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TWI280242B - Pharmaceutical compounds - Google Patents

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Publication number
TWI280242B
TWI280242B TW089125715A TW89125715A TWI280242B TW I280242 B TWI280242 B TW I280242B TW 089125715 A TW089125715 A TW 089125715A TW 89125715 A TW89125715 A TW 89125715A TW I280242 B TWI280242 B TW I280242B
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Taiwan
Prior art keywords
benzo
ethyl
carboxylic acid
morphine
dimethylamino
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TW089125715A
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Chinese (zh)
Inventor
John Milton
Nigel Vicker
Adrian John Folkes
Shouming Wang
William Alexander Denny
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Xenova Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/46—Phenazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

A compound which is a benzo[a]phenazine-11-carboxamide derivative of formula (I), hydroxyl, C1-C6 alkoxy which is unsubstituted or substituted, heteroaryloxy, C1-C6 alkyl which is unsubstituted or substituted, nitro, cyano, azido, amidoxime, CO2R10, CON(R12)2, OCON(R12), SR10, SOR11, SO2R11, SO2N(R12)2, N(R12)2, NR10SO2R11, N(SO2R11)2 NR10(CH2)n CN, NR10COR11, OCOR11 or COR10; each of R5 to R7, which are the same or different, is selected from hydrogen, halogen, hydroxy, C1-C6 alkoxy, C1-C6 alkyl, SR10 and N(R12)2; Q is C1-C6 alkylene which is unsubstituted or substituted by (i) C1-C6 alkyl which is unsubstituted or substituted, (ii) hydroxy, provided that the hydroxy group is not alpha to either of the N atoms adjacent to Q in formula (I), (iii) CO2R10, or (iv) CON(R12); R8 and R9, which are the same or different, are each hydrogen or C1-C6 alkyl, or R8 and R9 together with the nitrogen atom to which they are attached form a saturated 5- or 6-membered N-containing heterocyclic ring which may include one additional heteroatom selected from O, N and S, or one of R8 and R9 is an alkylene chain optionally interrupted by O, N or S, which is attached to a carbon atom on the alkylene chain represented by Q to complete a saturated 5- or 6-membered N-containing heterocyclic ring as defined above; R10 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, benzyl or phenyl; R11 is C1-C6 alkyl, C3-C6 cycloalkyl, benzyl or phenyl; each R12, which are the same or different, is hydrogen, C1-C6 alkyl, cycloalkyl, benzyl or phenyl, or the two R12 groups form, together with the nitrogen atom to which they are attached a 5- or 6-membered saturated N-containing heterocyclic ring which may include 1 or 2 additional heteroatoms selected from O, N and S; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof; with the proviso that at least one of R1 to R4 is other than hydrogen. These compounds are inhibitors of topoisomerase I and/or topoisomerase II and can be used to treat tumours, including tumours which express MDR.

Description

1280242 A7 B7 1 五、發明說明（） 本發明係關於取代之笨并[a]啡畊-11·羧醯胺及該等之 衍生物。此等化合物為細胞毒性藥劑，其經證明對拓樸異 構酶I及拓樸異構酶II有抑制作用，且具有防制多重藥物抗 性機制的能力。該等化合物因此而為有潛力之抗癌藥劑。 拓樸異構酶為多種已試驗成功之化學治療藥劑的重要 細胞標的物（Wang, Ann Rev. Biochem, 65,625-692，1996) ，且其為調節DNA拓樸異構學之必需性酵素，DNA拓樸異 構學為細胞進行分裂及增生時所必需（Wang，/oe cz7)。以拓 樸異構酶II為標的物之藥物，例如：多克莎盧比辛 (doxorubicin)及伊托波赛德（etoposide)，已被廣泛地使用在 癌症化學治療（Hande，Biophys，Acta 1400，173-184，1998) ，而以拓樸異構酶I為標的物之藥物，理論上為康普多莎辛 (camptothecin)之類似物，其已於近期形成一個重要之影響 :一個實例為CPT-11對結腸癌之治療（Dancey er a/，Br· J. Cancer 74, 327-338, 1996)。更近期地，拓樸異構酶已被展 現為供抗真菌、抗細菌及抗病毒藥物所使用之治療標的物 (Chen 以 a/，Rev. Pharmacol. Toxicol，34，191-218，1994)。 經濟部智慧財產局員工消費合作社印製 ----i-------裝--- (請先閱讀背面之主意事項再填寫本頁) 除了該等以拓樸異構酶I或II為標的物之化合物外，數 種拓樸異構酶I或π之共同抑制劑已被鑑別出來，並同時具 有治療固態腫瘤之效用。此等化合物包含因托卜立辛 (intoplicine)(Riou et al, Cancer Res. 53, 5987-5993, 1993) ' DACA/XR5000 (Finlay et al, Eur. J. Cancer 32 A, 708-714，1996)及TAS-103 (Utsugi a/，J. Cancer Res，88, 992-1002, 1997)，全部都已進入臨床評估。拓樸異構酶I或 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280242 A7 五、發明說明（） II之共同抑制劑的優點為其能夠不表現抗藥性，且能夠標 的兩種重要酵素而影響DNA拓樸異構學，該兩種酵素之活 性係在細胞週期之兩個不同的點上。 目前已發現有一族群之新穎的苯并[a]啡畊·丨丨·羧醯胺 為拓樸異構酶I及拓樸異構酶π之抑制劑。依據地，本發明 提供一個化合物，其為一個具有化學式⑴之苯并[a]啡啡 -11-羧醯胺的衍生物，1280242 A7 B7 1 V. INSTRUCTIONS () The present invention relates to substituted stupid [a] morphine-11·carboxamide and such derivatives. These compounds are cytotoxic agents which have been shown to inhibit topoisomerase I and topoisomerase II and have the ability to prevent multiple drug resistance mechanisms. These compounds are therefore potential anticancer agents. Topoisomerases are important cellular targets for a variety of successful chemotherapeutic agents (Wang, Ann Rev. Biochem, 65, 625-692, 1996) and are essential enzymes for the regulation of DNA topoisomerism, DNA. Topological isomerism is required for cell division and proliferation (Wang, /oe cz7). Drugs based on topoisomerase II, such as doxorubicin and etoposide, have been widely used in cancer chemotherapy (Hande, Biophys, Acta 1400, 173-184, 1998), and the drug with topoisomerase I as the standard, in theory, is an analog of camptothecin, which has recently formed an important influence: an example is CPT -11 treatment of colon cancer (Dancey er a/, Br J. Cancer 74, 327-338, 1996). More recently, topoisomerases have been shown to be therapeutic targets for antifungal, antibacterial and antiviral drugs (Chen, a/, Rev. Pharmacol. Toxicol, 34, 191-218, 1994). Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Print----i------- Pack--- (Please read the back of the subject matter and fill out this page) In addition to these topoisomerase I or In addition to II as a compound of the subject matter, several inhibitors of topoisomerase I or π have been identified and have the utility of treating solid tumors. Such compounds include intoplicine (Riou et al, Cancer Res. 53, 5987-5993, 1993) 'DACA/XR5000 (Finlay et al, Eur. J. Cancer 32 A, 708-714, 1996) and TAS-103 (Utsugi a/, J. Cancer Res, 88, 992-1002, 1997), all entered clinical evaluation. Topoisomerase I or this paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1280242 A7 V. Invention Description (II) The advantage of the common inhibitor is that it can not exhibit resistance, and The two important enzymes that can be targeted affect DNA topoisomerism, and the activities of the two enzymes are at two different points in the cell cycle. A novel group of benzo[a]morphin-carboxamides has been found to be an inhibitor of topoisomerase I and topoisomerase π. According to the present invention, the present invention provides a compound which is a derivative of benzo[a]morphine-11-carboxamide having the formula (1).

八中母個R至R係為相同或不同，且係選自於··氫、鹵 素、羥基、未取代或取代之C1_C6烷氧基 '雜芳基氧基、未 (請先閱讀背面之主意事項再填冩本頁) 裝 經濟部智慧財產局員工消費合作社印制衣The eighth to the parent R to R are the same or different and are selected from hydrogen, halogen, hydroxyl, unsubstituted or substituted C1_C6 alkoxy 'heteroaryloxy, not (please read the back idea first) Matters refilled on this page) Installed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printed Clothes

取代或取代之Cl-C6M、确基、m氮基、酿胺基砖 、co2Rl{>、c〇N(R12)2、OCON(Rl2)2、SR|。' S0Rll、s〇2Rll、 S〇2N(R12)2、NR丨。s〇2Rh、N(s〇2Rll)2、NRlQ(cH2)nCN、 NR10CORn ' OCOR11 或 C〇R10 ; 每一個r5至R7係為相同或不同，且係選自m素、 羥基、Cl_C6貌氧基、Ci:C^ 基、SRl〇 及 N(R12)2 ; Q係為-個未取代或取代之Gi.e6㈣基，且是被取代以⑴ 未取代或取代之C!.C6：^基，（丨⑽基，但有條件是該經基 對於化子式（I) _鄰接於Q的任_個氮原子而言非位為α位 置，（iii) C02R丨0或(iv)c〇N(Ri2)Substituted or substituted Cl-C6M, decyl, m-nitrogen, aramid brick, co2Rl{>, c〇N(R12)2, OCON(Rl2)2, SR|. 'S0Rll, s〇2Rll, S〇2N(R12)2, NR丨. s〇2Rh, N(s〇2Rll)2, NRlQ(cH2)nCN, NR10CORn ' OCOR11 or C〇R10 ; each of r5 to R7 is the same or different and is selected from the group consisting of m, hydroxy and Cl_C6 , Ci: C^ group, SRl〇, and N(R12)2; Q is an unsubstituted or substituted Gi.e6(tetra) group, and is substituted with (1) unsubstituted or substituted C!.C6:^ group, (丨(10)-based, but with the proviso that the radical is non-position to the α position for any nitrogen atom adjacent to Q of the formula (I) _, (iii) C02R丨0 or (iv)c〇N (Ri2)

訂. ，線· 1280242 五 J 經濟部智慧財產局員工消費合作社印製Order. , Line · 1280242 Five J Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

A7 B7 、發明說明（） R及R係為相同或不同’且為分別為：氫或院基，或 R8及R9與其等所相連之氮原子一起形成一個飽和之5•或卜 員含氮之雜環，該雜環可以包含一個另外之雜原子係選自 於氧、氮及硫’或R8及R9其中之一者係為一個當中可選擇 性地被夾以氧、氮或疏之烯鏈，該氧、氮或硫被連接至一 個位在以Q表示之烯鏈上的碳原子，俾以完成一個如上所 定義之飽和5_或6·員的含氮雜環； R10為氫、C丨-C6烷基、C1-C3環烷基、苄基或笨基； R11為C】-C6烷基、crC3環烷基、苄基或苯基； 每一個R12係為相同或不同，且係為：氫、烷基、環 烧基、节基或笨基，或兩個R12基團連同其等相連之氮原子 形成一個5-或6-員飽和之含氮雜環，該雜環可以包含一個 或兩個另外之雜原子係選自於氧、氮及硫；且 η為1、2或3 ; 或其一個製藥上可接受之鹽類； 但有條件為R至R4中之至少一者不是氫原子。 於一個本發明較佳之方面，苯并[a]啡畊_η•羧醯胺之 衍生物為化學式（la) (la) 、(ch2)广 nWxr9) 本紙張尺度適用中國國家標準（CNS)A4規格（21〇 X 297公釐） -----------裝— ίη先閡讀背面>:1音？事項再填寫本頁) 訂—Τ. 1280242 A7 發明說明（） 其中R1至R9係如上所定義者； p為1或2 ;且 R13為⑴氫原子，（ii)未取代或被取代以羥基、芳基或叫…、 之C! C6烧基其中R係如上所定義者，（iii)c〇2R10， (iv)CON(R12)2，或（v)芳基。 當化學式⑴中的其中之_者係為一個被被連 接至-個位在Q上之碳原子的烯鏈時，該具有化學式⑴之 化合物係具有下列結構式（Ib):A7 B7, invention description () R and R are the same or different 'and are respectively: hydrogen or a hospital base, or R8 and R9 together with the nitrogen atom to which they are connected form a saturated 5 or a nitrogenous a heterocyclic ring which may comprise a further hetero atom selected from the group consisting of oxygen, nitrogen and sulfur ' or one of R8 and R9 as one of which may optionally be sandwiched by an oxygen, nitrogen or alkene chain. The oxygen, nitrogen or sulfur is bonded to a carbon atom at the olefin chain represented by Q to form a saturated nitrogen-containing heterocyclic ring as defined above; R10 is hydrogen, C丨-C6 alkyl, C1-C3 cycloalkyl, benzyl or stupid; R11 is C]-C6 alkyl, crC3 cycloalkyl, benzyl or phenyl; each R12 is the same or different and Is: a hydrogen, an alkyl group, a cycloalkyl group, a benzyl group or a stupid group, or two R12 groups together with a nitrogen atom to which they are attached form a 5- or 6-membered saturated nitrogen-containing heterocyclic ring, which may contain One or two additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; and η is 1, 2 or 3; or a pharmaceutically acceptable salt thereof; but conditionally R to R4 At least one is not a hydrogen atom. In a preferred aspect of the invention, the derivative of benzo[a]morphine_η•carboxyguanamine is of the formula (la) (la), (ch2) wide nWxr9) The paper scale applies to the Chinese National Standard (CNS) A4. Specifications (21〇X 297 mm) ----------- Installed - ίη first read the back >: 1 tone? Matters refilled this page) Τ. 1280242 A7 Description of the invention () wherein R1 to R9 are as defined above; p is 1 or 2; and R13 is (1) a hydrogen atom, (ii) is unsubstituted or substituted with a hydroxyl group, An aryl group is a C, a C6 alkyl group wherein R is as defined above, (iii) c〇2R10, (iv) CON(R12)2, or (v) aryl. When the chemical formula (1) is an olefin chain which is bonded to a carbon atom at the Q position, the compound of the formula (1) has the following structural formula (Ib):

R1 °^N~W-((h H J (lb) (請先閱讀背面之:i意事項再填寫本頁) 裝 其中R至R係如上述對於化學式⑴所定義者· 經濟部智慧財產局員工消費合作社印製 R14為氫原子或CrC6烷基； w為一個直接鍵結或一個心·。烯鏈；且 Y及Z與其等所相連之氮及碳原子共同形成一個飽和之 或6·員的含氮雜環，該雜環可以包含一個另外之氧、氮或 硫原子。 一個CrC6烷基可以為直鏈或支鏈。一個CrQ烷基典 型為一個(：〗-<:4烷基，例如一個曱基、乙基、丙基、異·丙 基、正·丁基、二級丁基或三級（化r/) 丁基基團。一個C〗_C6 烷基團為未取代的或取代的，典型地為被一個或更多個選 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 5·R1 °^N~W-((h HJ (lb) (Please read the back of the back: i want to fill out this page again) Install R to R as defined above for the chemical formula (1) · Ministry of Economic Affairs Intellectual Property Office staff The consumer cooperative prints R14 as a hydrogen atom or a CrC6 alkyl group; w is a direct bond or a heart. The olefin chain; and Y and Z together with the nitrogen and carbon atoms connected thereto form a saturated or 6-membered a nitrogen-containing heterocyclic ring which may contain an additional oxygen, nitrogen or sulfur atom. A CrC6 alkyl group may be straight or branched. A CrQ alkyl group is typically a (:)-<:4 alkyl group, For example, a fluorenyl, ethyl, propyl, isopropyl, n-butyl, secondary butyl or tertiary (r/) butyl group. A C _C6 alkyl group is unsubstituted or Superseded, typically applied to the Chinese National Standard (CNS) A4 specification (210 X 297 public) by one or more paper grades.

經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 !28〇242 五、發明說明（ 自於下列之基團所取代：羥基-CrC6烷基（其中烷基原子團 部份為未取代或被取代以如同本案在此對基所具 體指明者），CVC6烷氧基，苯基，N(R12)2(其中R12之定義 如上文），及經基。羥基-Ci_C6烷基之範例包含如羥基曱基 、1·羥基甲基及2-羥基乙基。（^-(^烷撐基係為一個二價性 之如上文所定義之Cl-C6烷基。 一個芳基基團典型地為一個芳族的C6_C1〇碳環基團（ 如苯基或萘基）’其為未取代的或是被取代以鹵素、Cl-c6 烷基、羥基、（Vc6烷氧基、硝基(n〇2)、n(r12)2、co2r10 、氰基（CN)或全鹵素取代2Ci-c6烷基（wCf3)。 一個函素係為氟、氣、溴或碘。較佳為氟、氣或溴。 一個C!-CV垸氧基團可以為直鏈或支鏈。其典型地係為 一個CrC：4烷氧基團，例如：一個甲氧基、乙氧基、丙氧基 、異·丙氧基、正·丁氧基、二級丁氧基或三級（化以）丁氧基 團。一個CrC6烷氧基團為未取代或有取代，典型地被一個 或更多個選自於下列之基團所取代：N(R12)2、con(r12)2 、經基、CVC6燒氧基、CVC6烷基、c2-c6、烯基、c2-c6炔基 、氰基、C02R1G、COR10、一個飽和之5-或6-員的含氮雜環 基團或苯基，該苯基為未取代的或被一個或多個鹵素原子 所取代。 一個C3-C10環烷基團可以為環丙基、環丁基、環己基 、環庚基。典型地為c3-c6環烷基。一個C2-C6烯基包含一 個或多個不飽和鍵。其可以為，舉例而言：乙烯基、丙缔 基、丁烯基或戊烯基。一個飽和之5-或6-員的含氮雜環可 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） η ----i-------* 裝--- (請先閱讀背面之注意事項再填寫本頁) 灯： 1280242 A7 五、發明說明（） 以為，舉例而言·· 〇辰咬、呢呼、嗎琳或口比口各咬。 一個雜方基氧基為一個-〇}1以基，其中Het為一個未飽 和之5-或6-員的含氮雜環，其可包含一個或多個另外之氧 、氮或硫原子。該等之範例包含：呋喃、喧吩、毗咯、。引 哚、異口引嗓"比唾、味嗤、異啊、十坐"塞唾、異喧唾 比疋奎林、嗜噚琳、異邊琳' 嗔吩並吡啡、D比喃、嘧 疋》4 口比4 κ及三口秦。前述之雜環可以為未取代 或被-個或多個取代基取代，例如一個或多個取代基係選 自於經基，齒素，未取代或取代之c「c6烧基[例如，被函 素取代(如cf3)]，Cl-c6烷氧基，石肖基以及一種如上文所定 義之胺基基團n(r12)2。 於本發月之個較佳的方面，於化學式⑴、（⑷或⑽ 中，R至R每-個皆為氫，而R4則為除了氯以外之原子。 典型之RlCA烧氧基、㈣、C「C6·、經基、 烧基、睛或鹵素 於一個較佳系列之化合物中，化學式⑴、(Ia)或⑽ 中的R係為CrC6烷氧基或羥基，R7為羥基，且&丨至汉3、R5 及R6每一個皆為氫。同時為較佳之化合物是，其中“為 CrC6^氧基或經基’ R6為^氧基' _素或甲基硫代 ，且R1至R3、R5及R7全巧為氫。 於化學式（⑷中，Rn較佳為CA坑基更佳為甲基。 於化學式⑴及（la)中，一個較佳之Q的選擇為一個C2_ 或(：3-稀鏈，其相對於鄰接之酿胺i原子係呈被α·取代以如 上所定義的未取代或取代之Cl-C6烷基。較佳地’ Q之上的 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公g ) (請先K讀背面之注意事項再填寫本頁) 訂· J------ 經濟部智慧財產局員工消費合作社印製 1280242 A7 j--------—_ B7____ 1五、發明說明（7) 請 先 Β2 讀 背 面 意 事 再 填 寫 本 頁 取代基為未取代之CrC6烷基或羥基烷基（如羥基曱 基或經基乙基）。典型地，c2•或c3-烯鏈相對於鄰接之醯胺 氣原子係被α-取代以曱基、乙基、異丙基、羥基甲基、取 代之羥基曱基或^羥基乙基。 經濟部智慧財產局員工消費合作社印製 較佳之本發明化合物的範例為： 化合物名鳐 化合物編號 丁；^、-本背[冲^听-11邊酸(2_二¥基胺基_乙基>酿胺 1 3 &基·本开La〗啡啡_u•羧酸(2_二曱基胺基·乙基醯胺 2 4甲氧基-笨并[a]啡啡-11-羧酸(2-二曱基胺基-乙基)-醯胺 3 啡1酸(2·二曱基胺基-乙基V酿胺·· 4 知-本开㈤琊呀-ll-羧酸(2-二甲基胺基-乙基)-酿胺 5 基-笨并[a]啡啩·lu羧酸(2_二甲基胺基·乙基 > 醯胺 6 4-硝基-本开[a]啡啡·u•羧酸(2•二曱基胺基·乙基)·醯胺 7 4胺i甲乙基基,4:基冰羥基-笨并[樹·η·瓣二 8 勝笨并[a]朴η·賴2_二甲基 9 9、臭4-甲氧基·笨并㈤啡糾!·猶(2二乙基胺基·乙基)·醯胺 10 4-氛甲氧基-笨并[a]啡味·u叛酸^二曱基胺基-乙基^醯胺 11 4-卞暴礼基·本开㈤啡脅_ι丨·叛酸(2-二曱基胺基·乙基)福胺 12 炔基氧基·笨并㈨啡啡·11β羧酸(2·二甲基胺基-乙基 13 3,4-一甲氣基·笨并〖aj啡哜·j丨·羧酸仏二曱基胺基·乙基)·醯胺 14 4-乙氧基·本开[a]啡喷-⑴緩酸⑺二曱基胺基_6基)·酿胺 15 4-異丁氧基·笨并[a]啡呀·u•叛酸仏二甲基胺基-乙基)·酿胺 16 1(、41?^节基氧基)-苯并^]°非七11-緣酸(2-二甲基胺基-乙 基)·醒胺 17 4-(^-曱^基-乙氧基)·笨并[a]啡啡·二甲基胺基· 乙基)·酿胺 18 [11-(2·一曱基胺基·乙基胺甲酿基).苯并㈤啡併4•基氧基 醋酸乙醋 19 3-溴-4-羥基·本并[a]啡啡]丨邊g以2_二甲基胺某·乙基醯胺 20 4-(2-羥基·乙氧基)·苯并[a]啡啡·1]μ羧酸(2•二甲基胺基·乙 21 本紙張尺度適用中國國家標準(CNS)A4規格（21〇 X 297公爱) 1280242 A7 B7 8五、發明說明（） 經濟部智慧財產局員工消費合作社印製 基)·醯胺 4-(嘧啶-2-基氧基)-苯并[a]啡畔-11-羧酸(2-二曱基胺基-乙 基:醯胺 22 4-(2-嗎啉-4-基-乙氧基)-苯并[a]啡畊-11-羧酸(2-二曱基胺 基-乙基)-醯胺 23 4-(3-氰基-丙氧基)-笨并[a]啡畊-11-羧酸(2-二甲基胺基-乙 基)-醯胺 24 4-曱基-苯并[a]啡哜-11·羧酸(2-二甲基胺基-乙基)-醯胺 25 4-氟-苯并[a]啡畊-11-羧酸(2-二曱基胺基·乙基)-醯胺 26 4·(3-二甲基胺基-丙氧基)-苯并[a]啡畊-11-羧酸(2·二曱基 胺基·乙基)-酿胺 27 4-甲基續醯基-苯并[a]啡哄-11-羧酸(2-二甲基胺基-乙基)·醯胺 28 4-胺曱醯基甲氧基·苯并[a]啡阱-1卜羧酸(2-二甲基胺基·乙 基)-醯胺 29 4-甲氧基·苯并[a]啡哜-11-羧酸(3-胺基-2-羥基·丙基)-醯胺 30 4-曱氧基-苯并[a]啡啡-11-羧酸(3-二甲基胺基·丙基)·醯胺 31 4-溴-苯并[a]啡啡-11-羧酸(2·二甲基胺基·乙基)-醯胺 32 11-(2-二曱基胺基-乙基胺甲醯基)-苯并[a]啡畊4-基乙酸酯 33 4-(2-氧-丙氧基)-笨并[a]啡啩-11-羧酸(2-二曱基胺基-乙基 )-醯胺 34 4-曱氧基-苯并[a]啡啡-11-羧酸(2·二曱基胺基-1-曱基-乙 基)·酿胺 35 4-氰》基-苯弁[a]啡味-11·叛酸(2-二曱基胺基-乙基)-酿胺 36 11-(2-二甲基胺基·乙基胺甲醯基)·笨并[a]啡畊4-基乙基胺 基甲酸酯 37 3-石肖基-苯并[a]啡味-11-叛酸(2-二甲基胺基·乙基)·酿胺 38 4-甲磺醯基-笨并[a]啡啩-1卜羧酸(2-二甲基胺基+甲基-乙基)-醯胺 39 4-氣-苯并[a]啡哜-11-羧酸(2·二曱基胺基-乙基)-醯胺 40 4-疊氣基-苯并[3]啡味-11-緩酸(2-二甲基胺基-乙基)-Sfe胺 41 4-胺基·苯并[a]啡畊-1卜羧酸(2-二曱基胺基-乙基V醯胺 42 11-(2-二甲基胺基-乙基胺甲醯基)-笨并[a]啡畊4·基氧]醋 酸三氟乙酸鹽 43 ‘乙醯胺基-苯并[a]啡哜-11-羧酸(2-二甲基胺基·乙基)·醯胺 44 11-(2-二甲基胺基-乙基胺甲醯基)-苯并[a]啡畊斗羧酸甲酯 45 4-雙-(曱磺醯基胺基)-笨并[a]啡哜-11-羧酸(2-二曱基胺基· 乙基)-醯胺 46 (請先閱讀背面之:1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） 1280242 A7 B7 9 五、發3-胺基-苯并[a]啡哜曱基胺基-乙基 _ΓΜ« 3lcT< i ?ζ ΒάΖ W 3B5t ^ w r- :二------------- 4-(Ν-經基亞胺甲醯基)·^^]啡啡_u-叛酸2•二 基·乙基)-醢胺 4也基甲基-苯并[a]啡听·ιι·緩酸(2.二曱基胺基{基)屬f 1 un·二甲美脸其· r.苴於 m ^ .~：~——rr二 11 -(2-二甲表胺基-乙涵甲^基)·笨并㈤啡併各 丨氟乙酸鹽__4·甲基磺醯基-苯并[a]啡羧酸(2·二甲基胺^7^^： 醯胺；三氟乙酸鹽3-甲基磺醯暴·笨并[a]啡畊_u•羧酸(2_二曱基胺基·乙基)： 醯胺；三氟乙酸鹽3-乙醢胺基-苯并[a]啡併-1 μ竣酸(2-二甲基胺基·乙基 4-二甲基胺基-笨并[a]啡听-11脅酸(2·二曱基胺基-乙基)·酿备4-甲磺醯基胺基·笨并[a]琲啡-11-羧酸(2·二曱基胺基·乙^ )-醯胺 53 可 ----------1 裝--- (請先^讀背面之江意事瑣再填寫、本1) 經濟部智慧財產局員工消費合作社印製 4· 一甲基％醯暴-笨并[a]啡味-11·叛酸(2二甲基胺基·乙基)屬 胺 ________ 3-—甲基％醯基-笨并[a]啡啩·ιι·羧酸(2·二甲基胺裏 醯胺 58 4-(氰基甲基-胺基)·笨并[a]呀併·n，酸(2·二曱基胺基-乙 基)-酿胺 __'— 4，10-—甲氧基-笨并[a]啡味· 11 ·竣g曼(2·二曱基胺基·乙基)屬胺 ——---— 4-曱氧基-苯并[a]啡哜·ΐι·羧酸(2-二甲基胺基·丙基卜醯胺 61 笨并[a]啡啡·4，11·二羧酸-4-醯胺π_竣酸(2_二曱基胺基-乙 基)-醯胺];三氟乙酸鹽 ^ 62^ 1-氣-4，10-—曱氧基·苯并㈤啡畊·羧酸(2•二甲基胺基· 乙基)-醯胺 3-胺飧醯基-笨并[a]啡併·ΐι·竣酸(2·二曱基胺基·乙基)福胺 ^^64^^ 4-甲氧基·笨并问_啩-1卜羧酸(2·二甲基胺基·丨丨_二甲基· 乙基)-醯胺 ^^65 2·硝基-苯并[a]啡呀-11-羧酸(2-二甲基胺基_乙基醯胺— 4·甲氧基-8-甲基·苯并㈤啡哜_u•羧酸(2-二曱基胺基_乙 基)-醯胺 ^ 67 4，10-二羥基-笨并[a]啡味·11·叛酸(2.二曱基胺基·乙基 > 酿胺 -όΓ^ 3·二甲基胺基-2-[(4-甲氧基·苯并[a]啡啡羰基卜胺基] 丙酸甲基酯；三氟乙酸鹽 '^69 >二曱基胺基·2·[(4·甲氧基·苯并㈤啡哜]卜戴基>胺基] 丙酸甲基酯；氫氣酸 70 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公餐） -線· 1280242 A7 10五、發明說明（) 經濟部智慧財產局員工消費合作社印製 4曱氧基笨并|；a]啡曼〇•二曱基胺基曱基-丙基)·醯胺 71 ——1 ϋίί基·本并[a]啡0^11·鼓酸(2-二甲基胺基-1·甲基 72 ! 啡哜-11·羧酸(2-二曱基胺基-乙基)_醯胺 73 ι 二甲基Hi开㈤料⑴績1·二甲基胺基甲基·2_甲基 74 ! 心基:升^押畔七邊酸(2_二f基胺基至基甲基 75 以Si开1刪七销卜二曱基胺基曱基士笨基 76 tlii胺冬开㈤啡味七僅酸(2-二？‘胺基小⑸-甲基- 77 4乙Ιίί胺奉开㈤啡^11邊酸⑺二甲基㈢基士⑻·^^ 78 4-硝基-本开[a^n^3?I^7曱基-乙基)·酿i 79 ，硝基:本开[a]啡，11 -舰(2-二甲基胺基-1:曱基·乙基)-酿胺 80 4甲峨2·:甲基胺基·〗·⑸-經基 81 4基甲念二甲“基·笨并㈤朴11侧2·二甲基胺 82 基基4-乙甲以开㈤… 83 :丙曱基，甲基-遍 84 dt” 基胺基-乙 85 4甲乳基本开羧酸(2·^ϊ^η_乙基)·醯胺 86 87 10：^土甲軋非啡七-竣每gz?!^基-乙基)-醢胺 88 4Ιϋ本开酸乙基)·醯f 89 ‘ _甲ί基·本开-乙基)·酿W 4 田备甘 Vf Γ Τ ιΐ ι 90 A 谓备 ^ 44 r«i-jLIT -—----—- 91 4-2基本开 92 >1 (¾ —田^备甘 Γ Ί || _ _ 1 93 丨4,9·二甲—氧基-本 94 ---^-------@ -t--- {清先K讀背面之注意事項再填寫本頁) 訂： 本纸張尺度適用中國國豕4示準（CNS〉A4規格（21〇 X 297公楚） 1280242 A7 11五、發明說明（） 4,10-二甲氧基-苯并[a]啡啡-11·羧酸(2-二曱基胺基-1(S)-經基曱基-乙基)-酿胺 95 4-曱氧基-笨并[a]啡畊-11-羧酸(2-甲基胺基-乙基)-醯胺 96 10-羥基斗甲氧基-苯并[a]啡啡·11·羧酸(2-二曱基胺基 -1(S)-羥基曱基·乙基)-醯胺 97 (R)-4-甲氧基-笨并[a]啡啩-11·羧酸(1-二曱基胺基甲基-2· 乙基-丙基)-醯胺 98 4-甲氧基-苯并[a]啡畊·11·羧酸(1-甲基-咄咯咬-3-(R)-基)-醯胺 99 4-甲氧基-苯并[a]啡味·11-羧酸(2,3-(雙)-二甲基胺基-丙基)醯胺 100 具有化學式（I)之化合物可以藉由一種方法製備，該方 法包含： (a)使用一個具有化學式（III)之胺來處理一個具有化學式 (II)的化合物之被活化的衍生物： (請先閱讀背面之注意事項再填寫本頁)Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives! 28〇242 V. Invention Description (Replaced from the following group: hydroxy-CrC6 alkyl (where the alkyl group is unsubstituted or substituted as in this case) Specific to this pair of bases, CVC6 alkoxy, phenyl, N(R12)2 (wherein R12 is as defined above), and trans. hydroxy-Ci_C6 alkyl examples include, for example, hydroxy fluorenyl, 1· Hydroxymethyl and 2-hydroxyethyl. (^-(^) is a bivalent C-C6 alkyl group as defined above. An aryl group is typically an aromatic C6_C1〇 a carbocyclic group (such as phenyl or naphthyl) 'which is unsubstituted or substituted with halogen, Cl-c6 alkyl, hydroxy, (Vc6 alkoxy, nitro (n〇2), n (r12) 2, co2r10, cyano (CN) or perhalogen substituted 2Ci-c6 alkyl (wCf3). One element is fluorine, gas, bromine or iodine. Preferably fluorine, gas or bromine. A C!-CV The oxirane group may be straight or branched. It is typically a CrC:4 alkoxy group, for example: a methoxy group, an ethoxy group, a propoxy group, an iso-propoxy group. a base, n-butoxy, a secondary butoxy or a tertiary (butoxy)butoxy group. A CrC6 alkoxy group is unsubstituted or substituted, typically one or more selected from the group consisting of Substituted by: N(R12)2, con(r12)2, thiol, CVC6 alkoxy, CVC6 alkyl, c2-c6, alkenyl, c2-c6 alkynyl, cyano, C02R1G, COR10, a saturated 5- or 6-membered nitrogen-containing heterocyclic group or phenyl group which is unsubstituted or substituted by one or more halogen atoms. A C3-C10 cycloalkyl group may be cyclopropyl Base, cyclobutyl, cyclohexyl, cycloheptyl. Typically c3-c6 cycloalkyl. One C2-C6 alkenyl group contains one or more unsaturated bonds. It can be, for example, vinyl, propyl Alkyl, butenyl or pentenyl. A saturated 5- or 6-membered nitrogen-containing heterocycle can be applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) η ---- i-------* 装--- (Please read the note on the back and then fill out this page) Light: 1280242 A7 V. Invention description () Thought, for example, · 〇辰 biting, calling, Ms. Lin or her mouth bites each other. The heterocyclyloxy group is a mono-indenyl group, wherein Het is an unsaturated 5- or 6-membered nitrogen-containing heterocyclic ring which may contain one or more additional oxygen, nitrogen or sulfur atoms. Examples of such include: furan, porphin, pyrrole, 哚 哚, 口 嗓 嗓 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比 比Lin, Yibianlin ' 嗔 并 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡 吡The aforementioned heterocyclic ring may be unsubstituted or substituted with one or more substituents, for example, one or more substituents selected from the group consisting of a thiol group, a dentate, an unsubstituted or substituted c "c6 alkyl group [eg, a functional group substituted (e.g., cf3)], a Cl-c6 alkoxy group, a schlossyl group, and an amine group n(r12)2 as defined above. In a preferred aspect of this month, in the chemical formula (1), In (4) or (10), R to R are each hydrogen, and R4 is an atom other than chlorine. Typical RlCA alkoxy, (iv), C"C6·, thiol, alkyl, ocular or halogen in one In a preferred series of compounds, R in the chemical formula (1), (Ia) or (10) is a CrC6 alkoxy group or a hydroxyl group, R7 is a hydroxyl group, and & 丨 to Han 3, R5 and R6 are each hydrogen. A preferred compound is one in which "is a CrC6 oxy group or a thiol group, R6 is an oxy group, or a methylthio group, and R1 to R3, R5 and R7 are all hydrogen. In the chemical formula ((4), Rn Preferably, the CA pit group is more preferably a methyl group. In the chemical formulas (1) and (la), a preferred Q is selected as a C2_ or (:3-thin chain, which is present relative to the adjacent aramid i atom system. α Substituting an unsubstituted or substituted Cl-C6 alkyl group as defined above. Preferably, the paper size above 'Q' applies to the Chinese National Standard (CNS) A4 specification (210 X 297 g) (Please read K back Note: Please fill out this page) Set · J------ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1280242 A7 j--------__ B7____ 1 5, invention description (7) First, read the backside and fill in the page. The substituent is an unsubstituted CrC6 alkyl or hydroxyalkyl group (such as hydroxyindenyl or viaylethyl). Typically, the c2• or c3-alkenyl chain is adjacent to the 邻接The amine gas atom is α-substituted with a thiol group, an ethyl group, an isopropyl group, a hydroxymethyl group, a substituted hydroxy fluorenyl group or a hydroxy group. The Ministry of Economy, Intellectual Property Office, the Staff Consumer Cooperative, prints a preferred compound of the present invention. Examples are: compound name 鳐 compound number din; ^, - this back [rushing ^ -11 side acid (2 _ 2 基 胺 _ 乙基 乙基 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿_u•carboxylic acid (2-didecylamino)ethylguanamine 2 4 methoxy- benzo[a]morphine-11-carboxylic acid (2-didecylamino-ethyl)-oxime Amine 3 morphine 1 acid (2 · Di-decylamino-ethyl V-stamine·· 4 Know-Ben (5) Oyster-ll-carboxylic acid (2-dimethylamino-ethyl)-bristamine 5 base-stupid [a]啩 啩·lu carboxylic acid (2-dimethylaminoethyl) ethyl phthalamide 6 4-nitro-open [a] morphine·u•carboxylic acid (2•didecylamino)ethyl醯 醯 7 7 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 Oxygen stupid (5) morphine! · yur (2 diethylamino) ethyl) decyl 10 4- methoxy methoxy- benzo [a] morphine · u oxo acid ^ decylamino -ethyl amide amine 11 4-卞 礼 · · · 本 本 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ·11βcarboxylic acid (2. dimethylamino-ethyl 13 3,4-monomethyl group · stupid and aj 哜 哜 丨 丨 仏 仏 仏 仏 仏 仏 仏 仏 仏 仏 仏 乙基 乙基 乙基 乙基 乙基 乙基 乙基14 4-ethoxyl-open [a] morphine-(1) tempering acid (7) dimethylamino group -6 group), tyrosine 15 4-isobutoxy group, stupid [a] morphine · u • rebellion仏 仏 仏 仏 - 乙基 乙基 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 16 ·Awakening amine 17 4-(^-曱^-Ethyloxy)·Bist and [a]morphine·dimethylamino]ethyl)·enamine 18 [11-(2·monodecylaminoethylamine). Benzene And (5) morphine 4 ethoxy acetate, ethyl acetate 19 3-bromo-4-hydroxy, benzo[a] morphine] 丨 g g 2 - dimethylamine / ethyl decylamine 20 4- (2 -Hydroxy-ethoxylated)·Benzo[a]morphine·1]μcarboxylic acid (2•dimethylamino·B 21) This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 Love) 1280242 A7 B7 8 V. Invention Description () Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing base) · guanamine 4-(pyrimidin-2-yloxy)-benzo[a] phenanthrene-11-carboxylate Acid (2-didecylamino-ethyl: decyl 22 4-(2-morpholin-4-yl-ethoxy)-benzo[a]morphin-11-carboxylic acid (2-diindole) Amino-ethyl)-nonylamine 23 4-(3-cyano-propoxy)- benzo[a] phenanthrene-11-carboxylic acid (2-dimethylamino-ethyl)-anthracene Amine 24 4-mercapto-benzo[a]phloindole-11·carboxylic acid (2-dimethylamino-ethyl)-decylamine 25 4-fluoro-benzo[a]morphin-11-carboxylate Acid (2-didecylamino)ethyl)-decylamine 26 4·(3-dimethylamino-propoxy)-benzo[a]morphin-11-carboxylic acid (2·diindole) Amino group ethyl) Amine amine 27 4-methyl hydrazino-benzo[a] phenanthrene-11-carboxylic acid (2-dimethylamino-ethyl) decylamine 28 4-amine fluorenyl methoxy benzene And [a] porphyrin-1 carboxylic acid (2-dimethylaminoethyl)-decylamine 29 4-methoxybenzo[a] phenanthrene-11-carboxylic acid (3-amino group -2-hydroxy-propyl)-nonylamine 30 4-decyloxy-benzo[a]morphine-11-carboxylic acid (3-dimethylaminopropyl) decylamine 31 4-bromo- Benzo[a]morphin-11-carboxylic acid (2. dimethylamino)ethyl)-decylamine 32 11-(2-didecylamino-ethylaminecarbamyl)-benzo[ a] morphine 4-yl acetate 33 4-(2-oxo-propoxy)- benzo[a] phenanthrene-11-carboxylic acid (2-didecylamino-ethyl)-decylamine 34 4-decyloxy-benzo[a]morphine-11-carboxylic acid (2-didecylamino-1-indenyl-ethyl)-bristamine 35 4-cyano-phenyl-benzoquinone [a ]Synthesis-11·Resin (2-didecylamino-ethyl)-bristamine 36 11-(2-dimethylaminoethylethylcarbamyl)·Bist [a] 4-ethylethyl carbazate 37 3-石 肖基-benzo[a]morphine-11-rebel (2-dimethylaminoethyl)-bristamine 38 4-methanesulfonyl- Stupid [a] phenanthrene-1 carboxylic acid (2-dimethylamino + methyl-ethyl)-decylamine 39 4-gas-benzo[a ] 哜-11-carboxylic acid (2·didecylamino-ethyl)-decylamine 40 4-addoyl-benzo[3]-morphine-11-sodium-acid (2-dimethylamino group) -ethyl)-Sfeamine 41 4-Amino-benzo[a]morphine-1 carboxylic acid (2-didecylamino-ethyl valine 42 11-(2-dimethylamino) -ethylamine-methyl hydrazino)- benzo[a] cultivating 4 yloxy] acetic acid trifluoroacetate 43 'acetamido-benzo[a] phenanthrene-11-carboxylic acid (2-dimethyl Amino-ethyl)-guanamine 44 11-(2-dimethylamino-ethylamine-methyl fluorenyl)-benzo[a]morphine carboxylic acid methyl ester 45 4-double-(sulfonate) Mercaptoamine)- benzo[a] phenanthrene-11-carboxylic acid (2-didecylaminoethyl)-decylamine 46 (please read the back: 1) Paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280242 A7 B7 9 V. 3-Amino-benzo[a]morphinylamino-ethyl_ΓΜ« 3lcT< i ζ ΒάΖ W 3B5t ^ w r- : 二------------- 4-(Ν-pyridylpyridinyl)·^^]morphine_u-rebel 2• Diyl-ethyl)-decylamine 4-mercaptomethyl-benzo[a]morphine· ιι· ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ ̄ .苴于m ^ .~:~—— Rr di 11 -(2-dimethyleperyl-ethyl sulphate) · stupid (five) and each fluorinated acetate __4·methylsulfonyl-benzo[a]morphinecarboxylic acid (2· Dimethylamine^7^^: decylamine; trifluoroacetate 3-methylsulfonate turbidity; stupid [a] cultivating _u•carboxylic acid (2_didecylamino)ethyl: 醯Amine; trifluoroacetate 3-acetamido-benzo[a]morphin-1 μ decanoic acid (2-dimethylamino)ethyl 4-dimethylamino- benzo[a]morphine Listening to 1:1 ascorbic acid (2. dinonylamino-ethyl), brewing 4-methanesulfonylamino group, stupid [a] morphine-11-carboxylic acid (2·didecylamino) B ^ ) - decylamine 53 can be ----------1 Pack --- (Please read the back of the river and then fill it in, then fill in this, 1) Printed by the Intellectual Property Office of the Ministry of Economic Affairs 4· Monomethyl 醯 - - - stupid [a] odor -11 · tacrolimus (2 dimethylamino) ethyl amide ________ 3-methyl thiol-stupid [a]啩 啩 · ιι carboxylic acid (2 · dimethylamine linoleamide 58 4-(cyanomethyl-amino) · stupid [a] y y · n, acid (2 · dimercaptoamine - Ethyl)-bristamine __'-4,10--methoxy- benzo[a]morphine·11 ·竣gman(2·didecylamino)ethylamine-- - 4-methoxy- And [a] 哜 哜 · ΐ · carboxylic acid (2-dimethylamino propyl phthalamide 61 stupid [a] morphine 4,11. dicarboxylic acid 4- decylamine π_ decanoic acid (2_Didecylamino-ethyl)-decylamine]; trifluoroacetate^ 62^ 1-gas-4,10--decyloxybenzoic (penta) pentyl carboxylic acid (2·dimethyl Amino group · ethyl) - decylamine 3-amine fluorenyl- benzo[a] benzo- ΐ 竣 竣 竣 2 2 2 2 2 ^ ^ ^ ^ Methoxy-stupid and _啩-1 carboxylic acid (2. dimethylamino) 丨丨 dimethyl ethoxy) oxime ^ ^ 65 2 · nitro-benzo[a] brown呀-11-carboxylic acid (2-dimethylamino-ethyl decylamine-4. methoxy-8-methyl benzo(penta) quinone 哜 u carboxylic acid (2-didecylamino group _ Ethyl)-nonylamine^ 67 4,10-dihydroxy- benzo[a]morphine·11·rebel acid (2. Dimercaptoamine·ethyl) styrene-όΓ^ 3 dimethyl Amino-2-[(4-methoxybenzo[a]morphinylcarbonylamino]propionic acid methyl ester; trifluoroacetate '^69 > dimethylamino 2·[( 4·Methoxy·benzo(5)-anthracene]Budaiji>Amino]Methyl propionate; Hydrogen acid 70 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public meals) - Line · 1280242 A7 10 V. Invention Description () Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 4 曱 笨 并 ; |; a] morphine 曱 曱 胺 胺 胺 - - 71 71 71 71 71 71 ——1 ϋίί基·本和[a]啡0^11·Bacteric acid (2-dimethylamino-1·methyl72! 哜-11-carboxylic acid (2-didecylamino-B) )) 醯 醯 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 73 To the methyl group 75 to Si open 1 delete seven pin 曱 曱 胺 胺 胺 基 基 基 基 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 'Amino small (5)-methyl-77 4 Ι Ι ί ί ( 五 五 五 五 五 五 五 五 五 五 五 五 五 五 五 五 五 五 五 五 五 五 五 五 五 五 五 五 五 五 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 7-mercapto-ethyl)· brewing i 79 , nitro: open [a] brown, 11 - ship (2-dimethylamino-1: decyl-ethyl)-bristamine 80 4 formazan 2 ·: Methylamino group · 〗 〖 (5) - carboxylic acid 81 4 yl dimethyl dimethyl "based · stupid (five) Pak 11 side 2 · dimethylamine 82 base 4- ethyl acetamide to open (five) ... 83 : Base, methyl-permeate 84 dt" amino-amino-ethyl 85 4 methyl milk basic open carboxylic acid (2·^ϊ^η_ethyl)·decylamine 86 87 10:^ soil rolling morphine seven-竣 each Gz?!^基-ethyl)-decylamine 88 4Ιϋ本本酸ethyl)·醯f 89 ' _甲基基本开-ethyl)· Brewing W 4 田备甘 Vf Γ Τ ιΐ ι 90 A备备^ 44 r«i-jLIT -------- 91 4-2 basic open 92 > 1 (3⁄4 - Tian ^ 甘 Γ Ί || _ _ 1 93 丨 4,9 · dimethyl - Oxygen-本94 ---^-------@ -t--- {Precautions for reading the back of the K first page and then fill out this page) Order: This paper scale applies to China National Standard 4 (CNS) 〉A4 specification (21〇X 297 public Chu) 1280242 A7 11 V. Description of invention () 4,10-Dimethoxy-benzo[a]morphine-11· Acid (2-didecylamino-1(S)-ylhydrazinyl-ethyl)-bristamine 95 4-decyloxy-benzo[a]morphin-11-carboxylic acid (2-methyl) Amino-ethyl)-guanamine 96 10-hydroxy methoxy-benzo[a]morphine·11·carboxylic acid (2-didecylamino-1(S)-hydroxyindenyl·ethyl )-decylamine 97 (R)-4-methoxy- benzo[a] phenanthrene-11·carboxylic acid (1-didecylaminomethyl-2·ethyl-propyl)-decylamine 98 4-methoxy-benzo[a]morphine·11·carboxylic acid (1-methyl-indole)-3-(R)-yl)-decyl 99 4-methoxy-benzo[a ]Synamic 11-carboxylic acid (2,3-(bis)-dimethylamino-propyl) decylamine 100 The compound of formula (I) can be prepared by a method comprising: (a) Use an amine of formula (III) to treat an activated derivative of a compound of formula (II): (Please read the notes on the back and fill out this page)

