-7.75 (m, 1H), 7.56 (s, 1H), 7.02-7.05 (m, 2H), 6.77 (s, 1H), 3.90 (s, 3H), 0.86-1.57 (m, 27H). MS m/z 542 (MH⁺). Synthesis of 6- (tributylstannyl) -4′-methoxyflavone Compound 15 (500 mg, 1.51 mmol) in dioxane (36 mL) was mixed with bis (tributyltin) (0.95 mL), tetrakistriphenylphosphine palladium (72 mg). , 0.0623 mmol) and triethylamine (12 mL) were added, and the mixture was heated at 90 ° C. for 10 hours. The reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/10) as an elution solvent to obtain 6- (tributyl) -4′-methoxyflavone (Compound 17) as the target product. Got. Yield 562 mg (Yield: 68.8%) ¹ H NMR (300 MHz, CDCl ₃ ) δ8.31 (s, 1H), 7.88-7.92 (m, 2H), 7.68-7.75 (m, 1H), 7.56 (s , 1H), 7.02-7.05 (m, 2H), 6.77 (s, 1H), 3.90 (s, 3H), 0.86-1.57 (m, 27H). MS m / z 542 (MH ⁺ ).

6-(トリブチルスタニル)-4’-ヒドロキシフラボンの合成
化合物１６（50 mg, 0.158 mmol）のジオキサン溶液(4.5 mL)に、ビス（トリブチルスズ） (0.1 mL)、テトラキストリフェニルホスフィンパラジウム(7.5 mg)、トリエチルアミン（1.5 mL）を加え、90℃で17時間加熱した。反応溶媒を減圧留去し、残渣を酢酸エチル／ヘキサン( 1 / 5 )を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物である6-(トリブチルスタニル)-4’-ヒドロキシフラボン（化合物１８）を得た。収量 36 mg（収率：43.3%）¹H NMR（300 MHz, CDCl₃）δ8.31 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.50-7.55 (m, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.77 (s, 1H), 6.31 (s, 1H), 0.86-1.59 (m, 27H). MS m/z 527 (M⁺). Synthesis of 6- (tributylstannyl) -4'-hydroxyflavone Compound 16 (50 mg, 0.158 mmol) in dioxane (4.5 mL) was mixed with bis (tributyltin) (0.1 mL), tetrakistriphenylphosphine palladium (7.5 mg ), Triethylamine (1.5 mL) was added, and the mixture was heated at 90 ° C. for 17 hours. The reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/5) as an elution solvent to obtain 6- (tributylstannyl) -4'-hydroxyflavone (compound) 18) was obtained. Yield 36 mg (Yield: 43.3%) ¹ H NMR (300 MHz, CDCl ₃ ) δ8.31 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.50-7.55 (m, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.77 (s, 1H), 6.31 (s, 1H), 0.86-1.59 (m, 27H). MS m / z 527 (M ⁺ ).

6-ヨード-4’-メトキシフラボンの合成
化合物１７（450 mg, 0.831 mmol）のクロロホルム溶液(87 mL)に、ヨウ素のクロロホルム溶液(5 mL, 1 M)を室温で加えた。室温で30分間反応した後、飽和亜硫酸水素ナトリウム水溶液(30 mL)を加え、反応を終了させた。クロロホルム層を分液し、硫酸ナトリウムで乾燥、溶媒を減圧留去後、残渣を酢酸エチル／ヘキサン( 1 / 7 )を溶出溶媒とするシリカゲルクロマトグラフィに付し、目的物である6-ヨード-4’-メトキシフラボン（化合物１９）を得た。収量 227 mg（収率：72.2%）¹H NMR（300 MHz, CDCl₃）δ8.55 (s, 1H), 7.86-7.93 (m, 3H), 7.32 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 6.75 (s, 1H), 3.90 (s, 3H). MS m/z 378 (M⁺). Synthesis of 6-iodo-4′-methoxyflavone Compound 17 (450 mg, 0.831 mmol) in chloroform (87 mL) was added iodine in chloroform (5 mL, 1 M) at room temperature. After reacting at room temperature for 30 minutes, saturated aqueous sodium hydrogensulfite solution (30 mL) was added to terminate the reaction. The chloroform layer was separated, dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography using ethyl acetate / hexane (1/7) as an elution solvent to obtain 6-iodo-4 '-Methoxyflavone (Compound 19) was obtained. Yield 227 mg (Yield: 72.2%) ¹ H NMR (300 MHz, CDCl ₃ ) δ8.55 (s, 1H), 7.86-7.93 (m, 3H), 7.32 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 6.75 (s, 1H), 3.90 (s, 3H). MS m / z 378 (M ⁺ ).

6-ヨード-4’-ヒドロキシフラボンの合成
化合物１９（185 mg, 0.489 mmol）のジクロロメタン（85 mL）溶液に、氷冷下、撹拌しながら三臭化ホウ素のジクロロメタン溶液（4.9 mL）をゆっくり加え、30時間反応を行った。反応終了後、反応溶液に精製水(80 mL)を加え、ジクロロメタン層を抽出した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、残渣を酢酸エチル／ヘキサン( 1 / 4 )を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物である6-ヨード-4’-ヒドロキシフラボン（化合物２０）を得た。収量 79 mg（収率：44.3%）¹H NMR（300 MHz, DMSO₆）δ10.37 (s, 1H), 8.27 (s, 1H), 8.28-8.30 (m, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.7 Hz, 1H), 6.93-6.95 (m, 3H). MS m/z 364 (M⁺). Synthesis of 6-iodo-4'-hydroxyflavone To a solution of compound 19 (185 mg, 0.489 mmol) in dichloromethane (85 mL) was slowly added boron tribromide in dichloromethane (4.9 mL) with stirring under ice cooling. The reaction was performed for 30 hours. After completion of the reaction, purified water (80 mL) was added to the reaction solution, and the dichloromethane layer was extracted. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/4) as an elution solvent to obtain the desired 6-iodo-4'-hydroxyflavone. (Compound 20) was obtained. Yield 79 mg (Yield: 44.3%) ¹ H NMR (300 MHz, DMSO ₆ ) δ 10.37 (s, 1H), 8.27 (s, 1H), 8.28-8.30 (m, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.7 Hz, 1H), 6.93-6.95 (m, 3H). MS m / z 364 (M ⁺ ).

4-ニトロ安息香酸 2-アセチル-4-メトキシフェニルエステルの合成
氷浴中、4-塩化ニトロベンゾイル(1.72 g, 9.26 mmol)のピリジン溶液(20 mL)に5’-メトキシ-2’-ヒドロキシアセトフェノン (1.5 g, 9.03 mmol)を加えた。室温で30分間反応させた後、氷冷下1 N塩酸へ注ぎ、激しく攪拌させた。析出した沈澱を濾取し、精製水で洗浄後、目的物である4-ニトロ安息香酸 2-アセチル-4-メトキシフェニルエステル（化合物２１）を得た。収量2.49 g（収率：87.4%） Synthesis of 4-nitrobenzoic acid 2-acetyl-4-methoxyphenyl ester 5'-methoxy-2'-hydroxyacetophenone in a pyridine solution (20 mL) of 4-nitrobenzoyl chloride (1.72 g, 9.26 mmol) in an ice bath (1.5 g, 9.03 mmol) was added. After reacting at room temperature for 30 minutes, the mixture was poured into 1 N hydrochloric acid under ice cooling and stirred vigorously. The deposited precipitate was collected by filtration and washed with purified water to give the desired product, 4-nitrobenzoic acid 2-acetyl-4-methoxyphenyl ester (Compound 21). Yield 2.49 g (Yield: 87.4%)

1-(5-メトキシ-2-ヒドロキシフェニル)-3-(4-ニトロフェニル)プロパン-1,3-ジオンの合成
化合物２１（3.01 g, 9.55 mmol）をピリジン(50 mL)に溶解し、50℃まで加熱した。粉砕した水酸化カリウム(2.53 g, 45.1 mmol)を加え、15分間撹拌後、氷冷し、10%酢酸溶液を加えた。析出した淡黄色の沈澱を濾取し、目的物である1-(5-メトキシ-2-ヒドロキシフェニル)-3-(4-ニトロフェニル)プロパン-1,3-ジオン（化合物２２）を得た。収量2.93 g（収率：97.4%） Synthesis of 1- (5-methoxy-2-hydroxyphenyl) -3- (4-nitrophenyl) propane-1,3-dione Compound 21 (3.01 g, 9.55 mmol) was dissolved in pyridine (50 mL). Heated to ° C. Crushed potassium hydroxide (2.53 g, 45.1 mmol) was added, and the mixture was stirred for 15 minutes, cooled on ice, and 10% acetic acid solution was added. The precipitated pale yellow precipitate was collected by filtration to obtain 1- (5-methoxy-2-hydroxyphenyl) -3- (4-nitrophenyl) propane-1,3-dione (Compound 22) as the target product. . Yield 2.93 g (Yield: 97.4%)

6-メトキシ-4’-ニトロフラボンの合成
化合物２２（2.92 g, 9.26 mmol）、濃硫酸(1 mL)、酢酸(50 mL)の混液を1時間加熱還流した。室温に戻した後、氷片を反応溶液に加え、析出した結晶を濾取し、目的物である6-メトキシ-4’-ニトロフラボン（化合物２３）を得た。収量2.31 g（収率：84.1%） A mixture of 6-methoxy-4′-nitroflavone compound 22 (2.92 g, 9.26 mmol), concentrated sulfuric acid (1 mL), and acetic acid (50 mL) was heated to reflux for 1 hour. After returning to room temperature, ice pieces were added to the reaction solution, and the precipitated crystals were collected by filtration to obtain the desired 6-methoxy-4′-nitroflavone (Compound 23). Yield 2.31 g (Yield: 84.1%)

6-メトキシ-4’-アミノフラボンの合成
化合物２３（520 mg, 1.75 mmol）のエタノール（30 mL）溶液に、撹拌しながら塩化スズ(II)（3.32 g, 17.5 mmol）をゆっくり加え、1時間加熱還流した。反応終了後、反応溶液に1 N水酸化ナトリウム水溶液(150 mL)を加え、酢酸エチル 50 mL (150 mL)で抽出した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、目的物である6-メトキシ-4’-アミノフラボン（化合物２４）を黄色結晶として得た。収量 360 mg（収率：74.8%）¹H NMR（300 MHz, DMSO-d₆）δ7.91 (d, J = 8.7 Hz, 2H), 7.69-7.70 (m, 1H), 7.38-7.42 (m, 2H), 6.93 (d, J = 9.0 Hz, 2H), 6.82 (s, 1H), 3.86 (s, 2H). Synthesis of 6-methoxy-4'-aminoflavone To a solution of compound 23 (520 mg, 1.75 mmol) in ethanol (30 mL), tin (II) chloride (3.32 g, 17.5 mmol) was slowly added with stirring for 1 hour. Heated to reflux. After completion of the reaction, 1N aqueous sodium hydroxide solution (150 mL) was added to the reaction solution, and the mixture was extracted with 50 mL (150 mL) of ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 6-methoxy-4′-aminoflavone (Compound 24) as the target product as yellow crystals. Yield 360 mg (Yield: 74.8%) ¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.91 (d, J = 8.7 Hz, 2H), 7.69-7.70 (m, 1H), 7.38-7.42 (m , 2H), 6.93 (d, J = 9.0 Hz, 2H), 6.82 (s, 1H), 3.86 (s, 2H).

6-メトキシ-4’-ジメチルアミノフラボンの合成
化合物２４（630 mg, 2.36 mmol）とパラホルムアルデヒド（707 mg, 23.6 mmol）の酢酸溶液（30 mL）に水素化シアノホウ素ナトリウム（891 mg, 14.1 mmol）を撹拌しながらゆっくり加え、室温で 3時間撹拌した。反応終了後、反応溶液に1 N水酸化ナトリウム水溶液50 mLを加え、クロロホルム50 mL (25 mL x 2)で抽出した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、目的物である6-メトキシ-4’-メチルアミノフラボン（化合物２５）を黄色結晶として得た。収量 450 mg（収率：64.6%）¹H NMR（300 MHz, CDCl₃）δ8.31 (s, 1H), 7.69-7.75 (m, 3H), 7.39 (d, J = 8.7 Hz, 1H), 6.62-6.66 (m, 3H), 4.18 (s, 1H). 2.91 (s, 3H). Synthesis of 6-methoxy-4'-dimethylaminoflavone Compound 24 (630 mg, 2.36 mmol) and paraformaldehyde (707 mg, 23.6 mmol) in acetic acid solution (30 mL) and sodium cyanoborohydride (891 mg, 14.1 mmol) ) Was slowly added with stirring, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 50 mL of 1N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with 50 mL (25 mL x 2) of chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 6-methoxy-4′-methylaminoflavone (Compound 25) as the target product as yellow crystals. Yield 450 mg (Yield: 64.6%) ¹ H NMR (300 MHz, CDCl ₃ ) δ8.31 (s, 1H), 7.69-7.75 (m, 3H), 7.39 (d, J = 8.7 Hz, 1H), 6.62-6.66 (m, 3H), 4.18 (s, 1H) .2.91 (s, 3H).

6-メトキシ-4’-メチルアミノフラボンの合成
化合物２４（270 mg, 1.01 mmol）とパラホルムアルデヒド（152 mg, 5.05 mmol）のメタノール溶液（15 mL）に撹拌しながらナトリウムメチラートメタノール溶液（0.27 mL）をゆっくり滴下した。1時間加熱還流後、水素化ホウ素ナトリウム（306 mg, 8.08 mmol）を固体のまま少しずつ加えて、さらに2時間加熱還流した。反応溶媒を減圧留去し、残渣を酢酸エチル/ヘキサン( 1/ 1 )を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物である6-ブロモ-4’-メチルアミノフラボン（化合物２６）を得た。収量 120 mg（収率：42.2%）¹H NMR（300 MHz, CDCl₃）δ7.78 (d, J = 8.7 Hz, 2H), 7.59 (m, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.22-7.26 (m, 1H), 6.65-6.69 (m, 3H), 3.91 (s, 3H), 2.93 (s, 3H). Synthesis of 6-methoxy-4'-methylaminoflavone Compound 24 (270 mg, 1.01 mmol) and paraformaldehyde (152 mg, 5.05 mmol) in methanol solution (15 mL) with stirring, sodium methylate methanol solution (0.27 mL) ) Was slowly added dropwise. After heating under reflux for 1 hour, sodium borohydride (306 mg, 8.08 mmol) was added little by little as a solid, and the mixture was further heated under reflux for 2 hours. The reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/1) as an elution solvent to obtain 6-bromo-4'-methylaminoflavone (Compound 26) as the target product. Obtained. Yield 120 mg (Yield: 42.2%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.78 (d, J = 8.7 Hz, 2H), 7.59 (m, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.22-7.26 (m, 1H), 6.65-6.69 (m, 3H), 3.91 (s, 3H), 2.93 (s, 3H).

