TW438797B

TW438797B - Triazine containing anionic compounds useful as antiviral agents

Info

Publication number: TW438797B
Application number: TW86101818A
Authority: TW
Inventors: Yakov Gluzman; James Paul Larocque; Bryan Mark O'hara; John Edward Morin; George Alfred Ellestad
Original assignee: American Cyanamid Co
Priority date: 1996-02-13
Filing date: 1997-02-13
Publication date: 2001-06-07
Also published as: BR9700939A; CA2197393A1; ZA971185B; AU1470497A; NZ314225A

Abstract

This invention provides triazine ring containing anionic compounds, pharmaceutical compositions containing these compounds and methods utilizing these compounds for treating viral infections, particularly infections by respiratory syncitial virus, the compounds having the general structure, and the pharmaceutically acceptable salt thereof.

Description

經濟部中央標準居員工消費合作社印製 1^43 8 7 9 7 a? B7 五、發明説明（'）本發明傲關於含陰離子化合物之新三哄環，其有效用於治療病毒_染，持別是人類呼吸道合胞病毒【HUSV]。本發明亦保關於治療病毒威染之方法及因而俗關於醫藥組成物。發flfl背景人類呼吸道合睢病毒丨HRSV]首先於lg56年發現且分佈金世界。其為引起嬰兒與幼童権患上與下呼吸道疾病之重要成因，ϋ成美國每年約100, 〇〇(j人住院治療及5,〇q[) 人死亡（Chanock，R. H·，KU, η. k. , Brandt, c. d,，及 Parrott’ R. Η. 1982. Respiratory syncytial virus, pp 4 7 1 - 4 8 9 , in Viral Infections of flufflans , Second Edition, A. S. Evans, editor (Plenuia Press, NY).Printed by the Central Consumers Cooperative of the Ministry of Economic Affairs 1 ^ 43 8 7 9 7 a? B7 V. Description of the invention (') The present invention is about a new triad ring containing anionic compounds, which is effective for treating viruses. Not the human respiratory syncytial virus [HUSV]. The present invention also guarantees methods for treating viral infections and thus vulnerabilities to pharmaceutical compositions. Flfl background Human respiratory syncytial virus (HRSV) was first discovered and distributed in lg56 in the Golden World. It is an important cause of babies and young children suffering from upper and lower respiratory tract diseases. It causes about 100, 000 (j inpatients and 5, 0 [q]) deaths each year in the United States (Chanock, R.H., KU , η. k., Brandt, c. d, and Parrott 'R. Η. 1982. Respiratory syncytial virus, pp 4 7 1-4 8 9, in Viral Infections of flufflans, Second Edition, AS Evans, editor (Plenuia Press, NY).

G 1 e z e n , W P · , T a b e r，L · H .，F r a n k , A · L .，及 K a s e 1 , J. A·，1 9 86，Risk of primary infecti〇nfti<einfecti〇n with respiratory syncytial virus, A bi . j 〇is 〇hil 14 0; 5 4 3 - 5 4 6 . MacDonald , N. E. , Hall, c. B Suffin S· C.， Alexson. C.， Harris， P. j.，&Hauning j A 1982· Respiratory syncytial virus infection in infants with congenital heart disease. New England Journal of Medicine 3 0 7 ; 397-400) 0 約30%因急性呼吸道疾病而住院治療之幼童有呼吸道合胞病毒感染。對於較大孩童及成人，疾病較緩和。 HRSV顯然亦為老年人罹病與死亡之主要原因（相當於流行性感冒）（Fleming, β. M.及 Cross, K, if. 199 3. -3- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) 袈. 訂 A7 B7 經濟部中央標準局員工消费合作社印聚五、發明説明（ > ) 1 1 Re SP i r a t 〇 r y s y n c y t i a 1 V i r υ S 0 Γ i R f 1 u e η 2 a 9 L a n c e t 1 1 3 4 2 ； 1 50 7 - 15 10) 0 呼吸道合胞病毒染可及於呼吸道 1 之各段 > 通常伴隨發熱 » 咳嗽 » 流鼻涕及疲倦 > 而在臨請 1 先 1 床 t 診斷為支氣管炎細支氣管炎 3 柿炎 1 哮吼或病毒閱讀背面 1 烕染 0 對於較大孩里及成人 ϊ 病毒通常限於在上呼吸道 I 之 1 複製〇當呼 m 道擴展至肺部時則嬰兒更 ΒΞ. 嚴重地被牽累注意 I 〇肺部損傷可為永久性的 0 事項 1 I 再呼吸道合胞病毒之初次染發生於生命早期通常在填寫本笨年齡 4 歲以前 Q 孩童中由此病毒引起之疾病傾向於每頁 —> 1 I 年至少發生一次 » 持鑛數個月之突發期間〇流行病通常 1 1 限制為 3 至 5 ϋ 月〇家族研究中低年级學童常將病毒 1 I 引進家中 9 較 m 重地染家旋中較年幼之成貝更甚於其 i 訂他家族成貝〇感染之臨床結果在初次 lie 染時最為顆敝重而 1 衽經歷免疫之較成長锢體中變為較缓和 0 t I 呼吸道合胞病毒之效果涵蓋非顯性染至嚴重的肺炎 1 | 及死亡 0 呼吸道染産生大部分之症狀〇大多數情況下 1 1 在 1 至 3 插星期中因抗體 UkC- 之産生 ( 顯妷存留於 m -TF- 個生命 1 期 ) 而完金康復 0 在美國 J 約有 3 0 % 之一歲大嬰兒與 1 1 1 95 % 之五歲大孩 sdc. 里具有循 rtnr 環之呼吸道合胞病毒抗體 0 具 1 1 有抗體之較大嬰兒 ' 孩童及成人再感染時産生大部分威. I fsi m 形式之緩和上呼吸疾病對於嬰兒與幼童 Ϊ 疾病以廣 1 1 泛使用之抗病毒劑二氪唑核甙 (Γ i b a v i v i η )治療。此化 1 1 合物之使用因其毒性而駸格地被限制〇因此亟須治療 1 I H R S V感染之新治療劑 0 1 1 -4 1 1 i i 本紙張尺度適用中國國家標隼（CNS ) A4規格（210X29?公釐） NM3 87 9 7 A7 B7 五、發明説明（5 ) U.S.專利案第5,359,131號教示磺酸二苯乙烯，其15且礙由單純疱疹病毒（HSV),人類免疫不全病毒（HIV)及巨细胞病毒（CMV)引起之细胞感染。本發明係關於新穎三阱環陰離子化合物，其顯現抗病毒活性，特別是人類呼吸道合胞病毒[HiiSV]活性。發明槪诚本發明係闞於選自通式I之新化合物： X jh\ , , /~\ N — A— B'—^ N卜 N={ /=\ 式 ^^^1 ^^^^1 ^^^^1 n^n HH - —Β^ϋ ^^^^1 ^^^^1 nfl^ ^^^^1 「. (請先閱讀背面之注意事項再填寫本頁) 其中：經濟部中央標準扃員工消費合作社印製G 1 ezen, WP ·, T aber, L · H., F rank, A · L., And K ase 1, J. A ·, 1 9 86, Risk of primary infecti〇nfti < einfecti〇n with respiratory syncytial virus, A bi. j 〇is 〇hil 14 0; 5 4 3-5 4 6. MacDonald, NE, Hall, c. B Suffin S.C., Alexson. C., Harris, P. j., & Hauning j A 1982 · Respiratory syncytial virus infection in infants with congenital heart disease. New England Journal of Medicine 3 0 7; 397-400) 0 About 30% of young children hospitalized for acute respiratory diseases have respiratory syncytial virus infection. For older children and adults, the disease is less severe. HRSV is obviously also the main cause of illness and death in the elderly (equivalent to influenza) (Fleming, β. M. and Cross, K, if. 199 3. -3- This paper standard applies Chinese National Standard (CNS) A4 Specifications (210X297 mm) (Please read the notes on the back before filling out this page) 袈. Order A7 B7 Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (>) 1 1 Re SP irat 〇rysyncytia 1 V ir υ S 0 Γ i R f 1 ue η 2 a 9 Lancet 1 1 3 4 2; 1 50 7-15 10) 0 Respiratory syncytial virus can reach sections of respiratory tract 1 > usually accompanied by fever » Cough »Runny nose and tiredness > And in the immediate 1st 1 bed t diagnosed with bronchitis bronchiolitis 3 persimmon 1 roar or virus reading on the back 1 infection 0 for older children and adults 病毒 The virus is usually limited to Upper respiratory tract I-1 is replicated. When the umulus tract expands to the lungs, the infant is more beta. Severely drawn attention I 0 Lung injury can be permanent 0 Matter 1 I The first infection of re-respiratory syncytial virus occurs early in life and is usually caused by this virus in Q children who are 4 years old Tends per page— > 1 year at least once in I »Sudden period of several months of holding mines 0 Epidemics are usually limited to 3 to 5 months Month 0 Family studies Middle and lower grade school children often introduce virus 1 I into homes 9 Heavier dyed mussels in the family spine are heavier than their younger ones. The clinical results of infection in the family are the heaviest when they are infected for the first time, and 1) they have undergone immune changes in the growing carcass. To mitigate the effects of 0 t I respiratory syncytial virus from non-dominant to severe pneumonia1 | and death In the case of 1 1 in 1 to 3 weeks of insertion due to the production of antibody UkC- (significantly remained in m-TF- life 1) and complete recovery 0 in the United States J about 30% of one-year-old infants with 1 1 1 95% of five-year-old children sdc. Respiratory syncytial virus antibodies with rtnr loops in 0 0 1 1 Larger babies with antibodies' Most infected children and adults develop reinfection. I fsi m Relief of upper respiratory diseases For infants and young children Ϊ disease is treated with the antiviral agent dioxazole riboside (Γ ibavivi η) which is widely used. The use of this chemical compound is restricted due to its toxicity. Therefore, a new therapeutic agent for the treatment of 1 IHRSV infection is urgently needed. 0 1 1 -4 1 1 ii This paper is in accordance with Chinese National Standard (CNS) A4 (210X29? Mm) NM3 87 9 7 A7 B7 V. Description of the invention (5) US Patent No. 5,359,131 teaches stilbene sulphonate, 15 of which is hindered by herpes simplex virus (HSV), human immunodeficiency virus (HIV) ) And cytomegalovirus (CMV) -induced cellular infections. The present invention relates to a novel triple well ring anionic compound, which exhibits antiviral activity, especially human respiratory syncytial virus [HiiSV] activity. The present invention is based on a novel compound selected from the general formula I: X jh \,, / ~ \ N — A— B ′ — ^ N BU N = {/ = \ Formula ^^^ 1 ^^^^ 1 ^^^^ 1 n ^ n HH--B ^ ϋ ^^^^ 1 ^^^^ 1 nfl ^ ^^^^ 1 ". (Please read the notes on the back before filling this page) Among them: Economy Printed by the Central Standard of the Ministry of Education

A為遘自下列之基團 CA is a group 遘

反anti-

C' C,▲。各 -5 一本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐_ ) PA 3 A7 B7 五、發明説明（4 ) C'選自-S〇3H，-OSO 3 Η , -OH,或-C00H; B ·為-N IK - Ο 1 或 0 ; R1選自Η ,直鐽或低碳烷基，其中碳原子可視情況WC1, Br, F, 0H或CN取代； X為Cb F ,或下式基團C 'C, ▲. Each -5 paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm_) PA 3 A7 B7 V. Description of the invention (4) C 'is selected from -S〇3H, -OSO 3 Η, -OH , Or -C00H; B · is -N IK-Ο 1 or 0; R1 is selected from Η, straight 鐽 or lower alkyl, wherein the carbon atom may be substituted by WC1, Br, F, 0H or CN as appropriate; X is Cb F , Or a group of the formula

U'W' ’選自-S〇2 , -CO, -NC(0),或-NC(S);U'W '' is selected from -S〇2, -CO, -NC (0), or -NC (S);

•莖自下列基團 Z Y*• Stems from the following groups Z Y *

ZZ

-N Y、-N Y,

ZZ

/( -N^CH2)r Z 或 f==^ N^(CH2) - —- -- - — - ^^^1 —^n . ^^^1 I 1^1^1 ^^^1 \~^ (請先鬩讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 Y 為-(CH 2 ) n -; η為0至6 ; a為0至2 ; Z選自H , CH3 , CF3 ， -CH2-(鹵素），其中鹵素為C1 ，Br, F ，或 I ， -CH 2 〇H, -C00H, -COO(Ci-Cs)直 R2 / 鐽或支趟低碳烷基，-CONR 2 R 2 , CN或 _CH\ ;及 OH R2各分別選自H或（Ci -Ce )低碳烷基；及其醫藥容許鹽及酷。可理解m為0之情肜下，W'可為5員環。本發明化合物之翳槩容許鹽為彼等陽離子，其在達到 ~ 6 ~ 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐）經濟.部中夬標隼局員工消費合作杜印製 A7 B7 五、發明説明（5 ) 所要效果而不任意具有顯著藥理活性之投予劑量下實質上為無毒者。作為說明用，此等鹽包括彼等鹼金届者如 Na或K ;驗土金颶如Ca或Mg;包括之Ha族輕金靥；及有機一级，二鈒與二鈒胺或氨、納鹽較佳。链明詳钿說明在式I定義之化合物族群中，特定次族群之化合物一般較佳。一般較佳者為彼等化合物，或其翳藥容許鹽，其中A為C，/ (-N ^ CH2) r Z or f == ^ N ^ (CH2)-—---—-^^^ 1 — ^ n. ^^^ 1 I 1 ^ 1 ^ 1 ^^^ 1 \ ~ ^ (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Y is-(CH 2) n-; η is 0 to 6; a is 0 to 2; Z select From H, CH3, CF3, -CH2- (halogen), where halogen is C1, Br, F, or I, -CH2 0H, -C00H, -COO (Ci-Cs) straight R2 / 鐽 or branch low Carboalkyl, -CONR 2 R 2, CN or _CH \; and OH R2 are each selected from H or (Ci -Ce) lower alkyl; It can be understood that when m is 0, W 'can be a 5-membered ring. The permissive salts of the compounds of the present invention are their cations, which are applicable to the national standard (CNS) Λ4 specification (210X 297 mm) of the paper when the paper size reaches ~ 6 ~. Preparation A7 B7 V. Description of the invention (5) The desired effect without any significant pharmacological activity is essentially non-toxic at a dosage. By way of illustration, these salts include their alkali metals such as Na or K; soil testing gold such as Ca or Mg; included Ha group light gold tincture; and organic grade, dihydrazone with dioxamine or ammonia, Sodium salt is preferred. The detailed description clearly shows that among the group of compounds defined by formula I, compounds of a specific subgroup are generally preferred. Generally preferred are their compounds, or their peony allowable salts, where A is C,

特別較佳者為化合物，其中 C' = -S〇3H, B' = -NH, Y = -CH2-, Z = -CH2〇H 最佳者為化合物，其中 C = -S〇3H, B' = -NH, Y = -CH2CH2-, Z = -CONH2 高度最佳者為化合物，其中A為Particularly preferred are compounds, where C '= -S〇3H, B' = -NH, Y = -CH2-, Z = -CH2〇H. The best are compounds, where C = -S〇3H, B ' = -NH, Y = -CH2CH2-, Z = -CONH2 The most highly preferred compound is, where A is

