TW490462B - 2-Phenyl-4-quinazolinones compounds, 2-phenyl-4-alkoxy-quinazoline compounds and their pharmaceutical compositions - Google Patents

Abstract

Two series of 6,7,2',3',4',5'-substituted 2-phenyl-4-quinazolinones and 6,2',3',4',5'-substituted 2,3-dihydro-2-phenyl-4-quinazolinones are synthesized and evaluated for cytotoxicity against a panel of human tumor cell lines, such as epidermoid carcinoma of the nasopharynx (KB), lung carcinoma (A-549), ileocecal carcinoma (HCT-8), breast cancer (MCF-7), melanoma (SKMEL-2), ovarian cancer (1A9), glioblastoma (U-87-MG), bone (HOS), P-gp-expressing epidermoid carcinoma of the nasopharynx (KB-VIN), and prostate cancer (PC3) cell lines, and some of the compounds are found potent. The present invention also synthesizes 2-phenyl-4-alkoxy-quinazoline compounds, wherein some of the compounds exhibit antiplatelet activity.

Description

經濟部智慧財產局員工消費合作社印製 490462 A7 __ B7 五、發明說明（） 發明背景 微小管是維持細胞型態的重要骨架之一，同時在細胞 ***及染色質的傳遞上也扮演著重要角色，因此，微小管 成爲開發抗癌藥物的重要靶的。目前臨床上使用的有絲分 裂抑制劑包括長舂花生物鹼\上標數字代表列於說明書末 尾的參考文獻）及類紫杉醇2，分別抑制微小管聚合及促進 微小管聚合。秋水仙鹼3,4也是一著名的有絲***抑制劑’ 然而毒性太強不適用於抗癌之臨床用途，臨床上只用作痛 風之治療。 近年來發明人所屬的硏究室設計、合成了如下所示的 三大類的雜環酮：2-苯基-4-口查啉酮（PQ)4·7、2,3-雙氫-2-苯基-4-口2唑啉酮（DHPQ) 8及2-苯基-1，8-二嘹啶-4-酮（PN) 8-1Q，作爲新型的有絲***抑制劑並建立了初步的結構與活 性關係。Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 490462 A7 __ B7 V. Description of the invention () Background of the invention The microtube is one of the important skeletons to maintain the cell type, and also plays an important role in cell division and chromatin transmission. Therefore, microtubules have become important targets for the development of anticancer drugs. The mitotic inhibitors currently used in clinical practice include scopolamine alkaloids \ superscript numbers refer to the references listed at the end of the description) and paclitaxel-like 2 to inhibit microtubule polymerization and promote microtubule polymerization, respectively. Colchicine 3,4 is also a well-known mitotic inhibitor ’. However, it is too toxic for clinical use in anti-cancer, and is only used clinically for the treatment of gout. In recent years, the research laboratory to which the inventors belong has designed and synthesized three types of heterocyclic ketones as shown below: 2-phenyl-4-cholazolinone (PQ) 4.7, 2,3-dihydro-2 -Phenyl-4-oxo-2azolinone (DHPQ) 8 and 2-phenyl-1,8-dioxin-4-one (PN) 8-1Q, as a new type of mitotic inhibitor and established preliminary Structure-activity relationship.

綜觀這三類的雜環酮，在結構上都持有A、C兩個芳香 環，且在兩環之間係以***另一8環或碳氫鍵橋相連接， 但仍有少許結構差異存在其間。 在PQ類化合物中，若在A環的6 —位及C環的3’-位上有未 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） ------------------<—tr--------- (請先閱讀背面之注意事項再填寫本頁) 490462 A7 B7 五、發明說明（ 鍵結電子對的官能基存在，如：-〇CH3、-0CH20-、-NRR’、 Cl、FiPQr,)等，具有優越之細胞致毒活性，這兩個官能基 之間的距離約爲10〜ΠΑ，且可能是作爲質子受體而與微管 鍵結，因此，這兩個官能基在PQ類化合物的活性上具有顯 著之貢獻。在DHPQ類化合物中8，6-位及3’-位取代基 (DHPQO同樣也扮演著決定性的角色。然而，在PN類化合 物中，當3’-位取代基固定（如：〇CH3)，6-位取代基對其 活性的重要性似乎就不那麼明顯了，例如：Η (PN-1)、CH3 (PN-2)及 Cl (PN-3)。PQ1 至 PQ6，ΟΗΡ(^&ΡΝ-1 至 PN-3等化 合物被示於下：Looking at these three types of heterocyclic ketones, they have two aromatic rings, A and C, and they are connected by inserting another 8 ring or carbon-hydrogen bridge between the two rings, but there are still some structural differences. Exist in between. In the PQ compounds, if there is a paper size on the 6-position of the A ring and the 3'-position of the C ring, the Chinese paper standard (CNS) A4 specification (210 X 297 public love) applies ------ ------------ < -tr --------- (Please read the precautions on the back before filling this page) 490462 A7 B7 V. Description of the invention (bonding electronic pairs Functional groups, such as: -〇CH3, -0CH20-, -NRR ', Cl, FiPQr, etc., have superior cytotoxic activity, the distance between these two functional groups is about 10 ~ ΠΑ, and They may be bonded to microtubules as proton acceptors. Therefore, these two functional groups have a significant contribution to the activity of PQ compounds. In DHPQ compounds, the 8,6- and 3'-position substituents (DHPQO also plays a decisive role. However, in PN compounds, when the 3'-position substituent is fixed (such as: 0CH3) The importance of the 6-position substituent for its activity seems less obvious, for example: Η (PN-1), CH3 (PN-2), and Cl (PN-3). PQ1 to PQ6, ΟΗΡ (^ & Compounds such as PN-1 to PN-3 are shown below:

Ry ΟRy Ο

經濟部智慧財產局員工消費合作社印製Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

PQ 1 R6 = OCH3, R3 = 〇CH3 PQ2 R6,R7=OCH3，R3，= 〇CH3 PQ 3 R6 = F，R3. = OCH3 PQ4 R6 = Cl,R3，= 〇CH3 PQ 5 R6，R7= 0CH20，Ry = NRR· PQ 6 ^ , R7= 0CH20 , R3 = F PN PN1 匕=H PN2 匕=013 PN 3 匕=Cl ------------^ >. —I— i--------. (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 490462 A7 __ B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（PQ 1 R6 = OCH3, R3 = 〇CH3 PQ2 R6, R7 = OCH3, R3, = 〇CH3 PQ 3 R6 = F, R3. = OCH3 PQ4 R6 = Cl, R3, = 〇CH3 PQ 5 R6, R7 = 0CH20, Ry = NRRPQ 6 ^, R7 = 0CH20, R3 = F PN PN1 Dagger = H PN2 Dagger = 013 PN 3 Dagger = Cl ------------ ^ >. —I— i- -------. (Please read the precautions on the back before filling this page) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 490462 A7 __ B7 Employees of Intellectual Property Bureau, Ministry of Economic Affairs Printed by Consumer Cooperatives

0CH3 2,3-雙氫-2-苯基-4-战唑啉酮（DHPQZ)的抗癌活性在 1970年左右已有報導1μ2。最近又以NCI之人類腫瘤細胞重 新評估，發現其作用機轉類似秋水仙鹼，也是有效的微管 聚合抑制劑13。同時，2-苯乙烯唑啉-4-酮（SQZ) m5也被 證實是有效的微管聚合抑制劑。DHPQZ及SQZ化合物的結 構被示於下：The anti-cancer activity of 0CH3 2,3-dihydro-2-phenyl-4-oxazolinone (DHPQZ) has been reported around 1970, 1 μ2. Recently, it was re-evaluated with human tumor cells of NCI and found that its mechanism of action is similar to colchicine and it is also an effective microtubule polymerization inhibitor13. At the same time, 2-styrazolin-4-one (SQZ) m5 has also been proven to be an effective microtubule polymerization inhibitor. The structures of the DHPQZ and SQZ compounds are shown below:

R3,R3,

SQZ (請先閱讀背面之注意事項再填寫本頁) -裝 丨 I I 訂 ί- I------ ·#_SQZ (Please read the notes on the back before filling this page) -Install 丨 I I Order ί- I ------ · # _

DHPQZ 6 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 490462 A7 B7 五、發明說明（） 發明要旨 本發明合成了一系列具下式⑴至（IV)的化合物： (I) (II) (III)DHPQZ 6-This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 490462 A7 B7 V. Description of the invention () Summary of the invention The present invention synthesizes a series of compounds with the following formulae (I) to (IV): (I) (II) (III)

------------•裝------1 丨訂·--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 (IV)------------ • Equipment ------ 1 丨 Order · --------- (Please read the notes on the back before filling this page) Intellectual Property of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperatives (IV)

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

經濟部智慧財產局員工消費合作社印製 式中： R2，，R3，，R4,及 R5,獨立地爲 H，（CH2)nCH3，OH， 〇(CH2)nCH3, X，或 NR8R9，其中 n = 〇 〜4 的整數，x爲 ρ，ci， 或Br*，及118及119獨立地爲η或（CH2)nCH3，其中n =〇〜4的整 數； R 爲（CH2)nCHj(CH2)nCOO(CH2)nCH3,其中n的定義同 上；及 R6及 R7 獨立地爲 H，（CH2)nCH3, OH，0(CH2)nCH3, X， NR8R9，n；^]，:或心及心一起爲 _OCH2〇·，其 中η，X，118及119的定義同上。 本發明所合成的式（I)至（IV)化合物中的部分化合物在 經對抗人類腫瘤細胞之致毒活性及做爲微管聚合抑制劑的 評估後，發現具有相當優異的活性，因此有很高的潛能被 開發作爲用於治療癌症的醫藥組合物。 本發明所合成的式（I)至（IV)化合物中的部分化合物也 被發現具有明顯之血小板凝集抑制作用。 發明之詳細說明 本發明的一方案合成了一系列如下式（I)的 6,7,2，，3，，4，，5，-取代2-苯基-4-口$唑啉酮類衍生物： 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ^------^--------- (請先閱讀背面之注意事項再填寫本頁) 490462 A7 B7 五、發明說明（In the printed format of the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs: R2, R3, R4, and R5, independently H, (CH2) nCH3, OH, 〇 (CH2) nCH3, X, or NR8R9, where n = An integer of 0 to 4, x is ρ, ci, or Br *, and 118 and 119 are independently η or (CH2) nCH3, where n = an integer of 0 to 4; R is (CH2) nCHj (CH2) nCOO ( CH2) nCH3, where n has the same definition as above; and R6 and R7 are independently H, (CH2) nCH3, OH, 0 (CH2) nCH3, X, NR8R9, n; ^], or the heart and the heart together are _OCH2 〇, wherein η, X, 118 and 119 have the same definitions as above. Some of the compounds of the formulae (I) to (IV) synthesized in the present invention have fairly excellent activity after being evaluated against human tumor cells for their toxic activity and as inhibitors of microtubule polymerization, so they have very good activity. High potential is developed as a pharmaceutical composition for treating cancer. Some of the compounds of the formulae (I) to (IV) synthesized in the present invention were also found to have a significant platelet aggregation inhibitory effect. DETAILED DESCRIPTION OF THE INVENTION One embodiment of the present invention synthesizes a series of 6,7,2,3,4,5, -substituted 2-phenyl-4-oxazolone derivatives of formula (I) Material: This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) ^ ------ ^ --------- (Please read the precautions on the back before filling this page ) 490462 A7 B7 V. Description of the invention (

⑴ 其中R2，，R3，，R4’，、RjR7的定義同上。 本發明的另〜方案合成了-系列如下式（II)的 6’7’2 ’3 ’4，5 -取代2,3_雙氫_2·苯基-4· 口查唑啉酮類衍生 物··⑴ where R2 ,, R3 ,, R4 ', and RjR7 are as defined above. In another aspect of the present invention, a series of 6'7'2'3'4,5 -substituted 2,3_dihydro_2 · phenyl-4 · ketazolinone derivatives of the following formula (II) were synthesized: Things ...

經濟部智慧財產局員工消費合作社印製 (Π) 其中R2’，R3，，r4，，R5，，心及心的定義同上。 本發明的另〜方案合成了 一系列如下式（III)的 3,6,7,2’，3’，4’，5、取代2-苯基-4-口±唑啉酮類衍生物及 6,7,2，3，4，5 ·取代-2_苯基-4_院氧基坐啉類衍生物 (IV): -9 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------•裝------1 訂--------- (請先閱讀背面之注意事項再填寫本頁) 490462 A7 B7 五、發明說明（）Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (Π) where R2 ’, R3 ,, r4 ,, R5, and the definition of mind and mind are the same as above. Another series of the present invention synthesizes a series of 3,6,7,2 ', 3', 4 ', 5, substituted 2-phenyl-4-methyl ± azolinone derivatives of the following formula (III) and 6,7,2,3,4,5 · Substituted-2_phenyl-4_coxoxoline derivatives (IV): -9-This paper is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) ------------ • Install ------ 1 Order --------- (Please read the precautions on the back before filling in this page) 490462 A7 B7 V. Description of the invention ()

(III) (IV) 其中 R2，，R3，，R4，，R5，，R3, R，R6 及 R7 的定義同上。 本發明的又一方案提供一種用於治療癌症的醫藥組合 物，包含有效治療量的上述之式（1)或式（π)化合物或其藥 學上可接受的鹽作爲活性成份，和與之混合的用於該活性 成份的藥學上可接受的載體或稀釋劑。 - 本發明的又一方案提供一種用於抑制血小板凝集的醫 藥組合物，包含有效治療量的上述之式（111)或式（IV)化合 物或其藥學上可接受的鹽作爲活性成份，和與之混合的用 於該活性成份的藥學上可接受的載體或稀釋劑。 ------------裝丨 I--I J--訂 t-------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）(III) (IV) where R2 ,, R3 ,, R4 ,, R5 ,, R3, R, R6 and R7 are as defined above. Still another aspect of the present invention provides a pharmaceutical composition for treating cancer, comprising an effective therapeutic amount of the compound of the above formula (1) or formula (π) or a pharmaceutically acceptable salt thereof as an active ingredient, and mixing it with A pharmaceutically acceptable carrier or diluent for the active ingredient. -Another embodiment of the present invention provides a pharmaceutical composition for inhibiting platelet aggregation, comprising a therapeutically effective amount of the compound of the above formula (111) or formula (IV) or a pharmaceutically acceptable salt thereof as an active ingredient, and A pharmaceutically acceptable carrier or diluent for the active ingredient is mixed. ------------ Installation 丨 I--I J--Order t -------- (Please read the precautions on the back before filling this page) Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs The paper size printed by the consumer cooperative is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm)

、發明說明（ 經濟部智慧財產局員工消費合作社印製 依照流程1 _4的合成方法，合成了J，5-取代:2ϋ苯甲 醯胺（3, 10-11，16, 25-29)。如流程1所示，將5-氟胺基苯 甲酸（1)依次與氯化亞磺醯基及氨反應，即可得到5_·_2-胺基苯甲醯胺（3)。在流程2中，以4,5-取代-2-硝基苯甲酸 (4, 5)爲起始原料，將-COOH官能基仿照流程1之合成方法 先變成-CONH2，接著再將2-Ν02還原爲-Νη2，即可得到心 甲氧基及4,5-二甲氧基-2-胺基苯甲醯胺（10,11)。4,5-亞甲 二氧二基-2-胺基苯甲醯胺（16)則是以4,5-亞甲二氧二基-2-硝基苯甲醛（12)爲起始原料，先將-CHO取代基氧化爲-COOH (13)，再以相同的方法合成之（流程3)。在流程4中， 將5 -氯-2 -硝基苯甲酸（17)的-C Ο Ο Η官能基仿照流程1之合 成方法先變成-CONH2 (19)，接著以各種不同的二級胺在 5-C1取代基上進行親核性的取代反應，最後再進行氫化反 應將2-N02還原爲-NH2，即可得到6-烷基胺基-2-胺基苯甲 醯胺（25-29)。 如流程5所示，將上述化合物（3, 10_11，16, 2 5-2 9)分別 與甲氧苯甲醛（32-40)在N，N-二甲基乙醯胺（DM Ac)溶媒中 及亞硫酸氫鈉的存在下，經過熱脫水環化反應/去氫反應， 即可得到產率頗高的一系列取代-2-苯基-4- Π查唑啉酮類衍 生物（41-59)。 依照流程6的合成方法’合成一系列2，3 -雙氫-2 -苯基-4-崆唑啉酮類衍生物（60-68)，以2,3-雙氫-2-(3’-甲氧基苯 基）-4-咬唑啉酮（61)爲例說明如下·· 當2-胺基苯甲醯胺（30)與3-甲氧基苯甲醛（34)在N，N- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ^------11 -------- (請先閱讀背面之注音？事項再填寫本頁) 490462 A7 B7 五、發明說明（） 9 (請先閱讀背面之注意事項再填寫本頁) 二甲基乙醯胺溶媒中，溫度80°C下反應1小時，經管柱層析 分離後，可得到化合物61(融點：148-15CTC)及43(融點： 177-179°(：)，產率分別爲75%及15°/(>。 化合物43的結構經紅外線光譜、核磁共振光譜及質譜 等光譜分析的結果可以確認爲2-(3甲氧基苯基）-4-适唑 啉酮。而化合物61依其質譜（m/z 254, M + )及元素分析的結 果，可將其分子式定爲C15H14N202，與預期的2,3-雙氫-2-(3’-甲氧基苯基）-4-遗唑啉酮相吻合。在化合物61的核磁共 振氫譜中，出現（5 5.73 (H-2)、7·15 (NrH)及 8.34 (N3-H) 的訊號，在2D HMBC光譜中，也出現H-2與C-4 ( (5 1 63.77)、 C-8a (δ 147.98)、C-2’（<5 119.11)、C-6,（5 112.75)間的長 距離偶合，因此，這些光譜分析的結果可以將化合物61確 定爲2,3-雙氫·2-(3’-甲氧基苯基）-4-咬唑啉酮。 經濟部智慧財產局員工消費合作社印製 爲了提高化合物61的產率，將反應條件做調整以減少 化合物61變成化合物43的去氫化反應（dehydrogenation)。 首先，我們將反應溫度降至25 土 ，並延長反應時間爲4 小時，但經薄層層析檢查，其反應性不佳，仍有可觀量的 原料（30, 34)殘留反應液中。因此，我們再次於25土 2°C的 溫度下並加入催化劑對甲苯磺酸進行反應，結果反應於30 分鐘內完成，得到較高產率（89.0%)的61及較低產率（4.0%) 的43。於是，便以此反應條件合成化合物60及62-68，均得 到較高產率的預期化合物。 化合物60-68合成後是以外消旋混合物的狀態存在， 目前尙未進行其單離工作，一旦有特別優越的生物活性被 • 12 - 本紙張尺I適用中國國家標準（CNS)A4規格(21G X 297公爱) "一 一 490462 A7 B7___ 五、發明說明（1Q ) 發現時，我們將進一步單離出具有光學活性的異構物。 (請先閱讀背面之注意事項再填寫本頁) 我們同時也以在苯環上具有未鍵結電子對的取代基 (如：-OCH3、-0CH20-、-NRR’）的苯甲醯胺（10-11，16, 25-29) 爲起始原料，但最終卻未能如預期的得到2,3-雙氫產物， 在此反應過程中，由薄層層析的檢查顯示有預期的2,3-雙 氫產物存在，但在後續處理過程中（如··管柱層析、再結晶） 即自發性的進行去氫化反應而變成相對應的化合物（52_ 59) 〇 最後，我們以5-氟苯甲醯胺（3)爲起始原料，嘗試合成 2,3-雙氫-6-氟-2-苯基-4-α^唑啉酮，雖然F與C1是屬於同一 族的具拉電子能力的元素，但其安定性比2,3-雙氫-6-氯-2-苯基-4-唑啉酮差了許多，最終還是自發性的進行去氫化 反應而變成相對應的化合物51。 經濟部智慧財產局員工消費合作社印製 綜合以上結果，我們可以得到一個結論：在2,3-雙氫 -2-苯基-4-Π查唑啉酮的6-或7-位上有給電子基團或氟原 子存在時，很容易進行自發性的去氫化反應，因此，合成 這些化合物並測定其細胞致毒活性幾乎是不可能的，因爲 即使在做活性評估時，其在使用的溶媒中的安定性也是一 大問題。 依流程7的合成方法合成了取代2-苯基-4-烷氧基-口查 唑啉類衍生物（69-76)及取代2-苯基-4- π查唑啉類衍生物 (77-81)。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 490462 A7 B7Description of the invention (Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs in accordance with the synthetic method of Procedure 1_4, J, 5-substituted: 2ϋbenzamide (3, 10-11, 16, 25-29). As shown in Scheme 1, 5-fluoroaminobenzoic acid (1) is sequentially reacted with sulfenyl chloride and ammonia to obtain 5_ · _2-aminobenzamide (3). In Scheme 2, Using 4,5-substituted-2-nitrobenzoic acid (4, 5) as the starting material, the -COOH functional group was first changed to -CONH2 following the synthetic method of Scheme 1, and then 2-N02 was reduced to -Nη2. You can get cardiomethoxy and 4,5-dimethoxy-2-aminobenzamide (10,11). 4,5-Methylenedioxodi-2-aminobenzamide (16) using 4,5-methylenedioxydiyl-2-nitrobenzaldehyde (12) as the starting material, the -CHO substituent is first oxidized to -COOH (13), and then the same method Synthesized (Scheme 3). In Scheme 4, the -C Ο Ο Η functional group of 5-chloro-2-nitrobenzoic acid (17) was first changed to -CONH2 (19) following the synthesis method of Scheme 1, and then Various different secondary amines undergo nucleophilic substitution reactions on 5-C1 substituents, and finally undergo hydrogenation reaction By reducing 2-N02 to -NH2, 6-alkylamino-2-aminobenzamide (25-29) can be obtained. As shown in Scheme 5, the above compound (3, 10-11, 16, 2 5-2 9) After thermal dehydration cyclization / removal with methoxybenzaldehyde (32-40) in N, N-dimethylacetamide (DM Ac) solvent and the presence of sodium bisulfite, respectively By hydrogen reaction, a series of substituted 2-phenyl-4-II-chazolinone derivatives (41-59) can be obtained with a high yield. Follow the synthetic method of Scheme 6 to synthesize a series of 2, 3- Dihydro-2 -phenyl-4-oxazolinone derivatives (60-68), 2,3-bishydro-2- (3'-methoxyphenyl) -4-tetrazolinone (61) is explained as an example as follows: · When 2-aminobenzamide (30) and 3-methoxybenzaldehyde (34) are in N, N- This paper size applies the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) ^ ------ 11 -------- (Please read the phonetic on the back? Matters before filling out this page) 490462 A7 B7 V. Description of the invention () 9 (Please read first Note on the back page, please fill in this page again) In dimethylacetamide solvent, react for 1 hour at 80 ° C. After separation by column chromatography, you can get Compound 61 (melting point: 148-15CTC) and 43 (melting point: 177-179 ° (:), yields were 75% and 15 ° / (>. The structure of compound 43 was determined by infrared spectrum, nuclear magnetic resonance spectrum, and As a result of spectral analysis such as mass spectrometry, it was confirmed that it was 2- (3methoxyphenyl) -4-shizolinone. According to the mass spectrum (m / z 254, M +) and elemental analysis of compound 61, the molecular formula of compound 61 can be determined as C15H14N202, and the expected 2,3-dihydro-2- (3'-methoxyphenyl) ) -4-estazolinone coincides. In the NMR spectrum of compound 61, the signals (5 5.73 (H-2), 7.15 (NrH), and 8.34 (N3-H) appeared, and in the 2D HMBC spectrum, H-2 and C- Long distance coupling between 4 ((5 1 63.77), C-8a (δ 147.98), C-2 '(< 5 119.11), C-6, (5 112.75), therefore, the results of these spectral analyses can Compound 61 was identified as 2,3-dihydro · 2- (3'-methoxyphenyl) -4-tetrazolinone. Printed by the Consumer Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs in order to increase the yield of compound 61, The reaction conditions were adjusted to reduce the dehydrogenation of compound 61 into compound 43. First, we reduced the reaction temperature to 25 ° C and extended the reaction time to 4 hours, but the reactivity was not checked by TLC. There is still a considerable amount of raw materials (30, 34) remaining in the reaction solution. Therefore, we added the catalyst at a temperature of 25 ° C to 2 ° C and reacted with toluenesulfonic acid. As a result, the reaction was completed within 30 minutes. The higher yield (89.0%) of 61 and the lower yield (4.0%) of 43. Therefore, compounds 60 and 62-68 were synthesized under these reaction conditions. A higher yield of the expected compound is obtained. Compound 60-68 exists as a racemic mixture after synthesis. At present, it has not been isolated, and once it has a particularly superior biological activity, it is suitable for the country of China. Standard (CNS) A4 specification (21G X 297 public love) " One-490490 A7 B7___ V. Description of the invention (1Q) When found, we will further separate the optically active isomers. (Please read the back of the first Note: Please fill in this page again.) We also use benzamidine (10-11,16,16,11), which has substituents (such as: -OCH3, -0CH20-, -NRR ') on the benzene ring. 25-29) as the starting material, but ultimately failed to obtain the 2,3-dihydro product as expected. During this reaction, inspection by thin layer chromatography showed that the expected 2,3-dihydro product was expected. Existence, but during subsequent processing (such as column chromatography, recrystallization), the dehydrogenation reaction spontaneously becomes the corresponding compound (52_59). Finally, we use 5-fluorobenzidine (3) As a starting material, try to synthesize 2,3-dihydro-6-fluoro-2-phenyl-4-α ^ azole Although the F and C1 belong to the same group with electron-withdrawing ability, its stability is much worse than that of 2,3-dihydro-6-chloro-2-phenyl-4-azolinone. It also spontaneously undergoes a dehydrogenation reaction to become the corresponding compound 51. Based on the above results printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, we can draw a conclusion: at 2,3-dihydro-2-phenyl-4 When an electron-donating group or a fluorine atom is present at the 6- or 7-position of -IIchazolinone, it is easy to perform a spontaneous dehydrogenation reaction. Therefore, it is almost impossible to synthesize these compounds and determine their cytotoxicity. Because even when doing activity evaluation, its stability in the solvent used is a big problem. According to the synthetic method of Scheme 7, the substituted 2-phenyl-4-alkoxy-chazazolin derivatives (69-76) and the substituted 2-phenyl-4-πchazolin derivatives (77 -81). This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 490462 A7 B7

1111

F^^/COCl nh2 sochM^^ , I reflux 2 NH3，benzene· R.T.F ^^ / COCl nh2 sochM ^^, I reflux 2 NH3, benzene · R.T.