經濟部智慧財產局員工消費合作社印製 其中R1至R7係如上文中所定義者， H2N/Q"N(R8)(R9) (UI) 其中Q、R8及R9係如上文中所定義者；或 (b)在一種有機溶劑内或沒有之下，且於一個升高之溫度 下，使用一個如上所定義之具有化學式（III)之胺來處理一 個具有化學式（IV)之化合物： 本紙張尺度適用中國國家標準（CNTS)A4規格（210 X 297公釐） !28〇242Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed in which R1 to R7 are as defined above, H2N/Q"N(R8)(R9) (UI) where Q, R8 and R9 are as defined above; or b) treating a compound of formula (IV) with an amine of formula (III) as defined above in an organic solvent or at an elevated temperature: National Standard (CNTS) A4 Specification (210 X 297 mm) !28〇242

其中R1至R7及R11係如上文中所定義者；且 (C)如為所需，將所產生之一個具有化學式⑴之笨并[a]啡畊 •11-緩酿胺衍生物轉變為另一個此種衍生物，及/或將一 個具有化學式（I)之苯并[a]啡啩4丨_羧醯胺衍生物轉變為 其一個藥學上可接受之鹽類。 所產生之具有一個光學活性中心的化合物（例如：具有 化學式（la)的笨并[a]啡啡-11-叛酿胺衍生物及此等之鹽類） 的光學純度可藉由添加一種NMR相移試劑（例如2,2,2-三氟 -1(9·蒽基）乙醇）至同手型的化合物的NMR樣品中而被決定 之。 具有化學式（II)的起始化合物及該等之酯類（具有化學 式（IV)之化合物）係為新穎的，故其等構成本發明之另一個 方面。 經濟部智慧財產局員工消費合作社印製 於步驟（a)中化學式（II)之羧酸基團能夠被活化為對應 之氯酸，此可藉由以亞硫醯氣來處理化學式（II)之自由羧酸 而被得到。任擇地，該羧基基團可藉由以一種適當之醯胺· 偶合試劑（例如·· 1，1’-羧醯胺基二咪唑）來處理而被活化。 具有化學式（II)之化合物的被活化衍生物與具有化學 式（III)之胺兩者之間的反應典型地是於一種有機溶劑中來 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱Γ 1280242 13 A7 B7 五、發明說明（） 進行。適合之溶劑包含二甲基甲醯胺及二氯甲烷。活化具 有化學式（II)的化合物，以及以具有化學式（III)之胺來處理 該活化所產生之衍生物，此兩種處理步驟可以在無活化衍 生物之中間物被分離的情況下完成。於此情況下，所用之 方法通常包含··於有機溶劑中，使活化試劑或偶合試劑與 具有化學式（II)之化合物結合，然後將具有化學式（ΠΙ)之胺 添加至所產生之反應混合物中。 一個具有化學式（Π)之化合物能夠藉由一種方法被製 備，該方法包含： (a)於一種有機溶劑中，選擇性地在一種酸的存在下，使 用一個具有化學式（VI)之苯曱酸或其一酯或鹽類來處理一 個具有化學式（V)之1，2-萘酕： ------------裝--- (請先閱讀背面之:i意事項再填寫本頁) 訂·Wherein R1 to R7 and R11 are as defined above; and (C) if desired, one of the resulting formula (1) stupid [a] morphine 11-salt amine derivative is converted to another Such a derivative, and/or a benzo[a]phleoquinone-carbamoylamine derivative of formula (I) is converted into a pharmaceutically acceptable salt. The optical purity of the resulting compound having an optically active center (for example, the stupid [a] morphine-11-acropine derivative of the formula (la) and the salts thereof) can be obtained by adding an NMR A phase shifting reagent (e.g., 2,2,2-trifluoro-1 (9-mercapto)ethanol) is determined in an NMR sample of the compound of the same type. The starting compounds of the formula (II) and the esters (compounds of the formula (IV)) are novel, and thus they constitute a further aspect of the invention. The carboxylic acid group of the chemical formula (II) printed in step (a) of the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs can be activated to the corresponding chloric acid, which can be treated by sulfite gas. Free carboxylic acid is obtained. Optionally, the carboxyl group can be activated by treatment with a suitable guanamine coupling reagent (e.g., 1,1'-carboxylamidodiimidazole). The reaction between the activated derivative of the compound of formula (II) and the amine of formula (III) is typically in an organic solvent to the Chinese National Standard (CNS) A4 specification (210 X). 297 公爱Γ 1280242 13 A7 B7 V. Inventive Note (). Suitable solvents include dimethylformamide and methylene chloride. Activate compounds of formula (II) and amines of formula (III) Treating the derivative produced by the activation, the two treatment steps can be carried out in the case where the intermediate of the non-activated derivative is separated. In this case, the method generally comprises: in an organic solvent, the activation reagent Or a coupling reagent is combined with a compound of formula (II), and then an amine of the formula (ΠΙ) is added to the resulting reaction mixture. A compound of the formula (Π) can be prepared by a method comprising : (a) in an organic solvent, optionally in the presence of an acid, a benzoic acid of the formula (VI) or a monoester thereof or Class to handle a 1,2-naphthalene Mao formula (V) of: ------------ equipment --- (Please read the back of: i precautions to fill out this page) book ·

(V) 卜線 經濟部智慧財產局員工消費合作社印製 其中R1至R4如上文對化學式（I)之定義，(V) Line of the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, where R1 to R4 are as defined above for formula (I),

co2h 其中R5、R6及R7係如上文中對化學式（1)戶— (VI) 吓疋義者 該溶劑 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280242 A7 B7 14 五、發明說明（） 可以為，例如，乙醇或醋酸。藉由在反應混合物中使用1 至5當量之礦物酸，該反應之特定選擇性（regioselectivity) 可以被控制。使用約2當量或更多之酸，例如：由1.5至5 當量，則產生過量之所欲的特定異構物，意即一個具有化 學式（II)之笨并[a]啡畊-11·羧酸。礦物酸較佳為鹽酸，更佳 為濃鹽酸。具有化學式（VI)之苯甲酸鹽類的典型為為乙酸 鹽。 具有化學式（V)之1，2-萘醍之製備可藉由以二氧化硒 來處理對應之具有化學式（VII)之1-四氫萘酮（1-tetralone) -----------裝--- (請先閱讀背面之立意事項再填寫本頁)Co2h where R5, R6 and R7 are as described above for the chemical formula (1) - (VI) The solvent is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1280242 A7 B7 14 The invention description () may be, for example, ethanol or acetic acid. The specific selectivity (regioselectivity) of the reaction can be controlled by using from 1 to 5 equivalents of mineral acid in the reaction mixture. The use of about 2 equivalents or more of an acid, for example, from 1.5 to 5 equivalents, produces an excess of the desired specific isomer, meaning a stupid compound of formula (II) [a] acid. The mineral acid is preferably hydrochloric acid, more preferably concentrated hydrochloric acid. The benzoate salt of the formula (VI) is typically an acetate salt. The preparation of 1,2-naphthoquinone having the formula (V) can be carried out by treating the corresponding 1-tetralone of the formula (VII) with selenium dioxide. ---装--- (Please read the back of the matter and then fill out this page)

Ό (VII) tr 其中R1至R4係如上文對化學式（I)所定義者，（製備係依照 Tetrahedron Letters 1997，4219-4220所描述之方法）。具有 化學式（VII)之1-四氫萘酮係為已知化合物，或可藉由已刊 載發表之方法由已知化合物來製備（例如：描述於下文之參 考實施例中），於必-要之_使用傳統之實驗室技術予以調適 ，俾以達成所需之R1至R4的定義。已被刊載發表之方法包 含該等被描述於J. Med. Chem. 1997,姐，3014-3024; J. Org. Chem. 1984，4226; JACS. 1994, H6 pp. 4852-4857 及 J. Med. Chem. 1997, p.1049。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 線 經濟部智慧財產局員工消費合作社印製 A280242 A7 --—~-__B7 15 --- 五、發明說明（） 具有化學式（VI)之苯甲酸係為已知化合物，或可藉由 已被刊載發表之方法由已知化合物來製備（例如描述於下 文之參考實施例中），於必要之處使用傳統之實驗室技術予 以調適，俾以達成所需之R5至R7的定義。已被刊載發表之 方法包含該專被描述於Chem Perkin Trans. JL 1984 ρ· 210W τ λ/τ〇Η chem· 198'。 一個具有化學式（II)之化合物亦能夠藉由一種方法來 製備，該方法包含： (a)使用一個具有化學式（IV)之萘胺來處理一個具有化學 式（VIII)之2-鹵素·3-硝基苯甲酸： ---.-------串裝·！ (請先閱讀背面之注意事項再填寫本頁)Ό (VII) tr wherein R1 to R4 are as defined above for the formula (I) (preparation is carried out according to the method described in Tetrahedron Letters 1997, 4219-4220). The 1-tetralone of the formula (VII) is a known compound, or can be prepared from a known compound by a published method (for example, as described in the following Reference Examples), It is adapted using traditional laboratory techniques to achieve the desired definition of R1 to R4. Methods that have been published include those described in J. Med. Chem. 1997, Sister, 3014-3024; J. Org. Chem. 1984, 4226; JACS. 1994, H6 pp. 4852-4857 and J. Med Chem. 1997, p. 1049. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed A280242 A7 ---~-__B7 15 --- V. Invention Description () The benzoic acid of (VI) is a known compound, or can be prepared from known compounds by a method already published (for example, as described in the Reference Examples below), using conventional laboratory techniques where necessary. Adapted to achieve the desired definition of R5 to R7. The method that has been published includes the specific description of Chem Perkin Trans. JL 1984 ρ· 210W τ λ/τ〇Η chem· 198'. A compound of formula (II) can also be prepared by a process comprising: (a) treating a 2-halogen 3-nitrate of formula (VIII) using a naphthylamine of formula (IV) Benzoic acid: ---.------- stringed! (Please read the notes on the back and fill out this page)

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

、nh2 其中Hal為氣、溴、峨或氟 (IX) 其中R1至R4如上文對化$式⑴之定義；及 (b)將所產生之具有化學式（X)的化合物置於還原性環化作 用中： 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280242 A7 ------B7 16 五、發明說明（）And nh2 wherein Hal is gas, bromine, hydrazine or fluorine (IX) wherein R1 to R4 are as defined above for formula (1); and (b) subjecting the resulting compound of formula (X) to reductive cyclization In effect: This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280242 A7 ------B7 16 V. Invention description ()

ί請先¾讀背面之;is事項再填寫本頁) 其中R1至R4如上文對化學式（I)所定義者。 通常步驟（a)係在一種有機溶劑之中被進行。適合之範 例包含丁烷-2,3·二醇及乙二醇。一般實行步驟（b)係於曱氧 基鈉、乙氧基鈉或液態氫氧化鈉中，.以硼酸鈉（NaBH4)來 處理具有化學式（X)之化合物。此方法被描述於j. Med· Chem. 1987, i〇5 843-851。 一種具有化學式（IV)之化合物可藉由一個對應的具有 化學式（II)之化合物於標準之反應條件下之酯化反應來製 備，此係利用一個具有化學式Rn-〇H (其中R11係如上文中 所定義者）之醇來處理一個具有化學式（11)之自由羧酸化合 物。 具有化學式（III)之胺係為已知且為商業上可騰得之化 合物’或可由商業上可購得之起始材料使用傳統之技術（ 例如，描述於下文之參考實施例2)而被製造出。 經濟部智慧財產局員工消費合作社印製 一個具有化學式（I)之化合物可以藉由傳統之方法被 轉變為另一個具有化學$(1)之化合物。舉例而言，一個含 有一酯化羥基（如-OCOMe)之具有化學式（I)的化合物，其可 以藉由水解（例如驗性水解）而被轉變為另一個含有一自由 羥基之具有化學式（I)的化合物。一個含有一自由經基之具 有化學式（I)的化合物’其可以藉由醋化反應而被轉變為另 張尺度適用中國國家標準（CNS)A4規格〈210 X 297公釐) '— 2二 ----- 1280242ίPlease read the back of the first; fill the page with the is). R1 to R4 are as defined above for the chemical formula (I). Usually step (a) is carried out in an organic solvent. Suitable examples include butane-2,3·diol and ethylene glycol. Typically, step (b) is carried out in sodium oxooxide, sodium ethoxide or liquid sodium hydroxide. The compound of formula (X) is treated with sodium borate (NaBH4). This method is described in j. Med. Chem. 1987, i〇5 843-851. A compound of formula (IV) can be prepared by esterification of a corresponding compound of formula (II) under standard reaction conditions using a chemical formula of Rn-〇H (wherein R11 is as above) The alcohol of the formula) is used to treat a free carboxylic acid compound of formula (11). The amine of formula (III) is a known and commercially available compound' or can be obtained from commercially available starting materials using conventional techniques (for example, described in Reference Example 2 below). Made out. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, a compound of formula (I) can be converted into another compound with chemistry $(1) by conventional methods. For example, a compound of formula (I) containing an esterified hydroxyl group (e.g., -OCOMe) which can be converted to another chemical formula containing a free hydroxyl group by hydrolysis (e.g., analytical hydrolysis) )compound of. A compound of formula (I) containing a free radical, which can be converted to a different scale by acetalization, applies to the Chinese National Standard (CNS) A4 specification <210 X 297 mm) '-2 2 ---- 1280242

經濟部智慧財產局員工消費合作社印製 一個含有一酯化羥基之具有化學式⑴的化合物，例如藉由 與一個適合之羧酸、齒酸或酸酐反應。一個含有一自由羥 基的化合物亦可以被轉變為另一個含有一胺基甲酸酯基的 化合物，例如藉由於一種非質子極性溶劑中（如二曱基甲醞 細）以二乙基胺及異氰酸乙醋來作處理。 一個含有一硝基之具有化學式⑴的化合物，其可以藉 由還原反應而被轉變為一個含有一胺基之具有化學式⑴ 的化合物，例如藉由於一種有機溶劑中以銦及一個飽和之 氯化銨溶液來作處理。 一個含有一 CrC6烷氧基之化合物可以被轉變為含有 一羥基之化合物，例如藉由於一種齒化之碳氫化物溶劑（ 如二氯甲烷）中以三溴化硼來作處理，或於二甲基甲醯胺中 以硫代乙氧基鈉來作處理。一個含有一羥基之化合物可以 被轉變為含有一具選擇性取代之Cl_C6烷氧基的化合物，例 如藉由於一種鹼的存在下以一適合之烷基化試劑來作處理 。一個含有一羧基之化合物可以藉由還原反應而被轉變為 含有一羥基甲基之化合物，例如藉由於四氫呋喃中以氫化 鋁鋰鹽（LiAlH4)來作處理。 一個含有一齒素之化合物可以被轉變為含有一烷基磺 醯基或烷氧基化合物，巧如藉由於一種有機溶劑中分別地 以硫代烷氧化物或烷氧化物之鹽類來作處理。一個含有一 賸基之化合物可以被轉變為含有一N•羥基亞胺基甲醯基 之化合物，例如藉由於一種鹼（如碳酸鉀）之存在下以羥基 胺（選擇性地呈一種鹽類之型態）來作處理。The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, produces a compound of formula (1) containing an esterified hydroxyl group, for example by reaction with a suitable carboxylic acid, dentate or anhydride. A compound containing a free hydroxyl group can also be converted to another compound containing a monocarbamate group, for example, by an aprotic polar solvent (such as dimercaptocarboxamidine) with diethylamine and Ethyl cyanate is used for treatment. a compound of the formula (1) containing a mononitro group which can be converted into a compound of the formula (1) containing an amine group by a reduction reaction, for example, by indium and a saturated ammonium chloride in an organic solvent The solution is treated. A compound containing a CrC6 alkoxy group can be converted to a compound containing a hydroxyl group, for example, by treatment with boron tribromide in a toothed hydrocarbon solvent such as dichloromethane, or in dimethyl The carbamide is treated with sodium thioethoxylate. A compound containing a monohydroxy group can be converted to a compound containing an optionally substituted Cl_C6 alkoxy group, for example, by treatment with a suitable alkylating agent in the presence of a base. A compound containing a carboxyl group can be converted into a compound containing a monohydroxymethyl group by a reduction reaction, for example, by treatment with lithium aluminum hydride (LiAlH4) in tetrahydrofuran. A compound containing a dentate can be converted to an alkylsulfonyl or alkoxy compound by treatment with a salt of a thioalkoxide or an alkoxide, respectively, in an organic solvent. . A compound containing a residual group can be converted to a compound containing a N-hydroxyiminocarbamyl group, for example, by a hydroxyl group (selectively a salt) in the presence of a base such as potassium carbonate. Type) to deal with.

{請先閱讀背面之注意事項再填寫本頁) 裝 訂| ••線· 1280242 A7 B7 18 五、發明說明（） 一個在一苯環位置上被烷基胺基曱基取代之化合物， 可以在曼尼希縮合反應（Mannich reaction)條件下被製備， 其係先令一個被羥基對位取代在討論中之環上的化合物與 醋酸反應，再接著以一個烷基胺及一種配於水之甲醛溶液 來作處理。一個具有化學式（I)之化合物可以被乙醯基化， 例如於一個胺基上而形成一個乙醯基胺基取代基，其係藉 由於適當之條件下以氯乙醯來作處理。 苯并[a]啡畊-11-羧醯胺之衍生物可以被轉變為藥學上 可接受之鹽類，且該鹽類藉可由傳統方法被轉變為自由的 化合物。具有化學式⑴之苯并[a]啡啩羧醯胺衍生物的 藥學上可接受之鹽類包含無機酸（如氫氣酸、氫溴酸及硫酸 )之鹽類，及有機酸（如醋酸、草酸、蘋果酸、甲磺酸、三 氟乙酸、笨曱酸、檸檬酸及酒石酸）之鹽類。以具有化學式 1之化合物為例，當其中R^R4及R10為羧基（C00H)時，該 鹽類包含上文所提到之鹽類及鈉、卸、辦及録之鹽類，該 等之製備係以對應之金屬鹼類或氨來處理具有化學式i之 化合物或酸鹽。 多重藥物抗性（MDR)為一種現象，藉由該現象使一般 對化學治療藥物敏感之細胞，形成對該等藥物及一範圍廣 泛之無相關性的藥物有抗藥性。多重藥物抗性（MDRj代表 的是成功地癌症治療上一個首要的障礙。具有多重藥物抗 性（MDR)之癌症細胞能夠展現出許多種多樣性之細胞變化 ’其包含P-酶蛋白之過度表現（P-gp)、與多重藥物抗性相 關之蛋白質（MRP)的過度表現、拓樸異構酶η之含量降低( 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------裝--- (琦先閱璜背面之:it事項再填寫本頁} Y· ^=0 -線 *lw 經濟部智慧財產局員工消費合作社印製 1280242 經濟釙智慧財產局員工消費合作社印制π A7 B7 19 -五、發明說明（） 稱為異常之抗藥性）及拓樸異構酶I在數量變化上之表現。 ^ 多重藥物抗性（MDR)為一種非常重要之臨床問題，其涉及 多種腫瘤對多種化學治療藥物形成抗性，其包含該等以拓 樸異構酶I及拓樸異構酶II為專一性標的多種化學治療藥 物。 藉由同時抑制拓樸異構酶I及拓樸異構酶II，化合物（ 例如 DACA)(Finlay ei fl/·，Eur· J. Cancer 32A，708-714, 1996)當其藉由對拓樸異構酶I或拓樸異構酶II之分別地改 變，而形成對康普多莎辛（eamptothecin)或安紗克萊恩 (amsacrine)之抗藥性時，DACA顯示其活性沒有減弱。以 拓樸異構酶I或Π之抑制劑得到在細胞週期之事件點上的 數量性差異（Kaufman，Biochem. Biophys. Acta 1400, 195-212, 1998)。拓樸異構酶I或II之共同抑制劑顯示出結合 個別專一性抑制劑之特性，且作用遍及細胞週期（Haldane et al, Cancer Chemother. Pharmacol. 32:463-470, 1993) * || 此產生一個更強之抗腫瘤活性（Riou w a/.，Cancer Res· 53, 5987-5993, 1993)。 多重藥物抗性（MDR)係由於細胞膜轉運子（如Pv醣蛋 白）之過度表現（Gottesman ei a/，Annu. Rev. Biochem· 62, 385-427，1993);及與多重藥物抗性相關之蛋白質（MRP) (Loe et al，Eur. J. Cancer 32A，945-957，1996)被已知可降 低化學治療藥物（例如：貝克里泰克梭（paclitaxel)、多克莎 盧比辛（doxorubicin)及伊托波賽德（etoposide))之臨床療效 。若藥物能夠不表現此種多重藥物抗性（MDR)機制，則預 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------裝--- (請先閱讀背面之主意事項再填寫本頁) 訂----- 1280242 經濟部智慧財產局員工消費合作社印製 A7 B7 20 五、發明說明（） 期會顯示具有治療癌症之效益。 具有化學式I之苯并[a]啡畊-11-羧醯胺的衍生物，該等 之藥學可接受之鹽類及水合物及此等之溶劑化物（此後稱 之為“本發明之化合物”）已於生物測試中被發現具有抑制 拓樸異構酶I及拓樸異構酶II之活性。於本發明之一個方面 ，本發明之化合物為拓樸異構酶I及拓樸異構酶II之共同抑 制劑。 本發明之化合物可以因此而被使·用為拓樸異構酶I之 抑制劑。任擇地，本發明之化合物可以被使用為拓樸異構 酶II之抑制劑。於一個更進一步之具體例中，該等本發明 之化合物可以被使用為拓樸異構酶I及拓樸異構酶II之共 同抑制劑。其顯示能殺死人類腫瘤細胞，且不表現多重藥 物抗性（MDR)機制。故其具有癌症治療上之潛力。本發明 之化合物能夠被使用來治療的癌症型態範例包含血癌、淋 巴癌、肉瘤、腫瘤癌及腺癌。專一性範例包含乳癌、結腸 、腦、肺、卵巢、胰臟、胃及皮膚癌。 可以藉由一種方法來治療一個懷有一腫瘤之人體或動 物體，該方法包含對之投藥以一種本發明之化合物。特別 地，一種m/4m6 治療人類腫瘤[包含那些表現出多重藥物抗性（mdr) 者，例如於上文中所提到之多重藥物抗性（mdr)的型態] 的方法係包含將一個有效治療劑量之一個本發明化合物投 藥至一個身懷一腫瘤之病人。所有型態之腫瘤，包含那些 表現出多重樂物抗*性（K4DR)以及那些不表現者，因此可_ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ----------—仏裝--------訂L----r---線 {請先閱讀背面之主意事項再填寫本頁){Please read the notes on the back and fill out this page.) Binding | •• Line·1280242 A7 B7 18 V. INSTRUCTIONS () A compound substituted with an alkylamino thiol group at the position of a benzene ring, can be used in Mann Prepared under the conditions of Mannich reaction by first reacting a compound substituted with a hydroxy para position on the ring in question with acetic acid, followed by an alkylamine and a formaldehyde solution formulated with water. For processing. A compound of formula (I) can be acetylated, for example on an amine group, to form an ethoxylated amine substituent which is treated with chloroacetamide under appropriate conditions. A derivative of benzo[a]morphin-11-carboxamide can be converted into a pharmaceutically acceptable salt, and the salt can be converted into a free compound by a conventional method. The pharmaceutically acceptable salts of the benzo[a]phthylcarboxamide derivatives of the formula (1) include salts of inorganic acids such as hydrogen acid, hydrobromic acid and sulfuric acid, and organic acids such as acetic acid and oxalic acid. Salts of malic acid, methanesulfonic acid, trifluoroacetic acid, succinic acid, citric acid and tartaric acid. Taking the compound of the formula 1 as an example, when R^R4 and R10 are a carboxyl group (C00H), the salt includes the above-mentioned salts and sodium, unloading, handling and recording salts, and the like. The preparation is carried out by treating the compound or acid salt of formula i with the corresponding metal base or ammonia. Multidrug resistance (MDR) is a phenomenon by which cells that are generally sensitive to chemotherapeutic drugs develop resistance to these drugs and a wide range of unrelated drugs. Multi-drug resistance (MDRj represents a leading obstacle to successful cancer treatment. Cancer cells with multiple drug resistance (MDR) can exhibit many diverse cellular changes that contain excessive expression of P-enzyme protein (P-gp), excessive expression of multidrug resistance-related protein (MRP), and reduced content of topoisomerase η (this paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------装--- (Qi first read the back of the back: it matters and then fill out this page} Y· ^=0 - line *lw Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1280242 Economic, Intellectual Property Office, Staff and Consumers Cooperative Printed π A7 B7 19 -5, Invention Description () called abnormal drug resistance) and the performance of topoisomerase I in quantitative changes. ^ Multiple drug resistance (MDR) It is a very important clinical problem involving the formation of resistance to a variety of chemotherapeutic drugs, including a variety of chemotherapeutic drugs with topoisomerase I and topoisomerase II as specific markers. Simultaneous inhibition of topoisomerase I and topoisomerase II, a compound (such as DACA) (Finlay ei fl /, Eur J. Cancer 32A, 708-714, 1996) when it is separately changed by topoisomerase I or topoisomerase II, When formed against the resistance of eamptothecin or amsacrine, DACA showed no decrease in its activity. The inhibitor of topoisomerase I or guanidine was obtained at the event of the cell cycle. Quantitative differences (Kaufman, Biochem. Biophys. Acta 1400, 195-212, 1998). Co-inhibitors of topoisomerase I or II show binding to individual specific inhibitors and function throughout the cell cycle (Haldane et al, Cancer Chemother. Pharmacol. 32: 463-470, 1993) * || This produces a stronger antitumor activity (Riou wa/., Cancer Res. 53, 5987-5993, 1993). Resistance (MDR) is due to overexpression of cell membrane transporters (such as Pv glycoproteins) (Gottesman ei a/, Annu. Rev. Biochem. 62, 385-427, 1993); and proteins associated with multiple drug resistance ( MRP) (Loe et al, Eur. J. Cancer 32A, 945-957, 1996) is known to reduce chemotherapeutic drugs (eg, the clinical efficacy of paclitaxel, doxorubicin, and etoposide). If the drug does not exhibit this multidrug resistance (MDR) mechanism, the pre-paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------ --- (Please read the back of the subject matter and fill out this page) Order----- 1280242 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 20 V. Invention Description () Period will show the benefits of treating cancer . Derivatives of benzo[a]morphin-11-carboxamide of the formula I, pharmaceutically acceptable salts and hydrates thereof and solvates thereof (hereinafter referred to as "compounds of the invention") It has been found to have activity in inhibiting topoisomerase I and topoisomerase II in biological tests. In one aspect of the invention, the compounds of the invention are co-inhibitors of topoisomerase I and topoisomerase II. The compound of the present invention can thus be used as an inhibitor of topoisomerase I. Alternatively, the compounds of the invention may be used as inhibitors of topoisomerase II. In a still further embodiment, the compounds of the present invention can be used as a common inhibitor of topoisomerase I and topoisomerase II. It has been shown to kill human tumor cells and does not exhibit multiple drug resistance (MDR) mechanisms. Therefore, it has the potential for cancer treatment. Examples of cancer types that the compounds of the present invention can be used for treatment include blood cancer, lymphoma, sarcoma, tumor cancer, and adenocarcinoma. Specific examples include breast cancer, colon, brain, lung, ovary, pancreas, stomach, and skin cancer. A human or animal having a tumor can be treated by a method comprising administering a compound of the invention thereto. In particular, a method for m/4m6 treatment of human tumors [including those exhibiting multidrug resistance (mdr), such as the type of multidrug resistance (mdr) mentioned above] contains an effective A therapeutic dose of a compound of the invention is administered to a patient with a tumor. All types of tumors, including those that exhibit multiple musical resistance (K4DR) and those that do not, therefore can be used on this paper scale in accordance with the Chinese National Standard (CNS) A4 specification (210 X 297 mm) --- --------仏装--------Book L----r---Line{Please read the back of the subject matter and fill out this page)

1280242 A7 ----~~^--- /五、發明說明（） ί請先¾讀背面之、;i意事項再填寫本頁} 此方法被治療。本發明化合物係以一個可減少或除去腫瘤 之劑量被投藥。於本發明之—個方面，本發明之化合抽係 以口服投藥。於本發明之另一個方面，本發明之化合物係 以非經腸道投藥，例如··靜脈注射。 基於該等藥物之活性為拓樸異構酶I及拓樸異構酶II之 抑制劑，本發明之化合物亦能夠被使用為抗病毒、抗細菌 或抗真菌之藥物。本發明化合物能夠以多種劑量型態被投 藥例如· 口服的（諸如藥錠、膠囊、.糖衣-或膜衣藥錠）； 液態溶液或懸浮液或非經消化道，例如：肌肉内注射、靜 脈内注射或皮下注射。本發明之化合物可以藉由注射或輸 液注入而給藥。 劑量丈多種因素影響，該等因素包含年齡、體重、病 人之狀况及技藥之方式。然而，通常當本發明之一個化合 物被單獨投藥至成人體内時，每一種投藥方式所採用之劑 量為0.001至500毫克/公斤，最常用之範圍為〇〇1至1〇〇毫克 / A斤體重。可以施用如此之一個劑量，舉例而言：每曰^ 至5-人藉由小丸劑輸液注入，於數小時内輸液注入及/或多 次性投藥。 經濟部智慧財產局員工消費合作社印製 一個具有化學式（1)之苯并[a]啡啩-丨丨_羧醯胺衍生物 或其一個藥學上可接受，鹽類被配方來供使用作為一種藥 學或獸醫學之組成物，其亦包含一種藥學上或獸醫學上可 接受之載劑或稀釋劑。組成物之製備典型為依據常用之方 法’且是以一種藥學上或獸醫學上適合之型態被投藥。一 個供用以治療包含該等表現多重藥物抗性（MDR)的腫瘤之 本紙張尺度適用中國國家標準（CNS)A4規格（21C) X 297公g ) &quot;&quot; 「27 --— 1280242 A7 經濟部智慧財產局員工消費合作社印製 五、發明說明（ 包含有本發明之一化合物的藥物因此而被產生。 本發明之化合物的投藥能夠以任何一種常用之型態， 其舉例如下： A) 口服的，例如：藥錠、裹覆之藥錠、裹糖衣之藥丸 、片劑、口含藥片、液態或油狀之懸浮液、液態溶液、可 分散之粉末或顆粒、乳化劑 '硬或軟膠囊、或糖製或配劑 。欲供口服使用之組成物的製備可以依據任何一種本技藝 中已决之用以製造藥學組成物的方法，且此種組成物可以 含有一種或多種選自於含有甜味劑、調味劑、調色劑及保 存劑之群組的試劑，俾以提供藥學上精美及美味之製品。 藥錠係包含活性成份混合以非·毒性藥學上可接受之 賦形劑，該等賦形劑為適供用於藥鍵H此等賦形劑 可以例如為：惰性之稀釋劑、例如：碳酸鈣、碳酸鈉、乳 糖、葡萄糖、蔗糖、纖維素、玉蜀黍澱粉、馬鈴薯澱粉、 磷酸鈣或磷酸鈉；顆粒化或崩解化試劑，例如：玉蜀黍澱 粉、海藻酸、海藻膠或澱粉乙二醇鈉鹽；結合劑，例如： 澱粉、明膠或亞拉伯膠；潤滑劑，例如··矽土、硬脂酸鎂 或鈣、硬脂酸或滑石；發泡混合物；染料；甜味劑；濕 劑，例如：卵磷脂、聚山梨酸酯或月桂硫酸酯。藥錠可 為無袠覆的或可藉由已巧之技術予以袠覆，俾以延緩崩 及在腸胃道之吸收，且藉此提供在一較長之時間内之一 持績性的作用。舉例而言，一種使時間延緩材料（例如： 硬脂酸甘油酯或二硬脂酸甘油酯）皆可被使用。此等之製備 可以藉由一種已知之方法來製造，例如：藉由混合、顆粒 潤 以 解 種 單 -----------裝--------訂—'----*---線 (請先,«讀背面之注意事項再填寫本I )1280242 A7 ----~~^--- /5, invention description () ίPlease read the back of the 3⁄4; i want to fill out this page again} This method is treated. The compounds of the invention are administered in a dosage which reduces or eliminates tumors. In one aspect of the invention, the combination of the invention is administered orally. In another aspect of the invention, the compounds of the invention are administered parenterally, e.g., intravenously. The compounds of the present invention can also be used as antiviral, antibacterial or antifungal drugs based on the activity of these drugs as inhibitors of topoisomerase I and topoisomerase II. The compounds of the invention can be administered in a variety of dosage forms, for example, orally (such as ingots, capsules, coatings, or film-coated tablets); in liquid solutions or suspensions or in the digestive tract, for example, intramuscular injection, intravenous Intra or subcutaneous injection. The compounds of the invention may be administered by injection or infusion. The dose is affected by a number of factors, including age, weight, the condition of the patient, and the manner in which the medicine is administered. However, usually when a compound of the present invention is administered alone to an adult, the dosage for each administration is 0.001 to 500 mg/kg, and the most commonly used range is 〇〇1 to 1 mg/A kg. body weight. Such a dose can be administered, for example, by infusion of a bolus infusion per hour, infusion in a few hours, and/or multiple administrations. The Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs prints a benzo[a]pyrrole-indolecarboxamide derivative of the formula (1) or a pharmaceutically acceptable salt thereof for use as a A pharmaceutical or veterinary composition which also comprises a pharmaceutically or veterinarily acceptable carrier or diluent. The preparation of the composition is typically carried out according to a commonly used method&apos; and is administered in a pharmaceutically or veterinaryly suitable form. A paper scale for the treatment of tumors containing these multidrug resistance (MDR) is applicable to the Chinese National Standard (CNS) A4 specification (21C) X 297 g) &quot;&quot; "27 ---1280242 A7 economy Ministry of Intellectual Property Bureau employee consumption cooperative printing 5, invention description (a drug containing a compound of the present invention is thus produced. The compound of the present invention can be administered in any of the commonly used forms, and examples thereof are as follows: A) Oral Such as: medicinal tablets, coated tablets, coated sugar pills, tablets, buccal tablets, liquid or oily suspensions, liquid solutions, dispersible powders or granules, emulsifiers 'hard or soft capsules Or a sugar or a formulation. The composition to be used orally can be prepared according to any of the methods of the art for making a pharmaceutical composition, and such a composition may contain one or more selected from the group consisting of A reagent for the group of sweeteners, flavoring agents, toners, and preservatives, to provide a pharmaceutically elegant and delicious product. The medicinal tablet contains a mixture of active ingredients to be non-toxic and pharmaceutically acceptable. The excipients, which are suitable for use in the drug bond H, may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, glucose, sucrose, cellulose, maize. Starch, potato starch, calcium phosphate or sodium phosphate; granulation or disintegrating agent, for example: maize starch, alginic acid, seaweed gum or starch glycol sodium salt; binding agent, for example: starch, gelatin or arabe gum Lubricant, for example, alumina, magnesium or calcium stearate, stearic acid or talc; foaming mixture; dye; sweetener; wet agent, for example: lecithin, polysorbate or lauryl sulfate. The tablet may be uncoated or may be covered by a technique that delays the collapse and absorption in the gastrointestinal tract and thereby provides one of the performance effects over a longer period of time. For example, a time delaying material (e.g., glyceryl stearate or glyceryl distearate) can be used. Such preparation can be made by a known method, for example, by mixing, Particle Run to Solve Single -- ---------Install--------Set------*---Line (Please, first, read the notes on the back and fill in this I)

經濟部智慧財產局員工消費合作社印製 1280242 A7 _____B7___ .五、發明說明（） • 化、製錠、包裹糖衣或薄膜塗覆處理之方法。 供口服使用之配方亦能夠被呈現為硬明膠膠囊，其中 活性成份被混合以一種惰性固態稀釋劑（例如：碳酸鈣、磷 酸辦或高嶺土）；或呈現為軟明膠膠囊，其中活性成份係如 此被呈現，或疋被混合以水或一種油類介質（例如：花生油 、液態凡士林、或橄欖油）。 液態懸浮液係包含活性材料混合以適合用來製造液態 懸浮液之賦形劑溶。此種賦形劑為散浮劑（例如··羧甲基纖 維鈉鹽、甲基纖維素、羥丙基甲基纖維素、海藻酸鈉、聚 乙烯吼咯酮特拉加康斯樹膠及亞拉伯樹膠）；分散劑或濕潤 劑可以為天然存在之罐脂（例如：印碟脂），或一種環氧烧 與知肪酸之縮合產物（例如：聚氧乙烯硬脂酸醋）；或環氧 乙烷與長鏈脂族醇之縮合產物（例如··十七烷基環氧乙烷十 六烷醇）；或環氧乙烷與衍生自脂肪酸及一己醣醇之部分酯 類的縮合產物（例如··聚氧乙烯山梨醇單油酸酯）；或環氧 乙烷與衍生自脂肪酸及一己醣醇酸酐之部分酯類的縮合產 物（例如··聚氧乙烯山梨醣醇酐單油酸酯）。 此等液態懸浮液可以包含一種或多種防腐劑（例如：乙 基或η-丙基對-羥基笨甲酸鹽），一種或多種調色劑（例如蔗 | 糖或糖精）。 ^ 油狀懸浮液之配製可以藉由將活性成份懸浮在_種植 物油中（例如：花生油、橄欖油、芝麻油或椰子油），或羚 浮在一種礦物油中（例如··液態凡士林）。油狀懸浮液可以 包含一種稠化劑（例如：蜂蠟、硬凡士林或鯨蠟醇）。 太紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐1 ' =~_29， (請先閱讀背面之1意事項再填寫本頁) 裝 、訂· 卜線 經濟部智慧財產局員工消費合作社印製 1280242 A7 E_ 五、發明說明（24) 甜味劑（例如：該等列於上文之中）及調味劑可以被添 加’俾以提供一種美味之口服製劑。此等組成物之保存可 以藉由一種例如抗壞血酸之抗氧化劑的添加。適用於製備 種液態懸浮液之可分散性粉末及顆粒，其藉由水的添加 而提供活性成份與一種分散試劑或濕潤試劑、一種懸浮試 劑及一種或多種防腐劑溶為一種混合物。適當之分散劑或 濕潤試劑及懸浮試劑皆以該等於上文中所提為範例。此外 之賦形劑（例如：甜味劑、調味劑及調色劑）亦可以存在其 中。 本發明之藥學組成物亦可以為水包油之乳化劑型態。 油相可以為一種植物油（例如：橄禮油或花生油），或一種 礦物油（例如：液態凡士林或此等之混合物）。適當之乳化 劑可以為天然存在之樹膠（例如：亞拉伯樹膠或特拉加康斯 樹膠）、天然存在之磷脂（例如：大豆卵磷脂）；及酯類或衍 生自脂肪酸及己醣醇酸酐之部份酯類（例如：聚氧乙烯山梨 酶醇酐單油酸酯）。乳化劑亦可包含甜味劑及調味劑。糖装 及劑可以配製甜味劑（例如：甘油、山梨糖醇或蔗糖。尤 其一種供糖尿病患使用之糖漿，其能夠包含為只含產物之 載體’舉例而言，如山梨糖醇，其不被代謝為葡萄糖，或 只代謝為一個非常少量之葡萄糖。 此種配製亦可包含一種鎮痛劑、一種防腐劑及調味劑 及調色劑； B)非經腸道地，可以為皮下注射地、或靜脈内注射地 或肌肉内注射地，或藉由胸骨内地，或藉由輸液注入技術 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） —1--------I ^--------^---------Η —^—π (請先聞讀背面之:χ意事項再填寫本頁)Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives 1280242 A7 _____B7___ . V. Inventions () • Methods of chemical, ingot, coated sugar coating or film coating treatment. The formulation for oral use can also be presented as a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent (for example: calcium carbonate, phosphoric acid or kaolin) or as a soft gelatin capsule in which the active ingredient is so Presented, or mixed with water or an oily medium (eg peanut oil, liquid petroleum jelly, or olive oil). The liquid suspension comprises a mixture of active materials which are suitable for the dissolution of the excipients used to make the liquid suspension. Such excipients are dispersing agents (for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacons gum, and sub a laver gum; a dispersing or wetting agent may be a naturally occurring can fat (eg, a printing disc grease), or a condensation product of an epoxy burning compound with a fatty acid (eg, polyoxyethylene stearic acid vinegar); a condensation product of ethylene oxide with a long-chain aliphatic alcohol (for example, heptadecyl oxirane cetyl alcohol); or condensation of ethylene oxide with a partial ester derived from a fatty acid and a monohexitol a product (for example, polyoxyethylene sorbitan monooleate); or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a monohexanol anhydride (for example, polyoxyethylene sorbitan monoester) Acid ester). These liquid suspensions may contain one or more preservatives (e.g., ethyl or η-propyl p-hydroxyformate), one or more toners (e.g., cane | sugar or saccharin). ^ Oily suspensions can be prepared by suspending the active ingredient in _ plant oils (for example: peanut oil, olive oil, sesame oil or coconut oil), or antelope in a mineral oil (eg liquid Vaseline). The oily suspension may contain a thickening agent (for example: beeswax, hard petrolatum or cetyl alcohol). Too paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm 1 ' =~_29, (please read the back of the 1st matter and then fill out this page). Install, order, and line the Ministry of Economic Affairs Intellectual Property Office staff Consumer Cooperatives Printed 1280242 A7 E_ V. INSTRUCTIONS (24) Sweeteners (eg, as listed above) and flavoring agents can be added to provide a delicious oral preparation. The addition can be carried out by the addition of an antioxidant such as ascorbic acid, a dispersible powder and granules suitable for the preparation of a liquid suspension, which provides an active ingredient with a dispersing or wetting agent, a suspending agent and One or more preservatives are dissolved as a mixture. Suitable dispersing or wetting agents and suspending agents are all exemplified by the above. In addition, excipients (for example: sweeteners, flavoring agents, and toners) It may also be present. The pharmaceutical composition of the present invention may also be an oil-in-water emulsifier type. The oil phase may be a vegetable oil (for example: olive oil or peanut oil), or a mineral oil (eg, liquid petrolatum or a mixture of such). Suitable emulsifiers may be naturally occurring gums (eg, gum arabic or Tragacons gum), naturally occurring phospholipids (eg, soy eggs) Phospholipids; and esters or partial esters derived from fatty acids and hexitol anhydrides (for example: polyoxyethylene sorbitan alcohol monooleate). Emulsifiers may also contain sweeteners and flavoring agents. The agent may be formulated as a sweetener (for example, glycerin, sorbitol or sucrose. In particular, a syrup for use in diabetes, which can be included as a carrier containing only a product, such as sorbitol, which is not metabolized. Glucose, or only metabolized to a very small amount of glucose. This preparation may also contain an analgesic, a preservative and flavoring agent and toner; B) parenterally, may be subcutaneously injected, or intravenously Intra-injection or intramuscular injection, either by sternal intestine or by infusion technique. This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1-------- I ^ --------^---------Η—^—π (Please read the back: please fill out this page again)

1280242 A7 25 ' -五、發明說明（） (請先閱讀背面之注意事項再填寫本頁) ’呈無菌之可注射性液體或油質懸浮液的型態。此種懸浮 液之配製可以依照已知技藝，使用該等於上文中所提出之 適當的分散試劑或濕潤試劑及懸浮試劑。無菌可注射性製 備亦可以為一種無菌可注射性溶液或懸浮液，其係溶解於 種無毋性非口服可接受之稀釋劑或溶劑，例如為一種溶 於1，3-丁二醇之溶液。 於可被接受之載劑及溶劑之中，可以使用的是水、林 格氏（Ringer，s)溶液及等滲壓之氣化鈉溶液。此外，無菌、 固定態之油類通常被用做一種溶劑或懸浮性介質。為此目 的，任何一種溫和無刺激性之固定態油類可以被使用，其 等包含合成之單一或雙酸甘油酯。此外，如油酸之脂肪酸 可被用在可注射液之製備中。 C) 藉由吸入，以氣霧劑或溶液之型態供噴霧器之使用 t D) 藉由肛門地，以塞劑之型態，其製備係混合藥物與 一種適當之非刺激性賦形劑，該賦形劑於常溫下為固態， 但於肛溫下為液態且會藉此溶解在直腸内以釋放藥物。此 種材料為椰子油及聚乙二醇； 經濟部智慧財產局員工消費合作社印製 E) 局部性地，型態為乳液、軟膏、凝膠、眼藥水、溶 液或懸浮液。 每曰劑量能夠在寬廣之限量内而有不同，且其調整係 依個人於每一種特定治療上之需求。一般而言，供成人投 藥時，-個適當之每日劑量的範圍為約5亳克至約5〇〇毫克 ’然而當為緊急情況時，可以超過該上限。每日劑量之投 本紙張尺度適用中國Θ家標準（CNS)A4規格（21G x 297公餐）----------- 經濟部智慧財產局員工消費合作社印製 1280242 A7 ----------B7____ 五、發明說明（26) 藥可以為一單一劑量或區分之劑量。 本發明將於下列之實施例中做更進一步地闡釋 旌例1 :具有通式（π)之化合物的1280242 A7 25 ' - V. INSTRUCTIONS () (Please read the precautions on the back and fill out this page) ‘A form of sterile injectable liquid or oleaginous suspension. Such suspensions may be formulated according to the known art, using such suitable dispersing or wetting and suspending agents as set forth above. Sterile injectable preparation may also be a sterile injectable solution or suspension, which is dissolved in a non-orally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. . Among the acceptable carriers and solvents, water, Ringer's solution and isotonic sodium vaporized solution can be used. In addition, sterile, fixed oils are commonly used as a solvent or suspension medium. For this purpose, any mild, non-irritating, fixed-state oil may be used which comprises synthetic single or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectable solutions. C) by inhalation, in the form of an aerosol or solution for use by a nebulizer t D) by anal, in the form of a suppository, which is prepared as a mixed drug with a suitable non-irritating excipient, The excipient is solid at room temperature, but is liquid at the temperature of the anus and is thereby dissolved in the rectum to release the drug. This material is coconut oil and polyethylene glycol; printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives E) Locally, the form is emulsion, ointment, gel, eye drops, solution or suspension. Each dose can vary within a wide range of limits and is tailored to the individual's needs for each particular treatment. In general, when administered to an adult, a suitable daily dose will range from about 5 grams to about 5 milligrams. However, in the case of an emergency, the upper limit may be exceeded. The daily dose of the paper size is applicable to the China National Standard (CNS) A4 specification (21G x 297 public)----------- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1280242 A7 -- --------B7____ V. Description of the invention (26) The drug can be a single dose or a different dose. The invention will be further illustrated in the following examples. Example 1: Compounds of the general formula (π)

5-甲氧基-[1，2]萘醌（其製備係藉由以二氧化硒處理5· 甲氧基·四氫萘酮，A· Bekaert et al Tetrahedron Letters 38· 24, 4219-4220, 1997)(1.98克）、2,3-二胺基-笨曱酸之二乙酸 鹽（J· Chem· Soc· Perkin. Trans I，1984, ρ·2019)(4.03 克）及 濃鹽酸（2·2毫升）之一個混合物被加熱至迴流於2〇毫升之 乙醇中，歷時4小時。冷卻反應混合物，且以過濾收集沉澱 物，然後以乙醇及乙醚沖洗，產生本標題化合物，其為一 種米黃色固體（2.74克）。 NMR: (DMS〇)4.05 (s，3H)，7.05 (lH，d)，7.84-7.87(lH，m) ，7.99 (lH，d)，8·08_8·10 (1H，m)，8.41-8.49 (3H，m)， 8.63(lH，d)。 皇考實施例1 Β· 4_甲基-笨#丨a~|啡哄-11 ·雜酸（π·2) 從鄰-苯乙醛來製備5-甲基-1-四氫萘酮係依據參考文 獻（J. Med Chem 1997, 40, 3014-3024)所描述。以二氧化硒 來處理5-甲基-1-四氫萘酮產生5-甲基·|；1，2]萘酕係如參考 實施例1Α中所描述。此專物與2,3·二胺基-苯甲酸之二乙酸 鹽反應，如同參考實施例1Α中所描述，而產生本標題化合 物。 NMR.d6-DMS0 9.02(lH,d) » 8.51(lH,dd) J 8.47-8.44(2H,m) ，8.11-8.05(2H，m)，7.85-7.78(2H，m)，2.79 (3H，s)。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） --------------------訂----Η I I I (請先閱讀背面之注^事項再填寫本頁)5-methoxy-[1,2]naphthoquinone (prepared by treatment with selenium dioxide 5·methoxy·tetralone, A· Bekaert et al Tetrahedron Letters 38· 24, 4219-4220, 1997) (1.98 g), 2,3-diamino-cracked acid diacetate (J. Chem. Soc. Perkin. Trans I, 1984, ρ·2019) (4.03 g) and concentrated hydrochloric acid (2·) One of the 2 ml) mixtures was heated to reflux in 2 mL of ethanol for 4 hours. The reaction mixture was cooled and EtOAc (EtOAc m. NMR: (DMS 〇) 4.05 (s, 3H), 7.05 (1H, d), 7.84-7.87 (lH, m), 7.99 (lH, d), 8·08_8·10 (1H, m), 8.41-8.49 (3H,m), 8.63 (lH,d). Example 1 Β· 4_Methyl-Stup#丨a~|Phosphate-11 · Miscellaneous acid (π·2) Preparation of 5-methyl-1-tetralone from o-phenylacetaldehyde It is described in accordance with the reference (J. Med Chem 1997, 40, 3014-3024). Treatment of 5-methyl-1-tetralone with selenium dioxide produces 5-methyl·|; 1,2]naphthoquinone as described in Referential Example 1 . This specific compound was reacted with 2,3·diamino-benzoic acid diacetate as described in Reference Example 1 to give the title compound. NMR.d6-DMS0 9.02(lH,d) » 8.51(lH,dd) J 8.47-8.44(2H,m) ,8.11-8.05(2H,m),7.85-7.78(2H,m),2.79 (3H, s). This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) -------------------- Order----Η III (please read first On the back of the note ^ matters fill in this page)