6-ヒドロキシ-4’-ジメチルアミノフラボンの合成
化合物２５（200 mg, 0.68 mmol）のジクロロメタン（50 mL）溶液に、氷冷下、撹拌しながら三臭化ホウ素のジクロロメタン溶液（5 mL）をゆっくり加え、時間反応を行った。反応終了後、反応溶液に精製水(100 mL)を加え、ジクロロメタン層を抽出した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、残渣をクロロホルム／メタノール( 20 / 1 )を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物である6-ヒドロキシ-4’-ジメチルアミノフラボン（化合物２７）を得た。収量 25 mg（収率：13.1%）¹H NMR（300 MHz, DMSO-d₆）δ 9.94 (s, 1H), 7.90 (d, J = 9.0 Hz, 2H), 7.30 (m, 1H), 7.19-7.22 (m, 1H), 6.82 (d, J = 9.0 Hz, 2H), 6.73 (s, 1H), 3.03 (s, 6H). Synthesis of 6-hydroxy-4'-dimethylaminoflavone Compound 25 (200 mg, 0.68 mmol) in dichloromethane (50 mL) was slowly added boron tribromide in dichloromethane (5 mL) with stirring under ice-cooling. In addition, a time reaction was performed. After completion of the reaction, purified water (100 mL) was added to the reaction solution, and the dichloromethane layer was extracted. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform / methanol (20/1) as an elution solvent to obtain the desired 6-hydroxy-4'-dimethylaminoflavone. (Compound 27) was obtained. Yield 25 mg (Yield: 13.1%) ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.94 (s, 1H), 7.90 (d, J = 9.0 Hz, 2H), 7.30 (m, 1H), 7.19 -7.22 (m, 1H), 6.82 (d, J = 9.0 Hz, 2H), 6.73 (s, 1H), 3.03 (s, 6H).

6-ヒドロキシ-4’-メチルアミノフラボンの合成
化合物２６（270 mg, 0.96 mmol）のジクロロメタン（20 mL）溶液に、氷冷下、撹拌しながら三臭化ホウ素のジクロロメタン溶液（5 mL）をゆっくり加え、時間反応を行った。反応終了後、反応溶液に精製水(100 mL)を加え、ジクロロメタン層を抽出した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、残渣をクロロホルム／メタノール( 20 / 1 )を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物である6-ヒドロキシ-4’-メチルアミノフラボン（化合物２８）を得た。収量 15 mg（収率：5.8%）¹H NMR（300 MHz, DMSO-d₆）δ9.92 (s, 1H),7.83 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.7Hz, 1H), 7.30 (m, 1H), 7.18-7.22 (m, 1H), 6.64-6.67 (m, 3H), 2.76 (s, 3H). Synthesis of 6-hydroxy-4'-methylaminoflavone Compound 26 (270 mg, 0.96 mmol) in dichloromethane (20 mL) was slowly added boron tribromide in dichloromethane (5 mL) with stirring under ice cooling. In addition, a time reaction was performed. After completion of the reaction, purified water (100 mL) was added to the reaction solution, and the dichloromethane layer was extracted. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform / methanol (20/1) as an elution solvent to obtain the desired 6-hydroxy-4'-methylaminoflavone. (Compound 28) was obtained. Yield 15 mg (Yield: 5.8%) ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.92 (s, 1H), 7.83 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.7 Hz, 1H), 7.30 (m, 1H), 7.18-7.22 (m, 1H), 6.64-6.67 (m, 3H), 2.76 (s, 3H).

（２）カルコン誘導体の合成
(E)-1-(3-ブロモフェニル)-3-(4-ヒドロキシ-3-メトキシフェニル)プロパン-2-エン-1-オンの合成
3-ブロモアセトフェノン1.99 g (10 mmol)をエタノール(10 mL)に溶解し、１０％水酸化カリウム水溶液(30 mL)に氷冷下加えた。１５分間撹拌後、o-バニリン1.52 g (10 mmol)を固体のまま加え、さらに氷冷下１５分間撹拌した。室温に戻し、４時間撹拌した後、析出した結晶を吸引濾過し、ろ液を減圧留去し、酢酸エチル／ヘキサン（1／4）を溶出溶媒とするシリカゲルクロマトグラフィーに付し、目的物である化合物２９を得た。収量470 mg（収率14.1％）。¹H NMR（300 MHz, CDCl₃）δ8.14 (s, 1H), 8.04 (d, J = 15.9 Hz, 1H), 7.90-7.98 (m, 1H), 7.66-7.71 (m, 2H), 7.32-7.40 (m, 1H), 7.15-7.20 (m, 1H), 6.89-6.91 (m, 2H), 6.31 (s, 1H), 3.94 (s, 3H). (2) Synthesis of chalcone derivatives
Synthesis of (E) -1- (3-bromophenyl) -3- (4-hydroxy-3-methoxyphenyl) propan-2-en-1-one
3-Bromoacetophenone 1.99 g (10 mmol) was dissolved in ethanol (10 mL) and added to a 10% aqueous potassium hydroxide solution (30 mL) under ice cooling. After stirring for 15 minutes, 1.52 g (10 mmol) of o-vanillin was added as a solid, and the mixture was further stirred for 15 minutes under ice cooling. After returning to room temperature and stirring for 4 hours, the precipitated crystals were suction filtered, the filtrate was distilled off under reduced pressure, and subjected to silica gel chromatography using ethyl acetate / hexane (1/4) as an elution solvent. Some compound 29 was obtained. Yield 470 mg (yield 14.1%). ¹ H NMR (300 MHz, CDCl ₃ ) δ8.14 (s, 1H), 8.04 (d, J = 15.9 Hz, 1H), 7.90-7.98 (m, 1H), 7.66-7.71 (m, 2H), 7.32 -7.40 (m, 1H), 7.15-7.20 (m, 1H), 6.89-6.91 (m, 2H), 6.31 (s, 1H), 3.94 (s, 3H).

(E)-1-(3-(トリブチルスタニル)フェニル)-3-(4-ヒドロキシ-3-メトキシフェニル)プロパン-2-エン-1-オンの合成
化合物29（370 mg, 1.11 mmol）のジオキサン溶液(10 mL)に、ビス（トリブチルスズ） (1 mL)、テトラキストリフェニルホスフィンパラジウム(75 mg)、トリエチルアミン（5 mL）を加え、12時間加熱還流した。反応溶媒を減圧留去し、残渣を酢酸エチル／ヘキサン( 1 / 9)を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物である化合物３０を得た。収量 161 mg（収率：26.7%）¹H NMR（300 MHz, CDCl₃）δ8.10 (s, 1H), 8.03 (d, J = 15.9 Hz, 1H), 7.90-7.95 (m, 1H), 7.73 (d, J = 15.9 Hz, 1H), 7.62-7.68 (m, 1H), 7.41-7.49 (m, 1H), 7.15-7.20 (m, 1H), 6.87-6.89 (m, 2H), 6.24 (s, 1H), 3,94 (s, 3H), 0.86-1.65 (m, 27H). (E) -1- (3- (Tributylstannyl) phenyl) -3- (4-hydroxy-3-methoxyphenyl) propan-2-en-1-one synthetic compound 29 (370 mg, 1.11 mmol) Bis (tributyltin) (1 mL), tetrakistriphenylphosphine palladium (75 mg), and triethylamine (5 mL) were added to the dioxane solution (10 mL), and the mixture was heated to reflux for 12 hours. The reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/9) as an elution solvent to obtain the target compound 30. Yield 161 mg (Yield: 26.7%) ¹ H NMR (300 MHz, CDCl ₃ ) δ8.10 (s, 1H), 8.03 (d, J = 15.9 Hz, 1H), 7.90-7.95 (m, 1H), 7.73 (d, J = 15.9 Hz, 1H), 7.62-7.68 (m, 1H), 7.41-7.49 (m, 1H), 7.15-7.20 (m, 1H), 6.87-6.89 (m, 2H), 6.24 ( s, 1H), 3,94 (s, 3H), 0.86-1.65 (m, 27H).

(E)-3-(4-ヒドロキシ-3-メトキシフェニル)-1-(3-ヨードフェニル)プロパン-2-エン-1-オンの合成
化合物３０（150 mg, 0.28 mmol）のクロロホルム溶液(15 mL)に、ヨウ素のクロロホルム溶液(2 mL, 1.1 mM溶液)を室温で加えた。室温で30分間反応した後、飽和亜硫酸水素ナトリウム水溶液(20 mL)を加え、反応を終了させた。クロロホルム層を分液し、硫酸ナトリウムで乾燥、溶媒を減圧留去後、残渣を酢酸エチル／ヘキサン( 1 / 5 )を溶出溶媒とするシリカゲルクロマトグラフィに付し、目的物である化合物３１を得た。収量 47 mg（収率：44.8%） (E) -3- (4-Hydroxy-3-methoxyphenyl) -1- (3-iodophenyl) propan-2-en-1-one synthesis compound 30 (150 mg, 0.28 mmol) in chloroform (15 To the mixture (mL), a chloroform solution of iodine (2 mL, 1.1 mM solution) was added at room temperature. After reacting at room temperature for 30 minutes, a saturated aqueous sodium hydrogen sulfite solution (20 mL) was added to terminate the reaction. The chloroform layer was separated, dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography using ethyl acetate / hexane (1/5) as an elution solvent to obtain the target compound 31. . Yield 47 mg (Yield: 44.8%)

(E)-1-(4-ブロモフェニル)-3-(4-ニトロフェニル)プロパン-2-エン-1-オンの合成
４-ブロモアセトフェノン1.99 g (10 mmol)をエタノール(10 mL)に溶解し、１０％水酸化カリウム水溶液(30 mL)に氷冷下加えた。１５分間撹拌後、４−ニトロベンズアルデヒド1.51 g (10 mmol)を固体のまま加え、さらに氷冷下１５分間撹拌した。室温に戻し、４時間撹拌した後、酢酸エチル(50 mL)を加え、析出した結晶を吸引濾過し、酢酸エチルで十分洗い、目的物である化合物３２を得た。収量1.27 g（収率38.2％）。 Synthesis of (E) -1- (4-bromophenyl) -3- (4-nitrophenyl) propan-2-en-1-one 4-bromoacetophenone 1.99 g (10 mmol) dissolved in ethanol (10 mL) And added to a 10% aqueous potassium hydroxide solution (30 mL) under ice-cooling. After stirring for 15 minutes, 1.51 g (10 mmol) of 4-nitrobenzaldehyde was added as a solid, and the mixture was further stirred for 15 minutes under ice cooling. After returning to room temperature and stirring for 4 hours, ethyl acetate (50 mL) was added, and the precipitated crystals were suction filtered and washed thoroughly with ethyl acetate to obtain Compound 32, which was the desired product. Yield 1.27 g (yield 38.2%).

(E)-3-(4-アミノフェニル)-1-(4-ブロモフェニル)プロパン-2-エン-1-オンの合成
化合物３２（1.0 g, 3.01 mmol）のエタノール（15 mL）溶液に、撹拌しながら塩化スズ(II)（5.0 g, 26.4 mmol）をゆっくり加え、2時間加熱還流した。反応終了後、反応溶液に1 N水酸化ナトリウム水溶液(150 mL)を加え、酢酸エチル 50 mL (150 mL)で抽出した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、残渣を酢酸エチル／ヘキサン( 1 / 3 )を溶出溶媒とするシリカゲルクロマトグラフィに付し、目的物である化合物３３を得た。収量 556 mg（収率：61.1%） Synthesis of (E) -3- (4-aminophenyl) -1- (4-bromophenyl) propan-2-en-1-one Compound 32 (1.0 g, 3.01 mmol) in ethanol (15 mL) While stirring, tin (II) chloride (5.0 g, 26.4 mmol) was slowly added and heated to reflux for 2 hours. After completion of the reaction, 1N aqueous sodium hydroxide solution (150 mL) was added to the reaction solution, and the mixture was extracted with 50 mL (150 mL) of ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography using ethyl acetate / hexane (1/3) as an elution solvent to obtain the target compound 33. Yield 556 mg (Yield: 61.1%)

(E)-1-(4-ブロモフェニル)-3-(4-(ジメチルアミノ)フェニル)プロパン-2-エン-1-オンの合成
化合物３３（250 mg, 0.83 mmol）とパラホルムアルデヒド（400 mg, 13.4 mmol）の酢酸溶液（15 mL）に水素化シアノホウ素ナトリウム（250 mg, 3.98 mmol）を撹拌しながらゆっくり加え、室温で 3時間撹拌した。反応終了後、反応溶液に1 N水酸化ナトリウム水溶液50 mLを加え、クロロホルム50 mL (25 mL x 2)で抽出した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、残渣を酢酸エチル／ヘキサン( 1 / 12 )を溶出溶媒とするシリカゲルクロマトグラフィに付し、目的物である化合物３４を得た。収量 236 mg（収率：86.1%） (E) -1- (4-Bromophenyl) -3- (4- (dimethylamino) phenyl) propan-2-en-1-one compound 33 (250 mg, 0.83 mmol) and paraformaldehyde (400 mg) , 13.4 mmol) in acetic acid solution (15 mL), sodium cyanoborohydride (250 mg, 3.98 mmol) was slowly added with stirring and stirred at room temperature for 3 hours. After completion of the reaction, 50 mL of 1N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with 50 mL (25 mL x 2) of chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography using ethyl acetate / hexane (1/12) as an elution solvent to obtain the target compound 34. Yield 236 mg (Yield: 86.1%)

(E)-1-(4-(トリブチルスタニル)フェニル)-3-(4-(ジメチルアミノ)フェニル)プロパン-2-エン-1-オンの合成
化合物３４（220 mg, 0.67 mmol）のジオキサン溶液(10 mL)に、ビス（トリブチルスズ） (1 mL)、テトラキストリフェニルホスフィンパラジウム(84 mg)、トリエチルアミン（5 mL）を加え、2時間加熱還流した。反応溶媒を減圧留去し、残渣を酢酸エチル／ヘキサン( 1 / 18 )を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物である化合物３５を得た。収量 43 mg（収率：11.9%）¹H NMR（300 MHz, CDCl₃）δ7.91 (d, J = 9.0 Hz, 2H), 7.80 (d, J = 15.9 Hz, 1H), 7.51-7.65 (m, 3H), 7.35 (d ,J = 15.9 Hz, 1H), 6.69 (d, J = 9.0 Hz, 2H), 3.05 (s, 6H), 0.88-1.59 (m, 27H). (E) -1- (4- (Tributylstannyl) phenyl) -3- (4- (dimethylamino) phenyl) propan-2-en-1-one synthesis compound 34 (220 mg, 0.67 mmol) in dioxane Bis (tributyltin) (1 mL), tetrakistriphenylphosphine palladium (84 mg) and triethylamine (5 mL) were added to the solution (10 mL), and the mixture was heated to reflux for 2 hours. The reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/18) as an elution solvent to obtain Compound 35 as the target product. Yield 43 mg (Yield: 11.9%) ¹ H NMR (300 MHz, CDCl ₃ ) δ7.91 (d, J = 9.0 Hz, 2H), 7.80 (d, J = 15.9 Hz, 1H), 7.51-7.65 ( m, 3H), 7.35 (d, J = 15.9 Hz, 1H), 6.69 (d, J = 9.0 Hz, 2H), 3.05 (s, 6H), 0.88-1.59 (m, 27H).

