TWI293306B - Modified nucleosides for the treatment of viral infections and abnormal cellular proliferation - Google Patents

Modified nucleosides for the treatment of viral infections and abnormal cellular proliferation Download PDF

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TWI293306B
TWI293306B TW90126014A TW90126014A TWI293306B TW I293306 B TWI293306 B TW I293306B TW 90126014 A TW90126014 A TW 90126014A TW 90126014 A TW90126014 A TW 90126014A TW I293306 B TWI293306 B TW I293306B
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hydrogen
pharmaceutically acceptable
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pharmaceutical composition
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Stuyver Lieven
Watanabe Kyoichi
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Pharmasset Ltd
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Description

1293306 A7 B7 五、發明說明（1 ) [發明範圍] (請先閱讀背面之注意事項再填寫本頁) 本發明包含用於治療黃病毒科（Flaviviridae)、正黏液 病毒科（Orthomyxoviridae)、副黏液病毒科 (Paramyxoviridae)病毒感染及非正常細胞增生之化合物及 方法。 本申請案主張優先權2000年10月18曰申請之美國臨 時申請案No .60/241,488及2001年4月6曰申請之美國臨 時申請案No.60/282,156之優先權。 [發明背景] 黃病毒科病毒（Flaviviridae) 黃病毒科病毒為一種基因組大小在9至15kb之正向單 股RNA病毒。其為約40至50nm之被膜病毒。有關黃病 毒科病毒分類學之概述可得自“國際病毒分類學會 議’’（International Committee for Taxonomy of Viruses) 〇 黃 病毒科病毒包括三個屬。 經濟部智慧財產局員工消費合作社印剩衣 1.黃病毒（Flaviviruses)。這一屬的病毒包括登革熱病毒類 (登革熱病毒、登革熱病毒1型、登革熱病毒2型、登 革熱病毒3型、登革熱病毒4型），曰本腦炎病毒類（艾 弗病毒（Alfuy Virus)、曰本腦炎病毒、庫克布拉病毒 (Kookaburra virus)、克坦格病毒（Koutango virus)、肯金 病毒（Kunjin virus)、姆瑞谷（Murray Valley)腦炎病毒、 聖路易（St. Louis)腦炎病毒、史塔佛病毒（Stratford virus)、烏蘇病毒（Usutu virus)、西奈爾病毒（West Nile Virus))，莫道克（Modoc)病毒類、里約布拉弗（Rio Bravo) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1 91949 A7 經濟部智慧財產局員工消費合作社印製 1293306 B7 ___ 五、發明說明（2 ) 病毒類（艾波伊病毒（Apoi virus)、里約布拉弗病毒、薩 波亞病毒（Saboya virus))、尼塔亞（Ntaya)病毒類、壁兹 型腦炎病毒類（壁蝨型腦炎病毒）、特南尼（Tyuleniy)病毒 類、烏干達S病毒類、及黃熱病毒類。除了這幾種主要 病毒類外，尚有幾種黃病毒尚未分類。 2 ·肝病喜（Hepaciviruses)。這一屬的病毒只有一個品種， 即C型肝炎病毒（HCV)，其中包含許多種系分支、型與 亞型。 3 ·疫病毒（Pestiviruses)。這一屬病毒包括牛病毒性下痢病 毒-2(BVDV-2)、疫病毒1型（包含BVDV)、疫病毒2型 (包括豬霍亂病毒）及疫病毒3(包含邊緣疾病病毒 (Border Disease Virus)) 〇 人類最重要之黃病毒科病毒感染之一係由C型肝炎病 毒（HCV)引起。這種病毒為病毒性肝炎之第二大主因，估 計全世界有1億7000萬帶原者（World Health Organization ； Hepatitis C ： Global prevalence, Weekly Epidemiologigal Record, 1997, 72, 341)，其中 390 萬人住 在美國（疾病防治中心；未公佈之數據，http://www. cde. gov./ncidod/diseases/hepatitis/heptab3.htm)。 黃病毒科病毒之基因組結構有許多共同特色。通常使 用C型肝炎病毒（HCV)基因組為模式。HCV為一種小型被 膜病毒’病毒粒子内含有約9.6kb之正向單股RNA基因 組。基因組含有單獨一個開放讀碼區（0RF)，供編碼恰好 超過3000個胺基酸之聚蛋白質，可裂解產生成熟結構性及 本紙張尺度適用中關家標準（CNS)A4規格（21G X 297公髮) ----- 91949 (請先閱讀背面之注意事項再填寫本頁)1293306 A7 B7 V. INSTRUCTIONS (1) [Scope of the invention] (Please read the note on the back and then fill out this page) The present invention comprises for the treatment of Flaviviridae, Orthomyxoviridae, and paramucus. Compounds and methods for viral infection and abnormal cell proliferation of the genus Paramyxoviridae. The present application claims priority to U.S. Provisional Application No. 60/241,488, filed on Oct. 18, 2000, and the U.S. Provisional Application Serial No. 60/282,156, filed on Apr. 6, 2000. [Background of the Invention] Flaviviridae Flaviviridae is a forward single-stranded RNA virus having a genome size of 9 to 15 kb. It is a enveloped virus of about 40 to 50 nm. An overview of the taxonomy of the Flaviviridae virus can be obtained from the International Committee for Taxonomy of Viruses. The Flavivirus family of viruses includes three genera. Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printed Clothes 1 Flaviviruses. The viruses of this genus include dengue viruses (dengue virus, dengue virus type 1, dengue virus type 2, dengue virus type 3, dengue virus type 4), sputum encephalitis virus (Iver) Alfuy Virus, sputum encephalitis virus, Kookaburra virus, Koutango virus, Kunjin virus, Murray Valley encephalitis virus, St. Louis encephalitis virus, Stratford virus, Usutu virus, West Nile Virus, Modoc virus, Riobu Rio Bravo This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1 91949 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1293306 B7 _ __ V. INSTRUCTIONS (2) Viruses (Apoi virus, Rio Braver virus, Saboya virus), Ntaya virus, and wall-type brain Inflammatory viruses (tick-type encephalitis virus), Tyleniy (Tyuleniy) virus, Uganda S virus, and yellow fever virus. In addition to these major viruses, several yellow viruses have not yet been classified. · Hepaciviruses. There is only one species of this genus, the hepatitis C virus (HCV), which contains many germline branches, types and subtypes. 3 · Pestiviruses. This genus includes Bovine viral prion-2 (BVDV-2), plague virus type 1 (including BVDV), plague virus type 2 (including swine cholera virus) and plague virus 3 (including border disease virus) One of the important flavivirus infections is caused by hepatitis C virus (HCV), which is the second leading cause of viral hepatitis and is estimated to have 170 million carriers worldwide (World Health Organization; Hepatitis C : Global prevalence, Weekly E Pidemiologigal Record, 1997, 72, 341), of which 3.9 million live in the United States (Center for Disease Control; unpublished data, http://www.cde.gov./ncidod/diseases/hepatitis/heptab3.htm). The genome structure of the Flaviviridae virus has many features in common. The hepatitis C virus (HCV) genome is often used as a model. HCV is a small enveloped virus 'virion containing a forward single-stranded RNA genome of approximately 9.6 kb. The genome contains a single open reading frame (0RF) for encoding polyproteins of just over 3,000 amino acids, which can be cleaved to produce mature structures and to the paper scale (CNS) A4 specification (21G X 297)发) ----- 91949 (Please read the notes on the back and fill out this page)

2 1293306 Λ7 B7 五、發明說明（3 ) (請先閱讀背面之注意事項再填寫本頁) 非結構性病毒蛋白質。ORF側接長數百個核脊酸之5 ’與3 ’ 非轉譯區（NTRs)，對RNA之轉譯與複製很重要。轉譯之 聚蛋白質在N末端含有結構核心（C)及被膜蛋白質（E1、 經濟部智慧財產局員工消費合作社印製 E2、p7)，隨後接著非結構性蛋白質（NS2、NS3、NS4A、 NS4B、NS5A、NS5B)。成熟之結構性蛋白質係由宿主訊號 肽酶裂解產生（參見：Hijikata，M· et al· Proc. Nat. Acad. Sci.r USAr 1991，88, 5547 ; Hussy，P· et al· Virology, 1996, 224, 93 ； Lin, C. et al. T Virol.. 1994, 68, 5063 ; Mizushima， H. et al. J ViroK: 1994, 68, 2731 ； Mizushima, H. et al. L· Virol.. 1994, 68, 6215 ; Santolini，E· et al· J· ViroL，1994, 68, 3631 ; Selby，M. J· et al· Virolo^ 1994, 204, 114 ;及 Grakoui，A· et al· Proc. Nat. Acad. Sci.. USA. 1993，90， 10538)。NS2與NS3之間鏈結被NS2/NS3蛋白酶自體催化 性裂解（參見 Hijikata，M. et al· J. Virol” 1993，67，4665 及 Bartenschlager, R. et al. J. Virol·，1994，68，5045)，而其餘 四個鏈結則被與NS4A複合之NS3之N末端絲胺酸蛋白酶 功能部位裂解。（參見 Failla，C· et al· J. Virol” 1994，68， 3753 ; Lin，C· et al· J. Virol” 1994, 68, 8147 ; Tanji，Y. et al· •T. Virol·· 1995, 69, 1575 及 Tai5 C. L· et al· T ViroK. 1996, 70, 8477)，NS3蛋白質亦包含依賴NTP之解螺旋酶活性， 在複製期間解開RNA雙螺旋。NS5B蛋白質具有依賴RNA 之 RNA 聚合酶（RDRP)活性（參見：Behrens，S. Ε· et al· EMBO丄，1996, 15, 12 ; Lohmann，V. et al· J Virol.. 1997, 71，8416-8428 及 Lohmann，V· et al· Virology〕1998，249， 冢紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 3 91949 經濟部智慧財產局員工消費合作社印製 1293306 A7 B7 五、發明說明（4 ) 108)，其係病毒複製時必要之活性（Ferrari, E. et al. J, Virol.. 1999, 73, 1649)。此時要強調的是，HCV之複製未 涉及DNA，此點與HBV或HIV不同。近來在使用NS5B 之試管内實驗中，用鳥嘌呤核苷5、單磷酸（GMP)、5、二磷 酸（GDP)、5’-三磷酸（GTP)及2，_去氧與2，，3，-二去氧鳥嘌 呤核苷之5’-三磷酸（分別為dGTP與ddGTP)探討HCV-RDRP之受質專一性。該作者指出，HC V-RDRP對核糖核 苷5’-三攝酸有嚴苛之專一性且需要2、與3’-〇 Η基 (Lohmann ； Virology，108)。其實驗認為2’-與3，-取代基之 存在為核苷5’-三磷酸與HCV-RDRP交互作用及作為受質 或抑制劑之先決條件。2 1293306 Λ7 B7 V. INSTRUCTIONS (3) (Please read the notes on the back and fill out this page) Non-structural viral proteins. The 5' and 3' non-translated regions (NTRs) of the ORF side are several hundred nucleotide nucleates, which are important for RNA translation and replication. The translated polyprotein contains a structural core (C) and a envelope protein at the N-terminus (E1, E2, p7 printed by the Ministry of Economic Intelligence, Employees' Consumer Cooperatives), followed by non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A). , NS5B). Mature structural proteins are produced by cleavage of host signal peptidases (see: Hijikata, M. et al. Proc. Nat. Acad. Sci.r USAr 1991, 88, 5547; Hussy, P. et al. Virology, 1996, 224, 93 ; Lin, C. et al. T Virol.. 1994, 68, 5063 ; Mizushima, H. et al. J ViroK: 1994, 68, 2731 ; Mizushima, H. et al. L· Virol.. 1994 , 68, 6215 ; Santolini, E. et al. J. ViroL, 1994, 68, 3631; Selby, M. J. et al. Virolo^ 1994, 204, 114; and Grakoui, A· et al· Proc. Nat Acad. Sci.. USA. 1993, 90, 10538). The link between NS2 and NS3 is autocatalyzed by the NS2/NS3 protease (see Hijikata, M. et al. J. Virol) 1993, 67, 4665 and Bartenschlager, R. et al. J. Virol, 1994, 68,5045), while the remaining four chains are cleaved by the N-terminal serine protease functional site of NS3 complexed with NS4A (see Failla, C. et al. J. Virol) 1994, 68, 3753; Lin, C· et al· J. Virol” 1994, 68, 8147 ; Tanji, Y. et al. • T. Virol· 1995, 69, 1575 and Tai5 C. L· et al· T ViroK. 1996, 70, 8477 The NS3 protein also contains NTP-dependent helicase activity, which unwinds the RNA duplex during replication. The NS5B protein has RNA-dependent RNA polymerase (RDRP) activity (see: Behrens, S. Ε· et al· EMBO丄) , 1996, 15, 12 ; Lohmann, V. et al· J Virol.. 1997, 71, 8416-8428 and Lohmann, V· et al· Virology] 1998, 249, 冢 paper scale applicable to Chinese National Standard (CNS) A4 Specification (210 x 297 mm) 3 91949 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1293306 A7 B7 V. Invention Description (4) 108), its system The necessary activity for virulence replication (Ferrari, E. et al. J, Virol.. 1999, 73, 1649). It is emphasized at this time that the replication of HCV does not involve DNA, which is different from HBV or HIV. Intra-tube experiments using NS5B, using guanosine 5, monophosphate (GMP), 5, diphosphate (GDP), 5'-triphosphate (GTP) and 2,_deoxy and 2,, 3,- The 5'-triphosphate of dihydroguanosine nucleosides (dGTP and ddGTP, respectively) explores the specificity of HCV-RDRP. The authors point out that HC V-RDRP is strict with ribonucleoside 5'-tricarboxylic acid Harsh specificity requires 2 and 3'-mercapto (Lohmann; Virology, 108). The experiment suggests that the presence of 2'- and 3,- substituents interacts with nucleoside 5'-triphosphate and HCV-RDRP. Role and preconditions as a substrate or inhibitor.

V 已判別具有對抗C型肝炎黃病毒活性之抗病毒劑實例 包括： 1·干擾素與利巴韋林（ribavirin) (Battaglia，A· M. et al· Ann. Pharmacother. 2000，34,487 ; Berenguer，M. et al· Antivir. Ther. 1998, 3 (Suppl· 3)，125); 2. 以受質為主之NS3蛋白酶抑制劑（Attwood et al· PCT WO 98/22496，1998 ; Attwood et al· Antiviral Chemistry and Chemotherapy 1 999, 1 0, 259，； Attwood et al·德國專 利公告案 DE 19914474 ; Tung et al· PCT WO 98/17679)，包含a_酮基醯胺及肼基脲，及末端為親電 子物如：二羥硼酸或膦酸酯之抑制劑（Llinas-Brunet et· al. PCT WO 99/07734)； 3. 不以受質為主之抑制劑如：2,4,6-三羥基-3-硝基-苯醯胺 ^紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 4 91949 (請先閱讀背面之注意事項再填寫本頁)Examples of antiviral agents that have been identified as having anti-hepatitis C flavivirus activity include: 1. Interferon and ribavirin (Battaglia, A. M. et al. Ann. Pharmacother. 2000, 34, 487; Berenguer, M. et al. Antivir. Ther. 1998, 3 (Suppl. 3), 125); 2. NS3 protease inhibitors based on receptors (Attwood et al. PCT WO 98/22496, 1998; Attwood et al. Antiviral Chemistry and Chemotherapy 1 999, 1 0, 259,; Attwood et al. German Patent Publication DE 19914474; Tung et al. PCT WO 98/17679), comprising a-ketodecylamine and guanylurea, and terminal Electrophilic substances such as: inhibitors of diboronic acid or phosphonates (Llinas-Brunet et al. PCT WO 99/07734); 3. Inhibitors not dominated by receptors such as: 2,4,6-three Hydroxy-3-nitro-benzoguanamine ^ paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 4 91949 (Please read the note on the back and fill out this page)

1293306 a7 B7 五、發明說明（5 ) 衍生物（Sudo K· et al·，Biochemical and Biophysical R^Rearch Communications^ 1997，238，643 及 Sudo K· et al· Antiviral Chemistry and Chemotherapy 1998，9， 186)，包含RD3-4082及RD3-4078，前者之醯胺經一條 14個碳之鏈取代，後者則具有對位苯氧苯基； 4. 在使用NS3/4A融合蛋白質及NS5A/5B受質之逆相 HPLC分析法中展現相關抑制作用之噻唑啶衍生物 (Sudo K. et al. Antiviral Research 1996，32, 9)，尤指化 合物RD-1-6250，其具有經長鏈烷基取代之稠合肉桂醯 基部份基團，RD4 6205與RD4 6193 ; 5. 由 Kakiuchi N. et al· J. EBS Letters 421. 217 與 Takeshita N· et al· Analytical Biochemistry 1997，247, 242 判別之 噻唑啶與苯醯替苯胺； 6. —種自鏈黴菌之醱酵培養液中單離，且在SDS-PAGE與 自動放射照相分析法中展現對抗HCV蛋白酶活性之菲 醌’自青黴菌單離之Sch 68631 (Chu M. et al. Tetrahedron Letters 1996, 37, 7229) 與Sch 351633，其在閃爍近似分析法中證實具有活性 (Chu M· et al·，Bioorganic and Medicinal Chemistry Letters 9，1949); 7. 自水蛵中單離出之以大分子艾金素（el gin)c為主之選擇 性 NS3 抑制劑（Qasim Μ·A. et al· Biochemistry 1997，36, 1598)； 8· HCV解螺旋酶抑制劑（Diana G. D· et al·，美國專利案No. 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 5 (請先閱讀背面之注音？事項再填寫本頁) IT---------線—▲ 經濟部智慧財產局員工消費合作社印製 1293306 B7 五、發明說明（6 ) 5,633,358 及 Diana G· D· et al· PCT W0 97/36554); 9. HCV聚合酶抑制劑如··核苷酸類似物，支黴黏毒素 (gliotoxin) (Ferrari R. et al. Journal of VirolagX 1999， 73，1649)，及天然產物淺藍菌素（cerulenin) (Lohmann V· et al. Virology 1998, 249, 108); 10. 與HCV之至少一部份序列互補之反義硫代磷酸酯寡去 氧核苷酸（S-ODN) (Anderson et al·美國專利案No. 6，174,868)，及特別指5，-非編碼區（NCR)之伸長序列 (Alt M. et al. Hepatology 1995，22，707)或包含 NCR 之 3，-末端之核苷酸326-348及位於HCV RNA之核心編碼 區之核苷酸 37 1 - 388(Alt M. et al· Archives of YiT〇l〇.SJL 1997，142，589 及 Galderisi U· et al.，Journal of Cellular Physiology 1999, 81 ： 2151)； 11. 依賴IRES之轉譯作用抑制劑（Ikeda N et al.曰本專利公 告案JP-08268890 ; Kai Y. et al·日本專利公告案JP-10101591)； 12. 抗核酸酶之核糖酵素（Maccjak D.J. et al·，Hepatology 1999, 30,摘要 995); 13·金剛胺如：里曼塔定（rimantadine) (Smith，美國胃腸病 學會與AASLD年會報告摘要，1996年）； 14·喹諾酮類如：歐弗辛（ofloxacin)、赛普弗辛（ciprofloxacin) 及里弗辛（levofloxacin) (AASLD Abstracts，Hepatology, 1994 年 10 月，Program Issue, 20(4)，pt.2，abstract no.293)； 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) tr---------線—▲ 經濟部智慧財產局員工消費合作社印製 A7 經濟部智慧財產局員工消費合作社印制衣 1293306 B7__ 五、發明說明（7 ) 15·核苷類似物（Ismaili et al· WO 01/60315 ; Storer WO 01/32153)，包含 2，·去氧-L，核苷（Watanabeetal.WO 01/34618)及1_(召-]^-呋喃核糖基）_1，2,4-三唑_3-羧醯胺 (levovirinTM) (Tam WO 01/46212);及 16·其他類化合物包含1-胺基-烷基環己烷（Gold et al.美國 專利案No. 6,034，134)，烷基脂質（Chojkier等人，美國 專利案No· 5,922,757)，維生素-E及其他抗氧化劑 (Chojkier等人，美國專利案No· 5,922,757)，角鯊烯， 膽酸類（Ozeki等人，美國專利案No· 5,846,964)，N_(亞 磷羧乙醯基）-L-天冬胺酸（Diana等人，美國專利案No. 5,830,905)，苯二羧醯胺（Diana等人，美國專利案No. 5,633,388)，聚腺苷磷酸衍生物（Wang等人，美國專利 案 No· 5,496,546)，2，，3，-二去氧肌苷（Yarchoan 等人， 美國專利案No. 5,026,687)，苯并咪唑（Colacino等人， 美國專利案No· 5,891，874)，葡糖胺（Mueller等人， WO 01/08672)，經取代之1，5_亞胺基葡糖醇化合物 (Mueller 等人，WO 00/47198)。 正黏液病毒科病毒（Orthomyxoviridae) 正黏液病毒為'種基因組大小在10至13.6kb之節狀 負向單股RNA。其為約80至120run之被膜病毒。有關正 黏液病毒科病毒分類學之說明可得自國際病毒分類學會議 報告。正黏液病毒科病毒包括三個屬，可依據其病毒粒子 (NP)與間質蛋白質（M)之間抗原性差異區分。 1 ·座.感病毒A, B。這一屬的病毒包含流感病毒A與B，其 本紙張尺度適用中國國家標準（CNS)A4規格（21G X 297公复) ~ 91949 (請先閱讀背面之注意事項再填寫本頁)1293306 a7 B7 V. INSTRUCTIONS (5) Derivatives (Sudo K. et al., Biochemical and Biophysical R^Rearch Communications^ 1997, 238, 643 and Sudo K. et al. Antiviral Chemistry and Chemotherapy 1998, 9, 186) Containing RD3-4082 and RD3-4078, the former is substituted with a 14 carbon chain, the latter with p-phenoxyphenyl; 4. The reverse of the NS3/4A fusion protein and NS5A/5B A thiazolidine derivative exhibiting a related inhibitory effect in phase HPLC analysis (Sudo K. et al. Antiviral Research 1996, 32, 9), especially a compound RD-1-6250 having a long chain alkyl substitution fused Cinnamyl moiety, RD4 6205 and RD4 6193; 5. Thiazolidine and benzene identified by Kakiuchi N. et al. J. EBS Letters 421. 217 and Takeshita N. et al. Analytical Biochemistry 1997, 247, 242 Anthraquinone; 6. A species isolated from a fermentation broth of Streptomyces and exhibiting anti-HCV protease activity in SDS-PAGE and automated radiographic analysis of phenanthrene's from Penicillium sp. Chu M. et al. Tetrahedron Letters 1996, 37, 7229) And Sch 351633, which was confirmed to be active in scintillation approximation analysis (Chu M. et al., Bioorganic and Medicinal Chemistry Letters 9, 1949); 7. Macromolecular arginine (el) Gin)c-based selective NS3 inhibitor (Qasim A·A. et al·Biochemistry 1997, 36, 1598); 8. HCV helicase inhibitor (Diana G. D. et al., US Patent No. This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 5 (Please read the phonetic note on the back first and then fill out this page) IT---------Line-▲ Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1293306 B7 V. Invention Notes (6) 5,633,358 and Diana G·D· et al· PCT W0 97/36554); 9. HCV polymerase inhibitors such as nucleotide analogues, Gliotoxin (Ferrari R. et al. Journal of Virolag X 1999, 73, 1649), and the natural product cerulenin (Lohmann V. et al. Virology 1998, 249, 108); An antisense phosphorothioate oligodeoxynucleotide (S-ODN) complementary to at least a portion of the sequence of HCV (Anderson et al. Patent No. 6,174,868), and particularly to the elongation sequence of the 5,-non-coding region (NCR) (Alt M. et al. Hepatology 1995, 22, 707) or the nucleotide containing the 3,-end of NCR 326-348 and nucleotides 37 1 - 388 located in the core coding region of HCV RNA (Alt M. et al. Archives of YiT〇l〇. SJL 1997, 142, 589 and Galderisi U. et al., Journal of Cellular Physiology 1999, 81 : 2151); 11. IRES-dependent translation inhibitors (Ikeda N et al. 曰Patent Bulletin JP-08268890; Kai Y. et al. Japan Patent Bulletin JP-10101591); Nuclease ribozyme (Maccjak DJ et al., Hepatology 1999, 30, Abstract 995); 13·Amantadine such as: rimantadine (Smith, American Society of Gastroenterology and AASLD Annual Report Summary, 1996 14; quinolones such as: ofloxacin, ciprofloxacin and levofloxacin (AASLD Abstracts, Hepatology, October 1994, Program Issue, 20(4), pt. 2, abstract no.293); This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 91949 (Please read the note on the back and fill in this page) tr---------Line-▲ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed clothing 1293306 B7__ V. Description of the invention (7) 15. Nucleoside analogues (Ismaili et al. WO 01/60315; Storer WO 01/32153), containing 2, deoxy-L, nucleosides (Watanabe et al. WO 01/34618) And 1_(call-]^-ribofuranosyl)-1,2,4-triazole-3-carboxycarmine (levovirinTM) (Tam WO 01/46212); and 16· other compounds comprising 1-amino-alkane Cyclohexane (Gold et al. U.S. Patent No. 6,034,134), alkyl lipids (Chojkier et al., U.S. Patent No. 5,922,757), vitamin-E and other antioxidants (Chojkier et al., U.S. Patent No. 5,922,757), squalene, cholic acid (Ozeki et al., U.S. Patent No. 5,846,964), N_(phosphonium carbaryl)-L-aspartic acid (Diana et al., U.S. Patent No. 5,830,905), benzodiazepine (Diana et al., U.S. Patent No. 5,633,388), polyadenosine phosphate derivative (Wang et al., U.S. Patent No. 5,496,54) 6), 2,3,-dideoxyinosine (Yarchoan et al., U.S. Patent No. 5,026,687), benzimidazole (Colacino et al., U.S. Patent No. 5,891,874), glucosamine (Mueller) Et al., WO 01/08672), substituted 1,5-iminoglucosamine compound (Mueller et al., WO 00/47198). Orthomyxoviridae Orthomyxoviridae is a nodular single-stranded RNA with a genome size of 10 to 13.6 kb. It is a enveloped virus of about 80 to 120 run. A description of the taxonomy of the positive mucinous virus can be obtained from the International Conference on Virology Taxonomy. The Orthomyxoviridae virus includes three genera, which can be distinguished based on the antigenic difference between the virion (NP) and the interstitial protein (M). 1 · Block. Virus A, B. The virus of this genus contains influenza viruses A and B, and the paper size is applicable to the Chinese National Standard (CNS) A4 specification (21G X 297 public recovery) ~ 91949 (please read the notes on the back and fill out this page)

7 [293306 A7 B7 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 8 五、發明說明（8 各含8個不連續之題節段。流感病毒B之表面酷蛋 白變異性不大，而且只感染人類。另一方面，流感病毒 A之表面醣蛋白則有很大鬱| ， 變異，且依其血球凝集素（HA) 與神經醯胺酶（NA)醣蛋白之;^ 、 v ’哪变曰<抗原性質分成幾種亞型，且 會感染人類及豬、馬、海狗、宕▲ . ^ ^ ’ 豕禽、鴨、及其他許多鳥 類。 2產-感病毒c°這一屬病毒只含一個品種，流感病毒c， 其中只含七個不連續之RNA節段。流感病毒C只含有 一種多功能醣蛋白，而且主要感染人類，但亦已自中國 之豬體内單離出。 3.旅感病毒D。這一屬病毒包含流感病毒D，這種病毒為 在結構與遺傳上類似流感病毒A、B與C之壁蟲型病 毒。 人類最重要之正黏液病毒科病毒感染之一係由流感病 毒A引起。這些病毒為高度傳染性且造成急性呼吸道疾 病’自古早以來，即造成社會之流行病。流感病毒A流行 傳染病最早記錄之一可追溯到西元前412年之希波克拉底 時代（Hipp〇erates)。這些流行傳染病經常發生，而且經常 造成老年人死亡，然而，這些流行傳染病卻相當難以預料。 這些病毒為獨特之呼吸道病毒，會進行顯著之抗原性變 異。血液凝集素（HA)與神經醯胺酶（NA)二種醣蛋白可進行 抗原性漂移與遷移。其中有14種已知血液凝集素（H1_H14) 醣蛋白及9種已知神經醯胺酶（N1-N9)醣蛋白，例如：自從 1993年單離出第一種人類流感病毒以來，即已發生顯著之 91949 (請先閱讀背面之注咅心事項再填寫本頁)7 [293306 A7 B7 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed on this paper scale Applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) 8 V. Invention Description (8 each with 8 discontinuous topics The surface protein of influenza virus B has little variability and only infects humans. On the other hand, the surface glycoprotein of influenza A has a large stagnation, mutation, and its hemagglutinin (HA) and nerves. The indolease (NA) glycoprotein; ^, v 'which changes 曰< antigenic properties are divided into several subtypes, and will infect humans and pigs, horses, fur seals, 宕▲. ^ ^ ' 豕, duck, and Many other birds. 2 production-sensitive virus c° This genus virus contains only one species, influenza virus c, which contains only seven discrete RNA segments. Influenza virus C contains only one multifunctional glycoprotein, and mainly infection Humans, but also have been isolated from pigs in China. 3. Brigade virus D. This genus virus contains influenza virus D, which is structurally and genetically similar to the walls of influenza A, B and C. Insect virus. Human most important positive mucus virus One of the infections is caused by influenza A. These viruses are highly contagious and cause acute respiratory diseases. Since ancient times, they have caused social epidemics. One of the earliest records of influenza A infectious diseases can be traced back to 412 BC. The Hippocrates era (Hipp〇erates). These epidemics often occur and often cause death in the elderly. However, these epidemics are quite unpredictable. These viruses are unique respiratory viruses that carry significant antigens. Sexual variation. Hemagglutinin (HA) and neuropterinase (NA) can carry out antigenic drift and migration. Among them, there are 14 known hemagglutinin (H1_H14) glycoproteins and 9 known neural crests. Aminase (N1-N9) glycoproteins, for example, since the first human influenza virus was isolated in 1993, significant 91949 has occurred (please read the back of the note and fill out this page)

1293306 A7 B7 五、發明說明（9 ) 抗原性遷移。1957年時，H2N2亞型（亞洲型流感）替代了 H1N1亞型（西班牙型流感）。目前，流感之主要亞型為於 1977年重現江湖之H1N1及1968年再現之H3N2。 探討流感病毒基因表現及RNA複製時，最常利用流感 病毒A進行。流感病毒a病毒粒子之最大特色在於自脂質 被膜向外輻射狀排列之約500個釘狀物層（1〇至i4nm)。這 些釘狀物分一種· HA之棒狀針狀物及]sfA之磨蒜狀釘狀 物。HA與NA之比例會有變化，但通常在4至5比1之間。 母個基因段均編碼其自己的蛋白質，但第七個與第八個節 段例外’其分別編碼Ml與M2，及NS1與NS2。各vRNA 喊段之3’_末端頭12個核苷酸與5，-末端頭13個核苷酸均 保留出現在所有八個RNA節段中。第一個分析出其基因核 苷酸序列為HA，從此以後，即已測得所有14種已知HA 抗原性亞型及亞型内各種變量株。 vRNAs在已感染細胞中轉錄成mRNAs並複製。mRNA 合成法之特徵在於RNA之引子為衍生自新合成之宿主細 胞RNA聚合酶II轉錄本之5,封端片段。111&以人鏈延長， 直到在vRNAs之5,末端之前延長尿嘧啶核苷殘質達15至 22個核苷酸為止，其中添加轉錄末端及聚腺苷酸至mRNAs 中。為了•進行複製，需要另一種轉錄型態，以便產生全長 度vRNAs複本。mRNA合成期間，全長度轉錄本不使用弓j 子即可開始，且不在所使用之聚（A)位置終止。複製過程之 第二個步驟為模板RNAs複製成vRNAs。由於vRNAs包含 • 5 -二構酸化末端’因此此合成作用亦不需要引子即可進 91949 (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 --------^---------ΜΙ0,----------------------- 9 1293306 A7 B7 五、發明說明（1()) 行。所有這三種病毒專一性RNAs (mRNA、模板RNA與 VRNA)均於細胞核中合成。 已經判別為具有對抗流感病毒A活性之抗病毒劑實例 包含： 1. 放射菌素 D (Barry, R· D. et al. “Participation of deoxyribonucleic acid in the multiplication of influenza virus” Nature, 1962, 194, 11 39-1140); 2. 金剛胺（Van Voris，L. P. et al· “Antivirals for the chemoprophylaxis and treatment of influenza” Semin T?^spir Infect. 1992，7，61-70); 3. 4-胺基-或4-脈基-2-去氧-2,3-二去氮-D-N-乙酿基神經 胺酸：4-胺基-或 4-脈基-Neu 5 Ac2en (von Itzstein，M· et al. “Rational design of potent sialidase-based inhibitors of influenza virus replication’，Nature, 1993，363，41 8-423)； 4. 利巴韋林（ribavirin) (Van Voris, L. P. et al· “Antivirals for the chemoprophylaxis and treatment of influenza^ Semin Respir Infect, 1992，7，61-70); 5. 干擾素（Came，Ρ· E. et al. “Antiviral activity of an interferon-inducing synthetic polymer” Proc Soc Fxp Biol Med· 1969, 131? 443-446 ； Gerone, P. J. et al. ''Inhibition of respiratory virus infections of mice with aeresols of synthetic double-stranded ribonucleic acid，’ Infect Immun, 1971，3，323-327 ; Takano，K. et al. 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) 1T---------線' 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 11 1293306 A7 B7 五、發明說明（11 ) “Passive interferon protection in mouse influenza” J Tnfect Dis: 1991，164, 969-972); 6.去活性之流感病毒A與B疫菌（“Clinical studies on influenza vaccine-1978” Rev Infect Dis, 1983, 5, 721-764 ； Galasso, G. T. et al. "'Clinical studies on influenza vaccine· 1976” J Infect Dis· 1977，136 (suppl)，S341 _ S746 ; Jennings，R. et al· “Responses of volunteers to inactivated influenza virus vaccines^ J Hyg, 1981，86， 1-16 ; Kilboume，E. D. “Inactivated influenza vaccine” In : Plothin SA，Mortimer EA，eds. Vaccines Philadelphia· Saunders, 1988, 420-434； Meyer, H. M.? Jr. et al. “Review of existion vaccines for influenza” Am J Clin PathoL 1978, 70, 146-1 52 ; “Mortality and Morbidity Weekly Report. Prevention and control of Influenza · Part I? Vaccines. Recommendations of the Advisory Committee on Immunication Practices (ACIP)” MMWRr 1993, 42(RR-6)，1-14，· Palache，A. M. et al. "Antibody response after influenza immunization with various vaccine doses · A double-blind, placebo-controlled, multi-centre, dose-response study in elderly nursing-home residents and young volunteers^ Vaccine· 1993，11，3-9 ; Potter，C. W. “Inactivated influenza virus vaccine” In : Beare AS，ed· Basic and applied influeza research, Boca Raton，FL : CRC Press，1982，119-1 58) o 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁)1293306 A7 B7 V. INSTRUCTIONS (9) Antigenic migration. In 1957, the H2N2 subtype (Asian influenza) replaced the H1N1 subtype (Spanish flu). At present, the main subtype of influenza is the re-emergence of H1N1 in rivers and lakes and H3N2 reproduced in 1968. Influenza virus A is most commonly used when investigating influenza virus gene expression and RNA replication. The most distinctive feature of influenza virus a virions is the approximately 500 nail layers (1 〇 to i4 nm) radially radiated from the lipid envelope. These nails are divided into a rod-shaped needle of HA and a grinding-like nail of sfA. The ratio of HA to NA will vary, but is usually between 4 and 5 to 1. The parent gene segments encode their own proteins, with the exception of the seventh and eighth segments, which encode M1 and M2, and NS1 and NS2, respectively. The first 12 nucleotides at the 3'-end of each vRNA shunt segment and the first 13 nucleotides at the 5'-end are retained in all eight RNA segments. The first analysis showed that the nucleotide sequence of the gene was HA, and since then, all 14 known HA antigenic subtypes and various variable strains within the subtype have been determined. vRNAs are transcribed into mRNAs and replicated in infected cells. The mRNA synthesis method is characterized in that the primer for RNA is a 5, capped fragment derived from a newly synthesized host cell RNA polymerase II transcript. 111& is extended by human chain until the uracil residue is extended by 15 to 22 nucleotides before the end of vRNAs 5, and the transcription end and polyadenylation are added to the mRNAs. In order to replicate, another transcriptional pattern is required to generate a full-length copy of the vRNAs. During mRNA synthesis, full-length transcripts can be started without the use of a bow, and are not terminated at the poly(A) position used. The second step in the replication process is the replication of template RNAs into vRNAs. Since vRNAs contain • 5 - di-acidified ends, this synthesis does not require primers to enter 91949 (please read the notes on the back and fill out this page) Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs ----- ----^---------ΜΙ0,----------------------- 9 1293306 A7 B7 V. Description of invention (1 ( )) Row. All three viral-specific RNAs (mRNA, template RNA, and VRNA) are synthesized in the nucleus. Examples of antiviral agents that have been identified as having anti-influenza A activity include: 1. Baristine, R. D. et al. "Participation of deoxyribonucleic acid in the multiplication of influenza virus" Nature, 1962, 194, 11 39-1140); 2. Amantadine (Van Voris, LP et al. "Antivirals for the chemoprophylaxis and treatment of influenza" Semin T?^spir Infect. 1992, 7, 61-70); 3. 4-Amino group - or 4-cyano-2-deoxy-2,3-diaza-DN-ethyl-enyl neuraminic acid: 4-amino- or 4-cyano-Neu 5 Ac2en (von Itzstein, M· et Al. "Rational design of potent sialidase-based inhibitors of influenza virus replication', Nature, 1993, 363, 41 8-423); 4. ribavirin (Van Voris, LP et al· "Antivirals for the Chemoprophylaxis and treatment of influenza^ Semin Respir Infect, 1992, 7, 61-70); 5. Interferon (Came, Ρ· E. et al. “Antiviral activity of an interferon-inducing synthetic polymer” Proc Soc Fxp Biol Med· 1969, 131? 443-446; Gerone, PJ et al. ''Inhibition o f respiratory virus infections of mice with aeresols of synthetic double-stranded ribonucleic acid,' Infect Immun, 1971,3,323-327 ; Takano,K. et al. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 91949 (Please read the note on the back and fill out this page) 1T---------Line 'Ministry of Commerce, Intellectual Property Bureau, Staff Consumer Cooperative, Printed Economy Ministry, Intellectual Property Bureau, Staff Consumer Cooperative, Printed 11 1293306 A7 B7 V. Description of invention (11) “Passive interferon protection in mouse influenza” J Tnfect Dis: 1991, 164, 969-972); 6. Deactivated influenza A and B ("Clinical studies on influenza" Vaccine-1978” Rev Infect Dis, 1983, 5, 721-764 ; Galasso, GT et al. "'Clinical studies on influenza vaccine· 1976” J Infect Dis· 1977,136 (suppl), S341 _ S746 ; Jennings, R. et al· “Responses of volunteers to inactivated influenza virus vaccines^ J Hyg, 1981,86, 1-16 ; Kilboume, ED “Inactivated influenza vaccine” In : Plothin SA, Mortimer EA Eds. Vaccines Philadelphia· Saunders, 1988, 420-434; Meyer, HM? Jr. et al. “Review of existion vaccines for influenza” Am J Clin Patho L 1978, 70, 146-1 52 ; “Mortality and Morbidity Weekly Report. Prevention and control of Influenza · Part I? Vaccines. Recommendations of the Advisory Committee on Immunication Practices (ACIP)” MMWRr 1993, 42(RR-6), 1-14, · Palache, AM et al. "Antibody response after influenza Immunization with various vaccine doses · A double-blind, placebo-controlled, multi-centre, dose-response study in elderly nursing-home residents and young volunteers^ Vaccine· 1993,11,3-9 ; Potter,CW “Inactivated influenza virus Vaccine” In : Beare AS, ed· Basic and applied influeza research, Boca Raton, FL : CRC Press, 1982, 119-1 58) o This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (Please read the notes on the back and fill out this page)

A7 B7 1293306 五、發明說明（12 副黏液病毒科病奏（Paramyxoviridael 副黏液病毒科病毒為一種基因組大小為16至2〇kb之負 向單股RNA病毒。其係約150至30〇nm之被膜病毒。有 關副黏液病毒科病毒分類學之說明可得自國際病毒分類學 會議報告。副黏液病毒科包括二個亞科 1 ·副黏液病毒亞科。此亞科包括三個屬： a) 副黏液病毒（paramyxovirus)。這一屬病毒由聖代病 毒（Sendai virus)代表，且包括人類副流感病毒1與 3 ； b) 魯布拉病毒（rubulavirus)。這一屬病毒由人類流行性 腮腺炎病毒、猿病毒5、雞瘟病毒及人類副流感病 毒2與4代表； c) 麻療病毒。這一屬病毒由麻療病毒代表；及 2·肺病毒亞科。此亞科病毒比其他亞科編碼更多種As (10種，相對於其他之6或7種）且只包含一個屬： a)肺病毒：這一屬病毒之最佳代表為呼吸合胞體病毒 (RSV)，但亦包括牛 rsV(BRSV)、羊 RSV(ORSC)、 山羊RSV(CRSV)、小鼠之肺炎病毒（PVM)及火雞鼻氣 管炎病毒（TRTV)。 人類最重要之肺病毒亞科感染之一係由呼吸合胞體病 毒（RSV)引起。RSV為全世界嬰兒與兒童下呼吸道病毒性 疾病之最重要原因。在大多數地區，RSV為造成一歲以下 幼兒肺炎與支氣管炎之所有微生物病原菌之禍首。亦已發 現’ RSV感染為免疫受壓抑之成人及老年人罹病之重要因 本紙張尺度適用中國國家標準（CNS)A4規格⑵Gχ 297公髮）--- 91949 (請先閱讀背面之注音？事項再填寫本頁) # 訂---------線—一 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 12 1293306 A7 B7 五、發明說明（13 ) 素。此外，BRSV亦為對牛隻具有經濟影響力之疾病。 RSV基因組的RNA之3’末端由44個核苷酸外源性前 導區組成’據稱應含有主要病毒發動子。繼前導區之後為 10個病毒基因，然後為1 5 5個核苷酸之外源性尾端區。基 因組RNA之88%由10種主要蛋白質之ORFs負責形成。 每種基因均由保留之9個核苷酸基因起始訊號開始。每一 種基因均由訊號之第一個核苷酸開始轉錄。每種基因之末 端均為半保留之12至13個核苷酸基因末端訊號，此訊號 指揮轉錄結束及聚腺苷酸化。前面9種基因為非重疊且由 大小在1至52個核甘酸之基因間區域分隔。基因間區域不 含任何保留性序列要素或任何二級結構之顯著特色。最後 二種RSV基因有68個核苷酸重疊。因此其中一個基因起 始訊號位在另一個基因之内而非之後。 己判別具有對抗RSV活性之抗病毒劑實例包括： 1·利巴韋林（Hruska，J· F· et al· “In vivo inhibition of respiratory syncytial virus by ribavirin” Antimicrob Agents Chemother^ 1982，21，125-130);及 2·純化之人類靜脈内 IgG-IVIG (Prince，G· A· et al. ''Effectiveness of topically administered neutralizing antibodies in experimental immunotherapy of respiratory syncytial virus infection in cotton rats” J Virol· 1987，61， 1851-1954 ； Prince, G. A. et al. ''Immunoprophylaxis and immunotherapy of respiratory syncytial virus infection in cotton rats” Infect Tmmuri 1982，42，81-87) o 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注咅？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 13 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 14 1293306A7 B7 1293306 V. INSTRUCTIONS (12 paramyxoviridae Paramyxoviridae virus is a negative single-stranded RNA virus with a genome size of 16 to 2 kb. It is a membrane of about 150 to 30 〇 nm. Virus. A description of the taxonomy of the Paramyxoviridae virus can be obtained from the International Conference on Virology Taxonomy. The Paramyxoviridae includes two subfamilies of the submucosal submucosa. This subfamily consists of three genera: a) Paramyxovirus. This genus virus is represented by Sendai virus and includes human parainfluenza viruses 1 and 3; b) rubulavirus. This genus virus is represented by human mumps virus, prion 5, chicken plague virus and human parainfluenza viruses 2 and 4; c) aesthetic virus. This genus virus is represented by the acupuncture virus; and 2. The subfamily of the lung virus. This subfamily virus encodes more species As (10 species, 6 or 7 species than others) and contains only one genus: a) Pulmonary virus: the best representative of this genus is the respiratory syncytium Virus (RSV), but also includes bovine rsV (BRSV), sheep RSV (ORSC), goat RSV (CRSV), mouse pneumovirus (PVM), and turkey rhinotracheitis virus (TRTV). One of the most important subfamily infections of human pneumovirus is caused by respiratory syncytial virus (RSV). RSV is the most important cause of viral diseases in infants and children with lower respiratory tract worldwide. In most areas, RSV is the leading cause of all microbial pathogens causing pneumonia and bronchitis in children under one year of age. It has also been found that 'RSV infection is an important cause of rickets in immunosuppressed adults and the elderly. This paper scale applies Chinese National Standard (CNS) A4 specifications (2) Gχ 297 liters)--- 91949 (Please read the phonetic notes on the back first) Fill in this page) # 订--------- Line-I. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 12 1293306 A7 B7 V. Invention description (13). In addition, BRSV is also a disease that has economic impact on cattle. The 3' end of the RNA of the RSV genome consists of a 44 nucleotide exogenous leader', which is said to contain the major viral promoter. Following the leader region are 10 viral genes followed by a 15 5 nucleotide exogenous tail region. 88% of the genomic RNA is responsible for the formation of ORFs of the 10 major proteins. Each gene begins with a 9-nucleotide gene start signal. Each gene is transcribed from the first nucleotide of the signal. The end of each gene is a semi-retained 12 to 13 nucleotide end signal that directs transcription and polyadenylation. The first nine genes are non-overlapping and are separated by intergenic regions ranging in size from 1 to 52 nucleotides. The intergenic region does not contain any significant features of the retained sequence elements or any secondary structure. The last two RSV genes have a 68 nucleotide overlap. Therefore, one of the genes starts to be within the other gene rather than after. Examples of antiviral agents that have been identified to have anti-RSV activity include: 1. ribavirin (Hruska, J. F. et al. "In vivo inhibition of respiratory syncytial virus by ribavirin" Antimicrob Agents Chemother^ 1982, 21, 125- 130); and 2. Purified human intravenous IgG-IVIG (Prince, G·A· et al. ''Effectiveness of topically administered neutralizing antibodies in experimental immunotherapy of respiratory syncytial virus infection in cotton rats') J Virol· 1987, 61 , 1851-1954 ; Prince, GA et al. ''Immunoprophylaxis and immunotherapy of respiratory syncytial virus infection in cotton rats' Infect Tmmuri 1982,42,81-87) o This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (Please read the note on the back? Please fill out this page again) #订---------Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 13 Ministry of Economic Affairs Intellectual Property Bureau Employee consumption cooperative printed 14 1293306

五、發明說明（14 ) 常細晌.％ i 細胞之分化、生長、功能與死亡係受到多細胞生物體 内分子層面之複雜網路機制調節。在健康動物體或人體 内’這些機制使得細胞得以進行已設計妤之功能，然後以 漸進之速率死亡。 非正常細胞增生（主要指過度增生）可能由多種因素造 成’包括基因突變、曝露到毒素、自體免疫病變、或惡性 或良性腫瘤誘發。V. INSTRUCTIONS INSTRUCTIONS (14) Frequently, the differentiation, growth, function, and death of cells are regulated by complex network mechanisms at the molecular level within multicellular organisms. In healthy animals or humans, these mechanisms allow cells to perform their designed functions and then die at a progressive rate. Abnormal cell proliferation (mainly hyperproliferation) may be caused by a variety of factors, including genetic mutations, exposure to toxins, autoimmune diseases, or malignant or benign tumors.

有許多種皮膚病變與細胞過度增生有關。例如：牛皮 癖為一種良性人類皮膚病，其一般特徵為被增厚之鱗片覆 蓋成斑。這種疾病是由表皮細胞因不明原因而提高增生作 用所致。正常皮膚細胞自基底層移動至上面顆粒層時，需 耗費約5週時間。而牛皮癣之皮膚則只需要6至9天，其 部份歸因於增生細胞數目提高，且分裂之細胞比例提高（GThere are many types of skin lesions associated with excessive cell proliferation. For example, psoriasis is a benign human skin disease characterized by thickened scales that are covered with patches. This disease is caused by an increase in the proliferation of epidermal cells for unknown reasons. It takes about 5 weeks for normal skin cells to move from the basal layer to the upper granule layer. The skin of psoriasis only takes 6 to 9 days, partly due to an increase in the number of proliferating cells and an increase in the proportion of dividing cells (G

Grove，Int· J· Dermatol· 18 : 111，1979)。美國約 2%人口罹 患牛疲癬，其中約3%為白種人，約ι〇/ο為非裔美國人，但 很夕出現在美國原住民人種中。慢性濕療亦與表皮顯著過 度增生有關。其他因皮膚細胞過度增生引起之疾病包括·· 異位性皮膚炎、扁平苔蘚、疣、尋常天疱瘡、光化性角化 病、基底細胞癌瘤及鱗狀細胞癌瘤。 其他過度增生性細胞病變包括血管過度增生病變，纖 維變性病變、自體免疫病變、宿主對抗移植物之排斥作用、 腫瘤及癌症。 .血管增生病變包括新生血管形成及脈營分佑报占在 本紙張尺度適用中關家標準（CNS)A4 ^格⑵G X 297公爱)----------- 91949 (請先閱讀背面之注意事項再填寫本頁)Grove, Int J. Dermatol· 18: 111, 1979). About 2% of the population in the United States suffer from tired cows, of which about 3% are white, about ι〇/ο are African-American, but they appear in the Native Americans. Chronic wet therapy is also associated with significant hyperproliferation of the epidermis. Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, sputum, pemphigus vulgaris, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma. Other hyperproliferative cytopathies include hypervascular hyperplasia, fibrotic degeneration, autoimmune lesions, host rejection of grafts, tumors, and cancer. Vascular proliferative lesions including neovascularization and pulse camping are accounted for in this paper scale. The applicable standard (CNS) A4 ^ grid (2) G X 297 public) ------------- 91949 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 15 1293306 五、發明說明（I5 ) 變。金管組織中斑之發展過程中，平滑肌細胞增生會造成 例如：再狹窄、視網膜病變及動脈硬化。因動脈管壁之内 皮與平滑肌受損而出現過度發炎-增生性反應造成動脈硬 化症之深度傷害（Ross，R. Mature，1993, 362: 801-809)。細 胞移動與細胞增生二者均在動脈硬化性損傷之形成過程中 扮演某種角色。 纖維變性病變經常由細胞外間質不正常形成所致，纖 維變性病變實例包括：肝硬化及腎小球增生細胞病變。肝 硬化之特徵為細胞外間質組成份增加，形成肝症。肝硬化 會造成如：肝硬變之疾病。造成肝症之細胞外間質增加亦 可因病毒感染造成，如：肝炎。脂細胞似乎在肝硬化中扮 演重要角色。 腎小球病變則由腎小球細胞非正常增生造成。腎小球 過度增生性細胞病變包括各種人類腎病，如：腎小球腎炎、 糖尿病性腎病變、惡性腎硬化、栓塞性微血管病變症候群、 移植排斥及腎小球病變。 另一種增生性疾病為類風濕關節炎。類風濕關節炎通 常視為一種自體免疫疾病，被認為與自體反應性Τ細胞之 活性有關（參見例如：Harris，Ε· D.，Jr.，The New Kng1^n^ Journal of Medicine, 1990, 322 : 1277-1289)，且係由對抗 膠原及IgE而產生之自體抗體所引起。 其他可能涉及非正常細胞增生因素之病變包括貝希氏 (Behcet’s)症候群、急性呼吸窘迫症候群（ARDS)、絕血性 心臟病、透析後症候群、白血病、後天免疫缺乏症候群、 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注咅？事項再填寫本頁)Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 15 1293306 V. Invention description (I5) change. During the development of plaques in the golden tube tissue, smooth muscle cell proliferation can cause, for example, restenosis, retinopathy, and arteriosclerosis. Excessive inflammation-proliferative response due to impaired endothelium and smooth muscle of the arterial wall causes deep injury to arteriosclerosis (Ross, R. Mature, 1993, 362: 801-809). Both cell migration and cell proliferation play a role in the formation of arteriosclerotic lesions. Fibrotic lesions are often caused by abnormal formation of extracellular matrix. Examples of fibrotic lesions include cirrhosis and glomerular hyperplasia. Liver cirrhosis is characterized by an increase in extracellular matrix composition and formation of hepatic disease. Cirrhosis can cause diseases such as cirrhosis. The extracellular matrix that causes liver disease can also be caused by viral infections such as hepatitis. Lipid cells appear to play an important role in cirrhosis. Glomerular lesions are caused by abnormal proliferation of glomerular cells. Glomerular hyperproliferative cytopathies include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, embolic microangiopathy syndrome, transplant rejection, and glomerular lesions. Another proliferative disease is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease and is thought to be involved in the activity of autoreactive sputum cells (see, for example, Harris, Ε·D., Jr., The New Kng1^n^ Journal of Medicine, 1990). , 322: 1277-1289), and caused by autoantibodies produced against collagen and IgE. Other lesions that may be involved in abnormal cell proliferation factors include Behcet's syndrome, acute respiratory distress syndrome (ARDS), cardioembolic heart disease, post-dialysis syndrome, leukemia, acquired immunodeficiency syndrome, and the national standard for this paper scale. (CNS) A4 size (210 X 297 mm) 91949 (Please read the note on the back? Please fill out this page again)

1293306 A7 B7 經濟部智慧財產局員工消費合作社印製 16 五、發明說明（w 脈&炎、脂質性組織細胞症、敗血性休克及一般發炎。 腫瘤（亦稱為細胞增生物）為細胞無控制且漸進性地增 殖造成新生長之組織。良性腫瘤沒有侵略性質而且不會轉 移，通常被纖維性囊胞包圍。惡性腫瘤（亦即癌）則同時可 能侵略及轉移。惡性腫瘤亦比良性腫瘤出現較大程度之退 行發育（亦即細胞喪失分化、互相排列及軸向組織結構之能 力）。 母年約有120萬美國人被診斷患有癌症，其中8〇q〇 人為兒童。此外，單在美國一地，每年即有5〇〇，〇〇〇位美 國人死於癌症。攝護腺癌及肺癌名列男性癌症死因榜首， 而乳癌與肺癌則為女性癌症第一大死因。據估計，美國用 在疾病治療上之總費用中，約10〇/〇用於癌症相關病症上 (CNN. Cancer. Factshttp ： //www.cnn.com/HEALTH/9511/ conquer cancer/facts/index.html，page 2of 2，1999 年 7 月 18 曰）° 目刖’增生性病變用許多種化合物治療，包含：烧化 劑、抗代謝物、天然產物、酵素、生物反應改質劑、其他 製劑、放射性醫藥（例如：附掛在激素或抗體上之γ_90)、 激素與拮抗劑，如下文所示者。 烷化劑 氮芥類：氮芥（霍金氏症、非霍金氏淋巴瘤）、環磷醯 胺、異磷醯胺（Ifosfamide)(急性與慢性淋巴球性白血病、 霍金氏症、非霍金氏淋巴瘤、多發性骨髓瘤、神經母細胞 瘤、乳房、卵巢、肺、威姆氏（Wilm’s)腫瘤、子宮頸、睪 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公餐） 91949 (請先閱讀背面之注意事項再填寫本頁)1293306 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 16 V. Invention description (w pulse & inflammation, lipid histiocytosis, septic shock and general inflammation. Tumor (also known as cell augmentation) is cell-free Controlled and progressively proliferating tissue that causes new growth. Benign tumors have no aggressive nature and do not metastasize, usually surrounded by fibrous cysts. Malignant tumors (ie, cancer) may also invade and metastasize. Malignant tumors are also better than benign tumors. There is a greater degree of degenerative development (ie, the ability of cells to lose differentiation, interdependence, and axial organization). About 1.2 million Americans are diagnosed with cancer in their mother year, of which 8〇q are children. In the United States, there are 5 每年 per year, and the Americans die of cancer. Prostate cancer and lung cancer rank first in the death of men, while breast cancer and lung cancer are the leading cause of cancer in women. In the United States, about 10 〇 / 〇 is used for cancer-related conditions in the total cost of disease treatment (CNN. Cancer. Factshttp: //www.cnn.com/HEALTH/9511/ conquer Cancer/facts/index.html,page 2of 2,July 18, 1999 曰)° 刖 刖 'proliferative lesions are treated with a variety of compounds, including: burners, antimetabolites, natural products, enzymes, bioreactors Agents, other preparations, radiopharmaceuticals (eg γ_90 attached to hormones or antibodies), hormones and antagonists, as shown below. Alkylating agents nitrogen mustard: nitrogen mustard (Hawkin's disease, non-Hawkin's lymph Tumor), cyclophosphamide, isosfamide (acute and chronic lymphocytic leukemia, Hodgkin's disease, non-Hawkin's lymphoma, multiple myeloma, neuroblastoma, breast, ovary, lung, Wilm's tumor, cervix, and sputum paper scales are applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 meals) 91949 (please read the notes on the back and fill out this page)

A7 經濟部智慧財產局員工消費合作社印製 1293306 B7___ 五、發明說明（17 ) 丸、軟組織肉瘤）、苯丙胺酸氮芥（Melphalan)(左旋苯丙胺 酸氮芥）（多發性骨髓瘤、乳房、卵巢）、苯丁酸氮芥 (Chlorambucil)(慢性淋巴球性白血病、原發性巨球蛋白血 症、霍金氏症、非霍金氏淋巴瘤）。 乙基亞胺類與甲基蜜胺類：六甲基蜜胺（卵巢）、噻嗜 哌（Thiotepa)(膀胱、乳房、卵巢）。 烧基確酸醋：白金福思（Busulfan)(慢性粒細胞白jk 病）。 亞石肖基脲：卡氮芬（Carmustine) (BCNU)(霍金氏症、 非霍金氏淋巴瘤、原發性腦瘤、多發性骨髓瘤、惡性黑色 瘤）、環己亞硝脲（Lomustine) (CCNU)(霍金氏症、非霍金 氏淋巴瘤、原發性腦瘤、小細胞肺）、賽氮芥（Semustine)(甲 基-CCNU)(原發性腦瘤、胃、結腸）、鏈脲菌素（streptozocin) (STR)(惡性胰島瘤、惡性癌瘤）。 三畊類：氮烯咪胺（Dacarbazine) (DTIC ;二甲基三畊 并喃σ坐-緩醯胺）（惡性黑色瘤、霍金氏症、軟組織肉瘤）。 抗代謝物 葉酸類似物：胺甲蝶呤（amethopterin)(急性淋巴球性 白血病、絨毛膜癌、簟樣肉芽腫、乳房、頭與頸部、肺、 骨原性肉瘤）。 嘧啶類似物：氟尿嘧啶（5-氟尿嘧啶；5-FU)、5-氟去 氧尿苷（FUdR)(乳房、結腸、胃、胰、卵巢、頭與頸部、 膀脱、惡性則期皮膚損傷（局部））、阿糖胞昔（Cytarabine) (急性粒細胞與急性淋巴細胞白血病）。 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再填寫本頁)A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1293306 B7___ V. Invention description (17) Pill, soft tissue sarcoma), Melphalan (L-Phenylalanine mustard) (multiple myeloma, breast, ovary) , Chlorambucil (chronic lymphocytic leukemia, primary macroglobulinemia, Hawking's disease, non-Hodgkin's lymphoma). Ethyl imines and methyl melamines: hexamethyl melamine (ovary), Thiotepa (bladder, breast, ovary). Soda vinegar: Busulfan (chronic granulocyte white jk disease). Chrysosylurea: Carmustine (BCNU) (Hawkin's disease, non-Hodgkin's lymphoma, primary brain tumor, multiple myeloma, malignant melanoma), Cyclohexylnitrone (Lomustine) (CCNU (Hawkin's disease, non-Hodgkin's lymphoma, primary brain tumor, small cell lung), Semusting (methyl-CCNU) (primary brain tumor, stomach, colon), streptozoon Streptozocin (STR) (malignant islet tumor, malignant carcinoma). Three-tillage: Dacarbazine (DTIC; dimethyl tri-negative and sputum-stasis) (malignant melanoma, Hodgkin's disease, soft tissue sarcoma). Antimetabolite Folic acid analogue: amethopterin (acute lymphocytic leukemia, choriocarcinoma, mycosis fungoides, breast, head and neck, lung, osteosarcoma). Pyrimidine analogs: fluorouracil (5-fluorouracil; 5-FU), 5-fluorodeoxyuridine (FUdR) (breast, colon, stomach, pancreas, ovary, head and neck, bladder, malignant skin damage) Top)), Cytarabine (acute granulocytes and acute lymphocytic leukemia). This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public). (Please read the note on the back and fill out this page)

17 91949 1293306 A7 B7 五、發明說明（“） 嗓吟類似物與相關抑制劑：6 -氮硫基嗓吟 (Mercaptopurine ; 6-MP)(急性淋巴球性、急性粒細胞性及 t又性粒細胞性白血病）、6_硫鳥u票呤（Thioguanine ; TG)(急 性粒細胞性、急性淋巴球性、及慢性粒細胞性白血病）、本 妥抑制素（pentostatin) (2，_去氧賽弗黴素（2，_ deoxycyoformycin))(毛樣細胞白血病、簟樣肉芽腫、慢性 淋巴球性白血病）。 蔓長春花植物鹼：長春花鹼（VLB)(霍金氏症、非霍金 氏淋巴瘤、乳房、睪丸）、長春新鹼（急性淋巴球性白血病、 神經母細胞癌瘤 '威姆氏腫瘤、橫紋肌肉瘤、霍金氏症、 非霍金氏淋巴瘤、小細胞肺）。 表鬼臼毒素：依妥賽（Etopo side)(睪丸、小細胞肺及 其他肺、乳房、霍金氏症、非霍金氏淋巴瘤、急性粒細胞 性白金病、卡波西氏肉瘤）、丹普賽（Tenip〇side)(睪丸、小 細胞肺及其他肺、乳房、霍金氏症、非霍金氏淋巴瘤、急 性粒細胞性白血球、卡波西氏肉瘤）。 天然產物 抗生素··放射菌素D(絨毛膜癌、威姆氏腫瘤、橫紋肌 瘤、睪丸、卡波西氏肉瘤）、道諾紅菌素（道諾黴素；紅比 黴素）（急性粒細胞性與急性淋巴球性白血病）、道索紅黴素 (Doxorubicin)(軟組織、骨原性及其他癌瘤；霍金氏症、非 霍金氏淋巴瘤、急性白血病、乳房、生殖泌尿道、甲狀腺、 肺、月、神經母細胞癌）、博來黴素（Bleomycin)(睪丸、頭 與頸部、皮膚與食道、肺與生殖泌尿道、霍金氏症、非霍 (請先閱讀背面之注音？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 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 18 91949 經濟部智慧財產局員工消費合作社印製 19 129330617 91949 1293306 A7 B7 V. INSTRUCTIONS (“) 嗓吟 Analogs and related inhibitors: 6-azathiopurine (Mercaptopurine; 6-MP) (acute lymphoid, acute granulocytic and t-granular Cellular leukemia), 6_thiophene (Tioguanine; TG) (acute granulocytic, acute lymphocytosis, and chronic myelogenous leukemia), pentostatin (2, _ deoxygenation) Furanomycin (2, _ deoxycyoformycin) (hairy cell leukemia, mycosis fungoides, chronic lymphocytic leukemia). Vinca alkaloids: vinblastine (VLB) (Hawkin's disease, non-Hodgkin's lymphoma , breast, testicular), vincristine (acute lymphocytic leukemia, neuroblastoma 'Wem's tumor, rhabdomyosarcoma, Hawking's disease, non-Hawking's lymphoma, small cell lung). Table podophyllotoxin: Etopo side (sputum pills, small cell lungs and other lungs, breasts, Hawking's disease, non-Hawkin's lymphoma, acute granulocytic platinum disease, Kaposi's sarcoma), Tenip〇side ) (small pills, small cell lungs and other lungs, milk) House, Hawking's disease, non-Hawkin's lymphoma, acute granulocyte leukocyte, Kaposi's sarcoma. Natural product antibiotic · · actin D (choriocarcinoma, Wim's tumor, rhabdomyomas, testicular, card Boswell's sarcoma), daunorubicin (danomycin; erythromycin) (acute granulocytic and acute lymphocytic leukemia), erythromycin (Doxorubicin) (soft tissue, osteogenic and Other cancers; Hawking's disease, non-Hodgkin's lymphoma, acute leukemia, breast, genitourinary tract, thyroid, lung, month, neuroblastoma), Bleomycin (sputum, head and neck, Skin and esophagus, lung and genitourinary tract, Hodgkin's disease, non-hoo (please read the phonetic on the back? Please fill out this page). Order - - Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed Paper Scale for China Standard (CNS) A4 specification (210 X 297 mm) 18 91949 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 19 1293306

金氏淋巴瘤）、摺皺菌黴素（plicamycin) (mithramyein)(睪 丸、惡性高血鈣症）、絲裂黴素（絲裂黴素C)(胃、子宮頸、 結腸、乳房、胰、膀胱、頭與頸部）。 酵素· 天冬胺酸酶（急性淋巴球性白血病）。 生物反應改質劑：α_干擾素（毛樣細胞白血病、卡波 西氏肉瘤、黑色瘤、輕癌、腎細胞、卵巢、膀胱、非霍金 氏淋巴瘤、蕈樣肉芽腫、多發性骨髓瘤、慢性粒細胞性白 血病）。 其他製劑 舶配位錯合物：順氣胺銘（cisplatin)(順式-DDP) (Carboplatin)(睪丸、卵巢、膀胱、頭與頸部、肺、甲狀腺、 子宮頸、子宮内膜、神經母細胞瘤、骨原性肉瘤）。 蒽二酮：米散酮（Mixtozantrone)(急性粒細胞性白血 病、乳房）。 經取代之脲：經基腺（慢性粒細胞白金病、紅血球過多 症、自發性血小板增多症、惡性黑色瘤）。 甲基肼衍生物：甲基笮肼（N-甲基肼，MIH)(霍金氏 症）° 腎上腺皮質抑制劑：米特丹（Mitotane)(o，p，-DDD)(腎 上腺皮質）、胺基導眠能（Amino-glutethimide)(乳房）。 腎上腺皮質類固醇··潑尼松（Prednisone)(急性與慢性 淋巴球性白it病、非霍金氏淋巴瘤、霍金氏症、乳房）。 黃體製劑··羥基黃體酮癸酸鹽、甲孕酮乙酸鹽、甲地 孕酮乙酸鹽（子宮内膜、乳房）。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁)Gold's lymphoma), plicamycin (mithramyein) (sputum pills, malignant hypercalcemia), mitomycin (mitomycin C) (stomach, cervix, colon, breast, pancreas, bladder , head and neck). Enzyme · Aspartate (acute lymphoblastic leukemia). Bioreaction modifier: α-interferon (hairy cell leukemia, Kaposi's sarcoma, melanoma, light cancer, kidney cells, ovary, bladder, non-Hawkin's lymphoma, mycosis fungoides, multiple myeloma) , chronic myeloid leukemia). Other preparations are complexes: cisplatin (cis-DDP) (Carboplatin) (sputum, ovary, bladder, head and neck, lung, thyroid, cervix, endometrium, neuroblasts) Cell tumor, osteogenic sarcoma). Anthraquinone: Mixtozantrone (acute granulocyte leukemia, breast). Substituted urea: transbasal gland (chronic granulocyte leukemia, erythrocytosis, spontaneous thrombocytosis, malignant melanoma). Methyl hydrazine derivatives: methyl hydrazine (N-methyl hydrazine, MIH) (Hawkin's disease) ° Adrenal cortical inhibitors: Mitotane (o, p, -DDD) (adrenal cortex), amine Amino-glutethimide (breast). Adrenal corticosteroids · Prednisone (acute and chronic lymphocytic white disease, non-Hawkin's lymphoma, Hawking's disease, breast). Lutein preparation · Hydroxyprogesterone citrate, medroxyprogester acetate, megestrol acetate (endometrium, breast). This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (please read the notes on the back and fill out this page)

1293306 五、發明說明（20 ) 抵新血營形成舞丨 金管抑制素（angi〇statin)、内生抑制素（end〇statin)。 激素與括枕_1丨 雌激素：己烯雌酚乙炔雌二醇（乳房、攝護腺）。 抗雌激素：塔莫希芬（Tamoxifen)(乳房）。 雄激素·睪固酮丙酸鹽弗索睪固酮（Fiuxoniyesterone) (乳房）。 抗雄激素：弗塔醯胺（FluUmideX攝護腺）。 促性腺激素釋放激素類似物：白普萊德（leupr〇Hde) (攝護腺）。 與非正常增生細胞（包括癌症）之療法有關之毒性部份 肇因於藥物無法在正常細胞中選擇針對罹病細胞。為了克 服此限制，而需探討可提高專一性而且降低用於治療增生 性病變之藥物毒性之醫療法。其中一種積極探討之方法即 為針對目標之藥物。 基於此等疾病之嚴重性及其對動物（包括人類）之蔓延 =，本發：月之一，目的為提供一種供治療感染i述任^病 毒(包括黃病毒或疫病毒、流感病毒或呼吸胞合體病毒 (“RSV”))之宿主，包括動物，且尤指人類之化合物方法 及組合物。 2發明另-項目的為提供—種治療罹患非正常細胞增 生之値主，包括動物，且尤指人類之方法與組合物。 本發明另-項目的為提供一種治療已感染c型肝炎 BVDV之宿主’包括動物且尤指人類之方沬；人 一 本紙張I度適用中(CNS)A4規格_ 方法及、、且a物 20 f請先閱讀背面之注音？事項再填寫本頁} -線. -I I H . 91949 經濟部智慧財產局員工消費合作社印製 12933061293306 V. Description of the invention (20) Forming the maiko in the new blood camp, angi〇statin, end〇statin. Hormone and pillow _1 雌 Estrogen: diethylstilbestrol ethinyl estradiol (breast, prostate). Anti-estrogen: Tamoxifen (breast). Androgen, steroid ketone propionate (Fiuxoniyesterone) (breast). Antiandrogen: Fotamin (FluUmideX Prostate). Gonadotropin-releasing hormone analogue: leupr〇Hde (prostate). The toxic part associated with the treatment of non-normally proliferating cells (including cancer) is due to the inability of the drug to select for rickets in normal cells. In order to overcome this limitation, it is necessary to explore a medical treatment that increases specificity and reduces the toxicity of the drug used to treat proliferative lesions. One of the methods actively explored is the target drug. Based on the severity of these diseases and their spread to animals (including humans) = one of the purposes of this issue: to provide a treatment for infections (including flaviviruses or epidemic viruses, influenza viruses or respiration) Hosts of cell syncytia virus ("RSV")), including animals, and especially human compound methods and compositions. 2 Inventive--The item provides a method and composition for treating babies suffering from abnormal cell growth, including animals, and especially humans. Another object of the present invention is to provide a method for treating a host infected with hepatitis B BVDV, including animals and especially humans; a paper for the degree I (CNS) A4 specification _ method and 20 f Please read the phonetic transcription on the back first? Matters again on this page} - Line. -I I H . 91949 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1293306

五、發明說明（21 本發明另一項目的為提供一鍤、么 — π焚供種治療已感染流行性感冒 之伯主，包括動物，尤指人類之方法與組合物。 本發明另-項目的為提供一種治療已感染Rsv之宿 主，包括動物，尤指人類之方法與組合物。 本發明另一項目的為提供一種治療患有腫瘤（包括惡 性腫瘤）之宿主，包括動物，且尤指人類之方法與組合物。 本發明又另一項目的為提供一種可在宿主體内，包括 動物，尤指人體内，用於定量病毒濃度，特定言之BVDV 或HCV濃度之更有效方法。 [發明概要] 本發明誕供一種式（Ι)-(χχΐΠ)召-D或召-L核脊或其醫 藥上可接受之鹽或前藥，供治療感染黃病毒科、正黏液病 毋科及副黏液病毒科病毒之宿主。或者，式（ι)_(χχιιι)沒 -D或召-L核苷或其醫藥上可接受之鹽或前藥可用於治療 非正常細胞增生。 明確言之，本發明亦包括治療或預防下列感染之方 法： (a) 黃病毒科病毒感染，包括所有肝病毒（Hepaeivirus)屬 (HCV)、疫病毒屬（BVDV、CSFV、BDV)或黃病毒屬（登 革熱病毒、日本腦炎病毒（包括西奈爾病毒）及黃熱病 毒）； (b) 正黏液病毒科病毒感染，包括所有流感病毒a、B屬之 成員，特定言之流感病毒A及所有相關亞型，包括H1N1 及H3N2，及流感病毒B ; i紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ^ " 21 91949 (請先閱讀背面之注意事項再填寫本頁)V. INSTRUCTIONS OF THE INVENTION (21 Another item of the present invention is to provide a method for the treatment of influenza infected animals, including animals, especially humans. Provided is a method and composition for treating a host infected with Rsv, including animals, especially humans. Another object of the present invention is to provide a host for treating a tumor, including a malignant tumor, including an animal, and particularly Human methods and compositions. Yet another object of the present invention is to provide a more efficient method for quantifying viral concentrations, in particular BVDV or HCV concentrations, in a host, including animals, particularly humans. SUMMARY OF THE INVENTION The present invention provides a formula (Ι)-(χχΐΠ)-D or --L ridge or a pharmaceutically acceptable salt or prodrug thereof for the treatment of Flaviviridae, Orthomyxopathic and A host of the Paramyxoviridae virus. Alternatively, the formula (ι)_(χχιιι)--- or L-nucleoside or a pharmaceutically acceptable salt or prodrug thereof can be used to treat abnormal cell proliferation. The invention also includes treatment Or methods to prevent the following infections: (a) Flavivirus infection, including all Hepaeivirus genus (HCV), genus of genus (BVDV, CSFV, BDV) or flavivirus (dengue virus, Japanese encephalitis virus) (including Sinan virus) and yellow fever virus; (b) Orthomyxoviridae virus infection, including members of all influenza A and B genus, specifically influenza A and all related subtypes, including H1N1 and H3N2, And influenza virus B; i paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ^ " 21 91949 (please read the note on the back and fill out this page)

1293306 A7 __________B7 五、發明說明（ 22 (c) 副黏液病毒科病毒感染，包括呼吸胞合體病毒（RSV)感 染； (d) 非正常細胞增生，包括惡性腫瘤。 在一項具體實施例中，抗病毒或抗增生有效之核苷為 通式（I)或（II)泠-D核苷： X11293306 A7 __________B7 V. INSTRUCTIONS (22 (c) Paramyxoviridae virus infection, including respiratory syncytial virus (RSV) infection; (d) Abnormal cell proliferation, including malignant tumors. In a specific embodiment, Virucid or anti-proliferative nucleoside is a general formula (I) or (II) 泠-D nucleoside: X1

R1 X1R1 X1

X1X1

(請先閱讀背面之注意事項再填寫本頁) X1(Please read the notes on the back and fill out this page) X1

R1R1

八 X2 X1Eight X2 X1

V 經濟部智慧財產局員工消費合作社印製 [n-b] 或其醫藥上可接受之鹽或前藥，其中·· 各D為氫、烧基、醯基、單構酸根、二構酸根、三填酸根、 單磷酸酯、二磷酸酯、三磷酸酯、磷脂或胺基酸； 各W1與W2分別獨立為CH或N ; 各X1與X2分別獨立為氳〜鹵素”、。、；^*!)、！^!^、 NHR4、NR4R4’、NHOR4、NR4NR4，R4，，、〇H、OR4、SH 或 SR4 ； 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） 22 91949 1293306 A7 ---- B7 五、發明說明（23 ) 各Y1為0、S或Se ; 各Z為CH2或NH ; 各R1與R1’分別獨立為氫、低碳數烷基、低碳數烯基、低 碳數炔基、芳基、烷芳基、鹵素（F、C卜Br或I)、NH2、 NHR5、NR5R5’、NHOR5、NR5NHR5,、NR5NR5’R5”、OH、 OR5、SH、SR5、N02、NO、CH2OH、CH2OR5、C02H、C02R5、 CONH2、CONHR5、CONR5R5’或 CN ; 各R2與R2’分別獨立為氫或鹵素（F、ChBr或I)、〇H、SH、 〇CH3、SCH3、NH2、NHCH3、CH=CH2、CN、CH2NH2、CH2OH、 co2h ； 各R3與R3’分別獨立為氫或鹵素（F、Cl、Br或I)、OH、SH、 〇CH3、SCH3、NH2、NHCH3、CH3、C2H5、CH=CH2、CN、 CH2NH2、CH2OH、C02H ; 各R4、R4、R4、R5、R5’與R5”分別獨立為氳、低碳數烧 基、低碳數晞基、芳基、或芳烧基，如：末取代或經取代 之苯基或T基； 因此通式（I)或（II)各核苷中，R2與R2’中至少一者為氫，且 R3與R3’中至少一者為氫。 本發明另一項具體實施例中’抗病毒或抗增生有效之 核苷為通式（III)或（IV)点-L-核苷： 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注音？事項再填寫本頁) -I m I n ϋ ϋ ί ί ϋ』°J· I H ϋ ϋ ϋ ·ϋ ϋ I ϋ · 經濟部智慧財產局員工消費合作社印製 23 1293306 Α7 Β7 五、發明說明（24 X1V Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed [nb] or its pharmaceutically acceptable salt or prodrug, wherein each D is hydrogen, alkyl, sulfhydryl, mono-acid, di-acid, three-fill Acid, monophosphate, diphosphate, triphosphate, phospholipid or amino acid; each of W1 and W2 is independently CH or N; each X1 and X2 is independently 氲~halogen", ., ;^*! , !^!^, NHR4, NR4R4', NHOR4, NR4NR4, R4,, 〇H, OR4, SH or SR4; This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) 22 91949 1293306 A7 ---- B7 V. Inventive Note (23) Each Y1 is 0, S or Se; each Z is CH2 or NH; each R1 and R1' are independently hydrogen, lower alkyl, lower alkenyl , low carbon alkynyl, aryl, alkaryl, halogen (F, C, Br or I), NH2, NHR5, NR5R5', NHOR5, NR5NHR5, NR5NR5'R5", OH, OR5, SH, SR5, N02, NO, CH2OH, CH2OR5, C02H, C02R5, CONH2, CONHR5, CONR5R5' or CN; each of R2 and R2' is independently hydrogen or halogen (F, ChBr or I), 〇H, SH, 〇CH3, SCH3, NH2, N HCH3, CH=CH2, CN, CH2NH2, CH2OH, co2h; each of R3 and R3' is independently hydrogen or halogen (F, Cl, Br or I), OH, SH, 〇CH3, SCH3, NH2, NHCH3, CH3, C2H5, CH=CH2, CN, CH2NH2, CH2OH, C02H; each R4, R4, R4, R5, R5' and R5" are independently 氲, low carbon number, low carbon sulfhydryl, aryl, or aromatic An alkyl group, such as a terminally substituted or substituted phenyl or T group; thus, in each of the nucleosides of formula (I) or (II), at least one of R2 and R2' is hydrogen, and at least R3 and R3' One is hydrogen. In another specific embodiment of the present invention, 'antiviral or antiproliferative effective nucleoside is a general formula (III) or (IV) point-L-nucleoside: the paper scale applies to the Chinese national standard (CNS) )A4 size (210 X 297 mm) 91949 (Please read the phonetic note on the back? Please fill out this page again) -I m I n ϋ ϋ ί ί ϋ°J· IH ϋ ϋ ϋ ·ϋ ϋ I ϋ · Economy Ministry of Intellectual Property Bureau employee consumption cooperative printing 23 1293306 Α7 Β7 5, invention description (24 X1

,OD, OD

Rio、R3 X1Rio, R3 X1

[ΠΙ-c] [III-a] X1[ΠΙ-c] [III-a] X1

[IV-a] R2· R3· [III-b][IV-a] R2· R3· [III-b]

OD [IV-b] X1OD [IV-b] X1

[IV^c] (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制衣 或其醫藥上可接受之鹽或前藥，其中： 各 D、Wi、W2、χΐ、X2、γΐ、Z、Ri、R1，、R2、R2 與R3’如前述之定義； 因此通式（III)或（IV)各核苷中，R2與R2’中至少一者為氫且 R3與R3’中至少一者為氫。 本發明一項具體實施例中，抗病毒或抗增生有效之核 苷為通式（V)至（νπ)《-ο-碳化-糖核苷： R: 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 24 91949 1293306 A7 B7 五、發明說明（25 X1[IV^c] (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, printed clothing or its pharmaceutically acceptable salts or prodrugs, including: D, Wi, W2 Χΐ, X2, γΐ, Z, Ri, R1, R2, R2 and R3' are as defined above; therefore, in each of the nucleosides of the formula (III) or (IV), at least one of R2 and R2' is hydrogen and At least one of R3 and R3' is hydrogen. In a specific embodiment of the present invention, the antiviral or antiproliferative effective nucleoside is of the general formula (V) to (νπ) "-ο-carbo-glycosides: R: the paper scale applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) 24 91949 1293306 A7 B7 V. Description of invention (25 X1

R1 X1R1 X1

νώ/' R2Ώώ/' R2

R3，R2, [V-cJ X1R3, R2, [V-cJ X1

Y DO.Y DO.

R3 X1R3 X1

[VI-b] ,1¾1[VI-b] , 13⁄41

DODO

R3 [VI-c]R3 [VI-c]

[VI-a] DO[VI-a] DO

R3’ R2’ [Vll-a] X1R3’ R2’ [Vll-a] X1

X1X1

；wl (請先閱讀背面之注意事項再填寫本頁);wl (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制衣 25 或其醫藥上可接受之鹽或前藥，其中： 各 D、W1、W2、X1、X2、Y1、Z、R1、R1，、R2、R2,、R3 與R3’如前述之定義； 因此通式（V)或（VI)各核苷中，R2與R2’中至少一者為氫且 R3與R3’中至少一者為氫。 在一項具體實施例中，抗病毒或抗增生有效之核苷為 通式（VIII)至（X)冷-L-碳化-糖-核苷： 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 1293306 A7 B7 五、發明說明（26 X1Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed Clothes 25 or its pharmaceutically acceptable salts or prodrugs, where: D, W1, W2, X1, X2, Y1, Z, R1, R1, R2, R2, And R3 and R3' are as defined above; therefore, in each of the nucleosides of the formula (V) or (VI), at least one of R2 and R2' is hydrogen and at least one of R3 and R3' is hydrogen. In a specific embodiment, the antiviral or antiproliferative effective nucleoside is of the formula (VIII) to (X) cold-L-carbo-sugar-nucleoside: the paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 1293306 A7 B7 V. Description of invention (26 X1

.OD R2’ R3· [vra-b] X1.OD R2’ R3· [vra-b] X1

xlXl

Ar1 Y^N^RrAr1 Y^N^Rr

.OD.OD

[K-b][K-b]

,OD, OD

[IX-c][IX-c]

經濟部智慧財產局員工消費合作社印制衣 R2· R3, [X_b] 或其醫藥上可接受之鹽或前藥，其中 各 D、W1、W2、X1、X2、Y1、Z、R1 與R3’如前述之定義； 因此通式（VIII)或（IX)各核苷中，R2與R2’中至少一者為氫 且R3與R3’中至少一者為氫。 本發明另一項具體實施例中，抗病毒或抗增生有效之 召-D或泠-L-核苷分別為通式（XI)或（XII): R]Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Clothing R2·R3, [X_b] or its pharmaceutically acceptable salt or prodrug, where each D, W1, W2, X1, X2, Y1, Z, R1 and R3' As defined above; therefore, in each of the nucleosides of the formula (VIII) or (IX), at least one of R2 and R2' is hydrogen and at least one of R3 and R3' is hydrogen. In another embodiment of the invention, the antiviral or antiproliferative effective s-D or 泠-L-nucleoside is of the formula (XI) or (XII): R]

R2、R 2, R: (請先閱讀背面之注意事項再填寫本頁)R2, R 2, R: (Please read the notes on the back and fill out this page)

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 1293306 A7 -------B7 _ 五、發明說明（27 )This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 91949 1293306 A7 -------B7 _ V. Description of invention (27)

w DO. Λ/ w1 [Xl-a] X1w DO. Λ / w1 [Xl-a] X1

/OD/OD

[Xl-b] X1[Xl-b] X1

,OD, OD

[XI-c] x1[XI-c] x1

OD (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 [Xll-a] 或其醫藥上可接受之鹽或前藥，其中：各 D、Wl、W2、χ1、X2、Υ1、Z、R1、R1，、R2、R2’、R3 與R3’如前述之定義； 各Z與Z分別獨立為〇、s、CH2、nr6或Se ;各r6為氫、 低碳數燒基或低碳數醯基。 本發明另一項具體實施例中，抗病毒或抗增生有效之 /5 _D或召核苷（但以泠七較佳）如通式（xm):OD (please read the note on the back and then fill out this page) Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Cooperatives [Xll-a] or its pharmaceutically acceptable salts or prodrugs, including: D, Wl, W2 Χ1, X2, Υ1, Z, R1, R1, R2, R2', R3 and R3' are as defined above; each Z and Z are independently 〇, s, CH2, nr6 or Se; each r6 is hydrogen, low Carbon number or low carbon number. In another embodiment of the invention, the antiviral or antiproliferative effective /5 _D or the nucleoside (but preferably 泠7) is as defined by the formula (xm):

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） .R1 N 八 R1·This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). R1 N 八 R1·

C^R2· [XIH-d] R1 Rv — — — — — — — 11111111 I . 27 91949 1293306 A7 B7 Y^N^L2 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 28 五、發明說明（28 或其醫藥上可接受之鹽或前藥，其中： 各 D、R1、R1’、R2、R2’、R3 與 r3,如前述定義； 各 Y2 為 Ο、S、NH 或 NR7 ; 各 Y3 為 Ο、S、NH 或 NR8 ; 各X3為OR9或SR9 ;且 各R7、Rs與R9為氫、CleC6低碳數烷基、芳烷基或芳基； 因此通式（ΧΙΙΙ-d)各核苷中，R2與R2,中至少一者為氫且R3 與R3’中至少一者為氫。 另一項具體實施例中，抗病毒或抗增生有效之化合物 為泠-D或召核苷，但以召_D較佳，其係由添加小分子 (如：烷基次氯酸酯、烷基次溴酸酯、次溴酸或醯基^化物） 至適當嘧啶核苷中，形成如式（χιν)核苷： DO、χ Γ R3，R2· 或其醫樂上可接受之鹽或前藥，其中： 各 D、X1、Y1、z1、ϋ2， m _ R、R 、R3與R3如前述定義； 各L1為氫、Cl或Br ; 各 L2 為 OH、〇d、〇Γ W γλο tt 3 、〇c3H7、〇cf3、OAc 或 OBz ; 各z3可為o或ch2。 _項具體實或抗增生有效之核苷為 本紙張尺度適用中國國家標準（CNbM4規格（21〇χ 297公复）—---- 91949 (請先閱讀背面之注音？事項再填寫本頁)C^R2· [XIH-d] R1 Rv — — — — — — — 11111111 I . 27 91949 1293306 A7 B7 Y^N^L2 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 28 V. INSTRUCTIONS (28 or A pharmaceutically acceptable salt or prodrug wherein: D, R1, R1', R2, R2', R3 and r3 are as defined above; each Y2 is Ο, S, NH or NR7; each Y3 is Ο, S , NH or NR8; each X3 is OR9 or SR9; and each R7, Rs and R9 is hydrogen, CleC6 lower alkyl, aralkyl or aryl; thus, in the formula (ΧΙΙΙ-d) each nucleoside, R2 And at least one of R2 is hydrogen and at least one of R3 and R3' is hydrogen. In another specific embodiment, the antiviral or antiproliferative effective compound is 泠-D or nucleoside, but D is preferably obtained by adding a small molecule (such as an alkyl hypochlorite, an alkyl hypobromide, a hypobromous acid or a sulfhydryl compound) to an appropriate pyrimidine nucleoside to form a core of the formula (χιν). Glycosides: DO, χ Γ R3, R2· or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, X1, Y1, z1, ϋ2, m _ R, R, R3 and R3 are as defined above; L1 is hydrogen, Cl or Br; each L2 is OH, 〇d, 〇Γ W γλο tt 3 , 〇c3H7, 〇cf3, OAc or OBz; each z3 may be o or ch2. _ specific or anti-proliferative nucleoside is The paper scale applies to the Chinese national standard (CNbM4 specification (21〇χ 297 gong)---- 91949 (please read the phonetic on the back? Please fill out this page again)

經濟部智慧財產局員工消費合作社印劍衣 29 1293306 A7 _B7___ 五、發明說明（29 ) 通式（XV)二聚合核苷（各核苷係呈冷_D或冷-L組態），其中 二個核苷利用二硫化物鍵連接：Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Jian Jianyi 29 1293306 A7 _B7___ V. Description of invention (29) Generalized (XV) dimeric nucleosides (each nucleoside is cold _D or cold-L configuration), of which two Nucleosides are linked by disulfide bonds:

或其醫藥上可接受之鹽或前藥，其中： 各 D、Wi、W2、χΐ、Yi、Z3、Ri、R1’、R2、R2’、R3 與 R3’ 如前述定義； 一項具體實施例中，抗病毒或抗增生有效之核脊為通 式（XVI)卢-D或召-L C-核苷：Or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, Wi, W2, χΐ, Yi, Z3, Ri, R1', R2, R2', R3 and R3' are as defined above; Among them, the anti-viral or anti-proliferative nucleus is a general formula (XVI) Lu-D or CAM-L-nucleoside:

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁)This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (please read the notes on the back and fill out this page)

X1X1

R1 1293306 Α7 Β7 五、發明說明（3G ) 或其醫藥上可接受之鹽或前藥，其中： 各 D、W1、X1、X2、Yi、Z、Ri、R2、R2’、與 R3’如前 述之定義； 各W3分別獨立為N、CH或CR1 ; 各W4與W5分別獨立為N、CH、CX1或CR1’ ；且 各Z4與Z5分別獨立為NH或C^Y1); 因此若Z4與Z5利用共價鍵結合，當Z5為CpY1)時’則Z4 不為COY1)，且環氮不超過3個。 在一項具體實施例中，抗病毒或抗增生有效之核苷為 通式（XVII)召-D或泠分支鏈糖核苷： (請先閱讀背面之注意事項再填寫本頁)R1 1293306 Α7 Β7 V. Description of the invention (3G) or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, W1, X1, X2, Yi, Z, Ri, R2, R2', and R3' are as described above Definitions; each W3 is independently N, CH or CR1; each of W4 and W5 is independently N, CH, CX1 or CR1'; and each Z4 and Z5 are independently NH or C^Y1); therefore, if Z4 and Z5 By covalent bond bonding, when Z5 is CpY1), then Z4 is not COY1, and the ring nitrogen is not more than 3. In a specific embodiment, the antiviral or anti-proliferative effective nucleoside is a compound of the formula (XVII)-D or a branched-chain glycosidic glucoside: (Please read the back of the note first and then fill out this page)

經濟部智慧財產局員工消費合作社印製 X1Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed X1

R1 [XVII-b]R1 [XVII-b]

或其醫藥上可接受之鹽或前藥，其中： 各 D、W1、W2、X1、X2、Υΐ、Z3、Ri、R1’、R2、R: X1Or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, W1, W2, X1, X2, Υΐ, Z3, Ri, R1', R2, R: X1

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 30 91949 1293306This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 30 91949 1293306

五、發明說明（31 ) 與R3如前述定義； 各X4與X5分別獨立為氫、鹵素（F、Br或Σ)、化、nh NHR8、NR8R8’、〇H、〇R8、SH 或 SRs ;且 ' 各R8與R8’分別獨立為氫、低碳數烷基、低碳數烯基、芳 基或芳烷基，如：未取代或經取代之苯基或苄基· 因此通式（XVII_a)或（xVII_b)各核苷中，χ4不為〇h或 OR8 〇 在一項具體實施例中，抗病毒或抗增生有效之核苷為 通式（XVIII) a -D或a 核苷：5. Description of the invention (31) and R3 are as defined above; each of X4 and X5 is independently hydrogen, halogen (F, Br or Σ), chem, nh NHR8, NR8R8', 〇H, 〇R8, SH or SRs; ' Each R8 and R8' are independently hydrogen, lower alkyl, lower alkenyl, aryl or aralkyl, such as unsubstituted or substituted phenyl or benzyl. Thus, formula (XVII_a) Or (xVII_b) each nucleoside, χ4 is not 〇h or OR8 〇 In one embodiment, the antiviral or anti-proliferative effective nucleoside is of the formula (XVIII) a -D or a nucleoside:

[xvra-c] [xviim] 或其醫藥上可接受之鹽或前藥，其中： 各 D、Wi、W2、χΐ、X2、γΐ、Ri、R1’、R2、r2,、R3 與 R3, 如前述定義； 本發明之次項具體實施例中，抗病毒或抗增生有效之 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (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 31 1293306 A7 五、發明說明（32 ) 召-D或$ -L核苷如式（XIX):[xvra-c] [xviim] or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, Wi, W2, χΐ, X2, γΐ, Ri, R1', R2, r2, R3 and R3, eg The foregoing definitions; in the specific embodiment of the present invention, the anti-viral or anti-proliferative effective paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (please read the back note and then fill in the form) Page), %________ _________ Line Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 31 1293306 A7 V. Description of Invention (32) Call-D or $-L Nucleoside as Formula (XIX):

[XIX] 經濟部智慧財產局員工消費合作社印製 或其醫藥上可接受之鹽或前藥，其中： 各D、Ri、R4、與r4’如前述定義； 各R9為氫、_素（F、Cl、Br或I)或OP3 ; 各Ρ1為氳、低碳數烷基、低碳數烯基、芳基、芳烷基（如： 未取代或經取代之苯基或节基）、OH、OR4、NH2、NHR4 或 NR4R4’ ；且 各P2與P3分別獨立為氫、燒基、醯基、-Ms、-Ts、單雄 酸根、二磷酸根、三磷酸根、單磷酸酯、二磷酸酯、三磷 酸酯、磷脂或胺基酸，但以氫較佳。 本發明之特別之次項具體實施例中，抗病毒或抗增生 有效之式（XIX)卢-D或Θ -L核苷如下·[XIX] Printed by the Intellectual Property Office of the Ministry of Economic Affairs, or a pharmaceutically acceptable salt or prodrug thereof, where: D, Ri, R4, and r4' are as defined above; each R9 is hydrogen, _ , Cl, Br or I) or OP3; each Ρ1 is fluorene, lower alkyl, lower alkenyl, aryl, aralkyl (eg unsubstituted or substituted phenyl or benzyl), OH , OR4, NH2, NHR4 or NR4R4'; and each of P2 and P3 is independently hydrogen, alkyl, sulfhydryl, -Ms, -Ts, mono-androstate, diphosphate, triphosphate, monophosphate, diphosphate Ester, triphosphate, phospholipid or amino acid, but preferably hydrogen. In a particularly specific embodiment of the invention, antiviral or antiproliferative effective (XIX) Lu-D or Θ-L nucleosides are as follows

或I醫藥上可接受之鹽或前藥，其中. 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）^1— 32 91949 (請先閱讀背面之注意事項再填寫本頁)Or I pharmaceutically acceptable salts or prodrugs, of which. This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ^1—32 91949 (please read the notes on the back and fill out this page) )

1293306 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（33 ) 各D與P如七述疋義。在較佳具體實施例中，D與ρ2分 別獨立為氫。 另一項本發明次項具體實施例中，抗病毒或抗增生有 效之或3_L核苷如下式（χχ):1293306 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention Description (33) Each D and P is as described. In a preferred embodiment, D and ρ2 are independently hydrogen. In another sub-specific embodiment of the invention, the antiviral or anti-proliferative or 3_L nucleoside is as follows:

R1 [XX] 或其醫藥上可接受之鹽或前藥，其中： 各 D、pi、p2、P3、R1、r4、r4，與 r9 如前述定義。 另一項本發明次項具體實施例中，抗病毒或抗增生有 效之石-D或石-L核苷如式（χχι):R1 [XX] or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, pi, p2, P3, R1, r4, r4, and r9 are as defined above. In another sub-specific embodiment of the invention, the antiviral or anti-proliferative effective stone-D or stone-L nucleoside is as defined (χχι):

或其醫藥上可接受之鹽或前藥，其中： 各D、Ρ1、Ρ2、Ρ3、R1、R4與R4’如前述定義。 另一項本發明次項具體實施例中，抗病毒或抗增生有 效之召-D或冷-L核脊如式（XXI): 本紙張尺度適用中關家標準(CNS)A4規格（21G X 297公餐Ί 33 91949 (請先閱讀背面之注音？事項再填寫本頁)Or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, Ρ 1, Ρ 2, Ρ 3, R1, R4 and R4' are as defined above. In another sub-specific embodiment of the invention, the antiviral or anti-proliferative effective call-D or cold-L nucleus is as in the formula (XXI): This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (21G X 297). Public Ί 33 91949 (Please read the phonetic on the back? Please fill out this page again)

五、發明說明（34V. Description of the invention (34

12933061293306

.OH 或其醫藥上可接受之鹽或前藥，其中： 各D、P2與P3如前述定義。在較佳具體實施例中，D、p: 與P3分別獨立為氫。 另一項本發明次項具體實施例中，抗病毒或抗增生赛 效之Θ -D或$ -L核苷如式（χχπ): —--------— (請先閱讀背面之注意事項再填寫本頁).OH or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, P2 and P3 are as defined above. In a preferred embodiment, D, p: and P3 are each independently hydrogen. In another sub-specific embodiment of the invention, the antiviral or anti-proliferative effect is -D or $-L nucleoside as in the formula (χχπ): —------- (please read the back Please fill out this page again)

R1R1

OD 訂 經濟部智慧財產局員工消費合作社印製 [XXII] 或其醫藥上可接受之鹽或前藥，其中 各D、P1與P2如前述定義。在較佳具體實施例中，D與p 分別獨立為氫。 在本發明一項特別之次項具體實施例中，抗病毒或杭 增生有效之式（XXII)点_D或石-L核苷（但以万-L較佳）如 下： 2 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 34 91949OD Order Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative [XXII] or its pharmaceutically acceptable salt or prodrug, where each D, P1 and P2 are as defined above. In a preferred embodiment, D and p are each independently hydrogen. In a particular embodiment of the present invention, antiviral or hypertrophic effective (XXII) point _D or stone-L nucleoside (but preferably 10,000-L) is as follows: 2 This paper size is applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) 34 91949

五、發明說明（35 ) 1293306V. Description of invention (35) 1293306

戈其醫樂上可接受之鹽或前藥，其中： D如前述定義，且以η較佳。 本發明另一次項具體實施例中，抗病毒或抗增生有 之冷-D或f L核苷如式（χχπ〇 : (請先閱讀背面之注意事項再填寫本頁)A salt or prodrug acceptable to georg, wherein: D is as defined above and is preferably η. In another specific embodiment of the present invention, the antiviral or antiproliferative has a cold-D or f L nucleoside as in the formula (χχπ〇: (please read the back of the note first and then fill out this page)

[XXIII] 經濟部智慧財產局員工消費合作社印製 35 或其醫藥上可接受之鹽或前藥，其中： 各D、Ρ1、Ρ2、Ρ3、R1、R4與R4,如前述定義。 在特別之次項具體實施例中，抗病毒或抗增生有效3 式（XXIII)冷-D或召-L核苷如下：[XXIII] Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives 35 or its pharmaceutically acceptable salts or prodrugs, where: D, Ρ 1, Ρ 2, Ρ 3, R1, R4 and R4, as defined above. In a particular sub-specific embodiment, the antiviral or anti-proliferative effective formula (XXIII) cold-D or s-L nucleoside is as follows:

或其醫藥上可接受之鹽或前藥，其中 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 1293306 A7 B7 五、發明說明（38 ) (請先閱讀背面之注意事項再填寫本頁) 及與本文說明之HCV 5’-非編碼區互補；及 (h) —種探針分子，其設計用於螢光檢測核酸外切降解作用 及與本文說明之HCV編碼區互補；及 (〇 —種探針分子，其設計用於螢光檢測核酸外切降解作用 及與本文說明之HCV 3’-非編碼區互補；及 ⑴一種探針分子，其序列為5’-6-fam- CCTCCAGGACCCCCCCTCCC-tamara-3’（序列 ID No 4)，其引子之正意義序列為：5’_AGCCATGGCGTTAGTA (T/C)GAGTGT-3,（序列 ID No 5)且反義序列為：5’-TTCCGCAGACCACTATGG-3’（序列 ID No 6) 〇 [圖式之簡要說明] 第1圖說明實例51所述之細胞培養物中，當牛病毒性 下痢病毒（“BVDV”）濃度提高時，溶菌斑形成單位亦提高。 第1圖證實實例51方法提供一種可靠之BVDV定量法， 可定量4個log PFU/毫升之病毒。 經濟部智慧財產局員工消費合作社印製 第2圖說明MDBK細胞中BVDV複製循環，可測定最 適當收穫時間（感染後小時數相對於溶菌斑形成單位（PFU) 對數值），亦即感染後22小時，其大約相當於約一個複製 循環，此時病毒產量等於接種至細胞中之病毒量，如實例 52之說明。 第3圖為說明某些試驗化合物抑制溶菌斑形成單位數 之能力之長條圖，如實例40中對抗BVDV之說明。 第4圖為說明共同投與天然核苷（即胞苷與尿苷）時， 可預防“碳化糖’’（carba-sugar)核替於CEM細胞（人類T細胞 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 38 91949 1293306 A7Or a pharmaceutically acceptable salt or prodrug thereof, wherein the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 1293306 A7 B7 5. Inventive Note (38) (Please read the back of the note first) The matter is refilled with this page) and is complementary to the HCV 5'-noncoding region described herein; and (h) a probe molecule designed for fluorescence detection of exonucleolytic degradation and HCV coding region as described herein. Complementary; and (〇-a probe molecule designed for fluorescence detection of exonuclease degradation and complementation to the HCV 3'-noncoding region described herein; and (1) a probe molecule having a sequence of 5'- 6-fam-CCTCCAGGACCCCCCCTCCC-tamara-3' (sequence ID No 4), the positive sequence of the primer is: 5'_AGCCATGGCGTTAGTA (T/C) GAGTGT-3, (sequence ID No 5) and the antisense sequence is: 5 '-TTCCGCAGACCACTATGG-3' (Sequence ID No 6) 〇 [Brief Description of the Drawing] Fig. 1 illustrates the cell culture in Example 51, when the concentration of bovine viral prion ("BVDV") is increased, lysolysis The plaque forming unit is also improved. Figure 1 confirms that the example 51 method provides one A reliable BVDV quantitative method that can quantify 4 log PFU/ml of virus. Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Figure 2 illustrates the BVDV replication cycle in MDBK cells, which can determine the most appropriate harvest time (hours after infection) Relative to the plaque forming unit (PFU) logarithm), that is, 22 hours after infection, it corresponds to approximately one replication cycle, at which time the virus yield is equal to the amount of virus inoculated into the cells, as illustrated in Example 52. The figure is a bar graph illustrating the ability of certain test compounds to inhibit the number of plaque forming units, as described in Example 40 against BVDV. Figure 4 is a diagram showing the co-administration of natural nucleosides (ie, cytidine and uridine). It can prevent "carba-sugar" nucleus from replacing CEM cells (human T cell paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 38 91949 1293306 A7

五、發明說明（39 經濟部智慧財產局員工消費合作社印製 淋巴瘤）及SUDHL-1細胞（人類進行發育1細胞淋巴瘤細胞 株）中之細胞毒性。 第5圖提供本發明核苷之各種不設限實例及本文中用 於對照實例之已知核苷（利巴韋林）之結構式。 [本發明之詳細說明] 本發明提供一種通式（iHxxm)核苷或其醫藥上可接 X之鹽或前藥，供治療感染黃病毒科、正黏液病毒科或副 黏液病毒科病毒之宿主，或者，通式⑴-(χχιπ)核苷或其 醫藥上可接受之鹽或前藥可用於治療非正常細胞增生。 在一項具體實施例中，提供一種抗病毒劑或抗增生劑 之治療或預防方法，例如··供治療或預防病毒感染，包含 黃病毒科病毒感染，包含c型肝炎感染、流感病毒感染， 包含流感病毒Α(如：Η1Ν1與Η3Ν2)，及流感病毒Β與 RSV，及非正常細胞增生，#包含投與抗病毒或抗增生有 效量之本發明核苷，或其醫藥上可接受之鹽或前藥。 另-項具體實施財，冑供一種抗病毒劑或抗增生劑 之治療或預防方法，例如：供治療或預防黃病毒科病毒感 染，其包含使用抗病毒量之本發明核苷或其醫藥上可接受 之鹽或前藥於製造治療用之醫藥。 又 另一項具體實施例中，提供一種抗病毒劑或抗增生劑 之治療或預防方法，例如：供治療或預防流感病毒感染， 其包含使用抗病毒有效量之本發明核苷或其醫藥上可接受 之鹽或則樂，用於製造治療用之醫藥。 另-項具體實施例中’提供-種抗病毒劑或抗 本紙張尺度適用中國國家標準（CNS)A4規格(^〇 x 297公爱) 39 91949 (請先閱讀背面之注咅？事項再填寫本頁) # 訂---------線· 1293306V. Cytotoxicity in the invention (39 printed lymphoma of the Intellectual Property Office of the Ministry of Economic Affairs) and SUDHL-1 cells (human developmental 1-cell lymphoma cell line). Fig. 5 provides various non-limiting examples of the nucleosides of the present invention and the structural formula of the known nucleoside (ribavirin) used herein for the comparative examples. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a nucleoside of the formula (iHxxm) or a pharmaceutically acceptable salt or prodrug thereof for the treatment of a host of the Flaviviridae, Orthomyxoviridae or Paramyxoviridae virus. Alternatively, a nucleoside of the formula (1)-(χχιπ) or a pharmaceutically acceptable salt or prodrug thereof can be used to treat abnormal cell proliferation. In a specific embodiment, a method for treating or preventing an antiviral agent or an anti-proliferative agent, for example, for treating or preventing a viral infection, comprising a Flaviviridae virus infection, comprising a hepatitis C infection, an influenza virus infection, Including influenza virus Α (eg, Η1Ν1 and Η3Ν2), and influenza virus Β and RSV, and abnormal cell proliferation, #containing administration of an antiviral or antiproliferative effective amount of the nucleoside of the present invention, or a pharmaceutically acceptable salt thereof Or a prodrug. Another method for the treatment or prevention of an antiviral agent or an anti-proliferative agent, for example, for treating or preventing a Flaviviridae virus infection, which comprises using an antiviral amount of the nucleoside of the present invention or a pharmaceutical thereof An acceptable salt or prodrug is used in the manufacture of a medicament for treatment. In yet another embodiment, a method of treating or preventing an antiviral or anti-proliferative agent, for example, for treating or preventing influenza virus infection, comprising administering an antiviral effective amount of a nucleoside of the invention or a pharmaceutical thereof An acceptable salt or a remedy for the manufacture of a therapeutic medicine. In another specific example, 'providing an antiviral agent or anti-paper scale applies to the Chinese National Standard (CNS) A4 specification (^〇x 297 public) 39 91949 (please read the back note? This page) #订---------线· 1293306

之治療或預防方法，例毵^ J如·供治療或預防RSV感染，其包 含使用抗病毒有效量之士 里之本發明核苷或其醫藥上可接受之鹽 或前藥，用於製造治療用之醫藥。 另一項具體實施例φ ^ ω 、 、 j中 &供一種抗病毒劑或抗增生劑 之付療或預防方法，例如：供治療或預防出現非正常細胞 增生特性之疾病’其包含投與抗增生有效量之本發明核 苷。 另項/、體實施例中，本發明提供以本文說明之一種 化合物於製造醫藥供治療病毒感染或非正常細胞增生之用 途。 另一項具體實施例中，本發明提供以本文說明之一種 化合物於治療患有病毒感染或非正常細胞增生之宿主上用 途。 2一項具體實施例中’提供—種醫藥組成物，其包含 抗病毒或抗增生有效量之本發明核脊或其醫藥上可接受之 鹽或前藥’及根據本發明之醫藥上可接受之載體或稀釋 劑。 另一項具體實施例中，提供一種醫藥組成物，其包含 本發明核脊或其醫藥上可接受之鹽或前藥與一種或多種其 他抗病毒或抗增生有效製劑組合。 另一項具體實施例中，提供一種製備本發明核苷或其 醫藥上可接受之鹽或前藥之方法。A method for treating or preventing, for example, for treating or preventing RSV infection, which comprises using an antiviral effective amount of the nucleoside of the present invention or a pharmaceutically acceptable salt or prodrug thereof for use in the manufacture of a therapeutic Used medicine. Another specific embodiment φ ^ ω , , j & a method for the treatment or prevention of an antiviral or anti-proliferative agent, for example, a disease for treating or preventing abnormal cell proliferation characteristics An anti-proliferative effective amount of a nucleoside of the invention. In another embodiment, the invention provides the use of a compound described herein for the manufacture of a medicament for the treatment of viral infection or abnormal cell proliferation. In another embodiment, the invention provides a use of a compound described herein for the treatment of a host having viral infection or abnormal cell proliferation. 2 In a specific embodiment, 'providing a pharmaceutical composition comprising an antiviral or antiproliferative effective amount of a core ridge of the invention or a pharmaceutically acceptable salt or prodrug thereof' and pharmaceutically acceptable according to the invention Carrier or diluent. In another embodiment, a pharmaceutical composition comprising a ridge of the invention or a pharmaceutically acceptable salt or prodrug thereof in combination with one or more other antiviral or anti-proliferative effective agents is provided. In another embodiment, a method of preparing a nucleoside of the invention or a pharmaceutically acceptable salt or prodrug thereof is provided.