及 C’ = -S〇3H, B = -NH, Y = -CH2CH2-, Z = -C0NH2 本發明之新穎化合物可根據下述略圈製備。參見略圖 I ,在約ου及pH約6.5至約7.2下(其中A與L定義如上）與結構2_之三阱（其中X為Cl, F或Br)缩合取得中間體1。進一步在溫度約451至約551〇及0«6.5-7.2下 -7 — 本紙張尺度適用中國國家標準（CNS ) A4規格（2!0X 297公釐） ^^^1 I ^^^1 HH ^—^^1 ^^^^1 In ml lJ ws. 、va (請先閱讀背面之注意事項再填寫本頁) ^-43 87 9 7 A7 B7 五、發明説明（And C '= -S〇3H, B = -NH, Y = -CH2CH2-, Z = -C0NH2 The novel compounds of the present invention can be prepared according to the following outline. Referring to sketch I, intermediate 1 is obtained by condensing with a triple well (where X is Cl, F or Br) of structure 2_ at about ου and pH of about 6.5 to about 7.2 (where A and L are as defined above). Further at a temperature of about 451 to about 5510 and 0 «6.5-7.2-7-This paper size applies the Chinese National Standard (CNS) A4 specification (2! 0X 297 mm) ^^^ 1 I ^^^ 1 HH ^ — ^^ 1 ^^^^ 1 In ml lJ ws., Va (Please read the precautions on the back before filling in this page) ^ -43 87 9 7 A7 B7 V. Description of the invention (

使式4_化合物與式L化合物（其中（Γ，B’及1T定義如上）反應，接著在PH6.5-7.2及100-120t：下取得上逑式I所要產物，其於下略圖中稱為L。胳_ I 2The compound of formula 4_ is reacted with the compound of formula L (where (Γ, B 'and 1T are as defined above), and then the desired product of formula I above is obtained at pH 6.5-7.2 and 100-120t: For L. tick_ I 2

χγΝγ ΝγΝ XχγΝγ ΝγΝ X

X 0*C; pH 6.5-7.2 (請先閱讀背面之注意事項再填寫本頁) 袈. 11 ΑX 0 * C; pH 6.5-7.2 (Please read the precautions on the back before filling this page) 袈. 11 Α

Χ N=( B-(x NΧ N = (B- (x N

X 訂 4 2 /=\hbhQ, U'W'5 i 45-55'C; pH 6.5-7.2 ii 100-120*C; pH 6.5-7.2 經濟部中央標準局員工消費合作杜印製製造式I化合物之替代路徑，如略圖I所示，在約-5_ 至約5t：及PH6.5-7.2下使三阱(其中X為Π, Br或F) -8 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） > 五、發明説明（ Α7 Β7 與化合物上（其中B’與ST定義如上）反應取得縮合產物。在約45^至約55=0及“約6.5至7.2下使6_(其中8’與 ST定義如上及X為Cl, Br或F)輿1 (其中Α與Β’定義如上）反應，接著在約100T：至約120t及PH6.5-7.2下加熱取得ί。祺_ Π h-b，hQx5 UW， Ύ 丫 -5 -5*C,pH 6.5-7.2 n· nn* nn —^ϋ m ^ J. (請先閱讀背面之注意事項再填寫本頁) A-X order 4 2 / = \ hbhQ, U'W'5 i 45-55'C; pH 6.5-7.2 ii 100-120 * C; pH 6.5-7.2 Employees' cooperation with the Central Standards Bureau of the Ministry of Economic Affairs Du printed manufacturing type I The alternative route of the compound, as shown in sketch I, is to make the triple well (where X is Π, Br or F) at about -5_ to about 5t: and pH6.5-7.2 -8-This paper size applies Chinese national standards ( CNS) A4 specification (210 X 297 mm) > V. Description of the invention (Α7 Β7 reacts with the compound (where B 'and ST are as defined above) to obtain the condensation product. At about 45 ^ to about 55 = 0 and "about 6.5 6_ (wherein 8 ′ and ST are defined as above and X is Cl, Br or F) at 1 to 7.2 (wherein A and B ′ are defined as above), then at about 100T: to about 120t and pH 6.5-7.2 Heating to get ί. Qi_ Π hb, hQx5 UW, 丫丫 -5 -5 * C, pH 6.5-7.2 n · nn * nn — ^ ϋ m ^ J. (Please read the precautions on the back before filling this page) A-

B'-H U'W' 6 2B'-H U'W '6 2

i 45-55'C; ii 100-120*C 經濟.部中央標準局貝工消費合作社印製起始化合物L (如略圖I所示）及&_ (如略匾I所示）與 -9- 本紙張尺度適用中國國家標準（CMS ) A4規格（2丨0X 297公f ) 五、發明説明（8 A7 B7 經濟部中央標準局員工消費合作社印製三肼1(其中X為Cl, Br或F)之逐步縮合在適當鹼如氫氧化納或鉀，碳酸鹽.磷酸鹽或碳酸氫鹽存在下於水性或有機-水性介質中類似地反應。PH7.0之磷酸鹽媛衝液較佳。縮合之第一步驟係在pH約4至約8 ,較佳pH約6.5至約7.2及溫度約-10T至約3〇υ,較佳約-5C至的51下進行。三阱衍生物第二個鹵原子之交換係在枏同pH範圍及約1 0 C至約7 0 υ，較佳溫度約45 υ至約5 5 Γ下達到。三阱衍生物第三個鹵原子之交換係在相同pH範圍及溫度約80t至約150T!,較佳自10〇υ至120T：下完成。式6_ (略圖I )三阱衍生物第二個或第三掘鹵原子之交換亦在有機鹸如三烷基胺（包括三乙胺、二異丙基乙胺或Ν-(低碳 > 烷基六氫吡啶）存在下於有機介質中完成。用於略圖Σ與Ε所略述之一般合成程序中之起始物可自市面上取得或可根據H. Adkins, E. F. Steinbring, E . Pickering. J. A m e r. Chem. S o c. , v . 46, p . 1917(1924),英國專利案第 1,194,388 虢（1970年 6月 10 日）及美國專利案第5,359,131號（1994年10月25日）合成。式2起始化合物（其中B'為氧）可如略圃a所示自式2 之經$代的化合物（B ’ = -NH 2 )製得。i 45-55'C; ii 100-120 * C Economy. The Central Standards Bureau of the Ministry of Standards printed the starting compound L (shown in sketch I) and & _ (shown in sketch I) with- 9- This paper size is in accordance with Chinese National Standard (CMS) A4 specification (2 丨 0X 297 male f) V. Description of the invention (8 A7 B7 Trihydrazine 1 (where X is Cl, Br Or F) The stepwise condensation is similarly reacted in an aqueous or organic-aqueous medium in the presence of a suitable base such as sodium or potassium hydroxide, carbonate, phosphate or bicarbonate. Phosphate phosphate solution at pH 7.0 is preferred. The first step of condensation is carried out at a pH of about 4 to about 8, preferably a pH of about 6.5 to about 7.2, and a temperature of about -10T to about 30 °, preferably about -5C to 51. The third well derivative The exchange of three halogen atoms is achieved at the same pH range and about 10 C to about 7 0 υ, preferably at a temperature of about 45 υ to about 5 5 Γ. The exchange system of the third halogen atom of the triple well derivative is the same The pH range and temperature is about 80t to about 150T !, preferably from 100o to 120T: Formula 6_ (schema I) The exchange of the second or third halogen atom of the triple-well derivative is also performed in organic tritium. Such as trialkylamine (including triethylamine, diisopropylethylamine or N- (lower carbon> alkyl hexahydropyridine) in the presence of organic media. Used to outline the general outline of Σ and Ε The starting materials in the synthesis procedure can be obtained from the market or can be obtained according to H. Adkins, EF Steinbring, E. Pickering. J. A mer. Chem. So c., V. 46, p. 1917 (1924), Synthesized in British Patent No. 1,194,388 (June 10, 1970) and U.S. Patent No. 5,359,131 (October 25, 1994). The starting compound of Formula 2 (where B 'is oxygen) can be as shown in Fig. A Prepared from a substituted compound of formula 2 (B '=-NH2).

aM HNO, 略圔Ba[n+= n] 4 1 _ i ο _ 本紙張尺度適用中國國家標準（C:NS ) Λ4規格('2I0X 297公釐） —ϋι ^^^^1 ^^^^1 一OJ (請先閱讀背面之注意事項再填寫本頁) h3oaM HNO, slightly 圔 Ba [n + = n] 4 1 _ i ο _ _ This paper size applies the Chinese National Standard (C: NS) Λ4 specification ('2I0X 297 mm) —ϋ ^^^^ 1 ^^^^ 1 One OJ (Please read the notes on the back before filling this page) h3o

A Μ M3 87 9 A7 B7 五、發明説明（9 一级芳胺！_ (其中A定義如上）與亞硝酸或與其他用Μ 使一级胺重氮化之化學試劑（例如亞硝酸有機酯）反應產生重氮鹽其水解成含有酚基之式9_化合物。嘛圖IV cA Μ M3 87 9 A7 B7 V. Description of the invention (9 Primary aromatic amines! (Where A is as defined above) and nitrous acid or other chemical reagents that diazotize primary amines with Μ (such as organic nitrite esters) The reaction produces a diazonium salt which is hydrolyzed to a compound of formula 9_ containing phenolic groups. Well Figure IV c

XX

X C >νX C > ν

11 X X U'W'11 X X U'W '

Hr n^i ^^^^1 ^^^^1 fm nn ^11 4 ^^^^1-1J 穿 τβ (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製參見略圓IV,二苯乙烯系列之化合物（丄可藉由催化堪原，條件（氫-Pd/C)或藉由業界已知用Μ將經取代之二苯乙烯轉化為雙苄化合物之相Ml原條件轉形為雙苄糸列之化合物(11) t H u a n g ~ Μ i η 1 ο n , J. Aner. Cheat. Soc . ( 1 948 ) 70, 280 2 ]。 Z = _C00H之式丄化合物（U與U)可在f>H自7_5至10.0, 較佳8.0-8.5及自80至150^',較佳100至1201〇下藉由鹼 -11 _ 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） (ί=^3 6/97 Α7 Β7 五、發明説明（10 性水解製成化合物（J_i)(略_ V > :Hr n ^ i ^^^^ 1 ^^^^ 1 fm nn ^ 11 4 ^^^^ 1-1J Wear τβ (Please read the precautions on the back before filling this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Refer to the slightly round IV, stilbene series of compounds (丄 can be converted to bisbenzyl compounds by catalysis, conditions (hydrogen-Pd / C) or by known in the industry using M The phase M1 is transformed into the compound of dibenzyl hydrazone in the original condition (11) t H uang ~ M i η 1 ο n, J. Aner. Cheat. Soc. (1 948) 70, 280 2]. Z = _C00H丄 Compounds (U and U) can be used at f > H from 7_5 to 10.0, preferably from 8.0 to 8.5 and from 80 to 150 ^ ', preferably from 100 to 1201 〇 By the base -11 _ This paper size applies Chinese national standards (CNS) A4 specification (210X 297 mm) (ί = ^ 3 6/97 Α7 Β7 V. Description of the invention (10 hydrolysed to make compound (J_i) (略 _ V >:

RNVV 瞄_ V C'RNVV Sight_ V C '

RR

R C'R C '

R'R '

12: R1 = HN12: R1 = HN

so2n ,CH2CH2C〇NH2 、so2n, CH2CH2C〇NH2,

CH2CH2COOHCH2CH2COOH

R =HN飞次 ^CH2CH2COOH so2n ch2ch2cooh 1^1 n^i- ....... . I ^^^1 mu _^ϋ ^^^1 - - - --aJ. (請先閱讀背面之注意事項再填寫本頁〕 R = 經濟部中央標準局員工消费合作社印製 so2n(ch2ch2conh2)2 間-胺基苄醢胺u(其中U'為-so2或-CO, Y及z定義如上）根據略圖VI合成。本紙張尺度適用中國國家標準（CNS ) Λ4規格（2丨0X297公釐）五、發明説明（11 ) A7 B7R = HN fly times ^ CH2CH2COOH so2n ch2ch2cooh 1 ^ 1 n ^ i- ........ I ^^^ 1 mu _ ^ ϋ ^^^ 1-----aJ. (Please read the first Note: Please fill in this page again.] R = printed by so2n (ch2ch2conh2) 2 m-aminobenzylamine u (where U 'is -so2 or -CO, Y and z are as defined above) Thumbnail VI synthesis. This paper size applies the Chinese National Standard (CNS) Λ4 specification (2 丨 0X297 mm) 5. Description of the invention (11) A7 B7

略圈VICircle VI

ν>υΛ 一 zν > υΛ a z

Hj/Pd o2isi /^ν /γ_ζ \_/~ΌΛν_ζ η2ν ~Hj / Pd o2isi / ^ ν / γ_ζ \ _ / ~ ΌΛν_ζ η2ν ~

In ^^^^1 —^n R^^—1 m« H^I ^^^^1 -- mr ^^^^1 —^ϋ n^i 一OJ (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製醢亞胺i互使用醯胺化或甲苯磺醸化方法（Τ. W. Greene ,P . G . Η . Wilts, Protective Groups in Organic Chemistry, John Wiley & Sons, New York 1991, pp. 349-379)之適當變異法轉形為間-硝基磺酸鹽丄I。隨後硝基化合物li藉由催化氫化反應（氫- Pd/C)堪原為胺基 -化合物1_7。六氫咄阱衍生物n, 0(其中Z為-C00H或-C0NH2 )根據略圖V0自3,5 -二氫吡啶二羧酸U合成。芳環之還原及六氫吡啶衍生物D之間-硝基甲苯基磺醢化產生化合物 20,其埴原為含羧基之化合物21或藉由酯化及氨解轉化為含胺甲醣基之化合物22。 -13- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 143 87 9 7 A7 B7 五、發明説明（12 HOOC^^^JCOOH -In ^^^^ 1 — ^ n R ^^ — 1 m «H ^ I ^^^^ 1-mr ^^^^ 1 — ^ ϋ n ^ i-OJ (Please read the notes on the back before filling (This page) Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, Interim Amine or Toluene Sulfonation (T. W. Greene, P. G. Η. Wilts, Protective Groups in Organic Chemistry, John Wiley & Sons, New York 1991, pp. 349-379) is transformed into m-nitrosulfonate 丄 I. The nitro compound li is then converted to an amine-compound 1-7 by a catalytic hydrogenation reaction (hydrogen-Pd / C). The hexahydrofluorene derivative n, 0 (wherein Z is -C00H or -C0NH2) was synthesized from 3,5-dihydropyridinedicarboxylic acid U according to the sketch V0. The reduction of the aromatic ring and the nitrotolyl sulfonation between the hexahydropyridine derivative D yields compound 20, which is a carboxyl-containing compound 21 or is converted to a carbamate-containing compound by esterification and ammonolysis. twenty two. -13- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 143 87 9 7 A7 B7 V. Description of the invention (12 HOOC ^^^ JCOOH-