(E)-3-(4-(ジメチルアミノ)フェニル)-1-(4-ヨードフェニル)プロパン-2-エン-1-オンの合成
化合物３５（4 mg, 0.07 mmol）のクロロホルム溶液(5 mL)に、ヨウ素のクロロホルム溶液(2 mL, 1.1 mM溶液)を室温で加えた。室温で30分間反応した後、飽和亜硫酸水素ナトリウム水溶液(20 mL)を加え、反応を終了させた。クロロホルム層を分液し、硫酸ナトリウムで乾燥、溶媒を減圧留去後、残渣を酢酸エチル／ヘキサン( 1 / 9 )を溶出溶媒とするシリカゲルクロマトグラフィに付し、目的物である化合物３６を得た。収量 13 mg（収率：46.6%）¹H NMR（300 MHz, CDCl₃）δ7.82-7.88 (m, 3H), 7.71-7.78 (m, 2H), 7.53 (d, J = 9.0 Hz, 2H), 7.20-7.30 (m, 2H), 6.68 (d, J = 9.0 Hz, 2H), 3.05 (s, 6H).
（３）スチリルクロモン誘導体の合成 Synthesis of (E) -3- (4- (dimethylamino) phenyl) -1- (4-iodophenyl) propan-2-en-1-one Compound 35 (4 mg, 0.07 mmol) in chloroform (5 mL) ) Was added a solution of iodine in chloroform (2 mL, 1.1 mM solution) at room temperature. After reacting at room temperature for 30 minutes, a saturated aqueous sodium hydrogen sulfite solution (20 mL) was added to terminate the reaction. The chloroform layer was separated, dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography using ethyl acetate / hexane (1/9) as an elution solvent to obtain the target compound 36. . Yield 13 mg (Yield: 46.6%) ¹ H NMR (300 MHz, CDCl ₃ ) δ7.82-7.88 (m, 3H), 7.71-7.78 (m, 2H), 7.53 (d, J = 9.0 Hz, 2H ), 7.20-7.30 (m, 2H), 6.68 (d, J = 9.0 Hz, 2H), 3.05 (s, 6H).
(3) Synthesis of styrylchromone derivatives

(E)-2-アセチル -4-ブロモフェニルl 3-(4-ニトロフェニル)アクリレイト の合成
4-ニトロケイ皮酸クロリド(545 mg, 2.58 mmol)のピリジン溶液(10 mL)に5-ブロモ-2-ヒドロキシアセトフェノン(500 mg, 2.58 mmol)を加えた。室温で60分反応させた後、氷冷下1 N塩酸に注ぎ、激しく撹拌させた。析出した沈殿を瀘取し、精製水で洗浄後、目的物である化合物３７を得た。収量1.073 g (収率99.2%). ¹H NMR (300 MHz, CDCl₃) δ 8.29(d, J = 9.0 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.77-7.62 (m, 4H), 7.10 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 16.2 Hz, 1H). Synthesis of (E) -2-acetyl-4-bromophenyl l 3- (4-nitrophenyl) acrylate
5-Bromo-2-hydroxyacetophenone (500 mg, 2.58 mmol) was added to a pyridine solution (10 mL) of 4-nitrocinnamic acid chloride (545 mg, 2.58 mmol). After reacting at room temperature for 60 minutes, the mixture was poured into 1 N hydrochloric acid under ice cooling and stirred vigorously. The deposited precipitate was collected and washed with purified water to obtain the target compound 37. Yield 1.073 g (Yield 99.2%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.29 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.77-7.62 (m , 4H), 7.10 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 16.2 Hz, 1H).

1-(5-ブロモ-2ヒドロキシフェニル)-5-(4-ニトロフェニル)ペント-4-エン-1,3-ジオン の合成
化合物３７(500 mg, 1.28 mmol)をピリジン(12 mL)に溶解し、50℃まで加熱した。粉砕した水酸化カリウム(0.22 g, 3.84 mmol)を加え、30分間撹拌後、氷冷し、10%酢酸溶液を加えた。析出した淡黄色の沈殿を瀘取し、目的物3８を得た。収量410 mg(収率82.0%). Synthesis of 1- (5-bromo-2hydroxyphenyl) -5- (4-nitrophenyl) pent-4-ene-1,3-dione Compound 37 (500 mg, 1.28 mmol) dissolved in pyridine (12 mL) And heated to 50 ° C. Crushed potassium hydroxide (0.22 g, 3.84 mmol) was added, and the mixture was stirred for 30 minutes, cooled on ice, and 10% acetic acid solution was added. The precipitated pale yellow precipitate was collected to obtain the target product 38. Yield 410 mg (yield 82.0%).

6-ブロモ-4’-ニトロスチリルクロモン の合成
化合物３８(860 mg,2.20 mmol)、濃硫酸(1.2 mL)、酢酸(15 mL)の混液を1時間加熱還流した。室温に戻した後、氷片を反応溶液に加え、析出した結晶を瀘取し、目的物３９を得た。収量790 mg(収率 94.0%) A mixture of 6-bromo-4′-nitrostyrylchromone compound 38 (860 mg, 2.20 mmol), concentrated sulfuric acid (1.2 mL), and acetic acid (15 mL) was heated to reflux for 1 hour. After returning to room temperature, ice pieces were added to the reaction solution, and the precipitated crystals were collected and the target product 39 was obtained. Yield 790 mg (Yield 94.0%)

6-ブロモ-4’-アミノスチリルクロモン の合成
化合物３９(361 mg,0.97 mmol)のエタノール(30 mL)溶液に、撹拌しながら塩化スズ(II)(1.287 g, 4.74 mmol)をゆっくり加え、2時間加熱還流した。反応終了後、反応溶液に1 N水酸化ナトリウム水溶液(100 mL)を加え、酢酸エチル100 mLで抽出した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、目的物４０を得た。収量210 mg (収率 63.3%) ¹H NMR (300 MHz,CDCl₃) δ 8.30 (d, J = 2.4 Hz), 7.71(dd, 1H), 7.47-7.38 (m, 4H), 6.68 (d, J = 8.4 Hz, 2H), 6.55 (d, J = 15.9 Hz,1H), 6.25 (s,1H), 3.99(s, 2H). To a solution of 6-bromo-4'-aminostyrylchromone compound 39 (361 mg, 0.97 mmol) in ethanol (30 mL), tin (II) chloride (1.287 g, 4.74 mmol) was slowly added while stirring. Heated to reflux for hours. After completion of the reaction, 1N aqueous sodium hydroxide solution (100 mL) was added to the reaction solution, and the mixture was extracted with 100 mL of ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the desired product 40. Yield 210 mg (Yield 63.3%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.30 (d, J = 2.4 Hz), 7.71 (dd, 1H), 7.47-7.38 (m, 4H), 6.68 (d, J = 8.4 Hz, 2H), 6.55 (d, J = 15.9 Hz, 1H), 6.25 (s, 1H), 3.99 (s, 2H).

6-ブロモ-4’-メチルアミノスチリルクロモン の合成
化合物４０(710 mg, 2.07 mmol)とパラホルムアルデヒド(231 mg,7.70 mmol)のメタノール溶液(15 mL)に撹拌しながらナトリウムメチラートメタノール溶液(0.45 mL)をゆっくり滴下した。1時間加熱還流後、水素化ホウ素ナトリウム(270 mg, 7.13 mmol)を固体のまま少しずつ加えて、さらに2時間加熱還流した。反応溶媒を減圧留去し、残渣をクロロホルムを溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物４１を得た。収量690 mg (収率 96%) ¹H-NMR (300 MHz, CDCl₃) δ 8.30 (d, J = 2.4 Hz, 1H), 7.71 (dd, 1H), 7.45-7.29 (m, 4H), 6.61-6.56 (m, 3H), 6.25 (s, 1H), 4.18 (s, 1H), 2.89 (s, 3H). MS m/z 355. Synthesis of 6-bromo-4'-methylaminostyrylchromone Compound 40 (710 mg, 2.07 mmol) and paraformaldehyde (231 mg, 7.70 mmol) in methanol solution (15 mL) with stirring, sodium methylate methanol solution (0.45 mL) was slowly added dropwise. After heating under reflux for 1 hour, sodium borohydride (270 mg, 7.13 mmol) was added little by little as a solid, and the mixture was further heated under reflux for 2 hours. The reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform as an elution solvent to obtain the desired product 41. Yield 690 mg (Yield 96%) ¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.30 (d, J = 2.4 Hz, 1H), 7.71 (dd, 1H), 7.45-7.29 (m, 4H), 6.61 -6.56 (m, 3H), 6.25 (s, 1H), 4.18 (s, 1H), 2.89 (s, 3H). MS m / z 355.

6-ブロモ-4’-ジメチルアミノスチリルクロモン の合成
化合物４０(194 mg, 0.567 mmol)をとパラホルムアルデヒド(170 mg, 5.67 mmol)の酢酸溶液(10 mL)に水素化シアノホウ素ナトリウム(214 mg, 3.40 mmol)を撹拌しながらゆっくり加え、室温で3時間撹拌した。反応終了後、反応溶液に1 N水酸化ナトリウム水溶液50 mLを加え、クロロホルム50 mLで抽出した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し化合物４２を得た。収量0.15g (収率 71.5%) ¹H NMR (300MHz, CDCl₃) δ 8.31(d, J = 2.4 Hz, 1H), 7.71(dd, 1H), 7.56-7.46 (m, 3H), 7.39 (d, J = 8.7Hz, 1H), 6.72 (d, J = 2.7 Hz, 2H), 6.57 (d, J = 15.9 Hz, 1H), 6.24 (s, 1H), 3.04 (s, 6H). MS m/z 371. Synthesis of 6-bromo-4'-dimethylaminostyrylchromone 40 (194 mg, 0.567 mmol) and paraformaldehyde (170 mg, 5.67 mmol) in acetic acid solution (10 mL) sodium cyanoborohydride (214 mg, 3.40 mmol) was slowly added with stirring and stirred at room temperature for 3 hours. After completion of the reaction, 50 mL of 1 N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with 50 mL of chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain Compound 42. Yield 0.15 g (Yield 71.5%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.31 (d, J = 2.4 Hz, 1H), 7.71 (dd, 1H), 7.56-7.46 (m, 3H), 7.39 (d , J = 8.7Hz, 1H), 6.72 (d, J = 2.7 Hz, 2H), 6.57 (d, J = 15.9 Hz, 1H), 6.24 (s, 1H), 3.04 (s, 6H). MS m / z 371.

6-(トリブチルスタニル)-4’-アミノスチリルクロモン の合成
化合物４０(242 mg, 0.707 mmol)のジオキサン溶液(12 mL)に、ビス(トリブチルスズ)(0.5 mL)、テトラトリフェニルホスフィンパラジウム(40 mg, 0.034 mmol)、トリエチルアミン(8 mL)を加え、90℃で6時間加熱した。反応溶媒を減圧留去し、残渣を酢酸エチル/ヘキサン(2/3)を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物４３を得た。収量220 mg (収率56.3%) ¹H NMR (300 MHz, CDCl₃) δ8.28 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.54-7.48 (m, 3H), 7.42 (d, J = 9.0 Hz, 1H), 6.68 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 15.9 Hz, 1H), 6.27 (s, 1H), 4.07 (s, 2H), 0.86-1.54 (m, 27H). MS m/z 496. Synthesis of 6- (tributylstannyl) -4'-aminostyrylchromone Compound 40 (242 mg, 0.707 mmol) in dioxane (12 mL) was mixed with bis (tributyltin) (0.5 mL), tetratriphenylphosphine palladium (40 mg, 0.034 mmol) and triethylamine (8 mL) were added, and the mixture was heated at 90 ° C. for 6 hours. The reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (2/3) as an elution solvent to obtain the desired product 43. Yield 220 mg (Yield 56.3%) ¹ H NMR (300 MHz, CDCl ₃ ) δ8.28 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.54-7.48 (m, 3H), 7.42 (d, J = 9.0 Hz, 1H), 6.68 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 15.9 Hz, 1H), 6.27 (s, 1H), 4.07 (s, 2H), 0.86 -1.54 (m, 27H). MS m / z 496.

