TWI644665B

TWI644665B - Use of stilbene and benzofuran derivatives for the treatment of neurological diseases

Info

Publication number: TWI644665B
Application number: TW106143288A
Authority: TW
Inventors: 李文泰; 蕭永基; 翁芸芳
Original assignee: 衛生福利部國家中醫藥研究所
Priority date: 2017-12-08
Filing date: 2017-12-08
Publication date: 2018-12-21
Also published as: TW201924665A

Abstract

本發明揭示二苯乙烯及苯并呋喃衍生物或其醫藥上可接受之鹽類用於治療神經性疾病之用途，此等化合物具有神經保護及抗神經發炎活性。前述神經性疾病包括：腦部創傷、缺血性腦中風、痴呆症候群、癲癇、帕金森氏症及阿茲海默症或其組合。The present invention discloses the use of stilbene and a benzofuran derivative or a pharmaceutically acceptable salt thereof for the treatment of a neurological disease, such compounds having neuroprotective and anti-neuroinflammatory activities. The aforementioned neurological diseases include: brain trauma, ischemic stroke, dementia syndrome, epilepsy, Parkinson's disease, and Alzheimer's disease or a combination thereof.

Description

二苯乙烯及苯并呋喃衍生物用於治療神經性疾病之用途Use of stilbene and benzofuran derivatives for the treatment of neurological diseases

本發明揭示一種羥基-官能化二苯乙烯及2-芳基苯并[b]呋喃化合物或其醫藥上可接受之鹽類用於治療神經性疾病之用途，其中該神經性疾病包括：腦部創傷、缺血性腦中風、痴呆症候群、癲癇、帕金森氏症及阿茲海默症或其組合。The present invention discloses a use of a hydroxy-functionalized stilbene and a 2-arylbenzo[b]furan compound or a pharmaceutically acceptable salt thereof for treating a neurological disease, wherein the neurological disease includes: a brain Trauma, ischemic stroke, dementia syndrome, epilepsy, Parkinson's disease, and Alzheimer's disease or a combination thereof.

神經性疾病為腦、脊髓或其他神經系統的任何障礙，常見者包括中風、腦部創傷、癲癇和神經退化性疾病等產生明顯可識別的結構損傷。Neurological disorders are any disorder of the brain, spinal cord, or other nervous system, and common causes include stroke, brain trauma, epilepsy, and neurodegenerative diseases that produce clearly identifiable structural damage.

神經退化性疾病是一種腦部及脊髓細胞失去功能的症狀。腦部及脊髓是由神經元所構成，其負責不同功能，例如思考、運動、記憶、處理訊息等。神經元的損傷會造成神經退化性疾病，該疾病可大致分為兩種類型，第一種為造成動作障礙，如運動失調症、帕金森氏症，第二種為造成記憶問題，如老年失智症、阿茲海默症。Neurodegenerative diseases are symptoms of loss of function in the brain and spinal cord cells. The brain and spinal cord are made up of neurons that are responsible for different functions such as thinking, exercising, remembering, and processing messages. Neuronal damage can cause neurodegenerative diseases. The disease can be roughly divided into two types. The first is to cause movement disorders, such as movement disorders, Parkinson's disease, and the second is to cause memory problems, such as old age. Mental illness, Alzheimer's disease.

阿茲海默症是最常見的神經退化性疾病，其導致認知能力下降、不可逆的記憶喪失、方向迷失和語言障礙等。阿茲海默症的組織病理學標誌包括老年斑的類澱粉蛋白- β（amyloid- β，A β）肽的大量細胞外沉積，A β被認定是造成該病症的主要因子，因為A β可直接的對神經元產生毒性，也會啟動腦中的神經發炎反應，使微膠細胞（microglia）釋放出細胞激素，如 IL-1 β、TNF α及 IL-6。 Alzheimer's disease is the most common neurodegenerative disease that leads to cognitive decline, irreversible memory loss, loss of direction, and language barriers. Histopathological signs of Alzheimer's disease senile plaques comprising amyloid - β (amyloid- β, A β ) deposition of large extracellular peptide, A β was identified as the major factors causing the condition, can be used directly as A β is toxic to neurons, the brain will initiate a neural inflammation of the microgels cells (microglia) release of cytokines, such as IL-1 β, TNF α and IL-6.

雖然目前進行的臨床試驗用藥大多尋求減少A β的產生、聚集和毒性或促進A β清除，然而至今並沒有明確證明可以治癒或延緩阿茲海默症進展的藥物。 Although clinical trials of drugs currently seeking to reduce the production of A β mostly, accumulation and toxicity or promote A β clear, but so far there is no clear proof of the drug can cure or slow the progression of Alzheimer's disease.

有鑒於前述問題，本發明提出一種羥基-官能化二苯乙烯化合物或其醫藥上可接受之鹽類在治療神經性疾病之用途。In view of the foregoing, the present invention provides a use of a hydroxy-functionalized stilbene compound or a pharmaceutically acceptable salt thereof for the treatment of a neurological disorder.

具體而言，該羥基-官能化二苯乙烯係為式(I)化合物：式(I) 其中，R ¹為氫或CH=CHCO ₂R ¹⁰； R ²為氫、鹵素、(C ₁-C ₈)烷氧基、醛基或CH=CHCO ₂R ¹⁰； R ³為氫、(C ₁-C ₈)烷氧基或CH=CHCO ₂R ¹⁰； R ⁴為氫、羥基、(C ₁-C ₈)烷氧基或CH=CHCO ₂R ¹⁰； R ⁵為氫、羥基或(C ₁-C ₈)烷氧基； R ⁶為氫、鹵素或CH=CHCO ₂R ¹⁰； R ⁷為氫、羥基或(C ₁-C ₈)烷氧基； R ⁸及R ⁹係各自獨立為氫、羥基或(C ₁-C ₈)烷氧基，或R ⁸、R ⁹及與其鍵結之碳原子共同定義二氧戊環；且 R ¹⁰為氫或(C ₁-C ₆)烷基。 In particular, the hydroxy-functionalized stilbene is a compound of formula (I): Wherein R ¹ is hydrogen or CH=CHCO ₂ R ¹⁰ ; R ² is hydrogen, halogen, (C ₁ -C ₈ ) alkoxy, aldehyde or CH=CHCO ₂ R ¹⁰ ; R ³ is hydrogen , (C ₁ -C ₈ ) alkoxy or CH=CHCO ₂ R ¹⁰ ; R ⁴ is hydrogen, hydroxy, (C ₁ -C ₈ ) alkoxy or CH=CHCO ₂ R ¹⁰ ; R ⁵ is hydrogen, hydroxy Or (C ₁ -C ₈ ) alkoxy; R ⁶ is hydrogen, halogen or CH=CHCO ₂ R ¹⁰ ; R ⁷ is hydrogen, hydroxy or (C ₁ -C ₈ )alkoxy; R ⁸ and R ⁹ are Each independently is hydrogen, hydroxy or (C ₁ -C ₈ )alkoxy, or R ⁸ , R ⁹ and the carbon atom to which they are bonded define a dioxolane; and R ¹⁰ is hydrogen or (C ₁ -C ₆ )alkyl.

於一具體實施例中，式(I)化合物或其醫藥上可接受之鹽類之特徵在於，其中： R ¹為氫或CH=CHCO ₂R ¹⁰； R ²為氫、F、Cl、Br、(C ₁-C ₃)烷氧基或醛基； R ³及R ⁴係各自獨立為氫、(C ₁-C ₃)烷氧基或CH=CHCO ₂R ¹⁰； R ⁵為氫或羥基； R ⁶為氫、F、Cl、Br或CH=CHCO ₂R ¹⁰； R ⁷為氫、羥基或(C ₁-C ₃)烷氧基； R ⁸及R ⁹係各自獨立為羥基或(C ₁-C ₃)烷氧基，或R ⁸、R ⁹及與其鍵結之碳原子共同定義結構；且 R ¹⁰為氫或(C ₁-C ₃)烷基。 In a particular embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is hydrogen or CH=CHCO ₂ R ¹⁰ ; R ² is hydrogen, F, Cl, Br, (C ₁ -C ₃ ) alkoxy or aldehyde; R ³ and R ⁴ are each independently hydrogen, (C ₁ -C ₃ )alkoxy or CH=CHCO ₂ R ¹⁰ ; R ⁵ is hydrogen or hydroxy; R ⁶ is hydrogen, F, Cl, Br or CH=CHCO ₂ R ¹⁰ ; R ⁷ is hydrogen, hydroxy or (C ₁ -C ₃ ) alkoxy; R ⁸ and R ⁹ are each independently hydroxy or (C ₁ -C ₃ )alkoxy, or R ⁸ , R ⁹ and the carbon atom to which they are bonded define a structure; and R ¹⁰ is hydrogen or (C ₁ -C) ₃ ) an alkyl group.

於一具體實施例中，舉例而言，於式(I)中： R ¹為氫或CH=CHCO ₂R ¹⁰； R ²為氫、Br或醛基； R ³及R ⁴係各自獨立為氫、甲氧基或CH=CHCO ₂R ¹⁰； R ⁵為氫或羥基； R ⁶為氫或CH=CHCO ₂R ¹⁰； R ⁷為氫、羥基或甲氧基； R ⁸及R ⁹係各自獨立為羥基或甲氧基，或R ⁸及R ⁹共同定義-OCH ₂O-；且 R ¹⁰為乙基。 In one embodiment, for example, in formula (I): R ¹ is hydrogen or CH=CHCO ₂ R ¹⁰ ; R ² is hydrogen, Br or an aldehyde group; and R ³ and R ⁴ are each independently hydrogen. , methoxy or CH=CHCO ₂ R ¹⁰ ; R ⁵ is hydrogen or hydroxy; R ⁶ is hydrogen or CH=CHCO ₂ R ¹⁰ ; R ⁷ is hydrogen, hydroxy or methoxy; R ⁸ and R ⁹ are each independently Is a hydroxy or methoxy group, or R ⁸ and R ⁹ together define -OCH ₂ O-; and R ¹⁰ is an ethyl group.

於另一具體實施例中，該式(I)化合物或其醫藥上可接受之鹽類係選自以下任一者或其組合： 3-(4-((E)-3,4,5-三羥基苯乙烯基)苯基)丙烯酸 (E)-乙酯； 3-(3-((E)-3,4,5-三羥基苯乙烯基)苯基)丙烯酸 (E)-乙酯；以及 3-(3,4-二甲氧基苯乙烯基)-4-羥基-5-甲氧基苯甲醛。In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from any one or a combination of the following: 3-(4-((E)-3,4,5- (E)-ethyl ester of trihydroxystyryl)phenyl)acrylate; (E)-ethyl 3-(3-((E)-3,4,5-trihydroxystyryl)phenyl)acrylate; And 3-(3,4-dimethoxystyryl)-4-hydroxy-5-methoxybenzaldehyde.

具體而言，前述神經性疾病係選自於由腦部創傷、缺血性腦中風、痴呆症候群、癲癇、帕金森氏症及阿茲海默症所組成之群組。Specifically, the neurological disease is selected from the group consisting of brain trauma, ischemic stroke, dementia syndrome, epilepsy, Parkinson's disease, and Alzheimer's disease.

更具體而言，前述神經性疾病係為阿茲海默症。More specifically, the aforementioned neurological disease is Alzheimer's disease.

本發明另提出一種羥基-官能化2-芳基苯并[b]呋喃化合物或其醫藥上可接受之鹽類在治療神經性疾病之用途。The invention further provides the use of a hydroxy-functionalized 2-arylbenzo[b]furan compound or a pharmaceutically acceptable salt thereof for the treatment of a neurological disorder.

具體而言，該羥基-官能化2-芳基苯并[b]呋喃係為式(II)化合物：式(II) 其中，R ¹為氫或鹵素； R ²為氫、鹵素或CH=CHCO ₂R ¹⁰； R ³為氫或羥基； R ⁴為氫、羥基或(C ₁-C ₈)烷氧基； R ⁵為氫或羥基； R ⁶及R ⁷係各自獨立為氫或羥基，或R ⁶及R ⁷共同定義-OCH ₂O-； R ⁸為氫或羥基； R ⁹為氫、鹵素或CH=CHCO ₂R ¹⁰；且 R ¹⁰為氫或(C ₁-C ₆)烷基。 In particular, the hydroxy-functionalized 2-arylbenzo[b]furan is a compound of formula (II): Wherein R ¹ is hydrogen or halogen; R ² is hydrogen, halogen or CH=CHCO ₂ R ¹⁰ ; R ³ is hydrogen or hydroxy; R ⁴ is hydrogen, hydroxy or (C ₁ -C ₈ ) alkoxylate R ⁵ is hydrogen or hydroxy; R ⁶ and R ⁷ are each independently hydrogen or hydroxy, or R ⁶ and R ^{7 are} together defined as -OCH ₂ O-; R ⁸ is hydrogen or hydroxy; R ⁹ is hydrogen, halogen or CH=CHCO ₂ R ¹⁰ ; and R ¹⁰ is hydrogen or (C ₁ -C ₆ )alkyl.

於一具體實施例中，式(II)化合物或其醫藥上可接受之鹽類之特徵在於，其中： R ¹為氫、F、Cl或Br； R ²為氫、F、Cl、Br或CH=CHCO ₂R ¹⁰； R ³及R ⁵係各自獨立為氫； R ⁴、R ⁶及R ⁸係各自獨立為氫或羥基； R ⁷為羥基； R ⁹為氫或CH=CHCO ₂R ¹⁰；且 R ¹⁰為氫或(C ₁-C ₃)烷基。 In a particular embodiment, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein: R ¹ is hydrogen, F, Cl or Br; R ² is hydrogen, F, Cl, Br or CH =CHCO ₂ R ¹⁰ ; R ³ and R ⁵ are each independently hydrogen; R ⁴ , R ⁶ and R ⁸ are each independently hydrogen or hydroxy; R ⁷ is hydroxy; R ⁹ is hydrogen or CH=CHCO ₂ R ¹⁰ ; And R ¹⁰ is hydrogen or (C ₁ -C ₃ )alkyl.

於一具體實施例中，舉例而言，於式(II)中： R ¹為氫、F、Cl或Br； R ²及R ⁹係各自獨立為氫或CH=CHCO ₂R ¹⁰； R ³及R ⁵係各自獨立為氫； R ⁴、R ⁶及R ⁸係各自獨立為氫或羥基； R ⁷為羥基；且 R ¹⁰為氫或乙基。 In one embodiment, for example, in formula (II): R ¹ is hydrogen, F, Cl or Br; R ² and R ⁹ are each independently hydrogen or CH=CHCO ₂ R ¹⁰ ; R ³ and R ⁵ is each independently hydrogen; R ⁴ , R ⁶ and R ⁸ are each independently hydrogen or hydroxy; R ⁷ is hydroxy; and R ¹⁰ is hydrogen or ethyl.

於另一具體實施例中，該式(II)化合物或其醫藥上可接受之鹽類係選自以下任一者或其組合： 3-(2-(苯并呋喃-2-基)-4,5-二羥基苯基)丙烯酸 (E)-乙酯； 3-(7-羥基-2-(3,4,5-三羥基苯基)苯并呋喃-5-基)丙烯酸 (E)-乙酯； 5-(苯并呋喃-2-基)-4-溴苯-1,2,3-三醇； 4-(5-溴-7-羥基苯并呋喃-2-基)苯-1,2-二醇；以及 4-(4-溴-7-羥基苯并呋喃-2-基)苯-1,2-二醇。In another embodiment, the compound of formula (II) or a pharmaceutically acceptable salt thereof is selected from any one or a combination of the following: 3-(2-(benzofuran-2-yl)-4 (5-dihydroxyphenyl)acrylic acid (E)-ethyl ester; 3-(7-hydroxy-2-(3,4,5-trihydroxyphenyl)benzofuran-5-yl)acrylic acid (E)- Ethyl ester; 5-(benzofuran-2-yl)-4-bromobenzene-1,2,3-triol; 4-(5-bromo-7-hydroxybenzofuran-2-yl)benzene-1 , 2-diol; and 4-(4-bromo-7-hydroxybenzofuran-2-yl)benzene-1,2-diol.

為使本領域具有通常知識者可瞭解本發明的特點及功效，以下謹就說明書及申請專利範圍中提及的術語及用語進行一般性的說明及定義。除非另有指明，否則文中使用的所有技術及科學上的字詞，皆具有本領域具有通常知識者對於本發明所瞭解的通常意義，當有衝突情形時，應以本說明書的定義為準。To enable those skilled in the art to understand the features and functions of the present invention, the general description and definitions of the terms and terms mentioned in the specification and claims are hereby incorporated. Unless otherwise indicated, all technical and scientific terms used herein have the ordinary meaning of those of ordinary skill in the art, and in the case of a conflict, the definition of this specification shall prevail.

首先，本文某些部分是利用「一」、「一種」、「一個」或類似用語來描述本發明所述的成分和技術特徵，此種描述只是為了方便表達，並對本發明的技術特徵提供一般性的意義。因此，除非另有指明，否則此種描述應理解為包含一個或至少一個，且單數也同時包含複數。First of all, some parts of the text describe the components and technical features of the present invention by using "a", "an", "an" or the like. The description is only for convenience of expression and provides a general description of the technical features of the present invention. The meaning of sex. Therefore, unless otherwise indicated, such description is to be understood to include one or at least one

在本文中，用語「包含」、「包括」、「具有」、「含有」或其他任何類似用語均屬於開放性連接詞（open-ended transitional phrase），其意欲涵蓋非排他性的包含物。舉例而言，含有複數要素的一組合物或製品並不僅限於本文所列出的此等要素而已，而是還可包含未明確列出但卻是該組合物或製品通常固有的其他要素。除此之外，除非有相反的明確說明，否則用語「或」是指含括性的「或」，而不是指排他性的「或」。例如，以下任何一種情況均滿足條件「A或B」：A為真（或存在）且B為偽（或不存在）、A為偽（或不存在）且B為真（或存在）、A和B均為真（或存在）。此外，在本文中，用語「包含」、「包括」、「具有」、「含有」的解讀應視為已具體揭示了並同時涵蓋「由…所組成」及「實質上由…所組成」等封閉式或半封閉式連接詞。In this context, the terms "including", "including", "having", "containing" or any other similar terms are all open-ended transitional phrases, which are intended to cover non-exclusive inclusions. For example, a set of compositions or articles containing a plurality of elements is not limited to such elements as listed herein, but may also include other elements not specifically listed but which are generally inherent to the composition or article. In addition, the term "or" is used to mean an inclusive "or" rather than an exclusive "or" unless expressly stated to the contrary. For example, the condition "A or B" is satisfied in any of the following cases: A is true (or exists) and B is pseudo (or non-existent), A is pseudo (or non-existent), and B is true (or exists), A And B are both true (or exist). In addition, in this context, the interpretations of the terms "including", "including", "having" and "including" shall be deemed to have been specifically disclosed and covered by "consisting of" and "consisting essentially of", etc. Closed or semi-closed conjunction.

在本文中，所有以數值範圍或百分比範圍形式界定的特徵或條件（例如C ₁至C ₈）僅是為了簡潔及方便。據此，數值範圍或百分比範圍的描述應視為已涵蓋且具體揭示了所有可能的次範圍及範圍內的個別數值，特別是整數數值。舉例而言，「1至8」的範圍描述應視為已經具體揭示了如1至7、2至8、2至6、3至6、4至8、3至8等等所有次範圍，特別是由所有整數數值所界定的次範圍，且應視為已經具體揭示了範圍內如1、2、3、4、5、6、7、8等個別數值。除非另有指明，否則前述解釋方法適用於本發明全文的所有內容，不論範圍廣泛與否。 In this document, all features or conditions (eg, C ₁ to C ₈ ) defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience. Accordingly, the recitation of ranges of values or ranges of values should be construed as covering and specifically disclosing all possible sub-ranges and individual values, particularly integer values. For example, the description of the range of "1 to 8" should be regarded as having specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc. It is a sub-range defined by all integer values, and should be considered as having specifically disclosed individual values such as 1, 2, 3, 4, 5, 6, 7, 8, and the like. Unless otherwise indicated, the foregoing explanations apply to all aspects of the present invention, whether broad or not.

若數量或其他數值或參數是以範圍、較佳範圍或一系列上限與下限表示，則其應理解成是本文已特定揭示了由任一對該範圍的上限或較佳值與該範圍的下限或較佳值構成的所有範圍，不論該等範圍是否有分別揭示。此外，本文中若提到數值的範圍時，除非另有說明，否則該範圍應包含其端點以及範圍內的所有整數與分數。If the quantity or other value or parameter is expressed in the range, the preferred range, or a series of upper and lower limits, it should be understood that the upper or preferred value of the range and the lower limit of the range are specifically disclosed herein. And all ranges of preferred values, whether or not such ranges are disclosed separately. In addition, when a range of values is referred to herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

在本文中，在可達成發明目的的前提下，數值應理解成具有該數值有效位數的精確度。舉例來說，數字40.0則應理解成涵蓋從39.50至40.49的範圍。In this context, a numerical value should be understood to have an accuracy of the number of significant digits of the numerical value, if the object of the invention is achieved. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

在本文中，對於使用馬庫西群組（Markush group）或選項式用語以描述本發明特徵或實例的情形，本領域具有通常知識者應瞭解馬庫西群組或選項列表內所有成員的次群組或任何個別成員亦可用於描述本發明。舉例而言，若X描述成「選自於由X ₁、X ₂及X ₃所組成的群組」，亦表示已經完全描述出X為X ₁的主張與X為X ₁和/或X ₂的主張。再者，對於使用馬庫西群組或選項式用語以描述本發明的特徵或實例者，本領域具有通常知識者應瞭解馬庫西群組或選項列表內所有成員的次群組或個別成員的任何組合亦可用於描述本發明。據此，舉例而言，若X描述成「選自於由X ₁、X ₂及X ₃所組成的群組」，且Y描述成「選自於由Y ₁、Y ₂及Y ₃所組成的群組」，則表示已經完全描述出X為X ₁或X ₂或X ₃而Y為Y ₁或Y ₂或Y ₃的主張。 In this context, for the case of using a Markush group or an alternative term to describe a feature or example of the present invention, one of ordinary skill in the art should know the number of all members of the Markusi group or the list of options. Groups or any individual members may also be used to describe the invention. For example, if X is described as "selected from the group consisting of X _1, X ₂ and X ₃ the group consisting of," we have been fully described also represents an X and X ₁ to X claims for X ₁ and / or X ₂ Proposition. Furthermore, for those who use the Markusi group or the alternative language to describe features or examples of the present invention, those of ordinary skill in the art should be aware of subgroups or individual members of all members of the Markusi group or list of options. Any combination of these can also be used to describe the invention. Accordingly, for example, if X is described as "selected from a group consisting of X ₁ , X _{2 ,} and X ₃ ", and Y is described as "selected from Y ₁ , Y _{2 ,} and Y ₃ The group indicates that X is X ₁ or X ₂ or X ₃ and Y is Y ₁ or Y ₂ or Y ₃ .

以下具體實施方式本質上僅是例示性，並不欲限制本發明及其用途。此外，本文並不受前述背景技術或發明內容或以下具體實施方式或實施例中所描述的任何理論的限制。The following specific embodiments are merely illustrative in nature and are not intended to limit the invention. Further, the present invention is not limited by the foregoing background or the invention or the theory of the invention.

概言之，本發明係關於一種羥基-官能化二苯乙烯化合物或其醫藥上可接受之鹽類在治療神經性疾病之用途，例如製備治療神經性疾病之藥物的用途。In summary, the invention relates to the use of a hydroxy-functionalized stilbene compound or a pharmaceutically acceptable salt thereof for the treatment of a neurological disorder, for example for the preparation of a medicament for the treatment of a neurological disorder.