肱_ Ml HOOBrachial_ Ml HOO

Hypt laHypt la

V°°H H UV °° H H U

NH3/E10HNH3 / E10H

CH3N3 ^^-so2ciCH3N3 ^^-so2ci

COOHCOOH

1' _ n n ί I] _ . ^ I _ I I n —ϋ T (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印繁本發明亦包括治療經病毒感染之哺乳類，較佳為人類之方法，方法包含投予一或多個本發明之化合物及/或一或多個化合物之S藥容許鹽至遭感染之哺乳類。可使用本發明之化合物與方法治療之病毒感染包括該等由人類呼吸道合胞病毒，單純疱疹病毒、人類巨钿胞病毒及流疗性感冒病毒，特刖是副流行性感冒病毒3引起之感染。本發明之化合物可奴任一規定之方式（包括鼻内、口腋、局部、經皮、腸爾外及腹膜内）投予至需要之哺乳 -14- 本紙張尺度適用中國國家標率（CXS ) Λ4規格（210X297公釐） 14 3 8 Γ、‘ Α7Β7 經濟部中夹標準局員工消費合作社印製五、發明説明（15 ) 類。可了解治療哺乳類•較佳為人類需要活性化合物各種劑虽及各種療程•視各種因素而定，其包括特定個體之年舲、性別、尺寸，一般健康狀況及疾病程度，適當行路者決定之劑最與療法。在此投予之抗病毒有效量之化合物一般每日Μ —或多劑投予依動物體重計之約0.5 毫克/公斤至約500毫克/公斤。該等劑量較佳Μ每日二至四次分次投予或以持續釋放形式投予。對於大部分之大型哺乳類，總日劑量自約1至100毫克，較佳自約2 至80毫克。適於内眼之劑型包含約0.5至500牽克活性化合物直接與固態或液態》藥容許載劑混合。此劑療法可經調整Μ提供最佳治療反應。例如，數個分劑量可每曰投予或劑量可依治療情況之急需而依比例減少。本發明之化合物可與或不與其他抗病毒劑一起投予。本發明亦包括可Μ此等治療方法使用之路藥組成物。轚槩組成物可包含一或多個本發明之化合物.或其Κ槩容許a,及一或多個s槩容許載劑，稀釋劑，賦形蜊，填充劑，黏合劑，矯味劑等。供口眼投予用，含有化合物本發明之組成物包括固態或液態組成物如膠囊，錠劑 (troches)、糖衣、丸劑、淀劑（tablet)、粉劑、培化物、溶液、懸浮液及乳液。固型可由硬質或軟質明膠膠囊包膠，而可含有常用之皤藥容許賦形劑、填充劑、佐劑、稀釋劑、潤滑劑、崩散劑、懸浮液或安定劑及黏結劑，其包括，但不限於硬脂酸鎂、月桂基硫酸納、微晶型纖維素、聚乙烯基毗咯啶·、明膠、滿酸、*** -15 - i^i n^— - -- -- n I . m ·1 1 —r m3. 、-0 (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襟準（C'NS ) A4規格（2〗0'乂 297公;i ) it Λ A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（14 ) 1 i 膠撺 m 酸納、複合矽酸 m \ 碳酸鈣 Λ 甘胺酸糊精 Λ 1 i I 蔗糖山梨耱酵磷酸鈣 m 酸二鈣 % 硫酸鈣 % 糖 Λ 1 1 高嶺土 \ 甘 m 糖醇氯化納滑石 Λ 乾澱粉 ( 如玉米請 1 先 1 甘薯或木薯澱粉 ) 及耱粉〇 K 方亦可包括抗氧化劑如維閱讀 1 1 生素 E > 抗壞血酸 ΒΗΤ 及 BHA 〇如此之齧 m 製劑可含背 1 I 之 1 有例如 i 約〇. 05多至約 90¾ 之活性成分與載劑組合 J 更意 1 I 常介於約 5¾及 60¾ 重量比之間 ΰ 事項再 1 1 液態 α 眼 m 方之適當賦形劑包括稀釋劑如水 t 及醉如填寫本裝乙醇苄基醇及聚乙二酵 % 含或不含界面活性劑 Λ 懸浮頁 1 I 劑或乳化劑〇懸浮液可在甘油 Ή 液態聚乙二酵及其於油 1 1 中之 Μ 合物中製備 0 在般儲存與使用條件下 » 此等製 1 1 劑含有保 m 劑 Μ 防止微生物之生長〇 I 訂本發明之化合物亦可在生理容許稀釋 m 如無菌液體或 1 其混合物 ( 包括水 ·» 食鹽水 Λ 水性右旋糖及其他發藥容 1 I 許溶液 ) 酵如乙酵異丙醇或十 > - 酵二酵如丙二 m 1 1 或聚乙二酵甘油縮铜如 2， 2- 二甲基 -1 ,3 _ _ 二. ί戊環- 4- 1 1 甲醇 » 醚如聚 (乙二醇）400 强藥容許油脂昉酸脂 I 肪酸 m 或甘油 m 或含或不含添加睡藥容許界面活性劑如 I 皂或清 m 劑之乙鼸基化睹肪酸甘油酯懸浮劑如果膠 Λ ! 1 c a r b 〇 m e r s 、甲基纖維素、羥丙甲基纖維素或羧甲基纖 I 維素 Λ 乳化劑或醫藥佐劑〇所有情形下 I 劑型必須為無 1 I 菌且必須為流質 Μ 致注射器操作簡易〇在製造及儲存條 1 1 件下安定及必須保 Μ 使免於微生物如细菌與真菌之污染 1 I 作用 0 1 1 -16- i I 1 1 本紙張尺度適用中國國家標隼（CNS ) Α4規格（2! 0 X 297公釐） «243 87 97 绥濟部中央標準局員工消費合作社印製五、發明説明（15 ) 1 t 有效在此用於配方之 m 蕖容許油包括彼等 g 石油 Λ 1 ί I 動物植物或合成者 * 包括花生油、大豆油芝麻油 Ή t 1 棉籽油橄 m 油 > 葵花油石鼸脂及磯物油〇可使用之請 1 ! 脂肪酸包括油酸 Ή 硬 m 酸及異硬脂酸 r 而有用於此之腊閲讀 1 防酸 m 包括油酸乙 m 及肉豆蔻酸異丙酯〇缠用之皂包括背之 1 i 1 脂肪酸鹼金靨銨及三乙醇胺鹽〇可接受之清潔劑包括注意宣 I 陽離子清潔劑 % 例如二甲基二院基銨鹵化物院基吡啶争項再 | 鹵化物及院胺醋酸鹽及陰離子清 m 劑如烷基芳基及烯填寫本裝 \ 烴磺酸 _ » 烷基 m 烴、醚及單甘油酷硫酸鹽及磺酸基頁、_-· 1 i 丁二酸 m 0 有用之非陰離子清 Μ 劑可包括脂肪胺氧化物 \ i l > 脂肪酸烷酵釀胺及聚氧乙烯基聚丙烯共聚物 0 兩性 1 ! 清潔劑可包括燒基 -β - 胺基丙酸酯及 2- 烷基咪唑啉四級 1 訂鹽及其混合物〇 1 本發明之腸胃外組成物較佳含有約 0 . 5至約2 5¾重量比 1 1 之所說明之化合物於溶液中 0 無菌注射溶液或懸浮液形 1 I 式之腸戽外配方含有約〇. 05¾至約5¾懸浮劑於等滲性介 1 1 質中亦較佳〇可添加媛衡液及保 Μ 劑〇亦可添加適當界 I 面活性劑〇此等界面活性劑可包括聚乙烯去水山梨酵脂肪酸酷如去水山梨酵單油酸 m ，及環氧乙院與疏水性鹼 i 1 之高分子量加成物，由環氧丙院與丙二酵之縮合形成〇 1 本發明之轚藥組成物亦包括彼等用於局部及經皮投予 i | 者 0 此等配方可包括本發明化合物在用強化經皮吸收 1 1 之溶劑系統 ( 包括乙酵或二甲基亞礁 f 含或不含其他賦 1 | 形劑 ) 中之皮虜投予 0 較佳在此之局部與經皮組成物包 1 I -1 7- 1 1 1 1 本紙張尺度適用中國國家標準（CTNS ) Λ4規格（210X29*7公釐） B7 經濟部中央標率局員工消费合作社印製五、發明説明（ ib ) I 1 含將本發明之化合物加至貯槽及多孔膜類型之阽布中或 1 1 固態基質種類之貼布中 0 此等類型之經皮貼布説明於美 1 | 國專利案 3 , 7 4 2 , 9 5 1 ' 3 ,7 9 7 ,4 94 3 , 9 9 6 , 93 4、 4 ,〇 3 1 ,894 /—» 請 1 I 4 , 5 7 3 , 996 與 4 ,9 5 6 ,1 7 1 中〇先閲 1 1 讀 t 本發明之箅内配方及投予可呈鼻内滴劑或内噴 m 如背面 1 I 之 1 吸入 _ 投予〇配方可包括有用於鞸内投予之醫藥容許成注意 I 分之任一組合 > 包括無菌水食鹽水安定劑如分子量事項 1 I 再 1 範圍約 20G至約7 5 0 0之聚乙二二醇或其混合物。導爲裝本發明之化合物可用以預防或治療方式處理病毒 Μ 頁 ί 染〇供預防用 5 化合物可每曰以噴劑或霧劑或滴劑於 1 1 内投予以防止病毒 1 待別 m 疋 RS V 染〇治療期長度反應 1 I 特定病毒劑感染之跡象及可由流行情況及待定病患表現 1 1 之危險因子影 m 〇以此等方式傳輸之化合物在濃度 0 . 1 1 丁 1 至 3 0毫克/毫升之間 1 所傳輸之容量在 0 . 1至1 毫升/ 1 I 鼻孔之間 0 % i 化合樹可藉由 P 服或靜脈内投藥而作金 1 1 身傳輪〇供治療用 * 化合物可呈氣霧劑局部傳輸到肺部 1 1 或可藉由 □ 服或靜脈内投藥而全身傳輸〇可在控制病毒 I iJs 染所需之時段内進行如此之投藥〇 1 本發明之化合物輿其製備可進一步 m 由下述非限制性 1 | 實例了解〇使用丙 -2 -醇- 醋酸乙酷 -4¾氨於水 (8 :1 :1 Γ | 體積 / 體積 ) 作為溶 m 由矽凝 m 上進行薄層層析 (T L C } 1 1 及逆柑高性能液體層析 (R P - HP L C ) [管柱： V yd a c C 18 I I (4 .6 m m X 2 5 Cl), 5 ia m 9 移動相 A- 乙腈， B- 0 . 1 Μ醋酸銨 1 1 I 於水中 (PH5 • 5 ) ’ C -甲酵；梯度： 1 〇分鐘内自混合物A -Β 1 1 -1 8 - 1 1 1 1 本紙張尺度適用中國國家標準{ CNS ) A4規格（210 X 297公釐） A7 B7 五、發明説明（17 ) -C( 20:6 5:1 5,體積 / 體積）至混合物 A-B-C( 2 0:55: 請先閲 it 背 ιέ 之注意事項再填· 衰裝頁 2 5，體積/體積）]製備性R F - Η P L C在R a i n U梯度Η P L C 系統進行，使用Vydac C18呔/蛋白質製備性管柱（10 m b , 2 2 m b X 2 5 c m );移動相：A -甲醇-0, 1 Μ醋酸铵於水中 (ΡΗ5.5) (1:4,體積/體積）Β-甲醇-乙腈（1:4,體積 /體積）；梯度：18-32ΧΒ於10分鐘内。奮例1 4.4'-萼「4.6-二「3-胺呆某U-等（2 -防甲瞌某蓽）碏醚某亞胺某1-1.2.5-三11#-2-某胺某1_二笼7,烯-厂；>’ 二確酴在-3 -0C下將三聚氯化氰（3.87克^ 21毫莫耳 > 於二 1 丁經濟部中央標準局員工消費合作社印絮 Ϊ琴烷（25毫升）之溶液加人磷酸鹽媛衝液（100毫升，0.3Μ ,ΡΗ7)中，伴Κ攪拌，隨後在20分鐘内將4,4’-二胺基二笨乙烯-2,2’-二磺酸（3.70克，10毫莫耳）於1Η HaOH (20毫升）之溶液加人，pH藉由添加IN NaOH保持在6.5-7.2間。相同溫度及pH下再持續搅拌1小時，而藉由分析性HPLC(產率95¾)監控反應是否完全。在20分鐘内將 3-胺苯基-Ν,Ν-雙（2-胺甲醯基乙基）磺醢基亞胺（13.20 克，42奄莫耳）（英國専利案第1,194,388號；1970年6月 10日）於二甲基亞碘（DHS0M100毫升）之溶液加人及將溫度升至501C ◊在此溫度下再繼绩攪拌2,5小時，随後在 100-110它下攪拌40小時，pH藉由添加IN NaOH維持在 6.6_7.2。一旦由分析性HPLC(或TLC)測定反應完全，•混合物冷卻至20C及以5.6N鹽酸酸化至pH2 。將氛化納 -19- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公釐）經濟部中央標準局員工消费合作社印製 *=43 8 7 9 7 A7 B7 五、發明説明（18 ) (60毫升，4M)加入及過逋沈澱產物。藉由添加IN NaOH 至pH7而再溶解於最小容最之水中，藉由添加氛化納再沈澱。沈澱經過濾、Μ冷水（20毫升）、丙-2-酵（40毫升）、丙SB (60毫升）清洗及在真空及5〇υ下乾煉。產率13.0 克（:72¾)，熔點 >250"C 分解；UV (水）：273ϋΜ«Πο8ε 5.11), 350mn(loge4.89)； MS(ES)(ra/z)： Η*2 887.9； HW1821.2 〇實例2. 4.4·-零「[fi-二ί3 -防笼某-H.N-雩（2-防申醣某-7，某）磺瞄某亞防某1-1· 3 .Fi-三阱-2-某防某1-二Μ 7.烯-2. -二碏鹼.二納a 在密封之厚壁玻璃舍4,4’-二胺基二笨乙烯-2,2’-二磺酸二納鹽（l,21克，2·92毫莫耳）及2-氯-4,6-二[3-胺苯基-N,N-雙（2-胺甲醣基乙基）-磺醢基亞胺基]-l,3, 5 -三阱（實例6 M4.47克，6,44毫莫耳）於環丁 ftl (70毫升）及二異丙基乙胺（1.5毫升）之懸浮液加溫至115C。繼績加溫40小時。一旦由分析性HPLC(或TLC)測定反應完全，混合物冷卻至3 0 υ ,將1 N N a G Η (6 . 6毫升）加入及藉由添加丙-2-醇（200毫升）沈澱出產物。沈澱物經過溏、以丙酮（30毫升）溏洗及再溶解於最小蓋之水中，藉由添加乙酵再沈澱。過漶後沈澱物以***（30毫升）清洗及在50Τ下真空乾燥。產率4.84克（9U)。 m· s^m ^^^^1 I^^^1 ^^^^1 1 ^^[^1 In nm ^^^^1 ^^^^1 ^^^^1 1. .¾.-旮 (請先閱讀背面之注意事項再填寫本頁) 本纸張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐）經濟部中夹標準局員工消費合作社印繁 A7 B7五、發明説明（19 ) g例3 4.4'-够「4.6-二「3-防笼某-><.><-鰺（？-防甲繭基-7.某）碏醣某亞防某1-1. 3. 5 -三阱-2 -某防某1-二笼Z烯-2.2' -二碏麻.二鈉朗標題化合物使用實例1 一般條件製備，其中使2,4,6-三氟-1,3 ,5-三阱（304毫克，2.25奄莫耳）與4,4’-二胺基二苯乙烯-2,2〜二磺酸（45 5毫克，1.10毫莫耳）反應 1小時，皤後與3 -胺苯基- Ν,Ν -雙（2 -胺甲醯基乙基）磺豳基亞胺（1.45克，4.62毫莫耳）反應（英國專利案第 1,194,38δ號；1970年6月10日），接著純化取得所要化合物（1 · 2 1 克，61 % )。由實例1-3之程序合成的化合物根據HPLC, UV及質譜係為相同。富例4 「4.fi -二防笼某- H.H-等（2-防甲醢某-7』某）碏醢基亞胺基卜1 . 3 . 5-三哄-2-基胺基1_:1.筆-2^2 ’ -二碏_二納》標題化合物根據實例2之程序製備，使用4,4’-二胺基聯苯-2,2夂二磺酸二納鹽（1.02克，2.62毫其耳）及2-氯-4,6-二[3-胺苯基- N，N-雙（2-胺甲釀基乙基）磺醢基亞胺基]-1,3,5-三阱（實例6 )(4.26克，5.76毫莫耳）於 δΟ毫升DMS0-環丁硪（1:3,體積/體積）及二異丙基乙胺 (1.2毫升）中。產物呈無色固體取得（3.90克，833!);熔點 > 2 5 0 t：分解；U V (水）：2 7 2 n m (1 〇 g ε 4 · 8 6 ) ; M S (E S ) -21- I I . ! ph rp ί I I 和衣訂 (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隼（CNS ) Λ4規格（210X297公釐）經濟部中央標準局員工消費合作社印製 A 7 B7五、發明説明（2〇 ) (a/z): Μ·2 874·1; HW1794.2。實.例& 4.4’-簪「4.6-二「3-防笼某-><.>1-替（2-筠71基>礒醣某亞路某1-1. 三阱-2-某肪甚1-二笼7,烯-2.2’-二碏酸. 二納嫌檷題化合物根據用Μ實例2之程序製備，使用4,4’-二胺基二苯乙烯-2,2_-二磺酸（28毫克，0·0 75毫莫耳）及95毫克（0.15毫奠耳）2-氯-4,6-二[3-胺笨基-Ν,Ν-雙 (3-莖乙基）磺醢基亞胺基]-1,3,5-三阱（實例6 )於環丁硯（20毫升）及二異丙丁基胺（35毫升）中在UOt下18小時。冷卻之反應混合物與去離子水（40毫升）混合，而粗產物之溶液藉由製備性RP-HPLC純化。合併含有所要產物之溶離份，在真空UObbIU)及301C下將有機溶劑蒸發，濃縮產物，除Β及經十八基（C18)往（cartridgeHSOO 毫克，取自Burdick & Jackson)單離。該柱Μ水（30毫升）清洗，產物Μ甲酵（50毫升）再萃取。蒸發甲醇取得 1 2毫克（1 U )所要產物；熔點> 2 5 0 t分解；U V (水）： 273nm(loge 4.97), 350nni(loge 4.81)； MS(ES)(m/z) :Η·2 7 79 , 0 ; ΜίΠ604 . 0。富例6 2 -氲4.ft -二「3-胺茏某- N.N -蟹（2-胺甲醸某-7,某）碏iS 某亞防基1-1. 3, 5-三阱 -2〜0C及攪拌下逐滴將三聚氯化氰（4.2克，22.7毫莫耳）於二ϊ|烷（55毫升）之溶液加入磷酸鹽缓街液（120 裝訂 (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 ) Α4規格（210X 297公釐）經濟部中央標準局貝工消費合作社印製 1643 87 9 7 at B7 五、發明説明（21 ) 毫升，0.3M, PH7)及碎冰（10克）中。在3〇分_内將3-胺苯基-Ν,Ν-雙（2-胺甲釀基乙基）磺醣基亞胺# U5.0克， 47.8奄奠耳）（英國專利案第1.194,388; 1970年6月10日）於Ν,Ν-二甲基甲醢胺（125橐升）之溶液逐滴加入所得微细懸浮液中及pH藉由添加1Η KaOH維持在6.5-7.2。再繼續攪拌2.5小時，只一方面藉由分析性1^1^(或7^(：)監控反懕是否完全。一旦由分析性LPLC(或TLC)测定反應完全，混合物冷卻至將水（160毫升）加入及通濾產物沈澱物，以冷水（50奄升），丙酮（50奄升）清洗及在401 下真空乾燥。產率1 4 . 5克（8 6 S；);熔點> 2 5 0 分解：U V (DWSO): 282nm(i〇se4.77); MS(CI>(m/z): MH740.1。當俐7 4-「4.6-二「3-防笼某-><.卜<»(2-腌甲_某乙基）碏鶄某亞腌某=阱-2-某防某1-4’-「4-值-6 -「3-防关甚-Κ·Η-_ 肱田81某7.某）碏雔某亞肪甚-二阱-2-基胺基1-二笼7.锸-2.2'-二碏酴.二納鹽 -3〜OC及攪拌下將三聚氛化氰（205毫克，1.12奄舆耳）於二垮烷U.5牽升）之溶液加入磷酸蘧鑲銜液（10毫升，0 . 3 Μ , p Η 7 )中。將 4 , 4 ’ -二胺基二苯乙烯-2 , 2 ’ -二磺酸二納鹽（225奄克，0.54毫莫耳）於璘酸鹽緩衝液（3 毫升）之溶液加人及pH藉由添加IN HaOH維持在6.5-7.2 。在相同溫度及pH下再繼鑛攪拌1小時，另一方面藉由分析性HPLC(產率97¾)監控反應是否完全。在10分鐘内將3-胺苯基-Η,Η-雙（2-胺甲醣基乙基）磺釀基亞胺（700 -23™ 本紙張尺度適用中國國家標準（CNS ) Λ4規格（21〇κ297公釐） !. n m 1 i 裝 '1τ (請先閎讀背面之注意事項再填寫本頁) 經濟部中夬標隼局員工消費合作社印製 A7 B7五、發明説明（22 ) 毫克，2.23奄奠耳）於N，N-二甲基甲醯胺（10毫升）之溶液加入，將溫度升至6〇υ。在此溫度再繼鑛攪拌3小時及在100-110C下20小時，pH藉由添加IN HaOH維持在 6.6-7.2。一旦由分析性HPLC判定反應完全時，混合物冷卻至20C及M5.6N氫氯酸酸化至pH2,將氯化納（5毫升，4M)加人及過濾產物沈澱物，Μ冷水（2毫升）清洗及在40t：下真空乾燥。二份粗產物（約1克）於去離子水 (250毫升）之溶液分別Μ製備性RP-HPLC純化。合併含有所要產物之溶離份，有機溶劑在真空（1 0 n m H g )及3 0 t下蒸發，及濃縮產物，除鹽及經十八基（C18)柱（900毫克，取自Burdick & Jackson)單離。該柱从水（30毫升）清洗及產物Μ甲醇（50毫升）再萃取。蒸發甲醇取得268毫克 (3 2 所要產物，熔點> 2 5 0 t分解；U V (水）：2 7 3 n m (logs 4.83), 350nai(]〇ge4.44)； MS(ES)(ra/z)： M'2 749.1 5； HW 1 544 . 3 ° 窖例8 4.4夂學「4-氛-6 -「.Ί-脐笼某-N.N -響（2-防申醮某Z某）碏醜某亞防某1-1. 3. 5 -三阱-2 -某防某1-二笼7,烯-2.2’ -二碏酸.二納薷在~3〜01及攬拌下將三聚氛化氰（0.91克，4.95毫舆耳）於二垮烷（8毫升）之溶液加至磷酸醴緩衝液（30毫升，〇.3队0[17)中。將4,4’-二胺基二苯乙烯-2,2'-二磺酸二納鹽（1.00克，2·41毫莫耳）於去離子水（9毫升）之溶液加人，pH藉由添加1Η NaOH維持在6.5-7.2。在相 -24- 裝 . 訂 (請先閱讀背面之注意事項再填寫本頁) 本纸浪尺度適用中國國家標隼（CNS )八4規格（210X297公釐）經濟部中央標隼局員工消費合作社印製 A7 B7五、發明説明（25 ) 同溫度及pH下再繼鑛攪拌1小時，另一方面藉由分析性 HPLC監控反應是否完全（產率98¾)。在10分鐘内將3-胺笨基- Ν,Η-雙（2-胺甲釀基乙基）磺醸基亞胺（1.57克， 5.00毫莫耳）於Ν,Ν-二甲基甲醢胺（25毫升）之溶液加入及將溫度升至50Γ。在此溫度再繼績撹拌6小時，pH藉由添加1((^01{維持在6.6-7.2。一圼藉由分析性1^1^ (或TLC)判定反應完全時，混合物冷卻至0它及以5.6N氫氯酸酸化至PH2,將氯化納（5毫升，4M)加人及過濾產物沈澱，Μ冷水（8毫升）、丙瞌（20毫升}及***（20奄升）清洗及在40t下真空乾燥。產率2.37克（80¾)，熔點 > 3 0 0 1C 分解：U V (水）：2 7 3 n m (1 〇 g ε 4 . 5 7 ) , 3 5 0 ( 1 〇 g e 4,42); MS(ES)(n/z): Μ·2 610.1; MW1266.2。實.―倒』. 4 -「4.6-二「3-防茉某- Ν.Ν -孽（2-胺甲睹某7,某）磋瞄某亞防某1-1 .3.5 -三阱-2-某防某1-4夂「4 -「3-腌茏某-Ν. H -等（2 -胺甲醏某7,某）碏醸某亞防某1-6 -「3-胺采某-H-(2-防甲醏某7.某）-Ν’-(3-丙酸）1-1.3.5 -三阱-2-基胺基1 -二苯乙烯-2, 2 二磺酸.二納盥._ 及啻例1 0 4 -「4.fi -二「3-防茏基- N.N-簪（2-防甲鱅某Z某）碏醏某亞胺基1-1.3.5-三阱-2-某胺某1-4’-「4-「3-胺茏某1. N-簪（2-防申醮某Z某）碥醸某亞防某1-6-「3-防笼某-><. 卜等（3-丙餘）1-1.：；.5-三肼-?-某防某卜二茏又烯-2.2' -二碏酵.二納醻装訂 (請先閱讀^^9之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) Λ4規格（2! Ο X 297公釐）經濟部中央榡準局員工消費合作社印製把43 87 9 7 A7 B7五、發明説明（24 ) 將IN Na0H(300毫升）加人實例1 ( 2 00毫克，0.11毫莫耳）於去離子水（20毫升）之溶液及將混合物加熱至沸瞌。