另一項具體實施例中，提供—種治療患有病毒相關病 變之j乳動物之方法，其包括對該哺乳動物投斑醫越古W 表紙張尺度顧中國國家標準（CNS)A4規格⑵〇 x 297公髮） 91949 (請先閱讀背面之注意事項再填寫本頁) - I I - I I I I ·11111111 - 經濟部智慧財產局員工消費合作社印製 1293306In another specific embodiment, there is provided a method of treating a milk animal having a virus-related disease, comprising administering to the mammal an ancient W-paper size in accordance with the Chinese National Standard (CNS) A4 specification (2) x 297 mil. 91949 (Please read the note on the back and fill out this page) - II - IIII ·11111111 - Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed 1293306

五、發明說明（41 量之本發明核冑或其醫藥上可接受之鹽或前藥。 另一項具體實施例中，提供一種治療患有與非正常細 胞增生有關病變之哺乳動物之方法，純括對該哺乳動物 投與醫藥有效量之本發明㈣或其醫藥上可接受之鹽或前 藥。 特定言之’本發明包含以本文說明之化合物於治療或 預防下列病變之方法，或於治療或預防下列病變之用途， 或於製造醫藥供用於下列病變之用途： (a) 黃病毒科病毒感染，包含所有肝病毒屬（HCV)、疫病毒 屬（BVDV、CSFV、BDV)或黃病毒屬（登革熱病毒、曰本 腦炎病毒類（包含西奈爾病毒）及黃熱病毒）之所有成 員； (b) 正黏液病毒科病毒感染，包含流感病毒A、B屬所有成 員，特定言之流感病毒A及所有相關亞型（包含H1N1 及H3N2)及流感病毒B ; (c) 副黏液病毒科病毒感染，包含呼吸胞合體病毒（rsv)感 染；及 (d) 非正常細胞增生，包含惡性腫瘤。 本發明化合物 一項具體實施例中，抗病毒或抗增生有效之核苷為通 式σ)或（11)召-d核苷： (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5. Description of the Invention (41 Amount of the nucleoside of the present invention or a pharmaceutically acceptable salt or prodrug thereof. In another specific embodiment, there is provided a method of treating a mammal having a disease associated with abnormal cell proliferation, A pharmaceutically effective amount of the present invention (4) or a pharmaceutically acceptable salt or prodrug thereof is administered to the mammal. In particular, the present invention encompasses a method of treating or preventing the following conditions with a compound described herein, or Use for the treatment or prevention of the following lesions, or for the manufacture of medicines for the following conditions: (a) Flaviviridae infection, including all hepatic genus (HCV), genus (BVDV, CSFV, BDV) or flavivirus All members of the genus (dengue virus, sputum encephalitis virus (including Sinan virus) and yellow fever virus); (b) Orthomyxoviridae virus infection, including all members of the influenza virus A and B, specifically the flu Virus A and all related subtypes (including H1N1 and H3N2) and influenza B; (c) Paramyxoviral infection, including respiratory syncytial virus (rsv) infection; and (d) abnormal fine Hyperplasia, including malignant tumors. In a specific embodiment of the compound of the present invention, the antiviral or antiproliferative effective nucleoside is of the formula σ) or (11) called-d nucleoside: (please read the back note first and then fill in This page is printed by the Intellectual Property Office of the Ministry of Economic Affairs.

-· H ϋ I n I ϋ ί-^-Γοτ · n I n ϋ I n I I n ϋ ϋ ϋ n I I ϋ n n n i I I. I 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 41 91949 1293306 A7 B7 五、發明說明（42 X1-· H ϋ I n I ϋ ί-^-Γοτ · n I n ϋ I n II n ϋ ϋ II n II ϋ nnni I I. I This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 PCT) 41 91949 1293306 A7 B7 V. Description of invention (42 X1

R1 X1R1 X1

X1X1

V X1V X1

R1 X1R1 X1

- (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 或其醫藥上可接受之鹽或前藥，其中： 各D為氳、烷基、醯基、單磷酸根、二磷酸根、三磷酸根、 單磷酸酯、二磷酸酯、三磷酸酯、磷脂或胺基酸，但以氫 較佳； 各W1與W2分別獨立為CH或N ; 各X1與X2分別獨立為氫、鹵素（F、Cl、Br或I)、NH2、 NHR4、NR4R4’、NHOR4、NR4NR4’R4”、OH、OR4、SH 或 SR4 ； 各Y1為O、S或Se ; 各Z為CH2或NH ; 各R1與R1’分別獨立為氫 碳數炔基、芳基、烧芳基 低礙數烷基、低碳數烯基、低 鹵素（F、Cl、Br 或 I)、NH2、- (Please read the notes on the back and fill out this page.) Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs or its pharmaceutically acceptable salt or prodrug, where: D is 氲, alkyl, sulfhydryl, single Phosphate, diphosphate, triphosphate, monophosphate, diphosphate, triphosphate, phospholipid or amino acid, but preferably hydrogen; each W1 and W2 is independently CH or N; each X1 and X2 Independently hydrogen, halogen (F, Cl, Br or I), NH2, NHR4, NR4R4', NHOR4, NR4NR4'R4", OH, OR4, SH or SR4; each Y1 is O, S or Se; each Z is CH2 or NH; each of R1 and R1' is independently a hydrocarbyl alkynyl group, an aryl group, a aryl aryl group, a lower alkyl group, a lower halogen (F, Cl, Br or I), NH2.

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 42 91949 1293306 A7 B7 五、發明說明（43 ) NHR5、NR5R5’、NHOR5、NR5NHR5’、NR5NR5，R5，，、OH、 OR5、SH、SR5、N02、NO、CH2OH、CH2〇R5、C02H、C02R5、 CONH2、CONHR5、CONR5R5,或 CN ; 各R2與R2’分別獨立為氫或鹵素（F、Cl、Br或I)、〇H、SH、 OCH3、SCH3、NH2、NHCH3、CH=CH2、CN、CH2NH2、CH2OH、 C02H ； 各R3與R3’分別獨立為氫或鹵素（F、CM、Br或I)、〇H、SH、 OCH3、SCH3、NH2、NHCH3、CH3、C2H5、CH=CH2、CN、 ch2nh2、ch2oh、co2h; 各R4、R4’、R4”、R5、R5,與R5”分別獨立為氫、低碳數烷 基、低碳數烯基、芳基、或芳烷基，如··末取代或經取代 之苯基或T基； 因此通式（I)或（II)各核苷中，R2與R2’中至少一者為氫，且 R3與R3’中至少一者為氳。 本發明另一項具體實施例中，抗病毒或抗增生有效之 核苷為通式（III)或（IV)点-L-核苷·· (請先閱讀背面之注意事項再填寫本頁) --------訂---------線丨· 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 43 91949 1293306 A7 B7 五、發明說明（44 ) X1This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 42 91949 1293306 A7 B7 V. Invention description (43 ) NHR5, NR5R5', NHOR5, NR5NHR5', NR5NR5, R5,, OH, OR5 , SH, SR5, N02, NO, CH2OH, CH2〇R5, C02H, C02R5, CONH2, CONHR5, CONR5R5, or CN; each R2 and R2' are independently hydrogen or halogen (F, Cl, Br or I), 〇 H, SH, OCH3, SCH3, NH2, NHCH3, CH=CH2, CN, CH2NH2, CH2OH, C02H; each of R3 and R3' is independently hydrogen or halogen (F, CM, Br or I), 〇H, SH, OCH3, SCH3, NH2, NHCH3, CH3, C2H5, CH=CH2, CN, ch2nh2, ch2oh, co2h; each R4, R4', R4", R5, R5, and R5" are independently hydrogen, lower alkyl a lower alkyl, aryl, or aralkyl group, such as a substituted or substituted phenyl or T group; thus, in each of the nucleosides of formula (I) or (II), R2 and R2' At least one of them is hydrogen, and at least one of R3 and R3' is deuterium. In another embodiment of the present invention, the anti-viral or anti-proliferative effective nucleoside is a general formula (III) or (IV) point-L-nucleoside · (please read the back of the note first and then fill out this page) --------Book---------Line 丨· Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed This paper scale applies China National Standard (CNS) A4 specification (210 X 297 mm) 43 91949 1293306 A7 B7 V. Description of invention (44 ) X1

[Ill-a][Ill-a]

,OD wi〇6c, OD wi〇6c

.OD X1.OD X1

[IV-a] R2· R3, [ffl-b][IV-a] R2· R3, [ffl-b]

,OD, OD

[IV-b] R2’ R3· [ΠΙ-c] X1[IV-b] R2’ R3· [ΠΙ-c] X1

(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制衣 44 或其醫藥上可接受之鹽或前藥，其中： 各 D、Wi、W2、χΐ、X2、γΐ、Z、Ri、R1，、R2、R2,、R3 與R3’如前述之定義； 因此通式（III)或（IV)各核苷中，R2與R2’中至少一者為氫且 R3與R3’中至少一者為氫。 本發明一項具體實施例中，抗病毒或抗增生有效之核 苷為通式（V)至（VII)石-D-碳化-糖-核苷： 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 1293306 A7 B7 五、發明說明（45 )(Please read the notes on the back and then fill out this page.) Ministry of Economic Affairs Intellectual Property Office Employees' Cooperatives Printed Clothes 44 or its pharmaceutically acceptable salts or prodrugs, including: D, Wi, W2, χΐ, X2 ΐ ΐ, Z, Ri, R1, R2, R2, R3 and R3' are as defined above; therefore, in each nucleoside of the formula (III) or (IV), at least one of R2 and R2' is hydrogen and R3 At least one of R3' and R3' is hydrogen. In a specific embodiment of the present invention, the antiviral or antiproliferative effective nucleoside is the general formula (V) to (VII) stone-D-carbo-sugar-nucleoside: the paper scale applies to the Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) 91949 1293306 A7 B7 V. Description of invention (45)

DODO

X1X1

R2 R3，R2, [V-c] w1 X1R2 R3, R2, [V-c] w1 X1

[Vl-b] DO.[Vl-b] DO.

[VI-a] [VI-c] X1[VI-a] [VI-c] X1

RlRl

X1X1

經濟部智慧財產局員工消費合作社印製 或其醫藥上可接受之鹽或前藥，其中： 各 D、Wi、W2、χΐ、X2、γΐ、Z、Rl、R1，、R2、R2,、R3與R3’如前述之定義；因此通式（V)或（VI)各核苷中，R2與R2’中至少一者為氫且 R3與R3’中至少一者為氫。在一項具體實施例中，抗病毒或抗增生有效之核苷為 通式（VIII)至（X)yS-L-碳化-糖-核苷： (請先閱讀背面之注意事項再填寫本頁)Printed by the Consumer Intellectual Property Office of the Ministry of Economic Affairs, or its pharmaceutically acceptable salt or prodrug, where: D, Wi, W2, χΐ, X2, γΐ, Z, Rl, R1, R2, R2, R3 And R3' are as defined above; therefore, in each of the nucleosides of the formula (V) or (VI), at least one of R2 and R2' is hydrogen and at least one of R3 and R3' is hydrogen. In a specific embodiment, the antiviral or antiproliferative effective nucleoside is of the formula (VIII) to (X) yS-L-carbo-sugar-nucleoside: (Please read the back of the note first and then fill out this page )

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 45 91949 1293306 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（46 ) X1This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 45 91949 1293306 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (46) X1

,0D, 0D

R乂R3 R2’ R3· [Vin-b] R2 [IX-b] X1R乂R3 R2’ R3· [Vin-b] R2 [IX-b] X1

.OD.OD

,0D, 0D

R2· R3· [X_b] 或其醫藥上可接受之鹽或前藥，其中： 各 D、Wi、W2、χΐ、X2、γΐ、Z、Ri、R1，、R2、R2’、R3 與R3’如前述之定義； 因此通式（VIII)或（IX)各核苷中，R2與R2’中至少一者為氫 且R3與R3’中至少一者為氫。 本發明另一項具體實施例中，抗病毒或抗增生有效之 /5 -D或泠，L-核苷分別為通式（XI)或（XII): 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 46 91949 (請先閱讀背面之注意事項再填寫本頁) 1293306 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（47 )R2·R3· [X_b] or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, Wi, W2, χΐ, X2, γΐ, Z, Ri, R1, R2, R2', R3 and R3' As defined above; therefore, in each of the nucleosides of the formula (VIII) or (IX), at least one of R2 and R2' is hydrogen and at least one of R3 and R3' is hydrogen. In another specific embodiment of the present invention, the antiviral or antiproliferative effective /5-D or guanidine, L-nucleoside is respectively of the formula (XI) or (XII): the paper scale is applicable to the Chinese National Standard (CNS) A4 size (210 X 297 mm) 46 91949 (Please read the note on the back and fill out this page) 1293306 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (47)

[XII-a] X1[XII-a] X1

X1 DOX1 DO

[ΧΠ-b] X1[ΧΠ-b] X1

OD 或其醫藥上可接受之鹽或前藥，其中： 各 D、Wi、W2、χΐ、X2、Y1、Z、Ri、R1，、R2、R2,、R3與R3’如前述之定義；各Z1與Z2分別獨立為〇、S、NR6或Se ;各R6為氫、低 碳數烷基或低碳數醯基。本發明另一項具體實施例中，抗病毒或抗增生有效之 召-D或召-L-核苷（但以召-D較佳）如通式（XIII): Y2OD or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, Wi, W2, χΐ, X2, Y1, Z, Ri, R1, R2, R2, R3 and R3' are as defined above; Z1 and Z2 are each independently 〇, S, NR6 or Se; each R6 is hydrogen, a lower alkyl group or a lower carbon fluorenyl group. In another embodiment of the present invention, the antiviral or antiproliferative effective s-D or s-L-nucleoside (but preferably s-D is preferred) is as in the formula (XIII): Y2

R1 R1·R1 R1·

R3. R2. [ΧΙΠ-a]R3. R2. [ΧΙΠ-a]

DODO

DO.DO.

Y2lY X^N^R1, DO,Y2lY X^N^R1, DO,

R3’ R2· [xm-d] (請先閱讀背面之注意事項再填寫本頁)R3’ R2· [xm-d] (Please read the notes on the back and fill out this page)

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 47 91949 481293306 A7 B7 五、發明說明（ 或其醫藥上可接受之鹽或前藥，其中·· 各 D、R1、R1’、R2、R2’、R3 與 r3’如前述定義； 各 Y2 為 〇、S、或 NR7 ; 各 Υ3 為 Ο、S、1STH 或 NR8 ; 各X3為OR9或SR9 ;且 各R7、R8與R9為氫、（^至C6低碳數烷基、芳烷基或芳基； 因此通式（ΧΙΙΙ-d)各核苷中，y與r2,中至少一者為氫且R3 與R3’中至少一者為氫。 另一項具體實施例中，抗病毒或抗增生有效之化合物 為召-D或泠-L·核苷，但以召_D較佳，其係由添加小分子 (如··烷基次氯酸酯、烷基次溴酸酯、次溴酸或醯基自化物） 至適當嘧啶核苷中，形成如式（XIV)核苷：This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 47 91949 481293306 A7 B7 V. INSTRUCTIONS (or its pharmaceutically acceptable salts or prodrugs, where ··························· ', R2, R2', R3 and r3' are as defined above; each Y2 is 〇, S, or NR7; each Υ3 is Ο, S, 1STH or NR8; each X3 is OR9 or SR9; and each R7, R8 and R9 Is hydrogen, (^ to C6 lower alkyl, aralkyl or aryl; therefore, in each nucleoside of the formula (ΧΙΙΙ-d), at least one of y and r2 is hydrogen and at least R3 and R3' One is hydrogen. In another specific embodiment, the antiviral or antiproliferative effective compound is s-D or 泠-L· nucleoside, but it is preferred to add small molecules (such as · Alkyl hypochlorite, alkyl hypobromide, hypobromous acid or sulfhydryl self-organism) to the appropriate pyrimidine nucleoside to form a nucleoside of formula (XIV):

R3，R2· [XIV] 或其醫藥上可接受之鹽或前藥，其中： 各 D、Χΐ、Yi、Zi、Ri、R2、R2’、R3 與 R3’如前述定義； 各L1為氫、C1或Br ; 各 L2 為 OH、OCH3、OC2H5、OC3H7、OCF3、OAc 或 OBz ; 各Z3可為〇或CH2。 另一項具體實施例中，抗病毒或抗增生有效之核苷為 ------------# (請先閱讀背面之注音？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 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 48 91949 1293306 A7 _B7___ 五、發明說明（49 ) 通式（XV)二聚合核苷（各核苷係呈卢-D或召-L組態），其中 二個核苷利用二硫化物鍵連接： ς s-sR3, R2· [XIV] or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, Χΐ, Yi, Zi, Ri, R2, R2', R3 and R3' are as defined above; each L1 is hydrogen, C1 or Br; each L2 is OH, OCH3, OC2H5, OC3H7, OCF3, OAc or OBz; each Z3 may be hydrazine or CH2. In another specific embodiment, the antiviral or anti-proliferative effective nucleoside is ------------# (please read the phonetic transcription on the back side and then fill out this page). Order---- -----Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 48 91949 1293306 A7 _B7___ V. Description of invention (49) (XV) di-polymeric nucleosides (each nucleoside is in the Lu-D or the call-L configuration), in which two nucleosides are linked by a disulfide bond: ς ss

或其醫藥上可接受之鹽或前藥，其中： 各 D、Wi、W2、χΐ、Υΐ、Z3、Ri、R1，、R2、R2,、R3 與 R3, 如前述定義； 一項具體實施例中，抗病毒或抗增生有效之核苷為通 式（XVI)^ -D或冷-L C-核苷： (請先閱讀背面之注意事項再填寫本頁) · I I I !Or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, Wi, W2, χΐ, Υΐ, Z3, Ri, R1, R2, R2, R3 and R3, as defined above; Among them, antiviral or anti-proliferative nucleosides are of the general formula (XVI)^-D or cold-L C-nucleosides: (Please read the back of the precautions and fill out this page) · III !

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 49 91949 線_ 1293306 A7 B7 五、發明說明（50 或其醫藥上可接受之鹽或前藥，其中： 各 D、W1、X1、X2、Y1、Z、R1、R2、R2’、R3 與 R3 ’如前 述定義； 各W3分別獨立為N、CH或CR1 ; 各W4與W5分別獨立為N、CH、CX1或CR1’ ；且 各Z4與Z5分別獨立為NH或C^Y1); 因此若Z4與Z5利用共價鍵結合，當Z5為Ci^Y1)時，貝，j Z4 不為’且壞氮不超過3個。 在一項具體實施例中，抗病毒或抗增生有效之核苷為 通式（XVII)召-D或召-L-分支鏈糖核苷： (請先閱讀背面之注意事項再填寫本頁) X1This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 49 91949 Line _ 1293306 A7 B7 V. Description of invention (50 or its pharmaceutically acceptable salt or prodrug, where: D, W1 , X1, X2, Y1, Z, R1, R2, R2', R3 and R3' are as defined above; each W3 is independently N, CH or CR1; each of W4 and W5 is independently N, CH, CX1 or CR1' And each Z4 and Z5 are independently NH or C^Y1); therefore, if Z4 and Z5 are combined by a covalent bond, when Z5 is Ci^Y1), the shell, j Z4 is not 'and the bad nitrogen does not exceed 3 . In a specific embodiment, the antiviral or anti-proliferative effective nucleoside is a compound of the formula (XVII)-D or a-L-branched chain nucleoside: (Please read the back of the note first and then fill out this page) X1

R1 [ΧΥΠ-a] X1R1 [ΧΥΠ-a] X1

訂---------線- 經濟部智慧財產局員工消費合作社印划衣 X1Order ---------Line - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative prints X1

R1 R1· [XVII-c] [XVH-b] X1R1 R1· [XVII-c] [XVH-b] X1

X5 [XVU-d] 或其醫藥上可接受之鹽或前藥，其中： 各 D、W1、W2、X1、X2、Y1、Z3、R1、R1,、R2、R2,、R3 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 50 91949 1293306 A7 B7 五、發明說明（51 ) 與R3’如前述定義； 各X4與X5分別獨立為氫、鹵素（F、Cl、Br 1I)、n3、NH2、 NHR8、NR8R8’、OH、OR8、SH 或 SR8 ;且 各R8與R8分別獨立為氫、低碳數烧基、低碳數烯基、芳 基或芳烷基，如：未取代或經取代之苯基或苄基；因此通式（XVII-a)或（XVII_b)各核脊中，X4不為〇H或 OR8。 在一項具體實施例中，抗病毒或抗增生有效之核苷為 通式（XVIII) a -D或a 核苷： (請先閱讀背面之注意事項再填寫本頁) 0 經濟部智慧財產局員工消費合作社印製X5 [XVU-d] or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, W1, W2, X1, X2, Y1, Z3, R1, R1, R2, R2, R3 China National Standard (CNS) A4 Specification (210 X 297 mm) 50 91949 1293306 A7 B7 V. Description of Invention (51) and R3' are as defined above; each X4 and X5 are independently hydrogen, halogen (F, Cl, Br) 1I), n3, NH2, NHR8, NR8R8', OH, OR8, SH or SR8; and each of R8 and R8 is independently hydrogen, a low carbon number alkyl group, a low carbon number alkenyl group, an aryl group or an aralkyl group, such as : unsubstituted or substituted phenyl or benzyl; thus, in each nucleus of formula (XVII-a) or (XVII_b), X4 is not 〇H or OR8. In a specific embodiment, the antiviral or antiproliferative effective nucleoside is of the formula (XVIII) a -D or a nucleoside: (Please read the back note first and then fill out this page) 0 Ministry of Economic Affairs Intellectual Property Office Printed by employee consumption cooperatives

[xvm-c] [XVin-d] 或其醫藥上可接受之鹽或前藥，其中： 各 D、Wi、W2、χΐ、X2、γΐ、Ri、R1’、R2、R2,、R3 與 R3, 如前述定義。 本發明之次項具體實施例中，抗病毒或抗增生有效之 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 51 91949 I----II 訂1111111. ^^ I - !293306 A7 _ B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（52 ) 召-D或-L核苷如式（XIX): NHP1。办 或其醫藥上可接受之鹽或前藥，其中： 各D、Ri、R4、與R4’如前述定義； 各R9為氫、鹵素（F、Cl、Br或I)或〇p3 ; 各Ρ1為虱、低碳數烧基、低碳數烯基、芳基、芳烧基（如： 未取代或經取代之苯基或Τ基）、OH、〇R4、、NHR4 或 NR4R4’ ；且 各P2與P3分別獨立為氫、烷基、醯基、-Ms、_Ts、單雄 酸根、二磷酸根、三磷酸根、單磷酸酯、二磷酸酯、三項 酸酯、填脂或胺基酸，但以氫較佳。 本發明之特別次項具體實施例中，抗病毒或抗增生肩 效之式（XIX)点_D或Θ -L核苷如下：[xvm-c] [XVin-d] or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, Wi, W2, χΐ, X2, γΐ, Ri, R1', R2, R2, R3 and R3 , as defined above. In a specific embodiment of the present invention, the anti-viral or anti-proliferative effective paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 51 91949 I----II Order 1111111. ^^ I - !293306 A7 _ B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (52) Call-D or -L nucleoside such as formula (XIX): NHP1. Or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, Ri, R4, and R4' are as defined above; each R9 is hydrogen, halogen (F, Cl, Br or I) or 〇p3; a hydrazine, a low carbon number alkyl group, a lower alkylene group, an aryl group, an aryl group (such as an unsubstituted or substituted phenyl or fluorenyl group), OH, hydrazine R4, NHR4 or NR4R4'; P2 and P3 are independently hydrogen, alkyl, sulfhydryl, -Ms, _Ts, mono-androstate, diphosphate, triphosphate, monophosphate, diphosphate, triester, fat or amino acid However, it is preferred to use hydrogen. In a particular sub-specific embodiment of the invention, the antiviral or anti-proliferative shoulder (XIX) point-D or Θ-L nucleoside is as follows:

或其醫藥上可接受之鹽或前藥，其中： 本紙張尺度適时關家標準（CNS)A4規格⑵G x 297公爱）^ 52 91949 (請先閱讀背面之注音？事項再填寫本頁) 0 訂--------- 1293306 A7 __ B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（53 ) 各D與P2如前述定義。在較佳具體實施例中，d與P2分 別獨立為氫。 另一項本發明次項具體實施例中，抗病毒或抗增生有 效之0 -D或0 -L核苷如下式（XX):Or a pharmaceutically acceptable salt or prodrug thereof, wherein: This paper scales the appropriate time (CNS) A4 specification (2) G x 297 public) ^ 52 91949 (please read the phonetic on the back? Please fill out this page) 0 Order--------- 1293306 A7 __ B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5, Invention Description (53) Each D and P2 are as defined above. In a preferred embodiment, d and P2 are independently hydrogen. In another sub-specific embodiment of the invention, the antiviral or anti-proliferative effective 0-D or 0-L nucleoside is as follows: (XX):

[XX] 或其醫藥上可接受之鹽或前藥，其中： 各 D、P1、P2、P3、R1、R4 ' R4’與 R9 如前述定義。 另一項本發明次項具體實施例中，抗病毒或抗增生有 效之召_D或召-L核脊如式（XXI):[XX] or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, P1, P2, P3, R1, R4' R4' and R9 are as defined above. In another sub-specific embodiment of the invention, the antiviral or anti-proliferative effective _D or the call-L nucleus is as in the formula (XXI):

或其醫藥上可接受之鹽或前藥，其中： 各D、P1、P2、P3、R1、R4與R4’如前述定義。 另一項本發明次項具體實施例中，抗病毒或抗增生有 效之/3 -D或石_L核苷如式（XXI): 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 53 91949 (請先閱讀背面之注音？事項再填寫本頁) 0 •線· 1293306Or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, P1, P2, P3, R1, R4 and R4' are as defined above. In another embodiment of the present invention, the antiviral or antiproliferative effective /3 -D or the stone _L nucleoside is as shown in the formula (XXI): the paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297). Gong) 53 91949 (Please read the phonetic on the back? Please fill out this page again) 0 • Line · 1293306

五、發明說明（54 )V. Description of invention (54)

OP2 〇p3OP2 〇p3

.OH 或其醫藥上可接受之鹽或前藥，其中： 各D、P與P3如前述定義。在較佳具體實施例中，〇、f 與Ρ3分別獨立為氫。 另一項具體實施例中，使用Ν_羥基胞嘧啶作為鹼基f 接本申请案所述之任何糖或碳化碳部份基團上，如同其： 別完全說明為另一項明確之具體實施例。 ▲另一項本發明次項具體實施例中，抗病毒或抗增生； 效之/9 -D或/5 -L核苷如式（χχπ): (請先閱讀背面之注咅？事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製.OH or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, P and P3 are as defined above. In a preferred embodiment, 〇, f and Ρ3 are each independently hydrogen. In another embodiment, hydrazine-hydroxycytosine is used as base f on any of the sugar or carbonized carbon moiety groups described in this application, as it: fully exemplified as another specific implementation example. ▲ Another specific embodiment of the present invention, antiviral or anti-proliferative; effect / 9 -D or /5 -L nucleoside such as formula (χχπ): (Please read the back of the note? Page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

或其醫藥上可接受之鹽或前藥，其中： 各D、Ρ1與Ρ2如前述定義。在較佳具體實施例中，D與f 分別獨立為氫。 在特別之次項具體實施例中’抗病毒或抗增生有效4 式（XXII)/S -D或冷-L核甘（以召-L較佳）如下· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 54 91949 訂---------線！ 1293306 Α7 Β7 經濟部智慧財產局員工消費合作社印制衣 五、發明說明（55 )Or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, Ρ1 and Ρ2 are as defined above. In a preferred embodiment, D and f are each independently hydrogen. In the special sub-specific examples, 'antiviral or anti-proliferative effective 4 (XXII) / S - D or cold - L nuclear (better - called L - L) is as follows · This paper scale applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) 54 91949 Order --------- line! 1293306 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed clothing 5, invention description (55)

或其醫藥上可接受之鹽或前藥，其中： D如前述定義，且以Η較佳。 另一項次項具體實施例中，抗病毒或抗增生有效之召 -D或0 -L核苷如下式（XXIII):Or a pharmaceutically acceptable salt or prodrug thereof, wherein: D is as defined above and is preferably Η. In another sub-specific embodiment, the antiviral or anti-proliferative effective -D or 0-L nucleoside is as follows (XXIII):

或其醫藥上可接受之鹽或前藥，其中： 各D、Ρ1、Ρ2、Ρ3、R1、R4及R4’如前述定義。 在特別之次項具體實施例中，抗病毒或抗增生有效之 式（XXIII)冷-D或泠-L核苷如下：Or a pharmaceutically acceptable salt or prodrug thereof, wherein: each D, Ρ1, Ρ2, Ρ3, R1, R4 and R4' are as defined above. In a particular sub-specific embodiment, the anti-viral or anti-proliferative effective (XXIII) cold-D or 泠-L nucleoside is as follows:

或其醫藥上可接受之鹽或前藥，其中： _本紙張尺度適用中關家標準（CNS)A4規格（21G χ 297公爱) 55 91949 (請先閱讀背面之注音？事項再填寫本頁) ---------訂---------線· · A7Or a pharmaceutically acceptable salt or prodrug thereof, where: _ This paper scale applies to the China National Standard (CNS) A4 specification (21G 297 297 public) 55 91949 (please read the phonetic on the back? ) ---------Book --------- Line · · A7

1293306 五、發明說明（56 ) 各D、P與p3如前述定義。在較佳具體實施例中，D、p2 與P3分別為氫。 在較佳具體實施例中，通式（I_a)與（HPa)之召_D及召 -L核苷由下表1所示之不設限實例代表： 表11293306 V. INSTRUCTIONS (56) Each of D, P, and p3 is as defined above. In a preferred embodiment, D, p2 and P3 are each hydrogen. In a preferred embodiment, the general formula (I_a) and (HPa) and the -L-nucleoside are represented by the non-limiting examples shown in Table 1 below: Table 1

R3* Rr RWR3* Rr RW

[I-a] [ΙΠ-a][I-a] [ΙΠ-a]

ID X1 r-fjy：' Cr；Pi： y1 Rr R2 •·<： Κν -Τ%3 r<. 'Λ:-' 备:**， ；T.-tS :.*·：.:· r.·.· -1U II r-J·:: z.-..ι.*^:：··： . ,.: ·.，J - « 二 AA nh2 0 Η Η ΟΗ Η H OH AB nh2 0 Η Η ΟΗ Η H I AC nh2 0 Η Η ΟΗ Η H Cl AD nh2 0 Η Η ΟΗ Η H Br AE nh2 0 Η Η ΟΗ Η H S-CN (請先閱讀背面之注意事項再填寫本頁) _ 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）ID X1 r-fjy: ' Cr; Pi: y1 Rr R2 •·<: Κν -Τ%3 r<. 'Λ:-' Ready: **, ;T.-tS :.*·:.:· r.··· -1U II rJ·:: z.-..ι.*^::··: . ,.: ·.,J - « Two AA nh2 0 Η Η ΟΗ Η H OH AB nh2 0 Η HI ΟΗ HI HI AC nh2 0 Η Η ΟΗ Η H Cl AD nh2 0 Η Η ΟΗ Η H Br AE nh2 0 Η Η ΟΗ Η H S-CN (Please read the notes on the back and fill out this page) _ Ministry of Economics The property bureau employee consumption cooperative printed this paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

1 i^i —·1 ϋ ϋ^· n I ·ϋ _1 f —Bi i·— ϋ ϋ· i_^i 1_1 ·ϋ 1 mmmt 1_ϋ i^i ι> I an m ϋ 1_1 an n ϋ n I 56 91949 1293306 A7 B7 五、發明說明（57 )1 i^i —·1 ϋ ϋ^· n I ·ϋ _1 f —Bi i·— ϋ ϋ· i_^i 1_1 ·ϋ 1 mmmt 1_ϋ i^i ι> I an m ϋ 1_1 an n ϋ n I 56 91949 1293306 A7 B7 V. Description of invention (57)

經濟部智慧財產局員工消費合作社印製 ID X1 Y1 :::¾ 丨 -pi：· ㈡ AF nh2 0 H H OH H H n3 AG nh2 0 H H H Cl H OH AH nh2 0 H H H Br H OH AI nh2 0 H H H OH Br H AJ nh2 0 H H H OH H H AK nh2 0 H H H OH O-Ms H AL nh2 0 H H H OH O-Ts H AM nh2 0 H H O-Ms H H OH AN nh2 0 H H Cl H H OH AO nh2 0 D D OH H H OH AP nh2 0 F H OH H H OH AQ nh2 0 F H H OH H OH AR nh2 0 F H H OH H H AS nh2 0 F H H OH Cl H AT nh2 0 F H H OH Br H AU nh2 0 F H H Cl H OH AV nh2 0 F H H OH OTs H AW nh2 0 F H H OH O-Ms H AX nh2 0 Cl H H OH 0-Ms H 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 訂---------線丨 57 91949 1293306 A7 ______________ B7 五、發明說明（58 )IDM1 Y1 :::3⁄4 丨-pi:· (2) AF nh2 0 HH OH HH n3 AG nh2 0 HHH Cl H OH AH nh2 0 HHH Br H OH AI nh2 0 HHH OH Br H AJ nh2 0 HHH OH HH AK nh2 0 HHH OH O-Ms H AL nh2 0 HHH OH O-Ts H AM nh2 0 HH O-Ms HH OH AN nh2 0 HH Cl HH OH AO nh2 0 DD OH HH OH AP nh2 0 FH OH HH OH AQ nh2 0 FHH OH H OH AR nh2 0 FHH OH HH AS nh2 0 FHH OH Cl H AT nh2 0 FHH OH Br H AU nh2 0 FHH Cl H OH AV nh2 0 FHH OH OTs H AW nh2 0 FHH OH O-Ms H AX nh2 0 Cl HH OH 0-Ms H This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) -------线丨57 91949 1293306 A7 ______________ B7 V. Description of invention (58)

經濟部智慧財產局員工消費合作社印製 Π) . ... x1：； ：：；·：： ; ::.γ1ν:ν::: R1 R2 R? R3， AY nh2 0 Br H H OH O-Ms H AZ nh2 0 Br H H OH O-Ts H BA nh2 0 Br H H OH Cl H BB nh2 0 Br H H OH H OH BC nh2 o Br H OH H H OH BD nh2 0 I H H OH O-Ms H BE nh2 0 I H H OH Br H BF nh2 0 I H H OH O-Ts H BG nh2 0 I H H Cl H OH BH nh2 0 I H Br H H OH BI nh2 0 OH H OH H H OH BJ nh2 0 nh2 H H OH H OH BK nh2 0 ch3 H H OH Cl H BL nh2 NH H H OH H H OH BM nh2 S H H H Se-苯基 H H BN NH-(2-Ph-Et) 0 H H OH H H OH BO NH-COCH3 0 H H OH H H OH BP nh-nh2 0 H H OH H H OH BQ nh-nh2 0 F H OH H H OH 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 訂---------線！ 58 91949 1293306 Δ7 B7 五、發明說明（59Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives. ... x1:; ::;·:: ;:.γ1ν:ν::: R1 R2 R? R3, AY nh2 0 Br HH OH O-Ms H AZ nh2 0 Br HH OH O-Ts H BA nh2 0 Br HH OH Cl H BB nh2 0 Br HH OH H OH BC nh2 o Br H OH HH OH BD nh2 0 IHH OH O-Ms H BE nh2 0 IHH OH Br H BF nh2 0 IHH OH O-Ts H BG nh2 0 IHH Cl H OH BH nh2 0 IH Br HH OH BI nh2 0 OH H OH HH OH BJ nh2 0 nh2 HH OH H OH BK nh2 0 ch3 HH OH Cl H BL nh2 NH HH OH HH OH BM nh2 SHHH Se-phenyl HH BN NH-(2-Ph-Et) 0 HH OH HH OH BO NH-COCH3 0 HH OH HH OH BP nh-nh2 0 HH OH HH OH BQ nh-nh2 0 FH OH HH OH This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page). Order --------- Line! 58 91949 1293306 Δ7 B7 V. Description of invention (59

R3· R2· R2· R3· [I-a] [ΙΠ-a] 經濟部智慧財產局員工消費合作社印製 π> X1 Y1 R1 -.-^ ·—，·. R2 R2’ ' Ά.:: • * * R3 BR nh-nh2 0 ch3 H H OH H OH BS NH-OH o H H H OH H OH ΒΤ NH-OH o F H H OH H OH BU NH-OH 0 Br H H OH H OH BV NH-OH 0 I H H OH H OH BW NH-OH o H H OH H H OH ΒΧ OH o OH H OH H H OH BY OH o nh2 H H OH H OH BZ OH o F H OH H H OH CA OH o F H H O-Ts H OH CB OH 0 F H H O-Ms H O-Ms CC OH o F H H OH H OH CD OH 0 F H H OH H OTs CE OH 0 F H H H H OH CF O-Et 0 H H H O-Bz H O-Bz CG s-ch3 0 H H H F H OH CH SH 0 H H H OH H OH Cl SH o F H H OH H OH CJ n3 0 H H H H H H 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) -1線- 59 91949 1293306 A7 B7 五、發明說明（ H〇Y〇^ X1R3· R2· R2· R3· [Ia] [ΙΠ-a] Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print π> X1 Y1 R1 -.-^ ·—,·. R2 R2' ' Ά.:: • * * R3 BR nh-nh2 0 ch3 HH OH H OH BS NH-OH o HHH OH H OH ΒΤ NH-OH o FHH OH H OH BU NH-OH 0 Br HH OH H OH BV NH-OH 0 IHH OH H OH BW NH-OH o HH OH HH OH ΒΧ OH o OH H OH HH OH BY OH o nh2 HH OH H OH BZ OH o FH OH HH OH CA OH o FHH O-Ts H OH CB OH 0 FHH O-Ms H O- Ms CC OH o FHH OH H OH CD OH 0 FHH OH H OTs CE OH 0 FHHHH OH CF O-Et 0 HHH O-Bz H O-Bz CG s-ch3 0 HHHFH OH CH SH 0 HHH OH H OH Cl SH o FHH OH H OH CJ n3 0 HHHHHH This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) -1 line - 59 91949 1293306 A7 B7 5 , invention description (H〇Y〇^ X1

N八Rr R2 R1N eight Rr R2 R1

Y X1Y X1

N^R1' 《〇、R1 ,ΟΗ R3· R2, [I-a] R2· R3· pn-a] ID Υ1 ：· ;： ·；..：： Υ1 ；'；;： R1 .二 · R1’ R2 R2 R3 R31 CK NH-(2-Ph-Et) 0 Η Η Η ΟΗ Η ΟΗ CL OH 0 OH Η Η ΟΗ Η ΟΗ CM OH 0 Η Η Η ΟΗ Η Η 較佳具體實施例中，通式（I-b)與（Ill-b)泠-D與冷-L 核苷由表2所示之不設限實例代表。表2H0、3 2 ㈣ 經濟部智慧財產局員工消費合作社印製N^R1' "〇, R1, ΟΗ R3· R2, [Ia] R2· R3· pn-a] ID Υ1 :· ;: ·;..:: Υ1 ;';;: R1 .2 · R1' R2 R2 R3 R31 CK NH-(2-Ph-Et) 0 Η Η Η ΟΗ Η ΟΗ CL OH 0 OH Η ΟΗ Η ΟΗ CM OH 0 Η Η Η ΟΗ Η 较佳 In a preferred embodiment, the formula (Ib) The (Ill-b) 泠-D and cold-L nucleosides are represented by the non-limiting examples shown in Table 2. Table 2H0, 3 2 (4) Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

R3，R2· [I-b] Π) X1 : X2 W1 R2 R2· rV 二一·:·:.·. • ν ^ ：；> …UV ;二_隻 DA ΟΗ νη2 Ν Η ΟΗ Η OH DB ΟΗ νη2 CH F Η Η OH DC ΝΗ-環己基 Η CH Η Η Η H DD νη2 Η CH Η ΟΗ Η F DE νη2 Η CH Η Η Η H (請先閱讀背面之注意事項再填寫本頁)R3, R2· [Ib] Π) X1 : X2 W1 R2 R2· rV 一···:.·. • ν ^ :;>...UV; 二_DA ΟΗ νη2 Ν Η ΟΗ Η OH DB ΟΗ νη2 CH F Η Η OH DC ΝΗ-cyclohexyl Η CH Η Η Η H DD νη2 Η CH Η ΟΗ Η F DE νη2 Η CH Η Η Η H (Please read the back note first and then fill out this page)

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 60 91949 1293306 Α7 _________ Β7 五、發明說明（61 )This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 60 91949 1293306 Α7 _________ Β7 V. Invention description (61)

ID X2 w1 R2 R2* R? 纪· DF nh2 nh2 N H OH H OH DG nh2 nh2 CH H OH H OH DH Cl H CH F H H H DI Cl I CH H O-Ac H O-Ac DJ Cl H CH H OH H OH DK nh2 H CH H OH H H DL Cl H CH H OH H H (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 較佳具體實施例中，通式（ΙΙ-a)與（IV-a)召-D與召-L 核苷由表3所示不設限實例代表。 表3ID X2 w1 R2 R2* R? · DF nh2 nh2 NH OH H OH DG nh2 nh2 CH H OH H OH DH Cl H CH FHHH DI Cl I CH H O-Ac H O-Ac DJ Cl H CH H OH H OH DK nh2 H CH H OH HH DL Cl H CH H OH HH (Please read the back note first and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed in a better specific example, the general formula (ΙΙ-a ) and (IV-a) call-D and call-L nucleosides are represented by the unrestricted examples shown in Table 3. table 3

EA NH-Bz-(m-N02) 0 F Η Η Η 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 61 91949 1293306 A7 B7 五、發明說明（62 )EA NH-Bz-(m-N02) 0 F Η Η Η This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 61 91949 1293306 A7 B7 V. Description of invention (62)

[Π-a] PV-a] ID X1 Y1 R1 R2 R3 EB NH-Bz-(o-N02) 0 F H H H EC nh2 0 F H F H 較佳具體實施例中，通式（ΙΙ-b)與（IV-b)泠-D 核苷由表4所示不設限實例代表。表4[Π-a] PV-a] ID X1 Y1 R1 R2 R3 EB NH-Bz-(o-N02) 0 FHHH EC nh2 0 FHFH In a preferred embodiment, the formulae (ΙΙ-b) and (IV-b) The 泠-D nucleoside is represented by the unrestricted examples shown in Table 4. Table 4

(請先閱讀背面之注意事項再填寫本頁) . ^---------*5^ I. 經濟部智慧財產局員工消費合作社印制衣 Π> X1 (X2 ：厂.:：.:, W! R2 FA Cl H CH F H FB OH H CH H H FC nh2 F CH H H FD nh2 F CH F H FE nh2 H CH H H FF OH nh2 CH H H 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 62 91949 1293306 A7 B7(Please read the notes on the back and fill out this page.) ^---------*5^ I. Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed Clothes, > X1 (X2: Factory.:: .:, W! R2 FA Cl H CH FH FB OH H CH HH FC nh2 F CH HH FD nh2 F CH FH FE nh2 H CH HH FF OH nh2 CH HH This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 62 91949 1293306 A7 B7

/OH/OH

R2 五、發明說明（63 ) HO、 R2 _ [IV-b] ID X1 X1 w1 R3 FG OH H CH Η Η 較佳具體實施例中，通式（V-a)與（VIII-a)冷-D與召-L 核苷由表5所示不設限實例代表。 表5 (請先閱讀背面之注意事項再填寫本頁) X1R2 V. DESCRIPTION OF THE INVENTION (63) HO, R2 _ [IV-b] ID X1 X1 w1 R3 FG OH H CH Η 较佳 In a preferred embodiment, the general formula (Va) and (VIII-a) cold-D and The s-L nucleoside is represented by the unrestricted examples shown in Table 5. Table 5 (Please read the notes on the back and fill out this page) X1

R1R1

ΌΗ [vm-a]ΌΗ [vm-a]

經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 tJ ID X1 ”： . R1 plV -Κ.Γ 1 • . ：：：' . * GA nh2 o F H H OH Η ΟΗ GB OH H ch3 H H H Η Η GC OH 0 H H H H Η Η GD nh2 0 H H H OH Η ΟΗ GE nh2 〇 H H H H Η Η GF OH 0 F H H OH Η ΟΗ GG nh2 0 I H H H Η Η 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 63 91949 1293306 A7B7Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives printed tJ ID X1 ": . R1 plV -Κ.Γ 1 • . :::' . * GA nh2 o FHH OH Η ΟΗ GB OH H ch3 HHH Η Η GC OH 0 HHHH Η Η GD nh2 0 HHH OH Η ΟΗ GE nh2 〇HHHH Η GF GF OH 0 FHH OH Η GG GG nh2 0 IHHH Η Η This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 63 91949 1293306 A7B7

BB

ID X1 1 GH nh2 0 GI nh2 0 核 經濟部智慧財產局員工消費合作社印製 五、發明說明（64ID X1 1 GH nh2 0 GI nh2 0 Nuclear Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (64

訂 線！ (請先閱讀背面之注音？事項再填寫本頁) 較佳具體實施例中，通式（VII_a)與（x_a)点七 表6 X1 Y1* ^OH 較佳具體實施例中，通式（VII_b)與泠 64 91949 F由表6所示不設限實例代表。Order! (Please read the phonetic transcription on the back first and then fill out this page.) In a preferred embodiment, the general formula (VII_a) and (x_a) point seven table 6 X1 Y1* ^OH are preferred embodiments, the general formula (VII_b ) and 泠64 91949 F are represented by the unrestricted examples shown in Table 6.

[VH-a] m Κ · ；； · Λ-：-' · f X1 Y1 R1 Rr R2 R~ R3， HA nh2 0 H H H OH H OH HB nh2 0 F H H OH H OH HC νη·〇η 0 H H H OH H OH I度 尺 張 紙 I本 ^^7所示不設限實例代表〇 標準（CNS)A4 規格（210 X 297 公爱 1293306[VH-a] m Κ · ;; · Λ-:-' · f X1 Y1 R1 Rr R2 R~ R3, HA nh2 0 HHH OH H OH HB nh2 0 FHH OH H OH HC νη·〇η 0 HHH OH H OH I degree sheet paper I this ^^7 is not limited to the example representative 〇 standard (CNS) A4 specifications (210 X 297 public love 1293306

(請先閱讀背面之注意事項再填寫本頁) 較隹具體實施例中，通式（ΧΙ-a)與（ΧΙΙ-a)沒-D與万-L 核苷由表8所示不設限實例代表。 表8 X1 ·- ,ΟΗ HO、 ;線· 經濟部智慧財產局員工消費合作社印製 [XI-a] [ΧΠ-a] ED ·_ …… X1 Υ1 Y . V:.: . - · ζ1 .. - -.· 'r-·：·.:·；;. ..； ..rw2 . · …二' :' - Α • u^·· ·： ：：-：='<-·· =:-:3-% 斯 ir -; JA νη2 0 ο 0 H Η JB νη2 0 0 s F Η JC νη2 0 ο 0 F Η 65 較佳具體實施例中，通式（ΧΙΙ-b)召-L核苷由表9所示 不設限實例代表。 長尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 91949 1293306 A7 B7 五、發明說明（66 ) 表9(Please read the precautions on the back and then fill out this page.) In the specific examples, the general formula (ΧΙ-a) and (ΧΙΙ-a) are not -D and 10,000-L nucleosides are not limited as shown in Table 8. Example representative. Table 8 X1 ·- , ΟΗ HO, ; Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing [XI-a] [ΧΠ-a] ED ·_ ...... X1 Υ1 Y . V:.: . - · ζ1 . - -.· 'r-·:·.:·;;. ..; ..rw2 . · ...二' :' - Α • u^·· ·: ::-:='<-·· =:-:3-% s ir -; JA νη2 0 ο 0 H Η JB νη2 0 0 s F Η JC νη2 0 ο 0 F Η 65 In a preferred embodiment, the general formula (ΧΙΙ-b) calls-L Nucleosides are represented by the non-limiting examples shown in Table 9. Long-term application of China National Standard (CNS) A4 specification (210 X 297 public) 91949 1293306 A7 B7 V. Description of invention (66) Table 9

^OH DO、 [XI-b] [XII-b] Π) -Λ , V2 ' ' W1 V :Ζ、 , ·、 ' rmX JLJ 、 KA C1 Η CH Ο S KB C1 νη2 CH 0 S KC nh2 F CH ο S KD OH Η CH ο Ο (請先閱讀背面之注意事項再填寫本頁) 較佳具體實施例中，通式（ΧΙΙΙ-a)召-D核苷由表10所 示不設限實例代表。 表10 Y2^OH DO, [XI-b] [XII-b] Π) -Λ , V2 ' ' W1 V :Ζ, , ·, ' rmX JLJ , KA C1 Η CH Ο S KB C1 νη2 CH 0 S KC nh2 F CH ο S KD OH Η CH ο Ο (Please read the note on the back and then fill out this page) In a preferred embodiment, the general formula (ΧΙΙΙ-a)-D-nucleoside is represented by the unrestricted example shown in Table 10. . Table 10 Y2

R1 N R1' 經濟部智慧財產局員工消費合作社印製 66 r!〇、r2 R3· R2, [ΧΠΙ-a]R1 N R1' Printed by the Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative 66 r!〇, r2 R3· R2, [ΧΠΙ-a]

ID Υ2 Υ3 R1 - ^ — < · 1·-：- ' R1 R2 ,- J、 、^ - — τ R2- .R^'c，、' ： Φ： LA 0 ο F Η Η OH Η OH 較佳具體實施例中，通式（XIII-C)泠-D核苷由表1 1所 示不設限實例代表。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 1293306 A7 B7 五、發明說明（67 表11 Υ2ID Υ2 Υ3 R1 - ^ - < · 1·-:- ' R1 R2 , - J, , ^ - — τ R2- .R^'c,, ' : Φ: LA 0 ο F Η Η OH Η OH In a preferred embodiment, the formula (XIII-C) 泠-D nucleoside is represented by the non-limiting examples shown in Table 11. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 1293306 A7 B7 V. Description of invention (67 Table 11 Υ 2

0 〇 F Η Η OH0 〇 F Η Η OH

MC ^0 ϊϋ F1Γ 1Γ ΗMC ^0 ϊϋ F1Γ 1Γ Η

ΗIT Ο-Ms O^Ms Y2ΗIT Ο-Ms O^Ms Y2

NH 0 H H H O-Ac "oi" (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 ME NH mT MG ΝΪΓNH 0 H H H O-Ac "oi" (Please read the note on the back and fill out this page) Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs ME NH mT MG ΝΪΓ

IT F TIT F T

ITIT HITIT H

ITITIT ^5iT O-Ac 較佳具體實施例中，通式（XHI-d)冷-D核脊由表12所 示不設限實例代表。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 67 91949 1293306 A7 B7 五、發明說明（68 m "γ5 ΝΑ 表12 Υ2ITITIT ^5iT O-Ac In a preferred embodiment, the cold-D ridge of the general formula (XHI-d) is represented by the non-limiting examples shown in Table 12. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 67 91949 1293306 A7 B7 V. Description of invention (68 m "γ5 ΝΑ Table 12 Υ2

R1R1

Rr R2 Ry R3 R3? •, - 、 ' o o-ch3 hRr R2 Ry R3 R3? •, - , ' o o-ch3 h

HH

H O-Ac H O-Ac (請先閱讀背面之注音？事項再填寫本頁) 較佳具體實施例中，通式（XIV)万_D核苷由表13所示 不設限實例代表。 訂---------線！ 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 68 91949 1293306 五、發明說明（69 ) 表13 γΐ入人L2 R3’ R2’ [XIV] ID X1 Y1 R1 ... 舖議| R2 r;. 哥齡㈤;毀:#·:- ·； .—1 .* · ·· <A«：X. ：：. -C- · T 2, OA nh2 0 NH-OH OH OH H H OH H OH OB OH 0 0 F H OH H OH Cl o-ch3 OC OH 0 0 H H OH H OH Br o-ch3 OD OH 0 0 F H OH H OH Br O-COCHa OE OH 0 0 F H OH H OH Br o-ch3 OF OH 0 0 F H OH H OH Br O-Et OG OH 0 0 Cl H OH H OH Br o-ch3 較佳具體實施例中，通式（xv-a)核苷由表14所示不設 限實例代表。 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 ^---------^ ---------------------- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 69 91949 1293306 A7 B7 五、發明說明（ 表14H O-Ac H O-Ac (Please read the phonetic transcription on the back first. Then fill out this page) In a preferred embodiment, the general formula (XIV) 10,000-D nucleoside is represented by the non-limiting examples shown in Table 13. Order ---------line! Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed Paper Scale Applicable to China National Standard (CNS) A4 Specification (210 x 297 mm) 68 91949 1293306 V. Invention Description (69) Table 13 γ Intrusion L2 R3' R2' [ XIV] ID X1 Y1 R1 ... Discussion | R2 r;. Brother (5); Destroy: #·:- ·; ..1 .* · ·· <A«:X. ::. -C- T 2, OA nh2 0 NH-OH OH OH HH OH H OH OB OH 0 0 FH OH H OH Cl o-ch3 OC OH 0 0 HH OH H OH Br o-ch3 OD OH 0 0 FH OH H OH Br O- COCHa OE OH 0 0 FH OH H OH Br o-ch3 OF OH 0 0 FH OH H OH Br O-Et OG OH 0 0 Cl H OH H OH Br o-ch3 In a preferred embodiment, the formula (xv- a) Nucleosides are represented by the unrestricted examples shown in Table 14. (Please read the notes on the back and fill out this page.) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives ^---------^ ---------------- ------ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 69 91949 1293306 A7 B7 V. Description of invention (Table 14

R1R1

[XV-a] ID Y1 ζ3 R1 Rr R2 R2 R3 R3’ PA 0 0 Η Η Η OH H OH 較佳具體實施例中，通式（XV-b)核苷由表15所示不設 限實例代表。表15[XV-a] ID Y1 ζ3 R1 Rr R2 R2 R3 R3' PA 0 0 Η Η OH OH H OH In a preferred embodiment, the nucleoside of the formula (XV-b) is represented by the non-limiting examples shown in Table 15. . Table 15

(請先閱讀背面之注咅？事項再填寫本頁)(Please read the note on the back? Please fill out this page again)

訂---------線U 經濟部智慧財產局員工消費合作社印製Order ---------Line U Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

[XV-b] ID X1 w1 z3 R2 R2· R3 QA nh2 CH 0 H OH H OH 較佳具體實施例中，通式（XVI-a)核苷由表16所示不 設限實例代表。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 70[XV-b] ID X1 w1 z3 R2 R2· R3 QA nh2 CH 0 H OH H OH In a preferred embodiment, the nucleoside of the formula (XVI-a) is represented by the non-limiting examples shown in Table 16. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 70

9194T 1293306 A7 B7 五、發明說明（71 表169194T 1293306 A7 B7 V. INSTRUCTIONS (71 Table 16

Π) W3 Z4 W5 RA ~CH~ NCH3 C-OH RB CH NH C-NH2 RC CH NH C-NHAc RD — CH NH C-OH RE CH ~ NCH3 C-NH2 RF CH NH C-NHBz RG ~CH~ C=0 C-NH2 RH CH NH C-OH RI — CH NH C-NH2Π) W3 Z4 W5 RA ~CH~ NCH3 C-OH RB CH NH C-NH2 RC CH NH C-NHAc RD — CH NH C-OH RE CH ~ NCH3 C-NH2 RF CH NH C-NHBz RG ~CH~ C =0 C-NH2 RH CH NH C-OH RI — CH NH C-NH2

[XVI-a] N CO N C=0 "n c=o N C=0 ~N OO C-SH "n- c=o "n CO[XVI-a] N CO N C=0 "n c=o N C=0 ~N OO C-SH "n- c=o "n CO

R2 H1ΓITIT HIFIT HIT R2,oiT ^OH OH ^ΟΆ ^OHΈΓ "b7R2 H1ΓITIT HIFIT HIT R2,oiT ^OH OH ^ΟΆ ^OHΈΓ "b7

R3IT HIT H H ϋ"IT HITR3IT HIT H H ϋ"IT HIT

Ry O^Ts ^OH ^OH ^OH ^oiF ^OH "oh" 較佳具體實施例中，通式（XVI-C)核苷由表17所示不 設限實例代表。 經濟部智慧財產局員工消費合作社印制衣 (請先閱讀背面之注意事項再填寫本頁)Ry O^Ts ^OH ^OH ^OH ^oiF ^OH "oh" In a preferred embodiment, the nucleoside of the formula (XVI-C) is represented by the non-limiting examples shown in Table 17. Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperatives, printed clothing (please read the notes on the back and fill out this page)

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 71 91949 293306 A7 B7 經濟部智慧財產局員工消費合作社印製 72 五、發明說明（72 ) 表17 〇This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 71 91949 293306 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 72 V. Invention description (72) Table 17

R3’ R2* [XVI-c] ID W3 Z4 z5 w4 , R2 Rv R3 R3* SA CH n-ch3 oo N H OH H O-Ac 較佳具體實施例中，通式（XVI-d)核苷由表1 8所示不 設限實例代表。 表18R3' R2* [XVI-c] ID W3 Z4 z5 w4 , R2 Rv R3 R3* SA CH n-ch3 oo NH OH H O-Ac In a preferred embodiment, the nucleoside of the formula (XVI-d) is represented by There is no limit instance representation shown in Figure 18. Table 18

ID W3 Z4 rwS ' M.a ί :.vr：··：' · .：; .·.- ^ · :;·· ▼T u3' ：；.：： -Λ :-^ TA CH N C=NH N H OH 較佳具體實施例中，通式（XVI-f)核苷由表19所示不 設限實例代表。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注音？事項再填寫本頁)ID W3 Z4 rwS ' Ma ί :.vr:··:' · .:; ...- ^ · :;·· ▼T u3' :;.:: -Λ :-^ TA CH NC=NH NH OH In a preferred embodiment, the nucleoside of the formula (XVI-f) is represented by the non-limiting examples shown in Table 19. This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (please read the phonetic on the back? Please fill out this page)

293306293306

五、發明說明（73 ) 表19 X1V. Description of invention (73) Table 19 X1

(請先閱讀背面之注咅？事項再填寫本頁) 所示不 較佳具體實施例中，通式（XVII-d)核苷由表20 設限實例代表。 表20 訂---------線」 X5'(Please read the note on the back first, and then fill out this page.) In the less preferred embodiment shown, the nucleoside of the formula (XVII-d) is represented by the examples of Table 20. Table 20 Order --------- Line X5'

經濟部智慧財產局員工消費合作社印製 較佳具體實施例中，當核苷於適當之以細胞為 析法中測試時，其EU達到50%病毒抑制 之分 卜巾4之有^ 濃度）小於1 5 # Μ，更特定言之，小於1〇或5 ν 义 本紙張尺度適用中國國家標準（CNS)A4規格（2〗0 χ 297公釐） ---二較佳具 91949 73 [293306In the preferred embodiment of the printing of the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs, when the nucleoside is tested in a suitable cell assay, the EU has a 50% inhibition of the virus. 1 5 # Μ, more specifically, less than 1〇 or 5 ν The paper size applies to the Chinese National Standard (CNS) A4 specification (2〗 0 χ 297 mm) --- Two preferred with 91949 73 [293306

五、發明說明（ 體實施例中，核苷為高對映異構性。 異構性斑容能1 本發明化合物具有對掌中心，可出現並單離成光學活 性與消旋型式。有些化合物可呈多態性。本發明涵括具有 本文忒明之有用性質之本發明化合物之消旋型、光學活性 聖、多癌性或立體異構型或其混合物。光學活性型可利用 例如：經再結晶技術解析消旋型、由光學活性起始物合成、 進行對掌性合成法，或採用對掌性固相進行層析分離法或 酵素解析法製備。 如上已述，核苷含有至少二個關鍵性之對掌性碳原子 (*)。通常，核苷之對掌性碳上取代基[指明為嘌呤或嘧啶 鹼基（當使用糖環中間物編號時，稱為C1取代基）與Ch2〇h (稱為C4取代基）]可相對於糖環系呈順式（同侧）或反式（反 侧）。順式與反式二種消旋物構成一對光學異構物。因此， 每種化σ物各有4種立體異構物。這四種立體異構物則由 下列組態代表（當糖部份基團之方向為平行面時，貝卜〇_部 份基團在背面）··（1)順式，二個基團均“向上，，，指泠_D; 鏡像，亦即順式，二個基團均“向下，，，係々_L之鏡像；（3) 反式，C4取代基“向上，，而以取代基“向下，，（稱為fD); 及⑷反式，C4取代基“向下，，而C1取代基“向上，，（稱為[ L)。這二種順式對映異構物共同稱為㈣映異構物之消旋 混合物’而二種反式對映異構物則稱為^對映異構物之消 旋混合物。 表紙張尺度適用中國國家標準（CNS)A4規格⑵G x 297 _ 91949 (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 74 1293306 B7 五、發明說明（ 75V. DESCRIPTION OF THE INVENTION (In the examples, the nucleoside is highly enantiomeric. Isomerization spotting energy 1 The compound of the present invention has a palm center, which can occur and be isolated into an optically active and racemic form. Some compounds Polymorphisms may be present. The invention encompasses racemic, optically active, multi-cancerous or stereoisomeric forms of the compounds of the invention having useful properties as described herein, or mixtures thereof. For optically active forms, for example, The crystallization technique is analytically racemic, synthesized by optically active starting materials, subjected to palmar synthesis, or by chromatographic separation or enzymatic resolution of the palmitic solid phase. As mentioned above, the nucleoside contains at least two The key to the palm carbon atom (*). Usually, the nucleoside is a substituent on the palmitic carbon [specified as a purine or pyrimidine base (called a C1 substituent when numbered with a sugar ring intermediate) and Ch2 〇h (referred to as C4 substituent)] may be cis (ipsilateral) or trans (reverse) with respect to the sugar ring system. The cis and trans racemates form a pair of optical isomers. There are 4 stereoisomers for each sigma. These four The isomers are represented by the following configuration (when the direction of the sugar moiety is parallel, the Bebium_partial group is on the back) · (1) cis, both groups are "upward" ,,,指泠_D; Mirror, ie cis, both groups are "downward,", mirror image of 々L; (3) trans, C4 substituent "upward, and with substituents "Down, (referred to as fD); and (4) trans, the C4 substituent "downward, and the C1 substituent "upward," (called [L). These two cis enantiomers are common It is called the racemic mixture of the (tetra)anion and the two trans-enantiomers are called the racemic mixture of the enantiomer. The table paper scale is applicable to the Chinese National Standard (CNS) A4 specification (2) G x 297 _ 91949 (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 74 1293306 B7 V. Invention Description ( 75

申請專利權之化合物之四種可能立體異構物如下示The four possible stereoisomers of the patented compound are as follows

β -L (請先閱讀背面之注意事項再填寫本頁)β -L (please read the notes on the back and fill out this page)

Β 順式（β)顺 cis (β)

a-L 訂----------線· 經濟部智慧財產局員工消費合作社印製 75 反式⑻ III.定義 本文採用之烧基一祠，除非另有說明，否則指飽： 直鏈、分支或環狀之一級、二級或三級烴，包含（但不限 於）··彼等Ci至ci6烷基，明確言之包含甲基、乙基、声 基、異丙基、環丙基、丁基、異丁基、第三丁基、戊基 環戊基、異戊基、新戊基、己基、異己基、環己基、環 基甲基、3 -甲基戊基、2,2-二甲基丁基、及2,3-二甲基丁基 本紙張尺度適用中國國家標準（CNS)A4規格（21〇 X 297公釐） 91949 76 1293306 五、發明說明（76 ) =基：：需要經一個或多個選自下列之部份基團取代：燒 基、齒基、齒燒基、經基、叛基、醯基、醯氧基、胺基、 =胺乙瘦基衍生物、烷胺基、二烷胺基、芳胺基、烷氧 土方乳基、硝基、氰基、疊氮基、硫醇基、亞胺、谱酸、 硫酸根、續醯基、硫燒基、亞續酿基、胺續釀基、醋、繞 酸、醯胺、膦醯基、氧膦基、磷醯基、麟、硫醋、硫喊、 酸函化物、酸肝、膀、肼、胺基甲酸醋、膦酸、碟酸根、 2酸根、或任何其他不會抑制此化合物醫藥活性之可變官 能基，其係未保護，或必要時受保護，如熟諸此技藝者習 知者，例如：說明於Greene，et al·， °1^^~^^^’了〇1111贾以丫抓(！8〇118，第2版，1991， 己以引用之方式併入本文中。 本文採用之“低碳數烷基，，一詞除非另有說明，否則指 仏至C4飽和直鏈、分支，或若適當時為環狀（例如：環= 基）之燒基，包含取代型與未取代型。 伸烷基或“伸烯基”名詞指直鏈或分支組態之飽和烴 二基，包含（但不限於）彼等具有i至10個碳原子者。此名 詞範圍内包含：亞甲基、1，2-乙二基、1，1-乙二基、H丙 一基、1，2-丙二基、13_丁二基、！，仁丁二基，等等。本文 揭不之伸烷基或其他二價部份基團可視需要經一個或多個 t自下列之部份基團取代：烧基、i基、4燒基、經基、 羧基、醯基、醯氧基、胺基、醯胺基、羧基衍生物、烷胺 基、疊氮基、二烷胺基、芳胺基、烷氧基、芳氧基、硝基、 » 醇基、亞胺、磺醯基、硫烷基、亞績醯美、 本紙張尺度1¾ 準（CNS)A4規格⑵〇χ297公髮） ------ 91949 f請先閱讀背面之注音？事項再填寫本頁) Φ -------訂--------- 1293306 A7aL Order----------Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 75 Trans (8) III. Definitions The base used in this article, unless otherwise stated, means full: straight chain , branched or cyclic one, two or three hydrocarbons, including (but not limited to) · Ci to ci6 alkyl, specifically including methyl, ethyl, acyl, isopropyl, cyclopropane Base, butyl, isobutyl, tert-butyl, pentylcyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclomethyl, 3-methylpentyl, 2, 2-dimethylbutyl, and 2,3-dimethylbutyl paper scales applicable to China National Standard (CNS) A4 specification (21〇X 297 mm) 91949 76 1293306 V. Description of invention (76) = base: : need to be substituted by one or more groups selected from the group consisting of: an alkyl group, a dentate group, a dentate group, a thiol group, a thiol group, a decyl group, a decyloxy group, an amine group, an amine group , alkylamino, dialkylamine, arylamine, alkoxylate, nitro, cyano, azido, thiol, imine, spectroscopy, sulphate, ruthenium, thiol Sustained Amines, vinegar, acid, guanamine, phosphinium, phosphinyl, phosphonium, sulfonate, sulphuric acid, sulphur, acid, liver, bladder, sputum, urethane, Phosphonic acid, silicate, 2, or any other variable functional group that does not inhibit the pharmaceutically active nature of the compound, which is unprotected or, if desired, protected, as is known to those skilled in the art, for example: Greene, et al·, °1^^~^^^' has been captured by 〇1111 Jia (丫8〇118, 2nd edition, 1991, which has been incorporated herein by reference. The term "alkyl", unless otherwise indicated, refers to a C4 saturated straight chain, a branch, or, if appropriate, a cyclic (eg ring = group) alkyl group, including both substituted and unsubstituted forms. An alkyl or "alkenyl" term refers to a saturated hydrocarbon diradical of a straight or branched configuration, including but not limited to those having from i to 10 carbon atoms. The term includes: methylene, 1 , 2-ethanediyl, 1,1-ethanediyl, H-propyl, 1,2-propanediyl, 13-butanediyl, !, butyldinyl, and the like. The group or other divalent moiety may be substituted by one or more t groups from the following groups: an alkyl group, an i group, a 4 alkyl group, a trans group, a carboxyl group, a decyl group, a decyloxy group, an amine group. , amidino, carboxy derivative, alkylamino, azido, dialkylamino, arylamino, alkoxy, aryloxy, nitro, ethyl alcohol, imine, sulfonyl, sulfane Base, sub-performance, paper size 13⁄4 (CNS) A4 specifications (2) 〇χ 297 liters) ------ 91949 f Please read the phonetic notes on the back? Please fill out this page) Φ ----- --Book --------- 1293306 A7

胺磺醯基、酯、羧酸、醯胺、膦醯基、氧膦基、磷醯基、 膦、硫酯、硫醚、酸幽化物、酸酐、肟、肼、胺基甲酸酯、 膦酸、膦酸根、或任何其他不會抑制此化合物醫藥活性之 可變官能基，其係未保護，或必要時受保護，如熟諳此技 藝者習知者，例如：說明於Greene，et al，Prgt^et!^ Grmip, ilLilrganic -Syutkesis，John Wiley and Sons ’ 第 2 版，1991， 己以引用之方式併入本文中。 本文採用之“芳基，，，除非另有說明，否則指苯基、聯 苯基或萘基，且以苯基較佳。該名詞包含經取代及未取代 之部份基團。芳基可經一個或多個選自下列之部份基團取 代·溴、氣、氟、埃、羥基、疊氮基、胺基、燒胺基、芳 胺基、烷氧基、芳氧基、硝基、氰基、磺酸、硫酸根、膦 酸、磷酸根、或膦酸根，其係未保護或必要時受保護，其 係熟时此技藝之人士習知者，例如：如Greene，et al.， Pj〇tectlY£. Groups in Organic Svnth^^is John Wiley and Sons，第2版，1991之說明。 本文採用之“芳烷基’’ 一詞除非另有說明，否則指如上 述定義之芳基利用如上述定義之烧基連接分子。“烧芳基，， 或‘‘烷基芳基’’在本文中，除非另有說明，否則指如上述定 義之烷基利用如上述定義之芳基連接分子。此等基團中， 烷基可視需要如上述經取代，且芳基可視需要經一個或多 個選自下列之基團取代：烷基、幽基、齒烷基、羥基、羧 基、醯基、醯氧基、胺基、醯胺基、疊氮基、羧基衍生物、 烷胺基、二烷胺基、芳胺基、烷氧基、芳氧基、硝基、氰 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公复） 91949 (請先閱讀背面之注意事項再填寫本頁) I------訂---------線. 經濟部智慧財產局員工消費合作社印製 1293306 A7 B7 五、發明說明（78 ) 基、磺酸、硫醇基、亞胺、磺醯基、硫烷基、亞磺醯基、 胺磺醯基、酯、羧酸、醯胺、膦醯基、氧膦基、磷醯基、 膦、硫酯、硫醚、酸齒化物、酸酐、肟、肼、胺基甲酸酯、 鱗酸、膦酸根、或任何其他不會抑制此化合物醫藥活性之 可變官能基’其係未保護，或必要時受保護，如熟諳此技 ;者習知者’，如·說明於 Greene，ai，Protective Groups l^Qrganic Syml必h，John Wiley and Sons，第 2 版，1991， 己以引用之方式併入本文中。明確言之，芳基名詞之範圍 内包含苯基；萘基；苯甲基；苯乙基；3,4,5-三羥苯基；3,4，％ 三甲氧苯基；3,4,5-三乙氧苯基；4_氣苯基；4_甲基苯基； 3,5_二-第三丁基_4_羥基苯基；4_氟苯基；仁氯萘基；2_ 甲基-1-萘基甲基；2-萘基甲基；4-氣苯基甲基；4-第三丁 基苯基；4_第三丁基苯基甲基，等等。 烧胺基或方胺基名詞指分別含有一個或二個燒基 或芳基取代基之胺基。 鹵素一詞在本文中包括氟、氯、溴及埃。 本說明書全文中採用之“高對映異構性，，一詞指核苷中 其單一對映異構物之含量至少約95%，至少96%較佳，至 少97%更佳，至少98%甚至更佳，至少約99%或以上又甚 至更佳。當本說明書指出特定組態（D或L)之核苷時，則推 斷該核苷為高對映異構性核苷，除非另有說明。 本文採用之“宿主，，一詞指病毒可在其中複製之單細胞 或多細胞生物體，包含細胞株及動物，以人類較佳。或者， 很主可▼著一部份病毒基因組’可利用本發明化合物改 ‘紙張尺度適用中國國家標準（CNS)A4規格（21〇 x 297公釐） 91949 (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 78 1293306Aminesulfonyl, ester, carboxylic acid, decylamine, phosphonium, phosphinyl, phosphonium, phosphine, thioester, thioether, acid sulphuric acid, anhydride, hydrazine, hydrazine, urethane, phosphine An acid, phosphonate, or any other variable functional group that does not inhibit the pharmaceutically active activity of the compound, which is unprotected or, if desired, protected, as is known to those skilled in the art, for example, as illustrated by Greene, et al, Prgt^et!^ Grmip, ilLilrganic-Syutkesis, John Wiley and Sons' 2nd Edition, 1991, which is incorporated herein by reference. As used herein, "aryl," unless otherwise indicated, refers to phenyl, biphenyl or naphthyl, and preferably phenyl. The noun includes substituted and unsubstituted moieties. Substituting one or more groups selected from the group consisting of bromine, gas, fluorine, argon, hydroxyl, azide, amine, acryl, arylamine, alkoxy, aryloxy, nitro , cyano, sulfonic acid, sulphate, phosphonic acid, phosphate, or phosphonate, which are unprotected or, if necessary, protected, as is known to those skilled in the art, such as, for example, Greene, et al. , Pj〇tectlY£. Groups in Organic Svnth^^is John Wiley and Sons, 2nd edition, 1991. The term "aralkyl" as used herein, unless otherwise indicated, refers to an aryl group as defined above. A burnt-linking molecule as defined above is utilized. "Aromatic aryl," or "alkylaryl" as used herein, unless otherwise indicated, means that an alkyl group as defined above utilizes an aryl linking molecule as defined above. In such groups, an alkyl group It may be substituted as described above, and the aryl group may be optionally substituted with one or more groups selected from the group consisting of an alkyl group, a decyl group, a dentate group, a hydroxyl group, a carboxyl group, a decyl group, a decyloxy group, an amine group, an anthracene group. Amine, azide, carboxyl derivative, alkylamino, dialkylamine, arylamine, alkoxy, aryloxy, nitro, cyanide paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 replies) 91949 (Please read the notes on the back and fill out this page) I------Book---------Line. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1293306 A7 B7 V. Description of the invention (78), sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfonyl, ester, carboxylic acid, decylamine, phosphinium, Phosphine, phosphonium, phosphine, thioester, thioether, acid dentate, anhydride, hydrazine, hydrazine, urethane, squara, phosphonate, or any He does not inhibit the pharmaceutically active variable functional group of this compound's unprotected, or protected if necessary, such as familiarizing with this technique; known to those, as explained in Greene, ai, Protective Groups l^Qrganic Syml H, John Wiley and Sons, 2nd edition, 1991, incorporated herein by reference. Specifically, the aryl noun includes phenyl; naphthyl; benzyl; phenethyl; , 4,5-trihydroxyphenyl; 3,4,% trimethoxyphenyl; 3,4,5-triethoxyphenyl; 4-phenylphenyl; 4-methylphenyl; 3,5_2 - tert-butyl 4-hydroxyphenyl; 4-fluorophenyl; renonaphthyl; 2-methyl-1-naphthylmethyl; 2-naphthylmethyl; 4-phenylphenylmethyl; - a tert-butylphenyl group; a 4-tert-butylphenylmethyl group, etc. An acridine group or a arylamino group means an amine group each having one or two alkyl or aryl substituents. The term includes fluorine, chlorine, bromine, and argon as used herein. The phrase "high enantiomeric," as used throughout the specification, refers to a nucleoside having at least about 95% of its single enantiomer, at least 96. % is better, at least 97% is better, at least 98% even More preferably, at least about 99% or more is even better. When the specification indicates a nucleoside of a particular configuration (D or L), the nucleoside is inferred to be a high enantiomeric nucleoside unless otherwise stated. As used herein, the term "host," refers to a single or multicellular organism in which a virus can replicate, including cell lines and animals, preferably humans. Or, a major part of the viral genome can be utilized. The compound of the present invention is applied to the Chinese National Standard (CNS) A4 specification (21〇x 297 mm) for the paper scale. 91949 (Please read the note on the back and fill in the page) -------Book·--- -----Line. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 78 1293306

-複製或功能。宿主一詞明確言之，指已感染之細胞，經 所有或部份病毒基因組轉感染之細胞，及動物，尤指翁長 類(▲包含黑猩猩）及人類。在非正常細胞增生方面，“宿主; 一為指可在其中模擬非正常細胞增生之單細胞或多細胞生 物體。宿主-詞明確言之指因天然或非天然因素(例如：分 別因基因突變或基因工程)而不正常增生之細胞，及動物， 尤指靈長類（包含黑猩獲）及人類。在本發明大多數動物應 用中’宿主為人類患者。然而’本發明當然可用於獸醫學 某些適應症之用途上（如：牛之牛病毒性下痢病毒，豬之豬 霍亂病毒及綿羊之邊緣病病（border disease)病毒）。 本說明書全文中使用“醫藥上可接受之鹽或前藥，，一詞 來說明該化合物當投與患者後，可提供活性化合物時之任 何醫藥上可接受之形式（如：酯、磷酸酯、酯或相關基團之 鹽）。醫藥上可接受之鹽包含彼等衍生自醫藥上可接受之無 機或有機鹼及酸類者。合適鹽類包含彼等衍生自鹼金屬者 如·鉀與納，驗土金屬如：舞與鎂，及許多種其他醫藥技 藝上已知之酸類。醫藥上可接受之前藥指化合物可於宿主 内代謝，例如水解或氧化形成本發明化合物。前藥之典型 實例包含在活性化合物之官能基部份上具有生物上不安定 之保護基之化合物。前藥包含可經過氧化、還原、胺化、 去胺化、羥化、去羥化、水解、去水解、烷化、去烷化、 醯化、去醯化、磷酸化、去磷酸化，產生活性化合物之化 合物。 IV.醫藥上可接受之鹽與前藥 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 {請先閱讀背面之注音？事項再填寫本頁} — — — — — — — ^ ---11111· . 經濟部智慧財產局員工消費合作社印制衣 79 1293306- Copy or feature. The term host specifically refers to cells that have been infected, cells that have been transfected with all or part of the viral genome, and animals, especially the Wengchang (▲ contains chimpanzees) and humans. In terms of abnormal cell proliferation, "host; one refers to a single-cell or multi-cellular organism in which abnormal cell proliferation can be mimicked. The host-word clearly refers to natural or non-natural factors (eg, genetic mutations, respectively) Or genetically engineered cells that are not normally proliferating, and animals, especially primates (including chimpanzees) and humans. In most animal applications of the invention 'the host is a human patient. However, the invention is of course applicable to the beast Use of certain indications in medicine (eg, bovine bovine viral sputum virus, swine pig cholera virus and sheep border disease virus). "The pharmaceutically acceptable salt or The prodrug, the term is used to indicate that the compound, when administered to a patient, provides any pharmaceutically acceptable form (e.g., an ester, phosphate, ester or salt of a related group) of the active compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, soils such as: dance and magnesium, and many other acids known in the pharmaceutical arts. A pharmaceutically acceptable prodrug means that the compound can be metabolized, e.g., hydrolyzed or oxidized, to form a compound of the invention. Typical examples of prodrugs include compounds having a biologically labile protecting group on the functional moiety of the active compound. Prodrugs can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, deuterated, deuterated, phosphorylated, dephosphorylated, produced A compound of the active compound. IV. Pharmaceutically Acceptable Salts and Prodrugs This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 {Please read the phonetic transcription on the back first? Matters to fill out this page} — — — — — — — ^ ---11111· . Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed clothing 79 1293306

右化合物具有充份鹼性或酸性而足以形成安定之無毒 性酸或鹼鹽時，則該化合物適合呈醫藥上可接受之鹽投 藥。醫藥上可接受之鹽包含彼等衍生自醫藥上可接受之無 機或有機鹼與酸類者。合適鹽類包含彼等衍生自鹼金屬鹽 如·鉀與鈉，鹼土金屬鹽如：鈣及鎂，及醫藥技藝上習知 之許多種其他酸類者。特定言之，醫藥上可接受之鹽之實 例為與可形成生理上可接受之陰離子之酸形成之有機酸加 成鹽，例如：甲苯磺酸鹽、甲磺酸鹽、乙酸鹽、檸檬酸鹽、 丙一酸鹽、酒石酸鹽、琥珀酸鹽、苯甲酸鹽、抗壞血酸鹽、 明基戊二酸鹽、及α_甘油基磷酸鹽。亦可形成合適之 無機鹽’包括：硫酸鹽、硝酸鹽、碳酸氫鹽及碳酸鹽。 五、發明說明（⑹） (請先閱讀背面之注音？事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 醫藥上可接受之鹽類可使用相關技藝上習知之標準方 法得到，例如：由充份驗性化合物（如：胺）與可提供生理 上可接受之陰離子之合適酸反應。亦可製造緩酸之驗金屬 (例如：鈉、鉀或鋰）或鹼土金屬（例如：鈣）之鹽類。 本文說明之任何核苷均可呈核苷酸前藥投與，以提高 核苷之活性、生物利用性、安定性或改變其性質。已知有 許多種核苷酸前藥配位體。通常，核苷之單磷酸酯、二碌 酸醋或三麟酸酯之烧化、醯化、或其他親脂性修飾法均可 提高核香酸之安定性。可置換磷酸酯部份基團上一個或多 個氫之取代基實例為烷基、芳基、類固醇、碳水化合物（包 含糖類）、1，2-二醯基甘油及醇類。其中許多實例說明於R Jones and N. Bischofberger, Antiviral Research^ 27(1995) 1-17。任何此等基團均可與本文揭示之核甘組合，以達成 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 -· I------訂---------線· 1293306 A7 B7 五、發明說明（81 ) 所需效果。 活性核苷亦可呈5、磷基醚脂質或5’-醚脂質供應，如 下列參考文獻說明，此等文獻已以提及之方式併入本文 中：Kucera，L.S·，N· Iyer，E· Leake，A· Raben，Modest Ε·Κ·， D.L. W.? and C. Piantadosi. 1990. "Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation.^ AIDS Res. Hum. Retro Viruses. 6:491-501 ； Piantadosi, C.? J. Marasco C.J., S.L. Morris-Natschke, K.L. Meyer, F. Gumus, J.R. Surles, K.S. Ishaq, L.S. Kucera, N. Iyer, C.A. Wallen, S. Piantadosi, and E.J. Modest. 1991. '"Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV activity.^ J. Med. Chem. 34:1408.1414 ； Hosteller, K.Y.? D.D. Richman, D.A. Carson, L.M. Stuhmiller, G.M. T. van Wijk, and H. van den Bosch. 1992. "Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4_6C cells by 3’-deoxythymidine diphosphate dimyristoylglycerol, a lipid prodrug of 3,-deoxythymidine·’’ Antimicrob. Agents Chemother. 36: 2025.2029 ; Hosetler，K.Y·，L.M. Stuhmiller，Η·Β. Lenting， H. van den Bosch，and D.D. Richman，1990. “Synthesis and antiretroviral activity of phospholipid analogs of azidothymidine and other antiviral nucleosides.^ J. Biol. Chem. 265:61127. 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注咅？事項再填寫本頁) '衣--------訂---------線丨 經濟部智慧財產局員工消費合作社印製 81 經濟部智慧財產局員工消費合作社印製 1293306 A7 ____B7__五、發明說明（82 ) 揭示彼等可共價結合併入核脊中，最好併入核脊之 5’-OH位置之合適親脂性取代基或親脂性製劑之不設限美 國專利案實例包括美國專利案Nos.5，149,794 (Sep.22, 1992, Yatvin et al·) ; 5，194,654 (Mar· 16, 1993, Hostetler et al·，5,223,263 (June 29，1993，Hostetler et al·) ; 5,256,641 (Oct· 26，1993，Yatvin et al·); 5,411，947 (May 2，1995, Hostetler et al.) ； 5,463,092 (Oct. 31, 1995, Hostetler et al·); 5,543,389 (Aug. 6，1996，Yatvin et al.); 5,543,390 (Aug· 6, 1996, Yatvin et al·) ; 5,543,391 (Aug· 6，1996, Yatvin et al.) ； and 5,554,728 (Sep. 10，1996 ; Basava et al·)，其均 以引用之方式併入本文中。揭示彼等可附接本發明核苷之 親脂性取代基或親脂性製劑之國外專利申請案包含： WO 89/02733, WO 90/00555, WO 91/16920, WO 91/18914, WO 93/00910, WO 94/26273, WO 96/15132, EP 0 350 287, EP 93917054.4，與 WO 91/19721. V.醫藥組成物 以式（I)-(XXIII)召-D或召-L化合物或其醫藥上可接受 之鹽或前藥為主之醫藥組成物可製成醫療有效量，供治療 黃病毒科、正黏液病毒科或副黏液病毒科病毒感染或非正 常細胞增生，可視需要與醫藥上可接受之添加物、載體或 賦形劑組合。醫療有效量可隨待治療之感染或病症、其嚴 重性、所採用之療程、所使用藥劑之藥物動力學及所治療 之患者本身而變化。 根據本發明一方面，根據本發明化合物最好使用醫藥 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 82 91949 --------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 1293306When the right compound is sufficiently basic or acidic to form a stable non-toxic acid or base salt, the compound is suitable for administration as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metal salts such as potassium and sodium, alkaline earth metal salts such as calcium and magnesium, and many other acids conventionally known in the pharmaceutical arts. In particular, examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form physiologically acceptable anions, for example: tosylate, mesylate, acetate, citrate , propionate, tartrate, succinate, benzoate, ascorbate, ketoglutarate, and alpha-glyceryl phosphate. Suitable inorganic salts can also be formed' including: sulfates, nitrates, hydrogencarbonates and carbonates. V. INSTRUCTIONS ((6)) (Please read the phonetic transcription on the back side and then fill out this page.) The Ministry of Economic Affairs, Intellectual Property Office, Staff Cooperatives, and the printing of pharmaceutically acceptable salts can be obtained using standard methods known in the art, for example. : reacting with a suitable compound (eg, an amine) with a suitable acid that provides a physiologically acceptable anion. It is also possible to produce salts of acid-suppressed metals (for example: sodium, potassium or lithium) or alkaline earth metals (for example, calcium). Any of the nucleosides described herein can be administered as a nucleotide prodrug to increase the activity, bioavailability, stability, or properties of the nucleoside. Numerous nucleotide prodrug ligands are known. In general, the burning, sulphurization, or other lipophilic modification of nucleoside monophosphates, dibasic vinegars or ternary esters enhances the stability of the nucleic acid. Examples of the substituent of one or more hydrogens on the replaceable phosphate moiety are alkyl groups, aryl groups, steroids, carbohydrates (including sugars), 1,2-dimercaptoglycerols and alcohols. Many examples are described in R Jones and N. Bischofberger, Antiviral Research 27 (1995) 1-17. Any such group may be combined with the nucleus disclosed herein to achieve the Chinese National Standard (CNS) A4 specification (210 X 297 mm) for this paper scale. 91949 -· I------ ------Line · 1293306 A7 B7 V. Description of invention (81) Required effect. The active nucleoside may also be supplied as a 5, phosphoether ether lipid or 5'-ether lipid, as described in the following references, which are incorporated herein by reference: Kucera, LS., N. Iyer, E · Leake, A. Raben, Modest Ε·Κ·, DLW? and C. Piantadosi. 1990. "Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation.^ AIDS Res. Hum. Retro Viruses. 6:491-501 ; Piantadosi, C.? J. Marasco CJ, SL Morris-Natschke, KL Meyer, F. Gumus, JR Surles, KS Ishaq, LS Kucera, N. Iyer, CA Wallen, S. Piantadosi , and EJ Modest. 1991. '"Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV activity.^ J. Med. Chem. 34:1408.1414 ; Hosteller, KY? DD Richman, DA Carson, LM Stuhmiller, GMT 1992. "Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4_6C cells by 3'-deoxythymidine diphosphate dimyristoylgl Ycerol, a lipid prodrug of 3,-deoxythymidine·'' Antimicrob. Agents Chemother. 36: 2025.2029 ; Hosetler, KY·, LM Stuhmiller, Η·Β. Lenting, H. van den Bosch, and DD Richman, 1990. “Synthesis And antiretroviral activity of phospholipid analogs of azidothymidine and other antiviral nucleosides.^ J. Biol. Chem. 265:61127. This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (Please read the back Note? Matters to fill out this page) 'Clothes -------- Order --------------- Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed 81 Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed 1293306 A7 ____B7__ V. OBJECT DESCRIPTION OF THE INVENTION (82) discloses that they may be covalently incorporated into the ridge, preferably into the appropriate 5'-OH position of the ridge of the nucleus, or a lipophilic formulation. Examples of patents include U.S. Patent No. 5,149,794 (Sep. 22, 1992, Yatvin et al.); 5,194,654 (Mar. 16, 1993, Hostetler et al., 5,223,263 (June 29, 1993, Hostetler et al). ·); 5,256,641 (Oct· 26,1993, Yatvin et al.); 5,411,947 (May 2,1995, Hostetler et al.); 5,463,092 (Oct. 31, 1995, Hostetler et al.); 5,543,389 (Aug. 6, 1996, Yatvin et al.); 5,543,390 (Aug. 6, 1996, Yatvin et al.); 5,543,391 (Aug. 6, 1996, Yatvin et al.); and 5,554,728 (Sep. 10,1996; Basava et al -), which are incorporated herein by reference, to disclose their foreign patent applications to which the alimental or lipophilic formulations of the nucleosides of the invention can be attached Including: WO 89/02733, WO 90/00555, WO 91/16920, WO 91/18914, WO 93/00910, WO 94/26273, WO 96/15132, EP 0 350 287, EP 93917054.4, and WO 91/19721 V. The pharmaceutical composition can be made into a medically effective amount by using the pharmaceutical composition of the formula (I)-(XXIII)-D or the compound- or a pharmaceutically acceptable salt or prodrug thereof for the treatment of yellow Viral, Orthomyxoviridae or Paramyxoviridae virus infection or abnormal cell proliferation, optionally in combination with pharmaceutically acceptable additives, carriers or excipients. The medically effective amount may vary with the infection or condition to be treated, The severity, the course of treatment employed, the pharmacokinetics of the agent used, and the patient itself being treated vary. According to one aspect of the invention, the compound according to the invention is preferably used in accordance with the Chinese National Standard (CNS) A4. Specifications (210 X 297 mm) 82 91949 -------------------- Order --------- line (please read the notes on the back first) Fill in this page) 1293306

五、發明說明（83 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 上可接受之載體調配。通常，最好呈可經口投藥之形式投 與醫藥組成物，但調配物可經由經腸式、靜脈内、肌内、 穿皮式、頰内、皮下、塞劑或其他途徑投藥、經靜脈内及 肌内投藥之調配物最好呈無菌生理食鹽水投藥。習此技藝 之人士可在本說明書之指示下修改調配物，以提供用於特 定投藥途徑之多種調配物，同時不會使本發明組合物不安 定或破壞其醫療活性。特定言之，很容易由例行修飾法修 飾所％化合物（形成鹽、醋化，等等），使之例如··較易溶 於水或其他媒劑。 某些醫藥劑型中，以化合物之前藥型較隹，尤其包含 本發明化合物之醯化（乙醯化，等等）及醚衍生物、鱗酸酉旨 及各種鹽型。習此技藝之人士咸了解應如何修飾本發明化 合物形成前藥型，以促進活性化合物傳送至宿主生物體或 患者體内之目標位置。習此技藝之人士將擷取前藥型之有 利之藥物動力學參數之優點，若可行時，用於傳送所需化 &物至稍主生物體或患者體内目標位置’使化合物在治療 黃病毒科病毒（包含HCV)、正黏液病毒科病毒（包含流感病 毒Α與Β)、副黏液病毒科病毒（包含rsv)感染或與非正常 細胞增生有關之病症上達到最大功效。 根據本發明醫療活性調配物内包含之化合物用量可有 效治療感染或病症，在較佳具體實施例中可治療黃病毒科 病毒（包含HCV)、正黏液病毒科病毒（包含流感病毒a與 B)、副黏液病毒科病毒（包含RSV)感染或與非正常細胞增 生有關之病症。通常，醫藥劑型中本發明化合物之醫療有 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） "' ------------- 83 91949 (請先閱讀背面之注意事項再填寫本頁) 0 -------^---------^. 1293306V. Description of the invention (83 The Ministry of Economic Affairs' Intellectual Property Office employees' consumption cooperatives print acceptable carrier allocation. Usually, it is best to administer the pharmaceutical composition in the form of oral administration, but the preparation can be via enteral, intravenous Formulations for intralesional, intramuscular, transdermal, buccal, subcutaneous, suppository or other routes of administration, intravenous and intramuscular administration are preferably administered in sterile physiological saline. Those skilled in the art can use this specification. The formulation is modified to provide a plurality of formulations for a particular route of administration without rendering the compositions of the invention unstable or disrupting its medical activity. In particular, it is readily modified by routine modification of the % compound ( Forming a salt, vinegaring, etc.), such as being more soluble in water or other vehicles. In some pharmaceutical dosage forms, the previous formulation of the compound is relatively ambiguous, especially including the oxime of the compound of the present invention. And ether derivatives, squamous acid salts and various salt forms. Those skilled in the art will understand how to modify the compounds of the present invention to form prodrugs to promote activation. The substance is delivered to a target location in the host organism or patient. Those skilled in the art will appreciate the advantages of the advantageous pharmacokinetic parameters of the prodrug type and, if applicable, the delivery of the desired & Target location in the main organism or patient's compound in the treatment of Flaviviridae virus (including HCV), Orthomyxoviridae virus (including influenza virus sputum and sputum), Paramyxoviridae virus (including rsv) infection or non- Maximum efficacy is achieved in conditions associated with normal cell proliferation. The amount of the compound contained in the medically active formulation according to the present invention is effective to treat an infection or condition, and in a preferred embodiment can treat a Flaviviridae virus (including HCV), a positive mucus Viral virus (including influenza virus a and B), paramyxoviridae virus (including RSV) infection or a disease associated with abnormal cell proliferation. Generally, the medical compound of the present invention in the pharmaceutical dosage form has the paper scale applicable to the Chinese national standard. (CNS) A4 specification (210 X 297 mm) "' ------------- 83 91949 (Please read the notes on the back and fill out this page) 0 ------ -^ ---------^. 1293306

五、發明說明（84 合 作 社 印 製 效量範圍在約0·1毫克/公斤至約100毫克/公斤依所使用 化合物、所治療之病症或感染及投藥途徑而定。為了本發 明之目的，根據本發明之組成物之預防有效量範圍與上述 醫療有效量之濃度範圍相同，且通常與醫療有效量相同。 活性化合物之投藥法可為連續式（靜脈内點滴）至一天 經口投藥數次（例如：QID、BID，等等），且可包含經口、 局部、非經腸式 '肌内、靜脈内、皮下、穿皮式（其中可包 含滲透加強劑）、頰内及塞劑投藥，等等及其他投藥途徑。 亦可採用包覆腸溶性包衣之口服藥片，以加強經口投藥之 化合物之生物可利用性及安定性。最有效之劑型將依所選 用之特定藥劑之藥物動力學，及患者疾病之嚴重性而定。 口服劑型由於方便投藥且患者容易適應，因此特別佳。 為了製備根據本發明醫藥組成物，最好由醫療有效量 之種或多種根據本發明化合物與醫藥上可接受之載體依 〔習知用於製造劑型之醫藥化合技術混合。載體可呈多種 形式，依所需投藥之製劑形式而定，例如··口服或非經腸 式。製備口服劑型之醫藥組成物時，任何常用之醫藥介質 均可使用。因此，用於液體口服製劑如··懸浮液、酏劑與 溶液時，可使用之合適載體與添加物包含··水、二醇類、 油、醇、調味劑、防腐劑、著色劑，等等。用於固體口服 製劑如：散劑、錠劑、膠囊及如··塞劑之固體製劑時，可 使用之合適載體與添加物包含澱粉、糖載體，如··右旋糖、 甘露糖醇、乳糖及相關載體、稀釋劑、製粒劑、潤滑劑、 結合劑、崩解劑，等等。若需要時，錠劑或膠囊可利用標 本紙張尺度刺中國國家標準（CNS)A4規格（210 X 297公髮） (請先閱讀背面之注咅？事項再填寫本頁) -------訂---------線· 84 91949 12933〇6V. Description of the invention (84 Cooperative printing efficacy ranges from about 0.1 mg/kg to about 100 mg/kg depending on the compound used, the condition being treated or the infection and the route of administration. For the purposes of the present invention, The prophylactically effective amount of the composition of the present invention is the same as the above-mentioned medically effective amount, and is usually the same as the medically effective amount. The active compound can be administered continuously (intravenous drip) to oral administration several times a day ( For example: QID, BID, etc.), and may include oral, topical, parenteral 'intramuscular, intravenous, subcutaneous, transdermal (which may include penetration enhancers), buccal and suppository administration, Etc. and other routes of administration. Oral tablets coated with an enteric coating may also be used to enhance the bioavailability and stability of the orally administered compound. The most effective dosage form will depend on the drug power of the particular agent selected. Learning, and the severity of the patient's disease. Oral dosage forms are particularly preferred because they are easy to administer and the patient is easily adapted. In order to prepare the pharmaceutical composition according to the present invention, it is best The medically effective amount of the compound or a plurality of the compounds according to the present invention is mixed with a pharmaceutically acceptable carrier according to a conventional pharmaceutical compounding technique for producing a dosage form. The carrier may be in various forms depending on the form of the preparation to be administered, for example, · Oral or parenteral. Any pharmaceutical medium can be used when preparing pharmaceutical compositions for oral dosage forms. Therefore, it can be used when used in liquid oral preparations such as suspensions, elixirs and solutions. Carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc. For solid oral preparations such as powders, lozenges, capsules and solids such as suppositories Suitable carriers and additives for use in the preparation include starch, sugar carriers, such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, binding agents, disintegrating agents, Etc. If needed, tablets or capsules can be spurted to the National Standard (CNS) A4 specification (210 X 297 mil) using the standard paper scale (please read the notes on the back? Please fill out this page) --- ----Book --- ------Line· 84 91949 12933〇6

請 先 閱 讀 背 85 91949Please read back 85 91949

A7 1293306 五、發明說明（86 ) 預防性治療病毒感染之方法，特定言之黃病毒科（包含 HCV)、正黏液病毒科（包含流感病毒八與B)、副黏液病毒 科（包含RSV)病毒感染或與非正常細胞增生有關之病症。 根據本發明這一方面，本發明組成物可用於預防或延緩發 生黃病毒科（包含HCV)、正黏液病毒科（包含流感病毒a 與B)、副黏液病毒科（包含RSV)病毒感染或與非正常細胞 增生有關之病症。此預防方法包括對需要這種治療之患者 或有發展成該等病毒感染或病症危險之患者投與減輕、預 防或延緩發生該等病毒感染或病症有效量之根據本發明化 合物。根據本發明之預防性療法中，所使用之抗病毒或抗 增生藥劑為低毒性較佳，最好對患者無毒性。本發明特別 佳之方面為所使用之化合物應對該等病毒或病症具最大有 效|±且對患者具琅低毒性。若出現黃病毒科（包含Η。v)、 正黏液病毒科（包含流感病毒A與B)、副黏液病毒科（包含 RSV)病毒感染或與非正常細胞增生有關之病症時，可用於 治療此等疾病之根據本發明化合物之投藥劑量可在用於醫 療性治療時之相同劑量範圍内（亦即每天投與丨至4次口服 齊J i約250微克至1克），作為預防藥劑，供阻止黃病毒科 (匕a HCV)、正黏液病毒科（包含流感病毒a與b)、副黏 液病毒科（包含RSV)病毒感染或與非正常細胞增生有關之 病症，或者延緩黃病毒科（包含HCV)、正黏液病毒科（包含 流感病毒A與B)、副黏液病毒科（包含RSV)病毒感染或與 非正常細胞增生有關之病症出現臨床症狀。 此外，根據本發明化合物可與一種或多種抗病毒、抗 ^氏張尺度適时關家標準（CNS)A4規格⑵G x297公髮） ----— 86 91949 (請先閱讀背面之注咅？事項再填寫本頁) ·丨—丨丨丨丨訂·—丨丨丨丨—· 經濟部智慧財產局員工消費合作社印製 1293306 A7 B7 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 87 五、發明說明（87 ) HBV、抗HCV、或抗疱療劑或干擾素 '抗癌劑或抗細菌劑 組合或交替投藥，其中尚包含本發明其他化合物。根據本 發明某些化合物可藉由降低其他化合物之新陳代謝、分解 代謝或去活性而有效加強根據本發明某些藥劑之生物活 性，因此可共同投藥用於所需之效果。 下一節進一步說明本發明。其中包含實驗細節部份及 實例係協助了解本發明。這一節内容並無意（且不應解讀成） 以任何方式限制本文之後之申請專利範圍所示之本發明範 圍。 YL黃病毒科病毒感染之治療法 已知長期使用抗病毒劑治療後可能發生抗藥性病毒變 異體。抗藥性最主要由編碼病毒複製循環時所使用酵素之 基因發生突變所致，在HCV中，最常發生在依賴RNA之 RNA聚合酶。現已證實，藉由同時或交替投與本發明化合 物與第二種，及可能使用第三種可能誘發不同於主要藥物 所誘發之突變之抗病毒化合物時，可延長、加強或回復藥 物對抗病毒感染之效力。或者，藉由這種組合或交替療法， 可改變藥物動力學、生物分佈性或其他藥物參數。通常， 組合療法優於交替療法，因為前者會對病毒同時誘發多重 壓力。 已經判別具有對抗C型肝炎病毒活性且因此可用於與 一種或多種通式（ιΗχχΠΙ)核苷組合或交替投藥之藥劑實 例包含： (a)干擾素與利巴韋林（ribavirin)(Battaglia，A. M. et al. f紙張尺度適时國國家標準（CNS)A4規格⑵G χ 297公爱） -- 91949 --------IT---------線 C請先閲讀背面之注意事項存填寫本頁) 1293306 A7 B7 五、發明說明（88 )A7 1293306 V. INSTRUCTIONS (86) Methods for prophylactic treatment of viral infections, specifically the Flaviviridae (including HCV), the Orthomyxoviridae (including influenza virus VIII and B), and the Paramyxoviridae (including RSV) viruses An infection or condition associated with abnormal cell proliferation. According to this aspect of the invention, the composition of the invention can be used to prevent or delay the onset of the Flaviviridae (including HCV), the Orthomyxoviridae (including influenza viruses a and B), the Paramyxoviridae (including RSV) virus infection or A condition associated with abnormal cell proliferation. This method of prevention comprises administering to a patient in need of such treatment or a patient at risk of developing such viral infection or condition a compound according to the invention effective to alleviate, prevent or delay the onset of such viral infection or condition. In the prophylactic treatment according to the present invention, the antiviral or antiproliferative agent to be used is preferably low in toxicity, and is preferably nontoxic to the patient. It is a particularly preferred aspect of the invention that the compound used is most effective against such viruses or conditions | and is less toxic to the patient. It can be used to treat this if there is a disease of the Flaviviridae family (including Η.v), the Orthomyxoviridae (including influenza A and B), the Paramyxoviridae (including RSV) virus infection or the abnormal cell proliferation. The dosage of the compound according to the present invention may be administered in the same dosage range for medical treatment (that is, about 250 micrograms to 1 gram per day for 4 times of oral administration), as a preventive agent. Prevents Flaviviridae (匕a HCV), Orthomyxoviridae (including influenza viruses a and b), Paramyxoviridae (including RSV) virus infection or disorders associated with abnormal cell proliferation, or delays Flaviviridae (including HCV), positive mucinous virus family (including influenza virus A and B), paramyxoviridae (including RSV) virus infection or symptoms associated with abnormal cell proliferation have clinical symptoms. In addition, the compounds according to the invention may be combined with one or more anti-viral, anti-staple scales (CNS) A4 specifications (2) G x 297) ---- 86 91949 (please read the back note first? Matters to fill out this page) ·丨—丨丨丨丨定·—丨丨丨丨—· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1293306 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 87 V. Invention Description (87) HBV, anti-HCV, or anti-blister or interferon' anticancer or antibacterial agent combination or alternation, wherein other compounds of the invention are also included. Certain compounds according to the present invention are effective in enhancing the biological activity of certain agents according to the present invention by reducing the metabolism, catabolism or deactivation of other compounds, and thus can be co-administered for the desired effect. The invention is further illustrated in the next section. The experimental details and examples are included to assist in understanding the invention. This section is not intended to be (and should not be construed as) limiting the scope of the invention as set forth in the appended claims. Treatment of YL Flaviviridae virus infection It is known that drug-resistant virus variants may occur after long-term use of antiviral agents. Drug resistance is most commonly caused by mutations in the genes encoding the enzymes used in the viral replication cycle. In HCV, RNA-dependent RNA polymerases most commonly occur. It has been demonstrated that a drug can be prolonged, potentiated or reverted by concurrent or alternating administration of a compound of the invention with a second, and possibly a third antiviral compound that may induce a mutation different from that induced by the main drug. The effectiveness of the infection. Alternatively, pharmacokinetics, biodistribution, or other drug parameters can be altered by such combination or alternation therapy. In general, combination therapy is superior to alternation therapy because the former induces multiple stresses simultaneously on the virus. Examples of agents that have been identified to have anti-hepatitis C virus activity and are therefore useful for combination or alternation with one or more formula (ι) nucleosides include: (a) interferon and ribavirin (Battaglia, AM) Et al. f paper scale national standard (CNS) A4 specifications (2) G χ 297 public) -- 91949 -------- IT--------- Line C, please read the back Note: Please fill in this page) 1293306 A7 B7 V. Description of invention (88)