1280242 經¾部智慧財產局員工消費合作社印製 A7 B7 27 五、發明說明（） 以適合之有取代基之的醛做為起始，藉由一類似之方 法來製備下列具有化學式（II)之化合物： 4·氟-笨并[a]啡啡-11-羧酸（II.3)係製備自2-氟笨曱醛 NMR d6-DMS0，8.97(lH，d)，8.51(lH，dd)，8.43(lH,dd)， 8.38(lH，d)，8.11-8.06(2H，m)，7·95(1Η，πι)，7.80(lH,m); 3,4-二甲氧基-苯并[&amp;]啡啡-11-羧酸（11.4)係製備自3,4-二甲 氧基苯甲醛； NMR CDC13，8.79(lH，d)，8· 48 (2H，d)，8.37(lH，d)， 8.05(lH，t)，7.95(lH，d)，7.76(lH，d)，4.04(3H，s)，3.98(3H，s) o 參考實施例1C· 4-溴-茉并[al啡啡-11-羧酸（II.5) 依據參考文獻（J· Org. Chem 1984, ρ·4226)將溴化2-溴 苯轉變為5-臭-四氫萘飼。如參考實施例1 a所描述，以二氧 化硒與5-溴-四氫萘酮反應，其產生5-溴-[1，2]萘醌。此產物 與2,3-二胺基-笨甲酸之二乙酸鹽結合，如參考實施例ία所 描述，而產生本標題化合物。 NMR.d6-DMS0 9.24(lH，d)，8.48(2H，m)，8·33(1Η，m)， 8.26(lH，m)，8.20(lH，d)，M)8(lH，t)，7.87(lH，t) 參考實毯倒_1P· 4-氰基·笨共⑷啡啡-u·游酸6) 於一個5-溴-四氫萘哪（參閱參考實施例⑴八丨50克）溶 於Ν，Ν· —甲基甲酿fee (20毫升）之溶液中，添加銅⑴化氛 (6.39克），且反應混合物被加熱至迴流狀態下，歷時2〇小 時。然後冷卻反應混合物至8 0後，添加一個溶於水（3 8 毫升）之三氣化鐵（24克）溶液。於再多加45分鐘的攪拌後， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 53· -----------裝--------訂 i'----.--線—^ (請先閱讀背面之注意事項再填寫本頁)1280242 Printed by Aberdeen Intellectual Property Office Staff Consumer Cooperative A7 B7 27 V. INSTRUCTIONS () Starting with an aldehyde suitable for the substituent, the following formula (II) is prepared by a similar method. Compound: 4·Fluoro-p-benzo[a]morphine-11-carboxylic acid (II.3) was prepared from 2-fluoro cumenald NMR d6-DMS0, 8.97 (lH, d), 8.51 (lH, dd) , 8.43 (lH, dd), 8.38 (lH, d), 8.11-8.06 (2H, m), 7.95 (1 Η, πι), 7.80 (lH, m); 3,4-dimethoxy-benzene And [&amp;] morphine-11-carboxylic acid (11.4) was prepared from 3,4-dimethoxybenzaldehyde; NMR CDC 13, 8.79 (lH, d), 8. 48 (2H, d), 8.37 ( lH, d), 8.05 (lH, t), 7.95 (lH, d), 7.76 (lH, d), 4.04 (3H, s), 3.98 (3H, s) o Reference Example 1C· 4-Bromo-Mo And [alphine-11-carboxylic acid (II.5) According to the reference (J. Org. Chem 1984, p. 4226), 2-bromobenzene bromide was converted to 5-oxo-tetrahydronaphthalene. Selenium dioxide was reacted with 5-bromo-tetralone as described in Example 1 a to give 5-bromo-[1,2]naphthoquinone. This product was combined with the diacetate salt of 2,3-diamino-benzoic acid to give the title compound as described in Reference Example ί. NMR.d6-DMS0 9.24 (lH,d), 8.48 (2H,m),8·33 (1Η,m), 8.26 (lH,m), 8.20 (lH,d),M)8 (lH,t) , 7.87 (lH, t) Refer to the actual blanket, _1P·4-cyano·But (4), morphine-u·6, in a 5-bromo-tetrahydronaphthalene (see Reference Example (1) Gossip 50克) A solution of copper (1) (6.39 g) was added to a solution of hydrazine, hydrazine, methyl ketone (20 ml), and the reaction mixture was heated to reflux for 2 hrs. After cooling the reaction mixture to 80, a solution of tri-iron (24 g) dissolved in water (3 8 ml) was added. After a further 45 minutes of mixing, the paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 53· -----------Installation -------- Book i'----.--line-^ (please read the notes on the back and fill out this page)

經；s部智慧財產局員工消費合作社印製 1280242 A7 B7 28 五、發明說明（） 冷卻反應混合物，以水稀釋’萃取至曱笨中，以水沖洗、 乾燥（MgSCU)·，然後於抽氣下移除溶劑，而產生5·氰基一-四氫萘酮，為一種黃色固體。 如參考實施例1A所描述，以二氧化硒與5·氰-1-四氫萘 嗣反應’藉以產生5-氰基-[1，2]萘酸，其與2,3-二胺基-笨甲 酸之二乙酸鹽結合，如所述而產生本標題化合物。 NMR(d6-DMS0)，8.10-8.18(2H，m)，8.33(lH，d)，8.43(2H，m) ，8.48-8.54(2H，m)，9·48(1Η，d)。 MS DCI/NH3 m/z 300(MH+) 參考實施例IE. 4-氮-笨并丨al啡畊-11-鉍酸（ii.7、 5-胺基-1-四氫萘酮係依據參考文獻（j. Am. Chem. Soc. 1994, ρ·4852)製備自ex-四氫萘酮。5-胺基-1-四氫萘酮（8〇毫 克）及濃鹽酸（1毫升）之一個混合物被冷卻至〇°C。以滴注添 加一個亞硝酸鈉（35毫克）溶於水（0·5毫升）之溶液至攪拌中 之溶液。冷的重氮鹽溶液於此時被迅速倒入一個氣化銅 (1)(62毫克）溶於濃鹽酸（1毫升）之攪拌溶液中。反應之混合 物被允其回溫至周圍環境之溫度，然後攪拌1.5小時。再將 混合物以醋酸乙酯萃取，以水沖洗、乾燥（MgS04)，然後 於抽氣下移除溶劑，產生5-氣-1-四氫萘酮，為一種棕褐色 固體（87毫克）。 如參考實施例1A所描述，以二氧化硒與5-氣-1-四氫萘 酮反應，藉以產生5-氣-[1，2]萘酕，其與2,3-二胺基-苯曱酸 之二乙酸鹽結合，如同參考實施例1A所描述，而產生本標 題化合物。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ----------* 裝------------·—線 (請先閱讀背面之注意事項再填寫本頁) 1280242 經濟部智慧財產局員工消費合作社印制衣 A7 五、發明說明（) 施例1F:—甲確酿基-笨并丨啡g參（η.8) 5-曱基胺磺醢基-1-四氫萘酮係依據參考文獻（j· Med. Chem. 1997, p.1049)製備自5·羥基-1-四氫萘酮。5_曱基胺 石頁酿基·1-四氫萘酮（221毫克）及3-氣過笨甲酸（595毫克）之 一個混合物被攪拌於室溫下歷時;2小時。再將反應混合物以 二氯曱烷萃取，以水沖洗、乾燥（MgS04)，然後於抽氣下 移除溶劑’產生5 -甲確醯基-1·四氫萘嗣，其為一種灰白色 固體（210毫克）。 如參考實施例1A所描述，以二氧化硒與5-曱烷磺醯基 -1·四氫萘酮反應，藉以產生5-曱烷磺醯基41,2]萘酕，其與 2，3·二胺基·苯甲酸之二乙酸鹽結合，如同參考實施例1 a所 描述，而產生本標題化合物。 NMR d6-DMSO，9.61 (lH，d)，9.03(lH，d)，8.56(2H，m)， 8.43(lH，d)，8.32(lH，m)，8.16(2H，m)，3.51(3H，s)。質譜分 析法MS DCI/NH3 m/z 353(MH+) 參考實施你丨1G. 4-疊氮基-笨共[al啡畊-11·#醢（II.9) 5-胺基·1·四氫萎_係依據參考文獻（J. Am. Chem. Soc. 1994，p.4852)製備自ot-四氫萘酮。於5·胺基-1-四氫萘酮 (415毫克）溶於水（2毫升）及濃鹽酸（5毫升）一個冷溶液中， 加入一個亞硝酸鈉（186毫克）溶於水（1.2毫升）之溶液，溫度 維持在低溫。於40分鐘之後，以滴注添加疊氮化鈉（184毫 克）溶於水（1.2亳升）之一個溶液。允許該反應混合物回升至 室溫，於多加一個小時的攪拌之後，反應以水冷卻，萃取 至乙醚中，以碳酸氫鈉溶液沖洗、乾燥（MgS04)，然後於 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ----------^--------i I一-------線 (請先閱讀背面之注意事項再填寫本頁&gt;s Department of Intellectual Property Bureau employee consumption cooperative printed 1280242 A7 B7 28 V. Invention Description () Cool the reaction mixture, dilute with water 'extracted to sputum, rinse with water, dry (MgSCU) ·, then pump The solvent was removed to give the 5-cyano-tetralone as a yellow solid. Separation of selenium dioxide with 5·cyano-1-tetrahydronaphthylquinone as described with reference to Example 1A to generate 5-cyano-[1,2]naphthoic acid, which is related to 2,3-diamino- The diacetate salt of the benzoic acid is combined to give the title compound as described. NMR (d6-DMS0), 8.10-8.18 (2H, m), 8.33 (1H, d), 8.43 (2H, m), 8.48-8.54 (2H, m), 9.48 (1 Η, d). MS DCI/NH3 m/z 300 (MH+) Reference Example IE. 4-Nitro-Bist and 丨alphine-11-decanoic acid (ii.7, 5-Amino-1-tetralone) The literature (j. Am. Chem. Soc. 1994, ρ·4852) was prepared from ex-tetralone. 5-Amino-1-tetralone (8 mg) and concentrated hydrochloric acid (1 ml) The mixture was cooled to 〇 ° C. A solution of sodium nitrite (35 mg) dissolved in water (0.5 ml) was added dropwise to the stirred solution. The cold diazonium salt solution was quickly poured at this time. A gasified copper (1) (62 mg) was dissolved in a stirred solution of concentrated hydrochloric acid (1 ml). The mixture was allowed to warm to ambient temperature and then stirred for 1.5 hours. Extraction, rinsing with water, drying (MgS04), then removing the solvent under suction to give 5-y-l-tetralone as a tan solid (87 mg) as described in Reference Example 1A. Separating selenium dioxide with 5-air-1-tetralone to produce 5-a-[1,2]naphthoquinone, which is combined with diacetate of 2,3-diamino-benzoic acid, As described with reference to embodiment 1A, Produce the title compound. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ----------* 装------------· Line (please read the notes on the back and fill out this page) 1280242 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Clothing A7 V. Invention Description () Example 1F: - A true brewing base - stupid and phlegm g Η.8) 5-Mercaptoaminesulfonyl-1-tetralone is prepared from 5·hydroxy-1-tetralone according to the reference (j. Med. Chem. 1997, p. 1049). a mixture of hydrazine sulfonate, 1-tetralone (221 mg) and 3-gas over-formic acid (595 mg) was stirred at room temperature for 2 hours. The reaction mixture was again Extraction with chlorodecane, rinsing with water, drying (MgS04), then removing the solvent under suction to give 5-methyl-decyl-1-tetrahydronaphthalene, which is an off-white solid (210 mg). As described in Example 1A, selenium dioxide is reacted with 5-decanesulfonyl-1·tetralone to produce 5-decanesulfonyl 41,2]naphthoquinone, which is associated with 2,3·2 Amine-benzoic acid diacetate combination, such as The title compound was obtained as described in Example 1 a. NMR d6-DMSO, 9.61 (1H, d), 9.03 (1H, d), 8.56 (2H, m), 8.43 (lH, d), 8.32 (lH) , m), 8.16 (2H, m), 3.51 (3H, s). Mass spectrometry MS DCI / NH3 m / z 353 (MH +) Reference implementation of your 丨 1G. 4-azido-stup [alling -11·#醢(II.9) 5-Amino·1·tetrahydrofuran _ was prepared from ot-tetralone according to the reference (J. Am. Chem. Soc. 1994, p. 4852). Add a sodium nitrite (186 mg) to water (1.2 ml) in a cold solution of 5-amino-1-tetralone (415 mg) in water (2 mL) and concentrated hydrochloric acid (5 mL). ) The solution is maintained at a low temperature. After 40 minutes, a solution of sodium azide (184 mg) dissolved in water (1.2 liters) was added by dripping. Allow the reaction mixture to rise to room temperature. After stirring for an additional hour, the reaction is cooled with water, extracted into diethyl ether, rinsed with sodium bicarbonate solution, dried (MgS04), and then applied to the Chinese National Standard (CNS) on this paper scale. ) A4 size (210 X 297 mm) ----------^--------i I-------- line (please read the notes on the back and fill in again) This page&gt;

1280242 經濟部智慧財產局員工消費合作社印製 A7 發明說明（ 抽氣下移除溶劑，產生粗產物，其再使用閃爍層析法純化 ，產生5·疊氮基-1-四氫萘酮（77毫克）。 如參考實施例1A所描述，以二氧化硒與％疊氮基q· 四氫萘酮反應，藉以產生5·疊氮基·π，2]萘酕，其與2·3·二 胺基-笨曱酸之二乙酸鹽偶合，如同參考實施例1Α所描述 ，而產生本標題化合物。 參考施例1IL_笨_并「&amp;1啡哄-4,11-二羧酸4-甲篡鲢^1〇、 甲基5 -氧- 5,6,7,8·四氫·1·萘酸醋.係依據參考文獻（j.1280242 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed A7 Description of the invention (The solvent is removed under suction to produce a crude product which is then purified by flash chromatography to give 5·azido-1-tetralone (77) Mg). As described in Reference Example 1A, selenium dioxide is reacted with % azido q·tetralone to produce 5·azido·π,2]naphthoquinone, which is related to 2·3·2 Amino-bromic acid diacetate coupling, as described in Reference Example 1, produces the title compound. Reference Example 1 IL_ stupid_and "&amp; 1 morphine-4,11-dicarboxylic acid 4- Hyperthyroid^1〇, methyl 5-oxo-5,6,7,8·tetrahydro·1·naphthalic acid vinegar. According to the reference (j.

Org· Chem· 1976，ρ·2918)製備自 2·曱基-2,6,7,8-四氫-色稀 -5-酮（Tetrahedron Letters, 1975，第 3407 頁）。如參考實施例 1A所描述，以二氧化硒與曱基5·酮基·5,6,7,8-四氫·κ萘酯 反應而產生對應之1，2-萘酕，5,6-二氧-5,6-二氫-萘-1-羧酸 甲基δ旨’其與2,3·二胺基·苯曱酸之二乙酸鹽結合，如同參 考實施例1Α所描述，而產生本標題化合物。 NMR d6-DMS0，9.47 (lH，d)，9.02(lH，d)，8.53(lH，d)， 8.44(2H，m)，8.20(lH，d)，8.10(2H，m)，4.03(3H，s) 〇 參考實例Π. 4-乙氧基-笨并丨al啡哄-11-钕Shir in 5·羥基-1-四氫萘酮（2.00克）及氫氧化鈉（493毫克）之一 個混合物於乙醇（40毫升）中加溫至50°C。然後添加碘化乙 烷（3.94毫升），且加熱反應混合物予以迴流16小時。反應 混合物以2N之氫氣酸稀釋，萃取至醋酸乙酯中，乾燥並於 抽氣下移除溶劑，產生5-乙氧基-1-四氫萘酮，為一種白色 固體（2.06克）。 如參考實施例1A所描述，以二氧化硒與5-乙氧基-1- 本紙張尺度適用中國國家標準（CNS)A4規袼（210 X 297公釐） —30 丄_ -----------—裝--------訂L—l·—線 itt先閱讀背面之注意事項再填寫本頁}Org Chem. 1976, ρ. 2918) was prepared from 2,5-yl-2,6,7,8-tetrahydro-chromo-5-one (Tetrahedron Letters, 1975, p. 3407). The reaction of selenium dioxide with mercapto 5·keto·5,6,7,8-tetrahydro-kappa naphthyl ester produces the corresponding 1,2-naphthoquinone, 5,6- as described in Reference Example 1A. Dioxo-5,6-dihydro-naphthalene-1-carboxylic acid methyl δ is combined with the diacetate of 2,3·diaminobenzoyl acid, as described in Reference Example 1 The title compound. NMR d6-DMS0, 9.47 (1H, d), 9.02 (1H, d), 8.53 (1H, d), 8.44 (2H, m), 8.20 (1H, d), 8.10 (2H, m), 4.03 (3H) , s) 〇 Reference example Π. 4-Ethoxy-stupyl 丨 哄 哄 钕 11-钕 Shir in 5 · hydroxy-1-tetralone (2.00 g) and one of sodium hydroxide (493 mg) The mixture was warmed to 50 ° C in ethanol (40 mL). Then, ethyl iodide (3.94 ml) was added, and the reaction mixture was heated to reflux for 16 hours. The reaction mixture was diluted with aq. EtOAc (EtOAc) (EtOAc)EtOAc. As described with reference to Example 1A, the Chinese National Standard (CNS) A4 specification (210 X 297 mm) is applied to the scale of selenium dioxide and 5-ethoxy-1-paper - 30 丄 _ ----- -------装--------Book L-l·-line itt first read the back of the note and then fill out this page}

1280242 經濟部智慧財產局員工消費合作社印製 A7 B7 31 ，五、發明說明（） 四氫萘酮反應而產生5-乙氧基-[1，2]萘醍，其與2·3·二胺基-本甲酸之一乙酸鹽結合’如同參考實施例1 a所描述，而產 生本標題化合物。 NMRd6-DMS0. 1.52(3H，q)，4.33(2H，d)，7·85-7·90(1Η,ηι) ，8.00(lH，d)，8·08·8·11(1Η，ιη)，8.45-8.55(3H，m)，8.68(lH,d) ο 參考實施例1J. 4-甲基胺續醯基·芏并[al啡啡·n•鉍醢 (11.12) 於一個溶於乾燥之二曱基亞颯（DMSO)(32毫升）内之 4-氣·苯并[a]啡啡-11-羧酸（ΙΙ·3，參閱參考實施例ib)(58毫 克）攪拌溶液中，添加硫代曱氧基鈉（55毫克），然後混合物 冷卻至室溫’以醋酸冷卻’以醋酸乙醋萃取，以水沖洗， 乾燥並於抽氣下移除溶劑，產生本標題化合物，為一種紅 色固體（37毫克）。 NMR d6-DMS0· 9.00(lH，d)，8.52(2H，m)，8.45(lH，d)， 8.11(2H，m)，7.91(2H，m)，2.70(3H，s) 〇 質譜分析法MS DCI/NH3 m/z=321(MH+，100%) I考實施例IK· 4-苄基氣-茉并『alp非畊-11-翔酸（π. 13) 於一個溶於二氣甲烷（30毫升）之4-甲氧基-四氫萘酮 (Π.1，參閱參考實施例1A)(441毫克）溶液被冷卻至〇°c後， 添加一個溶於二氣甲院（7·25毫升）1.0 Μ之三溴硼酸溶液 。俟該反應混合物回升至室溫後，予以攪拌16小時。再將 混合物倒至冰/水之上，產生4-苄基氧-苯并[a]啡啡-11-羧酸 ，為一種红色/棕色固體，其係以過濾及空氣乾燥被收集之 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） yr ----------^--------I.----A---線 &lt;請先閱讀背面之;i意事項再填寫本頁)1280242 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 31, five, invention description () tetralone reaction to produce 5-ethoxy-[1,2]naphthoquinone, which is related to 2·3·diamine The acetate-binding of one of the base-formic acid is described as described in Reference Example 1 a to give the title compound. NMRd6-DMS0. 1.52(3H,q),4.33(2H,d),7·85-7·90(1Η,ηι),8.00(lH,d),8·08·8·11(1Η,ιη) , 8.45-8.55 (3H, m), 8.68 (lH, d) ο Reference Example 1 J. 4-Methylamine 醯 芏 芏 al [althyphine·n•铋醢 (11.12) in one dissolved in dry a 4-gas·benzo[a]morphin-11-carboxylic acid (ΙΙ·3, see Reference Example ib) (58 mg) in a stirred solution of dimercaptopurine (DMSO) (32 ml), Sodium thiosulphonate (55 mg) was added, then the mixture was cooled to room temperature 'cooled with acetic acid', extracted with ethyl acetate, washed with water, dried and evaporated to give solvent. Red solid (37 mg). NMR d6-DMS0· 9.00 (lH, d), 8.52 (2H, m), 8.45 (1H, d), 8.11 (2H, m), 7.91 (2H, m), 2.70 (3H, s) 〇 mass spectrometry MS DCI/NH3 m/z=321(MH+,100%) I test example IK· 4-benzyl gas-mosa”alp non-cultivated-11-cyanic acid (π. 13) in one dissolved in di-methane (30 ml) of 4-methoxy-tetralone (Π.1, see Reference Example 1A) (441 mg) solution was cooled to 〇°c, and a solution was added to the second gas chamber (7· 25 ml) 1.0 Μ tribromoboric acid solution. After the reaction mixture was allowed to warm to room temperature, it was stirred for 16 hours. The mixture was poured onto ice/water to give 4-benzyloxy-benzo[a]morphine-11-carboxylic acid as a red/brown solid which was collected by filtration and air drying. The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) yr ----------^--------I.----A---Line&lt; Please read the back side first; i want to fill out this page again)

1280242 經濟部智慧財產局員工消費合作社印製 A7 B7 32 五、發明說明（） (230毫克）。 NMR.d6-DMSO· 7.35(lH，d)，7.75(lH，m)，7.92(lH.d)， 8.08(lH，m)，8.47-8.55(4H，m)，10.72(lH，broad)。 加熱一個由溶於乙醇（2毫升）之4-羥基·笨并[a]啡畊 -11·羧酸（80毫克）、氫氧化鈉（34毫克）及溴化笨（ΙΟΟμί)所 構成的混合物並予以迴流4小時。反應混合物冷卻後，以醋 酸乙酯稀釋、以稀釋的酸清洗、乾燥（MgS04)，並於抽氣 下移除溶劑，產生粗製之本標題產物.，其為一種棕色固體 (50毫克）。 NMRd6-DMSO.包含5.35(2H，s) 下列化合物之製備係可以一種類似之方法，並使用適 當之烧化試劑’製備自4 ·經基-苯并[a]啡_ -11 -叛酸： 4-丙-2·炔基氧基·笨并[a]啡哄· 11 ·羧酸（1114)之製備係使 用溴丙炔； 4-異丁氧基-苯并[a]啡畊-11·羧酸（Π· 15)之製備係使用異丁 基溴； 4·(4-氯-笨氧基）·苯并[a]啡哜_n•羧酸（Π16)之製備係使用 溴化對氣甲笨； 4·(2·曱氧基-乙氧基）·苯并⑷啡畊•羧酸（π 17)之製備係 使用2-溴乙基甲基醚； 4·乙氧基羰基-甲氧基-苯并[a]啡啡·11-羧酸（n.l 8)之製備 係使用溴醋酸乙酯。此反應中使用溶於乾乙醇之乙醇鈉； 4-[2·(三級（ier〇· 丁基·二甲基·石夕烷氧基）·乙氧基]•苯并[a] 啡喷-11-羧酸（11.19)之製備係使用三級（化々&gt;丁基彳2-碘-乙 (η先閱讀背面之注意事項再填寫本頁) 裝 二al· 1280242 A7 B7 五、發明說明（ 氧基）-二曱基-矽烷。三級（ierr)-丁基-(2-碘-乙氧基V二曱基 •矽烷之製備係使用標準方法，製備自2-碘-乙醇。 垦考實施例1L. 茉并[al啡啡-11-#醢（11.20) 加熱一個由1，2-萘醌（可由商業上購得，2.0克）及2.3-二胺基-苯曱酸之二乙酸鹽（3.79克）所構成之混合物並於醋 酸（30毫升）中予以迴流2小時。於該反應混合物被冷卻後， 以抽氣移除溶劑，產生一種膠體。此膠體使用閃爍層析法 予以純化，而產生一個所欲之本標題化合物相對於非所需 之苯并[a]啡啡-8-羧酸（840毫克）為2 ·· 1之混合物。此兩種 異構物於進一步之改質後予以分離（參閱下列之參考實施 例 3B)。 NMR.d6-DMSO·包含 9.07-9.09(lH，m)，9.21-9.22(lH，m) 。比例：2:1。 垦考實施例1M._t甲基胺碏醯某-芏其⑷啡啡·n•瀚醅 0J.21)及3·-甲基胺石簧酿某-苯并『仏非哄d卜羧酸⑴22) 於氮氣下，將溶於氯磺酸（2毫升）之苯并 酸甲基酯（IV.20，參閱參考實施例3B，22〇毫克）加熱至18〇 °C，歷時6小時。待反應冷卻後倒至冰/水之上，且以過濾 經濟部智慧財產局員工消費合作社印製 ------------裝·-- (靖先閱讀背面之注意事項再填寫本頁) 收集，而產生一個4-氣胺磺醯基·苯并[a]啡啩_丨卜羧酸相對 於3-氯胺磺醯基·笨并[a]啡畊_u•羧酸約為丨：1之混合物 (182毫克）。 NMR.d6-DMSO·包含 9.41(1Hs)，93〇(1Hd)。 4·氣胺續酿基-苯并[a]啡畔⑴·幾酸與3-氣胺磺醯基-苯并[a]啡丼11-幾g曼之成合物（182毫克）被溶於二氣甲院（5 Μ氏張尺度適用中國國家標準（CNS)A4 ^Γ(210 x 297公爱 1280242 經濟部智慧財產局員工消費合作社印製 A7 34 五、發明說明（） 毫升胺）内。對之添加一個溶於5亳升水内之4〇%甲基胺溶 液。然後劇烈攪拌反應混合物4小時。此時再將反應混合物 傾倒至二氯甲烷並酸化處理（2N氫氣酸），萃取至二氯甲燒 内，乾燥（MgSCU)，然後抽氣移除溶劑，產生一個約1 : } 之本標題化合物（160毫克）。兩種異構物於進一步之化學改 質後予以分離。 NMR ( CDC13 + d4 曱醇）·包含 9.38(1H，s)，9.22(lH、d)， 2.61(3H，s)，2.55(3H，s)。 4·二曱基胺磺醯基-苯并[a]啡啡-li-羧酸（π·23)及3-二 甲基胺磺醯基·苯并[a]啡啡·11-羧酸（π.24)之製備係以類似 之方法，該方法係藉由二甲基胺與4-氯胺磺醯基-笨并[a] 啡哜-11-羧酸及3·氣胺磺醯基-苯并[a]啡畊·u •羧酸之混合 物反應。兩種異構物於進一步之化學改質後予以分離。混 合物之 NMR (d6-DMSO)包含 9.06(lH，d)，9.42(lH,s)， 2.93(6H，s)。1280242 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 32 V. Invention description () (230 mg). NMR.d6-DMSO· 7.35 (1H, d), 7.75 (lH, m), 7.92 (1H.d), 8.08 (1H, m), 8.47-8.55 (4H, m), 10.72 (lH, broad). Heating a mixture of 4-hydroxy-p-[a]-panning-11-carboxylic acid (80 mg), sodium hydroxide (34 mg) and brominated stupid (ΙΟΟμί) dissolved in ethanol (2 ml) It was refluxed for 4 hours. After the reaction mixture was cooled, diluted with EtOAc EtOAc EtOAc (EtOAc) NMRd6-DMSO. Contains 5.35 (2H, s) The following compounds can be prepared in a similar manner and prepared using a suitable burning agent' from 4 · thio-benzo[a]- _ -11 - oxic acid: 4 -propan-2-alkynyloxy) benzo[a] phenanthrene -11 carboxylic acid (1114) was prepared using bromopropyne; 4-isobutoxy-benzo[a] cultivating -11. The preparation of the carboxylic acid (Π·15) is carried out using isobutyl bromide; 4·(4-chloro-indolyl)·benzo[a]morphine-n•carboxylic acid (Π16) is prepared by using a brominated pair Gas is stupid; 4·(2·decyloxy-ethoxy)·benzo (4) morphine • carboxylic acid (π 17) is prepared by using 2-bromoethyl methyl ether; 4·ethoxycarbonyl- The preparation of methoxy-benzo[a]morphine-11-carboxylic acid (n18) was carried out using ethyl bromoacetate. In this reaction, sodium ethoxide dissolved in dry ethanol is used; 4-[2·(three-stage (ier〇· butyl dimethyl·oxacinoxy)·ethoxy] benzo[a] morphine spray The preparation of -11-carboxylic acid (11.19) is carried out using three grades (chemical 々 &gt; butyl hydrazine 2-iodo-B (η first read the back of the note and fill out this page). Install two al. 1280242 A7 B7 V. Invention Description (oxy)-dimercapto-decane. Preparation of tertiary (ierr)-butyl-(2-iodo-ethoxy V decyl decane) was prepared from 2-iodo-ethanol using standard procedures. Reference Example 1L. Molybdenum [almorphine-11-#醢(11.20) Heating one from 1,2-naphthoquinone (commercially available, 2.0 g) and 2.3-diamino-benzoic acid A mixture of diacetate (3.79 g) was refluxed for 2 hours in acetic acid (30 ml). After the reaction mixture was cooled, solvent was removed by suction to give a colloid. Purified to give a desired mixture of the title compound and the desired benzo[a]morphin-8-carboxylic acid (840 mg) as a mixture of 2··1. Modification Separation (refer to Reference Example 3B below). NMR.d6-DMSO· contains 9.07-9.09 (lH, m), 9.21-9.22 (lH, m). Ratio: 2:1. Reference Example 1M._t Methylamine 碏醯 芏 芏 ( ( 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 - - - - - - - - - - - - - - - - - - - - - The benzoic acid methyl ester (IV.20, see Reference Example 3B, 22 mg) dissolved in chlorosulfonic acid (2 ml) was heated to 18 ° C for 6 hours. Above the water, and printed by the Department of Intellectual Property of the Department of Intellectual Property of the Department of Filtering and Economy, ------------ Installed---(Jing Xian read the back of the note and fill out this page) a mixture of 4-amin sulfonyl-benzo[a]pyrrole-indole carboxylic acid relative to 3-chloroamine sulfonyl-p-benzoic acid-a carboxylic acid of about 丨:1 (182 mg). NMR.d6-DMSO· contains 9.41 (1Hs), 93〇 (1Hd). 4.············································· -Benzo[a]phlephthyl 11-glycine complex (182 mg) is dissolved in the second gas hospital (5 Μ Zhang scale applicable Chinese national standard) CNS)A4 ^Γ(210 x 297 公爱1280242 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 34 V. Invention description () ml amine). Add a 4%% dissolved in 5 liters of water Base amine solution. The reaction mixture was then stirred vigorously for 4 hours. At this time, the reaction mixture was poured into dichloromethane and acidified (2N hydrogen acid), extracted into dichloromethane, dried (MgSCU), and then removed by suction. Solvent, yielded a title compound (160 mg). The two isomers are separated after further chemical modification. NMR (CDC13 + d4 sterol)· contains 9.38 (1H, s), 9.22 (1H, d), 2.61 (3H, s), 2.55 (3H, s). 4· Dimercaptosulfonyl-benzo[a]morphine-li-carboxylic acid (π·23) and 3-dimethylaminesulfonyl·benzo[a]morphine·11-carboxylic acid The preparation of (π.24) is carried out in a similar manner by dimethylamine and 4-chloroamine sulfonyl- benzo[a] phenanthrene-11-carboxylic acid and 1,3-amine sulfonium sulfonate. A mixture of benzyl-benzo[a]morphine·u•carboxylic acid. The two isomers are separated after further chemical modification. The NMR (d6-DMSO) of the mixture contained 9.06 (1H, d), 9.42 (1H, s), 2.93 (6H, s).

4-胺磺醯基-笨并[a]啡啡•羧酸（π·25)及3·胺磺醯基 -笨并[a]啡味·11·羧酸（π.26)之製備係以類似之方法，該方 法係藉由氫氧化銨與4·氣胺磺醯基-笨并啡啩•羧酸 及3-氯胺磺醯基-苯并[a]啡畊·η_羧酸之混合物反應。兩種 異構物於進一步之化學『文質後予以分離。混合物之NMR (d6-DMSO)包含 9.39( lH，d)及 9.60( lH，s)。 t %±\ IN,_k硝基·茉并丨al啡啡·11·羧酸ΠΙ.27)及3-硝基-笨并fal啡呼·〗1-羧g# (ττ μ) 於0 °C之下，將5亳升濃硫酸及5毫升濃硝酸混合在一起 ‘紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公餐） &quot;-40 ftf先閱讀背面之注意事項再填寫本頁}Preparation of 4-amine sulfonyl-p-benzo[a]morphine-carboxylic acid (π·25) and 3-aminosulfonyl-benzo[a]morphin·11·carboxylic acid (π.26) In a similar manner, the method is carried out by ammonium hydroxide and 4·amine sulfonyl-phenyl benzoate carboxylic acid and 3-chloroamine sulfonyl-benzo[a]morphin·η_carboxylic acid The mixture reacts. The two isomers are separated after further chemical chemistry. The NMR (d6-DMSO) of the mixture contained 9.39 (1H, d) and 9.60 (1H, s). t %±\ IN, _k nitro, jasmine, morphine, 11·carboxylate ΠΙ.27) and 3-nitro-stupid fal morphine, 〗 1-carboxyg# (ττ μ) at 0 °C Underneath, mix 5 liters of concentrated sulphuric acid and 5 ml of concentrated nitric acid. 'Paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public meals) &quot;-40 ftf first read the back of the note and then fill out this page}

1280242 經濟部智慧財產局員工消費合作社印製 A7 五、發明說明（35) 。添加100亳克之笨并[a]啡啡羧酸（11.20)至此混合物中 ，並允該反應混合物慢慢地回升至室溫。於24小時之後， 將反應混合物傾倒至水上，產生一種黃色之沉殿物。此沉 澱物係以過濾收集，產生一個4_硝基·笨并[a]啡啩·u•羧酸 (Π.27)相對於3-硝基-笨并[a]啡啡•羧酸（π·28)為4:1之混 合物。兩種異構物於進一步之化學改質後予以分離。 NMR(d6-DMSO)，包含9e82(lH，d)，9.46(lH，d)，比例 1:4 MS MH@320 差i.考實施例10· 4·胺基·茉莽丨ai啡啡-丨ι·_ 29)及3-胺 i·笨并fal啡畊-11·#醅mn、 3毫升之氣化銨溶液及銦（cat )被添加至溶於乙醇（5毫 升）之得自參考實施例1N之4-硝基-笨并[a]啡啡·丨卜羧酸 (11.27)相對於3-硝基·苯并[a]啡畊-n•羧酸（π 28)為4:1的混 合物中。加熱反應混合物至迴流，然後冷卻並通過一個賽 力特矽藻土濾床過濾。過濾液以水稀釋，萃取至二氣甲烷 内，乾燥（MgS〇4)，然後以抽氣移除溶劑，產生μ毫克之 本標題化合物，並於進一步改質後予以分離。 NMR (d6-DMSO)，6.95(lH，d)，7.55(lH，t)，7.75(2H，m)， 8.20(lH，d)，8.65(lH，d) 兔考實施例IP· 3_溴經基-笨# fal啡啡·ι l-羧g* n 於室溫下，4·羥基-苯并[a]啡啩·li-羧酸（參閱參考實施 例1K，102毫克）及0.04毫升之溴被攪拌於3毫升之氣仿中， 歷時20小時。於抽氣下移除溶劑，然後使用閃爍層析法（ 溶於二氯甲烷内之10%甲醇），產生本標題化合物為一種黃 ___1_______-裝--------訂---------*·線--W {請先閱讀背面之注意事項再填寫本頁)1280242 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 V. Invention Description (35). 100 g of stupid and [a]morphinic acid (11.20) was added to the mixture, and the reaction mixture was allowed to slowly warm to room temperature. After 24 hours, the reaction mixture was poured onto water to give a yellow sink. This precipitate was collected by filtration to yield a 4-nitro-benzo[a]-p-anthracene-u-carboxylic acid (Π.27) relative to 3-nitro-benzo[a]morphinic-carboxylic acid ( π·28) is a 4:1 mixture. The two isomers are separated after further chemical modification. NMR (d6-DMSO), containing 9e82 (lH, d), 9.46 (lH, d), ratio 1:4 MS MH@320 差i. Example 10·4·Amino·Mum.丨ι·_ 29) and 3-amine i· stupid and faldy tillage-11·#醅mn, 3 ml of vaporized ammonium solution and indium (cat) were added to ethanol (5 ml) from reference Example 1N 4-nitro-abido[a]morphine-indole carboxylic acid (11.27) is 4 compared to 3-nitrobenzo[a]morphin-n•carboxylic acid (π 28): 1 in the mixture. The reaction mixture was heated to reflux, then cooled and filtered through a pad of Celite. The filtrate was diluted with water, extracted into di-methane, dried (M.sub.4), and then solvent was evaporated to give the title compound. NMR (d6-DMSO), 6.95 (lH, d), 7.55 (lH, t), 7.75 (2H, m), 8.20 (1H, d), 8.65 (1H, d) rabbit test example IP·3_bromo基基-笨# fal morphine·ι l-carboxyg* n at room temperature, 4·hydroxy-benzo[a]morphine·li-carboxylic acid (see Reference Example 1K, 102 mg) and 0.04 ml Bromine was stirred in 3 ml of air for 20 hours. The solvent was removed under suction and then flash chromatography (10% methanol in dichloromethane) was used to give the title compound as a yellow ___1_______------- ------*·Line--W {Please read the notes on the back and fill out this page)

A7 B7A7 B7

1280242 五、發明說明（） 褐色固體。 MS DCI/NH3，MH+ 369/371 (1:1) &gt;JMR (CDC13)，7.94(lH，d)，8·1·8·2(2Η,πι)，9.1(lHLd)。 I··考實施例IQ· 2·硝基-笨并畔· 1】-轉酸（ιι 32) 7-硝基-1-四氫萘酮之製備係依據參考文獻（J· Am1280242 V. INSTRUCTIONS () Brown solid. MS DCI/NH3, MH+ 369/371 (1:1) &gt; JMR (CDC13), 7.94 (lH, d), 8·1·8·2 (2Η, πι), 9.1 (lHLd). I··Test Example IQ·2·Nitro-Stupid·1]-Transacid (ιι 32) 7-Nitro-1-tetralone was prepared according to the reference (J· Am

Chem· Soc，1994, 116, Ρ·4852-4857)。如參考實施例丨 a所描 述，以二氧化硒與7-硝基·1·四氫萘酮反應，而產生對應之 7-硝基-[1，2]萘醌。此產物與2,3·二胺基-苯甲酸之二乙酸鹽 結合’如同參考實施例1Α所描述，而產生本標題化合物。 I一考實施例.1R· 2·甲氧基-苯#⑷啡哄-U·羧醢（11 33) 由8-胺基·萘磺酸（可由商業上購得）製備胺基·萘 醇，係依據參考文獻（J· 〇rg· Chem· 1949，第351頁）。小心 地添加氫化鈉（於礦物油中60%之分散液，3.2克）至一個溶 於80毫升之乾燥N，N-二甲基曱醯胺之8-胺基-萘-2·醇（8.00 克）溶液中。於攪拌4小時後，於一冰浴中冷卻反應混合物 ’並以逐滴地添加曱基蛾（3 · 13毫升）。然後於室溫下授拌 反應混合物，歷時3天。其後，再添加1 〇毫升之水，並於抽 氣下移除揮發物。殘基被溶解在氣仿中，以水沖洗，乾燥 (MgSCU)，然後於抽氣下移除溶劑，產生一種深色之油。 該油使用閃爍層析法（氯声）予以純化，而產生7-甲氧基·萘 -1-基胺，其為一種暗色之液體（2·92克）。 7-甲氧基-萘-1·基胺與2-溴-3·硝基·笨甲酸的反應，係 依據類似於 W. Rewcastl et al.，J. Med. Chem. 1987，ρ·843 所描述之方法，而產生2·(7-甲氧基-萘·1-基胺基）-3-硝基· 本紙張尺度適用中國國家標準（CNS)A4規格（210x 297公釐） -----------* 裝--------訂 ί&quot;-----·---線 ί請先¾請背面之;i意事項再填寫本頁}Chem. Soc, 1994, 116, Ρ 4852-4857). As described in Reference Example 丨 a, selenium dioxide is reacted with 7-nitro-1 quinone to give the corresponding 7-nitro-[1,2]naphthoquinone. This product was combined with the diacetate salt of 2,3.diamino-benzoic acid&apos; as described in Reference Example 1 to give the title compound. I. Test Example. 1R·2·Methoxy-Benzene#(4)Pentyl-U·Carboxylide (11 33) Amino-naphthol was prepared from 8-aminonaphthalenesulfonic acid (commercially available). According to the reference (J·〇rg·Chem. 1949, p. 351). Carefully add sodium hydride (60% dispersion in mineral oil, 3.2 g) to an 8-amino-naphthalen-2-ol (8.00) in 80 ml of dry N,N-dimethyl decylamine. g) in solution. After stirring for 4 hours, the reaction mixture was cooled in an ice bath and the hydrazine moth (3 · 13 ml) was added dropwise. The reaction mixture was then stirred at room temperature for 3 days. Thereafter, 1 liter of water was added and the volatiles were removed under suction. The residue was dissolved in a gas sample, rinsed with water, dried (MgSCU), and then the solvent was removed under suction to produce a dark oil. This oil was purified by flash chromatography (chlorination) to give 7-methoxy-naphthalen-1-ylamine as a dark liquid (2·92 g). The reaction of 7-methoxy-naphthalen-1-ylamine with 2-bromo-3.nitro-benzoic acid is based on a similarity to W. Rewcastl et al., J. Med. Chem. 1987, ρ·843 Describe the method to produce 2·(7-methoxy-naphthalenyl-1-ylamino)-3-nitro· This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x 297 mm) --- --------* Install -------- 订 ί&quot;---------Line ί Please first 3⁄4 please back; i intend to fill out this page}