反應混合物保持溫熱3小時，冷卻至OC及K5.6N氫氯酸酸化至ΡΗ2 。將氯化納（10毫升，4Η)加入及過濾產物沈澱，以冷水（2毫升）清洗及在真空與401C下乾燥。藉由製備性RP-HPLC純化粗產物（約180毫克）於蒸餾水（125 毫升）之溶液。合併含所要產物（實例9 )之溶離份，在真空（lOnaUg)及30Τ：下蒸發有機溶劑，濃縮產物、除鹽及經十八基（C18)柱（900毫克，取自Burdick £< Jackson) 單離。該柱以水（30毫升）清洗及產物Μ甲醇（5 0毫升）再萃取。蒸發甲酵取得24毫克（12¾)所要產物，熔點>250 笆分解；UV (水）：273nBn〇ge 5.02), 350nm(loge4.76) ；MS(ES)(m/z)： Μ'2 888.3； MW1822.6° 第二產物（實例10)藉由RP-HPLS-分離自其他含有所要化合物（實例10)之溶離份中單離出，同時使用與實例9 所述相同之濃縮、除鹽及經十八基（C 18)柱單離之程序。產率1 8笔克（9 )，熔點> 2 5 0 t分解，ϋ V (水）2 7 3 n a (logs 4.9 2 ), 350 πβ (1 οε e 4 , 69) ； HS(ES)(i/z)： Η'2 8 8 9 . 2 ; Μ \Π δ 2 4 _ 4。窖例η 4.4’-零「4.6-二「3-防笼某-衫.科-零（2-胺甲随某-7,基）碏腺某亞防某Ί-1. 3. 5-二阱-2-甚防某够节-2.2'-二碏勝.二納嫌氫大氣下實例1 (30毫克）於30毫升水-甲醇（1:1,體 , 1H 1 裝 I-云 (請先閲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 ) Α4規格（210X 297公釐） A7 經濟部中夬標準局員工消費合作枉印裝 B7五、發明説明（25 ) 積/體積）之溶液與鈀/木庚（10¾鈀）一起攪拌5天。過濾反應混合物及蒸發溶劑。產物藉由製備性RP-HPLC單雛。合併含有所要產物之溶離份，在真空（lOminHg)及30 Ό下蒸發有機溶劑及產物經由十八基（C18)柱（300毫克，取自Burdick & Jackson)單離。該柱Μ水（30毫升）清洗及產物Μ甲酵（50毫升）再萃取。蒸發甲醇取得16毫克 (5 0 S；)所要產物；熔點> 2 5 0 1C分解；（J V (水）：2 7 4 η ΙΒ (loge4.96), MS(ES)ti/z)： Μ'2 889.2； MW1824.4- 奮例1 2 4.4、替Γ4.ft-二「4-防笼某- Ν.Ν-替（2-防甲縮某-7.某）碏瞌某亞胺某1-1. 3. 5 -三阱-2 -基胺某1-二笼Ζ锸-2.21 -二磺酸.二納鹽標題化合物根據實例2合成所用之程序製備，使用4, 4’-二胺基二笨乙烯-2,2·-二磺酸（48毫克，0.125毫莫耳）及2-氯-4 ,6-二[4-胺苯基- Κ,Ν-雙（2-胺甲醢基乙基）磺醢基亞胺基]-1,3,5-三阱（實例18>(230毫克，0.310 毫莫耳）於二甲基亞魄（12毫升）及二異丙基乙胺（260奄升）中。產物呈無色固體（173毫克，77¾)取得；熔點 > 2 5 0 υ 分解；U V (水）：2 9 6 n m ( I 〇 s e 4 . 9 4 ) ; ( 1 〇 s e 4 . 5 7 ) ;H S ( E S ) (κι / z ) : r2 8 8 3 . 2 ; M W 1 8 2 2 _ 4。苜例1 .Ί 4.4’-尊U.6 -二「4-防笼某-H荸（2-防甲醣某-乙某）碏醸某亞防某1-1U -三阱-2-某防某1-瞄笼-2.2’-二 -碏除.二納雜裝訂 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中囡國家標準（CNS ) Λ4規格（2〖0Χ 297公釐） A7 B7 經濟部中央標準局員工消費合作社印製1 '_ nn ί I] _. ^ I _ II n —ϋ T (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs The present invention also includes the treatment of viral infections in mammals The method is preferably a human method, which method comprises administering one or more compounds of the present invention and / or one or more compound S drugs to allow salt to infected mammals. Viral infections that can be treated using the compounds and methods of the present invention include those caused by human respiratory syncytial virus, herpes simplex virus, human giant cell virus, and flu influenza virus, particularly those caused by parainfluenza virus 3 . The compounds of the present invention can be administered to any desired method (including intranasal, axillary, topical, transdermal, intestinal, and intraperitoneal) to the required breastfeeding. 14- This paper applies the Chinese National Standard (CXS ) Λ4 specification (210X297mm) 14 3 8 Γ, 'Α7Β7 Printed by the Consumers' Cooperative of the Standards Bureau of the Ministry of Economic Affairs. 5. Description of invention (15). Can understand the treatment of mammals. It is better for humans to require various compounds of active compounds although various courses of treatment. It depends on various factors, including the age, gender, size, general health status and disease degree of a specific individual. Most with therapy. The antiviral effective amount of the compound to be administered here is generally administered daily M—or in multiple doses of about 0.5 mg / kg to about 500 mg / kg based on the weight of the animal. These doses are preferably administered two to four times a day in divided doses or in a sustained release form. For most large mammals, the total daily dose is from about 1 to 100 mg, preferably from about 2 to 80 mg. A dosage form suitable for the internal eye contains about 0.5 to 500 grams of the active compound directly mixed with a solid or liquid drug carrier. This dose of therapy can be adjusted to provide the best therapeutic response. For example, several divided doses may be administered each day or the dose may be proportionally reduced according to the urgent need of the therapeutic situation. The compounds of the invention may be administered with or without other antiviral agents. The present invention also includes a road medicine composition that can be used in these treatment methods. The osmium composition may include one or more compounds of the present invention. Or its κ 容许 allows a, and one or more 槩槩 allowable carriers, diluents, excipients, fillers, binders, flavoring agents, and the like. For oral and oral administration, compounds containing the composition of the invention include solid or liquid compositions such as capsules, troches, dragees, pills, tablets, powders, cultures, solutions, suspensions and emulsions . The solid form may be encapsulated by hard or soft gelatin capsules and may contain commonly used peony allowable excipients, fillers, adjuvants, diluents, lubricants, disintegrating agents, suspensions or stabilizers and binding agents, including, But not limited to magnesium stearate, sodium lauryl sulfate, microcrystalline cellulose, polyvinylpyrrolidine, gelatin, full acid, arabic-15-i ^ in ^----n I. M · 1 1 —r m3., -0 (Please read the notes on the back before filling in this page) This paper size is applicable to China National Standard (C'NS) A4 specification (2〗 0 '乂 297mm; i) it Λ A7 B7 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the invention (14) 1 i Gelatin m sodium acid, composite silicic acid m \ calcium carbonate Λ glycine dextrin Λ 1 i I sucrose sorbic acid phosphate Calcium m Dicalcium acid% Calcium sulfate% Sugar Λ 1 1 Kaolin \ Glycol Sugar Alcohol Nanotalc Λ Dry starch (such as corn, please first 1 sweet potato or cassava starch) and gluten flour 0K can also include antioxidants Dimensional reading 1 1 Biotin E > Ascorbic acid BHT and BHA 〇 Such a preparation may contain a back 1 I 1 There are, for example, i from about 0.05 to about 90 ¾ Active ingredient and carrier combination J More preferably 1 I often Between about 5¾ and 60¾ by weight ΰ Matter 1 1 Liquid α Eye m Suitable excipients include diluent such as water t and drunk. Fill in this pack of ethanol benzyl alcohol and polyethylene glycol% with or without Surfactant Λ Suspension page 1 I agent or emulsifier 0 Suspension can be prepared in glycerol Ή liquid polyethylene glycol and its M compound in oil 1 1 Under normal storage and use conditions »These systems 1 1 agent contains a protection agent M to prevent the growth of microorganisms. The compounds of the present invention can also be diluted at physiologically acceptable levels such as sterile liquids or 1 mixtures thereof (including water · »salt water Λ aqueous dextrose and other Hair volume 1 I solution) Fermentation such as acetogenic isopropanol or ten >-Fermentation secondary fermentation such as malonyl m 1 1 or polyethylene glycol glycerol shrinkage such as 2, 2-dimethyl-1,3 _ _ 2. Pentamidine-4- 1 1 Methanol »Ethers such as poly (ethylene glycol) 400 strong drugs allow oils and fats I fatty acids m or glycerol m with or without added sleep drugs to allow surfactants such as I Sodium or acetamated acetylated fatty acid glyceride suspending agent if gum Λ! 1 carb omers, methyl cellulose, hydroxypropyl methyl cellulose or carboxymethyl cellulose I vitamin Λ emulsifier or medicine Adjuvants 〇 In all cases, the I dosage form must be free of 1 I bacteria and must be liquid to make the syringe easy to handle. ○ Stable and manufactured under the condition of 1 1 pieces and must be protected from contamination by microorganisms such as bacteria and fungi 1 I Function 0 1 1 -16- i I 1 1 This paper size is applicable to China National Standard (CNS) Α4 specification (2! 0 X 297 mm) «243 87 97 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Suiji V. Description of invention (15) 1 t m valid for use in the formula 蕖 Allowed oils include their g oil Λ 1 ί I Animals, plants or synthetics * Including peanut oil, soybean oil, sesame oil, t 1 cottonseed oil, olive oil > sunflower oil stone fat and rock oil. Please use 1! Fatty acids include oleic acid, stearic acid and isostearic acid r It is useful for this purpose. 1 Anti-acid m includes ethyl oleate and isopropyl myristate. Soaps used include 1 i 1 fatty acid alkali ammonium ammonium and triethanolamine salts. Acceptable cleaning Agents include Xuan I cationic detergent% such as dimethyl diammonium ammonium halide and aminyl pyridine. | Halides and amine acetates and anionic detergents such as alkylaryl and olefins. Sulfonic Acids »Alkyl Hydrocarbons, Ethers and Monoglycerides Youku sulphate and sulfonate, _- · 1 i succinic acid m 0 useful non-anionic cleansing agents may include fatty amine oxides \ il > fatty acid alkalase fermentation amines and polyoxyethylene polypropylene copolymerization Item 0 Amphoteric 1! Detergents may include alkyl-β-amino propionate and 2-alkylimidazoline quaternary salts and mixtures thereof. The parenteral composition of the present invention preferably contains about 0.5. To about 2 5¾ weight ratio 1 1 of the illustrated compound in solution 0 sterile injectable solution or suspension form 1 The parenteral formula of formula I contains about 0.052 to about 5¾ suspension agent in isotonic media 1 1 Medium is also better. Yuanyuan solution and M-retaining agent can be added. Suitable surfactants can also be added. These surfactants can include polyethylene sorbitan fatty acids as cool as sorbitan monooleic acid m. Polymers of epoxy resin and hydrophobic base i 1 The adducts are formed by the condensation of glycerol and malonase. The peony compositions of the present invention also include their use for topical and transdermal administration. I. These formulations may include compounds of the present invention in Dermal administration in a solvent system that enhances transdermal absorption 1 1 (including acetic acid or dimethylarylene f with or without other excipients 1 | vehicle) 0 is preferably a topical and transdermal composition here Package 1 I -1 7- 1 1 1 1 This paper size applies the Chinese National Standard (CTNS) Λ4 specification (210X29 * 7 mm) B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (ib) I 1 Contains the compound of the present invention added to the tank and porous membrane type cloth or 1 1 solid matrix type of patch 0 These types of transdermal patches are described in the United States 1 | National Patent Case 3, 7 4 2 , 9 5 1 '3, 7 9 7, 4 94 3, 9 9 6, 93 4, 4, 〇3 1, 894 / — »Please 1 I 4, 5 7 3, 996 and 4, 9 5 6, 1 7 1 Read 0 1 Read t 1 The internal formula of the present invention and administration can be in the form of intranasal drops or internal sprays such as 1 on the back 1 Inhalation_administration 0 The formula may include any combination of medicinal permissible ingredients for intraoral administration > including sterile aqueous saline stabilizers such as molecular weight matters 1 I re 1 ranging from about 20G to about 7 5 0 0 Polyethylene glycol or mixtures thereof. It is suggested that the compounds of the present invention can be used to prevent or treat the virus in the form of a virus. The dye can be used for prevention. 