流程2· XOC1Process 2 · XOC1

.COOH s〇C|2 9 benzene 、N02 reflux 6,7 NH3 , benzene -----------裝--------—訂 *-------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 、N〇2 8,9 H2 / Pd-C, methanol.COOH s〇C | 2 9 benzene, N02 reflux 6,7 NH3, benzene ----------- installation ---------- order * -------- ( (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, No. 02, 9 H2 / Pd-C, methanol

4.6.8.10 R6 = 〇CH3 ^R7 = H 5.7.9.11 R6 = R7 = 〇CH3 -14 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 490462 A7 B7 五、發明說明（i2 ) 流程3.4.6.8.10 R6 = 〇CH3 ^ R7 = H 5.7.9.11 R6 = R7 = 〇CH3 -14-This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 490462 A7 B7 V. Description of the invention ( i2) Flow 3.

Cr〇3 -pyridine-water reflux 13Cr〇3 -pyridine-water reflux 13

.COOH N〇2 .COC1 SOCI2 , benzene -^ reflux 0 一 ^ 、no2 14 NH3 , benzene R.T..COOH N〇2 .COC1 SOCI2, benzene-^ reflux 0 a ^, no2 14 NH3, benzene R.T.

〇、^\^CONH2/ I I〇, ^ \ ^ CONH2 / I I

H2/Pd-C p^^\^CONH2 methanol N〇2 nh2 15 16 -----------裝------1—訂-------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -15 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 490462 A7 B7 五、發明說明（13 ) 流程4. CK^/C〇〇H s〇ci25benzene C^^COCl 、N〇2 reflux 17 18 N02 NH3，benzene R.T. CK^x.CONH2H2 / Pd-C p ^^ \ ^ CONH2 methanol N〇2 nh2 15 16 ----------- install ------ 1-order -------- (please first Read the notes on the back and fill in this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -15 The paper size is applicable to the Chinese National Standard (CNS) A4 (210 x 297 mm) 490462 A7 B7 V. Description of the invention (13 ) Scheme 4. CK ^ / C〇〇 s〇ci25benzene C ^^ COCl, No 2 reflux 17 18 N02 NH3, benzene RT CK ^ x.CONH2

19 HNRR' NO2 DMF, 110° R，RN、^t\^CONH2 20-24 H2/Pd-C methanol ---- ^^nh2 25 - 2919 HNRR 'NO2 DMF, 110 ° R, RN, ^ t \ ^ CONH2 20-24 H2 / Pd-C methanol ---- ^^ nh2 25-29

20,25 NRR1 = =n：CH3 ch3 22,27 NRR 丨= 21，26 NRR， =nO 23,28 NRR 丨= N〔 24,29 NRR，= / N20,25 NRR1 = = n: CH3 ch3 22,27 NRR 丨 = 21,26 NRR, = nO 23,28 NRR 丨 = N 〔24,29 NRR, = / N

C (請先閱讀背面之注意事項再填寫本頁)H3 經濟部智慧財產局員工消費合作社印製 -16 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 490462 A7B7 五、發明說明（i4 ) 流程 5.C (Please read the notes on the back before filling this page) H3 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -16-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 490462 A7B7 5 Invention description (i4) process 5.

CONH2CONH2

3,10,11,16,25-31 30 R6 = R7 = H 31 R6 = C1，R7 = H3,10,11,16,25-31 30 R6 = R7 = H 31 R6 = C1, R7 = H

32 33 34 35 36 37 38 R2, = R3 R2* = R4 R2' = R3 R3' = R4 R4' — R5 R3, = R5 R3，= R4 =R4· = R5 = H =R5- = H, R2 =R5· = H, R3 =R5. = H，R4 =H, R2 =R3 = H,R2—R4 = H，R2=R5 39 r2, = r5. = H, R3· = R4 Afi = P-. = T4 P-». = R^ = och3 = och3 = och3 = och3 = och3 = och3 = och3 =APU,32 33 34 35 36 37 38 R2, = R3 R2 * = R4 R2 '= R3 R3' = R4 R4 '— R5 R3, = R5 R3, = R4 = R4 · = R5 = H = R5- = H, R2 = R5 · = H, R3 = R5. = H, R4 = H, R2 = R3 = H, R2—R4 = H, R2 = R5 39 r2, = r5. = H, R3 · = R4 Afi = P-. = T4 P- ». = R ^ = och3 = och3 = och3 = och3 = och3 = och3 = och3 = APU,

NaHS03NaHS03

N,N-dimethylacetamide 150°CN, N-dimethylacetamide 150 ° C

41 42 43 44 45 46 47 48 49 5041 42 43 44 45 46 47 48 49 50

Rg = R7 = 1^2 R6 = R7 R6 = R7 R6= R7 R6 = R7 r6=r7 R6=R7 R6= R*7 = R7 =R2 :R3 :R4 :r3 :r3R，R， :R3, = R4,= R5, = H :R4·= R5,= H，R2, = OCH3 :r3. = r5. = h，r3，= och3 :R4, = R5,= H，R4, = OCH3 :R5. = H, R2. = R3·: :R5' = H, R2' = R4': :R4. = H，R]，= R5,: :R5.= H, R3. == R4,: :R4.= H，R3,= R5,: =OCH3 :och3 = och3 = och3 :och3 R6 R7 = R2,= R4'= R5,= H, R3, = OCH3 51 R6 =\F, R7 = R2· = R4* = R5' = H, R3· = OCH3 52 R6 = 〇CH3, R7 = Rr = R4· = Rs· = H, R3- = 〇CH3 53 〜=R·/ = OCH3, R2, = R4, = R5, = H, R3, = OCH3 54 R6，R7 = 0CH20, R2-= R4-= = H, R3« = OCH3 ，R7 = R2'= R4,= R5,= H, R3, = OCH3 ,R7 = R2'= R41 = R5'= H, R3'= OCH3 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 55 R6 = NCCH3, ch3 56 R6 = 0 ’ 57 r6= o， 58 R6 = 59 Κβ= N~^0, ,R7 — R2' ~ R4' ~ ί^5'= H, R3'= OCH3 -17 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 490462 A7 B7 五、發明說日月（i5 ) 流程6 · R2，\ R3fRg = R7 = 1 ^ 2 R6 = R7 R6 = R7 R6 = R7 R6 = R7 r6 = r7 R6 = R7 R6 = R * 7 = R7 = R2 = R3: R4: r3: r3R, R,: R3, = R4 , = R5, = H: R4 · = R5, = H, R2, = OCH3: r3. = R5. = H, r3, = och3: R4, = R5, = H, R4, = OCH3: R5. = H , R2. = R3 ·:: R5 '= H, R2' = R4 ':: R4. = H, R], = R5 ,:: R5. = H, R3. == R4 ,:: R4. = H , R3, = R5 ,: = OCH3: och3 = och3 = och3: och3 R6 R7 = R2, = R4 '= R5, = H, R3, = OCH3 51 R6 = \ F, R7 = R2 · = R4 * = R5 '= H, R3 = OCH3 52 R6 = 〇CH3, R7 = Rr = R4 · = Rs = H, R3- = 〇CH3 53 ~ = R · / = OCH3, R2, = R4, = R5, = H , R3, = OCH3 54 R6, R7 = 0CH20, R2- = R4- = = H, R3 «= OCH3, R7 = R2 '= R4, = R5, = H, R3, = OCH3, R7 = R2' = R41 = R5 '= H, R3' = OCH3 (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 55 R6 = NCCH3, ch3 56 R6 = 0 '57 r6 = o, 58 R6 = 59 Κβ = N ~ ^ 0,, R7 — R2 '~ R4' ~ ί ^ 5 '= H, R3' = OCH3 -17-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Li) 490462 A7 B7 V. The invention of the sun and the moon (i5) Cheng 6 · R2, \ R3f

30,31 CONH2 + h4- nh2 I 4-toluenesulfonic acid "^4' i N,N-dimethylacetamide l R.T. ^ 33-40 R5’30,31 CONH2 + h4- nh2 I 4-toluenesulfonic acid " ^ 4 'i N, N-dimethylacetamide l R.T. ^ 33-40 R5 ’

R5R5

42-50 R5' 606162636465666768 R6 二 Ry = R4 = R2'= R4 R6 = Rr = 1¾¾ R6 = R4 = R5 R5 == R3'= R5 R5 = R3'= R4 R6 = R2,=尺5 R6 = R2' = R4 R6 = C1，R2，= =R5'= H, R2'= OCH3 =R5,= H，R3, = OCH3 = R5, = H，R4，=OCH3 = H，R2，= R3，=〇CH3 = H，R2.= R4，=〇CH3 = h，r2，=r5=och3 = H，R3，= R4- = 〇CH3 = h,r3.=r5，=och3 R4· = R5,= H，R3,= OCH3 ------------,·裝------1 丨tT--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -18 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 五、 發明說明（i6 ) 流程42-50 R5 '606162636465666768 R6 Two Ry = R4 = R2' = R4 R6 = Rr = 1¾¾ R6 = R4 = R5 R5 == R3 '= R5 R5 = R3' = R4 R6 = R2, = Rule 5 R6 = R2 ' = R4 R6 = C1, R2, = = R5 '= H, R2' = OCH3 = R5, = H, R3, = OCH3 = R5, = H, R4, = OCH3 = H, R2, = R3, = 〇CH3 = H, R2. = R4, = 〇CH3 = h, r2, = r5 = och3 = H, R3, = R4- = 〇CH3 = h, r3. = R5, = och3 R4 · = R5, = H, R3 , = OCH3 ------------, · Install ------ 1 丨 tT --------- (Please read the precautions on the back before filling this page) Economy Printed by the Employees' Cooperatives of the Ministry of Intellectual Property Bureau-18-This paper size applies to the Chinese National Standard (CNS) A4 (210 X 297 mm) V. Description of the Invention (i6) Process

69 R2· = R3. = R4. = Η，R = CH3 70 R2. = R3. = R4· = Η，R = CH2CH3 A7 B769 R2 · = R3. = R4. = Η, R = CH3 70 R2. = R3. = R4 · = Η, R = CH2CH3 A7 B7

請先閱 讀背 之 注 71 Rr = Rr = R4· = H , R = CH2COOEt ~~~~~~~— — — .— .——————— ............——* 72 R]· = R3’ = R4· = H，R = (CH2)3COOEt 73 R2· = R3· = R4· = H , R = (CH2)4COOEt 74 R2· = OCH3 , % = R4· = H , R = C2H5 75 R3- = OCH3 , Rr = R4« - H , R = C2H5 76 R4. = OCH3，Rz· = Ry = H，R = C2H5 77 Rt = R3* = R4. = H , R = CH3 78 R2· = Rt = R4· = H , R = CH2CH3 80 Ry = OCH3 , Rr = - H , R = C2h7 81 R4· = OCH3, R2.= R^. = H , R = C2H5 1 I 訂 實例 2-胺基-5-氟苯甲醯胺（3). 以2-胺基-5-氟苯甲酸（1.0 g，6.3 mmol)爲原料，懸浮於 苯（3 0 ml)中，加熱至迴流並慢慢滴加氯化亞磺醯基（1.5 g， 1 2·6 mmol)，繼續迴流4小時後，減壓濃縮除去溶媒及過量 之氯化亞磺醯基；再度以苯（200 ml)爲溶媒，於室溫下通 入氨氣，待反應完成，減壓濃縮除去溶媒，即可得到化合 物 3 (0.9 g);棕色粉末；MS m/z 154 (M + )。 2-胺基_5-甲氧基苯甲醯胺（10). -19 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） # 經濟部智慧財產局員工消費合作社印製 17 B7 17 B7 五 、發明說明（ 以5-甲氧基-2-硝基苯甲酸（4) (ι·〇 g, 5 .1 mmol)爲原 (請先閱讀背面之注意事項再填寫本頁) 料，參照3之合成方法，即可得到％甲氧基硝基苯甲醯 胺（8)。將化合物8溶於甲醇中，在;i 〇%鈀/活性碳的催化下 通入氫氣約6小時，過濾除去鈀/活性碳，濃縮後即可得到 10 (0.8 g);棕色粉末；MS m/z 166 (M + )。 胺基-4,5-二甲氧基苯甲醯胺（U)· 以4,5-二甲氧基-2-硝基苯甲酸（5) (1 .0 g, 4.4 mmol) 爲原料，參照10之合成方法，即可得到11 (0.8 g);棕色粉 末；MS m/z 196 (M + )。 2-胺基-4,5-亞甲二氧二基苯甲醯胺（16). 以4,5-亞甲二氧二基-2-硝基苯甲醛（1.0 g, 5.1 mmol) 爲原料，加入康弗斯試劑（Cr03-吡D定-水）（40 ml)，加熱迴 流4小時，將濃縮後的固體溶於水中，以1 〇%鹽酸酸化之， 並以乙酸乙酯抽取，經無水硫酸鎂脫水及濃縮後，接著參 照10的合成方法，即可得到16 (0.7 g);棕色粉末；MS m/z 180 (M + )。 經濟部智慧財產局員工消費合作社印製 2-胺基-5-(Ν,Ν·二甲胺基）苯甲醯胺（25). 以5-氯-2-硝基苯甲酸（17) (1.0 g，4.9 mmol)爲原料， 參照3之合成方法，即可得到5-氯-2-硝基苯甲醯胺（19)。 將19溶於二甲基醯胺（DMF)(10ml)中，於110°C下與二 甲胺反應3小時，再將反應液倒入冰水（200 ml)並收集沈 -20 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） A7 B7 五、發明說明（） 18 澱物，沈澱物用水洗滌，乾燥後仿照10的方法進行氫化反 應，即可得到25 (0.6 g):棕色粉末；MS m/z 179 (M + )。 (請先閱讀背面之注意事項再填寫本頁) 2-胺基-5-%咯啶基苯甲醯胺（26). 參照25之合成方法，以吡咯啶替換二甲胺，即可得到 26 (0.7 g);棕色粉末；MS m/z 205 (M + )。 2-胺基-5-六氫吡啶基苯甲醯胺（27). 參照25之合成方法，以六氫吡啶替換二甲胺，即可得 到 27 (0.8 g):棕色粉末；MS m/z 219 (M + )。 2-胺基-5-(4-甲六氫吡啶）苯甲醯胺（28). 參照25之合成方法，以4-甲六氫吡啶替換二甲胺，即 可得到 28 (0.8 g);棕色液體；MS m/z 233 (M + )。 2-胺基-5-嗎林基苯甲醯胺（29). 參照25之合成方法，以嗎林替換二甲胺，即可得到29 (0.8 g):棕色粉末；MS m/z 221 (M + )。 經濟部智慧財產局員工消費合作社印製 2-苯基-4-口 S唑啉酮（41). 以2-胺基苯甲醯胺（30) (1.0 g，7.3 mmol)及苯甲醛 (32) (0.8 g，7.3 mmol)爲原料，溶解於N，N-二甲基乙醯胺 (DMAC) (20 ml)中，力0 入亞硫酸氫鈉(0.8 g, 7.5 mmol)， 150°C之溫度下加熱攪拌2小時，倒入冰水（200 ml)並收集沈 -21 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱) " ---- 490462 經濟部智慧財產局員工消費合作社印製 A7 B7 _ 五、發明說明（） 19 澱物，沈澱物用水洗滌，乾燥後再以乙醇再結晶，即可得 到41 (1.5 g，92.6%);淡黃色針狀結晶；產率、融點及光譜 資料列於表1。 2-(2’-甲氧苯基）-4-硿唑啉酮（42). 以2-胺基苯甲醯胺（30) (1.0 g，7.3 mmol)及2 -甲氧苯 甲醒（33) (1.0 g，7.3 mmol)爲原料，參照41之合成方法， 即可得到42 (1.6 g，89.1%);淡黃色針狀結晶。 2-(3、甲氧苯基唑啉酮（43). 以2-胺基苯甲醯胺（30) (1.0 g，7.3 mmol)及3-甲氧苯 甲醛（34) (1.0 g，7.3 mmol)爲原料，參照41之合成方法， 即可得到43 (1.7 g，95.0%);淡黃色針狀結晶。 2-(4’-甲氧苯基）-4-口查唑啉酮（々ΜΗ]-胺基苯甲醯胺 （30)(1.0g，7.3mmol) 及 4-甲氧苯 甲Si (35)(1.0g，7.3mmol)爲原料，參照41之合成方法， 即可得到44 (1.8 g，96.4%);淡黃色針狀結晶。 2-(2’，3，-二甲氧苯基）-4-°2唑啉酮（45)· 以2-胺基苯甲醯胺（30) (1.0 g, 7.3 mmol)及2,3-二甲 氧苯甲醛（36)(1.2 g，7.3 mmol)爲原料，參照41之合成方 法，即可得到45 (1.8 g，86.0%);淡黃色針狀結晶。 -22 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------ — — — — 111 ^ ·111111! (請先閱讀背面之注意事項再填寫本頁) A7Please read back note 71 Rr = Rr = R4 · = H, R = CH2COOEt ~~~~~~~ — — — — — — — — — — ——————————————————————— …… .—— * 72 R] · = R3 '= R4 · = H, R = (CH2) 3COOEt 73 R2 · = R3 · = R4 · = H, R = (CH2) 4COOEt 74 R2 · = OCH3,% = R4 · = H, R = C2H5 75 R3- = OCH3, Rr = R4 «-H, R = C2H5 76 R4. = OCH3, Rz · = Ry = H, R = C2H5 77 Rt = R3 * = R4. = H, R = CH3 78 R2 · = Rt = R4 · = H, R = CH2CH3 80 Ry = OCH3, Rr =-H, R = C2h7 81 R4 · = OCH3, R2. = R ^. = H, R = C2H5 1 I Order example 2-amino-5-fluorobenzamide (3). Using 2-amino-5-fluorobenzoic acid (1.0 g, 6.3 mmol) as a raw material, suspended in benzene (30 ml), heated To reflux, slowly add sulfenyl chloride (1.5 g, 12 · 6 mmol), continue refluxing for 4 hours, and then concentrate under reduced pressure to remove the solvent and excess sulfinyl chloride; again with benzene (200 ml) was used as a solvent, and ammonia gas was introduced at room temperature. After the reaction was completed, the solvent was concentrated and removed under reduced pressure to obtain compound 3 (0.9 g); brown powder; MS m / z 154 (M +). 2-Amino_5-methoxybenzidine (10). -19-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) # Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Preparation 17 B7 17 B7 V. Description of the invention (with 5-methoxy-2-nitrobenzoic acid (4) (ι · 〇g, 5.1 mmol) as the original (please read the precautions on the back before filling in this Page), according to the synthesis method of 3, you can get% methoxynitrobenzamide (8). Compound 8 was dissolved in methanol, hydrogen was passed under the catalyst of i 0% palladium / activated carbon About 6 hours, filtered to remove palladium / activated carbon, and concentrated to obtain 10 (0.8 g); brown powder; MS m / z 166 (M +). Amino-4,5-dimethoxybenzamide (U) · Using 4,5-dimethoxy-2-nitrobenzoic acid (5) (1.0 g, 4.4 mmol) as a raw material, referring to the synthesis method of 10, 11 (0.8 g) can be obtained; Brown powder; MS m / z 196 (M +). 2-Amino-4,5-methylenedioxydiylbenzamide (16). With 4,5-methylenedioxydiyl-2- Nitrobenzaldehyde (1.0 g, 5.1 mmol) as raw material, add Confos reagent (Cr03-pyridine-water) (40 ml), heat and reflux 4 At this time, the concentrated solid was dissolved in water, acidified with 10% hydrochloric acid, and extracted with ethyl acetate. After dehydration and concentration with anhydrous magnesium sulfate, followed by the synthesis method of 10, 16 (0.7 g) was obtained. Brown powder; MS m / z 180 (M +). 2-Amino-5- (N, N · dimethylamino) benzamidine (25) printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5-Chloro-2-nitrobenzoic acid (17) (1.0 g, 4.9 mmol) is used as a raw material, and by referring to the synthesis method of 3, 5-chloro-2-nitrobenzamide (19) can be obtained. Dissolved in dimethylamidamine (DMF) (10ml), reacted with dimethylamine at 110 ° C for 3 hours, then poured the reaction solution into ice water (200 ml) and collected Shen-20-this paper size applies China National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 V. Description of the invention () 18 The precipitate and the precipitate are washed with water, dried and then subjected to a hydrogenation reaction according to the method of 10 to obtain 25 (0.6 g) : Brown powder; MS m / z 179 (M +). (Please read the precautions on the back before filling this page) 2-Amino-5-% pyridinyl benzamidine (26). Refer to Synthesis of 25 Method with pyrrolidine replacement Dimethylamine, you can get 26 (0.7 g); brown powder; MS m / z 205 (M +). 2-amino-5-hexahydropyridyl benzamidine (27). Refer to the synthesis method of 25 Replace dimethylamine with hexahydropyridine to obtain 27 (0.8 g): brown powder; MS m / z 219 (M +). 2-Amino-5- (4-methylhexahydropyridine) benzamidine (28). Refer to the synthesis method of 25 and replace the dimethylamine with 4-methylhexahydropyridine to obtain 28 (0.8 g); Brown liquid; MS m / z 233 (M +). 2-Amino-5-morpholinyl benzamidine (29). Refer to the synthesis method of 25 and replace dimethylamine with morphine to obtain 29 (0.8 g): brown powder; MS m / z 221 ( M +). Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 2-Phenyl-4-methyl Sazolinone (41). 2-Aminobenzamide (30) (1.0 g, 7.3 mmol) and benzaldehyde (32 ) (0.8 g, 7.3 mmol) as raw material, dissolved in N, N-dimethylacetamidamine (DMAC) (20 ml), force 0 into sodium bisulfite (0.8 g, 7.5 mmol), 150 ° C Heat and stir for 2 hours at room temperature, pour into ice water (200 ml) and collect Shen-21-This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 public love) " ---- 490462 Ministry of Economic Affairs Printed by the Consumer Property Cooperative of Intellectual Property Bureau A7 B7 _ V. Description of the invention (19) The precipitate, precipitate is washed with water, dried and recrystallized with ethanol to obtain 41 (1.5 g, 92.6%); light yellow needle-like Crystallization; yield, melting point and spectral data are listed in Table 1. 2- (2'-methoxyphenyl) -4-oxazolinone (42). 2-aminobenzamide (30) (1.0 g, 7.3 mmol) and 2-methoxybenzidine ( 33) (1.0 g, 7.3 mmol) as a raw material, referring to the synthesis method of 41, 42 (1.6 g, 89.1%) can be obtained; pale yellow needle-like crystals. 2- (3, methoxyphenylazolinone (43). 2-aminobenzamide (30) (1.0 g, 7.3 mmol) and 3-methoxybenzaldehyde (34) (1.0 g, 7.3 mmol) as a raw material, and by referring to the synthesis method of 41, 43 (1.7 g, 95.0%) can be obtained; pale yellow needle-like crystals. 2- (4'-methoxyphenyl) -4-cholazolinone (々 ΜΗ] -Aminobenzamide (30) (1.0 g, 7.3 mmol) and 4-methoxybenzyl Si (35) (1.0 g, 7.3 mmol) as raw materials, referring to the synthesis method of 41, 44 can be obtained (1.8 g, 96.4%); pale yellow needle-like crystals. 2- (2 ', 3, -dimethoxyphenyl) -4- ° 2 azolinone (45) · 2-aminobenzamide (30) (1.0 g, 7.3 mmol) and 2,3-dimethoxybenzaldehyde (36) (1.2 g, 7.3 mmol) as raw materials, referring to the synthesis method of 41, 45 (1.8 g, 86.0%) can be obtained ; Light yellow needle-like crystals. -22-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ------ — — — — 111 ^ · 111111! (Please read the Note: Please fill out this page again) A7