6-(トリブチルスタニル)-4’-メチルアミノスチリルクロモン の合成
化合物４１(300 mg,0.84 mmol)のジオキサン溶液(10 mL)に、ビス(トリブチルスズ) (0.6 mL)、テトラトリフェニルホスフィンパラジウム(41 mg, 0.035 mmol)、トリエチルアミン(7 mL)を加え、90℃で6時間加熱した。反応溶媒を減圧留去し、残渣を酢酸エチル/ヘキサン(1/4)を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物４４を得た。収量204 mg(収率42.8%) ¹HNMR (300 MHz, CDCl₃) δ8.28 (s, 1H), 7.74 (d, 1H), 7.54-7.43 (m,4H), 6.62-6.57 (m, 3H), 6.26 (s, 1H), 4.11 (s, 1H), 2.89 (s, 3H), 0.86-1.52 (m, 27H). MS m/z 567. Synthesis of 6- (tributylstannyl) -4'-methylaminostyrylchromone Compound 41 (300 mg, 0.84 mmol) in dioxane (10 mL) was mixed with bis (tributyltin) (0.6 mL), tetratriphenylphosphine palladium ( 41 mg, 0.035 mmol) and triethylamine (7 mL) were added, and the mixture was heated at 90 ° C. for 6 hours. The reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/4) as an elution solvent to obtain the desired product 44. Yield 204 mg (Yield 42.8%) ¹ HNMR (300 MHz, CDCl ₃ ) δ8.28 (s, 1H), 7.74 (d, 1H), 7.54-7.43 (m, 4H), 6.62-6.57 (m, 3H ), 6.26 (s, 1H), 4.11 (s, 1H), 2.89 (s, 3H), 0.86-1.52 (m, 27H). MS m / z 567.

6-(トリブチルスタニル)-4’-ジメチルアミノスチリルクロモン の合成
化合物４２(150 mg, 0.405 mmol)のジオキサン溶液(10 mL)に、ビス(トリブチルスズ)(0.3 mL)、テトラトリフェニルホスフィンパラジウム(20 mg, 0.017 mmol)、トリエチルアミン(5 mL)を加え、90℃で6時間加熱した。反応溶媒を減圧留去し、残渣を酢酸エチル/ヘキサン(1/4)を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物４５を得た。収量220 mg (収率37.4%) ¹H NMR (300 MHz, CDCl₃) δ8.23 (s, 1H), 7.74 (dd, 1H), 7.59-7.47 (m, 3H), 7.42 (d, 1H), 6.71 (d, J = 8.9Hz, 2H), 6.56 (d, J = 15.8 Hz, 1H), 6.27 (s, 1H), 3.04 (s, 6H), 0.86-1.74 (m, 27H). MS m/z 580. Synthesis of 6- (tributylstannyl) -4'-dimethylaminostyrylchromone Compound 42 (150 mg, 0.405 mmol) in dioxane (10 mL) was mixed with bis (tributyltin) (0.3 mL), tetratriphenylphosphine palladium ( 20 mg, 0.017 mmol) and triethylamine (5 mL) were added, and the mixture was heated at 90 ° C. for 6 hours. The reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/4) as an elution solvent to obtain the desired product 45. Yield 220 mg (Yield 37.4%) ¹ H NMR (300 MHz, CDCl ₃ ) δ8.23 (s, 1H), 7.74 (dd, 1H), 7.59-7.47 (m, 3H), 7.42 (d, 1H) , 6.71 (d, J = 8.9Hz, 2H), 6.56 (d, J = 15.8 Hz, 1H), 6.27 (s, 1H), 3.04 (s, 6H), 0.86-1.74 (m, 27H) .MS m / z 580.

6-ヨード-4’-アミノスチリルクロモン の合成
化合物４３(220 mg, 0.398 mmol)をクロロホルム5 mLに溶解し、撹拌下ヨウ素のクロロホルム溶液(3 mL, 0.25 M)を室温で加えた。室温で10分間反応させた後、飽和亜硫酸水素ナトリウム水溶液(15 mL)を加え、反応を終了させた。クロロホルム層を分液し、硫酸ナトリウムで乾燥、溶媒を減圧留去後、残渣を酢酸エチル/ヘキサン(1/2)を溶出溶媒とするシリカゲルクロマトグラフィに付し、目的物４６を得た。収量60 mg (収率38.8%) ¹H NMR (300 MHz, CDCl₃) δ8.50 (d, J = 9.0 Hz, 1H), 7.89 (dd, 1H), 7.53-7.39 (m, 3H), 7.27 (d, J = 8.7 Hz, 1H), 6.69 (d, J = 8.4 Hz, 2H), 6.56 (d, J = 15.9 Hz, 1H), 3.99 (s,2H). MS m/z 389. Synthesis compound 43 (220 mg, 0.398 mmol) of 6-iodo-4′- aminostyrylchromone was dissolved in 5 mL of chloroform, and a chloroform solution of iodine (3 mL, 0.25 M) was added at room temperature with stirring. After reacting at room temperature for 10 minutes, a saturated aqueous sodium hydrogen sulfite solution (15 mL) was added to terminate the reaction. The chloroform layer was separated, dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography using ethyl acetate / hexane (1/2) as an elution solvent to obtain the desired product 46. Yield 60 mg (Yield 38.8%) ¹ H NMR (300 MHz, CDCl ₃ ) δ8.50 (d, J = 9.0 Hz, 1H), 7.89 (dd, 1H), 7.53-7.39 (m, 3H), 7.27 (d, J = 8.7 Hz, 1H), 6.69 (d, J = 8.4 Hz, 2H), 6.56 (d, J = 15.9 Hz, 1H), 3.99 (s, 2H). MS m / z 389.

6-ヨード-4’-メチルアミノスチリルクロモン の合成
化合物４４(200 mg, 0.353 mmol)をクロロホルム7 mLに溶解し、撹拌下ヨウ素のクロロホルム溶液(4 mL, 0.25 M)を室温で加えた。室温で10分間反応させた後、飽和亜硫酸水素ナトリウム水溶液(15 mL)を加え、反応を終了させた。クロロホルム層を分液し、硫酸ナトリウムで乾燥、溶媒を減圧留去後、残渣を酢酸エチル/ヘキサン(1/3)を溶出溶媒とするシリカゲルクロマトグラフィに付し、目的物４７を得た。収量32 mg (収率22.4%) ¹H NMR (300 MHz, CDCl₃) δ8.50 (d, J = 2.1 Hz, 1H), 7.94 (dd, 1H), 7.59-7.42 (m, 3H), 7.28 (d, J = 8.2 Hz, 1H), 6.61 (d, J = 8.7 Hz, 2H), 6.54 (d, J = 15.6 Hz, 1H), 6.25 (s, 1H), 4.21 (s, 1H), 2.94 (s, 3H). MS m/z 403. Synthesis compound 44 (200 mg, 0.353 mmol) of 6-iodo-4′-methylaminostyrylchromone was dissolved in 7 mL of chloroform, and a chloroform solution of iodine (4 mL, 0.25 M) was added at room temperature with stirring. After reacting at room temperature for 10 minutes, a saturated aqueous sodium hydrogen sulfite solution (15 mL) was added to terminate the reaction. The chloroform layer was separated, dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography using ethyl acetate / hexane (1/3) as an elution solvent to obtain the desired product 47. Yield 32 mg (Yield 22.4%) ¹ H NMR (300 MHz, CDCl ₃ ) δ8.50 (d, J = 2.1 Hz, 1H), 7.94 (dd, 1H), 7.59-7.42 (m, 3H), 7.28 (d, J = 8.2 Hz, 1H), 6.61 (d, J = 8.7 Hz, 2H), 6.54 (d, J = 15.6 Hz, 1H), 6.25 (s, 1H), 4.21 (s, 1H), 2.94 (s, 3H). MS m / z 403.

6-ヨード-4’-ジメチルアミノスチリルクロモン の合成
化合物４５(35 mg, 0.06 mmol)をクロロホルム6 mLに溶解し、撹拌下ヨウ素のクロロホルム溶液(4 mL, 0.15 M)を室温で加えた。室温で10分間反応させた後、飽和亜硫酸水素ナトリウム水溶液(10 mL)を加え、反応を終了させた。クロロホルム層を分液し、硫酸ナトリウムで乾燥、溶媒を減圧留去後、残渣を酢酸エチル/ヘキサン(1/4)を溶出溶媒とするシリカゲルクロマトグラフィに付し、目的物４８を得た。収量18 mg (収率71.8%) ¹HNMR (300 MHz, CDCl₃) δ 8.45 (d, 1H), 7.94 (dd, 1H), 7.59-7.44 (m, 3H), 7.23 (d, 1H), 6.65 (d, J = 8.7 Hz, 2H), 6.65 (d, 1H), 6.25 (s, 1H), 3.04 (s, 6H). MS m/z 417. Synthesis compound 45 (35 mg, 0.06 mmol) of 6-iodo-4′-dimethylaminostyrylchromone was dissolved in 6 mL of chloroform, and a chloroform solution of iodine (4 mL, 0.15 M) was added at room temperature with stirring. After reacting at room temperature for 10 minutes, a saturated aqueous sodium hydrogen sulfite solution (10 mL) was added to terminate the reaction. The chloroform layer was separated, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography using ethyl acetate / hexane (1/4) as an elution solvent to obtain the desired product 48. Yield 18 mg (Yield 71.8%) ¹ HNMR (300 MHz, CDCl ₃ ) δ 8.45 (d, 1H), 7.94 (dd, 1H), 7.59-7.44 (m, 3H), 7.23 (d, 1H), 6.65 (d, J = 8.7 Hz, 2H), 6.65 (d, 1H), 6.25 (s, 1H), 3.04 (s, 6H). MS m / z 417.

(E)-2-アセチル-4-メトキシフェニル3-(4-ニトロフェニル)アクリレイト の合成
4-ニトロケイ皮酸クロリド(800 mg, 0.44 mmol)のピリジン溶液(10 mL)に5-メトキシ-2-ヒドロキシアセトフェノン(500 mg, 3.01 mmol)を加えた。室温で60分反応させた後、氷冷下1 N塩酸に注ぎ、激しく撹拌させた。析出した沈殿を瀘取し、精製水で洗浄後、目的物であるアセトフェノン４９を得た。¹H NMR(300 MHz, CDCl₃) δ8.28 (d, J = 8.7 Hz, 1H), 7.93 (s, 1H), 7.88-7.76 (m, 4H), 7.30 (d, 2H), 6.79 (d, J = 15.9 Hz, 1H), 3.87 (s, 3H), 2.56 (s, 3H). Synthesis of (E) -2-acetyl-4-methoxyphenyl 3- (4-nitrophenyl) acrylate
5-Methoxy-2-hydroxyacetophenone (500 mg, 3.01 mmol) was added to a pyridine solution (10 mL) of 4-nitrocinnamic acid chloride (800 mg, 0.44 mmol). After reacting at room temperature for 60 minutes, the mixture was poured into 1 N hydrochloric acid under ice cooling and stirred vigorously. The deposited precipitate was collected and washed with purified water to obtain the target acetophenone 49. ¹ H NMR (300 MHz, CDCl ₃ ) δ8.28 (d, J = 8.7 Hz, 1H), 7.93 (s, 1H), 7.88-7.76 (m, 4H), 7.30 (d, 2H), 6.79 (d , J = 15.9 Hz, 1H), 3.87 (s, 3H), 2.56 (s, 3H).

1-(5-メトキシ-2ヒドロキシフェニル)-5-(4-ニトロフェニル)ペント-4-エン-1,3-ジオン の合成
化合物４９ (126 mg, 3.19 mmol)をピリジン(20 mL)に溶解し、50℃まで加熱した。粉砕した水酸化カリウム(0.4 g, 1.11 mmol)を加え、30分間撹拌後、氷冷し、10%酢酸溶液を加えた。析出した淡黄色の沈殿を瀘取し、目的物５０を得た。収量902 mg (収率72.0%) ¹H NMR (300 MHz, CDCl₃) δ8.27 (d, J = 9.0 Hz, 2H), 7.72--7.69 (m, 4H), 7.14-7.12 (m, 3H), 6.97 (s, 1H), 6.77 (d, 1H), 3.83 (s, 3H). Synthesis of 1- (5-methoxy-2hydroxyphenyl) -5- (4-nitrophenyl) pent-4-ene-1,3-dione Compound 49 (126 mg, 3.19 mmol) dissolved in pyridine (20 mL) And heated to 50 ° C. Ground potassium hydroxide (0.4 g, 1.11 mmol) was added, stirred for 30 minutes, ice-cooled, and 10% acetic acid solution was added. The precipitated pale yellow precipitate was collected to obtain the target product 50. Yield 902 mg (Yield 72.0%) ¹ H NMR (300 MHz, CDCl ₃ ) δ8.27 (d, J = 9.0 Hz, 2H), 7.72--7.69 (m, 4H), 7.14-7.12 (m, 3H ), 6.97 (s, 1H), 6.77 (d, 1H), 3.83 (s, 3H).

6-メトキシ-4-ニトロスチリルクロモン の合成
化合物５０(900 mg, 2.64 mmol)、濃硫酸(1.0 mL)、酢酸(30 mL)の混液を1時間加熱還流した。室温に戻した後、氷片を反応溶液に加え、析出した結晶を瀘取し、目的物５１を得た。収量810 mg (収率90.0 %) A mixture of 6-methoxy-4-nitrostyrylchromone compound 50 (900 mg, 2.64 mmol), concentrated sulfuric acid (1.0 mL), and acetic acid (30 mL) was heated to reflux for 1 hour. After returning to room temperature, ice pieces were added to the reaction solution, and the precipitated crystals were collected to obtain the target product 51. Yield 810 mg (Yield 90.0%)

6-メトキシ-4-アミノスチリルクロモン の合成
化合物５１ (830 mg, 2.57 mmol)のエタノール(25 mL)溶液に、撹拌しながら塩化スズ(II) (2.5 g, 1.32 mmol)をゆっくり加え、2時間加熱還流した。反応終了後、反応溶液に1 N水酸化ナトリウム水溶液(50 mL)を加え、クロロホルム50 mLで抽出した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、目的物５２を得た。収量510 mg (収率61.4 %) . To a solution of 6-methoxy-4-aminostyrylchromone compound 51 (830 mg, 2.57 mmol) in ethanol (25 mL), tin (II) chloride (2.5 g, 1.32 mmol) was slowly added with stirring for 2 hours. Heated to reflux. After completion of the reaction, 1N aqueous sodium hydroxide solution (50 mL) was added to the reaction solution, and the mixture was extracted with 50 mL of chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the desired product 52. Yield 510 mg (61.4% yield).