本發明另關於一種羥基-官能化2-芳基苯并[b]呋喃化合物或其醫藥上可接受之鹽類在治療神經性疾病之用途，例如製備治療神經性疾病之藥物的用途。The invention further relates to the use of a hydroxy-functionalized 2-arylbenzo[b]furan compound or a pharmaceutically acceptable salt thereof for the treatment of a neurological disorder, for example for the preparation of a medicament for the treatment of a neurological disorder.

前述神經性疾病涵蓋但不限於神經退化性疾病，神經性疾病主要係包括腦部創傷、缺血性腦中風、痴呆症候群、癲癇、帕金森氏症及阿茲海默症等。The aforementioned neurological diseases include, but are not limited to, neurodegenerative diseases, and the main diseases include brain trauma, ischemic stroke, dementia syndrome, epilepsy, Parkinson's disease, and Alzheimer's disease.

於本文中，醫藥上可接受之鹽類主要係指離子性化合物，其中主要活性化合物經修飾而製成其酸或鹼之鹽類。醫藥上可接受之鹽類的實例包括鹼性基團（例如胺基）的無機或有機酸鹽類，或酸性基團（例如羧基）的無機或有機鹼鹽類。關於醫藥上可接受之鹽類的製備，可參見“Pharmaceutical Salts: Properties, Selection, and Use”一書，P. Heinrich Stahl及Camille G. Wermuth著，John Wiley & Sons Inc出版，2011年3月，其係全部併入本文作參考。As used herein, a pharmaceutically acceptable salt refers primarily to an ionic compound wherein the primary active compound is modified to form its acid or base salt. Examples of pharmaceutically acceptable salts include inorganic or organic acid salts of basic groups such as amine groups, or inorganic or organic base salts of acidic groups such as carboxyl groups. For the preparation of pharmaceutically acceptable salts, see "Pharmaceutical Salts: Properties, Selection, and Use", P. Heinrich Stahl and Camille G. Wermuth, published by John Wiley & Sons Inc, March 2011, All of them are incorporated herein by reference.

另一方面，本文所述之化合物的醫藥上可接受之鹽類可由母化合物透過傳統化學方法合成而得，其中母化合物含有一鹼性或酸性部分。一般而言，可將此等化合物的自由酸或鹼形態，與化學計量的適當鹼或酸在水或有機溶劑或二者之混合物中進行反應而製備此種鹽類；一般而言，較佳者為非水性媒介，例如醚、乙酸乙酯、乙醇、異丙醇或乙腈。許多適合鹽類的列表可見於Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams & Wilkins, (2005) ，其係全部併入本文作參考。In another aspect, the pharmaceutically acceptable salts of the compounds described herein can be synthesized from the parent compound by conventional chemical methods wherein the parent compound contains an alkaline or acidic moiety. In general, such salts can be prepared by reacting the free acid or base forms of such compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two; in general, preferred It is a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. A list of many suitable salts can be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams & Wilkins, (2005), which is incorporated herein by reference in its entirety.

於本文中，治療主要係指獲得所需的藥理及/或生理效果，該效果可為預防性，例如完全或部分預防疾病或其症狀；或可為治療性，例如對疾病可達部分或完全治癒；或可對於疾病有反向影響。As used herein, treatment primarily refers to obtaining the desired pharmacological and/or physiological effect, which may be prophylactic, such as complete or partial prevention of a disease or a symptom thereof; or may be therapeutic, for example, partial or complete to a disease Healed; or may have a reverse effect on the disease.

術語「烷基」包括直鏈或支鏈之飽和烴基團，例如C ₁至C ₁₂或C ₁至C ₆之烴基團，且可為例如甲基、乙基、1-丙基、2-丙基、1-丁基、2-甲基-1-丙基（異丁基，-CH ₂CH(CH ₃) ₂）、2-丁基（第二丁基，-CH(CH ₃)CH ₂CH ₃）、2-甲基-2-丙基（第三丁基，-C(CH ₃) ₃）、1-戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基等等，且並不以此為限。 The term "alkyl" includes straight-chain or branched saturated hydrocarbon groups such as C ₁ to C ₁₂ or C ₁ to C ₆ hydrocarbon groups, and may be, for example, methyl, ethyl, 1-propyl, 2-propane. Base, 1-butyl, 2-methyl-1-propyl (isobutyl, -CH ₂ CH(CH ₃ ) ₂ ), 2-butyl (second butyl, -CH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propyl (t-butyl, -C(CH ₃ ) ₃ ), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2- Butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl- 2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-di Methyl-2-butyl, 3,3-dimethyl-2-butyl and the like, and is not limited thereto.

術語「烷氧基」表示-O-烷基之基團，其中烷基如本文之定義。較佳之烷氧基包括例如甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、第三丁氧基、第二丁氧基、正戊氧基、正己氧基、1,2-二甲基丁氧基等。The term "alkoxy" denotes a radical -O-alkyl wherein alkyl is as defined herein. Preferred alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, second butoxy, n-pentyloxy, n-hexyloxy 1,2-dimethylbutoxy and the like.

術語「羥基」係指-OH基團；「醛基」係指具有甲醯基之基團，其具有-C(=O)-H之結構；「鹵素」表示氟、氯、溴及碘。The term "hydroxy" refers to an -OH group; "aldehyde" refers to a group having a methyl group having a structure of -C(=O)-H; "halogen" means fluorine, chlorine, bromine and iodine.

於本文中，若未特別指明，羥基-官能化二苯乙烯及2-芳基苯并[b]呋喃化合物或其醫藥上可接受之鹽類可製成各種劑型，例如可選自於由注射劑、錠劑、膠囊、沖劑、糖衣錠、粉劑、顆粒、***錠、用於重組之粉末、液體製劑及栓劑所組成之群組。Herein, the hydroxy-functional stilbene and the 2-arylbenzo[b]furan compound or a pharmaceutically acceptable salt thereof may be prepared into various dosage forms, for example, selected from injections, unless otherwise specified. , a group of tablets, capsules, granules, sugar-coated tablets, powders, granules, buccal tablets, powders for reconstitution, liquid preparations and suppositories.

於本文中，若未特別指明，羥基-官能化二苯乙烯及2-芳基苯并[b]呋喃化合物或其醫藥上可接受之鹽類係以治療有效量進行施用，例如在受治療主體上賦予治療效果所需要的活性化合物的量。如本領域具有通常知識者所認知，有效劑量會因為以下情況而有所變化，包括投藥途徑、賦形劑的使用以及與其他治療性處理共同使用的可能性。由美國衛生與公眾服務部食品和藥物管理局公告之「產業及審查人員在治療成人健康志願者臨床試驗評估安全起始劑量之基準」(Guidance for Industry and Reviewers Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers)揭示「人類等效劑量(HED)」可藉由下列公式計算獲得：HED = 動物劑量(mg/kg) * (動物重量(kg)/人類重量(kg)) ^0.33。 As used herein, unless otherwise specified, hydroxy-functional stilbene and 2-arylbenzo[b]furan compounds or pharmaceutically acceptable salts thereof are administered in a therapeutically effective amount, for example, in a subject to be treated The amount of active compound required to confer a therapeutic effect. As will be recognized by those of ordinary skill in the art, effective dosages will vary depending on the route of administration, the use of excipients, and the potential for use in conjunction with other therapeutic treatments. Guidance for Industry and Reviewers Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers reveals that the Human Equivalent Dose (HED) can be calculated by the following formula: HED = animal dose (mg/kg) * (animal weight (kg) / human weight (kg)) ^0.33 .

具體實施例Specific embodiment

在不欲限制本發明的範圍之條件下，下文提供根據本發明具體例之例示性的儀器、裝置、方法及其相關結果。需說明的是，標題或副標題可用於實施例中以方便讀者理解，其不應限制本發明的範圍。此外，本文提出並揭示某些理論；然而，無論其對或錯，均不應限制本發明的範圍，只要該發明係可根據本說明書實施而不考慮任何特定理論或作用流程。Exemplary instruments, devices, methods, and related results in accordance with specific embodiments of the present invention are provided below without departing from the scope of the invention. It should be noted that the title or subtitle may be used in the examples for the convenience of the reader, and should not limit the scope of the invention. In addition, certain theories are presented and disclosed herein; however, the scope of the invention should not be construed as being limited to the scope of the invention, as long as the invention can be practiced in accordance with the present specification without any particular theory or function.

本發明之主要實驗材料、儀器及裝置說明如下：The main experimental materials, instruments and devices of the present invention are described as follows:

主要試劑與儀器：所有反應均在乾燥的玻璃器皿中在 120 ℃ 的烘箱中過夜進行，之後的樣品並在乾燥器中冷卻。除非另有說明，否則所有使用之試劑來自商業供應商。二氯甲烷（DCM）和 N,N'-二甲基甲醯胺（DMF）在蒸餾前用氫化鈣乾燥 48 小時。四氫呋喃（THF）在氮氣下從鈉/二苯甲酮羰基中蒸餾出來。氫核磁共振 ( ¹H NMR) 光譜由 Bruker Avance 400（400MHz）、Varian Unity Inova 500（500MHz）和 Varian VNMRS600（600MHz）光譜儀上獲得。所有的 NMR 化學位移 δ 值都以百萬分之一（ppm）表示，偶合常數（J）以赫茲（Hz）表示。熔點係使用未校正之 Yanaco MP-S3 微熔點測定器測量。傅立葉轉換紅外線光譜係使用 Avatar 320 光譜儀收集。質譜和高解析質譜分別以 ThermoQuest Finnigan和 ThermoQExactive Focus 質譜儀記錄。使用快速管柱層析（Merck矽膠60，粒徑230-400目）的製備型分離進行純化。在預塗覆板（Merck矽膠60，F254）上進行分析型 TLC。在 TLC 板上用紫外光、碘蒸氣或鹼性高錳酸鉀水溶液加熱下分析化合物。所有用於生物試驗的化合物係使用 Shimadzu VP 系列 HPLC 結合 Shiseido Capcell PAK C18 管柱（250 mm × 4.6 mm，5 μm，流速1.0 mL / min）獲得的 HPLC 層析圖確認純度＞ 95 ％。 Main reagents and instruments: All reactions were carried out in a dry glassware in an oven at 120 °C overnight, after which the samples were cooled in a desiccator. All reagents used were from commercial suppliers unless otherwise stated. Dichloromethane (DCM) and N,N'-dimethylformamide (DMF) were dried with calcium hydride for 48 hours before distillation. Tetrahydrofuran (THF) was distilled from the sodium/benzophenone carbonyl under nitrogen. Hydrogen nuclear magnetic resonance ( ¹ H NMR) spectra were obtained on a Bruker Avance 400 (400 MHz), Varian Unity Inova 500 (500 MHz) and Varian VNMR S600 (600 MHz) spectrometers. All NMR chemical shifts δ are expressed in parts per million (ppm) and coupling constants (J) are expressed in hertz (Hz). Melting points were measured using an uncorrected Yanaco MP-S3 micro melting point tester. The Fourier transform infrared spectroscopy was collected using an Avatar 320 spectrometer. Mass spectra and high resolution mass spectra were recorded on a ThermoQuest Finnigan and ThermoQExactive Focus mass spectrometer, respectively. Purification was carried out using preparative separation of flash column chromatography (Merck(R) 60, particle size 230-400 mesh). Analytical TLC was performed on precoated plates (Merck(R) 60, F254). The compound was analyzed by heating on a TLC plate with ultraviolet light, iodine vapor or an aqueous alkaline potassium permanganate solution. All compounds used in the bioassay were confirmed to have a purity > 95% using an HPLC chromatogram obtained by Shimadzu VP series HPLC in combination with a Shiseido Capcell PAK C18 column (250 mm × 4.6 mm, 5 μm, flow rate 1.0 mL / min).

式formula (I)(I) 化合物之合成：Synthesis of compounds:

流程 1：合成羥基官能化二苯乙烯 Scheme 1: Synthesis of Hydroxyl Functionalized Styrene

流程 1 呈現合成羥基官能化二苯乙烯化合物代表性結構的策略，其合成方法如下。首先，用三溴化磷將三甲氧基芐醇 1溴化生成三甲氧基芐基溴。然後，使三甲氧基芐基溴與三苯膦反應生成三甲氧基芐基磷偶極體 2。再以威悌(Wittig)反應，將4-溴苯甲醛和磷偶極體 2反應形成約E/Z = 3/1選擇性的二苯乙烯 3。然後經由鈀催化的Heck偶合反應，將具有E-組態的溴取代二苯乙烯 3與丙烯酸乙酯偶合以製備(E)-丙烯酸乙酯取代的二苯乙烯 4。最後，使用三溴化硼由化合物 4將其甲氧基去保護以獲得羥基官能化二苯乙烯 5。 Scheme 1 presents a strategy for the synthesis of representative structures of hydroxy-functionalized stilbene compounds, which are synthesized as follows. First, trimethoxybenzyl alcohol 1 is brominated with phosphorus tribromide to form trimethoxybenzyl bromide. Then, trimethoxybenzyl bromide is reacted with triphenylphosphine to form trimethoxybenzylphosphorus diene 2 . Further, 4-bromobenzaldehyde and phosphorus diene 2 are reacted in a Wittig reaction to form stilbene 3 having an E/Z = 3/1 selectivity. The bromo substituted stilbene 3 having the E-configuration was then coupled with ethyl acrylate via a palladium catalyzed Heck coupling reaction to prepare (E)-ethyl acrylate substituted stilbene 4 . Finally, the methoxy group of the compound 4 is deprotected using boron tribromide to obtain a hydroxy-functionalized stilbene 5 .

表 1 羥基-官能化二苯乙烯化合物 <TABLE border="1" borderColor="#000000" width="85%"><TBODY><tr><td> 化合物編號 </td><td> R1</td><td> R2</td><td> R3</td><td> R4</td><td> R5</td><td> R6</td><td> R7</td><td> R8</td><td> R9</td></tr><tr><td>4</td><td> H </td><td> H </td><td> CH=CHCO2Et* </td><td> H </td><td> H </td><td> H </td><td> OCH3</td><td> OCH3</td><td> OCH3</td></tr><tr><td>5</td><td> H </td><td> H </td><td> CH=CHCO2Et* </td><td> H </td><td> H </td><td> H </td><td> OH </td><td> OH </td><td> OH </td></tr><tr><td>12</td><td> H </td><td> H </td><td> H </td><td> OCH3</td><td> OH </td><td> Br </td><td> H </td><td> OCH3</td><td> OCH3</td></tr><tr><td>13</td><td> H </td><td> H </td><td> H </td><td> OCH3</td><td> OCH3</td><td> H </td><td> H </td><td> -OCH2O- </td></tr><tr><td>14</td><td> H </td><td> OCH3</td><td> OCH3</td><td> OCH3</td><td> H </td><td> CH=CHCO2Et* </td><td> H </td><td> -OCH2O- </td></tr><tr><td>15</td><td> H </td><td> Br </td><td> H </td><td> OCH3</td><td> OH </td><td> Br </td><td> H </td><td> OCH3</td><td> OCH3</td></tr><tr><td>16</td><td> CH=CHCO2Et* </td><td> H </td><td> H </td><td> OCH3</td><td> OH </td><td> H </td><td> H </td><td> OCH3</td><td> OCH3</td></tr><tr><td>17</td><td> CH=CHCO2Et* </td><td> H </td><td> H </td><td> OCH3</td><td> OH </td><td> H </td><td> H </td><td> -OCH2O- </td></tr><tr><td>18</td><td> H </td><td> CH=CHCO2Et* </td><td> H </td><td> OCH3</td><td> OH </td><td> H </td><td> H </td><td> -OCH2O- </td></tr><tr><td>19</td><td> H </td><td> H </td><td> H </td><td> OCH3</td><td> OH </td><td> CH=CHCO2Et* </td><td> H </td><td> OCH3</td><td> OCH3</td></tr><tr><td>20</td><td> H </td><td> H </td><td> H </td><td> H </td><td> OH </td><td> CH=CHCO2Et* </td><td> H </td><td> OCH3</td><td> OCH3</td></tr><tr><td>21</td><td> CH=CHCO2Et* </td><td> H </td><td> H </td><td> OCH3</td><td> OH </td><td> H </td><td> OCH3</td><td> OCH3</td><td> OCH3</td></tr><tr><td>22</td><td> H </td><td> OCH3</td><td> OCH3</td><td> OCH3</td><td> H </td><td> CH=CHCO2Et* </td><td> H </td><td> OCH3</td><td> OCH3</td></tr><tr><td>23</td><td> H </td><td> H </td><td> H </td><td> OCH3</td><td> OH </td><td> CH=CHCO2Et* </td><td> H </td><td> -OCH2O- </td></tr><tr><td>24</td><td> H </td><td> H </td><td> H </td><td> CH=CHCO2Et* </td><td> H </td><td> H </td><td> OH </td><td> OH </td><td> OH </td></tr><tr><td>25</td><td> H </td><td> H </td><td> H </td><td> CH=CHCO2Et* </td><td> H </td><td> H </td><td> OCH3</td><td> OCH3</td><td> OCH3</td></tr><tr><td>26</td><td> H </td><td> Br </td><td> H </td><td> OCH3</td><td> OH </td><td> H </td><td> H </td><td> OCH3</td><td> OCH3</td></tr><tr><td>27</td><td> H </td><td> H </td><td> OCH3</td><td> H </td><td> H </td><td> CH=CHCO2Et* </td><td> H </td><td> -OCH2O- </td></tr><tr><td>28</td><td> H </td><td> H </td><td> OCH3</td><td> H </td><td> H </td><td> CH=CHCO2Et* </td><td> OCH3</td><td> OCH3</td><td> OCH3</td></tr><tr><td>29</td><td> H </td><td> Br </td><td> H </td><td> OCH3</td><td> OH </td><td> H </td><td> H </td><td> -OCH2O- </td></tr><tr><td>30</td><td> H </td><td> H </td><td> H </td><td> H </td><td> OH </td><td> Br </td><td> OCH3</td><td> OCH3</td><td> OCH3</td></tr><tr><td>31</td><td> H </td><td> H </td><td> H </td><td> OCH3</td><td> OH </td><td> H </td><td> H </td><td> -OCH2O- </td></tr><tr><td>32</td><td> H </td><td> H </td><td> OCH3</td><td> OH </td><td> H </td><td> H </td><td> H </td><td> -OCH2O- </td></tr><tr><td>33</td><td> H </td><td> OCH3</td><td> OCH3</td><td> OCH3</td><td> H </td><td> H </td><td> H </td><td> -OCH2O- </td></tr><tr><td>34</td><td> H </td><td> CHO </td><td> H </td><td> OCH3</td><td> OH </td><td> H </td><td> H </td><td> OCH3</td><td> OCH3</td></tr><tr><td>35</td><td> H </td><td> CH=CHCO2Me* </td><td> H </td><td> OCH3</td><td> OH </td><td> H </td><td> H </td><td> OCH3</td><td> OCH3</td></tr></TBODY></TABLE>*代表 E-異構物 Table 1 Hydroxy-functionalized stilbene compounds <TABLE border="1"borderColor="#000000"width="85%"><TBODY><tr><td> compound number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><Td>R5</td><td>R6</td><td>R7</td><td>R8</td><td>R9</td></tr><tr><td>4</td><td> H </td><td> H </td><td>CH=CHCO2Et*</td><td> H </td><td> H </td><td> H </td><td>OCH3</td><td>OCH3</td><td>OCH3</td></tr><tr><td>5</td><td> H </td><td> H </td><td>CH=CHCO2Et*</td><td> H </td><td> H </td><td> H </td><td> OH </td><Td> OH </td><td> OH </td></tr><tr><td>12</td><td> H </td><td> H </td><td> H </td><td>OCH3</td><td> OH </td><td> Br </td><td> H </td ><td>OCH3</td><td>OCH3</td></tr><tr><td>13</td><td> H </td><td> H </td><td> H </td><td>OCH3</td><td>OCH3</td><td> H </td><td> H </td><td>-OCH2O-</td></tr><tr><td>14</td><td> H </td><td>OCH3</td><td>OCH3</td><td>OCH3</td><td> H </td><td>CH=CHCO2Et*</td><td> H </td><td>-OCH2O-</td></tr><tr><td>15</td><td> H </td><td> Br </td><td> H </td><td>OCH3</td><td> OH </td><td> Br </td><td> H </td><td>OCH3</td><td>OCH3</td></tr><tr><td>16</td><td>CH=CHCO2Et*</td><td> H </td><td> H </td ><td>OCH3</td><td> OH </td><td> H </td><td> H </td><td>OCH3</td><td>OCH3</td></tr><tr><td>17</td><td> CH= CHCO2Et* </td><td> H </td><td> H </td><td>OCH3</td><td> OH </td><td> H </td><td> H </td><td>-OCH2O-</td></tr><tr><td>18</td><td> H </td><td>CH=CHCO2Et*</td><td> H </td><td >OCH3</td><td> OH </td><td> H </td><td> H </td><td>-OCH2O-</td></tr><tr><td>19</td><td> H </td><td> H </td><td> H </td><td>OCH3</td><td> OH </td><td>CH=CHCO2Et*</td><td> H </td><td>OCH3</Td><td>OCH3</td></tr><tr><td>20</td><td> H </td><td > H </td><td> H </td><td> H </td><td> OH </td><td>CH=CHCO2Et*</td><td> H </td><td>OCH3</td><td>OCH3</td></tr><tr><td>21</td><td>CH=CHCO2Et*</td><td> H </td><td> H </td><td >OCH3</td><td> OH </td><td> H </td><td>OCH3</td><td> OCH 3</td><td>OCH3</td></tr><tr><td>22</td><td> H </td><td>OCH3</td><td>OCH3</td><td>OCH3</td><td> H </td><td>CH=CHCO2Et*</td><td> H </td><td>OCH3</td><td>OCH3</td></tr><tr><td>23</td><td> H </td><td> H </td><td> H </td><td>OCH3</td><td> OH </td><td> CH=CHCO 2Et* </td><td> H </td><td>-OCH2O-</td></tr><tr><td>24</td><td> H </td><td> H </td><td> H </td><td>CH=CHCO2Et*</td><td> H </td><td> H </td><td> OH </td><td> OH </td><td> OH </td></tr><tr><td>25</td><td> H </td><td> H </td><td> H </td><td>CH=CHCO2Et*</td><td> H </td><td> H </td><td>OCH3</td><td>OCH3</td><Td>OCH3</td></tr><tr><td>26</td><td> H </td><td> Br </td><td> H </td><td>OCH3</td><td> OH </td><td> H </td><td> H </td ><td>OCH3</td><td>OCH3</td></tr><tr><td>27</td><td> H </td><td> H </td><td>OCH3</td><td> H </td><td> H </td><td>CH=CHCO2Et*</td><td> H </td><td>-OCH2O-</td></tr><tr><td>28</td><td> H </td><td> H </td><td>OCH3</td><td> H </td><td> H </td><td>CH=CHCO2Et*</td><td>OCH3</td><td>OCH3</td><td>OCH3</td></tr><tr><td>29</td><td> H </td><td> Br </td><td> H </td><td>OCH3</td><td> OH </td><td> H </td><td> H </td><td>-OCH2O-</td></tr><tr><td>30</td><td> H </t d><td> H </td><td> H </td><td> H </td><td> OH </td><td> Br </td><td>OCH3</td><td>OCH3</td><td>OCH3</td></tr><tr><td>31</td><td> H </td><td> H </td><td> H </td><td>OCH3</Td><td> OH </td><td> H </td><td> H </td><td>-OCH2O-</td></tr><Tr><td>32</td><td> H </td><td> H </td><td>OCH3</td><Td> OH </td><td> H </td><td> H </td><td> H </td><td>-OCH2O-</td></tr><tr><td>33</td><td> H </td><td>OCH3</td><td> OCH 3</td><td>OCH3</td><td> H </td><td> H </td><td> H </ Td><td>-OCH2O-</td></tr><tr><td>34</td><td> H </td ><td> CHO </td><td> H </td><td>OCH3</td><td> OH </td><td> H </td><Td> H </td><td>OCH3</td><td>OCH3</td></tr><tr><td>35</td><td> H </td><td>CH=CHCO2Me*</td><td> H </td><td>OCH3</td><td> OH </td><td> H </td><td> H </td><td>OCH3</td><td>OCH3</td></tr></TBODY></TABLE>* stands for E -isomer

製備preparation 5-(4-5-(4- 溴苯乙烯基Bromostyrene )-1,2,3-)-1,2,3- 三甲氧基苯（Trimethoxybenzene 33 ）)

將磷偶極體 2（354 mg，0.68 mmol）在THF（30 mL）中的溶液在氮氣下冷卻至0 ℃，分批加入叔丁醇鋰（108 mg，1.35 mmol）。混合物在0℃下攪拌30分鐘。在0 ℃逐滴加入4-溴苯甲醛（126 mg，0.68 mmol）的THF（7 mL）溶液，並將反應混合物加溫至室溫並攪拌24小時。將飽和的 NH ₄Cl 水溶液加到反應混合物中並用 EtOAc 萃取（20 mL × 3）。將合併的有機層以鹽水洗滌，用 MgSO ₄乾燥，過濾並濃縮。殘留物以矽膠管柱層析純化而得到 3（164 mg，合併產率69 ％，E/Z = 3/1）。 A solution of the phosphorous dilute 2 (354 mg, 0.68 mmol) in THF (30 mL) was cooled to EtOAc. The mixture was stirred at 0 ° C for 30 minutes. A solution of 4-bromobenzaldehyde (126 mg, 0.68 mmol) in THF (7 mL) was evaporated. Saturated NH ₄ Cl aqueous solution was added to the reaction mixture and extracted with EtOAc (20 mL × 3). The organic layers were combined, dried over MgSO ₄ washed with brine, filtered and concentrated. The residue was purified by silica gel column chromatography to give 3 (164 mg, combined yield 69%, E / Z = 3/1 ).