五、發明說明（） 20 經濟部智慧財產局員工消費合作社印製 h(2’，4’-二甲氧苯基）_4_硿唑啉酮（46). 以2·胺基苯甲醯胺（30) (1.0 g，7.3 mmol)及2,4-二甲 氧苯甲醛（37)(1.2 g，7.3 mmol)爲原料，參照41之合成方 法’即可得到46 (1.7 g，84.3%);淡黃色針狀結晶。 2-(2’，5’-二甲氧苯基）-4-口2唑啉酮（47). 以2-胺基苯甲醯胺（30) (1.0 g，7.3 mmol)及2,5-二甲 氧苯甲醛（38)(1.2 g，7.3 mmol)爲原料，參照41之合成方 法，即可得到47 (1.8 g，88.6%);淡黃色柱狀結晶。 2-(3’，4’-二甲氧苯基）-4-口查唑啉酮（48)· 以2-胺基苯甲醯胺（30) (1.0 g，7.3 mmol)及3,4-二甲 氧苯甲醛（39) (1.2 g，7.3 mmol)爲原料，參照41之合成方 法，即可得到48 (1.8 g，89.0%);淡黃色柱狀結晶。 2-(3’，5’-二甲氧苯基）-4-疃唑啉酮（49). 以2-胺基苯甲醯胺（30) (1.0 g, 7.3 mmol)及3,5-二甲氧苯 甲醛（40) (1.2 g，7.3 mmol)爲原料，參照41之合成方法， 即可得到49 (1.7 84.0%);淡黃色針狀結晶。 2-(3，-二甲氧苯基）·6-氯-4-口2唑啉酮（50)· 以2·胺基-5-氯苯甲醯胺（31) (1·〇 g，5.9 mmol)及3-甲氧苯 甲醒（34) (0.8 g，5.9 mmol)爲原料’參照41之合成方法’ 即可得到5 〇 (1.6 g，9 4 · 3 %);淡黃色針狀結晶。 -23 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐) ------------裝—·—訂---------- (請先閲讀背面之注意事項再填寫本頁) 490462 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（2i ) 2-(3，-甲氧苯基）-6-氟-4-口查唑啉酮（51)· 以 3 (1.0 g，6.5 mmol)及 3-甲氧苯甲醛（34) (0.9 g，6.5 mmol)爲原料，參照41之合成方法，即可得到51 (0.8 g， 4 6.8 %);淡黃色針狀結晶。 2-(3，-甲氧苯基）-6-甲氧基-4-口 2唑啉酮（52). 以 10 (1.0 g，6.0 mmol)及 3·甲氧苯甲醛（34) (0.8 g， 6.0 mmol)爲原料，參照41之合成方法，即可得到52 (0.7 g, 42.4%);淡黃色針狀結晶。 2-(3’-甲氧苯基）-6,7-二甲氧基-4-口垄唑啉酮（53). 以 11 (1.0 g，5.1 mmol)及 3-甲氧苯甲醛（34) (0.7 g， 5.1 mmol)爲原料，參照41之合成方法，即可得到53 (0.5 g, 30.8%);淡黃色柱狀結晶。 2-(3甲氧苯基）-6,7-(亞甲二氧二基）-4-口$唑啉酮（54). 以 16 (1.0 g，5.5 mmol)及 3-甲氧苯甲醒(34) (0.7 g, 5.5 mmol)爲原料，參照41之合成方法，即可得到54 (0.1 g， 8.8%);淡黃色針狀結晶。 2-(3’-甲氧苯基）-6-(N，N-二甲胺基）-4-口查唑啉酮（55). 以 25 (1.0 g，5.6 mmol)及 3-甲氧苯甲醛（34) (0.8 g， 5.6 mmol)爲原料，參照41之合成方法，即可得到55 (0.8 g， _____ 24 _ 本紙張尺度適用巾國國冢標準（CNS)A4規格（210 X 297公爱） -----------裝--------訂---------- (請先閱讀背面之注意事項再填寫本頁) 490462 A7 __ B7__ 五、發明說明（） 22 51.2%);淡黃色針狀結晶。 (請先閱讀背面之注意事項再填寫本頁} 2-(3’-甲氧苯基比咯啶基）-4-口查唑啉酮（56). 以 26 (1.0 g，4.9 mmol)及 3-甲氧苯甲醛（34) (0.7 g， 4.9 mmol)爲原料，參照41之合成方法，即可得到56 (0.6 g， 40.0%);淡黃色柱狀結晶。 2-(3’-甲氧苯基）-6-(六氫吡啶基）-4-岐唑啉酮（57). 以 27 (1.0 g，4.6 mmol)及 3-甲氧苯甲醛（34) (0.6 g， 4.6 mmol)爲原料，參照41之合成方法，即可得到57 (0.8 g， 55·0%);淡黃色柱狀結晶。 2-(3’-甲氧苯基）-6-(4·甲六氫吡啶基）-4-咬唑啉酮（58). 以 2 8(1.0 g，4.3 mmol)及 3 -甲氧苯甲酸(34) (0.6 g, 4·3 mmol)爲原料，參照41之合成方法，即可得到58 (0.9 g， 57.6%);淡黃色柱狀結晶。 2-(3’·甲氧苯基）-6-(嗎林基）-4-技唑啉酮（59). 經濟部智慧財產局員工消費合作社印製 以 29 (1.0 g，4.5 mmol)及 3-甲氧苯甲醛（34) (0.6 g， 4.5 mmol)爲原料，參照41之合成方法，即可得到59 (0.7 g， 48.3%);淡黃色針狀結晶。 2,3-雙氫-2-(3，-甲氧苯基）-4-口 S唑啉酮（61)·V. Description of the invention (20) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs h (2 ', 4'-dimethoxyphenyl) _4_oxazolinone (46). With 2 · aminobenzidine (30) (1.0 g, 7.3 mmol) and 2,4-dimethoxybenzaldehyde (37) (1.2 g, 7.3 mmol) as raw materials. Refer to the synthesis method of 41 to obtain 46 (1.7 g, 84.3%). ; Light yellow needle-like crystals. 2- (2 ', 5'-dimethoxyphenyl) -4-oxazolinone (47). 2-Aminobenzamide (30) (1.0 g, 7.3 mmol) and 2,5 -Dimethoxybenzaldehyde (38) (1.2 g, 7.3 mmol) as a raw material, referring to the synthesis method of 41, 47 (1.8 g, 88.6%) can be obtained; pale yellow columnar crystals. 2- (3 ', 4'-dimethoxyphenyl) -4-cholazolinone (48) · 2-aminobenzamide (30) (1.0 g, 7.3 mmol) and 3,4 -Dimethoxybenzaldehyde (39) (1.2 g, 7.3 mmol) as a raw material, according to the synthesis method of 41, 48 (1.8 g, 89.0%) can be obtained; pale yellow columnar crystals. 2- (3 ', 5'-dimethoxyphenyl) -4-oxazolinone (49). 2-Aminobenzamide (30) (1.0 g, 7.3 mmol) and 3,5- Dimethoxybenzaldehyde (40) (1.2 g, 7.3 mmol) was used as a raw material, and 49 (1.7 84.0%) was obtained by referring to the synthesis method of 41; pale yellow needle-like crystals. 2- (3, -dimethoxyphenyl) · 6-chloro-4-oxo2azolinone (50) · 2 · amino-5-chlorobenzamide (31) (1.0 g, 5.9 mmol) and 3-methoxybenzidine (34) (0.8 g, 5.9 mmol) as raw materials 'refer to the synthesis method of 41' can get 5 0 (1.6 g, 9 4 · 3%); light yellow needle-like crystallization. -23-The size of this paper is applicable to China National Standard (CNS) A4 (210 X 297 mm) ------------ installation ----- order ---------- ( (Please read the notes on the back before filling this page) 490462 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (2i) 2- (3, -methoxyphenyl) -6-fluoro-4- Oral Chazolinone (51) · Using 3 (1.0 g, 6.5 mmol) and 3-methoxybenzaldehyde (34) (0.9 g, 6.5 mmol) as raw materials, referring to the synthesis method of 41, 51 (0.8 g, 4 6.8%); pale yellow needle-like crystals. 2- (3, -methoxyphenyl) -6-methoxy-4-methyl-2-oxazolinone (52). With 10 (1.0 g, 6.0 mmol) and 3. · methoxybenzaldehyde (34) (0.8 g, 6.0 mmol) as raw materials, and 52 (0.7 g, 42.4%) can be obtained by referring to the synthesis method of 41; pale yellow needle-like crystals. 2- (3'-methoxyphenyl) -6,7-dimethoxy-4-oridazolinone (53). With 11 (1.0 g, 5.1 mmol) and 3-methoxybenzaldehyde (34 ) (0.7 g, 5.1 mmol) as a raw material, referring to the synthesis method of 41, 53 (0.5 g, 30.8%) can be obtained; pale yellow columnar crystals. 2- (3methoxyphenyl) -6,7- (methylenedioxydiyl) -4-oxazolinone (54). With 16 (1.0 g, 5.5 mmol) and 3-methoxybenzoyl Xing (34) (0.7 g, 5.5 mmol) was used as a raw material, and 54 (0.1 g, 8.8%) was obtained by referring to the synthesis method of 41; pale yellow needle-like crystals. 2- (3'-methoxyphenyl) -6- (N, N-dimethylamino) -4-cholazolinone (55). With 25 (1.0 g, 5.6 mmol) and 3-methoxy Benzaldehyde (34) (0.8 g, 5.6 mmol) is used as a raw material. With reference to the synthesis method of 41, 55 (0.8 g, _____ 24 _) can be obtained in accordance with the national standard (CNS) A4 (210 X 297) of this paper. (Public love) ----------- Installation -------- Order ---------- (Please read the precautions on the back before filling this page) 490462 A7 __ B7__ 5. Description of the invention () 22 51.2%); light yellow needle-like crystals. (Please read the precautions on the back before filling in this page} 2- (3'-methoxyphenylpyrrolidinyl) -4-mouthchazolinone (56). With 26 (1.0 g, 4.9 mmol) and 3-methoxybenzaldehyde (34) (0.7 g, 4.9 mmol) is used as a raw material, and 56 (0.6 g, 40.0%) can be obtained by referring to the synthesis method of 41; pale yellow columnar crystals. 2- (3'-form Oxyphenyl) -6- (hexahydropyridyl) -4-amidazolinone (57). With 27 (1.0 g, 4.6 mmol) and 3-methoxybenzaldehyde (34) (0.6 g, 4.6 mmol) As a raw material, by referring to the synthesis method of 41, 57 (0.8 g, 55.0%); pale yellow columnar crystals can be obtained. 2- (3'-methoxyphenyl) -6- (4.methanehexahydropyridine ) -4-tetrazolinone (58). Using 2 8 (1.0 g, 4.3 mmol) and 3-methoxybenzoic acid (34) (0.6 g, 4 · 3 mmol) as raw materials, refer to the synthesis method of 41 , You can get 58 (0.9 g, 57.6%); pale yellow columnar crystals. 2- (3 '· methoxyphenyl) -6- (morpholinyl) -4-techazolinone (59). Economic Printed by the Consumer Cooperatives of the Ministry of Intellectual Property Bureau using 29 (1.0 g, 4.5 mmol) and 3-methoxybenzaldehyde (34) (0.6 g, 4.5 mmol) as raw materials, and referring to the 41 synthesis method, 59 (0.7 g , 48.3%); light yellow needle-like crystals. 2,3-dihydro-2- (3, -methoxyphenyl) -4-oxazolone (61) ·

方法A ··以2-胺基苯甲醯胺（30) (1.0 g，7.3 mmol)及3-甲氧苯甲醒（34) (1·〇 g, 7.3 mmol)爲原料，溶解於DMAC _- 25 - 本紙張尺度適财國國家標準（CNS)A4規格（210 X 297 公釐） -- 490462 A7 B7 經濟部智慧財產局員工消費合作社印製 Π縣日月（23 ) (20 ml)中，於80°C下反應2小時，倒入冰水（200 ml)並收集 沈澱物，沈澱物用水洗滌，乾燥後再經管柱層析法分離（矽 膠一乙酸乙酯/正己烷）即可得到43 (0.3 g，15.0%)及61 (1.4 g，75.2%);淡黃色粉末；產率、融點及光譜資料列於 表 1 〇 方法B ··以2-胺基苯甲酿胺（30) (1 ·0 g，7.3 mmol)及3-甲氧苯甲醛（34) (1.0 g，7.3 mmol)爲原料，溶解於DM AC (20 ml)中，加入對甲苯磺酸（0.1 g，0.3 mmol)，室溫下攪 拌2小時，倒入冰水（200 ml)並收集沈澱物，沈澱物用水洗 滌，乾燥後再經管柱層析法分離（矽膠一乙酸乙酯/正己烷） 即可得到 43 (70.0 mg，4.0%)及 61 (1.7 g，89.0%);淡黃色粉 末。 2.3- 雙氫-2-(2，-甲氧苯基）-4-口2唑啉酮（60). 以2-胺基苯甲醯胺（30) (1.0 g，7.3 mmol)及2-甲氧苯甲 醒（33) (1.0 g，7.3 mmol)爲原料，參照61 (方法B)之合成 方法，即可得到 42 (90.0 mg，5.0%)及 60 (1.7 g，90.1%);淡 黃色粉末。 2.3- 雙氫-2-(4，-甲氧苯基）-4-口查唑啉酮（62). 以2-胺基苯甲醯胺（30) (1.0 g，7.3 mmol)及4·甲氧苯甲 醛（35) (1.0 g，7.3 mmol)爲原料，參照61 (方法B)之合成 方法，即可得到 44 (40.0 mg，2.0%)及 62 (1·7 g，93.3%);淡 黃色粉末。 -26 私紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------I I ------1 I --------- (請先閱讀背面之注意事項再填寫本頁) 490462Method A · 2-aminobenzamide (30) (1.0 g, 7.3 mmol) and 3-methoxybenzidine (34) (1.0 g, 7.3 mmol) were used as raw materials and dissolved in DMAC. -25-This paper is suitable for National Standards (CNS) A4 specifications (210 X 297 mm) of the country of wealth-490462 A7 B7 Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (23) (20 ml) , React at 80 ° C for 2 hours, pour into ice water (200 ml) and collect the precipitate. The precipitate is washed with water, dried and separated by column chromatography (silica gel, ethyl acetate / n-hexane) to obtain 43 (0.3 g, 15.0%) and 61 (1.4 g, 75.2%); light yellow powder; yield, melting point, and spectral data are listed in Table 10. Method B · 2-aminobenzylamine (30 ) (1.0 g, 7.3 mmol) and 3-methoxybenzaldehyde (34) (1.0 g, 7.3 mmol) as raw materials, dissolved in DM AC (20 ml), and added p-toluenesulfonic acid (0.1 g, 0.3 mmol), stirred at room temperature for 2 hours, poured into ice water (200 ml) and collected the precipitate, washed the precipitate with water, dried and separated by column chromatography (silica gel, ethyl acetate / n-hexane) to obtain 43 (70.0 mg, 4.0%) and 61 ( 1.7 g, 89.0%); pale yellow powder. 2.3- Dihydro-2- (2, -methoxyphenyl) -4-oxazolinone (60). 2-Aminobenzamide (30) (1.0 g, 7.3 mmol) and 2- Methoxybenzidine (33) (1.0 g, 7.3 mmol) was used as the raw material. With reference to the synthesis method of 61 (Method B), 42 (90.0 mg, 5.0%) and 60 (1.7 g, 90.1%) were obtained. Yellow powder. 2.3- Dihydro-2- (4, -methoxyphenyl) -4-cholazolinone (62). 2-Aminobenzamide (30) (1.0 g, 7.3 mmol) and 4 · Methoxybenzaldehyde (35) (1.0 g, 7.3 mmol) as raw material, with reference to the synthesis method of 61 (Method B), 44 (40.0 mg, 2.0%) and 62 (1 · 7 g, 93.3%) can be obtained; Light yellow powder. -26 Private paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) -------- II ------ 1 I --------- (please first (Read the notes on the back and fill out this page) 490462

24 經濟部智慧財產局員工消費合作社印製 2.3- 雙氫-2-(2’，3，-二甲氧苯基）-4-口$唑啉酮（63). 以2-胺基苯甲驢胺（3〇) (1 ·〇 g，7·3 mmol)及2,3-二甲氧 本甲醒（36) (1.2 g，7.3 mmol)爲原料，參照61 (方法B)之 合成方法’即可得到45 (80.1 mg, 4.0%)及63 (1.6 g， 78.1%);淡黃色粉末。 2.3- 雙氫·2-(2，，4，-二甲氧苯基）-4-口查唑啉酮（64). 以2-胺基苯甲醯胺（3〇) (i_〇 g，7.3 mmol)及2，4-二甲氧 苯甲醛（37) (1.2 g，7.3 mmol)爲原料，參照61 (方法B)之 合成方法，即可得到46 (99.9 mg，5.0%)及64 (1.8 g， 8 6 · 5 %);淡黃色粉末。 2.3- 雙氫-2-(2’，5，-二甲氧苯基）-4-口查唑啉酮（65). 以2-胺基苯甲醯胺（3〇) (1.0 g，7.3 mmol)及2,5-二甲氧 苯甲醛（38) (1.2 g，7·3 mmol)爲原料，參照61 (方法B)之 合成方法，即可得到47 (80.1 mg，4.0%)及65 (1.7 g， 80.3%);淡黃色粉末。 2,3·雙氫-2-(3’，4、二甲氧苯基）-4-口2唑啉酮（66). 以2-胺基苯甲醯胺（30) (1 ·0 g，7·3 mmol)及3,4-二甲氧 苯甲醛（39) (1.2 g，7.3 mmol)爲原料，參照61 (方法B)之 合成方法，即可得到48 (60.2 mg，3.1%)及66 (1.6 g， 80.2%);淡黃色粉末。 _ - 27 - 本紙張尺k適用巾國國家標準（CNS)A4規格（210 X 297公爱) """ - - I I *1 I I Ί I — — — — — —--' (請先閱讀背面之注意事項再填寫本頁) A724 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 2.3-Dihydro-2- (2 ', 3, -dimethoxyphenyl) -4-oxazolone (63). With 2-aminobenzyl Donkey amine (30) (1.0 g, 7.3 mmol) and 2,3-dimethoxybenzidine (36) (1.2 g, 7.3 mmol) were used as raw materials. Refer to the synthesis method of 61 (Method B) 'You get 45 (80.1 mg, 4.0%) and 63 (1.6 g, 78.1%); light yellow powder. 2.3- Dihydro · 2- (2,4, -dimethoxyphenyl) -4-chalazolinone (64). 2-Aminobenzamine (3〇) (i_〇g , 7.3 mmol) and 2,4-dimethoxybenzaldehyde (37) (1.2 g, 7.3 mmol) as raw materials. With reference to the synthesis method of 61 (Method B), 46 (99.9 mg, 5.0%) and 64 can be obtained. (1.8 g, 86.5%); pale yellow powder. 2.3- Dihydro-2- (2 ', 5, -dimethoxyphenyl) -4-chalazolinone (65). 2-Aminobenzamine (3〇) (1.0 g, 7.3 mmol) and 2,5-dimethoxybenzaldehyde (38) (1.2 g, 7.3 mmol) as raw materials. With reference to the synthesis method of 61 (Method B), 47 (80.1 mg, 4.0%) and 65 can be obtained. (1.7 g, 80.3%); pale yellow powder. 2,3 · dihydro-2- (3 ', 4, dimethoxyphenyl) -4-port 2oxazolinone (66). With 2-aminobenzamide (30) (1 · 0 g , 7 · 3 mmol) and 3,4-dimethoxybenzaldehyde (39) (1.2 g, 7.3 mmol) as raw materials, referring to the synthesis method of 61 (Method B), 48 (60.2 mg, 3.1%) can be obtained And 66 (1.6 g, 80.2%); pale yellow powder. _-27-This paper rule applies to the national standard (CNS) A4 (210 X 297).--II * 1 II Ί I — — — — — —-- '(Please (Please read the notes on the back before filling this page) A7

五、發明說明（） 25 2.3- 雙氫-2-(3’，5，-二甲氧苯基）-4-口莹唑啉酮（67)· (請先閱讀背面之注意事項再填寫本頁) 以2-胺基苯甲醯胺（3〇) (1〇 g，7.3 mmol)及3,5-二甲氧 苯甲醒（40) (1.2 g，7.3 mmol)爲原料，參照61 (方法B)之 合成方法’即可得到49 (40.2 mg，2.0%)及67 (1.9 g， 93.3%);淡黃色粉末。 2.3- 雙氫-2-(3，-甲氧苯基）-6-氯-4-口查唑啉酮（68). 以2·胺基-5-氯苯甲醯胺（31) (1·0 g，5.9 mmol)及3-甲氧 苯甲醛（34) (〇·8 g，5.9 mmol)爲原料，參照61 (方法B)之 合成方法’即可得到50 (20.0 mg，1.1%)及68 (1.6 g， 95.0%);淡黃色粉末。 4-甲氧基-2-苯基口2唑啉（69) and N3-甲基-2-苯基-4-口窆唑 啉酮（77). 將化合物41 (1.00 g，4.50 mmol)懸浮於四氫口夫喃（50 ml)中，加熱至50°C並分次慢慢加入氫化鈉（80%，0.15 g， 5.00 mmol)，繼續攪拌60分鐘後，加入碘甲烷（1.28 g， 經濟部智慧財產局員工消費合作社印製 9.00 mmol)並繼續反應60分鐘。將反應物溶於氯仿中， 過濾除去不溶之鹽類，氯仿抽取液經濃縮後以管柱層析法 分離（矽膠一氯仿/正己烷）得到69 (0.32 g，30.1%)及77 (0.70 g, 66.0%);白色粉末；產率、融點及光譜資料列於 表2。 -28 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 經濟部智慧財產局員工消費合作社印製 490462 A7 __ B7 五、發明說明（） 26 4-乙氧基-2-苯基口$唑啉（70) and N3-乙基-2-苯基-4-口窆唑 啉酮（78). 參照69及77之合成方法，將41 (1.00 g，4.50 mmol)與 碘乙烷（1.40 g，9.00 mmol)反應，即可得到70 (0,90 g， 80.0%)及 78 (0.12 g，11.0%);白色粉末。 4-乙氧羰基甲氧基-2-苯基碎唑啉（71) and N3-乙氧甲醯基 甲氧基-2-苯基-4-口 2唑啉酮（79). 參照69及77之合成方法，將41 (1.00 g，4.50 mmol)與 溴乙酸乙酯（1·50 g，9.00 mmol)反應，即可得到71 (1.25 g， 90.2%)及 79 (0.02 g，1.3%);白色粉末。 4-乙氧羰基丙氧基-2-苯基咬唑啉（72). 參照69之合成方法，將41 (1.00 g，4.50 mmol)與4-氯 丁酸乙酯（1.36 g，9.00 mmol)反應，即可得到72 (1.34 g， 88.6%);白色粉末。 4-乙氧羰基丁氧基-2-苯基硿唑啉（73). 參照69之合成方法，將41 (1.00 g，4.50 mm〇l)與5-溴 戊酸乙酯（1.88 g，9.00 mmol)反應，即可得到73 (1.25 g， 79.4%);白色粉末。 4-乙氧基-2-(2*-甲氧苯基）挖唑啉（74). 參照69之合成方法，將42 (1.13 g，4·5〇 mm〇i)與碘乙院 -29 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------裝---- (請先閱讀背面之注意事項再填寫本頁) 訂.--------禮. 經濟部智慧財產局員工消費合作社印製 MU462 A7 "------B7__ 五、發明說明（） 27 (!·4〇 g，9.00 mmol)反應，即可得到 74 (1.06 g，84.1%);白 色粉末。 4_乙氧基-2-(3匕甲氧苯基）口查唑啉（75) and N3-乙基_2-(3*-甲氧苯基）-4-。2唑啉酮（80). 參照69及77之合成方法，將43 (1.13 g，4.50 mmol)與 碘:乙院（1.40 g，9.00 mmol)反應，即可得到75 (1.04 g， 82.5%)及 80 (0.14 g，11.1%);白色粉末。 4-乙氧基-2-(4·-甲氧苯基）口2唑啉（76) and N3-乙基-2-(4·-甲氧苯基）-4-口查唑啉酮（81). 參照69及77之合成方法，將44 (1.13 g，4.50 mmol)與硤 乙烷（1.40 g，9.00 mmol)反應，即可得到 76(1.07 g，85.0%) 及 81 (0.11 g，8.8%);白色粉末。 表1列出了化合物41至68的物理及光譜數據；表2列出 了化合物69至81的物理及光譜數據。 細胞致毒活性試驗 所合成的化合物42-68於美國Chapel Hill之北卡羅來納 大學藥學院以人類及老鼠腫瘤細胞依照已發表論文中相同 方法進行體外細胞致毒活性試驗17。這些腫瘤細胞包括人 類卵巢癌（1A9)、迴盲腸癌（HCT-8)、肺癌（A-549)、神經膠 母細胞瘤（U-87-MG)、骨癌（HOS)、鼻咽表皮樣癌（KB)、P- -30 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） -----------裝------%—訂---------- (請先閱讀背面之注意事項再填寫本頁) A7V. Description of the invention () 25 2.3-Dihydro-2- (3 ', 5, -dimethoxyphenyl) -4-oxazolinone (67) · (Please read the precautions on the back before filling in this Page) Using 2-aminobenzamide (30) (10 g, 7.3 mmol) and 3,5-dimethoxybenzidine (40) (1.2 g, 7.3 mmol) as raw materials, refer to 61 ( The synthesis method of method B) can obtain 49 (40.2 mg, 2.0%) and 67 (1.9 g, 93.3%); light yellow powder. 2.3- Dihydro-2- (3, -methoxyphenyl) -6-chloro-4-loxazolinone (68). With 2 · amino-5-chlorobenzamide (31) (1 • 0 g, 5.9 mmol) and 3-methoxybenzaldehyde (34) (0.8 g, 5.9 mmol) as raw materials. Refer to the synthesis method of 61 (Method B) to get 50 (20.0 mg, 1.1%). And 68 (1.6 g, 95.0%); pale yellow powder. 4-methoxy-2-phenyl-2-oxazoline (69) and N3-methyl-2-phenyl-4-oxazolone (77). Compound 41 (1.00 g, 4.50 mmol) was suspended In tetrahydrobufran (50 ml), heat to 50 ° C and slowly add sodium hydride (80%, 0.15 g, 5.00 mmol) in portions. After stirring for 60 minutes, add methyl iodide (1.28 g, economical). The Ministry of Intellectual Property Bureau employee consumer cooperative printed 9.00 mmol) and continued to react for 60 minutes. The reaction was dissolved in chloroform, and the insoluble salts were removed by filtration. The chloroform extract was concentrated and separated by column chromatography (silica-chloroform / n-hexane) to obtain 69 (0.32 g, 30.1%) and 77 (0.70 g , 66.0%); white powder; yield, melting point and spectral data are listed in Table 2. -28-This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 490462 A7 __ B7 V. Description of Invention () 26 4-ethoxy-2 -Phenyloxazolin (70) and N3-ethyl-2-phenyl-4-oxazolone (78). Refer to the synthesis method of 69 and 77, and 41 (1.00 g, 4.50 mmol) and Iodoethane (1.40 g, 9.00 mmol) was reacted to obtain 70 (0,90 g, 80.0%) and 78 (0.12 g, 11.0%); white powder. 4-ethoxycarbonylmethoxy-2-phenyl triazoline (71) and N3-ethoxymethylmethoxy-2-phenyl-4-oxo-2 oxazolinone (79). Refer to 69 and The synthesis method of 77: react 41 (1.00 g, 4.50 mmol) with ethyl bromoacetate (1.50 g, 9.00 mmol) to obtain 71 (1.25 g, 90.2%) and 79 (0.02 g, 1.3%) ;White powder. 4-ethoxycarbonylpropoxy-2-phenyltetrazoline (72). Refer to the synthesis method of 69, and add 41 (1.00 g, 4.50 mmol) and ethyl 4-chlorobutanoate (1.36 g, 9.00 mmol). The reaction gave 72 (1.34 g, 88.6%); white powder. 4-ethoxycarbonylbutoxy-2-phenyloxazoline (73). According to the synthesis method of 69, 41 (1.00 g, 4.50 mm) and ethyl 5-bromovalerate (1.88 g, 9.00 mmol) reaction to obtain 73 (1.25 g, 79.4%); white powder. 4-ethoxy-2- (2 * -methoxyphenyl) oxazoline (74). Referring to the synthesis method of 69, 42 (1.13 g, 4.50 mm) and Iodine Ethylamine-29 -This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------ installation ---- (Please read the precautions on the back before filling this page) Order .-------- Li. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs MU462 A7 " ------ B7__ V. Description of the invention () 27 (! · 4〇g, 9.00 mmol) The reaction yielded 74 (1.06 g, 84.1%); white powder. 4-Ethoxy-2- (3-doxymethoxyphenyl) chlozoline (75) and N3-ethyl_2- (3 * -methoxyphenyl) -4-. 2 azolinone (80). Refer to the synthetic method of 69 and 77, and react 43 (1.13 g, 4.50 mmol) with iodine: Yiyuan (1.40 g, 9.00 mmol) to obtain 75 (1.04 g, 82.5%) And 80 (0.14 g, 11.1%); white powder. 4-ethoxy-2- (4 · -methoxyphenyl) 2-oxazoline (76) and N3-ethyl-2- (4 · -methoxyphenyl) -4-oxazolinone ( 81). Refer to the synthesis method of 69 and 77, and react 44 (1.13 g, 4.50 mmol) with ethane (1.40 g, 9.00 mmol) to obtain 76 (1.07 g, 85.0%) and 81 (0.11 g, 8.8%); white powder. Table 1 lists the physical and spectral data of compounds 41 to 68; Table 2 lists the physical and spectral data of compounds 69 to 81. Cytotoxicity test The synthesized compounds 42-68 were tested in vitro and in vitro for cytotoxicity of human and mouse tumor cells in the School of Pharmacy, University of North Carolina, Chapel Hill, USA17. These tumor cells include human ovarian cancer (1A9), ileocecal cancer (HCT-8), lung cancer (A-549), glioblastoma (U-87-MG), bone cancer (HOS), and nasopharyngeal epidermoid Cancer (KB), P--30-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 public love) ----------- install ------%-order ---------- (Please read the notes on the back before filling this page) A7