6-メトキシ-4-メチルアミノスチリルクロモン の合成
化合物５２(500 mg,1.7 mmol)とパラホルムアルデヒド(262 mg, 8.72 mmol)のメタノール溶液(15 mL)に撹拌しながらナトリウムメチラートメタノール溶液(0.46 mL)をゆっくり滴下した。1時間加熱還流後、水素化ホウ素ナトリウム(310 mg, 8.18 mmol)を固体のまま少しずつ加えて、さらに2時間加熱還流した。反応溶媒を減圧留去し、残渣をクロロホルムを溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物５３を得た。収量179 mg (収率34.4 %) Synthesis of 6-methoxy-4-methylaminostyrylchromone Compound 52 (500 mg, 1.7 mmol) and paraformaldehyde (262 mg, 8.72 mmol) in methanol (15 mL) with stirring, sodium methylate methanol solution (0.46 mL) ) Was slowly added dropwise. After heating under reflux for 1 hour, sodium borohydride (310 mg, 8.18 mmol) was added little by little as a solid, and the mixture was further heated under reflux for 2 hours. The reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform as an elution solvent to obtain the desired product 53. Yield 179 mg (Yield 34.4%)

6-メトキシ-4-ジメチルアミノスチリルクロモン の合成
化合物５２(270 mg, 0.92 mmol)をパラホルムアルデヒド(300 mg, 9.99 mmol)の酢酸溶液(15 mL)に水素化シアノホウ素ナトリウム(314 mg, 5.02 mmol)を撹拌しながらゆっくり加え、室温で3時間撹拌した。反応終了後、反応溶液に1 N水酸化ナトリウム水溶液50 mLを加え、クロロホルム50 mLで抽出した。無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し化合物５４を得た。収量0.20 g (収率70.9 %) ¹H NMR (300 MHz, CDCl₃) δ7.56 (d, J = 5.1 Hz, 1H), 7.54 (s, 1H), 7.48-7.42 (m, 3H), 7.25 (d, 1H), 6.74 (d, J = 9.0 Hz, 2H), 6.54 (d, J = 15.9 Hz, 1H), 6.24 (s, 1H), 3.89 (s, 3H), 3.02 (s, 6H). Synthesis of 6-methoxy-4-dimethylaminostyrylchromone Compound 52 (270 mg, 0.92 mmol) in acetic acid solution (15 mL) of paraformaldehyde (300 mg, 9.99 mmol) sodium cyanoborohydride (314 mg, 5.02 mmol) ) Was slowly added with stirring, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 50 mL of 1 N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with 50 mL of chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain Compound 54. Yield 0.20 g (Yield 70.9%) ¹ H NMR (300 MHz, CDCl ₃ ) δ7.56 (d, J = 5.1 Hz, 1H), 7.54 (s, 1H), 7.48-7.42 (m, 3H), 7.25 (d, 1H), 6.74 (d, J = 9.0 Hz, 2H), 6.54 (d, J = 15.9 Hz, 1H), 6.24 (s, 1H), 3.89 (s, 3H), 3.02 (s, 6H) .

6-ヒドロキシ-4-アミノスチリルクロモン の合成
化合物５２(270 mg, 0.92 mmol)をジクロロメタン40 mLに溶解させ、氷冷下三臭化ホウ素ジクロロメタン溶液4.6 mLをゆっくり加えた。氷上で時間反応させた後、反応液を少量ずつ氷水に加え、ジクロロメタン層と水層で分液抽出し目的物５５を得た。収量112 mg (収率40.9 %) ¹H NMR (300 MHz, CDCl₃) δ9.29 (s, 1H), 7.55-7.42 (m, 3H), 7.39-7.28 (m, 3H), 6.78 (d, J = 15.9 Hz, 1H), 6.68 (d, 1H), 6.24, (s,1H), 5.91 (s, 2H). Synthesis compound 52 (270 mg, 0.92 mmol) of 6-hydroxy-4-aminostyrylchromone was dissolved in 40 mL of dichloromethane, and 4.6 mL of boron tribromide dichloromethane solution was slowly added under ice cooling. After reacting for a time on ice, the reaction solution was added to ice water little by little, and liquid separation extraction was performed with a dichloromethane layer and an aqueous layer to obtain the target product 55. Yield 112 mg (Yield 40.9%) ¹ H NMR (300 MHz, CDCl ₃ ) δ9.29 (s, 1H), 7.55-7.42 (m, 3H), 7.39-7.28 (m, 3H), 6.78 (d, J = 15.9 Hz, 1H), 6.68 (d, 1H), 6.24, (s, 1H), 5.91 (s, 2H).

6-ヒドロキシ-4-メチルアミノスチリルクロモン の合成
化合物５３(179 mg, 0.58 mmol)をジクロロメタン25 mLに溶解させ、氷冷下三臭化ホウ素ジクロロメタン溶液2.9 mLをゆっくり加えた。氷上で時間反応させた後、反応液を少量ずつ氷水に加え、ジクロロメタン層と水層で分液抽出し目的物５６を得た。収量12 mg (収率7.1 %) ¹H NMR (300MHz, CDCl₃) δ9.92 (s,1H), 7.55-7.49 (m, 3H), 7.28 (d, 2H), 7.19 (dd, 1H), 6.81 (d, J = 15.9 Hz, 1H), 6.59 (d, J = 8.7 Hz, 2H), 6.25 (s, 1H), 3.23 (s, 1H), 2.52 (s, 3H). Synthetic compound 53 (179 mg, 0.58 mmol) of 6-hydroxy-4-methylaminostyrylchromone was dissolved in 25 mL of dichloromethane, and 2.9 mL of boron tribromide dichloromethane solution was slowly added under ice cooling. After reacting for hours on ice, the reaction solution was added to ice water little by little, followed by separation and extraction with a dichloromethane layer and an aqueous layer to obtain the desired product 56. Yield 12 mg (Yield 7.1%) ¹ H NMR (300MHz, CDCl ₃ ) δ9.92 (s, 1H), 7.55-7.49 (m, 3H), 7.28 (d, 2H), 7.19 (dd, 1H), 6.81 (d, J = 15.9 Hz, 1H), 6.59 (d, J = 8.7 Hz, 2H), 6.25 (s, 1H), 3.23 (s, 1H), 2.52 (s, 3H).

6-ヒドロキシ-4-ジメチルアミのスチリルクロモン の合成
化合物５４ (160 mg, 0.522 mmol)をジクロロメタン25 mLに溶解させ、氷冷下三臭化ホウ素ジクロロメタン溶液2.9 mLをゆっくり加えた。氷上で時間反応させた後、反応液を少量ずつ氷水に加え、ジクロロメタン層と水層で分液抽出し目的物５７を得た。収量80 mg (収率52.4 %) ¹H NMR (300 MHz, CDCl₃)δ 7.56-7.52(m, 3H), 7.27-7.22 (m, 3H), 6.87 (d, J = 17.7 Hz, 1H), 6.75 (d, J = 9.0 Hz, 2H), 6.26 (s, 1H), 2.99 (s,6H).
（４）クマリン誘導体の合成 Compound 6 (160 mg, 0.522 mmol) of 6-hydroxy-4-dimethylami styrylchromone was dissolved in 25 mL of dichloromethane, and 2.9 mL of boron tribromide in dichloromethane was slowly added under ice cooling. After reacting on ice for a time, the reaction solution was added to ice water little by little, and liquid separation extraction was performed with a dichloromethane layer and an aqueous layer to obtain the target product 57. Yield 80 mg (Yield 52.4%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.56-7.52 (m, 3H), 7.27-7.22 (m, 3H), 6.87 (d, J = 17.7 Hz, 1H), 6.75 (d, J = 9.0 Hz, 2H), 6.26 (s, 1H), 2.99 (s, 6H).
(4) Synthesis of coumarin derivatives

6-ブロモ-3-(4-ニトロフェニル)クマリンの合成
5-ブロモサリチルアルデヒド（300 mg, 1.5 mmol）、p-ニトロフェニル酢酸（280 mg, 1.6 mmol）、2-塩化-1-メチルピリジニウムヨージド（770 mg, 3.0 mmol）をアセトニトリル（15 mL）に溶解させた。トリエチルアミン（0.5 mL）を加えた後、加熱還流を３時間行った。反応溶媒を減圧留去した後、半固体状の残渣に希塩酸を加えて吸引濾過、沈殿を濾取し、目的物５８を得た。収量300 mg（収率57.8%）. Synthesis of 6-bromo-3- (4-nitrophenyl) coumarin
5-Bromosalicylaldehyde (300 mg, 1.5 mmol), p-nitrophenylacetic acid (280 mg, 1.6 mmol), 2-chloro-1-methylpyridinium iodide (770 mg, 3.0 mmol) in acetonitrile (15 mL) Dissolved. Triethylamine (0.5 mL) was added, followed by heating to reflux for 3 hours. After the reaction solvent was distilled off under reduced pressure, diluted hydrochloric acid was added to the semisolid residue, suction filtration was performed, and the precipitate was collected by filtration to obtain the desired product 58. Yield 300 mg (57.8% yield).

6-ブロモ-3-(4-アミノフェニル)クマリンの合成
化合物５８（150 mg, 0.43 mmol）をエタノール（25 mL）に溶解させ、塩化スズ(II)（380 mg, 2 mmol）を加えて加熱還流を2時間行った。反応溶媒を減圧留去した後、0.1 N水酸化ナトリウム水溶液を加え、酢酸エチルで抽出を行った。酢酸エチル相を回収し、酢酸エチルを減圧留去して目的物５９を得た。収量100 mg（収率74%）¹H NMR（300MHz, CDCl₃）δ 7.63 (m, 2H), 7.55 (m, 3H), 7.25 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 8.7 Hz, 2H), 3.88 (s, 2H). Synthetic compound 58 (150 mg, 0.43 mmol) of 6-bromo-3- (4-aminophenyl) coumarin is dissolved in ethanol (25 mL), and tin (II) chloride (380 mg, 2 mmol) is added and heated. Refluxing was performed for 2 hours. The reaction solvent was evaporated under reduced pressure, 0.1 N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate phase was recovered, and ethyl acetate was distilled off under reduced pressure to obtain the desired product 59. Yield 100 mg (74% yield) ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.63 (m, 2H), 7.55 (m, 3H), 7.25 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 8.7 Hz, 2H), 3.88 (s, 2H).

6-ブロモ-3-(4-メチルアミノフェニル)クマリンの合成
化合物５９（150 mg, 0.47 mmol）をメタノール（4.4 mL）に溶解させ、パラホルムアルデヒド（77 mg, 2.66 mmol）とナトリウムメチラートメタノール溶液（0.15 mL）を加え加熱還流を行った。0.5時間後、水素化ホウ素ナトリウム（95 mg, 2.5 mmol）を少しずつ加えて、さらに2時間還流を行った。反応溶媒を減圧留去し、残渣を酢酸エチル／ヘキサン（１／２）を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物６０を得た。収量32 mg（収率21%）¹H NMR（300 MHz, CDCl₃）δ 7.62 (s, 1H), 7.59 (d, J = 6.9Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.24 (d, J = 10.5 Hz, 1H), 6.65 (d, J = 8.4 Hz, 2H), 3.91 (s, 1H), 2.88 (s, 3H). Synthetic compound 59 (150 mg, 0.47 mmol) of 6-bromo-3- (4-methylaminophenyl) coumarin dissolved in methanol (4.4 mL), paraformaldehyde (77 mg, 2.66 mmol) and sodium methylate methanol solution (0.15 mL) was added and heated to reflux. After 0.5 hour, sodium borohydride (95 mg, 2.5 mmol) was added little by little, and the mixture was further refluxed for 2 hours. The reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/2) as an elution solvent to obtain the desired product 60. Yield 32 mg (21% yield) ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.62 (s, 1H), 7.59 (d, J = 6.9Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H) , 7.24 (d, J = 10.5 Hz, 1H), 6.65 (d, J = 8.4 Hz, 2H), 3.91 (s, 1H), 2.88 (s, 3H).

6-ブロモ-3-(4-ジメチルアミノフェニル)クマリンの合成
化合物６０（160 mg, 0.5 mmol）を酢酸（6.5 mL）に溶解させ、パラホルムアルデヒド（157 mg, 5.4 mmol）を加えて加熱還流を行った。0.5時間後、反応溶液を常温まで冷却し、シアノ水素化ホウ素ナトリウム（190 mg, 3.0 mmol）を加え室温で4時間後撹拌した。反応溶媒を減圧留去し、残渣をクロロホルムを溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物６１を得た。収量100 mg（収率58%）¹H NMR（300MHz, CDCl₃）δ 7.66 (s, 1H), 7.62 (d, J = 6.0 Hz, 2H), 7.23 (d, J = 9.2Hz, 1H), 6.76 (d, J = 8.4 Hz, 2H), 3.01 (s, 3H). Synthesis of 6-bromo-3- (4-dimethylaminophenyl) coumarin Compound 60 (160 mg, 0.5 mmol) is dissolved in acetic acid (6.5 mL), paraformaldehyde (157 mg, 5.4 mmol) is added, and the mixture is heated to reflux. went. After 0.5 hour, the reaction solution was cooled to room temperature, sodium cyanoborohydride (190 mg, 3.0 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform as an elution solvent to obtain the desired product 61. Yield 100 mg (Yield 58%) ¹ H NMR (300MHz, CDCl ₃ ) δ 7.66 (s, 1H), 7.62 (d, J = 6.0 Hz, 2H), 7.23 (d, J = 9.2Hz, 1H), 6.76 (d, J = 8.4 Hz, 2H), 3.01 (s, 3H).

6-(トリブチルスタニル)-3-(4-アミノフェニル)クマリンの合成
化合物５９（150 mg, 0.47 mmol）を1,4-ジオキサン（15 mL）に溶解させ、ビス（トリブチルスズ）（0.5 mL）、テトラキストリフェニルホスフィンパラジウム（30 mg, 0.026 mmol）、トリエチルアミン（7 mL）を加えて加熱還流を行った。反応溶媒を減圧留去し、残渣を酢酸エチル／ヘキサン（1／1）を溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物６２を得た。収量100 mg（収率40%）¹H NMR（300 MHz, CDCl₃）δ 7.73 (s, 1H), 7.57 (m, 4H), 7.32 (d, 1H), 6.7 (d, J = 8.4 Hz, 2H), 3.84 (s, 2H), 1.64 (m, 6H), 1.34 (m, 6H), 1.12 (m, 6H), 0.92 (m, 9H). Synthesis of 6- (tributylstannyl) -3- (4-aminophenyl) coumarin 59 (150 mg, 0.47 mmol) was dissolved in 1,4-dioxane (15 mL) and bis (tributyltin) (0.5 mL) , Tetrakistriphenylphosphine palladium (30 mg, 0.026 mmol) and triethylamine (7 mL) were added, and the mixture was heated to reflux. The reaction solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/1) as an elution solvent to obtain the desired product 62. Yield 100 mg (40% yield) ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.73 (s, 1H), 7.57 (m, 4H), 7.32 (d, 1H), 6.7 (d, J = 8.4 Hz, 2H), 3.84 (s, 2H), 1.64 (m, 6H), 1.34 (m, 6H), 1.12 (m, 6H), 0.92 (m, 9H).