製備preparation 3-(4-((E)-3,4,5-3-(4-((E)-3,4,5- 三甲氧基苯乙烯基Trimethoxystyryl )) 苯基Phenyl )) 丙烯酸acrylic acid (E)(E) 乙酯（Ethyl ester 44 ）)

在氮氣環境下，將(E)5-(4-溴苯乙烯基)-1,2,3-三甲氧基苯 3（300 mg，0.86 mmol）、丙烯酸乙酯（0.11 mL，1.03 mmol）、乙酸鈀（II）（10 mg, 0.045 mmol）、碘化銅（I）（9 mg，0.045 mmol）和三乙胺（0.24 mL）在N,N'-二甲基甲醯胺（10 mL）中的溶液在 70 ℃ 加熱 24 小時，直到反應以 TLC 顯示完成。反應混合物用水淬滅並用乙酸乙酯萃取。將有機層合併，用 MgSO ₄乾燥並濃縮。殘留物以管柱層析純化而得到呈白色固體狀 4（203 mg，64 ％）。 Mp = 178-180 ^oC; ¹H NMR (500 MHz, CDCl ₃): δ 7.66 (d, J= 16.0 Hz, 1H), 7.49 (s, 4H), 7.07 (d, J= 16.0 Hz, 1H), 6.98 (d, J= 16.0 Hz, 1H), 6.73 (s, 2H), 6.42 (d, J= 16.0 Hz, 1H), 4.24 (q, J= 7.5 Hz, 2H), 3.90 (s, 6H), 3.86 (s, 3H), 1.32 (t, J= 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 167.0, 153.0, 144.0, 139.5, 133.2, 132.2, 131.3, 129.5, 129.1, 127.9, 118.0, 106.1, 60.9, 60.5, 55.9, 14.3; ESMS m/z: 369.5 (M + 1)。 (E) 5-(4-bromostyryl)-1,2,3-trimethoxybenzene 3 (300 mg, 0.86 mmol), ethyl acrylate (0.11 mL, 1.03 mmol), Palladium(II) acetate (10 mg, 0.045 mmol), copper (I) iodide (9 mg, 0.045 mmol) and triethylamine (0.24 mL) in N,N'-dimethylformamide (10 mL) The solution in the solution was heated at 70 °C for 24 hours until the reaction was completed by TLC. The reaction mixture was quenched with water and extracted withEtOAc. The organic layers were combined, dried over MgSO ₄ and evaporated. The residue was purified by column chromatography to give a white solid 4 (203 mg, 64%) . Mp = 178-180 ^o C; ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.66 (d, J = 16.0 Hz, 1H), 7.49 (s, 4H), 7.07 (d, J = 16.0 Hz, 1H) , 6.98 (d, J = 16.0 Hz, 1H), 6.73 (s, 2H), 6.42 (d, J = 16.0 Hz, 1H), 4.24 (q, J = 7.5 Hz, 2H), 3.90 (s, 6H) , 3.86 (s, 3H), 1.32 (t, J = 7.5 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 167.0, 153.0, 144.0, 139.5, 133.2, 132.2, 131.3, 129.5, 129.1, 127.9, 118.0, 106.1, 60.9, 60.5, 55.9, 14.3; ESMS m/z: 369.5 (M + 1).

合成synthesis 3-(4-((E)-3,4,5-3-(4-((E)-3,4,5- 三羥基苯乙烯基Trihydroxystyrene )) 苯基Phenyl )) 丙烯酸acrylic acid (E)(E) 乙酯（Ethyl ester 55 ）)

在-60 ℃、N ₂環境下，將 4（220 mg，0.60 mmol）在乾燥二氯甲烷（15 mL）溶液中逐滴加入 BBr ₃（0.52 ml，5.40 mmol）。然後使反應混合物升溫至 -40 ℃ 並再攪拌 2 小時直到反應以 TLC 顯示完成。將反應在 0 ℃ 小心混合飽和 NaHCO ₃水溶液（20 mL）並攪拌 30 分鐘。將該混合物用乙酸乙酯萃取兩次（15 mL × 2），合併有機部分，進一步以鹽水洗滌，並用 MgSO ₄乾燥。將殘留物過濾，濃縮並以矽膠管柱層析純化而得到灰白色固體 5（147 mg，75 ％）。 ¹H NMR (600 MHz, CD ₃OD): δ 7.65 (d, J= 16.0, 1H), 7.55 (d, J= 8.4 Hz, 2H), 7.51 (d, J= 8.4 Hz, 2H), 7.02 (d, J= 16.4 Hz, 1H), 6.89 (d, J= 16.4 Hz, 1H), 6.59 (s, 2H), 6.48 (d, J= 16.0, 1H), 4.23 (q, J= 7.2 Hz, 2H), 1.32 (t, J= 7.2 Hz, 3H) ; ¹³C NMR (150 MHz, CD ₃OD): δ 168.9, 147.0, 145.8, 141.7, 135.0, 134.2, 131.8, 129.7, 127.6, 125.9, 118.0, 61.6, 14.6; ESMS m/z: 325.0 (M - 1) ^-。 At -60 ℃, N ₂ environment and the 4 (220 mg, 0.60 mmol) was added dropwise _{BBr 3 (0.52 ml, 5.40 mmol} ) in dry dichloromethane (15 mL). The reaction mixture was then warmed to -40 °C and stirred for additional 2 hours until the reaction was completed by TLC. The reaction was carefully mixed 0 ℃ saturated aqueous NaHCO ₃ (20 mL) and stirred for 30 min. The mixture was extracted twice with ethyl acetate (15 mL × 2), the organic portions were combined, washed further with brine, and dried over MgSO _4. The residue was filtered, concentrated and purified by silica gel column chromatography to give an off-white solid 5 (147 mg, 75%) . ¹ H NMR (600 MHz, CD ₃ OD): δ 7.65 (d, J = 16.0, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.02 ( d, J = 16.4 Hz, 1H), 6.89 (d, J = 16.4 Hz, 1H), 6.59 (s, 2H), 6.48 (d, J = 16.0, 1H), 4.23 (q, J = 7.2 Hz, 2H ), 1.32 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150 MHz, CD ₃ OD): δ 168.9, 147.0, 145.8, 141.7, 135.0, 134.2, 131.8, 129.7, 127.6, 125.9, 118.0, 61.6 , 14.6; ESMS m/z: 325.0 (M - 1) ^- .

化合物 12至化合物 35之合成係使用適當起始物及相似於化合物 5之製程製備。 The synthesis of compound 12 to compound 35 is carried out using a suitable starting material and a procedure similar to compound 5 .

(E)-2-(2- 溴 -4,5- 二 甲氧基苯乙烯基 )-6- 甲氧基苯酚 （ 12 ）: 白色固體; Mp = 156-158 ^oC; ¹H NMR (500 MHz, CDCl ₃): δ 7.00 (s, 1H), 6.75 (d, J= 12.0, 1H), 6.72-6.65 (m, 3H), 6.60 (t, J= 8.0 Hz, 1H), 5.77 (s, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.43 (s, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 148.8, 147.6, 146.6, 143.5, 129.6, 129.5, 124.8, 123.0, 122.1, 119.1, 115.0, 114.4, 113.2, 109.5, 56.0, 56.0, 55.6; ESMS m/z: 388.7 (M + 23) ⁺。 (E) -2- (2- bromo-4,5-methoxystyryl) -6-methoxyphenol (12): white ^{^{solid; Mp = 156-158 o C; 1}} H NMR (500 MHz, CDCl ₃ ): δ 7.00 (s, 1H), 6.75 (d, J = 12.0, 1H), 6.72-6.65 (m, 3H), 6.60 (t, J = 8.0 Hz, 1H), 5.77 (s, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.43 (s, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 148.8, 147.6, 146.6, 143.5, 129.6, 129.5, 124.8, 123.0, 122.1, 119.1, 115.0, 114.4, 113.2, 109.5, 56.0, 56.0, 55.6; ESMS m/z: 388.7 (M + 23) ⁺ .

(E)-5-(2,3- 二 甲氧基苯乙烯基 ) 苯并 [d][1,3] 二氧雜環戊烯 （ 13 ）: 白色固體; Mp = 143-145 ^oC; ¹H NMR (500 MHz, CDCl ₃): δ 6.76 (d, J= 8.0 Hz, 1H), 6.75-6.72 (m, 1H), 6.68 (d, J= 8.0 Hz, 1H), 6.62-6.57 (m, 4H), 6.52 (dd, J= 8.0, 2.0 Hz, 1H), 5.88 (s, 2H), 3.84 (s, 3H), 3.82 (s, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 147.3, 145.8, 131.1, 129.9, 129.3, 125.3, 123.5, 121.9, 121.6, 111.2, 109.9, 109.5, 109.2, 108.1, 100.8, 60.8, 55.7; EIMS m/z: 284.3 (M ) ⁺。 (E) -5- (2,3- dimethoxyphenyl) benzene, and [d] [1,3] dioxole (13): white solid; Mp = 143-145 ^o C; ¹ H NMR (500 MHz, CDCl ₃ ): δ 6.76 (d, J = 8.0 Hz, 1H), 6.75-6.72 (m, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.62-6.57 (m , 4H), 6.52 (dd, J = 8.0, 2.0 Hz, 1H), 5.88 (s, 2H), 3.84 (s, 3H), 3.82 (s, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 147.3, 145.8, 131.1, 129.9, 129.3, 125.3, 123.5, 121.9, 121.6, 111.2, 109.9, 109.5, 109.2, 108.1, 100.8, 60.8, 55.7; EIMS m/z: 284.3 (M) ⁺ .

3-(6-((E)-3,4,5- 三 甲氧基苯乙烯基 ) 苯并 [d][1,3] 二氧雜環戊烯 -5- 基 ) 丙烯酸 (E)- 乙酯（ 14 ）: 黃色固體; Mp = 123-125 ^oC; ¹H NMR (600 MHz, CDCl ₃): δ 8.04 (d, J= 15.6 Hz, 1H), 7.27 (d, J= 15.6 Hz, 1H), 7.03 (d, J= 6.6 Hz, 1H), 6.77 (d, J= 16.2 Hz, 1H), 6.71 (s, 2H), 6.23 (d, J= 15.6 Hz, 1H), 6.00 (s, 2H), 4.23 (q, J= 7.2 Hz, 2H), 3.90 (s, 6H), 3.85 (s, 3H), 1.31 (t, J= 7.2 Hz, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 167.1, 153.4, 149.7, 147.8, 141.5, 138.2, 133.1, 132.9, 131.5, 126.8, 124.6, 118.1, 106.3, 106.0, 103.8, 101.6, 61.0, 60.5, 56.2, 14.3; EIMS m/z: 412.1 (M) ⁺。 3- (6 - ((E) -3,4,5- three methoxystyryl) benzo [d] [1,3] dioxol-5-yl) acrylic acid (E) - Ethyl ester ( 14 ) : yellow solid; Mp = 123-125 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ): δ 8.04 (d, J = 15.6 Hz, 1H), 7.27 (d, J = 15.6 Hz, 1H), 7.03 (d, J = 6.6 Hz, 1H), 6.77 (d, J = 16.2 Hz, 1H), 6.71 (s, 2H), 6.23 (d, J = 15.6 Hz, 1H), 6.00 (s, 2H), 4.23 (q, J = 7.2 Hz, 2H), 3.90 (s, 6H), 3.85 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 167.1, 153.4, 149.7, 147.8, 141.5, 138.2, 133.1, 132.9, 131.5, 126.8, 124.6, 118.1, 106.3, 106.0, 103.8, 101.6, 61.0, 60.5, 56.2, 14.3; EIMS m/z: 412.1 ( M) ⁺ .

(E)-4- 溴 -2-(2- 溴 -4,5- 二甲氧基苯乙烯基 )-6- 甲氧基苯酚 （ 15 ） :白色固體; ¹H NMR (500 MHz, CDCl ₃): δ 7.39 (d, J= 16.5 Hz, 1H), 7.32 (d, J= 2.5 Hz, 1H), 7.15 (s, 1H), 7.12 (d, J= 16.5 Hz, 1H), 7.02 (s, 1H), 6.86 (d, J= 2.5 Hz, 1H), 5.88 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 149.4, 148.6, 147.3, 142.5, 129.3, 128.9, 125.1, 122.2, 121.4, 115.4, 115.1, 112.8, 111.7, 108.8, 56.4, 56.2, 56.1; EIMS m/z: 444.0 (M ⁺)。 (E)-4- bromo -2-(2- bromo -4,5 -dimethoxystyryl )-6- methoxyphenol ( 15 ) : white solid; ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.39 (d, J = 16.5 Hz, 1H), 7.32 (d, J = 2.5 Hz, 1H), 7.15 (s, 1H), 7.12 (d, J = 16.5 Hz, 1H), 7.02 (s, 1H), 6.86 (d, J = 2.5 Hz, 1H), 5.88 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 149.4, 148.6, 147.3, 142.5, 129.3, 128.9, 125.1, 122.2, 121.4, 115.4, 115.1, 112.8, 111.7, 108.8, 56.4, 56.2, 56.1; EIMS m/z: 444.0 (M ⁺ ).

3-(2-((E)-3,4- 二 甲氧基苯乙烯基 )-3- 羥基 -4- 甲氧基苯基 ) 丙烯酸 (E)- 乙酯（ 16 ）: 白色固體; Mp = 108-112 ^oC; ¹H NMR (500 MHz, CDCl ₃): δ 8.01 (d, J= 15.5 Hz, 1H), 7.14 (d, J= 8.5 Hz, 1H), 7.13 (d, J= 16.5 Hz, 1H), 7.07-7.04 (m, 2H), 6.88 (d, J= 16.5 Hz, 1H), 6.83 (d, J= 8.0 Hz, 1H), 6.78 (d, J= 8.5 Hz, 1H), 6.27 (d, J= 16.0 Hz, 1H), 4.22 (q, J= 7.0 Hz, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 1.27 (t, J= 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 167.1, 149.1, 149.0, 147.4, 143.8, 143.5, 136.4, 130.7, 127.0, 124.7, 120.1, 119.4, 119.3, 118.0, 11.1, 109.2, 109.0, 60.3, 56.2, 56.0, 55.9, 14.3; ESMS m/z: 407.1 (M + 23) ⁺,791.3 (2M + 23) ⁺。 3- (2 - ((E) -3,4- dimethoxybenzene vinyl) -3-hydroxy-4-methoxyphenyl) acrylic acid (E) - ethyl ester (16): white solid; Mp = 108-112 ^o C; ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.01 (d, J = 15.5 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 16.5 Hz, 1H), 7.07-7.04 (m, 2H), 6.88 (d, J = 16.5 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.27 (d, J = 16.0 Hz, 1H), 4.22 (q, J = 7.0 Hz, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 167.1, 149.1, 149.0, 147.4, 143.8, 143.5, 136.4, 130.7, 127.0, 124.7, 120.1, 119.4, 119.3, 118.0, 11.1, 109.2 , 109.0, 60.3, 56.2, 56.0, 55.9, 14.3; ESMS m/z: 407.1 (M + 23) ⁺ , 791.3 (2M + 23) ⁺ .

3-(2-((E)-2-( 苯并 [d][1,3] 二氧雜環戊烯 -5- 基 ) 乙烯基 )-3- 羥基 -4- 甲氧基苯基 ) 丙烯酸 (E)- 乙酯（ 17 ）: 黃色固體; Mp = 168-170 ^oC; ¹H NMR (500 MHz, CDCl ₃): δ 8.00 (d, J= 16.0 Hz, 1H), 7.12 (d, J= 8.0 Hz, 1H), 7.09 (d, J= 16.0 Hz, 1H), 7.08 (d, J= 1.5 Hz, 1H), 7.07 (d, J= 1.5 Hz, 1H), 6.93 (dd, J= 8.0, 1.5 Hz, 1H), 6.86 (d, J= 16.0 Hz, 1H), 6.77 (dd, J= 8.0, 1.5 Hz, 1H), 6.25 (d, J= 16.0 Hz, 1H), 6.00 (s, 1H), 5.95 (s, 2H), 4.23 (q, J= 7.0 Hz, 2H), 3.90 (s, 3H), 1.30 (t, J= 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 167.1, 148.1, 147.5, 147.4, 143.8, 143.5, 136.1, 132.1, 127.0, 124.5, 121.7, 119.5, 119.4, 118.0, 109.2, 108.3, 105.7, 101.1, 60.3, 56.1, 14.3; ESMS 369.1 m/z: (M + 1) ⁺。 3- (2 - ((E) -2- ( benzo [d] [1,3] dioxol-5-yl) ethenyl) -3-hydroxy-4-methoxyphenyl) Acrylic acid (E) -ethyl ester ( 17 ) : yellow solid; Mp = 168-170 ^o C; ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.00 (d, J = 16.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 16.0 Hz, 1H), 7.08 (d, J = 1.5 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 6.93 (dd, J = 8.0, 1.5 Hz, 1H), 6.86 (d, J = 16.0 Hz, 1H), 6.77 (dd, J = 8.0, 1.5 Hz, 1H), 6.25 (d, J = 16.0 Hz, 1H), 6.00 (s, 1H), 5.95 (s, 2H), 4.23 (q, J = 7.0 Hz, 2H), 3.90 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 167.1, 148.1, 147.5, 147.4, 143.8, 143.5, 136.1, 132.1, 127.0, 124.5, 121.7, 119.5, 119.4, 118.0, 109.2, 108.3, 105.7, 101.1, 60.3, 56.1, 14.3; ESMS 369.1 m/z : (M + 1) ⁺ .

3-(3-((E)-2-( 苯并 [d][1,3] 二氧雜環戊烯 -5- 基 ) 乙烯基 )-4- 羥基 -5- 甲氧基苯基 ) 丙烯酸 (E)- 乙酯（ 18 ）: 黃色固體; Mp = 155-157 ^oC; ¹H NMR (500 MHz, CDCl ₃): δ 7.63 (d, J= 15.5 Hz, 1H), 7.32 (d, J= 1.5 Hz, 1H), 7.19 (d, J= 16.5 Hz, 1H), 7.10 (d, J= 16.5 Hz, 1H), 7.09 (d, J= 1.5 Hz, 1H), 6.95 (dd, J= 8.0, 1.5 Hz, 1H), 6.92 (d, J= 1.5 Hz, 1H), 6.78 (d, J= 8.0 Hz, 1H), 6.32 (d, J= 16.0 Hz, 1H), 6.14 (s, 1H), 5.96 (s, 1H), 4.25 (d, J= 7.5 Hz, 2H), 3.93 (s, 3H), 1.32 (t, J= 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 167.2, 148.1, 147.4, 146.9, 145.3, 144.8, 135.2, 135.1, 132.1, 130.4, 129.9, 127.9, 126.4, 124.0, 121.7, 120.4, 120.2, 115.9, 108.4, 107.5, 105.7, 101.1, 60.4, 56.2, 14.4; ESMS m/z: 369.3 (M + 1) ⁺。 3- (3 - ((E) -2- ( benzo [d] [1,3] dioxol-5-yl) ethenyl) -4-hydroxy-5-methoxyphenyl) acrylic acid (E) - ethyl ester (18): yellow ^{^{solid; Mp = 155-157 o C; 1}} H NMR (500 MHz, CDCl 3): δ 7.63 (d, J = 15.5 Hz, 1H), 7.32 (d, J = 1.5 Hz, 1H), 7.19 (d, J = 16.5 Hz, 1H), 7.10 (d, J = 16.5 Hz, 1H), 7.09 (d, J = 1.5 Hz, 1H), 6.95 (dd, J = 8.0, 1.5 Hz, 1H), 6.92 (d, J = 1.5 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.32 (d, J = 16.0 Hz, 1H), 6.14 (s, 1H) , 5.96 (s, 1H), 4.25 (d, J = 7.5 Hz, 2H), 3.93 (s, 3H), 1.32 (t, J = 7.5 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 167.2, 148.1, 147.4, 146.9, 145.3, 144.8, 135.2, 135.1, 132.1, 130.4, 129.9, 127.9, 126.4, 124.0, 121.7, 120.4, 120.2, 115.9, 108.4, 107.5, 105.7, 101.1, 60.4, 56.2, 14.4 ; ESMS m/z: 369.3 (M + 1) ⁺ .