五、發明說明（） 28 (請先閱讀背面之注意事項再填寫本頁) gp-表現之鼻咽表皮樣癌（KB-VIN)、***癌（PC3)、乳癌 (MCF-7)及黑色瘤（SKMEL-2)，其結果以抑制半數腫瘤細胞 生長所需之藥物莫耳濃度（ED5(3)表示。 抗微小管試驗19,2() 電泳（Electrophoretically)均質化的胎牛腦部微管依照 已發表論文中相同方法純化處理，Combretastatin A-4由亞 利桑那州立大學的G. R. Pettit博士所提供。 經濟部智慧財產局員工消費合作社印製 此項微管聚合試驗乃依照已發表論文中相同方法進行 測試21。將1.2 mg/ml ( 12 μΜ)微管放入0.8 Μ麩酸鈉0.24 ml (pH 6.6 )中，與各種不同濃度的藥物於26t中預先培養15 分鐘。而藥物的儲備溶液是以二甲亞碉（DMS0)爲溶媒，且 最後溶媒濃度是4 % (V/V)。所有的濃度均是用最後的反應 體積0·25 ml來換算。反應混合物以冰塊冷卻後，加入1〇 mM 鳥糞44嘌呤核苷三磷酸（GTP) 10 μΐ。將檢品移入藉由 Gilford光譜光度計的電動溫度控制器調控在〇°c之測試管 中。基線設定在350 nm，約50秒後溫度將躍升到26°C，此 時開始進行聚合反應。20分鐘後，會出現混濁的情形，再 將溫度控制器設定在0°C。當去聚合反應完成時，會再度出 現混濁的情形。通常，約90%之混濁情形是對冷溫具有可 逆性（cold-reversible)，且這冷溫可逆性的混濁情形表示每 一個反應混合物聚集之程度。從不同濃度的藥物抑制聚合 反應的圖形中可得到IC5Q値。 每個實驗均用到4個光譜光度計，而每一組則有2個對 -31 - 本紙張尺度適用中國國家標準（CNS)A4規格（21G X 297公釐) 490462 A7 __—B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（） 29 照反應。一般而言，對照反應的誤差在其平均値的5%內 時’此聚合反應分析所得到的IC5〇値通常有很高的再現 性。一般來說，標準誤差爲平均値的20%內，但在某些例 子，標準誤差則是平均値的30-35%。因此，我們可保守地 估計，若IC5()値中有50%的差異則表示2個化合物的相對活 性有所不同。 抑制血小板凝集的試驗 從兔子耳朵動脈所收集到的血被與EDTA混合而獲得 一濃度爲6mM的溶液，再於室溫下以90g離心10分鐘而獲得 一富於血小板的血漿。再繼續以500g離心該富於血小板的 血漿10分鐘，所收集到血小板以Tyrode’s溶液（不含EDTA) 加以淸洗。在以相同條件下加予離心後，將血小板懸浮於 一 Tyrode’s 溶液並具有下列組成（mM): NaCl (136.8)，KC1 (2.8)，NaHC03 (11·9)，MgCl2 (1.1)，NaH2P04 (0.3 3)，CaCl (l.o)及葡萄糖（11.2)。血小板的數目以一 Coulter計數器 (Model ZM)加予計算並調整至4·5 X 108血小板/m卜 血小板凝集係使用一雙通道Lumi凝集計（Model 1020, Payton,力Π 拿大）依 turbidimetric方法[0’1314611，】.11.*1.(^1111· Pathol. 1962, 15,452]加予測量。所有玻璃器具均被矽酮 化。待測化合物在加入凝集引導劑之前的一分鐘被加入， 其中血小板懸浮液以900rpm速度加予攪拌。凝集百分比的 If C. M.; Chen, W. Y.; Ko, W. C.; Ouyang, C. Biochem. Biophys. Acta. 1987, 924, 375的論文中所載的方 -32 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） (請先閱讀背面之注意事項再填寫本頁) 裝 訂*--- #· 490462 A7V. Description of the invention () 28 (Please read the precautions on the back before filling out this page) gp-representative nasopharyngeal epidermoid carcinoma (KB-VIN), prostate cancer (PC3), breast cancer (MCF-7) and melanoma (SKMEL-2), and the results are expressed as the molar concentration of the drug required to inhibit the growth of half of the tumor cells (ED5 (3). Anti-microtubule test 19,2 () Electrophoretically) homogenized fetal bovine microtubules Purbretastatin A-4 was provided by Dr. GR Pettit of Arizona State University according to the same method as in the published paper. The microtubule polymerization test printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs was performed in the same way as in the published paper Test 21. Put 1.2 mg / ml (12 μM) microtubes in 0.8 M sodium glutamate 0.24 ml (pH 6.6), and incubate for 15 minutes with drugs of various concentrations in 26t. The stock solution of the drug is Diosmium (DMS0) is the solvent, and the final solvent concentration is 4% (V / V). All concentrations are converted using the final reaction volume of 0. 25 ml. After the reaction mixture is cooled with ice, add 10%. mM Guano 44 Purine Nucleoside Triphosphate (GTP) 10 μΐ. Move the sample into a test tube controlled at 0 ° C by a Gilford spectrophotometer. The baseline is set at 350 nm, and the temperature will jump to 26 ° C in about 50 seconds. The polymerization reaction begins at some time. After 20 minutes, turbidity will appear, and then the temperature controller is set to 0 ° C. When the depolymerization reaction is completed, the turbidity will appear again. Generally, about 90% of the turbidity is It is cold-reversible to cold temperature, and this turbidity of cold temperature reversibility indicates the degree of aggregation of each reaction mixture. IC5Q 値 can be obtained from the graph of drug concentration polymerization inhibition at different concentrations. 4 spectrophotometers are used, and each pair has 2 pairs -31-This paper size applies to China National Standard (CNS) A4 (21G X 297 mm) 490462 A7 __— B7 Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the consumer cooperative V. Description of the invention () 29. In general, when the error of the control reaction is within 5% of its average value, the IC50 obtained by this polymerization reaction analysis is usually highly reproducible. In general, the standard error is within 20% of the average 値, but in some cases, the standard error is 30-35% of the average 値. Therefore, we can conservatively estimate that if 50% of IC5 () 値The difference indicates that the relative activities of the two compounds are different. Inhibition of platelet aggregation test Blood collected from rabbit ear arteries was mixed with EDTA to obtain a 6 mM solution, which was then centrifuged at 90 g for 10 minutes at room temperature. A platelet-rich plasma is obtained. The platelet-rich plasma was further centrifuged at 500 g for 10 minutes, and the collected platelets were rinsed with Tyrode's solution (without EDTA). After centrifugation under the same conditions, the platelets were suspended in a Tyrode's solution and had the following composition (mM): NaCl (136.8), KC1 (2.8), NaHC03 (11 · 9), MgCl2 (1.1), NaH2P04 (0.3 3), CaCl (lo) and glucose (11.2). The number of platelets was calculated by adding a Coulter counter (Model ZM) and adjusted to 4 · 5 X 108 platelets / m 2 platelet agglutination system using a dual-channel Lumi agglutination meter (Model 1020, Payton, Force II Canada) according to the turbidimetric method [0'1314611,]. 11. * 1. (^ 1111 · Pathol. 1962, 15,452] plus measurement. All glassware was siliconeized. The test compound was added one minute before the agglutination guide was added, The platelet suspension was stirred at 900 rpm. If CM; Chen, WY; Ko, WC; Ouyang, C. Biochem. Biophys. Acta. 1987, 924, 375. This paper size applies to China National Standard (CNS) A4 (210 χ 297 mm) (Please read the precautions on the back before filling this page) Binding * --- # · 490462 A7

經濟部智慧財產局員工消費合作社印製 五、發明說明（3〇 ) 法進行。 本發明實施例之結果與討論 (1). PQZ及DHPQZ之細胞致毒活性評估： 6,7,2’，3’，4’，5’-取代-2-苯基-4-口2唑啉酮類化合物（42-59)及6,2’，3’，4’，5’-取代-2,3-雙氫-2-苯基-4-口±唑啉酮類化 合物（60-68)以10種人類及老鼠腫瘤細胞進行體外細胞致毒 活性試驗，這些腫瘤細胞包括人類卵巢癌（1A9)、迴盲腸癌 (HCT-8)、肺癌（A-549)、神經膠母細胞瘤（U-87-MG)、骨癌 (HOS)、鼻咽表皮樣癌（KB)、P-gp-表現之鼻咽表皮樣癌 (KB-VIN)、***癌（PC3)、乳癌（MCF-7)及黑色瘤 (SKMEL-2)。結果如表3所示，化合物55-58對多種腫瘤細胞 具有顯著之細胞致毒活性（ED5Q < 1.0 gg/ml)，但其中55對 於神經膠母細胞瘤（U-87-MG)及骨癌（HOS)並不具活性。値 得注意的是55-58對於卵巢癌（1A9)具有高度選擇性的細胞 致毒活性，例如，55對於1A9的ED5Q爲0.49 pg/ml，這個濃 度比抑制其他較不敏感腫瘤細胞（如：A-549、KB、PC3及 SKMEL-2)所需的濃度約低了 20-3 0倍。56-59同樣地也對卵 巢癌（1A9)具有高度選擇性的細胞致毒活性。此外，55-58 對P-gp-表現之腫瘤細胞（KB-VIN)之活性優於對其母細胞 (KB)之活性，55和57對於敏感腫瘤細胞之活性分別爲抗藥 腫瘤細胞活性的25倍及15倍。 雖然55和56在結構上的差異性很小，56的細胞致毒活 性卻明顯地強了許多，同時對KB-VIN的選擇性明顯降低， -33 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------------— ^--------- (請先閱讀背面之注意事項再填寫本頁) 490462 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（） 31 原因目前尙不淸楚，可能其作用機轉不盡相同，因此我們 將進一步做深入的硏究。 探討其結構與活性之關係，發現當PQZ衍生物（42-49) 的6-位上沒有取代基時，不具細胞致毒活性·，而在比較6-位上給電子基與拉電子基的效應時，顯示有6-OCH3給電子 基的化合物（52)比6-C1 (50)、6-F (51)拉電子基的化合物更 具活性。雖然（亞甲二氧二基）苯常在普多非倫毒、五加前 胡素及combretastatin A-2等多種天然有絲***抑制劑的結 構中出現，但6,7-(亞甲二氧二基）取代的PQZ (54)與其他6-位上沒有取代基的PQZ (43)、6-甲氧基PQZ (52)或6,7-二甲 氧基PQZ (53)比較，其活性並沒有增加。在6-位上導入單一 取代基對提升其抗癌活性頗有助益，例如6-甲氧基PQZ (52) 對所有腫瘤細胞的致毒活性約爲6,7-二甲氧基PQZ (53)的5 倍。因此，在6-位上具有雜環或N(CH3)2的化合物（55-59)均 呈現非常優越之活性，其中以6-吡略啶基PQZ (56)之活性最 爲優異，具有微毫莫耳（nM)濃度的ED50。 PQZ (42-50)和DHPQZ (60-68)兩系列化合物在活性的表 現上呈現極大的差異，前者對多種腫瘤細胞呈現微弱之致 毒活性，但後者對1A9及KB-VIN則呈現高度選擇性的致毒 活性，一般說來，若以相同取代基的化合物做比較時，發 現DHPQZ比PQZ更具活性。只是在此DHPQZ化合物均以外 消旋混合物進行活性測試，理論上相信其中一個光學異構 物應提供較高之活性。若在DHPQZ的3’-位上導入一個0CH3 官能基（61)，其活性約爲2’- 0CH3 (60)及4’-OCH3 (62)的15- -34 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------裝--------丨訂·--- (請先閱讀背面之注意事項再填寫本頁) #· 經濟部智慧財產局員工消費合作社印製 490462 A7 _____B7__ 五、發明說明（） 32 20倍，此外，61也比其他具多個甲氧基取代的化合物（63-67)更具活性。這些情形與其他作爲有絲***抑制劑的雜環 酮（PQ、DHPQ、PN等）的結果是一致的。另外，6-C1-3’-甲氧基DHPQZ (68)的活性比61又明顯增力0 ，其ED50&61小 了約5倍。 如表3所示，PQZ及DHPQZ特別對卵巢癌具有顯著的細胞 致毒活性，對抗藥的KB腫瘤細胞具有選擇性的細胞致毒活 性。這個結果不同於其他類似結構的雜環酮，因爲其他的 雜環酮幾乎對所有的腫瘤細胞都有活性，而不具特殊的選 擇性。原因目前尙不淸楚，我們將進一步探討其作用機轉。 (2).PQZ 、DHPQZ與微管間作用之評估： 在稍早的硏究中發現PQ、DHPQ和PN可抑制微管聚合 反應以及以同位素標誌的秋水仙鹼對微管的結合反應5_ 10。新合成的PQZ、DHPQZ系列與稍早的PQ、DHPQ系列在 結構上主要不同之處即在於B環上多了一個氮原子；而新 合成的PQZ 、DHPQZ之間的結構差異則在於B環的C(2)和 C(3)間化學鍵的氧化或還原狀態，而造成芳香A環和C環相 對位置的組態及構形改變。許多的硏究報告指出秋水仙鹼 和微管之間的結合是具有立體選擇性，且與三甲氧苯基A 環及草酚酮C環所構成的雙環系統之組態和構形均有極大 關連。因此，評估新合成的PQZ 、DHPQZ和微管之間的結 合反應將可進一步提供與秋水仙鹼的結合機轉。在先前的 報告指出16，PQZ系列中的某些化合物可抑制微管聚合反應 -35 - 本紙張尺度適用中ΐ國家標準（CNS)A4規格(210 X 297公釐） ' —I-------------- 訂 **--I----- f請先閱讀背面之注意事項再填寫本頁} 經濟部智慧財產局員工消費合作社印製 490462 A7 ____Β7 _ 五、發明說明（） 33 而作爲有絲***抑制劑。爲了進一步歸納其結構與活性之 關係，將所合成的PQZ及DHPQZ評估其作爲微管聚合抑制 劑之活性，並與傳統的有絲***抑制劑（如：秋水仙鹼、 普多非倫毒、combretastatin A-4等）做比較。結果如表4所 示，其對微管的抑制活性與細胞致毒活性的結果具有一致 性。具有細胞致毒活性的化合物（52, 55-57, 59, 68)同時也 是微管聚合抑制劑，其中細胞致毒活性最強的化合物（56, 68)也是活性最強的微管聚合抑制劑，且其活性幾乎與天然 的有絲***抑制劑相當。相反地，細胞致毒活性微弱的化 合物（42-51)幾乎不具抑制微管聚合的活性。 與PQ、PN和DHPQ相同的情形，在A環上沒有取代的 PQZ、DHPQZ之活性遠小於6-取代的PQZ、DHPQZ。3’-甲氧 基衍生物（43, 61)的活性比2’-甲氧基（42, 60)、4’·甲氧基 (44, 62)衍生物顯著，多個甲氧基取代的衍生物（45-49)則出 現活性降低的情形，化合物63-67甚至完全失去活性。 除了 6-位上是1-甲六氫吡啶取代基的58之外（IC5。= 10-20// Μ)，其餘在6-位上具有雜環的化合物（56，57，59)均呈 現顯著之活性，造成58失去活性的原因尙不淸楚，或許58 的1-甲六氫吡啶取代基的體積較之於其他雜環（如：吡咯η定 基）龐大也是其中一個因素。6-吡咯啶基DHPQZ (56)是這 些化合物中最強的微管聚合抑制劑（IC5Q < 1 // Μ)，其活性 幾乎與秋水仙鹼相當。而非環狀的6-(N，N-二甲胺基）取代的 化合物55也具有顯著之活性（IC5{) = 1-4/i M)。 化合物62-66對於微管聚合幾乎不具抑制活性（IC5() > -36 - 本紙張尺度適用中國國家標準（CNS)A4規格（21G X 297公爱) '-— ----------I· I I---I 訂·--— — — — — — — (請先閱讀背面之注意事項再填寫本頁) ^0462 A7Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description (30) method. Results and discussion of the examples of the present invention (1). Evaluation of the cytotoxic activity of PQZ and DHPQZ: 6,7,2 ', 3', 4 ', 5'-substituted-2-phenyl-4-yl-2-azole Porphyrinone compounds (42-59) and 6,2 ', 3', 4 ', 5'-substituted-2,3-dihydro-2-phenyl-4-methylazolinone compounds (60- 68) Perform in vitro cytotoxicity tests on 10 human and mouse tumor cells, including human ovarian cancer (1A9), ileocecal cancer (HCT-8), lung cancer (A-549), and glioblastoma (U-87-MG), bone cancer (HOS), nasopharyngeal epidermoid carcinoma (KB), P-gp-presenting nasopharyngeal epidermoid carcinoma (KB-VIN), prostate cancer (PC3), breast cancer (MCF- 7) and melanoma (SKMEL-2). The results are shown in Table 3. Compounds 55-58 had significant cytotoxic activity on a variety of tumor cells (ED5Q < 1.0 gg / ml), but 55 of them were on glioblastoma (U-87-MG) and bone Cancer (HOS) is not active. It should be noted that 55-58 has a highly selective cytotoxic activity against ovarian cancer (1A9). For example, 55 has an ED5Q of 0.49 pg / ml for 1A9, which is a concentration that inhibits other less sensitive tumor cells (such as: A-549, KB, PC3, and SKMEL-2) require about 20-30 times lower concentrations. 56-59 also has highly selective cytotoxic activity against nested carcinoma (1A9). In addition, the activity of 55-58 on P-gp-expressing tumor cells (KB-VIN) is better than that of its parent cells (KB), and the activity of 55 and 57 on sensitive tumor cells is that of drug-resistant tumor cells, respectively. 25 times and 15 times. Although the structural differences between 55 and 56 are small, the cytotoxic activity of 56 is obviously much stronger, and the selectivity to KB-VIN is significantly reduced. -33-This paper standard applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) -------------------— ^ --------- (Please read the precautions on the back before filling in this Page) 490462 Printed by the Consumer Property Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention () 31 The reason is not clear at present, and its role may not be the same, so we will do further research. The relationship between structure and activity was investigated, and it was found that when there is no substituent at the 6-position of the PQZ derivative (42-49), there is no cytotoxic activity, and the electron-donating group and the electron-drawing group at the 6-position are compared. In effect, the compound (52) showing 6-OCH3 electron-donating group is more active than the compound having 6-C1 (50) and 6-F (51) electron-drawing group. Although (methylenedioxydiyl) benzene is often found in the structure of many natural mitotic inhibitors, such as produrafiloxan, wujia procapsin, and combrestatatin A-2, 6,7- (methylenedioxo Group) substituted PQZ (54) compared with other PQZ (43), 6-methoxy PQZ (52) or 6,7-dimethoxy PQZ (53) without a substituent at the 6-position. No increase. The introduction of a single substituent at the 6-position is very helpful to improve its anti-cancer activity. For example, the toxic activity of 6-methoxy PQZ (52) on all tumor cells is about 6,7-dimethoxy PQZ ( 53). Therefore, compounds (55-59) with a heterocyclic ring or N (CH3) 2 at the 6-position all exhibit very excellent activity, of which the 6-pyrrolidinyl PQZ (56) has the highest activity and has a slight activity. ED50 at millimolar (nM) concentration. PQZ (42-50) and DHPQZ (60-68) two series of compounds show great differences in the performance of the activity, the former shows a weak toxic activity against a variety of tumor cells, but the latter shows a high selection of 1A9 and KB-VIN Generally speaking, when comparing compounds with the same substituents, it is found that DHPQZ is more active than PQZ. Only the DHPQZ compounds are tested for activity in the racemic mixture. It is theoretically believed that one of the optical isomers should provide higher activity. If a 0CH3 functional group (61) is introduced at the 3'-position of DHPQZ, its activity is about 15- -34 of 2'- 0CH3 (60) and 4'-OCH3 (62). (CNS) A4 specification (210 X 297 mm) ------------ install -------- 丨 order --- (Please read the precautions on the back before filling in this Page) # · Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 490462 A7 _____B7__ V. Description of the invention () 32 20 times, in addition, 61 is more active than other compounds with multiple methoxy substitutions (63-67) . These situations are consistent with the results of other heterocyclic ketones (PQ, DHPQ, PN, etc.) as mitotic inhibitors. In addition, the activity of 6-C1-3'-methoxy DHPQZ (68) was significantly stronger than that of 61, and its ED50 & 61 was about 5 times smaller. As shown in Table 3, PQZ and DHPQZ particularly have significant cytotoxic activity against ovarian cancer, and KB tumor cells with anti-drug have selective cytotoxic activity. This result is different from other heterocyclic ketones of similar structure, because other heterocyclic ketones are active on almost all tumor cells and are not particularly selective. The reason is not clear at this time, we will further explore its mechanism of action. (2). Evaluation of the interaction between PQZ, DHPQZ and microtubules: It was found in earlier studies that PQ, DHPQ and PN can inhibit the polymerization of microtubules and the binding reaction of colchicine labeled with isotopes to microtubules 5_ 10 . The main structural difference between the newly synthesized PQZ and DHPQZ series and the earlier PQ and DHPQ series is that there is one more nitrogen atom on the B ring; while the structural difference between the newly synthesized PQZ and DHPQZ is on the B ring The oxidation or reduction state of the chemical bond between C (2) and C (3) causes the configuration and configuration of the relative positions of the aromatic A ring and C ring to change. Many research reports indicate that the binding between colchicine and microtubules is stereoselective, and that the configuration and configuration of the bicyclic system composed of trimethoxyphenyl A ring and oxalone C ring are extremely large. linking. Therefore, evaluating the binding reactions between newly synthesized PQZ, DHPQZ and microtubules will further provide a mechanism for binding with colchicine. In previous reports, 16, certain compounds in the PQZ series can inhibit the polymerization of microtubules. -35-This paper is applicable to the China National Standard (CNS) A4 specification (210 X 297 mm) '—I ---- ---------- Order **-I ----- f Please read the notes on the back before filling out this page} Printed by the Intellectual Property Bureau Employee Consumer Cooperative of the Ministry of Economic Affairs 490462 A7 ____ Β7 _ V. Description of the invention (33) And as a mitotic inhibitor. In order to further summarize the relationship between structure and activity, the synthesized PQZ and DHPQZ were evaluated for their activity as inhibitors of microtubule polymerization, and compared with traditional mitotic inhibitors (such as colchicine, podofiloxin, combetastatin A -4 etc.) for comparison. The results are shown in Table 4. The inhibitory activity on microtubules was consistent with the results of cytotoxic activity. Compounds with cytotoxic activity (52, 55-57, 59, 68) are also microtubule polymerization inhibitors, of which the compound with the strongest cytotoxic activity (56, 68) is also the most active microtubule polymerization inhibitor, and Its activity is almost equivalent to that of a natural mitotic inhibitor. In contrast, compounds with weak cytotoxic activity (42-51) have little activity to inhibit microtubule polymerization. As in the case of PQ, PN and DHPQ, the activity of unsubstituted PQZ and DHPQZ on the A ring is much lower than that of 6-substituted PQZ and DHPQZ. 3'-methoxy derivative (43, 61) is more active than 2'-methoxy (42, 60) and 4 '· methoxy (44, 62) derivatives. Derivatives (45-49) show reduced activity, and compounds 63-67 even lose their activity completely. Except for the 1-methylhexahydropyridine substituent at the 6-position (IC5. = 10-20 // M), the other compounds with a heterocyclic ring at the 6-position (56, 57, 59) all present Significant activity, the reason for the inactivation of 58 is not clear. Perhaps the volume of the 1-methylhexahydropyridine substituent of 58 is larger than that of other heterocycles (such as pyrrolyl nyl). 6-pyrrolidinyl DHPQZ (56) is the strongest microtubule polymerization inhibitor of these compounds (IC5Q < 1 // M), and its activity is almost equivalent to that of colchicine. The non-cyclic 6- (N, N-dimethylamino) -substituted compound 55 also has significant activity (IC5 {) = 1-4 / i M). Compound 62-66 has almost no inhibitory activity on the polymerization of microtubules (IC5 () > -36-This paper size applies the Chinese National Standard (CNS) A4 specification (21G X 297 public love) '--- ------- --- I · I I --- I Order · --—— — — — — — — (Please read the notes on the back before filling this page) ^ 0462 A7