Ann. Pharmacother. 2000, 34, 487 ; Berenguer, M. et al. Antivir. Ther. 1998，3 (Suppl· 3)，125); (請先閱讀背面之注咅？事項再填寫本頁) (b) 以受質為主之NS3蛋白酶抑制劑（Attwood et al· PCT WO 98/22496，1998 ; Attwood et al. Antiviral Chemistry and Chemotherapy 1999，1 0，259, ; Attwood et al.德國專 利公告案 DE 19914474 ; Tung et al· PCT WO 98/17679)，包含a-酮基醯胺及肼基脲，及末端為親電 子物如：二羥硼酸或膦酸酯之抑制劑（1^1丨1^8-31*111^{61 al. PCT WO 99/07734)； (c) 不以受質為主之抑制劑如：2,4,6-三羥基-3-硝基-苯醯胺 衍生物（Sudo K· et al·，Biochemical and Biophysical Research Communications, 1997，238，643 及 Sudo K· et al. Antiviral Chemistry and Chemotherapy 1998，9， 186)，包含RD3-4082及RD3-4078，前者之醯胺經一條 14個碳之鏈取代，後者則具有對位苯氧苯基； 經濟部智慧財產局員工消費合作社印製 (d) 在使用NS3/4A融合蛋白質及NS5A/5B受質之逆相 HPLC分析法中展現相關抑制作用之噻唑啶衍生物 (Sudo K. et al. Antiviral Research 1996，32，9)，尤指化 合物RD-1-6250，其具有經長鍵燒基取代之稠合肉桂醯 基部份基團，RD4 6205與RD4 6193 ; (e) 由 Kakiuchi N· et al· J. EBS Letters 47 1 2 17 與 Takeshita N. et al· Analytical Biochemistry 1 997，247，242 判別之 噻唑啶與苯醯替苯胺； (f) 一種自鏈黴菌之醱酵培養液中單離，且在SDS-PAGE與 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 88 91949 A7 B7 1293306 五、發明說明（89 ) 自動放射照相分析法中展現對抗HCV蛋白酶活性之菲 6863 1 (Chu M. et al. Tetrahedron Letters 1996，37，7229) 與Sch 351633，其在閃爍近似分析法中證實具有活性 (Chu M. et al·，Bioorganic and Medicinal Chemi^try Letters 9，1949); (g) 自水蛭中單離出之以大分子艾金素（elgin)c為主之選擇 性 NS3 抑制劑（Qasim Μ·Α. et al· Biochemistry 1997, 36, 1598); (h) HCV解螺旋酶抑制劑（Diana G· D. et al·，美國專利案No. 5,633,358 A Diana G. D. et al. PCT WO 97/36554)； (i) HCV聚合酶抑制劑如：核苷酸類似物，支黴黏毒素 (gliotoxin) (Ferrari R. et al. Journal of Virology 1999, 73，1649)，及天然產物淺藍菌素（cenilenin) (Lohmann V. et al. Virology 1998，249，108); ⑴與HCV之至少一部份序列互補之反義硫代磷酸酯寡去 氧核苷酸（S-ODN) (Anderson et al.美國專利案No. 6，m，868)，及特別指5’-非編碼區（NCR)之伸長序列 (Alt M. et al. Hepatology 1995，22，707)或包括 NCR 之 3’-末端之核苷酸326-348及位於HCV RNA之核心編碼 區之核昔酸 371-388 (Alt Μ· et al. Archives of Virology 1997，142，589 及 Galderisi U. et al·，Journal of Cellular Physiology 1999? 81:2151)； (k)依賴IRES之轉譯作用抑制劑（ikeda N et al·日本專利公 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (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 89 1293306 Δ7 - B7 五、發明說明（90 ) 告案JP-08268890 ; Kai Y. et al.日本專利公告案JP-10101591); (l) 抗核酸酶之核糖酵素（Maccjak D. J. et al.，Hepatology 1999, 30,摘要 995); (m) 金剛胺如：里曼塔定（rimantadine) (Smith，美國胃腸病 學會與AASLD年會報告摘要，1996年）； (η)嗟諾酮類如：歐弗辛（〇fi〇xacin)、赛普弗辛（ciprofi〇xacin) 及里弗辛（levofloxacin) (AASLD Abstracts，Hepatology, 1994 年 10 月，Program Issue, 20(4)，pt.2，abstract no.293); (〇)核苷類似物（Ismaili et al· WO 01/60315 ; Storer WO 01/32153)，包含 2’-去氧-L-核有^Watanabe et al. WO 01/34618)及1-(卢-1^-咲喃核糖基）_1，2,4_三唑-3-羧醯胺 (levovirinTM) (Tam WO 01/46212);及 (P)其他類化合物包含1-胺基-烷基環己烷（Gold等人，美國 專利案No. 6,034，134)，烷基脂質（Chojkier•等人，美國 專利案No. 5,922,757)，維生素E及其他抗氧化劑 (Chojkier等人，美國專利案No· 5,922,757)，角鯊烯， 膽酸類（Ozeki等人，美國專利案No· 5,846,964)，N-(亞 磷叛乙醢基）-L-天冬胺酸（Diana等人，美國專利案No. 5,830，905)，苯二羧醯胺（Diana等人，美國專利案No. 5，633，388)，聚腺符構酸衍生物（Wang等人，美國專利 案 No· 5,496,546)，2%3’-二去氧肌苷（Yarch〇an 等人， 美國專利案No. 5,026,687)，苯并蛛嗤（c〇lacino等人， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (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 1293306 A7 B7 五、發明說明（91 美國專利案No· 5,891，8?4)，葡糖胺（Mueller等人，w〇 01/08672)，經取代之1,5-亞胺基_D_葡糖醇化合物 (Mueller 等人，WO 00/47198)。 —~矣黏液病毒科病毒感染之治療法 已知長期使用抗病毒劑治療後可能發生抗藥性流感病 毋變異體。抗藥性最主要由編碼病毒複製循環時所使用酵 素之基因發生突變所致，造成抗原性遷移或漂移。現已證 實’藉由同時或交替投與本發明化合物與第二種，及可能 使用第三種可能誘發不同於主要藥物所誘發之突變之抗病 毒化合物時，可延長、加強或回復藥物對抗流感病毒感染 之效力。或者’藉由這種組合或交替療法，可改變藥物動 力學、生物分佈性或其他藥物參數。通常，組合療法優於 交替療法，因為前者會對病毒同時誘發多重壓力。 已經判別具有對抗流感病毒活性且因此可用於與一種 或多種通式（I)-(XXIII)核苷組合或交替投藥之藥劑實例包 含： (a) 放射囷素 D (Barry，R. D. et al· “Participation of deoxyribonucleic acid in the multiplication of influenza virus” Mature, 1962，194，1139-1140); (b) 金剛胺（Van Voris，L· P· et al· “Antivirals for the chemoprophylaxis and treatment of influenza^ Semin Rgspir Infect, 1992, 7? 61-70)； (c) 4-胺基-或4-胍基-2-去氧-2,3-二去氳-D-N-乙醯基神經 胺酸：4-胺基-或 4·脈基 _Neu 5 Ac2en (von Itzstein, Μ· et 本紙張尺度適用中國國家標準（CNS)A4規袼（210 X 297公爱） 91949 (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 91 經濟部智慧財產局員工消費合作社印製 92 1293306 A7 B7 五、發明說明（92 ) al. "Rational design of potent sialidase-based inhibitors of influenza virus replication^ Nature, 1993，363，41 8-423)； (d) 利巴韋林（ribavirin) (Van Voris，L· P· et al· “Antivirals for the chemoprophylaxis and treatment of influenza” Semin Respir Infect· 1 992，7, 61 -70); (e) 干擾素（Came，P. E. et al· “Antiviral activity of an interferon-inducing synthetic polymer” Proc Soc Exp Biol Med· 1969, 131, 443-446 ； Gerone, P. J. et al. “Inhibition of respiratory virus infections of mice with aeresols of synthetic double-stranded ribonucleic acid^ Infect Immun, 1971, 3, 323-327 ； Takano, K. et al. “Passive interferon protection in mouse influenza” L Tnfect Pis. 1 991，1 64, 969-972);Ann. Pharmacother. 2000, 34, 487 ; Berenguer, M. et al. Antivir. Ther. 1998, 3 (Suppl· 3), 125); (Please read the note on the back? Please fill out this page again) (b NS3 protease inhibitors based on receptors (Attwood et al. PCT WO 98/22496, 1998; Attwood et al. Antiviral Chemistry and Chemotherapy 1999, 10, 259, ; Attwood et al. German Patent Publication DE 19914474) ; Tung et al. PCT WO 98/17679), comprising a-ketodecylamine and guanylurea, and an end inhibitor of an electrophile such as dihydroxyboric acid or phosphonate (1^1丨1^8) -31*111^{61 al. PCT WO 99/07734); (c) Inhibitors not dominated by acceptors such as 2,4,6-trihydroxy-3-nitro-benzoguanamine derivatives ( Sudo K. et al., Biochemical and Biophysical Research Communications, 1997, 238, 643 and Sudo K. et al. Antiviral Chemistry and Chemotherapy 1998, 9, 186), comprising RD3-4082 and RD3-4078, the former guanamine Replaced by a chain of 14 carbons, the latter having a para-phenoxyphenyl group; printed by the Ministry of Economic Intelligence's Intellectual Property Bureau employee consumption cooperative (d) using NS3/4A fusion protein and Thiazolidine derivative exhibiting a related inhibitory effect in reverse phase HPLC analysis of NS5A/5B (Sudo K. et al. Antiviral Research 1996, 32, 9), especially compound RD-1-6250, which has a long length Bonded thiolated thiol moiety, RD4 6205 and RD4 6193; (e) by Kakiuchi N. et al. J. EBS Letters 47 1 2 17 and Takeshita N. et al. Analytical Biochemistry 1 997 , 247, 242 discriminating thiazolidine and benzoxanil; (f) a single detached from the fermentation broth of Streptomyces, and applicable to the Chinese National Standard (CNS) A4 specification on SDS-PAGE and this paper scale (210) X 297 mm) 88 91949 A7 B7 1293306 V. INSTRUCTIONS (89) Philippine 6863 1 (Chu M. et al. Tetrahedron Letters 1996, 37, 7229) and Sch 351633 exhibiting anti-HCV protease activity in automated radiographic analysis. , which has been confirmed to be active in scintillation approximation analysis (Chu M. et al., Bioorganic and Medicinal Chemi^try Letters 9, 1949); (g) Macroindolin (elgin) isolated from leech C-based selective NS3 inhibitor (Qasim Μ·Α. et al· Biochemi Stry 1997, 36, 1598); (h) HCV helicase inhibitor (Diana G. D. et al., U.S. Patent No. 5,633,358 A Diana GD et al. PCT WO 97/36554); (i) HCV Polymerase inhibitors such as: nucleotide analogs, gliotoxin (Ferrari R. et al. Journal of Virology 1999, 73, 1649), and the natural product cenilenin (Lohmann V. Et al. Virology 1998, 249, 108); (1) Antisense phosphorothioate oligodeoxynucleotides (S-ODN) complementary to at least a portion of the sequence of HCV (Anderson et al. US Patent No. 6 , m, 868), and in particular the elongation sequence of the 5'-noncoding region (NCR) (Alt M. et al. Hepatology 1995, 22, 707) or the nucleotides 326-348 including the 3'-end of NCR And nucleotides 371-388 located in the core coding region of HCV RNA (Alt Μ· et al. Archives of Virology 1997, 142, 589 and Galderisi U. et al., Journal of Cellular Physiology 1999? 81: 2151); k) IRES-dependent translation inhibitors (ikeda N et al. Japanese patent paper size applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 (please Read the precautions on the back and fill out this page. Order---------Line, Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives Printed 89 1293306 Δ7 - B7 V. Invention Description (90) Telling JP-08268890 Kai Y. et al. Japanese Patent Publication JP-10101591); (l) Nuclease-resistant ribozyme (Maccjak DJ et al., Hepatology 1999, 30, Abstract 995); (m) Amantadine such as: Liman Ritandine (Smith, American Society of Gastroenterology and AASLD Annual Report Summary, 1996); (η) quinolone such as: 〇fi〇xacin, 赛普弗辛 (ciprofi〇xacin And levofloxacin (AASLD Abstracts, Hepatology, October 1994, Program Issue, 20(4), pt. 2, abstract no. 293); (〇) nucleoside analogues (Ismaili et al· WO) 01/60315; Storer WO 01/32153), containing 2'-deoxy-L-nucleus with ^Watanabe et al. WO 01/34618) and 1-(Lu-1^-pyranosyl)_1,2, 4_triazole-3-carboxamide (levovirinTM) (Tam WO 01/46212); and (P) other compounds comprising 1-amino-alkylcyclohexane (Gold et al., U.S. Patent No. 6,034 , 134), alkyl lipids (Chojk Ier et al., U.S. Patent No. 5,922,757), vitamin E and other antioxidants (Chojkier et al., U.S. Patent No. 5,922,757), squalene, cholic acid (Ozeki et al., U.S. Patent No. 5,846,964). , N-(phosphorus tetrandyl)-L-aspartic acid (Diana et al., U.S. Patent No. 5,830,905), benzodiazepine (Diana et al., U.S. Patent No. 5, 633,388), polyadenosolic acid derivatives (Wang et al., U.S. Patent No. 5,496,546), 2% 3'-dideoxyinosine (Yarch〇an et al., U.S. Patent No. 5,026,687), Benzopyrazine (c〇lacino et al., this paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (please read the note on the back and fill out this page) #订---- -----Line _ Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1293306 A7 B7 V. Invention Description (91 US Patent No. 5,891,8?4), Glucosamine (Mueller et al., w〇01/ 08672), substituted 1,5-imino-D-glucitol compound (Mueller et al., WO 00/47198). —~矣 Treatment of mucinous viral infections It is known that long-term use of antiviral agents may result in the development of resistant influenza sputum variants. Drug resistance is most likely caused by mutations in the genes encoding the enzymes used in the viral replication cycle, resulting in antigenic migration or drift. It has been demonstrated that by concurrently or alternatively administering a compound of the invention and a second, and possibly using a third antiviral compound that may induce a mutation different from that induced by the main drug, the drug may be prolonged, potentiated or responsive to the flu. The effectiveness of viral infections. Alternatively, pharmacokinetics, biodistribution, or other drug parameters can be altered by such combination or alternation therapy. In general, combination therapy is superior to alternation therapy because the former induces multiple stresses at the same time. Examples of agents that have been identified as having anti-influenza virus activity and are therefore useful for combination or alternation with one or more of the formula (I)-(XXIII) nucleosides include: (a) Radionuclide D (Barry, RD et al·" Participation of deoxyribonucleic acid in the multiplication of influenza virus" Mature, 1962, 194, 1139-1140); (b) Amantadine (Van Voris, L. P. et al. "Antivirals for the chemoprophylaxis and treatment of influenza^ Semin Rgspir Infect, 1992, 7? 61-70); (c) 4-Amino- or 4-mercapto-2-deoxy-2,3-desinoin-DN-ethionylneuraminic acid: 4-amine Base- or 4·Pulsyl_Neu 5 Ac2en (von Itzstein, Μ· et This paper scale applies to China National Standard (CNS) A4 Regulations (210 X 297 public) 91949 (Please read the notes on the back and fill in the form) Page) -------Book---------Line Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 91 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 92 1293306 A7 B7 V. Invention Description ( 92 ) al. "Rational design of potent sialidase-based inhibitors of influenza virus replication^ Nature, 1993, 363, 41 8-423); (d) ribavirin (Van Voris, L. P. et al. “Antivirals for the chemoprophylaxis and treatment of influenza” Semin Respir Infect· 1 992, 7, 61-70); (e) Interferon (Came, PE et al. "Antiviral activity of an interferon-inducing synthetic polymer" Proc Soc Exp Biol Med 1969, 131, 443-446; Gerone, PJ et al. "Inhibition of respiratory virus infections of mice with aeresols of synthetic double-stranded ribonucleic acid^ Infect Immun, 1971, 3, 323-327; Takano, K. et al. "Passive interferon protection in mouse influenza" L Tnfect Pis. 1 991 , 1 64, 969-972);

(f) 去活性之流感病毒A與B疫菌（“Clinical studies on influenza vaccine-1 97 8” Rev Infect Disr 1983，5，721-764 ； Galasso, G. T. et al. "Clinical studies on influenza vaccine-1976，，J Infect Disr 1977, 136 (suppl)，S341-S746 ; Jennings, R. et al. ''Responses of volunteers to inactivated influenza virus vaccines^ J Hyg: 1981，86， 1-16 ; Kilbourne，E. D. “Inactivated influenza vaccine” In · Plothin SA? Mortimer EA5 eds. Vaccines Philadelphia: Saunders，1988, 420-434; Meyer，Η. M·，Jr· et al· “Review of existion vaccines for influenza” Am J 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 --------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 1293306 A7 B7 五、發明說明（93 )(f) Deactivated influenza A and B ("Clinical studies on influenza vaccine-1 97 8" Rev Infect Disr 1983, 5, 721-764; Galasso, GT et al. "Clinical studies on influenza vaccine- 1976, J Infect Disr 1977, 136 (suppl), S341-S746; Jennings, R. et al. ''Responses of volunteers to inactivated influenza virus vaccines^ J Hyg: 1981,86, 1-16 ; Kilbourne, ED “ Inactivated influenza vaccine” In · Plothin SA? Mortimer EA5 eds. Vaccines Philadelphia: Saunders, 1988, 420-434; Meyer, Η. M·, Jr· et al· “Review of existion vaccines for influenza” Am J This paper scale applies China National Standard (CNS) A4 specification (210 X 297 mm) 91949 -------------------- Order --------- line (please first Read the notes on the back and fill out this page) 1293306 A7 B7 V. Description of invention (93)

Clin PathoL 1978, 70, 146-152 ; “Mortality and Morbidity Weekly Report. Prevention and control of Influenza · Part I? Vaccines. Recommendations of the Advisory Committee on Immunication Practices (ACIP)’’ MMWR: 1993, 42(RR-6), 1-14 ; Palache, A. M. et al. “Antibody response after influenza immunization with various vaccine doses ： A double-blind, placebo-controlled, multi-centre, dose-response study in elderly nursing-home residents and young volunteers” Yaccine. 1993, 11，3-9 ; Potter，C. W. “Inactivated influenza virus vaccine” In ·· Beare AS，ed. Basic and applied influeza research. Boca Raton, FL ·· CRC Press, 1982，119-158) o VIII. 副黏液病毒科病毒感染之治療法 已知長期使用抗病毒劑治療後可能發生抗藥性RSV 變異體。抗藥性最主要由編碼病毒複製循環時所使用酵素 之基因發生突變所致。現已證實，藉由同時或交替投與本 發明化合物與第二種，及可能使用第三種可能誘發不同於 主要藥物所誘發之突變之抗病毒化合物時，可延長、加強 或回復藥物對抗RSV感染之效力。或者，藉由這種組合或 交替療法，可改變藥物動力學、生物分佈性或其他藥物參 數。通常，組合療法優於交替療法，因為前者會對病毒同 時誘發多重壓力。 已經判別具有對抗RSV活性且因此可用於與一種或 多種通式（IHXXIII)核苷組合或交替投藥之藥劑實例包 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注音？事項再填寫本頁) ------—訂·-------- 經濟部智慧財產局員工消費合作社印製 93 經濟部智慧財產局員工消費合作社印製 94 1293306 B7 五、發明說明（94 ) 含： (a) 利巴韋林（Hruska，J· F· et al· “In vivo inhibition of respiratory syncytial virus by ribavirin” Antimicrob Agents Chemother· 1982，21，125-130);及 (b) 純化之人類靜脈内 IgG-IVIG (Prince，G. A· et al. “Effectiveness of topically administered neutralizing antibodies in experimental immunotherapy of respiratory syncytial virus infection in cotton rats” J Virol, 1987，61， 1851-1954 ; Prince，G. A. et al. “Immunoprophylaxis and immunotherapy of respiratory syncytial virus infection in cotton rats” Infect Immun, 1982，42，81-87) o IX.非正常細胞增生之治療法 已判別具有對抗非正常細胞增生活性且因此可與一種 或多種通式（IHXXIII)核苷組合或交替使用之藥劑實例包 含： A. 烧4匕劑 氮芥類：氮芬（霍金氏症、非霍金氏淋巴瘤）、環磷醯 胺、異填醯胺（Ifosfamide)(急性與慢性淋巴球性白金病、 霍金氏症、非霍金氏淋巴瘤、多發性骨髓瘤、神經母細胞 瘤、乳房、卵巢、肺、威姆氏（Wilms’）腫瘤、子宮頸、睪 丸、軟組織肉瘤）、苯丙胺酸氮芥（Melphalan)(左旋苯丙胺 酸氮芥）（多發性骨髓瘤、乳房、卵巢）、苯丁酸氮芥 (Chlorambucil)(慢性淋巴球性白血病、原發性巨球蛋白血 症、霍金氏症、非霍金氏淋巴瘤）。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 ------------------!訂·--------線 (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 1293306 A7 B7 五、發明說明（95 ) 乙基亞胺類與甲基蜜胺類：六甲基蜜胺（卵巢）、噻螬 哌（Thiotepa)(膀胱、乳房、卵巢）。 燒基續酸酯：白血福思（Busulfan)(慢性粒細胞白血 病）。 亞硝基脲：卡氮芥（Carmustine) (BCNU)(霍金氏症、 非霍金氏淋巴瘤、原發性腦瘤、多發性骨髓瘤、惡性黑色 瘤）、環己亞硝脲（Lomustine) (CCNU)(霍金氏症、非霍金 氏淋巴瘤、原發性腦瘤、小細胞肺）、賽氮芥（Semustine)(甲 基-CCNU)(原發性腦瘤、胃、結腸）、鏈脲菌素（Streptozocin) (STR)(惡性胰島瘤、惡性癌瘤）。 三畊類：氮烯咪胺（Dacarbazine) (DTIC ;二甲基三畊 并咪唑-羧醯胺）（惡性黑色瘤、霍金氏症、軟組織肉瘤）。 B.抗代謝物 葉酸類似物：胺甲蝶呤（amethopterin)(急性淋巴球性 白血病、絨毛膜癌、蕈樣肉芽腫、乳房、頭與頸部、肺、 骨原性肉瘤）。 嘧啶類似物：氟尿嘧啶（5-氟尿嘧啶；5-FU)、5-氟去 氧尿苷（FUdR)(乳房、結腸、胃、胰、卵巢、頭與頸部、 膀胱、惡性前期皮膚損傷（局部））、阿糖胞苷（Cytarabine) (急性粒細胞與急性淋巴細胞白金病）。 嘌呤類似物與相關抑制劑：6-氫硫基嘌呤 (Mercaptopurine ; 6-MP)(急性淋巴球性、急性粒細胞性及 慢性粒細胞性白血病）、6-硫鳥嘌呤（Thioguanine ; TG)(急 性粒細胞性、急性淋巴球性、及慢性粒細胞性白血球）、本 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公餐） 95 91949 (請先閱讀背面之注咅？事項再填寫本頁) 參 訂---------線· 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 96 1293306Clin PathoL 1978, 70, 146-152; "Mortality and Morbidity Weekly Report. Prevention and control of Influenza · Part I? Vaccines. Recommendations of the Advisory Committee on Immunication Practices (ACIP)'' MMWR: 1993, 42 (RR-6 ), 1-14 ; Palache, AM et al. "Antibody response after influenza immunization with various vaccine doses : A double-blind, placebo-controlled, multi-centre, dose-response study in elderly nursing-home residents and young volunteers" Yaccine. 1993, 11,3-9 ; Potter, CW “Inactivated influenza virus vaccine” In ·· Beare AS, ed. Basic and applied influeza research. Boca Raton, FL · CRC Press, 1982, 119-158) o VIII Treatment of paramyxoviral viral infections It is known that long-term use of antiviral agents may result in the development of drug-resistant RSV variants. Drug resistance is mainly caused by mutations in the genes encoding the enzymes used in the viral replication cycle. By simultaneously or alternately administering a compound of the invention with a second, and possibly using a third, may induce Prolongs, potentiates, or restores the effectiveness of a drug against RSV infection in a mutant drug-induced mutation of an antiviral compound. Alternatively, pharmacokinetics, biodistribution, or other drug parameters may be altered by such combination or alternation therapy. In general, combination therapy is superior to alternation therapy because the former induces multiple stresses simultaneously to the virus. Formulations of agents that have anti-RSV activity and are therefore useful for combination or alternate administration with one or more formula (IHXXIII) nucleosides have been identified. The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 91949 (Please read the phonetic note on the back first. Then fill out this page) ------—Book·-------- Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Co., Ltd. 93 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 94 1293306 B7 V. Inventions (94) Contains: (a) Ribavirin (Hruska, J. F. et al· "In vivo inhibition of respiratory syncytial virus by ribavirin" Antimicrob Agents Chemother· 1982, 21, 125-130); and (b) purified human intravenous IgG-IVIG (Prince, G. A· Et al. "Effectiveness of topically administered neutralizing antibodies in experimental immunotherapy of respiratory syncytial virus infection in cotton rats" J Virol, 1987, 61, 1851-1954; Prince, GA et al. "Immunoprophylaxis and immunotherapy of respiratory syncytial virus infection in cotton Rats" Infect Immun, 1982, 42, 81-87) o IX. Therapeutic methods for abnormal cell proliferation have been identified as having anti-apoptotic cell proliferation activity and thus can be combined or alternated with one or more formula (IHXXIII) nucleosides Examples of the medicament include: A. Burning 4 sputum nitrogen mustard: Nitrogen (Hawkin's disease, non-Hodgkin's lymphoma), cyclophosphamide, ifosfamide (acute and chronic lymphocytic leukemia) , Hawking's disease, non-Hawkin's lymphoma, multiple myeloma, neuroblastoma, breast, ovary, lung, Wilms' tumor, cervix, testicular, soft tissue sarcoma, amphetamine Melphalan) (Lymphalin) (multiple myeloma, breast, ovary), chlorambucil (Chlorambucil) (chronic lymphocytic leukemia, primary macroglobulinemia, Hawking's disease, non-Hawkin's lymphoma). This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 ------------------! Order ·-------- (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumers Co., Ltd. Printed 1293306 A7 B7 V. Description of Invention (95) Ethylimine and Methyl Melamine: Hexamethyl melamine (ovary), Thiotepa (bladder, breast, ovary). Pyrrolylate: Busulfan (chronic granulocyte leukemia). Nitrosoureas: Carmustine (BCNU) (Hawkin's disease, non-Hodgkin's lymphoma, primary brain tumor, multiple myeloma, malignant melanoma), Cyclohexylnitrite (Lomustine) CCNU) (Hawkin's disease, non-Hawkin's lymphoma, primary brain tumor, small cell lung), Semusting (Methyl-CCNU) (primary brain tumor, stomach, colon), streptozoon Streptozocin (STR) (malignant islet tumor, malignant carcinoma). Three-tillage: Dacarbazine (DTIC; dimethyl tri-n-imidazole-carboxamide) (malignant melanoma, Hodgkin's disease, soft tissue sarcoma). B. Antimetabolite Folic acid analogue: amethopterin (acute lymphocytic leukemia, choriocarcinoma, mycosis fungoides, breast, head and neck, lung, osteosarcoma). Pyrimidine analogues: fluorouracil (5-fluorouracil; 5-FU), 5-fluorodeoxyuridine (FUdR) (breast, colon, stomach, pancreas, ovary, head and neck, bladder, premalignant skin lesions (local) ), Cytarabine (acute granulocytes and acute lymphocytic leukemia). Indole analogs and related inhibitors: 6-hydroxythiopurine (Mercaptopurine; 6-MP) (acute lymphoid, acute granulocytic and chronic myelogenous leukemia), 6-thioguanine (THOguanine; TG) Acute granulocyte, acute lymphocytosis, and chronic granulocyte white blood cells), the paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public meals) 95 91949 (Please read the back of the note? Fill in this page) Participation---------Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 96 1293306

五、發明說明（％ 女抑制素（pentostatin) (2，_去氧賽弗黴素（2，_ deoxyCy〇f〇rmyein))(毛樣細胞白血病、蕈樣肉芽腫、慢性 淋巴球性白血病）。 蔓長春花植物鹼：長春花鹼（VLB)(霍金氏症、非霍金 氏淋巴瘤、乳房、睪丸）、長春新鹼（急性淋巴球性白血病、 神經母細胞癌瘤、威姆氏腫瘤、橫紋肌肉瘤、霍金氏症、 非崔金氏淋巴瘤、小細胞肺）。 表鬼W骨素·依妥賽（Et〇p〇 side)(睪丸、小細胞肺及 其他肺、乳房、霍金氏症、非霍金氏淋巴瘤、急性粒細胞 性白金病、卡波西氏肉瘤）、丹普赛（Tenip〇side)(睪丸、小 細胞肺及其他肺部、乳房、霍金氏症、非霍金氏淋巴瘤、 急性粒細胞性白金球、卡波西氏肉瘤）。 C. 天然產物 抗生素·放射菌素D(絨毛膜癌、威姆氏腫瘤、橫紋肌 瘤、睪丸、卡波西氏肉瘤）、道諾紅菌素（道諾黴素；紅比 黴素）（急性粒細胞性與急性淋巴球性白血病）、道索紅黴素 (Doxorubiein)(軟組織、骨原性及其他癌瘤；霍金氏症、非 霍金氏淋巴瘤、急性白血病、乳房、生殖泌尿道、甲狀腺、 肺、胃、神經母細胞瘤）、博來黴素（3卜〇1113^11)(睪丸、頭 與頸部、皮膚與食道、肺與生殖泌尿道、霍金氏症、非霍 金氏淋巴瘤）、摺皺菌黴素（Plieamyein) (mithraniycin)(睪 丸、惡性高血鈣症）、絲裂黴素（絲裂黴素C)(胃、子宮頸、 結腸、乳房、騰、膀胱、頭與頸部）。 _酵素·· L-天冬胺酸酶（急性淋巴玻性白鈿症、。 本紙張尺度適用中關_準（CNS)A4規^·⑵G χ 297公餐） 91949 (請先閱讀背面之注意事項再填寫本頁)V. Description of the invention (% statostatin (2, _ deoxyCy〇f〇rmyein) (hairy cell leukemia, mycosis fungoides, chronic lymphocytic leukemia) Vinca alkaloids: vinblastine (VLB) (Hawkin's disease, non-Hawkin's lymphoma, breast, testicular), vincristine (acute lymphocytic leukemia, neuroblastoma, Wilms' tumor, Rhabdomyosarcoma, Hodgkin's disease, non-Cui Jin's lymphoma, small cell lung.) E. W 骨 依 (Et〇p〇side) (睪丸, small cell lung and other lungs, breast, Hawking's disease) , non-Hawkin's lymphoma, acute granulocytic leukemia, Kaposi's sarcoma, Tenip〇side (sputum, small cell lung and other lungs, breast, Hawking's disease, non-Hawkin's lymph Tumor, acute granulocyte platinum, Kaposi's sarcoma. C. Natural product antibiotic · actin D (choriocarcinoma, Wim's tumor, rhabdomyomas, testicular, Kaposi's sarcoma), Dao Nuo Erythromycin (danomycin; erythromycin) (acute granulocytes) And acute lymphoblastic leukemia), Doxorubiein (soft tissue, osteogenic and other cancers; Hawking's disease, non-Hodgkin's lymphoma, acute leukemia, breast, genitourinary tract, thyroid, lung, Stomach, neuroblastoma), bleomycin (3 dips 1113^11) (ankle pills, head and neck, skin and esophagus, lung and genitourinary tract, Hodgkin's disease, non-Hawkin's lymphoma), wrinkles Plieamyein (mithraniycin) (sputum pills, malignant hypercalcemia), mitomycin (mitomycin C) (stomach, cervix, colon, breast, sputum, bladder, head and neck). _Enzyme · L-aspartylase (acute lymphatic white chalk disease. This paper scale applies to Zhongguan _ quasi (CNS) A4 regulations ^ (2) G χ 297 public meals) 91949 (Please read the back of the note first Please fill out this page again)

1293306 A7 B7 五、發明說明（97 ) 生物反應改質劑：α -干擾素（毛樣細胞白血病、卡波 西氏肉瘤、黑色瘤、輕癌、腎細胞、卵巢、膀胱、非霍金 氏淋巴瘤、蕈樣肉芽腫、多發性骨髓瘤、慢性粒細胞性白 金病）。 D. 其他製劑 鉑配位錯合物：順氯胺鉑（Cisplatin)(順式-DDP) (Carboplatin)(睪丸、卵巢、膀胱、頭與頸部、肺、甲狀腺、 子宮頸、子宮内膜、神經母細胞瘤、骨原性肉瘤）。 蒽二酮：米散酮（Mixtozantrone)(急性粒細胞性白血 病、乳房）。 經取代之脲：羥基脲（慢性粒細胞白血病、紅血球過多 症、自發性企小板增多症、惡性黑色瘤）。 甲基肼衍生物：甲基T肼（N-甲基肼，MIH)(霍金氏 症）。 腎上腺皮質抑制劑：米特丹（Mitotane)(o，p’-DDD)(腎 上腺皮質）、胺基導眠能（Amino-glutethimide)(乳房）。 腎上腺皮質類固醇：潑尼松（Prednisone)(急性與慢性 淋巴球性白血病、非霍金氏淋巴瘤、霍金氏症、乳房）。 黃體製劑：羥基黃體酮癸酸鹽、甲孕酮乙酸鹽、甲地 孕酮乙酸鹽（子宮内膜、乳房）。 E. 抗新血管形成劑 血管抑制素（angiostatin)、内生抑制素（endostatin)。 F. _激素與拮抗劑 雌激素：己烯雌酚乙炔雌二醇（乳房、攝護腺）。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 9T 91949 (請先閱讀背面之注意事項再填寫本頁) , 訂---------率 經濟部智慧財產局員工消費合作社印製 1293306 Α7 Β7 五、發明說明（98 ) 抗雌激素：塔莫希芬（Tamoxifen)(乳房）。 雄激素：睪固酮丙酸鹽弗索睪固酮（Fluxomyesterone) (乳房）。 抗雄激素：弗塔醯胺（Flutamide)(攝護腺）。 促性腺激素釋放激素類似物：白普萊德（Leuprolide) (攝護腺）。 X.合成法 式（I)-(XXIII)化合物可依相關技藝已知之任何方式合 成。特定言之，可利用三種不同途徑製備化合物：（a)由預 先形成之核苷製備；（b)由經修飾之糖或未修飾之核糖與嘌 呤或嘧啶縮合，及（c)組合這二種途徑。自從在核苷抗生 素：蟲草素（cordycepin)中發現3-去氧-D-咲喃赤蘚戊糠結 構以後，I960年代即有報告提出許多種此抗生素之完全合 成法（參見 Lee，W. W. et al. J. Am. Chem. Soc.r 1961，83， 1906; Walton, E. et al. J. Am. Chem. Soc.: 1964，86，2952; Suhadolnik, R. J. et al. Carbohvdr. Res . 1968, 61,545; Ikehara，M. et al· Chem. Pharm. Bull.. 1967, 15,94; Kaneko, M· et al· Chem. Pharm. Bull. 1972, 20, 63) 〇 在本發明較佳 具體實施例中，由核苷製備3’-去氧核苷之方法如下： A. Ia-c與IIIa-c型化合物 (i)由預先形成之核苷合成： 依 Marumoto，R. et al· Chem. Pharm. Bull. 1974, 22， 128之說明，其中以乙醯溴處理N4-乙醯基胞苷，產生2’，5’-二-Ο-乙醯基-3’-溴-3’-去氧-冷-D-呋喃木糖基-胞嘧啶（（2)， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) 參 訂---------線· 經濟部智慧財產局員工消費合作社印製 98 1293306 Α7 ---- Β7 五、發明說明（99 ) R=Ac)，N4-受保護之胞苷核苷則可依反應圖1所示，衍生 形成嘧啶核苷（I-a) 反應圖11293306 A7 B7 V. INSTRUCTIONS (97) Biological response modifier: α-interferon (hairy cell leukemia, Kaposi's sarcoma, melanoma, light cancer, kidney cells, ovary, bladder, non-Hawkin's lymphoma , mycosis fungoides, multiple myeloma, chronic myeloid platinum disease). D. Other formulations Platinum coordination complex: Cisplatin (cis-DDP) (Carboplatin) (sputum, ovary, bladder, head and neck, lung, thyroid, cervix, endometrium, Neuroblastoma, osteogenic sarcoma). Anthraquinone: Mixtozantrone (acute granulocyte leukemia, breast). Substituted urea: hydroxyurea (chronic myeloid leukemia, erythrocytosis, spontaneous thyroid hyperplasia, malignant melanoma). Methyl hydrazine derivative: methyl T肼 (N-methyl hydrazine, MIH) (Hawkin's disease). Adrenal cortical inhibitors: Mitotane (o, p'-DDD) (adrenal cortex), Amino-glutethimide (breast). Adrenal corticosteroids: Prednisone (acute and chronic lymphocytic leukemia, non-Hodgkin's lymphoma, Hawking's disease, breast). Lutein preparations: hydroxyprogesterone citrate, medroxyprogester acetate, megestrol acetate (endometrium, breast). E. Anti-angiogenic agents Angiostatin, endostatin. F. _ hormones and antagonists Estrogen: diethylstilbestrol ethinyl estradiol (breast, prostate). This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 9T 91949 (please read the note on the back and fill out this page), order --------- rate Ministry of Economics intellectual property Bureau employee consumption cooperative printed 1293306 Α7 Β7 5, invention description (98) anti-estrogen: Tamoxifen (breast). Androgen: steroidal propionate Fluxomyesterone (breast). Antiandrogen: Flutamide (prostate). Gonadotropin-releasing hormone analogue: Leuprolide (prostate). X. Synthetic Methods The compounds of formula (I)-(XXIII) can be synthesized in any manner known in the art. In particular, compounds can be prepared in three different ways: (a) from pre-formed nucleosides; (b) condensation of modified or unmodified ribose with purine or pyrimidine, and (c) combination of these two way. Since the discovery of the structure of 3-deoxy-D-purpurin quinone in the nucleoside antibiotic: cordycepin, many synthetic methods for this antibiotic have been reported in the 1960s (see Lee, WW et al). J. Am. Chem. Soc.r 1961, 83, 1906; Walton, E. et al. J. Am. Chem. Soc.: 1964, 86, 2952; Suhadolnik, RJ et al. Carbohvdr. Res. 1968, 61,545; Ikehara, M. et al. Chem. Pharm. Bull.. 1967, 15, 94; Kaneko, M. et al. Chem. Pharm. Bull. 1972, 20, 63) Preferred embodiments of the invention Among the methods for preparing 3'-deoxynucleosides from nucleosides are as follows: A. Ia-c and IIIa-c type compounds (i) are synthesized from pre-formed nucleosides: according to Marumoto, R. et al. Chem. Pharm Bull. 1974, 22, 128, in which N4-acetyl cytidine is treated with acetamidine bromide to produce 2',5'-di-indole-ethenyl-3'-bromo-3'-deoxygenated -Cold-D-furanosyl-cytosine ((2), this paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (Please read the note on the back and fill out this page) Participation---------Line · Ministry of Economic Affairs Hui Property Bureau employee consumption cooperative printed 98 1293306 Α7 ---- Β7 5, invention description (99) R = Ac), N4-protected cytidine nucleoside can be derivatized to form pyrimidine nucleus according to the reaction shown in Figure 1. Glycoside (Ia) reaction Figure 1

6a X = Br 6b X=H6a X = Br 6b X=H

55

(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 N4-受保護之D-胞苷核苷（1)可經醯基鹵化物（如··乙醯 溴）處理，產生相應之3，_鹵代木糖基-核苷（2)。（2)脫除乙 酿基’形成（3)，然後進行還原性脫除A基反應，產生所需 之去氧胞苷衍生物（4)。以酸處理（2)，以沸騰之乙酸水 溶液較佳，產生相應之受保護之尿嘧啶核苷（5)，其很容易 轉化成游離之3’-溴-木糖基核苷（6a)，經還原性脫除溴基 反應’即可得到3’-去氧尿苷衍生物（6b)。依類似方法，由 N4-^：保護之l_胞苷開始，可合成（4)與（6)之L_對映異構物 (III-a) 〇 _^ 一項製備核苷I-a之具體實施例中，由核糖核苷進 本紙張尺度適时國國家標準（CNS)A4規格⑵◦ χ 297公爱--------- 99 91949 訂---------線· 1293306 A7 B7 五、發明說明（1⑻） 行2%5’-二-〇_三苯甲基化反摩，產生（7)(112=1^，=1^)，再 轉化成相應之3，-0-甲磺酸酯（8)(反應圖2)-以稀氫氧化鈉 或化鉀處理（8)，經由脫水核苷（9)產生相應之木糖基衍生物 (1〇)，脫除Ο-三苯甲基後，產生（12)。（10)經甲磺酸化後， 脫除Ο-三苯甲基，產生3，-0-甲磺醯基-木糖基-核苷。當 以溴化鋰或碘化鈉處理（8)時，經由（9)形成相應之3，-去氧 -3’鹵基衍生物，經脫除〇_三苯甲基後，氳解，轉化成所 需3’-去氧尿苷衍生物（6b)。依類似方式，由l-核糖核苷開 始’合成（4)與（6)之 L-核脊（III_ a)對映體（counterparts)。 反應圖2 (請先閱讀背面之注音？事項再填寫本頁} 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製(Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed N4-protected D-cytidine nucleosides (1) can be thiol-based halides (eg · ethyl bromide) Processing to produce the corresponding 3,-haloxylosyl-nucleoside (2). (2) Removal of the B-formation (3), followed by reductive removal of the A-based reaction to produce the desired deoxycytidine derivative (4). Treatment with acid (2), preferably with boiling aqueous acetic acid, produces the corresponding protected uridine (5) which is readily converted to the free 3'-bromo-xylosyl nucleoside (6a). The 3'-deoxyuridine derivative (6b) can be obtained by reductively removing the bromine group reaction. According to a similar method, starting from N4-^: protected l-cytidine, the L_enantiomer (III-a) (_^ of (4) and (6) can be synthesized to prepare a specific nucleoside Ia. In the examples, the ribonucleoside enters the paper size and the national standard (CNS) A4 specification (2) ◦ 297 297 public--------- 99 91949 order--------- line · 1293306 A7 B7 V. Description of the invention (1(8)) Line 2% 5'-di-〇-trityl methylation anti-friction, yield (7) (112=1^,=1^), and then convert to the corresponding 3 ,-0-methanesulfonate (8) (reaction diagram 2) - treatment with dilute sodium hydroxide or potassium (8), the corresponding xylosyl derivative (1 〇) is produced via a dehydrated nucleoside (9), After the oxime-trityl group is removed, (12) is produced. (10) After mesylation, the oxime-trityl group is removed to produce 3,-0-methylsulfonyl-xylosyl-nucleoside. When (8) is treated with lithium bromide or sodium iodide, the corresponding 3,-deoxy-3'halo derivative is formed via (9), and after deuterium-tritylmethyl is removed, it is decomposed and converted into a A 3'-deoxyuridine derivative (6b) is required. In a similar manner, the L-nuclear ridge (III_a) enantiomers of (4) and (6) are synthesized by l-ribonucleosides. Reaction Figure 2 (Please read the phonetic on the back? Please fill out this page again.) Ministry of Economic Affairs, Intellectual Property, Bureau of Staff, Consumers, Co-operatives, Printing

ι-b型化合物嘌呤核苷之製備實例為合成3、去氧嘌呤 核苷（反應圖3)。以2-甲氧異丁醯基自化物（X=C1或Br)處 理核糖核苷（13)，產生3，-齒基·呋喃木糖基與2,_齒基_呋喃 阿拉伯糖基衍生物（⑽與⑽）。^解後m雜，盡今 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公31 )""""""' 100 91949 --------訂---------線·An example of the preparation of the ι-b type guanidine nucleoside is synthesis 3, deoxypurine nucleoside (reaction Figure 3). Treatment of ribonucleosides (13) with 2-methoxyisobutylindolyl (X=C1 or Br) to give 3,-dentyl-furanose and 2,-dentyl-furan arabinosyl derivatives ((10) With (10)). ^ After the solution, the paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public 31)""""""' 100 91949 -------- Order ---------Line·

[293306 五、發明說明（101 ) 相應之3、去氧核苷（1 2， 產生所需之3、去氧核則2〇、氣核甘（16)。（17)皂化後， 混合物，產4 I 人 )〇以鹼處理（14)與（15)之反應 此〇物，產生全收量之 仆轴声搜眩 衣氣化物（18)，當以碘化銨或 化鈉處理時，只產生3，_ 心 $糖基硬（19)。（19)氫解產生（20)。 (18)經還原劑（如： 產生（2〇)。 ，、虱化鋰鋁或氳硼化鈉）還原，亦 依類似方法，由嘌a τ τ , 、 核糖核苷開始，可合成（20)之 L-核甘對映體，屬於III_b。 反應圖3 核苷（反應圖4)。於溶劑中（如：醇或二甲基甲醯胺），於2< 艺至loot之溫度範圍内（以25。0至8〇t>c較佳），以疊氮仆 物離子處理5-確基尿苷（(21)，見上文）。疊氮化物離子與（21 之C-6進行親核性反應’形成酸式硝基鹽（22)，環化成 Μ氏張尺度腳帽國家鮮（CNS)A4規格（210 X 297"^ϋ~'~---- 91949 (請先閱讀背面之注意事項再填寫本頁) 0 經濟部智慧財產局員工消費合作社印製[293306 V. Inventive Note (101) Corresponding to 3. Deoxynucleoside (1 2, 3 required for production, 2 去 for deoxygen nucleus, 气 气 (16). (17) After saponification, mixture, production 4 I person) 〇 碱 碱 碱 碱 碱 碱 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应Produces 3, _ heart $ sugar base hard (19). (19) Hydrogenolysis (20). (18) Reduction by a reducing agent (such as: (2〇), lithium aluminum hydride or sodium bismuth boride), and similarly, starting from 嘌a τ τ , ribonucleoside, synthesis (20 The L-nucleoside enantiomer, which belongs to III_b. Reaction Figure 3 Nucleosides (Reaction Figure 4). In a solvent (such as alcohol or dimethylformamide), in the temperature range of 2 < art to loot (preferably 25.0 to 8 〇t > c), treated with an azide servant ion 5- Indeed uridine ((21), see above). The azide ion reacts with the (21 C-6 nucleophilic reaction to form an acid nitro salt (22), which is cyclized into a 尺度张张尺脚帽国鲜(CNS) A4 specification (210 X 297"^ϋ~ '~---- 91949 (Please read the note on the back and fill out this page) 0 Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative

101 訂---------線· 1293306 A7 B7 五、發明說明（ ） (23)。（23)中和後，產生雙環狀核苷（24)。 反應圖4101 Order --------- Line · 1293306 A7 B7 V. Invention Description ( ) (23). (23) After neutralization, a bicyclic nucleoside (24) is produced. Reaction Figure 4

(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 102 (ii)適當糖與驗基之縮合合成法 必須合成適當糖衍生物，供與特定鹼基縮合。雖然已 有數種合成3-去氧-D_呋喃赤蘚戊糖（3-去氧_D-呋喃核糖） 衍生物（參見：Lee, W· W· et al· J. Am Chem Sion 1961，83, 1906; Walton, E. et al. J. Am. Chem. Soc 1964，86，2952; Lin，T.-S. et al· L Med Chem 1991，34, 693; Ozols，A. M· et al·細thesis，1980，：557)之方法，但現已為本發明發展 出新方法，如反應圖5所示。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 1293306 A7 B7 五、發明說明（(Please read the precautions on the back and fill out this page.) Printed by the Ministry of Economic Affairs, Intellectual Property Office, Employees' Cooperatives 102 (ii) Condensation synthesis of appropriate sugars and assays It is necessary to synthesize appropriate sugar derivatives for condensation with specific bases. Although several derivatives of 3-deoxy-D_furan erythrose pentose (3-deoxy-D-ribofuranose) have been synthesized (see: Lee, W. W. et al. J. Am Chem Sion 1961, 83) , 1906; Walton, E. et al. J. Am. Chem. Soc 1964, 86, 2952; Lin, T.-S. et al. L Med Chem 1991, 34, 693; Ozols, A. M· et al The method of thesis, 1980,: 557), but a new method has been developed for the present invention, as shown in Figure 5. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 1293306 A7 B7 V. Description of invention (

(請先閱讀背面之注意事項再填寫本頁) 由1，2-0-亞異丙基-5-0-甲氧讓基-ck -D -咲啥木糖（2 5 ) 轉化成相應之3-硫羰基衍生物（26)，然後使用三烷基錫氫 化物，於自由基引發劑（如：2,2’-偶氮雙異丁腈）之存在下， 進行游離自由基去氧化反應。去氧產物（27)使用乙酸、乙 酸酐與硫酸之混合物醯化，產生（28)，再與矽烷化鹼基， 使用 Vorbruggen 氏方法縮合（參見 Niedballa，U· et al· L· Org. Chem…1976，41,2084; Vorbruggen, H. et al. Chem丄 Ber…1981，114，1234; Kazinierczuk，Z. et al· J. Am. Chem· Soc·· 1984, 106, 63 79)，得到嘧啶核苷（29)(I-a型）或相關之 嘌呤核苷（I-b型）。5-0H基或可使用其他醯基，如··苯甲 醯基、對硝基苯甲醯基、對氣苯甲醯基或對甲氧苯甲醯基， 及其他矽烷基保護，如··第三丁基二甲矽烧基或第三丁基 二苯基。同樣地，L-木糖亦可轉化成（25)之L-糖對映體， 其再衍化成（30)之L-核苷。 或者，如反應圖6所示，以甲磺醯氯、甲苯磺醯氯或 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 訂---------線- 經濟部智慧財產局員工消費合作社印剩衣 103 1293306 A7 B7 五、發明說明（1G4 ) 三敗乙磺醯氣（tresyl chloride)，於D比唆中’與l，2-0-亞異 丙基-5-0-(第三丁基二苯矽烷基）-a -D-呋喃木糖（31)進行 磺酸化，得到（32)。（32)經甲醇分解後，以鹼（如：甲醇鈉 之甲醇溶液）處理甲基木糖苷（33)，產生核糖-環氧化物 (34)。環氧化物（34)經氫化鋁進行立體選擇性開環反應，產 生3-去氧糖（36)。於丙酮或2-丁酮中，以溴化鋰或碘化鈉 處理（34)，產生3-i基-3-去氧木糖苷（3 5)。（3 5)進行還原 性脫除鹵基反應，產生（36)。以氟離子來源（如：含三正丁 基銨化氟之四氫呋喃或三乙基銨氟化氫）脫除5’-矽烷基保 護基，產生（37)。於硫酸之存在下，以乙酸酐及乙酸與（37) 進行醯化反應，產生三-0-乙醯基-3-去氧_D-咲喃核糖 (38)。此外，（33)經氟化物處理，轉化成（39)，乙醯化時， 產生（40)。這些乙醸化糖（3 8)與（40)可採用¥〇1*1>1*1^88611氏 方法，與全三甲碎烧基化癌唆或嗓呤驗基縮合’產生3’-經修飾之核苷。第三丁基二苯矽烷基保護基可改用第三丁 基二甲矽烷基。 反應圖6 --------------------訂---------線· (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(Please read the note on the back and fill out this page) Convert 1,2-0-isopropylidene-5-0-methoxy-keto-k-D-xylose (2 5 ) into the corresponding 3-thiocarbonyl derivative (26), followed by free radical deoxidation using a trialkyltin hydride in the presence of a free radical initiator such as 2,2'-azobisisobutyronitrile . The deoxygenated product (27) is deuterated using a mixture of acetic acid, acetic anhydride and sulfuric acid to give (28), which is then condensed with a decanolated base using the Vorbruggen method (see Niedballa, U. et al. L. Org. Chem... 1976, 41, 2084; Vorbruggen, H. et al. Chem丄Ber...1981, 114, 1234; Kazinierczuk, Z. et al. J. Am. Chem. Soc·· 1984, 106, 63 79), obtaining a pyrimidine nucleus Glycoside (29) (type Ia) or related purine nucleoside (type Ib). 5-0H groups may be used with other sulfhydryl groups, such as benzoyl sulfonyl, p-nitrobenzylidene, p-benzoyl fluorenyl or p-methoxybenzyl hydrazino, and other decyl groups, such as • Tert-butyl dimethyl decyl or tert-butyl diphenyl. Similarly, L-xylose can also be converted to the L-saccharide enantiomer of (25), which is re-derivatilized into the L-nucleoside of (30). Or, as shown in Figure 6, the standard of China National Standard (CNS) A4 (210 X 297 mm) is applied to methane sulfonium chloride, toluene sulfonium chloride or this paper scale. 91949 Order --------- Line - Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed Cloth 103 1293306 A7 B7 V. Invention Description (1G4) Three defeated tresyl chloride, in D 唆 ' ' and l, 2-0-Asian The propyl-5-0-(t-butyldiphenylnonyl)-a-D-furanose (31) is sulfonated to give (32). (32) After decomposition by methanol, methyl xyloside (33) is treated with a base (e.g., a solution of sodium methoxide in methanol) to produce a ribose-epoxide (34). The epoxide (34) undergoes a stereoselective ring opening reaction with aluminum hydride to produce 3-deoxy sugar (36). Treatment of (34) with lithium bromide or sodium iodide in acetone or 2-butanone yields 3-i-yl-3-deoxyxyloside (3 5). (3) Performing a reductive removal of the halogen group to produce (36). The 5'-nonylalkyl protecting group is removed by a fluoride ion source (e.g., tetrahydrofuran or triethylammonium fluoride containing tri-n-butylammonium) to give (37). The deuteration reaction with acetic anhydride and acetic acid (37) in the presence of sulfuric acid yields tris--0-ethylindol-3-deoxy-D-pyranose (38). Further, (33) is converted to (39) by fluoride treatment, and (40) is produced when acetylated. These acetylated sugars (38) and (40) can be condensed with the whole trimethoprim carcinoid or sputum by the method of ¥〇1*1>1*1^88611. Modified nucleoside. The third butyl diphenyl fluorenyl protecting group can be changed to a third butyl dimethyl sulfonyl group. Reaction Figure 6 -------------------- Order --------- Line · (Please read the notes on the back and fill out this page) Intellectual Property Bureau employee consumption cooperative printing

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 104 91949 1293306This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 104 91949 1293306

五、發明說明（1〇5 ) (ii〇合成後修飾法（1_6) (a)於’唆核苷之C-4進行修飾（I_a與 (28)或（38)與尿嘧啶或5_經 ^之尿嘧咬縮合後， 3五硫化狀較或切森試劑苯處理3，_去氧 衍生物（(29)’R5=Ch3〇co，r2=A(^r5=r2=Ac)，產 4 4·硫尿料核苷⑷），當以氨處理時，轉化成3，_去氧胞书 (43’Ri=R2=H)。或者，⑷）與甲基蛾或硫酸二甲醋於鹼_ 進行甲基化’產生4-S-甲基衍生物（42)。以各種親核性奉 置換（42)之4-S-甲基，產生相應之N4_經取代之3，_去氧康 有2 (43)。（29)亦可轉化成4-(三唑-2-基）衍生物（44),再與肩 或各種不同胺反應，產生（43)。或者，以各種醇或笨酚肩 理（44)，產生相應之4_〇_經取代之3，-去氧尿脊。 反應圖7 *V. DESCRIPTION OF THE INVENTION (1〇5) (ii) Post-synthesis modification method (1_6) (a) Modification of C-4 of 'purine nucleoside (I_a and (28) or (38) with uracil or 5_ ^ After the urinary thief bite condensation, 3 five-sulfurized or cleavage reagent benzene treatment 3, _ deoxy derivatives ((29) 'R5 = Ch3 〇 co, r2 = A (^r5 = r2 = Ac), produced 4 4 thiourea nucleoside (4)), when treated with ammonia, converted to 3,_deoxygenated (43'Ri=R2=H). Or, (4)) with methyl moth or dimethyl sulphate Alkaline _ methylation' yields a 4-S-methyl derivative (42). Substituting a variety of nucleophiles to replace the 4-S-methyl group of (42), resulting in a corresponding N4_substituted 3, _ Oxygen has 2 (43). (29) can also be converted to 4-(triazol-2-yl) derivatives (44), which are then reacted with shoulders or various amines to give (43). Alternatively, various alcohols Or stupid phenolic shoulder (44), resulting in a corresponding 4_〇_ substituted 3,-deoxyurinary ridge. Reaction Figure 7 *

£X (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£X (please read the notes on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

39，R2* =甲’ =Ac39, R2* = A' = Ac

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43 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 105 9194943 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 105 91949

1293306 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（1〇0 或者，由尿嘧啶核苷（如：糖受保護之尿苷（45)(R=H) 轉化成4-(甲基咪唑琳鎗）（46)(反應圖8)或4-0-(2,4,6-三異 丙基苯磺醯基）中間物（47)，然後以親核性劑處理，如：羥 胺，產生相應之C-4經修飾之核苷，如：N4-羥基-胞苷 ((48)，R=H) 〇 反應圖81293306 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (1〇0 or, by uridine nucleoside (such as: sugar protected uridine (45) (R = H) converted to 4- ( Methylimidazolium gun (46) (reaction Figure 8) or 4-0-(2,4,6-triisopropylbenzenesulfonyl) intermediate (47), then treated with a nucleophilic agent, such as : Hydroxylamine, producing the corresponding C-4 modified nucleoside, such as: N4-hydroxy-cytidine ((48), R=H) 〇 Reaction Figure 8

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0 46 r5〇\^J r3ooi0 46 r5〇\^J r3ooi

OF^ 47OF^ 47

0 依類似方法，由L-核苷對映體開始，製備相應之III- 汪核苷。 (b)嘧啶核苷之C-5之修飾法（I-a與III-a) ⑴鹵化法（反應圖9) 以氟化劑氟化3’-去氧尿苷（（6)，R=H)，氟化劑之一些 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 106 91949 (請先閱讀背面之注意事項再填寫本頁) --------II--------- 1293306 A7 B7 五、發明說明（ 107 灵例包含含氟之乙酸、含Selectfluor之惰性溶劑（如：四 虱咲喃）或含氟氧硫酸铯（cesium fluoroxi sulfate)之醇（參見 Stovber, S. et al. Jt.Chem. Soc Them. Cn^m1in 1983， 563) ’產生5_氟_3’_去氧尿苷。使用適當N_鹵代琥珀 醯亞胺得到5-氯、5-溴及5-碘尿苷衍生物（50_52)。以含溴 之水或含碘之乙酸，於氧化劑（如：硝酸）之存在下處理， 分別產生5-溴或5-碘-尿嘧啶核苷，胞嘧啶衍生物（43)(R=H) 亦可轉化成相應之5 -鹵基衍生物（44-56)。5 -氟-3，-去氧胞杳（53，R=H)之製法係由（28)或（38)與％氟胞嘧啶縮合後， 皂化。 反應圖9 (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In a similar manner, starting from the L-nucleoside enantiomer, the corresponding III-Wang nucleoside is prepared. (b) Modification of C-5 of pyrimidine nucleoside (Ia and III-a) (1) Halogenation method (Reaction Figure 9) Fluoration of 3'-deoxyuridine with a fluorinating agent ((6), R = H) Some of the fluorinating agents are applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 106 91949 (Please read the notes on the back and fill out this page) --------II- -------- 1293306 A7 B7 V. INSTRUCTIONS (107) The example contains fluorine-containing acetic acid, an inert solvent containing Selectfluor (such as tetrahydrofuran) or cesium fluoroxi sulfate. Alcohol (see Stovber, S. et al. Jt. Chem. Soc Them. Cn^m1in 1983, 563) 'Production of 5-fluoro-3-3'-deoxyuridine. Use of appropriate N-haloarene quinone to give 5 - Chlorine, 5-bromine and 5-iodouridine derivatives (50_52). Treatment with bromine-containing water or iodine-containing acetic acid in the presence of an oxidizing agent (eg nitric acid) to produce 5-bromine or 5-iodine, respectively - uridine, cytosine derivative (43) (R = H) can also be converted to the corresponding 5-halo derivative (44-56). 5-fluoro-3,-deoxycytidine (53, The method of R=H) is saponified by condensation of (28) or (38) with % fluorocytosine. Reaction Figure 9 (Please read the notes on the back and fill out this page) Printed by the Ministry of Economic Affairs, Finance and Industry Bureau

依類似方式，由L-核苷對映體開始，製備相應之ΠΙ-a核苷，反應圖1〇說明溴化化合物”經碳酸氫鈉溶液處 理，轉化成5-羥基-3，-去氧尿苷（63)。（55)經烷基碘使用鹼 進行烷化，產生（62)。（51)與鹼金屬氰化物長期反應，產生 l_^氰基尿嘧$衍生物（57)，經水合後，產生5_羧醯胺（58) 本紙張尺度適时國國家標準（CNS)A4規格⑵q χ撕公髮1--- 107 91949 訂---------線- 1293306 A7 -----B7 __ 五、發明說明（108 ) 及5_羧酸（5 9)。（59)轉化成燒基酯（6〇)後，經氫硼化納還 原產生％經甲基衍生物（61)。化合物（6〇)亦可經二氫u比 喃及觸媒量之酸（如：鹽酸、硫酸或對甲苯磺酸）處理，產 生2’，5、二·〇_受保護之核苷（64)。（64)經氫硼化鈉還原， 產生（65)。利用（65)之烯丙基性質，以甲磺醯氯或甲苯磺醯 亂處理’產生5-氯甲基尿痛唆衍生物（66)。（66)經烧醇鹽 處理後，脫除保護，產生相應之5-烷氧甲基-3，-去氧尿香 (69)。同樣地，由各種不同胺與（66)反應，產生（67)，經溫 和酸水解時，轉化成（68)。與（66)及硫脲反應，產生氫硫基 甲基衍生物（70，R=H)，而以硫醇鈉處理，則產生硫烷基 衍生物（70)(R=烷基），其可經過氧化氫氧化，形成相應之 碾（71)。依類似方式，由L-核苷對映體開始，製備相應之 ΙΙΙ-a核苷。 (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 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 108 91949 A7 1293306 _B7 五、發明說明（1G9 ) 反應圖10In a similar manner, starting from the L-nucleoside enantiomer, the corresponding ruthenium-a nucleoside is prepared. The reaction diagram 〇 illustrates that the brominated compound is treated with sodium bicarbonate solution and converted to 5-hydroxy-3,-deoxygenated. Uridine (63). (55) alkylation with an alkyl iodine using a base to give (62). (51) long-term reaction with an alkali metal cyanide to give a cyanoquinoline derivative (57). After hydration, produce 5_carboxamide (58) This paper scales the national standard (CNS) A4 specifications (2) q χ tearing hair 1--- 107 91949 order --------- line - 1293306 A7 -----B7 __ 5, invention description (108) and 5_carboxylic acid (5 9). (59) after conversion to alkyl ester (6 〇), sodium reduction by borohydride to produce % methyl-derived Compound (61). Compound (6〇) can also be treated with dihydro-u-pyrene and a catalytic amount of acid (such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid) to produce 2',5,2·〇_protected. Nucleoside (64). (64) Reduction by sodium borohydride to give (65). Using the allyl nature of (65), treatment with methanesulfonyl chloride or toluene to produce 5-chloromethyl Urinary sputum derivative (66). (66) After treatment with burning alkoxide In addition to protection, the corresponding 5-alkoxymethyl-3,-deoxyurethane (69) is produced. Similarly, the reaction of (67) with various amines produces (67), which is converted to a mild acid hydrolysis. (68) reacting with (66) and thiourea to produce a thiomethylmethyl derivative (70, R = H), while treating with sodium thiolate produces a thioalkyl derivative (70) (R = alkane) Base), which can be oxidized by oxidation to form the corresponding mill (71). In a similar manner, starting from the L-nucleoside enantiomer, the corresponding ΙΙΙ-a nucleoside is prepared. (Please read the notes on the back first. Fill in this page) --------Book----------Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed This paper scale applies China National Standard (CNS) A4 specification (210 X 297 mm) 108 91949 A7 1293306 _B7 V. Description of invention (1G9) Reaction diagram 10

68 69 70 71 (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制衣 (ii)硝化反應（反應圖11) 以含四氟硼酸銷鹽之環丁楓處理尿苷（6)(參見Huang， G.-F. et al. J Org Chem.. 1977? 42? 3281; Huang, G.-F. et al· J. Carbohvd. Nucleosides Nucleotides. 1978，5，317)，產 生相應之5-硝基衍生物（72)。硝基核苷（72)經催化性氫化 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐) 109 91949 1293306 A7 ______ B7 五、發明說明（11G ) 法，產生相應之5-胺基衍生物（73)。（73)經亞硝酸重氮化， 產生5-重氮基-3’-去氧尿苷（74)，當水解時，轉化成1，2,3-三唑（75)。已有報告提出5·胺基尿苷轉化成核糖矽烷基三 坐之類似反應（參見 Roberts, M· et al· J. Am Cherru Soc〕 1952, 74, 668; Thurber，T. C. et al. J. Am Chem. Soc 1973, 95, 3081; JL一Org，Chem·，1976, 41，1041)。（72)與疊氮化鈉 於二甲基甲醯胺中反應，產生三唑並嘧啶（8-氮雜嘌呤）核 苷（76)。 依類似方式，由L-核脊對映體開始，製備相應之πΐ-a核苷。 反應圖1168 69 70 71 (Please read the note on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printing and Printing (ii) Nitrification (Reaction Figure 11) Treated with Dingfengfeng containing tetrafluoroboric acid salt Uridine (6) (see Huang, G.-F. et al. J Org Chem.. 1977? 42? 3281; Huang, G.-F. et al. J. Carbohvd. Nucleosides Nucleotides. 1978, 5,317 ), the corresponding 5-nitro derivative (72) is produced. The nitronucleoside (72) is catalytically hydrogenated. The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 109 91949 1293306 A7 ______ B7 V. The invention description (11G) method produces the corresponding 5- Amino derivative (73). (73) by diazotization of nitrous acid to give 5-diazo-3'-deoxyuridine (74) which, when hydrolyzed, is converted to 1,2,3-triazole (75). A similar reaction has been reported to convert quinone uridine to ribose sulphate (see Roberts, M. et al. J. Am Cherru Soc) 1952, 74, 668; Thurber, TC et al. J. Am Chem. Soc 1973, 95, 3081; JL-Org, Chem., 1976, 41, 1041). (72) reacting with sodium azide in dimethylformamide to produce a triazolopyrimidine (8-azaindole) nucleoside (76). In a similar manner, starting from the L-nucleus ridge enantiomer, the corresponding πΐ-a nucleoside is prepared. Reaction Figure 11

一系列類似反.應示於反應圖12中，由3’-去氧胞苷（4) 製得5-硝基-3’-去氧胞苷（77)，然後形成5-胺基-3，-去氧胞 有^7 8)。然而，以亞硝酸處理（78)，可形成另一種8-氮雜 嘌呤核苷（79)。相同反應順序可用於相應之L-核香。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (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 110 1293306A series of similar inverses should be shown in Reaction Scheme 12 to obtain 5-nitro-3'-deoxycytidine (77) from 3'-deoxycytidine (4) and then form 5-amino-3. , - deoxygenated cells have ^ 7 8). However, treatment with nitrous acid (78) results in the formation of another 8-azaindole nucleoside (79). The same reaction sequence can be used for the corresponding L-nuclear fragrance. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 (Please read the note on the back and fill out this page) Order---------Line· Ministry of Economic Affairs Intellectual Property Bureau Employee consumption cooperative printed 110 1293306

五、發明說明（111 ) 反應圖12V. Description of the invention (111) Reaction Figure 12

(iii)羧甲基化反應 於驗中（如：氫氧化钟或氫氧化鈉水溶液），以甲駿處 理（6)(R=H，R5 =R3 =R3”H)，產生5_羥甲基-3’-去氧尿苷 (80)，如反應圖13所示，經鹽酸之乙醇溶液處理，轉化成 5-乙氧甲基-3’·去氧尿苷（81，X=OCH2CH3)。化合物（80) (R5’=R3’ = TBDPS)亦可由胸腺，咬衍生物（6)(R=CH3，R5’ = R3’ = TBDPS)經光化學溴化反應製得（81)(X=Br)後，水解而 成（Matulic-Adamic, J.et al· Chem. Pharm Hull 1988，36, 1554)。化合物（80)與鹽酸反應，轉化成5-氣甲基衍生物 (81，X=C1)，或經二乙胺基硫三氟化物（DAST)處理，轉化 成 5-氟甲基衍生物（81，X=F>(80)(R5 =R2=TBDPS，R3”=H) 經二氧化錳氧化，產生5-甲醯基衍生物（82)，其係各種不 同反應之良好受質，包括Wittig反應、Wittig-Horner反應、 Grignard反應或Reformatsky反應。例如：（82)經乙氧亞甲 基三苯基磷烷[EtOC(=0)CH=PPh3]處理，產生5_(2_乙氧羰 基）伸乙基-3’-去氧尿苷衍生物（83)，其可經由5-(伸乙基-2-羧酸）衍生物（84)轉化成5-伸乙基-、5-(2-氣伸乙基）-或 5-(2-溴伸乙基）-3’-去氧尿苷衍生物（85)。以DAST處理 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注音？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 111 1293306 A7 ___________ B7 五、發明說明（112 ) (82)，得到5-二氟甲基衍生物（86)。這些合成途徑均示於 反應圖13。 相同之反應順序可應用於相應之L-核苷ΙΙΙ-a。 反應圖13(iii) carboxymethylation reaction in the test (such as: hydrazine clock or sodium hydroxide aqueous solution), treated with AJ (6) (R = H, R5 = R3 = R3 "H), resulting in 5-hydroxyl Base-3'-deoxyuridine (80), as shown in Figure 13, is treated with ethanolic hydrochloric acid to convert to 5-ethoxymethyl-3'-deoxyuridine (81, X = OCH2CH3) Compound (80) (R5'=R3' = TBDPS) can also be obtained by photochemical bromination of thymus, bite derivative (6) (R=CH3, R5' = R3' = TBDPS) (81) (X After =Br), it is hydrolyzed (Matulic-Adamic, J. et al. Chem. Pharm Hull 1988, 36, 1554). Compound (80) is reacted with hydrochloric acid to be converted into a 5-methylmethyl derivative (81, X). =C1), or treated with diethylaminosulfur trifluoride (DAST), converted to 5-fluoromethyl derivative (81, X = F > (80) (R5 = R2 = TBDPS, R3" = H) Oxidation by manganese dioxide produces a 5-methylindenyl derivative (82) which is a good substrate for a variety of different reactions, including Wittig reaction, Wittig-Horner reaction, Grignard reaction or Reformatsky reaction. For example: (82) by B Oxymethylenetriphenylphosphazane [EtOC(=0)CH=PPh3] treatment, producing 5_(2_ethoxy Ethyl 3-de-deoxyuridine derivative (83) which can be converted to 5-ethylidene-, 5-- via 5-(ethylidene-2-carboxylic acid) derivative (84) (2-extended ethyl)- or 5-(2-bromo-extended ethyl)-3'-deoxyuridine derivative (85). The DAST treatment of this paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) 91949 (Please read the phonetic transcription on the back? Please fill out this page again) --------Book---------Line· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative 111 1293306 A7 ___________ B7 V. Inventive Note (112) (82), 5-difluoromethyl derivative (86) is obtained. These synthetic routes are shown in Reaction Scheme 13. The same reaction sequence can be applied to the corresponding L. - nucleoside ΙΙΙ-a. Reaction Figure 13

(iv)金屬化反應 在水性緩衝液中，以乙酸汞處理（6)或（4)後，以氯化鈉 處理，分別產生全收量之相應之5-氯汞衍生物（87)或（91) (反應圖14)。（87)或（91)與碘於乙醇中反應，分別產生5-碘衍生物（52)或（56)。化合物（52)可與1-炔及雙（三苯基膦） 鈀氯化物（Ph3P)2PdCl2，於碘化亞鋼及三乙胺之存在下反 應，轉化成5-乙炔基衍生物（88)。另一方面，以三氟碘甲 烷及銅粉末處理（52)，可轉化成5-三氟甲基-3’-去氧尿苷 (89)。（87)經氣化鈀鋰（Li2PdCl4)及烯丙基氯處理，產生5-烯丙基-3’-去氧尿苷（90)。丙烯酸甲酯與（87)或（91)於 Li2PdCl2之存在下反應，分別產生5-(五H2-甲氧基-羰基） 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) 訂---------線丨▲ 經濟部智慧財產局員工消費合作社印製 ^ ϋ ϋ n ϋ ϋ H ϋ H ϋ I ϋ ^1 ϋ ϋ ϋ ϋ H ϋ ϋ I ϋ _ 112 1293306 A7 B7 五、發明說明（113 乙烯基-3 -去氧尿脊（83)或-胞苷（92)。（83)皂化形成（84) 後，經N-鹵代琥珀醯亞胺處理，產生5_(五）_鹵代乙烯基尿 嘧啶核苷（85)(X=C1，Br或I)。（84)進行加熱脫除羧基反 應’產生5-乙稀基尿哺咬衍生物（85)(χ=Η)。化合物（85) (X二H)之製法亦可由（52)於乙酸鈀-三苯基膦複合物之存在 下，經乙酸乙烯酯處理。同樣地，（91)可轉化成相應之丙 烯酸酯衍生物（92)，水解成（93)後，與N-鹵代琥珀醯亞胺 反應’產生5_(£>(2-鹵代乙烯基）-3，·去氧胞苷（94)。應注 意’ 5-乙烯基衍生物之催化性氫化反應產生相應之5_乙基 嘧啶核苷。5-乙炔基-3，·去氧尿苷（88，R=H)與稀硫酸進行 水合反應，產生高收量之5-乙醯基-3、去氧尿脊。 依類似方式，但由L核苷對映體開始，製備相應之m_a 核苷。 (請先閱讀背面之注咅？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 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 113 91949 1293306(iv) metallization reaction in aqueous buffer, after treatment with mercury acetate (6) or (4), treated with sodium chloride, respectively yielding a full yield of the corresponding 5-chloromercury derivative (87) or ( 91) (Reaction Figure 14). (87) or (91) is reacted with iodine in ethanol to produce a 5-iodo derivative (52) or (56), respectively. Compound (52) can be reacted with 1-alkyne and bis(triphenylphosphine)palladium chloride (Ph3P)2PdCl2 in the presence of iodized steel and triethylamine to convert to 5-ethynyl derivative (88) . Alternatively, treatment with trifluoroiodomethane and copper powder (52) converts to 5-trifluoromethyl-3'-deoxyuridine (89). (87) Treatment with vaporized lithium palladium (Li2PdCl4) and allyl chloride yields 5-allyl-3'-deoxyuridine (90). Methyl acrylate is reacted with (87) or (91) in the presence of Li2PdCl2 to produce 5-(penta-H2-methoxy-carbonyl). The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 91949 (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 ^ ϋ ϋ n ϋ ϋ H ϋ H ϋ I ϋ ^1 ϋ ϋ ϋ ϋ H ϋ ϋ I ϋ _ 112 1293306 A7 B7 V. Description of the invention (113 vinyl-3-deoxyurinary ridge (83) or -cytidine (92). (83) saponification formation (84) Thereafter, treatment with N-halogenated amber imine produces 5-(penta)-halovinyluridine nucleoside (85) (X=C1, Br or I). (84) Heating to remove carboxyl groups' Producing a 5-ethylene urinary biting derivative (85) (χ=Η). The compound (85) (X 2 H) can also be produced by (52) in the presence of a palladium acetate-triphenylphosphine complex. Treated with vinyl acetate. Similarly, (91) can be converted to the corresponding acrylate derivative (92), hydrolyzed to (93), and reacted with N-haloarene quinone imine to produce 5_(£>( 2-halovinyl)-3,·deoxygenated (94) It should be noted that the catalytic hydrogenation of the 5-vinyl derivative produces the corresponding 5-ethylpyrimidine nucleoside. 5-Ethynyl-3, deoxyuridine (88, R = H) and rare The hydration reaction of sulfuric acid produces a high yield of 5-acetamido-3, deoxyurinary ridge. In a similar manner, but starting with the L nucleoside enantiomer, the corresponding m_a nucleoside is prepared. (Please read the back Note: Please fill out this page again} # 订--------- Line· Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed This paper scale applies China National Standard (CNS) A4 specification (210 X 297 mm) ) 113 91949 1293306

五、發明說明（114 ) 反應圖14V. Description of the invention (114) Reaction Figure 14

92, R = Chfe 94 93, R = H (e)嘴咬核苷之C-6之修飾法（I a與m a) (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 於室溫下’以含氰化鈉或化鉀之二甲基甲醯胺處理5-肩-3 -去氧尿苷（51，反應圖15)，產生高收量之心氰基_3，_ 去氧尿脊（95)。再於高溫下處理（95)，轉化成％氰基異構 物（59)。（95)水解後，產生3，_去氧乳清酸核苷（96)。（95) 經甲醇分解後，產生甲酯（97)，經氨解後，轉化成（98)，其 中R為G至C6低碳數烧基或〒基或苯基。（97)經氫硼化 鈉處理，產生6-羥甲基衍生物（99)，與鹽酸反應後，產生 6-氣甲基尿嘧唆核脊（100)。（1〇〇)與各種不同胺反應，轉化 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 114 9194992, R = Chfe 94 93, R = H (e) Modification method of C-6 for nucleus nucleosides (I a and ma) (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs Intellectual Property Office staff The consumer cooperative printed at room temperature to treat 5-shoulder-3-deoxyuridine (51, reaction diagram 15) with sodium cyanide or potassium dimethylformamide to produce high yield cyanide Base _3, _ deoxyurate ridge (95). It is then treated (95) at elevated temperature to convert to the % cyano isomer (59). (95) After hydrolysis, 3,-deoxyorotate nucleoside (96) is produced. (95) After decomposition by methanol, methyl ester (97) is produced, which is converted to (98) by aminolysis, wherein R is a G to C6 lower carbon group or a fluorenyl group or a phenyl group. (97) Treatment with sodium borohydride produces a 6-hydroxymethyl derivative (99) which, after reaction with hydrochloric acid, produces a 6-methylmethyluracil ridge (100). (1〇〇) Reacts with various amines, this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 114 91949

-ϋ n 1 I i ϋ 一(rjI I n ϋ ϋ ϋ I ϋ I I ϋ I I ϋ u ϋ n ϋ ϋ l I ϋ I I n ϋ ϋ I ϋ I 1293306 A7 —___________ B7 五、發明說明（115 ) 成相應之6-胺甲基-3’-去氧尿苷（101)。由3、去氧胞苷（55) 開始進行類似反應，經由6-氰基中間物（102)，產生3，-去 氧胞苷-6-基羧酸（103)或其甲酯（104)。以相應之胺處理 (104)，可得到各種6-羧基-醯胺基胞嘧啶核苷（1〇5)。（104) 經氫硼化物還原，產生之6-羥甲基衍生物（106)可經鹽酸轉 化成6-氯甲基-3’-去氧胞苷（107)。化合物（107)可與各種不 同胺反應，轉化成相應之6-胺甲基-3’-去氧胞苷（108)。相 同之反應可應用於相應之L-核苷III-a。 反應圖15-ϋ n 1 I i ϋ 1 (rjI I n ϋ ϋ ϋ I ϋ II ϋ II ϋ u ϋ n ϋ ϋ l I ϋ II n ϋ ϋ I ϋ I 1293306 A7 —___________ B7 V. Description of invention (115) 6-Aminomethyl-3'-deoxyuridine (101). A similar reaction is initiated by 3, deoxycytidine (55), via the 6-cyano intermediate (102), producing 3,-deoxygenation. Cytidine-6-ylcarboxylic acid (103) or its methyl ester (104). Treatment with the corresponding amine (104) gives various 6-carboxy-nonylaminocytidine nucleosides (1〇5). The 6-hydroxymethyl derivative (106) produced by reduction with borohydride can be converted to 6-chloromethyl-3'-deoxycytidine (107) by hydrochloric acid. Compound (107) can be combined with various amines. The reaction is converted to the corresponding 6-aminomethyl-3'-deoxycytidine (108). The same reaction can be applied to the corresponding L-nucleoside III-a.

w 103, R = OH 106, X = 〇H 104, R = OCH3 107, X = C! 105, R = NHR' 108, X = NR'R"w 103, R = OH 106, X = 〇H 104, R = OCH3 107, X = C! 105, R = NHR' 108, X = NR'R"

其他衍化反應示於反應圖16。尿嘧啶與胞嘧啶核苷之 鋰化法於 C-6 上進行（參見 Tanaka, H. et al· Tetrahedron Lett一 1979? 4755; Sergueeva, Z. A. et al. Nuclgosidgs, Nucleotides Nucleic Acids. 2000，19，275)。因此於-45°C 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (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 115Other derivatization reactions are shown in Figure 16. The lithiation of uracil and cytosine is carried out on C-6 (see Tanaka, H. et al. Tetrahedron Lett 1979? 4755; Sergueeva, ZA et al. Nuclgosidgs, Nucleotides Nucleic Acids. 2000, 19, 275 ). Therefore, at -45 °C, the paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (please read the notes on the back and fill out this page), ·-------- -Line _ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 115

1293306 A7 B7 五、發明說明（lib) 下，以正丁基經處理完全三甲矽烷基化之3，_去氧胞脊 (109，R3 =R3 =H)後，以甲基碘或二氧化碳處理，分別產 生6-甲基-3’-去氧胞苷（110)或3，-去氧胞苷_6_羧酸（1〇3)。 依類似方法，但改用L-核苷對映體開始，製備相應之Ιπ_ a核脊。 反應圖161293306 A7 B7 5. Inventive Note (lib), treated with methyl iodine or carbon dioxide after treating the 3,_deoxygenated ridge (109, R3 = R3 = H) with complete trimethyl hydrazide treated with n-butyl group. 6-Methyl-3'-deoxycytidine (110) or 3,-deoxycytidine-6-carboxylic acid (1〇3) are produced, respectively. In a similar manner, but starting with the L-nucleoside enantiomer, the corresponding Ιπ_a nucleus was prepared. Reaction Figure 16

於- 78°C下’以二異丙胺化鐘，於四氫咲喃中處理2，5，_ 二-0_(四氮 D比嚼-2 -基）-3’-去氧尿脊（6，R2 =R5’= THP， R3’=R3”=H)，然後與烷基鹵化物反應，形成6-烷基去氧 尿苷（111)。（111)(η=0)經二氧化砸氧化，產生3，-去氧尿脊 •6-羧基醛（112)，當於鹼之存在下，以硝基甲烷處理時，產 生硝基烯（113)。化合物（112)與各種Wittig試劑反應，產 生相應之烯烴114-117。（112)經格林納（Grignard)試劑處 理，產生6-羥烷基衍生物（121)。（121)氧化產生相應之6-酿基衍生物（120)(R=烧鼻）。另一方面，由經鐘化之 (6)(R5 =R2=THP，R3’=R3”=H)與苯甲酸反應，產生6_羥〒 基衍生物（119)，經過溫和氧化反應，轉化成6-苯甲醯基-3’-去氧尿脊（120，R=Ph)。此外，已鐘化之（6)亦可與二苯 基二硫化物反應，產生6-苯基硫-3’-去氧尿苷（118)，如反 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 ---------------------訂---------線 (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 116 1293306 A7 B7 五、發明說明（117) 應圖17所示。 依類似方法’ 改由L-核苷對映體開始，製備相應之 ΙΙΙ-a核苷。 反應圖17Treatment of 2,5, _ 2-0-(tetrazole D-pyrid-2-yl)-3'-deoxyurinary ridge in tetrahydrofuran at -78 °C , R2 = R5' = THP, R3' = R3" = H), and then reacted with an alkyl halide to form 6-alkyl deoxyuridine (111). (111) (η = 0) by cerium oxide Oxidation, production of 3,-deoxyurate ridge • 6-carboxyaldehyde (112), when treated with nitromethane in the presence of a base, produces nitrone (113). Compound (112) reacts with various Wittig reagents. Producing the corresponding olefin 114-117. (112) is treated with a Grignard reagent to produce a 6-hydroxyalkyl derivative (121). (121) Oxidation yields the corresponding 6-bromyl derivative (120) ( R = burning the nose. On the other hand, by the reaction of (6) (R5 = R2 = THP, R3 ' = R3" = H) with benzoic acid, a 6-hydroxydecyl derivative (119) is produced, After a mild oxidation reaction, it is converted to 6-benzimidyl-3'-deoxyurinary ridge (120, R = Ph). In addition, it has been reacted with diphenyl disulfide to produce 6-phenylthio-3'-deoxyuridine (118), such as the Chinese National Standard (CNS). A4 size (210 X 297 mm) 91949 --------------------- Order --------- line (please read the notes on the back first) Fill in this page again) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 116 1293306 A7 B7 V. Invention Description (117) It should be shown in Figure 17. The corresponding ΙΙΙ-a nucleoside was prepared by a similar method starting from the L-nucleoside enantiomer. Reaction Figure 17

OH=CHR 113, R = N02 114, R = H 115, R = C02R. 11β· R = CN 117, R = Ph 119 120 121 (d)嘌呤核苷之C-6之修飾法（I b與m b)OH=CHR 113, R = N02 114, R = H 115, R = C02R. 11β· R = CN 117, R = Ph 119 120 121 (d) Modification of C-6 of purine nucleosides (I b and mb )

kCH(〇H)R (請先閱讀背面之注音？事項再填寫本頁) ---------線—痛 經濟部智慧財產局員工消費合作社印制衣 化合物28或38經鹽酸或氫溴酸之乙酸溶液或氫溴囊 之二氣甲烧溶液處理，轉化成由化物（122)(反應圖18)，^ 用納代反應法，肖氯嗓呤於乙腈中縮合，產生3、去肩 核苷（123)。以氫氧化鈉或氫氧化鉀水溶液處理（123)，產j 3 -去氧肌苷（124)。以甲醇鈉之甲醇溶液處理（123)，產j 6-0-甲基-3 _去氧肌苷（125)。（123)經過溫和皂化後，催4 性氳解，產生3’-去氧水粉蕈素（3，-de〇xynebularine)(126) (123)與硫脲反應，產生硫嘌呤核苷（127)，（127)經§_夫 化成（128)。化合物（123)、（127)與（128)很容易與各種胺 本紙張尺度適用中國國豕標準（CNS)A4規格（210 X 297公爱） 117 91949kCH(〇H)R (Please read the phonetic transcription on the back? Please fill out this page again) --------- Line - Pain Economics Department Intellectual Property Bureau Staff Consumer Cooperative Printed Compound 28 or 38 via hydrochloric acid or Treated by a solution of hydrobromic acid in acetic acid or a hydrobrominated sulphuric acid in a gas-aeration solution, converted into a compound (122) (reaction shown in Figure 18), and condensed in a acetonitrile by a nano-reaction method to produce 3, Detachant nucleoside (123). Treatment with (123) with sodium hydroxide or potassium hydroxide aqueous solution yields j3-deoxyinosine (124). Treatment with a solution of sodium methoxide in methanol (123) yielded j 6-0-methyl-3-deoxyinosine (125). (123) After mild saponification, it is catalyzed by 4, resulting in the reaction of 3'-deoxoxyneine (126) (123) with thiourea to produce thiopurine nucleoside (127). , (127) by §_fu into (128). Compounds (123), (127) and (128) are easily compatible with various amines. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 117 91949

1293306 A7 B7 五、發明說明（ ） 幾胺、肼及胺基醇反應，產生3去氧腺脊類似物（129_ 133)。 （123)經疊氮化鈉處理，產生6_疊氮基嘌呤核苷 (134)。 採用相同反應過程形成相應之L-核苷ΠΙ-b。 反應圖1 81293306 A7 B7 V. INSTRUCTIONS ( ) The reaction of a few amines, anthraquinones and amino alcohols produces a 3deoxyadenosine analog (129_133). (123) Treatment with sodium azide produces 6-azidopurine nucleoside (134). The same reaction process is used to form the corresponding L-nucleoside ΠΙ-b. Reaction Figure 1 8

130, R = NH2 131, R = NH(CH2)hCH3130, R = NH2 131, R = NH(CH2)hCH3

132, R = NH(CH2)h〇H 133, R = NH(CH2)nNH2 此等化合物亦可由6-醯肼基嗓吟核眘（130)經亞;e;肖酸 處理而合成。（129)、（130)或（134)還原成3’_去氧腺苷（亦 即蛹蟲草菌素（cordycepin))。化合物（125)或蛹蠢草菌素應 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (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 118 1293306 A7 ------B7______^ 五、發明說明（119 ) 可於活體内經腺苷去胺酶作用，轉化成（124)-6-未取代之聲 呤核苷（126)可於活體内氧化成（124)。 (122)與2-經取代之6-氯嘌呤縮合，產生（123)之2-經 取代之類似物。6-氯官能基可經由親核性取代反應轉化成 各種官能基。因此2-胺基_6_氯嘌呤轉化成（135)(反應圖 19)，再轉化成各種2-胺基嘌呤核苷（136-147)。應注意， 2,6·二胺基-嘌呤（141)與2_胺基-嘌呤（138)核昏可作為3，_ 去氧鳥嗓呤核杳（136)之前體。依類似方式，但改由校脊 對映體開始，製備相應之ΙΠ-b核苷。 (請先閱讀背面之注意事項再填寫本頁)132, R = NH(CH2)h〇H 133, R = NH(CH2)nNH2 These compounds can also be synthesized from 6-mercaptopurine (130) by sub-; e; (129), (130) or (134) is reduced to 3'-deoxyadenosine (i.e., cordycepin). Compound (125) or stuporin should be applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) on the paper scale. 91949 (Please read the note on the back and fill out this page) Order----- ----Line· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 118 1293306 A7 ------B7______^ V. Description of invention (119) can be converted into (124) by adenosine deaminase in vivo -6-unsubstituted scorpion nucleoside (126) can be oxidized in vivo to (124). (122) Condensation with 2-substituted 6-chloropurine to give (123) a 2-substituted analog. The 6-chloro functional group can be converted to various functional groups via a nucleophilic substitution reaction. Thus 2-amino-6-chloropurine is converted to (135) (reaction Figure 19) and converted to various 2-aminopurine nucleosides (136-147). It should be noted that 2,6·diamino-indole (141) and 2-amino-indole (138) nuclear faint can be used as the precursor of 3,-deoxyguanine quinone (136). In a similar manner, but starting with the ridge enantiomer, the corresponding ΙΠ-b nucleoside was prepared. (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 本紙張尺度適用中國國家標準（CNS)A4規格（210 : 119 91949Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives. This paper scale applies the Chinese National Standard (CNS) A4 specification (210: 119 91949).