經濟部智慧財產局員工消費合作社印製 經濟部智慧財產局員工消費合作社印製 1280242 A7 ___ B7__ 37 p五、發明說明（） 笨甲酸。還原性環化作用是使用硼氫化鈉（J_ Med· Chem. 1987，第843頁），而產生所欲之本標題化合物。 NMR’d6-DMSO’ 14·44(1Η，寬峰，s)，8.55(lH，d)，8.48(lH，dd) ，8.42(lH，dd)，8.23(lH，d)，8.1(M.04(2H，m)，7.86(lH,dd)‘ ，4.02(3H，s) 〇 MH+ @305 3-甲氧基-笨并[a]啡啡-11·羧酸（II.34)之製備係以類似 之方法，且起始自5-胺基·萘-2-磺酸（可由商業上構得）。 NMR，d6-DMSO, 14.60( 1H，寬峰，s)，8.94(lH，d)，8.51(2H，d) ，8.23(lH，d)，8.10-7.96(2H，m)，7.67(lH，d)，7.55(lH.dd) ，3.99(3H，s)。 MH+ @305 t考實施AIR._2^ΙΙ·4·甲—氧某-芏养m啡啡-π·羧酸 (11.35、 一個由4-曱氧基-笨并[a]啡啡·丨卜羧酸（Π1)(1 〇〇毫克） 與溴（5滴）所構成之混合物於室溫下被攪拌歷時3天。反應 混合物於抽氣下被還原，且所欲之化合物係使用閃爍層析 法予以分離（25毫克）。 MS MH+ @383/385 (1 ： 1) NMR，CDC13，14.47( 1H，寬峰，s)，8 86(1H d)，8 33(1H d) ，7.95(lH，t)，7.78(lH，d)，6.97(lH，d)，6.12(lH，d)，5.75(lH，d) ，3.94(3H，s)。 參考貫苑例...LX：-—甲氧基-苯并ΓΜ啡哄· 11 -敌酸 (11.36) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ----------I --------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 1280242 A7 &quot; --— B7 ___ 五、發明說明（38) (請先閱讀背面之注意事項再填寫本頁) 2-胺基-6-甲氧基-3-硝基·笨并[a]啡畊-羧酸曱基酯 之製備’係使用類似參考文獻（Kim et ai j Med· Chem. 1993, p.23335)所描述之方法。甲基酯之水解反應是使用氫 氧化鉀，將之置在迴流之乙醇中，歷時2小時，產生2·胺基 ·6·甲氧基-3-硝基-笨甲酸。硝基之氫化作用在氫氣壓力為 5〇 psi下’於parr儀器上’在碳上鈀催化劑上，於醋酸/水 内被進行，而產生2,3-二胺基-6-曱氧基-苯甲酸。此產物與 5_曱氧基-[1，2]萘醍反應，如同參考實施例1A所描述，而產 生所欲之本標題化合物。 NMR，d6-DMSO，4.05(3H，s)，4.10(3H，s) , 7.45(lH,d), 7.78-7.82(lH，m)，7.92(lH，d)，8.03(lH，d)，8·36·8·40(2Η，ηι) ，8.78(lH，d) 袭主复施例ιυ·_!_·_甲氧基-8-甲基-茉#丨al啡啡鉍舲 (11.37) 自4-甲基鄰胺基笨甲酸製備2,3-二胺基·4·甲基笨甲酸 ，係依據Rewcastl et al·，J· Med· Chem· 1987, ρ·843所描述 經濟部智慧財產局員工消費合作社印製 之方法。藉此製備之2,3·二胺基-4-曱基苯甲酸與5_曱氧基 -[1，2]萘醍反應，如同參考實施例1A所描述，而產生所欲 之本標題化合物。 NMR，d6-DMSO 2.97(3H，s)，4.06(3H，s)，7.50(】H，d)， 7·85·7·90(1Η，γπ)，7.97(lH，d)，8.02(lH，d)，8·45.8·50(2Η，πι) ，8.57(lH，d)。 臭實施例IV· 9-氩4·甲氣基·笨# Μ啡听_ (ΙΙ.38) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱) 厂44 - 1280242 A7 B7 39 五、發明說明（） 5·氯-3硝基鄰胺基苯甲酸之製備，係依據Flippin et al (Biorg· Med. Chem· Letts 1996,第 477 頁）所描述之方法。該 化合物之氫化作用是在氫氣壓力為50 psi下，於parr儀器上 ，在碳上鈀催化劑上，於醋酸/水内被進行，歷時2小時， 而產生2,3-二胺基-5-氣-笨甲酸。此產物與5-曱氧基-[uj 萘醍反應，如同參考實施例1A所描述，而產生所欲之本標 題化合物。 NMR，d6-DMSO，4.05(3H，s)，7.48(lH，d)，7.82-7.86(lH,m) ，7.92(lH，d)，8.30(lH，d)，8.48(lH，d)，8.54(lH，d)，8.68(lH，d) ’ 14.1(1H，寬峰）。 兔考實施例2 :具有通式（III)之化合物的製備 i考實施例2A. 4-氮雜-DL-白胺酸甲某酯氣醅ΠΙΙ.η 以無水之氣化氫氣體飽和150毫升之甲醇。於該甲醇中 ，添加4.86克之4-氮雜-DL·白胺酸曱基酯（可由商業上購得 )，然後反應混合物被保持在室溫下攪拌過夜。以抽氣移除 溶劑並產生本標題化合物（定量化之產率） t考實施例2Β. W，7-二甲某-丁烷-1,2-二脍〔III.2、 經濟部智慧財產局員工消费合作社印製 N-(三級（ier…丁氧基羰基）-2·胺基丁酸甲酯之製備係 如參考文獻（J· Med. Chem. 1989,第1886頁）所描述。於-78 °C下以溶於甲苯之二異丁基氫化鋁來處理該化合物，歷時 1.5小時，而產生對應之醛（製備方法參閱：h. W. Scheeren et al，J· 〇rg. Chem· 1990, ρ·3998)。 於室溫下，一個由溶於甲醇内之1.85克之該醛、1.61 克之二曱基胺氣化氫、1.21克之乙酸鈉及0.83克之氰基溴 45 -----------I ^ - I I (請先Μ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） 1280242 A7 B7 經濟部智慧財產局員工消費合作社印製 , 40五、發明說明（） 化氫納之所構成混合物被授拌24小時。使用醋酸調整酸驗 值至6-7,並持續於反應過程中予以監測。該反應混合物於 抽氣下濃縮’然後將殘基溶解於醋酸乙酯中，並以水沖洗 。有機層以乾燥（MgS〇4)沖洗且抽氣移除溶劑，產生一種 無色之油，該油以閃爍層析法純化，得到所需之二曱基胺 衍生物，其為一種蒼白色之油（0.56克）^於此化合物中小 心地添加一個溶於環氧己烷（2亳升）之4.〇m氣化氫溶液，然 後授拌反應混合物90分鐘。再將該反應混合物於抽氣下濃 縮，產生所需之本標題化合物，其為一蒼白色之固體（定量 化之產率）。 I—考實施例2C'.__3A^，A^-三甲基-丁烷d·2·二脸I氩酸鹽 (III.3) 自DL·纈胺酸製備N-(三敍如丁氧基羰基&gt;DL•纈胺 酸甲基酯，係使用標準化之製備技術。再使用一種類似參 考貝&amp;例2B所:fe述之方法’將N-(三·敍丁氧基碳基 )-DL-纈胺酸甲基酯轉變為所需之本標題化合物。 鏡像異構上純（RWN^N1-三甲基-丁烷·i，2•二胺氫氣酸鹽 (III.3.a)之製備係使用D-纈胺酸當做起始材料。 I.考貫化例2D·——U - 一曱基-3·笨基-丙烧·ι·2 -二胺鱼氣 酸鹽ΠΙΙ.4) 自DL·苯丙胺酸製備Ν-(三敛丁氧基幾基）_DL-丙 胺酸甲基酯，係使用標準化之製備技術。使用一種類似參 考實施例2B所描述之方法，將N-(上·敍丁氧基幾基 )-DL-丙胺酸曱基轉變為所需之本標題化合物。 ------------裝--- 、意事*再嗔寫本頁) il. ..---線· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公茇） 46 Ϊ280242 A7 B7 經濟部智慧財產局員工消費合作社印製 _ 41五、發明說明（） M·實施例二（-S w7」#/—-二甲基·丙烷· u · -1胺1氣酸 藶 ΠΙΙ.5) 自L-丙胺酸製備2-(S)-[N-(三級（价小丁氧基羰基）胺基] 丙酸，係依據參考文獻（Chakravarty et al，J. Med. Chem 1989,第1886頁）所描述之方法。於室溫下，一個由2.62克之 醛、2.47克之二甲基胺氫氣酸、1.99克之乙酸鈉及1,43克之 氰基溴化氫鈉溶於45毫升曱醇（45毫升）所構成的混合物被 攪拌18小時。將反應混合物溶解於醋酸乙酯中，並以水沖 洗。有機層以乾燥（MgS04)沖洗且抽氣移除溶劑，產生一 種黏稠之油，該油溶解在二氣甲烷中，以檸檬酸萃取，再 以氫氧化鈉驗化，並以醋酸乙酯再度萃取。有機層於抽氣 下還原，產生二甲基胺之衍生物，其為一種白色固體（586 亳克）。 在室溫下，於此化合物（366毫克）中添加一個溶於5.5 毫升的環氧己烷内之4.0M氣化氫溶液。攪拌30分鐘之後， 於抽氣下移除揮發物，產生所需之本標題化合物，其為一 種黏稠之油（313毫克）。 I考實施例2F. (RWW-二甲基-丙烷-1,2·二胺ϋ f醅 鹽（ιιι·6、 自D-丙胺酸甲基（Me)酯氫氣酸製備2-(R)-[N-(三級 (化ri)· 丁氧基羰基）胺基]丙醛，係依據參考文獻 (Chakravarty et al，J_ Med. Chem 1989，ρ·1886)所描述之方 法。一個溶於250毫升曱醇之由該醛（16.21克）、二甲基胺 氫氯酸（15.28克）、乙酸鈉（11.53克）及氰基溴化氫鈉（8.24克 (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） 47 1280242 經濟部智慧財產局員工消費合作社印製 Α7 Β7 五、發明說明（42) )所構成之混合物於室溫下被授拌18小時，並以醋酸（AC〇H) 保持酸驗值在6-7。將反應混合物溶解於醋酸乙酯中，並以 水沖洗。有機層以乾燥（MgSCU)沖洗且以抽氣移除溶劑， 產生一種黏稠之油’該油使用閃爍層析法純化產生二曱基 胺之衍生物，其為一種白色固體（10·81克）。 在室溫下，於3.17克之此化合物中添加一個溶於2〇毫 升環氧己烧内之4.0Μ氣化氫溶液。攪拌1小時之後，於抽 氣下移除揮發物，產生所需之本標題化合物，其為一種黏 稠之油（2.79克）。 參考實施例2G· (S)-2 -胺基·3·二甲某-丙烧-1-醇氫氣酸鹽 αιι·7) 自D-絲胺酸-甲基酯氯化氫Ν-[(三·敍per…丁氧基）羰 基]-0_(三焱丁基二曱基曱矽烷基）-R-絲胺酸甲基酯 之製備係如參考文獻（H· W. Scheeren et al，J. Org. Chem. 1990,第3998頁）所描述。該化合物殄-78°C下以溶於曱笨之 二異丁基氫化鋁來處理歷時1.5小時，而產生對應之醛（H. W. Scheeren et al，J. Org· Chem· 1990, ρ·3998)。 一個由該醛（1·85克）、二曱基胺氯化氫（1.61克）、乙酸 鈉（1·21克）及氰基溴化氫鈉（0·83克）所構成之混合物於室 溫下於甲醇（55毫升）内被攪拌歷時24小時。水性混合物生 成一曱基胺衍生物。此衍生物被溶於二。惡院内，且對之添 加以一個配於二噁烷内之4.0 Μ鹽酸溶液，且混合物被攪拌 歷時20分鐘。於抽氣下濃縮混合物而生成粗製的所欲標題 化合物，有如一個白色固體。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 48 -----------裝--------訂—-----·線 (請先Κ讀背面之注意事項再填寫本頁)Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1280242 A7 ___ B7__ 37 p five, invention description () stupid formic acid. Reductive cyclization is the use of sodium borohydride (J_ Med. Chem. 1987, p. 843) to give the desired title compound. NMR 'd6-DMSO' 14·44 (1 Η, broad peak, s), 8.55 (lH, d), 8.48 (lH, dd), 8.42 (lH, dd), 8.23 (lH, d), 8.1 (M. Preparation of 04(2H,m), 7.86(lH,dd)',4.02(3H,s) 〇MH+ @305 3-methoxy-p-benzo[a]morphine-11·carboxylic acid (II.34) In a similar manner, starting from 5-aminonaphthalene-2-sulfonic acid (commercially available). NMR, d6-DMSO, 14.60 (1H, broad, s), 8.94 (lH, d ), 8.51 (2H, d), 8.23 (lH, d), 8.10-7.96 (2H, m), 7.67 (lH, d), 7.55 (lH.dd), 3.99 (3H, s). MH+ @305 t Test implementation of AIR._2^ΙΙ·4·A-oxygen---en Morphine-π·carboxylic acid (11.35, one consisting of 4-decyloxy-bromo-[a]morphine-indole carboxylic acid (Π1) (1 〇〇mg) and a mixture of bromine (5 drops) were stirred at room temperature for 3 days. The reaction mixture was reduced under suction and the desired compound was separated by scintillation chromatography ( 25 mg) MS MH+ @383/385 (1 : 1) NMR, CDC13, 14.47 (1H, broad, s), 8 86 (1H d), 8 33 (1H d), 7.95 (lH, t), 7.78 (lH, d), 6.97 (lH, d), 6.12 (lH, d), 5.75 (lH, d), 3.94 (3H, s). Reference Example: LX:--Methoxy-benzopyrenequinone·11-dione acid (11.36) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) --- -------I -------- order --------- line (please read the note on the back and fill out this page) 1280242 A7 &quot; --- B7 ___ five , invention description (38) (please read the note on the back and then fill out this page) 2-Amino-6-methoxy-3-nitro- benzo[a] morphine-carboxylic acid decyl ester preparation 'The method described in a similar reference (Kim et ai j Med. Chem. 1993, p. 23335) is used. The hydrolysis reaction of methyl ester is carried out in refluxing ethanol using potassium hydroxide for 2 hours. 2, Amino-6 methoxy-3-nitro-absuccinic acid. Hydrogenation of the nitro group at a hydrogen pressure of 5 psi psi on a parr instrument on a palladium catalyst on carbon, in acetic acid / The water is carried out to produce 2,3-diamino-6-nonyloxy-benzoic acid. This product is reacted with 5-methoxy-[1,2]naphthoquinone as described in Reference Example 1A. The desired title compound is produced. NMR, d6-DMSO, 4.05 (3H, s), 4.10 (3H, s), 7.45 (1H, d), 7.78-7.82 (1H, m), 7.92 (lH, d), 8.03 (lH, d), 8·36·8·40(2Η, ηι) , 8.78(lH,d) The main compound example ιυ·_!_·_methoxy-8-methyl-mol #丨almorphine铋舲 (11.37 Preparation of 2,3-diamino-4-methyl benzate from 4-methyl-o-amine-based benzoic acid, according to the wisdom of the Ministry of Economic Affairs according to Rewcastl et al., J. Med. Chem. 1987, ρ·843 The method of printing the property bureau employee consumption cooperatives. The 2,3·diamino-4-mercaptobenzoic acid thus prepared is reacted with 5-methoxy-[1,2]naphthoquinone as described in Reference Example 1A to give the desired title compound. . NMR, d6-DMSO 2.97 (3H, s), 4.06 (3H, s), 7.50 (H), 7.85. , d), 8·45.8·50 (2Η, πι), 8.57 (lH, d). Odor Example IV·9-Argon 4·甲气基·笨# Μ啡听_ (ΙΙ.38) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) Factory 44 - 1280242 A7 B7 39 V. INSTRUCTIONS (5) The preparation of chloro-3-nitro-o-aminobenzoic acid is based on the method described by Flippin et al (Biorg. Med. Chem. Letts 1996, p. 477). The hydrogenation of the compound was carried out on a palladium instrument at a hydrogen pressure of 50 psi on a palladium on carbon catalyst in acetic acid/water for 2 hours to yield 2,3-diamino-5- Gas - stupid formic acid. This product was reacted with 5-methoxy-[uj naphthoquinone as described in Reference Example 1A to give the desired title compound. NMR, d6-DMSO, 4.05 (3H, s), 7.48 (1H, d), 7.82-7.86 (1H, m), 7.92 (1H, d), 8.30 (lH, d), 8.48 (lH, d), 8.54 (lH, d), 8.68 (lH, d) ' 14.1 (1H, broad peak). Rabbit test Example 2: Preparation of compound having the general formula (III) i Test Example 2A. 4-Aza-DL- leucine methyl ester gas. η Saturated with anhydrous hydrogenated gas 150 ml Methanol. To the methanol, 4.86 g of 4-aza-DL·decyl leucine (commercially available) was added, and then the reaction mixture was stirred at room temperature overnight. The solvent was removed by suction and the title compound was obtained (quantitative yield). Example 2 W. W,7-dimethyl-butane-1,2-dioxi[III.2, Ministry of Economics, Intellectual Property The preparation of N-(tris(ier...butoxycarbonyl)-2.aminobutyric acid methyl ester by the Bureau of Staff Consumer Cooperatives is described in the reference (J. Med. Chem. 1989, p. 1886). The compound was treated with diisobutylaluminum hydride in toluene at -78 °C for 1.5 hours to give the corresponding aldehyde (for preparation: see: h. W. Scheeren et al, J. 〇rg. Chem · 1990, ρ·3998). At room temperature, 1.85 g of the aldehyde dissolved in methanol, 1.61 g of dinonylamine hydrogenation, 1.21 g of sodium acetate and 0.83 g of cyano bromide 45 ---- -------I ^ - II (Please read the note on the back and fill out this page) This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280242 A7 B7 Ministry of Economics Printed by the Bureau of Property and Staff of the Property Bureau, 40. Inventions () The mixture of hydrogen peroxide was mixed for 24 hours. The acid value was adjusted to 6-7 using acetic acid and continued. It is monitored during the reaction. The reaction mixture is concentrated under suction. Then the residue is dissolved in ethyl acetate and rinsed with water. The organic layer is washed with dry (MgS〇4) and pumped to remove solvent. A colorless oil which is purified by flash chromatography to give the desired dimethylamine derivative as a pale oil (0.56 g). (2 liters) of the 气m gasification of the hydrogen solution, and then the reaction mixture was stirred for 90 minutes. The reaction mixture was concentrated under suction to give the desired title compound as a pale solid ( Quantitative yield. I - Test Example 2C'.__3A^, A^-trimethyl-butane d·2·II II argonate (III.3) Preparation of N from DL·proline - (Sanxu, such as butoxycarbonyl) &lt; DL • proline methyl ester, using standardized preparation techniques. Then use a method similar to Reference &amp; Example 2B: Fe described 'N-(三· Conversion of the sodium salt of s-butoxycarbonyl)-DL-proline to the desired title compound. Mirror-isolated pure (RWN^N1-trimethyl-butyl) The preparation of alkane i,2•diamine hydrogenate (III.3.a) uses D-proline as a starting material. I. Test Example 2D·——U - a thiol-3· Stupid-acrylic acid·ι·2-diamine fish acid salt ΠΙΙ.4) Preparation of Ν-(three-butoxybutoxyl)-DL-alanine methyl ester from DL·phenylalanine, prepared by standardization The N-(super-s-butoxy)-DL-alanine thiol group was converted to the desired title compound using a procedure analogous to that described in Reference Example 2B. ------------Installation---, Ideas* and then write this page) il. ..---Line · This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 茇) 46 Ϊ280242 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Print _ 41 V. Inventions () M. Example 2 (-S w7)#/--Dimethyl·propane·u · -1 Amine 1 gas bismuth. 5) Preparation of 2-(S)-[N-(tertiary (butoxybutoxycarbonyl)amino)propionic acid from L-alanine, according to the reference (Chakravarty et al, J. Med. Chem 1989, p. 1886. The method described is 2.62 g of aldehyde, 2.47 g of dimethylamine hydrogen acid, 1.99 g of sodium acetate and 1,43 g of cyanohydrobromide at room temperature. The mixture of sodium dissolved in 45 ml of decyl alcohol (45 ml) was stirred for 18 hours. The reaction mixture was dissolved in ethyl acetate and washed with water. The organic layer was washed with dry (MgS04) and solvent was removed. Producing a viscous oil which is dissolved in di-methane, extracted with citric acid, tested with sodium hydroxide, and extracted again with ethyl acetate. The organic layer is reduced under suction to produce a methylamine derivative which is a white solid (586 gram). A 4.0 M hydrogenation solution dissolved in 5.5 ml of epoxy hexane is added to this compound (366 mg) at room temperature. After stirring for 30 minutes, the volatiles were removed in vacuo to give the desired title compound as a viscous oil (313 mg). I. Example 2F. (RWW-dimethyl-propane-1 ,2·diamine ϋ f醅 salt (ιιι·6, from D-alanine methyl (Me) ester hydrogen acid to prepare 2-(R)-[N-(tris(r) ri)·butoxycarbonyl) Amino]propanal is based on the method described in the reference (Chakravarty et al, J_ Med. Chem 1989, ρ 1886). One aldehyde (16.21 g), dimethylamine dissolved in 250 ml of sterol Hydrochloric acid (15.28g), sodium acetate (11.53g) and sodium cyanohydrobromide (8.24g (please read the back note first and then fill out this page) Binding: This paper scale applies to China National Standard (CNS) A4 Specifications (210 X 297 mm) 47 1280242 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed Α7 Β7 5, invention description (42)) The mixture was stirred at room temperature for 18 hours, and the acid value was maintained at 6-7 with acetic acid (AC〇H). The reaction mixture was dissolved in ethyl acetate and rinsed with water. The organic layer was dried (MgSCU) Rinse and remove the solvent by pumping to produce a viscous oil which was purified by flash chromatography to give the dimethylamine derivative as a white solid (10.81 g). To a solution of 3.17 g of this compound was added a 4.0 Torr hydrogen sulfide solution dissolved in 2 liters of epoxy hexane at room temperature. After stirring for 1 h, the title compound was obtained as a viscous oil (2.79 g). Reference Example 2G·(S)-2-Amino-3·Dimethyl-propan-1-ol Hydrogenate αιι·7) From D-serine-methyl ester hydrogen chloride-[(3· Preparation of per(butoxy)carbonyl]-0-(trimethylene butyl decyl decyl)-R-serine methyl ester is described in the literature (H. W. Scheeren et al, J. Org) Chem. 1990, p. 3998). The compound was treated with bismuth diisobutylaluminum hydride at -78 °C for 1.5 hours to give the corresponding aldehyde (H. W. Scheeren et al, J. Org Chem. 1990, ρ. 3998). a mixture of the aldehyde (1·85 g), dinonylamine hydrogen chloride (1.61 g), sodium acetate (1. 21 g) and sodium cyano hydrogen bromide (0·83 g) at room temperature It was stirred in methanol (55 ml) for 24 hours. The aqueous mixture produces a monodecylamine derivative. This derivative is dissolved in two. In the hospital, a 4.0 Μ hydrochloric acid solution in dioxane was added and the mixture was stirred for 20 minutes. The mixture is concentrated under suction to give the crude title compound as a white solid. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 48 -----------Installation--------Set-------Line ( Please read the notes on the back and fill out this page.)

1280242 A7 B7 經濟部智慧財產局員工消費合作社印製 43五、發明說明（） 差1.考實施例2H:_g_(.g上胺基二甲某-丁烷-2fSV醇1氯酸 鹽（ΙΙΙ·8) 將氣化氫氣體打氣通入一個溶於甲醇（5〇毫升）之d-酥 胺酸（20克）溶液中。所產生之溶液於室溫下攪拌5小時，並 接而於抽氣下被還原而產生D-酥胺酸甲基酯氣化氫，其為 一種白色固體（定量化之產率）。以溶於乙醯胯加上三乙基 胺之二-三，敍如叫丁基二碳酸酯來處理而產生Ν-(三.敎 (^/•小丁氧基羰基）-D-酥胺酸甲基酯。此化合物以溶於二氣 甲烷之三焱丁基二甲基甲矽烷基氣來處理而產生對 應之受TBDMS保護的醇。 該化合物於-78t：下以溶於甲苯之二異丁基氫化鋁來 處理歷時1.5小時，而產生對應之醛（製備方法參閱：h. w. Scheeren et al，J· Org· Chem· 1990, ρ·3998)。還原性胺基化 反應之進行係如參考貫施例2 G所描述，而產生對應之二曱 基胺基衍生物。去保護作用係如參考實施例2G所描述者， 使用溶於環氧己烷之4.0Μ HC1，而產生本標題化合物，其 為一種金色之油。 委考實施例21· 3-胺基-4·二甲基胺某·ι·醇氮氮酸鹽 (111.9) 以溶於曱醇之氯化氫氣體處理DL-高絲胺酸，產生對 應之内酯。以溶於二氯甲烷之三·敍丁基二曱基曱矽 烷基氣處理，產生對應之受三焱…丁氧基羰基保護的 衍生物。該化合物以溶於曱苯之二異丁基氫化鋁處理，係 於-78°C下歷時4小時，產生對應之鄰位羥基内醚（lactol)( (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） 49 1280242 經濟部智慧財產局員工消費合作社印製 A7 B7 44 - 五、發明說明（）1280242 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed 43 V. Inventions () Poor 1. Test Example 2H: _g_(.g-amino-dimethyl-butane-2fSV alcohol monochlorate (ΙΙΙ 8) Gasification of hydrogen gas into a solution of d-lysin (20 g) dissolved in methanol (5 ml). The resulting solution was stirred at room temperature for 5 hours and then pumped. It is reduced under gas to produce hydrogenated D-succinic acid methyl ester, which is a white solid (quantitative yield). It is dissolved in acetonitrile plus triethylamine. It is called butyl dicarbonate to be treated to produce Ν-(三.敎(^/•小丁oxycarbonyl)-D-chymidine methyl ester. This compound is dissolved in di-methane methane. Methyl formazan gas is treated to produce a corresponding TBDMS protected alcohol. The compound is treated with diisobutylaluminum hydride in toluene at -78t: for 1.5 hours to produce the corresponding aldehyde (preparation method) See: hw Scheeren et al, J. Org Chem. 1990, ρ·3998). The reductive amination reaction is carried out as described with reference to Example 2 G. The corresponding dimercaptoamine derivative is produced. Deprotection is carried out as described in Reference Example 2G using 4.0 Μ HCl in hexane to give the title compound as a gold oil. Test Example 21· 3-Amino-4·dimethylamine ι·Alcohol Nitrosate (111.9) DL-homoserine was treated with hydrogen chloride gas dissolved in decyl alcohol to produce the corresponding lactone. Treatment with tris-butylidene hydrazinyl methylene chloride in methylene chloride to give a corresponding derivative protected by tris-butyloxycarbonyl. This compound is diisobutylaluminum hydride hydride dissolved in toluene. The treatment is carried out at -78 ° C for 4 hours to produce the corresponding ortho-hydroxyl ether (lactol) ((Please read the back note first and then fill out this page) Binding · This paper scale applies to China National Standard (CNS) A4 size (210 X 297 mm) 49 1280242 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 44 - V. Invention description ()

製備方法參閱· H. W. Scheeren et al5 J. 〇% chenL· 199CK 第3998頁）。還原胺基化反應之進行，係如同參考實施例2G 所描述，藉此產生對應之二曱基胺基之衍生物。去保護作 用係使用溶於環氧己烷之4·0Μ氯化氫（HC1)，其如同參考 實施例2G所描述，藉此產生所欲之本標題化合物。 I考.實施例2J._k甲基-3-01V胺基-吡呔啶遗葡醅轉 (ΠΙΛΟ) 以溶於三焱如叫·丁醇（5毫升）内之三焱和⑺丁基二碳 酸鹽（1 _06克）來逐滴地處理一個溶於三錢…叫·丁醇（1 〇毫 升）及1 ·0Ν乳氧化舞溶液（4·8毫升）内之3R+)小苯基小胺 基吼咯啶（可由商業購得，847毫克）之溶液《於ι·5小時之 後’以抽氣移除三·錄丁醇，並將溶解於醋酸乙酯中 之殘餘物以水沖洗、乾燥（MgS〇4)且抽氣移除溶劑，產生 所欲之受3N-三·敍⑼叫-丁氧基羰基保護的衍生物，其為一 種無色膠體（1.26克）。 一個溶於四氫呋喃之受3N·三焱丁氧基羰基保 護的衍生物（800毫克）的溶液在1個大氣壓力之氫氣下，在 氫氧化鈀催化劑之存在下被攪拌歷時24小時。該反應混合 物通過赛力特矽藻土過濾，抽氣移除溶劑，產生所欲之3Ν· 三敍和叫-丁氧基羰基-3-(R)-胺基。比咯啶（定量化之產率） 〇 將溶於水之37%甲醛溶液（0.52毫升）及溴化氫鈉（271 毫克）添加至一個溶於甲醇（10毫升）之3N-三·敍丁氧 基幾基-3-(R)-胺基吼洛咬（437毫克）的溶液中。該反應混合 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 50 -----------裝--------tr-·丨 j----^—線 {請先閱讀背面之注意事項再填寫本頁) 1280242 經濟部智慧財產局員工消費合作社印製 A7 45 五、發明說明（） 物於室溫下被攪拌24小時，然後抽氣予以還原。將殘餘物 &gt;谷解於氣仿中’以濃鹽水及碳酸氫鈉溶液沖洗，以乾燥之 (MgS04)沖洗且抽氣移除溶劑，產生所欲之3N-三凝&quot;err)-丁氧基羰基-3-(R)·胺基·1-曱基nt咯啶，其為一種膠體（390 毫克）。去保護作用係使用溶於琿氧己烷之4.0M氣化氫 (HC1)，其如同上文所述，藉此產生所欲之本標題化合物。 1考實施例2K· 〜，兄卞^-四甲某-雨烷-丨丄弘三脍三 氫氮酸（in.ιη 於冰冷之亞硫醯氯（35毫升）中，逐滴地添加丨，3·二（二 甲基胺基）-丙烷-2-醇（4.91克，33.58毫莫耳，其為可由商業 上購待），並予以授拌歷時45分鐘。俟添加完成後，另外再 授拌該混合物4個小時。於減壓下移除過量之亞硫酿氣，產 生8 · 9克之一種乳脂狀固體，其為氫氣酸鹽。自由驗係得自 將溶於甲苯（18毫升）之氫氯酸鹽的一個懸浮液，以溶於水 (14毫升）之氫氧化鈉（24當量（eq))處理30分鐘。移除有機層 ’以乾燥之（MgSCU)沖洗、過濾且抽氣移除溶劑，產生2· 氯-N，N，N〗，N丨-四甲基丙烷·ι，3·二胺，其為一種黃色液體。 以酞醯亞胺鉀（1·98克，1〇·68毫莫耳）處理一個溶於甲 笨（14毫升）之2·氯·Ν，Ν，Ν丨，四曱基丙烷·1&gt;3•二胺（1·6克 ，9.71毫莫耳）溶液。於一種惰性氣體下，攪拌該溶液並加 熱予以迴流18小時，冷卻至周圍環境之溫度，並於減壓下 移除溶劑，產生一米黃色之固體，由二乙醚中再結晶可產 生一種淡黃褐色之固體（1.85克）。以聯胺水合物（〇·22毫升 ，6·93毫莫耳）來處理一個以〗〇毫升之乙醇溶解〇 953克之此 ------------^裝 i· Γ4先閱tt背¾之达意事項再填寫本頁) tr-· _張尺度適用中㈣家標準（CNS)A4規格（210 X 297公茇） • 51 1280242 A7 B7 五、發明說明（） 固體（3.46毫莫耳）所形成的溶液，並將混合物於環溫下攪 掉歷時18小時。經由過濾移除懸浮液，再將過濾物以2毫升 之2M氫氯酸予以酸化，以抽氣移除溶劑，產生產物為一種 乳脂狀固體（795毫克）。熔點126.5-128t，MIT432。 I考實施例3 :具有通式（IV)之化合物的繁# 支考實施例3A·_4-曱氧基-笨并|^1啡畊_11_羧酸甲篡西§ (ιν· η 以逐滴地添加乙酿氣（4.6毫升）至一個溶於甲醇（5〇毫 升）之4-甲氧基-苯并[a]啡啡-11-羧酸（Π·ι，參閱參考實施例 ΙΑ，4.9克）懸浮液中。該混合物被加熱並予以迴流4小時。 於抽氣下移除揮發物，產生本標題化合物，其為一種深色 固體（定量性之產率）。 NMR，d6-DMSO， 8.76(lH，d)，8.41(2H，d)，8.26(lH，d) ，8.00(lH，t)，7.90(lH，d)，7.78(lH，t)，7.43(1 H，d)，4.08(3H,s) ，4.03(3H，s) 〇 參考f施例3B. 笨并丨al啡唞·11-羧酸曱基酯（IV.2) 笨并[a]啡啩·11-羧酸（II.20)及苯并[a]啡阱-8-羧酸（885 毫克）之混合物，係製備如上文參考實施例1L所述參閱，將 之加熱至迴流在40毫升之甲醇及920μί之乙醯氣之混合物 中，歷時90分鐘。然後將反應混合物慢慢冷卻，產生本標 題化合物，其為一個單一之異構物，係以過濾法收集（377 毫克）。 NMR，d6-DMSO，9·53·9·55(1Η，πι)，9.06(lH，d)，8.57(lH，d) ，8.47(lH，d)，8.35(lH，d)，8-10-8.11(lH，m)，8.09-8.02(lH，m) 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W讀背面之注意事項再填寫本頁) 訂： “線- 經濟部智慧財產局員工消費合作社印製 1280242 A7 B7 47 ‘五、發明說明（） ，7.95-8.01(2H，m)，4.21(3H，s)。 皇.考實施例_3C.——!：_ 二甲基胺基-策并1^1啡毗·Η·羧酸甲 (ΐν·3)及？二：^_,平基胺基·笨并『al啡哄-11·跆酸曱基酯 (IV.4、 一個溶於Ν，Ν-二甲基甲醯胺（1〇毫升）内之胺基_苯并 [a]啡讲-11-叛酸（II.29)相對於3-胺基-笨并[a]啡喷_ 11 ·叛酸 (II.30)為4 ·· 1的混合物（48毫克），係得自參考實施例1 n， 於此混合物中添加曱基碘（0·5毫升）及二異丙基乙基胺（2 0 耄升）^該反應混合物被加熱至100°C，歷時4小時。將混合 物冷卻，以醋酸乙酯稀釋，以水沖洗 '乾燥（MgS〇4)且抽 氣移除溶劑，產生本標題化合物，其為一種紅色固體（29 亳克）。於進一步之化學改質後將之純化。 參-考實施例3D· 10-氟4-甲氡基-笨#哄-11 - #酸甲基 酯（IV.5) 經濟部智慧財產局員工消費合作社印製 2·胺基-6-氟-3-硝基笨甲酸曱酯之製備係依據參考文 獻（J· Med· Chem· 1993, p.2335)。於曱醇中在碳上紀上的氩 化作用產生2,3 -二胺基-6-氟·笨甲酸曱基醋。該化合物與5· 曱氧基-[1，2]-萘醍於含有濃鹽酸之冷乙醇酸中反應，產生 所欲之本標題化合物。 NMR，CDC13， 4.08(3H，s)，4.20(3H，s)，7.20(lH，d)， 7·65-7·75(2Η，πι)，7.92(lH，d)，8.35(lH，dd)，8.53(lH，d)， 8.91(lH，d) MS m/e 337 (MH+，100%) I考實施例3E. 4-甲氣基-10-甲基胺基·笨# ral,呼-ii 53 ------------- (清先B2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） 1280242 經濟部智慧財產局員工消費合作社印製 A? Β7 五、發明說明（）For the preparation method, see H. W. Scheeren et al 5 J. 〇% chenL· 199CK, p. 3998). The reductive amination reaction is carried out as described in Reference Example 2G, whereby a corresponding derivative of the dimethylamino group is produced. Deprotection is carried out using 4,0 Torr of hydrogen chloride (HC1) dissolved in hexanes as described in Reference Example 2G to give the desired title compound. I test. Example 2 J._k methyl-3-01V amino-pyridinium ruthenium (ΠΙΛΟ) dissolved in triterpenoids such as butanol (5 ml) in the triterpene and (7) butyl Carbonate (1 _06 g) to process a 3R+) small phenylamine which is dissolved in three money... called butanol (1 〇 ml) and 1 · 0 Ν milk oxidation dance solution (4·8 ml) A solution of pyridoxine (commercially available, 847 mg) was removed after 5 hours of extraction by venting with a gas, and the residue dissolved in ethyl acetate was rinsed with water and dried. (MgS〇4) and evacuation of the solvent gave the desired 3N-tris(9)-butoxycarbonyl protected derivative as a colorless colloid (1.26 g). A solution of a 3N-trimethylbutoxycarbonyl-protected derivative (800 mg) dissolved in tetrahydrofuran was stirred under a hydrogen atmosphere at atmospheric pressure for 24 hours in the presence of a palladium hydroxide catalyst. The reaction mixture was filtered through Celite, and the solvent was removed by suction to give the desired mixture of &lt;RTI ID=0.0&gt;&gt; Birolidine (quantitative yield) 添加 Add 37% formaldehyde solution (0.52 ml) and sodium hydrogen bromide (271 mg) dissolved in water to a 3N-trisium sulphate dissolved in methanol (10 ml) A solution of oxymethyl-3-(R)-aminoindole (437 mg). The reaction is mixed with the paper size applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 50 -----------Installation--------tr-·丨j-- --^—Line{Please read the notes on the back and fill in this page.) 1280242 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 45 V. Invention Description () The material is stirred at room temperature for 24 hours, then pumped Restore it. The residue &gt; gluten is dissolved in a gas imitation 'washed with concentrated brine and sodium bicarbonate solution, rinsed with dry (MgS04) and pumped to remove the solvent to produce the desired 3N-three coagulation &quot;err)- Oxycarbonyl-3-(R).amino-l-decyl nt-r-cyclopyridine, which is a colloid (390 mg). Deprotection is carried out using 4.0 M hydrogenated hydrogen (HC1) dissolved in hexanes as described above to give the desired title compound. 1 test example 2K·~, brother 卞^-four-a-rain-halo-three-trihydrogen acid (in.ιη in ice-cold sulfoxide (35 ml), add 丨 dropwise 3, bis(dimethylamino)-propan-2-ol (4.91 g, 33.58 mmol, commercially available) and allowed to mix for 45 minutes. After the addition is completed, another The mixture was stirred for 4 hours. Excess sulphurous gas was removed under reduced pressure to give 8.9 g of a creamy solid, which was a hydrogen sulphate. Freely obtained from toluene (18 ml) A suspension of the hydrochloride salt is treated with sodium hydroxide (24 equivalents (eq)) dissolved in water (14 ml) for 30 minutes. The organic layer is removed. The dried (MgSCU) is rinsed, filtered and pumped. The solvent is removed to give 2·chloro-N,N,N, N丨-tetramethylpropane·ι,3·diamine, which is a yellow liquid. Potassium imide (1·98 g, 1 〇·68 mM) Treat a solution of 2·chloro·Ν, Ν, Ν丨, tetradecylpropane·1&gt;3•diamine (1·6 g, 9.71 mmol) dissolved in a stupid (14 ml) Solution. In an inert Under the solution, the solution was stirred and heated to reflux for 18 hours, cooled to ambient temperature, and the solvent was removed under reduced pressure to give a beige solid which crystallised from diethyl ether to give a pale tan solid. (1.85 g). Treated with hydrazine hydrate (〇·22 ml, 6.93 mmol) with 〇 〇 ml of ethanol 〇 953 g ------------^ Install i· Γ4 first read tt back 3⁄4 and then fill out this page) tr-· _ Zhang scale applicable (four) home standard (CNS) A4 specification (210 X 297 mm) • 51 1280242 A7 B7 V. Invention description ( A solid (3.46 mmol) solution was formed and the mixture was stirred at ambient temperature for 18 hours. The suspension was removed via filtration and the filtrate was acidified with 2 mL of &lt;RTI ID=0.0&gt;&gt; Melting point 126.5-128t, MIT432. I test Example 3: A compound having the compound of the formula (IV). Example 3A·_4-曱-oxy-stupid|^1 cultivating _11_carboxylic acid carbaryl § (ιν·η Ethyl alcohol (4.6 ml) was added dropwise to a 4-methoxy-benzo[a]morphine-11-carboxylic acid (Π·ι, dissolved in methanol (5 mL), see Reference ExampleΙΑ The mixture is heated and refluxed for 4 hours. The volatiles are removed in vacuo to give the title compound as a dark solid (yield). NMR, d6- DMSO, 8.76 (lH, d), 8.41 (2H, d), 8.26 (lH, d), 8.00 (lH, t), 7.90 (lH, d), 7.78 (lH, t), 7.43 (1 H, d ), 4.08 (3H, s), 4.03 (3H, s) 〇 reference f Example 3B. Stupid and 丨alphinyl 11-carboxylic acid decyl ester (IV.2) stupid [a] phlegm · 11 - a mixture of carboxylic acid (II.20) and benzo[a]pyrano-8-carboxylic acid (885 mg) prepared as described above with reference to Example 1L, heated to reflux in 40 mL of methanol And a mixture of 920 μί of acetonitrile for 90 minutes. The reaction mixture is then slowly cooled to give the title compound. , which is a single isomer, collected by filtration (377 mg). NMR, d6-DMSO, 9·53·9·55 (1 Η, πι), 9.06 (lH, d), 8.57 (lH, d) , 8.47 (lH, d), 8.35 (lH, d), 8-10-8.11 (lH, m), 8.09-8.02 (lH, m) This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) -----------Installation - (Please read the note on the back and fill out this page) Order: "Line - Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1280242 A7 B7 47 '5, invention description (), 7.95-8.01 (2H, m), 4.21 (3H, s). Emperor. Example _3C.——!: _ dimethylamino-- and 1^1 brown毗···················································································· Amino-benzo[a]morphine-11-rebel (II.29) in dimethylformamide (1 ml) relative to 3-amino-p-[a]- morphine _ 11 A mixture of tickic acid (II.30) of 4··1 (48 mg) was obtained from Reference Example 1 n, and thiol iodine (0.5 ml) and diisopropylethylamine were added to the mixture. (2 0 soar) ^The The mixture is heated to 100 ° C for 4 hours. The mixture is cooled, diluted with ethyl acetate, washed with water &lt;RTI ID=0.0&gt; (29 grams). It is purified after further chemical modification. Reference Example 3D· 10-Fluoro-4-Minyl-Stupid #哄-11 - #Acid methyl ester (IV.5) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 2·Amino-6-Fluorine The preparation of -3-nitro-p-carboxylate is based on the reference (J. Med. Chem. 1993, p. 2335). The argonization in the carbon on the sterol produces 2,3-diamino-6-fluoro-p-formate decyl vinegar. This compound is reacted with 5· methoxy-[1,2]-naphthoquinone in cold glycolic acid containing concentrated hydrochloric acid to give the desired compound. NMR, CDC13, 4.08 (3H, s), 4.20 (3H, s), 7.20 (1H, d), 7·65-7·75 (2 Η, πι), 7.92 (lH, d), 8.35 (lH, dd ), 8.53 (lH, d), 8.91 (lH, d) MS m/e 337 (MH+, 100%) I test example 3E. 4-methyl-l--10-methylamino group stupid #ral, call -ii 53 ------------- (Notes on the back of B2 read the next page) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1280242 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed A? Β7 V. Invention Description ()

叛酸甲基酯（IV.M 10-氟4-曱氧基-苯并[a]啡啡·羧酸甲基酯（115)(1〇〇 亳克）及溶於四氫呋喃之2.0Μ曱基胺溶液的一個混合物，於 室溫下被攪拌歷時18小時。然後抽氣將溶劑移除，產生所 欲之本標題化合物之粗產物，其芩一種橘色固體。 金考實施例3F. 10·胺皋-4·曱氡某-笑并丨叫呻畊」1私沪 曱墓酯（IV.7) 10-氟·4·甲氧基-苯并[a]啡畊-；11-羧酸甲基酯（IV 5) (466毫克）及溶於n，N-二甲基甲醯胺（1〇毫升）之疊氮化納 (900毫克）的一個混合物被加熱維持在9(rc，歷時18小時。 然後將該反應混合物冷卻，以水稀釋，再添加氫氧化鈉溶 液以產生一種棕色的沉澱物。此沉殺物經由過滤收集，並 以水、醚類沖洗，產生所欲之本標題化合物，其為一種黃 色固體（242亳克）。 NMR，CDC13，4.08(3H，s)，4.20(3H，s)，7.25(lH，d)， 7.70-7072(2H，m)，7.90(lH，d)，8.36(lH，d)，8.52(lH，d)， 8.85(lH，d) MS DCI/NH3 m/z 334 (MH+，100%) 實施例l :製備具有通式m之化合物 實施例1Α·4·甲氧基·苯并[a]啡畊-1卜羧酸（2_二τ基胺基· 乙基）·醯胺 一個由4·甲氧基·苯并[a]啡啡-1卜羧酸（π 1)(129毫克) 及1·1、羰基二咪唑（138毫克）所構成之混合物於室溫下被 攪拌於乾燥之Ν，Ν-二甲基甲醯胺（8亳升）中歷時4小時。於 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 54 ---01-------&gt; Μ----------------^-- (請先Mtt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 1280242 A7 --------- -__ …五、發明說明（49) 此混合物中添加N，N-二甲基乙烯二胺（可由商業上購得 )(〇·5毫升），然後於室溫下又再攪拌該反應混合物3〇分鐘。 再以抽氣將揮發物移除。殘餘物被溶解於二氣乙烷中，以 水沖洗、乾燥（MgSCU)且抽氣移除溶劑，產生粗產物。其 經由閃爍層析法（5〇/0甲醇溶於二氯甲烷中）純化，產生所欲 之本標題化合物，其為一種亮黃色固體〇2〇毫克）。 下列具有化學式（I)之化合物的製備，係以一種類似之 方法，其使用適合之具有化學式（II)之酸及具有化學式（ΠΙ) 之胺做為起始。 3- 甲氧基·苯并[a]啡哜羧酸（2-二甲基胺基·乙基醯胺 係製備自3-甲氧基-苯并[a]啡啡·u•羧酸（π·34)及N，N-二甲 基乙烯二胺； 2-甲氧基-笨并[a]啡啡·η·羧酸（2·二甲基胺基-乙基）·醯胺 係製備自2·曱氧基·笨并[a]啡畊“卜羧酸（π·33)&amp;ν，ν_二甲 基乙怫二胺； 4- 硝基-苯并[a]啡啡·η_羧酸（2-二甲基胺基·乙基）·醯胺係 製備自4-硝基·苯并⑷啡σ^η_羧酸（1127)與3•硝基·苯并⑷ 非丼羧酸（π·28)之混合物，及Ν，Ν•二甲基乙烯二胺，然 後使用閃爍層析法予以純化； 4·苄基氧·笨并[a]啡畊·η•羧酸（2•二曱基胺基_乙基）·醯胺 係製備自4-苄基氧-笨并[a]啡啡·u•羧酸（1113)及ν，ν•二甲 基乙烯二胺； 4-丙-2·炔基氧基·笨并[a]啡啡_u•羧酸（2•二甲基胺基·乙基 )-醯胺係製備自4·丙-2-炔基氧基·笨并[a]啡畊_丨卜羧酸 本紙張尺度適用中國國豕標準（CNS)A4規格（210 X 297公爱） 55 -1 ^· - I (請先IK讀背面之;it事項再填寫本頁) » ••線Oxyacid methyl ester (IV.M 10-fluoro-4-decyloxy-benzo[a]morphinecarboxylic acid methyl ester (115) (1 g) and 2.0 thiol in tetrahydrofuran A mixture of the amine solution was stirred at room temperature for 18 hours. The solvent was then removed to give the desired crude product of the title compound as an orange solid. Amine 皋-4·曱氡某-笑笑丨叫呻耕”1 Private Shanghai 曱Tomb ester (IV.7) 10-Fluoro-4 methoxy-benzo[a] cultivating-; 11-carboxylic acid A mixture of methyl ester (IV 5) (466 mg) and sodium azide (900 mg) dissolved in n,N-dimethylformamide (1 mL) was heated to maintain 9 (rc) over time. 18 hours. The reaction mixture is then cooled, diluted with water, and a sodium hydroxide solution is added to produce a brown precipitate. The precipitate is collected by filtration and rinsed with water or ether to give the desired title. Compound, a yellow solid (242 g). NMR, CDC13, 4.08 (3H, s), 4.20 (3H, s), 7.25 (1H, d), 7.70-7072 (2H, m), 7.90 (lH) , d), 8.36 (lH, d), 8.52 (lH, d), 8.85 (1H, d) MS DCI / NH3 m / z 334 (MH +, 100%) Example 1 : Preparation of compound of formula m Example 1 ···················· A carboxylic acid (2-di-tausylamino)ethylamine amide from 4 methoxy benzo[a]morphine-1 carboxylic acid (π 1) (129 mg) and 1·1 The mixture of carbonyldiimidazole (138 mg) was stirred at room temperature in a dry state, and Ν-dimethylformamide (8 liters) was allowed to stand for 4 hours. The Chinese national standard was applied to the paper scale ( CNS)A4 size (210 X 297 mm) 54 ---01-------&gt; Μ----------------^-- (Please first Mtt back Note: Please fill out this page again) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1280242 A7 --------- -__ ... five, invention description (49) N, N-dimethyl added to this mixture Ethylene diamine (commercially available) (〇 5 ml), and then the reaction mixture was stirred for a further 3 minutes at room temperature. The volatiles were removed by pumping. The residue was dissolved in 2 air. In the alkane, rinse with water, dry (MgSCU) and pump to remove the solvent to produce a crude product. Purification by the method (5 〇 /0 MeOH in methylene chloride) afforded the desired title compound as a bright yellow solid 〇 〇 〇 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 In a similar manner, it is initiated using an acid of the formula (II) and an amine of the formula (ΠΙ). 3-Methoxy-benzo[a]morphincarboxylic acid (2-dimethylamino)ethylguanamine is prepared from 3-methoxy-benzo[a]morphine·u•carboxylic acid ( π·34) and N,N-dimethylethylenediamine; 2-methoxy-benzo[a]morphine·η·carboxylic acid (2·dimethylamino-ethyl)·amide Prepared from 2·曱oxy·Bist and [a] cultivating ” carboxylic acid (π·33) &amp; ν, ν dimethyl dimethyl hydrazine diamine; 4- nitro-benzo[a] morphine · η-carboxylic acid (2-dimethylaminoethyl) ethylamine is prepared from 4-nitrobenzoyl (4) morphine σ^η-carboxylic acid (1127) and 3 • nitro·benzo (4) a mixture of non-indole carboxylic acids (π·28), and hydrazine, hydrazine dimethyl dimethyl diamine, which is then purified by scintillation chromatography; 4·benzyloxy· benzo[a] cultivating η·carboxyl The acid (2•didecylamino)ethylamine is prepared from 4-benzyloxy-p-benzo[a]morphine·u•carboxylic acid (1113) and ν,ν•dimethylethylene II. Amine; 4-propan-2-alkynyloxy) benzo[a]morphine-u•carboxylic acid (2•dimethylamino)ethyl)-guanamine is prepared from 4·prop-2-yne氧基 · 笨 并 [ a ] _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 4 specifications (210 X 297 public) 55 -1 ^· - I (Please read IK first on the back; it will fill in this page again) » •• Line

1280242 五、發明說明（ (II.14)及N，N-二曱基乙烯二胺； 3,4-二曱氧基·笨并[a]啡坪七·㈣(2•二甲基胺基-乙基)· 酿胺係衣備自3,4-一曱氧基-笨并⑷啡_七·護酸⑴·4)及 Ν，Ν-二甲基乙烯二胺； 4-乙氧基·笨并[a]㈣·u•㈣(2•二曱基胺基·乙基）·臨胺 係製備自4·乙氧基·笨并㈤啡味七·缓酸⑴⑴及Ν 二甲 基乙烯二胺； 4-異丁氧基-苯并[a]啡味·η•致酸（2·二甲基胺基·乙基卜酿 胺係製備自4·異丁氧基.苯并㈤邊酸(η 15)及ν，ν_ 二曱基乙烯二胺； 4-(4-亂-苯基氧）·笨并[a]啡味·u•叛酸（2·二曱基胺基-乙基 )-酿胺係製備自4-(4-氯-苯基氧）·笨并[輕^•幾酸 (11.16)及N，N-二曱基乙稀二胺； 心(2-甲氧基·乙氧基）·笨并㈤啡^竣酸（2•二甲基胺基_ 乙基）·酿胺係製備自心(2·曱氧基-乙氧基苯并[a]啡啡-11-羧酸（II.17)及N，N-二曱基乙烯二胺； [11-(2·一甲基胺基-乙基羰基）_苯并[a]啡畊_4·基氧]-醋酸 乙基酯係製備自4·乙氧基羰基曱氧基·笨并[a]啡畊羧 酸（Π·18)及N，N-二甲基乙烯二胺； 3·溴-4·羥基·笨并[a]啡阱-u•羧酸（2•二甲基胺基·乙基）·醯 胺係製備自3-溴·4·羥基-苯并[a]啡啩卜羧酸（π·31)及 Ν，Ν·二甲基乙烯二胺； 4-[2·(三浚加〜·丁基·二曱基·矽烷基氧）·乙氧基]·苯并㈤ 啡呼11-緩酸（2- 一甲基胺基-乙基）-酿胺係製備自4-[2-(三 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ----------I ^--------^ i --------^ (請先K讀背面之注意事項再填寫本頁)1280242 V. INSTRUCTIONS (II.14) and N,N-dimercapto ethylenediamine; 3,4-dimethoxyoxy] benzo[a] pentylene VII (4) (2•dimethylamino) -ethyl)· Amine-based coats are prepared from 3,4-monodecyloxy-stupid (4)-?-seven acid acids (1)·4) and hydrazine, hydrazine-dimethylethylenediamine; 4-ethoxyl · stupid [a] (four) · u • (four) (2 • dimercaptoamine · ethyl) · amines are prepared from 4 · ethoxy · stupid ( five ) narcissine seven · slow acid (1) (1) and Ν dimethyl Ethylenediamine; 4-isobutoxy-benzo[a]morphine·η•acid (2. dimethylamino) ethyl bromide is prepared from 4 · isobutoxy. benzo (5) Branic acid (η 15) and ν,ν_ dimercapto ethylene diamine; 4-(4-disorgano-phenyloxy)· stupid [a] morphine·u• tacrotic acid (2·didecylamino)- Ethyl)-bristamine is prepared from 4-(4-chloro-phenyloxy). stupid [light ^• acid (11.16) and N,N-dimercaptoethylenediamine; heart (2-A) Oxy-ethoxyl)·Bist (5)- 啡 竣 2 2 2 2 2 2 酿 酿 酿 酿 酿 酿 酿 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Phenyl-11-carboxylic acid (II.17) and N,N-dimercaptoethylenediamine; [11-(2·monomethylamino-ethylcarbonyl)_ Benzo[a]morphine_4·yloxy]-acetic acid ethyl ester was prepared from 4·ethoxycarbonyl decyloxy·stup [a] phenyl carboxylic acid (Π·18) and N,N- Dimethylethylenediamine; 3·Bromo-4·hydroxy·Bisto[a]morphine-u•carboxylic acid (2•dimethylaminoethyl)ethylamine is prepared from 3-bromo-4 ·Hydroxy-benzo[a]morphinic acid (π·31) and Ν,Ν·dimethylethylenediamine; 4-[2·(三浚加~·butyl·didecyl·decyl) Oxygen)·ethoxy]·benzo (5) morphine 11-acid (2-monomethylamino-ethyl)-bristamine is prepared from 4-[2-(three paper scales applicable to Chinese national standards ( CNS)A4 specification (210 X 297 mm) ----------I ^--------^ i --------^ (Please read the back of the K first Please fill out this page again)