經濟部智慧財產局員工消費合作社印製 五、發明說明（） 34 40 " M)，推測可能與DHPQZ是以外消旋混合物進行測試有 關。在稍早的硏究中，DHPQ經過單離後的光學異構物比單 離前的外消旋混合物更具活性，因此我們有理由相信 DHPQZ經過單離後的光學異構物應呈現較強之活性，其細 胞致毒活性與抑制微管聚合活性間的關係就與其他雜環酮 一樣地具有一致性。同時，6-雜環DHPQZ經過單離後的光 學異構物也具有較強的及高選擇性的抗癌活性。 表5列出了化合物69及70對由凝血酶（thrombin)、花生 四嫌酸（arach id onic acid，AA)、膠原蛋白（collagen)及血小 板活化因子（platelet-activating factor，PAF)所引導的血小 板凝集的抑制活性。從其中可看出化合物69及70對由AA及 膠原蛋白所引導的血小板凝集具有較強的抑制活性，而對 凝血酶及PAF所引導的血小板凝集則具較差的抑制活性。 表6進一步列出了化合物69至79對由AA所引導的血 小板凝集的抑制活性。 參考文獻： 1. Rowinsky，E. K.; Donehower, R. C. The clinical pharmacology and use of antimicrotubule agents in cancer chemotherapeutics. Pharmacol. Ther. 1992，52， 35-84. 2. Verweij, J.; Clavel, M.; Chevalier, B. Paclitaxel (Taxol) and docetaxel (Taxotere): not simply two of a kind. Ann. Oncol. 1 994, 5, 495-505. -37 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 裝·------ 訂-—------- (請先閱讀背面之注意事項再填寫本頁) 490462 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（） 35 3. Hastie，S. B. Interactions of colchicine with tubulin. Pharmacol. Ther. 1991, 51, 377-401. 4. Brossi, A.; Yeh, H. J.; Chrzanowska, M.; Wolff, J.; Hamel，E·; Lin，C. M·; Quinn, F·; Suffness，M·; Silverton， J. Colchicine and its analogues: recent findings. Med. Res. Rev. 1988, 8, 77-94. 5 . Kuo, S. C.; Lee, Η. Z.; Juang, J. P.; Lin, Y. T.; Wu, T. S.; Chang, J. J.; Ledniced, D.; Pauli, K. D.; Lin, C. M.; Hamel, E.; Lee, K. H. Synthesis and cytotoxicity of 1,6,7,8 and 4f-substituted 2-pheny 1-4-quinolones and related compounds: identification as antimitotic agents interacting with tubulin. J. Med. Chem. 1993, 36, 1146-1156. 6. Li, L·; Eang，Η. K·; Kuo，S. C·; Lednicer，D·; Lin，C· M·; Hamel，E.;Lee，K.H.2’，3’，4'，5’，5,6,7-Substituted2-phenyl-4-quinolones and related compounds: their synthesis, cytotoxicity, and inhibition of tubulin polymerization. J. Med. Chem. 1994, 37 (8), 1 126-1 135. 7. Li, L.; Wang, Η. K.; Kuo, S. C.; Wu, T. S.; Mauger, A.; Lin, C. M.; Hamel, E.; Lee, K. H. Synthesis and biologicalevaluationof3’，6’，7-substituted2-phenyl-4-quinolones as antimitotic antitumor agents. J. Med. Chem. 1994, 37 (20), 3400-3407. 8. Xia，Y·; Yang，Ζ· Y·; Xia，P·; Bastow，K· F·; Tachibana， -38 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） ------------^-------1 ^---------' (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 490462 A7 —____B7_ 五、發明說明（） 36 Y.; Kuo, S. C.; Hamel, E.; Hackl, T.; Lee, K. Η. Synthesis and biological evaluation of 6,7,2,,3r54,-substituted -1,2,3,4-tetrahydro-2-phenyl-4-quinolones as a new class of antimitotic agents. J. Med· Chem. 1998, 41 (7), 1155-1162. 9. Chen, K.; Kuo, S. C.; Hsih, M.C.; Mauger, A.; Lin, C. M.; Hamel, E·; Lee，K. H. 2’，3’，4’，5,6,7-Substituted 2-phenyl-1，8-naphthyridin-4-ones: their synthesis， cytotoxicity, and inhibition of tubulin polymerization. J. Med. Chem. 1996, 40 (14), 2266-2275. 10. Chen, K.; Kuo, S. C.; Hsih, M.C.; Mauger, A.; Lin, C. M.; Hamel, E.; Lee, K. H. Synthesis and biological evaluation of substituted 2-aryl-1,8-naphthyridin-4(lH)-ones as antimitotic antitumor agents that inhibit tubulin polymerization. J. Med. Chem. 1997，40 (19)， 3049-3056. 11. Yale, H. J.; Kalkstein, M. Substituted 2,3-dihydro- 4( 1 H)-quinazolinones. A new class of inhibitors of cell multiplication. J. Med. Chem. 1 967, 1 0, 334-336. 12. Neil, G. L.; Li, L. H.; Buskirk, Η. H.; Moxlcy, T. E. Antitumor effects of the antispermatogenic agent, 2,3-dihydro-2-(1 - naphthy 1)-4( 1 H)-quinazolinones. Cancer Chemother. 1 972, 56, 1 63-1 73. 13. Hamel, E.; Lin, C. M.; Plowman, J.; Wang, Η. K.; Lee, K. -39 - 本紙張尺度適用中國國家標準(CNS)A4規格（21G x 297公釐） " ---------—裝·--— — If— --------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 A7 B7_ 1、發明說明（37 ) H.; Pauli, K. D. Antitumor 2,3-dihydro-2-(aryl)-4(lH)-quinazolinone derivatives. Interactions with tubulin. Biochem. Pharmacol. 1996, 51, 53-5 9. 14. Jiang, J. B.; Hesson, D. P.; Dusak, B. A.; Dexter, D. L.; Kang, G. J.; Hamel, E. Synthesis and biological evaluation of 2-styryl-quinazolin-4(3H)-ones, a new class of antimitotic anticancer agents which inhibit tubulin polymerization. J. Med. Chem. 1990, 33, 1721-1728. 15. Lin, C. M.; Kang, G. J.; Roach, M. C.; Jiang, J. B.; Hesson, D. P.; Luduena, R. F.; Hamel, E. Investigation of the mechanism of the interaction of tubulin with derivatives of 2-styrylquinazolin-4(3H)-one. Mol· Pharmacol. 1991, 40, 827-832. 16. Xia, Y.; Yang, Z. Y.; Hour, M. J.; Kuo, S. C.; Xia, P.; Bastow, K. F.; Nakanishi, Y.; Nampoothiri, P.; Hackl, T.; Hamel, E.; Lee, K. H. Synthesis and biological evaluation of substituted 2-arylquinazolinones. Bioorg. Med. Chem. Lett, (submitted) 17. Lee, K. H.; Lin, Y. M.; Wu5 T. S.; Zhang, D. C.; Yamagishi, T.; Hayashi, T.; Hall, I. H.; Chang, J. J.; Wu, R. Y.; Yang, T. H. The cytotoxic principles of Prunella vulgaris, Psychotria serpens, and Hyptis captitata: Ursolic acid and related derivatives. Planta Med. 1988, -40 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） ~~ -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 490462 A7 B7_ 五、發明說明（38 ) 54, 308-312. 18. Boyd, M. R. Status oh the NCI preclinical antitumor drug disovery screen. In Cancer: Principles and Practice of Oncology Updates^ De Vita, V. T., Heilman, S., Rosenberg, S. A., Eds; J. B. Lippincoft: Philadelphia, 1989; pp 1-12. 19. Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Pauli, K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Woiff, A.; Gray-Goodrich, M.; Campbell, H.; Mayo, J.; Boyd, M. Feasibility of a high-flux anticancer drug screen utilizing a derived panel of human tumor cell lines in culture. J. Natl. Cancer Inst. 199 1, 83, 757-766. 20. Hamel, E.; Lin, C. M. Separation of active tubulin and microtubule-associated proteins by ultracentrifugation and isolation of a component causing the formation of microtubule bundles. Biochemistry 1984, 23, 4173-4184. 21. D9Amato, R. J.; Lin, C. M.; Flynn, E.; Folkman, J.; Hamel, E. 2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site. Proc. Natl. Acad. Sci. U. S. A· 1994, 91, 3964-3968. -41 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） (請先閱讀背面之注意事項再填寫本頁) 一裝---- ·11111111 經濟部智慧財產局員工消費合作社印製 MU462 五、 A7 _B7__ 發明說明（39 )表1·6-院基胺基- 3··甲氧基-2-苯基-4· α宏哩琳嗣、2,3-雙氫 -3’-甲氧基_2-苯基-4-Π查唑啉酮及相關化合物之物理 及光譜數據 R6 R?Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of Invention () 34 40 " M), it is speculated that it may be related to the test of DHPQZ as a racemic mixture. In earlier studies, the optical isomers of DHPQ after isolation were more active than the racemic mixtures before isolation, so we have reason to believe that the optical isomers of DHPQZ after isolation should be stronger. The relationship between its cytotoxicity and inhibition of microtubule polymerization is as consistent as other heterocyclic ketones. At the same time, the optical isomers of 6-heterocyclic DHPQZ after isolation also have strong and highly selective anticancer activity. Table 5 lists compounds 69 and 70 guided by thrombin, arach id onic acid (AA), collagen and platelet-activating factor (PAF). Inhibitory activity of platelet aggregation. It can be seen that compounds 69 and 70 have strong inhibitory activity on platelet aggregation induced by AA and collagen, but have poor inhibitory activity on platelet aggregation induced by thrombin and PAF. Table 6 further lists the inhibitory activities of compounds 69 to 79 on platelet aggregation induced by AA. References: 1. Rowinsky, EK; Donehower, RC The clinical pharmacology and use of antimicrotubule agents in cancer chemotherapeutics. Pharmacol. Ther. 1992, 52, 35-84. 2. Verweij, J .; Clavel, M .; Chevalier, B. Paclitaxel (Taxol) and docetaxel (Taxotere): not simply two of a kind. Ann. Oncol. 1 994, 5, 495-505. -37-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Packing ------- Order ---------- (Please read the precautions on the back before filling out this page) 490462 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (35) Hastie, SB Interactions of colchicine with tubulin. Pharmacol. Ther. 1991, 51, 377-401. 4. Brossi, A .; Yeh, HJ; Chrzanowska, M .; Wolff, J .; Hamel , E ·; Lin, C. M ·; Quinn, F ·; Suffness, M ·; Silverton, J. Colchicine and its analogues: recent findings. Med. Res. Rev. 1988, 8, 77-94. 5. Kuo , SC; Lee, Η. Z .; Juang, JP; Lin, YT; Wu, TS; Chang, JJ; Ledniced, D .; Pauli, KD; Lin, CM; Hame l, E .; Lee, KH Synthesis and cytotoxicity of 1,6,7,8 and 4f-substituted 2-pheny 1-4-quinolones and related compounds: identification as antimitotic agents interacting with tubulin. J. Med. Chem. 1993 , 36, 1146-1156. 6. Li, L ·; Eang, Η. K ·; Kuo, S. C ·; Lednicer, D ·; Lin, C · M ·; Hamel, E .; Lee, KH2 ' , 3 ', 4', 5 ', 5,6, 7-Substituted2-phenyl-4-quinolones and related compounds: their synthesis, cytotoxicity, and inhibition of tubulin polymerization. J. Med. Chem. 1994, 37 (8) , 1 126-1 135. 7. Li, L .; Wang, Η. K .; Kuo, SC; Wu, TS; Mauger, A .; Lin, CM; Hamel, E .; Lee, KH Synthesis and biologicalevaluationof3 ' , 6 ', 7-substituted2-phenyl-4-quinolones as antimitotic antitumor agents. J. Med. Chem. 1994, 37 (20), 3400-3407. 8. Xia, Y ·; Yang, Z · Y ·; Xia , P ·; Bastow, K · F ·; Tachibana, -38-This paper size is applicable to China National Standard (CNS) A4 (210 x 297 mm) ------------ ^- ----- 1 ^ --------- '(Please read the notes on the back before filling Page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 490462 A7 —____ B7_ V. Description of the Invention () 36 Y .; Kuo, SC; Hamel, E .; Hackl, T .; Lee, K. Η. Synthesis and biological evaluation of 6,7,2,, 3r54, -substituted -1,2,3,4-tetrahydro-2-phenyl-4-quinolones as a new class of antimitotic agents. J. Med · Chem. 1998, 41 (7) , 1155-1162. 9. Chen, K .; Kuo, SC; Hsih, MC; Mauger, A .; Lin, CM; Hamel, E ·; Lee, KH 2 ', 3', 4 ', 5,6, 7-Substituted 2-phenyl-1,8-naphthyridin-4-ones: their synthesis, cytotoxicity, and inhibition of tubulin polymerization. J. Med. Chem. 1996, 40 (14), 2266-2275. 10. Chen, K .; Kuo, SC; Hsih, MC; Mauger, A .; Lin, CM; Hamel, E .; Lee, KH Synthesis and biological evaluation of substituted 2-aryl-1,8-naphthyridin-4 (lH) -ones as antimitotic antitumor agents that inhibit tubulin polymerization. J. Med. Chem. 1997, 40 (19), 3049-3056. 11. Yale, HJ; Kalkstein, M. Substituted 2, 3-dihydro- 4 (1 H) -quinazolinones. A new class of inhibi tors of cell multiplication. J. Med. Chem. 1 967, 1 0, 334-336. 12. Neil, GL; Li, LH; Buskirk, Η. H .; Moxlcy, TE Antitumor effects of the antispermatogenic agent, 2, 3-dihydro-2- (1-naphthy 1) -4 (1 H) -quinazolinones. Cancer Chemother. 1 972, 56, 1 63-1 73. 13. Hamel, E .; Lin, CM; Plowman, J. ; Wang, Η. K .; Lee, K. -39-This paper size applies to China National Standard (CNS) A4 (21G x 297 mm) " ----------- installation --- — — If— --------- (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7_ 1. Description of Invention (37) H .; Pauli, KD Antitumor 2,3-dihydro-2- (aryl) -4 (lH) -quinazolinone derivatives. Interactions with tubulin. Biochem. Pharmacol. 1996, 51, 53-5 9. 14. Jiang, JB; Hesson, DP; Dusak , BA; Dexter, DL; Kang, GJ; Hamel, E. Synthesis and biological evaluation of 2-styryl-quinazolin-4 (3H) -ones, a new class of antimitotic anticancer agents which inhibit tubulin polymerization. J. Med. Chem . 1990, 33 , 1721-1728. 15. Lin, CM; Kang, GJ; Roach, MC; Jiang, JB; Hesson, DP; Luduena, RF; Hamel, E. Investigation of the mechanism of the interaction of tubulin with derivatives of 2-styrylquinazolin -4 (3H) -one. Mol · Pharmacol. 1991, 40, 827-832. 16. Xia, Y .; Yang, ZY; Hour, MJ; Kuo, SC; Xia, P .; Bastow, KF; Nakanishi, Y .; Nampoothiri, P .; Hackl, T .; Hamel, E .; Lee, KH Synthesis and biological evaluation of substituted 2-arylquinazolinones. Bioorg. Med. Chem. Lett, (submitted) 17. Lee, KH; Lin, YM; Wu5 TS; Zhang, DC; Yamagishi, T .; Hayashi, T .; Hall, IH; Chang, JJ; Wu, RY; Yang, TH The cytotoxic principles of Prunella vulgaris, Psychotria serpens, and Hyptis captitata: Ursolic acid and related derivatives. Planta Med. 1988, -40-This paper size is applicable to China National Standard (CNS) A4 (210 x 297 mm) ~~ ----------- pack ----- --- Order --------- (Please read the notes on the back before filling out this page) 490462 A7 B7_ V. Description of the invention (38) 54, 3 08-312. 18. Boyd, MR Status oh the NCI preclinical antitumor drug disovery screen. In Cancer: Principles and Practice of Oncology Updates ^ De Vita, VT, Heilman, S., Rosenberg, SA, Eds; JB Lippincoft: Philadelphia, 1989; pp 1-12. 19. Monks, A .; Scudiero, D .; Skehan, P .; Shoemaker, R .; Pauli, K .; Vistica, D .; Hose, C .; Langley, J .; Cronise , P .; Vaigro-Woiff, A .; Gray-Goodrich, M .; Campbell, H .; Mayo, J .; Boyd, M. Feasibility of a high-flux anticancer drug screen utilizing a derived panel of human tumor cell lines in culture. J. Natl. Cancer Inst. 199 1, 83, 757-766. 20. Hamel, E .; Lin, CM Separation of active tubulin and microtubule-associated proteins by ultracentrifugation and isolation of a component causing the formation of microtubule bundles. Biochemistry 1984, 23, 4173-4184. 21. D9Amato, RJ; Lin, CM; Flynn, E .; Folkman, J .; Hamel, E. 2-Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site. P roc. Natl. Acad. Sci. US A · 1994, 91, 3964-3968. -41-This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) (Please read the precautions on the back before (Fill in this page) One pack ---- · 11111111 Printed by MU462 of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. A7 _B7__ Description of the invention (39) Table 1 · 6-Aminoamino-3 ·· methoxy-2 -Phenyl-4 · α macromolin 哩, 2,3-dihydro-3'-methoxy_2-phenyl-4-Πchazolinone and related compounds R6 R?

化合產率 mp UV，入随 IR，MS(M+) lH-NMR (DMS〇-,/6) δ 理論値，％ 物（。/。) (°C) (MeOH) (cm*1) 忉么 （計算値） .〜_ (log ε) C Η Ν 41 93 232- 237 233 (4.47) 42 89 198- 211 202 (4.50) 43 95 177- 218 179 (4.41) (請先閱讀背面之注意事項再填寫本頁) 一裝----- 經濟部智慧財產局員工消費合作社印製 44 96 215- 207 219 (4.38) 45 86 179- 223 181 (4.52) 1671 222 7.48-7.59 (4 H，m，H-6, H-3，，75.66 Η·4，，H-5，)，7.71-7.84 (2 H，（75·60) m, H-7, H-8), 8.13-8.20 (3 H, m，H-5, H-2’，H-6，)，12.56 (1 H，brs，NH) 1678 252 3.86 (3 H, s，OCH3)，7.05- 71.42 7.21 (2 H，m，H-3’，H-5’)，（71.40) 7.49-7.58 (2 H, m, H-41, H-6)，7.69-7.73 (2 H，m，H-6·， H-8), 7.83(1 H, ddd,J= 1.2, 8.0, 8.0 Hz, H-7), 8.15 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 12.13(1 H, brs,NH) 1672 252 3.86 (3 H, s, OCH3), 7.14 (1 71.42 H, dd, J = 2.2, 8.0 Hz, H-4f), (71.44) 7.41-7.56 (2 H, m, H-5f, H-6), 7.74-7.88 (4 H, m, H-2', Η-ό^, H-7, H-8), 8.15 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 12.55(1 H, brs, NH) 1678 252 3.83 (3 H, s, OCH3), 7.08 (2 71.42 H, d, J = 8.0 Hz, H-3f, H-5'), (71.39) 7.47 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-6), 7.67-7.85 (2 H, m, H-7, H-8), 8.10-8.20 (3 H, m，H-2’，H-6’，H-5)，12.42 (1 H，brs，NH) 1678 282 3.76 (3 H，s，2’-OCH3 or 3，- 68.08 OCH3)，3.87 (3 H，s，2，- (6805) OCH3 or 3'-OCH3), 7.18-7.28 4.54 12.61 (4.46) (12.52) 4.80 11.10 (4.83) (11.12) 4.80 11.10 (4.78) (11.07) 4.80 11.10 (4.81) (11.13) 5.00 9.92 (5.06) (9.88) 訂 % -42- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 490462 A7 B7 五、發明說明（40 ) 46 84 184- 207 186 (4.27) 1678 282 47 88 143- 220 1698 144 (4.70) 282 48 89 240- 226 242 (4.44) 1671 282 經濟部智慧財產局員工消費合作社印製 49 84 200- 221 203 (4.57) 1674 282 (3 H，m，H-4，，H-5，，H-6，)， 7.54 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-6), 7.70(1 H, dd, J =1.2, 8.0 Hz, H-8), 7.84 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-7), 8.16(1 H, dd, J= 1.2, 8.0 Hz, H-5), 12.23 (1 H, br s, NH) 3.85(3 H, s, 2f-OCH3 or 4f-OCH3)，3.89 (3 H，s，2，-OCH3 or 4，-OCH3)，6.65-6.72 (2 H，m，H-3丨，H-5，)， 7.49 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-6), 7.67 (1 H, dd, J =1.2, 8.0 Hz, H-8), 7.76-7.85 (2 H, m, H-6f, H-7), 8.12 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 11.82 (1 H, br s, NH) 3.77(3 H，s，2，-OCH3 or 5，-OCH3), 3.81 (3 H, s, 2f-OCH3 or 5’-OCH3)，7.10-7.12 (2H，m，H-3’，H-4，)，7.29-7.31 (1 H, m, H-6'), 7.53 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-6), 7.71 (1 H, dd, J = 1.2, 8.0 Hz, H-8), 7.83(1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-7), 8.14 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 12.10 (1 H, br s, NH) 3.84(3 H，s，3，-OCH3 or 4，-OCH3), 3.88 (3 H，s，3’-OCH3 or 4?-OCH3), 7.10 (1 H, d, J = 8.0 Hz, H-5f), 7.48 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-6), 7.69-7.89 (4 H, m, H-2', H-6', H-7, H-8), 8.13(1 H, dd, J = 1.2, 8.0 Hz, H-5), 12.44(1 H, brs, NH) 3.83 (6 H, s, 3'-OCH3 , 5f-OCH3), 6.69 (1 H, dd, J = 2.2, 2.2 Hz, H-4f), 7. 38 (2 H, d, J = 2.2 Hz, H-2f, H-6'), 7.52 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-6), 7.74(1 H, dd, J =1.2, 8.0 Hz, H-8), 7.83 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-7), 8.15 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 12.52 (1 H, br s, NH) 68.08 (68.13) 5.00 9.92 (4.96) (9.86) -43- 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 68.08 (68.00) 68.08 (67.99) 68.08 (68.11) 5.00 9.92 (4.95) (9.97) 5.00 9.92 (5.03) (9.89) 5.00 9.92 (5.06) (9.85) (請先閱讀背面之注意事項再填寫本頁) 裝---- ·11111111 490462 A7 B7 五、發明說明（ 50 94 245- 218 248 (4.60) 1678 286.5 51 46.8 246- 217 247 (4.70) 1680 270 52 42 216- 218 218 (4.69) 1659 282 53 30 266- 253 267 (4.55) 1658 312 54 8.8 269- 249 270 (4.48) 1665 296 經濟部智慧財產局員工消費合作社印製 55 51 239- 224 241 (4.79) 1659 295 3.86 (3 H，s，3，-OCH3)，7.16 (1 H, dd, J = 2.5, 8.0 Hz, H-4'), 7. 46 (1 H, dd, J = 8.0, 8.0 Hz, H-5f), 7.73-7.80 (3 H，m，H-2’，Η·6’，H-8)，7.87 (1 H, dd, J = 2.5, 8.0 Hz, H-7), 8.09 (1 H, d, J = 2.5 Hz, H-5), 12.70(1 H, brs, NH) 3.84 (3 H，s，3，-OCH3), 7.13 (1 H, dd, J = 2.5, 8.0 Hz, H-4f),7.44(lH, dd, J = 8.0, 8.0 Hz, H-5f), 7.68-7.84 (5 H, m, H-2f, H-6f} H-5, H-7, H-8), 12.61 (1 H, brs, NH) 3.86 (3 H, s, 3'-OCH3 or 6-OCH3), 3.96 (3 H，s，3·-OCH3 or6-OCH3), 7.11 (1 H, dd, J = 2.5, 8.0 Hz, H-4'), 7. 29-7.49 (2H, m, H-5', H-7), 7.53 (1 H, d, J = 2.5 Hz, H-5), 7.67-7.82 (3 H, m, H-21, H-61, H-8), 12.48 (1 H, br s, NH) 3.86 (3 H, s, 3,-OCH3 or 6-OCH3 or 7-OCH3), 3.89 (3 H，s，3，-OCH3 or 6-OCH3 or 7-OCH3), 3.94 (3 H, s, 3'-OCH3 or 6-OCH3 or 7-OCH3), 7.11 (1 H, dd, J = 1.2, 8.0 Hz，H-4’)，7.21 (1 H， s, H-8), 7. 43 (1 H, dd, J = 8.0, 8.0 Hz, H-5'),7.48(l H, s, H-5), 7.73-7.78 (2 H, m, H-2', H-6'), 12.40 (1 H, br s, NH) 3.85 (3 H, s, 3,-OCH3), 6.20 (2 H, s, OCH20), 7.11 (1 H, dd, J = 2.2, 8.0 Hz, H-4'), 7. 18 (1 H, s, H-8), 7.43 (1H, dd, J = 8.0, 8.0 Hz, H-5'), 7.44 (1 H, s, H-5), 7.68-7.75 (2 H，m，H-2’，H-6’)，12.46(1 H, br s, NH) 3.01 (s, 6 H, N(CH3)2), 3.85 (3 H, s, 3f-OCH3), 7.07 (1 H, dd, J = 2.5, 8.0 Hz, H-4'), 7. 21 (1H, d, J = 2.5 Hz, H-5), 7.33 (1 H, dd, J = 2.5, 8.0 Hz, H-7), 7.41 (1 H, dd, J = 8.0, 8.0 Hz, H-5'), 7.61 (1 H, 62.84 (62.78) 3.87 9.77 (3.80) (9.81) 66.66 (66.68) 68.08 (68.04) 65.38 (65.30) 64.86 (64.89) 69.14 (69.10) 4.10 10.37 (4.08) (10.41) 5.00 9.92 (5.06) (9.86) 5.16 8.97 (5.20) (8.91) 4.08 9.46 (4.03) (9.50) 5.80 14.23 (5.77) (14.20) (請先閱讀背面之注意事項再填寫本頁) 一裝---- 訂--------- -44- 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 490462 A7 B7 五、發明說明（42 56 40 261- 227 263 (4.54) 1653 57 55 222- 223 1668 225 (4.71) 58 57 212- 224 1663 215 (4.61) 經濟部智慧財產局員工消費合作社印製 59 48 254- 225 1673 257 (4.66) d, J = 8.0 Hz, H-8), 7.70-7.76 (2H，m，H-2’，H-6’)，12.26(1 H，brs，NH) 321 1.96-2.03 (4 H, m, 71.01 5.96 13.08 CH2CH2NCH2CH2), 3.30- (71.05) (5.90) (13.02) 3.34 (4 H, m, CH2NCH2), 3.85 (3 H, s, 3,-OCH3), 7.03-7.17 (3 H, m, H-4f, H-5, H-7), 7.41 (1 H, dd,J = 8.0, 8.0 Hz, H-51), 7.60 (1H, d, J = 8.0 Hz, H-8), 7.68-7.75 (2 H, m，H-2’，H-6’)，12.22(1 H，br s，NH) 335 1.55-1.60 (6 H, m, 71.62 6.31 12.53 (CH2)2CH,NCH2CH2), 3.25- (71.59) (6.28) (12.50) 3.30 (4 H, m, CH2NCH2), 3.85 (3 H，s，3，-OCH3)，7.09 (1 H, dd, J = 2.2, 8.0 Hz, H-41), 7.38-7.46 (2 H, m, U-5\ H-5), 7.53 (1 H, dd, J = 2.2, 8.0 Hz, H-7), 7.60 (1 H, d, J ==8.0 Hz, H-8), 7.70 -7.76 (2 H, m, H-2*, H-6f), 12.33 (1 H, br s, NH) 349 0.93 (3 H, d, J = 6.2 Hz, 72.18 6.63 12.03 CH3CH(CH,) 2N(CH2) 2)，（72.15) (6.60) (12.09) I. 20-1.26，1.68-1.74 (2 H each, both m, (NCH2CH2)X 2), 1.48-1.58 (1 H, m, CH3CH(CH2) 2N(CH2) 2), 2.71-2.82, 3.75-3.83 (2 H each, both m, (NCH2) X 2), 3.85 (3 H, s, 3,-OCH3), 7.09 (1 H, dd, J = 2.2, 8.0 Hz, H-4’)，7.38-7.46 (2 H，m，H-5，， H-5), 7.54 (1 H, dd, J = 2.2, 8.0 Hz, H-7), 7.61 (1 H, d, J = 8.0 Hz, H-8), 7.71 -7.77 (2 H, m, H-2f, H-6f), 12.34 (1 H, br s, NH) 337 3.23 (4 H, t, J = 4.7 Hz, 67.64 5.68 12.46 CH2NCH2), 3.75 (4 H, t, J = (67.61) (5.70) (12.50) 4.7 Hz, CH2OCH2), 3.85 (3 H, s, 3'-OCH3), 7.10 (1 H, dd, J = 2.5, 8.0 Hz, H-41), 7.43 (1 H, dd, J = 8.0, 8.0 Hz, H-5f), 7.45 (1 H, d, J = 2.5 Hz, H-5), 7.57 (1 H, dd, J =2.5, 8.0 Hz, H-7), 7.65 (1 H, d, J = 8.0 Hz, H-8), 7.71-7.77 (2 H, m, H-2’，H-6’)， 12.39(1 H, brs, NH) -45- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 一裝--------訂------ MU462Compound yield mp UV, with IR, MS (M +) lH-NMR (DMS〇-, / 6) δ Theoretical,% (%) (° C) (MeOH) (cm * 1) 忉(Calculation 値). ~ _ (Log ε) C Ν 41 41 232- 237 233 (4.47) 42 89 198- 211 202 (4.50) 43 95 177- 218 179 (4.41) (Please read the precautions on the back first (Fill in this page) One-pack ----- Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 44 96 215- 207 219 (4.38) 45 86 179- 223 181 (4.52) 1671 222 7.48-7.59 (4 H, m, H-6, H-3, 75.66 Η · 4, H-5,), 7.71-7.84 (2 H, (75 · 60) m, H-7, H-8), 8.13-8.20 (3 H , m, H-5, H-2 ', H-6,), 12.56 (1 H, brs, NH) 1678 252 3.86 (3 H, s, OCH3), 7.05- 71.42 7.21 (2 H, m, H -3 ', H-5'), (71.40) 7.49-7.58 (2 H, m, H-41, H-6), 7.69-7.73 (2 H, m, H-6 ·, H-8), 7.83 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-7), 8.15 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 12.13 (1 H, brs, NH) 1672 252 3.86 (3 H, s, OCH3), 7.14 (1 71.42 H, dd, J = 2.2, 8.0 Hz, H-4f), (71.44) 7.41-7.56 (2 H, m, H-5f, H-6 ), 7.74-7.88 (4 H, m, H-2 ', Η-ό ^, H-7, H-8), 8. 15 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 12.55 (1 H, brs, NH) 1678 252 3.83 (3 H, s, OCH3), 7.08 (2 71.42 H, d, J = 8.0 Hz, H-3f, H-5 '), (71.39) 7.47 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-6), 7.67-7.85 (2 H, m, H-7, H-8), 8.10-8.20 (3 H, m, H-2 ', H-6', H-5), 12.42 (1 H, brs, NH) 1678 282 3.76 (3 H, s, 2'- OCH3 or 3,-68.08 OCH3), 3.87 (3 H, s, 2,-(6805) OCH3 or 3'-OCH3), 7.18-7.28 4.54 12.61 (4.46) (12.52) 4.80 11.10 (4.83) (11.12) 4.80 11.10 (4.78) (11.07) 4.80 11.10 (4.81) (11.13) 5.00 9.92 (5.06) (9.88) Order% -42- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 490462 A7 B7 V. Description of the invention (40) 46 84 184- 207 186 (4.27) 1678 282 47 88 143- 220 1698 144 (4.70) 282 48 89 240- 226 242 (4.44) 1671 282 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 49 84 200- 221 203 (4.57) 1674 282 (3 H, m, H-4, H-5 ,, H-6,), 7.54 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H -6), 7.70 (1 H, dd, J = 1.2, 8.0 Hz, H-8), 7.84 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-7), 8.16 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 12.23 (1 H, br s, NH) 3.85 (3 H, s, 2f-OCH3 or 4f-OCH3), 3.89 (3 H, s, 2, -OCH3 or 4, -OCH3), 6.65-6.72 (2 H, m, H-3 丨, H-5,), 7.49 (1 H, ddd, J = 1.2, 8.0 , 8.0 Hz, H-6), 7.67 (1 H, dd, J = 1.2, 8.0 Hz, H-8), 7.76-7.85 (2 H, m, H-6f, H-7), 8.12 (1 H , dd, J = 1.2, 8.0 Hz, H-5), 11.82 (1 H, br s, NH) 3.77 (3 H, s, 2, -OCH3 or 5, -OCH3), 3.81 (3 H, s, 2f-OCH3 or 5'-OCH3), 7.10-7.12 (2H, m, H-3 ', H-4,), 7.29-7.31 (1 H, m, H-6'), 7.53 (1 H, ddd , J = 1.2, 8.0, 8.0 Hz, H-6), 7.71 (1 H, dd, J = 1.2, 8.0 Hz, H-8), 7.83 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-7), 8.14 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 12.10 (1 H, br s, NH) 3.84 (3 H, s, 3, -OCH3 or 4, and -OCH3 ), 3.88 (3 H, s, 3'-OCH3 or 4? -OCH3), 7.10 (1 H, d, J = 8.0 Hz, H-5f), 7.48 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-6), 7.69-7.89 (4 H, m, H-2 ', H-6', H-7, H-8), 8.13 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 12.44 (1 H, brs, NH) 3.83 (6 H, s, 3'-OCH3, 5f-OCH3), 6.69 (1 H, dd, J = 2.2, 2.2 H z, H-4f), 7. 38 (2 H, d, J = 2.2 Hz, H-2f, H-6 '), 7.52 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-6 ), 7.74 (1 H, dd, J = 1.2, 8.0 Hz, H-8), 7.83 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-7), 8.15 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 12.52 (1 H, br s, NH) 68.08 (68.13) 5.00 9.92 (4.96) (9.86) -43- This paper size applies the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 68.08 (68.00) 68.08 (67.99) 68.08 (68.11) 5.00 9.92 (4.95) (9.97) 5.00 9.92 (5.03) (9.89) 5.00 9.92 (5.06) (9.85) (Please read the precautions on the back first (Fill in this page) Installation ---- · 11111111 490462 A7 B7 V. Description of the invention (50 94 245- 218 248 (4.60) 1678 286.5 51 46.8 246- 217 247 (4.70) 1680 270 52 42 216- 218 218 (4.69) 1659 282 53 30 266- 253 267 (4.55) 1658 312 54 8.8 269- 249 270 (4.48) 1665 296 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 55 51 239- 224 241 (4.79) 1659 295 3.86 (3 H, s, 3, -OCH3), 7.16 (1 H, dd, J = 2.5, 8.0 Hz, H-4 '), 7. 46 (1 H, dd, J = 8.0, 8.0 Hz, H-5f), 7.73 -7.80 (3 H, m, H-2 ', Η · 6', H-8), 7.87 (1 H, dd, J = 2.5, 8.0 Hz, H-7), 8.09 (1 H, d, J = 2.5 Hz, H-5), 12.70 (1 H, brs, NH) 3.84 (3 H, s , 3, -OCH3), 7.13 (1 H, dd, J = 2.5, 8.0 Hz, H-4f), 7.44 (lH, dd, J = 8.0, 8.0 Hz, H-5f), 7.68-7.84 (5 H , m, H-2f, H-6f} H-5, H-7, H-8), 12.61 (1 H, brs, NH) 3.86 (3 H, s, 3'-OCH3 or 6-OCH3), 3.96 (3 H, s, 3 · -OCH3 or 6-OCH3), 7.11 (1 H, dd, J = 2.5, 8.0 Hz, H-4 '), 7. 29-7.49 (2H, m, H-5' , H-7), 7.53 (1 H, d, J = 2.5 Hz, H-5), 7.67-7.82 (3 H, m, H-21, H-61, H-8), 12.48 (1 H, br s, NH) 3.86 (3 H, s, 3, -OCH3 or 6-OCH3 or 7-OCH3), 3.89 (3 H, s, 3, -OCH3 or 6-OCH3 or 7-OCH3), 3.94 (3 H, s, 3'-OCH3 or 6-OCH3 or 7-OCH3), 7.11 (1 H, dd, J = 1.2, 8.0 Hz, H-4 '), 7.21 (1 H, s, H-8), 7. 43 (1 H, dd, J = 8.0, 8.0 Hz, H-5 '), 7.48 (l H, s, H-5), 7.73-7.78 (2 H, m, H-2', H- 6 '), 12.40 (1 H, br s, NH) 3.85 (3 H, s, 3, -OCH3), 6.20 (2 H, s, OCH20), 7.11 (1 H, dd, J = 2.2, 8.0 Hz , H-4 '), 7. 18 (1 H, s, H-8), 7.43 (1H, dd, J = 8.0, 8.0 Hz, H-5'), 7.44 (1 H, s, H-5 ), 7.68-7.75 (2 H, m, H-2 ', H-6' ), 12.46 (1 H, br s, NH) 3.01 (s, 6 H, N (CH3) 2), 3.85 (3 H, s, 3f-OCH3), 7.07 (1 H, dd, J = 2.5, 8.0 Hz, H-4 '), 7. 21 (1H, d, J = 2.5 Hz, H-5), 7.33 (1 H, dd, J = 2.5, 8.0 Hz, H-7), 7.41 (1 H, dd, J = 8.0, 8.0 Hz, H-5 '), 7.61 (1 H, 62.84 (62.78) 3.87 9.77 (3.80) (9.81) 66.66 (66.68) 68.08 (68.04) 65.38 (65.30) 64.86 (64.89) 69.14 ( 69.10) 4.10 10.37 (4.08) (10.41) 5.00 9.92 (5.06) (9.86) 5.16 8.97 (5.20) (8.91) 4.08 9.46 (4.03) (9.50) 5.80 14.23 (5.77) (14.20) (Please read the notes on the back first (Fill in this page again) One Pack ---- Order --------- -44- This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 490462 A7 B7 V. Description of the invention (42 56 40 261- 227 263 (4.54) 1653 57 55 222- 223 1668 225 (4.71) 58 57 212- 224 1663 215 (4.61) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 59 48 254- 225 1673 257 ( 4.66) d, J = 8.0 Hz, H-8), 7.70-7.76 (2H, m, H-2 ', H-6'), 12.26 (1 H, brs, NH) 321 1.96-2.03 (4 H, m, 71.01 5.96 13.08 CH2CH2NCH2CH2), 3.30- (71.05) (5.90) (13.02) 3.34 (4 H, m, CH2NCH2), 3.85 (3 H, s, 3, -OCH3), 7.03-7.17 (3 H, m, H-4f, H-5, H-7), 7.41 (1 H, dd, J = 8.0, 8.0 Hz, H-51), 7.60 (1H, d, J = 8.0 Hz, H-8), 7.68-7.75 (2 H, m, H-2 ', H-6'), 12.22 (1 H, br s, NH) 335 1.55-1.60 (6 H, m, 71.62 6.31 12.53 (CH2) 2CH, NCH2CH2), 3.25- (71.59) (6.28) (12.50) 3.30 (4 H, m, CH2NCH2 ), 3.85 (3 H, s, 3, -OCH3), 7.09 (1 H, dd, J = 2.2, 8.0 Hz, H-41), 7.38-7.46 (2 H, m, U-5 \ H-5 ), 7.53 (1 H, dd, J = 2.2, 8.0 Hz, H-7), 7.60 (1 H, d, J == 8.0 Hz, H-8), 7.70 -7.76 (2 H, m, H- 2 *, H-6f), 12.33 (1 H, br s, NH) 349 0.93 (3 H, d, J = 6.2 Hz, 72.18 6.63 12.03 CH3CH (CH,) 2N (CH2) 2), (72.15) ( 6.60) (12.09) I. 20-1.26, 1.68-1.74 (2 H each, both m, (NCH2CH2) X 2), 1.48-1.58 (1 H, m, CH3CH (CH2) 2N (CH2) 2), 2.71 -2.82, 3.75-3.83 (2 H each, both m, (NCH2) X 2), 3.85 (3 H, s, 3, -OCH3), 7.09 (1 H, dd, J = 2.2, 8.0 Hz, H- 4 '), 7.38-7.46 (2 H, m, H-5 ,, H-5), 7.54 (1 H, dd, J = 2.2, 8.0 Hz, H-7), 7.61 (1 H, d, J = 8.0 Hz, H-8), 7.71 -7.77 (2 H, m, H-2f, H-6 f), 12.34 (1 H, br s, NH) 337 3.23 (4 H, t, J = 4.7 Hz, 67.64 5.68 12.46 CH2NCH2), 3.75 (4 H, t, J = (67.61) (5.70) (12.50) 4.7 Hz, CH2OCH2), 3.85 (3 H, s, 3'-OCH3), 7.10 (1 H, dd, J = 2.5, 8.0 Hz, H-41), 7.43 (1 H, dd, J = 8.0, 8.0 Hz, H-5f), 7.45 (1 H, d, J = 2.5 Hz, H-5), 7.57 (1 H, dd, J = 2.5, 8.0 Hz, H-7), 7.65 (1 H, d, J = 8.0 Hz, H-8), 7.71-7.77 (2 H, m, H-2 ', H-6'), 12.39 (1 H, brs, NH) -45- This paper size applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) (Please read the precautions on the back before filling this page) One Pack -------- Order ------ MU462