5 The compound can be sprayed or sprayed within 1 1 to prevent the virus. RS V exposure. Length of treatment period response 1 I Signs of specific viral agent infection and risk factors that can be expressed by epidemic and pending patients 1 1 〇 Compounds transmitted in these ways at a concentration of 0.1 1 but 1 to 3 Between 0 mg / ml 1 The transferred volume is between 0.1 and 1 ml / 1 I Nostril 0% i The compound tree can be made gold by P administration or intravenous administration 1 1 body pass for treatment * The compound can be delivered locally to the lungs as an aerosol 1 1 or can be delivered systemically by administering or intravenously. Such administration can be performed within the time period required to control virus I iJs infection. 1 The present invention The compound can be further prepared by the following non-limiting example 1 | Example 〇 Propane-2-ol-acetic acid-4¾ ammonia in water (8: 1: 1 Γ | volume / volume) as a solution m by silicon Thin layer chromatography (TLC} 1 1 and reversed-phase high performance liquid chromatography (RP-HP LC) on coagulum [column: V yd ac C 18 II (4.6 mm X 2 5 Cl), 5 ia m 9 mobile phase A-acetonitrile, B- 0.1 M ammonium acetate 1 1 I in water (PH5 • 5) 'C-formazan; gradient: from mixture A -B 1 1 -1 8-1 within 10 minutes 1 1 1 This paper size applies the Chinese National Standard {CNS) A4 (210 X 297 mm) A7 B7 V. Description of the invention (17) -C (20: 6 5: 1 5, volume / volume) to the mixture ABC ( 2 0:55: Please read the precautions of it and then fill in. · Page 2 5, Volume / Volume)] Preparative RF-Η PLC is performed in Rain U gradient Η PLC system, using Vydac C18 呔 / protein Preparative column (10 mb, 2 2 mb X 2 5 cm); mobile phase: A-methanol-0, 1 M acetic acid In water (ΡΗ5.5) (1: 4, v / v) Beta-methanol - acetonitrile (1: 4, v / v); Gradient: 18-32ΧΒ in 10 minutes. Example 1 4.4'- 萼 "4.6-Di" 3-Amine, U-Etc. (2 -Antimethylamidine), Ether, Imine, 1-1.2.5-Tri 11 # -2-Amine 1_ER cage 7, ene-factory; > 'Erqianzhen will be cyanuric chloride (3.87 g ^ 21 millimoles) at -3-0C in the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs The solution of indocyanin (25 ml) was added to a phosphate buffer solution (100 ml, 0.3M, P7), stirred with K, and then 4,4'-diaminodibenzyl ethylene was dissolved in 20 minutes- 2,2'-Disulfonic acid (3.70 g, 10 mmol) was added to a solution of 1Η HaOH (20 ml), and the pH was maintained between 6.5 and 7.2 by adding IN NaOH. The stirring was continued at the same temperature and pH 1 hour, while monitoring the completion of the reaction by analytical HPLC (yield 95¾). The 3-aminophenyl-N, N-bis (2-aminomethylmethylethyl) sulfonylimine (13.20 g, 42 mol) (British Case No. 1,194,388; June 10, 1970) Add dimethyl iodide (DHS0M 100ml) to the solution and raise the temperature to 501C. Following stirring for 2,5 hours, followed by stirring at 100-110 for 40 hours, the pH was adjusted by The addition of IN NaOH is maintained at 6.6_7.2. Once the reaction is determined by analytical HPLC (or TLC), the mixture is cooled to 20C and acidified to pH 2 with 5.6N hydrochloric acid. Ambient Na-19- This paper size applies to China Standard (CNS) Λ4 specification (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs * = 43 8 7 9 7 A7 B7 V. Description of the invention (18) (60 ml, 4M) Addition and overdose precipitation products. Redissolved in the smallest volume of water by adding IN NaOH to pH 7, and reprecipitated by adding sodium hydroxide. The precipitate was filtered, cold water (20 ml), propan-2-enzyme (40 ml), and propane SB ( 60 ml) was washed and dried under vacuum and 50 °. Yield 13.0 g (: 72¾), melting point > 250 " C decomposition; UV (water): 273ϋM «Πο8ε 5.11), 350mn (loge4.89); MS (ES) (ra / z): Η * 2 887.9; HW1821.2 〇 Example 2. 4.4 · -zero "[fi- 二 ί3-Anti-cage-HN- 雩 (2-Anti-sugar--7, A) Sulfur 1-1, 3, Fi-triple-2--1, 1-diM 7.ene-2. -Dioxine. Dina a in sealed thick-walled glass house 4 , 4'-diaminodibenzyl-2,2'-disulfonic acid di Sodium salt (1.21 g, 2.92 mmol) and 2-chloro-4,6-di [3-aminophenyl-N, N-bis (2-aminomethylmethylethyl) -sulfonium Imino] -l, 3,5 -triplet (Example 6 M4.47 g, 6,44 mmol) suspended in cyclobutane ftl (70 ml) and diisopropylethylamine (1.5 ml) The solution was warmed to 115C. Following the warm up of 40 hours. Once the reaction was complete by analytical HPLC (or TLC), the mixture was cooled to 30 υ, 1 N Na G a (6.6 mL) was added and the product was precipitated by adding propan-2-ol (200 mL). The precipitate was washed with 溏, washed with acetone (30 ml) and redissolved in the water with the smallest cover, and reprecipitated by adding acetic acid. After washing, the precipitate was washed with ether (30 ml) and dried under vacuum at 50T. Yield: 4.84 g (9U). m · s ^ m ^^^^ 1 I ^^^ 1 ^^^^ 1 1 ^^ [^ 1 In nm ^^^^ 1 ^^^^ 1 ^^^^ 1 1. .¾.- 旮(Please read the precautions on the back before filling out this page) This paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) Employees ’Cooperatives of the China National Standards Administration Bureau of the Ministry of Economic Affairs Printing and Printing Co. A7 B7 V. Description of the invention ( 19) g example 3 4.4'-enough "4.6-two" 3-anti-cage->-<. &Gt; <-鲹 (? -Cocoonyl-7.some) -1. 3-5-Triple well-2-Some anti- 1-2 cage Zene-2.2 '-Diramie. The disodium title compound was prepared using the general conditions of Example 1, in which 2,4,6-tri Fluoride-1,3,5-triple (304 mg, 2.25 mol) with 4,4'-diaminostilbene-2,2 ~ disulfonic acid (45 5 mg, 1.10 mmol) After 1 hour, it was reacted with 3-aminophenyl-N, N-bis (2-aminomethylmethylethyl) sulfonylimine (1.45 g, 4.62 mmol) after 1 hour (UK Patent No. 1,194,38δ No .; June 10, 1970), followed by purification to obtain the desired compound (1.21 g, 61%). The compounds synthesized by the procedures of Examples 1-3 were the same according to HPLC, UV and mass spectrometry. Rich Example 4 " 4.fi- Two anti-cages-HH-etc. (2-antimethanyl-7-7) Some fluorenimines 1. 3. 5-trioxan-2-ylamino 1_: 1.pen-2 ^ 2 '-Difluorene_dina "The title compound was prepared according to the procedure of Example 2, using 4,4'-diaminobiphenyl-2,2 disulfonic acid dina salt (1.02 g, 2.62 micheles) and 2 -Chloro-4,6-bis [3-aminophenyl-N, N-bis (2-aminomethylethyl) sulfoamidoimino] -1,3,5-triple (Example 6) (4.26 g, 5.76 mmol) in δ0 ml DMS0-cyclobutane (1: 3, v / v) and diisopropylethylamine (1.2 ml). The product was obtained as a colorless solid (3.90 g, 833! ); Melting point > 2 5 0 t: decomposition; UV (water): 2 7 2 nm (10 g ε 4 · 8 6); MS (ES) -21- II.! Ph rp II and clothing staple ( Please read the notes on the back before filling in this page) This paper size is applicable to the Chinese National Standard (CNS) Λ4 specification (210X297 mm) Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A 7 B7 V. Invention Description (2) ) (a / z): Μ · 2 874 · 1; HW1794.2. Real examples & 4.4'- 簪「4.6- 二」 3-Anti-cage->-> -筠 71 基 > A certain sugar, a certain 1-1, a triple well, a certain fat, a 1-two cage, a 7-ene-2.2'-dicarboxylic acid. A dinazine compound was prepared according to the procedure of Example 2, using 4, 4'-Diaminostilbene-2,2_-disulfonic acid (28 mg, 0.075 mmol) and 95 mg (0.15 mmol) 2-chloro-4,6-bis [3- Aminobenzyl-N, N-bis (3-stemethyl) sulfonamidoimino] -1,3,5-triple (Example 6) in cyclobutane (20 mL) and diisopropylbutylamine (35 ml) at UOt for 18 hours. The cooled reaction mixture was mixed with deionized water (40 mL), and a solution of the crude product was purified by preparative RP-HPLC. The dissolved fractions containing the desired product were combined, and the organic solvent was evaporated under vacuum UObbIU) and 301C, and the product was concentrated, except for B and isolated via C18, (cartridgeHSOO mg, taken from Burdick & Jackson). The column was washed with water (30 ml), and the product M formate (50 ml) was re-extracted. Methanol was evaporated to obtain 12 mg (1 U) of the desired product; melting point > 2 50 t decomposition; UV (water): 273nm (loge 4.97), 350nni (loge 4.81); MS (ES) (m / z): Η · 2 7 79, 0; ΜίΠ604. 0.富例 6 2-氲 4.ft -Di "3-Amine"-NN-Crab (2-Amine form -7-Some) 碏 iS Some sub-defense group 1-1. 3, 5-Tritrap- Add cyanuric chloride (4.2 g, 22.7 mmol) in dioxane (55 ml) dropwise to the phosphate buffer solution (120 binding with 2 ~ 0C and stirring) (Please read the note on the back first) Please fill in this page again for this matter) This paper size applies Chinese National Standard (CNS) Α4 size (210X 297 mm) Printed by the Central Standards Bureau of the Ministry of Economy, Shellfish Consumer Cooperative, 1643 87 9 7 at B7 V. Description of invention (21) ml, 0.3M, PH7) and crushed ice (10 g). 3-aminophenyl-N, N-bis (2-aminomethylethyl) sulfosylimine # U5 within 30 minutes. 