經濟部智慧財產局員工消費合作社印製 56 1280242 經濟部智慧財產局員工消費合作社印製 A7 五、發明說明（51 ) ，敛小丁基-二甲基·矽烷基氧）-乙氧基]-苯并[a]啡畊-11-叛酸（IU9)及N，N-二甲基乙烯二胺； ‘甲基*笨并[a]啡啡-11-羧酸（2-二甲基胺基·乙基）-醯胺係 製備自仁甲基·笨并1&gt;]啡啡·11·羧酸（Π.2)及N，N-二曱基乙 烯二胺； 4·氣-笨并[a]啡哜·11β羧酸（2•二甲基胺基-乙基）_醯胺係製 備自4-氟-笨并[a]啡啩-u•羧酸（π·3)及Ν，Ν•二甲基乙烯二 胺； 心甲基續酿基·笨并[a]啡啡·11-羧酸（2-二甲基胺基-乙基）· 酿胺係製備自‘曱基磺醯基-笨并[a]啡哜-11-羧酸（II. 12)及 N，N-二甲基乙烯二胺； 4-溴-笨并[a]啡啡·n•羧酸（2_二曱基胺基-乙基&gt;醯胺係製 備自4-溴-笨并[a]啡啡_u •羧酸（π·5)及N，N•二甲基乙烯二 胺； 4-氰基-苯并[a]啡畊·羧酸（2_二甲基胺基-乙基）_酿胺係 製備自4-氰基·笨并[a]啡畊-u•羧酸（π·6)及N，N_:曱基乙 烯二胺； 3- 硝基·苯并[a]啡啡·η•羧酸（2_二曱基胺基-乙基）_醯胺係 製備自4-硝基-苯并[a]啡啡“卜羧酸（Ih27)與3·硝基-苯并㈤ 啡啡-11 -羧酸（11.28)之混合物，及n，N-二曱基乙烯二胺然後 使用閃爍層析法予以純化； 4- 甲磺醯基·笨并[a]啡啡·u_羧酸（2_二甲基胺基·乙基）_醯 胺係製備自4·甲磺醯基-苯并[a]啡啡_丨卜羧酸（π·8)及Ν，Ν· 二甲基乙烯二胺； 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -57 - ----1--------------1 ^--------—d· (請先閱讀背面之;i意事項再填寫本頁)Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 56 1280242 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing A7 V. Inventions (51), Condensation of Small Butyl-Dimethyl-decyl Oxygen)-Ethoxy]- Benzo[a]morphin-11-rebel (IU9) and N,N-dimethylethylenediamine; 'methyl* benzo[a]morphine-11-carboxylic acid (2-dimethylamine) Base ethyl)-guanamine is prepared from ketone methyl benzoate 1&gt;] morphine 11 carboxylic acid (Π.2) and N,N-dimercaptoethylenediamine; 4·gas-stupid [a] 哜 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 11 , Ν•Dimethylethylenediamine; Heart methyl sulphate, benzo[a] morphine, 11-carboxylic acid (2-dimethylamino-ethyl)·Acrylate is prepared from '曱基Sulfosyl- benzo[a] phenanthrene-11-carboxylic acid (II. 12) and N,N-dimethylethylenediamine; 4-bromo-p-benzo[a]morphine·n•carboxylic acid ( 2_didecylamino-ethyl&gt; guanamine is prepared from 4-bromo-p-benzo[a]morphine-u carboxylic acid (π·5) and N,N•dimethylethylenediamine; 4-cyano-benzo[a]morphine·carboxylic acid (2-dimethylamino) -ethyl) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ [a] morphine·η•carboxylic acid (2-didecylamino-ethyl)-decylamine is prepared from 4-nitro-benzo[a]morphine benzoic acid (Ih27) and 3· a mixture of nitro-benzo(penta)morphine-11-carboxylic acid (11.28) and n,N-dimercaptoethylenediamine are then purified by scintillation chromatography; 4-methylsulfonyl·stupid [a ]morphine·u_carboxylic acid (2-dimethylaminoethyl)ethylamine is prepared from 4·methylsulfonyl-benzo[a]morphine-indolecarboxylic acid (π·8) And Ν, Ν· dimethylethylene diamine; This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -57 - ----1----------- ---1 ^---------d· (Please read the back first; i will fill in this page again)

1280242 經濟部智慧財產局員工消費合作社印制衣 A7 五、發明說明（52) 4-氯-苯并[a]啡喷.u•缓酸（2_二曱基胺基-乙基）·酿胺係製 備自4-氣-笨并[a]啡喷_n•幾酸（π 7)及nn_二甲基乙稀二 胺； 4 a氮基-笨并[a]啡啡q丨·羧酸（2•二曱基胺基·乙基）_醯胺 係製備自4-疊氮基·笨并[a]啡啡_u•羧酸（Η·9)及Ν，Ν·二甲 基乙稀二胺； 11-(2甲基胺基·乙基羰基）·苯并[a]啡畊·4_羧酸甲基酯係製 備自苯并[a]啡啡-4，11·二羧酸‘甲基酯（ΙΙ·ΐ〇)及N，N-二甲 基乙烯二胺； 4·曱基胺磺醯基-笨并[a]啡啡_u_羧酸（2·二甲基胺基-乙基 )·醯胺；三氟乙酸鹽係製備自4_甲基胺磺醯基·苯并[a]啡畊 -11·羧酸（II.21)與3-甲基胺磺醯基-苯并[a]啡畊·u•羧酸 (11.22) 之混合物，及N，N_:甲基乙烯二胺。兩種異構物係 使用製備式高壓液態層析儀（HPLC)予以分離； 3·甲基胺磺醯基-笨并啡啡_1K羧酸（2·二甲基胺基-乙基 )-醯胺；三氟乙酸鹽係製備自4-甲基胺磺醯基_苯并[&amp;]啡畊 •11·羧酸（ΙΙ·21)與3·甲基胺磺醯基·笨并[a]啡啩·n•羧酸 (11.22) 之混合物，及N，N•二曱基乙烯二胺。兩種異構物係 使用製備式高壓液態層析儀（HPLC)予以分離； 4_二甲基胺橫酿基-苯并[a]啡啡-11·竣酸（2-二曱基胺基·乙 基）-醯胺；三氟乙酸鹽係製備自4-二甲基胺磺醯基.笨并㈤ 啡味-11-羧酸（11.23)與3·二甲基胺磺醯基·笨并[&amp;]啡0丼·η· 羧酸（11.24)之混合物，及Ν，Ν·二曱基乙烯二胺。兩種異構 物係使用閃爍層析法予以分離； ΐ紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱) 一 ：~58Γ----&gt; I I I · I I (請先Μ讀背面之注意事項再填寫本頁) J 訂·- ·»*線·1280242 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed clothing A7 V. Description of invention (52) 4-chloro-benzo[a]morphine spray.u•slow acid (2_didecylamino-ethyl) The amine is prepared from 4-a-p-benzo[a]-morphine-n-acid (π 7) and nn-dimethylethylenediamine; 4 a nitrogen-stupid [a]morphine q丨· Carboxylic acid (2•didecylamino)ethyl amide is prepared from 4-azido-p-benzo[a]morphine-u•carboxylic acid (Η·9) and Ν,Ν·dimethyl Ethyl ethylenediamine; 11-(2methylamino)ethylcarbonyl)benzo[a]physin-4-carboxylic acid methyl ester prepared from benzo[a]morphine-4,11· Dicarboxylic acid 'methyl ester (ΙΙ·ΐ〇) and N,N-dimethylethylene diamine; 4·decylamine sulfonyl- benzo[a]morphine_u_carboxylic acid (2·2 Methylamino-ethyl) decylamine; trifluoroacetate salt is prepared from 4-methylamine sulfonyl benzo[a] phenanthrene-11.carboxylic acid (II.21) and 3-methyl a mixture of amidoxime-benzo[a]physin·u•carboxylic acid (11.22), and N,N_:methylethylenediamine. The two isomers were separated using a preparative high pressure liquid chromatograph (HPLC); 3·Methylamine sulfonyl-benzophenanthine-1-carboxylic acid (2·dimethylamino-ethyl)- Indoleamine; trifluoroacetate salt is prepared from 4-methylamine sulfonyl benzoyl benzo [1] carboxylic acid (ΙΙ·21) and 3·methylamine sulfonyl yl] a] a mixture of morphine·n•carboxylic acid (11.22) and N,N•dimercaptoethylenediamine. The two isomers were separated using a preparative high pressure liquid chromatograph (HPLC); 4_dimethylamine cross-branched-benzo[a]morphine-11·capric acid (2-didecylamino) · Ethyl)-guanamine; trifluoroacetate salt is prepared from 4-dimethylamine sulfonyl group. Stupid (5) morphine-11-carboxylic acid (11.23) and 3 dimethyl sulfonyl sulfhydryl And [&amp;] a mixture of morphine 0 丼 η carboxylic acid (11.24), and hydrazine, hydrazine bis decyl ethylene diamine. The two isomers are separated by scintillation chromatography; the ΐ paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 public). One: ~58Γ----&gt; III · II (please Read the back note and fill out this page) J Book ·- ·»*线·

1280242 發明說明（ 3-二甲基胺磺醯基·笨并[a]啡哜_u•羧酸（2•二曱基胺基-乙 基）·醯胺；三氟乙酸鹽係製備自4·二甲基胺磺醯基_笨并卜] 啡畊-11-羧酸（11.23)與3-二曱基胺磺醯基_笨并[a]啡畊·η· 羧酸（11.24)之混合物，及Ν，Ν-二甲基乙烯二胺。兩種異構 物係使用閃爍層析法予以分離； 3-胺磺醯基-苯并[a]啡阱-u·羧酸（2_二甲基胺基-乙基）_醯 胺係製備自4-胺磺醯基-笨并[a]啡啡_u•羧酸（1125)與3•胺 磺醯基·苯并[a]啡啡-11·羧酸（11.26)之混合物，及N，N•二甲 基乙烯二胺。3-胺磺醯基-笨并[a]啡畊_u•羧酸（2•二甲基胺 基-乙基）·醯胺係使用閃爍層析法予以純化； 2-硝基-笨并[a]啡啡·11·羧酸（2·二甲基胺基-乙基）·醯胺係 製備自4·氣·苯并[a]啡哜-U-羧酸（π·32)及Ν，Ν•二甲基乙烯 二胺； 9·溴-4-甲氧基-苯并[a]啡啩·u•羧酸（2·二甲基胺基_乙基分 醯胺係製備自9-溴-4-甲氧基-苯并[a]啡啡-：11-羧酸（„·35) 及Ν，Ν·二曱基乙烯二胺； 4·硝基-苯并[a]啡啩·ΐΐ·羧酸（2·二甲基胺基-乙基）_醯胺係 製備自4-硝基·苯并[a]啡唯-η·敌酸（1127)與3·硝，基-苯并⑷ 啡啡-11-羧酸（11.28)之混合物，及ν，Ν·二甲基乙烯二胺。然 後使用閃爍層析法予以純化； 3·硝基-苯并[a]啡啡-11-羧酸（2-二甲基胺基-乙基）·醯胺係 製備自4·硝基·苯并[a]啡啡-羧酸⑴二乃與％硝基-苯并[a] 啡畊-11-羧酸（ΙΙ·28)之混合物，及ν，Ν·二曱基乙烯二胺。然 後使用閃爍層析法予以純化； 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） ----------.^w· Μ—----^^U^ (請先fistt背面之注意事項再填寫本頁&gt; 經濟部智慧財產局員工消費合作社印製 59 1280242 Α7 Β7 經濟部智慧財產局員工消費合作社印製 54 五、發明說明（） 31旌％ 1B:~k甲氧基·苯并[al啡啡-11-韃酸（2·二甲其拉芊 ^基）·醯胺 4·曱氧基·笨并[a]啡哜-11-羧酸曱基酯（Iv.1)(35〇毫克） 與1-二甲基胺基-2-丙基胺（2毫升）（可由商業上購得）之一 個混合物，於氮氣下被加熱至11()^，歷時4小時。然後將 該反應混合物冷卻，以抽氣移除過多之胺。使用閃爍層析 法將殘餘物予以純化（二氧化矽、乙酸乙酯，然後為溶入乙 酸乙酯之25%甲醇），產生本標題化合物，其為一種黃色固 體（164亳克）。 下列具有化學式（I)之化合物的製備，係以一種類似之 方法，其使用適合之具有化學式（IV)之酯及具有化學式（ΠΙ) 之胺做為起始： 4-甲氧基-笨并[a]啡喷·u.㈣仏二甲基胺基-丙基）_酿胺 係製備自4-甲氧基-笨并[a]啡啡巧卜竣酸甲基醋（ιν ^及” 二甲基胺）丙基胺（可由商業上購得）； 4·甲氧基·苯并[a]啡畔·u•叛酸（3-胺基士經基·丙基）·酿胺 係製備自4-甲氧基-笨并⑷啡σ井·u_竣酸甲基醋（ιν」）及 1，3·二胺基·2-羥基丙烷（可由商業上購得）： 4-甲氧基·苯并[a]啡呼·u，酸（2_二甲基胺基-丙基）_酿胺 係;裝備自4-甲氧基·笨并㈤啡啡-u•敌酸甲基醋及 Ν2，Ν2-二甲基·丙烷·丨，2•二胺(可由商業上購得广 4-二甲基胺基.苯并⑷啡啡⑴·㈣（2•二甲基胺基·乙基）· 醯胺係製備自4·二甲基胺基·笨并[a]啡併-⑴叛酸甲基醋 (IV.3)與3·—甲基胺基.苯并⑷啡啡·“·㈣甲基自旨（^)之 本紙張尺度適用中國國家標準（CNb)A4規格（2Κ) χ挪公楚「---；---—^ (請先K讀背面之沒意事項再填寫本頁) 裝 r. :線· 1280242 經濟部智慧財產局員工消費合作社印製 A7 B7 —五、發明說明（55) 、 混合物及N，N•二甲基-丙烷乙烯二胺，並進一步經由閃爍層 析法純化以移除微量之異構物； 4-甲氧基-10-甲基胺基·苯并[a]啡啡-n•羧酸（2-二甲基胺 基-乙基）-醯胺係製備自4·甲氧基-10-曱基胺基·苯并[a]啡 畊-11-羧酸甲基酯（IV.6)及N，N-二甲基-丙烷乙烯二胺；及 4·甲氧基-笨并[a]啡畊-11-羧酸（2·二甲基胺基_乙基）_醯胺 係製備自4-甲氧基-笨并[a]啡哜羧酸甲基酯（IV⑴及义 曱基乙婦二胺 與例1C·_4-甲氣基·笨并fal呻畊_11_羧酸（2-二甲基胺某 二1，1-二曱基-乙基V酿脖 4·曱氧基-苯并[a]啡哜-11·羧酸卩^:^與亞硫醯氣之一 個混合物被加熱至予以迴流6分鐘。然後以抽氣移除亞硫醯 氯。於0°C下，將殘餘物溶解於乾燥之二氣曱烷，然後添加 1-二甲基胺基-2·甲基-2-胺基丙烷（可由商業上購得）。於攪 拌2小時後’將反應混合物溶解於二氣甲烧中，以碳酸氫鈉 溶液' 乾燥之（MgS〇4)沖洗，並以抽氣移除溶劑，產生粗 產物。使用閃爍層析法將此粗產物純化以產生本標題化合 物。 下列具有化學式（I)之化合物的製備，係以一種類似之方 法，其使用適合之具有化學式（II)之酸及具有化學式（111) 之胺做為起始： 3-二甲基胺基-2-[(4-甲氧基·笨并[a]啡畊-π·羰基 &gt; 胺基]_ 丙酸甲基酯係製備自4-甲氧基·笨并[a]啡啡-11-羧酸（π. 1) 及4-aza-DL-白胺酸甲基酯·氣化氫（ΠΙ.1)，於吡啶之存在下 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 61 -----------Μ--------^---^----Γ (請先閱讀背面之;i意事項再填寫本頁) 1280242 Α7 Β7 五、發明說明（6) 。此製備係使用製備式高壓液態層析儀（HPLC)予以純化 (isocratic 60%/水/40%乙醯腈MeCN)，產生所欲之化合物之 三氟乙酸鹽； &lt;請先閱讀背面之注意事項再填寫本頁) 4,10-二甲氧基-笨并[a]啡啩·羧酸（2•二甲基胺基_乙基）· 酿知係製備自4，10-二甲氧基-苯升[3]啡_-1卜敌酸（1136) 及N，N-二甲基乙烯二胺； 以亞硫醯氯延長反應時間（使其超過i小時），俾使啡畊核體 產生氯化作用。因此，丨-氯·4，1〇•二甲氧基·笨并[a]啡畊·η· 羧酸（2-二甲基胺基-乙基）·醯胺係製備自係製備自4，10-二 甲氧基-苯并[a]啡哜-11·羧酸（ΙΙ.36)及Ν，Ν·二曱基乙烯二胺 4-甲氧基-8-甲基-笨并[a]啡啡-11β羧酸（2·二曱基胺基·乙基 )-醯胺係製備自4-甲氧基·笨并[a]啡畊-丨i •羧酸（1137)及 Ν，Ν·二甲基乙烯二胺； 9-氣-4-甲氧基-笨并[a]啡畊4丨·羧酸二甲基胺基·乙基）· 醯胺係製備自9-氯-4-甲氧基·苯并[a]啡啩]卜羧酸（π·38) 及N，N-二甲基乙烯二胺； 經濟部智慧財產局員工消費合作社印製 4，10-二甲氧基-苯并[a]啡啩·u_羧酸（2·二甲基胺基·乙基）· 醯胺係製備自4,10·二甲氧基·苯并[a]啡啡_丨卜羧酸（π 3 6) 及1-一曱基胺基· 2-丙基胺（可由商業上購得）； 4-曱氧基·苯并[a]啡啡七_敌酸⑴二甲基胺基乙基·丙基）· 醯胺係製備自4-甲氧基-笨并[a]啡啡羧酸（Π1)及〆,#· 一曱基-丁烷·1，2-二胺氣化氫（πΐ·2)，於三乙基胺之存在下 62 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 1280242 A7 B7 經濟部智慧財產局員工消費合作社印製 57 --五、發明說明（） t 心曱氧基-苯并[a]啡味-11·叛酸U-二曱基胺基曱基·2·甲基· 丙基）-酿胺係製備自4·曱氧基-苯并[a]啡畔-⑴叛酸⑴」) 及3#,#·二甲基·丁垸丄；^二胺氫氯酸鹽（ιπ.3)，於三乙基 胺之存在下；4-甲氧基苯并[a]啡哜-11·叛g曼（1·:甲基胺基甲基·2·笨基· 乙基）_醯胺係製備自4-曱氧基·笨并[a]啡哜羧酸（π. η 及二甲基-3-笨基·丙烷-υ·二胺.氩氣酸鹽（ΠΙ 4)，於 三乙基胺之存在下； 4-甲氧基·苯并[a]啡啡·π·羧酸（2_二曱基胺基甲基· 乙基）-醯胺係製備自4-甲氧基·苯并[a]啡啡·丨卜叛酸（η 〇 及（S)-A^W-二甲基·丁烷二胺氫氣酸鹽（ΠΙ·5)，於三 乙基胺之存在下； ‘曱氧基·苯并[a]啡畊-11·羧酸（2_二甲基胺基甲基· 乙基）·醯胺係製備自4·甲氧基-笨并[a]啡畊4卜羧酸（IM) 及（R)-#，#'二甲基·丁烷·丨，2·二胺氫氣酸鹽（ΙΠ·6)，於三 乙基胺之存在下； ‘甲氧基-笨并[a]啡啡-11-羧酸（2·二曱基胺基羥基 甲基·乙基）·醯胺係製備自4·甲氧基-苯并[a]啡啡·η·羧酸 (ΙΙ.1)及（S)-2·胺基-3-二曱基胺基-丙-1-醇.氫氣酸鹽（ΙΠ 7) ，於三乙基胺之存在下； 4-甲氧基-苯并[a]啡啡-11·羧酸（l(s)-二甲基胺基乙基 •2(S)_羥基·丙基）_醯胺係製備自4-甲氧基_笨并[a]啡畊·η· 羧酸（ΙΙ.1)及3(S)_胺基-4·二甲基胺基·丁-2(S)·醇·氫氣酸鹽 (III.8)，於三乙基胺之存在下； {請先閱讀背面之注意事項再填寫本頁) 裝 .·線· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 63 1280242 A71280242 Description of the invention (3-dimethylamine sulfonyl) benzo[a] morphine _u•carboxylic acid (2•didecylamino-ethyl)·decylamine; trifluoroacetate is prepared from 4 · dimethylamine sulfonyl ketone _ benzopyr] phenolic -11-carboxylic acid (11.23) and 3-dimercaptoamine sulfonyl _ benzo[a] cultivating η carboxylic acid (11.24) a mixture, and hydrazine, hydrazine-dimethylethylenediamine. The two isomers are separated by scintillation chromatography; 3-amine sulfonyl-benzo[a] porphyrin-u·carboxylic acid (2_ Dimethylamino-ethyl)-guanamine is prepared from 4-amine sulfonyl- benzo[a]morphine-u•carboxylic acid (1125) and 3•amine sulfonyl·benzo[a] a mixture of morphine-11·carboxylic acid (11.26), and N,N•dimethylethylenediamine. 3-Aminesulfonyl-stupid [a] cultivating _u•carboxylic acid (2•dimethyl Amino-ethyl)-guanamine is purified by scintillation chromatography; 2-nitro-abido[a]morphine·11·carboxylic acid (2·dimethylamino-ethyl)·decylamine Prepared from 4·gas·benzo[a]morphine-U-carboxylic acid (π·32) and Ν,Ν•dimethylethylenediamine; 9·bromo-4-methoxy-benzo[a] ] 啩 啩·u•carboxylic acid (2·dimethylamino-ethylpyridinium Prepared from 9-bromo-4-methoxy-benzo[a]morphine-:11-carboxylic acid („·35) and Ν,Ν·dimercaptoethylenediamine; 4·nitro-benzo[ a] 啩 啩·ΐΐ·carboxylic acid (2·dimethylamino-ethyl)-guanamine is prepared from 4-nitrobenzo[a]morphin-η·dole acid (1127) and 3· a mixture of nitrate, benzo-(4)morphin-11-carboxylic acid (11.28), and ν,Ν·dimethylethylenediamine, which is then purified by scintillation chromatography; 3·nitro-benzo[a ]Bryndin-11-carboxylic acid (2-dimethylamino-ethyl)·guanamine is prepared from 4·nitro-benzo[a]morphine-carboxylic acid (1) di- and nitro-benzene And [a] a mixture of cultivating -11-carboxylic acid (ΙΙ·28), and ν,Ν·dimercaptoethylenediamine, which is then purified by scintillation chromatography; the paper scale applies to the Chinese National Standard (CNS) A4 specifications (210 X 297 public) ----------.^w· Μ—----^^U^ (Please fill in the notes on the back of the fistt and then fill in this page &gt; Ministry of Economics Property Bureau Staff Consumer Cooperatives Printed 59 1280242 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed 54 V. Inventions () 31旌% 1B: ~k methoxy·benzene [alphine-11-decanoic acid (2. dimethoprim), indoleamine 4·decyloxy] stupid [a] quinone-11-carboxylic acid decyl ester (Iv. 1) ( 35 mg) and a mixture of 1-dimethylamino-2-propylamine (2 ml) (commercially available) were heated to 11 (?) over nitrogen for 4 hours. The reaction mixture was then cooled to remove excess amine by pumping. The residue was purified by flash chromatography eluting EtOAc (EtOAc) The following compounds of formula (I) are prepared in a similar manner starting with an ester of formula (IV) and an amine of formula (ΠΙ): 4-methoxy-stupid [a] morphine·u. (tetra) dimethylamino-propyl) ylamine is prepared from 4-methoxy-p- and [a] morphine phthalic acid methyl vinegar (ιν ^ and " Dimethylamine) propylamine (commercially available); 4. methoxy benzo[a] morphine·u• tacrolein (3-aminosyltrans) propylamine Prepared from 4-methoxy-stupid (4) morphine σ well·u_capric acid methyl vinegar (ιν) and 1,3·diamino-2-hydroxypropane (commercially available): 4-A Oxy-benzo[a]morphin-u, acid (2-dimethylamino-propyl)-branched amine; equipped with 4-methoxy-stupid (5)-morphine-u Base vinegar and hydrazine 2, hydrazine 2-dimethyl-propane hydrazine, 2 • diamine (commercially available in the wide range of 4-dimethylamino. benzo (4) morphine (1) · (d) (2 • dimethylamino group · Ethyl) · Amidoxime is prepared from 4 · dimethylamino group · stupid [a] benzo- (1) retinoic acid methyl vinegar (IV.3) and 3 - methyl amino group. benzo (4) brown · "· (4) Methyl from the purpose of (^) This paper scale applies Chinese National Standard (CNb) A4 specification (2Κ) χNegative Chu "---;----^ (Please read K on the back) Matters fill out this page) Install r. : Line · 1280242 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 —5, invention description (55), mixture and N,N• dimethyl-propane ethylene diamine, and Further purification by flash chromatography to remove traces of isomers; 4-methoxy-10-methylaminobenzo[a]morphine-n•carboxylic acid (2-dimethylamino)- Ethyl)-guanamine is prepared from 4·methoxy-10-decylamino·benzo[a]morphin-11-carboxylic acid methyl ester (IV.6) and N,N-dimethyl -propane ethylene diamine; and 4 · methoxy- benzo[a] morphine-11-carboxylic acid (2. dimethylamino-ethyl) amide amine is prepared from 4-methoxy-stupid And [a] morphine carboxylic acid methyl ester (IV (1) and sulfhydryl ethane diamine and Example 1C · _ 4-methyl group · stupid and fal plough _11 carboxylic acid (2-dimethylamine two 1,1-Dimercapto-ethyl V-lacquer 4·decyloxy-benzo[a]morphine-11·carboxylic acid 卩^: A mixture of sulphur and sulphur is heated to reflux 6 The sulphur sulphate chloride is then removed by pumping. The residue is dissolved in dry dioxane at 0 ° C, then 1-dimethylamino-2.methyl-2-amino group is added. Propane (commercially available). After stirring for 2 hours, 'resolve the reaction mixture in a methane toluene, rinse with sodium bicarbonate solution 'MgS〇4', and remove the solvent by pumping to produce The crude product was purified using flash chromatography to give the title compound. The following compounds of formula (I) are prepared in a similar manner starting with an acid of formula (II) and an amine of formula (111): 3-dimethylamino- 2-[(4-methoxy-p-benzo[a]-panning-π·carbonyl]-amino]-propionic acid methyl ester was prepared from 4-methoxy-p-benzo[A]morphine-11 -carboxylic acid (π. 1) and 4-aza-DL-methyl methionine · hydrogenated hydrogen (ΠΙ.1), in the presence of pyridine, this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 61 -----------Μ--------^---^----Γ (Please read the back first; i 1280242 Α7 Β7 V. Inventive Note (6) This preparation was purified by preparative high pressure liquid chromatography (HPLC) (isocratic 60% / water / 40% acetonitrile MeCN) to produce the desired compound Fluoroacetate; &lt;Please read the notes on the back and fill out this page.) 4,10-Dimethoxy-stupid [a] phenolic carboxylic acid (2•dimethylamino)-ethyl) The brewing system is prepared from 4,10-dimethoxy-benzene liter [3] phenanthrene-1 (1136) and N,N-dimethylethylene diamine; Sulfuryl chloride reaction time (hours beyond that i) to enabling generation coffee farming nucleus chlorination. Therefore, the preparation of 丨-chloro·4,1〇•dimethoxy·bromo[a]morphine·η·carboxylic acid (2-dimethylamino-ethyl)·guanamine is prepared from 4 , 10-dimethoxy-benzo[a] phenanthrene-11·carboxylic acid (ΙΙ.36) and Ν,Ν·dimercaptoethylenediamine 4-methoxy-8-methyl-stupid[ a] Morphine-11βcarboxylic acid (2·didecylaminoethyl)-decylamine is prepared from 4-methoxy-p-benzo[a]-cultivation-丨i•carboxylic acid (1137) and hydrazine , Ν·dimethyl dimethyl diamine; 9-gas-4-methoxy- benzo[a] cultivating 4 丨 carboxylic acid dimethylamino · ethyl) · guanamine is prepared from 9-chloro -4-Methoxy-benzo[a]morphine]bucarboxylic acid (π·38) and N,N-dimethylethylenediamine; Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 4,10-two Methoxy-benzo[a]morphine·u_carboxylic acid (2. dimethylaminoethyl) ethylamine is prepared from 4,10·dimethoxybenzo[a]morphine _ 丨 carboxylic acid (π 3 6) and 1-monodecylamino 2-propanamine (commercially available); 4-decyloxybenzo[a]morphine-7-dicarboxylic acid (1) Dimethylaminoethyl propyl)· decylamine is prepared from 4-methoxy-p-benzo[a]morphinecarboxylic acid (Π1) And 〆,#· 曱-butane·1,2-diamine hydrogenated hydrogen (πΐ·2), in the presence of triethylamine 62 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 Public Interest) 1280242 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 57 -- V. Invention Description ( ) t 曱 曱 - 苯 苯 a a a · · · · · · · · · U Aminomethyl 2, methyl propyl)-bristamine is prepared from 4 · methoxy-benzo[a] phenanthrene-(1) retinoic acid (1)") and 3#, #· dimethyl butyl二; diamine hydrochloride (ιπ.3) in the presence of triethylamine; 4-methoxybenzo[a] phenanthrene-11·re-gman (1·: methylamine Methyl-2·styl·ethyl)-guanamine is prepared from 4-decyloxy·p-benzo[a]pyrrolecarboxylic acid (π. η and dimethyl-3-indolyl propane-oxime) Diamine. Argonate (ΠΙ 4) in the presence of triethylamine; 4-methoxy·benzo[a]morphine·π·carboxylic acid (2-didecylaminomethyl) · Ethyl)-guanamine is prepared from 4-methoxy-benzo[a]morphin-indole acid (η 〇 and (S)-A^W-dimethyl butane diamine hydrogen acid Salt (ΠΙ·5) in the presence of triethylamine ; '曱oxy·benzo[a]morphin-11·carboxylic acid (2-dimethylaminomethyl·ethyl)·guanidine is prepared from 4·methoxy-brup [a] Cultivating 4 carboxylic acid (IM) and (R)-#, #' dimethyl butane hydrazine, 2 · diamine hydrogen hydride (ΙΠ·6) in the presence of triethylamine; Oxy-p-benzo[a]morphine-11-carboxylic acid (2-didecylamino-hydroxymethylethyl)-guanamine is prepared from 4·methoxy-benzo[a]morphine η·carboxylic acid (ΙΙ.1) and (S)-2·amino-3-didecylamino-propan-1-ol. Hydrogen acid salt (ΙΠ 7) in the presence of triethylamine; 4-methoxy-benzo[a]morphine-11·carboxylic acid (l(s)-dimethylaminoethyl•2(S)-hydroxypropyl)-decylamine is prepared from 4- Methoxy _ 笨 并 [a] crystallization η carboxylic acid (ΙΙ.1) and 3 (S) _ amino-4 dimethylamino butyl - 2 (S) · alcohol · hydrogenate (III.8), in the presence of triethylamine; {Please read the notes on the back and fill out this page.) Loading.·Line· This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 PCT) 63 1280242 A7

請 先 讀 背 面 意 事 項 再？ 填二 寫裝 本 _ 頁Please read the back of the matter first? Fill in two write this _ page

1280242 A7 經濟部智慧財產局員工消費合作社印製 ______B7______ 59 五、發明說明（） 醯胺係製備自4-曱氧基·苯并[a]啡啩-11-羧酸·甲 基-3-(R)·胺基吼咯啶·氫氣酸鹽（ΙΠ.10)，於三乙基胺之存在 下； (R)-4-甲氧基-苯并[a]啡畊-11-羧酸（1-二甲基胺基甲基-2· 甲基·丙基）-酿胺係製備自4-曱氧棊-苯并[a]啡味-11 -竣酸 (11.1)及（11)-3#;,#/-三曱基-丁烷-1，2-二胺.氫氣酸鹽（111.3.3) ，於三乙基胺之存在下； 4-曱氧基-苯并[a]啡啡-11-羧酸（2,3-雙）-二曱基胺基-丙基） 醯胺係製備自4-甲氧基-笨并[a]啡畊-η·羧酸（ΙΙ·ι)及 &lt;&lt;#2，#2-四甲基-丙烧-1，2,3-三胺.三氫氣酸鹽（111.11)， 於三乙基胺之存在下。 實施_Μ2_:具有化學式⑴之化合物問的相互韓蟧 依照實施例1製備的具有化學式⑴之化合物被轉變為 如下文所述之其他的（I)化合物。 實綠一倒2i·_4-羥基-笨并『ai啡畊•羚酸（2_二甲基胺基· 乙基）-醯胺：氫溴酸轉 4·曱氧基·笨并[a]啡啡·η•羧酸（2·二曱基胺基-乙基卜 醯胺（1.1)(727毫克）溶於15毫升乾燥二氣甲烷之一個溶液 被冷卻至-5°C後，添加一個溶於二氣甲烷（丨3.6毫升）之ΐ·〇Μ 的三溴化硼溶液。於攪拌4小時之後，反應混合物被傾倒至 冰/水之上，產生一沉澱物，其係以過濾收集。此收集之沉 澱物自一個熱甲醇/醋酸乙酯之混合物中被研磨後，產生本 標題化合物，其為一種米黃色固體（5〇5毫克）。 宽施例2ii·_Ui基-苯并丨ai啡呻-n-羧gM2-二甲基胺基· -----------^ ------ -- I ^----*---線--- (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公爱） 65 1280242 經濟部智慧財產局員工消費合作社印制衣 A7 B7 五、發明說明（60) 基）·酿胳 將380毫克之硫代乙醇鈉添加至3-甲氧基-笨并[a]啡畊 •11-羧酸（2-二曱基胺基-乙基）_醯胺（170毫克）溶於3毫升乾 燥N，N-二甲基曱酿胺之一個溶液中。然後於氬氣下將反應 混合物加熱至予以迴流3小時。冷部反應混合物，以稀鹽酸 將其酸化，並以抽氣移除揮發物。殘餘物之純化係使用管 柱層析法（20〇/〇甲醇，溶於二氯甲烷中），產生本標題化合物 ，其為一種紅色固體（142毫克）。 2·羥基-苯并[a]啡啩-11-羧酸（2·二甲基胺基·乙基 &gt; 醯 胺係以類之方法製備自2-曱氧基-笨并[a]啡哜-11-羧酸（2-一曱基胺基-乙基）-酿胺。 t施例2iii._i-氰基曱氣基-茉# fal啡哄-11-鉍s参Γ?·二甲 基胺基-乙基酿^胺 於230毫克之4-羥基-苯并[a]啡畊-η-羧酸（2-二甲基胺 基-乙基）-醯胺：氫溴酸鹽溶於3毫升之Ν，Ν·二曱基甲醯胺之 一個懸浮液中，先添加175毫克之三級（/er〇•丁醇舒，然後 再添加47 μ!^之漠乙勝。反應混合物被加熱至1 〇〇。(2下持續1 小時。然後將反應混合物冷卻，以醋酸乙酯稀釋，以碳酸 納溶液及濃鹽水沖洗，再乾燥（MgS〇4)，並以抽氣移除溶 劑，產生粗產物。此粗產物係使用閃爍層析法（二氧化矽， 25%曱醇溶於乙酸乙酯中），產生本標題化合物，其為一種 黃色固體（74毫克）。 下列具有化學式（I)之化合物的製備係以類似之方法 ，其使用4·羥基-笨并[a]徘畊-11-羧酸（2_二曱基胺基·乙基）_ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 66 ----------裝--------1T-—^----Γ —線 (請先Μ讀背面之注意事項再填寫本頁) 1280242 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（） 醯胺：氫溴酸鹽及適當之烷化試劑； 4·(嘧啶基-2·基氧）-笨并[a]啡畊-11·羧酸（2·二甲基胺基-乙 基）-醯胺之製備係使用2-溴咄啶； 4-(2-嗎琳基-4-基-乙氧基）-苯并[a]啡畊·11β羧酸（2·二曱基 胺基-乙基）-醯胺之製備係使用N-(2-氣乙基）嗎啉氣化氫； 4·(3-氰基-丙氧基）·笨并[a]啡啡-11-羧酸（2-二甲基胺基-乙 基）-醯胺之製備係使用4·溴丁基腈； 4-(3-二甲基胺基·丙氧基）-苯并[a]啡阱-11-羧酸（2-二甲基 胺基-乙基）-醯胺之製備係使用3 -二甲基胺基丙基氣氯化氫 9 4-羰基甲氧基·笨并[a]啡啡-11-羧酸（2-二曱基胺基-乙基）-醯胺之製備係使用2-溴乙烯醯胺； 4-(2-氧-丙氧基）-笨并[a]啡0^-11-敌酸（2-二甲基胺基·乙基 )·醯胺之製備係使用氣丙酮；及 [11-(2-二甲基胺基-乙基胺甲醯基）-笨并[a]啡畊·‘基氧]-醋酸三級（ieri) 丁基酯之製備係使用三級（化ri) 丁基溴乙烯 醢胺。 實施例2iv· 乙基-胺基甲酸11-(2-二曱基胺某-乙篡脍甲as 基）-笨并丨al啡哄-4-某S皆 將540毫克之4-M基-笨并[a]e非畊-11-竣酸（2-二甲基胺 基-乙基）-醯胺：氫溴酸鹽、0.51毫升之三乙基胺及0.29毫升 之異氰酸乙酯的一個混合物，攪拌於3毫升之乾燥的N，N-二甲基甲醯胺之中。產物自反應混合物中慢慢地沉澱下來 ，以過濾收集並以乙醚沖洗，產生本標題化合物，其為一 1本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱1 「67 · (請先閱讀背面之注意事項再填寫本頁) 裝 亦： 1280242 經濟部智慧財產局員工消費合作社印制取 A7 B7 五、發明說明（62) 種黃色固體（210毫克）。 里戈例 2ν·醋酸 啡畊-4-基酯 將45毫克之4-羥基-笨并[a]啡啡_u •羧酸（2•二曱基胺 基-乙基）·醯胺··氫溴酸鹽、71 μί之三乙基胺及2〇 pL之乙醯 亂溶於1 · 4毫升二氣甲燒的一個混合物，於室溫下授拌？小 時。所有的揮發物皆以抽氣移除，且殘餘物之純化係使用 管柱層析法（10%曱醇溶於二氣曱烷中），產生本標題化合物 ，其為一種黃色固體（27毫克）。 t您.例2vi· [11-(2-二甲基胺某-乙篡胺甲醯某v笑其『Μ 噔-4-基oxyl-醋酸三氟乙醅瞜 添加1毫升之三氟醋酸至18毫克之[11·(2·二甲基胺基-乙基胺曱醯基）-苯并[a]啡畊·4·基oxy]-醋酸三級（如〇 丁基 酯溶於1毫升之乾燥二氣曱烷的一個溶液中。於攪拌4小時 之後，以抽氣移除溶劑，產生本標題化合物，其為一種黃 色固體（10毫克）。 實施例2vii· 苯并丨al啡哄-4,11·二羚st 4-醯胺114(2-二甲_ 基胺基·乙基）酿胺1 ;三氟乙酸鹽 於20毫升之曱醇中，超音波震盪200毫克之[η·(2·二曱 基胺基-乙基胺甲酿基）-苯并[a]啡叫l _4·叛酸甲基酯，使其成 為一個均勻之懸浮液。於此懸浮液中，添加22毫克之氱化 鉀。然後將無水氨氣導入混合物中，歷時15分鐘。於室溫 下’’谷授摔反應混合物1 〇天，且每天皆將氨氣導入混合物中 。經10天之後，以抽氣移除揮發物，且使用閃爍層析法純 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） {請先W讀背面之注意事項再填寫本頁) 裝 卜！線· 1280242 經濟部智慧財產局員工消費合作社印製 A7 _____B7__ 63 ^五、發明說明（）1280242 A7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed ______B7______ 59 V. INSTRUCTIONS () The guanamine is prepared from 4-methoxy benzo[a] phenanthrene-11-carboxylic acid methyl-3- (R)-aminopyrrolidine·hydrogen acid salt (ΙΠ.10) in the presence of triethylamine; (R)-4-methoxy-benzo[a]morphin-11-carboxylic acid (1-Dimethylaminomethyl-2·methyl-propyl)-bristamine is prepared from 4-oxoanthracene-benzo[a]morphin-11-nonanoic acid (11.1) and (11) -3#;,#/-tridecyl-butane-1,2-diamine. Hydrogen acid salt (111.3.3) in the presence of triethylamine; 4-decyloxy-benzo[a Brownoid-11-carboxylic acid (2,3-bis)-didecylamino-propyl) guanamine is prepared from 4-methoxy-p-benzo[a]-panning-η·carboxylic acid (ΙΙ • i) and &lt;&lt;#2, #2-tetramethyl-propanone-1,2,3-triamine. Trihydrogenate (111.11) in the presence of triethylamine. Implementation _Μ2_: mutual compound of the compound of the formula (1) The compound of the formula (1) prepared according to Example 1 was converted into the other compound (I) as described below. Real green one down 2i·_4-hydroxy-stupid and “ai dynasty tangling acid (2_dimethylamino) ethyl) decylamine: hydrobromic acid to 4 曱 · · 笨 笨 [a] A solution of morphine·η•carboxylic acid (2·didecylamino-ethyldoxime (1.1) (727 mg) dissolved in 15 ml of dry di-methane was cooled to -5 ° C and then added The boron tribromide solution was dissolved in dioxane methane (丨 3.6 ml). After stirring for 4 hours, the reaction mixture was poured onto ice/water to give a precipitate which was collected by filtration. The collected precipitate was triturated from a hot methanol/ethyl acetate mixture to give the title compound as a beige solid (5 〇 5 mg). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI>呻-n-carboxyglycol gM2-dimethylamino group -----------^ ------ -- I ^----*---线--- (Please Read the notes on the back and fill out this page.) The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) 65 1280242 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed clothing A7 B7 V. Invention Description ( 60) base) · brewing 380 mg of sulfur Substituting sodium ethoxide to 3-methoxy-p- and [a] morphine 11-carboxylic acid (2-didecylamino-ethyl)-decylamine (170 mg) dissolved in 3 ml of dry N, N - a solution of dimethyl indoleamine. The reaction mixture was then heated to reflux for 3 hours under argon. The cold reaction mixture was acidified with dilute hydrochloric acid and the volatiles were removed by suction. The residue was purified using EtOAc EtOAc EtOAc (EtOAc) 2. Hydroxy-benzo[a]phlephthyl-11-carboxylic acid (2. dimethylamino)ethyl amide is prepared by the method of 2-methoxy-bromo-[a]哜-11-carboxylic acid (2-monodecylamino-ethyl)-bristamine. t. Example 2iii._i-cyanohydrazinyl-mosa# fal morphine-11-铋s ginseng? Methylamino-ethyl aryl amine in 230 mg of 4-hydroxy-benzo[a]morphin-η-carboxylic acid (2-dimethylamino-ethyl)-decylamine: hydrobromide Dissolve in a suspension of 3 ml of hydrazine, Ν·dimercaptocaramine, first add 175 mg of tertiary ((er〇•butanol), then add 47 μ!^ of the desert. The mixture was heated to 1 Torr. (2 hours for 1 hour. The reaction mixture was then cooled, diluted with ethyl acetate, rinsed with sodium carbonate and brine, dried (MgS 〇 4) and removed with suction. Solvent, the crude product was obtained. The crude product was obtained using flash chromatography (2HHHHHHHHHHHHHH The preparation of the compound of (I) is carried out in a similar manner, which 4. Hydroxy-stupid [a] 徘耕-11-carboxylic acid (2-didecylamino)ethyl _ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 66 - ---------装--------1T-—^----ΓΓ-line (please read the notes on the back and fill out this page) 1280242 Intellectual Property Office of the Ministry of Economic Affairs Consumer Cooperatives Print A7 B7 V. INSTRUCTIONS () Hydrazine: hydrobromide and appropriate alkylating agent; 4 · (pyrimidinyl-2 yloxy)- benzo[a] cultivating -11 carboxylic acid The preparation of (2. dimethylamino-ethyl)-guanamine is carried out using 2-bromoacridine; 4-(2-morphinyl-4-yl-ethoxy)-benzo[a] • Preparation of 11β-carboxylic acid (2·didecylamino-ethyl)-decylamine by hydrogenation of N-(2-ethylethyl)morpholine; 4·(3-cyano-propoxy) · Stupid [a] morphine-11-carboxylic acid (2-dimethylamino-ethyl)-decylamine is prepared using 4·bromobutyl nitrile; 4-(3-dimethylamino group· Preparation of propoxy)-benzo[a]pyrene-11-carboxylic acid (2-dimethylamino-ethyl)-guanamine using 3-dimethylaminopropyl hydrogen chloride 9 4- Carbonyl methoxy-pupid [a] morphine-11-carboxylic acid (2-didecyl) Preparation of 2-ethyl)-guanamine using 2-bromovinylamine; 4-(2-oxo-propoxy)-benzo[a]morpho[^-11-di-acid (2-dimethyl The preparation of amino-ethyl) guanamine is carried out using aerobic acetone; and [11-(2-dimethylamino-ethylamine-methyl fluorenyl)- benzo[a] morphine-yloxy]- The preparation of tertiary (ieri) butyl acetate is carried out using tertiary (chemical ri) butyl bromide decylamine. Example 2iv· Ethyl-Aminoformic acid 11-(2-didecylamine-ethylidene-asyl)-Bist and 丨alphin-4-A S will be 540 mg of 4-M group- Stupid [a]e non-cultivated -11-decanoic acid (2-dimethylamino-ethyl)-decylamine: hydrobromide, 0.51 ml of triethylamine and 0.29 ml of ethyl isocyanate A mixture was stirred in 3 ml of dry N,N-dimethylformamide. The product was slowly precipitated from the reaction mixture, collected by filtration and washed with diethyl ether to give the title compound, which is one of the paper sizes applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 public 1 "67 (Please read the notes on the back and fill out this page.) Pack also: 1280242 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (62) Yellow solid (210 mg). Rigo case 2ν· Phenylacetate-4-yl ester will be 45 mg of 4-hydroxy-p-benzo[a]morphine-u-carboxylic acid (2•didecylamino-ethyl)-decylamine hydrobromide, 71 μί of triethylamine and 2 〇pL of acetamidine were dissolved in a mixture of 1-4 ml of dioxane and allowed to mix at room temperature for hours. All volatiles were removed by pumping, and Purification of the residue by column chromatography (10% EtOAc in hexanes) eluted to afford the title compound as a yellow solid (27 mg). 2-Dimethylamine, a certain amount of acetaminophen, a sputum, 笑 噔-4-yloxyl-trifluoroacetic acid, 1 ml of trifluoroacetic acid Up to 18 mg of [11·(2·dimethylamino-ethylamine decyl)-benzo[a]morphine·4·yloxy]-acetic acid tertiary (such as butyl butyl ester dissolved in 1 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -4,11·二羚 st 4-decylamine 114 (2-dimethylamino-ethyl)-bristamine 1 ; trifluoroacetate in 20 ml of sterol, ultrasonic shock 200 mg [η · (2. Didecylamino-ethylamine methyl) - benzo[a] morphine l _4 · oleic acid methyl ester, making it a homogeneous suspension. In this suspension, add 22 mg of potassium telluride. Then, anhydrous ammonia gas was introduced into the mixture for 15 minutes. At room temperature, the reaction mixture was poured for 1 day, and ammonia gas was introduced into the mixture every day. After 10 days, The volatiles are removed by suction, and the paper size is purely using the Chinese National Standard (CNS) A4 specification (210 X 297 mm) using the scintillation chromatography. {Please read the note on the back before filling in this page.)卜!线· 1280242 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 _____B7__ 63 ^5, invention description ()