3-(2-((E)-2- 羥基 -3- 甲氧基苯乙烯基 )-4,5- 二甲氧基苯基 ) 丙烯酸 (E)- 乙酯（ 19 ）: 無定形粉末; ¹H NMR (500 MHz, CDCl ₃): δ 8.10 (d, J= 16.0 Hz, 1H), 7.53 (d, J= 16.0 Hz, 1H), 7.19 (d, J= 16.0 Hz, 1H), 7.16 (dd, J= 8.0, 1.0 Hz, 1H), 7.10 (s, 1H), 7.02 (s, 1H), 6.84 (t, J= 8.0 Hz, 1H), 6.77 (dd, J= 8.5, 1.5 Hz, 1H), 6.27 (d, J= 16.0 Hz, 1H), 6.01 (s, 1H), 4.25 (q, J= 7.5 Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.89 (s, 3H), 1.32 (t, J= 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 167.2, 150.9, 148.8, 146.7, 143.5, 141.8, 132.1, 125.9, 125.3, 125.3, 123.6, 119.6, 119.1, 117.6, 109.7, 108.8, 108.8, 60.4, 56.1, 56.0, 55.9; ESMS m/z: 407.4 (M + 23) ⁺, 791.6 (2M + 23) ⁺。 3- (2 - ((E) -2- hydroxy-3-methoxystyryl) -4,5-dimethoxyphenyl) acrylic acid (E) - ethyl ester (19): amorphous powder; ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.10 (d, J = 16.0 Hz, 1H), 7.53 (d, J = 16.0 Hz, 1H), 7.19 (d, J = 16.0 Hz, 1H), 7.16 ( Dd, J = 8.0, 1.0 Hz, 1H), 7.10 (s, 1H), 7.02 (s, 1H), 6.84 (t, J = 8.0 Hz, 1H), 6.77 (dd, J = 8.5, 1.5 Hz, 1H ), 6.27 (d, J = 16.0 Hz, 1H), 6.01 (s, 1H), 4.25 (q, J = 7.5 Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.89 (s , 3H), 1.32 (t, J = 7.5 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 167.2, 150.9, 148.8, 146.7, 143.5, 141.8, 132.1, 125.9, 125.3, 125.3, 123.6, 119.6, 119.1, 117.6, 109.7, 108.8, 108.8, 60.4, 56.1, 56.0, 55.9; ESMS m/z: 407.4 (M + 23) ⁺ , 791.6 (2M + 23) ⁺ .

3-(2-((E)-2- 羥基苯乙烯基 )-4,5- 二 甲氧基苯基 ) 丙烯酸 (E)- 乙酯（ 20 ）: 黃色固體; Mp = 158-161 ^oC; ¹H NMR (500 MHz, CDCl ₃): δ 8.10 (d, J= 16.2 Hz, 1H), 7.52 (dd, J= 7.8, 1.8 Hz, 1H), 7.45 (d, J= 16.2 Hz, 1H), 7.14 (dt, J= 7.8, 1.8 Hz, 1H), 7.13 (d, J= 16.2 Hz, 1H), 7.07 (s, 1H), 7.03 (s, 1H), 6.94 (dt, J= 7.8, 1.2 Hz, 1H), 6.79 (dd, J= 8.4, 1.2 Hz, 1H), 6.27 (d, J= 16.2 Hz, 1H), 4.25 (q, J= 7.2 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 1.32 (t, J= 7.2 Hz, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 167.3, 153.1, 150.1, 148.9, 141.9, 131.9, 128.9, 127.5, 126.5, 125.7, 125.4, 124.6, 121.2, 117.7, 116.0, 109.0, 108.8, 60.5, 56.0, 56.0, 14.4; ESMS m/z: 377.2 (M + 23) ⁺。 3- (2 - ((E) -2- vinyl-hydroxyphenyl) -4,5-methoxyphenyl) acrylic acid (E) - ethyl ester (20): yellow solid; Mp = 158-161 ^o C ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.10 (d, J = 16.2 Hz, 1H), 7.52 (dd, J = 7.8, 1.8 Hz, 1H), 7.45 (d, J = 16.2 Hz, 1H) , 7.14 (dt, J = 7.8, 1.8 Hz, 1H), 7.13 (d, J = 16.2 Hz, 1H), 7.07 (s, 1H), 7.03 (s, 1H), 6.94 (dt, J = 7.8, 1.2 Hz, 1H), 6.79 (dd, J = 8.4, 1.2 Hz, 1H), 6.27 (d, J = 16.2 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 167.3, 153.1, 150.1, 148.9, 141.9, 131.9, 128.9, 127.5, 126.5, 125.7 , 125.4, 124.6, 121.2, 117.7, 116.0, 109.0, 108.8, 60.5, 56.0, 56.0, 14.4; ESMS m/z: 377.2 (M + 23) ⁺ .

3-(3- 羥基 -4- 甲氧基 -2-((E)-3,4,5- 三 甲氧基苯乙烯基 ) 苯基 ) 丙烯酸 (E)- 乙酯（ 21 ）: 白色固體; Mp = 174-176 ^oC; ¹H NMR (500 MHz, CDCl ₃): δ 8.00 (d, J= 16.0 Hz, 1H), 7.15 (d, J= 16.5 Hz, 1H), 7.11 (d, J= 8.5 Hz, 1H), 6.85 (d, J= 16.5 Hz, 1H), 6.77 (d, J= 8.5 Hz, 1H), 6.72 (s, 1H), 6.27 (d, J= 16.0 Hz, 1H), 6.08 (s, 1H), 4.21 (q, J= 7.5 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 6H), 3.84 (s, 3H), 1.27 (t, J= 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 167.0, 153.2, 147.4, 143.7, 143.6, 138.1, 136.3, 133.3, 126.9, 124.3, 120.8, 119.4, 118.0, 109.3, 103.7, 60.8, 60.2, 56.0, 56.0, 14.5; ESMS m/z: 415.2 (M + 1) ⁺。 3- (3-hydroxy-4-methoxy -2 - ((E) -3,4,5- three-methoxystyryl) phenyl) acrylic acid (E) - ethyl ester (21): white solid ; Mp = 174-176 ^o C; ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.00 (d, J = 16.0 Hz, 1H), 7.15 (d, J = 16.5 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 16.5 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H), 6.72 (s, 1H), 6.27 (d, J = 16.0 Hz, 1H), 6.08 (s, 1H), 4.21 (q, J = 7.5 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 6H), 3.84 (s, 3H), 1.27 (t, J = 7.5 Hz, 3H ¹³ C NMR (125 MHz, CDCl ₃ ): δ 167.0, 153.2, 147.4, 143.7, 143.6, 138.1, 136.3, 133.3, 126.9, 124.3, 120.8, 119.4, 118.0, 109.3, 103.7, 60.8, 60.2, 56.0, 56.0, 14.5; ESMS m/z: 415.2 (M + 1) ⁺ .

3-(4,5- 二 甲氧基 -2-((E)-3,4,5- 三 甲氧基苯乙烯基 ) 苯基 ) 丙烯酸 (E)- 乙酯（ 22 ）: 白色固體; Mp = 116-118 ^oC; ¹H NMR (500 MHz, CDCl ₃): δ 7.83 (d, J= 16.0 Hz, 1H), 7.04 (s, 1H), 6.70 (s, 1H), 6.67 (d, J= 12.0 Hz, 1H), 6.62 (d, J= 12.0 Hz, 1H), 6.31 (s, 1H), 6.18 (d, J= 16.0 Hz, 1H), 4.18 (q, J= 7.0 Hz, 2H), 3.87 (s, 3H), 3.75 (s, 3H), 3.70 (s, 3H), 3.58 (s, 6H), 1.28 (t, J= 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 167.0, 152.7, 150.6, 148.4, 142.3, 137.3, 132.2, 132.1, 131.8, 127.1, 125.4, 116.9, 112.2, 108.5, 106.3, 60.8, 60.3, 55.9, 55.8, 55.8, 14.3; ESMS m/z: 451.4 (M + 23) ⁺。 3- (4,5-dimethoxy -2 - ((E) -3,4,5- three-methoxystyryl) phenyl) acrylic acid (E) - ethyl ester (22): white solid; Mp = 116-118 ^o C; ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.83 (d, J = 16.0 Hz, 1H), 7.04 (s, 1H), 6.70 (s, 1H), 6.67 (d, J = 12.0 Hz, 1H), 6.62 (d, J = 12.0 Hz, 1H), 6.31 (s, 1H), 6.18 (d, J = 16.0 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H) , 3.87 (s, 3H), 3.75 (s, 3H), 3.70 (s, 3H), 3.58 (s, 6H), 1.28 (t, J = 7.0 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 167.0, 152.7, 150.6, 148.4, 142.3, 137.3, 132.2, 132.1, 131.8, 127.1, 125.4, 116.9, 112.2, 108.5, 106.3, 60.8, 60.3, 55.9, 55.8, 55.8, 14.3; ESMS m/z: 451.4 (M + 23) ⁺ .

3-(6-((E)-2- 羥基 -3- 甲氧基苯乙烯基 ) 苯并 [d][1,3] 二氧雜環戊烯 -5- 基 ) 丙烯酸 (E)- 乙酯（ 23 ）: 白色固體; Mp = 168-170 ^oC; ¹H NMR (500 MHz, CDCl ₃): δ 8.08 (d, J= 16.0 Hz, 1H), 7.50 (d, J= 16.0 Hz, 1H), 7.17 (d, J= 16.0 Hz, 1H), 7.15 (dd, J= 8.0, 1.0 Hz, 1H), 7.13 (s, 1H), 7.00 (s, 1H), 6.83 (t, J= 8.0 Hz, 1H), 6.77 (dd, J= 8.0, 1.5 Hz, 1H), 6.22 (d, J= 16.0 Hz, 1H), 6.00 (s, 1H), 5.98 (s, 2H), 4.23 (q, J= 7.0 Hz, 2H), 3.90 (s, 3H), 1.31 (t, J= 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 167.2, 149.7, 147.6, 146.7, 143.6, 141.7, 133.8, 126.8, 125.7, 125.7, 123.5, 119.6, 119.2, 117.9, 109.7, 106.2, 105.9, 101.5, 60.4, 56.1, 14.3; ESMS m/z: 391.2 (M + 23) ⁺。 3- (6 - ((E) -2- hydroxy 3-methoxy-vinyl) benzo [d] [1,3] dioxol-5-yl) acrylic acid (E) - B Ester ( 23 ) : white solid; Mp = 168-170 ^o C; ¹ H NMR (500 MHz, CDCl ₃ ): δ 8.08 (d, J = 16.0 Hz, 1H), 7.50 (d, J = 16.0 Hz, 1H ), 7.17 (d, J = 16.0 Hz, 1H), 7.15 (dd, J = 8.0, 1.0 Hz, 1H), 7.13 (s, 1H), 7.00 (s, 1H), 6.83 (t, J = 8.0 Hz) , 1H), 6.77 (dd, J = 8.0, 1.5 Hz, 1H), 6.22 (d, J = 16.0 Hz, 1H), 6.00 (s, 1H), 5.98 (s, 2H), 4.23 (q, J = 7.0 Hz, 2H), 3.90 (s, 3H), 1.31 (t, J = 7.0 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 167.2, 149.7, 147.6, 146.7, 143.6, 141.7, 133.8 , 126.8, 125.7, 125.7, 123.5, 119.6, 119.2, 117.9, 109.7, 106.2, 105.9, 101.5, 60.4, 56.1, 14.3; ESMS m/z: 391.2 (M + 23) ⁺ .

(E)-3-(3-((E)-3,4,5- 三 羥基苯乙烯基 ) 苯基 ) 丙烯酸 (E)- 乙酯（ 24 ）: 黃色固體; Mp = 168-170 ^oC; ¹H NMR (500 MHz, CD ₃OD): δ 7.68 (d, J= 16.2, Hz, 1H), 7.68 (s, 1H), 7.52 (d, J= 7.8 Hz, 1H), 7.43 (d, J= 7.8 Hz, 1H), 7.35 (t, J= 7.8 Hz, 1H), 7.01 (d, J= 16.2 Hz, 1H), 6.89 (d, J= 16.2 Hz, 1H), 6.59 (s, 2H), 6.55 (d, J= 16.2 Hz, 1H), 4.24 (q, J= 7.2 Hz, 2H), 1.33 (t, J= 7.2 Hz, 3H); ¹³C NMR (125 MHz, CD ₃OD): δ 168.6, 147.1, 146.1, 140.1, 136.1, 134.8, 131.3, 130.3, 129.9, 128.9, 127.5, 127.1, 125.9, 119.2, 107.1, 61.6, 14.6; ESMS m/z: 325.3 (M - 1) ^-。 (E)-3-(3-((E)-3,4,5 - trihydroxystyryl ) phenyl ) acrylic acid (E) -ethyl ester ( 24 ) : yellow solid; Mp = 168-170 ^o C ¹ H NMR (500 MHz, CD ₃ OD): δ 7.68 (d, J = 16.2, Hz, 1H), 7.68 (s, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 16.2 Hz, 1H), 6.89 (d, J = 16.2 Hz, 1H), 6.59 (s, 2H) , 6.55 (d, J = 16.2 Hz, 1H), 4.24 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H); ¹³ C NMR (125 MHz, CD ₃ OD): δ 168.6, 147.1, 146.1, 140.1, 136.1, 134.8, 131.3, 130.3, 129.9, 128.9, 127.5, 127.1, 125.9, 119.2, 107.1, 61.6, 14.6; ESMS m/z: 325.3 (M - 1) ^- .

3-(3-((E)-3,4,5- 三 甲氧基苯乙烯基 ) 苯基 ) 丙烯酸 (E)- 乙酯（ 25 ）: 白色固體; Mp = 177-179 ^oC; ¹H NMR (500 MHz, CDCl ₃): δ 7.68 (d, J= 16.2 Hz, 1H), 7.62 (s, 1H), 7.48 (d, J= 7.8 Hz, 1H), 7.39 (d, J= 7.8 Hz, 1H), 7.34 (t, J= 7.8 Hz, 1H), 7.04 (d, J= 16.2 Hz, 1H), 6.97 (d, J= 16.2 Hz, 1H), 6.72 (s, 2H), 6.46 (d, J= 15.6 Hz, 1H), 4.25 (q, J= 7.2 Hz, 2H), 3.89 (s, 6H), 3.85 (s, 3H), 1.32 (t, J= 7.2 Hz, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 166.8, 153.4, 144.3, 138.1, 137.8, 134.8, 132.6, 129.5, 129.1, 128.0, 127.2, 127.0, 125.9, 118.5, 103.6, 60.9, 60.5, 56.0, 14.2; ESMS m/z: 339.2 (M - 1) ^-。 3- (3 - ((E) -3,4,5- three-methoxystyryl) phenyl) acrylic acid (E) - ethyl ester (25): white solid; Mp = 177-179 ^o C; ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.68 (d, J = 16.2 Hz, 1H), 7.62 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz , 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 16.2 Hz, 1H), 6.97 (d, J = 16.2 Hz, 1H), 6.72 (s, 2H), 6.46 (d , J = 15.6 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 3.89 (s, 6H), 3.85 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 166.8, 153.4, 144.3, 138.1, 137.8, 134.8, 132.6, 129.5, 129.1, 128.0, 127.2, 127.0, 125.9, 118.5, 103.6, 60.9, 60.5, 56.0, 14.2; ESMS m/ z: 339.2 (M - 1) ^- .

(E)-4- 溴 -2-(3,4- 二 甲氧基苯乙烯基 )-6- 甲氧基苯酚 （ 26 ）: 黃色固體; Mp = 105-107 ^oC; ¹H NMR (600 MHz, CDCl ₃): δ 7.29 (d, J= 2.4 Hz, 1H), 7.18 (d, J= 16.2 Hz, 1H), 7.08-7.04 (m, 3H), 6.85-6.83 (m, 2H), 5.84 (s, 1H), 3.93 (s, 3H), 3.89 (s, 6H); ¹³C NMR (150 MHz, CDCl ₃): δ 149.1, 149.0, 147.2, 142.6, 131.6, 130.5, 130.3, 125.5, 121.1, 120.2, 119.6, 112.3, 111.7, 111.2, 108.9, 56.4, 56.0; ESMS m/z: 365.5 (M + 1) ⁺。 (E) -4- bromo-2- (3,4-styryl) -6-methoxyphenol (26): yellow ^{^{solid; Mp = 105-107 o C; 1}} H NMR (600 MHz, CDCl ₃ ): δ 7.29 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 16.2 Hz, 1H), 7.08-7.04 (m, 3H), 6.85-6.83 (m, 2H), 5.84 (s, 1H), 3.93 (s, 3H), 3.89 (s, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 149.1, 149.0, 147.2, 142.6, 131.6, 130.5, 130.3, 125.5, 121.1, 120.2, 119.6, 112.3, 111.7, 111.2, 108.9, 56.4, 56.0; ESMS m/z: 365.5 (M + 1) ⁺ .

3-(6-((E)-4- 甲氧基苯乙烯基 ) 苯并 [d][1,3] 二氧雜環戊烯 -5- 基 ) 丙烯酸 (E)- 乙酯（ 27 ）: 白色固體; Mp = 84-86 ^oC; ¹H NMR (600 MHz, CDCl ₃): δ 8.07 (d, J= 15.6 Hz, 1H), 7.43 (dd, J= 7.2, 2.4 Hz, 2H), 7.25 (d, J= 15.6 Hz, 1H), 7.04 (s, 1H), 7.00 (s, 1H), 6.88 (dd, J= 7.2, 1.8 Hz, 2H), 6.81 (d, J= 15.6 Hz, 1H), 6.22 (d, J= 15.6 Hz, 1H), 5.98 (s, 2H), 4.24 (q, J= 7.2 Hz, 2H), 3.82 (s, 3H), 1.31 (t, J= 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl ₃): δ 167.2, 159.5, 149.7, 147.5, 141.6, 133.5, 131.0, 130.4, 129.9, 127.9, 126.6, 122.8, 117.9, 114.2, 113.6, 106.0, 105.9, 101.5, 60.4, 55.3, 14.3; ESMS m/z: 353.5 (M + 1) ⁺。 3- (6 - ((E) -4- methoxystyryl) benzo [d] [1,3] dioxol-5-yl) acrylic acid (E) - ethyl ester (27) : white solid; Mp = 84-86 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ): δ 8.07 (d, J = 15.6 Hz, 1H), 7.43 (dd, J = 7.2, 2.4 Hz, 2H), 7.25 (d, J = 15.6 Hz, 1H), 7.04 (s, 1H), 7.00 (s, 1H), 6.88 (dd, J = 7.2, 1.8 Hz, 2H), 6.81 (d, J = 15.6 Hz, 1H ), 6.22 (d, J = 15.6 Hz, 1H), 5.98 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H ¹³ C NMR (150 MHz, CDCl ₃ ): δ 167.2, 159.5, 149.7, 147.5, 141.6, 133.5, 131.0, 130.4, 129.9, 127.9, 126.6, 122.8, 117.9, 114.2, 113.6, 106.0, 105.9, 101.5, 60.4, 55.3, 14.3; ESMS m/z: 353.5 (M + 1) ⁺ .

3-(2,3,4- 三 甲氧基 -6-((E)-4- 甲氧基苯乙烯基 ) 苯基 ) 丙烯酸 (E)- 乙酯（ 28 ）: 黃色固體; Mp = 83-85 ^oC; ¹H NMR (600 MHz, CDCl ₃): δ 7.92 (d, J= 16.2 Hz, 1H), 7.43 (d, J= 6.6 Hz, 2H), 7.16 (d, J= 16.2 Hz, 1H), 6.89 (d, J= 6.6 Hz, 2H), 6.85 (s, 1H), 6.84 (d, J= 16.2 Hz, 1H), 6.40 (d, J= 16.2 Hz, 1H), 4.23 (q, J= 7.2 Hz, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 1.31 (t, J= 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl ₃): δ 167.7, 159.5, 154.3, 153.2, 141.7, 138.5, 134.7, 131.0, 130.0, 127.9, 124.9, 122.3, 120.3, 114.2, 105.8, 61.0, 60.8, 60.3, 56.0, 55.3, 14.3; ESMS m/z: 399.7 (M + 1) ⁺。 3- (2,3,4-trimethoxy -6 - ((E) -4- methoxystyryl) phenyl) acrylic acid (E) - ethyl ester (28): yellow solid; Mp = 83 -85 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ): δ 7.92 (d, J = 16.2 Hz, 1H), 7.43 (d, J = 6.6 Hz, 2H), 7.16 (d, J = 16.2 Hz, 1H), 6.89 (d, J = 6.6 Hz, 2H), 6.85 (s, 1H), 6.84 (d, J = 16.2 Hz, 1H), 6.40 (d, J = 16.2 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 167.7, 159.5, 154.3, 153.2, 141.7, 138.5, 134.7, 131.0, 130.0, 127.9, 124.9, 122.3, 120.3, 114.2, 105.8, 61.0, 60.8, 60.3, 56.0, 55.3, 14.3; ESMS m/z: 399.7 (M + 1) ⁺ .

(E)-2-(2-( 苯并 [d][1,3] 二氧雜環戊烯 -5- 基 ) 乙烯基 )-4- 溴 -6- 甲氧基苯酚 （ 29 ）: 白色固體; Mp ＞ 250 ^oC; ¹H NMR (600 MHz, CDCl ₃): δ 7.26 (d, J= 2.0 Hz, 1H), 7.14 (d, J= 16.5 Hz, 1H), 7.07 (d, J= 1.5 Hz, 1H), 7.03 (d, J= 16.5 Hz, 1H), 6.93 (dd, J= 8.0, 1.5 Hz, 1H), 6.83 (d, J= 2.5 Hz, 1H), 6.77 (d, J= 8.0 Hz, 1H), 5.95 (s, 2H), 3.88 (s, 3H); ¹³C NMR (150 MHz, CDCl ₃): δ 148.1, 147.3, 142.3, 131.9, 130.1, 125.3, 121.8, 121.0, 119.8, 112.4, 111.6, 108.4, 105.7, 101.1, 56.4; ESMS m/z: 371.03 (M + 23) ⁺。 (E) -2- (2- (benzo [d] [1,3] dioxol-5-yl) ethenyl) -4-bromo-6-methoxyphenol (29): White Solid; Mp > 250 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ): δ 7.26 (d, J = 2.0 Hz, 1H), 7.14 (d, J = 16.5 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 7.03 (d, J = 16.5 Hz, 1H), 6.93 (dd, J = 8.0, 1.5 Hz, 1H), 6.83 (d, J = 2.5 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.95 (s, 2H), 3.88 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 148.1, 147.3, 142.3, 131.9, 130.1, 125.3, 121.8, 121.0, 119.8, 112.4, 111.6, 108.4, 105.7, 101.1, 56.4; ESMS m/z: 371.03 (M + 23) ⁺ .

(E)-2-(2- 溴 -3,4,5- 三 甲氧基苯乙烯基 ) 苯酚（ 30 ）: 白色固體; Mp = 147-149 ^oC; ¹H NMR (600 MHz, CDCl ₃): δ 7.54 (dd, J= 7.5, 1.5 Hz, 1H), 7.44 (d, J= 16.0 Hz, 1H), 7.18 (d, J= 16.0 Hz, 1H), 7.17-7.13 (m, 1H), 7.01 (s, 1H), 6.95 (t, J= 8.0 Hz, 1H), 6.79 (d, J= 8.0 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 6H); ¹³C NMR (150 MHz, CDCl ₃): δ 153.1, 152.8, 150.9, 142.8, 133.2, 128.8, 128.6, 127.5, 125.2, 124.4, 121.2, 121.1, 116.0, 111.1, 105.4, 103.6, 61.2, 60.9, 56.2; ESMS m/z: 363.08 (M - 1) ^‒。 (E) -2- (2- bromo-3,4,5-methoxystyryl) phenol (30): white ^{^{solid; Mp = 147-149 o C; 1}} H NMR (600 MHz, CDCl 3 ): δ 7.54 (dd, J = 7.5, 1.5 Hz, 1H), 7.44 (d, J = 16.0 Hz, 1H), 7.18 (d, J = 16.0 Hz, 1H), 7.17-7.13 (m, 1H), 7.01 (s, 1H), 6.95 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 153.1, 152.8, 150.9, 142.8, 133.2, 128.8, 128.6, 127.5, 125.2, 124.4, 121.2, 121.1, 116.0, 111.1, 105.4, 103.6, 61.2, 60.9, 56.2; ESMS m/z: 363.08 (M - 1) ^‒ .