0 g, 47.8 moles) (British Patent No. 1.194,388; June 10, 1970) A solution of N, N-dimethylformamide (125 ml) was added dropwise to the resulting fine suspension And the pH was maintained at 6.5-7.2 by adding 1Η KaOH. Stirring was continued for 2.5 hours, only one side was monitored for analytical completeness by analytical 1 ^ 1 ^ (or 7 ^ (:). Once by analytical LPLC (or TLC) The reaction was determined to be complete and the mixture was cooled to Liter) was added and filtered through the product precipitate, washed with cold water (50 liters), acetone (50 liters) and dried under vacuum at 401. Yield 14.5 g (8 6 S;); melting point> 2 5 0 Decomposition: UV (DWSO): 282nm (iose 4.77); MS (CI > (m / z): MH740.1. Dangli 7 4- "4.6-II" 3-Anti-cage-> < .bu < »(2- pickled methyl_some ethyl) 碏鶄 some sub pickled = well-2-some prevent some 1-4 '-" 4-value-6-"3-proof off even- Κ · Η-_ Hutian 81, 7. 7.) A certain sub-fat-ditrap-2-ylamino 1-di cage 7. 7.-2.2'-difluorene. Di-naline-3 ~ OC A solution of trimeric cyanide (205 mg, 1.12 milliliters) in dipentane U.5 was added with stirring to a phosphoric acid phosphate solution (10 ml, 0.3 Μ, p Η 7). .Add a solution of 4, 4'-diaminostilbene-2, 2'-disulfonic acid di-nano salt (225 g, 0.54 mmol) in a phosphonate buffer solution (3 ml) and The pH was maintained at 6.5-7.2 by the addition of IN HaOH. At the same temperature and pH, the ore was stirred for another 1 hour. On the other hand, the reaction was monitored for completion by analytical HPLC (yield 97¾). Aminophenyl-fluorene, fluorene-bis 2-Aminosylethyl) Sulfoimine (700 -23 ™) This paper size applies to Chinese National Standard (CNS) Λ4 specification (21〇κ297 mm) !. nm 1 i Pack '1τ (please first (Please read the notes on the back and fill in this page again.) A7 B7 printed by the Consumers' Cooperative of the Ministry of Economic Affairs of the Bureau of Standards and Administration of the People's Republic of China. 5. Description of the invention (22) mg, 2.23 mg) in N, N-dimethylformamide ( 10 ml) solution was added and the temperature was raised to 60. After stirring at this temperature for 3 hours and 20 hours at 100-110C, the pH was maintained at 6.6-7.2 by adding IN HaOH. Once the reaction was determined to be complete by analytical HPLC, the mixture was cooled to 20C and M5.6N hydrochloric acid was acidified to pH 2, sodium chloride (5 ml, 4M) was added and the product precipitate was filtered, and washed with cold water (2 ml) And dried under vacuum at 40t. Two portions of the crude product (about 1 g) in deionized water (250 ml) were purified by preparative RP-HPLC. The fractions containing the desired product were combined, the organic solvent was evaporated under vacuum (10 nm H g) and 30 t, and the product was concentrated, desalted and passed through an octadecyl (C18) column (900 mg, from Burdick & Jackson) left alone. The column was washed with water (30 ml) and the product M methanol (50 ml) was re-extracted. Methanol was evaporated to obtain 268 mg (3 2 desired product, melting point> 2 50 t decomposition; UV (water): 2 7 3 nm (logs 4.83), 350nai (] 〇ge4.44); MS (ES) (ra / z): M'2 749.1 5; HW 1 544. 3 ° Cellar Example 8 4.4 "Learning-4- mood-6-". Ί-umbilical cage-NN-ringing (2- anti-send Z) * Ugly certain Asian defense 1-1. 3. 5-Triple well-2-Some defense 1-2 cage 7, ene-2.2 '-diacetic acid. Di-nantamidine will be mixed in ~ 3 ~ 01 and mixed. A solution of polycyanated cyanide (0.91 g, 4.95 mmol) in dibutane (8 ml) was added to the gadolinium phosphate buffer (30 ml, 0.3 team 0 [17). 4,4'-two Amino stilbene-2,2'-disulfonic acid disodium salt (1.00 g, 2.41 mmol) was added to a solution of deionized water (9 ml), and the pH was maintained at 6.5 by adding 1Η NaOH -7.2. At the -24-pack. Order (please read the notes on the back before filling in this page) The paper scale is applicable to China National Standards (CNS) 8-4 specifications (210X297 mm) Central Bureau of Standards, Ministry of Economic Affairs Printed by employee consumer cooperative A7 B7 V. Description of invention (25) Stirring for another hour at the same temperature and pH, on the other hand monitored by analytical HPLC Should it be complete (yield 98¾). 3-Aminobenzyl-N, fluorene-bis (2-aminomethylethyl) sulfoamidoimide (1.57 g, 5.00 mmol) is added to the product within 10 minutes. A solution of Ν, Ν-dimethylformamide (25 ml) was added and the temperature was raised to 50 °. At this temperature, stirring was continued for another 6 hours, and the pH was maintained by adding 1 ((^ 01 {maintained at 6.6-7.2. Once the reaction was judged to be complete by analytical 1 ^ 1 ^ (or TLC), the mixture was cooled to 0 and acidified to pH 2 with 5.6N hydrochloric acid. Sodium chloride (5ml, 4M) was added and the product was filtered. The precipitate was washed with cold water (8 ml), propane (20 ml) and ether (20 ml) and dried under vacuum at 40 t. Yield 2.37 g (80¾), melting point> 3 0 0 1C Decomposition: UV (water ): 2 7 3 nm (10 g ε 4.5 7), 3 50 (10 ge 4, 42); MS (ES) (n / z): M · 2 610.1; MW1266.2. Real. ―Down‖. 4-"4.6- 二" 3-Fang Mo-Ν.Ν-Nie (2-amine methylamine 7, 7,) Aiming at a certain Asian defense 1-1.3.5-Mitsui-2- Something 1-4 夂 4-"3-pickled 茏 -N. H-etc. (2 -Amine 醏醏 7 ,,) H- (2-Protection of a certain 7. Some) -N'- (3-propionic acid) 1-1.3.5 -Tritrap-2-ylamino 1-stilbene-2, 2 disulfonic acid. Di-naphthalene. And Example 1 0 4-"4.fi- Two "3-antipyridinyl group-NN-2- (2-antipyridine, Z, and so on), a certain imino group, 1-1.3.5, a triple well, a certain amine, and a 1-4 '-" 4- " 3-amine 茏 1. N- 簪 (2- defense application 醮 Z 碥醸) 碥醸 Asian defense 1-6- "3- anti-cage-> <. Bu etc. (3-propyl) 1-1.:; .5-trihydrazine-?-Some anti-dioxin-2.2'-dihydrazine. Diazine binding (please read the precautions of ^^ 9 before filling this page) This paper size applies the Chinese National Standard (CNS) Λ4 specification (2! 〇 X 297 mm) Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 43 87 9 7 A7 B7 V. Description of the invention (24) IN Na0H ( 300 ml) was added a solution of Example 1 (200 mg, 0.11 mmol) in deionized water (20 ml) and the mixture was heated to boiling. The reaction mixture was kept warm for 3 hours, cooled to OC and K5.6N hydrochloric acid was acidified to pH2. Sodium chloride (10 ml, 4 Torr) was added and the product precipitated, filtered, washed with cold water (2 ml) and dried under vacuum at 401C. A solution of the crude product (about 180 mg) in distilled water (125 ml) was purified by preparative RP-HPLC. The dissolved fractions containing the desired product (Example 9) were combined, the organic solvent was evaporated under vacuum (10 OnUg) and 30T: the product was concentrated, desalted and passed through a C18 column (900 mg, from Burdick £ < Jackson ) Single. The column was washed with water (30 ml) and the product M methanol (50 ml) was re-extracted. Evaporate formazan to obtain 24 mg (12¾) of the desired product, melting point> 250 bar decomposition; UV (water): 273nBnoge 5.02), 350nm (loge4.76); MS (ES) (m / z): Μ'2 888.3; MW1822.6 ° The second product (Example 10) was isolated by RP-HPLS- from other solvents containing the desired compound (Example 10), and the same concentration and salt removal as described in Example 9 were used. And the procedure of single detachment through the 18 base (C 18) column. Yield 18 grams (9), melting point > 2 5 0 t decomposition, ϋ V (water) 2 7 3 na (logs 4.9 2), 350 πβ (1 εε 4, 69); HS (ES) ( i / z): Η'2 8 8 9. 2; M \ Π δ 2 4 _ 4. Cellar example η 4.4'-zero "4.6-two" 3-anti-cage-shirt. Section-zero (2-aminomethyl with -7, base) yam gland a certain defense-1. 3. 5-two Trap-2-Even if you have enough knots -2.2'-dioxin. Example 2 (30mg) in the presence of hydrogen in 30ml of water-methanol (1: 1, body, 1H 1) I-cloud (please (Please read the notes on the back before filling this page) This paper size is applicable to Chinese National Standards (CNS) A4 specifications (210X 297 mm) A7 Consumer cooperation of the China Standards Bureau of the Ministry of Economic Affairs, printed B7 V. Invention Description (25) Volume / volume) solution was stirred with palladium / wooden (10 ¾ palladium) for 5 days. The reaction mixture was filtered and the solvent was evaporated. The product was passed through a preparative RP-HPLC single fraction. ) And the organic solvent evaporated at 30 ° C. and the product were separated through an octadecyl (C18) column (300 mg, taken from Burdick & Jackson). The column was washed with water (30 ml) and the product was formazan (50 ml). Re-extract. Evaporate methanol to obtain 16 mg (50 S;) of the desired product; melting point > 2 50 0 1C decomposition; (JV (water): 2 7 4 η IB (loge4.96), MS (ES) ti / z ): Μ'2 889.2 MW1824.4- Fen Case 1 2 4.4, Substitute Γ4.ft- 二「4-Anti-cage-N.N-Substitute (2-Anti-aminium--7..a.) 碏瞌 Imine-1.1-1. 3.5-Triwell-2 -ylamine 1-di cage ZY-2.21 -disulfonic acid. The title compound of dinaline salt was prepared according to the procedure used in the synthesis of Example 2, using 4, 4'-diamine dibenzyl. Ethylene-2,2 · -disulfonic acid (48 mg, 0.125 mmol) and 2-chloro-4,6-di [4-aminophenyl-K, N-bis (2-aminemethylethyl) ) Sulfonylimino] -1,3,5-Tritrap (Example 18) (230 mg, 0.310 mmol) in dimethyl sulfoxide (12 ml) and diisopropylethylamine (260 奄Liter). The product was obtained as a colorless solid (173 mg, 77¾); melting point > 2 50 υ decomposition; UV (water): 296 nm (10se 4.94); (10se 4. 5 7); HS (ES) (κι / z): r2 8 8 3. 2; MW 1 8 2 2 _ 4. Case of alfalfa 1.. H 荸 (2-antimethylose-B) 亚 Yaya 1-1U -Three wells-2-Aya-1-Sighting cage-2.2'-Two-Erase. Two-nano binding (please (Please read the notes on the back before filling in this page) Standard (CNS) Λ4 specification (2 〖0Χ 297 mm) A7 B7 Ministry of Economic Affairs Bureau of Standards staff printed consumer cooperatives