五、 發明說明（ 43 60 90 163- 222 1668 165 (4.54) 61 89 148- 222 150 (4.50) 1647 62 93 188- 225 190 (4.64) 1655 63 78 232- 224 233 (4.54) 1651 經濟部智慧財產局員工消費合作社印製 64 86 182- 225 183 (4.45) 1663 254 3.83 (3 H，s，OCH3)，6.02 (1 H, s, H-2), 6.66 (1 H, dd, J = 7.5, 7.5 Hz, H-6), 6.74-6.80 (2 H, m, H-8, N,H), 6.94 (1 H, dd, J = 7.5, 7.5 Hz, H-5f), 7.04 (1 H, d, J = 8.0 Hz, H-3f), 7.18-7.41 (3 H, m, H-4f, H-6f, H-7), 7.62 (1 H, dd, J = I. 0, 1.0 Hz, H-5), 8.02 (1 H, br s, N3H) 254 3.73 (3 H, s, OCH3), 5.73 (1 H, s, H-2), 6.68 (1 H, dd, J = 7.5, 7.5 Hz, H-6), 6.77 (1 H, d, J = 8.0 Hz, H-8), 6.90 (1 H, dd, J = 8.0, 2.5 Hz, H-4'), 7.04-7.07 (2 H, m, H-2f, H-6f), 7.15 (1 H, br s, N,H), 7.21-7.33 (2 H, m, H-5f, H-7), 8.15(1 H, dd,J= 1.0, 7.5 Hz, H-5), 8.34 (1 H, br s, N3H) 254 3.73 (3 H，s，OCH3), 5.70 (1 H, s, H-2), 6.67-6.75 (2 H, m, H-6, H-8), 6.91-6.95 (2 H, m, H-3，，Η·5’)，7.00 (1 H，br s, N,H), 7.24 (1 H, ddd, J = 1.5, 8.0, 8.0 Hz, H-7), 7.36-7.62 (2 H, m, H-2', H-6f), 7.60 (1 H, dd, J = 1.2, 7.5 Hz, H-5), 8.19 (1 H, br s, N3H) 284 3.78 (3 H, s, 2,-OCH3 or 3f- OCH3), 3.81 (3 H, s, 2f-OCH3 or 3,-OCH3), 6.03 (1 H, s, H-2), 6.63-6.75 (2 H, m, H-6, H-8), 6.79(1 H, br s, N,H), 7.04-7.10 (3 H, m, H-4\ H-5', H-6f), 7.23 (1 H, ddd, J = 1.0, 8.0, 8.0 Hz, H-7), 7.62(1 H, dd, J= 1.0, 8.0 Hz, H-5), 8.02 (1 H, br s, N3H) 284 3.75 (3 H, s, 2f-OCH3 or 4f- OCH3), 3.81 (3H，s，2’-OCH3 or 4'-OCH3), 5.94 (1 H, s, H-2), 6.49-6.77 (5 H, m, H-3’，H-5’，H-6，H-8, N,H ), 7.21 (1 H, ddd, J = I. 0, 8.0, 8.0 Hz, H-7), 7.31 (1 H, d, J = 8.0, H-6'), 7.61 (1 H, dd, J = 1.0, 7.5 Hz, H-5), 7.94(1 H, brs, N3H) 70.85 (70.91) 70.85 (70.81) 70.85 (70.79) 67.59 (67.55) 67.59 (67.53) 5.55 (5.53) 5.55 (5.49) 5.55 (5.59) 5.67 (5.71) 5.67 (5.63) 11.02 (11.10) 11.02 (11.08) 11.02 (10.95) 9.85 (9.80) 9.85 (9.81) (請先閱讀背面之注意事項再填寫本頁) 裝--------訂---------这 -46 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 〜462五、 發明說明（44 ) 65 75 163- 223 165 (4.53) 1653 A7 B7 284 66 80 210- 223 213 (4.61) 1655 284 67 93 89- 223 92 (4.54) 1658 284 68 95 193- 223 195 (4.57) 1658 288.5 經濟部智慧財產局員工消費合作社印製 3.66 (3 H，s，2，-OCH3 or 5，- 67.59 5.67 9.85 OCH3)，3·78 (3 H, s，2，- (67·54) (5.70) (9 88) OCH3 or 5’-OCH3)，5·98 (1 H, s, H-2), 6.68 (1 H, dd, J = 7.5, 7.5 Hz, H-6), 6.77 (1 H, d, J = 8.0 Hz, H-8), 6.84-7.00 (4 H, m, Η-3',Η-4', H-6', N^), 7.23(1 H, ddd, J= 1.0, 8.0, 8.0 Hz, H-7), 7.63 (1 H, dd, J = 1.0, 7.5 Hz, H-5), 8.02(1 H, brs,N3H) 3.73 (3 H, s, 3、OCH3 or 4，- 67.59 5.67 9.85 OCH3), 3.74 (3 H, s, 3f- (67·51) (5·70) (9·78) OCH3 or 4,-OCH3), 5.70 (1 H, s, H-2), 6.66 (1 H, dd, J = 7.5, 7.5 Hz, H-6), 6.75 (1 H, d, J = 7.5 Hz, H-8), 6.91-7.02 (3 H，m, H-2，，H-5，，H-6，)， 7.12(1 H，brs，N丨H)，7.25(1 H, ddd, J = 1.0, 7.5, 7.5 Hz, H-7), 7.61 (1 H, dd, J = 1.0, 7.5 Hz, H-5), 8.19(1 H,brs, n3h) 3.72 (6 H，s，3，-OCH3, 5，· 67.59 5.67 9.85 OCH3)，5.67 (1 H，s，H-2)，（67.63) (5.66) (9.88) 6.46 (1 H, s, H-4f), 6.64-6.77 (4 H, m, H-2f, H-6\ H-6, H-8), 7.13 (1 H, br s, N,H), 7.24 (1 H, ddd, J = 1.0, 7.5, 7.5 Hz, H-7), 7.60(1 H, dd, J =1.0, 7.5 Hz, H-5), 8.30 (1 H, br s, N3H) 3.74 (3 H, s, OCH3), 5.75 (1 62.40 4.54 9.70 H, s, H-2), 6.79 (1 H, d, J = (62.48) (4.50) (9.78) 8.0 Hz, H-8), 6.92(1 H, dd, J =2.5, 8.0 Hz, H-4f), 7.02- 7.05 (2 H, m, H-2’，H-6’)， 7.25-7.36 (3 H, m, H-5f, H-7, N.H), 7.53 (1 H, d, J = 2.5 Hz, H-5), 8.50 (1 H, br s, N,H) (請先閱讀背面之注意事項再填寫本頁) · n 1 n H ·1 >1 ϋ^OJ· n 1 «I ·1 n ϋ I ·V. Description of the invention (43 60 90 163- 222 1668 165 (4.54) 61 89 148- 222 150 (4.50) 1647 62 93 188- 225 190 (4.64) 1655 63 78 232- 224 233 (4.54) 1651 Intellectual property of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperatives 64 86 182- 225 183 (4.45) 1663 254 3.83 (3 H, s, OCH3), 6.02 (1 H, s, H-2), 6.66 (1 H, dd, J = 7.5, 7.5 Hz, H-6), 6.74-6.80 (2 H, m, H-8, N, H), 6.94 (1 H, dd, J = 7.5, 7.5 Hz, H-5f), 7.04 (1 H, d, J = 8.0 Hz, H-3f), 7.18-7.41 (3 H, m, H-4f, H-6f, H-7), 7.62 (1 H, dd, J = I. 0, 1.0 Hz, H-5), 8.02 (1 H, br s, N3H) 254 3.73 (3 H, s, OCH3), 5.73 (1 H, s, H-2), 6.68 (1 H, dd, J = 7.5, 7.5 Hz, H-6), 6.77 (1 H, d, J = 8.0 Hz, H-8), 6.90 (1 H, dd, J = 8.0, 2.5 Hz, H-4 '), 7.04-7.07 (2 H , m, H-2f, H-6f), 7.15 (1 H, br s, N, H), 7.21-7.33 (2 H, m, H-5f, H-7), 8.15 (1 H, dd, J = 1.0, 7.5 Hz, H-5), 8.34 (1 H, br s, N3H) 254 3.73 (3 H, s, OCH3), 5.70 (1 H, s, H-2), 6.67-6.75 (2 H, m, H-6, H-8), 6.91-6.95 (2 H, m, H-3, Η · 5 '), 7.00 (1 H, br s, N, H), 7.24 (1 H , ddd, J = 1.5, 8.0, 8.0 Hz, H-7), 7.36-7.62 (2 H, m, H-2 ', H-6f), 7.60 (1 H, dd, J = 1.2, 7.5 Hz, H-5), 8.19 (1 H, br s, N3H) 284 3.78 (3 H, s, 2, -OCH3 or 3f- OCH3), 3.81 (3 H, s, 2f-OCH3 or 3, -OCH3), 6.03 (1 H, s, H-2), 6.63-6.75 (2 H, m, H-6, H-8), 6.79 (1 H, br s, N, H), 7.04-7.10 (3 H, m, H-4 \ H-5 ', H-6f), 7.23 (1 H, ddd, J = 1.0, 8.0, 8.0 Hz, H-7), 7.62 (1 H, dd, J = 1.0, 8.0 Hz, H-5), 8.02 (1 H, br s, N3H) 284 3.75 (3 H, s, 2f-OCH3 or 4f- OCH3), 3.81 (3H, s, 2'-OCH3 or 4'-OCH3), 5.94 (1 H, s, H-2), 6.49-6.77 (5 H, m, H-3 ', H-5', H-6, H-8, N, H), 7.21 (1 H, ddd, J = I. 0, 8.0, 8.0 Hz, H-7), 7.31 (1 H, d, J = 8.0, H-6 '), 7.61 (1 H, dd, J = 1.0, 7.5 Hz, H-5), 7.94 (1 H, brs, N3H) 70.85 (70.91) 70.85 (70.81) 70.85 (70.79) 67.59 (67.55) 67.59 (67.53) 5.55 (5.53) 5.55 (5.49) 5.55 (5.59) 5.67 (5.71) 5.67 (5.63) 11.02 (11.10) 11.02 (11.08) 11.02 (10.95) 9.85 (9.80) ) 9.85 (9.81) (Please read the precautions on the back before filling out this page) Loading -------- Order --------- This-46-This paper size applies to Chinese National Standard (CNS A4 specifications 210 X 297 mm) ~ 462 V. Description of the invention (44) 65 75 163- 223 165 (4.53) 1653 A7 B7 284 66 80 210- 223 213 (4.61) 1655 284 67 93 89- 223 92 (4.54) 1658 284 68 95 193- 223 195 (4.57) 1658 288.5 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy 3.66 (3 H, s, 2, -OCH3 or 5,-67.59 5.67 9.85 OCH3), 3.78 (3 H, s , 2,-(67 · 54) (5.70) (9 88) OCH3 or 5'-OCH3), 5.98 (1 H, s, H-2), 6.68 (1 H, dd, J = 7.5, 7.5 Hz, H-6), 6.77 (1 H, d, J = 8.0 Hz, H-8), 6.84-7.00 (4 H, m, Η-3 ', Η-4', H-6 ', N ^ ), 7.23 (1 H, ddd, J = 1.0, 8.0, 8.0 Hz, H-7), 7.63 (1 H, dd, J = 1.0, 7.5 Hz, H-5), 8.02 (1 H, brs, N3H ) 3.73 (3 H, s, 3, OCH3 or 4,-67.59 5.67 9.85 OCH3), 3.74 (3 H, s, 3f- (67 · 51) (5 · 70) (9 · 78) OCH3 or 4,- OCH3), 5.70 (1 H, s, H-2), 6.66 (1 H, dd, J = 7.5, 7.5 Hz, H-6), 6.75 (1 H, d, J = 7.5 Hz, H-8) , 6.91-7.02 (3 H, m, H-2 ,, H-5 ,, H-6,), 7.12 (1 H, brs, N 丨 H), 7.25 (1 H, ddd, J = 1.0, 7.5 , 7.5 Hz, H-7), 7.61 (1 H, dd, J = 1.0, 7.5 Hz, H-5), 8.19 (1 H, brs, n3h) 3.72 (6 H , S, 3, -OCH3, 5, 67.59 5.67 9.85 OCH3), 5.67 (1 H, s, H-2), (67.63) (5.66) (9.88) 6.46 (1 H, s, H-4f), 6.64-6.77 (4 H, m, H-2f, H-6 \ H-6, H-8), 7.13 (1 H, br s, N, H), 7.24 (1 H, ddd, J = 1.0, 7.5, 7.5 Hz, H-7), 7.60 (1 H, dd, J = 1.0, 7.5 Hz, H-5), 8.30 (1 H, br s, N3H) 3.74 (3 H, s, OCH3), 5.75 (1 62.40 4.54 9.70 H, s, H-2), 6.79 (1 H, d, J = (62.48) (4.50) (9.78) 8.0 Hz, H-8), 6.92 (1 H, dd, J = 2.5 , 8.0 Hz, H-4f), 7.02- 7.05 (2 H, m, H-2 ', H-6'), 7.25-7.36 (3 H, m, H-5f, H-7, NH), 7.53 (1 H, d, J = 2.5 Hz, H-5), 8.50 (1 H, br s, N, H) (Please read the precautions on the back before filling this page) · n 1 n H · 1 > 1 ϋ ^ OJ · n 1 «I · 1 n ϋ I ·

本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 490462 A7 B7 五、發明說明（ 45 表2· 4-烷氧基-2-苯基硿唑啉及NM完基-2-苯基-4-Π查唑 啉酮之物理及光譜數據This paper size is in accordance with Chinese National Standard (CNS) A4 (210 x 297 mm) 490462 A7 B7 V. Description of the invention (45 Table 2. 4-alkoxy-2-phenyloxazoline and NM endyl-2 And Spectral Data of 2-Phenyl-4-ΠChazolinone

化合產率 mp UV，Amax IR，yc=0 MS(M+) !H-NMR (DMS〇-^6) δ 物（％) (°C) (MeOH) (cm'1) rnlz (log e)_^_Compound yield mp UV, Amax IR, yc = 0 MS (M +)! H-NMR (DMS〇- ^ 6) δ (%) (° C) (MeOH) (cm'1) rnlz (log e) _ ^ _