(E)-2-(2-( 苯并 [d][1,3] 二氧雜環戊烯 -5- 基 ) 乙烯基 )-6- 甲氧基苯酚 （ 31 ）: 白色固體; Mp = 141-143 ^oC; ¹H NMR (500 MHz, CDCl ₃): δ 7.23 (d, J= 15.0 Hz, 1H), 7.12 (dd, J= 8.0, 1.5 Hz, 1H), 7.09 (s, 1H), 7.08 (d, J= 15.0 Hz, 1H), 6.94 (dd, J= 8.0, 1.5 Hz, 1H), 6.82 (t, J= 8.0 Hz, 1H), 6.76 (d, J= 8.0 Hz, 1H), 6.74 (dd, J= 8.0, 1.5 Hz, 1H), 5.95 (s, 2H), 3.89 (s, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 148.1, 147.1, 146.7, 143.3, 132.5, 129.1, 123.8, 121.4, 121.3, 119.5, 118.6, 109.2, 108.3, 105.7, 101.0, 56.1; ESMS m/z: 270.2 (M + 1) ⁺。 (E) -2- (2- (benzo [d] [1,3] dioxol-5-yl) ethenyl) -6-methoxyphenol (31): white solid; Mp = 141-143 ^o C; ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.23 (d, J = 15.0 Hz, 1H), 7.12 (dd, J = 8.0, 1.5 Hz, 1H), 7.09 (s, 1H) , 7.08 (d, J = 15.0 Hz, 1H), 6.94 (dd, J = 8.0, 1.5 Hz, 1H), 6.82 (t, J = 8.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H) , 6.74 (dd, J = 8.0, 1.5 Hz, 1H), 5.95 (s, 2H), 3.89 (s, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 148.1, 147.1, 146.7, 143.3, 132.5 , 129.1, 123.8, 121.4, 121.3, 119.5, 118.6, 109.2, 108.3, 105.7, 101.0, 56.1; ESMS m/z: 270.2 (M + 1) ⁺ .

(E)-5-(2-( 苯并 [d][1,3] 二氧雜環戊烯 -5- 基 ) 乙烯基 )-2- 甲氧基苯酚 （ 32 ）: 白色固體; Mp = 139-141 ^oC; ¹H NMR (500 MHz, CDCl ₃): δ 7.01 (d, J= 19.0 Hz, 2H), 6.97 (d, J= 8.0 Hz, 1H), 6.91-6.84 (m, 4H), 6.77 (d, J= 8.0 Hz, 1H), 5.95 (s, 2H), 5.61 (s, 1H), 3.93 (s, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 148.1, 147.0, 146.7, 145.4, 132.1, 130.1, 127.0, 126.2, 121.0, 120.2, 114.5, 108.4, 108.1, 105.4, 101.1, 55.9; EIMS m/z: 270.0 (M ) ⁺。 (E) -5- (2- (benzo [d] [1,3] dioxol-5-yl) ethenyl) -2-methoxyphenol (32): white solid; Mp = 139-141 ^o C; ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.01 (d, J = 19.0 Hz, 2H), 6.97 (d, J = 8.0 Hz, 1H), 6.91-6.84 (m, 4H) , 6.77 (d, J = 8.0 Hz, 1H), 5.95 (s, 2H), 5.61 (s, 1H), 3.93 (s, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 148.1, 147.0, 146.7, 145.4, 132.1, 130.1, 127.0, 126.2, 121.0, 120.2, 114.5, 108.4, 108.1, 105.4, 101.1, 55.9; EIMS m/z: 270.0 (M) ⁺ .

(E)-5-(3,4,5- 三甲氧基苯乙烯基 ) 苯并 [d][1,3] 二氧雜環戊烯（ 33 ）: 白色固體; Mp = 129-131 ^oC; ¹H NMR (500 MHz, CDCl ₃): δ 6.77 (m, 2H), 6.69 (dd, J= 7.5, 0.5 Hz, 1H), 6.49 (s, 2H), 6.44 (d, J= 12.0 Hz, 1H), 6.39 (d, J= 12.0 Hz, 1H), 5.89 (s, 2H), 3.82 (s, 3H), 3.69 (s, 6H); ¹³C NMR (125 MHz, CDCl ₃): δ 152.9, 147.3, 146.6, 137.2, 132.5, 131.1, 129.4, 129.1, 122.9, 109.0, 108.1, 106.0, 100.9, 60.9, 55.9; EIMS m/z: 314.2 (M ) ⁺。 (E) -5- (3,4,5- trimethoxy styryl) benzene and [d] [1,3] dioxole (33): white solid; Mp = 129-131 ^o C ¹ H NMR (500 MHz, CDCl ₃ ): δ 6.77 (m, 2H), 6.69 (dd, J = 7.5, 0.5 Hz, 1H), 6.49 (s, 2H), 6.44 (d, J = 12.0 Hz, 1H), 6.39 (d, J = 12.0 Hz, 1H), 5.89 (s, 2H), 3.82 (s, 3H), 3.69 (s, 6H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 152.9, 147.3, 146.6, 137.2, 132.5, 131.1, 129.4, 129.1, 122.9, 109.0, 108.1, 106.0, 100.9, 60.9, 55.9; EIMS m/z: 314.2 (M) ⁺ .

3-(3,4- 二甲氧基苯乙烯基 )-4- 羥基 -5- 甲氧基苯甲醛 （ 34 ）: 白色固體; Mp = 157-159 ^oC; ¹H NMR (500 MHz, CDCl ₃): δ 9.85 (s, 1H), 7.69 (d, J= 1.5 Hz, 1H), 7.28 (d, J= 1.5 Hz, 1H), 7.26-7.18 (m, 2H), 7.10-7.07 (m, 2H), 6.85 (d, J= 8.0 Hz, 1H), 6.50 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.89 (s, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 191.1, 149.2, 149.1, 148.6, 147.3, 130.6, 130.4, 129.2, 124.4, 124.1, 120.2, 119.5, 111.2, 108.9, 106.9, 56.3, 55.9, 55.9; ESMS m/z: 337.13 (M +23) ⁺。 3-(3,4 -Dimethoxystyryl )-4 -hydroxy -5 -methoxybenzaldehyde ( 34 ) : White solid; Mp = 157-159 ^o C; ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.85 (s, 1H), 7.69 (d, J = 1.5 Hz, 1H), 7.28 (d, J = 1.5 Hz, 1H), 7.26-7.18 (m, 2H), 7.10-7.07 (m, 2H), 6.85 (d, J = 8.0 Hz, 1H), 6.50 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.89 (s, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 191.1, 149.2, 149.1, 148.6, 147.3, 130.6, 130.4, 129.2, 124.4, 124.1, 120.2, 119.5, 111.2, 108.9, 106.9, 56.3, 55.9, 55.9; ESMS m/z: 337.13 (M + 23) ⁺ .

3-(3-((E)-3,4- 二 甲氧基 苯乙烯基 )-4- 羥基 -5- 甲氧基 苯基 ) 丙烯酸 (E)- 乙酯（ 35 ）: 白色固體; Mp = 171-173 ^oC; ¹H NMR (500 MHz, CDCl ₃): δ 7.64 (d, J= 16.0 Hz, 1H), 7.34 (d, J= 1.5 Hz, 1H), 7.22 (d, J= 16.5 Hz, 1H), 7.13 (d, J= 16.5 Hz, 1H), 7.09-7.06 (m, 2H), 6.91 (d, J= 1.5 Hz, 1H), 6.85 (d, J= 8.0 Hz, 1H), 6.32 (d, J= 16.0 Hz, 1H), 6.18 (br, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 3.79 (s, 3H); ¹³C NMR (125 MHz, CDCl ₃): δ 167.6, 149.1, 149.0, 146.9, 145.3, 145.1, 130.6, 130.1, 126.3, 124.1, 120.3, 120.1, 120.0, 115.4, 111.2, 108.9, 107.4, 56.2, 55.9, 55.9, 51.6; ESMS m/z: 369.43(M -1) ^-。 3- (3 - ((E) -3,4- dimethoxy-styryl) -4-hydroxy-5-methoxyphenyl) acrylic acid (E) - ethyl ester (35): white solid; Mp = 171-173 ^o C; ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.64 (d, J = 16.0 Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H), 7.22 (d, J = 16.5 Hz, 1H), 7.13 (d, J = 16.5 Hz, 1H), 7.09-7.06 (m, 2H), 6.91 (d, J = 1.5 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.32 (d, J = 16.0 Hz, 1H), 6.18 (br, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 3.79 (s, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 167.6, 149.1, 149.0, 146.9, 145.3, 145.1, 130.6, 130.1, 126.3, 124.1, 120.3, 120.1, 120.0, 115.4, 111.2, 108.9, 107.4, 56.2, 55.9, 55.9, 51.6 ; ESMS m/z: 369.43 (M -1) ^- .

式formula (II)(II) 化合物之合成：Synthesis of compounds:

流程 2：合成羥基官能化 2-芳基苯并[b]呋喃 11 Scheme 2: Synthesis of Hydroxyl Functionalized 2-Arylbenzo[b]furan 11

流程2呈現合成羥基官能化2-芳基苯并[b]呋喃化合物代表性結構的策略，其合成方法如下。類似流程1，以威悌反應將取代的磷偶極體 7和水楊醛轉化為二苯乙烯 8。然後將二苯乙烯 8在鹼性碘溶液中環化得到溴取代的2-芳基苯并[b]呋喃 9，如流程2所示。再經由鈀催化的Heck偶合反應，將溴取代的2-芳基苯并[b]呋喃 9與丙烯酸乙酯偶合以製備(E)-丙烯酸乙酯取代的2-芳基苯并[b]呋喃 10 。最後，使用如流程1中所述的三溴化硼處理，從化合物 10中除去其甲氧基，以獲得產率令人滿意的羥基官能化2-芳基苯并[b]呋喃 11。 Scheme 2 presents a strategy for the synthesis of a representative structure of a hydroxy-functionalized 2-arylbenzo[b]furan compound, which is synthesized as follows. Similar to Scheme 1, the substituted phosphorus dipole 7 and salicylaldehyde were converted to stilbene 8 by a deuteration reaction. The stilbene 8 is then cyclized in an alkaline iodine solution to give the bromo-substituted 2-arylbenzo[b]furan 9 as shown in Scheme 2. The bromo-substituted 2-arylbenzo[b]furan 9 is coupled with ethyl acrylate via a palladium-catalyzed Heck coupling reaction to prepare (E)-ethyl acrylate-substituted 2-arylbenzo[b]furan. 10 . Finally, the methoxy group was removed from compound 10 using boron tribromide treatment as described in Scheme 1 to obtain a hydroxy-functionalized 2-arylbenzo[b]furan 11 of satisfactory yield.

表 2 羥基-官能化 2-芳基苯并[b]呋喃化合物 <TABLE border="1" borderColor="#000000" width="85%"><TBODY><tr><td> 化合物編號 </td><td> R1</td><td> R2</td><td> R3</td><td> R4</td><td> R5</td><td> R6</td><td> R7</td><td> R8</td><td> R9</td><td> </td></tr><tr><td>11</td><td> H </td><td> H </td><td> H </td><td> H </td><td> H </td><td> OH </td><td> OH </td><td> H </td><td> CH=CHCO2Et* </td><td> </td></tr><tr><td>36</td><td> Br </td><td> H </td><td> H </td><td> OCH3</td><td> H </td><td> -OCH2O- </td><td> H </td><td> H </td><td> </td></tr><tr><td>37</td><td> H </td><td> CH=CHCO2Et* </td><td> H </td><td> OH </td><td> H </td><td> OH </td><td> OH </td><td> OH </td><td> H </td><td> </td></tr><tr><td>38</td><td> H </td><td> H </td><td> H </td><td> H </td><td> H </td><td> OH </td><td> OH </td><td> OH </td><td> Br </td><td> </td></tr><tr><td>39</td><td> H </td><td> Br </td><td> H </td><td> OH </td><td> H </td><td> OH </td><td> OH </td><td> OH </td><td> H </td></tr><tr><td>40</td><td> H </td><td> Br </td><td> H </td><td> OH </td><td> H </td><td> OH </td><td> OH </td><td> H </td><td> H </td></tr><tr><td>41</td><td> H </td><td> Br </td><td> H </td><td> OH </td><td> H </td><td> H </td><td> OH </td><td> H </td><td> H </td></tr><tr><td>42</td><td> Br </td><td> H </td><td> H </td><td> OH </td><td> H </td><td> H </td><td> OH </td><td> OH </td><td> H </td></tr><tr><td>43</td><td> H </td><td> H </td><td> H </td><td> OH </td><td> H </td><td> OH </td><td> OH </td><td> H </td><td> CH=CHCO2Et* </td></tr><tr height="0"><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr></TBODY></TABLE>*代表 E-異構物 Table 2 Hydroxy-functionalized 2-arylbenzo[b]furan compounds <TABLE border="1"borderColor="#000000"width="85%"><TBODY><tr><td> compound number</td><td>R1</td><td>R2</td><td>R3</td><td>R4</td><Td>R5</td><td>R6</td><td>R7</td><td>R8</td><td>R9</td><td></td></tr><tr><td>11</td><td> H </td><td> H </td><td> H </td><td> H </td><td> H </td><td > OH </td><td> OH </td><td> H </td><td>CH=CHCO2Et*</td><td></td></tr><tr><td>36</td><td> Br </td><td> H </td><td> H </td><td>OCH3</td><td> H </td><td>-OCH2O-</td><td> H </td><td> H </td><td></td></tr><tr><td>37</td><td> H </td><td>CH=CHCO2Et*</td><td> H </td><td> OH </td><td> H </td><td> OH </td><td> OH </td ><td> OH </td><td> H </td><td></td></tr><tr><td>38</td><td> H </td><td> H </td><td> H </td><td> H </td><td> H </td><td> OH </td><td> OH </ Td><td> OH </td><td> Br </td><td></td></tr><tr><td>39</td><td> H </td><td> Br </td><td> H </td><td> OH </td><td> H </td><td> OH </td><td> OH </td><td> OH </td><td> H </td></tr><tr><td>40</td><td> H </td><td> Br </td><Td> H </td><td> OH </td><td> H </td><td> OH </td><td> OH </td><td> H </td><td> H </td></tr><tr><td>41</td><td> H </td><td> Br </td><td> H </td ><td> OH </td><td> H </td><td> H </td><td> OH </td><td> H </td><td> H </td></tr><tr><td>42</td><td> Br </td><td> H </td><td> H </td><td> OH </td><td> H </td><td> H </td><td> OH </td><td> OH </td><td> H </td></tr><tr><td>43</td><td> H </td><td> H </td><td> H </td><td> OH </td><td> H </td><td> OH </td><td> OH </td><td> H </td><td>CH=CHCO2Et*</td></tr><trheight="0"><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr></TBODY></TABLE>* stands for E -isomer

製備preparation 2-(2-2-(2- 溴bromine -4,5--4,5- 二甲氧基苯基Dimethoxyphenyl )) 苯并呋喃（Benzofuran 99 ）)

將2-(2-溴-4,5-二甲氧基苯乙烯基)苯酚 8（241 mg，0.72 mmol）在THF（20 mL）中的溶液與碳酸鉀（594 mg，4.3 mmol）和碘（1.09 g，4.3 mmol）混合。將混合物在室溫下攪拌 3 小時，直到反應以 TLC 顯示完成。將飽和的 NaHSO ₃水溶液加到溶液中，並將混合物用乙酸乙酯萃取。將有機層合併，用 MgSO ₄乾燥。殘留物以快速管柱層析純化而得到呈淡黃色固體狀的標題化合物 9（194 mg，81 ％）。 ¹H NMR (600 MHz, CDCl ₃): δ 7.60 (d, J= 7.8 Hz, 1H), 7.51 (d, J= 7.8 Hz, 1H), 7.45 (s, 1H), 7.44 (s, 1H), 7.29 (dt, J= 7.8, 1.8 Hz, 1H), 7.23 (dt, J= 7.8, 1.8 Hz, 1H), 7.13 (s, 1H), 3.96 (s, 3H), 3.91 (s, 3H); ¹³C NMR (150 MHz, CDCl ₃): δ 154.0, 153.2, 149.4, 148.4, 129.0, 124.5, 123.5, 122.9, 121.2, 116.7, 111.9, 111.5, 111.0, 105.9, 56.2, 56.2; ESMS m/z: 355.2 (M + 23) ⁺。 A solution of 2-(2-bromo-4,5-dimethoxystyryl)phenol 8 (241 mg, 0.72 mmol) in THF (20 mL) with potassium carbonate (594 mg, 4.3 mmol) (1.09 g, 4.3 mmol) mixed. The mixture was stirred at room temperature for 3 hours until the reaction was completed by TLC. A saturated aqueous solution of NaHSO _{3 was} added to the solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over MgSO _4. The residue was purified by flash column chromatography to give the title compound as a light yellow solid 9 (194 mg, 81%) . ¹ H NMR (600 MHz, CDCl ₃ ): δ 7.60 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.44 (s, 1H), 7.29 (dt, J = 7.8, 1.8 Hz, 1H), 7.23 (dt, J = 7.8, 1.8 Hz, 1H), 7.13 (s, 1H), 3.96 (s, 3H), 3.91 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 154.0, 153.2, 149.4, 148.4, 129.0, 124.5, 123.5, 122.9, 121.2, 116.7, 111.9, 111.5, 111.0, 105.9, 56.2, 56.2; ESMS m/z: 355.2 ( M + 23) ⁺ .

製備preparation 3-(2-(3-(2-( 苯并呋喃Benzofuran -2--2- 基base )-4,5-)-4,5- 二two 甲氧基Methoxy 苯基Phenyl )) 丙烯酸acrylic acid (E)(E) 乙酯Ethyl ester （( 1010 ）)

在乾燥壓力管中將 9（167 mg，0.50 mmol）、Pd(OAc) ₂（5 mg，0.02 mmol）、三苯膦（16 mg，0.06 mmol）和 Et ₃N（0.14 mL，0.99 mmol）加入除水的 DMF（15 mL）中，在氮氣下加入丙烯酸乙酯（0.081 mL，0.74 mmol）。丙烯酸乙酯在加入反應混合物之前需先脫氣。然後將管密封，並將混合物加熱至 110 ℃ 並攪拌 24 小時。將反應物冷卻至環境溫度，並在高真空下除去溶劑。將殘留物以矽膠管柱層析純化而得到黃色固體 10（123 mg，70 ％）。 ¹H NMR (400 MHz, CDCl ₃) d 8.28 (d, J= 15.6 Hz, 1H), 7.74 (d, J= 7.2 Hz, 1H), 7.67 (d, J= 8.0 Hz, 1H), 7.45-7.36 (m, 4H), 6.87 (s, 1H), 6.50 (d, J= 15.6 Hz, 1H), 4.21 (q, J= 7.2 Hz, 2H), 4.12 (s, 3H), 4.09 (s, 3H), 1.28 (t, J= 7.2 Hz, 3H); ESMS m/z: 353.1 (M + 1) ⁺。 9 (167 mg, 0.50 mmol), Pd(OAc) ₂ (5 mg, 0.02 mmol), triphenylphosphine (16 mg, 0.06 mmol) and Et ₃ N (0.14 mL, 0.99 mmol) were added to a dry pressure tube Ethyl acrylate (0.081 mL, 0.74 mmol) was added under nitrogen in water (MeOH). Ethyl acrylate needs to be degassed before it is added to the reaction mixture. The tube was then sealed and the mixture was heated to 110 ° C and stirred for 24 hours. The reaction was cooled to ambient temperature and the solvent was removed under high vacuum. The residue was purified by silica gel column chromatography to obtain a yellow solid 10 (123 mg, 70%) . ¹ H NMR (400 MHz, CDCl ₃ ) d 8.28 (d, J = 15.6 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.45-7.36 (m, 4H), 6.87 (s, 1H), 6.50 (d, J = 15.6 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 4.12 (s, 3H), 4.09 (s, 3H) , 1.28 (t, J = 7.2 Hz, 3H); ESMS m/z: 353.1 (M + 1) ⁺ .

合成synthesis 3-(2-(3-(2-( 苯并呋喃Benzofuran -2--2- 基base )-4,5-)-4,5- 二羥基苯基Dihydroxyphenyl )) 丙烯酸acrylic acid (E)(E) 乙酯Ethyl ester （( 1111 ）)

在 -60 ℃、N ₂環境下，將 10（254 mg，0.72 mmol）在乾燥二氯甲烷（20 mL）溶液中逐滴加入 BBr ₃（0.40 ml，4.32 mmol）。然後使反應混合物升溫至 -40 ℃ 並再攪拌 2 小時直到反應以 TLC 顯示完成。將反應在 0 ℃小心混合飽和 NaHCO ₃水溶液（30 mL）並攪拌 30 分鐘。將該混合物用乙酸乙酯萃取兩次（20 mL × 2），合併有機部分，進一步以鹽水洗滌，並用 MgSO ₄乾燥。將殘留物過濾，濃縮並以矽膠管柱層析純化而得到白色固體的化合物 11（168 mg，72 ％）。 Mp = 87-89 ^oC; ¹H NMR (600 MHz, CDCl ₃): δ 8.11 (d, J= 16.0 Hz, 1H), 7.58 (dd, J= 8.0, 1.2 Hz, 1H), 7.48 (dd, J= 8.0, 0.4 Hz, 1H), 7.34 (s, 1H), 7.27 (dt, J= 8.0, 0.4 Hz, 1H), 7.22-7.17 (m, 1H), 7.17 (s, 1H), 6.70 (s, 1H), 6.28 (d, J= 16.0 Hz, 1H), 5.95 (br, 1H), 5.87 (br 1H), 4.25 (q, J= 7.2 Hz, 2H), 1.32 (t, J= 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl ₃): δ 167.3, 154.7, 153.4, 145.4, 144.4, 143.0, 129.1, 126.4, 124.6, 124.5, 123.0, 121.1, 118.6, 115.1, 113.9, 111.1, 106.7, 60.6, 14.3; ESMS m/z: 347 (M + 23) ⁺。 At -60 ℃, N ₂ environment and the 10 (254 mg, 0.72 mmol) at -780C in dry dichloromethane (20 mL) was added dropwise _{BBr 3 (0.40 ml, 4.32 mmol} ). The reaction mixture was then warmed to -40 °C and stirred for additional 2 hours until the reaction was completed by TLC. The reaction was carefully mixed with saturated aqueous NaHCO ₃ (30 mL) and stirred for 30 min. The mixture was extracted twice with ethyl acetate (20 mL × 2), the organic portions were combined, washed with brine, and further dried over MgSO _4. The residue was filtered, concentrated and purified by silica gel column chromatography to give white solid compound 11 (168 mg, 72%) . Mp = 87-89 ^o C; ¹ H NMR (600 MHz, CDCl ₃ ): δ 8.11 (d, J = 16.0 Hz, 1H), 7.58 (dd, J = 8.0, 1.2 Hz, 1H), 7.48 (dd, J = 8.0, 0.4 Hz, 1H), 7.34 (s, 1H), 7.27 (dt, J = 8.0, 0.4 Hz, 1H), 7.22-7.17 (m, 1H), 7.17 (s, 1H), 6.70 (s , 1H), 6.28 (d, J = 16.0 Hz, 1H), 5.95 (br, 1H), 5.87 (br 1H), 4.25 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 167.3, 154.7, 153.4, 145.4, 144.4, 143.0, 129.1, 126.4, 124.6, 124.5, 123.0, 121.1, 118.6, 115.1, 113.9, 111.1, 106.7, 60.6 , 14.3; ESMS m/z: 347 (M + 23) ⁺ .