6-(トリブチルスタニル)-3-(4-メチルアミノフェニル)クマリンの合成
化合物６０（230 mg, 0.43 mmol）を1,4-ジオキサン（23 mL）に溶解させ、ビス（トリブチルスズ）（0.7 mL）、テトラキストリフェニルホスフィンパラジウム（46 mg）、トリエチルアミン（11 mL）を加えて加熱還流を行った。反応溶媒を減圧留去し、残渣を酢酸エチル／ヘキサン（1／4）溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物６３を得た。収量50 mg（収率20%）¹H NMR（300MHz, CDCl₃）δ 7.73 (s, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 8.7 Hz, 2H), 3.94 (s, 1H), 2.87 (s, 3H), 0.90-1.54 (m, 27H). MSm/z 541 Synthesis of 6- (tributylstannyl) -3- (4-methylaminophenyl) coumarin Compound 60 (230 mg, 0.43 mmol) was dissolved in 1,4-dioxane (23 mL) and bis (tributyltin) (0.7 mL) ), Tetrakistriphenylphosphine palladium (46 mg) and triethylamine (11 mL) were added, and the mixture was heated to reflux. The reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/4) as an elution solvent to obtain the desired product 63. Yield 50 mg (Yield 20%) ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.73 (s, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 8.7 Hz, 2H), 3.94 (s, 1H), 2.87 (s, 3H), 0.90-1.54 (m, 27H). MSm / z 541

6-(トリブチルスタニル)-3-(4-ジメチルアミノフェニル)クマリンの合成
化合物６１（150 mg, 0.44 mmol）を1,4-ジオキサン（15 mL）に溶解させ、ビス（トリブチルスズ）（0.5 mL）、テトラキストリフェニルホスフィンパラジウム（30 mg）、トリエチルアミン（7 mL）を加えて加熱還流を行った。5時間後、反応溶媒を減圧留去し、残渣を酢酸エチル／ヘキサン（1／5）溶出溶媒とするシリカゲルカラムクロマトグラフィに付し、目的物６４を得た。収量63 mg（収率26%）¹H NMR（300 MHz, CDCl.）δ 7.73 (s, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.55 (d, 2H), 7.28 (d, 1H), 6.77 (d, J = 9.0 Hz, 2H), 3.01 (s, 6H), 0.90-1.60 (m, 27H) .MSm/z 555 Synthesis of 6- (tributylstannyl) -3- (4-dimethylaminophenyl) coumarin 61 (150 mg, 0.44 mmol) was dissolved in 1,4-dioxane (15 mL) and bis (tributyltin) (0.5 mL ), Tetrakistriphenylphosphine palladium (30 mg), and triethylamine (7 mL) were added, and the mixture was heated to reflux. After 5 hours, the reaction solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate / hexane (1/5) elution solvent to obtain the desired product 64. Yield 63 mg (26% yield) ¹ H NMR (300 MHz, CDCl.) Δ 7.73 (s, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.55 (d, 2H), 7.28 (d, 1H), 6.77 (d, J = 9.0 Hz, 2H), 3.01 (s, 6H), 0.90-1.60 (m, 27H) .MSm / z 555

6-ヨード-3-(4-アミノフェニル)クマリンの合成
化合物６２（50 mg, 0.095 mmol）をクロロホルム（5 mL）に溶解させ、ヨウ素のクロロホルム溶液（3 mL, 1 M）を加えた。室温で10分間反応させた後、飽和亜硫酸水素ナトリウム水溶液（10 mL）を加えて反応を終了させた。クロロホルム相を回収し、クロロホルムを減圧留去後、残渣を酢酸エチル／ヘキサン（1／1）を溶出溶媒とするシリカゲルクロマトグラフィに付し、目的物６５を得た。収量30 mg（収率87%） Synthesis compound 62 (50 mg, 0.095 mmol) of 6-iodo-3- (4-aminophenyl) coumarin was dissolved in chloroform (5 mL), and a chloroform solution of iodine (3 mL, 1 M) was added. After reacting at room temperature for 10 minutes, a saturated aqueous sodium hydrogen sulfite solution (10 mL) was added to terminate the reaction. The chloroform phase was recovered and chloroform was distilled off under reduced pressure. The residue was subjected to silica gel chromatography using ethyl acetate / hexane (1/1) as an elution solvent to obtain the target product 65. Yield 30 mg (87% yield)

6-ヨード-3-(4-メチルアミノフェニル)クマリンの合成
化合物６３（40 mg, 0.074 mmol）をクロロホルム（5 mL）に溶解させ、ヨウ素のクロロホルム溶液（3 mL, 1 M）を加えた。室温で10分間反応させた後、飽和亜硫酸水素ナトリウム水溶液（10 mL）を加えて反応を終了させた。クロロホルム相を回収し、クロロホルムを減圧留去後、残渣を酢酸エチル／ヘキサン（1／2）を溶出溶媒とするシリカゲルクロマトグラフィに付し、目的物６６を得た。収量20 mg（収率72%）. MSm/z 377 Synthesis compound 63 (40 mg, 0.074 mmol) of 6-iodo-3- (4-methylaminophenyl) coumarin was dissolved in chloroform (5 mL), and a chloroform solution of iodine (3 mL, 1 M) was added. After reacting at room temperature for 10 minutes, a saturated aqueous sodium hydrogen sulfite solution (10 mL) was added to terminate the reaction. The chloroform phase was recovered and chloroform was distilled off under reduced pressure. The residue was subjected to silica gel chromatography using ethyl acetate / hexane (1/2) as an elution solvent to obtain the desired product 66. Yield 20 mg (72% yield). MSm / z 377

6-ヨード-3-(4-ジメチルアミノフェニル)クマリンの合成
化合物６４（30 mg, 0.054 mmol）をクロロホルム（5 mL）に溶解させ、ヨウ素のクロロホルム溶液（3 mL, 1 M）を加えた。室温で10分間反応させた後、飽和亜硫酸水素ナトリウム水溶液（10 mL）を加えて反応を終了させた。クロロホルム相を回収し、クロロホルムを減圧留去後、残渣を酢酸エチル／ヘキサン（1／4）を溶出溶媒とするシリカゲルクロマトグラフィに付し、目的物６７を得た。収量20 mg（収率95%）MSm/z 391. Synthetic compound 64 (30 mg, 0.054 mmol) of 6-iodo-3- (4-dimethylaminophenyl) coumarin was dissolved in chloroform (5 mL), and a chloroform solution of iodine (3 mL, 1 M) was added. After reacting at room temperature for 10 minutes, a saturated aqueous sodium hydrogen sulfite solution (10 mL) was added to terminate the reaction. The chloroform phase was recovered and chloroform was distilled off under reduced pressure. The residue was subjected to silica gel chromatography using ethyl acetate / hexane (1/4) as an elution solvent to obtain the desired product 67. Yield 20 mg (95% yield) MSm / z 391.

（５）ヨウ素標識実験
トリスズブチル前駆体 (1 mg/mL)のエタノール溶液50 μLと1 N 塩酸 50 μL、Na[¹²⁵I]I (1-5 μCi)をガラスバイアルにいれ、最後に過酸化水素水50 μL (3% W/V)を加えた。10分間室温で放置した後、飽和亜硫酸水素ナトリウム水溶液100 μLを加えることにより、反応を停止させた。飽和炭酸水素ナトリウム水溶液で中和した後、酢酸エチルで抽出した(1 mL x 2)。硫酸ナトリウムを入れたパスツールピペットに通して脱水し、窒素で酢酸エチルを蒸発させた後、残渣をエタノールに溶解し、逆相HPLC（水：アセトニトリル＝40：60）で精製した。非放射性化合物を票品として、254 nmにおける吸光をHPLCで分析し、それと一致する目的物を分取し、アセトニトリルを留去した。放射能を測定し、^１２５Ｉの比放射能 (2200 Ci/mmol)から、目的物の比放射能を計算した。 (5) Iodine labeling experiment Put 50 μL of tritin butyl precursor (1 mg / mL) in ethanol, 50 μL of 1 N hydrochloric acid, Na [ ¹²⁵ I] I (1-5 μCi) into a glass vial, and finally hydrogen peroxide. 50 μL of water (3% W / V) was added. After standing at room temperature for 10 minutes, the reaction was stopped by adding 100 μL of a saturated aqueous sodium hydrogen sulfite solution. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate (1 mL x 2). After dehydrating through a Pasteur pipette containing sodium sulfate and evaporating ethyl acetate with nitrogen, the residue was dissolved in ethanol and purified by reverse phase HPLC (water: acetonitrile = 40: 60). Absorbance at 254 nm was analyzed by HPLC using a non-radioactive compound as a vote, and the target product corresponding to it was collected, and acetonitrile was distilled off. The radioactivity was measured, and the specific activity of the target product was calculated from the specific activity of ¹²⁵ I (2200 Ci / mmol).

（６）Aβ(1-40)凝集体およびAβ(1-42)凝集体を用いたフラボン誘導体のインビトロ結合実験
Aβ凝集体は、10 mM sodium phosphateと1 mM EDTAを含んだ緩衝液(pH 7.4)に0.5 mg/mLの濃度に溶解し、37 ℃で36-42時間インキュベートした。結合実験は12×75 mm borosilicate glass tubesを用いて行った。10%エタノール溶液 900 μL、Aβ(1-40)凝集体溶液50 μL (57 nM)、種々の濃度の[¹²⁵I]化合物１０、[¹²⁵I]化合物１１、[¹²⁵I]化合物１９、[¹²⁵I]化合物２０、[¹²⁵I]化合物３１、[¹²⁵I]化合物３６、[¹²⁵I]化合物４６、[¹²⁵I]化合物４７、[¹²⁵I]化合物４８の50 μLを混和し、室温で3時間放置した。また、非特異的結合は非放射性化合物11(1 μM)を用いて算出した。Aβ凝集体と結合したフラボン、カルコン、スチリルクロモン、クマリン誘導体と結合していないフラボン、カルコン、スチリルクロモン、クマリン誘導体とはWhatman GF/B filtersを用いてBrandel M-24R cell harvesterによって分離した。濾過したフィルターに残存した物質の放射能はγカウンタで計測し、[¹²⁵I]化合物１１に関しては、スキャッチャード解析よりKd値を算出した。また、[¹²⁵I]化合物１１を放射性リガンドとして、Aβ(1-40)凝集体およびAβ(1-42)凝集体を用いる阻害実験は以下の方法で行った。10%エタノール溶液 850 μL、Aβ(1-40)凝集体およびAβ(1-42)凝集体溶液50 μL (57 nM)、種々の濃度の化合物１０、化合物１１、化合物１９、化合物２０の50 μLを混和し、室温で3時間放置した。また、非特異的結合は非放射性化合物11(1 μM)を用いて算出した。５０％阻害濃度はGraphPad Prism (GraphPad Software)を用いて算出し、阻害定数(Ki値)は、Cheng-Prusoffの式、Ki = IC50/(1 + [L]/Kd)より算出した。この式において、[L]は、実験に用いた[¹²⁵I]化合物１１の濃度、Kdは、[¹²⁵I]化合物１１のAβ(1-40)凝集体およびAβ(1-42)凝集体に対する解離定数を使用した。 (6) In vitro binding experiment of flavone derivatives using Aβ (1-40) aggregates and Aβ (1-42) aggregates
Aβ aggregates were dissolved in a buffer solution (pH 7.4) containing 10 mM sodium phosphate and 1 mM EDTA at a concentration of 0.5 mg / mL and incubated at 37 ° C. for 36-42 hours. The binding experiment was performed using 12 × 75 mm borosilicate glass tubes. 900 μL of 10% ethanol solution, 50 μL (57 nM) of Aβ (1-40) aggregate solution, various concentrations of [ ¹²⁵ I] compound 10, [ ¹²⁵ I] compound 11, [ ¹²⁵ I] compound 19, [ ¹²⁵ 50 μL of [I] Compound 20, [ ¹²⁵ I] Compound 31, [ ¹²⁵ I] Compound 36, [ ¹²⁵ I] Compound 46, [ ¹²⁵ I] Compound 47, and [ ¹²⁵ I] Compound 48 are mixed and allowed to stand at room temperature for 3 hours. I left it alone. Nonspecific binding was calculated using non-radioactive compound 11 (1 μM). Flavonone, chalcone, styrylchromone, and flavone, chalcone, styrylchromone, and coumarin derivatives not bound to Aβ aggregates were separated by Brandel M-24R cell harvester using Whatman GF / B filters. The radioactivity of the substance remaining on the filtered filter was measured with a γ counter, and for the [ ¹²⁵ I] compound 11, the Kd value was calculated by Scatchard analysis. Further, inhibition experiments using Aβ (1-40) aggregates and Aβ (1-42) aggregates with [ ¹²⁵ I] compound 11 as a radioligand were carried out by the following method. 850 μL of 10% ethanol solution, 50 μL (57 nM) of Aβ (1-40) and Aβ (1-42) aggregate solutions, 50 μL of various concentrations of Compound 10, Compound 11, Compound 19, and Compound 20 Were mixed and left at room temperature for 3 hours. Nonspecific binding was calculated using non-radioactive compound 11 (1 μM). The 50% inhibitory concentration was calculated using GraphPad Prism (GraphPad Software), and the inhibition constant (Ki value) was calculated from the Cheng-Prusoff equation, Ki = IC50 / (1+ [L] / Kd). In this formula, [L] is the concentration of [ ¹²⁵ I] compound 11 used in the experiment, and Kd is the A ¹²⁵ (1-40) aggregate and Aβ (1-42) aggregate of [ ¹²⁵ I] compound 11 The dissociation constant was used.