五、發明説明（2fci ) 標題化合物根據實例2合成所用之程序製備，使用4, 4’-二胺基_苯-2,2’-二磺酸，二鈉籩（113毫克，0.33 毫莫耳）及2 -氯-4,6 -二[4 -胺苯基-H,N -雙（2 -胺甲醢基乙基）磺醯基亞胺基]-1,3,5-三畊（實例18)(535毫克， 0.72毫莫耳）於25毫升DHSO -環丁 fiS (2:3，體積/體積）及二異丙基乙胺（350毫升）中。產物呈無色固體（450毫克，7 6 取得；熔點> 2 5 0 Γ分解；U V (水> :2 9 6 n b (丨〇 g e 5.13); MS(ES)(m/z): r2 874.4; MW1794.8。窖俐1 4 2-氲-4.β -二（‘V-碏醸防甚（Sulfoamido )笼防某）-1 . 3 5 -三哄 -2〜〇υ及攬拌下將三聚氨化氰（2.37克，12,9毫莫耳）於丙嗣（25毫升）之溶液逐滴加至隣酸鹽媛衝液（60毫升， 0.3Μ, ρΗ7)中。在20分鐘内將對一磺胺（4.35克，25.3 毫其耳）於丙酮（30毫升）之溶液逐滴加入所得微细懸浮液中，pH藉由添加IN NaOH維持在6.5-7,2〇再持鑛搅捽 30分鐘（OP, ρΗ7.0)^將溫度升至55C。再持續攪拌3 小時，另一方面藉由分析性HPLC(或TLC)監控反應是否完全。一旦由分析性HPLC(或TLC)判定反麽完全，混合物冷卻至01C,將水（100奄升）加入及過濾產物沈毅，以冷水（50毫升）清洗，逋器上乾燥及藉由溶解於熱丙嗣 (40毫升）中，Κ苯（150毫升）沈澱純化。產物經過漶，以丙-2-酵（20毫升）及***（30毫升）清洗，在30¾下真空乾燥。產率，3.72克（6U);熔點>250它分解；DV ^^^1 .^^^1 ^^^1 ^^^1 In ϋ— n t n m nn 1.^1. l" i-39 (請先鬩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 ) Λ4規格（210 X 29 7公釐）經濟部中央標準局員工消費合作社印袋 A7 B7 五、發明説明（W ) { N e Ο Η } : 2 7 7 ηι ( 1 o g £ 4.68); CI{ES)(i/z): MH456.0o 宽盤丄5 4 , 4 ' - 「4,5 -二「3-胺 M fl安某(suluhonvlaniido)] - 1 . 3 . ϋ -三哄-2 -某胺某]-二茉乙烯-2 . 2 '-二磋酴.…二納鹽標題化合物根據製備實例2所用程序製備，使用4,4' -二胺基二苯乙烯- -二磺酸，二鈉鹽（216毫克，0·52 毫莫耳）及2-氨-4 ,6-二（3'-礒醯胺基苯胺基）-1,3,5-三阱（實例1 4 ) ( 5 2 4毫克，〗 U毫莫耳）於環丁硯（1 5毫升）及二異丙基乙胺（2 5 0毫升）中，及在1 1 5 °C下4 ϋ小時。冷卽至2 (TC後，反應混合物以乙_( 1 0 I)毫升）稀釋及將1 Ν MaOH( 2. 08毫升）加人。離心後，殘渣與丙-2-醇（50毫升）一起攪拌直至結晶完全。固體經離心，以甲醇（2 X .3 0毫升）及***（2X30毫升）清洗，在30°C下真空乾燥。産率 (570 毫克，923i);熔點 >25Q°C 分解；UV(水）：273nm (1 〇 g £ 4.7 6 ), 350niro(log£ 4 . 5 2 ) 〇啻例lfi 4,4’-雙「4. 6 -二「3~胺笨基措酿基亞胺甚(sulphnnvlimido)l -1,3,5-三阱-2-基胺基聪苯-2,二磺酸，二納镧標題化合物根據製備實例2所用之程序製備，使用4, 4'-二胺基聯苯基-2, 2'-二磺酸（208毫克，ϋ. 60毫莫耳）及2 -氱-4，6 -二（3 '-磺醯胺基苯胺基）-1，3，5 -三阱（實例 ]4 ) ( ti (Π毫克，1 . 3 3毫莫耳）於環丁砵（2 0毫升）及二異丙基乙胺（8 5 0毫升）中及在1 1 5 °C下4 0小時。冷卻至2 Q°C後，反應混合物以乙醅U 5 0毫升）稀釋及將1 N N a 0 fi ( 2 . 4 0 -2 9- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公釐） - ^^^1 nt i^i ^^^1 1^1 ^^^1 ^^^1 nt (請先閲讀背面之注意事項再填寫本頁) 陛43 87 9 7 A7 B7 五、發明説明（28 ) 毫升）加入。離心後，殘渣輿丙-2-酵（50毫升）一起攪拌直至結晶完全。固體經雕心.Μ甲酵（4 0毫升）及***（2 X 2 0毫升）濟洗，在3 0 t：下真空乾燥。產率（5 0 5毫克， 7 2 3；);熔點 > 2 5 0 Γ 分解；IH (水）：2 7 6 n m ( 1 〇 s e 4 . 9 3 )。 g例1 7 4.4'-二筠某黼茉-2.2'-二確酪將碳酸納（8.6毫升，1.5M)溶液加入4,4’-二胺基聯苯 -2,2'-二磺酸（4.44克，12.9毫箕耳）於水（20毫升）之懸浮液中並加溫直至取得透明溶液。冷卻至51C後，將亞硝酸納（1.78克，12.9毫其耳）於水（3毫升）之溶液加入此溶液中。-5〜-21C及携拌下將所得溶液逐滴加入濃硫酸（3.8毫升）於水（13毫升）之溶液及碎冰（10克）中。再繼鳙攪拌30分鐘及將反應混合物加溫至65TC。維持溫度至氮放出。混合物冷卻至IOC及Μ無水碳酸納中和，蒸發溶液至殘渣。殘渣在5 0 下真空乾燥，與乙醇（2 2 5毫升）混合及過滅。蒸發滹液及在真空與40Ό下乾燥。產率 3 . 8 8 ( 8 7 S；)。熔點 > 2 5 0 13 分解；U V ( 0 . 0 5 N N a 0 Η ) : 2 5 0 η祖（loge 4.16), 311nm(loge 3,40); MS(ES)(b/z): (H-H)·1 345,0; MW346.0。經濟部中央標準局員工消費合作社印製裝訂 (請先閱讀背面之注意事項再填寫本頁) 窖例1 8 2-氩-4 . 6-二「4-胺苯基-N . 基二乙..基.)1滕某亞胺基1-〗.3. 5 -三阱標題化合物根據製備實例6所用之程序製備，使用4-胺苯基-N,H-雙（胺甲醢基乙基）磺豳基亞胺（3,3克，本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐） 4 ? 8 7 ρ ^ Α7 Β7 五、發明説明（29 ) 10,5毫奠耳）（英_專利第1,194,388號；1970年6月10日）及三聚氛化鎮（1.0克，5.4毫莫耳產物圼無色固體 (3,5克，88!1!3；)取得；熔點>2501^分解；0(0»^0):30 3 nm ( log e 4.84)； MS ( C I) ( m/z) : Μ Η 740 · 1。富锎1 9 Α 「4.6 -二「3-胺茏某- M.H -訾（2 -防申餡碑-乙y) 碏醣某亞胺基1-1.3 ,5-三肼-2-某氣基]-聪笼-2.；>，-二碴酴.二纳鹽在密封之厚壁玻璃管中將4,4'-羥基勝苯-2,2·-二換酸（實例17)(131毫克，0.34毫莫耳）及2-氯-4,6-二[3-胺笨基- 雙（2-胺甲醢基乙基）磺醢基亞胺基]-i,3, 5-三阱（實例6 >(550毫克，0,74毫莫耳）於環丁蜞-Ν,Ν-二甲基甲醢胺（15¾升，2:1體積/體積）及Na〇H(lH, 1.48毫升）之懸浮液加潙至115¾。再持績加溫50小時。經濟部中夹標準局員工消費合作社印繫 1· ^^^1 ^^^1 ^^^1 ^^^1 ^^^1 TJ (.請先閲讀背面之注意事項再填寫本頁) —旦藉由分析性HPLC(或TLC)判定反應完全，混合物冷卻至20 t：及產物藉由添加丙-2-酵（7 0毫升）沈澱，在漶器上Κ冷乙酵（15毫升）清洗及在真空與401C下乾煉。兩份粗產物（約0_6克）於去離子水（200毫升）之溶液分別藉由製備性RP-HPLC純化。合併含有所要產物之溶離份，在真空UOanHg)及30Τ：下蒸發有機溶劑及產物經濃縮、除體及經由十八基（C18)柱（900奄克，取自Burdick & Jackson)單離。該柱以水（30橐升）清洗及產物Μ甲酵 (50牽升）再萃取。蒸發甲酵取得171毫克（28¾)所得產物 ;溶點 >25〇t：分解；UV(水）：272nB(loge4.86); MS (ES)(a/z): ίΓ2875,2; MW1796.4。本紙張尺度適用中國國家標準（CNS ) A4規格（2)0X297公釐） BO. ta 12 iS'ii. 年片ί·ι .補无 A7 B7 五、發明説明（50 ) 官例20 m m -a . a· -m 「4.fi -二「3-防采甚一H.H -嗶(2-m 甲瞌基-7,某）碏皚甚亞防基1-1 瞪笼-2.V-二碏酹.二钠闊三阱-2-某踣甚1- 化合物根據製備實例2所用程序製備，使用5,5’-二甲基-4,4'-二胺基聯苯-2,2'-二磺酸，二納鹽（206毫克 ,〇.49毫莫耳）及2-氯-4,6-二[3-胺笨基-(1,|{-雙（2-胺甲醯基乙基）磺醯基亞胺基]-1,3,5 -三畊（實例6 )(805 毫克，1.08毫冥耳）於30毫升DMS0 -環丁硪（1:1,體積/ 體積）及二異丙基乙胺（200毫升）中在U5t：下50小時。 HPLC-純化後之產物呈無色固體（191毫克，取得；熔點 >25〇υ 分解；UV (水）：27 4nm(l〇se5.08); MS(ES) (b/z): Η_288δ3.3; MW1822.6。實.例21 短-4.fi -二「3-防笼甚-N.H-琴（2-1? 7,基）碏瞌甚亞防甚1 - 1 . 3 5 -三哄 i n li r::.L 奸衣 i. Γ 訂 li 線 (請先閱讀背面之注意事碩再填寫本頁) 經濟部中央標準局員工消費合作社印裝 -2至013及攪拌下將三聚氯化氣（135毫克，0.7 3毫莫耳）於二枵烷（55毫升）之溶液逐滴加人磷酸Μ媛衝疲 (120毫升，0.3Μ, ρΗ7)及碎冰（10克）中。在20分鐘内將 3-胺苯基- 雙（2-羥乙基）磺醯基亞胺（365毫克， 1.40毫莫耳）於Ν,Ν -二甲基甲醒胺（125毫升）之溶液逐滴加入所得微细愍浮液中，pH藉由添加IN NaOH維持在6.5 -7.2。再持缜搜拌1小時（0T：, pH7,0)及將溫度升至55 C。再持编探拌2.5小時，另一方面藉由分析性HPLC(或 -32- 本紙張尺度適用十國國家標华（CNS ) ΛΊ规栴（：：〇公兑）暇43 87 9 7 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（51 ) TLC)監控反應是否完全。一旦由分析性HPLC(或UC)判定反應完全，混合物冷卻至01,將水（160毫升）加人及過瀘產物沈澱，Μ冷卻水（50毫升）及丙嗣（50毫升）清洗及在4 0 t下真空乾燥。產率3 9 5毫克U 9 35);熔點> 2 5 0 t 分解；U V ( D M S 0 ) : 2 8 4 n b。當锎2?. H -零「4.R-二L3-胺茉某- N.N-零（2 -禅7,蓽）碏随某亞防某1-1. 3.5 -三阱-2-某防某1-瞄笼-2.2’-二碏酸.二納铺此化合物根據製備莨例2所用之程序製備，使用4,4’ -二胺基聯苯-2,2'-二磺酸（28毫克，0.08毫莫耳）及 115毫克（0.17毫莫耳）2-氯-4,6-二[3-胺苯基- Ν,Ν-雙（3 -羥乙基）磺醣基亞胺基]-1,3,5 -三阱（實例21)於瓖丁賜 (10毫升）及二異丙基乙胺（25奄升）中在UOt：下18小時。 HPLC-純化後產物呈無色固體（16毫克，13¾)取得；熔點 > 2 5 0 t：分解；U V (水）：2 7 2 n m ( 1 〇 S ε 4 8 8 ) ; M S ( E S ) ( b / z ) ：Μ*2 776.0ϊ HW1534.0° 實例 9.9-二氣基-2.7-螫「4.6-二「3-防茏基-><.><-等（2-胺甲鏞某7,某）碏SI某亞防某1-1. 三啪-2-基胺某1-二茏並睞盼-3.fi -二碏醉二納薷標題化合物根據製備實例〗所用之程序製備，使用三聚氯化氰（59毫克，0.32毫莫耳），9,9-二氧-2,7-二胺基-二苯並喀吩-3,6-二磺酸（77毫克，0.16毫莫耳）及2- (請先聞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 ) Λ4規格（210 X 297公釐）經濟部中央標準局貝工消費合作社印製 Α7 Β7 五、發明説明（》) 氨-4, 6-二[4-胺苯基- Ν,Ν -雙（2-胺甲醯基乙基）磺醯基亞胺基]-1,3, 5 -三阱（實例6 )(300毫克，0.96毫莫耳）於二枵烷（15毫升）及磷酸鹽缓衝液（2G毫升，0.3M, pH 7 )之溶液在1 1 (TC下1 8小時。Η P L C -純化後産物呈無色固體（6 4 毫克，1 1 3；)取得；熔點 > 2 5 0 °C 分解；H S ( E S ) ( m / ζ ) :Η 2 9 0 5 . 1 ; M W 1 8 5 8 2 0 窖例？4 H - ¥ U - Μ - 6 -二「4 -胺甚-K 1 3 -胺采某-N . Η -孽㈧- 跎甲醅甚乙某）磋醅某亞昤甚1-节醅胺1-彳.3.!^三哄-？-甚胺甚1-二栄乙烯-2. 二猎酷.二納鹽化合物稂據製備實例2所用之程序製備，使用4, 41-二胺基二苯乙烯〜2, 2'-二磺酸（20毫克，D.054毫莫耳）及112毫克（0.12毫莫耳）2,4-二氣-6-[4-胺基1'-[3-胺苯基- Ν,Ν -雙（2 -胺甲薛基乙基）磺醯基亞胺基]-苄醛胺] -1,3, 5 -三阱（實例26)於環丁魄（20毫升）及二異丙基乙胺（38毫升）中在UQ°C下18小時。HPLC-純化後産物呈無色固體（20毫克，235Π取得；熔點>250°C分解；UV(水）： 2 9 5 nm ( 1 og ε 4 . 5 4 ), 3 5 0 η in ( 1 ο £ 4.39); HS (ES) ( id / z ): M 2 7 2 7 . 1; H W 1 4 8 2 . 2 0 密例25 在.4'-雙 [4,6-[4-胺某-忖’-匕-踣栄甚->^-雙（2 -揮7, 甚）磋鹼甚亞胺甚1-荣碏醅胺1-1. .3.5 -三阱j -某胺甚1-二茱7.烯-2.2’-二磋醚.