化合物 36至化合物 43之合成係使用適當起始物及相似於化合物 11之製程製備。 The synthesis of compound 36 to compound 43 is carried out using a suitable starting material and a procedure similar to compound 11 .

5-(4- 溴 -7- 甲氧基 苯并呋喃 -2- 基 ) 苯并 [d][1,3] 二氧雜環戊烯（ 36 ）: 黃色固體; ¹H NMR (400 MHz, CDCl ₃): δ 7.40 (d, J= 7.6 Hz, 1H), 7.40 (s, 1H), 7.25 (d, J= 4.8 Hz, 1H), 6.87-6.85 (m, 2H), 6.64 (d, J= 7.6 Hz, 1H), 6.55 (s, 2H), 3.99 (s, 3H) ; ESMS m/z: 346.2 (M + 1) ⁺。 5- (4-Bromo-7-methoxy-benzofuran-2-yl) benzo [d] [1,3] dioxole (36): yellow solid; ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.40 (d, J = 7.6 Hz, 1H), 7.40 (s, 1H), 7.25 (d, J = 4.8 Hz, 1H), 6.87-6.85 (m, 2H), 6.64 (d, J = 7.6 Hz, 1H), 6.55 (s, 2H), 3.99 (s, 3H) ; ESMS m/z: 346.2 (M + 1) ⁺ .

3-(7- 羥基 -2-(3,4,5- 三羥基苯基 ) 苯并呋喃 -5- 基 ) 丙烯酸 (E)- 乙酯（ 37 ）: 產率: 64 %; Mp = 234-239 ^oC; IR nmax: 3412, 1685, 1629, 1451, 1287 cm ^-1; ¹H NMR (600 MHz, CD ₃OD): δ 7.67 (d, J= 16.2 Hz, 1H), 7.25 (d, J= 1.2 Hz, 1H), 6.94 (d, J= 1.2 Hz,1H), 6.91 (s, 2H), 6.85 (s, 1H), 6.39 (d, J= 16.2 Hz, 1H), 4.23 (q, J= 7.2 Hz, 2H), 1.32 (t, J= 7.2 Hz, 3H) ; ¹³C NMR (150 MHz, CD ₃OD): δ 169.1, 159.1, 147.3, 147.2, 146.1, 143.8, 135.8, 133.2, 131.7, 122.5, 117.1, 114.3, 109.9, 105.5, 100.7, 61.6, 14.6; ESMS m/z: 355.2 (M - 1) ^-。 (E) -ethyl 3-(7- hydroxy -2-(3,4,5 -trihydroxyphenyl ) benzofuran -5- yl ) acrylate ( 37 ) : Yield: 64 %; Mp = 234- 239 ^o C; IR nmax: 3412, 1685, 1629, 1451, 1287 cm ^-1 ; ¹ H NMR (600 MHz, CD ₃ OD): δ 7.67 (d, J = 16.2 Hz, 1H), 7.25 (d, J = 1.2 Hz, 1H), 6.94 (d, J = 1.2 Hz, 1H), 6.91 (s, 2H), 6.85 (s, 1H), 6.39 (d, J = 16.2 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H); ¹³ C NMR (150 MHz, CD ₃ OD): δ 169.1, 159.1, 147.3, 147.2, 146.1, 143.8, 135.8, 133.2, 131.7, 122.5, 117.1, 114.3, 109.9, 105.5, 100.7, 61.6, 14.6; ESMS m/z: 355.2 (M - 1) ^- .

5-( 苯并呋喃 -2- 基 )-4- 溴苯 -1,2,3- 三醇（ 38 ）: 產率: 62 %; Mp = 159-162 ^oC; IR nmax: 3419, 1613, 1507, 1452, 1187 cm ^-1; ¹H NMR (600 MHz, CD ₃OD): δ 7.58 (d, J= 7.2 Hz, 1H), 7.45 (dd, J= 7.8, 0.6 Hz, 1H), 7.31 (d, J= 0.6 Hz, 1H), 7.26 (dt, J= 7.2, 1.2 Hz, 1H), 7.20 (dt, J= 7.2, 1.2 Hz, 1H), 7.01 (s, 1H) ; ¹³C NMR (150 MHz, CD ₃OD): δ 155.8, 155.4, 146.1, 145.2, 136.2, 130.4, 125.2, 123.6, 123.0, 122.0, 111.6, 109.3, 100.9; ESMS m/z: 321.0 (M -1) ^-。 5-( benzofuran -2- yl )-4- bromobenzene -1,2,3- triol ( 38 ) : Yield: 62%; Mp = 159-162 ^o C; IR nmax: 3419, 1613, 1507, 1452, 1187 cm ^-1 ; ¹ H NMR (600 MHz, CD ₃ OD): δ 7.58 (d, J = 7.2 Hz, 1H), 7.45 (dd, J = 7.8, 0.6 Hz, 1H), 7.31 ( d, J = 0.6 Hz, 1H), 7.26 (dt, J = 7.2, 1.2 Hz, 1H), 7.20 (dt, J = 7.2, 1.2 Hz, 1H), 7.01 (s, 1H) ; ¹³ C NMR (150 MHz, CD ₃ OD): δ 155.8, 155.4, 146.1, 145.2, 136.2, 130.4, 125.2, 123.6, 123.0, 122.0, 111.6, 109.3, 100.9; ESMS m/z: 321.0 (M -1) ^- .

5-(5- 溴 -7- 羥基苯并呋喃 -2- 基 ) 苯 -1,2,3- 三醇（ 39 ）: 產率: 59 %; Mp = 224-227 ^oC; IR nmax: 3445, 1646, 1445, 1314, 1197 cm ^-1; ¹H NMR (500 MHz, CD ₃OD): δ 7.14 (d, J= 2.0 Hz, 1H), 6.90 (s, 2H), 6.80 (d, J= 2.0 Hz, 1H), 6.78 (s, 1H) ; ¹³C NMR (125 MHz, CD ₃OD): δ 159.1, 147.3, 144.2, 143.6, 135.9, 134.2, 122.4, 116.6, 115.2, 114.1, 105.6, 100.1; ESMS m/z: 337.1 (M - 1) ^-。 5-(5- Bromo -7- hydroxybenzofuran -2- yl ) benzene -1,2,3- triol ( 39 ) : Yield: 59%; Mp = 224-227 ^o C; IR nmax: 3445 , 1646, 1445, 1314, 1197 cm ^-1 ; ¹ H NMR (500 MHz, CD ₃ OD): δ 7.14 (d, J = 2.0 Hz, 1H), 6.90 (s, 2H), 6.80 (d, J = 2.0 Hz, 1H), 6.78 (s, 1H) ; ¹³ C NMR (125 MHz, CD ₃ OD): δ 159.1, 147.3, 144.2, 143.6, 135.9, 134.2, 122.4, 116.6, 115.2, 114.1, 105.6, 100.1; ESMS m/z: 337.1 (M - 1) ^- .

4-(5- 溴 -7- 羥基苯并呋喃 -2- 基 ) 苯 -1,2- 二醇（ 40 ）: 產率: 51 %; Mp = 221-224 ^oC; IR nmax: 3231, 2925, 1615, 1446, 1249, 1203 cm ^-1; ¹H NMR (400 MHz, CD ₃OD): δ 7.30 (d, J= 2.0 Hz, 1H), 7.25 (dd, J= 8.5, 2.0 Hz, 1H), 7.14 (d, J= 2.0 Hz, 1H), 6.84 (d, J= 8.5 Hz, 1H), 6.82 (s, 1H), 6.80 (d, J= 2.0 Hz, 1H) ; ¹³C NMR (125 MHz, CD ₃OD): δ 159.0, 147.8, 146.7, 144.2, 143.6, 134.2, 123.4, 118.4, 116.7, 116.6, 115.2, 114.1, 113.2, 100.0; ESMS m/z: 321.1 (M - 1) ^-。 4-(5- Bromo -7- hydroxybenzofuran -2- yl ) benzene -1,2- diol ( 40 ) : Yield: 51%; Mp = 221-224 ^o C; IR nmax: 3231, 2925 , 1615, 1446, 1249, 1203 cm ^-1 ; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.30 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 8.5, 2.0 Hz, 1H) , 7.14 (d, J = 2.0 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.82 (s, 1H), 6.80 (d, J = 2.0 Hz, 1H) ; ¹³ C NMR (125 MHz , CD ₃ OD): δ 159.0, 147.8, 146.7, 144.2, 143.6, 134.2, 123.4, 118.4, 116.7, 116.6, 115.2, 114.1, 113.2, 100.0; ESMS m/z: 321.1 (M - 1) ^- .

5- 溴 -2-(4- 羥基苯基 ) 苯并呋喃 -7- 醇（ 41 ）: 產率: 52 %; Mp = 255-258 ^oC; IR nmax: 3358, 1584, 1469, 1209 cm ^-1; ¹H NMR (600 MHz, CD ₃OD): δ 7.73 (dd, J= 6.6, 1.8 Hz, 2H), 7.14 (d, J= 1.8 Hz, 1H), 6.86 (d, J= 6.6 Hz, 2H), 6.85 (d, J= 1.8 Hz, 1H), 6.80 (d, J= 1.8 Hz, 1H) ; ¹³C NMR (150 MHz, CD ₃OD): δ 159.7, 158.9, 144.3, 146.6, 134.2, 127.7, 122.9, 116.7, 116.6, 115.2, 114.1, 99.9; ESMS m/z: 305.1 (M - 1) ^-。 5- bromo -2-(4 -hydroxyphenyl ) benzofuran -7- ol ( 41 ) : Yield: 52%; Mp = 255-258 ^o C; IR nmax: 3358, 1584, 1469, 1209 cm ^{- 1} ; ¹ H NMR (600 MHz, CD ₃ OD): δ 7.73 (dd, J = 6.6, 1.8 Hz, 2H), 7.14 (d, J = 1.8 Hz, 1H), 6.86 (d, J = 6.6 Hz, 2H), 6.85 (d, J = 1.8 Hz, 1H), 6.80 (d, J = 1.8 Hz, 1H); ¹³ C NMR (150 MHz, CD ₃ OD): δ 159.7, 158.9, 144.3, 146.6, 134.2, 127.7, 122.9, 116.7, 116.6, 115.2, 114.1, 99.9; ESMS m/z: 305.1 (M - 1) ^- .

4-(4- 溴 -7- 羥基苯并呋喃 -2- 基 ) 苯 -1,2- 二醇（ 42 ）: 產率: 67 %; Mp = 82-86 ^oC; IR nmax: 3220, 2924, 1486, 1186 cm ^-1; ¹H NMR (400 MHz, CD ₃OD): δ 7.33 (d, J= 2.5 Hz, 1H), 7.30 (d, J= 8.0 Hz, 1H), 7.12 (d, J= 8.0 Hz, 1H), 6.85 (d, J= 8.5 Hz, 1H), 6.83 (s, 1H), 6.61 (d, J= 8.5 Hz, 1H) ; ¹³C NMR (125 MHZ, CD ₃OD): δ 158.5, 148.0, 146.8, 144.3, 143.2, 133.4, 127.1, 123.2, 118.5, 116.7, 113.2, 112.3, 103.1, 100.2; ESMS m/z: 321.2 (M - 1) ^-。 4-(4- Bromo -7- hydroxybenzofuran -2- yl ) benzene -1,2- diol ( 42 ) : Yield: 67%; Mp = 82-86 ^o C; IR nmax: 3220, 2924 , 1486, 1186 cm ^-1 ; ¹ H NMR (400 MHz, CD ₃ OD): δ 7.33 (d, J = 2.5 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.83 (s, 1H), 6.61 (d, J = 8.5 Hz, 1H) ; ¹³ C NMR (125 MHZ, CD ₃ OD): δ 158.5, 148.0, 146.8, 144.3, 143.2, 133.4, 127.1, 123.2, 118.5, 116.7, 113.2, 112.3, 103.1, 100.2; ESMS m/z: 321.2 (M - 1) ^- .

3-( 4,5- 二羥基 -2-(7- 羥基苯并呋喃 -2- 基 ) 苯基 ) 丙烯酸 (E)- 乙酯（ 43 ）: 產率: 62 %; Mp = 171-176 ^oC; IR nmax: 3256, 2925, 1685, 1368, 1297 cm ^-1; ¹H NMR (400 MHz, CD ₃OD): δ 8.09 (d, J= 16.0, 1H), 7.25 (s, 1H), 7.18 (s, 1H), 7.08 (t, J= 8.0 Hz, 1H), 7.06 (dd, J= 8.0, 1.0 Hz, 1H), 6.74 (dd, J= 8.0, 1.0 Hz, 1H), 6.66 (s, 1H), 6.30 (d, J= 16.0 Hz, 1H), 4.22 (q, J= 7.0 Hz, 2H), 1.30 (t, J= 7.0 Hz, 3H) ; ¹³C NMR (125 MHz, CD ₃OD): δ 169.2, 155.3, 149.1, 147.8, 145.0, 144.7, 143.6, 132.3, 126.1, 125.3, 124.8, 117.8, 116.5, 114.4, 113.0, 111.7, 107.5, 61.6, 14.6; ESMS m/z: 339.1 (M - 1) ^-。 (E) -ethyl 4- ( 4,5 -dihydroxy -2-(7 -hydroxybenzofuran -2- yl ) phenyl ) acrylate ( 43 ) : Yield: 62 %; Mp = 171-176 ^o C; IR nmax: 3256, 2925, 1685, 1368, 1297 cm ^-1 ; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.09 (d, J = 16.0, 1H), 7.25 (s, 1H), 7.18 (s, 1H), 7.08 (t, J = 8.0 Hz, 1H), 7.06 (dd, J = 8.0, 1.0 Hz, 1H), 6.74 (dd, J = 8.0, 1.0 Hz, 1H), 6.66 (s, 1H), 6.30 (d, J = 16.0 Hz, 1H), 4.22 (q, J = 7.0 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H); ¹³ C NMR (125 MHz, CD ₃ OD) : δ 169.2, 155.3, 149.1, 147.8, 145.0, 144.7, 143.6, 132.3, 126.1, 125.3, 124.8, 117.8, 116.5, 114.4, 113.0, 111.7, 107.5, 61.6, 14.6; ESMS m/z: 339.1 (M - 1 ) ^- .

生物活性試驗Biological activity test

細胞培養：新生皮質神經元的初代培養之製備，可參見文獻Wenzel, E. et al., (2005), Metabolism and bioavailability of trans-resveratrol. Mol. Nutr. Food Res., 49, 472-481。國家中醫藥研究所的實驗動物照護及使用委員會已核准該動物計畫。簡而言之，將從 Sprague-Dawley大鼠幼崽斷頭分離的皮質在 0.5 mg/ml 木瓜蛋白酶中於 37 ℃ 消化 15 分鐘。經由抽吸研磨將組織在 Hibernate A 培養基（含有 B27 補充物）中解離。將細胞鋪板並保持在含有 B27 補充物、10 單位/ml 青黴素、10 μg/ml 鏈黴素和 0.5 μg/ml 麩醯胺酸的 Neurobasal 培養基中3天。然後將細胞暴露於胞嘧啶- β-D-***呋喃糖苷（5 μM）1天以消除非神經元細胞的增殖。細胞分別用於體外天數（DIV）5 和 DIV10 的 A β和麩胺酸實驗。神經元在 DIV5 易受 A β介導的毒性，並且在 DIV10 處表達麩胺酸受體。從大腦皮質製備初代混合神經膠質細胞並保持在含有 10％ FBS 的 DMEM/F12 培養基中 3 天。用新鮮培養基更換該培養基並培養 4 天。之後，將細胞在 Neurobasal 培養基 / B27補充物中培養 9 天以上。 Cell Culture: Preparation of primary cultures of neocortical neurons can be found in Wenzel, E. et al., (2005), Metabolism and bioavailability of trans-resveratrol. Mol. Nutr. Food Res. , 49 , 472-481. The Animal Care and Use Committee of the National Institute of Traditional Chinese Medicine has approved the animal program. Briefly, the cortex isolated from Sprague-Dawley rat pups was digested in 0.5 mg/ml papain for 15 minutes at 37 °C. Tissues were dissociated in Hibernate A medium (containing B27 supplement) via aspiration grinding. Cells were plated and maintained in Neurobasal medium containing B27 supplement, 10 units/ml penicillin, 10 μg/ml streptomycin and 0.5 μg/ml branic acid for 3 days. The cells were then exposed to cytosine- β -D-arabinofuranoside (5 μM) for 1 day to eliminate proliferation of non-neuronal cells. Number of cells were used for in vitro (DIV) A β and glutamic days 5 and DIV10 of experiments. In neurons vulnerable DIV5 A β-mediated toxicity, and the expression of glutamate receptor at DIV10. Primary mixed glial cells were prepared from the cerebral cortex and maintained in DMEM/F12 medium containing 10% FBS for 3 days. The medium was replaced with fresh medium and cultured for 4 days. Thereafter, the cells were cultured in Neurobasal medium/B27 supplement for more than 9 days.

動物管理和行政管理：國家中醫藥研究所的實驗動物照護及使用委員會已核准該動物計畫（IACUC 編號：100-A-04 和 102-417-3）。AD 的 APPswe/PS1ΔE9 雙轉殖基因小鼠模型（APP/PS1）購自傑克遜實驗室（Jackson Laboratory）（編號 005864），該小鼠表達一種嵌合小鼠/人類 APP695 攜帶瑞典 K670M/N671L 突變（APPswe）和人類 PS1 的外顯子- 9 缺失突變（PS1ΔE9）。在一個籠子裡飼養之性別比例是一隻雄性、兩隻雌性。使用 WT 同屬和 AD 轉殖基因雌性 C57BL/6J 小鼠進行實驗。將動物置於控制溫度（24±1 ℃）和濕度（55-65 ％）下配以12:12小時（07：00-19：00）的明暗循環。提供所有小鼠市售的囓齒動物正常飼料和隨意飲水。為了探索合成化合物的活體內作用，給予 5 個月大的 APP/PS1 小鼠餵食合成化合物（30 mg/kg/天）以進行行為測試。Animal Management and Administration: The Animal Care and Use Committee of the National Institute of Traditional Chinese Medicine has approved the animal program (IACUC numbers: 100-A-04 and 102-417-3). The APPswe/PS1ΔE9 double transgenic mouse model of AD (APP/PS1) was purchased from the Jackson Laboratory (No. 005864), which expresses a chimeric mouse/human APP695 carrying the Swedish K670M/N671L mutation ( APPswe) and exon-9 deletion mutant of human PS1 (PS1ΔE9). The sex ratio raised in a cage is one male and two female. Experiments were performed using WT homologous and AD transgenic female C57BL/6J mice. Animals were placed under controlled temperature (24 ± 1 °C) and humidity (55-65%) with a 12:12 hour (07:00-19:00) light and dark cycle. All rodent normal feeds and free drinking water are available from all mice. To explore the in vivo effects of the synthetic compounds, 5 month old APP/PS1 mice were fed a synthetic compound (30 mg/kg/day) for behavioral testing.

統計分析方法：結果以平均值 ± 平均值之標準誤差（SEM）表示，且採用以事後 Bonferroni 多重比較檢定（post-hoc Bonferroni multiple comparison tests）之變異數分析（ANOVA）進行分析。Statistical analysis methods: Results were expressed as mean ± standard error of the mean (SEM) and analyzed by post-hoc Bonferroni multiple comparison tests (ANOVA).

實施例Example 11 ：化合物對皮質神經元的神經細胞毒性之活性測試: Activity test of compounds on neurocytotoxicity of cortical neurons

fA β25-35 的製備和生物化學定性：將 fA β25-35溶解在H ₂O中至 1mM 並在 37 ℃ 老化 1 週以製備 fA β25-35。將 A β的稀釋溶液點在雲母載玻片上並使用 Agilent 5400 原子顯微鏡（Molecular Imaging Coorporation，Temp，A2）進行掃描，可參見文獻Tsay, H. J. et al., (2013), Amyloid β peptide-mediated neurotoxicity is attenuated by the proliferating microglia more potently than by the quiescent phenotype. J. Biomed. Sci., 20,78。 fA β preparation and biochemical characterization of 25-35: 25-35 to dissolve fA β 1 week of aging to 1mM and was prepared at 37 [deg.] C fA β 25-35 in H ₂ O in. The diluted solution was spotted on A β mica Agilent 5400 using a glass slide and atomic force microscopy (Molecular Imaging Coorporation, Temp, A2 ) are scanned, may be found in the literature Tsay, HJ et al., ( 2013), Amyloid β peptide-mediated neurotoxicity Is attenuated by the proliferating microglia more potently than by the quiescent phenotype. J. Biomed. Sci. , 20, 78.

以fA β25-35 或麩胺酸及合成化合物進行處理：將皮質神經元用載劑（0.1 ％二甲亞碸）或合成化合物預處理 30 分鐘。然後，將 fA β25-35 或麩胺酸直接加入到培養基中，分別培養 48 和 24 小時。 Treatment with fA β 25-35 or glutamic acid and synthetic compounds: Cortical neurons were pretreated with vehicle (0.1% dimethyl hydrazine) or synthetic compound for 30 minutes. Then, fA β 25-35 or glutamic acid was added directly to the medium for 48 and 24 hours, respectively.

細胞存活度測量：使用存活/死亡細胞存活度測定法和 MTT 的還原分析來評估細胞存活度。細胞載入 1 μM 的鈣黃綠素AM（calcein AM）和ethidium homodimer-1 在室溫下 30 分鐘。透過雷射掃描共軛焦顯微鏡（Jena，德國）觀察細胞。另使用 MTT 的還原來評估細胞存活度，細胞與 0.5 mg/ml MTT培養 1 小時，其 formazan 顆粒用 DMSO 溶解，使用酵素連結免疫吸附分析儀讀取器測量 OD _600nm。 Cell viability measurements: Cell viability was assessed using a survival/death cell viability assay and a reduction assay of MTT. Cells were loaded with 1 μM calcein AM (calcein AM) and ethidium homodimer-1 for 30 minutes at room temperature. The cells were observed by a laser scanning conjugated focus microscope (Jena, Germany). Cell viability was assessed using MTT reduction, cells were incubated with 0.5 mg/ml MTT for 1 hour, formazan particles were lysed in DMSO, and OD _{600 nm} was measured using an enzyme-linked immunosorbent analyzer reader.

免疫細胞化學：經處理的細胞在室溫下用 4 ％三聚甲醛固定 15 分鐘，並用 0.5 ％ Triton X-100 透化 10 分鐘。細胞用 10 ％對照驢血清於室溫封閉 2 小時。此後，將細胞暴露於抗-MAP2 單株抗體（1：100，Invitrogen）或山羊抗-tau 抗體（1：100，Santa Cruz）在 4 ℃ 過夜。洗滌後，細胞在含有異硫氰酸螢光素-標記的驢抗-小鼠 IgG 和RRX-標記的驢抗-山羊IgG（1:200; Jackson ImmunoResearch）的染色溶液中於 4 ℃ 在黑暗中培養過夜。然後將細胞在 PBS中洗滌並用Aqua Poly/Mount（Polyscience Inc.，Warrington，PA，USA）固定。用於異硫氰酸螢光素和RRX的激發/發射波長分別為488/520和570/590。使用 MetaMorph 軟體定量螢光強度。Immunocytochemistry: The treated cells were fixed with 4% paraformaldehyde for 15 minutes at room temperature and permeabilized with 0.5% Triton X-100 for 10 minutes. The cells were blocked with 10% control sputum serum for 2 hours at room temperature. Thereafter, the cells were exposed to anti-MAP2 monoclonal antibody (1:100, Invitrogen) or goat anti-tau antibody (1:100, Santa Cruz) at 4 °C overnight. After washing, the cells were stained in a staining solution containing luciferin-labeled donkey anti-mouse IgG and RRX-labeled donkey anti-goat IgG (1:200; Jackson ImmunoResearch) at 4 ° C in the dark. Cultivate overnight. The cells were then washed in PBS and fixed with Aqua Poly/Mount (Polyscience Inc., Warrington, PA, USA). The excitation/emission wavelengths for luciferin isothiocyanate and RRX were 488/520 and 570/590, respectively. Quantify fluorescence intensity using MetaMorph software.