經濟部智慧財產局員工消費合作社印製 120 1293306 A7 B7 五、發明說明（120 ) 反應圖19Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 120 1293306 A7 B7 V. Description of Invention (120) Reaction Figure 19

142, R = OH 143, R = Nhfe 144f R = NH(CH2)nCH3142, R = OH 143, R = Nhfe 144f R = NH(CH2)nCH3

145, R = NH(CH2)n〇H 146, R = NH(CH2)nNH2 依類似方式合成2 -氧代-、2 -甲氧基-、2 -硫代-、2 -烧 基氫硫基-、2-甲基-、2-甲胺基-、或2-二甲胺基-嘌呤核苷 (148-154)(反應圖20)。亦依類似方式，但改由相應之L-核苷開始，製備III-b型化合物。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁)145, R = NH(CH2)n〇H 146, R = NH(CH2)nNH2 Synthesize 2-oxo-, 2-methoxy-, 2-thio-, 2-alkylthiol in a similar manner -, 2-methyl-, 2-methylamino-, or 2-dimethylamino-purine nucleoside (148-154) (reaction Figure 20). In a similar manner, starting with the corresponding L-nucleoside, a compound of type III-b is prepared. This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (please read the notes on the back and fill out this page)

1293306 A71293306 A7

五、發明說明（m ) 反應圖20V. Description of the invention (m) Reaction diagram 20

(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 (e)嘌呤核脊之C-2之修飾法（j_b與In b) (135-147)之2_胺基可與各種烷醯或芳醯鹵化物醯化 而經修飾得到（155)(反應圖21)。（155)可再經硼烷_胺錯化 物還原，衍化成相應之2-烷胺基或2-芳胺基衍生物（156) (Sergueeva，Z. A. et al· Nucleosides Nucleotides Nucl^io A£iils_，2000，19, 275)。或者，化合物（135)之2_胺基可進行 Schiemann反應而經取代，於氟硼酸鹽之存在下重氮化 後，經熱分解，產生2-氟-6-氣嘌呤核苷（157)。此外，此 等核脊之6 _乳取代基可被上述各種親核性試劑置換。應注 意，2-氟取代基之存在可保護6-胺基，免於被去胺酶分解。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 121 91949 訂---------線· 1293306(Please read the precautions on the back and fill out this page.) Printed by the Ministry of Economic Affairs, Intellectual Property Office, and the Consumer Cooperatives. (e) Modification of the C-2 of the nucleus ridge (j_b and In b) (135-147) 2_ The amine group can be modified with various alkane or aryl halides to give (155) (reaction Figure 21). (155) can be further reduced to the corresponding 2-alkylamino or 2-arylamino derivative (156) by borane-amine complexation (Sergueeva, ZA et al. Nucleosides Nucleotides Nucl^io A£iils_, 2000, 19, 275). Alternatively, the 2-amino group of the compound (135) may be substituted by a Schiemann reaction, diazotized in the presence of a fluoroborate, and then thermally decomposed to give 2-fluoro-6-gas nucleoside (157). In addition, the 6-milk substituents of these ridges can be replaced by various nucleophilic reagents as described above. It should be noted that the presence of a 2-fluoro substituent protects the 6-amino group from being decomposed by the deaminase. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 121 91949 Order --------- Line · 1293306

反應圖21Reaction Figure 21

(f)嗓呤核苷（I-b)之C-8之修飾法 經濟部智慧財產局員工消費合作社印製 應庄思，g呤核苔之8_位置上修飾法很重要，因為此 位置之取代作用會使核苷之較佳構型改為同側型(syn)。 3蛹蟲草菌素（158，^ ，3,去氧肌苷（124，r3 = R —Η)與3 _去氧鳥嘌呤核杳（136，r3，=r3，，=h)之C 8位置 可於乙酸鈉之存在下，經溴於乙酸中處理，形成（159_ 161)(反應圖22)。（159-161)之C-8溴取代基可與硫脲反應 而經硫置換’得到（162-164)，其再經烷基或芳烷基鹵化物 於極性溶劑（如：水、醇或二甲基甲醯胺）中，於鹼（如：碳 酸鈉或碳酸鉀）之存在下烷基化或芳烷基化，產生65_ 167)。甲基氳硫基衍生物（165_167)(R=甲基）可氧化成相應 之楓（168-170)。以各種不同胺處理此等楓時，得到相應之 8-胺基衍生物（171-173)。（159-16ΐχ經胺處理即可直接得到 許多種8-胺基衍生物。（159)亦可經乙酸鈉於乙酸酐中處理 後，水解，轉化成8-氧代衍生物（174)。（174)經氣硼酸三 乙基氧鎗鹽進行0-烷化，產生卜乙氧蛹蟲草菌素（175)。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 122 91949 (請先閱讀背面之注意事項再填寫本頁) 訂---------線_ 1293306(f) Modification of C-8 of guanidine nucleoside (Ib) The Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperatives, printed, should be Zhuangsi, and the modification method of 88 position of g呤Nuweed is important because of the replacement of this position. The effect is to change the preferred configuration of the nucleoside to the same side (syn). 3 C 8 position of cordycepin (158, ^, 3, deoxyinosine (124, r3 = R - Η) and 3 _ deoxyguanine 嘌呤 (136, r3, = r3,, = h) It can be treated with bromine in acetic acid in the presence of sodium acetate to form (159_161) (reaction Figure 22). The C-8 bromine substituent of (159-161) can be reacted with thiourea to undergo sulfur substitution. 162-164), which is further subjected to an alkyl or aralkyl halide in a polar solvent such as water, an alcohol or dimethylformamide in the presence of a base such as sodium carbonate or potassium carbonate. Alkylation or aralkylation yields 65_167). The methyl sulfonium derivative (165_167) (R = methyl) can be oxidized to the corresponding maple (168-170). When these maples are treated with various amines, the corresponding 8-amino derivatives (171-173) are obtained. (159-16 guanidine can be directly obtained to obtain a variety of 8-amino derivatives. (159) can also be treated with sodium acetate in acetic anhydride, hydrolyzed, and converted to 8-oxo derivatives (174). 174) O-alkylation with triethyl oxysulfate salt to produce ethoxylated oxacillin (175). This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 122 91949 (Please read the notes on the back and fill out this page) Order --------- Line _ 1293306

五、發明說明（I23 ) 反應圖22V. Description of the invention (I23) Reaction Figure 22

158, X = NKfY = H 124, Χ*〇η,Υ = Η 136, Χ = 〇Η,Υ = Ν^ ·' Ul-I 159· Χ*ΝΙ^,Υ = Η 1βΟ· Χ = 〇Η·Υ=：η 161, X = OHtY = Ny158, X = NKfY = H 124, Χ *〇η, Υ = Η 136, Χ = 〇Η, Υ = Ν ^ · ' Ul-I 159· Χ *ΝΙ^, Υ = Η 1βΟ· Χ = 〇Η· Υ=:η 161, X = OHtY = Ny

162, Χ-Η^Υ-Η 163, X = OH,Y = H 164, X = OH,Y = Ny162, Χ-Η^Υ-Η 163, X = OH, Y = H 164, X = OH, Y = Ny

165t X = NK,Y = H 16$, X = 〇H,Y = H 167, X = 〇H,Y = Ny165t X = NK, Y = H 16$, X = 〇H, Y = H 167, X = 〇H, Y = Ny

XX

(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-烷基衍生物（17 6)之製法（反應圖23)係由（123 )(R5，= R2 =THP)經二異丙胺化鐘於_7〇 °c以下之四氫呋喃中處 理，然後以烷基鹵化物處理。此方法可成功地用於其他核 糖核苷（Tanaka，H. et al. Chem Pharm Bull.. 1983，31， 787)’但無法應用在3’-去氧核杳上。當改用二氧化碳替代 烷基鹵化物時，得到嘌呤核苷8-羧酸（177)。酯化成（178) 後，經氨解形成醯胺（181)，其脫水成8-氰基嘌呤核苷 (182)。（178)經硼烷-二甲基硫醚還原，產生醇（179)。經二 甲亞楓與草醯氯溫和氧化後，產生醛（180)。化合物（179) 與（180)為用於各種不同修飾反應之通用中間物。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 123 91949 --------訂---------線· 1293306 五、發明說明（I24 )(Please read the notes on the back and fill out this page.) The method of printing 8-alkyl derivatives (17 6) printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs (Reaction Figure 23) is based on (123) (R5, = R2) =THP) is treated with diisopropylation clock in tetrahydrofuran below -7 〇 ° C and then treated with an alkyl halide. This method can be successfully applied to other ribonucleosides (Tanaka, H. et al. Chem Pharm Bull.. 1983, 31, 787) but cannot be applied to 3'-deoxynucleoside. When carbon dioxide is used instead of the alkyl halide, the purine nucleoside 8-carboxylic acid (177) is obtained. After esterification to (178), the indoleamine (181) is formed by aminolysis, which is dehydrated to 8-cyanoguanidine nucleoside (182). (178) Reduction with borane-dimethyl sulfide affords the alcohol (179). The aldehyde (180) is produced by mild oxidation of thymidine and grass mash. Compounds (179) and (180) are general intermediates for a variety of different modification reactions. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 123 91949 -------- order --------- line · 1293306 V. Invention description (I24)

OR2· 123. R^sR^sTHPOR2· 123. R^sR^sTHP

R^^OR2* 176, n = 0-3,R = HorPhR^^OR2* 176, n = 0-3, R = HorPh

(請先閱讀背面之注意事項再填寫本頁) B· Ila-c與IVa-c型化合物 ⑴由預形成之核苷合成： 有數種方法可用於引進2’，3’-不飽和至預形成之杉^香 中。其實例示於反應圖24。 核苷（7)之選擇性〇-矽烷化反應，最好使用第三丁基 二甲矽烷基i化物或第三丁基二苯基矽烷基齒化物，於驗 中（以卩比唆較佳），於0°C至80°C下（以室溫較佳）進行，然後 磺酸化，最好使用甲磺醯氯或甲苯磺醯氯，於鹼中（以哦咬 較佳），於〇°C至8(TC (以室溫較佳）下進行，產生高收量之 (8)，其很容易經鹼處理，轉化成來蘇糖基-環氧化物（183)。 (183)與ώ離子（以職離子較佳）反應，如：以峨化鈉於丙_ 或甲基乙基酮中處理，只產生反式-碘代醇（184)，Χ=ΐχΐ84> 經甲磺酸化後，經由（185)產生高收量浠烴（186)。經過短反 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949(Please read the notes on the back and fill out this page.) B. Ila-c and IVa-c type compounds (1) are synthesized from pre-formed nucleosides: There are several methods for introducing 2', 3'-unsaturated to preformed The cedar ^ incense. An example of this is shown in Reaction Scheme 24. For the selective oxime-sulfanation reaction of nucleoside (7), it is preferred to use a third butyl dimethyl hydrazide or a third butyl diphenyl decyl dentate, which is preferred in the comparison. ), at 0 ° C to 80 ° C (preferably at room temperature), and then sulfonated, preferably using methyl sulfonium chloride or toluene sulfonium chloride, in a base (better than oh), in 〇 From °C to 8 (TC (preferably at room temperature), yields a high yield (8) which is easily converted to the lysyl-epoxide (183) by alkali treatment. (183) The ruthenium ion (preferred ion) reaction, such as: treatment with sodium hydride in propyl or methyl ethyl ketone, only produces trans-iodohydrin (184), Χ = ΐχΐ 84 > after mesylation Produce high-capacity terpene hydrocarbons (186) via (185). Applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) through short reverse paper scale 91949

訂---------線L 經濟部智慧財產局員工消費合作社印製 124 1293306 Α7 ------Β7 經濟部智慧財產局員工消費合作社印製 五、發明說明（125 ) 應時間後，單離出低收量之化合物（185)。（186)經氟化物 (如·四丁基銨化氟）去_〇_碎燒基化後，產生高收量之所需 烯烴（187)，II-a 型。 反應圖24------------------------------------------------------------------------ After the time, the low yield compound (185) was isolated. (186) After the fluoride (e.g., tetrabutylammonium fluoride) is de-sintered, a high yield of the desired olefin (187), type II-a is produced. Reaction Figure 24

亦可由2、去氧核苷（例如：（188))開始（反應圖25)，製 備Π-a型烯烴糖核苷。（188)磺酸化反應最好使用甲磺醯 氣，於吡啶中，於-l〇°c至80°C之溫度範圍内（以室溫較佳） 進行，產生二-〇_甲磺酸酯（189),當以鹼水溶液（如：氫氧 化鈉溶液）處理時，產生3，，5，-脫水糖核苷（190)。後者核苷 很容易於二甲亞楓中，於_;l〇°C至80°C之溫度範圍内（以室 溫較佳），以無水強鹼（如：第三丁醇鉀）處理10分鐘至一 夜，以1·5至3小時較佳，轉化成高收量之所需（187)。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 125 91949 (請先閱讀背面之注咅？事項再填寫本頁) --------訂---------線—表 A7It is also possible to prepare a Π-a type olefin glycoside starting from 2, deoxynucleoside (e.g., (188)) (reaction Fig. 25). (188) The sulfonation reaction is preferably carried out using methanesulfonate gas in pyridine at a temperature ranging from -10 ° C to 80 ° C (preferably at room temperature) to produce di-indole methanesulfonate. (189), when treated with an aqueous alkali solution (e.g., sodium hydroxide solution), produces 3,5,-anhydroglycosides (190). The latter nucleoside is easily used in dimethyl sulfoxide, in the temperature range of _; l 〇 ° C to 80 ° C (better at room temperature), treated with anhydrous strong base (such as: potassium t-butoxide) 10 Minutes to overnight, preferably from 1.5 to 3 hours, are converted to high yields (187). This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 125 91949 (please read the note on the back? Please fill out this page again) --------Book----- ----Line—Table A7

經濟部智慧財產局員工消費合作社印製 1293306 五、發明說明（126 反應圖25Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, Printing 1293306 V. Invention Description (126 Reaction Figure 25

製備ΙΙ-a型2’-經取代之烯烴糖核苷之實例示於反應 圖26。1-(2’-去氧-2、氟·召_d_呋喃阿拉伯糖基）胸腺嘧啶 (191) 於吡啶中，經選擇性保護，最好使用三苯甲基氣或第 三丁基二甲矽烷基氣或第三丁基二苯矽烷基氣保護，產生 (192) 。（192)最好使用甲續醯氣於吡啶中績酸化，產生甲績 酸酯（193)，經非親核性鹼（如：DBU或DBN)於無水惰性溶 劑（如：二氯甲烷）中處理時，產生2,3，_脫水核苷（194)。此 化合物經第三丁醇鉀於二甲亞楓中處理時，即可轉化成2，-氟-烯烴糖核苷（195)。（195)脫除保護基後，產生所需之2，-氟化ΙΙ-a型核普（1 96)。5 ’ -0-梦烧基保護法之總收量高於 三苯甲基保護法。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注音？事項再填寫本頁}An example of the preparation of a ΙΙ-a type 2'-substituted olefin glucoside is shown in Figure 26. 1-(2'-Deoxy-2, fluoro-callo-d-furan arabinosyl) thymine (191) In pyridine, it is selectively protected, preferably with trityl or tert-butyldimethylhydrazine or tributyldiphenylsulfanyl, to give (192). (192) Preferably, it is acidified in pyridine to produce a methyl ester (193), which is subjected to a non-nucleophilic base (eg, DBU or DBN) in an anhydrous inert solvent (eg, dichloromethane). Upon treatment, 2,3,- dehydrated nucleosides (194) are produced. When the compound is treated with potassium t-butoxide in dimethyl sulfoxide, it can be converted into a 2,-fluoro-olefin nucleoside (195). (195) After removal of the protecting group, the desired 2,-fluorenium-a type nucleus (1 96) is produced. The total yield of the 5'-0-dream base protection method is higher than the trityl protection law. This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (please read the phonetic on the back? Please fill out this page again)

126 1293306 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（ 127 反應圖2 6126 1293306 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (127 reaction diagram 2 6

r = Tr，SiMe2+Bu 或 SiPh：rt-Bur = Tr, SiMe2+Bu or SiPh: rt-Bu

196 所有此等反應均可用於相應之嘧啶L-核苷，製備IV- a型核脊。 ΙΙ-b型核苷很容易自（197)製備（反應圖27)。（197)之 5，-位置經例如：第三丁基二甲矽烷基或第三丁基二苯基石夕 烷基選擇性保護，產生（198)。於鹼（如：吡啶）中，與甲苯 續醯#化物或甲橫醯齒化物磺酸化，產生受保護之烯烴核 苷（199)。（199)經氟化物（如：四丁基銨化氟）脫除〇-矽烷 基，產生高收量所需烯烴200，II_b型核苷。 或者，以乙酸亞鉻處理（15)(見反應圖3)經鹼處理脫除 保護後，產生高收量（200)。 ---------------------訂---------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公釐） 127 91949 A7 B7 1293306 五、發明說明（似 ） 反應圖27196 All such reactions can be used for the corresponding pyrimidine L-nucleosides to prepare IV-a core ridges. The ΙΙ-b nucleoside is readily prepared from (197) (reaction Figure 27). The 5,-position of (197) is selectively protected by, for example, tert-butyldimethylcarbonyl or tert-butyldiphenylcarbenyl, resulting in (198). Sulfonation with toluene or a flavonoid in a base such as pyridine yields a protected olefin nucleoside (199). (199) Removal of the rhodium-decane group by fluoride (e.g., tetrabutylammonium fluoride) produces a high yield of the desired olefin 200, II b type nucleoside. Alternatively, high yield (200) is produced after deprotection with alkali treatment by treatment with chromous acetate (15) (see Reaction Scheme 3). --------------------- Order --------- line (please read the note on the back and fill in this page) This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 127 91949 A7 B7 1293306 V. Description of invention (like) Reaction Figure 27

依相同方法，但改用嘌呤L-核苷，可得到相應iV-b 型烯烴糖L-核苷。 (H)由鹼與不飽和糖衍生物縮合合成 可自商品取得之4·羥甲基-2-戊烯綱（201，反應圖28) 經矽烷基化，最好於鹼中（以吡啶較佳）使用第三丁基二甲 石夕烷基鹵化物處理，產生（202)，經氫硼化物還原，產生 (203)。經乙醯化後，產物（204)與矽烧基化驗（例如：5-經 取代之尿嘧啶）縮合。得到以變旋異構性核苷（2〇5)為主要 組成份之複雜混合物。變旋異構物（206)與（207)經層析分離 後，各變旋異構物經去矽烷化後，分別產生点-核脊2〇8(n_a 型）與 α _核苷（209)(XVIII-c 型）。 (請先閱讀背面之注意事項再填寫本頁) ------ I 丨-丨 I I I----. 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 128 91949 A7 1293306 _____B7 五、發明說明（129 ) 反應圖28According to the same method, but using 嘌呤L-nucleoside, the corresponding iV-b type olefin sugar L-nucleoside can be obtained. (H) Condensation of a base with an unsaturated sugar derivative to synthesize a commercially available 4-hydroxymethyl-2-pentene group (201, reaction scheme 28). Alkylation with a hydrazine, preferably in a base (based on pyridine) Preferably, treatment with a third butyl dimethyl oxalate halide yields (202), which is reduced by borohydride to yield (203). After acetylation, the product (204) is condensed with a thiol group assay (e.g., 5-substituted uracil). A complex mixture of the cyclogenic nucleosides (2〇5) as the main component is obtained. After the spinning isomers (206) and (207) are separated by chromatography, each of the racemic isomers is de-alkylated to produce a point-nuclear ridge 2〇8 (n_a type) and an α-nucleoside (209). ) (XVIII-c type). (Please read the notes on the back and fill out this page) ------ I 丨-丨II I----. Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, Printed Paper Size Applicable to China National Standard (CNS) A4 size (210 X 297 mm) 128 91949 A7 1293306 _____B7 V. Description of invention (129) Reaction diagram 28

206) R = StMe2*i"Bu 2079 R = SiM^-i*Bu 208, R = H (ll-a) 209, R = H (XVIlUc} (請先閱讀背面之注意事項再填寫本頁) 0 -------訂---------. 經濟部智慧財產局員工消費合作社印製 129 另一項實例示於反應圖29。由酸（210)與 PhJ^CFCC^Et進行Wittig縮合反應，產生2-氟内酯（212) 〇 經石夕燒基保護及DIB AH還原後，產物經乙醯化，產生 (213)。（213)與石夕烧基化嘌呤（如：6-氣嘌呤），於路易士酸 (如··三甲矽烷基三氟甲磺酸酯或四氣化錫）之存在下，於 惰性溶劑中（如：二氯甲烷或氯化乙烯）中縮合，產生變旋 異構物混合物（214)。此等變旋異構物於矽膠管柱上分離。 各組成份脫除矽烷基化，可得到相應之召-核苷215(II-b型） 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 91949 1293306 A7 _ B7 五、發明說明（13G ) 與 α -核苷 216(XVIII-d 型）。 反應圖29206) R = StMe2*i"Bu 2079 R = SiM^-i*Bu 208, R = H (ll-a) 209, R = H (XVIlUc} (Please read the back note first and then fill out this page) 0 -------Book---------. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 129 Another example is shown in Figure 29. From acid (210) and PhJ^CFCC^Et The Wittig condensation reaction is carried out to produce 2-fluorolactone (212). After the ruthenium-protection and DIB AH reduction, the product is acetylated to give (213). (213) :6-gas enthalpy), in the presence of Lewis acid (such as trimethylsulfonyl trifluoromethanesulfonate or tin tetra-sulphide) in an inert solvent (eg dichloromethane or vinyl chloride) Condensation produces a mixture of vortexomers (214). These isomers are separated on a ruthenium column. The components are removed by oximation, and the corresponding nucleoside 215 (II-b type) can be obtained. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 91949 1293306 A7 _ B7 V. Description of invention (13G) and α-nucleoside 216 (XVIII-d type) Reaction Figure 29

CHOCHO

210210

(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制衣 130 C·碳化糖核苷（v-χ)之合成法 目前天然界所發現到之唯一碳化核苷為腺嘌呤核苷， 亦即隱陡頭黴素（aristeromycin)與尼普拉素 (neplanocins) ’其相當昂貴而且無法自商品取得。因此這 類型核苷需由scratch化學合成。首先製備碳化_糖衍生 物，然後在糖上構築雜環系糖苷配基，製成碳化糖核苷， 或若要製備嘌呤核苷時，則由鹼基直接與碳化糖縮合。 反應圖30說明5 -氟-碳化胞杳之合成法（227, V-a型）。 碳化糖中間物（2 1 9)可依相關技藝已知之任何方式合成。此 方法揭示於 Ali et al.TTetrahedron Letters 1990，3 1， 1509) ’其係使D-核糖酸内酯（2 17)轉化成戊酮中間物 (218)。此酮（2 18)再經任何已知還原劑還原，以氫硼化鈉之 甲醇溶液較佳，於0°C下還原1小時，產生醇（219)。（219: 經磺酸化，最好使用甲磺醯氯，於二氯甲烷中，於三乙胺 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 1293306(Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumers Cooperatives, Printing and Garment 130 C·Carbonated Glucosides (v-χ) Synthetic Method The only carbonized nucleosides found in the natural world. It is an adenosine nucleoside, i.e., aristeomycin and neplanocins, which are quite expensive and cannot be obtained from commercial products. Therefore, this type of nucleoside needs to be chemically synthesized by scratch. First, a carbonized-sugar derivative is prepared, and then a heterocyclic aglycone is constructed on the sugar to prepare a carbonized sugar nucleoside, or if a purine nucleoside is to be prepared, the base is directly condensed with the carbonized sugar. Reaction Scheme 30 illustrates the synthesis of 5-fluoro-carbonized cytoplasm (227, Form V-a). The carbonized sugar intermediate (209) can be synthesized in any manner known in the art. This method is disclosed in Ali et al. TT etrahedron Letters 1990, 3 1, 1509) which converts D-ribonolactone (2 17) to a pentanone intermediate (218). This ketone (2 18) is then reduced by any known reducing agent, preferably with a solution of sodium borohydride in methanol, and reduced at 0 ° C for 1 hour to give the alcohol (219). (219: Sulfonated, preferably using methanesulfonyl chloride, in dichloromethane, on triethylamine. This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 1293306

五、發明說明（131 (請先閱讀背面之注意事項再填寫本頁) 之存在下，於0°C下進行2小時，產生（220)，其再經疊氮 化鈉於DMF中，於U(TC下處理一夜，產生（221)。疊氮 化（221)很容易使用任何已知還原劑還原，例如： Ph3P(Staudinger法）或催化性氫解法，最好使用以/〇進 行。所得胺（222)於DMF中，與召_甲氧丙烯醯基異氰酸酯 進行Warrener-Shaw反應，然後以氳氧化銨處理，經由線 性中間物（223)形成受保護之碳化尿苷（224)。由（224)與任 何氟化劑進行氟化反應，可得到受保護之5_氟_碳化尿苷 (225)。較佳氟化劑為含氟之乙酸。以鹼中止反應後（最好 使用三乙胺），類似反應圖7所述之方式轉化尿嘧啶核苷 (225)形成受保護之碳化-5-氟胞苷（226)。以酸脫除（226)之 保護基’最好使用三氟乙酸/水（2: 1，v/v)，於5〇 t下進 行3小時，產生（227)。 (219)使用三氟甲績醯氯，於二氯甲烷中，於三乙胺之 存在下磺酸化，產生三氟甲磺酸酯，當與嘌呤鹼基（如：腺 嘌呤）及氫化鈉於惰性溶劑中（如：乙腈或DMF)中反應時， 直接產生相應之嗓呤核苷（V-b型）。 經濟部智慧財產局員工消費合作社印製 依相同方法’但改由L-核糖酸内酯開始，可得到相應 L-核苷對映體（VIII型核苷）。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 131 91949 T1 293306 A7 B7 五、發明說明（132 ) 反應圖3 05. The invention description (131 (please read the note on the back first and then fill out this page), at 0 °C for 2 hours, produce (220), which is then passed through sodium azide in DMF, at U (Processing at TC overnight, yielding (221). Azidation (221) can be easily reduced using any known reducing agent, for example: Ph3P (Staudinger method) or catalytic hydrogenolysis, preferably with /. (222) In DMF, a Warrener-Shaw reaction with methoxypropenyl isocyanate followed by treatment with ammonium cerium oxide to form a protected carbonized uridine (224) via a linear intermediate (223). The fluorination reaction with any fluorinating agent provides a protected 5-fluoro-carbouric uridine (225). Preferably, the fluorinating agent is a fluorine-containing acetic acid. After the reaction is stopped with a base (preferably using triethylamine) The uridine nucleoside (225) is converted to form a protected carbonated-5-fluorocytidine (226) in a manner similar to that described in Figure 7. The protecting group for the removal of (226) by acid is preferably trifluoroacetic acid. /water (2: 1, v/v), carried out at 5 〇t for 3 hours, yielding (227). (219) using trifluoromethane, chlorine, Sulfonated in the presence of triethylamine in methyl chloride to produce triflate, when reacted with a purine base such as adenine and sodium hydride in an inert solvent such as acetonitrile or DMF Directly produce the corresponding purine nucleoside (Vb type). The Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative prints according to the same method' but starts with L-ribofanolactone to obtain the corresponding L-nucleoside enantiomer ( Type VIII nucleoside. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 131 91949 T1 293306 A7 B7 V. Description of invention (132) Reaction diagram 3 0

(請先閱讀背面之注意事項再填寫本頁) — — — — — — — ·11111111 . 經濟部智慧財產局員工消費合作社印製 132 或者’可自商品取得（lR)-(-)_氮雜雙環[2 2丨]庚-5_烯 _3-酮（228，反應圖31)經四氧化鐵氧化法轉化成2,3-二羥 基内醯胺（229)。（229)經鹽酸之甲醇溶液進行甲醇分解後， 產物（2 30)經2，2-二甲氧丙烧於丙酮中處理，或經ι，ι_二甲 氧環己烷於環己醇中處理，產生縮酮，例如：（23 1 )，（2 3 1) 經氩硼化鈉還原成（232)。胺基醇（232)與召·甲氧丙烯醯基 異氰酸酯反應後，經氨處理，轉化成2’，3、〇-亞環己基-碳 化尿苷。經酸處理，最好以三氟乙酸於甲醇中處理，產生 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 1293306 A7 B7 五、發明說明（133 ) 碳化尿苷（233)。由（233)依相關技藝已知方法很容易得到碳 化-5-氟胞苷（227)。 反應圖3 1(Please read the note on the back and then fill out this page) — — — — — — — · 11111111 . Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 132 or 'can be obtained from the commodity (lR)-(-)_aza Bicyclo[2 2 fluorene]hept-5-ene-3-one (228, reaction scheme 31) is converted to 2,3-dihydroxy decylamine (229) by iron oxide oxidation. (229) After methanolysis with methanolic solution of hydrochloric acid, the product (2 30) is treated with 2,2-dimethoxypropane in acetone or in ι,ι-dimethoxycyclohexane in cyclohexanol. Treatment produces a ketal such as: (23 1 ), (2 3 1) reduced to (232) by sodium argonborate. The amino alcohol (232) is reacted with a methoxypropenyl isocyanate and then converted to 2',3, fluorene-cyclohexylene-carburidine by ammonia treatment. After acid treatment, it is best to treat with trifluoroacetic acid in methanol to produce the paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm). 91949 1293306 A7 B7 V. Description of invention (133) Carbonated uridine ( 233). Carb-5-fluorocytidine (227) is readily obtained by (233) according to methods known in the art. Reaction Figure 3 1

228228

233233

VV

(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 依類似反應，但改以其他光學異構物開始，可得到 (1幻_(+)_氮雜雙環[2·2·1]庚-5-烯_3_酮，相應之^核苷類似 物（VIII)型。 由V型核昔製備VI型核苷。其實例示於反應圖32。 隱陡頭黴素（234)或任何碳化-核糖核苷經二甲基甲醯胺二 甲基縮酸於DMF中處理後’進行三苯甲基化反應，轉化 成相應之Ν-[(二甲胺基）亞甲基]-5，-0-三苯甲基衍生物 (235)。（235)與硫代羰基二咪唑反應，產生2，，3，_〇_硫代碳 酸酯（236)，於2,2、偶氮雙（2-甲基丙腈）之存在下，經三-正丁基锡風化物進行自由基還原反應，分別產生浠煙（237) -ϋ n n H ϋ ϋ I^OJ· n ϋ ϋ ϋ n «I I- I ϋ I ϋ n I ϋ .1 ϋ n I ϋ n I ϋ ϋ ϋ ϋ n ϋ ϋ ϋ 本紙張尺度過用中國國家標準（CNS)A4規格（210 X 297公釐） 133 91949 1293306 A7 B7 五、發明說明（134 ) 與3’-去氧_及2’-去氧·隱陡頭黴素衍生物（23 8)與（239)。此 等產物很容易經矽膠管柱分離。此等產物經酸處理時，分 別產生相應之游離核苷（240)、（241)及（242)。此方法特別 適合在短時間内製備少量數種核苷供篩選用。 依相同方法，但改用VIII型核苷替代V型，可得到相 應之IX型L_核苷。 反應圖3 2 (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(Please read the note on the back and then fill out this page.) The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative prints a similar response, but starts with other optical isomers, which can be obtained (1 magic _(+)_ aza double ring [2·2·1]hept-5-ene-3-one, corresponding to the nucleoside analog (VIII) type. A type VI nucleoside is prepared from a V-nuclear nucleus. An example thereof is shown in the reaction scheme 32. After the treatment of benzoic acid (234) or any carbonized-ribonucleoside by dimethylformamide dimethyl acetal in DMF, the tritylation reaction is carried out and converted into the corresponding oxime-[(dimethylamino) a methylene]-5,-0-trityl derivative (235). (235) is reacted with thiocarbonyldiimidazole to produce 2,3,_〇-thiocarbonate (236), In the presence of 2,2, azobis(2-methylpropionitrile), a radical reduction reaction is carried out by tri-n-butyltin weathering to produce a smoky (237)-ϋ nn H ϋ ϋ I^OJ·n ϋ ϋ ϋ n «I I- I ϋ I ϋ n I ϋ .1 ϋ n I ϋ n I ϋ ϋ ϋ ϋ n ϋ ϋ ϋ This paper scale has passed the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ) 133 91949 1293306 A7 B7 V. Description of invention (134) And 3'-deoxy- and 2'-deoxy-cryptoxanthomycin derivatives (23 8) and (239). These products are easily separated by a ruthenium column. When these products are acid-treated, respectively The corresponding free nucleosides (240), (241) and (242) are produced. This method is particularly suitable for preparing a small number of nucleosides for screening in a short time. According to the same method, instead of using type VIII nucleosides instead of type V The corresponding type IX L_ nucleoside can be obtained. Reaction Figure 3 2 (Please read the note on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

242242

241241

240 V型經立體選一择性轉化成VI型之反應亦示於反應圖 33。5-氟-碳化-尿苷（233)轉化成5’-0-三苯甲基-2，，3，-二·The reaction of the 240 V type by stereoselective conversion to Form VI is also shown in Reaction Scheme 33. 5-Fluoro-carbo-uridine (233) is converted to 5'-0-trityl-2,3. -two·

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 134 91949 經濟部智慧財產局員工消費合作社印制取 135 1293306 A7 B7 五、發明說明（135 ) 0-甲磺醯基衍生物（243)。（243)經鹼水溶液處理，經由2,2，-脫水核苷中間物（244)產生來蘇糖環氧化物（245)。環氧化物 於丙酮或丁酮中，經破化鈉開環，產生反式破代醇（246)， 經甲續酸化，經由（247)產生烯烴（248)。（247)脫除〇-三苯 甲基，產生（249)。亦可改用第三丁基二甲矽烷基或第三丁 基二苯矽烷基之矽烷基保護法替代5三苯甲基保護 法。亦可改用如：甲苯磺醯氯、三氟甲磺醯氣或三氟甲磺 酸酐等試劑之其他磺酸化法替代甲磺酸化法。 依相同方法，但改用VIII型核苷替代V型，可得到 IX型之相應L-核苷。 反應圖33This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 134 91949 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 135 1293306 A7 B7 V. Description of invention (135) 0-Methanesulfonyl derivative (243). (243) The threose epoxide (245) is produced via the 2,2,-anhydronucleoside intermediate (244) by treatment with an aqueous base. The epoxide is opened in acetone or methyl ethyl ketone by sodium sulfide to produce a trans-substituted alcohol (246) which is acidified to produce an olefin (248) via (247). (247) Removal of hydrazine-tritylmethyl group to give (249). Instead of the 5-tritylmethyl protection method, a decyl group protection method of a third butyl dimethyl decyl group or a tert-butyl diphenyl fluorenyl group may be used instead. Instead of the mesylation method, other sulfonation methods such as toluenesulfonium chloride, trifluoromethanesulfonate or trifluoromethanesulfonic anhydride may be used instead. According to the same method, but instead of the type V nucleoside instead of the type V, the corresponding L-nucleoside of the type IX can be obtained. Reaction Figure 33

249 248 247 246 亦可由2-環戊烯_1_酮（250，反應圖34)合成VI-b型核 符。第二丁氧甲基鐘銅酸鹽[(卜311〇€；112)2(1：111^]與（250)進行 Michael加成反應，產生加合物（25 1)Q (25〖）根據Wilsm等 本紙張尺度適用中國國豕標準（CNS)A4規格（210 X 297公髮） 一 91949 (請先閱讀背面之注意事項再填寫本頁)249 248 247 246 The VI-b type nucleus can also be synthesized from 2-cyclopentene-1-one (250, reaction scheme 34). The second butoxymethyl citrate [( 卜 〇 ; ; 112; 112) 2 (1:111^] and (250) undergo a Michael addition reaction to produce an adduct (25 1) Q (25 〖) according to This paper size such as Wilsm is applicable to China National Standard (CNS) A4 specification (210 X 297 mil). 91949 (Please read the note on the back and fill out this page)

1293306 ____ B7 五、發明說明（136 ) 人（Synthesis，1995，1465)進行之苯基硒化法主要在第三丁 氧甲基之反式上進行，產生（252)。DIB AH還原法以立體 選擇性方式還原羰基成為羥基，產生（253)。（253)經磺酸 化，最好於鹼中使用三氟甲磺醯氣或三氟甲磺酸酐進行， 形成（254)後，與納代嘌呤（由例如：腺嘌吟與鈉產生）於惰 性溶劑中如：乙腈中，依立體選擇性方式縮合，產生（255)。 硒化物（255)與過氧化氫於吡啶中氡化，順利地轉化成烯烴 (2S6)。（256)經溫和酸處理，產生游離核苷（240)。 或者，（253)乙醯化後，於三甲矽烷基三氟甲磺酸酯之 存在下，與矽烷基化嘧啶（如··參（三甲矽烷基）-5-氟胞嘧咬 縮合，產生高收量之相應之嘧啶核苷，由此產物氧化及經 酸脫除產物之第三丁基，很容易製成VI-a型核苷。 依相同方法，但改用VIII型核苷替代V型，可得到相 應IX型L-核甘。 反應圖34 (請先閱讀背面之注音？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1293306 ____ B7 V. INSTRUCTIONS (136) The phenyl selenization process carried out by the human (Synthesis, 1995, 1465) is carried out mainly on the trans-type of the third butoxymethyl group to give (252). The DIB AH reduction process reduces the carbonyl group to a hydroxyl group in a stereoselective manner, resulting in (253). (253) by sulfonation, preferably using trifluoromethanesulfonate or trifluoromethanesulfonic anhydride in a base, forming (254), and inerting with nanodairy (produced by, for example, adenine and sodium) In a solvent such as acetonitrile, condensation is carried out in a stereoselective manner to give (255). Selenide (255) is deuterated with hydrogen peroxide in pyridine and smoothly converted to olefin (2S6). (256) Treatment with a mild acid to produce a free nucleoside (240). Or, after (253) acetylation, in the presence of trimethyl decyl trifluoromethanesulfonate, thioalkylated pyrimidine (such as · ginseng (trimethyl decyl)-5-fluorocytosine condensate, resulting in high The corresponding pyrimidine nucleoside is obtained, and the product is oxidized and the third butyl group of the product is removed by acid, and the VI-a type nucleoside is easily formed. According to the same method, the VIII type nucleoside is replaced by the V type. The corresponding type IX L-nuclear can be obtained. Reaction Figure 34 (please read the phonetic on the back? Please fill out this page) Order---------Line _ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

253 250253 250

oso^f3 - 6ePh t-Βυ-Ο-· 254 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 136 91949 1293306Oso^f3 - 6ePh t-Βυ-Ο-· 254 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 136 91949 1293306

五、發明說明（137 此外2，3不飽和核苷之消旋性碳化類似物可由shi 等人（J，MM，Chenu 1999, 42, 859)之方法製備，其係由環 戊烯-4-羧酸乙酯經多步驟製備消旋性順式·3, 4_環氧-環戊 烧曱醇（257)(反應圖35)。以二苯基栖鍵打開環氧乙烧之 環，產生（258)，經乙醯化後，以過氧化物處理，產生二乙 酸酯（259)。由尿嘧啶或胞嘧啶衍生物與ν&η於二甲亞楓 中反應製備鈉代嘧啶，處理（259)，於Pd(I>ph3)4之存在下， 於惰性溶劑（例如：四氫呋喃）中反應，脫除乙醯基後，產 生（260)，收率10至70%。 反應圖35V. DESCRIPTION OF THE INVENTION (137 Further, the racemic carbonized analog of 2,3 unsaturated nucleosides can be prepared by the method of Shi et al. (J, MM, Chenu 1999, 42, 859), which is derived from cyclopentene-4- Preparation of racemic cis- 3,4-epoxy-cyclopentanol (257) by multiple steps of ethyl carboxylate (reaction Figure 35). Opening the ring of epoxy ethene with diphenyl hydrazone (258), after acetylation, treated with peroxide to produce diacetate (259). Preparation of sodium uracil by reaction of uracil or cytosine derivative with ν & η in dimethyl sulfoxide (259), in the presence of Pd(I>ph3)4, in an inert solvent (for example, tetrahydrofuran), after removal of the ethyl thiol group, (260) is produced in a yield of 10 to 70%.

(請先閱讀背面之注意事項再填寫本頁) 參 經濟部智慧財產局員工消費合作社印製 257 反應圖36出示VII型3，4-不飽和碳化核苷之合成法。 Wolfe 等人 dQrg· Chem，，1990, 55, 47 12)由 D-核糖酸内酯 製備（261)。以亞磺醯氯中止第三丁氧甲基（261，反應圖36) 之Michael加成反應，產物與碳酸鈣加熱，產生環戊稀酮 (262) 。以DIB AH還原（262)，然後磺酸化，產生（263)。 (263) (R=CF3較佳）與嘌呤鹼基如上述使用NaH縮合，產生 嗓11令核甘VII-b，例如：尼普拉素（neplanociii)A(264)。以 NaN3處理（263)(R=Me較佳），產生（265)，其可依反應圖30 已述之方法轉化成各種嘧啶核苷（VII-a)，包含（266)。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 137 91949 訂---------線· 1293306(Please read the notes on the back and fill out this page.) Participated in the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives. 257 Reaction Figure 36 shows the synthesis of VII type 3,4-unsaturated carbonized nucleosides. Wolfe et al. dQrg. Chem,, 1990, 55, 47 12) Prepared from D-ribonolactone (261). The Michael addition reaction of the third butoxymethyl group (261, reaction scheme 36) is stopped with sulfinium chloride, and the product is heated with calcium carbonate to produce cyclopentanone (262). Reduction (262) with DIB AH followed by sulfonation yields (263). (263) (R = CF3 is preferred) and the purine base is condensed with NaH as described above to produce 嗓11-nucleus VII-b, for example, neplanociii A (264). Treatment with NaN3 (263) (R = Me is preferred) yields (265) which can be converted to the various pyrimidine nucleosides (VII-a) according to the procedure described in Scheme 30, containing (266). This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 137 91949 Order --------- Line · 1293306

經 濟 部 智 慧 財 產 局 員 工 消 費 合 社 印 製 265 264 D.XI與XII型核苷之合成法 有數種方法可用於合忐^ ^ 成思些類型核苷。本發明採用之 一些核苷主要依下列方式芻I 飞裝備。由2,2-二甲氧乙酸之i-甲 酯（267，反應圖37)與硫代乙醢_松人 八己醇酸縮合，產生之非對映異構 物混合物(268)很容易於矽膠管柱上分離。以如叫於乙醇 中還原（268)後’乙醯化’產生（269)，（269)於四氯化錫之 存在下與我化驗基縮合，主要得到所需之受㈣之卜 核苷，經層析純化。脫除Ο·乙醯基後，產生相應之未保護 之核苷（270)。亦可由N-t-B〇C_L•脯土酸之2,2_二甲氧乙酯 線 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐 138 91949 1293306 A7 B7 五、發明說明（139 ) 製得（270)。以3當量硫乙醇酸於二氯甲烷中，在MgS04 與CAS之存在下處理（270)，產生（271)之非對映異構物混 合物，經層析分離。（271)之各非對映異構物於四氫呋喃中 經Li(t-BuO)3AlH還原，然後乙醯化，產生（272)，與矽烷 基化鹼基縮合後，脫除產物之保護基，產生（270)。 反應圖37Ministry of Economic Affairs, Intellectual Property, Bureau of Labor, Consumers, Consumers, Co., Ltd. Printed 265 264 Synthesis of D.XI and XII Type Nucleosides Several methods are available for the combination of nucleosides. Some of the nucleosides used in the present invention are mainly equipped in the following manner. Condensation of i-methyl 2,2-dimethoxyacetic acid (267, reaction scheme 37) with thioethenol-rosin octadecanoic acid produces a mixture of diastereomers (268) that is readily Separate on the hose column. After the reduction (268) in ethanol, it is produced (269), (269) is condensed with our test group in the presence of tin tetrachloride, and the desired nucleoside (4) is obtained. Purified by chromatography. Upon removal of the indole ethyl group, the corresponding unprotected nucleoside (270) is produced. It can also be applied to China National Standard (CNS) A4 specification (210 X 297 mm 138 91949 1293306 A7 B7) by NtB〇C_L•2,2-dimethoxyethyl phthalate. This paper (139) (270) was obtained by treating (270) with 3 equivalents of thioglycolic acid in dichloromethane in the presence of MgS04 and CAS to give (271) a mixture of diastereomers which were separated by chromatography. Each of the diastereomers is reduced in tetrahydrofuran by Li(t-BuO)3AlH, and then acetylated to give (272). After condensation with the oxime alkylation base, the protecting group of the product is removed and produced ( 270). Reaction Figure 37

267 HSCH2C02H -^267 HSCH2C02H -^

269 268269 268

-丨丨丨丨丨丨丨丨丨丨丨丨·丨 i叮 (請先閱讀背面之注咅？事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 271 本發明採用之XIII型核苷係採用相關技藝已知之方 式製備。在較佳具體實施例中，以文獻中提出之單步驟屬 兩步驟合成法製備ΧΙΙΙ-a型核香(Nucleic Acid Chem 197 8，1，272及343)，其係由磺酸化反應活化5，-〇H後， 以鹼處理，或直接以PhsP及偶氮二羧酸二乙酯處理未保讀 之核苷。 本發明採用之XIV型核苷之製法係採用彼等由 Duscliinsky 等人Chem.，1967, 10, 47)用於合成相 應之5-氟去氧尿苷加合物之類似方法合成。有些使用5_ 氟尿苷（273)之實例示於反應圖38。任何在C-5含有強力泰-丨丨丨丨丨丨丨丨丨丨丨丨·丨i叮 (please read the note on the back? Please fill out this page again) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 271 The XIII type core used in the present invention Glycosides are prepared in a manner known in the art. In a preferred embodiment, the ruthenium-a type nucleus (Nucleic Acid Chem 197 8, 1, 272 and 343) is prepared by a single-step synthesis method proposed in the literature, which is activated by a sulfonation reaction, 5 After 〇H, the unprotected nucleoside is treated with a base or directly with PhsP and diethyl azodicarboxylate. The method for preparing X-type nucleosides according to the present invention is synthesized by a similar method for the synthesis of the corresponding 5-fluorodeoxyuridine adduct by Duscliinsky et al. Chem., 1967, 10, 47). Some examples using 5-fluorouridine (273) are shown in Reaction Scheme 38. Anything in C-5 contains Power Thai

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 139 91949 1293306 五、發明說明（14〇 (請先閱讀背面之注意事項再填寫本頁) 電子取代基之—核脊進行類似加合物形成法。於甲醇中 使用漠處理（273)，產生加合物（274)，經催純氫化法還原 成（275)。於水中處理，產生溴代醇（277)，並同時盘溴於乙 酸中，在乙酸酐之存在下反應’產生（276)。亦可使用其他 次齒酸鹽（例如：次氯酸鹽）製備其他相應加合物，產生 (278)。此等加合物分別為非對映異構物混合物，且呈此混 合物形式用於篩選。 / 反應圖3 8This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 139 91949 1293306 V. Invention description (14〇 (please read the note on the back and fill out this page) Electronic Substitute - Core Ridge Similar to the adduct formation method. The use of desert treatment (273) in methanol produces the adduct (274), which is reduced to (275) by hydrogenation. It is treated in water to produce bromohydrin (277), and simultaneously Disk bromine is reacted in acetic acid in the presence of acetic anhydride to produce (276). Other corresponding adducts (eg, hypochlorite) can also be used to prepare other corresponding adducts to produce (278). The compounds are respectively a mixture of diastereomers and are used in the form of a mixture for screening. / Reaction Figure 3 8

經濟部智慧財產局員工消費合作社印製 E.XV-XVIII 型核脊 本發明採用之核苷係由4-硫尿脊與6-硫肌苷衍生物求 據相關技藝已知方式氧化製成。XVI型化合物為c_核脊。 XVI-a核苷係由驴-尿脊依相關技藝已知方法合成 (Watanabe，“The Chemistry of C-Nucleosides，，，Townsend 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公爱 140 91949 1293306 A7 B7 五、發明說明（w ) L.B·，Ed” In “Chemistry of Nucleosides and Nucleotides，，〕 Plenum，Publ·，New York，Vol·，3, 421，1994)或由芳香系化 合物與受保護之核糖酸内酯縮合後，操作產物合成（例如： Kabat et al·，LMed“Chem·，1987, 30, 924)。XVI-b 與 XVI-c 核苷係依據Pankiewicz等人發展之改良法製備(Carbohvdr^ Res“ 1984, 127,227 ； Nucleosides Nucleoiti1991，10， 1333)。嘌呤型XVI-d C-核苷依Chu等人提出之方法合成 (T Heterocycl. Chem.r 1980，17，1435)。本發明採用之 XVII 型核苷係由4’-甲醯基核苷與甲醛之交又醇醛反應合成或 由預形成之糖與鹼基縮合形成。有些XVIII型核苷之製法 已於前文中說明。 下列操作實例進一步說明本發明方法。此等實例只供 說明，並無意限制本發明範圍。可改用同等物、類似或合 適溶劑、試劑或反應條件替代彼等特定溶劑、試劑或反應 條件，但均仍未偏離本發明方法之一般範圍。 [實例] 熔點係於電熱式數據型熔點測定器上，於開口毛細管 中測定，且未校正。UV吸光光譜係於Uvikon 931(KONTRON)分光光度計上，於乙醇中記錄。1H-NMR 光譜則於室溫下，使用Varian Unity Plus 400分光光度計 測定。化學遷移係以離内參考物四甲基石夕烧之下磁場ppm 表示。進行氘交換法、去偶合實驗或2D-COS Y，以確認質 子位置。訊號多重性以s(單峯）、d(雙峯）、dd(雙重雙峯）、 t(三峯）、q(四峯）、br(寬）、m(多峯）代表。所有J-值均以 (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 本紙張尺度適用中國國家標準（CNS)A4規格（21〇 X 297公爱） 141 91949 1293306 A7 _ B7 五、發明說明（142 )Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperative of E.XV-XVIII type nucleus. The nucleosides used in the present invention are prepared by oxidation of 4-thiourate ridges and 6-thioinosine derivatives according to the known art. The XVI type compound is a c_nuclear ridge. XVI-a nucleosides are synthesized by the sputum-urinary ridge according to methods known in the art (Watanabe, "The Chemistry of C-Nucleosides,,, Townsend. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 public). 140 91949 1293306 A7 B7 V. Description of invention (w) LB·, Ed” In “Chemistry of Nucleosides and Nucleotides,,] Plenum, Publ·, New York, Vol·, 3, 421, 1994) or by aromatic compounds and After condensation of the protected ribolactone, the product is synthesized (for example: Kabat et al., LMed "Chem., 1987, 30, 924". XVI-b and XVI-c nucleosides are improved according to the development of Pankiewicz et al. Preparation (Carbohvdr^ Res "1984, 127,227; Nucleosides Nucleoiti 1991, 10, 1333). Indole XVI-d C-nucleosides were synthesized by the method proposed by Chu et al. (T Heterocycl. Chem. r 1980, 17, 1435). The XVII type nucleosides used in the present invention are synthesized by reacting 4'-formyl nucleosides with formaldehyde and aldols or by condensation of pre-formed sugars and bases. Some XVIII nucleosides have been prepared in the foregoing. Description. The following operation examples further illustrate this issue. The examples are for illustrative purposes only and are not intended to limit the scope of the invention, and equivalents, similar or suitable solvents, reagents or reaction conditions may be substituted for their particular solvents, reagents or reaction conditions, but without departing from the methods of the invention. The general range. [Example] The melting point is determined on an electrothermal data type melting point tester and measured in an open capillary tube. The UV absorption spectrum is recorded on a Uvikon 931 (KONTRON) spectrophotometer in ethanol. 1H- NMR spectra were measured at room temperature using a Varian Unity Plus 400 spectrophotometer. The chemical migration was expressed as ppm of the magnetic field below the internal reference tetramethyl sulphate. The enthalpy exchange method, decoupling experiment or 2D-COS was performed. Y, to confirm the proton position. Signal multiplicity is s (single peak), d (double peak), dd (double double peak), t (three peaks), q (four peaks), br (width), m (multiple Representative). All J-values are taken (please read the notes on the back and fill out this page) #订---------线< Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Print this paper scale Applicable to China National Standard (CNS) A4 specification (21〇X 2 97 public interest) 141 91949 1293306 A7 _ B7 V. Description of invention (142)

Hz表示。FAB質譜係於JEOL DX 300質譜儀上，以正離 子（FAB>〇)或負離子（FAB<0)模式記錄。基質為弘硝〒基醇 (NBA)或甘油與硫甘油（GT)之混合物（5〇 : 5〇，ν/ν)。此旋 光度係於Perkin-Elmer 241旋光光度計（光徑1公分）測 定’其單位為101 deg cm2 g1。元素分析係於Atiantic Mircolab Inc·，（Norcross GA)上進行。分析結果由元素或官 能基之代號表示，在理論值之土 0.4%内。薄層層析法係於 Whatman PK 5F石夕膠板上進行，使用UV吸光法目視檢查 產物，然後使用10%硫酸之乙醇溶液形成焦黑，並加熱。 管柱層析法係於常壓下，於矽膠（Fisher，SF33-1)進行。 實例1 — - 乙酿基-3-漠-3-去氧召-D-D夫喃木糖基乙 醯基胞嘧啶（2, R=H)。 在30分鐘内，於回流下，添加乙醯基溴（15毫升，〇 2 莫耳）至含N4·乙醯基胞苷（5 ·7克，0.02莫耳）之乙腈（300 毫升）懸浮液中。混合物回流4小時後，真空濃縮至乾。殘 質溶於二氣甲烷（150毫升）中，以水（15〇毫升）洗滌。有機 層脫水（Na2S04)，蒸發，殘質自乙醇中結晶，產生ι<2,5_ 二-0-乙醯基-3-溴-3-去氧-召-D-咲喃木糖基）-N4_乙醯基胞 嘧啶（2, R=H，3.4 克，40%)，mp 179-180 °C. NMR (CDC13) δ: 10.2 (bs, 1H, NHAc)9 8.1 (d, 1H, H«6, J5>6 = 7.5 Hz), 7.5 (d, 1H, H-5, J5>6 = 7.5 Hz), 6.0 (d, 1H, Η-Γ, J,^ <1 Hz), 5.5 (d, 1H, H-2% Jva. < 1, Jr,3, = 0 Hz)，4·2 - 4·7 ⑽ 4H，H-3，,4，，5，,5,〇, 2.CW.4 (3s, 9H，3Ac)· 依類似方法，但改用相應之N-醯基化胞苷，製備下列 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (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Hz is indicated. FAB mass spectra were recorded on a JEOL DX 300 mass spectrometer in positive ion (FAB > 〇) or negative ion (FAB < 0) mode. The matrix is quinone alcohol (NBA) or a mixture of glycerol and thioglycerol (GT) (5 〇: 5 〇, ν/ν). The optical rotation was measured on a Perkin-Elmer 241 optical illuminometer (1 cm diameter) in units of 101 deg cm2 g1. Elemental analysis was performed on Atiantic Mircolab Inc., (Norcross GA). The results of the analysis are represented by the code of the element or the functional base, within 0.4% of the theoretical value. The thin layer chromatography was carried out on Whatman PK 5F, and the product was visually inspected by UV absorption, and then blackened with 10% sulfuric acid in ethanol to form coke black and heated. Column chromatography was carried out under normal pressure in a silicone (Fisher, SF 33-1). Example 1 - - Ethyl-3-indol-3-deoxy-D-D-fusantosylcytosylcytosine (2, R=H). Ethyl bromo bromide (15 ml, 〇2 mol) was added to a suspension of acetonitrile (300 mL) containing N4 · acetyl cytidine (5 · 7 g, 0.02 mol) over 30 min. in. The mixture was refluxed for 4 h then concentrated in vacuo to dryness. The residue was dissolved in di-methane (150 mL) and washed with water (15 mL). The organic layer is dehydrated (Na2S04), evaporated, and the residue is crystallized from ethanol to give ι<2,5-di-O-acetyl--3-bromo-3-deoxy-callo-D-furanyl)- N4_Ethylcytosine (2, R=H, 3.4 g, 40%), mp 179-180 ° C. NMR (CDC13) δ: 10.2 (bs, 1H, NHAc) 9 8.1 (d, 1H, H «6, J5>6 = 7.5 Hz), 7.5 (d, 1H, H-5, J5>6 = 7.5 Hz), 6.0 (d, 1H, Η-Γ, J,^ <1 Hz), 5.5 ( d, 1H, H-2% Jva. < 1, Jr, 3, = 0 Hz), 4·2 - 4·7 (10) 4H, H-3,, 4,, 5,, 5, 〇, 2. CW.4 (3s, 9H, 3Ac)· According to a similar method, but using the corresponding N-thiolated cytidine, the following paper scales are prepared for the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (Please read the notes on the back and fill out this page.) Printed by the Consumer Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs.

I I I I I I °JI -I— n I ϋ n I I ϋ ϋ ϋ I- I ϋ I ϋ ϋ ϋ I I ϋ ϋ ϋ n ϋ ϋ ^1 ϋ ϋ I 142 A7 1293306 B7_ 五、發明說明（143 ) 核苷與其L·對映體： 1-(2,5-二-Ο-乙醯基-3-溴-3-去氧-冷-D-呋喃木糠基）-N4-乙醯基-5-氟胞嘧啶， 1-(2,5-二-0-乙醯基-3-溴-3-去氧-召-0-呋喃木糖基）-N4-乙酿基-5-氣胞嘴咬， 1-(2,5-二-0-乙醯基-3-溴-3_去氧-召-〇-呋喃木糖基）-N4-乙醯基-5-溴胞嘧啶， 1-(2,5-二-0-乙醯基-3-溴-3-去氧-冷-0-呋喃木糖基）-N4-乙醯基-5-碘胞嘧啶， 1-(2,5-二-0-乙醯基-3-溴-3-去氧-泠-〇-呋喃木糖基）-N4-乙醯基_5_甲基胞嘧啶， 1-(2,5-二-0-乙醯基-3-溴-3_去氧-石-0-呋喃木糖基）-N4-乙醯基-5-乙基胞嘧啶， 1-(2,5-二_0-乙醯基_3-溴-3-去氧-召-0-呋喃木糖基）-N4-乙醯基-5-正丙基胞嘧啶， 1-(2,5-二-0_乙醯基-3-溴-3-去氧-召-0-呋喃木糖基）-N4-乙醯基-5-異丙基胞嘧啶， 1_(2,5-二-0-乙醯基-3-溴-3-去氧-)8-0-呋喃木糖基）-N4-乙醯基-5-乙烯基胞嘧啶， 1-(2,5-二-0-乙醯基-3-溴-3-去氧-召-0-呋喃木糖基）-N4-乙醯基-5-(2-氣乙烯基）胞嘧啶， 1-(2,5-二-0-乙醯基_3-溴-3-去氧-点-〇-呋喃木糖基）-N4-乙醯基·5-(2-溴乙烯基）胞嘧啶， 1-(2,5-二-0-乙醯基-3-溴-3-去氧-召-D-呋喃木糖基）- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) 0 訂---------線· 經濟部智慧財產局員工消費合作社印製 143 1293306 A7 — B7 五、發明說明（144 ) N4-乙醯基-5-(2-碘乙烯基）胞嘧啶， 1·(2,5 -二- Ο-乙釀基-3->臭-3-去氧-点- π夫喃木糖基）_ Ν4-乙醯基-5-(2-甲氧羰基-乙烯基）胞嘧啶， 1-(2,5-二-0-乙醯基-3-溴-3-去氧-召_〇_呋喃木糖基）_ N4-乙醯基-5-(2-羥基羰基-乙烯基）胞嘧啶， 1-(2,5_二-0-乙酿基-3->臭-3-去氧-石-1)-咲喃木糖基）-N4-乙醯基-5-苯基胞嘧啶， 1-(2,5-二-0-乙酿基-3-漠-3-去氧-沒-1)-1]夫喃木糖基）-N4·乙醯基-5-T基胞嘧啶， 1-(2,5 -二_0-乙龜基- 3-?臭-3-去氧-召-D-Π夫喃木糖基）_ N4·苯甲醯基胞嘧·唆， 1-(2,5 -二-0-乙酿基-3-?臭-3 -去氧-石-D -D夫喃木糖某）_ 1^4_苯甲醯基-5-氟胞嘧啶， 1-(2,5-二- Ο-乙醯基-3 -溴-3-去氧-点-D-π夫喃木糖基）_ N4-苯甲醯基-5-氯胞嘧啶， 1-(2,5-二- Ο-乙醯基-3-漠-3_去氧-沒-D_D夫喃木糖基）_ N4-苯甲醯基-5-溴胞嘧啶， 1·"(2,5 -二- Ο-乙釀基-3 -漠-3-去氧-召-£) -吹喃木糖基）_ Ν4-苯甲醯基-5-碘胞嘧啶， 1-(2,5 -二- Ο-乙釀基-3-溴_3_去氧-召-D -陕靖木糖基）_ Ν4·苯甲醯基-5-甲基胞嘧啶， 1-(2,5-二-0-乙酿基_3-漠-3-去乳-石-1)-11夫喃木糖其）-Ν4-苯甲醯基-5-乙基胞嘧啶， 1-(2,5-二-〇-乙酿基_3_溴-3-去氧-召-1)-咲味木糖基）- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) 0 訂---------線· 經濟部智慧財產局員工消費合作社印製 144 經濟部智慧財產局員工消費合作社印製 145 1293306 B7IIIIII °JI -I- n I ϋ n II ϋ ϋ ϋ I- I ϋ I ϋ ϋ ϋ II ϋ ϋ ϋ n ϋ ϋ ^1 ϋ ϋ I 142 A7 1293306 B7_ V. Description of invention (143) Nucleosides and their L· Enantiomers: 1-(2,5-di-indole-ethenyl-3-bromo-3-deoxy-cold-D-furanyl)-N4-ethenyl-5-fluorocytosine, 1-(2,5-di-0-ethinyl-3-bromo-3-deoxy-callo-0-furanoxylan)-N4-ethyl-branched-5-pneumatic bite, 1-( 2,5-di-O-acetylindol-3-bromo-3-deoxy-callo-indole-furanose-N-acetamido-5-bromocytosine, 1-(2,5- 2-O-acetamido-3-bromo-3-deoxy-cold-0-furanoxylan)-N4-ethinyl-5-iodocytosine, 1-(2,5-di-0- Ethyl-3-bromo-3-deoxy-indole-indole-furanyl)-N4-ethenyl_5-methylcytosine, 1-(2,5-di-O-ethenyl -3-bromo-3_deoxy-stone-0-furanose)-N4-ethinyl-5-ethylcytosine, 1-(2,5-di-oxo-ethenyl-3- Bromo-3-deoxy-callo- 0-furanoxylyl)-N4-ethinyl-5-n-propylcytosine, 1-(2,5-di-O-ethenyl-3-bromo- 3-deoxy-callo-0-furanyl)-N4-ethinyl-5-isopropylcytosine, 1_(2,5-di-0-ethinyl-3-bromo-3-de Oxygen-)8-0-furanose -N4-Ethyl-5-vinylcytosine, 1-(2,5-di-O-ethenyl-3-bromo-3-deoxy-callo-0-furanyl)- N4-ethylindolyl-5-(2-vinylvinyl)cytosine, 1-(2,5-di-0-ethinyl-3-bromo-3-deoxy-dot-indole-furanose -N4-Ethyl-5-(2-bromovinyl)cytosine, 1-(2,5-di-O-ethenyl-3-bromo-3-deoxy-callo-D-furan Glycosyl) - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 (Please read the note on the back and fill out this page) 0 Order---------Line· Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 143 1293306 A7 — B7 V. Description of Invention (144) N4-Ethyl-5-(2-iodovinyl)cytosine, 1·(2,5-di-anthracene -Erytyl-3->odor-3-deoxy-dot-[p-xylopyryl)_Ν4-ethenyl-5-(2-methoxycarbonyl-vinyl)cytosine, 1-( 2,5-di-0-ethinyl-3-bromo-3-deoxy-callo_〇_furanyl)_N4-ethenyl-5-(2-hydroxycarbonyl-vinyl)cytosine , 1-(2,5_di-0-ethyl-branched-3->odor-3-deoxy-stone-1)-anthoxysyl)-N4-ethinyl-5-phenyl Pyrimidine, 1-(2,5-di-0-B Yl-3-indol-3-deoxy-n--1)-1]phora-xylyl)-N4·ethinyl-5-T-cytosine, 1-(2,5-di-_0-B Turtle base - 3-? odor-3-deoxy-callo-D-Fufu xylosyl)_ N4·benzimidyl cytosine, 1-(2,5-di-0-ethyl -3-?odor-3-deoxy-stone-D-D-fucaose xylose)_1^4_benzimidyl-5-fluorocytosine, 1-(2,5-di-anthracene-B Mercapto-3 -bromo-3-deoxy-dot-D-π-flomoxylenyl)_N4-benzimidyl-5-chlorocytosine, 1-(2,5-di-anthracene-ethene基-3-漠-3_deoxy-no-D_D xylanyl)_N4-benzimidyl-5-bromocytosine, 1·"(2,5-di-anthracene-ethyl -3 - desert-3-deoxy-call-£) - sulphonyl) Ν 4-benzylidene-5-iodocytosine, 1-(2,5-di-anthracene-ethene- 3-bromo_3_deoxy-callo-D-Shaanjing xylose)_Ν4·benzimidyl-5-methylcytosine, 1-(2,5-di-O-ethylidene) -Mix-3-de-milk-stone-1)-11-fucaose xylose-- 4-phenylmercapto-5-ethylcytosine, 1-(2,5-di-indole-ethyl ketone) 3_Bromo-3-deoxy-calli-1)-Azure xylose) - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (Please read the notes on the back first) Fill in this page) 0 Order---------Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 144 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 145 1293306 B7

五、發明說明（145) N4-苯甲醯基-5-正丙基胞嘧啶， 1-(2,5-二-Ο·乙釀基·3·溴·3·去氧喃木糖基）_ ]Sj4 -苯甲酿基-5-異丙基胞,σ定， 1-(2,5-二-Ο-乙醯基-3·溴·3_去氧-石_D_呋喃木糖基）_ N4 -苯甲醯基乙稀基胞喷σ定， 二·〇_乙酿基_3_溴_3_去氧H吹喃木糖基卜 ]Si4 -苯甲酿基-5-(2 -氯乙稀基）胞癌淀， ^(2，^二_〇_乙醯基_3_溴_3_去氧_点_〇_呋喃木糖基卜 N4 -苯甲酿基- 5-(2-漠乙稀基）胞嘴咬， 1_(2,5-二-0-乙釀基-3-漠-3-去氧HD夫喃木糖基）_ N4 -苯甲酿基- 5_(2-蛾乙稀基）胞嘴淀， 二-〇-乙釀基_3_溴_3_去氧_D_呋喃木糖基 N4-苯甲醯基-5-(2-甲氧羰基·乙烯基）胞嘧咬， 1-(2,5-二_0-乙醯基-3-溴-3-去氧-石-1)-11夫11南木糖某)_ N4 -苯甲酿基- 5-(2-幾基幾基-乙稀·基）胞喷唆， 1-(2,5-二-0_乙醯基-3-溴-3-去氧_点-1^呋喃木糖基^ N4-苯甲醯基-5-苯基胞嘧啶， 1·(2,5_二-0-乙酿基-3·溴-3-去氧-召-D-陕喃木糖某）_ N4-苯甲醯基-5-T基胞嘧啶， 1-(2,5-二-0-乙醯基-3-溴-3-去氧-召-1)-11夫喃木糖基）-N4-茴香酸基胞癌咬， 1-(2,5_二_0-乙醯基_3-溴-3-去氧_3-1)-11夫喃木糖基）-N4-茴香醯基_5_氟胞癌咬， 1_(2,5_二_0 -乙醯基_3_溴-3-去氧-点-D-口夫喃木糖基）_ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁)V. DESCRIPTION OF THE INVENTION (145) N4-Benzylmercapto-5-n-propylcytosine, 1-(2,5-di-anthracene-2-aryl bromide, 3·bromo-3 deoxypyranosyl) _ ]Sj4 -benzyl-5-isopropyl, sigma, 1-(2,5-di-indole-ethenyl-3·bromo-3_deoxy-stone_D_furanose ))_ N4 - benzylidene ethylene thiophene sigma, bismuth _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (2-chloroethyl) cell carcinoma, ^(2,^2_〇_乙醯基_3_bromo_3_deoxy_dot_〇_furanose-based N4-benzonitrile- 5-(2-Molybdenum) cytotoxin, 1_(2,5-di-0-ethyl-bromo-3-indolyl-3-deoxy-H-xylopyryl)_ N4 -benzyl - 5_(2-Mothyl) cytosine, di-anthracene-ethyl ketone_3_bromo_3_deoxy-D_furanose-based N4-benzylidene-5-(2-A Oxycarbonyl-vinyl) cytosine bite, 1-(2,5-di-oxo-ethenyl-3-bromo-3-deoxy-stone-1)-11-11 11 xylose)_ N4 - Benzoyl- 5-(2-monomethyl-ethlyl) sneezing, 1-(2,5-di-O-ethenyl-3-bromo-3-deoxy-dots- 1^furanylose^ N4-benzimidyl-5-phenylcytosine, 1·(2,5_二-0-ethyl-branched-3·bromo-3-deoxy-call-D-Shaan Xylose) _ N4-benzimidyl-5-T-cytosine, 1-(2,5-di-0-ethenyl-3-bromo-3-deoxy-call-1)-11 Cyclopyranosyl)-N4-anisylcytocarcinoma, 1-(2,5-di_0-ethenyl-3-bromo-3-deoxy-3-1)-11-flomoxylyl )-N4-Anisyl _5_Fluorine cell carcinoma bite, 1_(2,5_二_0-Ethyl _3_bromo-3-deoxy-dot-D-mouth xylosyl)_ This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (please read the notes on the back and fill out this page)

12933〇6 A7 B712933〇6 A7 B7

五、發明說明（146 ) 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 146 N4·茴香醯基-5-氯胞嘧啶， 4 U(2,5_二-0-乙酿基_3_溴-3-去氧^ _D_陕喃木糖基）_ N4_茴香醯基-5-溴胞嘧啶， 1(2,5-二-0·乙釀基-3-漠·3-去氧呋喃木糖基）_ 茴香醯基·5·碘胞嘧啶， 1-(2,5-二-0_乙醢基-3-溴-3-去氧n咲喃木糠基）_ Ν4_茴香醯基-5-甲基胞嘧啶， 1-(2,5-二-0-乙醯基-3·溴-3-去氧j_D_咲喃木糖基）_ Ν4-茴香醯基-5-乙基胞嘧啶， 1-(2,5·二-0-乙酿基-3-溴-3-去氧陕喃木糖基）_ Ν4-茴香醯基-5-正丙基胞嘧啶， Η2,5-二-0乙酿基_3·漠-3-去氧n吹喃木糖基）· Ν4-菌香醯基-5-異丙基胞嘧啶， ^2,5-二-0-乙醯基-3-溴-3-去氧^彻夫喃木糖基）_ Ν4·菌香醯基-5-乙浠基胞嘴咬， Η2,5·二·0·乙酿基冬溴-3·去氧木糖基）_ N -菌香酿基_5-(2 -乳乙稀.基）胞癌咬， 1-(2,5-二-Ο-乙醯基-3-漠-3-去氧吹喃木糖基）_ N4 -菌香酿基- 5- (2 ->臭乙稀基）胞嘴咬， 1-(2,5-二-0-乙醯基-3-溴-3·去氧-η咲喃木糖基）_ Ν4-®香醯基-5-(2-峨乙烯基）胞嘧啶， if，％二_〇乙酿基_3_漠_3_去氧·〇_咲喃木糖基> N4 -茴香酿基- 5- (2 -甲氧幾基-乙稀基）胞喷咬， 1_(2,5_二_0-乙醯基-3·溴-3-去氧·召_D_呋喃木糖基）_ 91949 (請先閱讀背面之注意事項再填寫本頁)V. Description of invention (146) Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 146 N4·Fenyl-5-chlorocytosine, 4 U(2,5_二-0-ethyl-branched_3_bromo-3-deoxy^ _D_Sharanyl xylate)_N4_Fenyl-5-bromocytosine, 1(2,5- 2--0·Butyl-3-carb·3-deoxyfuranyl)_ Anisyl-5·Iodocytosine, 1-(2,5-di-O-ethenyl-3-bromo -3- deoxyn-n-pyrylmyl)_Ν4_fensyl-5-methylcytosine, 1-(2,5-di-0-ethinyl-3·bromo-3-deoxyj_D _ 咲 木 木 ) _ Ν 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_ Ν 4-Fenyl decyl-5-n-propyl cytosine, Η 2,5-di-O-ethyl ketone _3 · Desert-3-deoxyn-n- xylosyl) · Ν4-菌香醯基-5 -isopropylcytosine, ^2,5-di-0-ethinyl-3-bromo-3-deoxy^cheftanyl xylate)_ Ν4·bacteria fluorenyl-5-acetylene Mouth bite, Η2,5·2·0·B-branched bromo-3·deoxyxylenyl)_N-bacteria fragrant base_5-(2-milk-diethyl-based) cell carcinoma bite, 1- (2,5-di-indole-ethenyl-3-indole-3-deoxybenzopyranyl)_N4 - bactericidal base - 5- (2 -> odorant base) , 1-(2,5-di-O-ethenyl-3-bromo-3·deoxy-η咲-xylosyl)_Ν4-® 香醯基-5-(2-峨vinyl) Pyrimidine, if, % 〇 〇 酿 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 咲 木 木 & N N N N N N N N N N N N N N N N N N N N N N N N N N Cellular biting, 1_(2,5_two_0-ethylindolyl-3·bromo-3-deoxy·calling_D_furanose)_ 91949 (Please read the back note first and then fill out this page )

12933061293306

五、發明說明（147 ) N4-菌香酿基·5_(2_羥基羰基_乙烯基）胞嘧啶， 1 (2,5_ 一 _〇_乙醯基_3·漠_3.去氧j-D-咲喃木糖基）_ -回香醯基-5-苯基胞喷咬，及 1-(2,5-二·0·乙醯基_3_漠_3·去氧j_D_呋嚼木糖基 •皆香醯基_5_T基胞喷咬力 ίΜΛ Η2,5-二〇_乙醯基_3_去氧n咲喊赤蘚戊糖基㈣乙酿基胞，咬取3 1 (2,5-一-〇-乙醯基-3·溴去氧-泠①了呋喃木糖 基）也乙醯基胞㈣（2 15克，5€莫耳）之5〇%甲醇水溶 液（100毫升）於碳酸鈣粉末（1克）與Pd-BaS〇4觸媒（〇 5克） 之存在下，於初壓45psi之帕爾器中氳化。過濾排除觸媒， 遽液真空濃縮。殘質自乙醇中結晶，產生卜(2»〇-乙 醯基-3-去氧·々-；〇-呋喃赤蘚戊糖基）^^乙醯基胞嘧啶（3, R=H，1.06g，60%), mp 174-1770C。 f請先閱讀背面之注音？事項再填寫本頁} 0V. Description of the invention (147) N4-bacteria fragrant base·5_(2-hydroxycarbonyl-vinyl)cytosine, 1 (2,5___〇_ acetyl group _3· desert _3. Deoxygenation jD-咲 木 糖 ) _ _ 回 回 回 回 回 回 回 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 及 - - - - - - Glycosyl • Allicinyl _5_T base cell squeezing force ΜΛ 2,5-two 〇 _ 醯 _ _3_ deoxyn 咲 藓 藓 藓 藓 糖 ( 四 四 四 四 四 四 四 四 四 四 四 四 四 四,5-mono-indole-ethenyl-3-bromo-deoxy-indole 1 furanose) also acetaminophen (4) (2 15 g, 5 € mol) of 5 % methanol aqueous solution (100 ml In the presence of calcium carbonate powder (1 g) and Pd-BaS〇4 catalyst (〇5 g), it was deuterated in a 45 psi Parr. The catalyst was removed by filtration, and the mash was concentrated in vacuo. Crystallization from ethanol produces bu (2»〇-acetamido-3-deoxy-indole-; 〇-furan erythrosyl pentose) ^^ acetyl cytosine (3, R=H, 1.06 g, 60%), mp 174-1770C. fPlease read the phonetic transcription on the back first? Then fill out this page} 0

I n 1 I n n ·ϋ=-OJ· ·ϋ «ϋ I n ϋ If I I I 經濟部智慧財產局員工消費合作社印製 lH NMR(CDC13) δ: 1030 (bs, IH, NfiAc), 8.05 (d, 1H, H-6, J5,6 = 7.5 Hz), 7.43 (d, 1H, H-5, J5,6 = 7.5 Hz), 5.90 (d, 1H, Η-Γ, = 1.0 Hz), 5.46 (m, 1H, H.2*), 4.30-4.80 (3H, m, H-4\5,,5,,)> 2.10,2.27 (2s, 9H, 3Ac), 1.60-2.00 (m, 2H, H-3\3M). 依類似方法，但改用相應之3’-溴·木糖核苷，製備下 列核苷與其L-對映體： 1-(2,5-二-〇-乙醯基-3-去氧-沒-〇_呋喃赤蘚戊糖基）_ N4 _苯〒醯基胞嘴唆， 1-(2,5-二-〇-乙醯基-3-去氧-冷-〇-咲喊赤蘚戊糖基）_ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 147 91949 經濟部智慧財產局員工消費合作社印製 148 1293306I n 1 I nn ·ϋ=-OJ· ·ϋ «ϋ I n ϋ If III Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed lH NMR (CDC13) δ: 1030 (bs, IH, NfiAc), 8.05 (d, 1H, H-6, J5,6 = 7.5 Hz), 7.43 (d, 1H, H-5, J5,6 = 7.5 Hz), 5.90 (d, 1H, Η-Γ, = 1.0 Hz), 5.46 (m , 1H, H.2*), 4.30-4.80 (3H, m, H-4\5,,5,,)> 2.10, 2.27 (2s, 9H, 3Ac), 1.60-2.00 (m, 2H, H -3\3M). In a similar manner, but using the corresponding 3'-bromo-xylosyl nucleoside, the following nucleosides and their L-enantiomers were prepared: 1-(2,5-di-indole-ethenyl) -3-deoxy-no-〇_furan erythrose pentose)) N4 _benzoquinone cytosine, 1-(2,5-di-indole-ethenyl-3-deoxy-cold- 〇-咲叫赤藓 戊糖基)_ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 147 91949 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print 148 1293306

五、發明說明（l48 ) N4-苯甲醯基-5-甲基胞嘧啶， 1-(2,5-二·0-乙醯基-3-去氧j_D_呋喃赤蘚戊糖基）_ N -本甲釀基_5_乙基胞癌唆， 1-(2,5-二-0-乙醯基·3·去氧_D_呋喃赤蘚戊糖基）_ N4-苯甲醯基-5-正丙基胞喊ti定， 1-(2,5-二-0-乙醯基_3_去氧-点_D_呋喃赤蘚戊糖基）_ N4-苯甲醯基-5-異丙基胞嘧啶， 1-(2,5_二_0_乙醯基-3-去氧-点呋喃赤蘚戊糖基）_ N4-苯甲醯基-5-苯基胞嘧啶， 1-(2,5-二-Ο-乙醯基·3·去氧-石呋喃赤蘚戊糖基）_ Ν4-苯甲醯基-5-苄基胞嘧啶， 1-(2,5_二-0-乙醯基_3_去氧j 呋喃赤蘚戊糖基）_ N4-茴香醯基胞嘧唆， 1-(2,5_二-0_乙醯基-3_去氧-石_〇_呋喃赤蘚戊糖基）_ N4_@香醯基-5-甲基胞嘴咬， 1-(2,5·二-Ο-乙醯基_3_去氧-yS 呋喃赤蘚戊糖基）_ N4-茴香醯基-5-乙基胞嘧啶， 1-(2,5-二-Ο-乙醯基-3-去氧-沒呋喃赤蘚戊糖基）_ N4-茴香醯基-5-正丙基胞嘧啶， 1-(2,5-二_0-乙醯基-3-去氧-点呋喃赤蘚戊糖基）_ N4-菌香醯基-5-異丙基胞嘧啶， 1-(2,5-二-Ο-乙醯基-3·去氧-石呋喃赤蘚戊糖基 N4-茴香醯基-5-苯基胞嘧啶，與 1-(2,5_二_0-乙醯基-3-去氧-召_D-呋喃赤蘚戊糖基）_ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁)V. DESCRIPTION OF THE INVENTION (l48) N4-Benzylmercapto-5-methylcytosine, 1-(2,5-dioxa--3-deoxyj-D_furan-erythropentyl)_ N - Benzyl _5_ethylcytopenia, 1-(2,5-di-0-ethinyl·3·deoxy_D_furan erythrosyl pentose)_N4-benzamide -5-5-n-propyl cyano ti, 1-(2,5-di-0-ethinyl_3_deoxy-dot_D_furan erythrose pentose)_N4-benzhydryl -5-isopropylcytosine, 1-(2,5-di-oxo-ethenyl-3-deoxy-dofuran-erythropentyl)_N4-benzimidyl-5-phenyl Pyrimidine, 1-(2,5-di-indole-ethenyl·3·deoxy-stonefuran erythrosyl pentose)_Ν4-benzylidene-5-benzylcytosine, 1-(2, 5_二-0-乙醯基_3_deoxyj furan erythrosyl pentose)_N4-Anisine cytosine, 1-(2,5_二-0_乙醯基-3_ Oxygen-stone_〇_furan erythrose pentose)_N4_@香醯基-5-methyl cytotoxin, 1-(2,5·di-indole-ethenyl_3_deoxy-yS furan Erythrylpentosyl)_N4-Anisyl-5-ethylcytosine, 1-(2,5-di-indole-ethenyl-3-deoxy-furfurylerythritol)-N4 -Fenyl-5-n-propylcytosine, 1-(2,5-di-oxo-ethenyl-3-deoxy-dofuran Erythrylpentosyl)_N4-bacteria-indenyl-5-isopropylcytosine, 1-(2,5-di-indole-ethenyl-3·deoxy-stonefuran-erythropentyl N4 -Fenyl-5-phenylcytosine, and 1-(2,5_di_0-ethinyl-3-deoxy-callo_D-furan-erythropentyl)) National Standard (CNS) A4 Specification (210 X 297 mm) 91949 (Please read the notes on the back and fill out this page)

1293306 A7 B7 五、發明說明（149 ) N4-茴香醯基-5-苄基胞嘧啶。 實例3 1-(3-溴-3-去氧-D-呋喃木糖基）胞嘧啶（3, R=H) 於〇°C下，以飽和氨之甲醇溶液（100毫升）處理1-(2,5-二-Ο-乙醯基-3-溴-3-去氧-点呋喃木糠基）-N4·乙醯基胞 嘧啶（4.31克，〇·〇ΐ莫界）3〇分鐘，然後於35°C以下溫度真 空濃縮。殘質自甲醇中結晶’產生1-(3-溴，3-去氧-点_D-呋喃木糖基）胞嘧啶（3, R=H)。其UV與1H NMR(D2〇)結果 與木糖結構一致。 依類似方法，但改用相應之N-醯化胞苷，製備下列核 苷與其L·對映體： 1-(3-溴-3-去氧-石呋喃木糖基）-5_氟胞嘧啶， 1-(3·溴-3-去氧-0 -D·咲喃木糖基）_5_氯胞癌σ定， 1-(3-漠-3-去氧-石-D-D夫喃木糖基）_5_漠胞癌咬， 1-(3-溴-3_去氧-泠呋喃木糖基）-5-碘胞嘧啶， 1-(3-溴_3_去氧-ϋ-呋喃木糖基）-5-甲基胞嘧啶， 1-(3-溴-3-去氧-谷呋喃木糖基）-5-乙基胞嘧啶， 1-(3-溴-3-去氧-0 -D-Π夫喃木糖基正丙基胞嘧啶， 1-(3-溴-3-去氧-0 -D-Π夫喃木糖基）_5_異丙基胞嘧啶， 1-(3-溴-3-去氧-D-呋喃木糖基）-5-乙烯基胞嘧啶， 1-(3-溴-3·去氧-万-D-呋喃木糖基）-5-(2-氣乙烯基）胞 喊σ定， 1-(3-漠-3-去氧·召-D-呋喃木糖基）-5-(2_溴乙烯基）胞 嘧啶， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公髮 91949 (請先閱讀背面之注意事項再填寫本頁) --------訂---------. 經濟部智慧財產局員工消費合作社印製 149 1293306 A7 '----------__ 五、發明說明（15〇 ) 一 --- h(3_溴去氧呋喃木糖基）-5_(2-碘乙烯基）胞 ^(3_溴去氧*"冷-D_呋喃木糖基）-5-(2-胺基羰基乙烯 基）胞癌唆， 1-(3-溴-3-去氧-石_D_呋喃木糖基）_5-(2_羥基羰基乙烯 基）胞嘧啶， 1-(3•溴-3-去氧-厶-d-d夫喃木糖基）-5_苯基胞嘧唆，與 1-(3-溴-3_去氧·沒-D_呋喃木糖基）苄基胞嘧啶。 實例4 3’-去氧胞苷（4, R=H) 取l-(2,5-一 - 〇-乙醯基去氧-沒_D-n夫喃赤蘚戊糖 基）-N4-乙醯基胞嘧啶（3, R==H，7〇〇毫克，2毫莫耳）溶於氨 之甲醇溶液中（20毫升，於0它下飽和），此溶液保持在室 溫下一夜。真空蒸發溶劑，殘質溶於乙醇（2〇毫升）中，然 後以2N硫酸調整溶液pH至3。收集沈澱，自水-乙醇中結 晶’產生3’-去氧胞苷（4)之半硫酸鹽（408毫克，74%)。Mp 202 至 203°C (分解）。 lE NMR (DaO) δ: 8.23 (d, 1¾ H-6, J5>6= 8.0 Hz), 6.27 (d, 1H, H-5, J5,6= 8.01293306 A7 B7 V. INSTRUCTIONS (149) N4-Anisyl-5-benzylcytosine. Example 3 1-(3-Bromo-3-deoxy-D-xylopyranosyl)cytosine (3, R=H) Treated with a solution of saturated ammonia in methanol (100 mL) at 〇 ° C. 2,5-di-indole-ethenyl-3-bromo-3-deoxy-p-furanyl fluorenyl)-N4·ethenyl cytosine (4.31 g, 〇·〇ΐ莫界) 3 〇, It was then concentrated in vacuo at a temperature below 35 °C. The residue crystallized from methanol to give 1-(3-bromo, 3-deoxy-dot-D-furanose) cytosine (3, R = H). The UV and 1H NMR (D2〇) results were consistent with the xylose structure. In a similar manner, but using the corresponding N-deuterated cytidine, the following nucleosides and their L. enantiomers were prepared: 1-(3-bromo-3-deoxy-stone-furanyl)-5-fluoro Pyrimidine, 1-(3.bromo-3-deoxy-0-D-pyrumolyl)_5_chlorocytosine sigma, 1-(3- desert-3-deoxy-stone-DD-fuca Glycosyl)_5_ desert cancer bite, 1-(3-bromo-3-deoxy-furfuryl-xylosyl)-5-iodocytosine, 1-(3-bromo-3_deoxy-indole-furan Xylose)-5-methylcytosine, 1-(3-bromo-3-deoxy-trofuranosyl)-5-ethylcytosine, 1-(3-bromo-3-deoxy- 0-D-Fufu xylinyl-n-propyl cytosine, 1-(3-bromo-3-deoxy-0-D-valfyl xylenyl)_5_isopropylcytosine, 1-( 3-bromo-3-deoxy-D-xylopyranosyl)-5-vinylcytosine, 1-(3-bromo-3.deoxy-wan-D-furanosyl)-5-(2 - gas vinyl) 喊 定 ,, 1- (3- desert-3-deoxy-callo-D-xylopyranosyl)-5-(2_bromovinyl) cytosine, this paper scale applies to China Standard (CNS) A4 specification (210 X 297 metric 91949 (please read the note on the back and fill out this page) --------Book---------. Ministry of Economic Affairs Intellectual Property Bureau Employee consumption Printing by the Society 149 1293306 A7 '----------__ V. Description of the Invention (15〇) One--- h(3_Bromodeoxyfuranylxylyl)-5_(2-iodoethylene )) (3_Bromodeoxygenated*"Cold-D_furanosyl)-5-(2-Aminocarbonylvinyl) Cell Carcinoma, 1-(3-Bromo-3-deoxy- _D_furanoxyl)_5-(2-hydroxycarbonylvinyl)cytosine, 1-(3•bromo-3-deoxy-indole-dd-fufenyl)-5-phenylcytosine唆, with 1-(3-bromo-3-deoxy-lan-D-furanose)benzylcytosine. Example 4 3'-deoxycytidine (4, R=H) Take l-(2 ,5-一-〇-acetyl-deoxy--no-Dn-fusino-p-pentosyl)-N4-ethenylcytosine (3, R==H, 7〇〇 mg, 2 mmol) Dissolve in methanol solution of ammonia (20 ml, saturated under 0), keep the solution at room temperature overnight, evaporate the solvent in vacuo, dissolve the residue in ethanol (2 mL), then adjust the pH of the solution with 2N sulfuric acid To 3. Collect the precipitate and crystallize from water-ethanol to produce 3'-deoxycytidine (4) hemisulfate (408 mg, 74%). Mp 202 to 203 ° C (decomposition). lE NMR (DaO) δ: 8.23 (d, 13⁄4 H-6, J5>6= 8.0 Hz), 6.27 (d, 1H, H-5, J5, 6= 8.0

Hz), 5_84 (41¾ Η-Γ, Jlvr = 1·0 Hz>, 4.6 (1¾ 1¾ H-2〇, 3·9 机3故114，,5，,5,〇，1.95· 2.15(m,2H,H-2*,n. 依類似方法，但改用相應之醯化3、去氧核脊，製備下 列核苷與其L-對映體： 3’-去氧-5_甲基胞苷、3、去氧-5-乙基胞苷、3，_去氧-5-正丙基胞苷、3’-去氧-5-異丙基胞苷、3、去氧-5-苯基胞 (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Hz), 5_84 (413⁄4 Η-Γ, Jlvr = 1·0 Hz), 4.6 (13⁄4 13⁄4 H-2〇, 3·9 machine 3, 114,, 5,, 5, 〇, 1.95· 2.15 (m, 2H , H-2*, n. According to a similar method, but using the corresponding deuterated 3, deoxyribo- ridge, the following nucleosides and their L-enantiomers were prepared: 3'-deoxy-5-methylcytidine, 3. Deoxy-5-ethylcytidine, 3,-deoxy-5-n-propylcytidine, 3'-deoxy-5-isopropylcytidine, 3, deoxy-5-phenyl (Please read the notes on the back and fill out this page) #订---------线's Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

A7 1293306 -----— B7___ 五、發明說明（151 ) 苷、與3’-去氧-5-苄基胞苷。 實例5 2’，5，-二-0_乙酿基- 3’-去氧尿脊 取2’，5’_二-〇-乙醯基-3’·去氧-N4-乙醯基胞苷（ι·〇6 克，3莫耳）溶於70%乙酸中，溶液溫和回流一夜。混合物 真空濃縮後，殘質自乙醇中結晶，產生2，，5，_二_〇_乙醯基 -3 -去氧尿甘（660毫克，96%)。NMR光譜顯示其中含 有一個乙釀基、二個亞甲基及二個稀煙系質子。 依類似方法，但改用相應之3，-去氧胞苷（4)，製備下 列2’，5’_二-Ο-乙醯基-3_去氧·尿香與其對映體：2，，5，_ 二-0-乙醯基-3-去氧-5 -甲基尿普、2’，5，-二乙醢基-3-去 氧_5_乙基尿普、2’，5’-二-Ο-乙醯基·3-去氧_5_正丙基尿 有2、2’，5、二乙醯基-3-去氧-5-異丙基尿杳、2，，5，-二·0-乙醯基-3-去氧_5_苯基尿苷及2’，5’-二乙醯基-3-去氧- 5-苄基尿苷。 依類似方法，但改用相應之3’_去氧胞嘧唆核香（2)， 製備下列尿嘧啶核苷與其L_對映體： 2’，5’-二乙醯基-3·去氧-5_氟尿苷， 2’，5 _二乙釀基-3-去氧_5·氣尿脊， 2’，5’-二_〇-乙醯基-3-去氧-5-溴尿苷， 2’，5’-二乙醯基-3-去氧-5·碘尿苷， 2’，5’-二乙醢基-3-去氧-5-甲基尿杳， 2’，5’-二乙醯基-3-去氧-5-乙基尿苷， 2’，5’-二·〇-乙醢基-3-去氧-5_正丙基尿有1， (請先閱讀背面之注意事項再填寫本頁) --------訂---------· 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210x 297公釐） 151 91949 1293306 五、發明說明（152 ) 2，5 -— 乙醯基_3_去氧巧_異丙基尿苷， 2，5 - —-Ο-乙醯基_3_去氧_5_乙烯基尿苷， 2’，5、二_〇_乙醯基去氧_5_(2_氯乙烯基）尿苷， 2，5 - —乙醯基_3_去氧_5_(2•溴乙烯基）尿苷， 2，5 - —-0-乙醯基_3_去氧_5_(2_碘乙烯基）尿苷， 苷 2，5 - —-0-乙醯基_3_去氧_5_(2•甲氧羰基乙烯基）尿 苷 2，5 — 乙醯基_3_去氧_5_(2•羥基羰基乙烯基）尿 2’，5’-二·〇-乙醯基_3_去氡苯基尿苷，與 2’，5’-二_〇-乙醯基_3_去氧苄基尿苷。 f例6 〇(2’5 乙醯基_3_溴_3·"去氧呋喃木糖基）尿嘧啶 取1 (2’5 乙醯.基_3_溴_3_去氧_沒七_呋喃木糖 基Μ·乙酿基胞喷祁，㈣，R，=CH3)(4.31克，〇·〇1莫耳 溶於观乙酸中，溶液溫㈣流4小時。混合物真^耳) 後，殘質自乙醇中姓曰方* c， a 展縮 * T、、，°日日，產生2，，5 -二乙醯基_3，_溴_3、 去乳尿甘（5，2.80克，91%)。lHNMR光譜顯示其中含有 二個乙醯基、二個亞甲基及二個烯烴系質子。 依類似方法，但改用相應之2，，5，_二_〇_乙醯基、溴 ·3’-去氧-N4_醯基胞苷（2)，製備下列1,5-二-〇-乙醯基 漠-3’-去氧尿苷與其L-對映體： __1_(2，％二^-0_乙酿基-3-去氧-石-D-呋喃木糖某V、愈尽 本紙張尺度適用中國規格⑵G x 297公爱 1 ^ 152 91949 經濟部智慧財產局員工消費合作社印製 153 1293306 A7 B7 五、發明說明（153 ) 1-(2,5 -二-0-乙酿基-3·去氧-万-D· 口夫喃木糖基）_5_氯尿 u密0定， 1-(2,5 -二- Ο-乙酸基-3_去氧-沒-D-D夫喃木糖基）-5-漠尿 1·(2,5-二-0-乙醯基-3-去氧-点-D-呋喃木糖基）-5-碘尿 1 - ( 2，5 -二-Ο -乙酿基_ 3 -去氧-yS - D -咲喃木糖基）-5 -甲基 尿嘴0定， 1·(2,5 -二-0_乙酿基-3-去氧-yS ·D-咲喃木糖基）-5-乙基 尿痛咬， 1 ·(2，5-二·0-乙酿基-3-去氧-万-D -咲喃木糖基）-5-正丙 基尿喷定， 1-(2,5 -二-0-乙酿基-3-去氧-点-D -咲喃木糖基）-5-異丙 基尿哺唆， 1 - ( 2，5 -二-Ο _乙酿基_ 3 -去氧-々-D _ D夫喃木糖基）-5 -乙稀 基尿嘧啶， 1-(2,5-二-0-乙醯基-3-去氧-召-D-呋喃木糖基）-5-(2- 氯乙浠基）尿癌唆， 1-(2,5-二-Ο-乙醯基-3-去氧-召-D-呋喃木糖基）-5-(2- 溴乙烯基）尿嘧啶， 1-(2,5_二- Ο-乙酿基-3-去氧-点-D-咲喃木糖基）-5-(2-碘乙烯基）尿嘧啶， 1-(2,5-二_0-乙醯基-3-去氧-点-〇_呋喃木糖基）-5-(2- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) 0 訂---------線·A7 1293306 ----- B7___ V. Description of the invention (151) Glycosides, and 3'-deoxy-5-benzylcytidine. Example 5 2',5,-di-O-E-branched- 3'-deoxyurinary ridge taken 2',5'-di-indolyl-3'-deoxy-N4-ethenyl The glycoside (ι·〇6 g, 3 mol) was dissolved in 70% acetic acid, and the solution was gently refluxed overnight. After the mixture was concentrated in vacuo, the residue was crystallized from ethanol to yield 2,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The NMR spectrum showed that it contained an ethyl, two methylene and two dilute protons. In a similar manner, but using the corresponding 3,-deoxycytidine (4), the following 2',5'-di-indolyl-3-deoxyuridine and its enantiomer are prepared: 2, , 5, _ 2--0-acetyl--3-deoxy-5-methylurea, 2',5,-diethyl decyl-3-deoxy-5-ethyl urate, 2', 5'-di-indole-ethenyl-3-deoxy-5_n-propylurine has 2,2',5,diethyl-decyl-3-deoxy-5-isopropyl uranium, 2, , 5,-Di-0-ethylindol-3-deoxy-5-phenyluridine and 2',5'-diethylindol-3-deoxy-5-benzyluridine. According to a similar method, but using the corresponding 3'_deoxycytosine nucleoside (2), the following uridine nucleosides and their L_enantiomers were prepared: 2',5'-diethyl fluorenyl-3. Oxy-5-fluorouridine, 2',5-diethyl-branched-3-deoxy-5, gas urinary tract, 2',5'-di-indole-ethenyl-3-deoxy-5- Bromouridine, 2',5'-diethylindol-3-deoxy-5.iodouridine, 2',5'-diethylindol-3-deoxy-5-methyluridine, 2 ',5'-diethylindol-3-deoxy-5-ethyluridine, 2',5'-di-indole-ethenyl-3-deoxy-5-n-propyl urine has 1, (Please read the notes on the back and fill out this page) --------Book---------· Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed Paper Scale Applicable to Chinese National Standards ( CNS) A4 size (210x 297 mm) 151 91949 1293306 V. Description of invention (152) 2,5 -—Ethyl hydrazine _3_deoxy _ isopropyl uridine, 2,5 - Ο-B醯基_3_deoxy_5_vinyl uridine, 2',5, bis- 〇 醯 去 deoxy_5_(2_chlorovinyl) uridine, 2,5 - acetyl group _ 3_deoxy_5_(2•bromovinyl)uridine, 2,5 --0-ethylidene _3_deoxy_ 5_(2_Iodovinyl)uridine, glycoside 2,5---0-ethylindolyl_3_deoxy-5_(2-methoxycarbonylvinyl)uridine 2,5-ethenyl_3 _Deoxy_5_(2•hydroxycarbonylvinyl)urine 2',5'-di-indole-ethenyl_3_deindolyl uridine, and 2',5'-di-〇-acetamidine Base_3_deoxybenzyl uridine. f Example 6 〇(2'5 醯 _ _3_ bromine_3·"deoxyfuranosyl) uracil 1 (2'5 醯 醯. _3_ bromine_3_deoxy_ 7-furanyl glucoside 乙 乙 基 基 祁, (4), R, = CH3) (4.31 g, 〇·〇1 molar dissolved in acetic acid, solution temperature (four) flow for 4 hours. The mixture is true) After the residue from the ethanol, the surname * c, a contraction * T,,, ° day, produce 2,5-diethyl hydrazine _3, _ bromine _3, de-urinary glutinous (5, 2.80 grams, 91%). The lH NMR spectrum showed that it contained two ethyl fluorenyl groups, two methylene groups and two olefinic protons. According to a similar method, but using the corresponding 2,5, _ _ _ 〇 醯 、, bromo 3 '-deoxy-N 4 醯 cytidine (2), the following 1,5-di- oxime was prepared. - 乙醯基漠-3'-deoxyuridine and its L-enantiomer: __1_(2,%二^-0_乙乙基-3-deoxy-stone-D-furanylose a V, more Apply the Chinese specifications to the paper scale (2) G x 297 public 1 ^ 152 91949 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 153 1293306 A7 B7 V. Invention description (153 ) 1-(2,5 -2-0-E -3-3·deoxy-wan-D· 口夫喃木糖基)_5_氯尿乌密0定, 1-(2,5-di-indole-acetoxy-3_deoxy-no-DD Cyclopyranosyl)-5-indifferent 1·(2,5-di-0-ethinyl-3-deoxy-dot-D-furanosyl)-5-iodine urine 1 - ( 2,5 -di-anthracene-ethyl ketone _ 3 -deoxy-yS-D-pyrumolyl)-5-methyl urination 0,1·(2,5 -2-0-ethyl aryl-3 -deoxy-yS ·D-purine xylosyl)-5-ethyl urinary pain bite, 1 ·(2,5-di-0-ethyl-bromo-3-deoxy-wan-D-咲木Glycosyl)-5-n-propyl urinary spray, 1-(2,5-di-0-ethyl-bromo-3-deoxy-dot-D-purpuryl xylenyl)-5-isopropylurea Feeding, 1 - ( 2,5 - -Ο _乙酿基_ 3 -Deoxy-々-D _ Dfu-xylosyl)-5-Ethyl uracil, 1-(2,5-di-O-ethenyl-3-de Oxygen-callo-D-furanosyl)-5-(2-chloroethylidene) urinary carcinoma, 1-(2,5-di-indole-ethenyl-3-deoxy-call-D- Furanosyl)-5-(2-bromoethenyl)uracil, 1-(2,5-di-indole-ethidyl-3-deoxy-dot-D-purpuryl)-5 -(2-iodovinyl)uracil, 1-(2,5-di-oxo-ethenyl-3-deoxy-dot-indole-furanose)-5-(2- This paper size applies China National Standard (CNS) A4 Specification (210 X 297 mm) 91949 (Please read the note on the back and fill out this page) 0 Order---------Line·

五、發明說明（ [293306 甲氧幾基乙稀基）尿喊咬， 1 (，5 — 〇_乙醯基去氧+D•咲淹木糖基）_5_(2_ 羥基羰基乙烯基）尿嘧啶， 1 (2,5 一 〇-乙醯基去氧_^_D_呋喃木糖基）_》·苯基 尿癌唆，與 1 (2’5 一乙醯基去氧_D_呋喃木糖基）巧_苄基 尿癌咬。 實例7 3’-去氧尿有2 (6b，R=H) 取2 ,5 · 一 ·〇_乙醯基、去氧尿苷（1〇6克，3莫耳） 溶於氨之甲醇溶液（10毫升，㈣。c下飽和）中一夜。、混合 物真空濃縮後，殘質自乙醇中結晶，產生3，·去氧尿苷（6b， 660 毫克，96%)。 依類類方法，但改用相應之醯化3、去氧尿嘧啶核苷 (6b)或其L-對映體，製備下列核苷：3-去氧甲基尿苷、 3-去氧-5-乙基尿苷、3_去氧正丙基尿苷、夂去氧_5_異丙 基尿苔、％去氧_5_苯基尿苷、與3-去氧-5_苄基尿苷。 實例8 1-(3-溴-3-去氧·召_d-咲喃木糖基）尿嘧啶（6a，R=H) 取1_(2’，5’-二-〇 -乙醯基-3’·漠·3’_去氧·沒_D-咲喃木 糖基）尿嘧啶（5, R=H)溶於氨之甲醇溶液（1〇毫升，於0。(：下 飽和）中。於〇°C下1小時後，混合物真空濃縮，殘質自乙 醇中結晶，產生3，-溴-3，-去氧尿苷（6a，660毫克，96%)。 --------tr---------線· (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 154 91949 經濟部智慧財產局員工消費合作社印製 155 1293306V. Description of the invention ([293306 methoxyethylidene) urinary squeak, 1 (,5 — 〇 _ 醯 去 去 去 + D D D _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ , 1 (2,5 〇-ethyl hydrazine deoxygenated _^_D_furanyl) _"·Phenyl urinary cancer 唆, with 1 (2'5-ethyl decyl deoxy-D-furanose Base) Qiao _ benzyl cancer bite. Example 7 3'-deoxyurine has 2 (6b, R = H) 2,5 · 〇 醯 醯 醯 、, deoxyuridine (1 〇 6 g, 3 mol) dissolved in ammonia methanol solution (10 ml, (four). C under saturation) overnight. After the mixture was concentrated in vacuo, the residue was crystallized from ethanol to yield 3,······················ According to the class method, but using the corresponding deuterated 3, deoxyuridine (6b) or its L-enantiomer, the following nucleosides were prepared: 3-deoxymethyluridine, 3-deoxy- 5-ethyluridine, 3-deoxy-n-propyluridine, dea-deoxy_5_isopropyl urethane, % deoxy-5-phenyluridine, and 3-deoxy-5-benzyl Uridine. Example 8 1-(3-Bromo-3-deoxy-callo-d-pyrylmyl)uracil (6a, R=H) Take 1_(2',5'-di-fluorenyl-ethenyl- 3'························································· After 1 hour at 〇 ° C, the mixture was concentrated in vacuo and residue was crystallised from ethanol to yield 3,-bromo-3,-deoxyuridine (6a, 660 mg, 96%). --tr---------Line· (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed on this paper scale, applicable to China National Standard (CNS) A4 specification ( 210 x 297 mm) 154 91949 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 155 1293306

五、發明說明（155 ) UV與1H NMR與結構式一致。 依類似方法，但改用相應之醯化3，_溴_呋喃木糖基尿 嘧啶，製備下列核脊與其L_對映體： 1-(3-漠-3-去氧夫喃木糖基）_5_氟尿嘧啶， 1-(3-溴-3-去氧·召-D-呋喃木糖基）_%氣尿嘧啶， 1-(3-溴-3-去氧-石-D-呋喃木糖基）_%溴尿嘧啶， 1-(3·溴-3·去氧-召-D-呋喃木糖基）-5_碘尿嘧啶， 1-(3-溴-3-去氧-D-呋喃木糖基）_5_甲基尿嘧啶， 1-(3-溴-3-去氧-石-D-呋喃木糖基）_5_乙基尿嘧啶， 1-(3-溴-3-去氧-召-D-呋喃木糖基）_5_正丙基尿嘧啶， 1-(3-溴-3-去氧-沒-D-呋喃木糖基卜5_異丙基尿嘧啶， 1-(3-溴-3_去氧-点-D·呋喃木糖基）_5_乙烯基尿嘴啶， 1-(3-溴-3-去氧-召-D-呋喃木糖基）_5-(2_氯乙烯基）尿 。密唆， 1·(3-溴-3-去氧-召-D-呋喃木糖基）_5_(2_溴乙烯基）尿 1-(3-溴-3-去氧-石-D-呋喃木糖基）_5_(2_碘乙烯基）尿 1-(3-溴-3-去氧-召-D_呋喃木糖基）_5_(2_胺基羰基乙稀 基）尿嘧啶， 1·(3-溴-3-去氧-点-D·呋喃木糖基）_5_(2_羥基羰基乙稀 基）尿嘧啶， 1-(3-溴-3-去氧j-D_呋喃木糖基苯基尿嘧啶，與 _ 1-(3-溴_3_去氧_Ρ·1^木糖基）_5_苄基尿嘧唆〇 本紙張尺度適用中國國家標準（CNS)A4規格)----- 91949 (請先閱讀背面之注咅？事項再填寫本頁)V. INSTRUCTIONS (155) UV and 1H NMR are consistent with the structural formula. The following nucleus and its L_enantiomer were prepared by a similar method, but using the corresponding deuterated 3,-bromo-furanose-based uracil: 1-(3-Moly-3-deoxyfuranyl xylanyl) )_5_fluorouracil, 1-(3-bromo-3-deoxy-callo-D-furanyl)-% uracil, 1-(3-bromo-3-deoxy-stone-D-furan Glycosyl)_% bromouracil, 1-(3.bromo-3.deoxy-callo-D-furanosyl)-5-iodouracil, 1-(3-bromo-3-deoxy-D -furanose)_5_methyluracil, 1-(3-bromo-3-deoxy-stone-D-xylopyranosyl)_5_ethyluracil, 1-(3-bromo-3- Deoxy-callo-D-furanosyl)_5_n-propyl uracil, 1-(3-bromo-3-deoxy-dis-D-furanyl glucopyr 5_isopropyl uracil, 1 -(3-Bromo-3-deoxy-dot-D-furanose)_5_Vinylpurine, 1-(3-bromo-3-deoxy-callo-D-furanosyl)_5 -(2_chlorovinyl) urine. Hydrazine, 1 (3-bromo-3-deoxy-callo-D-furanyl) _5_(2-bromovinyl) urine 1-(3-bromo- 3-deoxy-stone-D-furanosyl)_5_(2_iodovinyl)urine 1-(3-bromo-3-deoxy-callo-D-furanosyl)_5_(2-amino Carbonyl ethylene) uracil, 1 · (3-bromo-3-deoxy -D-D-furanose)_5_(2-hydroxycarbonylethyl) uracil, 1-(3-bromo-3-deoxyj-D-furanylphenylphenyluracil, with _ 1 -(3-Bromo_3_deoxy_Ρ·1^xylyl)_5_Benzylpyrimidine This paper scale applies to China National Standard (CNS) A4 specification)----- 91949 (Read first Note on the back? Please fill out this page again)

--------訂------- ——線I 1293306 A7 ---------B7 五、發明說明（156 ) 二三苯基甲墓尿苷（7, r=h) 取含尿苷（24.4克，0·1莫耳）與三笨基氣甲烷（83 5克， 0·3莫耳）之無水吡啶（250毫升）混合物於室溫下授拌一夜 後’回流4小時。冷卻至室溫後，混合物在激烈授拌下倒 至水令。傾析排除水，以水處理膠狀殘質，攪·拌，及傾析 水。重覆此過程數次，然後以熱水（500毫升）處理殘質，攪 拌’及傾析水。重覆此過程二次。殘質溶於二氯甲烷中， 脫水（NaJOj，真空濃縮。殘質溶於最少量苯中，以乙醚 稀釋溶液至混.濁，混合物於15°C下靜置一夜。收集沈澱， 自苯-乙醚中再結晶，產生（7)(R=H)(22.8克，31%)，mp 224-225°C。合併之濾液濃縮，殘質溶於二氣甲烷中，經矽 膠管柱使用二氣甲烷-乙醇（99: 1，v/v)，（98 : 2, v/v)及（97 : 3, v/v)層析。首先溶離出化合物（7)(10克，14%)，其次為 3’，5’-二-〇-三苯基甲基尿苷（31〇克，42.5%)。 依類似方法，但改用相應之核苷，製備下列2’，5’_二 -〇-受保護與3，，5’-二-Ο-受保護之核苷與其L-對映體： 2’，5’-二·〇_三苯基甲基-5-氟尿苷， 2，5 - 一 - 0_二苯基甲基_ 5 -乳尿甘’ 2’，5’-二三苯基甲基-5-溴尿苷， 2%5’-二_〇_三苯基甲基-5-碘尿苷.， 2’，5’-二_〇_三苯基甲基_5_甲基尿苷， 2’，5、二_〇_三苯基甲基-5-乙基尿苷， 2’，5’-二_〇_三苯基甲基-5-正丙基尿苷， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) 0 訂---------線· 經濟部智慧財產局員工消費合作社印製 156 經濟部智慧財產局員工消費合作社印製 1293306 A7 --- B7 五、發明說明（157) 2’，5’-二-0-三苯基甲基-5-異丙基尿苷， 2’，5’-二_0-三苯基甲基-5·乙稀基尿脊， 2’，5’-二-0_三苯基甲基-5-乙快基尿香， 2’，5’-二-〇·三苯基甲基_5_(2_氯乙烯基）尿苷， 2’，5’_二·0-三苯基甲基_5-(2-溴乙烯基）尿苷， 2，5 -一 - 0-二本基甲基- 5- (2-破乙稀基）尿普， 2’，5’-二-0-三苯基甲基-5-(2-甲氧羰基乙烯基）尿苷， 2，5 -—-0-二苯基甲基-5-(2-經基幾基乙烯基）尿苔， 2’，5’-二-0-三苯基甲基-5-苯基尿脊， 2’，5、二-Ο-三苯基甲基-5-T基尿苷， 3’，5’-二_〇 -三苯基甲基-5-氟尿脊， 3’，5’·二-0-三苯基甲基-5·氣尿苷， 3，，5’-二-0-三苯基甲基_5_溴尿苷， 3’，5’·二-0-三苯基甲·基-5-碘尿苷， 3’，5、二-0-三苯基甲基-5-甲基尿苷， 3’，5’-二-0-三苯基甲基-5-乙基尿苷， 3，，5，-二-0-三苯基甲基-5·正丙基尿普， 3’，5’·二- Ο-三苯基甲基-5_異丙基尿脊， 3，，5’-二_0 -三苯基甲基-5-乙稀基尿脊， 3’，5’·二_〇·三苯基甲基_5_乙炔基尿苷， 3，5 _二-0-二苯基甲基_5-(2 -氯乙稀基）尿脊， 3，5 -二-0-二苯基甲基- 5-(2 ->臭乙稀基）尿脊， 3’，5，-二·〇-三苯基甲基-:5-(2-碘乙烯基）尿苷， 3’，5’-二_〇-三苯基甲基-5-(2-甲氧羰基乙烯基）尿苷， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------------------訂---------線 (請先閱讀背面之注音？事項再填寫本頁) 157 91949 A7-------- Order ------- —— Line I 1293306 A7 ---------B7 V. Description of invention (156) Ditriphenylmethyl toluidine (7, r=h) Mix a mixture of uridine (24.4 g, 0.1 mol) with anhydrous pyridine (250 ml) of three stupid methane (83 5 g, 0.3 mol) at room temperature overnight. After 'reflow 4 hours. After cooling to room temperature, the mixture was poured to a water dregs under vigorous mixing. The water was removed by decantation, the gelatinous residue was treated with water, stirred and mixed, and decanted. This process was repeated several times, then the residue was treated with hot water (500 ml), stirred and decanted. Repeat this process twice. The residue was dissolved in dichloromethane, dehydrated (NaJOj, concentrated in vacuo. residue was dissolved in a minimum of benzene, diluted with diethyl ether to mixture and turbid, and the mixture was allowed to stand overnight at 15 ° C. The precipitate was collected from benzene - Recrystallization from diethyl ether gave (7) (R = H) (22.8 g, 31%), mp 224-225 ° C. The combined filtrate was concentrated, residue was dissolved in methane methane Methane-ethanol (99: 1, v/v), (98: 2, v/v) and (97: 3, v/v) chromatography. The compound (7) (10 g, 14%) was first dissolved. Followed by 3',5'-di-indole-triphenylmethyluridine (31 g, 42.5%). According to a similar method, but using the corresponding nucleoside, the following 2', 5'-di- 〇-protected and 3,5'-di-indole-protected nucleosides and their L-enantiomers: 2',5'-di-indole-triphenylmethyl-5-fluorouridine, 2 ,5 - mono- 0-diphenylmethyl _ 5 - urinary uranium 2',5'-ditriphenylmethyl-5-bromouridine, 2% 5'-di-hydrazine-triphenyl Methyl-5-iodouridine., 2',5'-di-p-triphenylmethyl-5-methyluridine, 2',5, di-p-triphenylmethyl-5- Ethyl uridine, 2', 5'-di-〇 _Triphenylmethyl-5-n-propyluridine, this paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 (please read the note on the back and fill out this page) 0 --------- Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 156 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1293306 A7 --- B7 V. Invention description (157) 2', 5' -di-O-triphenylmethyl-5-isopropyluridine, 2',5'-di-n-triphenylmethyl-5-eththyl urinary ridge, 2',5'-di -0_triphenylmethyl-5-ethyl-based urinary scent, 2',5'-di-anthracene-triphenylmethyl _5_(2-chlorovinyl) uridine, 2', 5'_ HT-triphenylmethyl_5-(2-bromoethenyl)uridine, 2,5-mono- 0-di-benylmethyl-5-(2-ethidyl) urinary, 2 ',5'-Di-O-triphenylmethyl-5-(2-methoxycarbonylvinyl)uridine, 2,5---0-diphenylmethyl-5-(2-trans Vinyl urethane, 2',5'-di-0-triphenylmethyl-5-phenyl urinary ridge, 2',5,di-anthracene-triphenylmethyl-5-T Uridine, 3',5'-di-indole-triphenylmethyl-5-fluorourine, 3 ',5'·di-0-triphenylmethyl-5·aeroside, 3,5'-di-O-triphenylmethyl-5-bromouridine, 3',5'·2 -0-triphenylmethyl-5-iodouridine, 3',5,di-0-triphenylmethyl-5-methyluridine, 3',5'-di-O-triphenyl Methyl-5-ethyluridine, 3,5,-di-O-triphenylmethyl-5-n-propyl urethane, 3',5'-di-indole-triphenylmethyl -5_isopropyl urinary ridge, 3,5'-di-n-triphenylmethyl-5-eththyl urinary ridge, 3',5'.di-tert-triphenylmethyl-5 _ ethynyl uridine, 3,5 _di-O-diphenylmethyl _5-(2- chloroethylene) urinary ridge, 3,5-di-O-diphenylmethyl-5- 2 -> odorant base) urinary ridge, 3',5,-di-anthracene-triphenylmethyl-: 5-(2-iodovinyl)uridine, 3',5'-di-〇 - Triphenylmethyl-5-(2-methoxycarbonylvinyl)uridine, this paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) ---------- ----------Book--------- line (please read the phonetic on the back first? Please fill out this page again) 157 91949 A7