化殘餘物，產生粗產物。其係使用製備式高壓液態層析儀 (HPLC)予以進一步純化產生本標題化合物，其為一種黃色 固體（10毫克P 實翻_·2·ν_Φ·_·_二甲某胺基-乙基胺曱醯某ν艽其 啡畊-4-羧酸三氟乙醢贛 於4毫升之甲醇與20毫升之氫氧化銨的一個混合物中 ，超音波震盪200毫克之11-(2-二曱基胺基-乙基胺甲醯基 苯并[a]啡啩-4羧酸甲基酯。然後將該懸浮液加熱至5〇t， 歷時92小時。所有之揮發物皆以抽氣移除，產生粗產物。 其係使用製備式高壓液態層析儀（HPLC)予以純化產生本 標題化合物（20亳克）。 實.1例2ίχ·_基甲某-茉#『a14啡-11-羧酸〔2-二甲某脖 基-乙基醯胺 於〇°C下，添加1.97毫升之2.0M氫化溴鋰鹽溶液，至317 毫克之11-(2 - —曱基胺基·乙基胺曱酿基）-笨并[a]啡啡·4叛 酸甲基酯溶於18毫升之四氫呋喃及10毫升之2·丙醇之一個 溶液中。反應混合物留置室溫下攪拌過夜，然後以氣化氨 溶液冷卻。該反應混合物被萃取至醋酸乙酯中，乾燥 (MgSCU)，並以抽氣濃縮。且殘餘物之純化係使用閃爍層 析法（10%曱醇（MeOH)溶於二氣甲烷中），產生本標題化合 物，其為一種黃色固體（98毫克）。 重-¾«例2χ· 4·(Ν·經基胺甲酿某酿亞胺基苯共丨p非哄 dJ-羧酸（2-二甲基胺某-乙篡V醯胺 20毫克之4-氰·苯并[a]啡啡-11-羧酸（2-二曱基胺基·乙 本紙張尺度適用中國國家標準（CNS)A4規格（210x 297公釐） · 69 - ----------^--------^------^---^ (請先閱讀背面之江意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1280242 A7 ___B7 _ 64 五、發明說明（） 基）醯胺、37亳克之碳酸鉀及19亳克之氫氧化胺氣化氫的一 個混合物被加熱至迴流於5亳升之乙醇中，歷時18小時。過 . 濾反應混合物，並收集過濾物，以抽氣移除溶劑後，產生 本（化合物（20毫克）。 兔座例訌i. 4_二甲&quot;_暴一胺_基甲棊-3-羥某·芏并[ql啡畊·n•雜 酸（2·二甲基胺臬-乙基醯胺 26毫克之3-k基·本并[a]啡味·ιι·叛酸（2_二曱基胺基· 乙基）·醯胺，以超音波震盪溶解於2毫升之醋酸中，俾以產 生一均勻之懸浮液。於此懸浮液中添加一個二曱基胺溶於3 宅升水之40%溶液及一個甲搭溶於3毫升水之η%溶液。留 置反應混合物於攪拌下’歷時2天。然後抽氣移除揮發物， 產生本標題化合物（29毫克）。 3-二甲基胺基甲基-4·羥基-笨并[a]啡畊“卜羧酸（2_二 曱基胺基-乙基）·醯胺係以類似之方法製備自4_經基·苯并 [a]啡啩-11-羧酸（2-二曱基胺基·乙基）_醯胺。 复旌例羥暴-乙氧啡畊·n-#n 二曱基胺基-乙基）·醒胺 於125毫克4-[2-(三級（ierij•丁基·二甲基·矽烷基氧基）_ 乙氧基·苯并[a]啡啡-11-緩酸（2-二甲基胺基·乙基）·醯胺溶 於5毫升之四氫呋喃的一個溶液中，添加12毫升之1〇14四 丁基氟化銨溶液。反應混合物於攪拌15小時之後，以醋酸 乙酯稀釋、以水沖洗、乾燥（MgS〇4)，並以抽氣濃縮，產 生之粗產物，其係使用閃燥層析法予以純化產生本標題化 合物，其為一種橘色固體（24毫克）。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --~70 -- {請先閱讀背面之注意事項再填寫本頁) 裝 線· 1280242 經濟部智慧財產局員工消費合作社印製 A7 B7 ，五、發明說明（6D) 實施^2xiii· 4-胺基·茉# [al啡哄-11-#酸（2·二甲基胺某. 乙基）-醯胺 一個由溶於20毫升乙醇之176毫克4-硝基-笨并[a]啡啩 -11·羧酸（2-二甲基胺基-乙基）-醯胺、154毫克銦及5毫升之 飽和氣化銨溶液所構成的混合物，摔加熱至予以迴流3小時 。冷卻反應混合物，以水冷卻然後再通過一個賽力特矽藻 土遽床過滤。以抽氣濃縮過濾、物，然後殘餘物以碳酸氫鈉 溶液處理，萃取至氣仿中，乾燥（MgS04)，並以抽氣移除 溶劑，產生本標題化合物，其為一種紅色固體（163毫克） 。3-胺基-苯并[a]啡啡-11-羧酸（2-二曱基胺基·乙基）·醯胺係 以類似之方法製備自3·硝基-苯并[a]啡啡-11·羧酸（2_二曱 基胺基··乙基）-醒胺。 您.例2xiv·——生-乙酿基胺基-茉并丨al啡g丼-Η·铁酸（2·二曱 基胺基·乙基）-酿胺 於一個溶於5毫升之20毫克的4-胺基·笨并[a]啡啡·ιι_ 羧酸（2-二甲基胺基-乙基）·醯胺四氫咬喃溶液中，添加〇1 毫升之ϋ比咬及乙醜氣。反應混合物於搜拌1小時之後 ，被萃取至醋酸乙酯中，以碳酸氫鈉溶液沖洗，乾燥（MgS〇4) ’並以抽氣移除溶劑。殘餘物與醚一起研磨，產生本標題 化合物，其為一種黃色固體（ίο毫克）。 3·乙醯基胺基-笨并[a]啡啡· n-羧酸（2-二曱基胺基-乙基）_ 醯胺係以類似之方法製備自3-胺基·笨并[a]啡畊·i丨·羧酸 (2·二甲基胺基-乙基）·醯胺及乙醯氣； 4·曱磺醯基胺基-笨并[a]啡啡“ ^羧酸（2•二曱基胺乙基 本紙張尺度適用中國國家標準(CNS)A4規格（21〇 X 297公爱） 71 ----------^--------^---------^ {請先Μ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 1280242 A7 ...... I..I Μ......... — 1 __ 66 ~ ------— 五、發明說明（） )-醯胺係以類似之方法製備自4_胺基·笨并[a]啡啡·1卜羧酸 (2-二甲基胺基-乙基）-醯胺及甲磺醯氯； 3- 曱確酿基胺基-笨并[a]啡味·u，酸（2-二曱基胺基-乙基 )-醯胺係以類似之方法製備自3_胺基·笨并[a]啡畊―丨卜羧酸 (2-二曱基胺基-乙基）-醯胺及曱磺醯氯； 4- 雙·（曱磺醯基胺基）-笨并[a]啡啡羧酸（2•二甲基胺基· 乙基）·醯胺係以類似之方法製備自4_胺基·笨并[a]啡畊·η· 羧酸（2·二甲基胺基-乙基）·醯胺，其使用過量之曱磺醯氯， 並以三乙基胺當做鹼； 實施倒4-(氰甲皋僅—基茉养ral呻啡-η •始齡门-二 甲基胺基-乙基醯胺 將1·〇毫升之曱醛（37%溶液）、102毫克之氰化鉀及1〇 宅升之2Ν乳化風（HC1)添加至溶於1〇毫升甲醇之μ毫克4· 胺基-苯并[a]啡啡·11·羧酸（2·二甲基胺基-乙基）_醯胺的一 個溶液中。反應混合物被加熱至5〇°C，歷時3小時。然後冷 卻反應混合物，以水、碳酸氫鈉溶液稀釋，萃取至二氣甲 烧中’乾無（MgS〇4) ’並以抽氣移除溶劑，產生粗產物。 其係使用閃爍層析法（10%曱醇溶於二氣甲院中）予以純化 產生本標題化合物，其為一種紫色固體（13亳克）。 ^fe.M.2xyi·_3-二甲—基胺基笨并 fal啡哄 _η· 羰基）胺基1-丙酸；氣化氫 於150毫克之3-二曱基胺基-2·[(4-曱氧基-苯并[a]啡畊 -11-幾基）胺基]•丙酸甲基δ旨及50毫升之iM氣化氫（HC1) 之一個混合物加熱至予以迴流1小時。所有之揮發物皆以抽 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 72 - (請先Ktt背面之注意事項再填寫本頁) ί裝 •線 1280242 經濟部智慧財產局員工消費合作社印製 A7 發明說明（ 氣移除，產生本標題化合物，其為一種紅色固體（定量化之 產率）。 H例2xvii· 4一J0-二經基·笨共幾酸〇•二甲 基胺基-乙基V醯脖 添加2.14毫升之一個三溴化硼溶於二氣甲烷的1〇Μ溶 液（9個當量）至96毫克之4，10·二甲氧基-笨并[a]啡哄 &lt; 卜羧 酸（2-二甲基胺基-乙基）·醯胺溶於2毫升二氣甲烷的一個冷 溶液中。攪拌反應混合物16小時後，將冰與碳酸鈉及氣化 鈉同時添加。萃取有機層至二氣甲烷中，乾燥（MgSa〇， 並以抽氣移除溶劑，產生一種橘色之化合物，其係自二氣 甲烷/曱醇/己烷中再結晶以產生本標題化合物（6毫克）。 例2xviii·. 10·羥基-4-甲氣基-茉养『叫啡呌·n_絲醢（2_ 一甲基胺基-乙某V醯胺 添加1.63毫升之一個三溴化硼溶於二氣曱烷的1 〇M溶 液（2.2個當量）至300毫克之4，10·二曱氧基-笨并[a]啡啩d卜 叛酸（2· 一甲基胺基-乙基）-酿胺溶於25毫升二氣甲烧的一 個冷溶液中。授拌反應混合物6小時後，將冰與碳酸鈉及氣 化鈉同時添加。萃取有機層至二氣甲院中，乾燥（MgS〇4) 並以抽氣移除溶劑，產生一種黃色固體，其係以閃爍層析 法純化產生本標題化合物（61毫克）。 10·羥基-4-甲氧基-笨并[a]啡啩-11-羧酸（2-二甲基胺基 甲基·乙基）-醯胺係以類似之方法製自4，1〇-二甲氧基 •笨并[a]啡畊·11·羧酸（2·二甲基胺基-1(R)·曱基-乙基醯 胺；且4-曱氧基-苯并[a]啡畊·11-羧酸（2·二甲基胺基-l(S)- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 73 {請先閱讀背面之注意事項再填寫本頁) 裝 1280242 68 A7The residue is taken to give a crude product. It was further purified using a preparative high pressure liquid chromatography (HPLC) to give the title compound as a yellow solid (10 mg of P. </ RTI> </ RTI> </ RTI> _ _ _ _ _ _ _ dimethyl amino-ethylamine Ultrasonic oscillation of 200 mg of 11-(2-didecylamine) in a mixture of 4 ml of methanol and 20 ml of ammonium hydroxide Methyl-ethylamine-mercaptobenzo[a]-p-anthracene-4carboxylic acid methyl ester. The suspension is then heated to 5 Torr for 92 hours. All volatiles are removed by pumping. The crude product was purified by preparative high pressure liquid chromatography (HPLC) to give the title compound (20 gram). 实. 1 2 χ _ _ 某 - 『 『 『 『 『 『 『 『 『 『 『 『 『 『 2-Dimethyl-ethyl decylamine was added at 〇 ° C, 1.97 ml of 2.0 M hydrogenated lithium bromate solution, to 317 mg of 11-(2- fluorenylaminoethylamine) Base)-stupid [a] morphine 4 acid methyl ester dissolved in 18 ml of tetrahydrofuran and 10 ml of 2 · propanol in a solution. The reaction mixture was left at room temperature and stirred overnight, then with gas The ammonia solution was cooled. The reaction mixture was extracted into ethyl acetate, dried (MgSCU), and concentrated with suction. The residue was purified by flash chromatography (10% methanol (MeOH) dissolved in methane. The title compound is produced as a yellow solid (98 mg). Weight -3⁄4 «Example 2χ·4·(Ν·经基胺甲的酒亚胺苯苯丨p non-哄dJ-carboxylic acid (2-Dimethylamine-acetamide-V-amine 20 mg of 4-cyano-benzo[a]morphine-11-carboxylic acid (2-didecylamino)-paper size applicable to Chinese national standards (CNS) A4 size (210x 297 mm) · 69 - ----------^--------^------^---^ (Please read the back first In addition, please fill out this page.) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1280242 A7 ___B7 _ 64 V. Description of Invention () Base) Amidoxime, 37 grams of potassium carbonate and 19 grams of ammonium hydroxide hydrogenation One of the mixtures was heated to reflux in 5 liters of ethanol for 18 hours. The reaction mixture was filtered and the filtrate was collected, and the solvent was removed by suction to give the product (the compound (20 mg).讧i. 4_ Dimethyl&quot;_暴一胺_基甲棊-3-hydroxy一·芏和[ql啡耕·n•杂酸(2·dimethylamine oxime-ethyl decylamine 26 mg 3-k group· Benzo [a] morphine · ιι · tarenic acid (2_didecylamino) ethyl decylamine, dissolved in 2 ml of acetic acid by ultrasonic vibration, to produce a homogeneous suspension. To the suspension was added a 40% solution of dimercaptoamine dissolved in 3 house liters of water and a η% solution of methacrylate dissolved in 3 ml of water. The reaction mixture was allowed to stand under stirring for 2 days. The volatiles were then removed in vacuo to give the title compound (29 mg). 3-Dimethylaminomethyl-4·hydroxy-p-benzo[a]-panning carboxylic acid (2-didecylamino-ethyl)-guanamine is prepared in a similar manner from 4_jing Benzo [a] phenanthrene-11-carboxylic acid (2-didecylaminoethyl) decylamine. Respiratory hydroxy violent-ethoxylated cultivating n-#n dimercaptoamine -ethyl)- awake amine in 125 mg 4-[2-(three-order (ierij•butyl-dimethyl-decyloxy)-ethoxy]benzo[a]morphine-11-acid (2-Dimethylaminoethyl)-guanamine was dissolved in a solution of 5 ml of tetrahydrofuran, and 12 ml of a solution of 1 〇14 tetrabutylammonium fluoride was added. The reaction mixture was stirred for 15 hours. Ethyl acetate was diluted, washed with water, dried (MgSO.sub.4) and evaporated to dryness eluted eluted Mg) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) --~70 -- {Please read the note on the back and fill out this page.) Installation line · 1280242 Ministry of Economic Affairs Intellectual Property Bureau Employee consumption cooperative printed A7 B7, five DESCRIPTION OF THE INVENTION (6D) Implementation ^2xiii· 4-Amino-Mo. # [alphine-11-# acid (2. dimethylamine. ethyl)-guanamine A solution of 176 mg dissolved in 20 ml of ethanol a mixture of 4-nitro-p-benzo[a]pyrrole-11-carboxylic acid (2-dimethylamino-ethyl)-decylamine, 154 mg indium and 5 ml of a saturated ammonium carbonate solution, The mixture was heated to reflux for 3 hours. The reaction mixture was cooled, cooled with water and then filtered through a celite crucible. The filtrate was concentrated by suction and the residue was treated with sodium bicarbonate solution and extracted to gas. The mixture was dried (MgS04) and solvent was evaporated to give the title compound as a red solid (163 mg). 3-amino-benzo[a]morphin-11-carboxylic acid (2) -Dimercaptoamine·ethyl)·guanamine is prepared in a similar manner from 3·nitro-benzo[a]morphin-11·carboxylic acid (2-didecylamino·ethyl) - 醒 amine. You. 2xiv · - raw - ethyl aryl amino - jasmine 丨 丼 丼 丼 丼 丼 铁 铁 铁 铁 铁 铁 铁 铁 铁 铁 酿 酿 酿 酿 酿 酿 酿 酿 酿 酿5 ml of 20 mg of 4-amino-p- and [a]-morphine-type carboxy In the acid (2-dimethylamino-ethyl)-guanamine tetrahydroanion solution, adding 1 ml of hydrazine is more than biting and ugly. The reaction mixture is extracted for 1 hour and then extracted to acetic acid. The ester was washed with a solution of sodium bicarbonate, dried (M.sub.4), and the solvent was removed. The residue was crystallized with ether to give the title compound as a yellow solid ( ίο. Mercaptoamino-p-benzo[a]morphine-n-carboxylic acid (2-didecylamino-ethyl)-decylamine is prepared in a similar manner from 3-amino-p-[a]-morphine Plough · 丨 · carboxylic acid (2 · dimethylamino - ethyl) · decylamine and acetamidine; 4 · sulfonyl sulfhydryl - benzo[a] morphine " ^ carboxylic acid (2 • Dimercaptoamine ethyl paper size applies to China National Standard (CNS) A4 specification (21〇X 297 public) 71 ----------^--------^---- -----^ {Please read the notes on the back and fill out this page.) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1280242 A7 ...... I..I Μ....... .. — 1 __ 66 ~ ------— V. INSTRUCTION DESCRIPTION ())-Proline is prepared in a similar manner from 4-amino-p-[a]morphine 1 carboxylic acid (2-dimethylamino-ethyl)-decylamine and methanesulfonyl chloride; 3- oxime-branched amino-pupid [a] morphine · u, acid (2-dioxin Alkyl-ethyl)-guanamine is prepared in a similar manner from 3-amino-p-benzo[a]-p-indole-carboxylic acid (2-didecylamino-ethyl)-guanamine and Sulfonium chloride; 4-bis(oxasulfonylamino)- benzo[a]morphinic acid (2•dimethylamino)ethyl) guanamine is prepared in a similar manner from 4 _Amino group, stupid [a] crystallization, η, carboxylic acid (2. dimethylamino-ethyl) decylamine, which uses an excess of sulfonium chloride, and uses triethylamine as a base; Implementation of the inversion 4-(cyanoguanidine-only jatropha morphine-η • primate-dimethylamino-ethyl decylamine 1 〇 ml of furfural (37% solution), 102 mg Potassium cyanide and 1 〇 升 2 2 emulsified air (HC1) was added to μ mg of 4·amino-benzo[a]morphine·11·carboxylic acid (2·dimethylamine) dissolved in 1 ml of methanol. A solution of benzyl-ethylamine amide. The reaction mixture was heated to 5 ° C for 3 hours. Then, the reaction mixture was cooled, diluted with water and a sodium hydrogencarbonate solution, and extracted to a dry gas (MgS?4) and was removed by suction to give a crude product. Purification by flash chromatography (10% sterol in hexanes) gave the title compound as a purple solid (13 g). ^fe.M.2xyi·_3-dimethyl-ylamino benzopyran 哄_η· carbonyl)amino-1-propionic acid; hydrogenated hydrogen to 150 mg of 3-didecylamino-2. (4-Methoxy-benzo[a]morphin-11-yl)amino]•propionic acid methyl δ is heated in a mixture of 50 ml of iM hydrogenated hydrogen (HC1) to reflux for 1 hour. . All volatiles are applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 72 - (Please fill out this page on the back of Ktt) ί装•线1280242 Ministry of Economics Intellectual Property Bureau employee consumption cooperative printed A7 invention description (gas removal, produced the title compound, which is a red solid (quantitative yield). H case 2xvii · 4 a J0-di-based · stupid acid 〇 • Dimethylamino-ethyl V-neck is added 2.14 ml of a solution of boron tribromide dissolved in dioxane (9 equivalents) to 96 mg of 4,10·dimethoxy-stupid [a] 哄 哄 carboxylic acid (2-dimethylamino-ethyl) decylamine is dissolved in a cold solution of 2 ml of di-methane. After stirring the reaction mixture for 16 hours, ice and sodium carbonate are added. And gasification of sodium is added at the same time. The organic layer is extracted into di-methane, dried (MgSa〇, and the solvent is removed by pumping to produce an orange compound from di-methane/methanol/hexane. Crystallization to give the title compound (6 mg). Example 2xviii·. 10·hydroxy-4-methyl group-mosa呌·n_ silk 醢 (2_ monomethylamino-ethyl valine amine added 1.63 ml of a solution of boron tribromide dissolved in dioxane in 1 〇M solution (2.2 equivalents) to 300 mg of 4, 10 · Dimethoxy-p- and [a] 啩 卜 卜 叛 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( After 6 hours of the mixture, the ice was added simultaneously with sodium carbonate and sodium carbonate. The organic layer was extracted into a gas chamber, dried (MgS〇4) and the solvent was removed by suction to give a yellow solid which was flashed. Purification by chromatography gave the title compound (61 mg). <RTI ID=0.0></RTI> </RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Indoleamine is prepared in a similar manner from 4,1 〇-dimethoxy- benzo[a] morphine·11·carboxylic acid (2·dimethylamino-1(R)·decyl-ethyl Indoleamine; and 4-decyloxy-benzo[a]morphine·11-carboxylic acid (2·dimethylamino-l(S)- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 73 {Please read the notes on the back and fill out this page) Install 1280242 68 A7

五、發明說明（ 羥基甲基-乙基）·酿胺係以類似之方法製自二甲氧芙 笨并[a]㈣-U-叛酸（2-二甲基胺基.1(s)·經基甲 酿胺。 复.1^.氧基-9-甲_4^^^111 啡畊·n_游 Μ (2-二甲1胺基-乙基V醯胺 9-氯·4·甲氧基-笨并[a]啡哜·η•羧酸（2•二曱基胺基·乙 基）-醯胺（85毫克）及硫代甲醇鈉（43毫克）溶於i毫升队沁二 甲基曱醯胺之一個混合物，被加熱至12〇χ：維持6小時，然 後加熱至60°C維持16小時。此時將反應混合物冷卻，以醋 酸乙酯稀釋，以水沖洗、乾燥（MgS〇4)，並以抽氣移除溶 劑，產生一種黃色固體，其係以閃爍層析法純化產生所欲 之本標題化合物（37毫克）。 !_jc^[2xx·——4.9-一甲-氧基·笨开『a]啡哄·ι〗·藉酸（2-二甲基 胺基-乙某V醯脍 (請先Μ讀背面之注意事項再填寫本頁) 裝 訂· 9-乳-4·甲氧基-本并[a]啡味-Π-竣酸（2-二曱基胺基·乙 基）-酿胺（85¾克）及一個25 %曱醇鈉溶液溶於4毫升曱醇的 一個混合物，被加熱至予以迴流6小時。然後將反應混合物 冷卻’以醋酸乙酯稀釋，以水沖洗、乾燥（MgS〇4)，並以 抽氣移除溶劑，產生一種黃色固體’其係以閃爍層析法純 化產生所欲之本標題化合物（42亳克）。 實·__2xxi·_4二甲氧基-笨并『al啡啡·11·羧醅（2-二甲某脍 基-1·經基曱基-乙基）·酿胺 於335毫克之3-二曱基胺基-2-[(4-曱氧基-苯并[a]啡啩 -11-叛基）胺基]•丙酸曱基酯及72毫克之氫化紹裡鹽溶於1〇 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 卜線- 經濟部智慧財產局員工消費合作社印製 74 經濟部智慧財產局員工消費合作社印製 1280242 Α7 Β7 五、發明說明（69) 毫升之四氫呋喃及10毫升之異丙醇的一個混合物被攪拌於 室溫下，歷時18小時。再添加另外5個當量之氫化鋁鋰鹽後 ，以另加之18小時攪拌混合物。以氣化銨溶液冷卻反應， 並以醋酸乙酯萃取，乾燥（MgS04)，並以抽氣移除溶劑， 產生一種棕色膠體，其純化係以閃.爍層析法且以乙醚研磨 產生所欲之本標題化合物，其為一種橘色粉末。 實施例3 :具有化學式（I)之化合物的生物體測試 量測具有化學式（I)之化合物的細胞毒性，係使用人類 小型肺癌細胞株：H69之親本（H69/P)，及藉由過量表現P-醣蛋白（Pgp)而具有抗藥性之人類小型肺癌細胞株： H69/LX4 〇細胞毒性之量測係以H69/LX4細胞株之IC50(殺 死細胞數量50°/。所欲之濃度）除以H69/P細胞株之細胞毒性 ，而產生一個指數為一化合物受倚賴-Pgp之多重藥物抗性 (MDR)影響之程度，且稱其為化合物之抗藥性因子（Rf)。 將H69/P及H69/LX4細胞吸取至96-凹槽組織培養盤内 ，然後予以培養於37°C下歷時4小時。其後添加濃度範圍由 O.OOlnM至5 μΜ之具有化學式（I)的化合物或標準組 TAS-103、多克莎盧比辛（Doxorubicin)及托波提肯 (Topotecan)。先將培養盤培養5-6天，然後添加AlamarBlue 至每一個凹槽並將培養盤移回培養箱中留置5-8小時，俾使 顏色產生出來。於此階段結束時，培養盤中之細胞數與測 量波長570 nm之吸光偯成正比（參考波長為600 nm)。 具有化學式（I)的化合物之活性在濃度範圍5nM至5 μΜ之間。挑選之化合物的專一性結果列述於表1。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 75 ----------Aw I ^ · I------^---------^ (請先M讀背面之ii意事項再填寫本頁) 1280242 Α7 Β7 五、發明說明（7()) 表1· 化合物 H69/P IC5〇(nM) H69/LX4 IC5〇(nM) 抗藥ΐϊίϊΤΠ TAS-103 21 22 1.1 多克莎盧比辛 (Doxorubicin) 27.3 3700 135 托波提肯 (Topotecan) 15.9 61.5 3.9 4 35 48 1.4 &quot; 3 35 49 1.4 11 28 24 0.9 94 19 25 1.3 68 19 25 1.3 75 23 28 1.2 91 20 25 1.2 78 24 31 1.3 98 21 20 1 84 19 19 1 ------------裝--- (請先閱讀背面之注意事項再填寫本頁) 於本案中描述之細胞毒性，其量測亦有使用人類非 小型肺癌細胞株COR-L23之親本（COR-L23/P)，及藉由過量 表現與多重藥物抗性相關之蛋白質（MRP)而具有抗藥性之 人類非小型肺癌細胞.株COR-L23R。細胞毒性之量測係以 COR-L23R細胞株之IC50(殺死細胞數量50%所欲之濃度）除 以COR-L23R/P細胞株之細胞毒性，而產生一個指數為一化 合物受倚賴-MRP之多重藥物抗性（MDR)影響之程度，且稱 其為化合物之抗藥性因子（Rf)。 將L23/P及L23/R細胞吸取至96-凹槽組織培養盤内， 然後予以培養於37°C下歷時4小時。其後添加濃度範圍由 O.OOlnM至5 μΜ之具有化學式（I)的化合物或標準組 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --線· 經濟部智慧財產局員工消費合作社印製 76 1280242 經濟部智慧財產局員工消費合作社印製 A7 B7 71 五、發明說明（） TAS-103、多克莎盧比辛（Doxorubicin)及托波提肯 (Topotecan)。於使用 Skehan et al，J Natl Inst 199CL 82，第 1107-1112頁所描述之sulphurhodamine B(SRB)分析法評估 細胞增生之前，先將培養盤培養5-6天。 化合物之活性在濃度範圍InM至5 μΜ之間。專一性樣 品被列述於表2。 表2· 化合物 L23/P IC5〇(nM) L23/R ICso(nM) 抗藥性因子R/ TAS-103 16.3 22 1.3 多克莎盧比辛 (Doxorubicin) 20.3 326.8 16.1 托涑提肯 (Topotecan) 13.6 20.8 1.5 4 、 14.7 16.8 1.1 3 14.4 19.9 1.4 11 6.1 17.7 2.9 94 5.7 3.8 0.7 68 13.1 44·4 3.4 75 13.0 17.2 1.3 91 4 12.4 3.1 78 7.6 8.9 1.2 98 9.6 · 8.8 0.9 於本案中描述之細胞毒性，其量測亦有使用JurKat人 類血癌細胞株（JLc)，及對安紗克萊恩（amsacrine)有抗藥性 之JurKat人類血癌細胞株（JLa)，還有對多克莎盧比辛 (Doxorubicin)有抗藥性之jurKat人類血癌細胞株（JLD)。細 胞毒性’其量測係以JLa或JLD細胞株之IC5G(殺死細胞數量 50%所欲之濃度）除以jLc細胞株之細胞毒性，產生一個指 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 77 ----------I ^ —--------- (請先閱讀背面之注意事項再填寫本頁) 1280242 Α7 Β7 72 五、發明說明（） 數為一化合物受非典型藥物抗藥性影響之程度，且稱其為 化合物之抗藥性因子（Rf)。所使用之方法已被描述於Finlay et al，Eur J· Cancer 32A，708-714, 1996。化合物之活性在濃 度範圍InM至5 μΜ之間。專一性樣品被列述於表2。 表3. 化合物 JLc IC5〇(nM) JLa IC50 (nM) 抗藥性因子 R/(JLa/ JLr) JL〇 IC50 (nM) 抗藥性因子 R/*(JLd./ JLr) TAS-103 5.4 302 55.9 384 71.1 多克莎盧比辛 (Doxorubicin) 7.0 25.9 3.7 109 15.6 4 19.0 26.6 L4 22.8 1.2 3 27.0 21.6 0.8 24.3 0.9 2 37 96 2.6 107 2.9 35 28 19 0.7 25 0.9 78 21 14 0.7 17 0.8 81 8.7 9.2 1.1 9.3 1.1 84 4.4 9.8 2.2 7.2 1.6 — 87 16 16 1.0 17 1.0 94 9.2 16 1.8 14 1.6 98 8.6 18 2.1 14 1.6 經濟部智慧財產局員工消費合作社印製 對化合物亦探討其在拓樸異構酶I或拓樸異構酶II存 在之下，安定可切割複合物的效力，主要係如Finlay etal， Eur J. Cancer 32A，708-714, 1996所描述。指示可切割複合 物之存在，係藉由電泳及自動放射性顯影之後所觀測到橫 紋（bands)之數量及密度的增加。該結果之表示是以有效濃 度範圍，此範圍所觀察到可切割複合物之增加，係相對於 無藥物存在之控制組。本案描述之多種化合物，係使用此 等方法及顯示在0.01-20 μΜ範圍内對拓樸異構酶I及拓樸 78 -----------裝· ！ (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） 1280242 A7 B7 7 73 ,五、發明說明（） 異構酶II具有毒性之化合物。專&quot;性樣品被列述於表4。ΜΛ 有效濃度範圍(μΜ) 化合物 拓樸異構酶I 拓樸異構酶II TAS-103 0.3-10.0 0.3-10.0 3 0.1-3.0 0.1-3.0 4 0.1-3.0 0·1·3·0 35 0.03-1.0 0.03-1.0 78 0.03-1.0 0.03-1.0 84 0.03-1.0 0.03-1.0 ------------裝— (請先M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 實施例4 :藥學組成物 藥錠，每錠重量為0· 15克，且含有25毫克之本發明化 合物，其係可以下列所述來製造： 用以贺造10,000片藥錠之組成物 本發明之化合物（250毫克） 乳糖（800克） 玉米澱粉（415克） 滑石粉（30克） 硬脂酸鎂（5克） 混合本發明之化合物、乳糖及半量之玉米殿粉。然後 迫使混合物通過一個篩目大小為〇.5nim之篩網、玉米澱粉 (1 〇克）被懸浮在90毫升之溫水中。所產生之糊被用來使粉 末結為顆粒。乾燥顆粒後，於一個篩目大小為丨4 mm之篩 網上將其壓成小片段。添加剩餘量之澱粉、滑石粉及硬脂 酸鎂，小心地混合並加工製成藥錠。 .-線- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 79 1280242 A7 _B7_ 74 五、發明說明（） 實施例5 :具有化學式⑴之化合物的定性分析 由實施例3製備之化合物是以質子之（N.M.R.)及予以 定性分析。所有之質子核磁共振皆以400MHz進行。由質譜 分析法進行定性分析是使用去吸附化學性離子化方法或電 子喷射離子化方法。結果詳列於下列之表内。 -----------* 裝--- (請先閱讀背面之注意事項再填寫本頁) 訂： ——線- 經濟部智慧財產局員工消費合作社印製 80 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280242 A7 B7 Ί. 五、發明說明（ 75 經濟部智慧財產局員工消費合作社印製 〇 Ό 00 On LT\ U) to cr D： 2: p p X % P Ο 2： U» 9 p Ϊ P P s P P Ρ s£ ί P £1 ί P P P P K； iT P 屮 &gt; 2 X + UJ # + w泠 2 jC oo fl 泠2： 年P g 2 于 u&gt; Di § u&gt; s 2 ? U) $ 2 toiiA-i 2 l^-l UJ Dl 减 e»W 嘛 quW 笏 · · 5 〇 έ交 赛5 5 ^ 一 $ 2s 00 bi s p α： r〇 P* 4 - ¥ pc to p UJ U)— =po Ξ 00 3 00 ο ij 3 U) I ^ 7s H I 00 S g 〇 Ξ妥 gs 〇 Ki ?° 'io 1o 2： ^ =# io ^ 吞5 3父 N·*^ Μ» .X IP —U) 2： 為r- 1a ^-&quot;to — 55 -P^ Ό ll N)— 33 U) 00 § P- s ?° § oi 〇\ Ή： ^ — g聋 §3 ITs oo Ϊ to •f 2 Q 7： = r CL W ^ μ &gt; i. t〇 在5 V圣 —窗 s^&gt; Q &gt; £ δ ;P〆 vi? 00 to 5交交 ^ = s =P- C 111 ;; &gt; Q 00 Μ* «Μ» 3： 2： Q- sT* II i C3 〇 1 — ·· 9s 3C 5 贫g龛 _ OO 00 — V5 Ξ ^ ·—— 务3 Ιϋ, s文 工彐 &gt; 二 3女 、00 έ| 一， -U ?° 〇 00 ^ V-, Ιέ 1异 κ 1 '-Ο — ^. Os 一 sr * is it ^ s 一 L/i HI — P f 〇 o !? ^ mmm It bo X £ 5 P- K) 一 C^ ί£Ξ ;g y 2 多？ K&gt; ?® a §2 00¾ ?! P to C: K&gt; X v£&gt; 从 mmrnk 3 9； IsJ T w ^ ?〇 S ^3 3 ^ ^ S β =： gd $ ^ 〇 2〇 b3 =芑 5 S Μ» 从 MS ! U) 一 S ??!? 设§ Ss^i V s ^ 3 L^J fv _ ^ 犬；彐？© |t^| if^ 匕ΐ垄 ^ - π: 11« U) — 泽3萁 UJ . ^ Ό II 云is S ut0 v-n v〇 00 li安 to ^ P g ^mrn l Lfi 安 3 r°它a 吴乙2 f AS 3耷一 .^ s =^ 90 s 3s 5 i— v〇 —— 53 oo ^ on It 53 U&gt; 00 bo 辦&amp; ^v »SJ Γ* 3片 N s 15 to ^ ^ 安？s Λ[· ^ ώ P ^ !〇 印i N oo ^ On 〇 v〇 ⑼V ΰ!| m 5 = έ s| Η &gt; |5 SToo 以 a 一 00 SD 译s 3译 1兵 yi UJ 1 工一 Z 2 η ----------I ^-------1^7---------^(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） 81 76,1280242 A7 B7 五、發明說明（ U·) ?3 C24H26N03 DCTNH3 m/e ±9(M+, 10s 024H27N5O2V. INSTRUCTION DESCRIPTION (Hydroxymethyl-ethyl)·Tainamine is prepared in a similar manner from dioxol and [a](tetra)-U-tagamic acid (2-dimethylamino.1(s) ·Alkylamine. Complex.1^.Oxy-9-甲_4^^^111 耕 · · n_游Μ (2-dimethyl 1 amino-ethyl V decylamine 9-chloro·4 ·Methoxy-p- and [a] quinone·η•carboxylic acid (2•didecylaminoethyl)-decylamine (85 mg) and sodium thiomethoxide (43 mg) dissolved in i ml A mixture of dimethyl decylamine, heated to 12 Torr: maintained for 6 hours, then heated to 60 ° C for 16 hours. The reaction mixture was cooled, diluted with ethyl acetate, rinsed with water, dried (MgS 〇 4), and the solvent was removed by suction to give a yellow solid which was purified by flash chromatography to give the desired title compound (37 mg). _jc^[2xx·——4.9- A-oxyl stupid "a] brown 哄 · ι〗 · Acid (2-dimethylamino-B-V 醯脍 (please read the back of the note before you fill out this page) Binding · 9- Milk-4·methoxy-benzo[a]morphin-indole-decanoic acid (2-didecylaminoethyl)-bristamine (853⁄4 g) and A 25% sodium sterol solution was dissolved in 4 ml of a mixture of decyl alcohol and heated to reflux for 6 hours. The reaction mixture was then cooled 'diluted with ethyl acetate, rinsed with water, dried (MgS 〇 4), and The solvent was removed by suction to give a yellow solid, which was purified by flash chromatography to give the desired title compound (42 g). __2xx·_4 dimethoxy-stuppy Carboxylic acid (2-dimethyl sulfhydryl-1·transyl hydrazino-ethyl)·bristamine in 335 mg of 3-dimercaptoamino-2-[(4-decyloxy-benzo[ a] phenanthrene-11-refenyl)amino]•propionate propionate and 72 mg of hydrogenated suri salt dissolved in 1 〇 paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm)线线- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 74 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1280242 Α7 Β7 V. Invention Description (69) A mixture of THF in tetrahydrofuran and 10 ml of isopropanol was stirred in At room temperature, it lasted for 18 hours. After adding another 5 equivalents of lithium aluminum hydride salt, it was stirred and mixed for another 18 hours. The reaction was cooled with a vaporized ammonium solution, extracted with ethyl acetate, dried (MgSO4), and solvent was evaporated to give a brown solid. The desired title compound is produced as an orange powder. Example 3: Biological test of a compound of formula (I) cytotoxicity of a compound of formula (I) using a human small lung cancer cell line : The parent of H69 (H69/P), and the human small lung cancer cell line resistant by overexpression of P-glycoprotein (Pgp): H69/LX4 The cytotoxicity of 〇 cytotoxicity is H69/LX4 cell line IC50 (kills the number of cells 50 ° /. The desired concentration) is divided by the cytotoxicity of the H69/P cell line to produce an index of the extent to which a compound is affected by the multidrug resistance (MDR) of the dependent-Pgp, and is referred to as the compound's drug resistance factor (Rf). ). H69/P and H69/LX4 cells were pipetted into a 96-groove tissue culture dish and then cultured at 37 ° C for 4 hours. Compounds of formula (I) or standard groups TAS-103, Doxorubicin and Topotecan are then added in concentrations ranging from O. OOlnM to 5 μΜ. The plates were first incubated for 5-6 days, then AlamarBlue was added to each well and the plates were returned to the incubator for 5-8 hours to produce a color. At the end of this phase, the number of cells in the plate was proportional to the absorbance at 570 nm (reference wavelength 600 nm). The activity of the compound of formula (I) is in the range of 5 nM to 5 μΜ. The specificity results of the selected compounds are listed in Table 1. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 75 ----------Aw I ^ · I------^-------- -^ (Please read the back of the ii and then fill out this page) 1280242 Α7 Β7 V. Invention description (7()) Table 1· Compound H69/P IC5〇(nM) H69/LX4 IC5〇(nM)药ΐϊίϊΤΠ TAS-103 21 22 1.1 Doxorubicin 27.3 3700 135 Topotecan 15.9 61.5 3.9 4 35 48 1.4 &quot; 3 35 49 1.4 11 28 24 0.9 94 19 25 1.3 68 19 25 1.3 75 23 28 1.2 91 20 25 1.2 78 24 31 1.3 98 21 20 1 84 19 19 1 ------------ Pack--- (Please read the notes on the back and fill out this page) The cytotoxicity described in this case was also measured using the parent of the human non-small lung cancer cell line COR-L23 (COR-L23/P) and the protein (MRP) associated with multidrug resistance by excess. The drug-resistant human non-small lung cancer cell line COR-L23R. The cytotoxicity was determined by dividing the IC50 of the COR-L23R cell line (the concentration required to kill 50% of the cells) by the cytotoxicity of the COR-L23R/P cell line, resulting in an index of a compound dependent on MRP. The degree of multidrug resistance (MDR) affects and is referred to as the compound's drug resistance factor (Rf). L23/P and L23/R cells were pipetted into a 96-well tissue culture dish and then cultured at 37 ° C for 4 hours. Subsequent addition of a concentration range from O.OOlnM to 5 μΜ of the compound of formula (I) or standard group paper size applicable to China National Standard (CNS) A4 specification (210 X 297 mm) - Line · Ministry of Economics intellectual property Bureau employee consumption cooperatives printed 76 1280242 Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed A7 B7 71 V. Invention Description () TAS-103, Doxorubicin and Topotecan. The plates were incubated for 5-6 days prior to evaluation of cell proliferation using Sulphurhodamine B (SRB) assay as described by Skehan et al, J Natl Inst 199CL 82, pp. 1107-1112. The activity of the compound is in the range of concentrations from InM to 5 μΜ. Specific samples are listed in Table 2. Table 2. Compound L23/P IC5〇(nM) L23/R ICso(nM) Drug resistance factor R/ TAS-103 16.3 22 1.3 Doxorubicin 20.3 326.8 16.1 Topotecan 13.6 20.8 1.5 4 , 14.7 16.8 1.1 3 14.4 19.9 1.4 11 6.1 17.7 2.9 94 5.7 3.8 0.7 68 13.1 44·4 3.4 75 13.0 17.2 1.3 91 4 12.4 3.1 78 7.6 8.9 1.2 98 9.6 · 8.8 0.9 The cytotoxicity described in this case, JurKat human blood cancer cell line (JLc), JurKat human blood cancer cell line (JLa) resistant to amsacrine, and resistant to Doxorubicin were also used for the measurement. The jurKat human blood cancer cell line (JLD). Cytotoxicity's measurement is based on the IC5G of JLa or JLD cell line (the concentration of 50% of the killed cells) divided by the cytotoxicity of the jLc cell line, resulting in a paper scale applicable to the Chinese National Standard (CNS) A4. Specifications (210 X 297 public) 77 ----------I ^ —--------- (Please read the note on the back and fill out this page) 1280242 Α7 Β7 72 V. DESCRIPTION OF THE INVENTION () The number is a degree to which a compound is affected by atypical drug resistance and is referred to as a compound's drug resistance factor (Rf). The method used has been described in Finlay et al, Eur J. Cancer 32A, 708-714, 1996. The activity of the compound is in the range of InM to 5 μΜ. Specific samples are listed in Table 2. Table 3. Compound JLc IC5〇(nM) JLa IC50 (nM) Drug resistance factor R/(JLa/ JLr) JL〇IC50 (nM) Drug resistance factor R/*(JLd./ JLr) TAS-103 5.4 302 55.9 384 71.1 Doxorubicin 7.0 25.9 3.7 109 15.6 4 19.0 26.6 L4 22.8 1.2 3 27.0 21.6 0.8 24.3 0.9 2 37 96 2.6 107 2.9 35 28 19 0.7 25 0.9 78 21 14 0.7 17 0.8 81 8.7 9.2 1.1 9.3 1.1 84 4.4 9.8 2.2 7.2 1.6 — 87 16 16 1.0 17 1.0 94 9.2 16 1.8 14 1.6 98 8.6 18 2.1 14 1.6 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printed on Compounds Also Discussed in Topoisomerase I or Topology The efficacy of diazepam-cleavable complexes in the presence of isomerase II is primarily as described by Finlay et al, Eur J. Cancer 32A, 708-714, 1996. Indicates the presence of the cleavable complex as an increase in the number and density of the bands observed by electrophoresis and automated radioactive development. The results are expressed as an effective concentration range in which an increase in the cleavable complex is observed relative to the control group in which no drug is present. The various compounds described in this case are using these methods and are shown in the range of 0.01-20 μΜ for the topoisomerase I and the topology 78 ----------- (Please read the notes on the back and fill out this page.) This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm). 1280242 A7 B7 7 73 , V. Description of invention () Isomerase II is toxic Compound. Special &quot; sex samples are listed in Table 4. ΜΛ Effective concentration range (μΜ) Compound topoisomerase I Topoisomerase II TAS-103 0.3-10.0 0.3-10.0 3 0.1-3.0 0.1-3.0 4 0.1-3.0 0·1·3·0 35 0.03- 1.0 0.03-1.0 78 0.03-1.0 0.03-1.0 84 0.03-1.0 0.03-1.0 ------------ Installed - (Please read the note on the back of the M and then fill out this page) Ministry of Economics Intellectual Property Bureau employee consumption cooperative printing Example 4: Pharmaceutical composition tablet, weighing 0.55 g per ingot, and containing 25 mg of the compound of the present invention, which can be manufactured as follows: Used to make 10,000 tablets Composition of the ingot Compound of the invention (250 mg) Lactose (800 g) Corn starch (415 g) Talc powder (30 g) Magnesium stearate (5 g) Mix the compound of the invention, lactose and half of the corn powder . The mixture was then forced through a sieve having a mesh size of 〇.5nim, and corn starch (1 gram) was suspended in 90 ml of warm water. The resulting paste is used to make the powder into particles. After drying the granules, they were pressed into small pieces on a sieve having a mesh size of 丨4 mm. The remaining amount of starch, talc and magnesium stearate were added and carefully mixed and processed into tablets. .-Line - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 79 1280242 A7 _B7_ 74 V. Inventive Note () Example 5: Qualitative analysis of compound of formula (1) by Example 3 The prepared compounds were analyzed by proton (NMR) and qualitatively. All proton nuclear magnetic resonances were performed at 400 MHz. Qualitative analysis by mass spectrometry is performed using a desorption chemical ionization method or an electron injection ionization method. The results are detailed in the table below. -----------* Pack--- (Please read the note on the back and fill out this page) Order: ——Line - Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print 80 This paper size applies China National Standard (CNS) A4 Specification (210 X 297 mm) 1280242 A7 B7 Ί. V. Invention Description (75 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 〇Ό 00 On LT\ U) to cr D: 2: Pp X % P Ο 2: U» 9 p Ϊ PP s PP Ρ s£ ί P £1 ί PPPPK; iT P 屮&gt; 2 X + UJ # + w泠2 jC oo fl 泠2: Year P g 2 u&gt; Di § u&gt; s 2 ? U) $ 2 toiiA-i 2 l^-l UJ Dl minus e»W 〔quW 笏· · 5 〇έ 5 5 5 ^ 一 $ 2s 00 bi sp α: r〇 P* 4 - ¥ pc to p UJ U)— =po Ξ 00 3 00 ο ij 3 U) I ^ 7s HI 00 S g 〇Ξ gs gs iKi ?° 'io 1o 2: ^ =# io ^ 吞5 3 parent N·*^ Μ» .X IP —U) 2: is r- 1a ^-&quot;to — 55 -P^ Ό ll N)— 33 U) 00 § P- s ?° § oi 〇\ Ή : ^ — g聋§3 ITs oo Ϊ to •f 2 Q 7: = r CL W ^ μ &gt; i. t〇 at 5 V Saint-window s^&gt; Q &gt; £ δ ;P〆vi? 00 To 5 handover ^ = s =P- C 11 1 ;; &gt; Q 00 Μ* «Μ» 3: 2: Q- sT* II i C3 〇1 — ·· 9s 3C 5 poor g龛_ OO 00 — V5 Ξ ^ ·—— 务 3 Ιϋ, s彐 彐 二 二 二 二 二 二 一 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 〇o !? ^ mmm It bo X £ 5 P- K) One C^ ί£Ξ ;gy 2 more? K&gt; ?® a §2 003⁄4 ?! P to C: K&gt; X v£&gt; From mmrnk 3 9; IsJ T w ^ ?〇S ^3 3 ^ ^ S β =: gd $ ^ 〇2〇b3 =芑5 S Μ» From MS ! U) One S ??!? Set § Ss^i V s ^ 3 L^J fv _ ^ Canine; 彐? © |t^| if^ 匕ΐ ^ ^ - π: 11« U) — 泽 3萁UJ . ^ Ό II Cloud is S ut0 vn v〇00 li An to ^ P g ^mrn l Lfi 安 3 r° It a 吴乙2 f AS 3耷一.^ s =^ 90 s 3s 5 i— v〇—— 53 oo ^ on It 53 U&gt; 00 bo office &amp; ^v »SJ Γ* 3 slices N s 15 to ^ ^ Ann? s Λ[· ^ ώ P ^ !〇印i N oo ^ On 〇v〇(9)V ΰ!| m 5 = έ s| Η &gt; |5 SToo to a 00 SD translation s 3 translation 1 yi yi UJ 1 work A Z 2 η ----------I ^-------1^7---------^ (please read the notes on the back and fill out this page) Paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 81 76,1280242 A7 B7 V. Invention description (U·) ?3 C24H26N03 DCTNH3 m/e ±9(M+, 10s 024H27N5O2