測定本發明之羥基官能化二苯乙烯和 2-芳基苯并[b]呋喃化合物對纖維性類澱粉蛋白 b25-35（fibril amyloid bprotein 25-35，fA b25-35）或麩胺酸介導的神經細胞毒性的神經保護作用，將皮質神經元與載劑（0.1％ DMSO）或最大無毒濃度的羥基官能化二苯乙烯和2-芳基苯并[b]呋喃化合物在暴露於A β（10 μM）48小時或麩胺酸（30 μM）24小時之前一起培養2小時，然後使用 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴鹽（MTT）還原分析評估神經元的細胞存活度。 Hydroxy functional assay of the present invention stilbenes and 2- arylbenzo [b] furan compounds fibrous amyloid b 25-35 (fibril amyloid b protein 25-35 , fA b 25-35) amine or bran Acid-mediated neuroprotection of neuronal cytotoxicity by exposure of cortical neurons to vehicle (0.1% DMSO) or maximum non-toxic concentrations of hydroxy-functionalized stilbene and 2-arylbenzo[b]furan compounds A β (10 μM) for 48 hours or glutamic acid (30 μM) for 2 hours before 24 hours, then 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl Tetrazolium bromide (MTT) reduction assay assesses cell viability of neurons.

表 3、表 4 顯示在神經保護測定中，本發明化合物 5、 11、 37、 40 、 42和 43顯示可保護神經元免於 A β介導的神經細胞毒性。其中，化合物 5、 11和 37對麩胺酸介導的神經細胞毒性亦產生保護作用。 Tables 3 and 4 show that compounds 5 , 11 , 37 , 40 , 42 and 43 of the present invention have been shown to protect neurons from Aβ- mediated neurocytotoxicity in neuroprotective assays. Among them, compounds 5 , 11 and 37 also have protective effects against glutamate-mediated neurocytotoxicity.

圖 1A至圖 1C 顯示本發明之羥基-官能化二苯乙烯和2-芳基苯并[b]呋喃保護皮質神經元抗 A β和麩胺酸誘導的神經突損傷。圖 1A 顯示皮質神經元與 50 μM 所示化合物在暴露於A β（10 μM）48小時或麩胺酸（30 μM）24小時之前培養 2 小時；圖 1B 顯示利用存活/死亡細胞存活度檢測以評估細胞存活度。依據鈣黃綠素 AM（calcein AM）陽性細胞的數量，計算相對於對照組之百分比；圖 1C 顯示存活細胞的螢光強度為基於鈣黃綠素AM 陽性細胞的平均螢光強度相對於對照組之百分比。結果以相對於單獨用載劑處理的細胞表示且由三個獨立的實驗代表平均值 ± SEM。用毒素和毒素加化合物處理的細胞之間的顯著差異如下所示：*代表p ＜ 0.05，**代表p ＜ 0.01 ， ***代表p ＜ 0.001。 1A to 1C show that the hydroxy-functionalized stilbene and 2-arylbenzo[b]furan of the present invention protect cortical neurons against Aβ and glutamate-induced neurite damage. Figure 1A shows that cortical neurons were incubated with 50 μM of the indicated compound for 2 hours before exposure to Aβ (10 μM) for 48 hours or glutamic acid (30 μM) for 24 hours; Figure 1B shows the use of survival/death cell viability assay Cell viability was assessed. The percentage relative to the control group was calculated based on the number of calcein AM positive cells; FIG. 1C shows that the fluorescence intensity of the viable cells is the percentage of the average fluorescence intensity based on the calcein AM positive cells relative to the control group. Results are expressed relative to cells treated with vehicle alone and represent the mean ± SEM from three independent experiments. Significant differences between cells treated with toxins and toxin plus compound are shown below: * represents p < 0.05, ** represents p < 0.01, and *** represents p < 0.001.

由圖 1 顯示存活/死亡細胞存活度測定以 10 μM 的 fA β25-35 誘導在鈣黃綠素染色（在細胞數量和螢光強度方面）降低了40 ％。然而，當細胞用50 μM 的化合物 5、 11、 37、 40或 42處理時，fA β25-35 誘導在鈣黃綠素染色的減少顯著減弱。同樣地，以 30 μM 麩胺酸誘導在鈣黃綠素染色（在細胞數目和螢光強度方面）降低了 50 ％，然而，用 50 μM 化合物 5、 11或 37處理顯著減弱了鈣黃綠素染色的減少。 The survival/death cell viability assay shown in Figure 1 was reduced by 40% in calcein staining (in terms of cell number and fluorescence intensity) with 10 μM of fA β 25-35. However, when cells were treated with 50 μM of compound 5 , 11 , 37 , 40 or 42 , the reduction in calcein staining was significantly attenuated by fA β 25-35 induction. Similarly, calcein staining (in terms of cell number and fluorescence intensity) was reduced by 50% with 30 μM glutamate induction, however, treatment with 50 μM of compound 5 , 11 or 37 significantly attenuated the reduction in calcein staining.

圖 2A 至圖 2F 顯示羥基官能化二苯乙烯和 2-芳基苯并[b]呋喃保護神經突抗 A β和麩胺酸誘導的細胞死亡。圖 2A 顯示皮質神經元與 50 μM 所示化合物在暴露於10 μM A β48小時之前培養 2 小時的 MAP2（紅色）和 tau（綠色）的免疫細胞化學影像；圖 2B 顯示皮質神經元與 50 μM 所示化合物在暴露於 30 μM 麩胺酸 24 小時之前培養 2 小時 MAP2（紅色）和 tau（綠色）的免疫細胞化學影像；圖 2C、圖 2E 顯示 MAP2 的螢光強度；圖 2D、圖 2F顯示tau 蛋白的螢光強度。結果以相對於單獨用載劑處理的細胞表示且由三個獨立的實驗代表平均值 ± SEM。用 A β和對照處理的細胞之間的顯著差異如下所示：**代表p ＜ 0.01 ， ***代表p ＜ 0.001。用 A β加載劑和化合物處理的細胞之間的顯著差異如下所示：#代表p ＜ 0.05；##代表p ＜ 0.01 ； ###代表p ＜ 0.001。 2A to 2F show that hydroxy-functionalized stilbene and 2-arylbenzo[b]furan protect neurites against Aβ and glutamate-induced cell death. Figure 2A shows immunocytochemical images of MAP2 (red) and tau (green) of cortical neurons and 50 μM of the compound cultured for 2 hours before exposure to 10 μM A β for 48 hours; Figure 2B shows cortical neurons with 50 μM The indicated compounds were cultured for 2 hours before exposure to 30 μM glutamic acid for 2 hours for immunocytochemical imaging of MAP2 (red) and tau (green); Figures 2C, 2E show the fluorescence intensity of MAP2; Figure 2D, Figure 2F shows The fluorescence intensity of the tau protein. Results are expressed relative to cells treated with vehicle alone and represent the mean ± SEM from three independent experiments. Significant differences between cells treated with A[ beta] and control were as follows: ** represents p < 0.01 and *** represents p < 0.001. Significant differences between cells treated with A beta loading and compound are shown below: # represents p <0.05;## represents p <0.01;### represents p < 0.001.

fA β25-35 誘導的細胞死亡與 MAP2 的 44 ％減少和 tau 蛋白的 36 ％減少顯示一致。化合物 11、 40和 42顯著減弱了 MAP2 的降低（圖 2A，圖 2C），然而沒有減弱 tau 蛋白的降低（圖 2A，圖 2D）。麩胺酸引起 MAP2（49％）和 tau（81％）免疫反應性的減低，用化合物 5、 11和 37處理顯著減弱 MAP2、tau 的降低（圖 2B、圖 2E、圖 2F）。 fA β 25-35 induced cell death was consistent with a 44% reduction in MAP2 and a 36% reduction in tau protein. Compounds 11 , 40 and 42 significantly attenuated the decrease in MAP2 (Fig. 2A, Fig. 2C), but did not attenuate the decrease in tau protein (Fig. 2A, Fig. 2D). Glutamic acid caused a decrease in MAP2 (49%) and tau (81%) immunoreactivity, and treatment with Compounds 5 , 11 and 37 significantly attenuated the decrease in MAP2 and tau (Fig. 2B, Fig. 2E, Fig. 2F).

本發明化合物對皮質神經元的神經細胞毒性之活性測試中，結果顯示在神經保護測定中，本發明化合物 5、 11、 37、 40 、 42和 43顯示可保護神經元免於 A β介導的神經細胞毒性。其中，化合物 5、 11和 37對麩胺酸介導的神經細胞毒性亦產生保護作用。在神經突保護測定中，本發明化合物 40和 42顯示可保護神經元免於 A β介導的神經細胞毒性（表 3、表 4、圖 1、圖 2）。 In the activity test of the compounds of the present invention against neurocytotoxicity of cortical neurons, the results showed that the compounds of the present invention 5 , 11 , 37 , 40 , 42 and 43 were shown to protect neurons from Aβ- mediated in a neuroprotective assay. Neurocytotoxicity. Among them, compounds 5 , 11 and 37 also have protective effects against glutamate-mediated neurocytotoxicity. In the neurite protection assay, compounds 40 and 42 of the invention were shown to protect neurons from Aβ- mediated neurocytotoxicity (Table 3, Table 4, Figure 1, Figure 2).

表 3 羥基官能化二苯乙烯和 2-芳基苯并[b]呋喃對皮質神經元和混合膠細胞的神經保護和抗神經發炎活性 ^a <TABLE border="1" borderColor="#000000" width="85%"><TBODY><tr><td> 化合物編號 </td><td> Aβ介導的神經元死亡 (%) </td><td> 麩胺酸介導的神經元死亡 (%) </td><td> LPS誘導的膠細胞 NO產生 (載劑之%) </td></tr><tr><td> 載劑 </td><td> 39.20 ± 0.88 </td><td> 41.22 ± 3.40 </td><td> 100 </td></tr><tr><td>5</td><td> 19.23 ± 4.66*** </td><td> 28.05 ± 3.40** </td><td> 72.93 ± 12.67* </td></tr><tr><td>11</td><td> 25.45 ± 6.14*** </td><td> 21.00 ± 0.89** </td><td> 49.61 ± 7.04* </td></tr><tr><td>17</td><td> 38.17 ± 1.53 </td><td> 49.21 ± 2.32 </td><td> 70.98 ± 16.18** </td></tr><tr><td>20</td><td> 36.56 ± 1.28 </td><td> 43.30 ± 2.09 </td><td> 73.27 ± 1.36** </td></tr><tr><td>24</td><td> 41.19 ± 2.36 </td><td> 42.05 ± 1.37 </td><td> 26.02 ± 2.39***</td></tr><tr><td>27</td><td> 41.62 ± 4.44 </td><td> 37.28 ± 2.97 </td><td> 74.88 ± 19.64*</td></tr><tr><td>28</td><td> 36.93 ± 0.60 </td><td> 41.07 ± 2.14 </td><td> 59.11 ± 3.05***</td></tr><tr><td>29</td><td> 45.74 ± 0.41 </td><td> 45.69 ± 1.40 </td><td> 48.79 ± 6.21***</td></tr><tr><td>34</td><td> 48.16 ± 3.08 </td><td> 37.02 ± 3.31 </td><td> 27.99 ± 11.95*</td></tr><tr><td>37</td><td> 21.18 ± 3.17*** </td><td> 24.48 ± 3.68*** </td><td> 40.35 ± 19.47** </td></tr><tr><td>38</td><td> 42.34 ± 1.69 </td><td> 41.89 ± 1.48 </td><td> 24.92 ± 7.68***</td></tr><tr><td>40</td><td> 16.95 ± 1.30*** </td><td> 31.45 ± 2.42 </td><td> 86.85 ± 6.71 </td></tr><tr><td>42</td><td> 4.11 ± 0.13*** </td><td> 40.83 ± 0.98 </td><td> 61.64 ± 12.53** </td></tr><tr><td>43</td><td> 31.58 ± 1.50** </td><td> 43.50 ± 1.45 </td><td> 38.13 ± 11.25*** </td></tr></TBODY></TABLE> ^a 皮質神經元與載劑（0.1％ DMSO）或最大無毒濃度的羥基官能化二苯乙烯和2-芳基苯并[b]呋喃在暴露於A β（10 μM）48小時或麩胺酸（30 μM）24小時之前一起培養2小時。用LPS處理混合膠細胞48小時後，收集培養基以測定亞硝酸鹽含量。結果為由三個獨立實驗的平均值 ± SD表示。用載劑和其它組處理的細胞組之間的顯著差異如下所示：*代表p ＜ 0.05； **代表p ＜ 0.01； ***代表p ＜ 0.001。 Table 3 Neuroprotective and anti-neuroinflammatory activities of hydroxy-functionalized stilbene and 2-arylbenzo[b]furan on cortical neurons and mixed gel cells ^a <TABLE border="1"borderColor="#000000" width ="85%"><TBODY><tr><td> Compound number</td><td>Aβ mediated neuronal death (%) </td><td> bran Amino acid-mediated neuronal death (%) </td><td> LPS-induced glial NO production (% of carrier) </td></tr><tr><td> Carrier </td ><td> 39.20 ± 0.88 </td><td> 41.22 ± 3.40 </td><td> 100 </td></tr><tr><td>5</td ><td> 19.23 ± 4.66*** </td><td> 28.05 ± 3.40** </td><td> 72.93 ± 12.67* </td></tr><tr><td>11</td><td> 25.45 ± 6.14*** </td><td> 21.00 ± 0.89** </td><td> 49.61 ± 7.04* </td></tr><Tr><td>17</td><td> 38.17 ± 1.53 </td><td> 49.21 ± 2.32 </td><td> 70.98 ± 16.18** </td></tr><tr><td>20</td><td> 36.56 ± 1.28 </td><td> 43.30 ± 2.09 </td><td> 73.27 ± 1.36** /td></tr><tr><td>24</td><td> 41.19 ± 2.36 </td><td> 42.05 ± 1.37 </td><td> 26.02 ± 2.39***</td></tr><tr><td>27</td><td> 41.62 ± 4.44 </td><td> 37.28 ± 2.97 </td><td> 74.88 ± 19.64*</td></tr><tr><Td>28</td><td> 36.93 ± 0.60 </td><td> 41.07 ± 2.14 </td><td> 59.11 ± 3.05***</td></tr><tr><td>29</td><td> 45.74 ± 0.41 </td><td> 45.69 ± 1.40 </td><td> 48.79 ± 6.21***</td></tr><tr><td>34</td><td> 48.16 ± 3.08 </td><td > 37.02 ± 3.31 </td><td> 27.99 ± 11.95*</td></tr><tr><td>37</td><td > 21.18 ± 3.17*** </td><td> 24.48 ± 3.68*** </td><td> 40.35 ± 19.47** </td></tr><tr><td>38 </td><td> 42.34 ± 1.69 </td><td> 41.89 ± 1.48 </td><td> 24.92 ± 7.68***</td></ Tr><tr><td>40</td><td> 16.95 ± 1.30*** </td><td> 31.45 ± 2.42 </td><td> 86.85 ± 6.71 /td></tr><tr><td>42</td><td> 4.11 ± 0.13*** </td><td> 40.83 ± 0.98 </td><td > 61.64 ± 12.53** </td></tr><tr><td>43</td><td> 31.58 ± 1.50** </td><td> 43.50 ± 1.45 </ td><td> 38.13 ± 11.25 *** </ td></tr></TBODY></TABLE> a cortical neurons with vehicle (0.1% DMSO) The maximum non-toxic concentration of the hydroxy-functionalized stilbene and 2-arylbenzo [b] furan exposure to A β (10 μM) 48 hours, or Glutamate (30 μM) incubated 24 hours prior to 2 hours. After treating the mixed gel cells with LPS for 48 hours, the medium was collected to determine the nitrite content. Results are expressed as the mean ± SD of three independent experiments. Significant differences between the vehicle groups treated with vehicle and other groups are as follows: * represents p <0.05; ** represents p <0.01; *** represents p < 0.001.

實施例Example 22 ：化合物對混合膠細胞培養的抗神經發炎活性測試: Anti-neuroinflammatory activity test of compound on mixed gelatin cell culture

亞硝酸鹽的測量：透過將培養基與等體積的 Griess 試劑（0.05 ％ N-(1-萘基)-乙二胺二鹽酸鹽、0.5 ％磺胺和 1.25 ％磷酸）培養來測量亞硝酸鹽含量（NO 釋放）。培養後，使用以 NaNO ₂作為標準的微量盤式分析儀在540 nm 波長下檢測光密度。 Nitrite measurement: nitrite content was measured by culturing the medium with an equal volume of Griess reagent (0.05% N-(1-naphthyl)-ethylenediamine dihydrochloride, 0.5% sulfonamide and 1.25% phosphoric acid). (NO release). After the incubation, the optical density was measured at a wavelength of 540 nm using a microplate analyzer using NaNO ₂ as a standard.

本發明將混合膠細胞（mixed glial cells）培養 16 天，此時微膠細胞（microglia）表現出樹狀細胞樣外觀。然後膠細胞功能根據由100 ng/mL 的脂多醣（LPS）誘導的一氧化氮（NO）的產生為特徵。用 50 μM 本發明之合成化合物處理混合膠細胞更新培養基後以 LPS 活化處理混合膠細胞 2 天，收集培養基以測定亞硝酸鹽含量。表 4 列出描述所示化合物抑制 NO 產生的程度的EC ₅₀值。 In the present invention, mixed glial cells are cultured for 16 days, at which time microglia exhibits a dendritic appearance. The gel cell function is then characterized by the production of nitric oxide (NO) induced by 100 ng/mL lipopolysaccharide (LPS). The mixed gelatin cells were treated with 50 μM of the synthetic compound of the present invention, and the mixed gel cells were treated with LPS activation for 2 days, and the medium was collected to determine the nitrite content. Table 4 lists the compounds that inhibit the ₅₀ values shown in the extent described in NO production EC.

用 LPS 活化的混合膠細胞培養物產生 NO 之變化評價本發明之合成化合物的抗神經發炎作用。該測定的結果顯示本發明之 13 種化合物 5、 11、 17、 20、 24、 27、 28、 29、 34、 37、 38、 42和 43具有抗神經發炎活性，其中，最具活性為化合物 24、 34、 37和 38（表 3 和表 4）。 The anti-neuroinflammatory effect of the synthetic compounds of the present invention was evaluated by the change in NO produced by the LPS-activated mixed gel cell culture. The results of this assay show that the 13 compounds of the present invention, 5 , 11 , 17 , 20 , 24 , 27 , 28 , 29 , 34 , 37 , 38 , 42 and 43 have anti-neuroinflammatory activity, of which the most active compound 24 , 34 , 37 and 38 (Tables 3 and 4).

表 4 羥基官能化二苯乙烯和 2-芳基苯并[b]呋喃的神經保護和抗神經發炎活性、抑制 CYP3A4 和抗氧化能力 ^a <TABLE border="1" borderColor="#000000" width="85%"><TBODY><tr><td> 化合物編號 </td><td> Aβ介導的神經元死亡(EC50,mM) </td><td> 麩胺酸介導的神經元死亡 (EC50,mM) </td><td> LPS誘導的膠細胞 NO (EC50,mM) </td><td> CYP3A4 抑制 (IC50,mM) </td><td> 抗氧化能力 (TEAC, mM) </td></tr><tr><td>5</td><td> 40.89 ± 6.45 </td><td> ＞MNTC </td><td> 99.24 ± 9.89 </td><td> 36.2 ± 4.2 </td><td> 0.14 ± 0.01 </td></tr><tr><td>11</td><td> ＞MNTC </td><td> 46.08 ± 7.36 </td><td> ＞MNTC </td><td> 11.2 ± 3.6 </td><td> 0.01 ± 0.01 </td></tr><tr><td>17</td><td> ＞MNTC </td><td> ＞MNTC </td><td> 66.96 ± 17.51 </td><td> n.d. </td><td> n.d. </td></tr><tr><td>24</td><td> ＞MNTC </td><td> ＞MNTC </td><td> 48.94 ± 14.02 </td><td> n.d. </td><td> n.d. </td></tr><tr><td>29</td><td> ＞MNTC </td><td> ＞MNTC </td><td> 84.81 ± 4.68 </td><td> n.d. </td><td> n.d. </td></tr><tr><td>34</td><td> ＞MNTC </td><td> ＞MNTC </td><td> 42.95 ± 5.47 </td><td> n.d. </td><td> n.d. </td></tr><tr><td>37</td><td> 52.95 ± 6.33 </td><td> 32.99 ± 5.41 </td><td> 56.60 ± 11.34 </td><td> 21.7 ± 2.2 </td><td> 0.94 ± 0.08 </td></tr><tr><td>38</td><td> ＞MNTC </td><td> ＞MNTC </td><td> 39.24 ± 11.94 </td><td> n.d. </td><td> 0.97 ± 0.06 </td></tr><tr><td>40</td><td> 36.45 ± 7.86 </td><td> ＞MNTC </td><td> ＞MNTC </td><td> 23.5 ± 4.7 </td><td> 0.06 ± 0.04 </td></tr><tr><td>42</td><td> 26.71 ± 5.39 </td><td> ＞MNTC </td><td> ＞MNTC </td><td> n.d. </td><td> 0.12 ± 0.13 </td></tr><tr><td>43</td><td> ＞MNTC </td><td> ＞MNTC </td><td> 82.55 ± 19.07 </td><td> n.d. </td><td> 0.20 ± 0.07 </td></tr></TBODY></TABLE> ^a 研究結果表示EC ₅₀值代表三個獨立實驗的平均值 ± SD。 n.d. 表示未確定。 MNTC表示最大無毒濃度。 Table 4 Neuroprotective and anti-neuroinflammatory activities of hydroxy-functionalized stilbene and 2-arylbenzo[b]furan, inhibition of CYP3A4 and antioxidant capacity ^a <TABLE border="1"borderColor="#000000" width= "85%"><TBODY><tr><td> Compound No.</td><td>Aβ mediated neuronal death (EC50, mM </td><td> glutamate-mediated neuronal death (EC50,mM) </td><td> LPS-induced glial cell NO (EC50, mM) </td><td> CYP3A4 inhibition (IC50,mM) </td><td> antioxidant capacity (TEAC, mM) </td></tr ><tr><td>5</td><td> 40.89 ± 6.45 </td><td>>MNTC</td><td> 99.24 ± 9.89 </td><td > 36.2 ± 4.2 </td><td> 0.14 ± 0.01 </td></tr><tr><td>11</td><td>>MNTC</td><Td> 46.08 ± 7.36 </td><td>>MNTC</td><td> 11.2 ± 3.6 </td><td> 0.01 ± 0.01 </td></tr><tr><td>17</td><td>>MNTC</td><td>>MNTC</td><td> 66.96 ± 17.51 </td><td> nd </td><td> nd </td></tr><tr><td>24</td><td>>MNTC</td><td>>MNTC</td><td> 48.94 ± 14.02 </td><td> nd </td><td> nd </td></tr><tr><td>29 </td><td>>MNTC</td><td>>MNTC</td><td> 84.81 ± 4.68 </td><td> nd </td><td> nd </ Td></tr><tr><td>34</td><td>>MNTC</td><td>>MNTC</td><td> 42.95 ± 5.47 </ Td><td> nd </td><td> nd </td></tr><tr><td>37</td><td> 52.95 ± 6.33 </td><td> 32.99 ± 5.41 </td><td> 56.60 ± 11.34 </td><td> 21.7 ± 2.2 </td><td> 0.94 ± 0.08 </td></tr><tr><td>38</td><td>>MNTC</td><td>>MNTC</td><td> 39.24 ± 11.94 </td><td> nd </td><td > 0.97 ± 0.06 </td></tr><tr><td>40</td><td> 36.45 ± 7.86 </td><td>>MNTC</td><Td>>MNTC</td><td> 23.5 ± 4.7 </td><td> 0.06 ± 0.04 </td></tr><tr><td>42</td><td> 26.71 ± 5.39 </td><td>>MNTC</td><td>>MNTC</td><td> nd </td><td> 0.12 ± 0.13 </td></tr><tr><td>43</td><td>>MNTC</td><td>>MNTC</td><td> 82.55 ± 19.07 </td><td> nd </td><td> 0.20 ± 0.07 </td></tr></TBODY></TABLE> ^a Study results indicate that the EC ₅₀ values represent the mean ± SD of three independent experiments. Nd means not determined. MNTC indicates the maximum non-toxic concentration.