1293306 五、發明說明（l58 ) 3’，5、二-Ο-三苯基甲基-5-(2-羥基羰基乙烯基）尿苷， 3’，5’_二-0-三苯基甲基-5-苯基尿苷，與 3，，5’-二-0-三苯基甲基-5-T基尿苷。 實例1 3’-0-甲磺醯基_2，，5，-二-0-三苯基甲基尿脊（8，11=11) 滴加甲磺醯氣（1毫升）至含2，，5，-二-0-三苯基甲基尿 苷（7, 7.28克，1毫莫耳）之吡啶（1〇〇毫升）冷溶液中， 反應保持在4C下一仪。添加乙醇（5毫升）中止反應。於室 溫下攪拌2小時後，混合物真空濃縮。殘質與乙醇（25〇毫 升）碾磨，收集固體，自乙醇中再結晶，產生（8)(R=H)(7 45 克，92%)，mp 225 至 226〇C 〇 依類似方法，但改用相應之核苷，製備下列2,，5，-二 -0_三苯基甲基化與3’，5’-二-Ο-三笨基甲基化之核苷與其 L-對映體： 3、0-甲磺醯基-2’，5’-二-0-三笨基甲基_5-氟尿苷， 3’_0_甲磺醯基-2’，5’-二-0-三笨基甲基_5_氣尿苷， 3、0_甲績醯基-2’，5’-二-0-三笨基甲基_5_溴尿眘， 3、0·甲續醯基-2，，5’-二-Ο-三笨基甲基-5_峨尿替， 3’_0_甲磺醯基-2’，5’_二-〇-三笨基甲基-5_甲基尿苷， 3，-0-甲磺醯基-2’，5’-二三笨基甲基-5_乙基尿苷， 3，-0·甲磺醯基-2，，5，-二三笨基甲基正丙基尿 甘， 3’-0 -甲續醯基-2’，5’-二·〇"二笨基甲基-5-異丙基展 苷， __ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱)^' 91949 (請先閱讀背面之注咅？事項再填寫本頁) 0 訂---------線. 經濟部智慧財產局員工消費合作社印製 158 經濟部智慧財產局員工消費合作社印製 1293306 A7 B7 五、發明說明（159) 3’-Ο-甲續酿基-2’，5’-二-0-二苯基甲基-5-乙稀基尿 甘， 3’-〇-甲磺醯基-2’，5，-二-0-三苯基甲基_5-.乙炔基尿 甘， 3 ’ - 0 甲石黃酿基-2 ’，5 二-Ο -二苯基甲基- 5- (2•氯乙稀基) 尿苷， 3’-0-甲磺醯基-2，，5’-二-Ο-三苯基甲基-5-(2-溴乙烯基) 尿苷， 3，·0-甲磺醯基·2’，5，_二-Ο-三苯基甲基-5-(2-碘乙烯基） 尿苷， 3’·0-甲磺醯基-2’，5’-二-0-三苯基甲基-5-(2-甲氧羰基 乙烯基）尿苷， 3 ’ -0-甲續隨基-2 ’，5 ’ _二 0_二苯基甲基·5 _(2 -經基魏基 乙烯基）尿苷， 3、0-甲磺醯基-2，，5’-二-0-三苯基甲基-5-苯基尿苷， 3’-0_甲磺醯基-2’，5’_二-0-三苯基甲基-5-〒基尿苷， 2’-0_甲磺醯基-3，，5’-二-0-三苯基甲基-5-氟尿苷， 2’-0-甲磺醯基-3’，5’-二-0-三苯基甲基-5-氣尿苷， 2，-0-甲磺醯基-3，，5’_二-0_三苯基甲基_5_溴尿苷， 2’-0-甲磺醯基-3’，5’_二-0-三苯基甲基-5-碘尿苷， 2、〇_甲磺醯基-3’，5’-二-0-三苯基甲基-5_甲基尿苷， 2’_〇-甲磺醯基_3’，5，-二-0_三苯基甲基-5-乙.基尿苷， 2’- 0-甲績酿基-3’，5’-二- Ο-二苯基甲基-5-正丙基尿 甘， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 9 訂---------線· 159 91949 1293306 A7 B7 五、發明說明（16G) 2 ’ - 0 -甲績酿基-3 ’，5 ’ -二-Ο -二苯基甲基-5 ·異丙基尿 甘， 2’-0-甲磺醯基-3，，5’-二_0-三苯基甲基-5-乙烯基尿 甘， 2’-0-甲磺醯基-3，，5’-二-0-三苯基甲基-5-乙炔基尿 甘， 2’- 0-甲續酿基-3 ’，5’-二-0-二苯基甲基- 5- (2-乳乙稀基） 尿苷， 2’ ·0-甲續釀基-3 ’，5，_二-0-二苯基甲基-5- (2->臭乙稀基) 尿苷， 2’-Ο-甲磺醯基-3’，5，-二-0-三苯基甲基-5-(2-碘乙烯基） 尿苷， 2’-0-甲磺醯基-3’，5’-二·0-三苯基甲基-5-(2-甲氧羰基 乙浠基）尿脊， 2’-0-甲磺醯基-3’，5’-二-0-三苯基甲基-5-(2-羥基羰基 乙烯基）尿苷， 2’-0-甲磺醯基-3’，5’-二-0-三苯基甲基-5-苯基尿苷， 與 2 ’ - 0 -甲石黃酿基-3 ’，5 ’ -二-0 -二苯基甲基-5 -卞基尿甘。 實例11 2，3’-脫水- l- (2,5 -二- Ο-二苯基甲基-石-D-咲喃木糖基）尿癌 啶（9, R=H, Χ，= 0Η) 取3’-0-甲磺醯基-2’，5’·二-Ο-三苯基甲基尿苷（806毫 克，1亳莫耳）、苯甲酸鈉（2克）之二甲基甲醯胺（40毫升） 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) 0 訂---------線 經濟部智慧財產局員工消費合作社印製 160 經濟部智慧財產局員工消費合作社印製 161 1293306 A7 ______ B7 五、發明說明（161 ) 此合物於130至140 °C下加熱一夜。混合物冷卻至室溫， 授拌倒至1升水上。傾析收集沈澱，與乙醇（丨〇〇毫升）碾 磨，產生3、脫水-l-(2,5-二〇-三苯基甲基-召-D-呋喃木糠 基）尿嘧啶（9, R=H，X，= OH)，（500 毫克，75%)，mp 237°C。 依類似方法，但改用相應之5·經取代之3、〇-甲磺醯 基_2’，5’-二_〇_三苯基甲基尿苷（8)，製備下列2,3，-脫水-二 -0-三苯基甲基化核苷與其L-對映體： 2,3’-脫水-ΐ·(2,5-二_〇_三苯基甲基-^-呋喃木糖 基）-5-氟尿嘧咬， 2,3’-脫水二三苯基甲基j-D-呋喃木糖 基）-5 -氯尿喷σ定， 2.3 脫水]_(2,5_二三苯基甲基j 呋喃木糖 基）-5 -溴尿喷σ定， 2,3’-脫水“-(2,5_二-〇_三苯基甲基_0-1>呋喃木糖 基）-5-換尿喷咬， 2.3 -脫水- i_(2,5-二-〇_三苯基甲基呋喃木糖 基）-5_甲基尿喊咬， 2,3-脫水_1-(2,5-二_〇-三苯基甲基_3-|>呋喃木糖 基）-5-乙基尿，咬， 2,3’·脫水-_二_〇_三苯基甲基-^-咲喃木糖 基）-5-正丙基尿嘴唆， 2,3’_脫水4-(2,5-:-0-三苯基甲基-p-唉喃木糖 基）-5-異丙基尿嘴唆， _ 2,3 _脫水二j^(2,5-二-0-三苯基甲基j 呋喃木糖 _ 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐) 91949 (請先閱讀背面之注意事項再填寫本頁)1293306 V. INSTRUCTIONS (l58) 3',5,Di-indole-triphenylmethyl-5-(2-hydroxycarbonylvinyl)uridine, 3',5'-di-O-triphenyl 5--5-phenyluridine, with 3,5'-di-O-triphenylmethyl-5-T-uridine. Example 1 3'-0-Methanesulfonyl 2,5,-di-O-triphenylmethyl urinary ridge (8,11=11) dropwise with methyl sulfonate (1 ml) to contain 2, , 5,-Di-O-triphenylmethyluridine (7, 7.28 g, 1 mmol) in pyridine (1 mL) cold solution, the reaction was kept at 4C next. The reaction was stopped by the addition of ethanol (5 ml). After stirring at room temperature for 2 hours, the mixture was concentrated in vacuo. The residue was triturated with ethanol (25 mL), and the solid was collected and recrystallized from ethanol to give (8) (R = H) (7 45 g, 92%), mp 225 to 226 〇C. However, by using the corresponding nucleosides, the following 2,5,-di-O-triphenylmethylation and 3',5'-di-indole-trisylmethylated nucleosides and their L-pairs were prepared. Peptide: 3,0-methylsulfonyl-2',5'-di-0-trisylmethyl-5-fluorouridine, 3'_0_methylsulfonyl-2',5'-di -0-Trisylmethyl _5_ uridine, 3, 0 _ 醯 醯 base-2', 5'-two-0-triptyl methyl _5_ bromine, 3,0· A continued 醯基-2,,5'-di-Ο-triptylmethyl-5_峨 尿, 3'_0_Methanesulfonyl-2',5'_二-〇-三笨基甲-5-methyluridine, 3,-0-methylsulfonyl-2',5'-ditriphenylmethyl-5-ethyluridine, 3,-0.methylsulfonyl-2 ,,5,-two or three stupid methyl-n-propyl urethane, 3'-0-methyl thiol-2',5'-di·〇" dipyridylmethyl-5-isopropyl exhibit Glycoside, __ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) ^' 91949 (Please read the note on the back first? Fill in this page) 0 Order---------Line. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 158 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1293306 A7 B7 V. Invention Description (159) 3' -Ο-甲再酿基-2',5'-di-0-diphenylmethyl-5-ethlyluridine, 3'-〇-methanesulfonyl-2',5,-di- 0-triphenylmethyl _5-. ethynyl urethane, 3 ' - 0 甲石黄-based 2 ',5 bis-indole-diphenylmethyl-5-(2•chloroethidyl) Uridine, 3'-0-methylsulfonyl-2,,5'-di-indole-triphenylmethyl-5-(2-bromovinyl)uridine, 3,·0-methylsulfonyl · 2',5,_Di-indole-triphenylmethyl-5-(2-iodovinyl) uridine, 3'·0-methylsulfonyl-2', 5'-di-0-three Phenylmethyl-5-(2-methoxycarbonylvinyl)uridine, 3 '-0-methyl contiguous with base-2 ',5 ' _2 0-diphenylmethyl·5 _(2 - Urethane, uridine, 3,0-methylsulfonyl-2,5'-di-O-triphenylmethyl-5-phenyluridine, 3'-0-methylsulfonyl -2',5'-di-O-triphenylmethyl-5-mercaptouridine, 2'-0-methylsulfonyl-3,, 5'-di-O-triphenylmethyl- 5- Uridine, 2'-0-methylsulfonyl-3',5'-di-0-triphenylmethyl-5-uridine, 2,-0-methylsulfonyl-3,, 5' _二-0_triphenylmethyl_5_bromouridine, 2'-0-methylsulfonyl-3',5'-di-O-triphenylmethyl-5-iodouridine, 2 ,〇_Methanesulfonyl-3',5'-di-0-triphenylmethyl-5-methyluridine, 2'-〇-methylsulfonyl_3',5,-two-0 _Triphenylmethyl-5-ethyl uridine, 2'- 0-methyl-branched-3',5'-di-indole-diphenylmethyl-5-n-propyl urethane, The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) 9 Order---------Line 159 91949 1293306 A7 B7 Five , invention description (16G) 2 ' - 0 - Achievery -3 ',5 '-di-indole -diphenylmethyl-5 ·isopropyl urethane, 2'-0-methylsulfonyl- 3,5'-di-_0-triphenylmethyl-5-vinyl urethane, 2'-0-methylsulfonyl-3,, 5'-di-O-triphenylmethyl-5 -ethynyl urethane, 2'- 0-methyl mercapto-3 ',5'-di-O-diphenylmethyl-5-(2-lactyl) uridine, 2' ·0- A continued brewing base-3 ' 5,_Di-O-diphenylmethyl-5- (2-> odoryl) uridine, 2'-indole-methylsulfonyl-3',5,-di-O-triphenyl Methyl-5-(2-iodovinyl)uridine, 2'-0-methylsulfonyl-3',5'-dioxa-5-(2-methoxycarbonyl) Acetyl) urinary ridge, 2'-0-methylsulfonyl-3',5'-di-O-triphenylmethyl-5-(2-hydroxycarbonylvinyl)uridine, 2'-0 -Methanesulfonyl-3',5'-di-O-triphenylmethyl-5-phenyluridine, with 2'-0-methylglycoside-3',5'-two-0 - Diphenylmethyl-5-mercaptopurine. Example 11 2,3'-anhydro- l-(2,5-di-indole-diphenylmethyl-stone-D-purpuryl) urinary cancer pyridine (9, R=H, Χ, = 0Η Take 3'-0-methylsulfonyl-2',5'.di-indole-triphenylmethyluridine (806 mg, 1 mol), sodium benzoate (2 g) of dimethylformate Indoleamine (40ml) This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 (Please read the note on the back and fill out this page) 0 Order--------- Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives Printed 160 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 161 1293306 A7 ______ B7 V. Description of Invention (161) The compound was heated at 130 to 140 °C overnight. The mixture was cooled to room temperature and poured onto 1 liter of water. The precipitate was collected by decantation and milled with ethanol (丨〇〇 ml) to give 3, dehydrated-l-(2,5-di-n-triphenylmethyl-callo-D-furanyl) uracil (9) , R = H, X, = OH), (500 mg, 75%), mp 237 °C. According to a similar method, but using the corresponding 5·substituted 3, hydrazine-methylsulfonyl 2', 5'-di-hydrazine-triphenylmethyluridine (8), the following 2, 3 are prepared. - dehydrated-di-O-triphenylmethylated nucleoside and its L-enantiomer: 2,3'-anhydro-indole (2,5-di-indole-triphenylmethyl-^-furanyl) Glycosyl)-5-fluorouracil, 2,3'-anhydrotritrimethylmethyljD-furanose)-5-chlorine sputum, 2.3 dehydration]_(2,5_2 Phenylmethyl j furanose)-5-bromouridine sulphonate, 2,3'-dehydration "-(2,5-di-indole-triphenylmethyl_0-1) furanose )-5-Change urine bite, 2.3 - Dehydrate - i_(2,5-di-indole_triphenylmethylfuranyl)-5_methyluria shout, 2,3-dehydrate_1- (2,5-di-indole-triphenylmethyl_3-|>furanose)-5-ethylurine, bite, 2,3'·dehydration-_di-〇_triphenyl- --^-咲 xylosyl)-5-n-propyl urinary guanidine, 2,3'-dehydrated 4-(2,5-:-0-triphenylmethyl-p-purpuryl xylanyl )-5-isopropyl urethane 唆, _ 2,3 _ dehydrated two j^(2,5-di-0-triphenylmethylj furanose _ This paper scale applies to China National Standard (CNS) A4 Specifications (210 x 297 mm) 91949 (Please read the notes on the back and fill out this page)

2,3’-脫水-1_(2>5、二 从 基乙炔基尿嘧啶， 〜笨基甲基-石-D-呋喃木糖 2,3’-脫水-1-(255_二_〇_ 基）·5_(2·氯乙烯基）尿嘧啶，〜求基甲基j -D-呋喃木糖 2,3’_脫水-1_(2,氕二 _〇一 #基）-5-(2-溴乙豨基）尿喷咬 基甲基-沒-D-咲喃木糖 2,3，-脫水 _1-(2，夂二_〇 二从 基）-5-(2-碘乙烯基）尿嘧啶，笨基甲基-D-呋喃木糖 2,3’-脫水 •0、 基）-5-(2-甲氧羰基乙烯基）尿嘧变"，甲 2,3’-脫水-1-(2,5_ 二-〇_三笨旯 基）-5-(2_羥基羰基乙烯基）尿嘧 _石呋喃木糖 j -D-呋喃木糖 請 先 閱 讀 背 面 之 注 意 事 項 再 填 寫 本 頁 鶬2,3'-dehydration-1_(2>5, di-isoacetylene uracil, ~stylmethyl-stone-D-furanose 2,3'-dehydrate-1-(255_di_〇_ ))·5_(2·chlorovinyl) uracil, ~ succinylmethyl j-D-furan xylose 2,3'_dehydration-1_(2, 氕二_〇一# base)-5-(2 -Bromoethylidene) urinary sputum methyl-no-D-purine xylose 2,3,-dehydration_1-(2, 夂二_〇二从基)-5-(2-iodovinyl ) uracil, stupid methyl-D-furanose 2,3'-dehydrated·0, yl)-5-(2-methoxycarbonylvinyl) uranium ", A 2,3'-dehydration -1-(2,5_二-〇_三笨旯基)-5-(2-hydroxycarbonylvinyl) uracil_shifuran xylose j-D-furan xylose Please read the notes on the back and fill in This page鶬

I II I

訂 • I I 2,3’_脫水-1_(2,5-二_〇_二 基）_5_苯基尿鳴咬，與 笨基甲基_万-D-呋喃木糖 2,3’-脫水·1-(2,5-二-〇-二絮 | ~本基甲基-点-D-呋喃木糖 基）-5-节基尿喊咬。 kBook • II 2,3'_dehydration-1_(2,5-di-〇-diyl)_5_phenyl urinary bite, and stupid methyl _wan-D-furanose 2,3'-dehydration · 1-(2,5-di-indole-two floc|~benylmethyl-dot-D-furanosyl)-5-group urinary shouting. k

經 濟 部 智 慧 財 產 局 合 作 社 印 製 依類似方法，但改用相應之5_經取代之2，_0_甲磺醯 基_3，5’-二-0-二苯基甲基尿苷，製備下列2,2、脫水_3，，5, 二-0-三苯基甲基化核苷與其L_對映體： 2,2’_脫水-1_(3,5-二-0_三苯基甲基-召-D-咲喃阿拉伯 糖基）-5-氟尿痛咬， 2,2’-脫水-1-(3,5-二-0-三苯基甲基-召-〇-呋喃阿拉伯 糖基）-5-氣尿嘧啶， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 162 91949 1293306 A7 B7 五、發明說明（⑹） 2.2、 脫水-1-(3,5、二 糖基）-5-溴尿嘧啶， 2,2’-脫水·1-(3,5、二 糖基）_5_碘尿嘧啶， 2,2，-脫水-1-(3,5_ 二 糖基）-5-甲基尿癌啶， 2，2’-脫水-1-(3,5、二 糖基）-5-乙基尿嘧啶， 2.2、 脫水-1-(3,5、二 糖基）-5-正丙基尿癌啤， 2,2，-脫水-1-(3,5、二 糖基）-5-異丙基尿癌啤， 2,2’-脫水-1-(3,5、二 糖基）-5·乙稀基尿喊变， 2,2’-脫水- l-(3,5-二、 糖基）-5-乙炔基尿癌《定， 2，2’-脫水-1-(3,5 -二 〇一二苯基〒基-沒_D-D夫喃阿拉伯 〇 一二本基甲基- 咲喃阿拉伯 Ο ·〇_ α .〇 -〇· 〇. 〇. 本基甲基-点-D_咲喃阿拉伯 苯基甲基-沒-D-D夫喝阿拉伯 苯基甲基-泠-D-呋喃阿拉伯 請 先 閱 讀 背 面 之 注 意 事 項 再 填 寫 本 頁 本基甲基-泠-D-映鳴阿拉伯 本基甲基-沒-D-咲喃阿拉伯 笨基甲基-点-D-咲喃阿拉伯 I I I訂 線 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 苯基甲基-召-D-咲喃阿拉伯 糠基）-5-(2-氣乙烯基）尿^_， 2,2’_脫水-1-(3,5、二、 '二笨基甲基"召咲喃阿拉伯 糖基）-5-(2-溴乙烯基）展靖— 2，2 ’ -脫水-1-(3，5 -〜α '二苯基甲基-石-D-咲喃阿拉伯 糖基）-5-(2-械乙稀基）尿喷η定， 2,2’-脫水-1_(3,5_二_0-三苯基甲基^ _D_呋喃阿拉伯 糖基）-5-(2 -甲氧基乙稀基）展癌σ定， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 163 91949 1293306 Α7 Β7 經濟部智慧財產局員工消費合作社印製 164 五、發明說明（164 ) ，2 -脫水-1-(3,5-二-ο-三笨基甲基_D_呋喃阿拉伯 糖基）-5-(2-羥基羰基乙烯基）尿嘧啶， 2,2 -脫水_1-(3,5-二-〇_三笨基甲基_D_咲喃阿拉伯 糖基）-5 -苯基尿哺σ定，與 2,2_脫水-1_(3,5-二-〇-三笨基甲基_万_;〇_呋喃阿拉伯 糖基）-5-节基尿癌咬。 實例12 3_去氧-3’_碘-2’，5’-二_〇_三苯基甲基尿苷（1111=11，又=1， X，=OH) 取含3’-〇-甲磺醯基_2’，5，_二_〇_三苯基甲基尿苷（8， 1.61克’ 2毫莫耳）、碘化鈉（3克，2〇亳莫耳）之二甲 氧乙烷（40毫升）混合物回流加熱一夜。真空蒸發排除容 劑，殘質溶於二氯甲烷中。依序以5〇/〇硫代硫酸鈉及水洗 滌，以硫酸鈉脫水，真空濃縮至乾。殘質經矽膠管柱使用 二乳甲烧-乙醚（3: l，v/v)為溶離液層析，產生7〇3毫克 (42%)3’_去氧 _3，_碘 _2，，5，_二 _〇-三苯基甲基尿苷（11，r=h， X=I，X，=OH) 〇 依類似方法，但改用相應之5-經取代之3，-〇-甲石黃醯 基-2’，5’-二三苯基甲基尿苷（8)，製備下列3，_碘衍生物 與其L-對映體·· 3’-去氧-3，_碘_2，，5，-二-0-三苯基甲基_5-氟尿苷， 3，-去氧_3，_碘-2%5，_二-〇-三苯基甲基_5_氣尿苷， 3 -去氧-3 -蛾-2，，5 ’ 二-Ο -二本基甲基-5 - >臭尿有1， 3’-去氧-3，-碘-2，，5，-二-0-三苯基甲基_5_碘尿脊， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁)The Ministry of Economic Affairs, the Intellectual Property Bureau Cooperative, printed a similar method, but switched to the corresponding 5_substituted 2,_0_methylsulfonyl-3,5'-di-O-diphenylmethyluridine to prepare the following 2, 2, dehydration _3,, 5, di-O-triphenylmethylated nucleoside and its L_enantiomer: 2,2'-dehydration-1_(3,5-di-O-triphenyl Methyl-callo-D-arginine arabinosyl)-5-fluorourine bite, 2,2'-anhydro-1-(3,5-di-0-triphenylmethyl-callo-purine-furan Arabinyl)-5-purine uracil, this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 162 91949 1293306 A7 B7 V. Description of invention ((6)) 2.2, dehydration-1-(3 ,5,disaccharyl)-5-bromouracil, 2,2'-dehydrated 1-(3,5,disaccharyl)-5-iodouracil, 2,2,-dehydrate-1-(3, 5_disaccharyl)-5-methyluridine, 2,2'-anhydro-1-(3,5,disaccharyl)-5-ethyluracil, 2.2, dehydrated-1-(3,5 , disaccharide)-5-n-propyl urinary cancer beer, 2,2,-anhydro-1-(3,5,disaccharyl)-5-isopropyl urinary cancer beer, 2,2'-dehydration 1-(3,5,disaccharyl)-5·ethylidene urinary shunt, 2,2'-dehydration- l-(3,5- , glycosyl)-5-ethynyl urinary cancer "Determination, 2,2'-anhydro-1-(3,5-dioxadiphenyl fluorenyl-no-DD phenanthrene fluorene-diylmethyl) - 咲 Ο Ο 〇 α α α α 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本. Furan Arabia, please read the notes on the back and then fill out this page. The methyl group - 泠-D- 映 阿拉伯 阿拉伯 阿拉伯 阿拉伯 阿拉伯 阿拉伯 阿拉伯 阿拉伯 D D D D D 阿拉伯 阿拉伯 D 阿拉伯 D 阿拉伯 III III III III III III III III Threading Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printing Phenylmethyl-C-D-咲-Arabiyl )-)-5-(2-Vinyl) Urine ^_, 2,2'_Dehydrated-1- (3,5,2, 'di-p-methylamino" 咲 咲 阿拉伯 arabinosyl)-5-(2-bromovinyl) 展 - 2,2 ' - dehydration-1-(3,5 -~ α 'diphenylmethyl-stone-D-arginium arabinosyl)-5-(2-armethyl) urinary spray η, 2,2'-dehydration-1_(3,5_two_0 -Triphenylmethyl^ _D_furan arabinosyl)-5-(2-methoxyethenyl) cancer sigma, this paper scale applies to Chinese national standard CNS A4 specification (210 X 297 public) 163 91949 1293306 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 164 V. Invention description (164), 2 - dehydration-1-(3,5-di- ο-Trisylmethylmethyl_D_furan arabinosyl)-5-(2-hydroxycarbonylvinyl)uracil, 2,2-dehydration_1-(3,5-di-indole_tristyl _D_咲-arabinosyl)-5-phenylurine glucosinolate, with 2,2_dehydrate-1_(3,5-di-indole-trisylmethyl- _ _ 〇 _ furan Arabia Glycosyl)-5-based urinary cancer bites. Example 12 3_Deoxy-3'-iodo-2',5'-di-indole-triphenylmethyluridine (1111=11, again = 1, X, =OH) 3'-〇- Methanesulfonyl 2',5,_di-p-triphenylmethyluridine (8, 1.61 g '2 mmol), sodium iodide (3 g, 2 mol) The mixture of oxyethane (40 mL) was heated at reflux overnight. The solvent was removed by evaporation in vacuo and the residue was dissolved in dichloromethane. It was washed with 5 〇 / 〇 thiosulfate and water, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed with a solution of di-milk-diethyl ether (3:1, v/v) via a gel column to yield 7〇3 mg (42%) of 3'-deoxy-3,_iodine-2. ,5,_Di-〇-triphenylmethyluridine (11, r=h, X=I, X, =OH) 〇 according to a similar method, but use the corresponding 5-substituted 3,-〇 -methystin-2',5'-ditriphenylmethyluridine (8), the following 3, iodine derivatives and their L-enantiomers · 3'-deoxy-3, iodine 2,5,-di-O-triphenylmethyl_5-fluorouridine, 3,-deoxy-3, iodine-2%5,_di-indole-triphenylmethyl_5_ Gastrin, 3 -deoxy-3 - moth-2,, 5 'di-indole - dibenylmethyl-5 - > odorous urine has 1,3'-deoxy-3,-iodine-2, ,5,-di-O-triphenylmethyl_5_iodine urinary ridge, this paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 (please read the notes on the back and fill in the form) This page)

12933061293306

五 、發明說明（i65 ) ， 〇 5苯基甲基甲基尿苷， 3，-去氧-3，-碘-2%5，_二-〇_一奉， 苯基甲基-5-乙基尿苷，3，-去氧-3，-碘-2，，5，-二〆不η =笨基甲基-5-正丙基尿 3，-去氧_3，_碘-2，，5、二本磬广-苯基甲基異丙基尿 ，’·去氧 _3，_碘_2，，5,^，C, - Ο-三苯基甲基-5一乙稀基尿 入去氧-3、碘-2，，5，_〆-◦一 ♦ 苷， 苷， 苷， 苷， 尿苷， π，- D〆苯基甲基-%乙快基尿 3，_去氧-3，·碘-2，，5、二不土一 苯基甲基- 5- (2-氣乙烯3，-去氧-3、碘-2，，5，-二-〇_〆个土 ，c, - Ο-三苯基甲基_5-(2_溴乙烯基） ，去氧-3’·碘 _2，，5，-二_0 一个 ，去氧_3，·块_2，，5，-二-〇-三苯基甲基·5·(2’乙稀基） 3，_去氧_3,_碘-2,，5，-二-〇-三苯基甲基-5-(2-甲氧幾基乙烯基）尿脊， 3，·去氧_3，_峨_2，，5,-二-〇-三苯基甲基-5-(2-經基幾基乙烯基）尿苷， 3,_去氧_3,_峨_2，，5,_二-〇-三苯基甲基_5-苯基尿香，與 3,_去氧_3,_破_2,，5，-二-〇-三苯基甲基_5·节基尿苷。 依類似方法，但改用相應之5_經取代之2’_〇·甲磺酿 基-3，,5，-二-0-三苯某甲基尿苷，製備下列2’·碘衍4… 氏張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 尿苷， 尿苷， (請先閱讀背面之注意事項再填寫本頁)V. Description of the invention (i65), 〇5-phenylmethylmethyluridine, 3,-deoxy-3,-iodine-2%5, _di-〇_一奉, phenylmethyl-5-B Uridine, 3,-deoxy-3,-iodo-2,5,-dioxime η=stupylmethyl-5-n-propyluridine 3,-deoxy-3, iodine-2, , 5, bis, 磬- phenylmethyl isopropyl urinary, '·deoxy _3, _ iodine 2,, 5, ^, C, - Ο-triphenylmethyl-5-ethylene Urine into deoxy-3, iodine-2,5, _〆-◦1 ♦ glycosides, glycosides, glycosides, glucosides, uridine, π,- D〆 phenylmethyl-% B-based urinary 3, _ go Oxygen-3, iodine-2,5, bis-phenyl-methyl- 5-(2-ethylene-3,-deoxy-3, iodine-2,5,-di-〇_〆 Soil, c, - Ο-triphenylmethyl _5-(2_bromovinyl), deoxy-3'·iodine_2,,5,-two_0 one, deoxygenated_3,·block _ 2,5,-di-indole-triphenylmethyl·5·(2'ethenyl) 3,_deoxy_3,_iodo-2,5,-di-indole-triphenyl 5-(2-methoxyxyvinyl) urinary ridge, 3, deoxy-3, 峨 2,, 5,-di-indole-triphenylmethyl-5-(2- Urethane, uridine, 3, _deoxy_3, _峨_2,, 5, _ Indole-triphenylmethyl-5-phenylurine, and 3,_deoxy-3,_broken-2,5,-di-indole-triphenylmethyl-5. According to a similar method, but using the corresponding 5'-substituted 2'_〇·methylsulfonyl-3,5,-di-O-triphenylmethyluridine, the following 2'·iodine 4 was prepared. ... The Zhang scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). Uridine, uridine, (please read the notes on the back and fill out this page)

165 91949 經濟部智慧財產局員工消費合作社印剧衣 1293306 A7 B7 五、發明說明（166) 其L-對映體： 2’_去氧-2’-碘-3’，5’-二-0_三苯基甲基_5_氟尿苷， 2，-去氧_2’-碘_3，，5，_二-0-三苯基甲基-5-氯尿苷， 2’-去氧-2’-埃-3’，5’-二-0_二苯基甲基-5->臭尿甘’ 2，-去氧-2’_碘-3’，5、二-0-三苯基甲基-5-碘尿苷， 2，-去氧-2，-碘-3，，5，-二-0-三苯基甲基-5-甲基尿苷， 2’-去氧-2’·碘·3，，5’_二-0_三苯基甲基-5-乙基尿苷， 2，-去氧- 2’ -埃-3，，55 -二-0 -二苯基甲基-5 -正丙基尿 甘， 2’·去氧- 2’ -破-3 ’，5’-二-0-二苯基甲基-5-異丙基展 甘， 2’-去氧-2’-峨-3’，5，-二-Ο-三苯基甲基-5-乙烯基尿 甘， 2’-去氧- 2’-填_3’，5’_二-Ο-三苯基甲基-5-乙快基尿 甘， 2’-去氧-2’-碘_3’，5’_二-Ο-三苯基甲基-5-(2-氯乙烯基） 尿苷， 2，-去氧-2，-碘·3’，5’_二-Ο-三苯基甲基-5-(2-溴乙烯基） 尿苷， 2’-去氧-2’-碘-3，，5，-二-0-三苯基甲基-5-(2-碘乙烯基） 尿苷， 2，_去氧-2，_碘-3，，5，-二-0-三苯基甲基-5_(2-甲氧羰基 乙浠基）尿脊， 2，-去氧-2，·碘-3’，5’-二-0-三苯基甲基_5-(2-羥基羰基 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 0 訂---------線· 166 91949 1671293306 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（ 乙烯基）尿苷， 2’-去氧_2’_碘-3’，5’_二-〇_三苯基甲基_5_苯基尿苷，與 2’-去氧-2’-碘_3’，5’_二三苯基甲基苄基尿苷。 實例13 3’-埃-3’-去氧尿脊 取3、去氧-3，-碘-2，，5、二-〇·三苯基甲基尿苷（84〇毫 克’ 1毫莫耳）（11，R=H，X=I5 X’ = 〇H)溶於二氣甲烧與三氟 乙酸之10· 1混合物（20毫升），混合物保持在室溫下。真 空排除溶劑，殘質與乙醚（15毫升X 2)碾磨。醚不可溶殘質 自甲醇醚中結晶，產生3，-碘-3，-去氧尿苷（3 12毫克， 88.1%)。 依類似方法，但改用相應之5-經取代之3’_去氧_3，-碘-2’，5’-二三苯基甲基尿苷，製備下列3’-碘尿苷衍生 物與其L-對映體· 3’-去氧- 3’-蛾-5-氣尿甘、3’ -去氧- 3’-峨 -5-氣尿甘、3’-去氧-3’·蛾-5-溴尿香、3’-去氧-3’·峨_5-蛾尿 苷、3’-去氧-3，-碘·5_甲基尿苷、3，-去氧-3、碘_5-乙基尿 苷、3、去氧-3’-碘·5-正丙基尿苷、3，-去氧-3’-碘異丙基 尿苷、3’_去氧-3’-蛾-5-乙烯基尿脊、3，-去氧-3’-峨-5-乙炔 基尿甘、3 -去氧- 3’-填- 5·(2 -氣乙稀基）尿甘、3 -去氧_3’_ 碘-5-(2-溴乙烯基）尿苷、3、去氧-3,·碘-5-(2-碘乙烯基）尿 苷、3’·去氧-3’·碘-5-(2-甲氧羰基乙烯基）屎苷、3，-去氧-3，-碘-5_(2-羥基羰基乙烯基）尿苷、3，-去氧-3，-碘-5-笨基尿苷 與3’-去氧-3’-碘-5-苄基尿苷。 依類似方法，但改用相應之5-經取代之2’_去氧-2，- --------------------^--------- (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） 167 91949 A7 1293306 五、發明說明（168 ) 碘-3’，5’·二-Ο-三苯基甲基尿苷，製備下歹"，，尿苷衍生 物與其L-對映體去氧_2，_蛾么氣尿脊、2’_去氧_2，誠 -5_氣尿苷、2’去氧_2，冬5•漠尿脊、2，_去氧_2，_蛾小破尿 脊、2，-去氧-2，-蛾-5_甲基尿脊、2，_去氧_2,峨_5_乙基尿 去氧-2，-硪巧_正丙基尿奋、2，去氧·2,峨_5異丙基 尿杳、2，-去氧-2，-峨_5_乙稀基尿苷、2,_去氧_2，·換-5_乙块 基尿苷、2’-去氧-2，-碘-5-(2·氣乙烯基）尿苷、2，_去氧_2，· =-5-(2-漠乙烯基）尿苷、r_去氧_2，_換_5_(2_碘乙烯基）尿 苷、2’-去氧-2’-碘·5-(2-甲氧羰基乙烯基）尿苷、2，_去氧_2,_ 碘-5-(2-羥基羰基乙烯基）尿苷、2，_去氧_2、碘_5_苯基尿苷 與2、去氧-2’-碘-5-苄基尿苷。 實例14 9-(2-0-乙醯基-3-溴-3-去氧j -D-呋喃木糖基）腺嘌呤（14， R=H? X=Br, Y=NH25 Z-H) 取化合物（14)(R=255,5_三甲基_1，3_二氧戊環-心__2_ 基，X=Br，Y=NH2, Z=H，500毫克，1亳莫耳）溶於鹽酸之 甲醇溶液中（其製法為滴加3滴乙醯氣至1〇毫升甲醇中 於室溫下30分鐘後，添加3亳升飽和碳酸氫鈉溶液，混合 物真空濃縮至乾。殘質與乙醇碾磨，直到上澄液不再於 260nm下顯著吸收UV為止。乙醇萃液濃縮，殘質自甲醇 中結晶，產生所需之（14) (R=H，X=Br，Y=NH2，Z=H)，325g (87%) 91949 (請先閱讀背面之注意事項再填寫本頁) # 訂---------赛 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 制 1293306 A7 _____ B7 五、發明說明（169) 8·16,832 (2s，Ηβ2 與 H-8), 6 _ 5.1 Hz), 4.38 (dt, 1H, H-4\ Jr4.- 5 ι τ te,^ γ …T ^ 斗山，4 2.09 (s，3H，Ac)· ，4 51，b，一 = 5·0 Hz)，3·79 恤 2H，H- 5，,5,〇， 依類似方法，但改用相應之嘌呤核苷，製備下列2，_ Ο-乙醯基-3 -溴-3’-去氧-D-木糖核苷（14)與其L_對映體： 9_(2·0-乙醯基·3-溴_3_去氧_D_呋喃木糖基）鳥嘌 口令， 9-(2-0-乙醯基-3-溴-3-去氧-召_D_呋喃木糖基）-6_氯 嘌呤， 9-(2_0-乙醯基_3_溴-3-去氧_D呋喃木糖基）-2,6_二 氣嘌呤， 9-(2-0-乙醯基-3_漠_3·去氧j_D_呋喃木糖基）2胺 基-6-氯嗓呤， 9-(2-0-乙醯基-3-溴-3_去氧j-D_呋喃木糖基）-6•甲 基硫嘌呤，與 9-(2-0-乙醯基-3-溴-3-去氧-石呋喃木糖基）_6_甲 氧基嘌呤。 實例 9-[2-0-乙醯基-3-溴-3-去氧·5_〇-(2,5,5·三甲基二氧戊 環-4-酮-2-基）-召-D-呋喃木糖基]腺嘌呤（l4 R=2 5 5_三甲 基-1,3-二氧戊環·2_ 酮 _2·基，X=Br，Υ=ΝΗ2 Z=H) 取含腺苷（13, Y=NH2, Z=H，10克，〇 op莫卑）與α _ 乙醯氧基·異丁醯溴（24克，0.117莫耳）之乙膳（12〇毫升） 本紙張尺度過用Τ國團豕棕準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) 0 訂---------線. 經濟部智慧財產局員工消費合作社印製 169 A7 1293306 五、發明說明（17G ) 混合物於室溫下攪拌45分鐘。真空排除溶劑，殘質溶於乙 酸乙酯中，以碳酸氫鈉溶液及水洗滌，以硫酸鈉脫水，真 空濃縮。殘質自甲醇中結晶，產生6.5克（3 5%)之（14) (X=Br，Υ=丽 2，Z=H)，mp=169-170oC · hNMROVDMSO);: 8.17,8.26(2s，各 1Η,Η-2與 11-6), 6.16(41¾ H-l，，J1%r = 3.5Hz)，5.94(d41HH-2，，Jr>2，= 3.5 Hz, }r^ = 3-0 Hz), 4.92 (dd, 1H, H-3% J2^-3.0 Hz, J3%4-= 4.8 Hz), 4.54 (m, 1H, H-4*), 3·94 机 2li mj，5)，2.10 (s, 3¾ Ac), 1·73,1·58，1.47 (3s，3H each^ CH3 groups on 5，)· β NMR判斷化合物（14)之結晶母液含有2，-溴-2，-去氧-D-阿拉伯糖基異構物（15)。 依類似方法，但改用相應之嘌呤核苷，製備下列3\ 溴_3’·去氧-衍生物（14)與其L_對映體： 9·[2-0-乙醯基-3-溴 去氧-5-0-(2,5,5-三甲基-1，3-二 氧戊環基）夫喃木糠基]烏嗓呤， 9-[2-0 -乙醯基-3-溴-3-去氧- 5-0-(2,5,5·三甲基-1，3-二 氧戊環-4-酮-2_基）-召-D-呋味木糠基]_6_氣嗓呤， 9-[2·0_ 乙醯基-3-溴-3_去氡-5-0-(2,5,5-三甲基-1，3-二 氧戊環-4-_ -2-基）-泠-D-咲喃木糖基]_2,6·二氣嘌呤， 9-[2-0-乙醯基-3-溴-3·去氧_5-0-(2,5,5-三甲基-1，3-二 氧戍環-4_酮_2-基）-D_呋喃木糖基]胺基-6-氣嘌呤， 9 [2-0·乙醯基-3-溴-3-去氧- 5-0-(2，5,5-三甲基-1,3-二 氧戊環-4-酮-2-基）-彡-D-呋喃木糠基]-6-甲基硫嘌呤， 9-[2-0_ 乙醯基·3_溴-3_去氧 _5-〇-(2,5,5-三甲基-1,3-二 氧戊環-4-酮-2-基）-召-D-咲喃木糖基]-6·甲氧基嘌呤， 91949 (請先閱讀背面之注意事項再填寫本頁) 0165 91949 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing costume 1293306 A7 B7 V. Description of invention (166) Its L-enantiomer: 2'_deoxy-2'-iodo-3', 5'-two-0 _Triphenylmethyl_5_fluorouridine, 2,-deoxy-2'-iodo_3,,5,_di-0-triphenylmethyl-5-chlorouridine, 2'- go Oxy-2'-A-3',5'-di-O-diphenylmethyl-5-> Odor 2 '-deoxy-2'-iodo-3', 5, 2-0 -triphenylmethyl-5-iodouridine, 2,-deoxy-2,-iodo-3,5,2-di-O-triphenylmethyl-5-methyluridine, 2'- Deoxy-2'·iodine·3,5'-di-O-triphenylmethyl-5-ethyluridine, 2,-deoxy-2'-e-3,,55-two-0 -diphenylmethyl-5-n-propyl urethane, 2'-deoxy-2'-broken-3',5'-di-0-diphenylmethyl-5-isopropyl, 2'-Deoxy-2'-峨-3',5,-di-indole-triphenylmethyl-5-vinyl urethane, 2'-deoxy-2'-filled _3', 5' _Di-indole-triphenylmethyl-5-ethyl fast urinary, 2'-deoxy-2'-iodo-3',5'-di-indole-triphenylmethyl-5-(2 -chlorovinyl) uridine, 2,-deoxy-2,-iodine·3',5'_di-Ο- Triphenylmethyl-5-(2-bromoethenyl)uridine, 2'-deoxy-2'-iodo-3,5,-di-O-triphenylmethyl-5-(2- Iodoethylidene), uridine, 2,_deoxy-2, iodine-3,5,-di-O-triphenylmethyl-5-(2-methoxycarbonylethenyl) urinary ridge, 2, -Deoxy-2,-iodo-3',5'-di-O-triphenylmethyl_5-(2-hydroxycarbonyl basic paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (Please read the note on the back and then fill out this page) 0 Order---------Line· 166 91949 1671293306 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5, Invention Description (Vinyl) Uridine, 2'-deoxy-2'-iodo-3',5'-di-indole-triphenylmethyl-5-phenyluridine, and 2'-deoxy-2'-iodine-3 ',5'-Ditriphenylmethylbenzyl uridine. Example 13 3'-A-3'-deoxyurate ridge 3, deoxy-3,-iodo-2,,5, di-anthracene Triphenylmethyluridine (84 mg mg '1 mmol) (11, R = H, X = I5 X' = 〇H) is dissolved in a mixture of dioxane and trifluoroacetic acid 10 (1) ML), the mixture is kept at room temperature. . Residue with diethyl ether (15 mL X 2) milling ether insoluble residue was crystallized from methyl ether, to produce 3 - iodo-3 - deoxy uridine (312 mg, 88.1%). In a similar manner, but using the corresponding 5-substituted 3'-deoxy-3,-iodo-2',5'-ditriphenylmethyluridine, the following 3'-iodouridine derivatives were prepared. And its L-enantiomer · 3'-deoxy-3'-moth-5-qiuridine, 3'-deoxy-3'-峨-5-qiuridine, 3'-deoxy-3'· Moth-5-bromouridine, 3'-deoxy-3'·峨_5-mothuridine, 3'-deoxy-3,-iodine·5-methyluridine, 3,-deoxy-3 , iodine 5-ethyluridine, 3, deoxy-3'-iodine·5-n-propyluridine, 3,-deoxy-3'-iodoisopropyluridine, 3'-deoxy- 3'-Moth-5-vinyl urinary ridge, 3,-deoxy-3'-indol-5-ethynyl urethane, 3-deoxy-3'-filling- 5·(2-vinylidene) Urinary glycoside, 3-deoxy-3'_iodo-5-(2-bromoethenyl)uridine, 3,deoxy-3,-iodo-5-(2-iodovinyl)uridine, 3'· Deoxy-3'-iodo-5-(2-methoxycarbonylvinyl)purine, 3,-deoxy-3,-iodo-5-(2-hydroxycarbonylvinyl)uridine, 3,-deoxygenated -3,-iodo-5-stupyluridine and 3'-deoxy-3'-iodo-5-benzyluridine. According to a similar method, but use the corresponding 5-substituted 2'_deoxy-2,- --------------------^------ --- (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) 167 91949 A7 1293306 V. Invention description (168) Iodine-3' , 5'·di-indole-triphenylmethyluridine, preparation of sputum ", uridine derivative and its L-enantiomer deoxygenated 2, _ moth urinary ridge, 2' deoxygenation _2, Cheng-5_ gas uridine, 2' deoxygenated 2, winter 5 • urinary ridge, 2, _ deoxygenated 2, _ moth small broken urinary tract, 2, - deoxy-2, - moth -5_Methyl urinary ridge, 2,_deoxy-2, 峨_5_ethylurine deoxy-2,-硪巧_正propyl 尿奋, 2, deoxygen-2, 峨_5 isopropyl Basal urinary tract, 2,-deoxy-2,-峨_5_ethyl uridine, 2,_deoxy-2,·-5-ethyl uridine, 2'-deoxy-2, - iodine-5-(2·gas vinyl) uridine, 2,_deoxy-2,·-5-(2- desert vinyl) uridine, r_deoxy-2, _exchange_5_( 2_Iodovinyl)uridine, 2'-deoxy-2'-iodo-5-(2-methoxycarbonylvinyl)uridine, 2,_deoxy-2,_iodo-5-(2- Hydroxycarbonyl vinyl) urine Glycoside, 2,_deoxy-2, iodine-5-phenyluridine and 2, deoxy-2'-iodo-5-benzyluridine. Example 14 9-(2-0-Ethyl-3-bromo-3-deoxyj-D-furanose) adenine (14, R=H? X=Br, Y=NH25 ZH) (14) (R=255,5_trimethyl-1,3-dioxolane-heart __2_ group, X=Br, Y=NH2, Z=H, 500 mg, 1 亳mol) The solution of hydrochloric acid in methanol was prepared by adding 3 drops of acetonitrile to 1 liter of methanol at room temperature for 30 minutes, then adding 3 liters of saturated sodium hydrogencarbonate solution, and the mixture was concentrated to dryness in vacuo. Milling until the supernatant liquid no longer absorbs UV significantly at 260 nm. The ethanol extract is concentrated and the residue is crystallized from methanol to give the desired (14) (R=H, X=Br, Y=NH2, Z =H),325g (87%) 91949 (Please read the note on the back and fill out this page) #订---------The Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed 1293306 A7 _____ B7 Five , invention description (169) 8·16,832 (2s, Ηβ2 and H-8), 6 _ 5.1 Hz), 4.38 (dt, 1H, H-4\ Jr4.- 5 ι τ te,^ γ ...T ^ Doosan, 4 2.09 (s,3H,Ac)· , 4 51,b, one = 5·0 Hz), 3·79 shirt 2H, H- 5,, 5, 〇, according to similar methods, but use instead The following 2,_ Ο-ethinyl-3-bromo-3'-deoxy-D-xyloside (14) and its L_enantiomer were prepared as the nucleosides: 9_(2·0-B Indole·3-bromo_3_deoxy_D_furanose) guanine password, 9-(2-0-ethinyl-3-bromo-3-deoxy-callo_D_furanose Base)-6-chloropurine, 9-(2_0-acetamido_3_bromo-3-deoxy-D-furanyl)-2,6_dioxane, 9-(2-0-acetamidine) Base-3_漠_3·Deoxidation j_D_furanose)2Amino-6-chloropurine, 9-(2-0-acetamido-3-bromo-3_deoxyj-D_ Furanoxylan)-6•methylthioindole, and 9-(2-0-ethinyl-3-bromo-3-deoxy-stone furanose)_6-methoxyfluorene. Example 9-[2-0-Ethyl-3-bromo-3-deoxy-5_〇-(2,5,5·trimethyldioxolan-4-one-2-yl)-call -D-furanose] adenine (l4 R=2 5 5_trimethyl-1,3-dioxolan-2-inone-2-yl, X=Br, Υ=ΝΗ2 Z=H) A meal containing adenosine (13, Y=NH2, Z=H, 10 g, 〇op Mobei) and α _ ethoxylated isobutyl bromo (24 g, 0.117 mol) (12 ml) This paper scale has been used in the national standard 豕 豕 豕 (CNS) A4 specifications (210 X 297 mm) 91949 (please read the back of the note before you fill out this page) 0 order --------- line. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 169 A7 1293306 V. Inventive Note (17G) The mixture was stirred at room temperature for 45 minutes. The solvent was removed in vacuo, the residue was taken in ethyl acetate, washed with sodium bicarbonate and water, dried over sodium sulfate and evaporated. The residue was crystallized from methanol to give 6.5 g (3 5%) of (14) (X = Br, Υ = 2 2, Z = H), mp = 169-170 °C · hNMROV DMSO): 8.17, 8.26 (2 s, 1Η, Η-2 and 11-6), 6.16(413⁄4 Hl,, J1%r = 3.5Hz), 5.94 (d41HH-2,, Jr>2, = 3.5 Hz, }r^ = 3-0 Hz) , 4.92 (dd, 1H, H-3% J2^-3.0 Hz, J3%4-= 4.8 Hz), 4.54 (m, 1H, H-4*), 3·94 machine 2li mj, 5), 2.10 ( s, 33⁄4 Ac), 1·73, 1.58, 1.47 (3s, 3H each^ CH3 groups on 5,)·β NMR judged that the mother liquor of the compound (14) contains 2,-bromo-2,-deoxy- D-arabinosyl isomer (15). In a similar manner, but using the corresponding purine nucleosides, the following 3\bromo-3'deoxy-derivatives (14) and their L_enantiomers were prepared: 9·[2-0-ethenyl-3- Bromo-deoxy-5-0-(2,5,5-trimethyl-1,3-dioxolanyl)phoranyl]isanthine, 9-[2-0-ethenyl- 3-bromo-3-deoxy-5-0-(2,5,5·trimethyl-1,3-dioxolan-4-one-2-yl)-callo-D-furan hibiscus Base]_6_ gas 嗓呤, 9-[2·0_ ethoxymethyl-3-bromo-3_dehydro-5-0-(2,5,5-trimethyl-1,3-dioxolane -4- -2-yl)-泠-D-咲 xylenyl]_2,6·二气嘌呤, 9-[2-0-ethenyl-3-bromo-3·deoxy_5- 0-(2,5,5-trimethyl-1,3-dioxocyclo-4-keto-2-yl)-D-furanose]amino-6-gas, 9 [2- 0·Ethyl-3-bromo-3-deoxy-5-0-(2,5,5-trimethyl-1,3-dioxolan-4-one-2-yl)-indole- D-furanyl fluorenyl]-6-methylthioindole, 9-[2-0_ethylidene·3_bromo-3_deoxy-5-anthracene-(2,5,5-trimethyl-1 , 3-dioxolan-4-one-2-yl)-callo-D-furanosyl]-6-methoxy oxime, 91949 (please read the notes on the back and fill out this page) 0

-------^---------^ I 經濟部智慧財產局員工消費合作社印製 170 1293306 A7 ------ B7 五、發明說明（171 ) 9-[3-0-乙醯基-2_溴-2_去氧-5-0-(2,5,5-三甲基-l，3-二 氧戊％ -4-酮-2-基）-石-D-咲喃阿拉伯糖基]鳥嘌吟， (請先閱讀背面之注意事項再填寫本頁) 9-[3-0 乙醯基-2-溴-2_去氧 _5-0-(2,5,5-三甲基-1，3-二 氧戊環_4_酮-2-基）-召-D_呋喃阿拉伯糖基]_6_氣嘌呤， 9-[3-0-乙醯基-2-溴 去氧 _5-〇-(2,5,5_三甲基-1,3-二 氧戊環-4-酮-2-基）-冷-D_呋喃阿拉伯糖基卜2,6_二氣嘌 9·[3-0_ 乙醯基-2-溴-2_去氧-5-0_(2,5,5-三甲基-1，3-二 氧戊環-4-酮-2-基）-D-呋喃阿拉伯糖基卜2_胺基_6_氣嘌 ， 9-[3-0-乙醯基-2-溴-2-去氧-5-0-(2,5,5-三甲基-1，3-二 氧戊環-4-酮-2-基）-泠-D-呋喃阿拉伯糖基卜6-甲基硫嘌 呤，與 9-[3-0-乙醯基-2-溴-2-去氧-5-0-(2,5,5-三甲基-153-二 氧戊環-4-酮_2_基）_召-D-咲喃阿拉伯糖基]-6_甲氧基嗓 βφ- 〇 實例16 經濟部智慧財產局員工消費合作社印剩衣 2’，3’_脫水腺苷（18, Υ=ΝΗ2, Ζ=Η) 於室溫下，以1Μ甲醇鈉之甲醇溶液（20毫升）處理9-[2-0_乙醯基-3-溴-3-去氧_5-0-(2，5,5-三甲基-1,3•二氧戊環 -4-酮-2-基）-泠_I>-咲喃木糖基]腺嘌呤（14)(5·〇克，〇 〇1莫 耳）1小時。以冰醋酸中和混合物，保持在冷藏室中一夜。 過濾收集沈積之結晶（18)，2· 1克（84%)。此樣本之1H NMR 光譜與改用 Mendez，Ε· et al.，,τ Virol^ 1998, 72, 4737 之方 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公髮） 171 91949 1293306 A7 ' --------B7______ 五、發明說明（172 ) 法製得之樣本一致。 依類似方法，但改用相應之嘌呤核苷，製備下列2，，3，-脫水核糖衍生物（18)與其L-對映體： 2,3 -脫水·鳥嘌呤核苔、9-(2,3-脫水-沒_d_D夫喃核糖 基）_6_甲基氫硫基嘌呤與9_(2,3-脫水_D_呋喃核糖基）_ 2_胺基-6-甲氧基喝呤。 實例17 9-(3-去氧-3-碘-泠-D-呋喃木糖基）腺嘌呤（19, χ=：Ι，y==nh25 Z=H) 取含（18)(Y=NH2, Z=H，1克，4毫莫耳）、碘化鈉（ι·5 克’10毫莫耳）、乙酸鈉（100毫克）與乙酸（5毫升）之丁酮（30 毫升）混合物溫和回流3小時。真空蒸發溶劑，殘質與水碾 磨，產生（19) (X = I, Y =卿，Z 喝，1·2 g (80%)· lH NMR (D6-DMSO> δ: 8*24, 8.34 (2s，各 1H，H-2 與 Η·8}，5·90 (4 1H, Η·Γ, Jl，,2, = 4·7 Hz), 4·96 <dd, 1H，H-2，，Jl，，2,= 4.7, J2，，3, = 4·9 Hz)，4.60 (d4 1H，H-3，, J2，,3, = 4.9, J3’,4’ = 4.7 Hz), 4·80 (d* 2¾ H· 5,,5,,),4.4a(m,IH,H-4,). 依類似方法，但改用相應之2’，3、脫水-D-核糖嘌呤核 苷（14)，製備下列3、去氧-3、碘-D-木糖核苷與其L-對映 體· 9-(3-去氧-3-填-泠-D·咲喃核糖基）烏嗓吟’ 9-(3-去氧-3_块-石-D-咲痛核糖基）-6 -甲基氮硫基嗓 口令， 9-(3-去氧-3-碘-召-D-呋喃核糖基）-6-甲氧基嘌呤， (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 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 172 91949 [293306 A7 B7 五、發明說明（173 經濟部智慧財產局員工消費合作社印製 9-(3-去氧H点-D_呋喃核糖基胺基-6-甲基氫硫 基嗓呤，與 9-(3-去氧-3-碘-召-D_呋喃核糖基）_2_胺基_6_甲氧基嘌 口令〇 實例18 3、去氧腺苷（20, Y=NH2, Z=H) 取含（19)( Y=NH2, Z=H，380毫克，1毫莫耳）之甲醇（75 毫升）溶液於氫大氣下，於5% pd/BaS〇4觸媒（1〇〇毫克）與 二乙胺（1毫升）之存在下，於初壓3atm下振盪一夜。排除 觸媒後，真空蒸發溶劑，殘質自甲醇中結晶，產生3，_去氧 腺苷（20)(Y=NH2, Z=H)，200 毫克（8〇%)。此樣本之 iHNMR 光譜與蛹蟲草菌素一致。 依類似方法，但改用相應之3，_碘-D_木糖嘌呤核苷 (19)，製備下列3’-去氧核苷與其L_對映體·· 9_(3_去氧 呋喃赤蘚戊糖基）鳥嘌呤，9_(3_去氧_沒_〇_呋喃赤蘚戊 糖基）嘌呤，9-(3_去氧-召-D-呋喃赤蘚戊糖基）_6_甲氧基嘌 吟’ 9-(3-去氧-召-D-呋喃赤蘚戊糖基胺基嘌呤與^(3- 去氧_D-呋喃赤蘚戊糖基胺基甲氧基嘌呤。 實例19^ 3-(y8 -D-0夫喃核糖基）_8-氮離黃嘌呤素（24, χ=〇Η，γ=Ν) 添加疊氮化鈉（100毫克）至含5_硝基尿苷（3〇〇毫克）之 DMF(60毫升）溶液中，混合物於室溫下攪拌一夜。真空排 除;谷劑’殘質溶於最少量水中，以稀鹽酸調至pH3至4。 _ 水中再結晶，mp 164 至 166°C (分解 · ‘紙張尺度翻W國冢標準（CNS)A4規格（210 X 297公爱）--- 173 91949 (請先閱讀背面之注意事項再填寫本頁) 0 訂---------線· 1293306 A7 ___ B7 五、發明說明（174 ) H2〇 計算值：C，35·64; Η，4·29; 23·1;實測值：c，35.96 ; Η，4·01 ; Ν，23·43。 實例20 1，2_0-亞異丙基-5-0-甲氧羰基-3-0-苯氧硫羰基-α -D-呋 喃木糠（26, R=Ph) 滴加含氣硫逐甲酸苯酯（50克，0.3莫耳）之乙腈（100 毫升）溶液至含1,2-0-亞異丙基-5·0-甲氧羰基·α 呋喃 木糖（25, 25.0克，0.1莫耳）與4-二甲胺基吡啶（25克，0.2 莫耳）之無水吡啶（250毫升）溶液中，反應混合物於50至60 °C下攪拌24小時。溶液真空濃縮，殘質分佈在二氣甲烷與 水之間。有機層依序以水、〇·1Ν氫氧化鈉、水o.in鹽酸 及水洗滌，經硫酸鈉脫水，真空濃縮，產生全收量（26)(R=Ph) 之漿狀物（38.2克）。此漿狀物直接用於下一個步驟。 實例21 3_去氧·1，2-0-亞異丙基-5-0•甲氧羰基呋喃赤蘚戊 糖（27) 在3小時内添加含三-正丁基錫氳化物（58克，〇 2莫 耳）之甲苯（3 00亳升）溶液至含上述化合物（26)(11=?11)(19.2 克，50毫莫耳）與2,2’-偶氮雙異丁腈（2.5克，15毫莫耳） 之甲苯（400毫升）溶液中。混合物真空濃縮，殘質溶於乙腈 (300毫升）中’以石油醚（4Χ 1〇〇毫升）萃取溶液，排除三-正丁基錫衍生物。乙腈層濃縮。殘質之薄層層析法顯示有 一個主要圓點，且1H NMR光譜顯示含有三個甲基且沒有 芳香系質子，但含有少量丁基錫衍生物雜質。在未純化下 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁)-------^---------^ I Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 170 1293306 A7 ------ B7 V. Invention Description (171) 9-[3 -0-acetamido-2_bromo-2_deoxy-5-0-(2,5,5-trimethyl-l,3-dioxolan-4-one-2-yl)-石-D-咲 arabinose] guanine, (please read the notes on the back and fill out this page) 9-[3-0 acetyl-2-bromo-2_deoxy_5-0-( 2,5,5-trimethyl-1,3-dioxolan-4-ol-2-yl)-call-D_furan arabinosyl]_6_ gas, 9-[3-0-B Mercapto-2-bromodeoxy-5-indole-(2,5,5-trimethyl-1,3-dioxolan-4-one-2-yl)-cold-D_furan arabinosyl卜2,6_二气嘌9·[3-0_Ethyl-2-bromo-2_deoxy-5-0_(2,5,5-trimethyl-1,3-dioxolane- 4-keto-2-yl)-D-furan arabinosyl 2-2-amino-6-gas, 9-[3-0-acetamido-2-bromo-2-deoxy-5-0- (2,5,5-Trimethyl-1,3-dioxolan-4-one-2-yl)-indole-D-furan arabinosylbi 6-methylthiopurine, with 9-[3 -0-acetamido-2-bromo-2-deoxy-5-0-(2,5,5-trimethyl-153-dioxolan-4-one-2-yl)_call-D -pyranose arabinosyl]-6_methoxy 嗓βφ- 〇 Example 16 Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printing 2, 3'_Dehydrated adenosine (18, Υ = ΝΗ 2, Ζ = Η) at room temperature, treated with 1 mM sodium methoxide in methanol (20 mL) 9- [2-0_Ethyl-3-bromo-3-deoxy-5-0-(2,5,5-trimethyl-1,3•dioxolan-4-one-2-yl) -泠_I>-咲木糖基]Adenine (14) (5·〇克,〇〇1莫耳) 1 hour. The mixture was neutralized with glacial acetic acid and kept in the refrigerator for one night. The deposited crystals (18) were collected by filtration, 2.1 g (84%). The 1H NMR spectrum of this sample was changed to the Chinese National Standard (CNS) A4 specification (210 X 297 metric) using Mendez, Ε· et al., τ Virol^ 1998, 72, 4737. 171 91949 1293306 A7 ' --------B7______ V. Description of the invention (172) The samples obtained by the law are consistent. In a similar manner, but using the corresponding purine nucleosides, the following 2,3,-anhydroribose derivatives (18) and their L-enantiomers were prepared: 2,3 - dehydrated guanine nucleus, 9-(2 , 3- dehydrated - no _d_D fluoropyranosyl) _6_methylhydrothioguanidine and 9_(2,3-dehydrated_D_ribofuranosyl)-2-amino-6-methoxy. Example 17 9-(3-Deoxy-3-iodo-indole-D-furanose) adenine (19, χ=:Ι, y==nh25 Z=H) Take (18) (Y=NH2) , Z = H, 1 gram, 4 millimolar), mild mixture of sodium iodide (Ig 5 g '10 mmol), sodium acetate (100 mg) and acetic acid (5 ml) butanone (30 ml) Reflux for 3 hours. The solvent was evaporated in vacuo, and the residue was triturated with water to give (19) (X = I, Y = s, Z, s, 2, 2 g (80%) · lH NMR (D6-DMSO > δ: 8*24, 8.34 ( 2s, each 1H, H-2 and Η·8}, 5.90 (4 1H, Η·Γ, Jl,, 2, = 4·7 Hz), 4·96 <dd, 1H, H-2, , Jl,, 2, = 4.7, J2,, 3, = 4·9 Hz), 4.60 (d4 1H, H-3,, J2,, 3, = 4.9, J3', 4' = 4.7 Hz), 4 · 80 (d* 23⁄4 H· 5,, 5,,), 4.4a (m, IH, H-4,). According to a similar method, but use the corresponding 2', 3, dehydrated-D-ribose nucleus Glycoside (14), the following 3, deoxy-3, iodine-D-xylosyl nucleoside and its L-enantiomer·9-(3-deoxy-3-fill-泠-D·pyranosyl) were prepared. Wuqi '9-(3-deoxy-3_block-stone-D-咲 pain ribosyl)-6-methylazinothiol oxime, 9-(3-deoxy-3-iodo-calli- D-ribofuranosyl)-6-methoxy oxime, (please read the notes on the back and fill out this page) # 订---------Line - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 172 91949 [293306 A7 B7 V. Invention Description (173 Ministry of Economic Affairs Intellectual Property Office employees Co-operatively printed 9-(3-deoxy H-dosyl-D-ribofuranosylamino-6-methylhydrothioguanidine, with 9-(3-deoxy-3-iodo-callo-D_furan Ribosyl) 2_amino _6_methoxy oxime 〇 18 Example 18 3. Deoxyadenosine (20, Y=NH2, Z=H) Take (19) (Y=NH2, Z=H, 380 a milligram, 1 mmol of methanol (75 ml) solution in a hydrogen atmosphere at 5% pd/BaS〇4 catalyst (1 mg) and diethylamine (1 ml) at initial pressure After shaking at 3 atm overnight, after removing the catalyst, the solvent was evaporated in vacuo, and the residue was crystallized from methanol to give 3,-deoxyadenosine (20) (Y = NH2, Z = H), 200 mg (8 %). The iHNMR spectrum of this sample is consistent with cordycepin. The following 3'-deoxynucleosides and their L_ pairs were prepared by a similar method, but using the corresponding 3, iodine-D_xylose nucleoside (19). ··· 9_(3_deoxyfuran erythrose pentose) guanine, 9_(3_deoxy_n_〇_furan erythrose pentose) 嘌呤, 9-(3_deoxy-call - D-furan erythrosyl pentose)_6_methoxy 嘌吟' 9-(3-deoxy-callo-D-furan erythrosylamine oxime and ^(3-deoxy-D-furan Pentylamino group Purine group. Example 19^ 3-(y8-D-0-glucopyranosyl)_8-nitrogen from baicalein (24, χ=〇Η, γ=Ν) Add sodium azide (100 mg) to 5-nitro In a solution of uridine (3 mg) in DMF (60 ml), the mixture was stirred at room temperature overnight. Vacuum was removed; the residue of the granules was dissolved in a minimum amount of water and adjusted to pH 3 to 4 with dilute hydrochloric acid. _ Recrystallization in water, mp 164 to 166 ° C (decomposition · 'paper scale turning W national standard (CNS) A4 specifications (210 X 297 public)) - 173 91949 (please read the notes on the back and then fill out this Page) 0 Order---------Line·1293306 A7 ___ B7 V. Description of invention (174) H2〇 Calculated value: C, 35·64; Η, 4·29; 23·1; measured value: c, 35.96 ; Η, 4·01 ; Ν, 23·43. Example 20 1,2_0-isopropylidene-5-0-methoxycarbonyl-3-0-phenoxythiocarbonyl-α-D-furan糠(26, R=Ph) A solution of benzene-containing phenyl phenyl ester (50 g, 0.3 mol) in acetonitrile (100 ml) was added dropwise to a mixture containing 1,2-0-isopropylidene-5·0- Oxycarbonyl-α-furanose (25, 25.0 g, 0.1 mol) and 4-dimethylaminopyridine (25 g, 0.2 mol) in anhydrous pyridine (250 ml), the reaction mixture is 50 to 60 ° Stir for 24 hours under C. The solution is concentrated in vacuo, and the residue is distributed between di-methane and water. The organic layer is washed with water, hydrazine, sodium hydroxide, water o.in hydrochloric acid and water, and dehydrated with sodium sulfate. Concentrate in vacuo to yield a full yield (26) (R = Ph) of syrup (38.2 g). Directly used in the next step. Example 21 3_Deoxy·1,2-0-isopropylidene-5-0•methoxycarbonylfuran erythrose pentose (27) Adds tri-n-butyltin in 3 hours A solution of hydrazine (58 g, 〇 2 mol) in toluene (300 liters) to the above compound (26) (11 = ? 11) (19.2 g, 50 mmol) and 2,2'-azo A solution of diisobutyronitrile (2.5 g, 15 mmol) in toluene (400 mL). The mixture was concentrated in vacuo and the residue was dissolved in acetonitrile (300 mL). The tri-n-butyltin derivative was excluded. The acetonitrile layer was concentrated. The thin layer chromatography of the residue showed a major dot, and the 1H NMR spectrum showed three methyl groups and no aromatic protons, but contained a small amount of butyltin derivative impurities. In the unpurified paper scale, the Chinese National Standard (CNS) A4 specification (210 X 297 mm) is applied. 91949 (Please read the note on the back and fill out this page)

II 訂---------線_ 經濟部智慧財產局員工消費合作社印製 174 經濟部智慧財產局員工消費合作社印製 175 !293306II 订--------- Line _ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 174 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 175 !293306

五、發明說明（m 即於下一個步驟中使用此產物。 f例22 1，2·二〇-乙醯基去惫 氣5-〇_甲氧羰基-D_呋喃赤蘚戊糖 (28) 於冰冷卻下，以伴拄 保符，皿度在B至25°C之滴加速率下 滴加濃硫酸(3毫升）至含(23)(2 32克，gqi莫耳）之乙酸（6 宅升)與广酸酐(6毫升)混合物之攪拌溶液中。於室溫下舊 置夜後加冰（25〇克）至溶液中’以二氯f燒（3x50毫升 萃取合併之萃液以飽和碳酸氫鈉溶液（3x30毫升 洗務，以硫酸鈉脫水，及真n產生⑽(2 8克， /〇)為變靛異構物之混合物.。此化合物之純度足以在 未純化下即用於下一個步驟。 實例23 1-(2·0_乙醯基_3_去氧_5_〇_甲氧羰基_点_〇_呋喃赤蘚戊糖 基）-5-氟尿嘧啶（29, χ==〇Η，Z=F) 取含％氟尿嘧啶（2 6克，〇 〇2莫耳）、硫酸銨（約3q毫 克）之六甲基二秒胺烷（15毫升）混合物回流至得到澄清溶 液止。真空排除溶劑，殘質溶於1，2-二氣乙烷（20毫升）中， 添加含1，2_二.〇_乙醯基冬去氧小〇_甲氧羰基_D_呋喃赤 蘚戊糖（28，5.5克，0·02莫耳）之12_二氣乙烷（2〇毫升）。 在此溶液中添加四氣化錫（5.2克，0.02莫耳），混合物於| 溫下授摔一夜，再於40至50°C下加熱3小時。添加飽和 碳酸氫鈉溶液（40毫升），攪拌至二氧化碳停止釋出為止。 1合物、經t 過濾。分離有機層，小心地以飽和碳醇 表紙張尺度適用中國國iii^NS)A4規格一(210 x 297公b ---： 91949 (請先閱讀背面之注意事項再填寫本頁)5. Description of the invention (m) This product was used in the next step. f Example 22 1,2·diindole-ethenyl-deuterium 5-indole-methoxycarbonyl-D_furan erythrose (28) Under ice cooling, concentrated sulfuric acid (3 ml) was added dropwise to the acetic acid containing (23) (2 32 g, gqi mol) with a drop rate of B to 25 ° C. Add a mixture of a large amount of acetic anhydride (6 ml) in a stirred solution at room temperature, add ice (25 g) to the solution at room temperature, and burn with dichloro-f (3 x 50 ml of the combined extract to saturate Sodium bicarbonate solution (3x30 ml washing, dehydration with sodium sulfate, and true n yield (10) (28 g, /〇) as a mixture of ruthenium isomers. The purity of this compound is sufficient to be used without purification. The next step. Example 23 1-(2·0_ethylindolyl_3_deoxy-5_〇_methoxycarbonyl_dot_〇_furan erythropentyl)-5-fluorouracil (29, χ= =〇Η,Z=F) A mixture of hexamethyldihydroalkane (15 ml) containing % fluorouracil (26 g, 〇〇2 mol) and ammonium sulphate (about 3 q mg) was refluxed until a clear solution was obtained. The solvent is removed by vacuum, and the residue is dissolved in 1,2- In the ethane (20 ml), the addition of 1,2_二.〇_乙醯基冬氧氧小〇_methoxycarbonyl_D_furan erythrose pentose (28,5.5 g, 0. 02 mol) 12_ di-ethane (2 〇 ml). Add tetra-glycine tin (5.2 g, 0.02 m) to the solution, and the mixture was dropped at a temperature for one night and then heated at 40 to 50 °C. Add 3 hours of saturated sodium bicarbonate solution (40 ml), stir until the carbon dioxide stops to be released. 1 compound, filtered through t. Separate the organic layer, carefully apply to the scale of saturated carbon alcohol paper for China iii^NS) A4 size one (210 x 297 b) ---: 91949 (please read the notes on the back and fill out this page)

A7 1293306 五、發明說明（176厂^ 一"" 氳納溶液（20毫升χ2)及水（2〇毫升χ2)洗蘇，以硫酸納脫 水，及真空濃縮至乾。殘質自乙醇中結晶’產生(29)(43 克，62%) 〇 依類似方法，但改用相應之嘧啶鹼基，製備下列2,，5，_ 受保護之3’-去氧核苷與其L-對映體： 1-(2-0-乙釀基_3_去氧_5_〇_甲氧叛基υ咲喃赤蘚 戊糖基）-5-氣尿嘴咬， 1-(2-0-乙醯基去氧-5_〇_甲氧羰基_沒_〇_咲喃赤蘚 戊糖基）_5_溴尿喷咬， 1-(2-0-乙醯基_3·去氧-5_〇_甲氧羰基咲喃赤蘚 戊糖基）_5_碘尿嘧啶， M2-0-乙醯基-3-去氧·5_〇_甲氧羰基j_D_呋喃赤蘚 戊糖基）-5-氰基尿喷咬， 1-(2-0-乙醯基-3-去氧-5-0-甲氧羰基^ 呋喃赤蘚 戊糖基）-5-乙氧魏基尿喊咬， 1-(2-0-乙醯基-3-去氧-5-0-甲氧羰基-〇_呋喃赤薄 戊糖基）-5-胺基羰基尿嘴咬， 1-(2-0-乙醯基_3_去氧-5-0-甲氧羰基呋喃赤蘚 戊糖基）-5-乙醯基尿嘧啶， 1-(2-0-乙醯基-3-去氧-5-0-甲氧羰基_点咲喃赤蘚 戊糖基）-5-甲基尿嘧啶， 1-(2-0-乙醯基-3·去氧-5-0-甲氧羰基呋喃赤蘚 戊糖基）-5-乙基尿痛咬， 1-(2-0-乙醯基-3-去氧_5-0-甲氧羰基_沒_D-呋喃赤 --------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 x297公釐） 176 91949A7 1293306 V. Description of the invention (176 plants ^ a "" Cannes solution (20 ml χ 2) and water (2 〇 ml χ 2) washed with sodium, dehydrated with sodium sulphate, and concentrated to dryness in vacuo. Residue from ethanol Crystallization 'produces (29) (43 g, 62%) according to a similar method, but using the corresponding pyrimidine base to prepare the following 2, 5, _ protected 3'-deoxynucleoside and its L-antagonism Body: 1-(2-0-ethyl-branched _3_deoxy_5_〇_methoxyoxinyl erythroquinolyl)-5-gas urinary mouth bite, 1-(2-0- Ethyl decyl deoxy-5_〇_methoxycarbonyl _ _ _ _ 咲 藓 藓 藓 糖 ) ) _ _ 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- _〇_methoxycarbonyl 咲 藓 藓 藓 糖 )) _5_iodouracil, M2-0-acetamido-3-deoxy·5_〇_methoxycarbonyl j_D_furan erythrose 5-cyanourine urinary bite, 1-(2-0-ethinyl-3-deoxy-5-0-methoxycarbonyl^furan erythrosyl pentose)-5-ethoxycarbyl urinary shit, 1-(2-0-Ethyl-3-deoxy-5-0-methoxycarbonyl-indole-furan-erythropentyl)-5-aminocarbonyl urinary mouth bite, 1-(2-0- Ethyl hydrazine _3_deoxy-5-0-methoxycarbonylfuran erythrosyl pentyl)-5-ethyl uracil, 1-( 2-0-Ethyl-3-deoxy-5-0-methoxycarbonyl-p-amyl erythropentyl)-5-methyluracil, 1-(2-0-ethinyl-3 ·Deoxy-5-0-methoxycarbonylfuran erythrosyl pentyl)-5-ethyl urinary pain bite, 1-(2-0-ethinyl-3-deoxy-5-0-methoxycarbonyl _没有_D-furanchi-------------------- order--------- line (please read the notes on the back and fill out this page The Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs printed the paper scale for the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 176 91949

TJ 293306 五、發明說明（177 )TJ 293306 V. Description of invention (177)

經濟部智慧財產局員工消費合作社印製 戊糖基）-5-正丙基尿喷啤， 1-(2-0-乙醯基去氣、5_〇_甲氧羰基j 戊糖基）-5 -異丙基氣尿脅。定 1-(2-0_乙酿基-3-去氡、5_〇_甲氧羰基j 戊糖基）-5 -乙烯基尿哺啤， 1_(2-0·乙酿基-3-去氣5七甲氧鑠基^ 戊糖基）-5 -稀丙基尿喷啤， 1_(2_0_乙醯基_3-去氣甲氧辣基 戊糖基）-5 -乙快基尿嗦η定， 1-(2-0-乙醯基_3_去氣、5_〇_甲氧羰基 戊糖基）-5-(2-氣乙烯基）尿^咬， 1-(2-0-乙醯基-3-去氣、5:_甲氧難基-点 戊糖基）-5-(2-溴乙烯基）尿喷咬， 1-（2·0·乙醯基_3_去氧·5_〇_甲氧羰基 戊糖基）-5-(2-块乙烯基）尿嘧咬， 1-(2-0-乙醯基-3-去氧_5_〇_甲氧幾基^ 戊糖基）-5-(2-甲氧羰基乙烯基）尿喷咬， 1-(2-0-乙釀基-3-去氧_5·〇田备 U-甲氣羰基j 戊糖基）-5-(2-經基幾基乙烯基）尿續啤 1-(2-0-乙醯基-3-去氧-5-0-甲盡、 戊糠基）-5-苯基屎嘧啶， a ~ 1-(2_0 -乙酿基-3-去氧- 5-0-甲氣 戊糖基）-5-T基尿嘧啶， 呋喃赤蘚 -D-呋喃赤蘚 •D-呋喃赤蘚 •D-呋喃赤蘚 •D-呋喃赤蘚 •D-咲喃赤蘚 •D-咲喃赤蘚 _D-咲喃赤蘚 _D-咲喃赤蘚 •D-咲喃赤蘚 -D-P夫喃赤蘚 ---------------- (請先閱讀背面之注意事項再填寫本頁) 訂_ 丨線- 1 -（2_0·乙醯基-3-去氧-5_0-甲氣羯| & 田 cb 爾古 4* 推 、Λ /1 描梭〆 91Π κ 9Q7 //S 兹、曰 ^紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） _D-咲喃赤蘚 177 91949 A7 經濟部智慧財產局員工消費合作社印製 1293306 B7__ 五、發明說明（Μ ) 戊糖基）-5-氟胞嘴咬， 1-(2-0-乙醯基-3-去氧-5-0-甲氧羰基-召-D-呋喃赤蘚 戊糖基）-5-氣胞嘧啶， 1-(2-0-乙醯基-3-去氧-5-0-甲氧羰基-召-D-呋喃赤蘚 戊糖基）-5-溴胞癌咬， 1-(2-0-乙醯基-3-去氧-5-0-甲氧羰基-召-D-呋喃赤蘚 戊糖基）-5-碰胞喊咬， 1-(2-0-乙醯基-3_去氧-5-0-甲氧羰基-沒-D-呋喃赤蘚 戊糖基）-5-氰基胞嘧啶， 1-(2-0-乙醯基-3-去氧-5-0-甲氧羰基-召-D-呋喃赤蘚 戊糖基）-5-乙氧羰基胞嘧啶， 1-(2-0-乙醯基-3-去氧-5-0-甲氧羰基-卢-D-呋喃赤蘚 戍糖基）-5 -胺基幾基胞癌唆， 1-(2-0-乙醯基-3-去氧-5-0-甲氧羰基-冷-D-呋喃赤蘚 戊糖基）-5-乙醯基胞嘧啶， 1-(2-0-乙醯基-3-去氧-5-0·甲氧羰基-点_D-呋喃赤蘚 戊糖基）-5-甲基胞，唆， 1-(2-0-乙醯基-3-去氧-5-0-甲氧羰基-冷-D-呋喃赤蘚 戊糖基）-5-乙基胞癌唆， 1-(2-0-乙醯基-3-去氧-5-0-甲氧羰基-召-D-呋喃赤蘚 戊糖基）-5-正丙基胞嘧啶， 1-(2-0-乙醯基-3·去氧-5-0•甲氧羰基·泠-D-呋喃赤蘚 戍糖基）-5-異丙基胞嘴咬’ 1-(2-0-乙醯基-3-去氧-5-0-甲氧羰基-泠-D-呋喃赤蘚 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁)Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed pentose based)-5-n-propyl urinary spray beer, 1-(2-0-acetamido degassing, 5_〇_methoxycarbonyl j pentose)- 5-isopropyl urinary stress. 1-(2-0_Ethyl-3-dehydropurine, 5_〇_methoxycarbonylj-pentanosyl)-5-vinyl urinary beer, 1_(2-0·乙牛基-3- Degas 5,5-methoxyanthryl^pentanosyl)-5-dilute urinary spray beer, 1_(2_0_acetamido_3-deoxymethoxypentanosyl)-5-B-based urinary嗦η定, 1-(2-0-ethylindolyl_3_degas, 5_〇_methoxycarbonylpentosyl)-5-(2-vinylvinyl) urinary bite, 1-(2- 0-acetamido-3-degas, 5:_methoxyphenoxy-pivalosyl)-5-(2-bromovinyl) urine squirt, 1-(2·0·ethinyl_3 _Deoxy·5_〇_methoxycarbonylpentanosyl)-5-(2-block vinyl) uracil bite, 1-(2-0-ethinyl-3-deoxy_5_〇_甲Oxy-oxyl-pentanosyl-5-(2-methoxycarbonylvinyl) urine squirt, 1-(2-0-ethyl-bromo-3-deoxy-5) 〇田备U-methoxy carbonyl j pentose))-5-(2-transyl-vinyl) urinary continuous beer 1-(2-0-ethinyl-3-deoxy-5-0-methyl, pentyl)-5 -phenylpyrimidine, a ~ 1-(2_0-ethyl-bromo-3-deoxy-5-0-methylpentanosyl)-5-T-based uracil, furan-erythro-D-furan D-furan erythroquinone•D-furan erythroquinone•D-furan erythroquinone•D-咲咲赤藓•D-咲喃Akasaka _D-咲咲赤藓_D-咲咲赤藓•D-咲咲赤藓-DP Furan Akasaka---------------- (Please read the back first Precautions and fill in this page) Order _ 丨 line - 1 - (2_0 · ethoxylated-3-deoxy-5_0-methyst 羯 | & field cb ergu 4* push, Λ /1 〆 shuttle 〆 91Π κ 9Q7 //S 兹, 曰^ paper scale applicable to China National Standard (CNS) A4 specification (210 x 297 mm) _D-咲咲赤藓177 91949 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1293306 B7__ V. DESCRIPTION OF THE INVENTION (Μ) Pentacyl)-5-fluorocytidine bite, 1-(2-0-acetamido-3-deoxy-5-0-methoxycarbonyl-call-D-furan erythrose pentose 5-)-cytosine, 1-(2-0-acetamido-3-deoxy-5-0-methoxycarbonyl-callo-D-furan erythrosyl pentose)-5-bromocytocarcinoma Bite, 1-(2-0-ethinyl-3-deoxy-5-0-methoxycarbonyl-callo-D-furan-erythropentyl)-5-collision, 1-(2- 0-acetamido-3_deoxy-5-0-methoxycarbonyl-no-D-furan erythrosyl pentose)-5-cyanocytosine, 1-(2-0-ethenyl-3 -deoxy-5-0-methoxycarbonyl-callo-D-furan erythrosyl pentose)-5-ethoxycarbonylcytosine, 1-(2-0-ethinyl-3-deoxy- 5-0-methoxycarbonyl-lu-D-furan erythrosyl)-5-amino-based cell carcinoma, 1-(2-0-ethinyl-3-deoxy-5-0- methoxycarbonyl-cold-D-furoerythropentyl)-5-ethenylcytosine, 1-(2-0-ethinyl-3-deoxy-5-0.methoxycarbonyl-dot_ D-furan erythrosyl pentose)-5-methyl, hydrazine, 1-(2-0-ethinyl-3-deoxy-5-0-methoxycarbonyl-cold-D-furan erythrin Glycosyl)-5-ethylcytocarcinoma, 1-(2-0-acetamido-3-deoxy-5-0-methoxycarbonyl-callo-D-furan erythrosyl pentose)-5- N-propyl cytosine, 1-(2-0-ethinyl-3·deoxy-5-0•methoxycarbonyl·泠-D-furan erythro-glycosyl)-5-isopropyl cytosine ' 1-(2-0-Ethyl-3-deoxy-5-0-methoxycarbonyl-indole-D-furan erythrene) This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 91949 (Please read the notes on the back and fill out this page)

178 經濟部智慧財產局員工消費合作社印製 179 [293306 A7 ___B7_____ 五、發明說明（179 ) 戊糖基）-5-乙烯基胞嘧啶， 1-(2-0-乙醯基-3-去氧-5-0·甲氧羰基-召-D-呋喃赤蘚 戊糖基）-5-烯丙基胞嘧啶， 1-(2-0-乙醯基_3_去氧-5_〇-甲氧羰基_D-呋喃赤蘚 戊糖基）-5-乙炔基胞嘧啶， 1-(2-0-乙醯基-3-去氧_5_0_甲氧羰基·点-D-D夫喃赤蘚 戊糖基）-5-(2-氣乙稀基）胞癌唆’ 1-(2-0-乙醯基-3-去氧-5-0-f氧羰基-沒-D-咲喃赤蘚 戊糖基）-5-(2-溴乙烯基）胞嘧啶， 1-(2-0-乙醯基-3·去氧-5-0-甲氧羰基-召-D-呋喃赤蘚 戊糠基）-5-(2-碘乙烯基）胞嘧啶， 1-(2-0-乙醯基-3-去氧-5-0·甲氧羰基-召-D·呋喃赤蘚 戊糖基）-5-(2-甲氧羰基乙烯基）胞嘧啶’ 1-(2-0-乙醯基_3-去氧-5-0-甲氧羰基-召-D-呋喃赤蘚 戊糖基）-5-(2-羥基羰基乙，烯基）胞嘧啶’ 1-(2-0_乙醯基-3-去氧-5-0-甲氧羰基-召-D-呋喃赤蘚 戊糖基）-5_苯基胞嘧啶，與 1-(2-0-乙醯基-3-去氧-5·0-甲氧羰基-召-D-呋喃赤蘚 戊糖基）-5-卞基胞癌咬。 依類似方法，但改用相應之嘧啶與嘌呤鹼基，製備下 列2’，5，·二·0-乙醯基-3，-去氧-核苷與其L-對映體： 1-(2,5·二-〇-乙酿基去氧-召-D-咲σ南赤蘚戊糖基）-5-氯尿嘧啶， __乙蘸基-3-去HD-P夫喃赤蘚戊糖基）-5- t纸張尺度適用中國國家標準（CNS)A4規格（2〗0 X 297公釐)-----—____ 91949 (請先閱讀背面之注意事項再填寫本頁)178 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 179 [293306 A7 ___B7_____ V. Description of Invention (179) Pentacyl)-5-vinylcytosine, 1-(2-0-ethinyl-3-deoxygenation -5-0·methoxycarbonyl-callo-D-furan-erythropentyl)-5-allylcytosine, 1-(2-0-ethinyl_3_deoxy-5_〇-甲Oxycarbonyl _D-furan erythrosyl pentyl)-5-ethynyl cytosine, 1-(2-0-ethinyl-3-deoxy-5_0_methoxycarbonyl·dot-DD Glycosyl)-5-(2-ethylidene) cell carcinoma 1-' 1-(2-0-acetamido-3-deoxy-5-0-f oxycarbonyl-n-D- 咲 藓 藓Pentosyl)-5-(2-bromoethenyl)cytosine, 1-(2-0-ethenyl-3·deoxy-5-0-methoxycarbonyl-callo-D-furan-erythroquinone 5-(2-iodovinyl)cytosine, 1-(2-0-ethinyl-3-deoxy-5-0.methoxycarbonyl-callo-D·furan-erythropentyl) -5-(2-methoxycarbonylvinyl)cytosine 1- 1-(2-0-ethenyl-3-deoxy-5-0-methoxycarbonyl-call-D-furan-erythropentyl) -5-(2-hydroxycarbonylethyl, alkenyl) cytosine ' 1-(2-0-ethenyl-3-deoxy-5-0-methoxycarbonyl-call-D-furan erythropentyl )-5_phenylcytosine Bian-yl bite -5- cancer cells - and 1- (furan-called -D- erythritol pentofuranosyl 2-0- acetyl-3-deoxy-0- -5-methoxycarbonyl). In a similar manner, but using the corresponding pyrimidine and purine bases, the following 2',5,.di-O-decyl-3,-deoxy-nucleoside and its L-enantiomer are prepared: 1-(2 ,5·二-〇-B-based deoxygenation-call-D-咲σ南赤藓 pentose-based)-5-chlorouracil, __ acetyl -3-, HD-P Glycosyl)-5-t paper scale applicable to China National Standard (CNS) A4 specification (2〗 0 X 297 mm)------____ 91949 (Please read the note on the back and fill out this page)

1293306 A7 B7 五、發明說明（180 ) 溴尿哺唆， 1-(2,5·二-Ο-乙醯基-3·去氧-D_呋喃赤蘚戍糖基）-5- 蛾尿喊咬， 1-(2,5-二-0-乙醯基-3-去氧-冷呋喃赤蘚戊糖基）-5- 氰基尿癌咬， 1-(2,5-二_0-乙醯基-3-去氧-D-呋喃赤蘚戊糖基）-5- 乙氧羰基尿嘧啶， 1-(2,5-二-0-乙醯基-3-去氧-召-D-呋喃赤蘚戊糖基）-5- 胺基羰基尿嘧啶， 1-(2,5-二-0_乙醯基-3-去氧-召-D-呋喃赤蘚戊糖基）-5· 乙醯基尿，咬， 1-(2,5-二-0-乙醯基-3-去氧-召-D-呋喃赤薄戊糖基）-5-甲基尿癌咬， 1-(2,5-二·0-乙醯基-3-去氧-召_D_呋喃赤蘚戊糠基）-5-乙基尿嚀啶， 1-(2,5-二-0-乙醯基_3_去氧-冷-D-呋喃赤蘚戊糖基 正丙基尿癌唆， 1-(2,5-二-Ο-乙醯基-3-去氧-召-D-呋喃赤蘚戊糖基）-5- 異丙基尿'癌啶， 1-(2,5-二-0-乙醯基-3-去氧-召_D-呋喃赤蘚戊糖基）·5- 乙烯基尿痛.咬， 1-(2,5-二-0-乙醯基-3-去氧-泠-D-呋喃赤蘚戊糖基）-5- 烯丙基尿嘧.咬， 1-(2,5-二-0-乙醯基-3-去氧-召-〇-呋喃赤蘚戊糖基）-5- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (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 180 A7 1293306 B7___ 五、發明說明（181 ) 乙炔基尿癌唆， 1-(2,5·二- Ο-乙酿基-3-去氧-点-D-咲喃赤鲜戍糖基）-5-(2-氯乙烯基）尿嘧啶， 1-(2,5-二-Ο-乙醯基-3-去氧-泠-D-咲喃赤蘚戍糖基）-5-(2-溴乙烯基）尿嘧啶， 1-(2,5-二-0-乙酿基-3-去氧-D -咲:喃赤鲜戊糖基）-5-(2-碘乙烯基）尿嘧啶， 1_(2,5·二-0_乙酿基-3-去氧-沒-D-咲喃赤鲜戍糖基）-5- (2-甲氧羰基，乙烯基）尿嘧啶， 1-(2,5-二-0-乙醯基-3-去氧-点-D-呋喃赤蘚戊糖基）-5- (2-羥基羰基乙稀基）尿嘧啶， 1_(2,5_二-0-乙醯基-3-去氧-点-D-呋喃赤蘚戊糖基）-5- 苯基尿嘴唆， 1-(2,5-二-0-乙醯基-3-去氧-沒-D-呋喃赤蘚戊糖基）-5- 〒基尿喷咬， 1-(2,5-二-0-乙基-3_去氧-万-D-呋喃赤蘚戊糖基）_5- 氟胞喊淀， 1·(2,5-二_0-乙醯基-3-去氧-召-D-呋喃赤蘚戊糖基）-5- 氯胞嚓啶， 1-(2,5-二-0-乙醯基-3-去氧-泠-D·呋喃赤蘚戊糖基）-5- 溴胞嘧啶， 1-(2,5-二-Ο-乙醯基_3_去氧-沒-D•咲喃赤蘚戊糖基）-5- 蛾胞嘴咬， 1-(2,5-二-0-乙醯基-3-去氧-万-D-呋喃赤蘚戊糖基）-5- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) -------訂·-------- · 經濟部智慧財產局員工消費合作社印製 181 1293306 A7 B7 五、發明說明（182 ) 氰基胞癌淀， 1-(2,5-二-Ο-乙醯基-3-去氧-D-呋喃赤蘚戊糖基）-5- 乙氧羰基胞嘧啶， 1-(2,5-二-0-乙醯基-3-去氧-召-0-呋喃赤蘚戊糖基）-5_ 胺基羰基胞嘧啶， 1-(2,5-二-0-乙醯基-3-去氧_D-呋喃赤蘚戊糖基）-5-乙醯基胞喷咬， 1-(2,5-二-0-乙醯基-3_去氧-泠_D-呋喃赤蘚戊糖基）·5· 甲基胞嘧啶， 1-(2,5-二-0-乙醯基-3-去氧-泠-〇-呋喃赤蘚戊糖基）-5_ 乙基胞嘧啶， 1-(2,5-二-0-乙醯基-3-去氧-泠-D-呋喃赤蘚戊糖基）-5-正丙基胞嘧啶， 1_(2,5_二-0-乙醯基-3-去氧-召-D_呋喃赤蘚戊糖基）-5_ 異丙基胞嘧啶， 1-(2,5-二-0-乙醯基-3-去氧，冷-D-呋喃赤蘚戊糖基）-5-乙烯基胞嘧啶， 1-(2,5-二-Ο-乙醯基-3-去氧-冷-D-呋喃赤蘚戊糖基）-5- 烯丙基胞嘧啶， 1-(2,5-二-0-乙醯基-3-去氧-泠-0-呋喃赤蘚戊糖基）-5-乙炔基胞嘧啶， 1-(2,5-二-0-乙醯基-3-去氧-沒-〇-呋喃赤蘚戊糖基）-5-(2-氣乙烯基）胞嘧啶， 1-(2,5-二_0-乙醯基-3-去氧-冷-〇_呋喃赤蘚戊糖基）-5- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (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 ί 2933061293306 A7 B7 V. INSTRUCTIONS (180) Bromouridine, 1-(2,5·di-indole-ethenyl-3·deoxy-D_furan erythro-glycosyl)-5- moth Bite, 1-(2,5-di-0-ethinyl-3-deoxy-coldfuran erythrosyl pentose)-5-cyanourine cancer bite, 1-(2,5-di_0- Ethyl-3-deoxy-D-furan erythrosyl pentyl)-5-ethoxycarbonyl uracil, 1-(2,5-di-0-ethinyl-3-deoxy-call-D -furan erythrosyl pentose)-5-aminocarbonyl uracil, 1-(2,5-di-0-ethinyl-3-deoxy-callo-D-furan erythrosyl pentose)-5 · Acetyl-based urine, bite, 1-(2,5-di-0-ethylindol-3-deoxy-callo-D-furan-erythropentose)-5-methyl urine cancer bite, 1- (2,5-dioxa--3-deoxy-callo_D_furan-erythroquinone)-5-ethyluridine, 1-(2,5-di-0-B醯基_3_deoxy-cold-D-furan erythrosyl pentyl-n-propyl urinary carcinoma, 1-(2,5-di-indole-ethenyl-3-deoxy-callo-D-furan Erythryl pentose)-5-isopropyl uranium 'carcinidine, 1-(2,5-di-0-ethinyl-3-deoxy-callo_D-furan erythrosyl pentose)·5 - Vinyl dysuria. Biting, 1-(2,5-di-0-ethinyl-3-deoxy-indole-D-furan erythrosyl pentose)-5-allyl uracil. Bite, 1-(2,5-di-0-ethinyl-3-deoxy-callo-oxime-furan-erythropentyl)-5- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 (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 180 A7 1293306 B7___ V. Invention Description ( 181 ) acetylene-based urinary cancer, 1-(2,5·di-indole-ethyl-bromo-3-deoxy-dot-D-purpurinyl glucosyl)-5-(2-chlorovinyl) Uracil, 1-(2,5-di-indole-ethenyl-3-deoxy-indole-D-purpurinyl)-5-(2-bromovinyl)uracil, 1- (2,5-di-0-ethyl-bromo-3-deoxy-D-indole: succinic acid pentose)-5-(2-iodovinyl) uracil, 1_(2,5·di- 0_乙丁基-3-deoxy-no-D-咲咲赤戍戍 glycosyl)-5-(2-methoxycarbonyl, vinyl) uracil, 1-(2,5-di-0- Ethyl-3-deoxy-dot-D-furan erythrosyl pentyl)-5-(2-hydroxycarbonylethlyl) uracil, 1_(2,5-di-0-ethenyl-3 -deoxy-dot-D-furan erythrosyl pentose)-5-phenyl urinary guanidine, 1-(2,5-di-0-ethinyl-3-deoxy-no-D-furan Pentose -5- 〒-based urine squirting, 1-(2,5-di-O-ethyl-3_deoxy-wan-D-furan erythrosyl pentose)_5- fluorocytidine, 1·(2 ,5-di-_0-acetamido-3-deoxy-callo-D-furan erythrosyl pentyl)-5-chlorocytidine, 1-(2,5-di-O-ethenyl- 3-deoxy-泠-D·furan erythrosyl pentose)-5- bromocytosine, 1-(2,5-di-indole-ethenyl_3_deoxy-no-D•咲 赤Pentoseose)-5- moth, bite, 1-(2,5-di-0-ethinyl-3-deoxy-wan-D-furan-erythropentyl)-5- Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 (Please read the note on the back and fill out this page) -------Book ·------- · Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 181 1293306 A7 B7 V. Description of Invention (182) Cyanocytosis, 1-(2,5-di-indole-ethenyl-3-deoxy-D-furan Pentosyl)-5-ethoxycarbonylcytosine, 1-(2,5-di-0-ethinyl-3-deoxy-callo-0-furan erythrosyl pentose)-5-aminocarbonyl Pyrimidine, 1-(2,5-di-O-acetylindol-3-deoxy-D-furan-erythropentyl)-5-ethionyl cytosolic, 1-(2,5-di- 0-acetamido-3_deoxy-indole_D-furan Indole pentosyl)·5·methylcytosine, 1-(2,5-di-0-ethinyl-3-deoxy-indole-indole-furan-erythropentyl)-5_ethylcytosine , 1-(2,5-di-0-ethinyl-3-deoxy-indole-D-furan erythrosyl pentose)-5-n-propylcytosine, 1_(2,5_2-0 -Ethyl-3-deoxy-callo-D_furan-erythropentyl)-5-isopropylcytosine, 1-(2,5-di-0-ethinyl-3-deoxy, cold -D-furan erythrosyl pentose)-5-vinylcytosine, 1-(2,5-di-indole-ethenyl-3-deoxy-cold-D-furan erythrosyl pentose)- 5-Allylcytosine, 1-(2,5-di-0-ethinyl-3-deoxy-indole-0-furylerythritoltosyl)-5-ethynylcytosine, 1-( 2,5-di-O-ethylindolyl-3-deoxy-n-indole-furan erythropentyl)-5-(2-vinylvinyl)cytosine, 1-(2,5-di- 0-Ethyl-3-deoxy-cold-〇_furan erythrose pentose)-5- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (Please read the back first Note: Please fill out this page) Order--------Line· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print ί 293306

五、發明說明（⑻） (2_溴乙烯基）胞嘧啶， 1-(2,5_二-〇_乙醢基-3»去裊 〇 ^ , 氣j -D-呋喃赤蘚戊糖基）_5_ (2-碘乙烯基）胞嘧啶， 1-(2,5_ 二 _〇_ 乙酿基·3 -去裊 〇 , 太氣呋喃赤蘚戊糖基）_5_ (2-甲氧羰.基乙烯基）胞嘧啶， - 一^_〇·乙酿基去氧 + 乳/S-D-呋喃赤蘚戊糖基）_5_ (2_羥基羰基乙烯基）胞嘧啶，1-(2,5-二_〇-乙釀基-3-去氧_点 苯基胞喊唆， •D_呋喃赤蘚戊糖基）-5- 呋喃赤蘚戊糖基）-5- (請先閱讀背面之注音？事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1 _(2,5_ 二-〇_ 乙醯基-3-去轰 η n rT+ + 4- ^ 太氧_沒_D_呋喃赤蘚戊糖基）_ N6-苯甲醯腺嘌呤， 1_(2,5-二-0-乙酿基-3-去盡 p τλ 丄从 太氣-召-D·呋喃赤蘚戊糖基）-6- 氯嘌呤， 1-(2,5-二-〇_乙醯基-3_去氧_D_呋喃赤蘚戊糖基）_ 2,6-二氯嘌呤， 1_(2,5_二-0-乙醯基-3_去氧❾-呋喃赤蘚戊糖基）_2_ 乙酿胺基-6-氣嗓呤， 1_(2,5_二-〇·乙醯基-3-去氧_D_呋喃赤蘚戊糖基卜2-乙醯胺基-6-甲氧基嘌呤， 1-(2,5-二-0-乙醯基-3-去氧·点-D_呋喃赤蘚戊糖基）_6-甲氧基嘌呤，與 1-(2,5_二-〇-乙醯基-3-去氧-万-D-呋喃赤藓戊糖基）-6- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 183 91949 -I I I I I I I 訂· — — — — — — — —V. INSTRUCTIONS ((8)) (2_Bromovinyl)cytosine, 1-(2,5-di-indole-ethenyl-3» depurinated ^, gas j-D-furan erythrosyl pentose )_5_(2-iodovinyl)cytosine, 1-(2,5_di-〇_ethylidene·3-deutero, acetofuran pentose glucosyl)_5_(2-methoxycarbonyl. Vinyl)cytosine, - ^^〇·ethyl alcohol deoxygenated + milk/SD-furan erythrosyl pentose)_5_ (2-hydroxycarbonylvinyl) cytosine, 1-(2,5-di_ 〇-B-Bottyl-3-Deoxy_Phenyl phenyl sulphonate, • D_Furan erythrosyl pentose)-5-furan erythrose pentose)-5- (Please read the phonetic notes on the back first? Fill in this page again) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1 _(2,5_二-〇_乙醯基-3-去轰η n rT+ + 4- ^太氧_没_D_furan Pentose)) N6-benzamide 嘌呤, 1_(2,5-di-0-ethyl-branyl-3-depletion p τλ 丄 from too gas-call-D·furan erythrosyl pentose)- 6-chloropurine, 1-(2,5-di-indole-3-ethenyl-3_deoxy_D_furan-erythropentyl)_ 2,6-dichloropurine, 1_(2,5_two -0-acetamido-3_deoxypurine-furan erythrosyl pentose)_2_ ethoxylated-6-gas呤, 1_(2,5_di-oxime-ethenyl-3-deoxy-D_furan erythrosyl pentyl 2-ethylamino--6-methoxy oxime, 1-(2,5 -2-0-ethinyl-3-deoxy-dot-D_furan-erythropentyl)_6-methoxyindole, with 1-(2,5-di-indole-ethenyl-3- Deoxy-wan-D-furan erythrosyl pentose)-6- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 183 91949 -IIIIIII order · — — — — — — —

五、發明說明（ 184 經濟部智慧財產局員工消費合作社印製 1293306 甲基氣硫基嗓呤。 實例 1 _(2-〇l乙醯基_3_去氧·5_〇•甲氧幾基j _D_咲喃赤蘚戊糖 基）-6_ 氣嘌呤（3〇, x=ci，Y=H) 取各6氯^呤（3 1克，〇 〇2莫耳）、硫酸铵（約3 〇亳克） 、甲基一發胺燒（2 5毫升）混合物回流到得到澄清溶液 止。真空排除溶劑，殘質溶於1，2-二氣乙烷（3〇毫升）中， 添加1，2·二_〇_乙醯基_3_去氧甲氧羰基咲喃赤蘚 戊糖（28，5.5克，〇·02莫耳）之it二氯乙烷（2〇毫升）。在 此;谷液中添加四氣化錫（5 2克，〇 〇2莫耳），混合物於室溫 下授摔一夜，再於4〇至5(rc下加熱3小時。添加飽和碳 酸氮納溶液（50毫升），攪拌至二氧化碳停止釋出為止。混 否物經貝式鹽塾過濾。分離有機層，小心地以飽和碳酸氫 納溶液（30毫升X 2)及水（30毫升X 2)洗滌，以硫酸鈉脫 水’及真空濃縮至乾。殘質自乙醇中結晶，產生（30)(4 3 克，62%) 〇 依類似方法，但改用相應之嘌呤鹼基，製備下列2,，5，-受保護之3、去氧核苷與其l-對映體·· 乙醯基-3-去氧-5-0-甲氧羰基·石_D-呋喃赤蘚 戊糖基）-N6-笨甲醯基腺嘌呤， 1-(2-〇-乙醯基-3-去氧-5-0-甲氧羰基_石-D-呋喃赤蘚 戊糖基）-6-氣嘌呤， 乙醯基-3-去氧-5-0-甲氧羰基-石_D-呋喃赤蘚 戊糖基）-2,6-二氣嗓呤， 本紙張尺度適用T國國家標準（CNS)A4規格（210 X 297公釐） - 91949 (請先閱讀背面之注意事項再填寫本頁)V. Description of the invention ( 184 Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative printed 1293306 methyl thiol hydrazine. Example 1 _(2-〇l acetyl _3_deoxy-5_ 〇 methoxy group j _D_咲咲赤藓 藓 糖 )))-6_ 嘌呤 (3〇, x=ci, Y=H) Take 6 chloro 呤 (3 1 g, 〇〇 2 mol), ammonium sulphate (about 3) 〇亳克), methyl-monoamine (25 ml) mixture is refluxed until a clear solution is obtained. The solvent is removed in vacuo, and the residue is dissolved in 1,2-diethane (3 mL). 2·二_〇_乙醯基_3_deoxymethoxycarbonyl oxime erythrose pentose (28,5.5 g, 〇·02 mol) of it dichloroethane (2 〇 ml). Here; Add four vaporized tin (5 2 g, 〇〇 2 mol) to the solution, and the mixture was dropped at room temperature for one night, and then heated at 4 〇 to 5 (rc for 3 hours). Add saturated sodium bicarbonate solution (50 (ml), stirring until the carbon dioxide stops to be released. The mixture is filtered through a shell of salt. The organic layer is separated and carefully washed with saturated sodium bicarbonate (30 mL) and water (30 mL) Dehydration of sodium sulfate and vacuum concentration The residue is crystallized from ethanol to give (30) (43 g, 62%) in a similar manner, but using the corresponding purine base to prepare the following 2, 5, - protected 3, go Oxynucleosides and their l-enantiomers · Ethyl-3-deoxy-5-0-methoxycarbonyl·stone _D-furan erythrosyl pentyl)-N6-Arachnid adenine, 1 -(2-〇-ethinyl-3-deoxy-5-0-methoxycarbonyl_stone-D-furan erythrosyl pentose)-6-gas, acetyl-3-deoxy-5 -0-methoxycarbonyl-stone_D-furan erythrosyl pentose)-2,6-dioxane, this paper scale applies to National Standard (CNS) A4 specification (210 X 297 mm) - 91949 (Please read the notes on the back and fill out this page)

184 A7 1293306 B7_________ 五、發明說明（185 ) 1-(2-0-乙醯基_3_去氧-5-0-甲氧幾基-点_D-呋喃赤蘚 戊糖基）-2·乙醯胺基_6_氯嘌呤， 1_(2_0_乙醯基_3·去氧-5_0-甲氧羰基_万_d-咲喃赤蘚 戊糖基）-2 -乙醯胺基-6—甲氧基嗓吟， 1-(2-0-乙醯基_3·去氧_5_〇_甲氧羰基_〇_呋喃赤蘚 戊糖基）-6 -甲氧基嗓呤，與 1-(2-0-乙醯基_3_去氧_5_〇甲氧羰基-点·!&gt;_唉喃赤蘚 戊糖基）-6 -甲基氫硫基u票呤。 實例25 1，2-〇-亞異丙基-5_〇_第三丁基二苯矽烷基·以_D_咲喃木糖 (31) 取含1，2-0-亞異丙基-〇^-〇-呋喃木糖（3 8.〇克，0.2莫 耳）、第三丁基二苯基氣矽烷（70克，0·25莫耳）與咪唑（21.5 克，0.4莫耳）之Ν，Ν_二甲基甲醯胺（5〇毫升）混合物於室溫 下授拌1小時。真空排除溶劑，殘質溶於乙酸乙酯（1升） 中，以水（300毫升χ 2)及鹽水（300毫升）萃取，以硫酸鈉脫 水’真空濃縮至乾，產生粗產物（31)(86克，1〇〇%)，未再 純化即直接用於下一個步驟。 實例26 1，2-亞異丙基_3-〇_甲磺醯基-5-〇-第三丁基二苯矽烷基_以_ D-呋喃木糖（32, R=Ms) 滴加甲磺醯氣（17克，〇·15莫耳）至含粗產物（3 0(43 克’ 0·1莫耳）之吡啶00毫升）溶液中，混合物保持靜置在 室溫下。添加碎冰（1升）至混合物中，以二氣甲烷门〇〇毫 本紙張尺度適用中國國家標準（CNS)A4^格（21〇 χ 297公爱) ------- 91949 (請先閱讀背面之注咅？事項再填寫本頁) — — — — — — I—』«J« — — — — — — I— . 經濟部智慧財產局員工消費合作社印製 185 1293306 A7 B7 五、發明說明（1½ ) 升X 3)萃取產物。合併萃液，以水（300毫升X 2)及鹽水（300 毫升）洗滌，以硫酸鈉脫水，真空濃縮至乾。與曱苯重覆共 沸蒸餾排除微量吡啶。殘質溶於二氯甲烷（5〇〇毫升）中，以 〇·1Ν鹽酸（250毫升X 2)及水洗滌，以硫酸鈉脫水，及濃縮 至乾，產生粗產物（32)(R=Ms)，50.1克（99%)。此物質之 4 NMR光譜證實其純度足以直接用於下一個步驟。 實例27 甲基3-0-甲磺醯基-5-〇-第三丁基二苯矽烷基呋喃木糖 苷（33, R=Ms) 取含粗產物（32)(50克，0·1莫耳）之1 %鹽酸之無水甲 醇溶液（1升）保持在室溫下一夜後，真空蒸發成漿狀物，分 佈在水（100毫升）與二氯甲烷（150毫升）之間。分離有機 層’以水（100毫升）洗滌，以硫酸鈉脫水，及真空濃縮，產 生粗產物（33)之漿狀物，48克（100%)。此物質未再純化即 直接用於下一個步驟。 實例28 甲基2,3-脫水_5_〇_第三丁基二苯矽烷基_D_咲喃核糖苷（34) 取粗產物（3 3)(48克，0.1莫耳）溶於二氯甲烷（1〇〇毫升） t ’以2M甲醇鈉之甲醇溶液（60毫升）處理，回流2小時， 過濾排除不可溶性鹽，濾液真空濃縮至乾。殘質溶於二氯 甲烷（150毫升）中，以水（100毫升χ 2)洗滌，以硫酸鈉脫 水’濃縮至乾，產生粗產物（30)(38克，100%)，未再經此 即直接用於下一個步驟。 (請先閱讀背面之注音？事項再填寫本頁) 0 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製184 A7 1293306 B7_________ V. INSTRUCTIONS (185 ) 1-(2-0-Ethyl-3_deoxy-5-0-methoxybenzyl-dot-D-furan-erythropentyl)-2· Acetylamino-6_chloropurine, 1_(2_0_acetamido_3.deoxy-5_0-methoxycarbonyl _wan_d-purpurinyl pentose)-2-acetamido-6 - methoxy oxime, 1-(2-0-ethinyl_3.deoxy-5_〇_methoxycarbonyl_〇_furan erythrosyl)-6-methoxy oxime, and 1-(2-0-Ethylidene_3_deoxy-5_〇methoxycarbonyl-dot·!&gt;_唉唉赤藓 pentose)-6-methylhydrothiol. Example 25 1,2-〇-isopropylidene-5_〇_t-butyldiphenyl sulfonyl group. _D_pyridose (31) was taken to contain 1,2-0-isopropylidene- 〇^-〇-furan xylose (3 8. gram, 0.2 mole), tert-butyldiphenyl gas decane (70 g, 0.25 mol) and imidazole (21.5 g, 0.4 mol) A mixture of hydrazine, hydrazine-dimethylformamide (5 mM) was stirred at room temperature for 1 hour. The solvent was removed in vacuo. EtOAc (EtOAc) (EtOAc) 86 g, 1% by weight), used directly in the next step without further purification. Example 26 1,2-isopropylidene-3-pyrene-methylsulfonyl-5-indole-t-butyldiphenylfluorene-_D-furanose (32, R=Ms) Sulfonium gas (17 g, 〇15 mol) was added to a solution containing the crude product (30 g (43 g, &lt;RTIgt; Add crushed ice (1 liter) to the mixture, apply the Chinese National Standard (CNS) A4^ grid (21〇χ 297 public) on the second methane threshold. ------- 91949 (Please Read the back of the note first? Then fill out this page) — — — — — — I—』«J« — — — — — — I — . Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 185 1293306 A7 B7 V. Description of the invention (11⁄2) liter X 3) Extract product. The combined extracts were washed with EtOAc EtOAc m. Repeated azeotropic distillation with toluene to remove traces of pyridine. The residue was dissolved in dichloromethane (5 mL). EtOAc (EtOAc m. ), 50.1 grams (99%). The 4 NMR spectrum of this material confirmed its purity to be used directly in the next step. Example 27 Methyl 3-0-methanesulfonyl-5-indole-t-butyldiphenylindoleoxyfuranose (33, R=Ms) containing crude product (32) (50 g, 0·1 Mo The 1% hydrochloric acid in anhydrous methanol (1 liter) was maintained at room temperature overnight and then evaporated in vacuo to dryness eluting with water (100 ml) and dichloromethane (150 ml). The organic layer was separated, washed with water (100 ml), dried over sodium sulfate, and concentrated in vacuo to give a crude product (33) s. This material was used directly in the next step without further purification. Example 28 Methyl 2,3-dehydrated_5_〇_t-butyldibenzoylalkyl_D_pyranoside (34) The crude product (3 3) (48 g, 0.1 mol) was dissolved in two Methyl chloride (1 mL) <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTIgt; The residue was dissolved in EtOAc (EtOAc (EtOAc)EtOAc. That is, it is used directly in the next step. (Please read the phonetic transcription on the back? Please fill out this page again) 0 Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Co., Ltd.