Dsm/e 厶84/486 3:1 β sowDsm/e 厶84/486 3:1 β sow

C25H28N4P E+m/z416 (M+12%)； 346(100%)； 329(58%)； 02102 MS DCTNH3, m/e 389 (MH+, 100%)C25H28N4P E+m/z416 (M+12%); 346 (100%); 329 (58%); 02102 MS DCTNH3, m/e 389 (MH+, 100%)

C2I 【lvl+H】+ ^.it: 405C2I [lvl+H]+ ^.it: 405

C24II22N4P MS DC1+NH3, m/e399 (MH+, 100%)C24II22N4P MS DC1+NH3, m/e399 (MH+, 100%)

C28H26N4P MS ix:l+N 一 B, m/e 451 (MH+JOO%)C28H26N4P MS ix: l+N a B, m/e 451 (MH+JOO%)

C15P MS DCI3, m/e 400 (MmJOO%) -----------1 裝 *-- (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 CS13 ; 2.69(6H, s)，2.92-3.52H, In)； 3.49(3H, s)； 3·83-3·93(2Η, t, J1.4HZ)； 3·94-4·10{2Η,旦 +28-4.40{2H, t, J1.4HZ)； 7.22(1=d, J=8oHZ)； 7OO00H, t)； 7.84-7.96{2H, m, JI.7HZ, 8.3Ht^ 8.37( 1H, d, J&quot;8.2HZ)； 8.54( 1H, d, J J.4HZ)； 8.82( 1H, d, J&quot;7.4HZ)； 8.90{ 1 H:o. 二.10(1H, ^ 3W- 3W- ^ ^ ^ ^ Tss, ^ i-SNW- βί, ^ -- ^ r^&gt;s., ^ SOS ^ Tss, 10.30(1=s). none - ^§β s, ^ Ϊβ r?,^ i OZN^ 3W- 3W- 3W- ^ 2.24(1=m)； 1·11(6=d, J-6.8HZ)· &amp;6MSO; 1.52(3=CA9HZ)，2.35(6H, s)，2.65(2H,CH5.9HZ)，3 J2-3.75(2H, m)， 4.30{2=q, J 本 9IIZ)，7.43(1=d, J=8.6, 1.611Z)，8.450H, d, J4.5H 芬 8.94( 1H, d, J=8.2HZ)，1 P25( 1H, t, J=5oHZ). ODCI3 ;1P82(1H,料命，s)9.11(1H, d, J 8.9)，?®91(1H, d, J 73)，8.40·8.30{2Η, m)，7.997.8K2H, m)，l^ ^ β ^ ^ ^ β ^ ^ ^.ow- ^.ββC15P MS DCI3, m/e 400 (MmJOO%) -----------1 Pack *-- (Please read the note on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative CS13; 2.69(6H, s), 2.92-3.52H, In); 3.49(3H, s); 3·83-3·93(2Η, t, J1.4HZ); 3·94-4·10{ 2Η,旦+28-4.40{2H, t, J1.4HZ); 7.22(1=d, J=8oHZ); 7OO00H, t); 7.84-7.96{2H, m, JI.7HZ, 8.3Ht^ 8.37( 1H, d, J&quot;8.2HZ); 8.54( 1H, d, J J.4HZ); 8.82( 1H, d, J&quot;7.4HZ); 8.90{ 1 H:o. II.10(1H, ^ 3W- 3W- ^ ^ ^ ^ Tss, ^ i-SNW- βί, ^ -- ^ r^&gt;s., ^ SOS ^ Tss, 10.30(1=s). none - ^§β s, ^ Ϊβ r?, ^ i OZN^ 3W- 3W- 3W- ^ 2.24(1=m); 1·11(6=d, J-6.8HZ)· &amp;6MSO; 1.52(3=CA9HZ), 2.35(6H, s), 2.65 (2H, CH5.9HZ), 3 J2-3.75(2H, m), 4.30{2=q, J 9IIZ), 7.43 (1=d, J=8.6, 1.611Z), 8.450H, d, J4 .5H 芬8.94( 1H, d, J=8.2HZ), 1 P25( 1H, t, J=5oHZ). ODCI3 ;1P82(1H, material life, s)9.11(1H, d, J 8.9),?® 91(1H, d, J 73), 8.40·8.30{2Η, m), 7.997.8K2H, m), l^ ^ β ^ ^ ^ β ^ ^ ^.ow- ^.ββ

nan^ .- ^ ^ r^.s, ^ Ϊ 0INW- 3W-^ ^ Tss, 3W- 3W- 05(1H, dd, Jn8.50,1.6HZ)，8.500 H, d, J=9ooHZ)，8.95( 一^&amp;, tH^ 10.800 H, §)· _I ORC - ^ ss, ^ £ 0XNW- 3W- ^ 3W- 3W- ^.β - X, β Trs, 8.63(lH,d,J=9.4HZ)，9oo-9o7(2H,m)，10.90{1ϋ t,#). nDCB ; 236{6H, S)，2·68(2Η, U=5.9HZ)，3bor3bo4{2n m)，5o2(2H, s)，7.33.7.49C4H, m)， 7.55(2H, d, J&quot;7.2HZ)，7.73-7.77(一 H,m)，7.95-8o2(2H, m)，8.4aH, dd,lr8.61,1.5Ϊ 8.63( 1H, d, J=9.4HZ)，9.00-9o7(2ii m)，10.900 H, !:❖)· 、'§J- .線· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 82 1280242 A7 _B7_77 〃五、發明說明（） , HI ~Kl ΰΐ §1 sNan^ .- ^ ^ r^.s, ^ Ϊ 0INW- 3W-^ ^ Tss, 3W- 3W- 05(1H, dd, Jn8.50, 1.6HZ), 8.500 H, d, J=9ooHZ), 8.95 (一^&amp;, tH^ 10.800 H, §)· _I ORC - ^ ss, ^ £ 0XNW- 3W- ^ 3W- 3W- ^.β - X, β Trs, 8.63(lH,d,J=9.4HZ ), 9oo-9o7(2H,m), 10.90{1ϋ t,#). nDCB ; 236{6H, S), 2·68(2Η, U=5.9HZ), 3bor3bo4{2n m), 5o2(2H, s), 7.33.7.49C4H, m), 7.55(2H, d, J&quot;7.2HZ), 7.73-7.77 (a H, m), 7.95-8o2 (2H, m), 8.4aH, dd, lr8.61 , 1.5Ϊ 8.63 ( 1H, d, J=9.4HZ), 9.00-9o7 (2ii m), 10.900 H, !:❖)·, '§J-. Line · This paper scale applies to China National Standard (CNS) A4 Specifications (210 X 297 mm) 82 1280242 A7 _B7_77 〃5, invention description (), HI ~Kl ΰΐ §1 s

C22H22N0S mI+m/z390 (M+,100%)C22H22N0S mI+m/z390 (M+,100%)

C26H3IN5P DCT{NH3) m/z 446 (MH+, 100%) C2-H19FN0 nvl+H】+ 363 C22H22N0 【Mirl+ 359C26H3IN5P DCT{NH3) m/z 446 (MH+, 100%) C2-H19FN0 nvl+H】+ 363 C22H22N0 [Mirl+ 359

C25H25N5P DCTCNH3) m/z 428 (MIT, 100%)C25H25N5P DCTCNH3) m/z 428 (MIT, 100%)

C27H31N5PC27H31N5P

Dc+oim) ni/z 474 (i+, 100%) 025=242:403 DCI+13) m/z439 (MlTJOs/0) o23=4no3 a+^H3) m/z 办 05 1+,100%) C2l=9ib2 DC1+NH3: m/z 439/441 (一:1 (MH+)Dc+oim) ni/z 474 (i+, 100%) 025=242:403 DCI+13) m/z439 (MlTJOs/0) o23=4no3 a+^H3) m/z Office 05 1+,100%) C2l =9ib2 DC1+NH3: m/z 439/441 (one: 1 (MH+))

C25H26N4P Q+fNH3} m/z447 (M+, 1) ------------裝 * — (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 ODCI3; 10.79( 1H, £#)； 9·32( 1H, m)； 9.02( 1H, dd, JH7.2,1.5HZ)； 8.63 三 8.42( 1H, dd, J&quot;8&gt;K5HZ)，8.05( 1H, d, J=97HZ)； 7.99( 1H, m)； 7.76{2=m)； 3.90{2= 2.66(3H,S)；2.43(6H,S)._ 0只13; 2」5-2.21(2H, m)，134(6H, s)，2.t(6H, s)，163(2H, u=7.2h^ 3W- ίβ ^ 3W- §β 3W._ 0813) 10.67 (1H, s,辦布)，9.22(1H, d, J 8·1)，8.970H, dd, J 7.3, 1.5)，8.36{u^ 8k)9(lH, d, J 9·5)，7.97(1H, d, J 9.5)，193(1H, dd, J 8.5, 7.2)，7.71(5^ 5.5)，2.68(2ΗΛ J 5.8)，2.37(6H, s)· ,_ (CDCI3) 10.88(1=辦斧 S)，9.34(1H, d, J 7·9)，&gt;02(1Η, dd, J 7.3, 1.5)，8.4¾^ 8.31(lH,d,J^.7HZ)，9o5(lH,dd,J=72,r5HZ)&gt;*08(lH,d,J=8.2HZ)，lo』^ _ ORC - 3, ^ββ ^ s,s^ 3W- ^ =-w- 5β r^M 3W-Bw-3.X-βTP 8.56{ 1H, d, JA.7HZ)，9.05( 一 Hk, J=7.2,1.5HZ)，9.08( 一 H,d,J=82HZ)J 0.83^ 0DC13 ; ^ 3, ^ s.oi ^ 3W. 3W- ^ 3W- 3W-8.41(lH,dd, J=8.5J.5HZ)，8.55(lH,p-J=9.5HZ)，9ol-9o5(2H, m)Jp80 ODC13 ; ^ 3W- i ISP ^ «.so^ ^ s.^XNW- ^-=- β TP ^.^SNW- CRB ; 1P690H,矜命)；8.93(1H, dd, J=73, 1·5ΗΖ)； 8.800H, d, J=83HZ)； ε 7.二(1H, d, J=7.9HZ)；.^27(2J=3)； 4·二(2H, m)； 3.83(2H, q, J=5.7HZ)； 2.68(2H, t, J=6oHN)；i 2.35(6H,S)._ CDC13 ; 2·44(6Η, s)； 2·76{2Η, u=6o)，3_89(2H q,¢--1^37.840^^^8.7).7.90^0.0^2=3)，1 8.39{ 1H,p-lrsONx 8.58( 1H, d, J=9.6)，8005( 1H, d, J=8.8)，8.99{ 1H, ^ CDC13 ; 10.76OH,㈣逢；9010H, d,lr8.2HZ}; 8.940H, dd, J=73, 1.5HZ)； 8.580H, d, JJ5HZ)； ssx, β s, ^ ^ v«.os ίβ ^ p s- - XNW- ^ 3W- - .sx, ^ s- - Fw._ Ί · 今0 卜線· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83 781280242 A7 B7 五、發明說明（ U) Lr\ U) Π22Η 一 9NbC25H26N4P Q+fNH3} m/z447 (M+, 1) ------------ Pack* — (Please read the note on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative ODCI3; 10.79( 1H, £#); 9·32( 1H, m); 9.02( 1H, dd, JH7.2, 1.5HZ); 8.63 three 8.42 ( 1H, dd, J&quot;8&gt;K5HZ), 8.05 (1H, d, J=97HZ); 7.99( 1H, m); 7.76{2=m); 3.90{2= 2.66(3H,S);2.43(6H,S)._ 0 only 13; 2”5 -2.21(2H, m), 134(6H, s), 2.t(6H, s), 163(2H, u=7.2h^ 3W- ίβ ^ 3W- §β 3W._ 0813) 10.67 (1H, s, do cloth), 9.22 (1H, d, J 8·1), 8.970H, dd, J 7.3, 1.5), 8.36{u^ 8k)9(lH, d, J 9·5), 7.97 (1H , d, J 9.5), 193 (1H, dd, J 8.5, 7.2), 7.71 (5^5.5), 2.68 (2ΗΛ J 5.8), 2.37 (6H, s)·, _ (CDCI3) 10.88 (1=do Axe S), 9.34 (1H, d, J 7·9), &gt;02 (1Η, dd, J 7.3, 1.5), 8.43⁄4^ 8.31 (lH, d, J^.7HZ), 9o5 (lH, dd , J=72, r5HZ)&gt;*08(lH,d,J=8.2HZ),lo』^ _ ORC - 3, ^ββ ^ s,s^ 3W- ^ =-w- 5β r^M 3W- Bw-3.X-βTP 8.56{ 1H, d, JA.7HZ), 9.05 (a Hk, J=7.2, 1.5HZ), 9.08 (a H, d, J=82HZ) J 0.83^ 0DC13 ; ^ 3, ^ s.oi ^ 3W. 3W- ^ 3W- 3W-8. 41 (lH, dd, J=8.5J.5HZ), 8.55 (lH, pJ=9.5HZ), 9ol-9o5(2H, m)Jp80 ODC13; ^ 3W-i ISP ^ «.so^ ^ s.^XNW - ^-=- β TP ^.^SNW- CRB ; 1P690H, life command); 8.93 (1H, dd, J=73, 1·5ΗΖ); 8.800H, d, J=83HZ); ε 7. 1H, d, J=7.9HZ);.^27(2J=3); 4·2(2H, m); 3.83(2H, q, J=5.7HZ); 2.68(2H, t, J=6oHN) ;i 2.35(6H,S)._ CDC13 ; 2·44(6Η, s); 2·76{2Η, u=6o), 3_89(2H q,¢--1^37.840^^^8.7).7.90 ^0.0^2=3),1 8.39{ 1H,p-lrsONx 8.58( 1H, d, J=9.6), 8005( 1H, d, J=8.8),8.99{ 1H, ^ CDC13 ; 10.76OH, (4) ;9010H, d,lr8.2HZ}; 8.940H, dd, J=73, 1.5HZ); 8.580H, d, JJ5HZ); ssx, β s, ^ ^ v«.os ίβ ^ p s- - XNW- ^ 3W- - .sx, ^ s- - Fw._ Ί · Today 0 Line · This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 83 781280242 A7 B7 V. Invention Description ( U ) Lr\ U) Π22Η a 9Nb

C23H24N4P DC1+1 m/z389 (ΜΗ+ιο)C23H24N4P DC1+1 m/z389 (ΜΗ+ιο)

C24H24N4P MS DCT13) ιη/ζ417 (ΜΗ1+100%) H03 (Μιφ) ΡΙΙΓΒΓΝΟ Q+m/z 423 :425 (1:1, ΜΗ+, 98%)C24H24N4P MS DCT13) ιη/ζ417 (ΜΗ1+100%) H03 (Μιφ) ΡΙΙΓΒΓΝΟ Q+m/z 423 :425 (1:1, ΜΗ+, 98%)

C23H24ZP DC+13) 389 (MH+) O2III20N4O3 DCT(i) m/z377 (ΜΗ 十，100%) C23=zb3 DC1+2H3) ιη/ζ 4100 lT, 100%) -----------I --- (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 8.10-8.00(3,2H)，3.72(q, 2H)，2.62(UH)，2.35(s, 6H)._ none- ^.ΰβ ^ I.^s, β χρ β ϊρ^.£, ^ 3, 3, 3W- 3W- γβ r£, ^ 5β ^ β t^y lp9(lH,d,llr7.2HZ)._ ^.s ^ ^ ^ ^ ^ -1- 3W- 3W- β - X- ^ ΐ^&gt; - &gt;β 8.63( 1 Η, d, J J.6HZ)，903( 1Η dd,ll7.2 J .6ΗΖ)，9· 15( 一 Η, d, J=8.1 Hz)，10·8^ ^sso.. ΰίέ, ^ s X.OW- ^ s 0W- 7.99( 1ΗΛ J=ooo)，?°08( 1 Η, d, J J.6)，8· 12( 1ΗΛΪ7·8)，8.31 (ΞΛ J J.6)«^ 8.75( 一 Η, d, J&quot;7.0)，9.3 8( 1 Η, d, JH8.I3._ ORC- ^ ios βί, r^y r£,, ζβ ^ ίs_ 2.69(2Η,^#C=5.9HZ)； 2.37(6Η, S). __ ^ ^ t β Λ- Ϊ-^INW- §β ^ ^ ΐ ^ ^ τβ, - X, ^ Ιβ - X, ^ ^ T^$s, ^.β -1- ^ I.SP - X- ^ - X, ^ 9ί 1Η, S. ___ 0DCL3; 2.810H, dd, J12.6,7.5HZ)，2.97(1H, dd, JI2.6,3.7HZ)，3.793.75(1 Η, m)， - a X, ^ - X, ^ s ^.β - X, ^ 8008( 1H, d, J=6.1 Hz)，二·2( 1H,辦^)· OH^NH2^^s?J5sf&amp;»#^ti{NMR)t ODC13 A2^D4--s«MeoH} 7.70-7.72(1 Η, m)，7.90-7.95(2H,m)，8.35( 1 Η, d4 J=1 ·5,8·5ΗΖ)，8.53(1 Η, CUA.8HZ)， Oo.860=dd, J=7.2,1.5ΧΖ)Λ95(1X, d, J=?°3HZ). ο__ 訂： -線- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 84 1280242 A7 B7 I 79，五、發明說明（） ^ L〇1 UJ U) ^ to— 〇 s〇 oo C23H25N5PS2 DQ+NH3, MH+,516C23H24ZP DC+13) 389 (MH+) O2III20N4O3 DCT(i) m/z377 (ΜΗ10, 100%) C23=zb3 DC1+2H3) ιη/ζ 4100 lT, 100%) ---------- -I --- (Please read the notes on the back and fill out this page) Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Cooperatives 8.10-8.00(3,2H), 3.72(q, 2H), 2.62(UH), 2.35 (s, 6H)._ none- ^.ΰβ ^ I.^s, β χρ β ϊρ^.£, ^ 3, 3, 3W- 3W- γβ r£, ^ 5β ^ β t^y lp9(lH, d,llr7.2HZ)._ ^.s ^ ^ ^ ^ ^ -1- 3W- 3W- β - X- ^ ΐ^&gt; - &gt;β 8.63( 1 Η, d, J J.6HZ),903 (1Η dd,ll7.2 J .6ΗΖ),9·15(一Η, d, J=8.1 Hz),10·8^ ^sso.. ΰίέ, ^ s X.OW- ^ s 0W- 7.99( 1ΗΛ J=ooo),?°08( 1 Η, d, J J.6), 8·12(1ΗΛΪ7·8), 8.31 (ΞΛ J J.6)«^ 8.75 ( 一Η, d, J&quot;7.0) , 9.3 8( 1 Η, d, JH8.I3._ ORC- ^ ios βί, r^yr£,, ζβ ^ ίs_ 2.69(2Η,^#C=5.9HZ); 2.37(6Η, S). __ ^ ^ t β Λ- Ϊ-^INW- §β ^ ^ ΐ ^ ^ τβ, - X, ^ Ιβ - X, ^ ^ T^$s, ^.β -1- ^ I.SP - X- ^ - X , ^ 9ί 1Η, S. ___ 0DCL3; 2.810H, dd, J12.6, 7.5HZ), 2.97 (1H, dd, JI2.6, 3.7HZ), 3.793.75 (1 Η, m), - a X, ^ - X, ^ s ^.β - X, ^ 8008( 1H, d, J=6.1 Hz), 2·2( 1H, do ^)· OH^NH2^^s?J5sf&amp;»#^ti {NMR)t ODC13 A2^D4--s«MeoH} 7.70-7.72(1 Η, m), 7.90-7.95(2H,m), 8.35( 1 Η, d4 J=1 ·5,8·5ΗΖ), 8.53 (1 Η, CUA.8HZ), Oo.860=dd, J=7.2, 1.5ΧΖ)Λ95(1X, d, J=?°3HZ). ο__ Order: -Line - This paper scale applies to Chinese national standards ( CNS)A4 size (210 X 297 mm) 84 1280242 A7 B7 I 79, V. Description of invention () ^ L〇1 UJ U) ^ to— 〇s〇oo C23H25N5PS2 DQ+NH3, MH+,516

C23H22N4P m/z 為 03 (MH+)C23H22N4P m/z is 03 (MH+)

CBH23N5P MH+,402 C2I06 οοτζδ m/z419 (ΜΗ+, 100%) 02 一 H2Z50 DCTNH3, MH+, 360 cl ΓΜ + Η+ 386 pllrCINb DCT2:H3 m/z379 (i+, 103CBH23N5P MH+,402 C2I06 οοτζδ m/z419 (ΜΗ+, 100%) 02 A H2Z50 DCTNH3, MH+, 360 cl ΓΜ + Η+ 386 pllrCINb DCT2:H3 m/z379 (i+, 103

C22H22N03S C21MI9N03 C24H25N503 α+{ΝΗ3) m/z423 (ΜΗ+,50%)C22H22N03S C21MI9N03 C24H25N503 α+{ΝΗ3) m/z423 (ΜΗ+,50%)

Dcio; i+,390 DQ+NH3 §1 (請先M讀背面之注意事項再填寫本頁) 裝 經濟部智慧財產局員工消費合作社印製 ^noocw.· ^ ^ γβ ^.3β Λ- J.p s- ^ t^.p sdx. ^ IP 3W- i^ ^ s.p 9.680H,d, J=8.1)，1P650H,^#) (CDC13)，2·35(6Η, s, 2 窗 CH3)，140{3H, S,CH3)，2.65(2H&gt;cs)，3·8&lt;Χ2Η, q,CH2)， ^ ^ MX- 3- §, 3- β. β - X, ^ ^ I- ^ &gt;i 8J0{lH,d,Ar3,oo.80{lH,d, ΑΓΗ)，5100H, £^z3 7SO60H, ζ J=7.8)，8070H, d, JJ.8)，835丨 S0{2H, 3)，^000=d, J=7.2)，9b(lH, d, 9.68(lH,d,J=8.1)，10.65(ui t#) 7001 丨 7ΟΟ60Η, m)，8.000Η, d, J=8.0HZXooo8 丨8·‘12(1Η, m)，8.45Η, d, J=7.8HZ)，8·55·8·62 丘 8005(lH,d,t8.1HZ)，1Ρ10Η,科#).2盒學fi〇H 澌枷！ ^ ^ ηβ 3- ηβ &gt;β - X, ^ 3- &gt;£w- β - X- ^ &gt;-.=w-« ^ ^ ρ - X- ^ &gt;aw-Η·0{1Η, IL#,NH) (CDC!3)； 1P750H, ##)，^.300=d, J 8.2)，9.S0H, d, J 7.3)，8·42(2Η, t, J 8.4)，8oo(2H, t, J 700)，I 7.85( ΞΛ Jvo· 1 )，7.63( l=d, J 7.8x3.90{2H,q, Ι:1#)，2.76(2ΗΛ ltl^)，2.45(6H,s)_ nHP ΰ^β ^ ^ 3- S.0XNW- ^ s.os 7·72(1Η, d, JA.9, 600HZ)； 7.940H, U1.3, 7.2HZ)； 8.04OH, d, J=9.5HZ)； 8.51( 1H, d, J=9.4HZ)； 8.98(1 H, d, J=1 ·5,5.6HZ)； 9,99(1 H1^J&quot;8.0HZ)； 10.600 H, _ ^X, ? S, β-X, ^ β-X- S, 3^ 8.400Η, d, J=9.8HZ)； 8‘24{2Η, 3)； 4·04{2Η, ：g&gt;%, 3)； 3.57(3Η, s)； 3.53(2Η, t^, t, J=63HZ)； 2.99(6H,S)· _ BRCW- ^ ίηβ ^ ηβ ^ ηβ β &gt;5- ^ - X, ^ ^.β - X, ^ ^ β &gt;^.3- - X, ^ §, 9.90{ 1 Η, d, ArH&gt;, 1ρ40{ 1 Η,^^ΖΗ}_ d6-DMSO; P9(3H, C=H4HZ)，2.犬 6iEs)，2.75(2¾ 蚪杳，3.37(2H, t, J从.42芒)，53(2H ㈣^)，^ ^ τ^.β r ^ ί ΰβ ^ J=8.43HZ)，8.95(一 Η, d, J=6.72HZ)，9.21(lH,d, J=764HZ)，10.76ΟΗ,l^Jlr)丨窗 ΝΗ 澌糸； -il· 一線- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 85 801280242 A7 B7 五、發明說明（Dcio; i+,390 DQ+NH3 §1 (Please read the note on the back of the M and then fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs, employee consumption cooperatives ^noocw.· ^ ^ γβ ^.3β Λ- Jp s- ^ t^.p sdx. ^ IP 3W- i^ ^ sp 9.680H,d, J=8.1),1P650H,^#) (CDC13), 2·35(6Η, s, 2 window CH3), 140{3H , S, CH3), 2.65 (2H&gt;cs), 3·8&lt;Χ2Η, q,CH2), ^ ^ MX- 3- §, 3- β. β - X, ^ ^ I- ^ &gt;i 8J0{ lH,d,Ar3,oo.80{lH,d, ΑΓΗ),5100H, £^z3 7SO60H, ζ J=7.8),8070H, d, JJ.8),835丨S0{2H, 3),^000 =d, J=7.2), 9b(lH, d, 9.68(lH,d,J=8.1), 10.65(ui t#) 7001 丨7ΟΟ60Η, m), 8.000Η, d, J=8.0HZXooo8 丨8· '12(1Η, m), 8.45Η, d, J=7.8HZ),8·55·8·62 Qiu 8005(lH,d,t8.1HZ),1Ρ10Η,科#).2Box学fi〇H Hey! ^ ^ ηβ 3- ηβ &gt;β - X, ^ 3- &gt;£w- β - X- ^ &gt;-.=w-« ^ ^ ρ - X- ^ &gt;aw-Η·0{1Η, IL#, NH) (CDC! 3); 1P750H, ##), ^.300=d, J 8.2), 9.S0H, d, J 7.3), 8·42 (2Η, t, J 8.4), 8oo (2H, t, J 700), I 7.85( ΞΛ Jvo· 1 ), 7.63 ( l=d, J 7.8x3.90{2H,q, Ι:1#), 2.76(2ΗΛ ltl^), 2.45(6H ,s)_ nHP ΰ^β ^ ^ 3- S.0XNW- ^ s.os 7·72(1Η, d, JA.9, 600HZ); 7.940H, U1.3, 7.2HZ); 8.04OH, d , J=9.5HZ); 8.51( 1H, d, J=9.4HZ); 8.98(1 H, d, J=1 ·5,5.6HZ); 9,99(1 H1^J&quot;8.0HZ); 10.600 H, _ ^X, ? S, β-X, ^ β-X- S, 3^ 8.400Η, d, J=9.8HZ); 8'24{2Η, 3); 4·04{2Η, :g&gt ;%, 3); 3.57(3Η, s); 3.53(2Η, t^, t, J=63HZ); 2.99(6H,S)· _ BRCW- ^ ίηβ ^ ηβ ^ ηβ β &gt;5- ^ - X, ^ ^.β - X, ^ ^ β &gt;^.3- - X, ^ §, 9.90{ 1 Η, d, ArH&gt;, 1ρ40{ 1 Η,^^ΖΗ}_ d6-DMSO; P9( 3H, C=H4HZ), 2. Canine 6iEs), 2.75 (23⁄4 蚪杳, 3.37 (2H, t, J from .42 awn), 53 (2H (4)^), ^ ^ τ^.β r ^ ί ΰβ ^ J=8.43HZ), 8.95 (one Η, d, J=6.72HZ), 9.21 (lH, d, J=764HZ), 10.76ΟΗ, l^Jlr)丨ΝΗ disappear Shito; -il · line - This paper scale applicable Chinese National Standard (CNS) A4 size (210 X 297 mm) 85 801280242 A7 B7 V. invention will be described (

OS -UOS -U

C2IPS m/z 438 1+)C2IPS m/z 438 1+)

Lh ϋΐΐ !ΚΊ ^ — Ο Ο OC qLh ϋΐΐ !ΚΊ ^ — Ο Ο OC q

C22H23N5PS m/z 4300 023Η25Ν50C22H23N5PS m/z 4300 023Η25Ν50

C23H23N5PC23H23N5P

n24li24「3Nb5 SN24li24"3Nb5 S

n24=4*TJ3Nb5 S ο24α:2·=η3Ν405 n^fpN24=4*TJ3Nb5 S ο24α:2·=η3Ν405 n^fp

C22H2Z6P C21C22H2Z6P C21

DC+NH3, MH+3S DC13, MH+402 DC—3 m/e438 (i+)， 1 DCI—3 m/z 438(MIT)， 1 m/z389 1 CI+m/z375 (i+JOO%) —3 DCTNH3; Μιτ,360 (請先閱讀背面之注意事項再填寫本頁) 裝 經濟部智慧財產局員工消費合作社印製 β ^ s, -X- ^ -1- β β β 9β ^ β 3.71(2ΗΛ 6.2)，3.25(31 u)，3.18(6Η, S)_ (d4 丨 MeoH) d8.98(lH)，8.79(lH},00.65(lH)，f»42(lH},8.s(lH},8.s-7.92(3H,mx^22^ 3.70{2H, t)，3·24(3Η, s)，3.18(6H, s)，澌尜咖 ίπΝΗ (CDC13)，2·40{6Η, s, 2 窟 05)，2.70{2Η, t,ηΗ2)，2·90{6Η, s, 2^CH3)，3.85(2Η, q, CH2)， 7·4φ Η, d, ΑΓΗ)，7 JO〇 Η,ζ ΑΓΗ)，7·90{2Η, dd, ΑΓ3, so( 1 Η, dd, ΑΓΗ)，8.53( 1 Η, d, ΑγΗΧ 8.95( 1 Η, dd, ΑΓΗ)，9· 10{ 1 Η, d,ArH)，1ρ85( 1 Η,^JlrNH)DC+NH3, MH+3S DC13, MH+402 DC—3 m/e438 (i+), 1 DCI—3 m/z 438(MIT), 1 m/z389 1 CI+m/z375 (i+JOO%) —3 DCTNH3; Μιτ,360 (Please read the note on the back and fill out this page) Installed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed β ^ s, -X- ^ -1- β β β 9β ^ β 3.71 ( 2ΗΛ 6.2), 3.25(31 u), 3.18(6Η, S)_ (d4 丨MeoH) d8.98(lH), 8.79(lH}, 00.65(lH),f»42(lH},8.s( lH}, 8.s-7.92 (3H, mx^22^ 3.70{2H, t), 3·24(3Η, s), 3.18(6H, s), 澌尜咖ίίΝΗ (CDC13), 2·40{ 6Η, s, 2 穴05), 2.70{2Η, t, ηΗ2), 2·90{6Η, s, 2^CH3), 3.85(2Η, q, CH2), 7·4φ Η, d, ΑΓΗ), 7 JO〇Η,ζ ΑΓΗ),7·90{2Η, dd, ΑΓ3, so( 1 Η, dd, ΑΓΗ), 8.53( 1 Η, d, ΑγΗΧ 8.95( 1 Η, dd, ΑΓΗ), 9· 10 { 1 Η, d, ArH), 1ρ85( 1 Η,^JlrNH)

^ ηβ ^.ββ ^ ^ ηβ ηβ β —w- fs, ? ZXW- β &gt;5- β IW- ^ IW-10.75(1 hulzH)_I ODCB^MeoD 2·62(3Η, s)，3bl(6H, s)，3.66{2H, t)，4J3(2H, t)，7.92—7.99(1 H, m)， 8o2-8o8(3H,m)，8.15(m,dd)，8.800H,dd)，9.49(lH,d).»^;t^NHS -尜E^NleoDS^^ CDC13/CL4丨M5D 2.67(3=s)，3o5(6H, s)，3.62(2H, t)，4.25(2H, t)，800 丨 8.10{3H,m)， 3W- ^ si, ^ ^ - Ss5a$^r ιοο·48-8·58(3 H, m)，9.17( 1 lj d, J=9.8)，9.41 (1 Hra., J&quot;8.2)l&gt;82( 1H, t)_ 0DC13; 】0.£(1H, %#)； 8.92(lH,dd, J=7.1, K5HZ)； 8OO00H, dd,t7.1, 1·5ΗΖ)； 8.24{2H, m)； 7.860 H,m)； 7.69(3 H, m)； 5.09(2H, S)一 3oo3(2H,彐)；2.85(2H, s m)； 2.50C6H, ?w_ |d6-DMS0; 2.33(6H, s)，2.63(2H, t, JH5.91HZX 169·3.78(2Η,3)Λ16{1Η, s)，7bo(ln 蚪^)， Ι9·48-9·52(1Η,3)，1P16-1P250H, %f) __ (CDC13)，2·45(6Η, s, 2窗CH3)，2.90{2HU CH2)，3.95(2H, q, ΠΗ2)，445(2H 蚪布，NH2)， β §, - X, ^ ^-1- ^ 3 Vi - X, ^ &gt;i 8.35( 一 H, d, ArH}, 8.85(一 H, d, ArH}, 11.05(1¾1^Ι#,ΖΗ}_ 勺 -線- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 86 1280242 A7 ___ B7 _ 811五、發明說明（） ^ 5] ^1 ~al~ΈΙ SI si~2l gl ^^ ηβ ^.ββ ^ ^ ηβ ηβ β —w- fs, ? ZXW- β &gt;5- β IW- ^ IW-10.75(1 hulzH)_I ODCB^MeoD 2·62(3Η, s), 3bl(6H , s), 3.66{2H, t), 4J3(2H, t), 7.92—7.99(1 H, m), 8o2-8o8(3H,m), 8.15(m,dd),8.800H,dd), 9.49(lH,d).»^;t^NHS -尜E^NleoDS^^ CDC13/CL4丨M5D 2.67(3=s),3o5(6H, s), 3.62(2H, t), 4.25(2H, t),800 丨8.10{3H,m), 3W- ^ si, ^ ^ - Ss5a$^r ιοο·48-8·58(3 H, m), 9.17( 1 lj d, J=9.8), 9.41 (1 Hra., J&quot;8.2)l&gt;82( 1H, t)_ 0DC13; 】0.£(1H, %#); 8.92(lH,dd, J=7.1, K5HZ); 8OO00H, dd,t7. 1, 1·5ΗΖ); 8.24{2H, m); 7.860 H,m); 7.69(3 H, m); 5.09(2H, S)-3oo3(2H,彐); 2.85(2H, sm); 2.50 C6H, ?w_ |d6-DMS0; 2.33(6H, s), 2.63(2H, t, JH5.91HZX 169·3.78(2Η,3)Λ16{1Η, s),7bo(ln 蚪^), Ι9·48 -9·52(1Η,3),1P16-1P250H, %f) __ (CDC13), 2·45(6Η, s, 2 window CH3), 2.90{2HU CH2), 3.95(2H, q, ΠΗ2), 445 (2H 蚪 cloth, NH2), β §, - X, ^ ^-1- ^ 3 Vi - X, ^ &gt;i 8.35 (a H, d, ArH}, 8.85 (a H, d, ArH}, 11.05(13⁄41^Ι#,ΖΗ}_ spoon-line-ben Zhang scale applicable Chinese National Standard (CNS) A4 size (210 X 297 mm) 86 1280242 A7 ___ B7 _ 811 Fifth, the invention is described in () ^ 5] ^ 1 ~ al ~ ΈΙ SI si ~ 2l gl ^

C23H24N4PC23H24N4P

Dci3 m/z389 (i+,10) C21H1Z503 m/z390 (ΜΗ 十) C— ΜΗ+ 斉阵：403 (—0)_Dci3 m/z389 (i+,10) C21H1Z503 m/z390 (ΜΗ10) C—ΜΗ+ 斉 ::403 (—0)_

ρ一 H2Z5PS DCI+ZH3 1+)424 C23H23QN403ρ一 H2Z5PS DCI+ZH3 1+)424 C23H23QN403

Dci3 — 43— (i+, 11/0) 024=22 2:504 m/z 3800 1Dci3 — 43— (i+, 11/0) 024=22 2:504 m/z 3800 1

C23H24N4P DCTNH3, ΜΗ+389 C23H2Z403 DCI/NH3 H05 1+,10) 023=22:60 c23=5Nb3sC23H24N4P DCTNH3, ΜΗ+389 C23H2Z403 DCI/NH3 H05 1+,10) 023=22:60 c23=5Nb3s

C23H25N5PS S+ZH3 MNH4+,±6 DC1+NH3 MH+(452) DCIB ΜΗ 十(452} ------------裝— (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 nsy ISSN· 730(lH,d)，7.75-7 J9(m,彐)，7.82( lH,d,J=9.4HZ)，8o3(lH,d,JJ.7H 8.90(lH,d,J=7.4HZ)，9.03(lH,d,J=8oHZ)，10.95( 1H, £❖). β ^.0- - X- ^ β «.S,«.0^^^3W- I- β S, ρ β 3.59(2Η, q, 5.6Χ 2.92(6Η, d, 5·0)_ ssso^ ^ββ ^ββ ^ββ ^.i 5- ^ 5- ^&gt;0 - XW- ^ ^ SF0 ΰββ - ρβ_ ^ΐίβ S9(1H1CL,J4.5HZ)·_^_C23H25N5PS S+ZH3 MNH4+, ±6 DC1+NH3 MH+(452) DCIB ΜΗ Ten (452} ------------ Installed - (Please read the notes on the back and fill out this page) Intellectual Property Bureau employee consumption cooperative printed nsy ISSN· 730 (lH, d), 7.75-7 J9 (m, 彐), 7.82 ( lH, d, J = 9.4HZ), 8o3 (lH, d, JJ.7H 8.90 (lH,d,J=7.4HZ), 9.03 (lH,d,J=8oHZ), 10.95( 1H, £❖). β ^.0- - X- ^ β «.S,«.0^^^ 3W- I- β S, ρ β 3.59(2Η, q, 5.6Χ 2.92(6Η, d, 5·0)_ ssso^ ^ββ ^ββ ^ββ ^.i 5- ^ 5- ^&gt;0 - XW - ^ ^ SF0 ΰββ - ρβ_ ^ΐίβ S9(1H1CL,J4.5HZ)·_^_

162SW- ^ ϊ-ow- ^ Ιβ 3W-8·51 (1 Η, dd, J=8.7AK4)，8,65( 1 Η, d, J=9.8)，8.82( 1 Η, dd, J=6.9^0.5)，SO.27( Ξ 新尜輙irJNH ns^ §^χ, βί,β - ^5W- - χ,3^ - χί, xti ^ s ODnc· ^.β^ί. - β ^.^.3β3, ^ 6J8(lH,t#)，7L-9(lH,d,J=7JHZ)，7.63-7.70c2if )，7.S 8.45( 1 H,d,J=9.4HZ)roo.950 H1Q,,JH8.2HZ)._ Ηββ ίηβ ^ ηβ ηβ WSK- ^ ηβ ^ —w-^ X- ^ β —w- &gt;^.3- ^.β - X. ^ §, Ek-9o5(lH,d,ATH}, 1P950H, tl^rzH}.补 HazHl^l^l^_ οαησ- ΰ ^.β0^Δ.^Ρ 1032( 一 H,蚪#) ____ β«xts.ss, ^ β3, ^.β - 9.09( 1Η0.Ϊ.84ΗΖ)，9.85( 1H1P-JH8.1 Hz)，10·54{1ϋ1^1^)__ .-線· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 87 1280242 A7 B7 五、發明說明（82) 經濟部智慧財產局員工消費合作社印製162SW- ^ ϊ-ow- ^ Ιβ 3W-8·51 (1 Η, dd, J=8.7AK4), 8,65 ( 1 Η, d, J=9.8), 8.82 ( 1 Η, dd, J=6.9 ^0.5), SO.27(Ξ新ΞirJNH ns^ §^χ, βί,β - ^5W- - χ,3^ - χί, xti ^ s ODnc· ^.β^ί. - β ^.^ .3β3, ^ 6J8(lH,t#), 7L-9(lH,d,J=7JHZ), 7.63-7.70c2if ), 7.S 8.45( 1 H,d,J=9.4HZ)roo.950 H1Q ,,JH8.2HZ)._ Ηββ ίηβ ^ ηβ ηβ WSK- ^ ηβ ^ —w-^ X- ^ β —w- &gt;^.3- ^.β - X. ^ §, Ek-9o5(lH, d, ATH}, 1P950H, tl^rzH}. Complement HazHl^l^l^_ οαησ- ΰ ^.β0^Δ.^Ρ 1032(一H,蚪#) ____ β«xts.ss, ^ β3, ^ .β - 9.09( 1Η0.Ϊ.84ΗΖ), 9.85( 1H1P-JH8.1 Hz),10·54{1ϋ1^1^)__ .-Line· This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 87 1280242 A7 B7 V. Description of invention (82) Printing by the Intellectual Property Office of the Ministry of Economic Affairs

Di to S s P = $ P P w z P p = :2 P P = n 5 P £ P £ Z P Ο == s P P rT- 2； p ta«B« P + 1R 昤3： ^ * &lt;-n 5| s IS S re 1 ie 2 .+ I 11 芝1 2 X 斉 | 3 11 義： w泠 § IIS + mmm^k Is N) OO ^ S $ r Ξ i nT-&quot; j 1 _ : _ f3w ^ R &gt; s^S s茗茗二 一 U) 00 产 辽二3塋 t 云貝 w ^ ^ 2： S s C； k&gt;产〆 心工 5§- 岁t s U) K) 隹is pts ?〇 &quot; N ?® o 2Sbi5 9 = S 山一 .· &gt;C X S-°°a 〇〇 - Θ §§; £|t 以il a® -J X 缽〇袅 W f 9® 竺c s T ji c： S 3： ak ^ OO 〇Ί Lr* 〇8 Ξ Ξ l&gt; &quot;· έ各 f萁 S^SI U)—— &lt; ^ = = X CL CL CL 川 l许户n 气巧！ ❹P w &quot; Ό —3： P* 〇；ig bkf r^ S ^ξ| 'oo^ X P p° §： to — ^ oo&gt;^ ^ f OO 二 -Q. ?® 3 3 ^ ^ 111 ^ i； C- 〇 c： w I Q. v〇 On OO _ if s =Co ^ » N EV^ $|| be 工s ti ώ- 又；π Ξ2 eg is s« 00 /-^ &gt;^V p ώϋϋ ^ OO 亥1 OO to W〇« n d〇 -!j *F 5 〇 ^ rt Q CO 广 11¾ 其S! 苎5匕 2= s g 1^1 s§k 3¾ V ON - T IS兵 ^ 1-Ξ表 CL = 以| XX 2 P-2 ^ V V n ^R 呢 XCIuj α. X 3： su )〇 3 芸d $ V-. — PS吴 Ό v〇 fit Ώ工 ϊ^3 s “ W6S ==:- ti ^ 00 O. :-:-9^ If! P上s § k&gt; P ϊ 5 po -g ^ 具it to P； 芸52 gle f s d^ .!i gs II os S| ?£ ^ 'U Η ϋ, 壬？ S? 1¾ Ξ UJ -^1 Q. ㈢s U) K) 7 ^3P 3 〇〇 &gt;&gt; t：苎苎 l^s 1# N 00 〆；〇 1! tk S X it to i s 3 &gt; 11 s! it ll —^ Os 111 i5i έίψ t泛1 Is- ill *\ x ^ iit A ^ 'Os m m vm H 11 Sx 兵1 Sg S li I ----------*裝--------訂---------線 (請先閱讀背面之立意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 88 1280242 A7 B7 五、發明說明（83 22 C24H22N03 DC—3 MH+391 (100%) 024H26N403 m/zc+419 (MH+, 100%)；305 (55%) n23H24N403 DC13 MH+405000%)Di to S s P = $ PP wz P p = :2 PP = n 5 P £ P £ ZP Ο == s PP rT- 2; p ta«B« P + 1R 昤3: ^ * &lt;-n 5 s IS S re 1 ie 2 .+ I 11 芝 1 2 X 斉| 3 11 义: w泠§ IIS + mmm^k Is N) OO ^ S $ r Ξ i nT-&quot; j 1 _ : _ f3w ^ R &gt; s^S s茗茗二一U) 00 产 辽2 3茔t 云贝 w ^ ^ 2: S s C; k&gt; 〆心心工5§-year ts U) K) 隹is pts ? 〇&quot; N ?® o 2Sbi5 9 = S 山一·· &gt;CX S-°°a 〇〇- Θ §§; £|t to il a® -JX 钵〇袅W f 9® 竺cs T ji c: S 3: ak ^ OO 〇Ί Lr* 〇8 Ξ Ξ l&gt;&quot;· έ each f萁S^SI U)—— &lt; ^ = = X CL CL CL Sichuan l Xu household n dexterity! ❹P w &quot; Ό —3: P* 〇; ig bkf r^ S ^ξ| 'oo^ XP p° §: to — ^ oo&gt;^ ^ f OO II-Q. ?® 3 3 ^ ^ 111 ^ i C- 〇c: w I Q. v〇On OO _ if s =Co ^ » N EV^ $|| be s ti ώ- again; π Ξ2 eg is s« 00 /-^ &gt;^V p Ώϋϋ ^ OO hai 1 OO to W〇« nd〇-!j *F 5 〇^ rt Q CO 广113⁄4 Its S! 苎5匕2= sg 1^1 s§k 33⁄4 V ON - T IS兵^ 1- Ξ table CL = to | XX 2 P-2 ^ VV n ^R XCIuj α. X 3: su ) 〇 3 芸d $ V-. — PS 吴Ό v〇fit ϊ工ϊ^3 s “ W6S == :- ti ^ 00 O. :-:-9^ If! P on s § k&gt; P ϊ 5 po -g ^ with it to P; 芸52 gle fsd^ .!i gs II os S| ?£ ^ ' U Η ϋ, 壬? S? 13⁄4 Ξ UJ -^1 Q. (3) s U) K) 7 ^3P 3 〇〇&gt;&gt; t:苎苎l^s 1# N 00 〆;〇1! tk SX it To is 3 &gt; 11 s! it ll —^ Os 111 i5i έίψ tPan 1 Is- ill *\ x ^ iit A ^ 'Os mm vm H 11 Sx 兵1 Sg S li I -------- --*装--------Book---------Line (Please read the back of the matter and then fill out this page) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 88 1280242 A7 B7 V. Description of the invention (83 22 C24H22N03 DC-3 MH+391 (100%) 024H26N403 m/zc+419 (MH+, 100%); 305 (55%) n23H24N403 DC13 MH+405000%)

C23H25N5P MH+at404C23H25N5P MH+at404

C23H24N4P s+m/z 4S(MH+ 1) C22H2Z503 DCI/NH3 i+404 Π22Η2 一 NQ3C23H24N4P s+m/z 4S(MH+ 1) C22H2Z503 DCI/NH3 i+404 Π22Η2 one NQ3