理論値，％ (計算値） C Η N 69 30 50-51 254 (4.50) 80 54-56 255 (4.53) 71 90 64-65 256 (4.52) 1763 經濟部智慧財產局員工消費合作社印製 72 89 63-66 254 (4.46) 1728 236 4.26 (3 Η, s, CH3), 7.45- 7.54 (4 H, m, H-6, H-3', H-4', H-5f), 7.79 (1 H, ddd, J =1.2, 8.0, 8.0 Hz, H-7), 7.98 (1 H, dd, J = 1.2, 8.0 Hz, H-8), 8.13 (1 H, dd, J =1.2, 8.0 Hz, H-5), 8.57-8·62 (2 H, m，H-2，，H-6’） 250 1.56 (3 H, t, J = 7.0 Hz, CH3)，4.76 (2 H，q，J = 7.0 Hz, CH2), 7.45-7.53 (4 H, m, H-6, H-3f, H-4\ H-5'), 7.79 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-7), 7.97 (1 H, dd, J = 1.2, 8.0 Hz, H-8), 8.16 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 8.54-8.59 (2 H，m，H-2，，H-6，） 308 1.26 (3 H, t, J = 7.0 Hz, CH3), 4.26 (2 H, q, J = 7.0 Hz, CH2CH3), 5.16 (2 H, s, OCH2CO), 7.46-7.57 (4 H, m, H-6, H-3', H-4', H-5f), 7.82 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-7), 8.00 (1 H, dd, J = 1.2, 8.0 Hz, H-8), 8.23 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 8.48-8.53 (2 H, m, H-2', H-61) 336 1.22 (3 H, t, J = 7.0 Hz, CH3), 2.25-2.32 (2 H, m, O CH2CH2CH2CO), 2.62 (2 H, t, J = 7.0 Hz, O CH2CH2CH2CO), 4.12 (2 H, q, J = 7.0 Hz, CH2CH3), 4.75 (2 H, t, J = 7.0 Hz, 76.25 5.12 11.86 (76.33) (4.99) (11.72) 76.78 5.64 11.19 (76.64) (5.68) (11.09) 70.12 5.23 9.09 (70.29) (5.31) (9.13) 71.41 5.99 8.33 (71.35) (5.86) (8.28) (請先閱讀背面之注意事項再填寫本頁) ’裝—— 訂-------- •48- 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 490462 A7 B7 五、發明說明（ 46 73 79 62-63 254 (4.62) 1728 350 74 84 154- 210 155 (4.54) 280 75 83 85-86 213 (4.53) 280 經濟部智慧財產局員工消費合作社印製 76 85 65-66 211 (4.54) 280 OCH2CH2CH2CO), 7.43- 7.55 (4 H, m, H-6, H-3f, H-4’，H-5’)，7.79 (1 H, ddd，J =1.2, 8.0, 8.0 Hz, H-7), 7.97 (1 H, dd, J = 1.2, 8.0 Hz, H-8), 8.13 (1 H, dd, J =1.2, 8.0 Hz, H-5), 8.51- 8.58 (2 H, m, H-2f, H-6f) 1.24 (3 H, t, J = 7.0 Hz, 71.98 6.33 7.99 CH3), 1.90-1.99 (4 H, m, O (71.86) (6.39) (7.92) CH2(CH2)2CH7CO), 2.44 (2 H, t, J = 7.0 Hz, O (CH〇3CHX〇), 4.12 (2 H, q, J = 7.0 Hz, CH2CH3), 4.72 (2 H, t, J = 7.0 Hz, OCH2(CH2)3CO), 7.45- 7.53 (4 H, m, H-6, H-3', H-4\ H-5f), 7.79 (1 H, ddd, J =1.2, 8.0, 8.0 Hz, H-7), 7.97 (1 H, dd, J = 1.2, 8.0 Hz, H-8), 8.15 (1 H, dd, J =1.2, 8.0 Hz, H-5), 8.53- 8.58 (2 H, m, H-2', H-6') l. 11 (3 H, t, J = 7.0 Hz, 72.84 5.75 9.99 CHXH3), 3 63 (i H, m, J (72.80) (5.82) (9.97) =7.0 Hz, CH2), 3.79 (3 H, s, OCHj), 4.22 (1 H, m, J = 7.0 Hz, CH2X 6.99(1 H, d, J 二 8.0 Hz, H-3丨)，7.08 (1 H，ddd，J = 1.2, 8.0, 8.0 Hz, H-6)，7.44-7.54 (3 H， m, H-7, H-8, H-51), 7.73 (2 H, m, H-4，，H-6，)，8.32 (1 H, dd, J = 1.2, 8.0 Hz, H-5) 1.55 (3 H, t, J = 7.0 Hz, 72.84 5.75 9.99 CH2CH3), 3.92 (3 H, s, (72.78) (5.89) (9.91) OCH3), 4.75 (2 H, q, J = 7.0 Hz, CH:), 7.03 (1 H, ddd, J - 1.2, 1.2, 8.0 Hz, H-6f), 7.40 (1 H, dd, J = 8.0, 8.0 Hz, H-5丨)，7.49 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-6), 7.79(1 H, ddd, J =1.2, 8.0, 8.0 Hz, H-7), 7.97 (1 H, dd, J = 1.0, 8.0 Hz, H-8), 8.13-8.20 (3 H, m, H-5, H-2’，H-4’） 1.54 (3 H, t, J = 7.0 Hz, 72.84 5.75 9.99 CH2CH3), 3.87 (3 H, s, (72.89) (5.67) (9.87) OCH3), 4.74 (2 H, q, J == 7.0 Hz, CH2), 7.00 (2 H, d, J = 8·0 Hz，H-3，，H-5，)， -49- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注咅？事項再填寫本頁) 490462 A7 B7 五、發明說明（47 77 66 125- 229 127 (4.52) 78 11 111- 207 113 (4.43) 79 1.3 130- 226 1682 132 (4.67) 80 11 79-82 223 (4.51) 經濟部智慧財產局員工消費合作社印製 81 8.8 131- 226 134 (4.55) 7.44 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-6), 7.76 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-7), 7.92 (1 H, dd, J = 1.2,8.0 Hz, H-8), 8.12(1 H, dd, J = 1.2, 8.0 Hz, H-5), 8.53 (2 H, d, J = 8.0 Hz，H-2，, H-4，） 1682 236 3.47 (3 H, s, CH3), 7.47- 76.25 5.12 11.86 7.56 (6 H, m, H-6, H-2f, H- (76.10) (5.20) (11.72) 3f, H-41, H-5', H-6'), 7.71-7.74 (2 H, m, H-7, H-8), 8.30(1 H, dd, J= 1.2, 8.0 Hz, H-5) 1675 250 1.19 (3 H, t, J = 7.0 Hz, 76.78 5.64 11.19 CH3), 4.01 (2H, q, J = 7.0 (76.89) (5.70) (11.23) Hz, CH2), 7.47-7.51 (6 H, m，H-6, H-2，，H-3’，H-4，， H-5f，H-6’)，7.70-7.74 (2 H, m, H-7, H-8), 8.31 (1 H, dd, J = 1.2, 8.0 Hz, H-5) 308 1.23 (3 H, t, J = 7.0 Hz, 70.12 5.23 9.09 CH3), 4.19 (2 H, q, J = 7.0 (70.04) (5.33) (9.00) Hz, CH，CH3), 4.62 (2 H, s, NCH2), 7.46-7.57 (6 H, m, H-6, H-2f, H-3', H-4', H-5,，H-6，)，7.75-7.78 (2 H， m, H-7, H-8), 8.30 (1 H, dd,J= 1.2, 8.0 Hz, H-5) 1686 280 1.21 (3 H, t, J = 7.0 Hz, 72.84 5.75 9.99 CH2CH3), 3.84 (3 H, s, (72.79) (5.86) (9.87) OCH3), 4.02 (2 H, q, J = 7.0 Hz, CH2), 7.00-7.10 (3 H, m, H-2，，H-4’，H-6，)， 7.37-7.52 (2 H, m, H-6, H-5'), 7.68-7.74 (2 H, m, H-7, H-8), 8.31 (1 H, dd, J = I. 2, 8.0 Hz, H-5) 1674 280 1.19 (3 H, t, J = 7.0 Hz, 72.84 5.75 9.99 CH2CH3), 3.85 (3 H, s, (72.80) (5.77) (9.92) OCH3), 4.05 (2 H, q, J = 7.0 Hz, CH2), 7.00 (2 H, J =8.0 Hz, H-31, H-5f), 7.42-7.51 (3 H, m, H-6, H-2', H-6’)，7.66-7_77(2H，m，H-7, H-8), 8.29 (1 H, dd, J = 1.2, 8.0 Hz，H-5)_ (請先閱讀背面之注意事項再填寫本頁) 裝---1 訂--------- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -50- 490462 A7 B7 五、發明說明（48 ) 表 3· 6,7,2’，3’，4\5、取代-2-苯基-4-岐唑啉酮（42-59)及 6,2’，3·，4\5·-取代-2,3-雙氫-2-苯基-4-口2 唑啉酮（60-68) 之體外細胞致毒活性 經濟部智慧財產局員工消費合作社印製 化合物 lA9b HCT-8b A-549b ED50("g/ml)a U-87- HOS KBb MGb ΚΒ- VINb PC3b MCF-7b SKMEL-2 請 先 閱 I 1 1 1 42 > 20(8)( ΝΑ >20(15) ΝΑ >20(5) >20(6) >20(9) ΝΑ >20(23) ΝΑ 背 1 43 >20(27) >20(8) >20(21) ΝΑ >20(6) ΝΑ >20(12) >20(16) 26 >20(12) S 1 44 >20(22) >20(29) >20(42) ΝΑ >20(21) >20(23) >20(40) >20(32) >20(42) >20(24) 之 1 I 45 ΝΑ ΝΑ >20(19) ΝΑ ΝΑ ΝΑ >20(11) >20(17) >20(24) ΝΑ 注 1 I 46 ΝΑ >20(14) >20(31) >20(16) >20(7) >20(5) >20(8) >20(16) >20(15) >20(5) 畫 | 47 >20(19) >20(21) >20(33) ΝΑ >20(20) >20(10) >20(21) >20(30) >20(20) >20(9) 爭 項 1 48 >20(34) >20(15) >20(29) ΝΑ >20(11) >20(12) >20(22) >20(26) >20(48) >20(15) 7\ 再 49 ΝΑ ΝΑ >20(29) ΝΑ ΝΑ ΝΑ >20(12] 1 >20(8) >20(28) >20(5) 填 50 >20(29) 6.0 3.2 10.0 17.0 11.5 6.5 4.5 17.8 4.8 裝 51 ΝΑ >20(31) 16.5 >20(30) ΝΑ >20(39) 18.0 20.0 >20(40) >20(41) | 52 3.4 16.5 12.5 >20(11) >20(43) 17.5 3.5 >20(37) 8.0 >20(49) 貝 1 I 53 16.5 >20(37) >20(49) >20(28) >20(27) >20(45) 19.8 15.0 12.0 18.0 層 | 54 >20(26) ΝΑ >20(11) ΝΑ >20(6) >20(16) >20(19) >20(12) >20(40) >20(14) 1 55 0.49 1.05 14.0 >20(17) >20(46) 10.0 0.42 15.0 0.85 19.0 1 56 0.09 0.06 0.50 13.8 7.0 0.23 0.10 15.0 0.22 0.09 1 ， 57 0.90 4.3 2,8 9.0 15.4 10 0.60 10.0 8.5 4.5 1 58 0.80 4.0 6.0 15.5 14.4 10.8 2.5 12.4 10.0 7.5 訂 59 3.8 10.4 10.9 20 12.5 8.2 3.7 13.4 4.5 4.8 w 4 • » 60 14.7 >20(21) >20(44) ΝΑ >20(38) >20(32) 10.2 >20(30) >20(48) <20(52)d 1 61 1.0 1.5 3.0 >20(35) >20(42) 3.0 1.20 >20(43) >20(48) >20(49) 1 | 62 20 >20(19) >20(34) ΝΑ >20(13) >20(14) >20(39) >20(14) >20(44) >20(23) 1 I 63 11.4 >20(39) >20(39) ΝΑ >20(34) >20(41) 8.6 >20(20) >20(40) <20(53) 屢 I 64 12.5 >20(29) >20(43) ΝΑ >20(40) >20(43) 7.6 >20(28) >20(44) >20(37) 1 65 10.0 >20(32) >20(42) >20(5) >20(40) >20(40) 8.4 >20(22) >20(42) >20(44) 1 66 14.6 >20(25) >20(41) ΝΑ >20(24) >20(28) 16.0 >20(30) 20 >20(24) 1 λΑ 67 1.92 3.0 5.0 >20(37) >20(41) 4.7 1.6 >20(44) >20(49) 4.4 % 68 0.27 0.48 0.6 >20(37) 20.0 0.95 0.42 2.5 16.0 <2.5(56) a ED5。爲可使細胞數在培養3至4天後減少50%的化合物濃度。· b人類卵巢 癌(1A9)、迴盲腸癌(HCT-8)、肺癌(A-549)、神經膠母細胞瘤(U-87-MG)、骨癌 (HOS)、鼻咽表皮樣癌(KB)、P-gp-表現之鼻咽表皮樣癌(KB-VIN)、***癌 (PC3)、乳癌（MCF-7)及黑色瘤(SKMEL-2)等細胞株，在最高測試濃度下，進 行ED5()測定之抑制情形(括號內爲所觀察到的百分比）。d高原期之劑量呈現 明顯的最大作用。雖然以低劑量可達50%之抑制效果’但是高原期涵蓋廣泛 之劑量範圍(括號內爲抑制値範圍）。 -51 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 490462 A7 _B7_ 五、發明說明（49 ) 表 4. 6,7,2^，4'，5，-取代-2-苯基-4_口查唑啉酮（42-59)及 6,2’，3\4’，5^取代-2,3-雙氫-2·苯基-4-p查唑啉酮（60-68) 之抗微管聚合活性Theoretical value,% (calculated value) C Η N 69 30 50-51 254 (4.50) 80 54-56 255 (4.53) 71 90 64-65 256 (4.52) 1763 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 72 89 63-66 254 (4.46) 1728 236 4.26 (3 Η, s, CH3), 7.45- 7.54 (4 H, m, H-6, H-3 ', H-4', H-5f), 7.79 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-7), 7.98 (1 H, dd, J = 1.2, 8.0 Hz, H-8), 8.13 (1 H, dd, J = 1.2, 8.0 Hz , H-5), 8.57-8 · 62 (2 H, m, H-2 ,, H-6 ') 250 1.56 (3 H, t, J = 7.0 Hz, CH3), 4.76 (2 H, q, J = 7.0 Hz, CH2), 7.45-7.53 (4 H, m, H-6, H-3f, H-4 \ H-5 '), 7.79 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz , H-7), 7.97 (1 H, dd, J = 1.2, 8.0 Hz, H-8), 8.16 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 8.54-8.59 (2 H , M, H-2, H-6,) 308 1.26 (3 H, t, J = 7.0 Hz, CH3), 4.26 (2 H, q, J = 7.0 Hz, CH2CH3), 5.16 (2 H, s , OCH2CO), 7.46-7.57 (4 H, m, H-6, H-3 ', H-4', H-5f), 7.82 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H- 7), 8.00 (1 H, dd, J = 1.2, 8.0 Hz, H-8), 8.23 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 8.48-8.53 (2 H, m, H-2 ', H-61) 336 1.22 (3 H, t, J = 7. 0 Hz, CH3), 2.25-2.32 (2 H, m, O CH2CH2CH2CO), 2.62 (2 H, t, J = 7.0 Hz, O CH2CH2CH2CO), 4.12 (2 H, q, J = 7.0 Hz, CH2CH3), 4.75 (2 H, t, J = 7.0 Hz, 76.25 5.12 11.86 (76.33) (4.99) (11.72) 76.78 5.64 11.19 (76.64) (5.68) (11.09) 70.12 5.23 9.09 (70.29) (5.31) (9.13) 71.41 5.99 8.33 (71.35) (5.86) (8.28) (Please read the precautions on the back before filling out this page) 'Installation-Order -------- • 48- This paper size applies to China National Standard (CNS) A4 Specifications (210 x 297 mm) 490462 A7 B7 V. Description of the invention (46 73 79 62-63 254 (4.62) 1728 350 74 84 154- 210 155 (4.54) 280 75 83 85-86 213 (4.53) 280 Ministry of Economic Affairs Printed by the Intellectual Property Bureau's Consumer Cooperatives 76 85 65-66 211 (4.54) 280 OCH2CH2CH2CO), 7.43- 7.55 (4 H, m, H-6, H-3f, H-4 ', H-5'), 7.79 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-7), 7.97 (1 H, dd, J = 1.2, 8.0 Hz, H-8), 8.13 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 8.51- 8.58 (2 H, m, H-2f, H-6f) 1.24 (3 H, t, J = 7.0 Hz, 71.98 6.33 7.99 CH3), 1.90-1.99 (4 H, m, O (71.86) (6.39) (7.92) CH2 (CH2) 2CH7CO), 2.44 (2 H, t, J = 7.0 Hz, O (CH〇3CHX〇), 4.12 (2 H, q, J = 7.0 Hz, CH2CH3), 4.72 (2 H, t, J = 7.0 Hz, OCH2 (CH2) 3CO), 7.45- 7.53 (4 H, m, H-6, H-3 ', H-4 \ H-5f), 7.79 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-7) , 7.97 (1 H, dd, J = 1.2, 8.0 Hz, H-8), 8.15 (1 H, dd, J = 1.2, 8.0 Hz, H-5), 8.53- 8.58 (2 H, m, H- 2 ', H-6') l. 11 (3 H, t, J = 7.0 Hz, 72.84 5.75 9.99 CHXH3), 3 63 (i H, m, J (72.80) (5.82) (9.97) = 7.0 Hz, CH2), 3.79 (3 H, s, OCHj), 4.22 (1 H, m, J = 7.0 Hz, CH2X 6.99 (1 H, d, J 2 8.0 Hz, H-3 丨), 7.08 (1 H, ddd , J = 1.2, 8.0, 8.0 Hz, H-6), 7.44-7.54 (3 H, m, H-7, H-8, H-51), 7.73 (2 H, m, H-4, H -6,), 8.32 (1 H, dd, J = 1.2, 8.0 Hz, H-5) 1.55 (3 H, t, J = 7.0 Hz, 72.84 5.75 9.99 CH2CH3), 3.92 (3 H, s, (72.78 ) (5.89) (9.91) OCH3), 4.75 (2 H, q, J = 7.0 Hz, CH :), 7.03 (1 H, ddd, J-1.2, 1.2, 8.0 Hz, H-6f), 7.40 (1 H, dd, J = 8.0, 8.0 Hz, H-5 丨), 7.49 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-6), 7.79 (1 H, ddd, J = 1.2, 8.0 , 8.0 Hz, H-7), 7.97 (1 H, dd, J = 1.0, 8.0 Hz, H-8), 8.13-8. 20 (3 H, m, H-5, H-2 ', H-4') 1.54 (3 H, t, J = 7.0 Hz, 72.84 5.75 9.99 CH2CH3), 3.87 (3 H, s, (72.89) ( 5.67) (9.87) OCH3), 4.74 (2 H, q, J == 7.0 Hz, CH2), 7.00 (2 H, d, J = 8.0 Hz, H-3, H-5,),-- 49- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the note on the back first? Please fill in this page again for matters) 490462 A7 B7 V. Description of invention (47 77 66 125- 229 127 (4.52) 78 11 111- 207 113 (4.43) 79 1.3 130- 226 1682 132 (4.67) 80 11 79-82 223 ( 4.51) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 81 8.8 131- 226 134 (4.55) 7.44 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-6), 7.76 (1 H, ddd, J = 1.2, 8.0, 8.0 Hz, H-7), 7.92 (1 H, dd, J = 1.2, 8.0 Hz, H-8), 8.12 (1 H, dd, J = 1.2, 8.0 Hz, H-5) , 8.53 (2 H, d, J = 8.0 Hz, H-2 ,, H-4,) 1682 236 3.47 (3 H, s, CH3), 7.47- 76.25 5.12 11.86 7.56 (6 H, m, H-6 , H-2f, H- (76.10) (5.20) (11.72) 3f, H-41, H-5 ', H-6'), 7.71-7.74 (2 H, m, H-7, H-8) , 8.30 (1 H, dd, J = 1.2, 8.0 Hz, H-5) 1675 250 1.19 (3 H, t, J = 7.0 Hz, 76.78 5.64 11.19 CH3), 4.01 (2H, q, J = 7.0 (76.89 ) (5.70) (11.23) Hz, CH2), 7.47-7.51 (6 H, m, H-6, H-2 ,, H-3 ', H-4 ,, H-5f, H-6'), 7.70-7.74 (2 H, m, H-7, H-8), 8.31 (1 H, dd, J = 1.2, 8.0 Hz, H-5) 308 1.23 (3 H, t, J = 7.0 Hz, 70.12 5.23 9.09 CH3), 4.19 (2 H, q, J = 7.0 (70.04) (5.33) (9.00) Hz, CH, CH 3), 4.62 (2 H, s, NCH2), 7.46-7.57 (6 H, m, H-6, H-2f, H-3 ', H-4', H-5 ,, H-6,) , 7.75-7.78 (2 H, m, H-7, H-8), 8.30 (1 H, dd, J = 1.2, 8.0 Hz, H-5) 1686 280 1.21 (3 H, t, J = 7.0 Hz , 72.84 5.75 9.99 CH2CH3), 3.84 (3 H, s, (72.79) (5.86) (9.87) OCH3), 4.02 (2 H, q, J = 7.0 Hz, CH2), 7.00-7.10 (3 H, m, H-2 ,, H-4 ', H-6,), 7.37-7.52 (2 H, m, H-6, H-5'), 7.68-7.74 (2 H, m, H-7, H- 8), 8.31 (1 H, dd, J = I. 2, 8.0 Hz, H-5) 1674 280 1.19 (3 H, t, J = 7.0 Hz, 72.84 5.75 9.99 CH2CH3), 3.85 (3 H, s, (72.80) (5.77) (9.92) OCH3), 4.05 (2 H, q, J = 7.0 Hz, CH2), 7.00 (2 H, J = 8.0 Hz, H-31, H-5f), 7.42-7.51 ( 3 H, m, H-6, H-2 ', H-6'), 7.66-7_77 (2H, m, H-7, H-8), 8.29 (1 H, dd, J = 1.2, 8.0 Hz , H-5) _ (Please read the precautions on the back before filling in this page) Packing-1 order ---------- This paper size applies to China National Standard (CNS) A4 (210 X 297) Mm) -50- 490462 A7 B7 V. Description of the invention (48) Table 3. 6, 7, 2 ', 3', 4 \ 5, Substituted 2-phenyl-4-imidazolinone (42-59 ) And 6,2 ', 3 ·, 4 \ 5 ·- Substituted in vitro cytotoxic activity of -2,3-dihydro-2-phenyl-4-oxazolone (60-68) Compound 1A9b HCT-8b A-549b ED50 (" g / ml) a U-87- HOS KBb MGb ΚΒ- VINb PC3b MCF-7b SKMEL-2 Please read I 1 1 1 42 > 20 (8) (ΝΑ > 20 (15) ΝΑ > 20 (5) > 20 (6) > 20 (9) ΝΑ > 20 (23) ΝΑ back 1 43 > 20 (27) > 20 (8) > 20 (21) ΝΑ > 20 (6) ΝΑ > 20 (12) > 20 (16) 26 > 20 (12) S 1 44 > 20 (22) > 20 (29) > 20 (42) ΝΑ > 20 (21 ) > 20 (23) > 20 (40) > 20 (32) > 20 (42) > 20 (24) 1 I 45 ΝΑ ΝΑ > 20 (19) ΝΑ ΝΑ ΝΑ > 20 ( 11) > 20 (17) > 20 (24) ΝΑ Note 1 I 46 ΝΑ > 20 (14) > 20 (31) > 20 (16) > 20 (7) > 20 (5) > 20 (8) > 20 (16) > 20 (15) > 20 (5) painting | 47 > 20 (19) > 20 (21) > 20 (33) ΝΑ > 20 ( 20) > 20 (10) > 20 (21) > 20 (30) > 20 (20) > 20 (9) Issue 1 48 > 20 (34) > 20 (15) > 20 (29) ΝΑ > 20 (11) > 20 (12) > 20 (22) > 20 (26) > 20 (48) > 20 (15) 7 \ 4949 ΝΑ ΝΑ > 20 (29) ΝΑ ΝΑ ΝΑ > 20 (12) 1 > 20 (8) > 20 (28) > 20 (5) Fill in 50 > 20 (29) 6.0 3.2 10.0 17.0 11.5 6.5 4.5 17.8 4.8 Pack 51 ΝΑ > 20 (31) 16.5 > 20 (30) ΝΑ > 20 (39) 18.0 20.0 > 20 (40) > 20 (41) | 52 3.4 16.5 12.5 > 20 (11) > 20 (43) 17.5 3.5 > 20 (37) 8.0 > 20 (49) Shell 1 I 53 16.5 > 20 (37) > 20 (49) > 20 (28) > 20 (27) > 20 (45) 19.8 15.0 12.0 18.0 layers | 54 > 20 (26) ΝΑ > 20 (11) ΝΑ > 20 (6) > 20 (16) > 20 (19) > 20 (12) > 20 (40) > 20 (14) 1 55 0.49 1.05 14.0 > 20 (17) > 20 (46) 10.0 0.42 15.0 0.85 19.0 1 56 0.09 0.06 0.50 13.8 7.0 0.23 0.10 15.0 0.22 0.09 1, 57 0.90 4.3 2,8 9.0 15.4 10 0.60 10.0 8.5 4.5 1 58 0.80 4.0 6.0 15.5 14.4 10.8 2.5 12.4 10.0 7.5 Order 59 3.8 10.4 10.9 20 12.5 8.2 3.7 13.4 4.5 4.8 w 4 • »60 14.7 > 20 (21) > 20 (44) ΝΑ > 20 (38) > 20 (32) 10.2 > 20 (30) > 20 (48) < 20 (52) d 1 61 1.0 1.5 3.0 > 20 (35) > 20 (42) 3.0 1.20 > 20 (43) > 20 (48) > 20 (49) 1 | 62 20 > 20 (19) > 2 0 (34) ΝΑ > 20 (13) > 20 (14) > 20 (39) > 20 (14) > 20 (44) > 20 (23) 1 I 63 11.4 > 20 (39 ) > 20 (39) ΝΑ > 20 (34) > 20 (41) 8.6 > 20 (20) > 20 (40) < 20 (53) Repeat I 64 12.5 > 20 (29) > 20 (43) ΝΑ > 20 (40) > 20 (43) 7.6 > 20 (28) > 20 (44) > 20 (37) 1 65 10.0 > 20 (32) > 20 ( 42) > 20 (5) > 20 (40) > 20 (40) 8.4 > 20 (22) > 20 (42) > 20 (44) 1 66 14.6 > 20 (25) > 20 (41) ΝΑ > 20 (24) > 20 (28) 16.0 > 20 (30) 20 > 20 (24) 1 λΑ 67 1.92 3.0 5.0 > 20 (37) > 20 (41) 4.7 1.6 > 20 (44) > 20 (49) 4.4% 68 0.27 0.48 0.6 > 20 (37) 20.0 0.95 0.42 2.5 16.0 < 2.5 (56) a ED5. To reduce the number of cells by 50% of the compound concentration after 3 to 4 days of culture. B Human ovarian cancer (1A9), ileocecal cancer (HCT-8), lung cancer (A-549), glioblastoma (U-87-MG), bone cancer (HOS), nasopharyngeal epidermoid carcinoma ( KB), P-gp-presenting nasopharyngeal epidermoid carcinoma (KB-VIN), prostate cancer (PC3), breast cancer (MCF-7), and melanoma (SKMEL-2) cell lines, at the highest test concentration, Inhibition by ED5 () assay (percentages observed in parentheses). d. The plateau dose showed a significant maximum effect. Although the inhibitory effect is as low as 50% at low doses', the plateau phase covers a wide range of doses (inhibition range in parentheses). -51-This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 490462 A7 _B7_ V. Description of the invention (49) Table 4. 6,7,2 ^, 4 ', 5, -Replace- 2-Phenyl-4-chazazolinone (42-59) and 6,2 ', 3 \ 4', 5 ^ substituted-2,3-dihydro-2 · phenyl-4-pchazolin Anti-microtubule polymerization activity of ketone (60-68)