186 91949 1293306 A7 ___- __B7 五、發明說明（187 ) 甲基3-去氧-3-破-5-0-第三丁基二苯矽烷基呋喃核糖苷 (35, X=I) 取含（34)(38克，〇·〗莫耳）、碘化鈉（6〇克，〇 4莫耳）、 乙酸鈉（0·6克）與乙酸（7〇毫升）之丙酮（500毫升）混合物回 流加熱8小時。真空排除丙酮，殘質分佈在二氣甲烷（5〇〇 毫升）與水（250毫升）之間。分離有機層，以各25〇毫升水、 0· 1Μ硫代硫酸鈉溶液、水洗滌，以硫酸鈉脫水。真空排除 溶劑後，殘質自乙醇中結晶，產生31克（60·5%)(35)(Χ=Ι)。 實例30 甲基3-去氧-5-0-第三丁基二苯矽烷基_D_呋喃赤蘚戊糖苷 (37，來自（35)) 取化合物（35)(X=I，25.6克，0.05莫耳）於乙酸乙酯（250 毫升）中，使用5% Pd/C(2克）氳北。待氳氣停止釋出後， 混合物過濾，以水（150毫升X 2)洗滌濾液，以硫酸鈉脫水， 濃縮至乾，產生粗產物（37)(19克，全收量），其純度足以 直接用於下一個步驟。 實例31 甲基3-去氧- 5-0-第二丁基二苯碎烧基咲喃赤蘚戊糖苷 (36，來自（34)) 取含氫化鋰鋁（8·4克，〇·2莫耳）之無水乙醚（220毫升） 懸浮液於氮氣下攪拌，於冰浴中冷卻。在此懸浮液中以保 持溫度在25°C以下之速度滴加含（34)(19克，〇·〇5莫耳）之 無水四氫咲喃（250毫升）溶液。2小時後，再加1克氫化鋰 紹，混合物於室溫下攪拌一夜〇攪拌之混合物於冰浴中冷 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐 91949 (請先閱讀背面之注意事項再填寫本頁) I Aw · I------訂---------線· 經濟部智慧財產局員工消費合作社印製 187 經 濟 部 智 慧 財 產 局 消 費 合 作 社 印 製 1293306 A7 --------B7_______ 五、發明說明（188 ) 部’滴加異丙醇（1〇〇毫升）後，滴加丙酮（50毫升）。混合物 真空濃縮，殘質分佈在乙醚（250毫升）與水（150毫升）之 間。經寅式鹽塾過濾不可溶物，以乙醚洗滌。分離醚層， 依序以0·2Ν鹽酸（150毫升X 2)及水（150毫升X 2)洗滌，以 硫酸鉤脫水，濃縮至乾，產生粗產物（36)(16.5克，87%)。 甲基％去氧-D-呋喃赤蘚戊糖苷（37) 滴加1M三乙基銨氟化氫（1〇〇毫升）溶液至含粗產物 (36)(13克’ 0Q3莫耳）之四氳呋喃（320毫升）溶液中，混合 物授拌24小時。混合物真空濃縮，殘質溶於水（2〇〇毫升） 中。添加碳酸齊粉末（2〇克），混合物於室溫下擾拌一夜， 過濾。濾液真空濃縮至形成漿物，溶於氯仿（2〇〇毫升）中， 過濾’真空蒸發，產生粗產物（37)(4.5克，1〇〇%)。 實例33 1，2,5-三-〇·乙醯基_3_去氧_D_咲喃赤蘚戊糖（38) 依序添加乙酸酐（40毫升）與硫酸（4毫升）至含粗產物 甲基3_去氧-D_呋喃赤蘚戊糖苷（37)(4 5克，〇 〇3莫耳）與 乙酸（80毫升）之激烈攪拌混合物中，反應混合物於室溫下 攪拌仗。混合物分佈在二氯甲燒（150毫升）與冰水（4 〇〇 毫升）之間。以二氯甲烷（100毫升χ 2)萃取水層。合併之有 機層以等體積之飽和碳酸氳鈉溶液洗滌2次，以水洗務1 次，以硫酸鈉脫水，真空濃縮至乾。與甲苯共沸蒸餾數次 排除微量乙酸，產生粗產物（38)(5]克，66〇/〇)。其iHNMr 顯示此產物之主要組成份含有3個乙醯基，且為沒-變旋展 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公髮) —- 188 91949 (請先閱讀背面之注音？事項再填寫本頁) 麵 訂---------線—赢186 91949 1293306 A7 ___- __B7 V. Description of the invention (187) Methyl 3-deoxy-3-branched-5-0-t-butyldiphenylnonanylfuranosyl glucoside (35, X=I) 34) (38 g, 〇·〗 Mo), sodium iodide (6 g, 〇 4 mol), sodium acetate (0.6 g) and acetic acid (7 ml) acetone (500 ml) mixture reflux Heat for 8 hours. The acetone was removed in vacuo and the residue was partitioned between di-methane (5 mL) and water (250 mL). The organic layer was separated, washed with water each 25 mL of water, &lt;RTIgt; After the solvent was removed in vacuo, the residue was crystallized from ethanol to yield 31 g (60.5%) (35) ( Χ = Ι). Example 30 Methyl 3-deoxy-5-0-t-butyldibenzoylalkyl_D_furoerythroside glucoside (37 from (35)) Compound (35) (X = I, 25.6 g, 0.05 mol) in ethyl acetate (250 ml) using 5% Pd/C (2 g). After the helium gas ceased to be liberated, the mixture was filtered, and the filtrate was washed with water (150 ml of EtOAc), dried over sodium sulfate and concentrated to dryness to give crude product (37) (19 g, total yield) Used in the next step. Example 31 Methyl 3-deoxy-5-0-t-butyldiphenyl-pyrrolidinopurine erythroside (36, from (34)) Lithium aluminum hydride (8.4 g, 〇·2) Anhydrous diethyl ether (220 ml) was stirred under nitrogen and cooled in an ice bath. A solution containing (34) (19 g, 〇·〇5 mol) of anhydrous tetrahydrofuran (250 ml) was added dropwise to the suspension at a temperature below 25 °C. After 2 hours, add 1 gram of lithium hydride, stir the mixture at room temperature overnight, stir the mixture in an ice bath, and apply the Chinese National Standard (CNS) A4 specification (210 X 297 mm 91949). Read the notes on the back and fill out this page) I Aw · I------Book---------Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print 187 Ministry of Economic Affairs Intellectual Property Bureau Consumer Cooperative Printing 1293306 A7 --------B7_______ V. Description of the invention (188) After adding 'isopropanol (1 ml), add acetone (50 ml) dropwise. The mixture was concentrated in vacuo and the residue was distributed. Between diethyl ether (250 ml) and water (150 ml), the insoluble material was filtered through hydrazine salt and washed with diethyl ether. The ether layer was separated, followed by 0. 2 Ν hydrochloric acid (150 ml X 2 ) and water (150) ML X 2) Washed, dehydrated with sulfuric acid hook, concentrated to dryness to give crude product (36) (16.5 g, 87%). Methyl % deoxy-D-furan erythroside glucoside (37) 1 M triethyl A solution of the ammonium hydrogen fluoride (1 ml) to the crude product (36) (13 g of '0Q3 mol) of tetrahydrofuran (320 ml) In the mixture, the mixture was stirred for 24 hours. The mixture was concentrated in vacuo and the residue was dissolved in water (2 mL). The mixture was mixed with water (2 g), and the mixture was stirred overnight at room temperature and filtered. The slurry was formed, dissolved in chloroform (2 mL), filtered and evaporated in vacuo to give crude product (37) (4.5 g, 1%). Example 33 1,2,5-tri-〇·B醯基_3_deoxy_D_咲 藓 藓 藓 ( (38) Add acetic anhydride (40 ml) and sulfuric acid (4 ml) to the crude product methyl 3-deoxy-D_furan In an vigorously stirred mixture of pentose glycoside (37) (45 g, 〇〇3 mol) and acetic acid (80 ml), the reaction mixture was stirred at room temperature. The mixture was partitioned between methylene chloride (150 ml) and ice. Between water (4 ml). Extract the aqueous layer with dichloromethane (100 ml χ 2). The combined organic layer was washed twice with an equal volume of saturated sodium sulphate solution and washed with water once. Dehydrated, concentrated to dryness in vacuo. Azeotropic distillation with toluene several times to remove a small amount of acetic acid to give crude product (38) (5 g, 66 〇 / 〇). r shows that the main component of this product contains 3 ethyl fluorenyl groups, and it is applicable to the Chinese National Standard (CNS) A4 specification (210 χ 297 liters) for the non-variable spin-on paper scale — 188 91949 (please read the back first) The phonetic? Matters fill out this page) Face-to-order line--win

、發明說明（189 ) 構物。 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 ^93306 L (3-去氧-召-D-呋喃赤蘚戊糖苷）_5_氟屎嘧啶（3，_去氧_5-氟尿苷，6b，X=〇H，R=F) 取含（39)之乙醯基衍生物（χ==〇Η，Z=F，3 3克，〇 〇1莫 耳）與二乙胺（3氅升）之甲醇（1〇〇毫升）混合物於室溫下攪 拌—夜。混合物真空濃縮至乾，殘質自乙醇中結晶，產生 3 -去氧-5-氟尿嘧咬核脊（2 〇克，μ%) mp 169-171 °C·虫 NMR (D6-DMSO) δ: 11·7 (bs，1Η，Ν3·Η，可交換），&amp;44 (屯 1Η，Η«6, J6，F= 7·1 Hz), Μ (4 1Η, 2，-〇Η,可交換)，5·5 (窄峯 m m H-l，)，5.3 ft 1¾ 5，-〇Η，可交換)，4·14·5 (m，2Η，Η·2,與 Η4,) 3 5.，3 9 m，2H,H-5，,5，％ 1.6-2.2 (m,2H，H-3，,3,〇· ， ·、 依類似方法’但改用相應之2，，5，_二_〇•乙醯基-嘧啶與 嘌呤核苷，製備下列3，-去氧核苷與其L_對映體： 1_(3_去氧_^-D-呋喃赤蘚戊糖基）_5_氣尿嘧啶， 1-(3-去氧呋喃赤蘚戊糖基）_5_溴尿嘧啶， 1-(3-去氧-召-D-呋喃赤蘚戊糖基）-5_碘尿嘧啶， 1-(3-去氧·召-D-呋喃赤蘚戊糖基）_5_氰基尿嘧啶， 1-(3·去氧j-D·呋喃赤蘚戊糖基）-5-乙氧羰基尿嘧 啶 (3-去氧-冷-D-呋喃赤蘚戊糖基）-5-胺基幾基尿嘴 啶 K3-去氧·点-D-呋喃赤蘚戊糖基）-5-乙醯基尿喷咬， 丨 1-(3·去氧-召-D-呋喃赤蘚戊糖基）_5_甲基尿♦哈， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 --------------------訂---------^ (請先閱讀背面之注意事項再填寫本頁) 189 A7 1293306 五、發明說明（190 ) 1-(3·去氧呋喃赤蘚戊糖基）_5_乙基尿嘧啶， 1-(3-去氧-石-D-呋喃赤蘚戊糖基卜弘正丙基尿嘧啶， 1-(3-去氧-呋喃赤蘚戊糖基）_弘異丙基尿嘧啶， 1-(3-去氧-召-D-呋喃赤蘚戊糖基）_5_乙烯基尿嘧啶， 1-(3-去氧-点_D_呋喃赤蘚戊糖基）-5_烯丙基尿嘧啶， 1-(3·去氧_沒_D-呋喃赤蘚戊糖基）-5_乙炔基尿嘧啶， 1-(3-去氧-召-D-呋喃赤蘚戊糖基）-5_(2_氯乙烯基）尿 1-(3-去氧-召-D·呋喃赤蘚戊糖基）_5_(2_溴乙烯基）尿 嘧啶， 1-(3-去氧-yS -D-呋喃赤蘚戊糖基）-5-(2-碘乙烯基）尿 癌咬， 1-(3-去氧-召_D-呋喃赤蘚戊糖基）_5_(2_甲氧羰基乙烯 基）尿嘴咬， 1-(3-去氧-点-D-呋喃赤蘚戊糖基）-5-(2_羥基羰基乙烯 基）尿喊唆， 1-(3-去氧·召-D-呋喃赤蘚戊糖基）_5_苯基尿嘧啶， 1_(3-去氧-冷-D-呋喃赤蘚戊糖基）_5_苄基尿嘧啶， 1-(3-去氧-呋喃赤蘚戊糖基）胞嘧啶， 1-(3-去氧，冷-D-呋喃赤蘚戊糖基）_5_氟胞嘧啶， 1-(3-去氧·冷-D-呋喃赤蘚戊糖基）_%氯胞嘧啶， 1-(3-去氧-冷-D-呋喃赤蘚戊糖基）_5_溴胞嘧啶， 1_(3_去氧-召-D-呋喃赤蘚戊糖基）_5_蛾胞嘲咬， 卜(3-去氧-沒-D-呋喃赤藓戍糖基）_5_氦篡腧嘧说， 本紙張尺度過用中國國豕標準（CNS)A4規格（210 X 297公髮） 91949 (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 190 1293306 A7 B7 五、發明說明（191 ) 1-(3-去氧-沒-D-呋喃赤蘚戊糖基）_5_乙氧羰基胞嘧 咬， 1-(3-去氧-々-D-呋喃赤蘚戊糖基）胺基羰基胞嘧 0定， 1-(3-去氧-点呋喃赤蘚戊糖基）_5_乙醯基胞嘧啶， 1_(3_去氧-点-D-呋喃赤蘚戊糖基）甲基胞嘧啶， 1-(3-去氧-沒_D-呋喃赤蘚戊糖基）_5_乙基胞嘧啶， 1-(3-去氧-石-D-呋喃赤蘚戊糖基）正丙基胞嘧啶， 1-(3·去氧-点-D-呋喃赤蘚戊糖基）_5-異丙基胞嘧啶， 1-(3-去氧-点-D-呋喃赤蘚戊糖基）_5_乙烯基胞嘧啶， 1-(3-去氧-点-D-呋喃赤蘚戊糖基兴5-烯丙基胞嘧啶， 1_(3_去氧-石_〇_呋喃赤蘚戊糖基）_5_乙炔基胞嘧啶， 1-(3-去氧_D-呋喃赤蘚戊糖基）-5-(2-氯乙烯基）胞 1-(3-去氧-点-D-呋喃赤蘚戊糖基&gt;5-(2_溴乙烯基）胞 1_(3_去氧·点-D-呋喃赤蘚戊糖基）_5_(2_碘乙烯基）胞 1-(3-去氧-D-呋喃赤蘚戊糖基）-5_(2-甲氧羰基乙烯 基）胞嘧啶， 1-(3·去氧-石_D-呋喃赤蘚戊糖基）_5-(2_羥基羰基乙烯 基）胞嘴咬， 1_(3_去氧_々-D-呋喃赤蘚戊糖基）苯基胞嘧啶， _去氧-D-呋喃赤蘚戊糖基）_5_苄基胞嘧噔， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公复） 91949 (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 訂-------------------------------- 191 A7 1293306 __ B7_— —___ 五、發明說明（192 ) 1-(3-去氧-沒-D-咲喃赤蘚戊糖基）-2·氣腺嗓吟， 1-(3_去氧-石-D-呋喃赤蘚戊糖基）-6 -氯嗓呤， 1-(3-去氧-召-D-咲喃赤蘚戊糖基）-2,6-二氣嗓吟， 1_(3_去氧-召-D-呋喃赤蘚戊糖基）-2、乙醯胺基-6_氯嗓 σ令 ， 1-(3-去氧-泠-D-咲喃赤蘚戊糖基）-2-乙醯胺基_6-甲氧 基嘌呤， 1-(3-去氧-召-D-咲喃赤蘚戊糖基）_6-甲氧基嗓吟，盘 1-(3-去氧-泠-D-呋喃赤蘚戊糖基）-6-甲基氫硫基嗓 υφ&quot; 〇 實例35 · 1-(2,5-二-0 -乙醯基-3-0-甲橫醯基-石-D-H夫嗔木糖基）_5 氟尿癌咬, invention description (189) structure. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed ^93306 L (3-deoxy-callo-D-furan erythroside glucoside) _5_fluoropyrimidine (3,_deoxy_5-fluorouridine, 6b, X =〇H,R=F) Take the acetamino derivative containing (39) (χ==〇Η, Z=F, 3 3 g, 〇〇1 mol) and diethylamine (3 liters) The mixture of methanol (1 mL) was stirred at room temperature overnight. The mixture was concentrated to dryness in vacuo, and the residue was crystallized from ethanol to give 3 -deoxy-5-fluoroacetatrione nucleus (2 gram, μ%) mp 169-171 °C · worm (D6-DMSO) δ : 11·7 (bs,1Η,Ν3·Η, exchangeable), &amp;44 (屯1Η,Η«6, J6,F= 7·1 Hz), Μ (4 1Η, 2,-〇Η, can Exchange), 5·5 (narrow peak mm Hl,), 5.3 ft 13⁄4 5,-〇Η, exchangeable), 4·14·5 (m, 2Η, Η·2, and Η4,) 3 5.,3 9 m, 2H, H-5,, 5, % 1.6-2.2 (m, 2H, H-3,, 3, 〇· , ·, according to similar methods 'but use the corresponding 2, 5, _ 2醯•Acetyl-pyrimidine and purine nucleoside, the following 3,-deoxynucleoside and its L_enantiomer are prepared: 1_(3_deoxy-^-D-furan erythrosyl pentose)_5_ urinary Pyrimidine, 1-(3-deoxyfuran erythrosyl pentose)_5_bromouracil, 1-(3-deoxy-callo-D-furylerythrosyl)-5-iodouracil, 1- (3-deoxy·call-D-furan erythrosyl pentose)_5-cyano uracil, 1-(3·deoxyjD·furan erythrosyl pentose)-5-ethoxycarbonyl uracil (3 -deoxy-cold-D-furan erythrosyl pentose)-5-amino-based guanidine K3-deoxy-dot-D-furan erythropentyl )-5-Ethyl-based urinary squirting, 丨1-(3·deoxy-callo-D-furan erythrose pentose) _5_methyl urinary ♦ Ha, this paper scale applies to China National Standard (CNS) A4 Specifications (210 X 297 mm) 91949 -------------------- Order ---------^ (Please read the notes on the back and fill in This page) 189 A7 1293306 V. INSTRUCTIONS (190) 1-(3·deoxyfuran erythrosyl pentose)_5_ethyl uracil, 1-(3-deoxy-stone-D-furan erythrin Glycosyl hong propyl uracil, 1-(3-deoxy-furan erythrosyl pentose) _ isopropyl uracil, 1-(3-deoxy-callo-D-furan erythrose pentose )_5_vinyl uracil, 1-(3-deoxy-dot_D_furan erythrosyl pentose)-5-allyl uracil, 1-(3·deoxy-no-D-furan Indole pentose)-5-ethynyl uracil, 1-(3-deoxy-callo-D-furan erythrosyl pentose)-5_(2-chlorovinyl)-urine 1-(3-deoxy- ～D·furan erythrosyl pentose)_5_(2_bromovinyl)uracil, 1-(3-deoxy-yS-D-furan erythrosyl pentose)-5-(2-iodovinyl ) urine cancer bite, 1-(3-deoxy-callo_D-furan erythrosyl pentose)_5_(2_methoxycarbonyl vinyl) urinary bite 1-(3-deoxy-dot-D-furan erythrosyl pentose)-5-(2-hydroxycarbonylvinyl) urinary sputum, 1-(3-deoxy-callo-D-furan erythroquinone Glycosyl)_5_phenyluracil, 1_(3-deoxy-cold-D-furan erythrosyl pentose)_5-benzyl uracil, 1-(3-deoxy-furan erythrosyl pentose) Cytosine, 1-(3-deoxy, cold-D-furan erythrosyl pentose)_5_fluorocytosine, 1-(3-deoxy-cold-D-furan erythrosyl pentose)_% chlorine Cytosine, 1-(3-deoxy-cold-D-furan erythrosyl pentose)_5_bromocytosine, 1_(3_deoxy-callo-D-furan erythrosyl pentose)_5_moth Mocking, Bu (3-deoxy-no-D-furan erythroside) _5_ 氦篡腧 说 说, this paper scale used China National Standard (CNS) A4 specifications (210 X 297 metric) 91949 (Please read the notes on the back and fill out this page) Order---------Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 190 1293306 A7 B7 V. Invention Description (191) 1-( 3-deoxy-no-D-furan erythrosyl pentose)_5_ethoxycarbonylcytosine, 1-(3-deoxy-indole-D-furan erythrosyl) aminocarbonylcytosine Ding, 1-(3-deoxy-dofuran erythroside )_5_ acetyl cytosine, 1_(3_deoxy-dot-D-furan erythrosyl) methylcytosine, 1-(3-deoxy-no-D-furan erythrosyl )_5_ethylcytosine, 1-(3-deoxy-stone-D-furan erythrosyl pentose) n-propyl cytosine, 1-(3·deoxy-dot-D-furan erythrose pentose )5-isopropylcytosine, 1-(3-deoxy-dot-D-furan erythrosyl pentose)_5_vinylcytosine, 1-(3-deoxy-dot-D-furan Pentyl pentose 5-octylcytosine, 1_(3_deoxy-stone_〇_furan erythrosyl pentose)_5_ethynyl cytosine, 1-(3-deoxy-D-furan Indole pentose)-5-(2-chlorovinyl)-cell 1-(3-deoxy-dot-D-furylerythritol pentose group&gt; 5-(2-bromovinyl)cell 1_(3_ Deoxy-dot-D-furan erythrosyl pentose)_5_(2_iodovinyl)-cell 1-(3-deoxy-D-furan erythrosyl pentose)-5_(2-methoxycarbonylvinyl Cytosine, 1-(3·deoxy-stone_D-furan erythrosyl pentose)_5-(2-hydroxycarbonylvinyl) cytotoxin, 1_(3_deoxy-々-D-furan Indole pentyl)phenylcytosine, _deoxy-D-furan erythrosyl pentose)_5_benzylcytosine, this paper scale applies to China National Standard (CNS) A4 Specification (210 X 297) 91949 (Please read the note on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Cooperatives Printed ------------ -------------------- 191 A7 1293306 __ B7_--___ V. Description of invention (192) 1-(3-deoxy-no-D-咲 赤Indole pentose)-2·gas adenine, 1-(3_deoxy-stone-D-furan erythrosyl pentose)-6-chloropurine, 1-(3-deoxy-call-D - 咲 藓 藓 藓 糖 )) -2,6-dione, 1_(3_deoxy-callo-D-furan erythrosyl ,, 1-(3-deoxy-indole-D-indolyl erythrosyl)-2-ethinylamino-6-methoxyindole, 1-(3-deoxy-call-D-咲藓 藓 pentose glycosyl) _6-methoxy oxime, dish 1-(3-deoxy-indole-D-furan erythrosyl pentose)-6-methylhydrothio 嗓υ φ &quot; 〇 Example 35 · 1-(2,5-di-0-ethinyl-3-0-methyl fluorenyl-stone-DH xylinyl)_5 Fluorosis

取含5 -氟尿喷唆（0.02莫耳）、硫酸銨（約3〇毫克）之六 甲基二碎胺燒（15毫升）混合物回流至得到澄清溶液止。真 空排除溶劑，殘質溶於1，2-二氯.乙烷（20毫升）中，添加含 1，2,5_三-0-乙醯基- 3-0-甲石黃醯基_D-咲喃木糖基（55克， 0.02莫耳）之1，2-二氣乙烷（20毫升）。在此溶液中添加四氯 化錫（5.2克，0·02莫耳），混合物於室溫下攪拌一夜，再於 40至50°C下加熱3小時。添加飽和碳酸氫鈉溶液（4〇毫 升），挽拌至二氧化碳停止釋出為止。混合物經寅式鹽塾過 濾。分離有機層，小心地以飽和碳酸氳鈉溶液（20毫升x 2) 及水（20毫升X 2)洗藤，以硫酸鈉脫水，真空濃縮至乾。殘 質自乙醇中結晶，產生標題產物（62%)。以樣本之NMR 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注咅？事項再填寫本頁) 0 訂---------線· 經濟部智慧財產局員工消費合作社印製 192 A7 1293306 B7 五、發明說明（l93 ) 光譜符合指定之結構式。 (請先閱讀背面之注意事項再填寫本頁) 依類似方法，但改用相應之嘧啶與嘌呤驗基，製備下 列2’，5’-二-Ο-乙醯基-3’-經取代之木糠核苷與其L-對映 體：* 1 - ( 2，5 -二-Ο -乙龜基_ 3 - Ο -甲確^酿基-点-D -咲喃木糖 基）-5-氯尿癌咬， 1 - ( 2，5 -二-Ο -乙酿基-3 - Ο -甲確'酿基-D - 喃木糖 基）-5-溴尿嘧啶， 1-(2,5-二-Ο乙醯基-3-0-甲磺醯基-召-D-呋喃木糖 基）-5_破尿嘴淀， 1-(2,5·二_0-乙醯基-3-0-甲磺醯基-卢-D-呋喃木糖 基）-5-氰基尿嘧啶， 1-(2,5-二-0-乙醯基-3-0-甲磺醯基-召-D-呋喃木糖 基）-5 -乙氧幾基尿癌β定， 1-(2,5-二-0_乙醯基-3-0-甲磺醯基-召-D-呋喃木糖 基）-5 -胺基幾基尿定’ 經濟部智慧財產局員工消費合作社印製 1 _( 2，5 -二-Ο -乙酿基-3 - Ο -甲確'酿基-石-D _咲喃木糖 基）-5-乙贐基尿痛咬， 1-(2,5-二-0-乙醯基-3-0-甲磺醯基-召-D-呋喃木糖 基）-5-甲基尿嘧啶， 1 _ ( 2，5 -二-0 -乙釀基_ 3 _ Ο -甲績酿基-/S - D - D夫喃木糖 基）-5-乙基尿嘴咬， 1_(2,5_二-0_乙醯基-3-0-甲磺醯基-召-D-呋喃木糖 基）-5 -正丙基尿癌σ定， 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 193 91949 經濟部智慧財產局員工消費合作社印製 194 1293306 A7 B7 五、發明說明（194 ) 1-(2,5 -二- Ο-乙酿基-3-0-甲石夤酿基-沒-D-咲:喃木糖 基）-5 -異丙基尿癌咬’ 1-(2,5 -二- Ο-乙酿基-3- Ο-甲續酿基_々-D-咲喃木糖 基）-5-乙烯基尿，唆， 1-(2,5-二-Ο-乙醯基-3-0-甲磺醯基-召-D-呋喃木糖 基）-5-浠丙基.尿，唆， 1-(2,5·二-0-乙醯基-3-0-甲磺醯基-召-D-呋喃木糖 基）-5-乙炔基尿癌咬， 1 _( 2，5 -二·0 -乙酸基-3 - 0 -甲績酿基-点-D -咲喃木糖 基）-5-(2-氯乙烯基）尿嘧啶， 1 - ( 2,5 -二-Ο -乙酿基-3 _0 -甲礦蕴基_沒-D -咲喃木糖 基）-5-(2-溴乙烯基）尿嘧咬， 1-(2,5-二-Ο-乙醯基-3-0·甲磺醯基-冷-D-呋喃木糖 基）-5-(2-磺乙烯.基）尿嘧啶， 1·(2,5 -二·0-乙酿基-3_0-甲績酿基-万-D-咲喃木糖 基）-5-(2-甲氧羰基乙烯基）尿嘧啶， 1-(2,5_二-0-乙酿基-3-0-甲績酿基-yS -D-口夫喃木糖 基）-5-(2-羥基羰基乙烯基）尿嘧啶， 1 - ( 2，5 -二-0 -乙酿基-3 - 0 -甲績酿基_万-D _咲喃木糖 基）-5-苯基尿嘧啶， 1 - ( 2，5 _二_ Ο -乙酿基· 3 - Ο -甲續酿基-- D -咲喃木糖 基）-5-苄基尿嘧啶， 1-(2,5-二-0-乙醯基-3-0·甲磺醯基-召-D-呋喃木糖 基）-5-氟胞嘴咬， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) — — — — — — — — — — I — n — — — — — — — — — — — H — — — — — — A7 1293306 B7__ 五、發明說明（195 ) 1 - ( 2，5 -二-Ο -乙酿基 3 - Ο -甲石黃釀基-々-D - D夫喃木糖 基）-5-氯胞嘧啶， 1 - (2，5 -二-Ο·乙酿基-3 - Ο -甲罐^釀基-D - 口夫喃木糖 基）-5 -溴胞嘴咬， 1 - ( 2，5 -二-Ο -乙酸基-3 - Ο -甲續'酿基-卢-D -咲喃木糖 基）-5-碘胞嘧啶， 1-(2,5 -二-0-乙酿基-3 - Ο -甲績酿基-点-D - 口夫喃木糖 基）-5-氰基胞，咬， 1 - ( 2，5 -二-Ο -乙酿基-3 - Ο -甲續'酿基-/8 - D -咲喃木糖 基）-5 -乙氧魏基胞齋咬’ 1-(2,5-二-0-乙醯基-3-0-甲磺醯基-点-D-呋喃木糖 基）-5 -胺基幾基胞癌唆’ 1_(2,5_二-0-乙醯基-3_0-甲磺醯基-沒-D-呋喃木糖 基）-5-乙醯基胞嘧啶， 1-(2,5_二-0-乙酿基-3_0-甲石黃釀基-万-D-吹喃木糖 基）-5-甲基胞嘧啶， 1-(2,5-二-0-乙醯基-3-0-甲磺醯基-召-D-呋喃木糖 基）-5-乙基胞癌咬’ 1-(2,5-二_0-乙醯基-3-0-甲磺醯基-点-D-呋喃木糖 基）-5-正丙基胞嘧啶， 1 - ( 2，5 -二-Ο -乙酿基-3 - Ο -甲續^酿基-万_ D -咲喃木糖 基）-5-異丙基胞嘧啶， 1-(2,5-二-0-乙醯基-3-0-甲磺醯基-沒-D-呋喃木糖 基）-5-乙烯基胞嘧啶， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) -禳 訂---------線· 經濟部智慧財產局員工消費合作社印製 195 A7 1293306 _B7_ 五、發明說明（196 ) 1-(2,5-二-0-乙醯基_3-0•甲磺醯基-冷-D-呋喃木糖 基）-5-烯丙基胞嘧啶， 1_(2,5_二_0-乙醯基-3-0-甲磺醯基-冷-D-呋喃木糖 基）-5-乙炔基胞嘧啶， 1 - ( 2，5 -二-Ο -乙酿基-3 - Ο -甲頌'釀基-万-D - 口夫喃木糖 基）-5-(2-氯乙稀基）胞,σ定’ 1_(2,5_二_0-乙醯基-3-0-甲磺醯基-石-D-呋喃木糖 基）-5-(2 -&gt;臭乙稀基）胞嘴咬’ 1-(2,5-二-0-乙醯基-3-0-甲磺醯基_召-D-呋喃木糖 基）-5-(2-職乙稀基）胞,ϋ定’ 1-(2,5-二-0-乙醯基-3-0-甲磺醯基-D-呋喃木糖 基）-5-(2-甲氧羰基乙烯基）胞嘧啶， 1_(2,5_二-0-乙醯基-3-0-甲磺醯基-/3 -D•呋喃木糖 基）-5-(2-經基幾基乙稀基）胞喊咬’ 1-(2,5-二-Ο-乙醯基-3-0-甲磺醯基-冷-D-呋喃木糠 基）-5-苯基胞嘧啶， 1 - ( 2，5 -二-Ο -乙酿基-3 _0 -甲續^酿基-点-D -咲味木糖 基）-5-〒基胞嘧啶， 1 - ( 2，5 -二-Ο -乙釀基-3 - 0 -甲續^釀基-点_ D -咲喃木糖 基）-N6-苯甲醯基腺嘌呤， 1-(2,5-二-Ο-乙醯基-3-0-甲磺醯基-石_D-呋喃木糖 基）-6-氯嘌呤， 1-(2,5-二-0-乙醯基-3_0-甲磺醯基-召-D-呋喃木糖 基）-2,6-二氣嘌呤， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 -------------4--------^---------^ 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 196 1293306 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（197 ) 1·(2,5_二-0_乙醯基-3-0-甲磺醯基-冷-D-呋喃木糖 基）· 2 -乙蕴胺基-6 -乳u票岭’ 1-(2,5-二-0-乙醯基-3-0甲磺醯基-D•呋喃木糖 基）-2-乙醯胺基-6-甲氧基嘌呤， 1 - ( 2，5 -二· 0 -乙酿基-3 _ 0 -甲績酿基-万-D -咲喃木糖 基）-6-甲氧基嘌呤， 1 - ( 2，5 -二_ 0 _乙酿基-3 - 0 •甲續^酿基-点-D _ 口夫喃木糖 基）-6 -甲基氮硫基1^票11令’ 1-(2,5-二-0-乙醯基-3-0-甲苯磺醯基-点-D-呋喃木糖 基）-5-氣尿嘧啶， 1-(2,5 -二-0-乙酿基_ 3 - Ο -甲苯續酿基-石-D -咲喃木糖 基）-5-溴尿嘴淀， 1-(2,5-二-0-乙醯基-3-0·甲苯磺醯基-点-D-呋喃木糖 基）-5-埃尿癌唆， 1-(2,5-二-0-乙醯基·3_0-甲苯磺醯基-沒-D-呋喃木糖 基）-5-氰基尿喊咬， 1 - ( 2，5 -二-0 -乙酸基-3 - 0 -甲苯確酿基-々-D -咲喃木糖 基）-5 -乙氧幾基尿喊咬’ 1-(2,5-二-0-乙醯基-3-0-甲苯磺醯基-石-D-呋喃木糖 基）-5-胺基羰基尿嘧啶， 1 - ( 2，5 -二-0 -乙酿基-3 - Ο -甲苯續^酿基-/5 - D -咲喃木糖 基）-5-乙醢基尿嘴唆， 1-(2,5-二_0-乙醯基-3-0-甲苯磺醯基-召-D-呋喃木糖 基）-5-甲基屎嘧啶， (請先閱讀背面之注意事項再填寫本頁) ·111111 !線#1— 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 197 91949 1293306 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（198 ) 1_(2,5_二-0-乙醯基-3-0-甲苯磺醯基-冷-D-呋喃木糖 基）-5-乙基尿嘧啶， 1·(2,5-二-0_乙醯基-3-0-甲苯磺醯基-冷-D-呋喃木糖 基）-5-正丙基尿嘧啶， 1 - ( 2，5 -二-0 -乙酿基-3 - Ο -甲苯續^酿基-^8 - D ·咲喃木糖 基）-5 -異丙基尿癌e定’ 1 - ( 2，5 -二· Ο -乙酸基-3 - Ο -甲苯確^酿基-yS - D -咲喃木糖 基）-5-乙烯基尿嘧啶， 1-(2,5-二-0-乙醯基-3-0-甲苯磺醯基-召-D-呋喃木糖 基）-5-烯丙基尿嘧啶， 1-(2,5_二-Ο-乙醯基-3-0•甲苯磺醯基-召-D-呋喃木糖 基）-5-乙炔基尿嘧啶， 1-(2,5-二-Ο-乙醯基-3·0-甲苯磺醯基-召-D-呋喃木糖 基）-5-(2-氯乙烯基）尿嘧啶， 1·(2,5-二-0-乙醯基-3_0-甲苯磺醯基-召-D-呋喃木糖 基）-5-(2 -&gt;臭乙稀基）尿癌唆， 1-(2,5_二-0-乙醯基-3-0-甲苯磺醯基-召-D-呋喃木糖 基）-5-(2-碘乙烯基）尿嘧啶， 1 - ( 2，5 _二-0 -乙酿基-3 - Ο -甲苯績酿基-点-D -咲喃木糖' 基）-5-(2-甲氧羰基乙烯基）尿嘧啶， 1_(2,5_二-Ο-乙醯基-3-0甲苯磺醯基-冷-D-呋喃木糖 基）-5-(2-經基羰基乙浠基）尿嘴咬， 1-(2,5-二-0-乙醯基-3-0-甲苯磺醯基-泠-D-呋喃木糖 基）-5-苯基尿嘧啶， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁)A mixture of hexamethyldihydroamine (15 ml) containing 5-fluorourine sputum (0.02 mol) and ammonium sulfate (about 3 mg) was refluxed until a clear solution was obtained. The solvent was removed in vacuo, and the residue was dissolved in 1,2-dichloroethane (20 mL). &lt;RTI ID=0.0&gt;&gt;&gt; 1,2-diethane (20 ml) of xylosyl (55 g, 0.02 mol). To the solution was added tin tetrachloride (5.2 g, 0. 02 mol), and the mixture was stirred at room temperature overnight, and then heated at 40 to 50 ° C for 3 hours. Saturated sodium bicarbonate solution (4 Torr) was added and the mixture was stirred until carbon dioxide ceased to be released. The mixture was filtered through a hydrazine salt. The organic layer was separated, washed with EtOAc EtOAc EtOAc (EtOAc) The residue was crystallized from ethanol to give the title product (62%). For the NMR paper size of the sample, the Chinese National Standard (CNS) A4 specification (210 X 297 mm) is applied. 91949 (Please read the back of the note first, then fill out this page) 0 Order--------- Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 192 A7 1293306 B7 V. Description of Invention (l93) The spectrum conforms to the specified structural formula. (Please read the precautions on the back and then fill out this page.) According to a similar method, but use the corresponding pyrimidine and test groups to prepare the following 2',5'-di-indolyl-3'-substituted Hirudin and its L-enantiomer: * 1 - ( 2,5 -di-fluorene-ethenyl- 3 - fluorene-methyl-branched-dot-D-anthyl)- Chlorothacarcinoma bite, 1 - ( 2,5 -di-indole-ethyl-branched-3 - Ο-methyl-'-bristyl-D-pyridyl)-5-bromouracil, 1-(2,5 - bis-indolyl-3-0-methylsulfonyl-callo-D-furanyl glucosyl)-5_ broken urinary tract, 1-(2,5·di_0-ethenyl-3 -0-Methanesulfonyl-L-D-furanosyl)-5-cyanouracil, 1-(2,5-di-0-ethinyl-3-0-methylsulfonyl-call -D-furanosyl)-5-ethoxyxyl urinary cancer β-, 1-(2,5-di-0-ethinyl-3-0-methylsulfonyl-callo-D-furan Glycosyl)-5-Amino-based uridines' Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed 1 _( 2,5 -di-Ο-乙酿基-3 - Ο-甲确'-bristled-stone- D _ 咲 xylosyl)-5-ethyl hydrazine pain bite, 1-(2,5-di-0-ethinyl-3-0-methylsulfonyl-callo-D-furanyl )-5-methyluracil, 1 _ ( 2,5 -2-0 -B-branched _ 3 _ Ο - A-flavored base -/S - D - D-fucaose) 5--ethyl urinary mouth bite, 1_(2,5_two -0_Ethyl-3-0-methylsulfonyl-callo-D-furanosyl)-5-n-propyluria sigma, this paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 193 91949 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 194 1293306 A7 B7 V. Description of Invention (194 ) 1-(2,5 -Di-Ο-乙酿基-3-0-甲石夤Stuffed base - no -D-咲: 木木糖基)-5-isopropyl urinary cancer bite ' 1-(2,5 -di- Ο-ethyl aryl-3- Ο-甲 酿 基 _ 々 - D-pyrumolyl)-5-vinylurine, hydrazine, 1-(2,5-di-indole-ethenyl-3-0-methylsulfonyl-callo-D-furanosyl) -5-浠propyl.Urine, hydrazine, 1-(2,5·di-O-ethylindol-3-0-methylsulfonyl-callo-D-furanosyl)-5-ethynyl urinary Cancer bite, 1 _( 2,5 -2·0-acetoxy-3 - 0 -methyl-branched-dot-D-purpuryl) 5-(2-chlorovinyl)uracil, 1 - ( 2,5 -di-anthracene-ethyl-branched-3 _0-methyl ore-based _----pyrylmyl)-5-(2-bromovinyl) uracil, 1-(2 ,5-di-Ο-ethinyl-3-0· Sulfhydryl-cold-D-furanoxyl)-5-(2-sulfoethyl.) uracil, 1·(2,5-di-0-ethyl-branched-3_0-A-flavor-based -D-purine xylosyl)-5-(2-methoxycarbonylvinyl)uracil, 1-(2,5-di-0-ethyl-branyl-3-0-methyl-branched-yS- D-mouth xylosyl)-5-(2-hydroxycarbonylvinyl)uracil, 1 - (2,5-di-0-ethyl-branched-3 - 0 - A-branched _ _-D _ 咲 xylosyl)-5-phenyl uracil, 1 - ( 2,5 _ _ Ο 乙 - ethyl aryl · 3 - Ο - 续 酿 - - D - 咲 xylosyl)-5 -benzyl uracil, 1-(2,5-di-0-ethinyl-3-0.methanesulfonyl-callo-D-furanosyl)-5-fluorocytidine bite, paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 (Please read the back note first and then fill out this page) — — — — — — — — — I — n — — — — — — — — — — — H — — — — — — A7 1293306 B7__ V. INSTRUCTIONS (195 ) 1 - ( 2,5 -Di-Ο-Ethylene 3 - Ο -甲石黄-基-々-D - D Fusaryl glucosyl)-5-chlorocytosine, 1 - (2,5-di-anthracene基-3 - Ο - A cans - Stuffed base - D - Kungfu xylosyl) - 5 - Bromo mouth bite, 1 - ( 2,5 - di-indole - acetate - 3 - Ο - A continued Stuffed base-Lu-D-purine xylosyl)-5-iodocytosine, 1-(2,5-di-0-ethyl-branched-3 - Ο-A-flavored-point-D-manipulator Cyclopyranosyl)-5-cyano, biting, 1 - (2,5-di-indole-ethyl-branched-3 - oxime--continuation of 'bristyl-/8-D-pyrumolyl) -5-Ethoxydicarbyl sulphate' 1-(2,5-di-0-ethinyl-3-0-methylsulfonyl-dot-D-furanosyl)-5-amino group Basal cell carcinoma 1 1 1((2,5_二-0-ethinyl-3_0-methanesulfonyl-no-D-furanyl)-5-acetylcytosine, 1-(2,5 _二-0-乙牛基-3_0-甲石黄毛-万-D- 吹 xylosyl)-5-methylcytosine, 1-(2,5-di-0-ethenyl- 3-0-Methanesulfonyl-C-D-furanosyl)-5-ethylcytocarcinoma bite 1-(2,5-di_0-ethinyl-3-0-methylsulfonyl) -D-F-xylopyranosyl)-5-n-propylcytosine, 1 - (2,5-di-indole-ethyl-branched-3 - oxime-a continued ^bristyl-wan_D-咲Xylose)-5-isopropylcytosine, 1-(2,5-di-0-ethinyl-3-0-methylsulfonyl-dis-D-furanyl)-5- Vinyl cytosine, this paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 (please read the notes on the back and fill out this page) - ---------- Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 195 A7 1293306 _B7_ V. Description of Invention (196) 1-(2,5-Di-O-Ethyl _3-0•Methanesulfonyl-Cold-D -furanoxyl)-5-allylcytosine, 1_(2,5_di_0-ethinyl-3-0-methylsulfonyl-cold-D-furanosyl)-5- Acetylene cytosine, 1-(2,5-di-indole-ethyl-branched-3 - fluorene-methylhydrazine'-branched-wan-D-mouthmanganyl)-5-(2-chloroethylene) )), σ定 ' 1_(2,5_二_0-Ethyl-3-0-methylsulfonyl-stone-D-furanosyl)-5-(2 -&gt; Base) bite bite ' 1-(2,5-di-0-ethinyl-3-0-methylsulfonyl-callo-D-furanosyl)-5-(2-beta) Cell, ϋ定 ' 1-(2,5-di-O-ethenyl-3-0-methylsulfonyl-D-furanosyl)-5-(2-methoxycarbonylvinyl)cytosine , 1_(2,5_di-0-ethinyl-3-0-methylsulfonyl-/3-D-furanyl)-5-(2-ylaminoethyl) Bite ' 1-(2,5- Di-indole-ethenyl-3-0-methanesulfonyl-cold-D-furanyl)-5-phenylcytosine, 1 - (2,5-di-indole-ethene-3 _0 - A continued ^ brewing base - point - D - astringent xylose) - 5 - thiol cytosine, 1 - ( 2,5 - di- Ο - ethyl aryl -3 - 0 - A continued -dot_D-pyrumolyl)-N6-benzhydryl adenine, 1-(2,5-di-indole-ethenyl-3-0-methylsulfonyl-stone-D-furan Xylose)-6-chloropurine, 1-(2,5-di-0-ethinyl-3_0-methylsulfonyl-callo-D-furanosyl)-2,6-dione, This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 -------------4--------^------- --^ I (please read the notes on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees of the Ministry of Economic Affairs 196 1293306 A7 B7 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives Printed V. Inventions (197) 1· (2,5_二-0_Ethyl-3-0-methylsulfonyl-cold-D-furanyl)) 2 -Ethylamino-6-乳乌票岭' 1-(2 ,5-di-O-ethylindol-3-0-methylsulfonyl-D-furanose)-2-ethinylamino-6-methoxyindole, 1 - (2,5-di· 0 - B Styrene-3 _ 0 - A-flavored-based-wan-D-anthyl xylosyl)-6-methoxy oxime, 1 - ( 2,5 -di _ 0 _ ethoxylated-3 - 0 • A Continuation of the base - point - D _ koufu xylosyl) -6 - methyl thiazyl 1 ^ votes 11 order ' 1- (2,5-di-0-ethyl fluorenyl-3-0-toluene Sulfosyl-dot-D-xylopyranosyl)-5-aerouracil, 1-(2,5-di-0-ethyl-branched- 3 - fluorene-toluene-branched-stone-D-furan Xylose)-5-bromo urinal, 1-(2,5-di-0-ethinyl-3-0-toluenesulfonyl-d-d-furanyl)-5-emergence Carcinoma, 1-(2,5-di-0-ethinyl·3_0-toluenesulfonyl-no-D-furanosyl)-5-cyanourine shout, 1 - ( 2,5 - Di-2-O-acetoxy-3-0-toluene-branched-indole-D-purinyl xylyl)-5-ethoxy group urinary shouting ' 1-(2,5-di-0-acetylene) Benzyl-3-0-toluenesulfonyl-stone-D-xylopyranosyl)-5-aminocarbonyl uracil, 1 - ( 2,5 -di-0-ethyl-branched-3 - fluorene-toluene ^ Stucco-/5 - D - mercapto-based) 5-ethoxylated urinary guanidine, 1-(2,5-di-oxo-ethenyl-3-0-toluenesulfonyl-call -D-furanosyl)-5-methylpyrimidine, (please read the precautions on the back and fill out this ·111111 !线#1— This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 197 91949 1293306 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (198) 1_ (2,5-di-0-ethylindol-3-0-toluenesulfonyl-cold-D-furanyl)-5-ethyluracil, 1·(2,5-two-0_ Ethyl-3-O-toluenesulfonyl-cold-D-furanosyl)-5-n-propyl uracil, 1 - ( 2,5 -di-0-ethyl-branched-3 - Ο - Toluene continuation - 88 - D · 咲 xylenyl) - 5 - isopropyl urinary cancer e ding ' 1 - ( 2,5 - di· Ο - acetate -3 - Ο - toluene ke-yS-D-anthoxylyl)-5-vinyl uracil, 1-(2,5-di-0-ethinyl-3-0-toluenesulfonyl-callo-D-furan Glycosyl)-5-allyluracil, 1-(2,5-di-indole-ethenyl-3-0-toluenesulfonyl-callo-D-furanosyl)-5-ethynyl Uracil, 1-(2,5-di-indole-ethenyl-3·0-toluenesulfonyl-callo-D-furanosyl)-5-(2-chlorovinyl)uracil, 1 ·(2,5-di-0-ethylindolyl-3_0-toluenesulfonyl-callo-D-furanosyl)-5-(2 -&gt; stinky) urinary cancer唆, 1-(2,5_di-0-ethinyl-3-0-toluenesulfonyl-callo-D-furanosyl)-5-(2-iodovinyl)uracil, 1 - ( 2,5 _2-0-ethyl-branched-3 - fluorene-toluene-branched-dot-D-pyroside) keto-5-(2-methoxycarbonylvinyl)uracil, 1_( 2,5-di-indole-ethenyl-3-0-toluenesulfonyl-cold-D-furanosyl)-5-(2-carbamoylidene) urinary bite, 1-(2 ,5-di-0-ethylindol-3-0-toluenesulfonyl-indole-D-furanosyl)-5-phenyluracil, this paper scale applies to China National Standard (CNS) A4 specification ( 210 X 297 mm) (Please read the notes on the back and fill out this page)

P 訂---------線· 198 91949 A7 1293306 B7__ 五、發明說明（199 ) 1-(2,5-二-Ο-乙醯基-3-0-甲苯磺醯基-沒-D-咲喃木糖 基）-5-苄基尿嘧啶， 1-(2,5-二-Ο-乙醯基·3-0-甲苯磺醯基-召_D-呋喃木糖 基）-5-氟胞嘧啶， 1 - ( 2，5 -二-Ο -乙酿基-3 ·0 -甲苯績龜基•点-D - 口夫喃木糖 基）-5-氯胞嘧啶， 1-(2,5-二-0-乙醯基-3-0-甲苯磺醯基-召-D-呋喃木糖 基）-5 - &gt;臭胞,σ定’ 1-(2,5-二-0-乙醯基-3-0-甲苯磺醯基-召-D-呋喃木糖 基）-5-埃胞鳴咬， 1-(2,5-二-Ο-乙醯基-3-0-甲苯磺醯基-召-D-呋喃木糖 基）-5 -鼠基胞♦咬’ 1-(2,5-二-Ο-乙醯基-3-0-甲苯磺醯基-召-D-呋喃木糖 基）-5-乙氧羰基胞嘧啶， 1-(2,5-二-Ο-乙醯基-3-0-甲苯磺醯基-召-D-呋喃木糖 基）-5 -胺基幾基胞癌咬， 1-(2,5-二-0-乙醯基-3-0•甲苯磺醯基-召-D-呋喃木糖 基）-5-乙醯基胞嘧啶， 1-(2,5-二_0_乙酿基_3-0_甲苯績酿基-万-D-咲喃木糖 基）-5-甲基胞嘴咬， 1_(2,5_二-Ο-乙醯基_3_0-甲苯磺醯基-召-D-呋喃木糖 基）-5 -乙基胞癌σ定’ 1-(2,5-二-0-乙醯基-3-0-甲苯磺醯基-召-D-呋喃木糖 基）_5_正丙基胞嘧啶， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) .0 訂---------線—康 經濟部智慧財產局員工消費合作社印製 199 A7P Order---------Line· 198 91949 A7 1293306 B7__ V. Description of Invention (199 ) 1-(2,5-Di-indole-ethenyl-3-0-toluenesulfonyl-no -D-indolyl)-5-benzyl uracil, 1-(2,5-di-indole-ethenyl·3-0-toluenesulfonyl-callo-D-furanyl) -5-Fluorocytosine, 1 - ( 2,5 -di-indole-ethyl-branched -3 · 0 -toluene-turmeric base - point-D - oral fumonyl)-5-chlorocytosine, 1 -(2,5-di-0-ethinyl-3-0-toluenesulfonyl-callo-D-furanosyl)-5 - &gt; stinky cell, σ定' 1-(2,5- 2-O-ethylindol-3-0-toluenesulfonyl-callo-D-furanosyl)-5-epione, 1-(2,5-di-indole-ethenyl-3 -0-toluenesulfonyl-callo-D-furanosyl)-5-murine cytokines ♦ bite 1-(2,5-di-indole-ethenyl-3-0-toluenesulfonyl- -D-furanoxyl)-5-ethoxycarbonylcytosine, 1-(2,5-di-indole-ethenyl-3-0-toluenesulfonyl-callo-D-furanyl )-5-Amino-based cell carcinoma bite, 1-(2,5-di-0-ethinyl-3-0-toluenesulfonyl-callo-D-furanosyl)-5-acetamidine Cytosine, 1-(2,5-di-#-ethylidene_3-0_toluene-wan-D-anthyl xylosyl)-5-methyl Mouth biting, 1_(2,5_di-indole-ethenyl_3_0-toluenesulfonyl-callo-D-furanosyl)-5-ethylcytosine sigma ' 1-(2,5- 2--0-Ethyl-3-O-toluenesulfonyl-callo-D-furanyloxy)_5_n-propylcytosine, this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 91949 (Please read the notes on the back and fill out this page) .0 Book---------Line-Ken Economics Department Intellectual Property Bureau Staff Consumer Cooperative Printed 199 A7

1293306 五、發明說明（200 ) 1-(2,5-二-0-乙醯基-3-0-甲苯磺醯基-沒_D-呋喃木糖 基）-5-異丙基胞痛唆， 1-(2,5_ — - 乙醯基- 3-0 -甲苯磺醯基-点-D-咲喃木糖 基）-5-乙烯基胞嘧啶， 1_(2,5_二_0乙醯基-3_〇-甲苯磺醯基一石-D_呋喃木糠 基）-5 -稀丙基胞喊唆， 1-(2,5-二-0·乙醯基-3-0-甲苯磺醯基-召-D-呋喃木糖 基）-5-乙炔基胞嘧啶， 1-(2,5-二-0-乙醯基-3-0-甲苯磺醯基-D·呋喃木糠 基）-5-(2-氣乙稀基）胞喷咬， 一- 0_乙酿基_3_〇 -甲苯續酿基-泠-D-口夫喃木糖 基）-5-(2-溴乙烯基）胞嘧啶， 1-(2,5-二-0-乙醯基-3-0-甲苯磺醯基-点-D-呋喃木糖 基）-5-(2-埃乙稀基）胞癌咬， 1-(2,5-二-0-乙醯基-3-〇_甲苯磺醯基-点-D_呋喃木糖 基）-5-(2-甲氧羰基乙烯基）胞嘧啶， 1-(2,5-二_0-乙醯基-3-0-甲苯磺醯基-召-D-呋喃木糖 基）-5-(2-羥基羰基乙烯基）胞嘧啶， 1-(2,5_二-0-乙醯基_3_〇_甲苯磺醯基-召-D-咲喃木糠 基）_5_苯基胞癌咬， 1-(2,5-二_0-乙醯基·3-0_甲苯磺醯基万-D_呋喃木糠 基）-5-T基胞嘴咬， 1·(2,5_二-0-乙醯基-3-0-甲苯磺醯基·召-D-呋喃木糖 基）-Ν6-苯甲醯基腺嘌呤， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 f靖先閱讀背面之&gt;i音？事項再填寫本頁) 一--------訂---------線· 經濟部智慧財產局員工消費合作社印製 200 A7 1293306 五、發明說明（2〇l ) 1-(2,5-二_〇_乙醯基小〇 基）-6-氯嗓呤’ 以酿基ID-㈣木糖 1_(2,5_二-〇_ 乙醯基-3_〇_ 甲 基）-2,6-二氯嗓呤， 本4基+D-咲鳴木糖 1-(2,5-二 _〇-乙醯基-3-〇_ 基)-2-乙醯胺基-6-氯嗓吟，㈣醯基+D-呋喊木糖 1-(2,5-二_〇_ 乙醯基_3_〇_ 甲直 基）-2-乙醯胺基_6_甲氧基嗓呤，S醯基·石_D·呋喃木糖 乙酿基_3_〇_甲笨續 基）-6-甲氧基嘌呤，與 不糖 Η2,5-二-0-乙酿基·3_〇_甲苯續 基）-6-甲基氫硫基嘌呤。 Ρ υ天嗝木糖 實例36 卜⑽-三办乙酸基l南木糖基)胸腺⑽ 取3胸腺料(0则耳)、硫 3 基二矽胺烷(15毫升)之混合物 、克)之，、’1293306 V. INSTRUCTIONS (200) 1-(2,5-Di-O-ethenyl-3-0-toluenesulfonyl-non-D-furanosyl)-5-isopropylcytosine , 1-(2,5_ — -Ethyl- 3-0-toluenesulfonyl-dot-D-indolyl)-5-vinylcytosine, 1_(2,5_二_0乙Mercapto-3_〇-toluenesulfonyl-stone-D_furanylsulfonyl)-5-dilylpropyl sulfonium, 1-(2,5-di-0-ethinyl-3-0-toluene Sulfosyl-callo-D-furanosyl)-5-ethynylcytosine, 1-(2,5-di-O-ethenyl-3-0-toluenesulfonyl-D·furan raft Base)-5-(2-ethylenediyl) cell blasting, one- 0_ethyl aryl _3_〇-toluene flavonyl-泠-D-mouth xylosyl)-5-(2 -bromovinyl)cytosine, 1-(2,5-di-0-ethinyl-3-0-toluenesulfonyl-d-d-furanyl)-5-(2-Ethylene) Cell carcinoma bite, 1-(2,5-di-0-ethinyl-3-indole-toluenesulfonyl-d-d-furanyl)-5-(2-methoxycarbonylvinyl Cytosine, 1-(2,5-di_0-ethinyl-3-0-toluenesulfonyl-callo-D-furanosyl)-5-(2-hydroxycarbonylvinyl)cytosine , 1-(2,5_二-0-Ethyl)_3_〇_Toluenesulfonyl-Call-D-咲糠基)_5_phenyl cell carcinoma bite, 1-(2,5-di-oxo-ethenyl·3-0-toluenesulfonyl-D-furanyl)-5-T base Bite, 1·(2,5_2-0-ethinyl-3-0-toluenesulfonyl-callo-D-furanyl)-Ν6-benzhydryl adenine, this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 f Jing Xian read the back of the &gt;i tone? Matters fill out this page) I--------Book---------Line· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 200 A7 1293306 V. Invention description (2〇l) 1 -(2,5-di-〇_Ethyl hydrazino)-6-chloroindole' as the base ID-(iv) xylose 1_(2,5_di-〇_ 醯 -3-3_〇_ Methyl)-2,6-dichloropurine, this 4 base + D- 咲 木 xylose 1-(2,5-di-indole-ethenyl-3-indoleyl)-2-acetamide Base-6-chloropurine, (iv) fluorenyl + D-furose xylose 1-(2,5-di-[indolyl]-indenyl_3_〇_methyl-methyl)-2-ethinylamino-6 _Methoxy oxime, S 醯 ·············································· Ethyl alcohol · 3_〇_toluene hexyl)-6-methylhydrosulfanyl hydrazine. Ρ υ υ 嗝 嗝 实例 实例 实例 36 36 36 36 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ,, '

古处秘W W杰, 口机至件到澄清溶液為止C 真空排除洛劑，殘質溶於i ^ w? . 5 ^ n 〜氟乙烷（20毫升）中，添办 3 (，’二’Ο.乙酿基各吹喃木糖（5.5克，0.02莫耳）々 U-一乳乙燒(20毫升在溶液中添加四氣化錫(52克， 〇.〇2莫耳)，混合物於室溫下攪拌一夜後，於4〇至π。。 加熱3小時’添加飽和碳酸氫鈉溶液(4〇毫升卜攪拌至_ 氧化礙停止釋出為止。混合物經寅式鹽塾過濾，分離有相 層’小心地以飽和碳酸氫鈉溶液（2〇毫升χ2)與水（2〇毫力 丨X 2)洗滌’以硫酸鈉脫水及真空濃縮至乾。殘質自乙醇 本紙張尺度_ + _家標準（CNS)A4規格（210 X 297公髮、---&quot;— -^ (請先閱讀背面之注音？事項再填寫本頁) •a 線丨·· 經濟部智慧財產局員工消費合作社印製 201 91949 A7 1293306 -------— _ 五、發明說明（202 ) 結晶（4.3纟’ 62%)’此樣本之1ην·光譜符合所指定之 結構式。 依類似方法，但改用相應之嘧啶與嘌呤鹼基，製備下 列2’，5’-二-0_乙醯基3，-經取代之木糖核苷與其L_對映 體： 1-(2,3,5-三·〇-乙醯基-点呋喃木糖基）_5_氟尿嘧 啶， 1-(2,3,5_三-〇_乙醯基_D_呋喃木糖基）_5_氯尿嘧 口定， 1-(2,3,5-三-〇-乙醯基-点_1^呋喃木糖基）_5_溴尿嘧 唆， 1-(2,3,5-二乙醯基_D-呋喃木糖基）_5_職尿嘧 啶， 1-(2,3,5-三-〇-乙醯基_D_呋喃木糖基卜5-氰基尿嘧 咬， 1-(2,3,5-二乙醯基-点-D-呋喃木糖基）_5•乙氧羰基 尿癌咬， 1-(2,3,5-三-〇-乙醯基-沒-D-呋喃木糖基）_5_胺基羰基 尿癌0定， 1-(2,3,5-三-0-乙醯基-D-D夫喃木糖基）-5-乙醯基尿 1-(2,3,5·三-0_乙醯基-卢-D-D夫喃木糠基）_5•甲基尿癌 啶， 1_(2,3,5-三·0-乙醯基-泠-D-D夫喃木糖基）_5_乙基尿嘧 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公-- 91949 (請先閱讀背面之注音？事項再填寫本頁) -------訂---------線—一 經濟部智慧財產局員工消費合作社印製 202 1293306 A7 B7 五、發明說明（203 ) 啶， 1-(2,3,5-三-Ο-乙醯基-点-D-呋喃木糖基）-5-正丙基尿 1-(2,3,5_三-0-乙酿基-万-D -咲喃木糖基）-5 -異丙基尿 癌咬， 1-(2,3,5 -三-0-乙酿基-万-D -咲喃木糖基）-5 -乙稀基尿 1-(2,3,5 -三-0-乙酿基-万-D -咲喃木糖基）-5 -稀丙基尿 癌TJ定， 1-(2,3,5-三·0-乙醯基-yS -D-呋喃木Α糖基）_5_乙炔基尿 1-(2,3,5-三-0-乙醯基-召-D-呋喃木糖基）-5-(2-氣乙烯 基）尿癌σ定， 1-(2,3,5 -三- Ο-乙酿基-yS -D-唉喃木糖基）-5-(2-&gt;臭乙稀 基）尿癌唆， 1-(2,3,5 -三-0-乙酿基-D -咲喃木糖基）-5-(2 -破乙稀 基）尿嘴咬， 1-(2,3,5-三-0-乙醯基-冷-D-呋喃木糖基）-5-(2-甲氧羰 基乙烯基）尿癌咬， 1-(2,3,5-三-0-乙醯基-召-D-呋喃木糖基）-5-(2-羥基羰 基乙浠基）尿α密咬， 1-(2,3,5-三-0-乙醯基·点-D-呋喃木糖基）-5-苯基尿嘧 啶， 1-(2,3,5-三-0-乙酿基_点-〇-咲喃木糖基）-5-卞基尿, 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 203 91949 (請先閱讀背面之注意事項再填寫本頁) 訂--------- 線丨_ 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制衣 1293306 A7 B7 五、發明說明（204 ) 啶， 1-(2,3,5-三-0-乙醯基-点-D-呋喃木糖基）-5-氟胞嘧 咬， 1-(2,3,5-三-0-乙醯基-点-〇-呋喃木糖基）-5-氯胞嘧 啶， 1-(2,3,5-三-0-乙醯基-点-D-呋喃木糖基）-5-溴胞嘧 淀， 1-(2,3,5_三-0-乙酿基-万-D -咲喃木糖基）-5_破胞癌 口定， 1-(2,3,5-三-Ο-乙醯基-石-D·呋喃木糖基）-5-氰基胞嘧 °定， 1-(2,3,5-三-Ο-乙醯基-召-D-呋喃木糖基）·5-乙氧羰基 胞癌唆， 1-(2,3,5 -三- Ο-乙酿基-点-D-D夫喃木糖基）-5-胺基魏基 胞嘧啶， 1-(2,3,5-三-Ο-乙醯基-万-D-呋喃木糖基）-5-乙醯基胞 1-(2,3,5-三-0-乙醯基-yS -D-呋喃木糖基）-5_甲基胞嘧 啶， 1-(2,3,5-三-Ο·乙醯基-万-D-呋喃木糖基）-5-乙基胞嘴 0定， 1-(2,3,5_三-0_乙醯基-召-D-呋喃木糖基）-5-正丙基胞 癌β定， 1-(2,3,5 -三- Ο-乙酿基-点-D -咲喃木糖基）-5 -異丙基胞 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 馨·The ancient secrets WW Jie, the mouth machine to the clear solution until the C vacuum exclusion agent, the residue is soluble in i ^ w? 5 ^ n ~ fluoroethane (20 ml), add 3 (, 'two' Ο. Each of the brewed base is boiled xylose (5.5 g, 0.02 m) 々 U--European B (20 ml of tetra-iron (52 g, 〇.〇2 mol) is added to the solution, the mixture is After stirring at room temperature for one night, at 4 Torr to π. Heating for 3 hours 'added saturated sodium bicarbonate solution (4 〇 ml of stirring until _ oxidization stopped releasing. The mixture was filtered through hydrazine salt, separated phase The layer 'carefully washed with saturated sodium bicarbonate solution (2 mL χ 2) and water (2 Torr 丨X 2). Dehydrated with sodium sulfate and concentrated in vacuo to dryness. Residue from ethanol on paper scale _ + _ home Standard (CNS) A4 specification (210 X 297 mil, ---&quot; — -^ (please read the phonetic on the back? Please fill out this page again) • a line 丨·· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative System 201 91949 A7 1293306 -------- _ V. Description of invention (202) Crystallization (4.3纟' 62%)' The 1ην· spectrum of this sample conforms to the specified structural formula. Similar to the method, but using the corresponding pyrimidine and purine bases, the following 2',5'-di-O-ethenyl 3,-substituted xylan nucleoside and its L_enantiomer are prepared: 1-(2 ,3,5-tris-indole-ethenyl-p-furanyl)_5_fluorouracil, 1-(2,3,5-tri-indole-ethenyl-D-furanose)_5-chlorine Urinary thiophene, 1-(2,3,5-tri-indole-ethenyl-dot-1^furanyl)_5_bromouracil, 1-(2,3,5-diethylhydrazine _D-furanosyl)_5_ uracil, 1-(2,3,5-tri-indole-ethenyl-D-furanose-based 5-cyanoquinone, 1-( 2,3,5-diethylindenyl-d-d-xylopyranosyl)_5•ethoxycarbonyl urinary cancer bite, 1-(2,3,5-tris-indolyl-no-D- Furanose) _5_Aminocarbonylurea urinary cancer 0, 1-(2,3,5-tri-O-ethinyl-DD-xylopyranosyl)-5-acetamido-urine 1-(2 ,3,5·三-0_乙醯基-卢-DD夫喃木糠基)_5•Methylurea pyridine, 1_(2,3,5-tris-0-ethylidene-泠-DD It is applicable to China National Standard (CNS) A4 specification (210 X 297 public -- 91949 (please read the phonetic on the back? Please fill out this page) ----- --Book ------- --Line-I. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed 202 1293306 A7 B7 V. Description of Invention (203 ) Acridine, 1-(2,3,5-tri-anthracene-ethenyl-dot-D-furan Xylose)-5-n-propyluric 1-(2,3,5-tri-O-ethylidene-wan-D-anthyl xylosyl)-5-isopropyl urinary cancer bite, 1- (2,3,5-three-0-ethyl aryl-wan-D-anthyl xylosyl)-5-ethylene urinary 1-(2,3,5-three-0-ethyl aryl-10,000 -D-purine xylosyl)-5-dilute urinary cancer TJ, 1-(2,3,5-tris-0-ethenyl-yS-D-furanyl glucosyl)_5_acetylene Basaluria 1-(2,3,5-tri-O-ethenyl-callo-D-furanosyl)-5-(2-gasovinyl) urinary carcinoma sigma, 1-(2,3, 5 - tri-anthracene-ethyl ketone-yS-D-purine xylosyl)-5-(2-&gt; odorant ethylene) urinary cancer 唆, 1-(2,3,5 -three-0- Ethyl-D-anthoxysyl)-5-(2-ethylidene) urinary bite, 1-(2,3,5-tri-O-ethylidene-cold-D-furan Glycosyl)-5-(2-methoxycarbonylvinyl) urinary cancer bite, 1-(2,3,5-tri-0-ethinyl-callo-D-furanosyl)-5-(2 -hydroxycarbonylethenyl)urine alpha-bite, 1-(2,3,5-tri-O-acetylindolyl-d-xylopyranosyl)-5-phenyluracil, 1-(2 , 3,5-three-0-ethyl ketone _p-〇-咲 xylosyl)-5-fluorenyl urinary, this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 203 91949 (Please read the note on the back and fill out this page) Order--------- Line 丨 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printed Economy Ministry Intellectual Property Bureau Employees Consumption Cooperatives Printed Clothes 1293306 A7 B7 V. DESCRIPTION OF THE INVENTION (204) Acridine, 1-(2,3,5-tri-O-ethenyl-d-d-furanoyl)-5-fluorocytosine, 1-(2,3 ,5-tri-O-acetyl-p-oxime-furanose--5-chlorocytosine, 1-(2,3,5-tri-O-ethenyl-d-d-furanyl Glycosyl)-5-bromocytosine, 1-(2,3,5_tri-O-ethylidene-wan-D-anthoxylyl)-5_Breeding cancer, 1-( 2,3,5-tri-indolyl-stone-D-furanose)-5-cyanocytosine, 1-(2,3,5-tri-anthracene-ethenyl- -D-furanosyl)·5-ethoxycarbonylcytocarcinoma, 1-(2,3,5-tri-anthracene-ethidyl-dot-DD-xylopyryl)-5-amino Weiji cytosine, 1-(2,3,5-tri-indolyl-wan-D-furanyl xylenyl)-5-acetamidyl 1-(2,3,5-tri-0 -Ethyl-yS-D-furan Glycosyl)-5-methylcytosine, 1-(2,3,5-tris-indolyl-wan-D-furanylxy)-5-ethyl cytosolic 0, 1-( 2,3,5_three-0_Ethyl-callo-D-furanosyl)-5-n-propylcytopenia β, 1-(2,3,5-tri-anthracene-ethyl - Dot-D-purine xylosyl)-5-isopropyl cell paper size applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (Please read the note on the back and fill out this page) Xin·

ϋ n n ϋ H ϋ ·ϋ 一OJ« Λ— mmmme H ϋ I I ϋ I —1 n ϋ i-i I ·1 i-i i_i i-i -n ϋ ϋ I ϋ ϋ ϋ ϋ ϋ ϋ I 204 91949 經濟部智慧財產局員工消費合作社印剩衣 1293306 A7 B7 五、發明說明（205 ) 癌σ定， 1-(2,3,5-三-Ο-乙醯基-冷-D-呋喃木糖基）-5-乙烯基胞 1-(2,3,5 -三- Ο-乙酸基-卢-D -咲喃木糖基）-5-稀丙基胞 喷σ定， 1-(2,3,5-三-0_乙酿基-点-D -咲喃木糖基）-5-乙快基胞 癌咬， 1·(2,3,5 -三- Ο-乙酿基-万-D -口夫喃木糖基）-5-(2-氯乙稀 基）胞嘧啶， 1_(2,3,5_三- Ο-乙酿基-点-D -咲喃木糖基）-5-(2-&gt;臭乙稀 基）胞嘧啶， 1_(2,3,5-三-0-乙酿基-万-0-咲喃木糖基）-5-(2-雄〇稀 基）胞癌唆， 1 -（2,3,5_三- Ο-乙酿基-卢-D -咲喃木糖基）_5-(2 -甲氧叛 基乙烯基）胞嘧啶， 1-(2,3,5-三-0-乙祕基-石-0-咲喃木糖基）-5-苯基胞續 淀， 1-(2,3,5-三-Ο-乙醯基-召-D-呋喃木糖基）-N6-苯甲醯 基腺嘌呤， 1-(2,3,5-三-0·乙醯基-召-D-呋喃木糖基）-6-氣嘌呤， 1-(2,3,5-三-Ο-乙醯基-召-D-呋喃木糖基）_2,6_二氣嘌 口令， 1-(2,3,5 -二-Ο -乙酿基-万-D -咲喃木糖基）-2 -乙酿胺基_ 6-氯嘌呤， 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐) 205 91949 (請先閱讀背面之注意事項再填寫本頁) ;0 訂---------線_表ϋ nn ϋ H ϋ ·ϋ an OJ« Λ—mmmme H ϋ II ϋ I —1 n ϋ ii I ·1 ii i_i ii -n ϋ ϋ I ϋ ϋ ϋ ϋ ϋ ϋ I 204 91949 Ministry of Economic Affairs Intellectual Property Office staff consumption Cooperatives printed leftovers 1293306 A7 B7 V. Description of invention (205) Cancer sigma, 1-(2,3,5-tri-anthracene-ethenyl-cold-D-furanosyl)-5-vinyl 1-(2,3,5-tris-fluorenyl-acetic acid-lu-D-indolyl)-5-dilute cytometry, 1-(2,3,5-three-0_ B-branched-dot-D-purine xylosyl)-5-B-cell cancer bite, 1·(2,3,5-tri-anthracene-ethene-wan-D-muffin 5-(2-chloroethlyl)cytosine, 1_(2,3,5-tri-anthracene-ethidyl-dot-D-indolyl)-5-(2-&gt; Styrozine) cytosine, 1_(2,3,5-tri-O-ethylidene-Wan-0-anthosyl)-5-(2-androstene) cell carcinoma, 1 -(2,3,5_tri-anthracene-ethyl-based-lu-D-anthyl xylosyl)_5-(2-methoxyhistylvinyl)cytosine, 1-(2,3,5- 3--0- 乙基基-石-0-咲木糖基)-5-phenyl cytosine, 1-(2,3,5-tri-anthracene-ethenyl-calli-D-furan Glycosyl)-N6-benzhydryl adenine, 1-(2,3,5-tri-O-acetyl -C-D-furanose)-6-gas, 1-(2,3,5-tri-indole-ethenyl-callo-D-furanosyl)_2,6_dioxin , 1-(2,3,5-di-indole-ethrolyl-wan-D-anthyl xylosyl)-2-ethanoamine _ 6-chloropurine, this paper scale applies to Chinese national standards (CNS A4 size (210 x 297 mm) 205 91949 (please read the notes on the back and fill out this page); 0 order---------line_table

I 293306 A7 B7 五、發明說明（m ) 1-(2,3,5-三_0-乙醯基呋喃木糖基）_2_乙醯胺基_ 6-甲氧基嗓呤， 1-(2,3,5-三乙醯基呋喃木糖基）_6•甲氧基嘌 呤，與 ^^。^◦乙醯基-^^夫喃木糖基^-甲基 風硫 經濟部智慧財產局員工消費合作社印製 基嗓吟。 1例37 1_(3-去氧小0_甲磺醯基4 咲喃木糖基）-5_氟尿嘧咬 取含1-(2,5-二-0-乙醢基-3-0-甲磺醯基_沒_〇_吹喃木 糖基）-5 -氟嘧啶（4.24克，〇.01莫耳）之氨之甲醇溶液（1〇〇 毫升）混合物於0°C下攪拌3〇分鐘，真空濃縮至乾，殘質 自乙醇中結晶，產生1-(3-去氧-3-0·甲確醯基召_D_咲喃木 糖基）_5_ 氟尿嘧啶（2.82 克 ’ 83%)。ijj NMR(D6-DMSO)顯示 分子中沒有乙醯基但有一個甲磺醯基。 依類似方法，但改用相應之2，，5’-二-〇-乙醯基嘧咬與 嘌呤核苷，製備下列3，-0-甲磺醯基-核苷與其對映體： 1-(3-0-甲磺醯基-冷-D-呋喃木糖基）_5_氯尿嘧啤， 1-(3-0-甲續醯基-召-D-咲喃木糖基）_5_溴尿嘧咬， 1-(3·0-甲績醯基-召-D-咲喃木糖基）_5_埃尿喷咬， 1-(3_0-甲磺醯基-点-D-呋喃木糖基）_5_氰基尿嘧啶， 1-(3-0-甲磺醯基-泠-D-咲喃木糖基）_ 5 -乙氧羰基尿喊 1-(3 _0_甲續醯基，召-D-咲喃木糖基）-5-胺基羰基尿喷I 293306 A7 B7 V. INSTRUCTIONS (m) 1-(2,3,5-tri-_0-ethylmercaptofuranyl)_2_acetamido- 6-methoxyindole, 1-( 2,3,5-triethylmercaptofuranyl)_6•methoxy oxime, with ^^. ^◦乙醯基-^^夫喃木糖基^-Methyl Wind Sulphur Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing basis. 1 case of 37 1_(3-deoxy small 0-methylsulfonyl 4 mercapto-xylyl)-5_fluorouracil bite containing 1-(2,5-di-0-ethinyl-3-0 -Methanesulfonyl _ _ _ _ 吹 xylosyl) 5-fluoropyrimidine (4.24 g, 〇.01 mol) of ammonia in methanol solution (1 〇〇 ml) mixture at 0 ° C stirring 3 〇 minute, concentrated to dryness in vacuo, and the residue crystallized from ethanol to give 1-(3-deoxy-3-0······························· ). Ijj NMR (D6-DMSO) showed no ethyl thiol group in the molecule but a methylsulfonyl group. In a similar manner, but using the corresponding 2,5'-di-indole-acetylpyridinium and purine nucleosides, the following 3,-0-methylsulfonyl-nucleoside and its enantiomer were prepared: 1- (3-0-methanesulfonyl-cold-D-furanyl)-5_chlorouridine, 1-(3-0-methyl sulfonyl-callo-D-purpuryl xylate)_5_ Bromouracil bite, 1-(3·0-甲醯醯基-召-D-咲木糖基)_5_埃尿喷,1(3_0-Methanesulfonyl-d-D-furan Glycosyl)_5_cyanouracil, 1-(3-0-methylsulfonyl-indole-D-purpuryl) 5- 5-ethoxycarbonyl urinary 1-(3 _0_甲醯醯基, call-D-purine xylosyl)-5-aminocarbonyl urinary spray

206 91949 (請先閱讀背面之注音？事項再填寫本頁) 訂-------- •線丨· [293306206 91949 (Please read the phonetic on the back? Please fill out this page again) Order -------- • Line 丨 · [293306

五、發明說明（207 W3-0-甲續酿基nQ夫喃木糖基）冬 啶 乙醯基尿喊 啶 啶 啶 1 〇_甲=醯基木糖基）_5_甲基尿喷咬 Ο甲％醯基呋喃木糠基）-5-乙基尿嘧啶 1-(3-0-甲績醯基nD夫喃木糖基）_5_正丙基尿喷 1 (3 o-h醯基nD夫喃木糖基異丙基尿喊 1 (3-〇_甲％醯基n咲喃木糖基）_5_乙烯基尿喷 1-(3-0-甲磺醯基-万-D_呋喃木糖基）_5_烯丙基尿嘧 (請先閱讀背面之注意事項再填寫本頁) 啶 1- (3-0-甲磺醯基_冷夫喃木糖基）_5_乙炔基尿嘧 啶 訂--------- 經濟部智慧財產局員工消費合作社印製 l-(3-〇-甲磺醯基n〇夫喃木糖基）_5_(2-氣乙稀基） 尿喊唆， 1-(3-0-甲磺醯基·泠-D-Π夫喃木糖基）_5_(2_溴乙烯基） 尿嘴唆， 1-(3-〇·甲磺醯基-泠-D-D夫喃木糖基）-5_(2-碘乙烯基） 尿喷咬， 1-(3-0-甲磺醯基-石-D-呋喃木糖基&gt;5-(2-甲氧羰基乙 稀基）尿濟Ϊ1 定， 1(3-0-甲磺醯基-石-D-呋喃木糖基）_5_(2-羥基羰基乙l二婦基)是^ 口定， ^紙張尺國家標準（Cns)A4規格（210 X297公髮巧 ---- 207 91949 線· 經濟部智慧財產局員工消費合作社印製 208 1293306 A7 B7 五、發明說明（208 ) 1-(3-0-甲磺醯基-点-D-呋喃木糖基）-5-苯基尿嘧啶， 1_(3-〇-甲磺醯基-3 -D-呋喃木糖基）·5-〒基尿嘧啶， 1-(3-0-甲磺醯基-召-D-呋喃木糖基）胞嘧啶， 1-(3_〇-甲磺醯基-冷-D-呋喃木糖基）-5-氟胞嘧啶， 1-(3-0-甲磺醯基-点-D-呋喃木糖基）-5-氣胞嘧啶， 1-(3-0-甲磺醯基-点-D-呋喃木糖基）-5-溴胞嘧啶， 1_(3-〇-甲磺醯基召呋喃木糖基）-5-碘胞嘧啶， 1-(3-0-甲磺醯基-点-D-呋喃木糖基）-5-氰基胞嘧啶， 1-(3-0-甲磺醯基-万-D_呋喃木糖基）-5-乙氧羰基胞喊 啶， 1-(3-0-甲磺醯基-D-呋喃木糖基）-5-胺基羰基胞癌 口定， 1_(3·〇·甲磺醯基召-D-呋喃木糖基）-5-乙醯基胞嘧 啶， 1-(3_0-甲磺醯基-点-D-呋喃木糖基）-5_甲基胞嘧啶， 1-(3-0-甲磺醯基-召-D-呋喃木糖基）-5·乙基胞嘧啶， 1-(3-0-甲磺醯基·々-D-呋喃木糖基）-5-正丙基胞嘧 啶， 1-(3-0-甲磺醯基-点-D-呋喃木糖基）-5-異丙基胞嘧 0定， 1_(3-〇-甲磺醯基-点-D-呋喃木糖基）-5-乙烯基胞嘧 口定， 1-(3-0-甲磺醯基-点-D-呋喃木糖基）-5-烯丙基胞嘧 啶， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) .. 線丨% 經濟部智慧財產局員工消費合作社印製 209 1293306 A7 B7 五、發明說明（209 ) 1-(3_0-甲磺醯基-点-D-呋喃木糖基）-5-乙炔基胞嘧 啶， 1-(3-0-甲磺醯基-点-D·呋喃木糖基）-5-(2-氯乙烯基） 胞嘧啶， 1-(3-〇-甲磺醯基-召-D-呋喃木糖基）-5-(2-溴乙烯基） 胞痛咬， 1-(3-0-甲磺醯基-石-D-呋喃木糖基）-5-(2-碘乙烯基） 胞嘧啶， 1_(3-〇-甲磺醯基-点-D·呋喃木糖基）-5-(2-甲氧羰基乙 烯基）胞嘧啶， 1-(3-0 -甲續釀基_D -咲喃木糖基）-5-(2 -經基幾基乙 浠基）胞嘴咬， 1-(3-〇-甲磺醯基-沒-D-呋喃木糖基）-5-苯基胞嘧啶， 1-(3-0-甲磺醯基-D-呋喃木糖基）-5-T基胞嘧啶， 1-(3-0-甲磺醯基-召-D-呋喃木糖基）-2-氯腺嗓呤， 1-(3-0-甲磺醯基-冷_D-呋喃木糖基）-6-氯嘌呤， 1_(3-〇-甲磺醯基-沒-D-呋喃木糖基）-2,6-二氯嘌呤， 1_(3-〇-甲磺醯基-々-D-呋喃木糖基）-2_乙醯胺基_6_氯 嗓呤， 1_(3-〇-甲磺醯基-点-D-呋喃木糖基）-2-乙醯胺基-6-甲 氧基嘌呤， 1-(3-0-甲磺醯基-点-D-呋喃木糖基）-6-甲氧基嘌呤， 與 1_(3-〇-甲磺醯基-点-D-呋喃木糖基）-6-甲基氳硫基嘌 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁)V. Description of the invention (207 W3-0-A continuation of the base nQ xylanyl) chlorinated acetophenone urinary chlorpyrifos 1 〇 _ A = 醯 xylosyl) _5_ methyl urinary sputum A 醯 醯 呋 呋 1- 1- ( ( ( ( _ _ _ ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Xylose isopropyl urinary shark 1 (3-〇_甲% 醯 咲 n咲 xylosyl)_5_vinyl urinary spray 1-(3-0-methylsulfonyl-wan-D-furanose Base)_5_allyl uracil (please read the note on the back and then fill out this page) pyridine 1- (3-0-methylsulfonyl _ cold cumyl xylosyl) _5_ ethynyl uracil set - -------- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed l-(3-〇-methanesulfonyl n-fusyl xylosyl)_5_(2-ethylenediyl) 1-(3-0-Methanesulfonyl-indenyl-D-valfyl xylenyl)_5_(2_bromovinyl) urinary mouth, 1-(3-〇·methylsulfonyl-indole-DD Fusaryl glucosyl)-5_(2-iodovinyl) urinary blast, 1-(3-0-methylsulfonyl-stone-D-furanose)&gt; 5-(2-methoxycarbonyl B Diluted) urinary hydrazine 1 , 3 (3-0-methylsulfonyl-stone-D-furanosyl)_5_(2-hydroxyl基乙l二妇基) is ^ 口定, ^ paper ruler national standard (Cns) A4 specification (210 X297 public hair Qiao---- 207 91949 line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 208 1293306 A7 B7 V. INSTRUCTIONS (208) 1-(3-0-Methanesulfonyl-dot-D-furanosyl)-5-phenyluracil, 1_(3-indole-methylsulfonyl-3-D -furanose)·5-mercaptouracil, 1-(3-0-methanesulfonyl-callo-D-furanosyl)cytosine, 1-(3_〇-methylsulfonyl- cold-D-furanosyl)-5-fluorocytosine, 1-(3-0-methylsulfonyl-dot-D-furanosyl)-5-cytosine, 1-(3-0 -Methanesulfonyl-dot-D-furanosyl)-5-bromocytosine, 1_(3-indolemethamidyl)-iodocytosine, 1-(3- 0-Methanesulfonyl-dot-D-furanosyl)-5-cyanocytosine, 1-(3-0-methylsulfonyl-wan-D-furanose)-5-ethoxy Carbonyl cyanosine, 1-(3-0-methylsulfonyl-D-furanosyl)-5-aminocarbonyl cell carcinoma, 1_(3·〇·methylsulfonyl-D-furan Xylose)-5-ethenylcytosine, 1-(3_0-methylsulfonyl-dot-D-furanosyl)-5-methylcytosine 1-(3-0-Methanesulfonyl-C-D-furanyl)-5-ethylcytosine, 1-(3-0-methylsulfonyl-indole-D-furanosyl) -5-n-propylcytosine, 1-(3-0-methanesulfonyl-d-d-furanoyl)-5-isopropylcytosine, 1_(3-indolesulfonate) Base-dot-D-furanose)-5-vinylcytosine, 1-(3-0-methylsulfonyl-dot-D-furanosyl)-5-allylcytosine , This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (please read the note on the back and fill out this page).. 丨%% Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 209 1293306 A7 B7 V. INSTRUCTIONS (209) 1-(3_0-Methanesulfonyl-dot-D-xylopyranosyl)-5-ethynylcytosine, 1-(3-0-methylsulfonyl-dots -D·furanosyl)-5-(2-chlorovinyl)cytosine, 1-(3-indole-methylsulfonyl-callo-D-furanosyl)-5-(2-bromoethene Cytotoxic bite, 1-(3-0-methylsulfonyl-stone-D-xylopyranosyl)-5-(2-iodovinyl) cytosine, 1_(3-indole-methylsulfonyl) -dot-D·furanosyl)-5-(2-methoxycarbonylvinyl)cytosine, 1- (3-0 - a continuation of the base _D - chloropyranosyl) - 5 - (2 - benzyl group), bite bite, 1-(3-〇-methylsulfonyl-n- D-furanosyl)-5-phenylcytosine, 1-(3-0-methylsulfonyl-D-xylopyranosyl)-5-T-cytosine, 1-(3-0-A Sulfosyl-callo-D-furanosyl)-2-chloroadenine, 1-(3-0-methylsulfonyl-cold_D-furanyl)-6-chloropurine, 1_( 3-〇-Methanesulfonyl-N-D-furanyl)-2,6-dichloroindole, 1_(3-indole-methylsulfonyl-indole-D-furanosyl)-2_ Acetylamino-6_chloropurine, 1_(3-indole-methylsulfonyl-d-d-furanyl)-2-ethinylamino-6-methoxyindole, 1-(3 -0-Methanesulfonyl-dot-D-furanosyl)-6-methoxyindole, and 1-(3-indole-methylsulfonyl-dot-D-furanosyl)-6- Based on the sulphur-based enamel paper size, the Chinese National Standard (CNS) A4 specification (210 X 297 mm) is applicable. 91949 (Please read the note 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 210 1293306 五、發明說明（210 ) 岭° 實例3 8 呋喃木糖基）_5_氟尿嘧啶 取含1_(2,3,5_三-〇-乙醯基-沒-D-呋喃木糖基）-5-氟尿 嘧啶（3 _88克，0.01莫耳）盥二 卄厂、一乙胺（3笔升）之甲醇（J 〇〇毫升） 遙合物於室溫下攪拌_夜。混合物真空濃縮至乾，殘質自 乙醇中結晶，產生呋喃木糖基）巧-氟尿嘴咬（2.0 克，76%)。此樣本之uv與屮NMR(Mej〇叫與產物結 構式一致。 依類似方法，但改用相應之2，，5，_二_〇_乙醯基嘧啶與 嘌呤鹼基，製備下列木糖核苷與其L_對映體： 、 1-(石-D-口夫喃木糖基）_5_氯尿嘴咬， l-(^S-D-n夫喃木糖基溴尿嘧啶， 1-(石-D-呋喃木糖基）_5_碘尿嘧啶， 1_(石-D-呋喃木糖基）_%氰基尿嘧啶， 1-(冷-D-呋喃木糖基乙氧羰基尿嘧啶， 1-(沒-D-呋喃木糖基）_5-胺基羰基尿嘧啶， 1 (沒D Π夫喃木糖基）_ $ _乙酿基尿喊唆， 1-(泠-D-呋喃木糖基）-5_甲基尿嘧啶， 1-(召-D-呋喃木糖基）_5_乙基尿嘧啶， 1-(召-D-呋喃木糖基）_5-正丙基尿嘧啶， 1-(冷-D-呋喃木糖基異丙基尿嘧啶， 呋喃木糖基）_5_乙烯基尿嘧啶， , 冷-D_呋喃木糖基）-5-烯丙基尿嘧啶， 本紙張尺斤用中國國幻⑽x 297一/?1- 91949Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 210 1293306 V. Description of the Invention (210) Ling ° Example 3 8 Furanose) _5_Fluorouracil contains 1_(2,3,5_tri-indole-ethenyl- No-D-furanosyl)-5-fluorouracil (3 _88 g, 0.01 mol) 盥二卄厂, monoethylamine (3 liters) of methanol (J 〇〇 ml) remote compound at room temperature Stirring_night. The mixture was concentrated to dryness in vacuo and residue was crystallised from ethanol to yield furose s s s s s s s s s s s s s s s s s s s s s s The uv and 屮 NMR of this sample are consistent with the structural formula of the product. According to a similar method, the corresponding xylose nucleus is prepared by using the corresponding 2, 5, _ _ 〇 醯 醯 嘧啶 pyrimidine and fluorenyl bases. Glycosides and their L_enantiomers: , 1-(stone-D-mouth xylosyl)_5_chlorine urinary bite, l-(^SDnfu-xylyl bromouracil, 1-(stone-D -furanose)_5_iodouracil, 1_(stone-D-furanosyl)_% cyanouracil, 1-(cold-D-furanyl ethoxycarbonyl uracil, 1-( No-D-furanosyl)_5-aminocarbonyl uracil, 1 (no D Π 喃 xylosyl)_ _ _ B-based urinary shout, 1-(泠-D-furanosyl) -5_methyluracil, 1-(call-D-furanosyl)_5_ethyluracil, 1-(call-D-furanosyl)_5-n-propyluracil, 1-( Cold-D-furanyl isopropyl uracil, furosexyl)_5_vinyl uracil, , cold-D_furanose)-5-allyl uracil, used in paper Chinese National Fantasy (10) x 297 one /? 1- 91949

(請先閱讀背面之注意事項再填寫本頁) 0 訂---------線·(Please read the notes on the back and fill out this page) 0 Order---------Line·

I 293306 A7 B7 五、發明說明（211 夫喃木糖基）_5_乙炔基尿，唆， 石·D-陕喃木糖基）-5-(2-氣乙烯基）尿脅雙 1-(点_D-0夫喃木糖基）_5_(2_溴乙烯基）展鳴^ ’ 1 (沒D-D夫喃木糖基）_5_(2_鐵乙烯基）尿喷口定 1(万D 11 夫喃木糖基）_5-(2 -甲氧幾基乙缔 1-(冷-D-呋喃木糖基）_5_(2_羥基羰基乙烯尿嘧啶， 1_(石-D-呋喃木糖基）苯基尿嘧啶，土）尿喷咬， 1_(沒_D-呋喃木糖基）基尿嘧啶， 1-(点_D-呋喃木糖基）胞嘧啶， 1-(石-D-n夫喃木糖基）_5_氟胞嘧啶， 呋喃木糖基）-5_氯胞嘧啶， 1-(万_D-呋喃木糖基）-5_溴胞嘧啶， 1·(点-D-呋喃木糖基）_弘碘胞嘧啶， l-(^S-D-a夫喃木糖基）_5_氰基胞嘧啶， l-(々-D_fl夫喃木糖基）乙氧羰基胞嘧啤， l_dD_a夫喃木糖基卜5-胺基羰基胞嘧啤， 1-(石_D-a夫喃木糖基）_5_乙醯基胞嘧啶， 1-(点-D-n夫喃木糖基）_5_甲基胞嘧啶， 1-(点-D-D夫喃木糖基）_%乙基胞癌啶， 1-(点-D-a夫喃木糖基兴5_正丙基胞嘧啶， l-(々-D_咲喃木糖基）_5_異丙基胞嘧啶， 1·(点-D-n夫喃木糖基）乙烯基胞嘧啶.， · 1·(石呋喃木糖基）_5_烯丙基胞嘧啶， 1_(召_D-呋喃木糖基）_%乙炔，基胞嘧啶， 1本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公餐) 91949 f靖先閱讀背面之注意事項再填寫本頁} -1^__^--------訂---------線. 經濟部智慧財產局員工消費合作社印製 211 A7 經濟部智慧財產局員工消費合作社印製 1293306 _______B7______ 五、發明說明（212 ) 1-(万-D-呋喃木糖基）_5_(2_氣乙烯基）胞嘧啶， l-(yS-D-呋喃木糖基）_5_(2-溴乙烯基）胞嘧啶， 1兴泠-D-呋喃木糖基）_5_(2-碘乙烯基）胞嘧啶， 1-(万-D-呋喃木糖基）_5_(2_甲氧羰基乙烯基）胞嘧啶， 1-(召-D-呋喃木糖基）_5_(2-羥基羰基乙烯基）胞嘧啶， 1-(召-D·呋喃木糖基）_5_苯基胞嘧啶， 1-(沒-D-呋喃木糖基）_5_苄基胞嘧啶， 1-(泠-D-呋喃木糖基）_2_氯腺嘌呤， 1·(召-D-U夫脅木糖基）.6 -氣嗓呤， 1-(冷-D_呋喃木糖基）_2,6_二氣嘌呤， 1-(召_D-呋喃木糖基）_2•乙醯胺基_6·氯嘌呤， 1-(召-D-呋喃木糖基）_2_乙醯胺基_6_甲氧基嘌呤， 1-(石-D_呋喃木糖基）_6_甲氧基嘌呤，與 1-(点-D-呋喃木糖基）_6_甲基氳硫基嘌呤。 實例39 2，3 _0-亞異丙基_5’_〇_三苯甲基_^_經基胞脊 於〇 C下，添加2,4,6-三異丙基苯磺醯氯（115克）與 DMAP(232毫克）至含2’，3’_〇_亞異丙基_5_〇_三苯基甲基尿 苷（1克）之50毫升無水乙腈與三乙胺（〇76克）之攪拌溶液 中，反應混合物於室溫下攪拌1天。添加羥胺鹽酸鹽（263 亳克），混合物再於室溫下攪拌丨天。加水中止反應，以氯 仿（200毫升）萃取產物。以鹽水洗滌有機層，以皿0〇4脫 水，真空濃縮。殘質經矽膠管柱層析純化（5%Me〇H之 CHC13溶液），產生2, 3，_0_亞異丙基_5，_〇_三苯甲基…气 冬，我浪乂度週用1f國國豕標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁)I 293306 A7 B7 V. INSTRUCTIONS (211 F. xylosyl)_5_ethynyl urinary, hydrazine, stone·D-Shaanyl xylosyl)-5-(2-vinyl-vinyl) urinary valence double 1-( Point _D-0 verbose xylate) _5_(2_bromovinyl) sings ^ '1 (no DD xylan) _5_(2_ iron vinyl) urine vent 1 (10,000 D 11 husband Cycloxylenyl)_5-(2-methoxyxoyldiethyl 1-(cold-D-furanosyl)_5_(2-hydroxycarbonylvinyluracil, 1_(stone-D-furanosyl)benzene Urinary chlorpyrifos, soil) urinary squirt, 1_(no _D-furanosyl)-based uracil, 1-(dot_D-furanosyl) cytosine, 1-(stone-Dn-flomoose Base)_5_fluorocytosine, furofyranosyl)-5-chlorocytosine, 1-(wan-D-furanosyl)-5-bromocytosine, 1·(dot-D-furanosyl _ 弘 iodine cytosine, l-(^SDa xylosyl)_5_cyanocytosine, l-(々-D_flfu-xylosyl) ethoxycarbonyl cyanosine, l_dD_a verbose 5-aminocarbonyl cytosolic beer, 1-(stone-Da-flomoxylosyl)_5_acetylcytosine, 1-(dot-Dn-fusylxylyl)_5-methylcytosine, 1 -(dot-DD-xylinyl)_%ethyl Carcinylpyridine, 1-(dot-Da-fucaose) 5_n-propylcytosine, l-(々-D_咲-xylosyl)_5_isopropylcytosine, 1·(dot-Dn Vinyl cytosine, vinylcytosine, 1, 1 (sulphur xylosyl)_5-allylcytosine, 1_(callo-D-furanosyl)_% acetylene, cytosine, 1 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public meals) 91949 f Jing Xian read the back of the precautions and then fill out this page} -1^__^-------- order--- ------Line. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 211 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1293306 _______B7______ V. Description of invention (212) 1-(wan-D-furanylose )_5_(2_gas vinyl) cytosine, l-(yS-D-furanosyl)_5_(2-bromovinyl)cytosine, 1 泠-D-furanosyl)_5_(2- Iodovinyl)cytosine, 1-(wan-D-furylxylosyl)_5_(2-methoxycarbonylvinyl)cytosine, 1-(call-D-furanosyl)_5_(2-hydroxycarbonyl Vinyl)cytosine, 1-(call-D-furanyl)_5_phenylcytosine, 1-(no-D-furanosyl)_5 _Benzylcytosine, 1-(泠-D-furyl xylosyl)_2_chloroadenine, 1·(召-杜夫重量xy-glycosyl).6 - gas 嗓呤, 1-(cold-D_ Furanoxylated)_2,6_dioxane, 1-(calling_D-furanylxy)_2•acetamido_6·chloropurine, 1-(call-D-furanosyl)_2 _ 醯 醯 _ _6_methoxy oxime, 1-(stone-D_furanyl xylenyl)_6_methoxy oxime, and 1-(dot-D-furanosyl)_6_methyl hydrazine Sulfur-based hydrazine. Example 39 2,3 _0-isopropylidene_5'_〇_tritylmethyl_^_ via the ridge of the base 〇C, 2,4,6-triisopropylbenzenesulfonium chloride (115) g) with DMAP (232 mg) to 50 ml of anhydrous acetonitrile and triethylamine (〇76) containing 2',3'_〇_isopropylidene_5_〇_triphenylmethyluridine (1 g) The stirred mixture was stirred at room temperature for 1 day. Hydroxylamine hydrochloride (263 g) was added and the mixture was stirred at room temperature for another day. The reaction was quenched with water and extracted with chloroform (200 mL). The organic layer was washed with brine, dried with EtOAc EtOAc. The residue was purified by ruthenium column chromatography (5% Me〇H in CHC13) to give 2,3,_0_isopropylidene_5,_〇_trityl...gas winter, my wave week Use the 1f National Standard (CNS) A4 specification (210 X 297 mm) 91949 (please read the notes on the back and fill out this page)

212 1293306 A7 --—----- B7 五、發明說明（213 ) 經基胞苷（7 23毫克，70%)之白色固體。212 1293306 A7 -------- B7 V. Description of the invention (213 ) A white solid via cytidine (7 23 mg, 70%).