實施例Example 33 ：化合物對: compound pair CYP3A4CYP3A4 抑制活性之測試Inhibition activity test

細胞色素 P450 3A4（CYP3A4）活性測定：具有 N-末端修飾的野生型 CYP3A4 的構建體由 F.Peter Guengerich 博士（Nashville, TN, USA）提供。酶表達和膜製備之進行，可參見前文獻：Ueng, Y. F. et al., (2013), Mechanism-based inhibition of CYP1A1 and CYP3A4 by the furanocoumarin chalepensin. Drug Metab. Pharmacokinet., 28,229-238。細胞色素 P450 含量可參見：Omura, T. et al., (1964), The carbon monoxide‑binding pigment of liver microsomes. Evidence for its hemeprotein nature. J. Biol. Chem., 239,2370-2378. 報導的光譜方法測定。CYP3A4 的尼菲迪平（Nifedipine）氧化活性可根據：Guengerich, F.P. et al., (1986), Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug metabolism. J. Biol. Chem., 261,5051-5060. 報導的方法測定。測定 CYP3A4 活性的 3-4 個平均值是在羥基官能化的二苯乙烯或 2-芳基苯并[b]呋喃增加濃度的存在下用來計算 IC ₅₀（催化活性之50％抑制所需的濃度）。使用 Grafit 軟體（從 0 開始，定義結束；Erithacus Software Ltd.，Staines，UK）通過曲線擬合計算 IC ₅₀。 Cytochrome P450 3A4 (CYP3A4) Activity Assay: The construct of wild-type CYP3A4 with N-terminal modification was provided by Dr. F. Peter Guengerich (Nashville, TN, USA). For enzyme expression and membrane preparation, see the previous literature: Ueng, YF et al., (2013), Mechanism-based inhibition of CYP1A1 and CYP3A4 by the furanocoumarin chalepensin. Drug Metab. Pharmacokinet. , 28, 229-238. The cytochrome P450 content can be found in: Omura, T. et al., (1964), The carbon monoxide-binding pigment of liver microsomes. Evidence for its hemeprotein nature. J. Biol. Chem. , 239, 2370-2378. Spectroscopic method determination. The oxidative activity of Nifedipine of CYP3A4 can be based on: Guengerich, FP et al., (1986), Characterization of rat and human liver microsomal cytochrome P-450 forms involved in nifedipine oxidation, a prototype for genetic polymorphism in oxidative drug Metabolism. J. Biol. Chem. , 261, 5051-5060. Reported method determination. Determination of CYP3A4 activity is the average of 3-4 hydroxyl functionalized stilbene or 2-arylbenzo [b] furan increases used to calculate IC _{50 (50%} inhibition of catalytic activity present in a concentration of the desired concentration). Using Grafit software (from 0, define end; Erithacus Software Ltd., Staines, UK ) is calculated by curve fitting IC _50.

發明人在進行動物測定之前先進行化合物 5、 11、 37及 40的體外 ADMET 的初步評估。CYP3A4 為人類肝臟中最豐富的細胞色素 P450 異構體，為了評估與 CYP3A4 受質的潛在相互作用，發明人試圖測定羥基官能化二苯乙烯（化合物 5）和 2-芳基苯并[b]呋喃（化合物 11、 37及 40）對 CYP3A4 活性的影響。結果顯示化合物 5、 11、 37及 40可能抑制 CYP3A4 之代謝（表 4）。 The inventors performed a preliminary assessment of in vitro ADMET of compounds 5 , 11 , 37 and 40 prior to animal assays. CYP3A4 is the most abundant cytochrome P450 isoform in human liver. To assess potential interactions with CYP3A4 receptors, the inventors attempted to determine hydroxy-functionalized stilbene (Compound 5 ) and 2-arylbenzo[b] The effect of furan (compounds 11 , 37 and 40 ) on CYP3A4 activity. The results showed that compounds 5 , 11 , 37 and 40 may inhibit the metabolism of CYP3A4 (Table 4).

實施例Example 44 ：化合物抗氧化活性測試: Compound Antioxidant Activity Test

抗氧化劑活性的評價：合成化合物的抗氧化劑活性為透過trolox等價抗氧化能力（trolox equivalent antioxidant capacity ，TEAC）測定，可參見前文獻：Re, R. et al., (1999), Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radic. Biol. Med., 26,1231-1237。 Evaluation of antioxidant activity: The antioxidant activity of the synthetic compound is determined by the trolox equivalent antioxidant capacity (TEAC). See, for example, Re, R. et al., (1999), Antioxidant activity applying An improved ABTS radical cation decolorization assay. Free Radic. Biol. Med. , 26, 1231-1237.

結果顯示化合物 5、 11、 37、 38、 40、 42及 43具有抗氧化活性（表 4）。 The results showed that Compounds 5 , 11 , 37 , 38 , 40 , 42 and 43 had antioxidant activities (Table 4).

實施例Example 55 ：築巢測試: Nesting test

小鼠在灌胃給藥 60 天後，評估其築巢能力，可參見前文獻：Yeh, C. W. et al., (2015), Impaired cognition and cerebral glucose regulation are associated with astrocyte activation in the parenchyma of metabolically stressed APPswe /PS1dE9 mice. Neurobiol. Aging, 36,2984-2994。在黑暗週期之前1小時將兩個巢料(nestlets)（約 5 g）置於籠中，過夜後測定築巢分數和未撕碎的巢料的重量。築巢品質以 1-5 級分估評：1，顯示巢料的觸動不明顯；2 ，顯示巢料被部分撕碎散落在地板上；3 ，顯示巢料大部分被撕碎，但只有建立一扁平巢； 4，顯示巢是可識別但扁平的；5 ，顯示巢建成洞穴形。 The mice were evaluated for their nesting ability after 60 days of intragastric administration. See the previous literature: Yeh, CW et al., (2015), Impaired cognition and cerebral glucose regulation are associated with astrocyte activation in the parenchyma of metabolically stressed APPswe /PS1dE9 mice. Neurobiol. Aging , 36, 2984-2994. Two nestlets (about 5 g) were placed in the cage 1 hour before the dark cycle, and the nesting fraction and the weight of the unshredded nest were measured overnight. Nesting quality is estimated by 1-5 points: 1. It shows that the touch of the nest material is not obvious; 2, it shows that the nest material is partially shredded and scattered on the floor; 3, it shows that most of the nest material is shredded, but only established A flat nest; 4, showing that the nest is recognizable but flat; 5, showing the nest built into a cave shape.

圖 3顯示化合物 11和 37能夠恢復 APP/PS1 小鼠的築巢行為缺失。5 個月大的野生型小鼠口服給予載劑（WT），而 APP/PS1 小鼠在進行築巢試驗前 60 天給予口服載劑（V）以及化合物 11或 37。圖 3A 顯示築巢分數和圖 3B 顯示未撕碎的巢料的重量。所有 WT 或 APP/PS1 小鼠的結果以平均值 ± SD 表示。WT 和 APP/PS1 組之間的顯著差異如下所示：***代表p ＜ 0.001。化合物處理和對照組（V）之間的顯著差異如下所示：#代表p ＜ 0.05；##代表p ＜ 0.01； ###代表p ＜ 0.001。 Figure 3 shows that compounds 11 and 37 were able to restore nesting behavioral loss in APP/PS1 mice. Wild animals of 5 months old were orally administered with vehicle (WT), while APP/PS1 mice were given oral vehicle (V) and compound 11 or 37 60 days prior to the nesting test. Figure 3A shows the nesting score and Figure 3B shows the weight of the un-tashed nest. Results for all WT or APP/PS1 mice are expressed as mean ± SD. Significant differences between the WT and APP/PS1 groups are as follows: *** represents p < 0.001. Significant differences between compound treatment and control (V) are shown below: # represents p <0.05;## represents p <0.01;### represents p < 0.001.

本發明之築巢檢測，因築巢行為涉及廣泛的大腦區域網絡。結果顯示，APP/PS1 小鼠的築巢分數較低，而巢料的撕碎率比 WT 小鼠來得少，用化合物 11和 37處理的 APP/PS1 小鼠比用載劑處理（圖3A）表現出更高的築巢分數，並呈現更明顯的巢料撕碎行為（圖3B），顯示化合物 11和 37能夠恢復 APP/PS1 小鼠的築巢行為缺失。 The nesting detection of the present invention involves a wide network of brain regions due to nesting behavior. The results showed that the nesting score of APP/PS1 mice was lower, and the rate of shredded nests was less than that of WT mice. APP/PS1 mice treated with compounds 11 and 37 were treated with vehicle (Fig. 3A). It showed a higher nesting score and a more pronounced nest shredded behavior (Fig. 3B), indicating that compounds 11 and 37 were able to restore nesting behavior in APP/PS1 mice.

由前述可知，本發明所揭示的羥基官能化二苯乙烯（式(I)）化合物和羥基官能化 2-芳基苯并[b]呋喃（式(II)）化合物具有：(1) 對皮質神經元免於A β和麩胺酸介導的神經細胞毒性之神經保護活性，(2) 對混合膠細胞免於神經細胞毒性之抗神經發炎活性，和 (3) 抗氧化等活性。再者，本發明更進一步揭示活體測試，顯示本發明化合物能夠改善 APP/PS1 小鼠的築巢行為。由於氧化、發炎和神經興奮性毒性為加劇神經性疾病進展的重要因素，因此，本發明具有神經保護、抗神經發炎和抗氧化等活性之式(I)、式(II) 化合物可用於治療神經性疾病，該神經性疾病包括：腦部創傷、缺血性腦中風、痴呆症候群、癲癇、帕金森氏症及阿茲海默症等。由於神經性疾病如阿茲海默症目前尚無有效可供治療的藥物，因此，本發明提供一種治療神經性疾病之新穎方法，其具有高醫療價值與未來商業潛力。 It can be seen from the foregoing that the hydroxy-functionalized stilbene (formula (I)) compound and the hydroxy-functionalized 2-arylbenzo[b]furan (formula (II)) compound disclosed by the present invention have: (1) a cortex neuroprotective activity of neurons against a β and glutamate mediated toxicity of nerve cells, (2) from an anti-inflammatory activity neural toxicity of nerve cells, and (3) mixing anti-oxidation activity on glia. Furthermore, the present invention further reveals in vivo tests showing that the compounds of the invention are capable of improving nesting behavior in APP/PS1 mice. Since oxidative, inflammatory and neurotoxic excitotoxicity are important factors for aggravating the progression of neurological diseases, the present invention has the functions of neuroprotection, anti-neuritis and anti-oxidation, and the compound of formula (I) and formula (II) can be used for treating nerves. Sexual diseases, including brain trauma, ischemic stroke, dementia syndrome, epilepsy, Parkinson's disease, and Alzheimer's disease. Since neurological diseases such as Alzheimer's disease currently have no effective drugs for treatment, the present invention provides a novel method for treating neurological diseases with high medical value and future commercial potential.

以上實施方式本質上僅為輔助說明，且並不欲用以限制申請標的的實施例或該等實施例的應用或用途。在本文中，用語「例示性」代表「作為一實例、範例或說明」。本文中任一種例示性的實施方式並不必然可解讀為相對於其他實施方式而言為較佳或較有利者。The above embodiments are merely illustrative in nature and are not intended to limit the application or the application or use of the embodiments. In this document, the term "exemplary" means "as an example, example or description." Any of the illustrative embodiments herein are not necessarily to be construed as preferred or advantageous over other embodiments.

此外，儘管已於前述實施方式中提出至少一例示性實施例或比較例，但應瞭解本發明仍可存在大量的變化。同樣應瞭解的是，本文所述的實施例並不欲用以通過任何方式限制所請求的申請標的的範圍、用途或組態。相反的，前述實施方式將可提供本領域具有通常知識者一種簡便的指引以實施所述的一或多種實施例。再者，申請專利範圍包含已知的均等物及在本專利申請案提出申請時的所有可預見均等物。In addition, although at least one exemplary embodiment or comparative example has been presented in the foregoing embodiments, it is understood that the invention may be susceptible to numerous modifications. It should also be understood that the embodiments described herein are not intended to limit the scope, use, or configuration of the claimed subject matter in any manner. Rather, the foregoing embodiments are provided to provide a brief description of one or more embodiments. Furthermore, the scope of the patent application includes the known equivalents and all foreseeable equivalents in the application of the present application.

無no

圖 1A 至圖 1C 顯示羥基-官能化二苯乙烯和 2-芳基苯并[b]呋喃保護皮質神經元抗 A β和麩胺酸誘導的神經突損傷。圖 1A 顯示皮質神經元與不同化合物培養經暴露於 A β或麩胺酸後之染色照片；圖 1B 顯示存活細胞數量百分比的長條圖；圖 1C 顯示存活細胞螢光強度百分比的長條圖。 1A to 1C show that hydroxy-functionalized stilbene and 2-arylbenzo[b]furan protect cortical neurons against Aβ and glutamate-induced neurite damage. Figure 1A shows photographs of staining of cortical neurons with different compound cultures after exposure to Aβ or glutamate; Figure 1B shows a bar graph showing the percentage of viable cells; Figure 1C shows a bar graph showing the percentage of viable cell fluorescence intensity.

圖 2A 至圖 2F 顯示羥基-官能化二苯乙烯和 2-芳基苯并[b]呋喃保護神經突抗 A β和麩胺酸誘導的細胞死亡。圖 2A 顯示皮質神經元與不同化合物培養經暴露於 A β後之 MAP2 和 tau 的免疫細胞化學影像；圖 2B 顯示皮質神經元與不同化合物培養經暴露於麩胺酸後之 MAP2 和 tau 的免疫細胞化學影像；圖 2C、圖 2E 顯示 MAP2 的螢光強度的長條圖；圖 2D、圖 2F 顯示 tau 蛋白的螢光強度的長條圖。 2A to 2F show that hydroxy-functionalized stilbene and 2-arylbenzo[b]furan protect neurites against Aβ and glutamate-induced cell death. 2A shows cortical neurons to different compounds upon exposure to the culture of the A β MAP2 and tau chemical imaging of immune cells; FIG. 2B shows the cortical neurons to different compounds upon exposure to the culture after the glutamate MAP2 and tau immune cells Chemical image; Fig. 2C and Fig. 2E show the bar graph of the fluorescence intensity of MAP2; Fig. 2D and Fig. 2F show the bar graph of the fluorescence intensity of tau protein.

圖 3A、圖 3B 顯示不同化合物恢復 APP / PS1 小鼠的築巢行為缺失。圖 3A 顯示築巢分數的長條圖；圖 3B 顯示未撕碎的巢料重量圖。Figure 3A and Figure 3B show that different compounds restored the nesting behavior of APP/PS1 mice. Figure 3A shows a bar graph of the nesting score; Figure 3B shows the un-shredded nest weight map.

Claims

一種式(I)化合物或其醫藥上可接受之鹽類用於製備治療神經性疾病之藥物的用途，其中，R¹為氫或CH=CHCO₂R¹⁰；R²為氫、鹵素、(C₁-C₈)烷氧基、醛基或CH=CHCO₂R¹⁰；R³為氫、(C₁-C₈)烷氧基或CH=CHCO₂R¹⁰；R⁴為氫、羥基、(C₁-C₈)烷氧基或CH=CHCO₂R¹⁰；R⁵為氫、羥基或(C₁-C₈)烷氧基；R⁶為氫、鹵素或CH=CHCO₂R¹⁰；R⁷為氫、羥基或(C₁-C₈)烷氧基；R⁸及R⁹係各自獨立為氫、羥基或(C₁-C₈)烷氧基，或R⁸、R⁹及與其鍵結之碳原子共同定義二氧戊環；且R¹⁰為氫或(C₁-C₆)烷基，其中式(I)化合物或其醫藥上可接受之鹽類係選自以下任一者：3-(4-((E)-3,4,5-三羥基苯乙烯基)苯基)丙烯酸(E)-乙酯；3-(3-((E)-3,4,5-三羥基苯乙烯基)苯基)丙烯酸(E)-乙酯；以及 3-(3,4-二甲氧基苯乙烯基)-4-羥基-5-甲氧基苯甲醛。 Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a neurological disorder, Wherein R ¹ is hydrogen or CH=CHCO ₂ R ¹⁰ ; R ² is hydrogen, halogen, (C ₁ -C ₈ ) alkoxy, aldehyde or CH=CHCO ₂ R ¹⁰ ; R ³ is hydrogen, (C ₁ -C ₈ ) alkoxy or CH=CHCO ₂ R ¹⁰ ; R ⁴ is hydrogen, hydroxy, (C ₁ -C ₈ ) alkoxy or CH=CHCO ₂ R ¹⁰ ; R ⁵ is hydrogen, hydroxy or (C ₁ -C ₈ ) alkoxy; R ⁶ is hydrogen, halogen or CH=CHCO ₂ R ¹⁰ ; R ⁷ is hydrogen, hydroxy or (C ₁ -C ₈ ) alkoxy; R ⁸ and R ⁹ are each independently hydrogen a hydroxy or (C ₁ -C ₈ )alkoxy group, or R ⁸ , R ⁹ and a carbon atom bonded thereto, together define a dioxolane; and R ¹⁰ is hydrogen or (C ₁ -C ₆ )alkyl, Wherein the compound of the formula (I) or a pharmaceutically acceptable salt thereof is selected from any one of the following: 3-(4-((E)-3,4,5-trihydroxystyryl)phenyl)acrylic acid ( E)-ethyl ester; 3-(3-((E)-3,4,5-trihydroxystyryl)phenyl)acrylic acid (E)-ethyl ester; and 3-(3,4-dimethoxy Styryl)-4-hydroxy-5-methoxybenzaldehyde.

如請求項1所述之用途，其中該神經性疾病係選自於由腦部創傷、缺血性腦中風、痴呆症候群、癲癇、帕金森氏症及阿茲海默症所組成之群組。 The use according to claim 1, wherein the neurological disease is selected from the group consisting of brain trauma, ischemic stroke, dementia syndrome, epilepsy, Parkinson's disease, and Alzheimer's disease.

如請求項2所述之用途，其中該神經性疾病為阿茲海默症。 The use of claim 2, wherein the neurological disease is Alzheimer's disease.

一種式(II)化合物或其醫藥上可接受之鹽類用於製備治療神經性疾病之藥物的用途，其中，R¹為氫或鹵素；R²為氫、鹵素或CH=CHCO₂R¹⁰；R³為氫或羥基；R⁴為氫、羥基或(C₁-C₈)烷氧基；R⁵為氫或羥基；R⁶及R⁷係各自獨立為氫或羥基，或R⁶及R⁷共同定義-OCH₂O-；R⁸為氫或羥基；R⁹為氫、鹵素或CH=CHCO₂R¹⁰；且 R¹⁰為氫或(C₁-C₆)烷基，其中式(II)化合物或其醫藥上可接受之鹽類係選自以下任一者：3-(2-(苯并呋喃-2-基)-4,5-二羥基苯基)丙烯酸(E)-乙酯；3-(7-羥基-2-(3,4,5-三羥基苯基)苯并呋喃-5-基)丙烯酸(E)-乙酯；5-(苯并呋喃-2-基)-4-溴苯-1,2,3-三醇；4-(5-溴-7-羥基苯并呋喃-2-基)苯-1,2-二醇；以及4-(4-溴-7-羥基苯并呋喃-2-基)苯-1,2-二醇。 Use of a compound of formula (II) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a neurological disorder, Wherein R ¹ is hydrogen or halogen; R ² is hydrogen, halogen or CH=CHCO ₂ R ¹⁰ ; R ³ is hydrogen or hydroxy; R ⁴ is hydrogen, hydroxy or (C ₁ -C ₈ )alkoxy; R ⁵ Is hydrogen or hydroxy; R ⁶ and R ⁷ are each independently hydrogen or hydroxy, or R ⁶ and R ^{7 are} together defined as -OCH ₂ O-; R ⁸ is hydrogen or hydroxy; R ⁹ is hydrogen, halogen or CH=CHCO ₂ R ¹⁰ ; and R ¹⁰ is hydrogen or (C ₁ -C ₆ )alkyl, wherein the compound of the formula (II) or a pharmaceutically acceptable salt thereof is selected from any one of the following: 3-(2-(benzo) (E)-ethyl ester of furan-2-yl)-4,5-dihydroxyphenyl)acrylate; 3-(7-hydroxy-2-(3,4,5-trihydroxyphenyl)benzofuran-5 -yl)acrylic acid (E)-ethyl ester; 5-(benzofuran-2-yl)-4-bromobenzene-1,2,3-triol; 4-(5-bromo-7-hydroxybenzofuran -2-yl)benzene-1,2-diol; and 4-(4-bromo-7-hydroxybenzofuran-2-yl)benzene-1,2-diol.

一種式(II)化合物或其醫藥上可接受之鹽類用於製備治療神經性疾病之藥物的用途，其中，R¹為氫、F、Cl或Br；R²及R⁹係各自獨立為氫或CH=CHCO₂R¹⁰；R³及R⁵係各自獨立為氫；R⁴、R⁶及R⁸係各自獨立為氫或羥基；R⁷為羥基；且R¹⁰為氫或乙基。 Use of a compound of formula (II) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a neurological disorder, Wherein R ¹ is hydrogen, F, Cl or Br; R ² and R ⁹ are each independently hydrogen or CH=CHCO ₂ R ¹⁰ ; R ³ and R ⁵ are each independently hydrogen; R ⁴ , R ⁶ and R ⁸ Each is independently hydrogen or hydroxy; R ⁷ is hydroxy; and R ¹⁰ is hydrogen or ethyl.

如請求項5所述之用途，其中該神經性疾病係選自於由腦部創傷、缺血性腦中風、痴呆症候群、癲癇、帕金森氏症及阿茲海默症所組成之群組。 The use according to claim 5, wherein the neurological disease is selected from the group consisting of brain trauma, ischemic stroke, dementia syndrome, epilepsy, Parkinson's disease, and Alzheimer's disease.

如請求項6所述之用途，其中該神經性疾病為阿茲海默症。 The use of claim 6, wherein the neurological disease is Alzheimer's disease.