（７）マウス体内放射能分布実験
放射性ヨウ素標識体（化合物１０、１１、１９、２０、３１、４６、４７、４８）は5-10%エタノールを含む生理食塩水を用いて希釈した。1群3-5匹の５週齢ddY系雄性マウス(25-30 g)に、それぞれの標識体100 μL (0.5-1 μCi)を静脈内投与2, 10, 30, 60分後に、断頭、採血した後、臓器を摘出し、重量と放射能を測定した。 (7) Mouse radioactivity distribution experiment Radiolabeled iodine (compounds 10, 11, 19, 20, 31, 46, 47, 48) was diluted with physiological saline containing 5-10% ethanol. Each group of 3-5 5-week-old male ddY mice (25-30 g) was given 100 μL (0.5-1 μCi) of each label intravenously, 2, 10, 30, 60 minutes later, decapitation, After blood collection, the organ was removed and the weight and radioactivity were measured.

（８）アルツハイマー病患者脳組織を用いた結合実験
アルツハイマー病の患者脳側頭葉部位の組織をホルマリン固定しパラフィン包埋した。同パラフィンブロックから5ミクロン厚の切片を作製し、通常のキシレン、エタノール処理により脱パラフィンを実施した（Lippa,C.F., Nee,L.E., Mori,H & George-Hyslop,P.(1998) The Lancet 352:1117-1118.）。最終的に燐酸緩衝液による中和を施した後に、化合物、１０、１１、１９、２０を100 nMの濃度条件で、室温で10分間反応させた。反応停止は、燐酸緩衝液、50%エタノールにて各３回の洗浄により実施した。その後、アルコール、キシレン処理により脱水処理をしてエンテランニュー包埋した。該化合物結合の確認は、蛍光顕微鏡（オリンパスBX50）に附属したCCDカメラ（ M-3204C ）により画像観察によって実施した。 (8) Binding experiments using brain tissue of Alzheimer's disease patients
The tissue in the brain temporal lobe region of a patient with Alzheimer's disease was formalin-fixed and embedded in paraffin. A 5-micron-thick section was prepared from the paraffin block and deparaffinized by ordinary xylene and ethanol treatment (Lippa, CF, Nee, LE, Mori, H & George-Hyslop, P. (1998) The Lancet 352 : 1117-1118.). Finally, after neutralization with a phosphate buffer, compounds 10, 11, 19, and 20 were reacted at room temperature for 10 minutes under a concentration condition of 100 nM. The reaction was stopped by washing 3 times each with a phosphate buffer and 50% ethanol. Thereafter, dehydration treatment was performed by alcohol and xylene treatment to embed Enteran New. The compound binding was confirmed by image observation with a CCD camera (M-3204C) attached to a fluorescence microscope (Olympus BX50).

〔実験結果〕
（１）化合物の合成
図１、図２及び図３にフラボン誘導体の合成経路を示す。フラボン骨格の形成はBaker-Venkataraman反応により行った。この合成過程において、ヒドロキシアセトフェノンをベンゾイルエステル(化合物２、化合物１３、化合物２１)に変換し、さらにアルカリ処理を行うことによって、1,3-ジケトン(化合物３、化合物１４、化合物２２)に変換した。このジケトン体を酸で処理することにより、目的とするフラボン誘導体(化合物４、化合物１５、化合物２３)を得た。化合物４および化合物２３のニトロ基の還元は、塩化スズ(II)を還元剤として行った。生成したアミノ基のジメチル化およびモノメチル化はいずれも常法に従い行った。また図２及び図３のフラボン誘導体(化合物１５、化合物１９、化合物２５、化合物２６)のメトキシ基の脱メチル化反応は三臭化ホウ素により行った。それぞれのブロモ化合物はパラジウムを触媒とするビス（トリブチルスズ）との反応により、トリブチルスズ体に変換した。これらトリブチルスズ体は、ヨウ素との反応により容易に化合物へと変換した。図４にカルコン誘導体の合成経路を示す。カルコン誘導体は、アセトフェノン体とアルデヒド体とのカリウム存在下での縮合反応により、カルコンの基本骨格を形成した。以降の還元、メチル化、トリブチルスズ化、トリブチルスズ-ヨウ素の交換反応はフラボン誘導体の合成方法と同様に行った。図５および６にスチリルクロモン誘導体の合成経路を示す。スチリルクロモン誘導体は、ニトロ桂皮酸クロリドとブロモヒドロキシベンゾフェノンを出発原料に用いて、フラボン誘導体と同様の方法を用いて合成を行った。図７にクマリン誘導体の合成経路を示す。クマリン誘導体の合成は、ブロモヒドロキシベンズアルデヒドとニトロベンゾ酢酸を出発原料に用いて行い、ニトロ基の還元、メチル化、トリブチルスズ化、ヨウ素化はフラボン誘導体と同様の方法に従い行った。 〔Experimental result〕
(1) Synthesis of Compound FIG. 1, FIG. 2 and FIG. 3 show synthesis routes of flavone derivatives. The flavone skeleton was formed by Baker-Venkataraman reaction. In this synthesis process, hydroxyacetophenone was converted to benzoyl ester (compound 2, compound 13, compound 21), and further converted to 1,3-diketone (compound 3, compound 14, compound 22) by alkali treatment. . By treating this diketone body with an acid, the desired flavone derivatives (compound 4, compound 15, compound 23) were obtained. Reduction of the nitro group of Compound 4 and Compound 23 was carried out using tin (II) chloride as a reducing agent. Both the dimethylation and monomethylation of the produced amino group were carried out according to conventional methods. Further, the demethylation reaction of the methoxy group of the flavone derivatives (compound 15, compound 19, compound 25, compound 26) of FIGS. 2 and 3 was performed with boron tribromide. Each bromo compound was converted to a tributyltin body by reaction with bis (tributyltin) using palladium as a catalyst. These tributyltin bodies were easily converted into compounds by reaction with iodine. FIG. 4 shows a synthetic route for chalcone derivatives. The chalcone derivative formed the basic skeleton of chalcone by a condensation reaction of acetophenone and aldehyde in the presence of potassium. Subsequent reduction, methylation, tributyltination, and tributyltin-iodine exchange reactions were performed in the same manner as the synthesis method of the flavone derivative. 5 and 6 show the synthesis route of the styrylchromone derivative. The styrylchromone derivative was synthesized using the same method as the flavone derivative using nitrocinnamic acid chloride and bromohydroxybenzophenone as starting materials. FIG. 7 shows a synthesis route of the coumarin derivative. The synthesis of the coumarin derivative was carried out using bromohydroxybenzaldehyde and nitrobenzoacetic acid as starting materials, and the reduction, methylation, tributyltination and iodination of the nitro group were carried out in the same manner as the flavone derivative.

（２）ヨウ素標識実験
図８に示すように、放射性ヨウ素標識は過酸化水素を酸化剤として用いて、スズ-ヨウ素交換反応により、目的とする放射性ヨウ素-125標識体を放射化学的収率50-80%で得た。標識反応後、逆相HPLCを用いて分離精製を行い、放射化学的収率98%以上で無担体の標識化合物を得た。 (2) Iodine labeling experiment As shown in FIG. 8, radioiodine labeling uses hydrogen peroxide as an oxidizing agent, and the target radioiodine-125 label is obtained by radiochemical yield 50 by tin-iodine exchange reaction. Obtained at -80%. After the labeling reaction, separation and purification were performed using reverse phase HPLC to obtain a carrier-free labeled compound with a radiochemical yield of 98% or more.

（３）Aβ(1-40)凝集体及びAβ(1-42)凝集体を用いたインビトロ結合実験
図９には、種々濃度の[¹²⁵I]化合物１０、[¹²⁵I]化合物１１、[¹²⁵I]化合物１９をAβ凝集体の存在下、Aβ凝集体の非存在下、大過剰の非放射性化合物１１の存在下で反応を行い、セルハーベスターで濾過後、濾紙に残存した放射能を測定した結果を示す。Aβ凝集体が存在しない場合および大過剰の非放射性化合物が存在する場合、いずれも濾紙に残存した放射能は低値を示したのに対して、Aβ凝集体の存在下で反応を行った場合、[¹²⁵I]化合物１０、[¹²⁵I]化合物１１、[¹²⁵I]化合物１９は顕著に高い値を示した。このことから、フラボン誘導体である、[¹²⁵I]化合物１０、[¹²⁵I]化合物１１、[¹²⁵I]化合物１９はいずれもAβ凝集体への高い結合性を示すことが明らかとなった。その結合性は、[¹²⁵I]化合物１１ > [¹²⁵I]化合物１０ > [¹²⁵I]化合物１９の順で高くなった。また、[¹²⁵I]化合物３１、[¹²⁵I]化合物３６、[¹²⁵I]化合物４６、[¹²⁵I]化合物４７、[¹²⁵I]化合物４８に関しても同様の実験を行った。その結果、フラボン誘導体と同様に、カルコン誘導体（化合物３１及び化合物３６）およびスチリルクロモン誘導体（化合物４６、化合物４７及び化合物４８）はアミロイド凝集体への高い結合親和性を示した（図１０及び図１１）。さらに[¹²⁵I]化合物１１に関しては、Aβ(1-40)凝集体およびAβ(1-42)凝集体を用いて飽和実験から得られた値をスキャッチャード解析により分析を行った(図１２)。その結果、直線性を示したことから、フラボン化合物とアミロイド凝集体との結合部位はひとつであることが明らかとなった。また解離平衡定数Kd値は、Aβ(1-40)凝集体に対して、12.3±2.3 nM、 Aβ(1-42)凝集体に対して、17.6±5.7 nMとなり、アミロイド凝集体への高い結合親和性を有することが示された。さらに、化合物１０、１１、１９、２０に関しては、[¹²⁵I]化合物１１を放射性リガンドとする阻害実験を行った（表２９）。その結果、いずれの化合物もAβ(1-40)凝集体およびAβ(1-42)凝集体に対する高い結合性を示した。その結合性は、化合物１１、１０、１９、２０の順に高い値を示した。Aβ(1-40)凝集体（図１２Ａ）への結合性とAβ(1-42)凝集体（図１２Ｂ）への結合性には大きな差異は確認されなかった。 (3) In vitro binding experiment using Aβ (1-40) aggregate and Aβ (1-42) aggregate FIG. 9 shows various concentrations of [ ¹²⁵ I] compound 10, [ ¹²⁵ I] compound 11 and [ ¹²⁵ I] Compound 19 was reacted in the presence of Aβ aggregates, in the absence of Aβ aggregates, in the presence of a large excess of non-radioactive compound 11, and after filtration with a cell harvester, the radioactivity remaining on the filter paper was measured. Results are shown. In the absence of Aβ aggregates and in the presence of a large excess of non-radioactive compounds, the radioactivity remaining on the filter paper was low, whereas the reaction was performed in the presence of Aβ aggregates. , [ ¹²⁵ I] compound 10, [ ¹²⁵ I] compound 11 and [ ¹²⁵ I] compound 19 showed remarkably high values. From this, it was clarified that [ ¹²⁵ I] compound 10, [ ¹²⁵ I] compound 11 and [ ¹²⁵ I] compound 19 which are flavone derivatives show high binding properties to Aβ aggregates. The binding properties increased in the order of [ ¹²⁵ I] compound 11> [ ¹²⁵ I] compound 10> [ ¹²⁵ I] compound 19. Further, the same experiment was performed on [ ¹²⁵ I] compound 31, [ ¹²⁵ I] compound 36, [ ¹²⁵ I] compound 46, [ ¹²⁵ I] compound 47, and [ ¹²⁵ I] compound 48. As a result, like the flavone derivative, the chalcone derivative (compound 31 and compound 36) and the styrylchromone derivative (compound 46, compound 47 and compound 48) showed high binding affinity to amyloid aggregates (FIGS. 10 and 10). 11). Furthermore, regarding [ ¹²⁵ I] compound 11, the values obtained from the saturation experiment using Aβ (1-40) aggregates and Aβ (1-42) aggregates were analyzed by Scatchard analysis (FIG. 12). ). As a result, since it showed linearity, it became clear that there was one binding site between the flavone compound and the amyloid aggregate. The dissociation equilibrium constant Kd value is 12.3 ± 2.3 nM for Aβ (1-40) aggregates, and 17.6 ± 5.7 nM for Aβ (1-42) aggregates. High binding to amyloid aggregates It was shown to have affinity. Further, with respect to compounds 10, 11, 19, and 20, inhibition experiments using [ ¹²⁵ I] compound 11 as a radioligand were performed (Table 29). As a result, all of the compounds showed high binding properties to Aβ (1-40) aggregates and Aβ (1-42) aggregates. The binding properties showed higher values in the order of compounds 11, 10, 19, and 20. There was no significant difference between the binding to the Aβ (1-40) aggregate (FIG. 12A) and the binding to the Aβ (1-42) aggregate (FIG. 12B).

（４）マウス体内放射能分布実験
表３０、３１、３２にそれぞれフラボン誘導体、カルコン誘導体、スチリルクロモン誘導体を正常マウスに投与後の体内放射能分布の結果を示す。 (4) Mouse body radioactivity distribution experiment Tables 30, 31, and 32 show the results of radioactivity distribution in the body after administration of flavone derivatives, chalcone derivatives, and styrylchromone derivatives to normal mice, respectively.

表３０に示すように、いずれのフラボン誘導体も、血液から速やかなクリアランスを示す一方で、投与初期から約4%ID/gと脳内アミロイド画像化を行うために十分高い脳への移行性を示した。脳への放射能動態は、3種類のフラボン誘導体により異なったが、いずれも速やかな脳からの洗い出しが観察された。その消失速度は、[¹²⁵I]化合物１９が最も早く、次に、[¹²⁵I]化合物２０、[¹²⁵I]化合物１０と[¹²⁵I]化合物１１はほぼ同等であった。体内放射能動態はいずれも主に肝臓から胆管、腸管への***経路をとることが示された。また、カルコン誘導体（[¹²⁵I]化合物３１）は投与後、脳への移行性が確認され、その後の速やかに洗い出されることが示された（表３１）。スチリルクロモン誘導体のマウスにおける体内放射能分布を表３２に示した。化合物４８では、血液中への高い放射能滞留が観察され、脳への移行性は低値を示したのに対して、化合物４６及び化合物４７は、血液から脳への高い移行性を示した（化合物では4.9%ID/g、化合物４７では3.0%ID/g）。さらに、化合物４６及び化合物４７は、脳移行後に速やかな放射能消失を示した。 As shown in Table 30, all flavone derivatives show rapid clearance from the blood, while having about 4% ID / g from the beginning of administration and sufficiently high migration to the brain for amyloid imaging in the brain. Indicated. Radioactivity dynamics to the brain differed depending on the three flavone derivatives, but all were promptly washed out from the brain. [ ¹²⁵ I] Compound 19 had the fastest disappearance rate, followed by [ ¹²⁵ I] Compound 20, [ ¹²⁵ I] Compound 10 and [ ¹²⁵ I] Compound 11. It was shown that the radioactivity in the body mainly took the excretion route from the liver to the bile duct and intestinal tract. Moreover, the chalcone derivative ([ ¹²⁵ I] Compound 31) was confirmed to be transferred to the brain after administration, and then quickly washed out (Table 31). Table 32 shows the in vivo radioactivity distribution of styrylchromone derivatives in mice. In Compound 48, high radioactivity retention in the blood was observed, and the transferability to the brain was low, whereas Compound 46 and Compound 47 showed high transferability from the blood to the brain. (4.9% ID / g for compound, 3.0% ID / g for compound 47). Furthermore, Compound 46 and Compound 47 showed rapid loss of radioactivity after brain transfer.