Mp: 99-101 °C. lH NMR (CDC13) δ 134 (s, 3H), 1.56 (s, 3H), 3.40-3.73 (m, 2H), 4.26 (br s, 1H), 4.79-4.81 (m, 2H), 534 (d, J = 8.12 Hz, 1H), 5.88 (br s, 1H), 6.88 m(d, J = 8.12 Hz, 1H), 7.22-7.41 (m, 15H). 依類似方法，但改用相應之5_經取代之尿嘧啶核苷， 製備下列N4-經基-2’，3’_〇-亞異丙基_5，_〇_三苯基甲基胞脊 衍生物： 2’，3’-0-亞異丙基_5’_〇_三苯基甲基-5_氣_尺4_經基胞 苷， 2’，3’_0_亞異丙基_5’_〇三苯基甲基^-氣…、羥基胞 苷， 2，3’-0-亞異丙基_5’_〇•三苯基甲基溴·N4_羥基胞 甘， 2，3 -Ο-亞異丙基-5’-〇-三苯基甲基Hn4_經基胞 甘， 2，3 ·0-亞異丙基_5’_〇-三苯基甲基-5-甲基-N4-經基 胞苷， 土 2，3 -0-亞異丙基- 5’-〇-三苯基甲基_5_乙基_n4-經基 胞苷， 2’，3、0_亞異丙基_5，_〇_三苯基甲基_5_正丙基_以4_羥 基胞苷， 2，3 -〇-亞異丙基-5’_0-三苯基甲基-5-異丙基經 基胞苷， _2，3 -0-亞異丙基-5’-0-三苯基甲基-5 •乙浠基 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注咅？事項再填寫本頁) -I a— «ϋ ϋ I ·1. J &lt; β Βϋ ·ϋ I ·ϋ ϋ ϋ - 言 線% 經濟部智慧財產局員工消費合作社印製 213 1293306Mp: 99-101 °C. lH NMR (CDC13) δ 134 (s, 3H), 1.56 (s, 3H), 3.40-3.73 (m, 2H), 4.26 (br s, 1H), 4.79-4.81 (m , 2H), 534 (d, J = 8.12 Hz, 1H), 5.88 (br s, 1H), 6.88 m (d, J = 8.12 Hz, 1H), 7.22-7.41 (m, 15H). In a similar manner, However, instead of the corresponding 5_substituted uridine nucleoside, the following N4-trans-based-2',3'-〇-isopropylidene-5,_〇_triphenylmethyl ridge derivative was prepared: 2',3'-0-isopropylidene_5'_〇_triphenylmethyl-5_气_尺4_ via cytidine, 2',3'_0_isopropylidene_5' _〇Triphenylmethyl^-gas..., hydroxycytidine, 2,3'-0-isopropylidene _5'_〇•triphenylmethyl bromide·N4_hydroxycytidine, 2,3 - Ο-isopropylidene-5'-indole-triphenylmethyl Hn4_ via cytosine, 2,3 ·0-isopropylidene _5' 〇-triphenylmethyl-5-methyl -N4-transcytidine, soil 2,3-0-isopropylidene-5'-indole-triphenylmethyl_5_ethyl_n4-transcytidine, 2',3,0_ Isopropyl _5,_〇_triphenylmethyl _5_n-propyl _ as 4-hydroxycytosine, 2,3-indole-isopropylidene-5'_0-triphenylmethyl- 5-isopropyl cytidine, _2,3 -0- Isopropyl-5'-0-triphenylmethyl-5 • Ethylquinone basic paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 (Please read the note on the back first? Fill in this page again) -I a— «ϋ ϋ I ·1. J &lt; β Βϋ ·ϋ I ·ϋ ϋ ϋ - Line % Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 213 1293306

基胞杳， 2，，3，-。·亞異丙基·〜三苯基甲基-5-乙 基胞苷， 炔基_N4-羥 2’，3’_0-亞異丙基_5 N4_經基胞脊，2’，3’-〇-亞異丙基_5 N4-羥基胞苷， 2’，3’-〇_亞異丙基_5 N4-羥基胞苷， 2’，3’-〇·亞異丙基 稀基）-N4-經基胞脊， 2’，3’-〇-亞異丙基_5 烯基）-N4_羥基胞苷， 2’，3’-〇_亞異丙基 胞苷，與2’，3’-〇_亞異丙基 胞苷。 二苯基甲基-5-(2-氣乙烯基）_ 二苯基甲基_5-(2_溴乙 烯基 二苯基甲基_5_(2•碘乙烯基）_ ’_〇_三苯基甲基-5-(2-甲氧羰基乙 ·〇_二苯基甲基-5-(2-羥基羰基乙 〇-三苯基甲基-5-苯基-N4· 羥基 二苯基甲基基-N4-羥基 (請先閱讀背面之注音？事項再填寫本頁) 0 I------訂--------- 經濟部智慧財產局員工消費合作社印製 214 依類似方法，但改用相座 用相應之5-經取代之2，，5，-二乙 醯基_3’_去氧尿脊，製備下 4 甘农爾下列贝-羥基_2，，5，-二·〇-乙醯基 3’-去氧胞脊衍生物： 1-(2,5-二乙醯基_3_去氧_〇_呋喃赤蘚戊糖基）_ N4-經基胞喷咬， 1·(2,5-二-〇_乙醯基_3_去氧-沒_D_咲喃赤藓戊糖基）_ 5-氟-N4_^基胞喊唆， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 經濟部智慧財產局員工消費合作社印製 215 1293306 A7 B7 五、發明說明（215 ) 1-(2,5 -二-0 -乙酿基·3_去氧·々-D·咲喃赤鲜戍糖基）_ 5-氯-Ν4-羥基胞嘧啶， 1-(2,5 -二- Ο-乙酿基-3-去氧-々-D-咲喃赤蘇戍糖基）-5-溴-Ν4-羥基胞嘴咬， 1-(2,5-二-0-乙酿基-3-去氧-万-0-咲喃赤蘇戍糖基）_ 5-蛾-Ν4-經基胞癌唆， 1-(2,5_二-0 -乙酿基-3-去氧-沒-D-咲喃赤鲜戊糖基）_ 5-氰基-Ν4-羥基胞嘧啶， 1-(2,5 -二-0-乙酿基-3-去氧-点-D-咲喃赤解戍糖基）_ 5-乙氧羰基-Ν4-羥基胞嘧啶， 1-(2,5 -二- Ο-乙酿基-3-去氧-D-咲喃赤鲜戍糖基）-5-胺基羰基-N4-羥基胞嘧啶， 1-(2,5 -二·0·乙酿基-3-去氧-点-D-咲喃赤鲜戍糖基）_ 5-乙醯基-N4-羥基胞癌淀， 1·(2,5 -二-0-乙酿基-3-去氧-万-D·咲喃赤蘇戍糖基）_ 5-甲基-Ν4-羥基胞癌咬， 1-(2,5-二-0-乙酿基-3-去氧-点-0-唉痛赤餐戍糖基）-5-乙基-Ν4-羥基胞嘧啶， 1-(2,5-二-0·乙醯基-3-去氧-卢-D-呋喃赤蘚戊糖基）-5-正丙基-Ν4-羧基胞癌咬， 1-(2,5_二-0 -乙釀基-3-去氧-石-D -咲喃赤戍糖基）_ 5-異丙基-N4-羥基胞嘧啶， 1-(2,5 -二-0-乙酿基-3-去氧-点-D -咲喃赤蘇戊糖基）_ 5_乙烯基-N4-羥基胞嘧啶， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) --------訂---------線» 1293306 A7 B7 五、發明說明（2i〇 l-(2,5-二-Ο-乙醯基I去呋喃㈣戊糖基 5-烯丙基-N4-羥基胞嘧啶， (請先閱讀背面之注意事項再填寫本頁) 1 一（ 2，5 -二 0 -乙酿基-3 -去盡 O T\ pr-f* ^ Λ, ^ ^ f氧-卢-D-呋喃赤蘚戊糖基）_ 5-乙炔基-N4-羥基胞嘧啶， 1-(2,5-二-〇-乙醯基」·去氧咲喃赤蘚戊糖基 5-(2·乳乙稀基）-N4·經基胞喷咬， 1·(2,5-二〇-乙醯基_3_去氧呋喃㈣戊糖基）_ 5-(2_&gt;臭乙稀基）-N4 -經基胞喊咬， 1-(2,5-二-〇-乙醯基_3_去氧_点_1)_咲喃赤蘚戊糖基）_ 5-(2-磁乙稀基）-N4-經基胞喷咬， 1-(2,5-二-〇-乙醯基-3_去氧·点_D_呋喃赤蘚戊糖基）_ 5-(2-甲氧幾基乙烯基）_N4_羥基胞嘧啶， 1-(2,5-二-〇-乙醯基_3_去氧-点_D_呋喃赤蘚戊糖基）· 5-(2•經基羰基乙烯基）七4-羥基胞嘧咬， 1-(2,5_二-〇_乙醯基_3-去氧^呋喃赤蘚戊糖基卜 5-苯基-Ν4-經基胞癌咬，與 經濟部智慧財產局員工消費合作社印製 —1_(2,5-二-〇-乙醯基_3-去氧呋喃赤肆戊糖基）_ 5-卞基-N4-經基胞癌咬。 依類似方法’但改用相應之5_經取代之3,，5，二_〇乙 醯基-2’-去氧尿苷，製備下列N4_羥基_3，，5,_二_〇_乙醯基_ N4-羥基-2、去氧胞脊衍生物·· 3’，5’-二_〇_乙醯基_2、去氧氺4_羥基胞苷， 3’，5’_二-〇-乙醯基_2，_去氧_5_氟_;^4_羥基胞苷， 3%5’-二乙醯毛^·去笋夂_ _m4_絲竿栌符， 本紙張尺度適用中國國家標準（CNS)A4規!Γ^ΙΓχ 297 )--— 216 91949 1293306 A7 經濟部智慧財產局員工消費合作社印製 B7__五、發明說明（2Π ) 3，，5，-二-0-乙醯基-2’-去氧-5_溴-1^4-羥基胞苷， 3，，5，-二-0-乙醯基-2’-去氧_5-碘-1^4-羥基胞脊， 3，，5，-二-0-乙醯基-2’-去氧-5-氰基-1^4-羥基胞苷， 3，，5，-二-0-乙醯基-2，-去氧-5-乙氧羰基-1^4-羥基胞 甘， 3，，5，-二-0-乙醯基-2’-去氧-5-胺基羰基-尺4-羥基胞 甘， 3，，5，-二-0_乙醯基-2’-去氧-5-乙醯基-&gt;^4-羥基胞脊， 3，，5，_二-〇_乙醯基-2，-去氧-5-甲基-：^4-羥基胞苷， 3，，5，-二-0-乙醯基-2’-去氧-5-乙基-1^4-羥基胞脊， 3，，5，-二-0_乙醯基-2，-去氧-5-正丙基-：^4-羥基胞苷， 3，，5，-二-0-乙醯基-2’-去氧-5-異丙基-忖4-羥基胞苷， 3，，5，-二-0-乙醯基-2，-去氧-5-乙烯基-：^4-羥基胞苷， 3，，5，-二-0-乙醯基-2，-去氧-5-烯丙基-N4-羥基胞苷， 3，，5，-二-Ο-乙醯基_2，_去氧_5_乙炔基-N4-羥基胞苷， 3，，5，-二_0-乙醯基-2’-去氧-5-(2-氯乙烯基）-1^4-羥基 胞苷， 3，，5，-二-0-乙醯基-2，-去氧-5-(2-溴乙烯基）-尺4-羥基 胞苷， 3，，5，_二_〇_乙醯基-2’-去氧-5-(2-碘乙烯基）-N4-羥基 胞苷， 3，，5，_二-〇-乙醯基-2，-去氧-5-(2-甲氧羰基乙烯基）- N4_經基胞苷， 3, 5，_二-〇-乙醯基-2，-去氧-5-(2-羥基羰基乙烯基）- (請先閱讀背面之注意事項再填寫本頁) 線丨_ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 217 91949 1293306 Α7 ______ Β7 五、發明說明（218) N4-羥基胞苷， 3’，5、二乙醯基_2’_去氧-5-苯基-N4·羥基胞脊，與 (請先閱讀背面之注音？事項再填寫本頁) 3’，5’_二_〇_乙醯基_2，_去氧_5_苄基-N4_羥基胞苷。 實例40 N4-羥基胞苷 取2’，3’_〇_亞異丙基_5，_〇_三苯甲基-N4$基胞苷（5〇〇 毫克’ 0.92毫莫耳）溶於50毫升三氟乙酸與水（2:1，v/v) 混合物中，溶液於50°C下攪拌3小時。冷卻至室溫後，蒸 發排除溶劑，與乙醇（3x 20毫升）共蒸發。殘質經矽膠管柱 層析法純化（20% MeOH之CHC13溶液），產生N4-羥基胞苷 (215毫克）之白色固體，自乙醇中再結晶， mp.173-176 °C. lR NMRiDMSO-de) δ 3.66-3.71(m, 2Η), 3.93 (br s, 1H), 4.08-4.15 (m, 2H)，5.17-5.23 (m，2¾ D20 可交換）,5.43 (4 J = 6·00 Hz，1H，DiO 可交換）， 5.73 (d, J = 8.16 Hz, 1H), 5.90 (d, J = 8.12 Hz, 1H), 7.28 (d, J = 8.40 Hz, 1H), 9.65 (s, 1¾ D20可交換 ），10.15 (s, 1H，D20可交換 ）·分析C9H13N306:計算值C， 41.70; H，5·05; N，16·21·實測值:C, 41·85; Η, 5.14; N, 16.34. 經濟部智慧財產局員工消費合作社印製 依類似方法，但改用相應之5-經取代之2,，3,-Ο-亞異丙 基-5-0-三苯基甲基-Ν4-羥基胞嘧啶核苷，製備下列Ν4-羥基 -5 -經取代之胞脊： 5_氟-1^4-羥基胞苷， 5-氯-Ν4_羥基胞苷， 5-溴-Ν4-羥基胞苷， 5-碘-Ν4-羥基胞苷， 5-甲基-Ν4_羥基胞苷， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 218 91949 1293306 A7 _ B7 五、發明說明（219) 5-乙基-N4-羥基胞苷， 5_正丙基-N4-羥基胞苷， 5-異丙基-N4 -經基胞甘， 5-乙烯基·Ν4-羥基胞苷， 5-乙炔基_Ν4-羥基胞苷， 5-(2-氣乙烯基）-Ν4-羥基胞苷， 5-(2-&gt;臭乙稀基）-N4 -經基胞有1， 5-(2_碘乙烯基）-N4-羥基胞苷， 5-(2-甲氧羰基乙烯基）-N4-羥基胞苷， 5-(2-羥基羰基乙烯基）_!^·經基胞苷， 5_本基_1^4-經基胞脊，與 5-T基-N4-羥基胞苷。 依類似方法，但改用氨之甲醇溶液替代三氟乙酸，及 改用相應之5_經取代之^仏弘二小·乙醯基_3-去氧-召-D-咲喃赤蘚戊糖基）-N九羥基胞嘧啶核苷，製備下列N4-羥基-5_經取代之3，-去氧胞苷： 5-氟-3、去氧-N4_羥基胞苷， 5-氣_3’-去氧-N4-羥基胞苷， 5-溴-3、去氧-N4_羥基胞苷， 5-攝-3’-去氧-N4_羥基胞苷， 5·甲基-3’-去氧_]sj4-羧基胞苷， 5-乙基_3’_去氧·Ν4_羥基胞苷， . 5_正丙基_3，·去氧-Ν4-羥基胞苷， _5_異丙基_3’_去氣-Ν4-鞀某臉芬， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 -------------§ (請先閱讀背面之注意事項再填寫本頁)Basal 杳, 2,, 3, -. · isopropylidene~~triphenylmethyl-5-ethylcytidine, alkynyl_N4-hydroxy 2',3'_0-isopropylidene_5 N4_ via basal ridge, 2',3 '-〇-isopropylidene_5 N4-hydroxycytidine, 2',3'-〇_isopropylidene_5 N4-hydroxycytidine, 2',3'-〇·isopropylidene )-N4-trans-basal ridge, 2',3'-〇-isopropylidene-5 alkenyl)-N4_hydroxycytidine, 2',3'-〇-isopropylidene cytidine, and 2 ',3'-〇_isopropylidene cytidine. Diphenylmethyl-5-(2-vinylvinyl)-diphenylmethyl_5-(2-bromovinyldiphenylmethyl_5_(2•iodovinyl)_ '_〇_3 Phenylmethyl-5-(2-methoxycarbonylethyl-indole-diphenylmethyl-5-(2-hydroxycarbonylethenyl-triphenylmethyl-5-phenyl-N4.hydroxydiphenyl) Methyl-N4-hydroxy (please read the phonetic on the back? Please fill out this page) 0 I------Book--------- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print 214 According to a similar method, but with the corresponding 5-position substituted 2,5,-diethylhydrazinyl_3'_deoxyurinary ridge, the following 4 cannons are prepared as follows: 5,-Di-indole-ethenyl 3'-deoxyribone derivative: 1-(2,5-diethylhydrazine_3_deoxy-indole_furan-erythropentyl)_N4- Base cell squeezing, 1·(2,5-di-〇_乙醯基_3_deoxy-no _D_咲咲赤藓 pentose)) 5-Fluorine-N4_^ base cell shouting, Ben The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 91949 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 215 1293306 A7 B7 V. Invention Description (215) 1-(2,5 -2-0 -B-Baked Base·3_Deoxidized·々 -D·咲咲赤戍糖戍)_ 5-Chloro-indole 4-hydroxycytosine, 1-(2,5-di-indole-ethanoyl-3-deoxy-indole-D-咲-ran Glycosyl)-5-bromo-indole 4-hydroxycytidine bite, 1-(2,5-di-0-ethyl-bromo-3-deoxy-wan-0-indolyl sulphate)_ 5 - moth-Ν4- via cell carcinoma, 1-(2,5_di-0-ethenyl-3-deoxy-do-D-purine erythropentyl)_ 5-cyano-Ν4 -hydroxycytosine, 1-(2,5-di-0-ethyl-bromo-3-deoxy-dot-D-nonyl-erythro-glycosyl)_ 5-ethoxycarbonyl-indole 4-hydroxycytosine, 1-(2,5-di-indole-ethyl-bromo-3-deoxy-D-purpurinyl glucosyl)-5-aminocarbonyl-N4-hydroxycytosine, 1-(2,5- ··················································· Ethyl 3-deoxy-wan-D·咲 赤 赤 戍 ) _ _ 5-methyl-Ν 4-hydroxycytocarcinoma bite, 1-(2,5-di-0-ethyl aryl-3 - deoxy-dots - 0 - 唉 pain red meal 戍 glycosyl) 5-ethyl-indole 4-hydroxycytosine, 1-(2,5-di-0·ethinyl-3-deoxy-lu- D-furan erythrosyl pentose)-5-n-propyl-indole 4-carboxycytocarcinoma, 1-(2,5-di-0-ethyl-bromo-3-deoxy-stone-D-咲 赤Glycosyl _ 5-isopropyl-N4-hydroxycytosine, 1-(2,5-di-0-ethyl-bromo-3-deoxy-dot-D-nonyl-erythro-pentosyl)_ 5_vinyl -N4-hydroxycytosine, this paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 (please read the notes on the back and fill out this page) -------- -------- Line » 1293306 A7 B7 V. Description of the invention (2i〇l-(2,5-di-indole-ethenyl I defuran (tetra)pentanosyl 5-allyl-N4-hydroxyl Cytosine, (please read the notes on the back and fill out this page) 1 1 (2,5 - 2 0 - B-based - 3 - OT\ pr-f* ^ Λ, ^ ^ f Oxygen - Lu - D-furan erythrosyl pentose) 5-ethynyl-N4-hydroxycytosine, 1-(2,5-di-indole-ethenyl)·deoxypurpurin pentoseose 5-(2) ·Milkyl)-N4·Breaked by the base cell, 1·(2,5-diindole-ethenyl_3_deoxyfuran(tetra)pentyl)) 5-(2_&gt; stinyl) -N4 - bite by base cell, 1-(2,5-di-indole-ethenyl_3_deoxy_dot_1)_咲咲赤藓 pentose)) 5-(2-magnetic B Dilute base)-N4-transplantation by base cell, 1-(2,5-di-indole-ethenyl-3_deoxy-dot_D_furan-erythropentyl)_ 5-(2-A Oxygen Vinyl)_N4_hydroxycytosine, 1-(2,5-di-indole-ethenyl_3_deoxy-dot_D_furanerythrosyl)- 5-(2•ylcarbonyl) Vinyl)-seven 4-hydroxycytosine, 1-(2,5-di-indole-ethenyl-3-deoxy-furan-erythro-pivalose-based 5-phenyl-indole 4-bitocellular carcinoma bite Printed with the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives - 1_(2,5-di-indole-ethenyl_3-deoxyfuran-erythropentyl)_ 5-mercapto-N4-peripheral carcinoma bite. According to a similar method', but using the corresponding 5_substituted 3,5, bis-indolyl-2'-deoxyuridine, the following N4_hydroxy_3,5,_____ Ethyl hydrazine _ N4-hydroxy-2, deoxyribone derivative · 3', 5'-di- 〇 醯 醯 _2 、, deoxy 氺 4 hydroxycytidine, 3 ', 5 ' _ -〇-acetamido_2,_deoxy_5_fluoro_;^4_hydroxycytidine, 3%5'-diethylhydrazine^·to bamboo shoot _ _m4_ silk fierce, this paper scale Applicable to China National Standard (CNS) A4 Regulations! Γ^ΙΓχ 297 )--- 216 91949 1293306 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed B7__ five, invention description (2Π) 3,,5,-two-0 -ethinyl-2'-deoxy-5-bromo-1^4-hydroxycytidine, 3,5,-di-O-ethenyl-2'-deoxy-5-iodo-1^4 -hydroxycytosolic, 3,5,-di-O-acetyl- 2'-deoxy-5-cyano-1^4-hydroxycytidine, 3,5,-di-O-acetyl Base-2,-deoxy-5-ethoxycarbonyl-1^4-hydroxycytosine, 3,5,-di-O-ethenyl-2'-deoxy-5-aminocarbonyl-foot 4 -hydroxycytosine, 3,5,-di-O-O-acetyl- 2'-deoxy-5-ethenyl-&gt;^4-hydroxy ridge, 3,,5,_di-〇_ B Base-2,-deoxy-5-methyl-:^4-hydroxycytidine, 3,5,-di-O-ethenyl-2'-deoxy-5-ethyl-1^4- Hydroxy ridge, 3,5,-di-O-O-acetyl-2,-deoxy-5-n-propyl-: 4-hydroxycytidine, 3,5,-di-O-acetyl -2'-deoxy-5-isopropyl-indole 4-hydroxycytidine, 3,5,-di-O-ethenyl-2,-deoxy-5-vinyl-:^4- Hydroxycytidine, 3,5,-di-O-ethylindolyl-2,-deoxy-5-allyl-N4-hydroxycytidine, 3,5,-di-indenyl-ethenyl 2,_Deoxy_5_ethynyl-N4-hydroxycytidine, 3,5,-di-oxo-indenyl-2'-deoxy-5-(2-chlorovinyl)-1^4 -hydroxycytidine, 3,5,-di-O-ethylindolyl-2,-deoxy-5-(2-bromoethenyl)- ft 4-hydroxycytidine, 3,5, _ 〇_乙醯基-2'-deoxy-5-(2-iodovinyl)-N4-hydroxycytidine, 3,5,-di-indenyl-ethenyl-2,-deoxy-5- (2-methoxycarbonylvinyl)-N4_ via cytidine, 3, 5, bis-indenyl-ethenyl-2,-deoxy-5-(2-hydroxycarbonylvinyl)- (please Read the notes on the back and fill out this page. Line 丨 _ This paper scale applies to China National Standard (CNS) A4 Grid (210 X 297 mm) 217 91949 1293306 Α7 ______ Β7 V. Description of invention (218) N4-hydroxycytidine, 3',5,diethylindenyl 2'-deoxy-5-phenyl-N4· Hydroxy ridges, and (please read the phonetic on the back first? Please fill in this page again) 3',5'_二_〇_Ethyl 2,_deoxy_5_benzyl-N4_hydroxycytidine. Example 40 N4-hydroxycytidine taken 2',3'_〇_isopropylidene_5,_〇_trityl-N4$-cytidine (5〇〇 mg '0.92 mmol) dissolved in 50 The mixture was stirred at 50 ° C for 3 hours in a mixture of trifluoroacetic acid and water (2:1, v/v). After cooling to room temperature, the solvent was evaporated and evaporated with ethanol (3×20 mL). The residue was purified by EtOAc EtOAc EtOAc (EtOAc) elute De) δ 3.66-3.71(m, 2Η), 3.93 (br s, 1H), 4.08-4.15 (m, 2H), 5.17-5.23 (m, 23⁄4 D20 exchangeable), 5.43 (4 J = 6·00 Hz ,1H,DiO exchangeable), 5.73 (d, J = 8.16 Hz, 1H), 5.90 (d, J = 8.12 Hz, 1H), 7.28 (d, J = 8.40 Hz, 1H), 9.65 (s, 13⁄4 D20 Exchangable), 10.15 (s, 1H, D20 exchangeable)·Analysis C9H13N306: Calculated value C, 41.70; H,5·05; N,16·21·Measured value: C, 41·85; Η, 5.14; N 16.34. The Ministry of Economic Affairs' Intellectual Property Office staff consumption cooperative prints a similar method, but uses the corresponding 5-substituted 2,3,-Ο-isopropylidene-5-0-triphenylmethyl- Ν 4-hydroxycytidine nucleoside, the following Ν4-hydroxy-5-substituted ridges were prepared: 5-fluoro-1^4-hydroxycytidine, 5-chloro-Ν4-hydroxycytidine, 5-bromo-indole 4- Hydroxycytidine, 5-iodo-indole 4-hydroxycytidine, 5-methyl-indole 4-hydroxycytidine, this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 218 91949 1293306 A7 _ B7 V. INSTRUCTIONS (219) 5-Ethyl-N4-hydroxycytidine, 5-propyl-N-hydroxycytidine, 5-isopropyl-N4-trans-glycol, 5 -vinyl·Ν4-hydroxycytidine, 5-ethynyl-Ν4-hydroxycytidine, 5-(2-vinylvinyl)-indole 4-hydroxycytidine, 5-(2-&gt; stinyl)- N4 - via the unit cell, 5-(2-iodovinyl)-N4-hydroxycytidine, 5-(2-methoxycarbonylvinyl)-N4-hydroxycytidine, 5-(2-hydroxycarbonylvinyl Base) _!^· via cytidine, 5_bens-1-4 through the basal ridge, and 5-T-N-hydroxycytidine. According to a similar method, but instead use ammonia methanol solution instead of trifluoroacetic acid, and use the corresponding 5_ substituted ^仏弘二小·乙醯基_3-deoxy-callo-D-咲 藓 藓 藓 藓))-N nonhydroxycytosine nucleoside, the following N4-hydroxy-5-substituted 3,-deoxycytidine: 5-fluoro-3, deoxy-N4 hydroxycytidine, 5-gas _3 '-Deoxy-N4-hydroxycytidine, 5-bromo-3, deoxy-N4_hydroxycytidine, 5-photo-3'-deoxy-N4_hydroxycytidine, 5·methyl-3'- Deoxygenated _]sj4-carboxycytidine, 5-ethyl_3'-deoxy-indole 4-hydroxycytidine, .5_n-propyl-3, deoxy-purine 4-hydroxycytidine, _5_isopropyl Base_3'_Degas-Ν4-鼗一芬芬, This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 -------------§ ( Please read the notes on the back and fill out this page.)

Ιϋ ϋ ϋ ϋ ·ϋ —_&gt;i I 一^&gt; 1 ·.1 I 1« Λκ§ -n ·ϋ I 線丨# 經濟部智慧財產局員工消費合作社印製 219 [293306 A7 B7 五、發明說明（22〇) 5·乙晞基-3’-去氧_Nt羥基胞苷， 5·乙炔基_3’-去氧_]^4-羥基胞杳， 5-(2-氯乙烯基）_3，_去氧·N4_羥基胞苷， 5-(2-溴乙烯基）_3，-去氧-：^4-羥基胞苷， 5-(2•碘乙烯基）_3，_去氧_N、羥基胞苷， 5-(2_甲氧羰基乙烯基）_3’_去氧-N4_經基胞普， 5-(2-羥基羰基乙烯基）-3，_去氡_N、羥基胞苷， 5-苯基-3、去氧_N4_羥基胞苷，與 5-T基-3’-去氧-N4_羥基胞苷。 依類似方法，但改用氨之甲醇溶液替代三氟乙酸，及 改用相應之5_經取代之3，，5，_二_〇_乙醯基_2、去氧_n4_羥 基胞嘧啶核苷，製備下列！^_羥基_5_經取代之2、去氧胞 苷： 、 5-氟-2’·去氧-N4-羥基胞苷， 5-氯_2’_去氧羥基胞苷， 5-溴-2’-去氧-N4-羥基胞苷， 5_碘-2’-去氧_N4-羥基胞苷， 5-甲基-2’-去氧-N4-羥基胞苷， 5_乙基-2，-去氧_n4-羥基胞苷， 5_正丙基-2、去氧-N4-羥基胞苷， 5-異丙基_2, ·去氧-N4-羧基胞苷， 5_乙烯基_2’_去氧-N4-羥基胞苷， 5_乙炔基-2’·去氧-N4-羥基胞苷， 5-(2-乳乙烯基）_2’-去氧-N4-經基胞苷 91949 (請先閱讀背面之注音？事項再填寫本頁) — — — — — — — ^ ·11111111 ». 經濟部智慧財產局員工消費合作社印製 220 A7 1293306 B7_ 五、發明說明（221 ) 5_(2_溴乙烯基）-2，-去氧-N4-羥基胞苷， 5-(2-碘乙烯基）-2，-去氧-N4-羥基胞苷， 5-(2•甲氧羰基乙烯基）-2’-去氧-N4-羥基胞苷， 5_(2_羥基羰基乙烯基)-2’-去氧-N4-羥基胞苷， 5-苯基-2’-去氧-N4-羥基胞苷，與 5-卞基-2’-去氧-N4-幾基胞脊。 實例41 2,3’·脫水-1·(2-去氧-2-氟-5-0-三苯甲基-D-呋喃來蘇糖 基）胸腺嘧啶（194，R=Tr) 取含1-(2•去氧·2·氟-3_0-甲磺醯基·5-0-三苯甲基-召-D-呋喃阿拉伯糖基）胸腺嘧啶（i93，R=Tr，6·0克）與DBU(3.0 毫升）之二氣甲烷（50毫升）溶液回流加熱16小時。混合物 真空濃縮後，殘質使用氣仿為溶離液，經矽膠管柱層析， 產生4·4克2,3’_脫水-1-(2，-去氧-2，-氟-5-0_三苯甲基-D_呋喃來蘇糖基）胸腺嘧啶（194, R=Tr)，自甲醇中再結晶 後， mp 252-255 °C. lH NMR (DMSO-de); δ 1.80 (s, 3H, Me), 4.61 (1H, m), 5.40 (dm, 1H), 5.89 (1H, ddd), 5.96 (1¾ dd, Η-Γ), 7.30 (15H, Tr), 7.66(s,lH,H-6). 實例42 1- (2,3-二去氧-2，-氟-5’-〇-三苯甲基-泠-〇-甘油基-呋喃戊- 2- 烯糖基）胸腺嘧啶（195，R=Tr) 取含（194)(646 毫克）與 t-BuOK(270 毫克）之 DMSO(10 毫升）懸浮液於室溫下攪拌2小時後，過濾。濾液真空濃 --------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 221 91949 經濟部智慧財產局員工消費合作社印製 1293306 A7 _B7___ 222 五、發明說明（ ） 縮，殘質經石夕膠管柱層析（CHCl3/MeOH，49:1，v/v)，產生 600 毫克（195)， mp· 176-180 °C (自 EtOH)· 4 NMR (DMSOO δ 1.27 (¾ 3H, Me), 3.21 (m, 2H, H-5,5^ 4.98 (m, 1H, 6.17 (t, 1H, Η-Γ, = = L5 Hz), 6.81 (m, 1H, Η^*), 732 (m, 16H, H-6, Tr), 11.52 (s, 1H, NH 可交換 &gt;· 實例43 l-(2,3-二去氧-2-氟·沒-D -甘油基-2-咲喃戍-2·稀糖基）胸腺 嘧啶（196) 取含（195)(600毫克）之80%乙酸水溶液（10毫升）回流 加熱20分鐘，然後真空濃縮至乾。殘質經矽膠管柱層析 (CHCl3/MeOH，9 :1，v/v)，產生 100 毫克（196)， mpl54»159°C (自 Et0H-H20)· ^NMRCDMSO-de) δ 1.76(8,311，1^)，3.61(吼 2Η，Η-5，,5”), 4.79 (m, 1Η, Η·4，), 5·15 仏 1¾ 5，·ΟΗ,可交換）,5·99 (取 1Η, Η-Γ)， 6·76 (m, 1¾ Η·3’)，7·88 (s，1Η, Η·6), 11·43 (s, 1Η, NH 可交換）· 實例44 (lS，2S，3R，4R)-4-(第三丁氧甲基）-2,3-(亞異丙基二氧）環戊 烷-1-醇（219) 於〇°C下，添加NaBH4(1.01克）至含4-(第三丁氧甲基） 環戊烷-2,3-二醇（218，5 克）與 CeCl3 · 7Η20(7·69 克）之甲 醇（80亳升）溶液中，混合物於〇°c下攪拌1小時。添加冷 水中止反應，以乙酸乙酯（2χ 300毫升）萃取。合併之有機 萃液以鹽水（2χ 200毫升）洗滌，以Na2S04脫水，真空濃 縮。殘質經矽膠管柱層析（30〇/〇乙酸乙酯之正己烷溶液），產 生（219)(4.8克，95%)之漿狀物。 ^^1 «1^ n ·ϋ ϋ— a·— n 1_1 ·ϋ me§ · —ϋ ·ϋ in I— n an J—、β ϋ ·1 ·ϋ n -ϋ an 1ϋ I -- t ^ (請先閱讀背面之注意事項再填寫本頁)Ιϋ ϋ ϋ ϋ ·ϋ —_&gt;i I 一^&gt; 1 ·.1 I 1« Λκ§ -n ·ϋ I Line丨# Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 219 [293306 A7 B7 V. Invention Description (22〇) 5·Ethyl-3'-deoxy_Nthydroxycytidine, 5·ethynyl_3'-deoxy-]^4-hydroxycytidine, 5-(2-chlorovinyl) _3,_deoxy-N4_hydroxycytidine, 5-(2-bromovinyl)_3,-deoxy-: 4-hydroxycytidine, 5-(2•iodovinyl)_3,_deoxy_ N, hydroxycytidine, 5-(2-methoxycarbonylvinyl)_3'-deoxy-N4_trans-cytosine, 5-(2-hydroxycarbonylvinyl)-3, _dein-N, hydroxy Cytidine, 5-phenyl-3, deoxy-N4_hydroxycytidine, and 5-T-based-3'-deoxy-N4-hydroxycytidine. According to a similar method, but instead use ammonia methanol solution instead of trifluoroacetic acid, and use the corresponding 5_ substituted 3,5,_di_〇_acetamido_2, deoxy-n4_hydroxycytosine Nucleosides, prepare the following! ^_Hydroxy_5_substituted 2, deoxycytidine: 5-fluoro-2'-deoxy-N4-hydroxycytidine, 5-chloro-2'-deoxyhydroxycytidine, 5-bromo- 2'-deoxy-N4-hydroxycytidine, 5_iodo-2'-deoxy-N4-hydroxycytidine, 5-methyl-2'-deoxy-N4-hydroxycytidine, 5-ethyl- 2,-deoxy-n4-hydroxycytidine, 5-n-propyl-2, deoxy-N4-hydroxycytidine, 5-isopropyl-2, deoxy-N4-carboxycytidine, 5_ethylene Base 2'-deoxy-N4-hydroxycytidine, 5-ethynyl-2'-deoxy-N4-hydroxycytidine, 5-(2-lactylvinyl)_2'-deoxy-N4-radio Cytidine 91949 (Please read the phonetic transcription on the back? Please fill out this page again) — — — — — — — ^ 11111111 ». Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 220 A7 1293306 B7_ V. Invention description (221 ) 5-(2-bromovinyl)-2,-deoxy-N4-hydroxycytidine, 5-(2-iodovinyl)-2,-deoxy-N4-hydroxycytidine, 5-(2-methoxy Carbonyl vinyl)-2'-deoxy-N4-hydroxycytidine, 5-(2-hydroxycarbonylvinyl)-2'-deoxy-N4-hydroxycytidine, 5-phenyl-2'-deoxy- N4-hydroxycytidine, and 5-mercapto-2'-deoxy-N4-single cell . Example 41 2,3'·dehydration-1·(2-deoxy-2-fluoro-5-0-trityl-D-furanosyl) thymine (194, R=Tr) -(2•deoxy·2·fluoro-3_0-methylsulfonyl·5-0-trityl-callo-D-furan arabinosyl) thymine (i93, R=Tr, 6·0 g) It was heated under reflux with DBU (3.0 mL) in dioxane (50 mL) for 16 h. After the mixture was concentrated in vacuo, the residue was subjected to gas chromatography as a solvent, and subjected to silica gel column chromatography to give 4·4 g of 2,3'-dehydrate-1-(2,-deoxy-2,-fluoro-5-0). _ trityl-D-furanthretonyl) thymine (194, R=Tr), after recrystallization from methanol, mp 252-255 ° C. lH NMR (DMSO-de); δ 1.80 (s , 3H, Me), 4.61 (1H, m), 5.40 (dm, 1H), 5.89 (1H, ddd), 5.96 (13⁄4 dd, Η-Γ), 7.30 (15H, Tr), 7.66(s,lH, H-6). Example 42 1-(2,3-Dideoxy-2,-fluoro-5'-indole-trityl-indole-indole-glyceryl-furanyl-2-enlenose) thymus Pyrimidine (195, R = Tr) A suspension of (194) (646 mg) and t-BuOK (270 mg) in DMSO (10 ml) was stirred at room temperature for 2 hr and filtered. The filtrate is vacuum-------------------- order--------- line (please read the notes on the back and fill in this page) The property bureau employee consumption cooperative printed this paper scale applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 221 91949 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1293306 A7 _B7___ 222 V. Invention description ( ) The residue was chromatographed (CHCl3 / MeOH, 49:1, v/v) to yield 600 mg (195), mp 176-180 ° C (from EtOH) · 4 NMR (DMSOO δ 1.27 (3⁄4) 3H, Me), 3.21 (m, 2H, H-5, 5^ 4.98 (m, 1H, 6.17 (t, 1H, Η-Γ, = = L5 Hz), 6.81 (m, 1H, Η^*), 732 (m, 16H, H-6, Tr), 11.52 (s, 1H, NH exchangeable) Example 43 l-(2,3-Dideoxy-2-fluoro·----glyceryl-2 - 咲 戍 戍 · · 稀 稀 胸 胸 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 196 Column chromatography (CHCl3/MeOH, 9:1, v/v) yields 100 mg (196), mpl 54»159 ° C (from Et0H-H20) · ^NMRC DMSO-de) δ 1.76 (8,311,1^) 3.61 (吼2Η,Η-5,,5”), 4.79 (m, 1Η, Η·4,), 5·15 仏13⁄4 5,·ΟΗ, exchangeable), 5·99 (take 1Η, Η-Γ ), 6·76 (m, 13⁄4 Η·3'), 7·88 (s, 1Η, Η·6), 11·43 (s, 1Η, NH interchangeable) · Example 44 (lS, 2S, 3R, 4R)-4-(t-butoxymethyl)-2,3-(isopropylidene dioxy)cyclopentan-1-ol (219) NaBH4 (1.01 g) was added at 〇 ° C to a solution of 4-(t-butoxymethyl)cyclopentane-2,3-diol (218,5 g) and CeCl3 · 7Η20 (7·69 g) in methanol (80 liters), mixture at 〇° The mixture was stirred for 1 hour. The reaction was quenched with EtOAc EtOAc (EtOAc m. (30 〇 / 〇 ethyl acetate in n-hexane) afforded ( 219) ( 4.8 g, 95%). ^^1 «1^ n ·ϋ ϋ— a·—n 1_1 ·ϋ me§ · —ϋ ·ϋ in I— n an J—, β ϋ ·1 ·ϋ n -ϋ an 1ϋ I -- t ^ ( Please read the notes on the back and fill out this page.)

A7 1293306 _____B7______ 五、發明說明（223 ) !H-NMR (CDCI3) δ 1.13 (s, 9H, f-Bu), 134 (s, 3H, Me), 1.48 (s, ^ 3H，Me)，1·83 (m, 2ft 5Μ&gt;-Η), 2·19 (m, 1H, 4«H), 2·44 (4 OH，可交換）,3.20 (租 J « 4.5, 8.8 Hz, 1H, 6a-H), 3.31 (dd, J « 4.5,8.8 Hz, 1H, 6b-H), 4.23 (m, 1H, 1-H), 4.44 (m, 2Η，2·Η,3_Η)·分析 C13H24〇4:計算值 C, 63.91;Η，9·90·實測值：C, 64.09;Η,9·87· f例45 (13,28,311，411)-4-(第三丁氧甲基）-：2,3_(亞異丙基二氧）-：1- 甲磺醯氧環戊烷（220) 於〇°C下，滴加甲磺醢氣（4.73克）至含（219)(6.50克） 與三乙胺（7.3克）之二氣甲烷（170亳升）溶液中，45分鐘 後，加水（270毫升）。以二氣甲烷（3χ 200毫升）萃取水層。 合併有機層’以鹽水（2χ 200毫升）洗務，以Na2S04脫水， 真空濃縮，產生粗產物（220)，其純度足供直接用於下一個 步驟。 實例46 (18,28,3尺，41〇-1-疊氮基-4-(第三丁氧甲基）-2,3-(亞異丙基 二氧）環戊烷（221) 取含上述得到之（220)與疊氮化鈉（17.3克）之DMF(300 毫升）於140°C下攪拌加熱一夜。混合物過濾，濾液真空濃 縮，殘質分佈在乙酸乙酯（150毫升）與水（50毫升）之間。有 機層經Na2S04脫水，真空濃縮，殘質經矽膠管柱層析 至4%梯度，含乙酸乙酯之正己烷），產生（221)(5.9克）之油 狀物。 --------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210x297公釐） 223 91949 經濟部智慧財產局員工消費合作社印製 1293306 A7 ______ B7 五、發明說明（224 ) lH NMR (CDCI3) δ 1.18 (s, 9H, r-Bu), L30 (s, 3H, Me), 1.46 (s, 3H, Me), L71 (m, 1H, 5a-H), 2.29 (m, 2¾ 4-H, 5b-H), 3.29 (dd, J = 6.7, 8.8 Hz, 1H, 6a-H), 3.37 (dd, J * 7.0, 8.8 Hz, 1H, 6b-H), 3.96 (m, 1H, 1-H), 4.40 (dd, J = 2.3, 6.1 Hz, 1H, 3·Η), 4·48 (dd, J = 2.0，6·1 1¾ 1H, 2-H)·分析 Cl3H23N3O30.13EtOAc:計算值 c，57·95; Η, 8·65, N, 14·99·實測值： C, 58,25; H, 8.71; N, 14.76. 實例47 (lS,2S,3R，4R)-4-(第三丁氧甲基）-2,3-(亞異丙基二氧）·1_ 環戊胺（222) 取含（221)(4.0克）與10% Pd/C(1.0克）之無水乙醇（140 毫升）懸浮液於20 psi H2下振盪5小時。混合物過濾，濾 液真空濃縮，產生粗產物（222)(3.6克，全收量），未再純 化即直接用於下一個步驟。A7 1293306 _____B7______ V. INSTRUCTIONS (223) !H-NMR (CDCI3) δ 1.13 (s, 9H, f-Bu), 134 (s, 3H, Me), 1.48 (s, ^ 3H, Me), 1· 83 (m, 2ft 5Μ&gt;-Η), 2·19 (m, 1H, 4«H), 2·44 (4 OH, exchangeable), 3.20 (rent J « 4.5, 8.8 Hz, 1H, 6a-H ), 3.31 (dd, J « 4.5, 8.8 Hz, 1H, 6b-H), 4.23 (m, 1H, 1-H), 4.44 (m, 2Η, 2·Η, 3_Η)·Analysis C13H24〇4: Calculation Value C, 63.91; Η, 9·90·Measured value: C, 64.09; Η, 9·87· f Example 45 (13, 28, 311, 411) -4- (t-butoxymethyl)-: 2, 3_ (isopropylidene dioxy)-: 1-methanesulfonyloxycyclopentane (220) at 〇 ° C, adding methotrexate (4.73 g) to (219) (6.50 g) and triethyl A solution of the amine (7.3 g) in a two-gas methane (170 liters), after 45 minutes, water (270 mL). The aqueous layer was extracted with di-methane (3 χ 200 mL). The combined organic layers were washed with brine (2 EtOAc (EtOAc) (EtOAc) elute Example 46 (18, 28, 3 ft, 41 〇-1-azido-4-(t-butoxymethyl)-2,3-(isopropylidene dioxy)cyclopentane (221) The above obtained (220) and sodium azide (17.3 g) in DMF (300 ml) were stirred and warmed overnight at 140 ° C. The mixture was filtered, and the filtrate was concentrated in vacuo. The organic layer was dehydrated with Na2SO4, concentrated in vacuo, EtOAc EtOAc EtOAc EtOAc . -------------------- Order --------- line (please read the notes on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Office staff Consumer Cooperatives Printed Paper Standards Applicable to China National Standard (CNS) A4 Specification (210x297 mm) 223 91949 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1293306 A7 ______ B7 V. Inventions (224) lH NMR (CDCI3) δ 1.18 (s, 9H, r-Bu), L30 (s, 3H, Me), 1.46 (s, 3H, Me), L71 (m, 1H, 5a-H), 2.29 (m, 23⁄4 4-H, 5b -H), 3.29 (dd, J = 6.7, 8.8 Hz, 1H, 6a-H), 3.37 (dd, J * 7.0, 8.8 Hz, 1H, 6b-H), 3.96 (m, 1H, 1-H) , 4.40 (dd, J = 2.3, 6.1 Hz, 1H, 3·Η), 4·48 (dd, J = 2.0,6·1 13⁄4 1H, 2-H)·Analysis Cl3H23N3O30.13 EtOAc: Calculated c, 57 · 95; Η, 8·65, N, 14·99·Found: C, 58,25; H, 8.71; N, 14.76. Example 47 (lS, 2S, 3R, 4R) -4- (third Oxymethyl)-2,3-(isopropylidene dioxy)·1_cyclopentylamine (222) Containing (221) (4.0 g) and 10% Pd/C (1.0 g) in absolute ethanol (140 ml) The suspension was shaken for 5 hours at 20 psi H2. The mixture was filtered and the filtrate was concentrated in vacuo to afford crude material ( 222) (3.6 g,

'H NMR (CDCfe) δ L18 (s, 9H, /-Bu), 1.28 (s, 3H, Me), 1,36 (m, 1H, 5a-H), 1.45 (s, 3H, Me), 1.89 (br s, 2H, NH2), 2.24-236 (m, 2H, 4· H, 5b-H), 334-3.43 (m, 3H, 1-H, 6a,b-H), 4.21 (dd, J = 2·6,6.2 Hz, 1H, 3-H), 4.48 (dd, J =2·8, 6·2 Hz, 1H, 2·Η)·分析 CuH26N03O.16H2〇:計算值 C, 63·41; H，10.37, n, 5.69.實測值:C, 63·09; Η, 10·16; N, 5.59. ' * 實例48 ]^-{[(1尺，28,3厌，4&amp;)_4-(第三丁氧甲基）-2,3-(亞異丙基二氧） 環戊基]胺幾基}-3 -甲氧基-2-丙稀醯胺（2 23) 取含氰酸銀（7_60克，於黑暗中，1〇〇。(；下，經五氧化 磷真空乾燥3小時）、石-甲氧丙烯醯基氯（2.64克）之無水 苯（3 0毫升）混合物回流加熱3 0分鐘，然後冷卻至室溫。待 沈澱物沈降後，在15分鐘内添加22.5毫升含有yS-甲氧丙 烯醯基異氰酸酯之上澄液至-15至-20°C及氮氣下，含 ------------f--------訂---------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公复） 224 91949 1293306 A7 B7 225 五、發明說明（ (222)(3.0克）之無水DMF(50毫升）溶液中，混合物於_15t 下攪拌2小時後，於室溫及氮氣下再攪拌1 〇小時。真空濃 縮後，與甲苯（2x 20毫升）共蒸發，產物（223)固化（4 〇克）。 !H NMR(CDG13) δ 1.17 (s, 9H, ί-Bu), 1.28 (s, 3H, Me), 1.47 (s, 3H, Me), 1.58 (m, 1H, 5fa-H), 2.28 (m, 1H, 4-H), 236-2.43 (m, 1H, S^H), 3.33-3.42 (m, 2H, e^b-H), 3.73 (s, 3H, OMe), 4.20 (m, 1H，3’-H)，4·45 (m, 2H, Γ-Η； 5.35 (d, J == 12.3 Hz, 1¾ 5·Η), 7·67 (4 J = 12·3 1¾ 1H, 6·Η)，8·72 (hr s, 1¾ NH), 9·35 (br s，1H，NH).分析 Cl8H30N2〇6: 計算值 C，5S.36; Η, 8·16, N，7.56.實測值：C, 58·28; H, 8.16; N, 7.60· 實例49 (1’12’8,3’14，尺)_1-[4-(第三丁氧甲基）-2,3_亞異丙基二氧） 環戊烷-1-基]尿嘧啶（5、第三丁基-2,，3,-〇-亞異丙基-碳化 尿苷，224) 取含（223)(4.2克）之乙醇（25毫升）與氫氧化銨（30%， 11毫升 &gt;之溶液於100°C之不銹鋼彈形容器中加熱12小 時。排除溶劑後，殘質經矽膠管柱層析（乙酸乙酯-正己烷， 1:1，v/v)，產生（224)(3.21克）之白色泡沫狀物。 UV (MeOH) W 266.0 rnn. ^NMRCCDCla) δ U9 (s, 9H, i-Bu), 1.30 (s, 3H, Me), 1.54 (s, 3H, Me), 1.97 (m, 1H, S^a-H), 2.32-2Λ1 (m, 2H, 4^H, 5VH), 3.43-3.50 (m, 2H, 4.48 (dd, J ^ 4.1,6.5 Hz, 1H, 4.65- 475 (m, 2H, 5.72 (d, J = 8.0 Hz, 1H, 5-H), 7.35 (d, J = 8-0 Hz, 1H, 6-H), 8.63 (br s, 1H，NH)·分析 C17H26N205:計算值 C, 6034; H 7.74,风 8.28.實測值：C, 60.06; a 7J0;N, 8.14. 實例50 (1'2,3,3，14，幻小[4-(第三丁氧甲基）-2,3-(亞異丙基二 氧）環戊燒_1-基]-5-氟尿嘧啶（5’-〇-第三丁基-2，，3，-〇-亞異 丙基-碳化-5-1尿苷，225) G張尺度適用中國國家標準（CNS)A4規格⑵0 X 297公爱) --- 225 91949 ϋ ϋ I I ϋ ϋ n ϋ I n I · ϋ n n n n I ml-^-reJ I n I f ϋ ϋ ϋ 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 經濟部智慧財產局員工消費合作社印製 1293306 A7 五、發明說明（226 ) 使含5 %氟之氟-氮混合氣體小心地通入室溫下，含 (224)(2.50克）之乙酸（600毫升）溶液中3〇分鐘。混合物授 拌至TLC板上不再檢測到UV吸收為止。真空排除溶劑， 殘質與乙酸（20毫升）共蒸發至乾。於5〇 °c下，以三乙胺處 理殘質1.5小時，然後真空濃縮至乾，殘質經矽膠管枉層 析純化（乙酸乙醋·正己燒，1:1，v/v)，產生（225)(1.31克） 之白色泡沫狀物。 UV (MeOH) λπ^ 271.5 nm. lR NMR (CDC13) δ 1.22 (s, 9H, /-Bu), 1.31 (s, 3H, Me), 1.55 (s, 3H, Me), 1.85 (m, 1H, S^a-H), 238-2.51 (m, 2H, 4*-Η, 5^-Η), 3.44-3.52 (m, 2H, 4.47 (dd, J = 3.4, 6.2 Hz, 1H, Τ-Ή)9 4.58 (t, J = 6.0 Hz, 1H, Γ-Η), 4.87 (dd, J = 8.9, 14.5 Hz, 1H, 2*-H), 7.61 (d, J - 6.1 Hz, 1H, 6-H), 8.77 (br s, 1H, NH).分析 C17H25FN205 0·25Η2Ο··計算值 C, 56·58; H, 7·12, N, 7 76 實測^ 實例51 (1’11，2’8,3’1154’11)-1-[4-(第三丁氧甲基）-2,3-亞異丙基二氧) 環戊烷-1_基]-5-氟胞嘧啶（226)(5，-0-第三丁基-2，，3，·0·亞 異丙基-碳化-5-氟胞苷） 取含（225)(350毫克）、三乙胺（190毫克、2,4,6_三異丙 基苯磺醯氣（590毫克）與DMAP(230毫克）乙腈（50毫升）混 合物於室溫下攪拌1天。添加氳氧化銨溶液（30%，15亳 升），混合物再攪拌5小時。添加氣仿（250毫升）及水（1〇 毫升）中止反應。以鹽水洗滌有機層，以Na2S04脫水及真 空濃縮。殘質經矽膠管柱層析純化（5%MeOH之CHC13溶 液，v/v)產生（226)(205 毫克），mp 128-130°C · (請先閱讀背面之注意事項再填寫本頁)'H NMR (CDCfe) δ L18 (s, 9H, /-Bu), 1.28 (s, 3H, Me), 1,36 (m, 1H, 5a-H), 1.45 (s, 3H, Me), 1.89 (br s, 2H, NH2), 2.24-236 (m, 2H, 4· H, 5b-H), 334-3.43 (m, 3H, 1-H, 6a, bH), 4.21 (dd, J = 2 ·6,6.2 Hz, 1H, 3-H), 4.48 (dd, J =2·8, 6·2 Hz, 1H, 2·Η)·Analysis of CuH26N03O.16H2〇: Calculated value C, 63·41; H , 10.37, n, 5.69. Measured: C, 63·09; Η, 10·16; N, 5.59. ' * Example 48 ]^-{[(1 ft, 28, 3 厌, 4&amp;)_4-( Third butoxymethyl)-2,3-(isopropylidene dioxy)cyclopentyl]amine-based}-3-methoxy-2-propanylamine (2 23) (7_60 g, in the dark, 1 〇〇. (under, vacuum drying with phosphorus pentoxide for 3 hours), stone-methoxypropenyl chloride (2.64 g) of anhydrous benzene (30 ml) mixture under reflux heating 3 0 minutes, then cooled to room temperature. After the sediment has settled, add 22.5 ml of yS-methoxypropenyl isocyanate over 15 minutes to -15 to -20 ° C under nitrogen, containing -- ----------f--------Book---------Line· (Please read the notes on the back and fill in this page) This paper size applies to China Household Standard (CNS) A4 Specification (210 X 297) 224 91949 1293306 A7 B7 225 V. Inventive Note ((222) (3.0 g) in anhydrous DMF (50 ml), the mixture was stirred at _15t for 2 hours. After that, it was stirred at room temperature under nitrogen for additional 1 hour, concentrated in vacuo, and then evaporated with toluene (2×20 mL). The product (223) was solidified (4 g).H NMR (CDG13) δ 1.17 (s, 9H, ί-Bu), 1.28 (s, 3H, Me), 1.47 (s, 3H, Me), 1.58 (m, 1H, 5fa-H), 2.28 (m, 1H, 4-H), 236-2.43 (m, 1H, S^H), 3.33-3.42 (m, 2H, e^bH), 3.73 (s, 3H, OMe), 4.20 (m, 1H, 3'-H), 4·45 (m, 2H, Γ-Η; 5.35 (d, J == 12.3 Hz, 13⁄4 5·Η), 7·67 (4 J = 12·3 13⁄4 1H, 6·Η), 8·72 (hr s, 13⁄4 NH) , 9·35 (br s, 1H, NH). Analysis Cl8H30N2〇6: Calculated C, 5S.36; Η, 8·16, N, 7.56. Found: C, 58·28; H, 8.16; , 7.60· Example 49 (1'12'8,3'14, ft)_1-[4-(Tertidinoxymethyl)-2,3-isopropylidene dioxy)cyclopentan-1-yl Uracil (5, tert-butyl-2,,3,-indole-isopropylidene-carburized uridine, 224) containing (223) (4.2 g) of ethanol (25 ml) Ammonium hydroxide (30%, 11 ml &gt; 12 hours the solution was heated at 100 ° C in a vessel of stainless steel bomb. After the solvent was removed, the residue was purified mjjjjjjjjjjjjj UV (MeOH) W 266.0 rnn. ^NMRCCDCla) δ U9 (s, 9H, i-Bu), 1.30 (s, 3H, Me), 1.54 (s, 3H, Me), 1.97 (m, 1H, S^aH ), 2.32-2Λ1 (m, 2H, 4^H, 5VH), 3.43-3.50 (m, 2H, 4.48 (dd, J ^ 4.1, 6.5 Hz, 1H, 4.65- 475 (m, 2H, 5.72 (d, J = 8.0 Hz, 1H, 5-H), 7.35 (d, J = 8-0 Hz, 1H, 6-H), 8.63 (br s, 1H, NH)·Analysis C17H26N205: Calculated C, 6034; H 7.74, wind 8.28. Found: C, 60.06; a 7J0; N, 8.14. Example 50 (1'2,3,3,14, phantom [4-(th-butoxymethyl)-2,3- (isopropylidene dioxy)cyclopentanol-1-yl]-5-fluorouracil (5'-fluorene-tert-butyl-2,3,-indole-isopropylidene-carbonated-5-1 urine Glycoside, 225) G-scale applicable to Chinese National Standard (CNS) A4 specification (2) 0 X 297 public) --- 225 91949 ϋ ϋ II ϋ ϋ n ϋ I n I · ϋ nnnn I ml-^-reJ I n I f ϋ ϋ ϋ I (please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Ministry of Printing and Economy Ministry Intellectual Property Bureau Employees Consumption Cooperatives Printed 1293306 A7 V. Inventions (226) 5% Fluorine-nitrogen mixed gas carefully passed to room temperature, containing (224) (2.50 g In a solution of acetic acid (600 ml) for 3 minutes, the mixture was stirred until no UV absorption was detected on the TLC plate. The solvent was removed in vacuo and the residue was evaporated to dryness with acetic acid (20 mL). The residue was treated with triethylamine for 1.5 hours, then concentrated to dryness in vacuo. The residue was purified by EtOAc (EtOAc, hexane, 1:1, v/v) to yield (225) (1.31 g) White foam. UV (MeOH) λπ^ 271.5 nm. lR NMR (CDC13) δ 1.22 (s, 9H, /-Bu), 1.31 (s, 3H, Me), 1.55 (s, 3H, Me) , 1.85 (m, 1H, S^aH), 238-2.51 (m, 2H, 4*-Η, 5^-Η), 3.44-3.52 (m, 2H, 4.47 (dd, J = 3.4, 6.2 Hz, 1H, Τ-Ή)9 4.58 (t, J = 6.0 Hz, 1H, Γ-Η), 4.87 (dd, J = 8.9, 14.5 Hz, 1H, 2*-H), 7.61 (d, J - 6.1 Hz) , 1H, 6-H), 8.77 (br s, 1H, NH). Analysis C17H25FN205 0·25Η2Ο··Calculation value C, 56·58; H, 7·12, N, 7 76 Measured ^ Example 51 (1' 11,2'8,3'1154'11)-1-[4-(Tertidinoxymethyl)-2,3-isopropylidene dioxy)cyclopentane-1_yl]-5-fluoro Cytosine (226) (5,-0-t-butyl-2,3,·0·isopropylidene-carbonated-5-fluorocytidine) Mix a mixture of (225) (350 mg), triethylamine (190 mg, 2,4,6-triisopropylbenzenesulfonate (590 mg) and DMAP (230 mg) in acetonitrile (50 ml) at room temperature Stir for 1 day. A solution of cerium ammonium oxide (30%, 15 liters) was added and the mixture was stirred for a further 5 hours. The reaction was stopped by adding gas (250 ml) and water (1 ml). The organic layer was washed with brine, dried over Na 2 EtOAc and evaporated. The residue was purified by hydrazine column chromatography (5% MeOH in CHC13, v/v) to yield (226) (205 mg), mp 128-130 ° C. (Please read the back note and fill out this page)

本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 226 91949 A7 1293306 ___B7 _____ 五、發明說明（227 ) (請先閱讀背面之注意事項再填寫本頁) UV (MeOH) λ^χ 2Ζ6.5 nm. lH NMR (CDC13) δ U9 (s, 9H, i-Bu), 1.29 (s, 3H, Me), 1.53 (s, 3H, Me), 2.02 (dt, J - 10.2,12-8 Hz, 1H, S^H), 2.32 (m, 1H, 4^H), 2.42 (dt, J -8.0,12.7 Hz, 1H, 5^-Η), 3.42 (dd, J = 6.1, 8.7 Hz, 1H, ό^α-Η), 3.52 (dd, J = 4-1, 8.8 Hz, 1H, ό^Η), 4.49 (dd, J = 5.1,6.3 Hz, 1H, 39-Ή)9 4.60 (m, 1H, Γ-Η), 4.79 (dd, X = 5.0,6.4This paper size applies to China National Standard (CNS) A4 specification (210 x 297 mm) 226 91949 A7 1293306 ___B7 _____ V. Description of invention (227) (Please read the note on the back and fill out this page) UV (MeOH) λ ^χ 2Ζ 6.5 nm. lH NMR (CDC13) δ U9 (s, 9H, i-Bu), 1.29 (s, 3H, Me), 1.53 (s, 3H, Me), 2.02 (dt, J - 10.2, 12-8 Hz, 1H, S^H), 2.32 (m, 1H, 4^H), 2.42 (dt, J -8.0, 12.7 Hz, 1H, 5^-Η), 3.42 (dd, J = 6.1, 8.7 Hz, 1H, ό^α-Η), 3.52 (dd, J = 4-1, 8.8 Hz, 1H, ό^Η), 4.49 (dd, J = 5.1, 6.3 Hz, 1H, 39-Ή)9 4.60 (m, 1H, Γ-Η), 4.79 (dd, X = 5.0, 6.4

Hz, 1H, 2，·Η), 7·49 (4 J = 6·1 Hz, 1氏 6·Η)· HR-FAB MS實測值:m/z 356.1981·計算值 for C17H26FN3O4： m/z 356.1986 (M + 1)+. 實例52 (1，1152,8,3，11，4，11)_1-[2,3-二羥基-4_(羥甲基）環戊烷-1-基]- 5-氟胞嘧啶（碳化-5-氟胞苷，227) 取含（226)(180毫克）之三氟乙酸與水之2:1 (v/v)混合 物（40毫升）溶液於50°C下攪拌3小時。真空排除溶劑，殘 質與乙醇（2x 30毫升）共蒸發，經矽膠管柱純化（皿6〇11- CHC13，1:5，v/v)，產生（227)(47.5毫克）之泡沫狀物。 UV (Η20) 284 nm (ε 5,876, pH 7), 293.5 xm (ε 7,440, pH 2), 284 5 nm (ε 5,883, pH 11). lH NMR (DMSO-de) δ 1.19 (m, 1¾ L92 (m, 1H, 2.00 (ddd, J = 8.3, 8.7,12.5 Hz, 1H, S^-H), 3.42 (m, 2H, 經濟部智慧財產局員工消費合作社印製 fi^ab-H), 3.70 (dd, J = 2.9, 5.3 Hz, 1¾ 3$b-H), 3.98 (dd, J « 5.2, 9.0 Hz, 1H, T-H)r 4.10 (cU = 4·5,1H, OH,可交換）,4·51 (br s, 1H, OH,可交換）,4·60 (dd,卜 9·0, 18·2 取 1Η，Γ·Η), 4.73 (d, J « 6·1 Hz, 1¾ OH,可交換），7.33 (bs, 1H, 可交換），7·55 (bs, 1H,可交換）,7·98 (d,J = 7·3 Hz, 1¾ 6-H). HR-FAB MS 實測值:m/2 260.1054· C|7H26FN3〇4:計算值 m/z 260.1047 (M + 1)+· 依類似方法，但改用相應之5-經取代之衍生物’製備 下列5-經取代之碳化核苷： 5-氣-碳化-尿苷， 5 -漠-碳化-尿甘’ 5·埃-碳化-尿甘’ 5-氰基-碳化-尿苷， 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 227 91949 1293306 A7 經濟部智慧財產局員工消費合作社印制衣Hz, 1H, 2,·Η), 7·49 (4 J = 6·1 Hz, 1·6·Η)· HR-FAB MS measured value: m/z 356.1981·calculated value for C17H26FN3O4: m/z 356.1986 (M + 1)+. Example 52 (1,1152,8,3,11,4,11)_1-[2,3-dihydroxy-4_(hydroxymethyl)cyclopentan-1-yl]- 5 -Fluorocytosine (carbonated-5-fluorocytidine, 227) A solution containing (226) (180 mg) of trifluoroacetic acid in water in a 2:1 (v/v) mixture (40 ml) at 50 ° C Stir for 3 hours. The solvent was removed in vacuo and the residue was evaporated with EtOAc (EtOAc (EtOAc) (EtOAc) (EtOAc (EtOAc) . UV (Η20) 284 nm (ε 5,876, pH 7), 293.5 xm (ε 7,440, pH 2), 284 5 nm (ε 5,883, pH 11). lH NMR (DMSO-de) δ 1.19 (m, 13⁄4 L92 ( m, 1H, 2.00 (ddd, J = 8.3, 8.7, 12.5 Hz, 1H, S^-H), 3.42 (m, 2H, Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, printed fi^ab-H), 3.70 ( Dd, J = 2.9, 5.3 Hz, 13⁄4 3$bH), 3.98 (dd, J « 5.2, 9.0 Hz, 1H, TH)r 4.10 (cU = 4·5,1H, OH, exchangeable), 4.51 (br s, 1H, OH, exchangeable), 4·60 (dd, Bu 9·0, 18·2 take 1Η, Γ·Η), 4.73 (d, J « 6·1 Hz, 13⁄4 OH, exchangeable ), 7.33 (bs, 1H, exchangeable), 7·55 (bs, 1H, exchangeable), 7·98 (d, J = 7·3 Hz, 13⁄4 6-H). HR-FAB MS measured value: m/2 260.1054· C|7H26FN3〇4: Calculated m/z 260.1047 (M + 1)+· In a similar manner, but using the corresponding 5-substituted derivative' to prepare the following 5-substituted carbonized core Glycoside: 5-gas-carbonization-uridine, 5----carbonization-uranium' 5·A-carbonization-uranium' 5-cyano-carbo-uridine, this paper scale applies to China National Standard (CNS) A4 Specifications (210 x 297 mm) 227 91949 1293306 A7 Ministry of Economic Affairs Intellectual Property Office staff consumption Social printed clothing

---------g-7 __ 五、發明說明（228 ) 碳化-尿杳_5_叛酸， 5-乙氧羰基-碳化-尿苷， 碳化-尿苷_5-羧醯胺， 5_羥基甲基-碳化-尿苷， 5-硝基-碳化-尿苷， 5 -胺基-化-尿苷^， 5 -乳-碳化-胞脊， 5-溴_碳化-胞苷， 5-蛾-碳化-胞脊， 5-氰基-碳化·胞苷， 碳化-胞有叛酸， 5 -乙氧幾基·碳化-胞脊， 碳化-胞有2 -5-羧醯胺， 5-羥基甲基-碳化-胞苷， 5 -硝基_碳化-胞脊，與 5-胺基-碳化-胞苷。 友!.生物方法 本發明尚提供一種採用定量性快速逆轉錄聚合酶連鎖 反應（“Q-RT-PCR”）定量宿主體内病毒濃度之有效方法。此 方法涉及使用可與目標病毒DNA或RNA雜化之消光螢光 探針分子。因此當受到核酸外切酶分解時，可追緞到可檢 測之螢光訊號。因此可藉由追蹤螢光訊號之存在而快速檢 測RT-PCR擴增之DNA或RNA。 在本發明明確具體實施例中，提供一種採用RT-PCR 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 228 91949 (請先閱讀背面之注咅？事項再填寫本頁) I n I ϋ ϋ I^OJa n I I ϋ ·ϋ ϋ n 9 線丨# 了 — — — — — — I — A7 經濟部智慧財產局員工消費合作社印製 1293306 B7__ 五、發明說明（229 ) 定量黃病毒科病毒濃度之用途。 更明確具體實施例中，提供一種採用RT-PCR定量 MDBK細胞株或宿主樣本中B VD V病毒濃度之用途。 另一項本發明具體實施例中，提供一種探針分子，其 設計用於在受核酸外切酶分解待發出螢光，並與BVDV NADL NS5B區互補。 本發明另一項明確具體實施例中，提供一種探針分 子，其序列為 5’ 6-fam-AAATCCTCCTAACAAGCGGGTTCCAGG_tamara 3,（序列ID No 1)，其引子之正意義序列為： 5，-AGCCTTCAGTTTCTTGCTGATGT-3,（序列 ID No 2)且反 義序列為：5，-TGTTGCGAAAGCACCAACAG-3’（序列 ID No 3) 〇 本發明明確具體實施例中，提供一種以RT-PCR於衍 生自宿主之樣本中或細胞株中快速定量HCV病毒濃度上 之用途。 本發明更明確具體實施例中，提供一種探針分子，其 設計用於在受核酸外切酶分解待發出螢光並與HCV基因 組互補。 本發明更明確具體實施例中，提供一種探針分子，其 設計用於在受核酸外切酶分解待發出螢光，並與HCV 5’ 未轉譯區互補。 本發明更明確具體實施例中，提供一種探針分子，其 序列為 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁)---------g-7 __ V. Description of invention (228) Carbonization-urinary 杳_5_ tacrotic acid, 5-ethoxycarbonyl-carbonization-uridine, carbonization-uridine-5-carboxylate Amine, 5-hydroxymethyl-carbo-uridine, 5-nitro-carbo-uridine, 5-amino-chemical-uridine, 5-mercapto-carbonation-cylinder, 5-bromo-carbonization-cell Glycosides, 5-moth-carbonized-cylinder, 5-cyano-carbo-cytidine, carbonization-cells with retinoic acid, 5-ethoxylated carbonation-cylinder, carbonization-cells with 2-5-carboxylate Amine, 5-hydroxymethyl-carbo-cytidine, 5-nitro-carbonization-cylinder, and 5-amino-carbo-cytidine. Bio! Methods The present invention also provides an efficient method for quantifying viral concentrations in a host using a quantitative rapid reverse transcription polymerase chain reaction ("Q-RT-PCR"). This method involves the use of an extinction fluorescent probe molecule that hybridizes to the target viral DNA or RNA. Therefore, when decomposed by the exonuclease, the satin can be traced to a detectable fluorescent signal. Therefore, RT-PCR amplified DNA or RNA can be quickly detected by tracking the presence of fluorescent signals. In a specific embodiment of the present invention, an RT-PCR paper size is applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 228 91949 (please read the back note first and then fill out this page) I n I ϋ ϋ I^OJa n II ϋ ·ϋ ϋ n 9 丨# —————————— I — A7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1293306 B7__ V. Invention Description (229) Quantification The use of the Flaviviridae virus concentration. In a more specific embodiment, there is provided a use of RT-PCR to quantify BVD V virus concentration in an MDBK cell line or a host sample. In another embodiment of the invention, a probe molecule is provided which is designed to be fluoresced by exonuclease and complementary to the BVDV NADL NS5B region. In another specific embodiment of the present invention, a probe molecule is provided, the sequence of which is 5' 6-fam-AAATCCTCCTAACAAGCGGGTTCCAGG_tamara 3, (sequence ID No 1), and the positive sequence of the primer is: 5, -AGCCTTCAGTTTCTTGCTGATGT-3 , (SEQ ID NO 2) and the antisense sequence is: 5, -TGTTGCGAAAGCACCAACAG-3' (SEQ ID NO 3). In a specific embodiment of the invention, a RT-PCR is provided in a sample derived from a host or a cell The use of rapid quantification of HCV virus concentration in strains. In a more specific embodiment of the invention, a probe molecule is provided which is designed to be fluoresced by a nucleic acid exonuclease and to be complementary to the HCV genome. In a more specific embodiment of the invention, a probe molecule is provided which is designed to be fluoresced by an exonuclease and is complementary to the 5' untranslated region of HCV. In a more specific embodiment of the present invention, a probe molecule is provided, the sequence of which is the Chinese National Standard (CNS) A4 specification (210 X 297 mm) for the paper scale. 91949 (Please read the back note first and then fill in the page) )

229 經濟部智慧財產局員工消費合作社印製 1293306 A7 B7 五、發明說明（231 ) (正意義序列：5’-AGCCTTCAGTTTCTTGCTGATGT-3’[序 列ID No 2];及反義序列： 5、TGTTGCGAAAGCACCAACAG-3,[序列 ID No 3])，使其 與B VDV NADL NS5B區域互補。於50微升RT-PCR混合 物中共分析10微升RNA。定量性PCR中採用之試劑與條 件購自PE_Applied Biosystems。採用未稀釋之病毒菌種， 由每份RT-PCR混合物6000個溶菌斑形成單位（PFU)至0.6 個PFU，作成標準曲線。照例得到延伸4個對數值之線性 範圍。 可採用類似方法測定臨床檢體或組織培養樣本中其他 黃病毒科病毒量（較著重於HCV、YFV、登革熱、西奈爾病 毒，等等）。例如：採用下列引子： (5，-TTCCGCAGACCACTATGG-3,[序列 ID No. 4]與 5，-AGCCATGGCGTTAGTATGAGTGT-3’ [序列 ID No. 5]) 及探針（5，-6-fam-CCTCCAGGACCCCCCCTCCC-tamara-3’ [序列ID No· 6])，組合HCV RNA純化法與快速RT-PCR 法，結果可在7個對數值線性範圍内檢測病毒濃度。 B · 細胞/病毒材料 疫病毒屬中最有特色之成員之一為BVDV。BVDV與 HCV之共同特色至少有三點，如下：（1)此二者均可進行 IRES所媒介之轉譯作用；（2)其NS3絲胺酸蛋白酶需要 NS4A輔因子；及（3)其在非結構性區域内均進行類似之聚 蛋白質加工處理，尤指NS5A及NS5B接合位置。 採用BVDV複製系統探討抗黃病毒科病毒化合物。本 $1^長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項再填寫本頁) -------訂---------線— 0 231 91949 經濟部智慧財產局員工消費合作社印製 [293306 A7 B7 五、發明說明（232 ) 文說明之化合物可活性對抗疫病毒、肝病毒及/或黃病毒。 使Maldin-Darby牛腎（MDBK)細胞於補充1〇〇/0受熱去 活性之馬血清之改良伊格培養基（DMEM/F12 ; GibcoBRL) 中，於37°C之潮濕5% C〇2培養箱中生長及維持。 此等細胞感染牛病毒性下痢病毒（B VDV)，NADL菌株 後，造成細胞致病性效應（CPE)。 C.抗病毒分析法 採用騰蛋白酶-EDTA，依標準技術單離出於 DMEM/F12 _10%馬血清（HS)中生長之MDBK細胞。細胞接 種在96孔板中’ 5χ 10個細胞/孔’添加試驗化合物（2〇〆 Μ濃度）’總體積為1 〇 〇微升。1小時後，排出典養美，於 總體積50微升中，依感染倍率（ΜΟΙ)〇 〇2或〇 〇〇2感染細 胞45分鐘。之後，排出病毒，以100微升分析培養基洗滌 細胞2次。最後，已感染之細胞於含試驗化合物濃度1〇、 40或100以Μ之總體積1〇〇微升中培養。22小時後，採用 低速離心法，排除細胞碎片，收集細胞上澄液，隨後定量 病毒。 .. C·抗黃癌毒科病奏化合物之細胞毒性訧脸 本文採用之細胞毒性試驗法為標準技術。簡言之，·在 96孔板令接種各種不同濃度之細胞（依細胞型態、分析時 間長短而定），典型地每孔含有5χ 1〇3個細胞，及含濃度 逐漸提高之試驗化合物（〇、！、3、10、33及。培 養3天後，添加MTS染料（promega)，然後培養3小時， 測定細1活力及粒線體活性。之後，取含有遙极★ μ 本紙張尺度㈣國家標準（CNS)乂i規格（210 X 297公髮)--~ ----- ^ ^ ^ 91949 (請先閱讀背面之注意事項再填寫本頁) 訂---------線」 232 1293306 A7 B7 233 五、發明說明（ 於490nm下讀數。此等方法已由製造商（Promeg公）詳細說明 及提供。 (請先閱讀背面之注意事項再填寫本頁) 實例53 BVDV RT-PCR定量標準曲線 依例行溶菌斑分析法（Mendez，E· et al·，J. Virol. 1998, 72, 4737)測定含2x 106 PFU/毫升之標準BVDV病毒保存 液。自140微升以菌種材料中萃取病毒RNA，使用60微 米溶離緩衝液自管柱中溶離出。此純化之RNA材料可再自 10“逐步稀釋至10·5。採用快速RT-PCR擴增技術，測試 10微升各稀釋液。此系列稀釋液結果作圖示於第1圖，其 係PFU與標準物濃度之相關性。由此實驗清楚可見，此技 術可以在4個對數值範園内可靠地定量病毒濃度（每份添 加之擴增混合物測定6000至0.6PFU)。此實驗之檢測下限 為0.6PFU或_0·22 log PFU。因此，低於此檢測下限之試驗 樣本之快速RT-PCR定量值則不可靠。 實例54 MDBK細胞中BVDV複製循環 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 為了測定MDBK細胞中BVDV產量及在某較時間内測 定最適當收穫時間，每孔接種5x 104個細胞，依m〇I==〇 或Μ01=0·002進行感染。感染後，排出接種菌，以培養基 洗滌細胞2次。在不同時間點收穫細胞上澄液，測定病毒 量，並與原有接種菌及細胞洗液比較。至少需要2個洗綠 步驟才可排除接種菌病毒，如第2圖所示。感染約22小時 後，病毒產量約與用於接種細胞之病毒量相等。依據此等 本紙張尺度適用中國國家標準（CNS)A4規格（21G X 297公餐)&quot; -------- 233 91949 A7 1293306 五、發明說明（234 ) —— 結果得知，MDBK細胞中BVDV—個複製㈣需要⑴、 時。應注意’此等實驗所設定之檢挪程度係依據標準曲線 所測得之檢測下限而定。 實例55 使用RT_PCR評估抗病毒化合物 接種MDBK細胞，5x 1〇4個/孔，感染b vdv ,感染倍 率(MOI)等於0.02 ’並於試驗化合物之存在下生長η小 時。以未使用試驗化合物處理之細胞作為陰性對照組以 利巴韋林作為陽性對照.組。萃取病毒RNa，利用快速 RT-PCR分析。如第3圖所示之典型實驗證明陰性對照組 及大多數經過處理之細胞均產生相當多量病毒（每份添加 量1.5至2 log PFU) ’其中有效地顯示試驗化合物沒有活 性。然而，經陽性對照組（利巴韋林，RIB)或經5羥基尿苷 (沒-D-CL)處理之細胞則幾乎完全沒有病毒RNA。在22小 時繁殖期間’ RIB與召-D-CL使病毒產量減少約2 i〇g pfu 或99%。此等化合物之真正效力並無法由這種實驗推斷， 因為此實驗之檢測下限定在-0.22 log PFU，且在指定之實 驗條件下只進行一個病毒複製循環。 依類似實驗過程，但在較大之試驗化合物濃度範圍内 (0、1、3、10、33、100// M)測定抗BVDV化合物抑制病 毒產量達50%或90%時之效力或有效化合物濃度（分別指 EC5G或EC9G值）。EC9。值指在22小時期間之病毒產量降低 卜log時所需之濃度。展現強力抗病毒活性之化合物示於 表21。此表提出感染後22小時，在指定濃度下觀察到之 本紙張尺度適用中國國家標準（CNS)A4規格（210x 297公釐） … 234 91949 -------------JP (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 1293306 A7 B7 五、發明說明（235 ) 病毒濃度最大降低程度。 表21 :感染22小時後BVDV病毒濃度 經濟部智慧財產局員工消費合作社印製 ID η 濃度（μΜ) 下降之平均對數值 β-D-AA 4 100 2.43 β-D-AI 3 100 1.52 β-D-AJ 3 100 1.34 β-D-AK 4 100 1.90 β-D-AL 3 100 1.55 β-D-AN 2 100 L21 β-D-AO 2 100 2.24 β-D-AP 3 100 L36 β-D-AQ 3 100 0.87 P-D-AT 4 100 1.42 (請先閱讀背面之注意事項再填寫本頁) 0 訂------- ——線—_------------------------ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 235 91949 1293306 A7 B7 五、發明說明（23〇 經濟部智慧財產局員工消費合作社印製 ID η 濃度如构 下降之平均對數值 P_D_BE 3 100 1.23 β-D-BL 2 100 1.20 β-D-BO 3 100 0.80 β-D-BS 2 10 1.48 β-D-CL 6 40 3.10 β-D-CM 3 40 L77 β-D-DJ 1 40 1.58 β-D-DK 2 100 2.17 β-D-DL 2 ι 100 133 β-D-HA 1 100 2.87 β-D-HB 2 100 2.26 β-D-MD 1 100 2.16 β-D-JVIE 4 100 2.41 β-D-MF 4 100 1.41 β-D-QA 1 100 1.50 β-D-TA 1 100 L30 β-D-VA 1 100 469 β-L-FC 2 100 239 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 訂---------線」 236 91949 A7 1293306 __B7 _ 五、發明說明（237 ) 實例56 測定抗病毒活性之另一種細胞培養系統 上述分析法可藉由改變細胞系統及病毒病原菌而應用 在其他黃病毒科病毒成員上。測定此等抗病毒化合物之效 力之方法包括標準技術之改良法，如說明於：Holbrook，MR et al. Virus Res. 2000, 69 (1 )，31; Markland，W et al· Antimicrob. Agents. Chemother. 2000^ 44(4)，859; Diamond， MS et al。J. Virol. 2000, 74 (17), 7814; Jordan, I. et al. JL Tnfect. Pis. 2000. 182? 1214; Sreenivasan? V. et al. J. Virol· Methods 1993, 45 (1)，1;或 Baginski，SG et al· Proc. Natl. Acad. ScL U.S.A. 2000, 97 (14)，7981，或快速 RT-PCR 技 術。明確言之，可採用HuH7細胞中之HCV複製子系統 (Lohmann，V et al· Science, 1999, 285 (5424)，110)或其改 良法（Rice et al· 2000，abstract Xth International Symposium for Viral Hepatitis and Liver Disease, Atlanta, GA) 〇 實例57 候選化合物之細胞毒性試驗 本文採用之細胞毒性試驗為標準技術。簡言之，在96 孔板中接種不同濃度之細胞（依細胞型態、分析時間長短而 定），典型地為每孔5χ 1〇3個細胞，其中含有濃度逐漸提 高之試驗化合物（0、1、3、10、33及100 βΜ)。培養3天 (Vero細胞）、或4天（CEM細胞）或5天（ΡΒΜ細胞）後，添 加MTT染料（Promega)，然後培養8小時，測定細胞活力 (請先閱讀背面之注意事項再填寫本頁) 訂---------線一 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（21〇 X 297公爱） 237 91949 Α7 Β7 [293306 五、發明說明（238 ) 及粒線體活性。之後添加中止反應溶液固定含染料之培養 板，隨後培養8小時。最後於570nm下讀取吸光度。此等 方法已由製造商（Promega)詳細說明並提供。 此方法測試之化合物列表示於表22中。雖然所測試之 化合物通常無細胞毒性，但泠-D-GA對CEM細胞卻有選 擇性細胞毒性效應。 表22 : V-a與Villa之細胞毒性* (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5衣 ID PBM細胞* CEM細胞* Vero細跑* β-D-GA &gt;100(11.3) 1.9 &gt;57.4 β-D-GF &gt; 100(-46.2) &gt;100(11.2) &gt; 100 (43) β-L-GA &gt;100 (-113.2) &gt;100(1.1) &gt; 100 (27.9) β-L-GB &gt;100(33) &gt;100(8.3) 〜171 p-L-GC &gt; 100 (-53.2) &gt;100 (-1.2) &gt;100 (-13.4) β-L-GD &gt; 100 (·12·9) &gt;100 (-79.7) &gt;100(0.8) β-L-GE &gt; 100(-59.7) &gt;100(0.0) &gt;100(10.6) p-L-GF &gt; 100(-70.4) &gt;100(35.1) &gt;100(33.8) β-L-GG &gt; 100 (-34.6) &gt; 100 (17.3) &gt; 100 (33.6) β-L-GH &gt;100 (-52.1) &gt;100(19·7) &gt;100(27.0) β-L-GI &gt; 100 (·47·8) &gt;100(18.0) &gt;100(31.9) *IC5〇，μΜ (於 100 μΜ 時之抑制 實例58 ^OJ ϋ n ϋ ϋ -ϋ ^1 I I ϋ I n n n n n It I ϋ i-i -ϋ 1 ϋ ϋ n ϋ I ϋ ^1 _ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 238 91949 1293306 Δ7 Α7 ______Β7 五、發明說明（239) 候選化合物對呼吸道病毒之抗病毒試驗 在此等實驗期間，測試通式⑴化合物對抗一系列感染 上呼吸道之病毒之抗病毒活性。其中詳細說明為了此等目 的而採用之方法。下列方法為來自vir〇1〇gy Branch，229 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1293306 A7 B7 V. Description of Invention (231) (Positive meaning sequence: 5'-AGCCTTCAGTTTCTTGCTGATGT-3' [Sequence ID No 2]; and antisense sequence: 5. TGTTGCGAAAGCACCAACAG-3 , [Sequence ID No 3]), making it complementary to the B VDV NADL NS5B region. A total of 10 microliters of RNA was analyzed in 50 microliters of RT-PCR mixture. The reagents and conditions used in the quantitative PCR were purchased from PE_Applied Biosystems. Using an undiluted virus strain, a standard curve was prepared from 6000 plaque forming units (PFU) to 0.6 PFU per RT-PCR mixture. As usual, a linear range extending from 4 logarithms is obtained. A similar method can be used to determine the amount of other Flaviviridae viruses in clinical specimens or tissue culture samples (more emphasis on HCV, YFV, dengue, cyanovirus, etc.). For example, the following primers are used: (5,-TTCCGCAGACCACTATGG-3, [Sequence ID No. 4] and 5,-AGCCATGGCGTTAGTATGAGTGT-3' [Sequence ID No. 5]) and probe (5,-6-fam-CCTCCAGGACCCCCCCTCCC- Tamara-3' [SEQ ID NO: 6]), combined with HCV RNA purification and rapid RT-PCR, results in detection of virus concentration in seven logarithmic linear ranges. B · Cell/Virus Material One of the most distinctive members of the genus Epidemic Virus is BVDV. There are at least three points in common with BVDV and HCV, as follows: (1) both can be translated by IRES media; (2) NS3A serine protease requires NS4A cofactor; and (3) its non-structural Similar polyprotein processing is performed in the sexual regions, especially the NS5A and NS5B junction sites. The anti-flavivirus family of viral compounds was explored using the BVDV replication system. The $1^ long scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) (please read the notes on the back and fill out this page) -------Book -------- -线— 0 231 91949 Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative [293306 A7 B7 V. INSTRUCTIONS (232) The compounds described are active against epidemic, hepatic and/or flaviviruses. Maldin-Darby bovine kidney (MDBK) cells were cultured in modified Ig medium (DMEM/F12; GibcoBRL) supplemented with 1〇〇/0 heated deactivated horse serum at 37 ° C in a humidified 5% C〇2 incubator Medium growth and maintenance. These cells are infected with bovine viral sputum virus (B VDV), a strain of NADL that causes a cytopathic effect (CPE). C. Antiviral assay MDBK cells grown in DMEM/F12 _10% horse serum (HS) were isolated using Tetase-EDTA according to standard techniques. The cells were seeded in a 96-well plate at '5 χ 10 cells/well' and the test compound (2 〇〆 Μ concentration) was added in a total volume of 1 〇 〇 microliter. After 1 hour, the sputum was taken out and the cells were infected for 45 minutes in a total volume of 50 μl depending on the infection rate (ΜΟΙ) 〇 〇 2 or 〇 〇〇 2 . Thereafter, the virus was drained, and the cells were washed twice with 100 μl of the assay medium. Finally, the infected cells were cultured in a total volume of 1 〇〇 microliter containing test compound at a concentration of 1 〇, 40 or 100 Μ. After 22 hours, cell debris was removed by low-speed centrifugation, and the cells were collected and the virus was quantified. .. C. Anti-yellow cancer drug cytotoxicity of the compound. The cytotoxicity test method used in this paper is the standard technique. In short, inoculation of cells of various concentrations (depending on cell type and length of analysis) in a 96-well plate, typically containing 5χ1〇3 cells per well, and a test compound with increasing concentration ( 〇, !, 3, 10, 33 and. After 3 days of culture, MTS dye (promega) was added, and then cultured for 3 hours to determine the activity of fine 1 and the activity of mitochondria. After that, the scale of the paper containing the polar electrode was measured. National Standard (CNS) 乂i Specifications (210 X 297 mil) --- ----- ^ ^ ^ 91949 (Please read the notes on the back and fill out this page) Order --------- Line 232 1293306 A7 B7 233 V. INSTRUCTIONS (Reading at 490nm. These methods have been detailed and provided by the manufacturer (Promeg). (Please read the note on the back and fill out this page) Example 53 BVDV RT - PCR Quantitative Standard Curve A standard BVDV virus stock solution containing 2 x 106 PFU/ml was determined by routine plaque assay (Mendez, E. et al., J. Virol. 1998, 72, 4737). Viral RNA was extracted from the strain material and eluted from the column using a 60 μm dissolution buffer. This purified RN A material can be further diluted from 10 to 10. 5. Using rapid RT-PCR amplification technology, test 10 microliters of each dilution. The results of this series of dilutions are shown in Figure 1, which is PFU and standard Correlation of concentration. It is clear from this experiment that this technique can reliably quantify the virus concentration in four logarithmic ranges (6000 to 0.6 PFU per amplified mixture). The lower limit of detection for this experiment is 0.6 PFU or _0·22 log PFU. Therefore, the rapid RT-PCR quantitative value of the test sample below the lower limit of detection is not reliable. Example 54 BVDV replication in the MDBK cells, Ministry of Intellectual Property, Intellectual Property Office, Staff Consumer Cooperative Printed to determine MDBK cells In the BVDV production and the most appropriate harvest time in a certain time, 5x 104 cells per well were inoculated, and infection was carried out according to m〇I==〇 or Μ01=0·002. After infection, the inoculum was discharged and the cells were washed with medium. 2 times. Harvest the cells at different time points, measure the amount of virus, and compare with the original inoculum and cell wash. At least 2 green washing steps are required to exclude the inoculum virus, as shown in Figure 2 After about 22 hours of infection, the virus production is about the same as the amount of virus used to inoculate the cells. According to these paper scales, the Chinese National Standard (CNS) A4 specification (21G X 297 public meals) is applicable. - 233 91949 A7 1293306 V. INSTRUCTIONS (234) - As a result, it was found that BVDV-folding (4) in MDBK cells requires (1), time. It should be noted that the degree of detection set by these experiments is based on the lower limit of detection measured by the standard curve. Example 55 Evaluation of antiviral compounds using RT-PCR MDBK cells were seeded, 5 x 1 4 /well, infected with b vdv , infection magnification (MOI) equal to 0.02 ' and grown for n hours in the presence of test compound. Cells treated with no test compound were used as a negative control group and ribavirin was used as a positive control group. Virus Rna was extracted and analyzed by rapid RT-PCR. A typical experiment as shown in Figure 3 demonstrates that the negative control and most of the treated cells produced a significant amount of virus (1.5 to 2 log PFU per serving), which effectively showed no activity of the test compound. However, cells treated with a positive control (ribavirin, RIB) or with 5-hydroxyuridine (not-D-CL) were almost completely free of viral RNA. During the 22 hour breeding period, RIB and CAM-D-CL reduced virus yield by approximately 2 i〇g pfu or 99%. The true potency of these compounds was not inferred from this experiment because the assay for this experiment was limited to -0.22 log PFU and only one viral replication cycle was performed under the indicated experimental conditions. Efficacy or potency compounds for anti-BVDV compounds inhibiting viral production by 50% or 90%, depending on the experimental procedure, but within a larger concentration of test compound (0, 1, 3, 10, 33, 100//M) Concentration (referred to as EC5G or EC9G values, respectively). EC9. Value refers to the concentration required to reduce viral production during the 22 hour period. Compounds exhibiting potent antiviral activity are shown in Table 21. This table proposes the Chinese National Standard (CNS) A4 specification (210x 297 mm) for the paper size observed at the specified concentration 22 hours after infection... 234 91949 -------------JP (Please read the precautions on the back and fill out this page.) Booking #· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1293306 A7 B7 V. Invention Description (235) The maximum reduction in virus concentration. Table 21: BVDV virus concentration after 22 hours of infection Ministry of Economic Affairs Intellectual Property Office Staff Consumption Cooperative Printed ID η Concentration (μΜ) Average logarithm of decline β-D-AA 4 100 2.43 β-D-AI 3 100 1.52 β-D -AJ 3 100 1.34 β-D-AK 4 100 1.90 β-D-AL 3 100 1.55 β-D-AN 2 100 L21 β-D-AO 2 100 2.24 β-D-AP 3 100 L36 β-D-AQ 3 100 0.87 PD-AT 4 100 1.42 (Please read the notes on the back and fill out this page) 0 订------- ——Line—_-------------- ---------- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 235 91949 1293306 A7 B7 V. Invention Description (23) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative The average value of the ID η concentration such as the structural decrease P_D_BE 3 100 1.23 β-D-BL 2 100 1.20 β-D-BO 3 100 0.80 β-D-BS 2 10 1.48 β-D-CL 6 40 3.10 β-D -CM 3 40 L77 β-D-DJ 1 40 1.58 β-D-DK 2 100 2.17 β-D-DL 2 ι 100 133 β-D-HA 1 100 2.87 β-D-HB 2 100 2.26 β-D- MD 1 100 2.16 β-D-JVIE 4 100 2.41 β-D-MF 4 100 1.41 β-D-QA 1 100 1.50 β-D-TA 1 100 L30 β-D-VA 1 100 469 β -L-FC 2 100 239 This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page). Order --------- Line 236 91949 A7 1293306 __B7 _ V. Description of the invention (237) Example 56 Another cell culture system for determining antiviral activity The above assay can be applied to other members of the Flaviviridae virus by altering the cellular system and viral pathogens. Methods for the efficacy of such antiviral compounds include standard techniques, as described in: Holbrook, MR et al. Virus Res. 2000, 69 (1), 31; Markland, W et al. Antimicrob. Agents. Chemother. 2000^ 44(4), 859; Diamond, MS et al. J. Virol. 2000, 74 (17), 7814; Jordan, I. et al. JL Tnfect. Pis. 2000. 182? 1214; Sreenivasan? V. et al. J. Virol·Method 1993, 45 (1), 1; or Baginski, SG et al. Proc. Natl. Acad. ScL USA 2000, 97 (14), 7981, or fast RT-PCR technology. Specifically, the HCV replication system in HuH7 cells (Lohmann, V et al. Science, 1999, 285 (5424), 110) or its modified method (Rice et al. 2000, abstract Xth International Symposium for Viral Hepatitis) can be used. And Liver Disease, Atlanta, GA) 〇 Example 57 Cytotoxicity Test for Candidate Compounds The cytotoxicity assays used herein are standard techniques. Briefly, 96-well plates were seeded with different concentrations of cells (depending on cell type and length of analysis), typically 5χ 1〇3 cells per well, containing a test compound with increasing concentrations (0, 1, 3, 10, 33 and 100 βΜ). After culturing for 3 days (Vero cells), or 4 days (CEM cells) or 5 days (ΡΒΜ cells), MTT dye (Promega) was added, and then cultured for 8 hours to measure cell viability (please read the notes on the back and fill in the form) Page) Order--------- Line 1 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed This paper scale applies Chinese National Standard (CNS) A4 specification (21〇X 297 public) 237 91949 Α7 Β7 [293306 5. Description of the invention (238) and mitochondrial activity. Thereafter, the suspension reaction solution was added to fix the dye-containing culture plate, followed by incubation for 8 hours. Finally, the absorbance was read at 570 nm. These methods have been detailed and provided by the manufacturer (Promega). The column of compounds tested by this method is shown in Table 22. Although the compounds tested are generally not cytotoxic, 泠-D-GA has a selective cytotoxic effect on CEM cells. Table 22: Cytotoxicity of Va and Villa* (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Office Staff Cooperatives Print 5 Clothing ID PBM Cells* CEM Cells* Vero Fine Running* β-D-GA &gt;100(11.3) 1.9 &gt;57.4 β-D-GF &gt; 100(-46.2) &gt;100(11.2) &gt; 100 (43) β-L-GA &gt;100 (-113.2) &gt;100( 1.1) &gt; 100 (27.9) β-L-GB &gt;100(33) &gt;100(8.3) ~171 pL-GC &gt; 100 (-53.2) &gt;100 (-1.2) &gt;100 (-13.4 β-L-GD &gt; 100 (·12·9) &gt;100 (-79.7) &gt;100(0.8) β-L-GE &gt; 100(-59.7) &gt;100(0.0) &gt;100( 10.6) pL-GF &gt; 100(-70.4) &gt;100(35.1) &gt;100(33.8) β-L-GG &gt; 100 (-34.6) &gt; 100 (17.3) &gt; 100 (33.6) β- L-GH &gt;100 (-52.1) &gt;100(19·7) &gt;100(27.0) β-L-GI &gt; 100 (·47·8) &gt;100(18.0) &gt;100(31.9) *IC5〇,μΜ (inhibition at 100 μΜ 58 ^OJ ϋ n ϋ ϋ -ϋ ^1 II ϋ I nnnnn It I ϋ ii -ϋ 1 ϋ ϋ n ϋ I ϋ ^1 _ This paper scale applies to China Standard (CNS) A4 specification (210 X 297 mm) 238 91949 1293306 Δ7 Α7 ______Β7 V. (239) Antiviral Test of Candidate Compounds Against Respiratory Viruses During these experiments, the antiviral activity of a compound of formula (1) against a series of viruses infected with the upper respiratory tract was tested. The method employed for these purposes is detailed. The following method is from vir〇1〇gy Branch,

Division of Microbiology and infeeti〇ns Disease，niaid， NIH.(國家衛生總署NIAID微生物與傳染病部份，病毒學 分部）之標準操作法。Division of Microbiology and infeeti〇ns Disease, niaid, NIH. (National Health Administration NIAID Microbiology and Infectious Diseases, Virology Division) Standard Practice.

Α· I篩選法採用之病毒邀細臉梓 (Ό流感病毒A邀B 病毒菌種：A/北京/262/95(Η1Ν1)(來源CDC) ; A/雪梨 /05/97(H3N2)(來源 CDC) ; B/北京/184/93(來源 CDC) 細胞株：Maldin Darby犬腎臟（MDCK) (ii) 呼吸合胞體病喜fRSV、 病毒菌株A2(來源ATCC) 細胞株：非洲綠猴腎臟（MA-104)細胞 (iii) 副流感病喜3剞 病毒菌株：14702(來源：單離株5/95 Boivin，加拿大 蒙特婁） 細胞株：非洲綠猴腎臟（MA-104)細胞 B.抗病毒活性試驗法 (i)病毒細胞致病效應（CPE)之抑制作用 此試驗係於96孔微滴定板上進行。此CPE抑制試驗 中添加4種l〇g1Q稀釋度之各試驗化合物至3個含單層細胞 之杯子中；在5分鐘内，添加病毒，板子密封，於 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注意事項再填寫本頁) -------訂---------*^1 經濟部智慧財產局員工消費合作社印製 239 1293306 A7Α· I screening method using the virus to invite the face 梓 (Ό influenza virus A invite B virus strain: A / Beijing / 262/95 (Η 1Ν 1) (source CDC); A / Sydney 05/97 (H3N2) (source CDC); B/Beijing/184/93 (Source CDC) Cell line: Maldin Darby canine kidney (MDCK) (ii) Respiratory syncytial disease fRSV, virus strain A2 (source ATCC) Cell line: African green monkey kidney ( MA-104) cells (iii) Parainfluenza virus 剞3 剞 virus strain: 14702 (Source: detached strain 5/95 Boivin, Montreal, Canada) Cell line: African green monkey kidney (MA-104) cells B. Antiviral Activity test method (i) Inhibition of viral cell pathogenic effect (CPE) This test was carried out on a 96-well microtiter plate. Four test compounds of l〇g1Q dilution were added to the CPE inhibition test to three In a single-layer cell cup; add virus in 5 minutes, the board is sealed, and the Chinese National Standard (CNS) A4 specification (210 X 297 mm) is applied to the paper scale. 91949 (Please read the notes on the back and fill in the form) Page) -------Book---------*^1 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 239 1293306 A7

五、發明說明（240 ) 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 培養，當未處理之已感染對照組發展到3至4+ CPE(約72 至120小時）時，在顯微鏡下讀取〇ρΕ。各試驗在使用試驗 樂物之平行試驗中分析已知之陽性對照組藥物。此藥物為 用於流感、麻疹、RSV及副流感之利巴韋林。 (ii)—中性紅（NR诗料啜收吾摇高 此試驗係用於判斷初試驗中所觀察到之CPE抑制作 用之有效性，且待CPE已轉呈紅色後，利用此相同96孔 微滴定板進行。添加中性紅至培養基中；未受病毒破壞之 細胞吸收較多染料，並於電腦化之微滴定板讀數機上讀 數。採用 McManus 說明之方法（Appl. Enviroment. Microbiol· 3 1:35-3 8,1976)。由此染料吸收量測定 EC50。 Liii)確認試驗：CPE病毒性輿痣毒產量分析法 經CPE抑制作用及NR染料吸收量判定具有活性之化 合物將再使用CPE抑制作用及降低對病毒產量之效應再 測試一次。自初次試驗收集溶出液，由一系列稀釋液於有 反應之細胞之單層細胞上分析病毒效價。此等細胞中之 CPE發展即代表有感染性病毒存在情形。由此等數據測定 抑制病毒產量達Ι-log之藥物之ECgo。 表23出示抗病毒試驗之部份結果。召_D-BS具有強力 抗黃病毒科病毒活性，且在活體外具有對抗流感病毒A與 B之強力抗病毒能力，並對RSV具有一些活性。但對副流 感3型病毒則無活性，此表示此化合物對某些RNA病毒具 有特定抗病毒效應’並非對抗所有病毒。 此外，化合物召-D-CL在活體外為強力之抗Rsv化合 本&amp;張尺度適用中國國家標準（CNS)A4規格（21G X 297公爱] ________ 閱 言ί 背 面 之 注 意 事 項 再 填 寫 頁V. Description of invention (240) Printed and cultivated by the Consumers' Cooperatives of the Intellectual Property Office of the Ministry of Economic Affairs. When the untreated infected control group developed to 3 to 4+ CPE (about 72 to 120 hours), read 〇ρΕ under the microscope. . Each test analyzed a known positive control drug in a parallel test using the test substance. This drug is ribavirin for flu, measles, RSV and parainfluenza. (ii) Neutral Red (NR 诗 啜 吾 此 此 此 This test is used to determine the effectiveness of the CPE inhibition observed in the initial test, and after the CPE has been turned red, use the same 96-well Microtiter plates were performed. Neutral red was added to the medium; cells that were not damaged by the virus absorbed more dye and were read on a computerized microtiter plate reader. The method described by McManus (Appl. Enviroment. Microbiol·3) 1:35-3 8, 1976). The EC50 is determined by the amount of dye absorption. Liii) Confirmation test: CPE viral scorpion sputum yield analysis method CPE inhibition and NR dye absorption are determined to be active compounds will be reused CPE The effect of inhibition and reduction of virus production was tested again. The eluate was collected from the initial test and the virus titer was analyzed on a single layer of cells of the reacting cells from a series of dilutions. The development of CPE in these cells represents the presence of an infectious virus. From this data, the ECgo of the drug which inhibits the virus production up to Ι-log is determined. Table 23 shows some of the results of the antiviral test. _D-BS has potent anti-flavivirus activity and has strong antiviral ability against influenza A and B in vitro and has some activity against RSV. However, it is inactive against the parainfluenza type 3 virus, indicating that this compound has a specific antiviral effect on certain RNA viruses' not against all viruses. In addition, Compound Call-D-CL is a powerful anti-Rsv compound in vitro. The scale is applicable to the Chinese National Standard (CNS) A4 specification (21G X 297 public interest). ________ Read the comments on the back side.