化合物 Re R7 r2. r3. r4, r5. ITPa ic50("m) 經濟部智慧財產局員工消費合作社印製 42 Η Η 43 Η Η 44 Η Η 45 Η Η 46 Η Η 47 Η Η 48 Η Η 49 Η Η 50 C1 Η 51 F Η 52 och3 Η 53 och3 och3 54 OCH.O 55 Η 56 Ο Η 57 ο Η 58 〇-ch3 Η 59 /~\ nw° Η 60 Η Η 61 Η Η 62 Η Η 63 Η Η 64 Η Η 65 Η Η 66 Η Η 67 Η Η 68 秋水仙鹼 C1 Η Η II η Η Η H »1 II i n n η η T1 chhccchhhhhhhho ooo rrp rp Η Η Η Hchhhchchchhhho ooo 3 3 33333333 3 TIHiHlrlHHHHHHHH H hchchhcccccccc co o oooooooo o 3 3 3 3 3 3 3 3 Η Η Η ίΗΠΗΙΙΗΗΗ c c c hchchhccco o o o o ooo hhochochochhhhhhh η η η h hhochhochhochhh Η 17± 1 Η 12 ± 1 Η 12±2 Η 15 士 0.07 Η 10 ±0.4 och3 11 ±0·9 Η 15 土 2 och3 11 ±2 Η 12 ±0.9 Η 14±2 Η 6.7 士 0.08 Η 9·1 土 0.9 Η 9·6 土 0·6 Η 3.5 土 0.3 Η 1.1 土 0.02 Η 9.3 土 2 Η 12 ±0.3 Η 4.4 士 0.1 Η >40 Η 5·6± 1 Η >40 Η >40 Η >40 och3 32 士 4 Η >40 och3 12 士 3 Η 1.5 ±0.01 0.8 (請先閱讀背面之注意事項再填寫本頁) 裝—— 訂---------繞 %, a ITP =微管聚合反應的抑制. -52- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 經濟部智慧財產局員工消費合作社印製 490462 ΚΙ _Β7___ 五、發明說明（5〇 ) 表5化合物69及70對由凝血酶（thrombm)、花生四烯酸 (arachidonic acid，AA)、膠原蛋白（collagen)及血小板活 化因子（platelet-activating factor，PAF)所引導的血小板 凝集的抑制活性a) 化合物^g/ml) 凝集百分比 凝血酶 AA 膠原蛋白 PAF 广''對照 92.9±0.7(4) 89.2±0.9(5) 90.3±0.8(4) 91·9±0·6(4) 』9,00 2.8 土 2.3(3)*** 0.0±0.0(4)*** 0.0±0.0(4)*** 2·1±1.8(4)*** 〜/ 50 13.3±5.3(3)*** 38.1±8.3(4)*** 20 88.1±0.8(3)*** 0.0±0.0(4)*** 87·9±1·8(4)*** 10 0.0±0.0(4)*** 1.1 土 0.9(4)*** 5 15.0±11.8(4)*** 31.5±6.4(4)*** 2 35.3 土 14.9(4)*** 43.0±6.4(4)*** 1 65.0±8.1(4)*** 52.6±7.5(4)*** 0.5 86.0±1.2(4)*** 76.2±3.7(4)*** 0.2 88.4±1.9(4)*** ic5〇 7.20//Μ 8.47Μ 照 92.9±0.7(4) 89.2±0.9(5) 90·3±0·8(4) 91.9±0.6(4) (79^00 11.7±6.5(4)*** 0.0±0.0(5)*** 0·0±0·0(4)*** 2.1±1·8(4)… 〆50 75.1±7.3(4)* 0.0±0.0(4)*** 19.8±7.0(4)*** 20 91.5±1.2(4) 10.3±6.0(4)*** 88.8 土 1·0(4)* 10 19.3±9.8(4)*** 5 30.1±9.0(4)*** 2 35.0±10.3(4)** * 1 0.0±0.0(5)*** 47.1±6.6(4)*** 0.5 33.8 土 13.4(5)*** 63.9±7.4(4)** 0.2 76.9 土 5.4(5)* 78.5±4.7(4)* 0.1 85.5±2.0(5) 86.4±2.9(4) ic5〇 1.60//Μ 9.20//Μ a)血小板懸浮液與待測化合物或0.5% DMSO在37°C培養一分鐘，接著凝血酶 (0.1 U/ml)，AA(100//M)，膠原蛋白(10/ig/ml)或 PAF (2 ng/ml)被加入以起 始凝集。表中的値以平均値±S· E表示，n=3-6。*·· ρ<0·05, Ρ<0·01，***·· Ρ0.001。 -53- 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） (請先閱讀背面之注意事項再填寫本頁)Compound Re R7 r2. R3. R4, r5. ITPa ic50 (" m) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 42 42 Η 43 Η Η 44 Η Η 45 Η Η 46 Η Η 47 Η Η 48 Η Η 49 Η Η 50 C1 Η 51 F Η 52 och3 Η 53 och3 och3 54 OCH.O 55 Η 56 Ο Η 57 ο Η 58 〇-ch3 Η 59 / ~ \ nw ° Η 60 Η Η 61 Η Η 62 Η Η 63 Η Η Η 64 Η Η 65 Η Η 66 Η Η 67 Η 68 o 3 3 3 3 3 3 3 3 15 soil 2 och3 11 ± 2 Η 12 ± 0.9 Η 14 ± 2 Η 6.7 ± 0.08 Η 9 · 1 soil 0.9 Η 9 · 6 soil 0 · 6 Η 3.5 soil 0.3 Η 1.1 soil 0.02 Η 9.3 soil 2 Η 12 ± 0.3 Η 4.4 ± 0.1 Η > 40 Η 5 6 ± 1 Η > 40 Η > 40 Η > 40 och3 32 4 Η > 40 och3 12 士 3 Η 1.5 ± 0.01 0.8 (Please read the precautions on the back before filling in this page) Installation-Order --------- Winding%, a ITP = Microtubule Polymerization -52- This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 490462 ΚΙ_Β7 ___ V. Description of the invention (50) Table 5 Compound 69 And 70 inhibitory activities on thrombocyte (thrombm), arachidonic acid (AA), collagen and platelet-activating factor (PAF) -induced platelet aggregation a) compounds ^ g / ml) agglutination percentage thrombin AA collagen PAF wide `` control 92.9 ± 0.7 (4) 89.2 ± 0.9 (5) 90.3 ± 0.8 (4) 91 · 9 ± 0 · 6 (4) 『9,00 2.8 soil 2.3 (3) *** 0.0 ± 0.0 (4) *** 0.0 ± 0.0 (4) *** 2 · 1 ± 1.8 (4) *** ~ / 50 13.3 ± 5.3 (3) *** 38.1 ± 8.3 (4) *** 20 88.1 ± 0.8 (3) *** 0.0 ± 0.0 (4) *** 87 · 9 ± 1 · 8 (4) *** 10 0.0 ± 0.0 (4) *** 1.1 Soil 0.9 (4) *** 5 15.0 ± 11.8 (4) *** 31.5 ± 6.4 (4) *** 2 35.3 Soil 14.9 (4) *** 43.0 ± 6.4 (4) *** 1 65.0 ± 8.1 ( 4) *** 52.6 ± 7.5 (4) *** 0.5 86.0 ± 1.2 (4) *** 76.2 ± 3.7 (4) *** 0.2 88.4 ± 1.9 (4) *** ic50〇7.20 // M 8.47 Μ Photo 92.9 ± 0.7 (4) 89.2 ± 0.9 (5) 90 · 3 ± 0 · 8 (4) 91.9 ± 0.6 (4) (79 ^ 00 11.7 ± 6.5 (4) *** 0.0 ± 0.0 (5) * ** 0 · 0 ± 0 · 0 (4) *** 2.1 ± 1 · 8 (4)… 〆50 75.1 ± 7.3 (4) * 0.0 ± 0.0 (4) *** 19.8 ± 7.0 (4) ** * 20 91.5 ± 1.2 (4) 10.3 ± 6.0 (4) *** 88.8 Soil 1.0 · (4) * 10 19.3 ± 9.8 (4) *** 5 30.1 ± 9.0 (4) *** 2 35.0 ± 10.3 (4) ** * 1 0.0 ± 0.0 (5) *** 47.1 ± 6.6 (4) *** 0.5 33.8 soil 13.4 (5) *** 63.9 ± 7.4 (4) ** 0.2 76.9 soil 5.4 (5) * 78.5 ± 4.7 (4) * 0.1 85.5 ± 2.0 (5) 86.4 ± 2.9 (4) ic50.60 // M 9.20 // M a) Platelet suspension was incubated with the test compound or 0.5% DMSO at 37 ° C. Minutes, followed by thrombin (0.1 U / ml), AA (100 // M), collagen (10 / ig / ml) or PAF (2 ng / ml) were added to initiate agglutination.値 in the table is represented by mean 値 ± S · E, n = 3-6. * · Ρ < 0 · 05, P < 0 · 01, *** ·· P0.001. -53- This paper size is applicable to Chinese National Standard (CNS) A4 (210 x 297 mm) (Please read the precautions on the back before filling this page)

490462490462

7 7 A B IV. 經濟部智慧財產局員工消費合作社印製 五、發明說明（51 ) 表6化合物69至79對由AA所引導的血小板凝集的抑制 活性a) 化合物 Rr R2， r4， R Ι〇50(μΜ) 69 Η Η Η ch3 7.20 70 Η Η Η c2h5 1.60 71 Η Η Η CH2C〇〇Et 26.95 72 Η Η Η (CH2)3C〇〇Et 30.65 73 Η Η Η (CH2)4C〇〇Et 173.43 74 〇ch3 Η Η c2h5 214.35 75 Η 〇ch3 Η c2h5 69.29 76 Η Η 〇ch3 c2h5 5.36 77 Η Η Η ch3 182.63 78 Η Η Η c2h5 184.00 79 Η Η Η CH2C〇〇Et >270 Indomethacin 0.25 阿斯匹靈 20.00 a)血小板懸浮液與待測化合物或0.5°/。DMSO在37°C培養一分鐘，接著AA (100 //M)被力[[入以起始凝集。Indomethacin及阿斯匹靈爲正對照。表中的値以平均 値土S. E.表示，n=3-6。 -54- (請先閱讀背面之注意事項再填寫本頁) ’裝------- —訂---------, 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）7 7 AB IV. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (51) Table 6 Inhibitory activities of compounds 69 to 79 on platelet aggregation induced by AA a) Compounds Rr R2, r4, R Ι〇 50 (μΜ) 69 Η Η ch3 7.20 70 Η Η Η c2h5 1.60 71 Η Η Η CH2C〇〇Et 26.95 72 Η Η CH (CH2) 3C〇〇Et 30.65 73 Η Η CH (CH2) 4C〇〇Et 173.43 74 〇ch3 Η 2 c2h5 214.35 75 Η 〇ch3 Η c2h5 69.29 76 Η Η 〇ch3 c2h5 5.36 77 Η Η ch3 182.63 78 Η Η 2 c2h5 184.00 79 Η Η Η CH2C00〇Et > 0.25 Indomethin a) Platelet suspension with test compound or 0.5 ° /. DMSO was incubated at 37 ° C for one minute, and then AA (100 // M) was forced [[into initiate agglutination. Indomethacin and aspirin were positive controls. The 値 in the table is expressed by the average 値 soil S. E., n = 3-6. -54- (Please read the precautions on the back before filling this page) 'Packing ------- --- Order ---------, This paper size applies to China National Standard (CNS) A4 specifications ( 210 X 297 mm)

Claims (1)

490462 經濟部智慧財產局員工消費合作社印製490462 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 式中： R2，，R3’，R4,及 R5,獨立地爲 H，（CH2)nCH3, OH， 0(CH2)nCH3, X，或 NR8R9，其中n = 〇~4的整數，X爲F，Cl， 或Br，及仏8及119獨立地爲H或（CH2)nCH3，其中n =0〜4的整 數；及 反6 及 R7 獨立地爲 H，（CH2)nCH3, OH，0(CH2)nCH3, X， nr8r9, nQ , {^，或 Ν〇";或116及一起爲-〇ch2o-， 其中η，X，118及119的定義同上。 2. 如申請專利範圍第1項的化合物，其中R2，，R3，，R4, 及R5,獨立地爲Η或0(CH2)nCH3，且其中至少有一個爲 0(CH2)nCH3，其中η = 0〜4的整數。 3. 如申請專利範圍第2項的化合物，其中R2，，R4,及R5, 爲Η，及R3,爲甲氧基。 4. 如申請專利範圍第2項的化合物，其中R6及R?獨立 地爲 H，0(CH2)nCH3, X，NR8R9，nQ，Q，或 ;或 • 55 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 490462 Α8 Β8 C8 (2002年3月修正） ______ D8 六、申請專利範圍 R6及R7 —'起爲- OCH2O-’其中η，X’ R8及R9的定義同申請 專利範圍第1項。 (請先閱讀背面之注意事項再填寫本頁) 5·如申請專利範圍第3項的化合物，其中：^6及117獨立 地爲 H，0(CH2)nCH3, X，NR8R9，NQ，〇，或 >Q0 ;或 R6及R7—起爲-0CH20-，其中η，X，118及119的定義同申請 專利範圍第1項。 6.如申請專利範圍第4項的化合物，其中R7爲Η，及116 爲NR8R9，N^]，0,或nQd;其中118及119的定義同申請 專利範圍第1項。 7. 如申請專利範圍第6項的化合物，其中、及化9爲甲 基。 8. 如申請專利範圍第5項的化合物，其中R7爲H，及化6 爲NR8R9，N^=，^，或\);其中R8及R9的定義同申請 專利範圍第1項。 經濟部智慧財產局員工消費合作社印製 9. 如申請專利範圍第8項的化合物，其中118及化9爲甲 基。 10. 如申請專利範圍第5項的化合物，其中R6及R7獨立 地爲Η，甲氧基或X，其中X的定義同申請專利範圍第1項。 -56 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 490462 Α8 Β8 C8 D8 (2002年3月修正） 六、申請專利範圍 11 · 一種用於治療癌症的醫藥組合物，該癌症係選自 人類卵巢癌（1A9)、P-gp-表現之鼻咽表皮樣癌（KB-VIN)、鼻 咽表皮樣癌（KB)、黑色瘤（SKMEL-2)、迴盲腸癌（HCT-8)、 乳癌（MCF-7)及肺癌（A-549)所組成之族群，該醫藥組合物 包含有效治療量的申請專利範圍第1項至第10項中任一項 的化合物或其藥學上可接受的鹽作爲活性成份，和與之混 合的用於該活性成份的藥學上可接受的載體或稀釋劑。 12. —種具下式（II)的化合物： (請先閱讀背面之注意事項再填寫本頁)Where: R2 ,, R3 ', R4, and R5 are independently H, (CH2) nCH3, OH, 0 (CH2) nCH3, X, or NR8R9, where n = an integer from 0 to 4, and X is F, Cl, or Br, and 仏 8 and 119 are independently H or (CH2) nCH3, where n = an integer from 4 to 4; and trans 6 and R7 are independently H, (CH2) nCH3, OH, 0 (CH2) nCH3, X, nr8r9, nQ, {^, or NO " or 116 and -0ch2o- together, wherein η, X, 118 and 119 have the same definitions as above. 2. For example, the compound in the scope of patent application, wherein R2, R3, R4, and R5 are independently Η or 0 (CH2) nCH3, and at least one of them is 0 (CH2) nCH3, where η = An integer from 0 to 4. 3. For the compound in the second item of the patent application, wherein R2, R4, and R5 are fluorene, and R3 is methoxy. 4. For the compound in the second item of the patent application, in which R6 and R? Are independently H, 0 (CH2) nCH3, X, NR8R9, nQ, Q, or; or 55-This paper size applies Chinese national standards ( CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back before filling out this page) 490462 Α8 Β8 C8 (Amended in March 2002) ______ D8 VI. Range of patent application R6 and R7 — 'from- OCH2O- 'where η, X' R8 and R9 have the same definitions as those in the first patent application. (Please read the precautions on the back before filling out this page) 5. If the compound in the scope of patent application No. 3, where: ^ 6 and 117 are independently H, 0 (CH2) nCH3, X, NR8R9, NQ, 0, Or> Q0; or R6 and R7—from -0CH20-, where η, X, 118, and 119 have the same definitions as those in the first patent application. 6. If the compound of the scope of patent application No. 4, wherein R7 is Η, and 116 is NR8R9, N ^], 0, or nQd; where the definition of 118 and 119 is the same as the scope of patent application No. 1. 7. For the compound in the scope of application for patent No. 6, wherein and 9 are methyl. 8. If the compound in the scope of patent application No. 5 in which R7 is H and Chem6 is NR8R9, N ^ =, ^, or \); where the definitions of R8 and R9 are the same as those in the scope of patent application No. 1. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 9. For the compounds in the scope of patent application No. 8, 118 and 9 are methyl. 10. As for the compound in the scope of patent application, R6 and R7 are independently fluorene, methoxy or X, and the definition of X is the same as that in scope of patent application. -56-This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 490462 Α8 Β8 C8 D8 (as amended in March 2002) 6. Application for patent scope 11 · A pharmaceutical composition for treating cancer The cancer is selected from human ovarian cancer (1A9), P-gp-presenting nasopharyngeal epidermoid carcinoma (KB-VIN), nasopharyngeal epidermoid carcinoma (KB), melanoma (SKMEL-2), and ileocecal cancer (HCT-8), breast cancer (MCF-7) and lung cancer (A-549), the pharmaceutical composition contains a therapeutically effective amount of a compound in any one of the scope of claims 1 to 10 of the patent application, or A pharmaceutically acceptable salt thereof is used as an active ingredient, and a pharmaceutically acceptable carrier or diluent for the active ingredient is mixed therewith. 12. —A compound with the following formula (II): (Please read the precautions on the back before filling this page) 經濟部智慧財產局員工消費合作社印製 式中： R2，，R3，，R4,及 R5,獨立地爲 H，（CH2)nCH3, OH， 0(CH2)nCH3, X，或 NR8R9，其中 η = 0〜4 的整數，X爲 F，C1， 或Br，及118及119獨立地爲Η或（CH2)nCH3，其中η =0〜4的整 數；及 R6 及 R7 獨立地爲 H，（CH2)nCH3, OH，0(CH2)nCH3, X， NR8R9, nQ , (3，或"Ο ;或仏6 及 R7 一起爲-〇CH20-， 其中η，X，118及119的定義同上。 -57 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 490462 A8 B8 C8 (2002年3月修正) D8 六 經濟部智慧財產局員工消費合作社印製 申請專利範圍 * 13. 如申請專利範圍第u項的化合物，其中]^7爲η。 (請先閱讀背面之注意事項再填寫本頁) 14. 如申請專利範圍第I3項的化合物，其中r2，，r3，， R4’及Rv獨立地爲Η或0(CH2)nCH3，且其中至少有一個爲 〇(CH2)nCH3，其中n = 〇〜4的整數。 15·如申請專利範圍第14項的化合物，其中r2，，r4，及 Rs’爲Η，及R3,爲甲氧基。 16·如申請專利範圍第15項的化合物，其中116爲乂，其 中X的定義同申請專利範圍第1項。 17. 如申請專利範圍第16項的化合物，其中X爲C1。 18. —種用於治療癌症的醫藥組合物，該癌症係選自 人類卵巢癌（1A9)、P-gp-表現之鼻咽表皮樣癌（KB-VIN)、鼻 咽表皮樣癌（KB)、黑色瘤（SKMEL-2)、迴盲腸癌（HCT-8)、 乳癌（MCF-7)及肺癌（A-549)所組成之族群，該醫藥組合物 包含有效治療量的申請專利範圍第12項至第1 7項中任一項 的化合物或其藥學上可接受的鹽作爲活性成份，和與之混 合的用於該活性成份的藥學上可接受的載體或稀釋劑。 19. 一種具下式（III)或（IV)的化合物： -58 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 490462 六 經濟部智慧財產局員工消費合作社印製 A8 B8 C8 (2002年3月修正） D8 申請專利範圍In the print format of the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs: R2, R3, R4, and R5, independently H, (CH2) nCH3, OH, 0 (CH2) nCH3, X, or NR8R9, where η = An integer of 0 to 4, X is F, C1, or Br, and 118 and 119 are independently Η or (CH2) nCH3, where η = 0 to 4; and R6 and R7 are independently H, (CH2) nCH3, OH, 0 (CH2) nCH3, X, NR8R9, nQ, (3, or "〇; or 仏 6 and R7 together are -〇CH20-, where η, X, 118 and 119 have the same definitions as above. -57 -This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 490462 A8 B8 C8 (as amended in March 2002) D8 Sixth Intellectual Property Bureau of the Ministry of Economic Affairs printed the scope of patent application for application by consumers' cooperatives * 13. If For compounds in the scope of application for item u, where] ^ 7 is η. (Please read the precautions on the back before filling this page) 14. For compounds in scope of application for item I3, where r2 ,, r3 ,, R4 ' And Rv is independently Η or 0 (CH2) nCH3, and at least one of them is 〇 (CH2) nCH3, where n = an integer from 0 to 4. 15. As the 14th in the scope of patent application Compounds, wherein r2, r4, and Rs' are fluorene, and R3 is methoxy. 16. · For example, the compound of the 15th scope of the patent application, of which 116 is 乂, where X has the same definition as the first scope of the patent application. Item 17. The compound according to item 16 of the scope of patent application, wherein X is C1. 18. A pharmaceutical composition for treating cancer, the cancer is selected from human ovarian cancer (1A9), P-gp-expressing Nasopharyngeal Epidermoid Carcinoma (KB-VIN), Nasopharyngeal Epidermoid Carcinoma (KB), Melanoma (SKMEL-2), Ileum Cancer (HCT-8), Breast Cancer (MCF-7), and Lung Cancer (A-549) The group consists of a pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of claims 12 to 17 or a pharmaceutically acceptable salt thereof as an active ingredient, and a mixture thereof for use as an active ingredient. A pharmaceutically acceptable carrier or diluent for the active ingredient. 19. A compound having the following formula (III) or (IV): -58-This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297) (%) 490462 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A8 B8 C8 (Amended in March 2002 D8 Patent Application range (III) (IV) 式中： R2’，R3，，R4’及 R5’獨立地爲 H，（CH2)nCH3, OH， 〇(CH2)nCH3, X，或 NR8R9，其中 n = 〇〜4 的整數，X爲 F，C1， 或Br，及Rs及R9獨立地爲Η或（CH2)nCH3，其中η =0〜4的整 數； R 爲（CH2)nCH3 或（CH2)nCOO(CH2)nCH3，其中 η 的定義 同上；及 R6 及 R7 獨立地爲 H，（CH2)nCH3, OH, 0(CH2)nCH3, X， nr8r9, nQ , (3,或 NG。；或以及尺7一起爲_0CH20-，其 中η，X，R8及R9的定義同上。 20. 如申請專利範圍第19項的化合物，其中Rv，R6及 R7均爲Η。 21. 如申請專利範圍第20項的化合物，其中η爲0或1。 22. 如申請專利範圍第21項的化合物，其具有式（ΠΙ) 的結構。 -59 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------------^^衣-------•—訂---------線 j (請先閱讀背面之注意事項再填寫本頁) 490462 A8 § (2002年3月修正) D8 六、申請專利範圍 23·如申請專利範圍第22項的化合物，其中R爲 (CH2)nCH3，其中 η爲 0或 1。 (請先閱讀背面之注意事項再填寫本頁) 24. 如申請專利範圍第23項的化合物，其中R2，，R3，， 及R4,獨立地爲Η或OCH3。 25. 如申請專利範圍第24項的化合物，其中R2，，R3,及 R4,均爲Η。 26. 如申請專利範圍第24項的化合物，其中R2,及R3， 均爲 Η，R4,爲 〇CH3。 27. 如申請專利範圍第26項的化合物，其中R爲 CH2CH3 〇 經濟部智慧財產局員工消費合作社印製 28. —種用於抑制血小板凝集的醫藥組合物，包含有 效治療量的申請專利範圍第1 9項至第27項中任一項中的化 合物或其藥學上可接受的鹽作爲活性成份，和與之混合的 用於該活性成份的藥學上可接受的載體或稀釋劑。 -60 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）(III) (IV) In the formula: R2 ', R3 ,, R4' and R5 'are independently H, (CH2) nCH3, OH, 〇 (CH2) nCH3, X, or NR8R9, where n = 〇 ~ 4 Integer, X is F, C1, or Br, and Rs and R9 are independently Η or (CH2) nCH3, where η = 0 ~ 4; R is (CH2) nCH3 or (CH2) nCOO (CH2) nCH3, Where η has the same definition as above; and R6 and R7 are independently H, (CH2) nCH3, OH, 0 (CH2) nCH3, X, nr8r9, nQ, (3, or NG.), Or together with ruler 7 is _0CH20- , Where η, X, R8 and R9 have the same definitions as above. 20. For example, the compound in the scope of patent application No. 19, wherein Rv, R6 and R7 are all Η. 0 or 1. 22. If the compound in the scope of patent application No. 21, it has the structure of formula (ΠΙ). -59-This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) --- ----------- ^^ 衣 ------- • —Order --------- line j (Please read the precautions on the back before filling this page) 490462 A8 § (Amended in March 2002) D8 VI. Scope of Patent Application Of compounds of the above, wherein R is (CH2) nCH3, where η is 0 or 1. (Please read the notes on the back before filling out this page) 24. For the compound of the 23rd scope of the patent application, where R2 ,, R3, , And R4 are independently fluorene or OCH3. 25. If the compound in the scope of the patent application is No. 24, wherein R2, R3, and R4 are all 26. 26. If the compound in the scope of patent application No. 24, where R2 , And R3 are both Η, R4, 〇CH3. 27. For example, the compound in the scope of patent application No. 26, where R is CH2CH3 〇 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 28.-a kind of platelet inhibition Pharmaceutical composition comprising, as an active ingredient, a compound of any one of claims 19 to 27 or a pharmaceutically acceptable salt thereof in an effective therapeutic amount, and mixed therewith for the active ingredient Pharmaceutically acceptable carrier or diluent. -60-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)