（５）アルツハイマー病患者脳組織を用いた結合実験
アルツハイマー病の確定診断には、患者脳側頭葉部位において、老人斑の沈着と神経原線維変化という２大病変の確認が必要である。アルツハイマー病患者脳組織を用いた結合実験において、化合物１１は、老人斑と特異的に結合していることが示された（図１３）。また脳血管アンギオパチーは、老人斑同様にアルツハイマー病に見られる病変であるが、これも同じアミロイド蛋白が異常沈着していることが知られている。化合物１１は、図１４に見られるように、脳血管アミロイドにも特異的に結合していることが見られることから、アルツハイマー病脳組織にあるアミロイド沈着病変を特異的に認識結合していることが示された。さらに、図１５-B, Hに示すように、化合物１１は、神経変性突起を持つ老人斑、神経原線維変化にも結合性が確認された。また、他の置換基を有する化合物１０、１９，２０を用いて、アルツハイマー病患者脳組織を用いた結合実験を行った場合も、化合物１１と同様に、いずれの化合物もアミロイド斑、神経変性突起を持つ老人斑、脳血管アミロイド、神経原線維変化を認識、結合していることが確認された（図１５）。従って、フラボン誘導体である化合物１０、１１、１９、２０はいずれもアミロイド画像化薬剤に有用な性質を持つことが示された。 (5) Coupling experiment using brain tissue of Alzheimer's disease patients For the definite diagnosis of Alzheimer's disease, it is necessary to confirm two major lesions of senile plaque deposition and neurofibrillary tangles in the patient's brain temporal lobe. In a binding experiment using brain tissue of Alzheimer's disease patients, Compound 11 was shown to specifically bind to senile plaques (FIG. 13). In addition, cerebrovascular angiopathy is a lesion observed in Alzheimer's disease like senile plaques, and it is also known that the same amyloid protein is abnormally deposited. As seen in FIG. 14, Compound 11 specifically binds to cerebral vascular amyloid, and therefore specifically recognizes and binds to amyloid deposited lesions in Alzheimer's disease brain tissue. It has been shown. Furthermore, as shown in FIGS. 15-B and H, Compound 11 was also confirmed to bind to senile plaques having neurodegenerative processes and neurofibrillary tangles. In addition, when a binding experiment using brain tissue of an Alzheimer's disease patient was performed using compounds 10, 19, and 20 having other substituents, as in the case of compound 11, all of the compounds were amyloid plaques, neurodegenerative processes. It was confirmed that senile plaques, cerebrovascular amyloid, and neurofibrillary tangles were recognized and bound (FIG. 15). Therefore, it was shown that compounds 10, 11, 19, and 20, which are flavone derivatives, all have properties useful for amyloid imaging agents.

本明細書は、本願の優先権の基礎である日本国特許出願（特願2004-341370号）の明細書および／または図面に記載されている内容を包含する。また、本発明で引用した全ての刊行物、特許および特許出願をそのまま参考として本明細書にとり入れるものとする。   This specification includes the contents described in the specification and / or drawings of the Japanese patent application (Japanese Patent Application No. 2004-341370) which is the basis of the priority of the present application. In addition, all publications, patents and patent applications cited in the present invention are incorporated herein by reference as they are.

フラボン誘導体の合成法（１）を示す図（図中の番号は化合物の番号を示す）。The figure which shows the synthesis method (1) of a flavone derivative (the number in a figure shows the number of a compound). フラボン誘導体の合成法（２）を示す図（図中の番号は化合物の番号を示す）。The figure which shows the synthesis method (2) of a flavone derivative (the number in a figure shows the number of a compound). フラボン誘導体の合成法（３）を示す図（図中の番号は化合物の番号を示す）。The figure which shows the synthesis method (3) of a flavone derivative (the number in a figure shows the number of a compound). カルコン誘導体の合成法を示す図（図中の番号は化合物の番号を示す）。The figure which shows the synthesis method of a chalcone derivative (the number in a figure shows the number of a compound). スチリルクロモン誘導体の合成法（１）を示す図（図中の番号は化合物の番号を示す）。The figure which shows the synthesis method (1) of a styryl chromone derivative (the number in a figure shows the number of a compound). スチリルクロモン誘導体の合成法（２）を示す図（図中の番号は化合物の番号を示す）。The figure which shows the synthesis method (2) of a styryl chromone derivative (the number in a figure shows the number of a compound). クマリン誘導体の合成法を示す図（図中の番号は化合物の番号を示す）。The figure which shows the synthesis method of a coumarin derivative (the number in a figure shows the number of a compound). フラボン、カルコン、スチリルクロモン、クマリン誘導体の放射性ヨウ素による標識法を示す図。The figure which shows the labeling method by the radioactive iodine of a flavone, a chalcone, a styrylchromone, and a coumarin derivative. 化合物１０（Ａ）、化合物１１（Ｂ）、及び化合物１９（Ｃ）のAβ凝集体との結合性を示す図（●：Aβ凝集体存在下、■：Aβ凝集体非存在下、▲：非特異的結合）。Figures showing the binding of compound 10 (A), compound 11 (B), and compound 19 (C) to Aβ aggregates (●: in the presence of Aβ aggregate, ■: in the absence of Aβ aggregate, ▲: non Specific binding). 化合物３１（Ａ）、及び化合物３６（Ｂ）のAβ凝集体との結合性を示す図（●：Aβ凝集体存在下、■：Aβ凝集体非存在下）。The figure which shows the binding property with the A (beta) aggregate of compound 31 (A) and compound 36 (B) (-: In presence of A (beta) aggregate, (3): In the absence of A (beta) aggregate). 化合物４６（Ａ）、化合物４７（Ｂ）、及び化合物４８（Ｃ）のAβ凝集体との結合性を示す図（●：Aβ凝集体存在下、■：Aβ凝集体非存在下）。The figure which shows the binding property with the A (beta) aggregate of the compound 46 (A), the compound 47 (B), and the compound 48 (C) (-: In presence of A (beta) aggregate, ■: In the absence of A (beta) aggregate). 化合物１１のAβ凝集体との飽和実験により得られたスキャッチャードプロットを示す図。The figure which shows the Scatchard plot obtained by the saturation experiment with the A (beta) aggregate of the compound 11. FIG. アルツハイマー病脳組織における老人斑アミロイドへの化合物１１の結合状態を示す写真（×４０倍対物レンズ使用、Gフィルター使用）。アミロイド老人斑（中央部分）と脳血管アミロイド（左下）に化合物１１（白く見える）が結合している。A photograph showing the binding state of Compound 11 to senile plaque amyloid in Alzheimer's disease brain tissue (× 40 × objective lens, G filter used). Compound 11 (appears white) is bound to amyloid senile plaques (central part) and cerebrovascular amyloid (lower left). アルツハイマー病脳組織における老人斑アミロイドへの化合物１１の結合状態を示す写真（×２０倍対物レンズ使用、Gフィルター使用）。脳血管アミロイド（中央付近の４箇所、左上の１箇所）に化合物１１（白く見える）が結合している。The photograph (* 20 time objective lens use, G filter use) which shows the binding state of the compound 11 to the senile plaque amyloid in Alzheimer's disease brain tissue. Compound 11 (appears white) is bound to cerebrovascular amyloid (4 sites near the center, 1 site on the upper left). アルツハイマー病脳組織における病理学的変化への化合物１０（A-D）、１１(E-H)、１９(I-L)、２０(M-P)の結合状態を示す写真（×４０倍対物レンズ使用、Gフィルター使用）。アミロイド斑（A, E, I, M）、神経変性突起をもつ老人斑(B, F, J, N)、脳血管アミロイド(C, G, K, O)、神経原線維変化(D, H, L, P)を写真中央に示す。A photograph showing the binding state of compounds 10 (A-D), 11 (E-H), 19 (I-L), and 20 (M-P) to pathological changes in Alzheimer's disease brain tissue (× 40 × objective lens used, G filter used). Amyloid plaques (A, E, I, M), senile plaques with neurodegenerative processes (B, F, J, N), cerebrovascular amyloid (C, G, K, O), neurofibrillary tangles (D, H , L, P) are shown in the center of the photo.

Claims (9)

一般式（III）
〔式中、Ｒ^１、Ｒ^２、Ｒ^３、及びＲ^４は、互いに独立して、水素原子、ハロゲン原子、水酸基、カルボキシル基、スルホン基、ジメチルアミノ基、メチルアミノ基、アミノ基、ニトロ基、炭素数１〜４のアルキル基、炭素数１〜４のアルコキシ基、２−フルオロエトキシ基、３−フルオロプロポキシ基、４−フルオロブトキシ基、又は５−フルオロペントキシ基を示し、Ｒ^８は下記置換基群Ａから選ばれた１若しくは２以上の置換基によって置換されていてもよいアリール基、又は下記置換基群Ａから選ばれた１若しくは２以上の置換基によって置換されていてもよい芳香族複素環基を示し、置換基群Ａは、ハロゲン原子、水酸基、カルボキシル基、スルホン基、ジメチルアミノ基、メチルアミノ基、アミノ基、ニトロ基、炭素数１〜４のアルキル基、及び炭素数１〜４のアルコキシ基からなる群である。〕
で表される化合物又はその医薬上許容される塩を含有するアミロイド関連疾患診断用組成物。 General formula (III)
[Wherein R ¹ , R ² , R ³ , and R ⁴ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a sulfone group, a dimethylamino group, a methylamino group, an amino group, or a nitro group. , An alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a 2-fluoroethoxy group, a 3-fluoropropoxy group, a 4-fluorobutoxy group, or a 5-fluoropentoxy group, and R ⁸ is An aryl group which may be substituted by one or more substituents selected from the following substituent group A, or an aryl group which may be substituted by one or more substituents selected from the following substituent group A Represents an aromatic heterocyclic group, and the substituent group A includes a halogen atom, a hydroxyl group, a carboxyl group, a sulfone group, a dimethylamino group, a methylamino group, an amino group, a nitro group, Alkyl group, and a group consisting of alkoxy group having 1 to 4 carbon atoms. ]
A composition for diagnosing amyloid-related diseases, which comprises a compound represented by the formula: or a pharmaceutically acceptable salt thereof. 一般式（III）におけるＲ^１、Ｒ^２、Ｒ^３、Ｒ^４のいずれかが、ハロゲン原子である請求項１記載のアミロイド関連疾患診断用組成物。 The composition for diagnosing amyloid-related diseases according to claim 1, wherein any one of R ¹ , R ² , R ³ and R ^{4 in} the general formula (III) is a halogen atom. 一般式（III）におけるＲ^１、Ｒ^２、Ｒ^３、Ｒ^４のいずれかが、ヨウ素原子である請求項１記載のアミロイド関連疾患診断用組成物。 The composition for diagnosing amyloid-related diseases according to claim 1, wherein any one of R ¹ , R ² , R ³ and R ^{4 in} the general formula (III) is an iodine atom. 一般式（III）で表される化合物が、放射性核種で標識されている化合物である請求項１乃至３のいずれか一項記載のアミロイド関連疾患診断用組成物。   The composition for diagnosing amyloid-related diseases according to any one of claims 1 to 3, wherein the compound represented by the general formula (III) is a compound labeled with a radionuclide. 放射性核種が、陽電子放出核種である請求項４記載のアミロイド関連疾患診断用組成物。   The composition for diagnosing amyloid-related diseases according to claim 4, wherein the radionuclide is a positron emitting nuclide. 放射性核種が、γ線放出核種である請求項４記載記載のアミロイド関連疾患診断用組成物。   The composition for diagnosing amyloid-related diseases according to claim 4, wherein the radionuclide is a γ-ray-emitting nuclide. アミロイド関連疾患が、アルツハイマー病である請求項１乃至６のいずれか一項記載のアミロイド関連疾患診断用組成物。   The amyloid-related disease diagnostic composition according to any one of claims 1 to 6, wherein the amyloid-related disease is Alzheimer's disease. アミロイド関連疾患のモデル動物に被験物質を投与する工程、前記モデル動物に請求項１乃至７のいずれか一項記載のアミロイド関連疾患診断用組成物を投与する工程、及び前記モデル動物の脳中に含まれる一般式（III）で表される化合物の分布又は量を調べる工程を含むアミロイド関連疾患の治療薬又は予防薬のスクリーニング方法。   A step of administering a test substance to a model animal of amyloid-related disease, a step of administering a composition for diagnosing amyloid-related disease according to any one of claims 1 to 7 to the model animal, and a brain of the model animal A screening method for a therapeutic or prophylactic agent for amyloid-related diseases, comprising a step of examining the distribution or amount of the compound represented by the general formula (III). アミロイド関連疾患のモデル動物に前記疾患の治療薬又は予防薬を投与する工程、前記モデル動物に請求項１乃至７のいずれか一項記載のアミロイド関連疾患診断用組成物を投与する工程、及び前記モデル動物の脳中に含まれる一般式（III）で表される化合物の分布又は量を調べる工程を含むアミロイド関連疾患の治療薬又は予防薬の評価方法。   A step of administering a therapeutic or prophylactic agent for the disease to a model animal of amyloid-related disease, a step of administering the composition for diagnosing amyloid-related disease according to any one of claims 1 to 7 to the model animal, and A method for evaluating a therapeutic or prophylactic agent for amyloid-related diseases, comprising a step of examining the distribution or amount of a compound represented by the general formula (III) contained in the brain of a model animal.