訂 I I I I I 、4Book I I I I I, 4

240 91949 1293306 A7 B7 五、發明說明（241 ) 物，其選擇性指數為150。 表23 :對呼吸道病毒之抗病毒效應 初試驗，採用CPE抑制作用篩選對抗呼吸道病毒之抗病毒 化合物（目視） β-D-AJ β-D-BS β-D-CL β-D-DJ 流感病毒A ec50_ 150 1.5 &gt;5 &gt;500 (H1N1) SI** 2 50 0 0 流感病毒A Ε〇5〇(μΜ) &gt;500 1.5 &gt;5 &gt;500 (H3N2) SI** 0 50 0 0 Ε〇5〇(μΜ) 150 0.5 &gt;5 50 流感病毒B SI** 2 150 0 &gt;10 ec50_ &gt;500 0.5 0.5 500 RSV* SI** 0 80 150 0 副流感病毒 Ε05〇(μΜ) &gt;500 &gt;500 90 &gt;500 3型 SI** 0 0 0 0 (請先閱讀背面之注意事項再填寫本頁) 訂--------- 經濟部智慧財產局員工消費合作社印製 初試驗，採用中性紅篩選對抗呼吸道病毒之抗病毒化合物 -H ϋ H ϋ ϋ ϋ n I ϋ n I— ·.1 ϋ ϋ n I I -ϋ 一 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 241 91949 1293306 五、發明說明（w ) β-D-AJ β-D-BS β-D-CL β-D-DJ 流感病毒A EC50 (M^M) 150 1.2 8 &gt;500 (H1N1) SI** &gt;3.3 116 LI 0 流感病毒A Ε05〇(μΜ) &gt;500 4 &gt;5 &gt;500 (H3N2) SI** 0 20 0 0 流感病毒B Ε05〇(μΜ) 150 1,2 &gt;5 110 SI** &gt;3.3 133 0 &gt;4·5 RSV* Ε〇5〇(μΜ) &gt;500 &lt;0·5 &lt;0.5 &gt;500 SI** 0 &gt;30 &gt;170 0 副流感 Ε〇5〇(μΜ) &gt;500 40 40 500 3型病毒 SI** 0 1 1 &gt;1 (請先閱讀背面之注意事項再填寫本頁) 確認試驗：採用目視法篩選對抗呼吸道病毒之抗病毒化合 物（ec50) β-D-BS 流感病毒A Η05〇(μΜ) 13 (H1N!) SI料 &gt;246 流威病毒A Η05〇(μΜ) 0·5 (H3N2) SI** &gt;640 流感病毒B Η05〇(μΜ) SI** 0.6 &gt;533 經濟部智慧財產局員工消費合作社印製 確認試驗，依產量篩選對抗呼吸道病毒之抗病毒化合物 (EC90)_—_ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 242 91949 A7 1293306 -— R7 五、發明說明（243 ) β-D-BS 流感病毒A (H1N1) EC5〇 (μΜ) SI** 0.4 &gt;800 流感病番A (H3N2) ECso (μΜ) SI** 0.32 &gt;1000 流感病毒B EC50 (μΜ) SI** 0.6 &gt;533 *RSV :呼吸合胞體病毒a &quot;si:選擇性指數（ic5(&gt;/EC9()) 實例59 對抗黃病毒科病毒之候選化合物之抗病毒試驗 AJjuh7細胞中HCV i製子系統 含有HCV複製子之Huh7細胞可於DMEM培養基(高 量葡萄糖，無丙酮酸鹽，含10〇/〇胎牛血清、1χ非必需胺基 酸、Pen-Strep-Glu(分別為100單位/升，1〇〇微克/升，及 2.92氅克/升）與500至1〇〇〇微克/毫升G418)中培養。抗病 毒篩選分析法可於不含G418之相同培養基中培養，其方 法如下·為了保持細胞在對數生長期中，在96孔板中接種 低密度細胞，例如：每孔1000個細胞。揍種細胞後，立即 添加試驗化合物，於37 °c培養箱中培養3至7天。然後排 除培養基’準備細胞供萃取全部核酸（包括複製子rNA及 宿主RNA)。複製子RNA可再於Q-Rt-PCR方法中擴增， 並定量。複製子RNA定量結果之顯著差異為表現試驗化合 物之抗病毒效力之方式之一。典型實驗證實，在陰性對照 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公复） '— --”二 91949 (請先閱讀背面之注咅3事項再填寫本頁) 丨#--------訂---------線」 經濟部智慧財產局員工消費合作社印製 243 經濟部智慧財產局員工消費合作社印制衣 1293306 A7 B7 五、發明說明（244) 組及無活性化合物處理組中，產生相當多量複製子。其原 因為這二種處理法中，HC V RT-PCR測定之循環閥值相當 接近。此等實驗中，表現化合物抗病毒有效性之一種方式 為以試驗化合物之RT-PCR循環閥值減去陰性對照組之 RT-PCR循環平均閥值。此數值稱為DeltaCt(ACt或DCt)。 △ Ct為3.3時，等於複製子產量下降1-log(等於EC9。）。使 HC V複製子RNA含量下降2ACt值以上（複製子RNA減少 75%)之化合物可作為抗病毒療法之候選化合物。此等候選 化合物屬於通式（IHXXIII)結構式。表24出示之平均A Ct 值（N :試驗次數）係由目標化合物依上述方法培養96小時 後得到。陽性對照組則採用重組體干擾素^-2&amp;(11〇£61*〇11-A，Hoffmann-Roche，New Jersey，USA) 〇 然而，此HCV A Ct值不包括編碼依賴病毒RNA之 RNA聚合酶之複製子之任何專一性參數。在典型處理條件 下，化合物可能同時降低宿主RNA聚合酶活性及複製子編 碼之聚合酶之活性。因此，定量rRN A(或任何其他宿主RNA 聚合酶I產物）或泠-肌動蛋白mRNA(或任何其他宿主RNA 聚合酶II)，並與無藥物對照組之RNA含量比較，即為試 驗化合物對宿主RNA聚合酶之影響之相對測定值。表24 亦出示試驗化合物對rRNA之A Ct值。 利用HCV A Ct數據及rRNA A Ct，可得到專一性參 數。此參數係由二個A Ct值互減而得，結果產生Delta-DeltaCT值（A ACt或DDCt);數值大於0表示對複製子編 碼之聚合酶具有較高抑制效應，△ A Ct值小於0表示宿主 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 244 91949 (請先閱讀背面之注意事項再填寫本頁) I ϋ ϋ ϋ ϋ ϋ ϋ ϋ I ϋ I ϋ ϋ ϋ H ϋ If n ϋ 1 ϋ ϋ I ϋ 1 ϋ ϋ I ϋ ϋ A7 1293306 B7____ 五、發明說明（245 ) rRNA含量受影響程度大於複製子含量。以值表示 之試驗化合物之抗病毒活性示於表24。通常，△ ACt值大 於2時，則視之與無藥物處理之對照組有顯著差異，因此 具有相當高抗病毒活性。然而，△△ Ct值小於2，但展現 有限之分子細胞活性數據（rRNA A CT在0與2之間）之化 合物亦為可能之活性化合物。 另一種典型條件中，化合物可能降低宿主RNA聚合酶 活性，但不會降低宿主DNA聚合酶活性。因此，定量rDNA 或召-肌動蛋白DNA(或任何其他宿主DNA片段），並與無 藥物對照組之DNA含量比較，為試驗化合物對細胞dNa 聚合酶之抑制效應之相對測定值。表25出示試驗化合物對 rDNA 之△ Ct 值。 利用HC V A Ct數據及及rDNA △ Ct，可得到專一性 參數。此參數係由二個△ ct值互減而得，結果產生△ △ Ct 值；數值大於0表示對複製子編碼之聚合酶具有較高抑制 效應，△△ Ct值小於〇表示宿主rDNA含量受影響程度大 於複製子含量。以值表示之試驗化合物之抗病毒活 性示於表25。通常，值大於2時，則視之與無藥物 處理之對照組有顯著差異，因此值得進一步分析此化合 物。然而，△△ Ct值小於2，但展現有限之分子細胞活性 數據（rDNA △ CT在〇與2之間）之化合物亦可保留。 可使HCV複製子RNA含量專一性下降但細胞RNA及 /或DNA含量下降程度有限之化合物為可用於抗病毒療法 之候選化合物。屬於通式（ΙΗΧΧΙΠ)之候選化合物可分析 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱) ' — 91949 (請先閱讀背面之注意事項再填寫本頁) 0240 91949 1293306 A7 B7 V. Description of invention (241), with a selectivity index of 150. Table 23: Antiviral effects against respiratory viruses. Initial test for screening antiviral compounds against respiratory viruses using CPE inhibition (visual) β-D-AJ β-D-BS β-D-CL β-D-DJ influenza virus A ec50_ 150 1.5 &gt;5 &gt;500 (H1N1) SI** 2 50 0 0 Influenza virus A Ε〇5〇(μΜ) &gt;500 1.5 &gt;5 &gt;500 (H3N2) SI** 0 50 0 0 Ε〇5〇(μΜ) 150 0.5 &gt;5 50 Influenza virus B SI** 2 150 0 &gt;10 ec50_ &gt;500 0.5 0.5 500 RSV* SI** 0 80 150 0 Parainfluenza virus Ε05〇(μΜ) &gt ;500 &gt;500 90 &gt;500 Type 3 SI** 0 0 0 0 (Please read the note on the back and fill out this page) Order --------- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative Initial test, using neutral red to screen antiviral compounds against respiratory viruses-H ϋ H ϋ ϋ ϋ n I ϋ n I—·1 ϋ II n II -ϋ A paper scale applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) 241 91949 1293306 V. Description of invention (w) β-D-AJ β-D-BS β-D-CL β-D-DJ Influenza virus A EC50 (M^M) 150 1.2 8 &gt;500 (H1N1) SI** &gt;3.3 116 LI 0 Influenza virus A Ε05〇(μΜ) &gt;500 4 &gt;5 &gt;500 (H3N2) SI** 0 20 0 0 Influenza virus B Ε05〇(μΜ) 150 1,2 &gt;5 110 SI** &gt;3.3 133 0 &gt;4·5 RSV* Ε〇5〇(μΜ) &gt;500 &lt;0·5 &lt;0.5 &gt;500 SI** 0 &gt;30 &gt;170 0 Parainfluenza 5Ε〇(μΜ) &gt;500 40 40 500 Type 3 virus SI** 0 1 1 &gt;1 (Please read the note on the back and fill out this page) Confirmation test: Visually screen antiviral compounds against respiratory viruses (ec50) β- D-BS Influenza A Η05〇(μΜ) 13 (H1N!) SI material&gt;246 威威病毒 A Η05〇(μΜ) 0·5 (H3N2) SI** &gt;640 Influenza virus B Η05〇(μΜ) SI** 0.6 &gt; 533 Ministry of Economic Affairs Intellectual Property Office Employees' Cooperatives Print Confirmation Test, Screening Antiviral Compounds Against Respiratory Viruses by Production (EC90)___ This paper scale applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 242 91949 A7 1293306 - R7 V. Inventive Note (243) β-D-BS Influenza A (H1N1) EC5〇(μΜ) SI** 0.4 &gt;800 Influenza A (H3N2) ECso (μΜ) SI** 0.32 &gt;1000 flu Toxic B EC50 (μΜ) SI** 0.6 &gt; 533 *RSV: Respiratory syncytial virus a &quot;si: Selectivity index (ic5(&gt;/EC9()) Example 59 Compound compounds against Flaviviridae virus Antiviral assay AHCu7 cells in the HCV i system Huh7 cells containing HCV replicon can be used in DMEM medium (high glucose, no pyruvate, containing 10 〇 / 〇 fetal bovine serum, 1 χ non-essential amino acid, Pen- Strep-Glu (100 units/liter, 1 〇〇 microgram/liter, and 2.92 gram/liter, respectively) and 500 to 1 〇〇〇 microgram/ml G418) were cultured. The anti-virus screening assay can be cultured in the same medium without G418 as follows. In order to keep the cells in the logarithmic growth phase, low density cells are seeded in 96-well plates, for example, 1000 cells per well. Immediately after the seeding, the test compound was added and cultured in a 37 ° C incubator for 3 to 7 days. The medium is then removed&apos; to prepare cells for extraction of all nucleic acids (including replicon rNA and host RNA). Replicon RNA can be amplified and quantified in the Q-Rt-PCR method. A significant difference in the quantitative results of replicon RNA is one of the ways to demonstrate the antiviral efficacy of the test compound. Typical experiments confirmed that the Chinese National Standard (CNS) A4 specification (210 X 297 public) is used in the negative control paper scale '- --" 2 91949 (please read the back note 咅 3 matters and then fill out this page) 丨# --------Book --------- Line" Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 243 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing clothing 1293306 A7 B7 V. Invention description ( 244) A considerable amount of replicon was produced in the group and the inactive compound-treated group. Because of these two treatment methods, the cycle thresholds measured by HC V RT-PCR are quite close. One way to demonstrate the antiviral effectiveness of a compound in these experiments was to subtract the RT-PCR cycle mean threshold of the negative control group from the RT-PCR cycle threshold of the test compound. This value is called DeltaCt (ACt or DCt). When Δ Ct is 3.3, it is equal to the replicon yield decreased by 1-log (equal to EC9.). Compounds that reduce the HC V replicon RNA content by more than 2 ACt (replication of replicon RNA by 75%) can be used as candidate compounds for antiviral therapy. These candidate compounds belong to the formula (IHXXIII). The average A Ct value (N: number of trials) shown in Table 24 was obtained by culturing the target compound for 96 hours as described above. The positive control group was treated with recombinant interferon^-2&amp;(11〇£61*〇11-A, Hoffmann-Roche, New Jersey, USA). However, this HCV A Ct value does not include RNA polymerization encoding viral-dependent RNA. Any specific parameter of the replicon of the enzyme. Under typical processing conditions, the compound may simultaneously reduce host RNA polymerase activity and replicon-encoded polymerase activity. Thus, quantification of rRN A (or any other host RNA polymerase I product) or 泠-actin mRNA (or any other host RNA polymerase II) and comparison with the RNA content of the drug-free control group is the test compound pair Relative measurement of the effect of host RNA polymerase. Table 24 also shows the A Ct values of the test compounds for rRNA. Specificity parameters can be obtained using HCV A Ct data and rRNA A Ct. This parameter is obtained by subtracting the two A Ct values, resulting in a Delta-DeltaCT value (A ACt or DDCt); a value greater than 0 indicates a higher inhibitory effect on the replicon-encoded polymerase, and the Δ A Ct value is less than 0. Indicates that the host paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 244 91949 (please read the back note before completing this page) I ϋ ϋ ϋ ϋ ϋ ϋ ϋ I ϋ I ϋ ϋ ϋ H ϋ If n ϋ 1 ϋ ϋ I ϋ 1 ϋ ϋ I ϋ ϋ A7 1293306 B7____ V. Description of the invention (245) The rRNA content is affected to a greater extent than the replicon content. The antiviral activity of the test compounds expressed by values is shown in Table 24. In general, when the Δ ACt value is more than 2, it is considered to be significantly different from the drug-free control group, and thus has a relatively high antiviral activity. However, a compound having a ΔΔ Ct value of less than 2, but exhibiting limited molecular cell activity data (rRNA A CT between 0 and 2) is also a possible active compound. In another typical condition, the compound may reduce host RNA polymerase activity without reducing host DNA polymerase activity. Thus, rDNA or CAM-actin DNA (or any other host DNA fragment) is quantified and compared to the DNA content of the drug-free control group as a relative measure of the inhibitory effect of the test compound on cellular dNa polymerase. Table 25 shows the Δ Ct values of the test compound versus rDNA. Specificity parameters can be obtained using HC V A Ct data and rDNA Δ Ct. This parameter is obtained by subtracting the two Δ ct values, and the result is △ △ Ct value; the value greater than 0 means that the polymerase encoding the replicon has a higher inhibitory effect, and the △ △ Ct value is less than 〇 indicates that the host rDNA content is affected. The extent is greater than the replicon content. The antiviral activity of the test compounds expressed by values is shown in Table 25. In general, when the value is greater than 2, it is considered to be significantly different from the control group without drug treatment, so it is worthy of further analysis of the compound. However, a compound having a ΔΔ Ct value of less than 2, but exhibiting limited molecular cell activity data (rDNA ΔCT between 〇 and 2) may also be retained. Compounds that reduce the specificity of HCV replicon RNA content but have a limited decrease in cellular RNA and/or DNA content are candidate compounds for antiviral therapy. Candidate compounds belonging to the general formula (ΙΗΧΧΙΠ) can be analyzed. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 public) ' — 91949 (please read the back note and fill out this page) 0

訂---------線I 經濟部智慧財產局員工消費合作社印製 245 1293306 A7 B7 五、發明說明（246 ) 其降低黃病毒科病毒RNA(包括B VDV與HC V)之專一性能 力，並檢測強效力之化合物（表21、24與25)。 表24 (請先閱讀背面之注意事項再填寫本頁) 0 訂---------手痛 經濟部智慧財產局員工消費合作社印製 -I I I I ϋ I I ϋ ϋ ϋ ϋ 1 1_· ϋ ϋ ϋ ϋ _ ID η HCV RNA 平均值 △Ct rRNA 平均值 △ Ct △ △Ct 平均值 β-D-AA 3 3.83 2.41 L42 β-D-AI 3 2.93 2.43 0.48 β-D-AJ 22 2.92 1,74 1.18 p-D-AK 4 3.73 2.48 1.25 β-D-AL 2 3,08 2.72 0.36 P-D-AN 6 3.33 2.11 1.22 P-D-AO 1 4.10 2.13 1·97 β-D-AP 2 3.27 3.23 0.05 β-D-AQ 7 4.45 3.22 1.22 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） 246 91949 1293306 A7 B7 五、發明說明（247 ) 經濟部智慧財產局員工消費合作社印制衣 η HCV RNA 平均值 △ Ct rRNA 平均值 ACt A ACt 平均值 β_υ·ΑΤ 2 3.71 3.07 0.64 β-D-BE 2 4.44 2.80 1.64 β-D-BF 2 4.37 2.69 1.68 β-D-BH 1 3.06 0.91 2.15 β-D-BJ 2 5.06 3.62 1.44 β-D-BL 1 2.28 1.93 0.35 β-D-BO 1 4.52 2.95 1.57 β-D-BS 40 4.89 1.05 3.83 p-D-BT 5 4.83 3.59 1.24 β-D-BU 4 3.46 2.18 1.06 β-D-BV 3 1.88 0.65 1.22 p-D.CC 6 5.04 4.82 0.21 p-D-DD 1 6.60 4.99 1.61 β-D-DH 3 4.13 2.91 1.21 β-D-DJ 5 3.51 3.62 -0.11 β·Ι)-ΕΒ 1 3.33 1.42 1.90 β-D-FA 2 3.80 3.58 1.44 β-D-GA 4 6.04 2.10 3.93 β-D-HA 2 5.52 3.85 1.68 β-D-HB 5 2.94 1.65 1.30 β-D-KB 2 3.61 2.52 1.10 β-D-LA 3 3.85 4.10 0.89 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) - -------訂---------線|一 247 91949 1293306 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（248 ) η HCV RNA 平均值 △Ct rRNA 平均值 ACt △ △Ct 平均值 β-D-MD 3 3.57 1.95 1.62 P-D-ME 1 2.89 1.25 1.64 β-D-MF 2 3.79 2.69 1·10 β-D-OE 1 4.51 4.20 031 β-D-QA 3 2.91 3.81 •0.89 β-D-RJB 2 430 3.18 1.12 β-D-TA 1 4.00 3.31 0.69 P-D-UA 1 2.91 1.61 1.3 β-D-VA 1 5.56 4.17 1·39 P-L-FC 3 5.55 5.13 0.42 β-L-JB 1 3.65 4.55 •0.90 β-L-KA 1 4.10 4.84 -0.74 β-L-KC 2 1.19 1.35 -0·16 IFN 4 5.21 0.69 4.52 里巴菲林 2 3·13 2.35 0.78 (請先閱讀背面之注意事項再填寫本頁) -1111111 ·11111111 —AVI — — — — — - — — — — — — — — — — — — — — — — 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 248 91949 A7 1293306 B7 五、發明說明（249 ) 表25 HCV RNA rDNA 平均值 平均值 AACt ID η △ Ct 平均值 β-D-AA 3 3.83 2.53 1.88 β-D-Al 1 3.76 -0.96 4.55 β-D-AJ 16 2.75 0.43 2.33 (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 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 249 91949 1293306 經濟部智慧財產局員工消費合作社印製 A7 B7 、發明說明（ 250 ) ID HCV RNA 平均值 η rDNA 平均值 △ Ct △ ACt 平均值 β-D-AK 1 3.51 2.69 0.79 β-D-AL 1 3.18 2.56 0.61 β-D-AN 2 3.86 2.53 1.88 β-D-AO 1 4.10 1.84 2.26 β-D-AP 2 3.27 2.26 1.02 β-D-AQ 3 4.75 1.78 2.73 β-D-AT 1 3.81 2.43 1·43 β-D-BE 1 4.99 2·06 2.98 β-D-BF 1 5.27 2.04 3.28 β-D-BH 1 3.06 1.42 1.64 β-D-BJ 1 4.34 0.81 3.53 β-D-BL 1 2.28 1.62 0.65 β-MS 14 4.81 038 4.45 β-D-BT 2 4.44 1.17 339 β-D-BU 4 3.46 1.10 1.16 β-D-BV 3 1.88 0.31 1.65 β-D-CC 3 5.84 2.17 3.66 β-D-DD 1 6.60 3.30 3.30 β-D-DH 1 4.14 0.89 3.25 β-D-DJ 1 4.84 2.70 2.14 β-D-EB 1 3.33 0.96 2.37 β-D-FA 2 3.80 1.92 0.78 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 250 91949 (請先閱讀背面之注音？事項再填寫本頁) ^OJI ϋ n ·1 I -I n I 0^^^ ϋ ϋ n ϋ ϋ n ϋ I- ϋ ϋ ·1 n 1· ϋ ϋ H ϋ ϋ ϋ I ϋ ϋ - [293306 經濟部智慧財產局員工消費合作社印製 A7 B7 、發明說明（ 251 ) ID HCV RNA 平均值 η rDNA 平均值 △ Ct Δ ACt 平均值 β-L-FC 1 4.41 1.00 3.41 β-D-HA 1 5.12 2.04 3.16 P-D-HB 1 1.90 1.19 0.40 β-D^KB 1 3.81 0.00 3.81 β-L-JB 1 3.65 1.20 2.45 β-L-KA 1 4.10 0.42 3.69 β-L-KC 1 2.73 -0.81 3.54 . β-D-LA 1 3.54 1.56 1.98 β-D-MD 2 3.50 1·58 1.46 β-D-ME 1 2.89 1.53 136 β-D-MF 2 3.79 2.17 1.65 β-D-OE 1 4.51 -0.04 4.60 β-D-QA 1 4.85 230 2.55 p-D-RB 1 400 1.27 2.74 β-D-TA 1 4.00 3.07 0.93 β-D-UA 1 2.91 0.50 2.41 實例60 冷-D-GA之毒性形態 本文採用之細胞毒性試驗為標準技術。簡言之，在96 表紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 251 91949 (請先閱讀背面之注意事項再填寫本頁)Order ---------Line I Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 245 1293306 A7 B7 V. Description of Invention (246) It reduces the specificity of flavivirus RNA (including B VDV and HC V) Sexual ability and detection of potent compounds (Tables 21, 24 and 25). Table 24 (Please read the notes on the back and fill out this page) 0 Order---------Hand pain Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed-IIII ϋ II ϋ ϋ ϋ ϋ 1 1_· ϋ ϋ ϋ ϋ _ ID η HCV RNA Average △Ct rRNA Average △ Ct △ △Ct Average β-D-AA 3 3.83 2.41 L42 β-D-AI 3 2.93 2.43 0.48 β-D-AJ 22 2.92 1,74 1.18 pD-AK 4 3.73 2.48 1.25 β-D-AL 2 3,08 2.72 0.36 PD-AN 6 3.33 2.11 1.22 PD-AO 1 4.10 2.13 1·97 β-D-AP 2 3.27 3.23 0.05 β-D-AQ 7 4.45 3.22 1.22 The paper size is applicable to China National Standard (CNS) A4 specification (210 297 297 mm) 246 91949 1293306 A7 B7 V. Description of invention (247) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed clothing η HCV RNA average △ Ct rRNA average ACt A ACt average β_υ·ΑΤ 2 3.71 3.07 0.64 β-D-BE 2 4.44 2.80 1.64 β-D-BF 2 4.37 2.69 1.68 β-D-BH 1 3.06 0.91 2.15 β-D-BJ 2 5.06 3.62 1.44 β-D-BL 1 2.28 1.93 0.35 β-D-BO 1 4.52 2.95 1.57 β-D-BS 40 4.89 1.05 3.83 pD-BT 5 4.83 3.59 1.24 β-D-BU 4 3.46 2.18 1.06 β-DB V 3 1.88 0.65 1.22 pD.CC 6 5.04 4.82 0.21 pD-DD 1 6.60 4.99 1.61 β-D-DH 3 4.13 2.91 1.21 β-D-DJ 5 3.51 3.62 -0.11 β·Ι)-ΕΒ 1 3.33 1.42 1.90 β- D-FA 2 3.80 3.58 1.44 β-D-GA 4 6.04 2.10 3.93 β-D-HA 2 5.52 3.85 1.68 β-D-HB 5 2.94 1.65 1.30 β-D-KB 2 3.61 2.52 1.10 β-D-LA 3 3.85 4.10 0.89 This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) - -------Book ------- --Line|一247 91949 1293306 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5, Invention Description (248) η HCV RNA Average △Ct rRNA Average ACt △ △Ct Average β-D-MD 3 3.57 1.95 1.62 PD-ME 1 2.89 1.25 1.64 β-D-MF 2 3.79 2.69 1·10 β-D-OE 1 4.51 4.20 031 β-D-QA 3 2.91 3.81 •0.89 β-D-RJB 2 430 3.18 1.12 β- D-TA 1 4.00 3.31 0.69 PD-UA 1 2.91 1.61 1.3 β-D-VA 1 5.56 4.17 1·39 PL-FC 3 5.55 5.13 0.42 β-L-JB 1 3.65 4.55 •0.90 β-L-KA 1 4.10 4.84 -0.74 β-L-KC 2 1.19 1.35 -0·16 IFN 4 5.21 0.69 4.52 Ribafelin 2 3·13 2.35 0.78 (Please read the note on the back and fill out this page) -1111111 ·11111111 —AVI — — — — — — — — — — — — — — — — — — — — — — — — — This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 248 91949 A7 1293306 B7 V. Description of invention (249) Table 25 HCV RNA rDNA Mean average AACt ID η △ Ct Average β-D -AA 3 3.83 2.53 1.88 β-D-Al 1 3.76 -0.96 4.55 β-D-AJ 16 2.75 0.43 2.33 (Please read the notes on the back and fill out this page) --------Book --- ------ Line Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed This paper scale applies China National Standard (CNS) A4 specification (210 X 297 mm) 249 91949 1293306 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7, invention description (250) ID HCV RNA mean η rDNA average △ Ct △ ACt average β-D-AK 1 3.51 2.69 0.79 β-D-AL 1 3.18 2.56 0.61 β-D-AN 2 3.86 2.53 1.88 β -D-AO 1 4.10 1.84 2.26 β-D-AP 2 3.27 2.26 1.02 β-D-AQ 3 4.75 1.78 2.7 3 β-D-AT 1 3.81 2.43 1·43 β-D-BE 1 4.99 2·06 2.98 β-D-BF 1 5.27 2.04 3.28 β-D-BH 1 3.06 1.42 1.64 β-D-BJ 1 4.34 0.81 3.53 β-D-BL 1 2.28 1.62 0.65 β-MS 14 4.81 038 4.45 β-D-BT 2 4.44 1.17 339 β-D-BU 4 3.46 1.10 1.16 β-D-BV 3 1.88 0.31 1.65 β-D-CC 3 5.84 2.17 3.66 β-D-DD 1 6.60 3.30 3.30 β-D-DH 1 4.14 0.89 3.25 β-D-DJ 1 4.84 2.70 2.14 β-D-EB 1 3.33 0.96 2.37 β-D-FA 2 3.80 1.92 0.78 Paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 250 91949 (Please read the phonetic transcription on the back first? Matters fill out this page) ^OJI ϋ n ·1 I -I n I 0^^^ ϋ ϋ n ϋ ϋ n ϋ I- ϋ ϋ ·1 n 1· ϋ ϋ H ϋ ϋ ϋ I ϋ ϋ - [293306 Economy Ministry of Intellectual Property Bureau employee consumption cooperative printed A7 B7, invention description (251) ID HCV RNA average η rDNA average △ Ct Δ ACt average β-L-FC 1 4.41 1.00 3.41 β-D-HA 1 5.12 2.04 3.16 PD-HB 1 1.90 1.19 0.40 β-D^KB 1 3.81 0.00 3.81 β-L-JB 1 3.65 1.20 2.45 β-L-KA 1 4.10 0.42 3.69 β-L-KC 1 2.73 -0.81 3.54 . β-D-LA 1 3.54 1.56 1.98 β-D-MD 2 3.50 1·58 1.46 β-D-ME 1 2.89 1.53 136 β-D-MF 2 3.79 2.17 1.65 β-D-OE 1 4.51 -0.04 4.60 β-D-QA 1 4.85 230 2.55 pD-RB 1 400 1.27 2.74 β-D-TA 1 4.00 3.07 0.93 β-D-UA 1 2.91 0.50 2.41 Example 60 Toxicity of cold-D-GA The cytotoxicity test used herein is standard. In short, the Chinese National Standard (CNS) A4 specification (210 X 297 mm) is applied to the 96-sheet paper scale. 251 91949 (Please read the note on the back and fill out this page)

--I----訂·--------I —II 1293306 Α7 ------- Β7 五、發明說明（ 252 ) 孔板中接種各種不同濃度之細胞（依細胞型態、分析時間長 短而定），典型地每孔含有5χ 1〇3個細胞，並含有濃度逐 漸提高之試驗化合物（〇、1、3、10、33與1〇〇//Μ)。與試 驗化合物之培養時間可隨細胞型態而改變，但通常在3至 5天之範圍内。添加ΜΤΤ染料（Promega)並培養8小時， 測定細胞活力及粒線體活性。之後添加中止反應溶液固定 含有染料之培養板，然後培養8小時。最後於570nm下讀 取570nm。此等方法已由製造商（Promega)詳細說明及提 供。 雖然試驗化合物通常沒有細胞毒性，但令人驚詞1的 是，泠-D-GA對CEM細胞展現選擇性細胞毒性效應（表 21)。為了探討此化合物之完全潛力，由一組人類惡性T 與B細胞及各種不同踵瘤細胞株與不同濃度之石—D-GA培 養，讀取吸光度後，計算IC50值。同時採用Ara-C、5FU 及環己醯亞胺作為對照組（表26)。 召-D-GA在人類惡性T與B細胞中具有強力毒性，但 在人類PBM細胞及非T或B贅生細胞中則無毒性，相較 於Ara-C與5-FU，点-D-GA對T與B細胞則具有相當高 選擇性之抗癌活性。 表26: -D-GA對抗各種不同腫瘤細胞株之毒性形態（ic50, β Μ)* 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 (請先閱讀背面之注音？事項再填寫本頁} -11 11 111 a叮·1111111 » l_ 經濟部智慧財產局員工消費合作社印製 252 1293306 五、發明說明（253 ) β -D-GA Ara-C 5-FU 環己醯亞胺 PBM &gt;100 7 13.7 2.6 Vero &gt;100 0.8 65 2.1 CEM 2.9 0.6 90.5 0.1 SUDHL-1 0.7 3.7 O 03 SupTl 0.3 O 53.6 0.6 H9 1.4 o 14.2 1 JY 3 o 7.5 0.8 BL41 &lt;L0 o 24.1 0.3 LNCaP 45.7 0 22.1 2.4 SK-MES-1 &gt;100 o 13.1 3.4 SK-MEL-28 &gt;100 0 11.2 1 HEPG2 &gt;100 a 40.6 3.6 MCF-7 &gt;100 o 43.7 1.5 *ΜΤΤ分析法（培養時間3至5天） ΡΒΜ ··人類周邊血液單核細胞 Vero :非洲綠猴腎臟細胞株 CEM :人類T細胞淋巴瘤細胞株 SUDHL-1 :人類退行發育大型T細胞淋巴瘤細胞株 SupTl ：人類T細胞淋巴母細胞細胞株 H9 :人類T細胞淋巴母細胞細胞株 JY :人類B細胞淋巴瘤細胞株（經EBV轉形） 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949 ------------# (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--I----订·-------I-II 1293306 Α7 ------- Β7 V. Description of the invention ( 252 ) Inoculation of various concentrations of cells in the well plate (depending on cell type) The state, depending on the length of the analysis, typically contains 5χ1〇3 cells per well and contains test compounds with increasing concentrations (〇, 1, 3, 10, 33 and 1〇〇//Μ). The incubation time with the test compound may vary depending on the cell type, but is usually in the range of 3 to 5 days. Anthraquinone dye (Promega) was added and cultured for 8 hours, and cell viability and mitochondrial activity were measured. Thereafter, the suspension reaction solution was added to fix the dye plate, and then cultured for 8 hours. Finally, 570 nm was read at 570 nm. These methods have been detailed and provided by the manufacturer (Promega). Although the test compounds are generally not cytotoxic, it is surprising that 泠-D-GA exhibits a selective cytotoxic effect on CEM cells (Table 21). To investigate the full potential of this compound, a panel of human malignant T and B cells and various tumor cell lines and different concentrations of stone-D-GA were cultured, and the IC50 values were calculated after reading the absorbance. Ara-C, 5FU and cycloheximide were used as a control group (Table 26). CAM-D-GA is highly toxic in human malignant T and B cells, but not toxic in human PBM cells and non-T or B twin cells, compared to Ara-C and 5-FU, point-D- GA has a highly selective anticancer activity against T and B cells. Table 26: Toxicity profile of -D-GA against various tumor cell lines (ic50, β Μ)* This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 (Please read the phonetic transcription on the back)事项111111 » l_ Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 252 1293306 V. Invention Description (253) β-D-GA Ara-C 5-FU Cyclohexane Imine PBM &gt;100 7 13.7 2.6 Vero &gt;100 0.8 65 2.1 CEM 2.9 0.6 90.5 0.1 SUDHL-1 0.7 3.7 O 03 SupTl 0.3 O 53.6 0.6 H9 1.4 o 14.2 1 JY 3 o 7.5 0.8 BL41 &lt;L0 o 24.1 0.3 LNCaP 45.7 0 22.1 2.4 SK-MES-1 &gt;100 o 13.1 3.4 SK-MEL-28 &gt;100 0 11.2 1 HEPG2 &gt;100 a 40.6 3.6 MCF-7 &gt;100 o 43.7 1.5 *ΜΤΤanalysis (culture time 3 to 5 days) ΡΒΜ · Human peripheral blood mononuclear Vero: African green monkey kidney cell line CEM: Human T cell lymphoma cell line SUDHL-1 : Human degenerative development Large T cell lymphoma cell line SupTl : Human T cell Lymphocyte cell line H9: human T cell lymphoblast cell line JY: human B cell lymph Tumor cell line (transformed by EBV) This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91949 ------------# (Please read the notes on the back first) Fill in this page again) Printed by the Consumer Intellectual Property Office of the Ministry of Economic Affairs

253 [293306253 [293306

五、發明說明（254 經濟部智慧財產局員工消費合作社印製 BL41 ··人類B細胞淋巴瘤細胞株 LNCap :人類攝護腺腺癌瘤細胞株 SK_MES-1 :人類肺鱗狀癌瘤細胞株 SK-MEL-28 ·人類黑色瘤細胞株 HEPG2 :人類肝癌瘤細胞株 MCF-7 ·人類乳房癌瘤細胞株 添加天然核苷，探討其在CEM細胞（人類了細胞淋巴 瘤）及SUDHL-1細胞（人類退行發育大型了細胞淋巴瘤細胞 株）中預防與召-D-GA有關之細胞毒性之效應。添加5〇以μ 天然核苷至培養基中，開始進行實驗，同時含有濃度逐漸 提高之召-D-GA。每孔接種2500個CEM細胞，培養4天 (=快速生長之細胞株，其生長達加倍量時所需時間為約i 3 天）。SUDHL_1細胞每孔接種10000個細胞，培養3天卜 緩慢生長之細胞株，其生長達加倍量時所需時間為約3 天）。此實驗結果示於第4圖。此圖顯示，胞苷與尿苔在 SUDHL-1細胞及CEM細胞中（類似圖示，但未出示）顯著 防止召-D-GA毒性。2，-去氧胞苷具有中度之預防性活性效 應。由此等數據可知，召-D-GA對抗生長緩慢之SUDHL-1細胞之效力與對抗生長較快速之CEM細胞之效力相同， 胞苷與尿苷在這二種細胞株中均預防與化合物有關之毒 性。yS -D-GA之作用可能與宿主RNA分子之合成及功能有 關，但與DNA無關。 本發明已引用各種明確且較佳具體實施例及技術說 表紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 254 91949 (請先閱讀背面之沒杳？事項再填寫本頁) 暴V. Description of Invention (254 Ministry of Economic Affairs Intellectual Property Office Staff Consumption Cooperative Printed BL41 · Human B Cell Lymphoma Cell Line LNCap: Human Prostate Adenocarcinoma Cell Line SK_MES-1 : Human Lung Squamous Cell Line SK -MEL-28 · Human melanoma cell line HEPG2: human hepatocarcinoma cell line MCF-7 · Human breast cancer cell line with natural nucleoside added to investigate CEM cells (human cell lymphoma) and SUDHL-1 cells ( The effect of cytotoxicity associated with the call-D-GA in the development of a large human cell lymphoma cell line. Adding 5 〇 to the natural nucleoside to the medium, the experiment is started, and the concentration is gradually increased. D-GA: Inoculate 2500 CEM cells per well and culture for 4 days (= fast-growing cell line, the time required for growth to increase the amount is about i 3 days). SUDHL_1 cells inoculate 10000 cells per well, culture 3 The cell line that grows slowly is about 3 days long when it grows to double the amount. The results of this experiment are shown in Figure 4. This figure shows that cytidine and urinary moss significantly prevent the D-GA toxicity in SUDHL-1 cells and CEM cells (similar to the illustration, but not shown). 2,-Deoxycytidine has a moderate prophylactic activity. From the data, it can be seen that the efficacy of the call-D-GA against the slow-growing SUDHL-1 cells is the same as that of the CEM cells which are faster to grow, and both cytidine and uridine are prevented from being compound-related in both cell lines. Toxicity. The role of yS-D-GA may be related to the synthesis and function of the host RNA molecule, but not to DNA. The invention has been described with reference to various specific and preferred embodiments and techniques. The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 254 91949 (please read the back of the book first? Storm

訂---------線丨I A7 經濟部智慧財產局員工消費合作社印製 1293306 B7 五、發明說明（255 ) 明。然而，應了解，習此技藝之人士可由上述本發明詳細 說明但仍在本發明之精神與範圍内進行各種變化與修飾。 (請先閱讀背面之注意事項再填寫本頁)Order ---------Line 丨 I A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1293306 B7 V. Invention description (255) Ming. However, it will be appreciated that those skilled in the art can devise various modifications and changes in the present invention. (Please read the notes on the back and fill out this page)

-·ϋ ϋ ϋ 1 i_i —i ϋ 一 0mi ·ϋ Βϋ i·— ϋ ϋ 1 I 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 255 91949-·ϋ ϋ ϋ 1 i_i —i ϋ 一 0mi ·ϋ Βϋ i·— ϋ ϋ 1 I This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 255 91949

Claims (1)

1293306 A8B8C8D8 第90126014號專利申請案 (96 年 8 月 24 “、 -«I ·ι 1··Ι ^ι·1 &quot; ) 9乙年分只冲日終(黧）ϊϋ太 六、申請專利範圍 1· 一種治療或預防宿主之黃病毒科（Flaviviridae)、正黏液 病毒科（Orthomyxoviridae)或副黏液病毒科 (Paramyxoviridae)病毒感染之醫藥組成物，其包括通式 (I)或（II)化合物：1293306 A8B8C8D8 Patent application No. 90125514 (August 24, 1996 ", -«I ·ι 1··Ι ^ι·1 &quot; ) 9 B-year-old only rushed to the end of the day (黧)ϊϋ太六, the scope of application for patents A pharmaceutical composition for treating or preventing a viral infection of the host's Flaviviridae, Orthomyxoviridae or Paramyxoviridae, comprising a compound of the formula (I) or (II): X1X1 n^n^x2 DO, wn^n^x2 DO, w R3· R2. [I-b] R2 X1R3· R2. [I-b] R2 X1 (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 [Π-a] [II-b] 或其/5 -L-對映異構物或其醫藥上可接受之鹽，其中： 各D為氣， 各W1與W2分別獨立為ch或N ; 各X1與X2分別獨立為氫、鹵素（F、Ci、Br或工） NH2、NHR4、NHOR4 或 〇H ; 各Y1為0 ; 各R1與R1分別獨立為氫、函素（F、Ch Br或U NH2 或 OH ; 各R2與R2分別獨立為氫或鹵素（F、c卜Br或 本紙張尺度適用中國國家標準（CNS)A4規格（210^7^7 256 91949(修正本) ，裝 • n n n n n n mmmmm 訂-------- 1293306 A8B8C8D8 第90126014號專利申請案 (96年8月24日） 六、申請專利範圍 或0H ; 各R3與R3分別獨立為氫或鹵素（F、C卜Br或I)、 0H、0-甲石黃酿基、〇甲苯磺醯基、或〇_乙醯基； 各R為氫、C(〇)CH3、或經n〇2取代之苄基； 因此通式（I)核苷中，R2與r2,中至少一者為氫，且 R3與R3’中至少一者為氫； 其中’當該病毒感染為黃病毒科病毒感染，且該化 合物具通式[I-a]時，r3與r3’不同時為氫； 中$該病毋感染為黃病毒科病毒感染，且該化 合物具通式[I-a]時，R3’不為氟； /、中¥該病f感染為黃病毒科病毒感染，且該化 合物具通式[I-a]時，則r2’為〇H時，r3不為〇H ; 其中’當該病毒感染為黃病毒科病毒感染，且該化 合物具通式[I-b]時，則R3與R3’同時為氫時，χ1不為 0Η ;以及 其中，當該化合物具通式[Ι-a]或士…時，該黃病毒 科病毒感染不為C型肝炎。 (請先閱讀背面之注意事項再填寫本頁) 訂---------. 經濟部智慧財產局員工消費合作社印製 2·如申請專利範圍第1項之醫藥組成物，其中，式（I a)石 -D核苷為選自下列之一：(Please read the notes on the back and fill out this page.) Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Cooperatives [Π-a] [II-b] or its /5-L-enantiomer or its medicinal Accepted salts, wherein: each D is gas, each of W1 and W2 is independently ch or N; each X1 and X2 is independently hydrogen, halogen (F, Ci, Br or work) NH2, NHR4, NHOR4 or 〇H; Each of Y1 is 0; each of R1 and R1 is independently hydrogen or a nutrient (F, Ch Br or U NH2 or OH; each of R2 and R2 is independently hydrogen or halogen (F, c, Br or this paper scale applies to China) Standard (CNS) A4 specification (210^7^7 256 91949 (amendment), installation • nnnnnn mmmmm order-------- 1293306 A8B8C8D8 Patent application No. 90126014 (August 24, 1996) Patent application scope or 0H; each of R3 and R3 is independently hydrogen or halogen (F, C, Br or I), 0H, 0-methyl stellite, fluorenyl sulfonyl, or oxime oxime; R is hydrogen, C(〇)CH3, or benzyl substituted by n〇2; therefore, in the nucleoside of formula (I), at least one of R2 and r2 is hydrogen, and at least one of R3 and R3' Is hydrogen; where 'when the disease When the infection is a Flaviviridae virus infection, and the compound has the general formula [Ia], r3 and r3' are not hydrogen; the disease is infected with the Flaviviridae virus, and the compound has the general formula [Ia] When R3' is not fluorine; /, the disease is infected with the Flaviviridae virus, and when the compound has the general formula [Ia], when r2' is 〇H, r3 is not 〇H; When the virus is infected with a Flaviviridae virus and the compound has the general formula [Ib], when R3 and R3' are simultaneously hydrogen, χ1 is not 0Η; and wherein, when the compound has the formula [Ι-a ] or Shishi... The Flaviviridae virus infection is not hepatitis C. (Please read the notes on the back and fill out this page) Order---------. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative The pharmaceutical composition of claim 1, wherein the stone-D nucleoside of the formula (I a) is one selected from the group consisting of: 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 257 91949(修正本） 1293306 A8 B8 C8 D8 第90126014號專利申請案 (96年8月24曰） 六、申諳專利範圍 經濟部智慧財產局員工消費合作社印製 X1 Y1 R1 R1 R2 R2 RJ nh2 0 H H H OH O-Ts H nh2 0 H H Cl H H OH nh2 0 D D OH H H OH nh2 0 F H OH H H OH nh2 0 F H H OH H OH nh2 0 F H H OH H H nh2 0 F H H OH Cl H nh2 0 F H H OH Br H nh2 0 F H H Cl H OH nh2 0 F H H OH O-Ts H nh2 0 F H H OH O-Ms H nh2 0 Cl H H OH O-Ms H nh2 0 Br H H OH O-Ms H nh2 0 Br H H OH O-Ts H nh2 0 Br H H OH Cl H nh2 0 Br H H OH H OH nh2 0 Br H OH H H OH nh2 0 I H H OH O-Ms H nh2 0 I H H OH Br H nh2 0 I H H OH O-Ts H nh2 0 I H H Cl H OH nh2 0 I H Br H H OH nh2 0 OH H OH H H OH nh2 0 nh2 H H OH H OH nh-coch3 0 H H OH H H OH NH-OH 0 H H H OH H OH NH-OH 0 F H H OH H OH NH-OH 0 Br H H OH H OH NH-OH 0 I H H OH H OH NH-OH 0 H H OH H H OH OH 0 OH H OH H H OH OH 0 nh2 H H OH H OH OH 0 F H OH H H OH OH 0 F H H OH H OH OH 0 F H H OH H O-Ts OH 0 F H H H H OH OH 0 OH H H OH H OH 或其冷-L-對映異構物或其醫藥上可接受之鹽。 3.如申請專利範圍第1項之醫藥組成物，其中，式（I-b)y5 -D核苷為選自下列之一： X1 X2 w1 R2 R2’ R3 R3’ OH nh2 N H OH H OH OH nh2 CH F H H OH nh2 H CH H OH H F 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 258 91949(修正本) (請先閱讀背面之注意事項再填寫本頁) 訂---------： 1293306 098899 ABCD 第90126014號專利申請案 (96年8月24曰) 六、申 斧利範·This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 257 91949 (amendment) 1293306 A8 B8 C8 D8 Patent No. 90126014 (August 24, 1996) VI. Application scope Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed X1 Y1 R1 R1 R2 R2 RJ nh2 0 HHH OH O-Ts H nh2 0 HH Cl HH OH nh2 0 DD OH HH OH nh2 0 FH OH HH OH nh2 0 FHH OH H OH nh2 0 FHH OH HH nh2 0 FHH OH Cl H nh2 0 FHH OH Br H nh2 0 FHH Cl H OH nh2 0 FHH OH O-Ts H nh2 0 FHH OH O-Ms H nh2 0 Cl HH OH O-Ms H nh2 0 Br HH OH O-Ms H nh2 0 Br HH OH O-Ts H nh2 0 Br HH OH Cl H nh2 0 Br HH OH H OH nh2 0 Br H OH HH OH nh2 0 IHH OH O-Ms H nh2 0 IHH OH Br H Nh2 0 IHH OH O-Ts H nh2 0 IHH Cl H OH nh2 0 IH Br HH OH nh2 0 OH H OH HH OH nh2 0 nh2 HH OH H OH nh-coch3 0 HH OH HH OH NH-OH 0 HHH OH H OH NH-OH 0 FHH OH H OH NH-OH 0 Br HH OH H OH NH-OH 0 IHH OH H OH NH-OH 0 HH OH HH OH OH 0 OH H OH HH OH OH 0 nh2 HH OH H OH OH 0 FH OH H H OH OH 0 F H H OH H OH OH 0 F H H OH H O-Ts OH 0 F H H H H OH OH 0 OH H H OH H OH or its cold-L-enantiomer or a pharmaceutically acceptable salt thereof. 3. The pharmaceutical composition according to claim 1, wherein the y5-D nucleoside of the formula (Ib) is one selected from the group consisting of X1 X2 w1 R2 R2' R3 R3' OH nh2 NH OH H OH OH nh2 CH FHH OH nh2 H CH H OH HF This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 258 91949 (Revised) (Please read the note on the back and fill out this page) Order--- ------: 1293306 098899 ABCD Patent No. 90125514 (August 24, 1996) VI. Shen Axi Lifan· 或其/3 -L-對映異構物或其醫藥上可接受之鹽 4·如申請專利範圍第1項之醫藥組成物，其中，式（n_a)召 -D核苦為選自下列之一： _NH-Bz-(m-NO?) _NH-Bz-(q-NQ2) nh2 Y1- Ο Ο Ο R R* F F F Η Η Η Η Η F Η Η Η 或其/3 -L-對映異構物或其醫藥上可接受之鹽 5·如申請專利範圍第1項之醫藥組成物，其中，式（II_b)万 D核苷為選自下列之一：Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition of the formula (n_a)-D-nucleus is selected from the group consisting of One: _NH-Bz-(m-NO?) _NH-Bz-(q-NQ2) nh2 Y1- Ο Ο Ο RR* FFF Η Η Η Η Η F Η Η Η or its /3 -L-enantiomer Or a pharmaceutically acceptable salt thereof. 5. The pharmaceutical composition according to claim 1, wherein the formula (II-b) 10,000 D nucleoside is selected from one of the following: (請先閱讀背面之注意事項再填寫本頁) _裝-丨丨丨丨丨-丨訂· 經濟部智慧財產局員工消費合作社印製 或其yS-L-對映異構物接受之鹽 6. -種治療或預防宿主之黃病毒科病毒感染：非正常細 胞增生之醫藥組成物，其包括通式化合物：.R1(Please read the notes on the back and fill out this page) _装-丨丨丨丨丨-丨定·Issue of the Intellectual Property Office of the Ministry of Economic Affairs or the yS-L-enantiomer accepting salt 6 - a Flaviviridae virus infection for treating or preventing a host: a pharmaceutical composition of abnormal cell proliferation, comprising a compound of the formula: .R1 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公*T --- 259 91949(修正本） 1293306 A8 B8 C8 D8 第90126014號專利申請案 (96年8月24曰） 六、申請專利範圍 或其/5 -L-對映異構物或其醫藥上可接受之鹽，其中： 各D、X1、Y1、R2、R2’、R3與R3’如前述之相同定 義；以及 各R1與R1’分別獨立為氫、鹵素（F、Cl、Br或I)或 NH2 ; 因此通式（V-a)核苷中，R2與R2’中至少一者為氫且 R3與R3’中至少一者為氫。 7.如申請專利範圍第6項之醫藥組成物，其中，式（V-a)/5 D核苷為選自下列之一： X1 YA R1 R1 R2 R2 R0 nh2 0 F H H OH H OH OH 0 H H H H H H nh2 0 H H H OH H OH nh2 0 H H H H H H OH 0 F H H OH H OH nh2 0 I H H H H H nh2 0 I H H OH H OH nh2 0 Cl H H OH H OH 或其/5 -L-對映異構物或其醫藥上可接受之鹽。 8. —種治療或預防宿主之黃病毒科病毒感染之醫藥組成 物，其包括通式（XI)化合物： X1 -χ1This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public*T --- 259 91949 (amendment) 1293306 A8 B8 C8 D8 Patent No. 90125014 (August 24, 1996) The patent scope or its /5-L-enantiomer or a pharmaceutically acceptable salt thereof, wherein: each D, X1, Y1, R2, R2', R3 and R3' are as defined above; and each R1 And R1' are independently hydrogen, halogen (F, Cl, Br or I) or NH2; therefore, in the general (Va) nucleoside, at least one of R2 and R2' is hydrogen and at least one of R3 and R3' 7. The pharmaceutical composition of claim 6, wherein the formula (Va)/5 D nucleoside is selected from one of the following: X1 YA R1 R1 R2 R2 R0 nh2 0 FHH OH H OH OH 0 HHHHHH nh2 0 HHH OH H OH nh2 0 HHHHHH OH 0 FHH OH H OH nh2 0 IHHHHH nh2 0 IHH OH H OH nh2 0 Cl HH OH H OH or its /5-L-enantiomer or pharmaceutically acceptable 8. A pharmaceutical composition for treating or preventing a flavivirus infection of a host, comprising a compound of the formula (XI): X1 -χ1 [ΧΙ-a] [闕 或其召-L-對映異構物或其醫藥上可接受之鹽，其中： 各D、W1、W2、X1、X2與Y1如前述定義； (請先閱讀背面之注意事項再填寫本頁) · 1 H 1 1 1 n B1 一^ f— 1 I H «1 «I - 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 260 91949(修正本) 1293306[ΧΙ-a] [阙 or its s-L-enantiomer or a pharmaceutically acceptable salt thereof, wherein: each D, W1, W2, X1, X2 and Y1 are as defined above; (please read the back first) Note: Please fill out this page) · 1 H 1 1 1 n B1 1 ^ f-1 IH «1 «I - Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed This paper scale applies to China National Standard (CNS) A4 specification ( 210 X 297 mm) 260 91949 (amendment) 1293306 第90126014號專利申請案 (96年8月24曰） 六、申請專利範圍各 R1 與 R1 分 ^ 〜獨立為氫、鹵素(F、Cl、Br或I)或 NH2 ;以及 各Z1與Z2分別獨立為Ο或S。 9·如申請專利範圍第8項之醫藥組成物，其中，式(xi_a) /Q . Π ^ ^ /3 -D核苷為選自下列 之 X1 —. nh2 ——H： TL1 R1 R1 Ο 或其-對醫藥上可·ϊ·受之Ϊ 10·如中1專利I圍第8項之醫藥組成物’其中’式（XU) /5 -D核苷為自下列之一：Patent Application No. 9012614 (August 24, 1996) VI. The scope of application for patents R1 and R1 are separately ~ independently hydrogen, halogen (F, Cl, Br or I) or NH2; and each Z1 and Z2 are independent For Ο or S. 9. The pharmaceutical composition of claim 8 wherein the formula (xi_a) / Q . Π ^ ^ / 3 -D nucleoside is selected from the group consisting of X1 —. nh2 — H: TL1 R1 R1 Ο or It is a pharmaceutical composition that can be used in medicine. 10· The pharmaceutical composition of the first item of the first patent of the first patent, 'the 'XU' /5-D nucleoside is one of the following: 或其冷-L-對映異構物或其醫藥上可接受之鹽 11 ·種/σ療或預防伤主之黃病毒科病毒感染之醫藥組成 物，其包括通式（ΧΙΙΙ)化合物： (請先閱讀背面之注意事項再填寫本頁) 裝 — II 訂·！ ！· P 經濟部智慧財產局員工消費合作社印製 Υ3' Ky R2' [XIII-a] Υ2 XOr a pharmaceutical composition thereof, or a cold-L-enantiomer or a pharmaceutically acceptable salt thereof, for the treatment of a Flaviviridae virus infection, comprising a compound of the formula (ΧΙΙΙ): Please read the notes on the back and fill out this page. Pack — II Book·! ! · P Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing Υ 3' Ky R2' [XIII-a] Υ 2 X 或其/5 _L-對映異構物或其醫藥上可接受之鹽，其中 各D、R2、R2’、…與尺^’如前述之相同定義； 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 261 91949(修正本) 1293306 第90126014號專利申請案 (96年8月24曰） 六、申請專利範圍 各R1與R1’分別獨立為氫、鹵素(F、C卜Br或I)或 nh2 ； 各Y2為〇或nh ;以及 各Y3為〇。 12·如申请專利範圍第11項之醫藥組成物，其中，式（XIII-a) 沒_D核苷為選自下列之—β· XI ~〇 &quot;όΙΓ Η ΟΗ 或其/3 _L-對映異構物或其醫藥上可接受之鹽 13·如申請專利範圍第11項之醫藥組成物，其中，式（XIII-c) /3-D核苦為選自下列之一： Υ 0 F R R Η R ΝΗ Ο Η OH Η Η O-Ms Ο-Ms Η Ο-Ac 或其/5 _L·對映異構物或其醫藥上可接受之鹽&lt; 14.-種治療或預防宿主之黃病毒科病毒感染:醫藥組成 物，其包括通式（XIV)化合物： 麵 X1 或其/5-L-對映異構物或其醫藥上可接受之鹽，其中： 91949(修正本） 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1293306 0q888 ABCD 第90126014號專利申請案 (96年8月24曰) 經濟部智慧財產局員工消費合作社印製 六、申請專利範圍 各D、X1、γ1、R2、R2 ’、r3與r3如前述之相同定 義； 各R1為氫、鹵素（F、Cl、或I)或NH2 ; 各L1為氫、Cl或Br ; 各 L2為 oh、〇CH3、OC2H5 或 〇C3H7 ’ 以及 各Z3為〇。 15·如申請專利範圍第14項之醫藥組成物，其中，式（XIV) -D核苷為選自下列之一： X1 R1 一R2 R2' RJ R3 L1 L2 OH 0 F Η OH H OH Cl O-CH3 OH 0 Η Η OH H OH Br O-CH3 OH 0 F Η OH H OH Br o-ch3 OH 0 F Η OH H OH Br O-Et OH 0 Cl Η OH H OH Br O-CH3 或其/5 對映異構物 或其醫i 藥上可接 受之鹽 0 1 6. —種治療或預防宿主之黃病毒科病毒感染之醫藥組成 物，其包括投予有效量之通式（xv)化合物：Or a /5-L-enantiomer thereof or a pharmaceutically acceptable salt thereof, wherein each D, R2, R2', ... and the ruler' is as defined above; the paper scale applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) 261 91949 (amendment) 1293306 Patent No. 90126014 (August 24, 1996) VI. Patent application scope R1 and R1' are independently hydrogen and halogen (F, C Bra or I) or nh2; each Y2 is 〇 or nh; and each Y3 is 〇. 12. The pharmaceutical composition of claim 11, wherein the formula (XIII-a) has no _D nucleoside selected from the group consisting of -β· XI ~〇&quot;όΙΓ Η ΟΗ or its /3 _L-pair Or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 11, wherein the formula (XIII-c) / 3-D is selected from the group consisting of: Υ 0 FRR Η R ΝΗ Ο Η OH Η Η O-Ms Ο-Ms Η Ο-Ac or its /5 _L· enantiomer or a pharmaceutically acceptable salt thereof 14. A therapeutic or preventive host of flavivirus Family virus infection: a pharmaceutical composition comprising a compound of the formula (XIV): face X1 or its/5-L-enantiomer or a pharmaceutically acceptable salt thereof, wherein: 91949 (amendment) Applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) 1293306 0q888 ABCD Patent No. 90126014 (August 24, 1996) Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives VI. , X1, γ1, R2, R2 ', r3 and r3 are as defined above; each R1 is hydrogen, halogen (F, Cl, or I) or NH2; each L1 is hydrogen, Cl or Br; each L2 is oh, 〇CH3, OC2H5 or 〇C3H7' and each Z3 is 〇. 15. The pharmaceutical composition of claim 14, wherein the formula (XIV)-D nucleoside is selected from the group consisting of: X1 R1 - R2 R2' RJ R3 L1 L2 OH 0 F Η OH H OH Cl O -CH3 OH 0 Η OH OH H OH Br O-CH3 OH 0 F Η OH H OH Br o-ch3 OH 0 F Η OH H OH Br O-Et OH 0 Cl Η OH H OH Br O-CH3 or its/5 An enantiomer or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for treating or preventing a Flaviviridae virus infection in a host comprising administering an effective amount of a compound of the formula (xv): [XV-b] 或其/5 -L-對映異構物或其醫藥上可接受之鹽，其中： 各d、w1、w2、X1、z3、R2、R2、R3與R3 如前述 之相同定義。 17.如申請專利範圍第16項之醫藥組成物，其中，式（XV-b) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 263 91949(修正本) (請先閱讀背面之注意事項再填寫本頁) n n Mmt ΛΜ— 1· n n · ammmm MmMm ·1 B1B« 1 p 1293306 098899 ABCD 第90126014號專利申請案 (96年8月24曰） 六、申請專利範圍 如下列定義~cn R 18· ^ ± η r--------^ OH ’/、A _L-對映異構物或其醫藥上可接受之鹽。 療或預防彳g主之黃病毒科病毒感染之醫藥組成 物’其包括投予有效量之通式（XVI)化合物： DO,[XV-b] or its /5-L-enantiomer or a pharmaceutically acceptable salt thereof, wherein: each d, w1, w2, X1, z3, R2, R2, R3 and R3 are as defined above definition. 17. The pharmaceutical composition of claim 16 of the scope of application, wherein formula (XV-b) applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 263 91949 (amendment) (please Read the notes on the back and fill out this page) nn Mmt ΛΜ — 1· nn · ammmm MmMm ·1 B1B« 1 p 1293306 098899 ABCD Patent No. 90126014 (August 24, 1996) VI. The scope of application for patents is as follows Definitions ~cn R 18· ^ ± η r--------^ OH '/, A _L-enantiomer or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for treating or preventing a Flaviviridae virus infection of the genus, which comprises administering an effective amount of a compound of the formula (XVI): DO, X1X1 經濟部智慧財產局員工消費合作社印彻衣 R3, R2, 陶-a] [XVI-d] [XVI-f] 或其点-L-對映異構物或其醫藥上可接受之鹽，其中： 各D、wl、X1、X2、R2、R2’、R3與R3’如前述之相 同定義； 各W3分別獨立為ch ; 各W4與W5分別獨立為n或C-NH2;以及 各Z4與Z5分別獨立為nh或CpU1); 因此若z4與z5為共價鍵時，則當z5為cpu1)時，Z4 不為cpu1); u1為〇或nh ;以及 ^^氮不超過3個。 19·如申請專利範圍第18項之醫藥組成物，其中，式（XVI_a) /3 -D核苷為下列各者： W3 Z4 W5 W4 Ί? CH NH C-NH? N C = 0 Η OH Η OH CH NH C-NH^ N c=o Η Br Η OH 本紙張尺度適用中國國豕標準（CNS)A4規格（21〇 X 297公釐 264 91949(修正本） (請先閱讀背面之注意事項再填寫本頁) · n n 1 n n n n 一， n MMBm e§e tm— immm i i !2933〇6 A8B8C8D8 第90126014號專利申請案 (96年8月24曰） 申請專利範圍 U或其召-L·對映異構物或其醫藥上可接受之鹽。 申μ專利範圍第丨8項之醫藥組成物，其中，式（xvi_d) 点A核苷如下列定義： — w4 R0 rj ~ 或N H OH — 21 3 /、万_L-對映異構物或其醫藥上可接受之鹽。 1·如申請專利範圍第18項之醫藥組成物，其中，式（XVI_f) 石如下列定義： RJ RJ R3 &quot;oh&quot; ^ -----_IL· OH H 〇 3 ”々-L-對映異構物或其醫藥上可接受之鹽。 22 •一種治療或預防宿主之黃病毒科病毒感染之醫藥組成 物’其包括通式（χνπ)化合物：Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, India, R3, R2, Tao-a] [XVI-d] [XVI-f] or its point-L-enantiomer or its pharmaceutically acceptable salt, : Each D, wl, X1, X2, R2, R2', R3 and R3' are as defined above; each W3 is independently ch; each of W4 and W5 is independently n or C-NH2; and each Z4 and Z5 Independently for nh or CpU1); therefore, if z4 and z5 are covalent bonds, then when z5 is cpu1), Z4 is not cpu1); u1 is 〇 or nh; and ^^ nitrogen does not exceed three. 19. The pharmaceutical composition of claim 18, wherein the formula (XVI_a) / 3 -D nucleoside is the following: W3 Z4 W5 W4 Ί? CH NH C-NH? NC = 0 Η OH Η OH CH NH C-NH^ N c=o Η Br Η OH This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 mm 264 91949 (Revised)) (Please read the notes on the back and fill in the form) This page) · nn 1 nnnn 一, n MMBm e§e tm— immm ii !2933〇6 A8B8C8D8 Patent Application No. 9012614 (August 24, 1996) Patent Application U or its Call-L·Dynamics A structure or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 8 of the invention, wherein the formula (xvi_d) point A nucleoside is as defined below: — w4 R0 rj ~ or NH OH — 21 3 / , _L-enantiomer or a pharmaceutically acceptable salt thereof. 1. The pharmaceutical composition of claim 18, wherein the formula (XVI_f) is as defined below: RJ RJ R3 &quot;oh&quot ; ^ -----_IL· OH H 〇3 ”々-L-enantiomer or a pharmaceutically acceptable salt thereof. 22 • A flavivirus disease for treating or preventing a host Infection pharmaceutical composition 'comprising formula (χνπ) compound: (請先閱讀背面之注意事項再填寫本頁) ，裝 * n H 1_1 a— n n n 訂--------- X5〆 IXVII-d] p. 經濟部智慧財產局員工消費合作社印製 或其冷-L-對映異構物或其醫藥上可接受之鹽，其中 各W1、W2、X1、X2、與z3如、前述之相同定義； 各X4與X5分別獨立為氫或OH。 23·如申請專利範圍第22項之醫藥組成物，其中，式（χνιι 冷-D核苷如下列定義： ^~~ ~X1 ~ W1 X4 X5 nh2 F CH Η OH 或其β -L-對映異構物或其醫藥上可接受之鹽 &amp;張尺度適用中國國冢標準（CNS)A4規巧咖χ挪） -—— 265 91949(修 1293306 (96年8月24曰）(Please read the notes on the back and fill out this page), install * n H 1_1 a- nnn order --------- X5〆IXVII-d] p. Printed by the Intellectual Property Office of the Ministry of Economic Affairs Or a cold-L-enantiomer thereof or a pharmaceutically acceptable salt thereof, wherein each of W1, W2, X1, X2, and z3 is as defined above; and each of X4 and X5 is independently hydrogen or OH. 23. The pharmaceutical composition of claim 22, wherein the formula (χνιι cold-D nucleoside is as defined below: ^~~ ~X1 ~ W1 X4 X5 nh2 F CH Η OH or its β-L-alignment Isomers or their pharmaceutically acceptable salts &amp; Zhang scale applicable to China National Standards (CNS) A4 rules and regulations) - 265 91949 (Revision 1293306 (August 24, 1996) 六、申請專利範圍 24·—種治療或預防宿主之黃病毒科、正黏液病毒科或副黏 液病毒科病毒感染之醫藥組成物，其包括通式（χιχ)化 合物：VI. Scope of application for patents 24. A pharmaceutical composition for treating or preventing a host's flavivirus, orthomyxoviridae or paramyxoviral virus infection, which comprises a compound of the formula (χιχ): 請 先 閲 讀 背 面 之 注 經濟部智慧財產局員工消費合作社印制衣 或其/5對映異構物或其醫藥上可接受之鹽，其中： 各D與R4如前述定義；各Rl為氫、i素（F、Cl、Br或I)或ΝΗ2 ;各R9為氫、i素（F、CM、Br或I)、OH、〇_醯基、 〇_曱磺醯基或〇-甲苯磺醯基； 各P1為氫、OH、R4或OR4 ;以及 各P2為氫；以及 當該病毒感染為黃病毒科病毒感染時，則R9為鹵 素（F、CH、Br或I)、〇_醯基、〇_甲磺醯基或〇_甲苯磺 醯基；以及其中，該黃病毒科病毒感染不為C型肝炎。 25·—種治療或預防宿主之正黏液病毒科或副黏液病毒科 病毒感染之醫藥組成物，其包括如下通式化合物： 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 266 91949(修正本) 項 再 填窝 本 頁 裝 I I I I I 訂 I I I 麵 1293306 A8 第90126014號專利申請案 B8 (96年8月24曰）Please read the note on the back of the Ministry of Economic Affairs, Intellectual Property Office, Staff Cooperatives Printing, or its/5-enantiomer or its pharmaceutically acceptable salt, where: D and R4 are as defined above; each Rl is hydrogen, i (F, Cl, Br or I) or ΝΗ2; each R9 is hydrogen, i (F, CM, Br or I), OH, 〇 醯 、, 〇 曱 sulfonyl or 〇-toluene sulfonate Each P1 is hydrogen, OH, R4 or OR4; and each P2 is hydrogen; and when the virus is infected with a Flaviviridae virus, R9 is halogen (F, CH, Br or I), 〇 醯 醯, 〇 甲 甲 醯 〇 or 〇 甲苯 甲苯 ; ;; and wherein the Flaviviridae virus infection is not hepatitis C. 25. A pharmaceutical composition for treating or preventing a positive mucinous or paramyxoviral infection of a host, comprising a compound of the formula: The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ) 266 91949 (Revised) Refilled Pages IIIII Book III Face 1293306 A8 Patent No. 90126014 Patent Application B8 (August 24, 1996) 或對映異構物或其醫藥上可接受之鹽，其中 各D與P2如前述定義。 26·種/口療或預防伤主之黃病毒科、正黏液病毒科或副黏 液病毒科病毒感染之醫藥組成物，其包括通式（χχ)化合Or an enantiomer or a pharmaceutically acceptable salt thereof, wherein each D and P2 are as defined above. 26. A pharmaceutical composition comprising a species of genus or genus or a visceral virus, or a viscous virus infection, comprising a compound of the formula (χχ) [XX] (請先閱讀背面之注意事項再填寫本頁) Βϋ n n n s I n 一 K n an n 11 —Hi I I #- 經濟部智慧財產局員工消費合作社印製 或其-L-對映異構物或其醫藥上可揍受之鹽，其中： 各D與Ρ1如前述定義； R1為氫、_素（卩、α、Br或I)或ΝΗ2 ; Ρ2為Η、醯基、甲磺醯基或甲苯磺醯基； R9為氫、鹵素（F、Cl、Br或I)或ΟΗ ;以及 其中’該百病毒科病毒感染不為C型肝炎。 2 7 · —種治療或預防宿主之黃病毒科、正黏液病毒科或副黏 液病毒科病毒感染之醫藥組成物，其包括通式（XXI)化 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 267 91949(修正本) 1293306 A8 B8 C8 D8 第90126014號專利申請案 (96 年 8 月 24 “ ') 六、申請專利範圍 合物： ΝΗΡ1[XX] (Please read the notes on the back and fill out this page) Βϋ nnns I n Kn an n 11 — Hi II #- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing or its -L-enantiomer Or a pharmaceutically acceptable salt thereof, wherein: each D and Ρ1 are as defined above; R1 is hydrogen, _ 卩 (卩, α, Br or I) or ΝΗ 2; Ρ 2 is ruthenium, osmium, sulfonyl Or tolsulfonyl; R9 is hydrogen, halogen (F, Cl, Br or I) or hydrazine; and wherein the viral infection is not hepatitis C. 2 7 · A pharmaceutical composition for the treatment or prevention of the host's Flaviviridae, Orthomyxoviridae or Paramyxoviridae virus infection, including the general (XXI) paper size applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 267 91949 (amendment) 1293306 A8 B8 C8 D8 Patent Application No. 90125514 (August 24, 1996 “') VI. Patent Scope: ΝΗΡ1 [XXI] 或其/5 對映異構物或其醫藥上可接受之鹽，其中： 各D與Ρ1如前述定義； R1為氫、！|素、C卜仏或^或丽2 ; P2為Η、醯基、甲磺醯基或甲苯磺醯基·， R9為氫、鹵素（F、CH、Br或I)或〇Η ;以及 其中’該黃病毒科病毒感染不為C型肝炎。 2 8 · —種治療或預防宿主之黃痣卷斜、不卖 &amp; κ病毋科正黏液病毒科或副黏 液病毒科病毒感染之醫藥組成物，其包括如下通式化人 物： ^ (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[XXI] or its/5-enantiomer or a pharmaceutically acceptable salt thereof, wherein: each D and Ρ1 are as defined above; R1 is hydrogen,! |素, C仏 or ^ or 丽2; P2 is hydrazine, fluorenyl, sulfonyl or toluene sulfhydryl, R9 is hydrogen, halogen (F, CH, Br or I) or hydrazine; 'The Flaviviridae virus infection is not hepatitis C. 2 8 · A medical composition for treating or preventing the host's jaundice, not selling & κ 毋 正 正 正 副 副 或 或 或 或 或 或 或 或 或 ^ ^ ^ ^ ^ ^ ^ ^ ^ Read the precautions on the back and fill out this page) --------^-------- Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative 或其点_L-對映異構物或其醫藥上可接受之鹽，其中 各D如前述定義； P2為Η、醯基、甲磺醯基或甲笨磺醯基； 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 268 91949(修正本) 1293306 098899 ABCD 第90126014號專利申請案 (96年8月24曰） 六、申請專利範圍 p3為氫；以及 其中’該黃病毒科病毒感染不為c型肝炎。 29·—種治療或預防宿主之黃病毒科病毒感染或非正常細 胞增生之醫藥組成物，其包括通式（χχπι)化合物：Or a _L-enantiomer thereof or a pharmaceutically acceptable salt thereof, wherein each D is as defined above; P2 is hydrazine, fluorenyl, methanesulfonyl or methanesulfonyl; National Standard (CNS) A4 Specification (210 X 297 mm) 268 91949 (Revised) 1293306 098899 ABCD Patent No. 90126014 (August 24, 1996) VI. The patent application scope p3 is hydrogen; and The Flaviviridae virus infection is not hepatitis C. 29. A pharmaceutical composition for treating or preventing a flavivirus infection or abnormal cell proliferation of a host, comprising a compound of the formula (χχπι): [XXIII] 或其/3 -L-對映異構物或其醫藥上可接受之鹽，其中 各D與Ρ1如前述定義；R1為氫、鹵素（F、Cl、Br或I)或ΝΗ2 ; Ρ2為Η、醯基、甲磺醯基或甲苯磺醯基；以及 R9為氫、鹵素（F、Cl、Br或I)或〇Η。 3 0·—種治療或預防宿主之黃病秦科病毒感染或非正常海 胞增生之醫藥組成物，其包括如下通式化合物： (請先閱讀背面之注意事項再填寫本頁) ▼裝--------訂--------- 經濟部智慧財產局員工消費合作社印製 F、Or a pharmaceutically acceptable salt thereof, wherein each D and hydrazine 1 are as defined above; R1 is hydrogen, halogen (F, Cl, Br or I) or hydrazine 2; Ρ2 is hydrazine, fluorenyl, methanesulfonyl or toluenesulfonyl; and R9 is hydrogen, halogen (F, Cl, Br or I) or hydrazine. 30. A pharmaceutical composition for treating or preventing a yellow disease of a host, a Qin virus infection or an abnormal cell proliferation, comprising a compound of the following formula: (Please read the note on the back and then fill out this page) ▼ -------Book--------- Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed F, OP2 OP3 或其；3 -L-對映異構物或其醫藥上可接受之鹽，其中 各D如前述定義； 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 269 91949(修正本;） r1293306 A8 B8 C8 D8 第90126014號專利申請案 (96年8月24曰） 一申請專利範圍 / — P2為Η、酸基、甲石黃醯基或甲苯石黃醯基；以及 ρ3為氫。 3 i種治瘵或預防宿主之正黏液病毒科或副黏液病毒科 病毒感染之醫藥組成物’其包括如下通式化合物：OP2 OP3 or a 3-L-enantiomer thereof or a pharmaceutically acceptable salt thereof, wherein each D is as defined above; the paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 269 91949 (amendment;) r1293306 A8 B8 C8 D8 Patent Application No. 9012614 (August 24, 1996) A patent application scope / P2 is hydrazine, acid group, methystine or toluene xanthine; and ρ3 is hydrogen . A pharmaceutical composition for treating or preventing a host's orthomyxoviridae or paramyxoviridae virus infection, which comprises a compound of the following formula: 或其醫藥上可接受之鹽。 32.一禮治療或預防宿主之黃病毒科、正黏液病毒科或副黏 液病毒科病毒感染之醫藥組成物，其包括如下通式化合 物： HN /OHOr a pharmaceutically acceptable salt thereof. 32. A pharmaceutical composition for treating or preventing a host's Flaviviridae, Orthomyxoviridae or Paramyxoviridae virus infection, comprising a compound of the formula: HN / OH c靖先閱讀背面之注意事項再填寫本頁} Ί裝 訂·· HO % 聲 OH OH 或其醫藥上可接受之鹽； 其中，該黃病毒科病毒感染不為c型肝炎。 3 3 · —種治療或預防宿主之正黏液病毒科或副黏液病毒科 病毒感染之醫藥組成物，其包括如下通式化合物： 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 270 91949(修正本)c Jingxian read the back of the precautions and then fill out this page} 装·· HO % OH OH or its pharmaceutically acceptable salt; wherein the Flaviviridae virus infection is not hepatitis C. 3 3 · A pharmaceutical composition for treating or preventing a positive mucinous or paramyxoviral infection of a host, which comprises a compound of the following formula: This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 PCT) 270 91949 (amendment) 1293306 A8 B8 C8 D8 第90126014號專利申請案 (96年8月24曰) 六、申請專利範圍 0 HO、 N1293306 A8 B8 C8 D8 Patent Application No. 90125514 (August 24, 1996) VI. Patent Application Scope 0 HO, N 0H OH 或其醫藥上可接受之鹽。 3 4. —種治療或預防宿主之黃病毒科、正黏液病毒科或副黏 液病毒科病毒感染之醫藥組成物，其包括如下通式化合 物： C10H OH or a pharmaceutically acceptable salt thereof. 3 4. A pharmaceutical composition for treating or preventing a host's Flaviviridae, Orthomyxoviridae or Paramyxoviridae virus infection, comprising the following compounds: C1 或其醫藥上可接受之鹽； 其中，該黃病毒科病毒感染不為C型肝炎。 35·—種治療或預防宿主之黃病毒科病毒感染或非正常 胞增生之醫藥組成物，其包括如下通式化合物： (請先閱讀背面之注意事項再填寫本頁) - a— n n n —e n n^&quot;J0 n ϋ I 1 n ϋ ϋ 經濟部智慧財產局員工消費合作社印製Or a pharmaceutically acceptable salt thereof; wherein the Flaviviridae virus infection is not hepatitis C. 35. A pharmaceutical composition for treating or preventing a host's Flaviviridae virus infection or abnormal cell proliferation, comprising a compound of the following formula: (Please read the back note and then fill out this page) - a - nnn -enn ^&quot;J0 n ϋ I 1 n ϋ 印 Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative 或其醫藥上可接受之鹽。 36.—種治療或預防宿主之C型肝炎病毒感染之醫藥組成 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 271 91949(修正本) 1293306 ’、申δ月專利範圍 37二其包括申請專利範圍第6至23項中任一項之化合物 .種治療或預防宿主之C型肝炎病毒感染之醫藥組成 物，其包括式（XIX)y3-D核苷：Or a pharmaceutically acceptable salt thereof. 36. A pharmaceutical composition for treating or preventing hepatitis C virus infection in a host. This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 271 91949 (amendment) 1293306 ', the application scope of the δ month A pharmaceutical composition comprising a compound of any one of claims 6 to 23, which comprises a pharmaceutical composition for treating or preventing hepatitis C virus infection in a host, which comprises a y3-D nucleoside of the formula (XIX): 閱 讀 背 面 之 注 經濟部智慧財產局員工消費合作社印制衣 或其/5 -L-對映異構物或其醫藥上可接受之鹽，其中： 各D與R4如俞述定義； 各R1為氫、鹵素（F、cn、Br或I)或NH2 ; 各r9為_素（F、CM、Br或I)、Ο-醯基、Ο-甲磺醯 基或〇-甲苯磺醯基； 各pl為氫、OH、R4或〇R4 ;以及 各P2為氫；其可視需要含在醫藥上可接受之載體中。 38·—種治療或預防宿主之c型肝炎病毒感染之醫藥組成 物’其包括式（XX)々-D核苷： 項 再 填 寫 本 頁 裝 I I 1 [ I 訂 « [ I % 本紙張尺度適用中國國家標準（Cns)A4規格(210 X 297公釐 272 91949(修正本;） 1293306 A8 B8 C8 D8 第90126014號專利申請案 (96年8月24日、) 六、申請專利範圍Read the note on the back of the Ministry of Economic Affairs, the Intellectual Property Office, the Consumer Cooperatives Printing, or its /5-L-enantiomer or its pharmaceutically acceptable salt, wherein: D and R4 are as defined in Yushu; Hydrogen, halogen (F, cn, Br or I) or NH2; each r9 is _ (F, CM, Br or I), fluorenyl-fluorenyl, fluorenyl-methylsulfonyl or fluorene-toluenesulfonyl; Pl is hydrogen, OH, R4 or 〇R4; and each P2 is hydrogen; it may optionally be contained in a pharmaceutically acceptable carrier. 38. A pharmaceutical composition for treating or preventing hepatitis C virus infection in a host' which comprises the formula (XX) 々-D nucleoside: Item Refilled on this page II 1 [ I order « [ I % This paper scale applies China National Standard (Cns) A4 Specification (210 X 297 mm 272 91949 (amendment;) 1293306 A8 B8 C8 D8 Patent Application No. 90125014 (August 24, 1996) VI. Application for Patent Scope [XX] 經濟部智慧財產局員工消費合作社印制衣 或其/3 -L-對映異構物或其醫藥上可接受之鹽，其中： 各0與P1如前述定義； R1為氫、_ 素0、CM、Br 或 I)或 NH2 ;P2為Η、醯基、甲磺醯基或甲苯磺醯基；以及 R9為氫、鹵素（F、Cl、Br或I)或QH ;其中，當P1為氫、R9為0H、且Ri為氟時，p2為醯 基、甲磺醯基或甲苯磺醯基； 其中，當P1為OR4、及1與化4為氫、且尺9為〇11時，p 為酿基、甲石只基或甲苯石黃酿基； 其町視需要含在醫藥上可接受之載體中。 39·—種治療或預防宿主之c型肝炎病毒感染之醫藥組成 物，其包括式（XXI)/3 -D核苷：[XX] Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing clothing or its /3 -L-enantiomer or its pharmaceutically acceptable salt, wherein: 0 and P1 are as defined above; R1 is hydrogen, _素, CM, Br or I) or NH2; P2 is hydrazine, fluorenyl, methanesulfonyl or toluenesulfonyl; and R9 is hydrogen, halogen (F, Cl, Br or I) or QH; When P1 is hydrogen, R9 is 0H, and Ri is fluorine, p2 is a fluorenyl group, a methanesulfonyl group or a toluenesulfonyl group; wherein, when P1 is OR4, and 1 and 4 are hydrogen, and the ruler 9 is 〇11 In the case of p, the p is a brewing base, a stone base or a toluene yellow base; the choline is required to be contained in a pharmaceutically acceptable carrier. 39. A pharmaceutical composition for treating or preventing a hepatitis C virus infection in a host, which comprises a formula (XXI)/3-D nucleoside: 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 273 91949(修正本) (請先閱讀背面之注意事項再填寫本頁) ，· «I n 1 I n n JrJ ϋ 1 1 1 n -ϋ n I * 会° 1293306 第90126014號專利申請案 (96年8月24曰）This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 273 91949 (Revised) (Please read the note on the back and fill out this page), «I n 1 I nn JrJ ϋ 1 1 1 n -ϋ n I * will ° 1293306 Patent No. 90125514 (August 24, 1996) 申請專利範圍 或其召-L-對映里拔 、〃構物或其醫藥上可接受之鹽 各D與P1如前述定義；R2為氣、_素、C卜Br或I)或丽2 ;$ γ 酿基、甲續酿基或甲苯石黃醯基；R為氫、自素（F、C卜Br或I)或QH ; 八中’當Pl為氫、R9為OH、且R1為氟時 甲磺醯基或甲笨磺醯基； 、 其中’ 為〇R4、r4為氫、Rl OH時，P2A酼苴 m L A鼠 為l基、甲磺醯基或甲苯磺醯基； 丨可視需要含在冑藥上可接受之載體中 ·-種治療或預防宿主之c型肝 。 物，其包括如下式^核苦： 之醫樂組成 其中： 以及 基 P2為醯 且R9為 (請先閱讀背面之注意事項再填寫本頁)The scope of the patent application or its call-L-opposite, 〃 structure or its pharmaceutically acceptable salt D and P1 are as defined above; R2 is gas, _, C, Br or I) or 丽 2; $ γ brewing base, orthodonyl or toluene xanthine; R is hydrogen, self-priming (F, C, Br or I) or QH; VIII' when Pl is hydrogen, R9 is OH, and R1 is fluorine Sulfhydryl or oxasulfonyl; wherein ''R4, r4 is hydrogen, Rl OH, P2A酼苴m LA is l-, methanesulfonyl or toluenesulfonyl; A drug that is acceptable for the treatment or prevention of a type C liver of a host. Object, which includes the following formula: The composition of the medical treatment: where: and the base P2 is 醯 and R9 is (please read the back of the note first and then fill out this page) 經濟部智慧財產局員工消費合作社印制衣 .OH 或其/5 -L-對映異構物或其醫藥上可接受之職豆 各D如前述定義； ’、中 P2為醯基、甲磺醯基或甲苯磺醯基； . 乂及 P為氫； 其可視需要含在醫藥上可接受之載體中。 41·一種治療或預防宿主之c型肝炎病毒感 .^ ^ &lt;邊樂組成 物，其包括式（XXII) /3 _L核苷： 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 91949(修正本) 1293306 098899 ABCD 第90126014號專利申請案 (96年8月24曰) 六、申請專利範圍Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed Clothes. OH or its /5-L-enantiomer or its pharmaceutically acceptable Bean D as defined above; ', P2 is sulfhydryl, methyl sulfonate Mercapto or toluenesulfonyl; . and P are hydrogen; they may be included in a pharmaceutically acceptable carrier as desired. 41. A method for treating or preventing hepatitis C virus in a host. ^ ^ &lt; Bianle composition, including formula (XXII) / 3 _L nucleoside: This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 91949 (amendment) 1293306 098899 ABCD Patent No. 90126014 (August 24, 1996) VI. Application for patent scope [XXII] 42 或其冷對映異構物或其醫藥上可接受之鹽，其中 各D與P1如前述定義；以及 R1為氫、鹵素（F、CM、Br或I)或NH2 ; 其中’當P1為氫時，R1為鹵素（F、CU、Br或I)或NH: 其邛視需要含在醫藥上可接受之載體中。 一種治療或預防宿主之C型肝炎病毒感染之醫藥組成 其包括如下式/3 -L核苷： 物 NH，[XXII] 42 or a cold enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein each D and P1 are as defined above; and R1 is hydrogen, halogen (F, CM, Br or I) or NH2; When P1 is hydrogen, R1 is halogen (F, CU, Br or I) or NH: it is required to be contained in a pharmaceutically acceptable carrier. A pharmaceutical composition for treating or preventing hepatitis C virus infection in a host, which comprises the following formula /3 -L nucleoside: NH, F N OD (請先閱讀背面之注意事項再填寫本頁) ，裝---- 訂-------- 經濟部智慧財產局員工消費合作社印制衣 或其石對映異構物或其醫藥上可接受之鹽，其中 D如前述定義； 其^視需要含在醫藥上可接受之載體中。 43·—種治療或預防宿主之C型肝炎病毒感染之醫藥組成 物，其包括式（XXIII)点-D核苷： 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 275 91949(修正本) !2933〇6 第90126014號專利申請案 (96年8月24曰)FN OD (please read the precautions on the back and fill out this page), install---- order-------- Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printed clothing or its stone enantiomer or A pharmaceutically acceptable salt thereof, wherein D is as defined above; it is optionally included in a pharmaceutically acceptable carrier. 43. A pharmaceutical composition for treating or preventing hepatitis C virus infection in a host, comprising a dot-D nucleoside of formula (XXIII): This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 275 91949 (amendment) ! 2933〇6 Patent application No. 90125514 (August 24, 1996) 六、申請專利範Sixth, apply for a patent R1 OP2 或其召-L. 對映 各D與p1如 [XXIII] 異構物或其醫藥上可接受 之鹽，其中： W述定義；R2為氫、幽素(F、C卜Br或I)或簡2; %為Η、醯基、甲確酿基或甲苯石黃酿基；以及 R為氫、南素（F、C卜Br或I)或ΟΗ ; 44 _ 2可視需要含在醫藥上可接受之載體中。 種心療或預防宿主之c型肝炎病毒感染之醫藥組成 物，其包括如下通式核苦：R1 OP2 or its -L. enantiomers each D and p1 such as the [XXIII] isomer or a pharmaceutically acceptable salt thereof, wherein: W is defined; R2 is hydrogen, spectrin (F, C, Br or I) ) or Jane 2; % is Η, 醯, A, or toluene; and R is hydrogen, nitrite (F, C, Br or I) or ΟΗ; 44 _ 2 can be included in the medicine In an acceptable carrier. A pharmaceutical composition for treating or preventing a hepatitis C virus infection in a host, which comprises the following general formula: N \〇 0 I — I I s I I - (請先閱讀背面之注意事項再填寫本頁) DO. 經濟部智慧財產局員工消費合作社印製N \〇 0 I — I I s I I - (Please read the notes on the back and fill out this page) DO. Printed by the Intellectual Property Office of the Ministry of Economic Affairs 或其/3 _L-對映異構物或其醫藥上可接受之鹽，其中 各D如前述定義； P為Η、醯基、甲磺醯基或甲苯磺醯基；以及 Ρ3為氫； 其可視需要含在醫藥上可接受之載體中。 私紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 276 91949(修正本） 1293306 A8 B8 C8 D8 第90126014號專利申請案 (96年8月24曰) 六、申請專利範圍 45·—種治療或預防宿主之C型肝炎病毒感染之醫藥組成 物，其包括如下通式核苷：Or a -3-L-enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein each D is as defined above; P is hydrazine, fluorenyl, methanesulfonyl or toluenesulfonyl; and hydrazine 3 is hydrogen; It may be included in a pharmaceutically acceptable carrier as needed. The private paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 276 91949 (amendment) 1293306 A8 B8 C8 D8 Patent No. 90126014 (August 24, 1996) VI. Patent application scope 45 A pharmaceutical composition for treating or preventing hepatitis C virus infection in a host, which comprises the following nucleosides: 或其醫藥上可接受之鹽；其可視需要含在醫藥上可接受 之載體中。 46·—種通式I、XIX、XX及XXI化合物之用途，係用於製造 醫藥，以治療黃病毒科、正黏液病毒科或副黏液病毒科 病毒感染。 47·— 種通式 II、V、XI、XIII、XIV、XV、XVI、XVII及 XXIII化合物之用途，係用於製造醫藥，以治療黃病毒 科病毒感染。 48·—種治療或預防宿主之黃病毒科、正黏液病毒科或副黏 液病毒科病毒感染之醫藥組成物，其包括通式（VII)化合 物： (請先閱讀背面之注意事項再填寫本頁) &gt;裝----- 11111_ 經濟部智慧財產局員工消費合作社印剩衣Or a pharmaceutically acceptable salt thereof; it may be contained in a pharmaceutically acceptable carrier, as desired. 46. The use of compounds of the general formula I, XIX, XX and XXI for the manufacture of medicine for the treatment of Flaviviridae, Orthomyxoviridae or Paramyxoviridae virus infections. 47. Use of a compound of the general formula II, V, XI, XIII, XIV, XV, XVI, XVII and XXIII for the manufacture of a medicament for the treatment of Flaviviridae infection. 48. A pharmaceutical composition for treating or preventing a host of the Flaviviridae, Orthomyxoviridae or Paramyxoviridae virus infection of a host, comprising a compound of the formula (VII): (Please read the notes on the back and fill out this page. ) &gt;装----- 11111_ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperatives print leftovers 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 277 91949(修正本) 1293306 A8B8C8D8 第90126014號專利申請案 (96年8月24曰) 六 、申請專利範圍 或其/5-L-對映異構物或其醫藥上可接受之鹽，其中： 各D X、Y、R2、R2，、R3與R3’如前述之相同定 義；以及 各R與R分別獨立為氣或齒素^、^、^或^。 49·種4 V與XXin化合物之用途，係用於治療羅患非正常 細胞增生之宿主。 50·種'療或預主之c型肝炎病毒感染之醫藥組成 物，其包括申請專利範圍第48項之化合物。 51·如申請專利範圍第48項之醫藥組成物，其中，式（νΠ4 D才j -D核苷為選自下列之_This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 277 91949 (amendment) 1293306 A8B8C8D8 Patent No. 90126014 (August 24, 1996) VI. Patent application scope or its/5 An L-enantiomer or a pharmaceutically acceptable salt thereof, wherein: each DX, Y, R2, R2, R3 and R3' are as defined above; and each R and R are independently a gas or a tooth Prime ^, ^, ^ or ^. 49. The use of 4 V and XXin compounds is used to treat a host suffering from abnormal cell proliferation. 50. A pharmaceutical composition of a 'healing or pre-hosted hepatitis C virus infection, which includes a compound of claim 48. 51. The pharmaceutical composition of claim 48, wherein the formula (νΠ4 D is a j-D nucleoside selected from the group consisting of _ 或其万心對映 ;2·-種治療或預防宿主之c型肝炎病毒感染之;藥組成 物’其包括通式（I)化合物： IOr a heart-to-heart mapping; 2 - a treatment or prevention of hepatitis C virus infection in a host; a pharmaceutical composition comprising a compound of the formula (I): I 經濟部智慧財產局員工消費合作社印製 Μ氏張 R3 R: D0\ R3 R2 R3, R2 R3. R2' [I-a] [I-b] 或J-L·對映異構物或其醫藥上可接受之鹽，其中 各D為氯；Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed R. R3 R: D0\ R3 R2 R3, R2 R3. R2' [Ia] [Ib] or JL·Enantiomer or a pharmaceutically acceptable salt thereof, Wherein each D is chlorine; 各W與W2分別獨立為CH或N ; 各X1與X2分別獨立為氫、齒素（F、C1、Br或工） 尺度適财關家標準（oi—規格 278 91949(修正 --------I---i I I I---^« — — —— — — 1 (請先閱讀背面之注意事項再填寫本頁) 1293306 A8 B8 C8 D8 第90126014號專利申請案 (96年8月24日') 六、申請專利範圍 NH2、NHR4、NH0R4 或 〇只； 各Y1為ο ; 各R1與Rl’分別獨立為氫 或 nh2 ; 鹵素（F、C卜Br或u 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 各R2與R2分別獨 哥立為氫或鹵素（F、C卜Br或I)、 或OH ; 各R3與R分別獨立 4词立為氧或鹵素（F、cn、Br或I)、 ΟΗ、基、笨料基、$ 〇_乙酿基； 各R為氫C(〇)ch3、或經Ν〇2取代之〒基； 因此通式（I)核普中士與r2，中至少一者為氫，且 R3與R3’中至少一者為氫； 其中，當該化合物具通式[La]時： 其中，當Xl為NH2且R1為氫時： (a) R3不為〇H ;以及 (b) R3’不為氟； 其中’當X1為NH2且Ri為氟時·· (a) R與R3不同時為〇H ;以及 (b) R與R3不同時為〇H ; 其中，當X1為NH2且R1為氫、氟或碘時： (a) R3與R3’不同時為η ; 其中，當X1為NHOR4、R4為η、且R1為氫或氟 時 (a) R2’與R3’不同時為〇Η ;以及 (b) R2與R3’不同時為〇H ; 請 先 閱 讀 背 之 注 意 項 再 填 本 頁 1 I I 訂 I 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 279 91949(修正本) 1293306 第90126014號專利申請案 A8 (96年8月24曰) DO C8 D8 六、申請專利範圍 其中，當X1為NHOR4、R4為C(0)CH3、且R1為 氫時： (請先閱讀背面之注意事項再填寫本頁) (a) R2’與R3’不同時為OH ; 其中，當X1為OH且R1為F、Br或I時： (a) R2’與R3’不同時為OH ;以及 (b) R2與R3’不同時為OH ; 其中，當X1為OH且R1為F時： (a) R2與R2’不同時為氫； 其中，當X1為OH且R1為氳或F時： (a) R3與R3’不同時為氫； 其中，當X1為OH、R1為氫、且R3’為OH時： (a) R2為氫或鹵素（F、Cl、Br或I);以及 (b) R2’為氫、F、I 或 OH ; 其中，當該化合物具通式[I-b]，X1不為OH，以及： 其中，當X1為NH2、X2為氫、且R2’為OH時： (a) R3與R3’不同時為氫； 經濟部智慧財產局員工消費合作社印製 其中，當X1為NH2、X2為C1或NH2、且W1為 CH時： (a) R2’與R3’不同時為OH ; 其中，當X1為C1且X2為氫、C1或NH2時·· (a) R2’與R3’不同時為OH ;以及 其中，當X1為氫且X2為氫時： (a) R2’與R3’不同時為OH。 53·如申請專利範圍第52項之醫藥組成物，其中，式（I-a) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 280 91949(修正本) 1293306 098899 ABCD 第90126014號專利申請案 (96年8月24曰) 六、申請專利範圍 冷-D核苷為選自下列之一： 經濟部智慧財產局員工消費合作社印製 X1 Y1 R1 R1 R2 R2 RJ R3 nh2 0 H H OH H H OH nh2 0 H H OH H H I nh2 0 H H OH H H Cl nh2 0 H H OH H H Br nh2 0 H H H Cl H OH nh2 0 H H H Br H OH nh2 0 H H H OH Br H nh2 0 H H H OH O-Ms H nh2 0 H H H OH O-Ts H nh2 0 H H Cl H H OH nh2 0 D D OH H H OH nh2 0 F H H OH Cl H nh2 0 F H H OH Br H nh2 0 F H H Cl H OH nh2 0 F H H OH O-Ts H nh2 0 F H H OH O-Ms H nh2 0 Cl H H OH O-Ms H nh2 0 Br H H OH O-Ms H nh2 0 Br H H OH O-Ts H nh2 0 Br H H OH Cl H nh2 0 Br H H OH H OH nh2 0 Br H OH H H OH nh2 0 I H H OH O-Ms H nh2 0 I H H OH Br H nh2 0 I H H OH O-Ts H nh2 0 I H H Cl H OH nh2 0 I H Br H H OH nh2 0 nh2 H H OH H OH NH-COCHs 0 H H OH H H OH NH-OH 0 Br H H OH H OH NH-OH 0 I H H OH H OH OH 0 nh2 H H OH H OH OH 0 F H H OH H O-Ts OH 0 F H H H H OH OH 0 H H H OH H H 或其冷-L-對映異構物或其醫藥上可接受之鹽。 •如申請專利範圍第52項之醫藥組成物， 其中， 式（I-b) /3 -D核苷為選自下列之一 X1 X2 W1 R2 R2 R3 R3’ nh2 Η CH Η ΟΗ Η F nh2 Η CH Η Η Η H nh2 νη2 Ν Η ΟΗ Η OH 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 281 91949(修正本) (請先閱讀背面之注意事項再填寫本頁) ，裝----- 1111111« 1293306 第90126014號專利申請案 A8 (96年8月24日） C8 D8 六、申請f利範圍2 X X w1 R2 R2 R3 R3 Cl Η CH F H H H Cl Η CH H OH H H 或其_L-對映異構物或其醫藥上可接受之鹽。 (請先閱讀背面之注意事項再填寫本頁) 零裝--------訂-------- 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 282 91949(修正本)Each of W and W2 is independently CH or N; each of X1 and X2 is independently hydrogen, dentate (F, C1, Br, or work). The scale is suitable for fiscal standards (oi-specification 278 91949 (amendment----- ---I---i II I---^« — — ———— — 1 (Please read the note on the back and fill out this page) 1293306 A8 B8 C8 D8 Patent Application No. 90126014 (96 years 8) On the 24th of the month') VI. The scope of application for patents NH2, NHR4, NH0R4 or 〇 only; each Y1 is ο; each R1 and Rl' are independently hydrogen or nh2; halogen (F, C, Br or u Ministry of Economic Affairs Intellectual Property Bureau) The employee consumption cooperative prints each of R2 and R2 as hydrogen or halogen (F, C, Br or I), or OH; each of R3 and R is independently oxygen or halogen (F, cn, Br or I), ΟΗ, 、, base, $ 乙 乙 ;; each R is hydrogen C (〇) ch3, or 〒 2 substituted sulfhydryl; therefore general formula (I) nucleus and r2 At least one of them is hydrogen, and at least one of R3 and R3' is hydrogen; wherein, when the compound has the formula [La]: wherein, when X1 is NH2 and R1 is hydrogen: (a) R3 is not Is 〇H; and (b) R3' is not fluorine; When 'X1 is NH2 and Ri is fluorine· (a) R is different from R3 as 〇H; and (b) R is different from R3 as 〇H; wherein, when X1 is NH2 and R1 is hydrogen, fluorine Or iodine: (a) R3 and R3' are not η; wherein, when X1 is NHOR4, R4 is η, and R1 is hydrogen or fluorine (a) R2' is different from R3'; b) When R2 and R3' are not the same as 〇H; please read the back note and fill in this page. 1 II Book I This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 279 91949 (Revised Ben. 1293306 Patent No. 90126014 A8 (August 24, 1996) DO C8 D8 VI. Patent application scope, where X1 is NHOR4, R4 is C(0)CH3, and R1 is hydrogen: (Please Read the precautions on the back and fill out this page. (a) R2' is not OH with R3'; where X1 is OH and R1 is F, Br or I: (a) When R2' is different from R3' OH ; and (b) R 2 and R 3 ' are not OH; wherein, when X 1 is OH and R 1 is F: (a) R 2 and R 2 ' are hydrogen; wherein, when X 1 is OH and R 1 is 氲 or F: (a) R3 and R3' are not hydrogen; When X1 is OH, R1 is hydrogen, and R3' is OH: (a) R2 is hydrogen or halogen (F, Cl, Br or I); and (b) R2' is hydrogen, F, I or OH; When the compound has the general formula [Ib], X1 is not OH, and: wherein, when X1 is NH2, X2 is hydrogen, and R2' is OH: (a) R3 and R3' are not hydrogen; The Intellectual Property Office employee consumption cooperative prints out that when X1 is NH2, X2 is C1 or NH2, and W1 is CH: (a) R2' is different from R3' when it is OH; wherein, when X1 is C1 and X2 is hydrogen When C1 or NH2 (a) R2' and R3' are not OH; and wherein, when X1 is hydrogen and X2 is hydrogen: (a) R2' is different from R3' as OH. 53. For the pharmaceutical composition of claim 52, where the formula (Ia) is of the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 280 91949 (amendment) 1293306 098899 ABCD No. 90125014 Patent Application (August 24, 1996) VI. Application for Patent Range The cold-D nucleoside is selected from one of the following: Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed X1 Y1 R1 R1 R2 R2 RJ R3 nh2 0 HH OH HH OH nh2 0 HH OH HHI nh2 0 HH OH HH Cl nh2 0 HH OH HH Br nh2 0 HHH Cl H OH nh2 0 HHH Br H OH nh2 0 HHH OH Br H nh2 0 HHH OH O-Ms H nh2 0 HHH OH O-Ts H nh2 0 HH Cl HH OH nh2 0 DD OH HH OH nh2 0 FHH OH Cl H nh2 0 FHH OH Br H nh2 0 FHH Cl H OH nh2 0 FHH OH O-Ts H nh2 0 FHH OH O-Ms H Nh2 0 Cl HH OH O-Ms H nh2 0 Br HH OH O-Ms H nh2 0 Br HH OH O-Ts H nh2 0 Br HH OH Cl H nh2 0 Br HH OH H OH nh2 0 Br H OH HH OH nh2 0 IHH OH O-Ms H nh2 0 IHH OH Br H nh2 0 IHH OH O-Ts H nh2 0 IHH Cl H OH nh2 0 IH Br HH OH nh2 0 nh2 HH OH H OH N H-COCHs 0 HH OH HH OH NH-OH 0 Br HH OH H OH NH-OH 0 IHH OH H OH OH 0 nh2 HH OH H OH OH 0 FHH OH H O-Ts OH 0 FHHHH OH OH 0 HHH OH HH or Its cold-L-enantiomer or a pharmaceutically acceptable salt thereof. • The pharmaceutical composition of claim 52, wherein the formula (Ib) /3 -D nucleoside is selected from one of the following X1 X2 W1 R2 R2 R3 R3' nh2 Η CH Η ΟΗ Η F nh2 Η CH Η Η Η H nh2 νη2 Ν Η ΟΗ OH OH This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 281 91949 (Revised) (Please read the notes on the back and fill out this page) ----- 1111111« 1293306 Patent No. 90126014 A8 (August 24, 1996) C8 D8 VI. Application f range 2 XX w1 R2 R2 R3 R3 Cl Η CH FHHH Cl Η CH H OH HH or _L-enantiomer or a pharmaceutically acceptable salt thereof. (Please read the notes on the back and then fill out this page) Zero------------------------------------------------------------------------------------------------------------------------------------------------------------------ CNS) A4 specification (210 X 297 mm) 282 91949 (amendment)
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TWI639613B (en) * 2014-12-03 2018-11-01 瑞典商米迪維艾克提伯拉公司 Hcv polymerase inhibitors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI639613B (en) * 2014-12-03 2018-11-01 瑞典商米迪維艾克提伯拉公司 Hcv polymerase inhibitors

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