C23I54P 0231 一 2Z402 DC1+NH3 MHl+404 m/z389 (MH+) DCI3 m/z389iMH 十，100%) (請先閱讀背面之注意事項再填寫本頁) 裝 經濟部智慧財產局員工消費合作社印製 私00MHz, CDC13 s^tis, 8001 (1 H,d,J=8.2HZ)J 1.65( 1 H,£^)，l 6.17( 1 H,s). 400MHz 释iK：DCI3 1.21 (一 H, t^)； 9.27( 一 H,e=8.2HZ)； 9.02( 一 H,dd,lr7.3i&amp; 1.5HZ)； β^ϊ.β., ίββ 2.88(lHlcLd,Jll3.1&amp;4100HZ)； 2.36{6H,S)； 一.37(3h1cl,j=6.4hz)·_ 400 MHz, C8I3 - ^ 1¾V^.^.OXNW. s^ts.^s, s^xts.^x^ 11.700H,^#)，16.2(1H,S). ODC13:二·92( 1 H,m)，11 · 12( 1 H,m)，8oo0{ 1 H,e=8.33HZ)，8.45H,d,J4.531t^ ^.^sxts&gt;£, - - s, - SNW- _ 8.±(lH,d,J=9.5HZ)； s5(lHCLd,J&quot;8.6&amp;r-5HZ)； 7.90{lH,m)； 7.860^^ 2.88( 一 H,dd,Jl 2.4IRP7.4HZ)； 2.39(6H,S)._ I2XAOOOCW- β ^ ^.βί,β -χρ -0 ^.βχ.3, ^^^〇.〇〇{ 1H13J0.45(一Η,辦1#). (4S MHz, CDC13)： 1 ·53(3Η,P-J=6.5, f ^Me)，2.38(6H, s, NMe2)，2.51 丨2.600 H,m)， 2.82-2.900 Η,3)Λ 11 (3H,s,-fiB^*Meo)，4·5£·65( 1H, moHV7.29{ 1 Η,CL, J=8.2)， ^ β - s rs, β ^ ^ ^ ϊ-^w- β ^ ^ ^ rs, 9lo3(lH,d,J=73)_I__ si- a si ^, ^.β - lp9(lH,lt&quot;72HZ)._ 1 · 兮0 -線- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 89 1280242 A7 B7 五、發明說明（84) 經濟部智慧財產局員工消費合作社印製 S v〇 S § §§ 00 p .3- Z： P 0 1 P P Ρ ΓΟ t^ Ζ iP z P P •mm Λ- UJ Z ρ 2： P Ρ ν·Λ i 11 § S 5 |IS k) C3 Il§ ^ i ro uj 1IS ^51 Kj C3 Il'S 3^1 k) C3 2 **-l g i IIS 551 k&gt; C 00 -^3 4^ s ^ | μ* Mh =工孑 fee η •τ&quot; L*J 乒乒to 00 ^ ^ Ξ d迂 Π X 1 3 « r^l P c： ^ 工v山 -1 c III g备 =v; Cl ^ V s N hJ 萁吴 00 Lr&gt; 二 == t ^ ——J 9 〇〇 8 ? H 2 1 〇0 «-r· ti x ό 9 3 2 2： ^ ζΛ s ^ ¢^1 is 二 s g ^ « a 一私 c = Ξ -D In X ^ f s 旦3 « &gt;&lt; 5 έ X ^ p ο Ψ X s 3芟 ^ mrnrnA Zu 00^14^ ii S | ?® s § 3 Di片 N r-N 5 5 n i2- i3- n 彐3 S ^ ^ Uj 00 ^ s ^ io ^ ^ so bo ϊ 3 3 ^ r ^ ^ 00 P-¥&gt;* | n： v2 w -^ Lr, 2 &gt;w^ κ&gt; &quot; P 窗 u&gt; U&gt; O 2〇 3： 〇〇 9 淤^ S f | ^ vh- 3 «丄 &amp;夯3 00〆 Ή ^ 00 ο 'X Ξ ^ 3 Η Έ ^. 〇〇 ml s - 3 s -^ 2 r〇 II .W » JT t p V^, LO is Μ oc ZC /--s 二 IS OO -«J 11 u&gt; — x Ξ 00 為 5 1 fF 〇 n sS 3 S ss —N) 工&gt;5 乒έ Ό 〇 S is a ^ ^ X Ρ3 Lt\ Ξ 1 ^ s Π S3 £ 5 g? 8 i 5 c; 5 ί 13 〇 'Ua «&gt; =C e 灰芒i ^ 9° oo Bb^ ^ 山-r* p| ^ 5 V ώκ U) v〇 ! έ S Z t y 5¾ § to — §5 ίί έ X $ ^ 良 X ξ έ s| ^ &gt;ί ^ p X X X X g ^ a. jsi 二 n 5s^§ 沖 — |!ii 减 γ。n: 屮t 3 把矣态b ^ =: x iS ‘迂3 c !贫二； S - s棻1 fe fo P- ?° d p° S&gt;l p§ s - X -^. 11 ^ o §B U) i - 3^ X 工二 3 L Xo^ 乂 F 5具 3C &quot; if X ^ V* ·_ 吴1 P^ S A C： 4 ξ ί s 異 ---^-------.^w&gt; Μ--------^W------線 (請先Ktt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） 90 I&quot;&quot;&quot;^ ： &quot; ^1280242 A7 B7 ^五、發明說明（85) f 声 H ^ ^ ^ ^C23I54P 0231 A 2Z402 DC1+NH3 MHl+404 m/z389 (MH+) DCI3 m/z389iMH X, 100%) (Please read the note on the back and fill out this page) Install the Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Private 00MHz, CDC13 s^tis, 8001 (1 H,d,J=8.2HZ)J 1.65( 1 H,£^),l 6.17( 1 H,s). 400MHz Release iK:DCI3 1.21 (一H, t^ 9.27 (a H, e = 8.2HZ); 9.02 (a H, dd, lr7.3i &amp;1.5HZ); β^ϊ.β., ίββ 2.88 (lHlcLd, Jll3.1 &amp;4100HZ); 2.36{6H , S); I.37 (3h1cl, j=6.4hz)·_ 400 MHz, C8I3 - ^ 13⁄4V^.^.OXNW. s^ts.^s, s^xts.^x^ 11.700H,^#) , 16.2(1H,S). ODC13: 2·92( 1 H,m),11 · 12( 1 H,m),8oo0{ 1 H,e=8.33HZ),8.45H,d,J4.531t^ ^.^sxts&gt;£, - - s, - SNW- _ 8.±(lH,d,J=9.5HZ); s5(lHCLd,J&quot;8.6&amp;r-5HZ);7.90{lH,m); 7.860^^ 2.88 (a H, dd, Jl 2.4IRP7.4HZ); 2.39(6H,S)._ I2XAOOOCW- β ^ ^.βί,β -χρ -0 ^.βχ.3, ^^^〇.〇 〇{ 1H13J0.45(一Η,办1#). (4S MHz, CDC13): 1 ·53 (3Η, PJ=6.5, f ^Me), 2.38 (6H, s, NMe2), 2.51 丨 2.600 H, m), 2.82-2.900 Η, 3) Λ 11 (3H, s, -fiB^*Meo), 4·5 £·65 ( 1H , moHV7.29{ 1 Η,CL, J=8.2), ^ β - s rs, β ^ ^ ^ ϊ-^w- β ^ ^ ^ rs, 9lo3(lH,d,J=73)_I__ si- a Si ^, ^.β - lp9(lH,lt&quot;72HZ)._ 1 · 兮0 - line - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 89 1280242 A7 B7 V. Invention Description (84) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Print S v〇S § §§ 00 p .3- Z: P 0 1 PP Ρ ΓΟ t^ Ζ iP z PP •mm Λ- UJ Z ρ 2: P Ρ ν·Λ i 11 § S 5 |IS k) C3 Il§ ^ i ro uj 1IS ^51 Kj C3 Il'S 3^1 k) C3 2 **-lgi IIS 551 k&gt; C 00 -^3 4^ s ^ | μ* Mh =工孑fee η •τ&quot; L*J Table tennis to 00 ^ ^ Ξ d迂Π X 1 3 « r^l P c: ^ 工v山-1 c III g备=v; Cl ^ V s N hJ 萁吴00 Lr&gt; Two == t ^ ——J 9 〇〇8 ? H 2 1 〇0 «-r· ti x ό 9 3 2 2: ^ ζΛ s ^ ¢^1 is two sg ^ « a 私 c = Ξ -D In X ^ fs dan 3 « &gt;&lt; 5 έ X ^ p ο Ψ X s 3芟^ mrnrnA Zu 00^14^ ii S | ?® s § 3 Di piece N rN 5 5 n i2- i3- n 彐3 S ^ ^ Uj 00 ^ s ^ io ^ ^ so bo ϊ 3 3 ^ r ^ ^ 00 P-¥&gt;* | n: v2 w -^ Lr, 2 &gt;w^ κ&gt;&quot; P window u&gt;U&gt; O 2〇3: 〇〇9 淤^ S f | ^ vh- 3 «丄&amp;夯3 00〆Ή ^ 00 ο 'X Ξ ^ 3 Η Έ ^. 〇〇ml s - 3 s -^ 2 r〇II .W » JT tp V^, LO is Μ oc ZC /--s II IS OO -«J 11 u&gt; — x Ξ 00 is 5 1 fF 〇 n sS 3 S ss —N) Work&gt;5 Table tennis Ό 〇S is a ^ ^ X Ρ3 Lt\ Ξ 1 ^ s Π S3 £ 5 g? 8 i 5 c; 5 ί 13 〇'Ua «&gt; = C e 灰芒 i ^ 9° oo Bb^ ^ Mountain-r* p| ^ 5 V ώκ U) v〇! έ SZ ty 53⁄4 § to — §5 ίί έ X $ ^ 良X ξ έ s| ^ &gt; ^ ^ p XXXX g ^ a. jsi two n 5s^§ 冲— |! ii minus γ. n: 屮t 3 put the state b ^ =: x iS '迂3 c ! lean two; S - s棻1 fe fo P- ?° dp° S&gt;lp§ s - X -^. 11 ^ o §BU ) i - 3^ X 2 2 L Xo^ 乂F 5 with 3C &quot; if X ^ V* ·_ Wu 1 P^ SAC: 4 ξ ί s I---^-------.^ w&gt; Μ--------^W------ Line (please fill in this page on the back of Ktt) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297厘) 90 I&quot;&quot;&quot;^ : &quot; ^1280242 A7 B7 ^5, invention description (85) f sound H ^ ^ ^ ^

C25H29N5P MH+432 0212C25H29N5P MH+432 0212

Dci3 m/z387 (i+1000/0)Dci3 m/z387 (i+1000/0)

C25H28N4P 023H24N4O4 0i5 m/e 421 (MH+1) p-ip DC—3 m/e 3610 (MH+) n24=zb4 DC13 m/e65 (i+, 100%) c2=24Nb3 ESI +ve m/e 421 1+, 100%) ------------^w— --- (請先M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 nan0 =.3W- w.00,w.sox.3w- ^ 8.42(lH,d,JH8.5)roo.5IOQ(lH,d,.N9.6)roc.98_9lo3(2l=m)_ ^00MHZ,CDCI3 s.s^s, 3.13.3.18(lH,m)，4J0{3H,S)，ζ04·98(1Η,3)，7.260HCL)，7.75—7.8^H,m)， ^sss&gt;, s,§^3, _ ηση^ z .00 β - St ^.y - s, ^ ^ s, β - =- ^ ^ β 8.±( 1H, dd, J 8.5, 1.5)，7·97(2Η,3)，7.75( 1 H,c8.1 )，7.25H, d, J 7·7)&gt; 2.89(l=dd,j 12.6,9.32.64{lH,dd,j 12.6,5.1)，2.34(6H,S)， • 10{3H,d,J2.4)_；_ isxN- ODOC ^ss- ^ - ^έ§ε, ^.ί.β - =.3W- - fw- s^ss.^p 15oo20H,s) ίβ3, ^έ^β3, w- 8.95-902(1 H,彐)，11.08( Ξ,衿#) _ ^S$F ORC ^β^ΐρ ^ββχρ ΐβ^τ^χρ w- 8.45( 1 H,d,J=9.7HZ)，8.91 (1 H,e&quot;8.2HZ)· 000^ 8.70{ 1=e=3oHZ)，8.99( 1 H,d,J=8oHZ)，10.92( 1 H,^+). J. 今0 ί線· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91C25H28N4P 023H24N4O4 0i5 m/e 421 (MH+1) p-ip DC—3 m/e 3610 (MH+) n24=zb4 DC13 m/e65 (i+, 100%) c2=24Nb3 ESI +ve m/e 421 1+ , 100%) ------------^w— --- (Please read the note on the back of the M and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed nan0 =.3W - w.00, w.sox.3w- ^ 8.42(lH,d,JH8.5)roo.5IOQ(lH,d,.N9.6)roc.98_9lo3(2l=m)_ ^00MHZ,CDCI3 ss^ s, 3.13.3.18(lH,m),4J0{3H,S),ζ04·98(1Η,3), 7.260HCL),7.75-7.8^H,m), ^sss&gt;, s,§^3, _ ηση^ z .00 β - St ^.y - s, ^ ^ s, β - =- ^ ^ β 8.±( 1H, dd, J 8.5, 1.5), 7·97(2Η,3),7.75 ( 1 H,c8.1 ), 7.25H, d, J 7·7)&gt; 2.89 (l=dd,j 12.6,9.32.64{lH,dd,j 12.6,5.1), 2.34(6H,S) , • 10{3H,d,J2.4)_;_ isxN- ODOC ^ss- ^ - ^έ§ε, ^.ί.β - =.3W- - fw- s^ss.^p 15oo20H,s ) ίβ3, ^έ^β3, w- 8.95-902(1 H,彐),11.08( Ξ,衿#) _ ^S$F ORC ^β^ΐρ ^ββχρ ΐβ^τ^χρ w- 8.45( 1 H ,d,J=9.7HZ),8.91 (1 H,e&quot;8.2HZ)· 000^ 8.70{ 1=e=3oHZ),8.99( 1 H,d,J=8oHZ),10.92( 1 H,^+ ). J. Today 0 线 line · This paper size applies to China National Standard (CNS) A4 Specification (210 X 297 mm) 91

Claims (1)

1280242 A8 B8 C8 D8 六、申請專利範圍 第89125715料利_請案巾請專利範圍修正本 修正日期：95年5月 1· 一種化合物，其為一具有化學式（1)之苯并㈨啡啡 羧醯胺衍生物：1280242 A8 B8 C8 D8 VI. Patent application No. 89125715 Material profit _ Please cover the scope of the patent. Amendment date of this amendment: May, 1995. 1. A compound which is a benzo(nine) morphine carboxylate of formula (1) Indoleamine derivatives: 經濟部智慧財產局員工消費合作社印製 其中每一個Rl至R3係氫，且R4係選自於：_素、羥 基、未取代或以氰基、苯基、C^C6炔基、鹵苯基、 、元氧基C! C(5烧氧基魏基、經基、嗎福琳基、二 丈兀基胺基、胺基甲醯基、烷醯基或羧基取代之 CkC6烷氧基、嘧啶基氧基、未取代或以二烷基胺 基或經基取代2CKC6烷基、硝基、氰基、疊氮基、醯 月女基脖、co2r10、con(r12)2、OCON(Ri2)2、SRl0、s〇2Rll ^ S02N(R12)2 . N(R12)2 . NR10SO2Rn . N(S02Rn)2 , NR10(CH2)nCN &gt; NR10C〇Rn &gt; 〇CORn^COR10 ； 每一個R至R係為相同或不同，且係選自於··氫、鹵素 、羥基、Q-Q烷氧基、CkC6烷基、sr1、n(r1、； Q係為一個未取代或取代之Ci_C6烷撐基，且是被取代 以⑴未取代或取代之CKC6烷基，（ii)羥基，但有條件是 該羥基對於化學式（1)中鄰接於Q的任一個氮原子而言 非位為0C位置，或（iii)c〇2Ri〇; 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱〉 92 1280242 AS BS C8 D8 、申凊專利範圍 R及R係、為相同或不同 或R8及箄所二刀別為.風或⑽基’ 5或6-貝含I之雜環，該雜環可以包含—個另外之雜原 子:該雜原子係氧，或r&gt;r9其中之—者係為—個婦鍵 ’该乳、氮或硫被連接至-個位在叫表示之烤鏈上的 Μ子’俾以完成—個如上所定義之飽和5，或6_員的含 氮雜環； R10為氫或cKc6烷基； R為Ci-c6烧基； 每一個Rl2係為相同或不同，且係為：氫或Cl-C6烧基； 且 n為1、2或3 ; 或其一製藥上可接受之鹽類。 2· —種化合物，其係化學式（Ia)的苯并[a]啡畊-u_羧醯胺 衍生物： (請先閱讀背面之注意事'^:填寫本頁) 1 -裝· 訂· 經濟部智慧財產局員工消費合作社印製Each of the R1 to R3 hydrogens is printed by the Intellectual Property Office of the Ministry of Economic Affairs, and the R4 is selected from the group consisting of: _, hydroxy, unsubstituted or cyano, phenyl, C^C6 alkynyl, halophenyl , C. alkoxy C! C (5 alkoxy group, a thiol group, a phenanthrenyl group, a fluorenylamino group, an aminomethyl fluorenyl group, an alkyl fluorenyl group or a carboxyl group substituted CkC6 alkoxy group, pyrimidinyl group Oxygen, unsubstituted or substituted with dialkylamino or trans-group 2CKC6 alkyl, nitro, cyano, azido, 醯月女 collar, co2r10, con(r12)2, OCON(Ri2)2 SRl0, s〇2Rll ^ S02N(R12)2 . N(R12)2 . NR10SO2Rn . N(S02Rn)2 , NR10(CH2)nCN &gt; NR10C〇Rn &gt;〇CORn^COR10; Each R to R system is The same or different, and are selected from hydrogen, halogen, hydroxyl, QQ alkoxy, CkC6 alkyl, sr1, n (r1; Q is an unsubstituted or substituted Ci_C6 alkylene group, and is Substituting (1) unsubstituted or substituted CKC6 alkyl, (ii) hydroxyl, provided that the hydroxyl group is non-position to the 0C position for any nitrogen atom adjacent to Q in formula (1), or (iii)c 〇2Ri〇; paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 public love) 92 1280242 AS BS C8 D8, application for patent range R and R, for the same or different or R8 and 箄 为 .. '5 or 6-Bei containing a heterocyclic ring of I, the heterocyclic ring may contain - another hetero atom: the hetero atom is oxygen, or r&gt;r9 of which is - a female bond 'the milk, nitrogen or Sulfur is attached to a tweezers in the indicated chain to complete - a saturated 5, or 6-membered nitrogen-containing heterocycle as defined above; R10 is hydrogen or cKc6 alkyl; R is Ci-c6 alkyl; each Rl2 is the same or different and is: hydrogen or Cl-C6 alkyl; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof. a compound of the formula (Ia) of benzo[a]morphine-u-carboxylamine derivative: (Please read the note on the back first)^^:fill this page) 1 -装·订· Ministry of Economics Property Bureau employee consumption cooperative printing (la) Y CH^(CH2)p—N(R8)(R9) Η 其中R1至R9係如申請專利範圍第1項中所定義者； P是1、2或3 ;且 13 R係為⑴氫’（ii)未取代或被取代以羥基、芳基或 衣紙張尺度適闬中國國家標準（cns)A4規格（210 x 297公釐 93 - 1280242 AS BS C8 D8 經濟部智慧財產局員工消費合作社印製 、申請專利範圍 N(R12)2之Cl-C6烷基，其中係如申請專利範圍第工項 中所定義者，（iii) C02R10，（iv)芳基。 3·如申請專利範圍第1或2項的化合物，其中R4為Ckc6烷 氧基、羥基、CrC6烷基、羥基-Cl_c6烷基、腈或鹵素 〇 4·如申請專利範圍第1或2項的化合物，其中R7為經基。 5· —種化合物，其係選自於： ‘甲氧基-苯并[a]啡啡-1卜羧酸(2_二甲基胺基_乙基醯胺、 ‘羥基-苯并[a]啡啡-n_羧酸（2_二甲基胺基_乙基）_醯胺 ;氫溴酸鹽、 ‘硝基-苯并[a]啡畊-U —羧酸（2_二甲基胺基-乙基）_醯胺 4_二甲基胺基甲基-3-羥基-苯并[a]啡啼羧酸（2-二 曱基胺基-乙基）-醯胺、 9-溴4-甲氧基··苯并[a]啡啩q ^羧酸（2_二曱基胺基-乙 基）-醯胺、 ‘氰甲氧基-苯并[a]啡羧酸（2_二甲基胺基-乙基）_ 醯胺、 4-乍基氧基-苯并[a]啡畊-u-鲮酸（2_二甲基胺基-乙基卜 醯胺、 4-丙-2·炔基氧基-苯并[a]啡畊羧酸二甲基胺基-乙基 )-醯胺、 4_乙氧基-苯并[a]啡啡-11-幾酸(2_二甲基胺基_乙基)·醯胺' 本紙張尺度適用中國國家標準（CNS〉A4規格（210 X 297公爱〉 (請先閱讀背面之注意事:填寫本頁) 1 -裝 訂- 94 1280242 AS BS C8 D8 經濟部智慧財產局員工消費合作社印製 六、申請專利範圍 4-異丁氧基-苯并[a]啡畊]卜緩酸(2_二甲基胺基-乙基）_ 醯胺、 4-(4-氯-苄基氧基）-苯并[a]啡畊4卜羧酸（2_二甲基胺基 -乙基）-S备胺、 4-(2-甲氧基-乙氧基）-苯并[a]啡畊-11-羧酸（2-二甲基胺 基-乙基）-S盘胺、 [1H2-二甲基胺基-乙基胺甲醯基&gt;苯并[a]啡畊_4_基氧 基l·醋酸乙酯、 4-(2-羥基-乙氧基）-苯并[a]啡啩_丨卜羧酸（2_二甲基胺基 -乙基）-S藍胺、 4-(嘧啶-2-基氧基）-苯并[a]啡啡羧酸（2_二甲基胺基 -乙基）-醯胺、 4-(2-嗎琳-4-基-乙氧基）_苯并[a]啡讲·h_魏酸（2·二甲基 胺基··乙基）-S&amp;胺、 4-(3-氰基-丙氧基）-苯并〇]啡啡_1^魏酸（2_二甲基胺基 -乙基）-酿胺、 4-甲基-苯并[a]啡啡-11-緩酸（2-二甲基胺基-乙基）-醯胺、 4-氟-苯并[a]啡啡-11-羧酸（2-二曱基胺基-乙基）_醯胺、 4-(3-二甲基胺基-丙氧基）-苯并[a]啡啡-11-羧酸（2-二甲 基胺基-乙基）·醯胺、 4-甲基石黃醯基-苯并[a]啡η井-11-緩酸（2-二甲基胺基-乙 基）-醯胺、 4-胺甲醯基甲氧基-苯并[a]啡哄-Π-羧酸（2-二甲基胺基 (請先閱讀背面之注意事項再填寫本頁) I·· 裝 訂· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280242 8888 ABCP 經濟部智慧財產局員工消費合作社印製 申請專利範圍-乙基;l·醯胺、 4-甲氧基-笨并[a]啡畊-u_羧酸（3-胺基-2-羥基-丙基）_ 醯胺、 4-甲氧基-苯并[a]啡畊竣酸(3-二甲基胺基-丙基)-醯胺、 心溴-苯并[a]啡畊-11-羧酸（2-二甲基.胺基-乙基）_醯胺、 11-(2-二甲基胺基·乙基胺甲醯基)_苯并[a]啡畊基乙酸酯、 4-(2-酮基-丙氧基）-笨并[a]啡讲-11-羧酸（2-二甲基胺基 -乙基）-酿胺、 4-甲氧基-苯并[a]啡畊羧酸（2-二甲基胺基甲基_ 乙基）-醯胺、 4-氰基-苯并[a]啡啩-1]U羧酸（2_二甲基胺基-乙基）_醯胺 、 U-(2_二甲基胺基-乙基胺甲醯基）-苯并[a]啡哚4-基乙 基胺基甲酸醋、 4-甲石頁醯基-苯并[a]啡啩·羧酸（2_二甲基胺基-乙基）_ 醯胺、 4-氯-苯并幾酸（2•二甲基胺基-乙基），胺、 4-疊氮基-苯并刚吟⑴叛酸(2_二甲基胺基·乙基酿胺、 4-胺基-苯并[a]啡啡.竣酸(2-二甲基胺基-乙基）·酿胺 [11♦二甲基胺基-乙基胺甲醯基）-苯并[a]_+4-基氧] 醋酸三氟乙酸鹽、 4-乙醯胺基·苯并⑷哪啡·n_幾酸(2·二甲基胺基_乙基)· 醯胺、 (請先閱讀背面之注意事填寫本頁) I: 裝·. 訂- 尽成放尺度過用r 國豕杯準（CNS〉A4規格（210 X 297公爱 96 1280242 AS s D8 六、申請專利範圍 11-(2-二曱基胺基-乙基胺甲醯基）_笨并[a]啡畊_4_羧酸 曱基酯、 4-雙-(甲石頁醯基胺基）_苯并⑷啡讲“^羧酸（2_二曱基胺 基-乙基）-醯胺、 4-(Ν-羥基胺曱醯亞胺基&gt;笨并㈤啡啡]卜羧酸二甲 基胺基-乙基）-S藍胺、 4-羥基曱基-苯并[a]啡畊羧酸（2-二曱基胺基_乙基戶 醯胺、 4-甲基氨磺醯基-苯并[a]啡畊q卜羧酸（2_二甲基胺基-乙基）-S&amp;胺；三氟乙酸鹽、 4-二甲基胺基-笨并[a]啡畊羧酸（2_二甲基胺基乙 基）-醯胺、 4-甲基磺醯基胺基-苯并[a]啡啡羧酸（2_二曱基胺基 -乙基）-酿胺、 4-二甲基氨磺醯基-笨并[a]啡啡4^羧酸（2_二曱基胺基 -乙基）-醯胺、 4-(氰基甲基-胺基）-苯并[a]啡畊-u_羧酸（2_二甲基胺基 -乙基）-醯胺、 經濟部智慧財產局員工消費合作社印製 4，10-二甲氧基-苯并[a]啡畊羧酸（2_二甲基胺基-乙 基）-醯胺、 4-甲氧基-苯并[a]啡啡-11-羧酸二甲基胺基_丙基y醯胺、 本并[a]啡讲-4,11·一幾酸-4-胺-11_[ (2-二甲基胺基_ 乙基）-醯胺];三氟乙酸鹽、 4-甲氧基-苯并[a]啡_-11·羧酸（2·二甲基胺基4 ^二甲 97 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱〉 8 0088 ABCD 1280242 t、申請專利範圍 基-乙基）-酿胺、 2-硝基-苯并[a]啡畊-11-羧酸（2-二甲基胺基-乙基)-醯胺 、 4-甲氧基-8-甲基-苯并[a]啡畊-11-羧酸（2-二甲基胺基-乙基）-醯胺、 4，10-二羥基-苯并[a]啡讲-11-羧酸（2-二甲基胺基-乙基 )-醯胺、 4-甲氧基-苯并[a]啡啡-11-羧酸（1-二甲基胺基甲基-丙 基）-醯胺、 4，10-二曱氧基-苯并[a]啡畊-11-羧酸（2_二甲基胺基-；[_ 甲基-乙基)-醯胺、 9-氯-4-甲氧基-苯并[a]啡啡-11-羧酸（2-二甲基胺基-乙 基）-醯胺、 4-甲氧基-苯并[a]啡啡-11-羧酸（1-二曱基胺基曱基-2-甲基-丙基）-醯胺、 4-甲氧基-苯并[a]啡畊-11-羧酸（2-二甲基胺基-1-羥基 甲基-乙基）-醯胺、 經濟部智慧財產局員工消費合作社印i衣 4-甲氧基-苯并[a]啡啡-11-羧酸（1-二甲基胺基甲基-2-苯基-乙基）-酿胺、 4-甲氧基-苯并[a]啡讲-11-羧酸（2-二曱基胺基-1-(S)-甲 基-乙基）-醯胺、 4-甲氧基-苯并[a]啡畊-11-羧酸（2-二甲基胺基-1-(R)-甲 基-乙基）-酿胺、 4-硝基-苯并[a]啡畊-11-羧酸（2-二曱基胺基-1-甲基-乙 98 本紙張尺度適用中國國家標準（CNS)A4規格（210x 297公釐〉 A8BSC8D8 1280242 六、申請專利範圍 基）-醯胺、 4-曱氧基·苯并[a]啡畊-11-羧酸（2-二曱基胺基q_(s)-羥 基甲基-乙基）-醯胺、 4-甲氧基-10-甲基胺基-苯并[a]啡哚•羧酸（2_二曱基 胺基-乙基）-酿胺、 10-羥基-4-甲氧基-苯并[a]啡啡羧酸（2-二曱基胺基一 l(Rl·甲基-乙基）-醯胺、 4-甲氧基-苯并[a]啡啡-羧酸（1-二曱基胺基甲基 多里基·丙基）-酿胺、 10-羥基-4-甲氧基-苯并[a]啡啡4^羧酸（2-二甲基胺基-乙基）-醯胺、 4-甲氧基-笨并[a]啡啡-11-羧酸（2_π辰啶―丨—基―乙基）_醯 胺、 4-甲氧基-苯并[a]啡啡-Η —羧酸二甲基胺基-1-(2-羥 基乙基）]-乙基醯胺、 10-胺基-4-甲氧基-苯并[a]啡羧酸二甲基胺基_ 乙基:l·醯胺、 4·甲氧基·苯并[a]啡啡-u•羧酸（2-嗎啉|基-乙基）·醯 胺、 4-甲氧基-苯并[a]啡畊-11-幾酸(2_吼咯啶小基_乙基醯胺、 4-甲氧基-苯并[a]啡畊羧酸{2_[雙气羥基-乙基）_胺 基]-乙基卜醯胺、 4-甲氧基-苯并[a]啡畊-Η-綾酸二乙基胺基_乙基卜醯胺、 4-甲氧基-9-曱基磺醯基-苯并羧酸（2-二甲基 本紙張尺度適用中國國家標準（CNS)A4規格（210x 297公爱〉 -------------l··裝--- (睛先閱讀背面之注意事寫本頁) 訂· 丨 經濟部智慧財產局員工消費合作社印製 1280242 A8 BS C8 D8 申請專利範圍 胺基-乙基）-醯胺、 4.9- 二甲氧基-苯并[a]啡畊-11·羧酸（2-二甲基胺基_乙基 )-醯胺、 4.10- 二甲氧基-苯并[a]啡啡-羧酸（2·二甲基胺基 -1(S)-|^基甲基-乙基）-酿胺、 4-曱氧基-苯并[a]啡畊-11-羧酸（2_曱基胺基_乙基）_醯胺 10_羥基-‘曱氧基-苯并[a]啡畊羧酸二甲基胺基 -l(s)-羥基甲基-乙基 &gt; 醯胺、 (R广‘甲氧基-苯并⑷啡畊-11-羧酸（1·二甲基胺基甲基 -2-乙基-丙基）-酿胺、 4-甲氧基-苯并[a]啡畊]^羧酸（1_甲基^比咯啶 基）-酸胺、 4-甲氧基-苯并[a]啡畊—u_羧酸〇(雙&gt;二甲基胺義 丙基）酿胺， 土 及其一製藥上可接受之鹽類。 種（、用作為/σ療腫瘤或抗病毒、抗細菌或抗真菌試 經濟部智慧財產局員工消費合作社印製 的藥學組成物，其包含—種藥學上可接受之載劑或稀ς 劑’以及作為—種活性成份之一個如申請專利範圍第1 、2或5項所定義之化合物。 7. 一種用以產生—種如申請專利範圍第1項所界定之化入 物的方法，該方法包含： 之化° ⑷使κ®具有化學式(m)之胺來處理 式m的化合物之·化的衍生物： /、有化子(la) Y CH^(CH2)p—N(R8)(R9) Η wherein R1 to R9 are as defined in claim 1; P is 1, 2 or 3; and 13 R is (1) Hydrogen '(ii) is unsubstituted or substituted with hydroxyl, aryl or clothing paper scales appropriate to China National Standards (cns) A4 specifications (210 x 297 mm 93 - 1280242 AS BS C8 D8 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed, patented range N (R12) 2 Cl-C6 alkyl, which is defined in the scope of work of the patent application, (iii) C02R10, (iv) aryl. a compound of 1 or 2, wherein R4 is Ckc6 alkoxy, hydroxy, CrC6 alkyl, hydroxy-Cl-c6 alkyl, nitrile or halogen 〇4. A compound according to claim 1 or 2 wherein R7 is a trans group a compound selected from the group consisting of: 'methoxy-benzo[a]morphin-1-carboxylic acid (2-dimethylamino-ethylamine, 'hydroxy-benzo[ a]morphine-n-carboxylic acid (2-dimethylamino-ethyl)-decylamine; hydrobromide, 'nitro-benzo[a]morphine-U-carboxylic acid (2_two Methylamino-ethyl)-decylamine 4_dimethylaminomethyl-3-hydroxy- And [a] morphine carboxylic acid (2-didecylamino-ethyl)-decylamine, 9-bromo 4-methoxy-benzo[a] phenanthrenequinone q-carboxylic acid (2_dioxin) Amino-ethyl)-guanamine, 'cyanomethoxy-benzo[a]morphinic acid (2-dimethylamino-ethyl)-decylamine, 4-decyloxy-benzo [a]Planting-u-decanoic acid (2-dimethylamino-ethyldoxime, 4-propan-2-alkynyloxy-benzo[a]morphinic acid dimethylamino -ethyl)-nonylamine, 4_ethoxy-benzo[a]morphine-11-acid (2-dimethylamino-ethyl)-decylamine] This paper scale applies to Chinese national standards ( CNS>A4 specification (210 X 297 public love) (Please read the back note: fill out this page) 1 - Binding - 94 1280242 AS BS C8 D8 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing VI, patent application scope 4 -isobutoxy-benzo[a]morphine]buproic acid (2-dimethylamino-ethyl)-decylamine, 4-(4-chloro-benzyloxy)-benzo[a ]Planting 4 carboxylic acid (2-dimethylamino-ethyl)-S-preparative amine, 4-(2-methoxy-ethoxy)-benzo[a]morphin-11-carboxylic acid (2-dimethylamino-ethyl)-S-padamine, [1H2-dimethylamino-ethylamine Mercapto&gt; benzo[a]morphine_4_yloxyl.ethyl acetate, 4-(2-hydroxy-ethoxy)-benzo[a]morphine-indole carboxylic acid (2_ Dimethylamino-ethyl)-S leucine, 4-(pyrimidin-2-yloxy)-benzo[a]morphinecarboxylic acid (2-dimethylamino-ethyl)-decylamine 4-(2-Molin-4-yl-ethoxy)-benzo[a]morphin·h_weilic acid (2.dimethylamino)ethyl)-S&amp;amine, 4- (3-cyano-propoxy)-benzopyrene]morphine-1^weilic acid (2-dimethylamino-ethyl)-bristamine, 4-methyl-benzo[a]morphine -11-glycolic acid (2-dimethylamino-ethyl)-decylamine, 4-fluoro-benzo[a]morphine-11-carboxylic acid (2-didecylamino-ethyl)_ Indoleamine, 4-(3-dimethylamino-propoxy)-benzo[a]morphine-11-carboxylic acid (2-dimethylamino-ethyl)-decylamine, 4-methyl Basestone xanthene-benzo[a]-anthracen-11-hypo-acid (2-dimethylamino-ethyl)-decylamine, 4-aminoformamidomethoxy-benzo[a]morphine -Π-carboxylic acid (2-dimethylamino group (please read the back note first and then fill out this page) I·· Stapling · This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 12 80242 8888 ABCP Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printing Patent Application - Ethyl; l-decylamine, 4-methoxy-stupid [a] cultivating-u-carboxylic acid (3-amino-2 -hydroxy-propyl)-decylamine, 4-methoxy-benzo[a]morphine (3-dimethylamino-propyl)-decylamine, cardiac bromine-benzo[a]morphine Cultivated -11-carboxylic acid (2-dimethyl.amino-ethyl)-decylamine, 11-(2-dimethylaminoethylamine)-benzoic acid Acetate, 4-(2-keto-propoxy)- benzo[a]morphin-11-carboxylic acid (2-dimethylamino-ethyl)-bristamine, 4-methoxy -Benzo[a]morphinic acid (2-dimethylaminomethyl-ethyl)-decylamine, 4-cyano-benzo[a]phthyl-1] U-carboxylic acid (2_2 Methylamino-ethyl)-decylamine, U-(2-dimethylamino-ethylamine-mercapto)-benzo[a]phthyl-4-ylethylaminocarbamate, 4- Mesquite-benzo-[benzo]pyrene·carboxylic acid (2-dimethylamino-ethyl)-decylamine, 4-chloro-benzoic acid (2•dimethylamino-B Base, amine, 4-azido-benzoglycolate (1) retinoic acid (2-dimethylaminoethyl ethylamine, 4-amino-benzo[a]morphine. decanoic acid (2- Dimethyl Base-ethyl)·has amine [11♦ dimethylamino-ethylamine methyl fluorenyl)-benzo[a]-+4-yloxy] acetic acid trifluoroacetate, 4-ethylammonium Benzo(4) morphine·n_acid (2·dimethylamino-ethyl)· decylamine, (please read the note on the back) (Insert this page) I: 装·. 订- Use the country's 豕 cup standard (CNS> A4 specification (210 X 297 public love 96 1280242 AS s D8 VI, patent application range 11-(2-didecylamino-ethylamine methyl fluorenyl) _ stupid [a ] ____carboxylic acid decyl ester, 4-bis-(methyl sulphonylamino) benzoyl (4) morphine, " carboxylic acid (2 - dinonylamino-ethyl) - decylamine 4-(Ν-Hydroxyamine quinone imine) &gt; stupid (five) morphine] carboxylic acid dimethylamino-ethyl)-S leucine, 4-hydroxyindolyl-benzo[a]morphine Cultivated carboxylic acid (2-didecylamino) ethyl ethylamine, 4-methylsulfamoyl-benzo[a] phenolic q-carboxylic acid (2-dimethylamino-ethyl) -S&amp;amine;trifluoroacetate, 4-dimethylamino-p-benzo[a]morphinic acid (2-dimethylaminoethyl)-decylamine, 4-methylsulfonylamine Benzo-benzo[a]morphinancarboxylic acid (2-didecylamino)- -,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, -Amino)-benzo[a]morphine-u-carboxylic acid (2-dimethylamino-ethyl)-decylamine, Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, 4,10-Dimethoxy Benzo-benzo[a]morphinic acid (2-dimethylamino-ethyl)-decylamine, 4-methoxy-benzo[a]morphine-11-carboxylic acid dimethylamino _propyl y decylamine, benzo[a] tranexyl-4,11·monoacid-4-amine-11_[(2-dimethylamino-ethyl)-decylamine]; trifluoroacetate , 4-methoxy-benzo[a]morphine_-11·carboxylic acid (2·dimethylamino 4 ^ dimethyl 97) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 〉 8 0088 ABCD 1280242 t, the patent application range base-ethyl)-bristamine, 2-nitro-benzo[a]morphin-11-carboxylic acid (2-dimethylamino-ethyl)-oxime Amine, 4-methoxy-8-methyl-benzo[a]morphin-11-carboxylic acid (2-dimethylamino-ethyl)-decylamine, 4,10-dihydroxy-benzo [a] morphine-11-carboxylic acid (2-dimethylamino-ethyl)-decylamine, 4-methoxy-benzo[a] Phenyl-11-carboxylic acid (1-dimethylaminomethyl-propyl)-decylamine, 4,10-dimethoxy-benzo[a]morphin-11-carboxylic acid (2-dimethyl Amino-[|methyl-ethyl)-decylamine, 9-chloro-4-methoxy-benzo[a]morphine-11-carboxylic acid (2-dimethylamino-ethyl - indoleamine, 4-methoxy-benzo[a]morphine-11-carboxylic acid (1-didecylaminodecyl-2-methyl-propyl)-decylamine, 4-methoxy Benzo-benzo[a]morphin-11-carboxylic acid (2-dimethylamino-1-hydroxymethyl-ethyl)-decylamine, Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative Oxy-benzo[a]morphin-11-carboxylic acid (1-dimethylaminomethyl-2-phenyl-ethyl)-bristamine, 4-methoxy-benzo[a]morphine -11-carboxylic acid (2-didecylamino-1-(S)-methyl-ethyl)-decylamine, 4-methoxy-benzo[a]morphin-11-carboxylic acid ( 2-Dimethylamino-1-(R)-methyl-ethyl)-bristamine, 4-nitro-benzo[a]morphin-11-carboxylic acid (2-didecylamino)- 1-Methyl-B 98 This paper scale applies to China National Standard (CNS) A4 specification (210x 297 mm > A8BSC8D8 1280242 VI. Patent application base) - decylamine, 4-decyloxy benzene [a]Planting-11-carboxylic acid (2-didecylamino q_(s)-hydroxymethyl-ethyl)-decylamine, 4-methoxy-10-methylamino-benzo[ a] 哚 哚 carboxylic acid (2-didecylamino-ethyl)-bristamine, 10-hydroxy-4-methoxy-benzo[a]morphinecarboxylic acid (2-didecylamino group) 1-(Rl.methyl-ethyl)-decylamine, 4-methoxy-benzo[a]morphine-carboxylic acid (1-didecylaminomethyl-doriylpropyl)- Amine, 10-hydroxy-4-methoxy-benzo[a]morphine 4 carboxylic acid (2-dimethylamino-ethyl)-decylamine, 4-methoxy-stupid [a] Morphine-11-carboxylic acid (2_π-n-decyl-fluorenyl-ethyl)-decylamine, 4-methoxy-benzo[a]morphine-indole-carboxylic acid dimethylamino-1-( 2-hydroxyethyl)]-ethylguanamine, 10-amino-4-methoxy-benzo[a]morphinecarboxylic acid dimethylamino _ ethyl: l-decylamine, 4 methoxy Benzo[a]morphine-u•carboxylic acid (2-morpholine|yl-ethyl)·guanamine, 4-methoxy-benzo[a]morphin-11-acid (2_吼 啶 小 小 _ 醯 醯 _ _ 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯 醯Oxy-benzo[a]morphine-indole-decanoic acid Amino-ethyl bromide, 4-methoxy-9-mercaptosulfonyl-benzocarboxylic acid (2-dimethyl basic paper scale applicable to China National Standard (CNS) A4 specification (210x 297 public) 〉 -------------l··装--- (Read the first note on the back of this page) Book · 丨 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1280242 A8 BS C8 D8 patent application range Amino-ethyl)-decylamine, 4.9-dimethoxy-benzo[a]morphine-11·carboxylic acid (2-dimethylamino-ethyl)-decylamine, 4.10 - Dimethoxy-benzo[a]morphine-carboxylic acid (2. dimethylamino-1(S)-|methyl-ethyl)-nitramine, 4-decyloxy-benzene And [a] cultivating -11-carboxylic acid (2- mercaptoamino-ethyl) decylamine 10 hydroxy-' decyloxy-benzo[a] phenolic carboxylic acid dimethylamino-l (s)-hydroxymethyl-ethyl&gt; decylamine, (R-poly-methoxy-benzo-(4) phage-11-carboxylic acid (1. dimethylaminomethyl-2-ethyl-propyl) Carboxylic acid, 4-methoxy-benzo[a]morphine]carboxylic acid (1-methylpyrrolidyl)-acid amine, 4-methoxy-benzo[a]morphine Plowing-u_carboxylic acid hydrazine (double &gt; dimethylaminoyipropyl) lanthanum, earth and A pharmaceutically acceptable salts thereof. (a pharmaceutical composition printed by the Consumers' Consortium of the Intellectual Property Office of the Department of Anti-Virus, Anti-Virus, Anti-Bacterial or Anti-Fungal Trial Economics, which contains a pharmaceutically acceptable carrier or diluent) And as a compound of the active ingredient as defined in claim 1, 2 or 5 of the patent application. 7. A method for producing a compound as defined in claim 1 of the patent application, the method Including: Chemicalization (4) A derivative of a compound of the formula m obtained by kappa® having an amine of the formula (m): /, an acant Μ氏張尺度適用 1280242Μ氏张Scale applies 1280242 、申請專利範圍Patent application scope (Π) 其中R至R7係如申請專利範圍第W中所定義者， (III) 圍第1項中所定義者 + Q ' R及R9係如申請專利範 或 種有機溶劑内或沒有之下，且於一個升高之溫 ::使用—個如上所定義之具有化學式_之胺來處 理一個具有化學式（IV)之化合物：(Π) where R to R7 are as defined in the W scope of the patent application, (III) defined in the first item + Q 'R and R9 are in the patent application or in the organic solvent or not And at an elevated temperature:: treating a compound of formula (IV) using an amine of formula _ as defined above: (IV) 其中R至R7及R11係如申請專利範圍第i項中所定義者 經濟部智慧財產局員工消費合作社印製 :且 ⑷士為所需’藉由例行的化學修飾方法將所產生之苯 并[a]啡畊-11-羧醯胺衍生物轉變為另一個此種衍生 物，及/或將一個苯并[a]啡啡羧醯胺衍生物轉變 為其一藥學上可接受之鹽類。 8· 一個具有化學式（II)之化合物： 本紙張尺度適用中國國家標準（CNS〉A4規格（210 X 297公釐 1280242 A8 B8 C8 D8 六、申請專利範圍(IV) where R to R7 and R11 are printed as defined in item i of the scope of application of the patent, Ministry of Economic Affairs, Intellectual Property Office, Staff Consumption Cooperative: and (4) is required as required by routine chemical modification methods. Conversion of a benzo[a]morphin-11-carboxamide derivative to another such derivative, and/or conversion of a benzo[a]morphinecarboxamide derivative to a pharmaceutically acceptable Salt. 8. A compound of formula (II): This paper scale applies to Chinese national standards (CNS>A4 specification (210 X 297 mm 1280242 A8 B8 C8 D8 VI. Patent application scope) (IQ 其中R至尺係如申請專利範圍第1項中所定義者，或其 一個藥學上可接受之鹽類。 9· #用以產生—個如中請專利範圍第8項中所界定之化 合物的方法，該方法包含： ⑷於有機溶劑中，使用-個具有化學式㈤之 苯曱I或其一酯或鹽類來處理一個具有化學式 (V)之1，2-萘醌：(IQ where R to ruler is as defined in item 1 of the scope of the patent application, or a pharmaceutically acceptable salt thereof. 9) #使用产生— as defined in item 8 of the scope of patent application A method of a compound comprising: (4) treating a 1,2-naphthoquinone having the formula (V) by using a benzoquinone I having the formula (5) or a monoester or a salt thereof in an organic solvent: (V) 其中Rl至r4係如申請專利範圍第1項中所定義者，(V) where R1 to r4 are as defined in item 1 of the scope of the patent application, R6 (VI) 經濟部智慧財產局員工消費合作社印製 其中R5、R6及R7係如申請專利範圍 r罘1項中所定義者 木紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐〉 102 . 1280242 AS g ___ D8 ~ — — —一^w ____ 六、申請專利範圍 10·如申請專利範圍第9項之方法，該方法係於丨至5當量之 個礦物酸的存在下被進行者。 11.如申請專利範圍第6項之藥學組成物，其係供用作為一 個拓樸異構酶I抑制劑。 12·如申請專利範圍第6項之藥學組成物，其係供用作一個 拓樸異構酶II抑制劑。 13·如申請專利範圍第6項之藥學組成物，其係供用作為一 個拓樸異構酶1與拓樸異構酶II之共同抑制劑。 14如申請專利範圍第6項之藥學組成物，其係供用於治療 一個腫瘤。 15·如申請專利範圍第14項之藥學組成物，其中該腫瘤表 現多重藥物抗性。 16. 如申請專利範圍第15項之藥學組成物，其中該多重藥 物抗性（MDR)係為P-醣蛋白調節之多重藥物抗性、 (MDR) 〇 17. 如申請專利範圍第15項之藥學組成物，其中該多重藥 物抗性（MDR)係為與多重藥物抗性相關之蛋白質 (MRP)所調節之多重藥物抗性（mdr)。 18·如申請專利範圍第15項之藥學組成物，其中該多重藥 物抗性（MDR)係為非典型之多重藥物抗性（MDR)。 19.如申請專利範圍第6項之化合物，其係供用作為一抗病 毒、抗細菌或抗真菌試劑。 本紙張尺度適用中國國豕標準（CNS)A4規格（210 X 297公爱） (請先閱讀背面之注意事項為填寫本頁) :裝 ，ίτ·. 經濟部智慧財產局員工消費合作社印製 103R6 (VI) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed R5, R6 and R7 are as defined in the scope of application for patents r罘1. The wood paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 PCT> 102. 1280242 AS g ___ D8 ~ — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — The pharmaceutical composition of claim 6 is for use as a topoisomerase I inhibitor. 12. The pharmaceutical composition of claim 6 is for use as a Topoisomerase II inhibitor. 13. The pharmaceutical composition of claim 6, which is used as a co-inhibitor of topoisomerase 1 and topoisomerase II. The pharmaceutical composition of the sixth aspect of the invention, which is for use in the treatment of a tumor. The pharmaceutical composition of claim 14, wherein the tumor exhibits multiple drug resistance. Pharmaceutical composition, Wherein the multidrug resistance (MDR) is a P-glycoprotein-regulated multiplex drug resistance, (MDR) 〇 17. The pharmaceutical composition of claim 15 wherein the multidrug resistance (MDR) system Multidrug resistance (mdr) regulated by a protein associated with multidrug resistance (MRP). 18. A pharmaceutical composition according to claim 15 wherein the multidrug resistance (MDR) is atypical Multiple drug resistance (MDR) 19. A compound as claimed in claim 6 which is intended for use as an antiviral, antibacterial or antifungal agent. This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 public) (Please read the note on the back to fill out this page): Install, ίτ·. Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed 103
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