二納鹽標題化合物根據製備實例2所用之程序製備，使用4, -3 4 - 本紙張尺度適用中國國家標準（CNS ) A4说格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) -=" 經濟部中央標準局員工消費合作社印製 kdi> ' A7 B7五、發明説明（Μ ) 4’-二胺基二苯乙烯-2,2、二磺酸（20毫克，0.054毫奠耳}及203毫克（0.22毫莫耳>2-氯- 4,6-二[4-胺基- N’-[ 3-胺苯基- Ν,Ν-雙（2-羥乙基）磺釀基亞胺基]-苯磺釀胺] -1,3,5 -三哄（實例27)於環丁硪（20毫升）及二異丙基乙胺（38毫升）中在1101下18小時。HPLC-純化後產物呈無色固體（3 0毫克，2 5 3S)取得；熔點> 2 5 0 Γ分解；U V (水）： 295na(loge 5.21), 350nai(loge 4.69), MS(ES)(a/z)： Μ·2 1 08 9.3； HW22 26 . 6 ° 管例2fi 之-在-二氲-已-厂在-防某^-防笼基-^卜等（2-防_瞌基乙基）磺醯基亞胺基1 -苄随胺1 -1, 3 , 5-三哄 -2t：及搅拌下將三聚氯化氰（56毫克，0.3毫莫耳）於二噚烷U毫升）之溶液加入瞵酸鼸媛衝液（12毫升，0.3Η ,ΡΗ7)中。將4-胺基- fT-[3-胺苯基- Ν,Ν-雙（2-胺甲醢基乙基）磺醢基亞胺基]苄醢胺（130毫克，0.3毫莫耳）於二甲基甲酺胺（2毫升）之溶液逐滴加入所得懸浮液中，pH藉由添加IN NaOH維持在6.5-7.2。再持鑛攪拌1 小時（0C, PH7.0),再將水（20毫升）加人，過漶產物沈豭，以冷水（10毫升）、丙酮（5毫升）清洗及在2〇υ下真空乾燥取得108毫克（62%)所要產物；熔點>250C分解； UV (DHS0) ； 285ηι ° 實例27 2-M -4.fi -二「4 -防某-^-「3-防茇某 U -够（2 -筠 7,某）碥醢基亞胺基苯礒醯胺]-1,3, 5-三阱 -35- 裝訂 (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 ) Λ4規格（210X 297公釐）經濟部中央標準肩員工消費合作社印裂 A7 B7五、發明説明（34 ) 標題化合物根據製備實例6所用之程序製備，使用4-胺基- Ν’- [3-羥乙基 > 磺醣基亞胺基]苯磺醵胺（125奄克， 0.31毫莫耳）及三聚氣化氰（28毫克，0·15毫奠耳）。產物圼無色固體U05毫克，74¾)取得；熔點>25〇υ分解； ϋV (DMS0) ： 298ηπ 〇窗例28 4.二硪某-2. 2’-二瞄笼二甲酴分次將2,2’-二聯苯二甲酸（Aldrich, 50.0克，206毫莫耳）加人500毫升3:1 90UN〇3/H2S〇4中，使溫度維持低於10C。在冰浴中攪拌清激溶液1小時，再於約 7 5 0克冰上小心淬溫。白色固體藉由真空過濾單離，其為所示2:1比例之異構物。此混合物藉由在1.5公斤混於8:2異丙酵/氫氧化铵中之矽凝膠中靨析純化及K相同溶劑混合物溶解。產物先自管往溶離•實際上與溶劑前方一起流出。少里異構物稍後自管柱流出（參見P.R. 232-11)。產物溶離份在旋轉式蒸發器上濃縮。濃縮之溶液以（1(：1酸化至？111,及過濾取得31.9克4,4'-二硝基-2,2’-二聯笨二甲酸。30(^}^^1^(0«$0(^): 5 7.55(1H, d, J = 8.7)； 8.45UH, dd, J = 2.5, 8,7)； 8.68UH, d, J = 2.5), ·13(1Η, br s)°CHN:理論值： C:48.60*! H:2.77S! H:3.105i。計算理論值含有 0,75 莫耳水，實測值：C:48.68!K H:2.72!« N:7.42S：。 4.4’-二硝某-2.2'-二瞄笼二申酸 -36- lp^i> I · ^^^^1 ^^^^1 ^^^^1 nn -Ί (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國囤家標準（CNS ) Λ4規格（210 X 297公釐）經濟部中央標準局員工消費合作社印繁 ^43 87 9 7 A7 B7五、發明説明（35) 4,4’-二硝基-2,2’-二聯苯二甲酸（實例28, 10.10克， 30.1毫莫耳；P.R.23 2-9 )懸浮於90毫升水中及以飽和 NaHCO 3 (可使用 NaOH)滴定至 pH7。將 10¾ M/C(0.5克； AJdrich)加入及混合物在30psi H2下遒原1小時。觸媒藉由過滅去除及濾液濃縮至約20毫升。小心地將丙_ (40毫升）加入漘縮瑢液中，使產物圼二納鹽沈澱。藉由真空過瀘收集及真空乾燥取得9.2克呈二納鹽之4, 4'-二硝基-2,2·-二聯苯二甲酸。300MHz NMR(D2 0): 5 4.70 f-NH 2 , s)； 6.7H1H, dd, J = 2.4, 8.25)； 6.79(1H, d, *1 = 2.4); 7.00(1H, d, J = 8.25)aCHN:理論值：C: 49.64 H:3.72 N:8.27(計算含有1.25莫耳水 >。實測值：C ： 49.5 5 Η ： 3 . 72 N ： 7 . 90 « 奮例30 14’-鳔-U.6-零U -「罅- (2-防甲膝某-7.甚）-防碏瞌某1 -¾防某三阱某防甚1-艏笼-2.2’-二铋胖. 二納皤在密封之厚壁玻璃管中將4,4’-二胺基二聯苯二甲酸二納鹽（霣例2 9, 66毫克，0.19毫其耳）及2-氯-4,6-二 [3-胺苯基- Η,Ν-雙（2-胺甲醯基乙基）-磺醸基亞胺基]-1,3,5 -三阱（實例6 )(300毫克，0.40笔莫耳）於環丁魄 (10毫升）及二異丙基乙胺（0.3毫升）之懸浮液加溫至115 C。持縯加溫5 0小時，一旦賴由分析性Η P L C (或TL C )判定反應完全，混合物冷卻至20t,及產物藉由添加丙-2 -醇（70毫升）沈澱，在漶器上Μ冷乙醇（15毫升）清洗及 I. . . ^I 策 I 訂 {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 ) Α4規格（210X297公釐） A7 經濟部中夹標準局員工消費合作社印裝 B7五、發明説明（5b ) 在40C下真空乾燥。二份粗產物（約0.3克）於去離子水 (200毫升）之溶液分別藉由製備性RP-HPLC純化。合併含有所要產物之溶離份，在真空（1 0 hi b H g >及3 0 t下蒸發有機溶劑及產物經濃縮、除醵及經由十八基（C18)柱（900 毫克，取自Burdick & Jackson}單離。該柱Μ水（20毫升）清洗及產物Μ甲酵（40毫升）再萃取。蒸發甲醇取得 112毫克（34¾)所要產物；熔點> 2 5 0 1分解；MS(ES)b/z ：Μ'2 840.2； MW1 724 . 4。實..例_.3丄防笼某等（2 -申氬某糖某-Z某）碏瞌某亞防在loot下將3-胺基苯磺醢胺（3克，17.4毫莫耳）溶於硝基笨（55毫升）中。鼸後將溫度降至90°C,將丙烯酸甲酿（5毫升.55.5毫莫耳）及1'「丨1;〇[18(0.4毫升，40»：於HeOH)加入。反應容器配備有強冷凝器及使運作20小時。TLC顯示反應完全。將HC1溶液（30毫升，1M於二 ***）加至反應混合物中Μ產生黏狀油。此溶於50¾醋酸乙酯/己烷中及裝載至矽凝膠管柱。所要產物Μ己烷溶離出。蒸發溶劑取得3.9克（65¾)所要產物；（m/Z): HH 343 . 2，熔點 59-60 υ。啻例3 2 3-防笼某-^-尊甲甚防甲醣某-7,某）碏随蓽亞防室溫及撹拌下將3 -胺笨基-H,N -雙（2 -甲氧基羰基-乙基）磺醯基亞胺（實例31, 0.5克，1.45毫莫耳）於乙酵 (10毫升）之溶液加至甲胺溶液（10毫升，S.03H, 33¾於 ^^^1 n ^ T ί 、-& (請先鬩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 ) Λ4規格（210X297公漦） A7 經濟部中央標準局員工消費合作社印製 B7五、發明説明) 乙醇）中。24小時後，TLC顯示反應完全。將水加入反應中，化合物Μ氛仿萃取及在硫酸納（50毫克）上乾燥。產率為 300 毫克（60¾) ; MS(ES)ra/z:345.2(M+H>+ 。啻例33 (4-LW蒈- (?-申某防Φ縮某-7.某）-胺碏髓某1-茏肪某ΐ-6 -镊- Μ.3.5]三阱-2-某防甚）-呆碏睡某1-(2-申某腌甲酴某-Z某）-防某1-N -申某-丙醣防 01下將三聚氯化镇（550毫克，2.98毫莫耳）於二枵烷 (4毫升）之溶液加至瞵酸鹽媛衝液（15毫升，ΡΗ = 7)中。於乳狀混合物中加入3 -胺苯基- Ν,Ν -雙- (2 -甲基胺甲醣基-乙基）磺醣基亞胺（實例32, 2.0克，5.84毫莫耳）於二甲基甲醯胺（25毫升）中，另一方面pH藉由添加1Ν氫氧化納溶液維持在6.5-7.2範圍内。添加後，溫度升至55 υ達2小時，在彼時，H P L C分析顯示反應完全。混合物 Μ水（100毫升）稀釋，Μ氯化納飽和及Μ醋酸乙酯（4Χ 150毫升）萃取。將合併之萃取物濃縮成黏狀油（3.5克），其溶於乙腈（30毫升）中及在冷藏室中留置過夜。膠黏狀沈澱與***（20毫升）一起攪拌直至所有沈澱轉為细粉末，其透過過濾單離。取得琥珀色固體（1.8克，78¾產率） ;熔點 >25〇υ 分解；HS(ES)ra/z 795.7(H+H)+ 。窗例：U 4.4·_嗶-「「4.β_等-「U -「「替甲胺甚3 —氬某丙某1 胺某1碏醣某Ί笼某1防某1-1. 5 -三哄-2-某Ί防基1「1.1’ -脳呆某1 -? · 2 二碏酸.二钠铺 m-ί i —c·—- nn I J ^^^^1 ^^^^1 ^^^^1 ^^^^1 ^^^^1 1 V (請先閲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 ) Λ4規格（2丨0〆297公釐）經濟部中央標準局員工消費合作社印裂 " A7 B7 五、發明説明（W ) 在litre下於密封管中將3-[[3-(4-{3-[雙- (2-甲基胺甲醯基-乙基）-胺磺醯基]-苯胺基卜6 -氣-[1,3,5]三阱-2 -基胺基）-苯磺醯基]-(2 -甲基胺甲醯基-乙基卜胺基卜 N -甲基-丙醯胺（實例33，200毫克，0.25毫莫耳），4, -二胺基聯苯-2, 2'-二磺酸二納鹽（41毫克，tl.il毫莫耳）及二異丙基乙胺（5G毫升，0.28毫莫耳）於二甲基亞魄 (4毫升）之混合物加熱2 5小時。如上之類似單離程序産生白色固體（40毫克^ 19%);熔點>25(TC分解；MS(ES) ffi/z 9 3 0 . 5 (Μ 2 } ; H W 1 9 0 8 . 1 0 4. - (4. β -雙-(.Ί -「雙- (2-甲某胺申醯基-乙某）-胺磋驗11二蓋._胺_.基1-[丄，3,51三胼-2-基胺基）-聪苯-2,2'-二羧酸，二.1鹽.. 於3-Π3-(4-{3-ί雙-{2-甲基胺甲醯基-乙基）-胺磺醯基卜苯胺基）-6-氯-[1，3, 5]三阱-2-基胺基）-苯磺醯基] -(2 -甲基胺甲醯基-乙基）-胺基卜N -甲基-丙醯胺（實例 33, 200毫克，0.25毫莫耳），4,4'-二胺基聯苯-2,2’- 二羧酸，二納鹽（3 7毫克，0 . 1 2毫莫耳）於二甲基亞峨（4 毫升）之溶液中加入磷酸鹽緩衝液（3毫升，pH = 7)中。混合物在1 1 CTC下加熱2 4小時。冷卻後，將水（1 〇 Cl毫升）加入及混合物在製備性HP LC管柱分離。産率為60毫克 (27¾)白色固體；熔點 >25(TC 分解；MS(ES)m/z 894.5 {Μ 2 ); MW1836Ο0 -4 0 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1--I ii— - - I ^ ^^^1 ^^^1 ^^^1 ------- (請先聞讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印聚陷 43 87 9 7 A7 B7 五、發明説明（59) 苷例 H-零- U.fi-謦-厂1「_-(?-胺甲醸某-7.甚）-胺碏醣某1-茉防某三阱-?-某肪某）-黼笼- 2.2' -二羧酵.二甲某SN 在11〇1〇下將2-氯-4,6-二[3-胺笨基-队（(-雙（2-胺甲醯基乙基）-磺醸基亞胺基]-1,3,5-三阱（茛例6 , 200毫克，0.27毫莫耳），4,4’-二胺基-2,2’-二聯苯二甲酸二甲酯2 (38毫克，0.13毫萁耳）及二異丙基乙胺（55毫升， 0.31毫奠耳）之混合物加熱30小時。冷卻後，將異丙酵 (50毫升）加入。沈澱經過濾，K異丙酵清洗。乾燥固體 (190毫克）藉由HPLC純化取得白色固體（53毫克，2U產率）；熔點 >250ΐ：分解；MS(ES)b/z 854.8(M + 2H)2t; MW 1707.8 ^ 窗例：Ϊ7 3-硝某笼某- N.H-尊（2 -筠丙某ΐ碏藤某亞肪於二異丙醇胺（50.0克，75毫莫耳）在水（500毫升）之攪拌溶液中將對-硝基苯磺醢氛（57.1克，35毫莫耳）加入。室溫下將混合物_烈攪拌25小時。過滹所得懋浮液，固體ΚΗ 2 0(2X40 0毫升）淸洗，乾煉及自醋酸乙醮/ 己烷混合物中再結晶取得圼白色结晶之所要產物。產率 65.8克（88黑）；熔點114-1161：;1[1-}^1?(〇0(；13, 300 ΜΗζ) 5 8 . 67 (d, J 5.1Hz, 1H), 8.44(d, 1H), 8.15 (t, J 6.0Hz, 1H), 7.77(ffi, 1H). 4.78(st 2H), 4.18 (m, 2H), 3.10(0, J 5.9Hz, 4H), 1.16(dd, 6H)； MS (ES)m/z 319. 5 (M + H) + ^ ^^1- ^^^1 n it In ^^^1 f ml ^ Jt .¾ 二-5 (請先鬩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（CN'S ) Λ4規格（210X 297公釐） A7 B7 η 8 7 9 7 五、發明説明（ρ ) 審例μ 3-胺荣某- H.N -等（2 -掷丙甚）碏瞌甚亞踣在把觸媒（1U Pd/C, 1克）上使3 -硝基苯基- Ν,Ν -雙-(2 -羥丙基）磺醯基亞胺（實例37， 10.0克，31. 4毫莫耳）於甲醇U Q 0毫升）之溶液氫化1 . 5小時。所得混合_通過 C e ] i t e墊過濾，去除溶劑及所得黏狀油藉由矽凝膠上進行管柱層析而純化，籍由醋酸乙酯/己烷4:1混合物溶離。所要産物呈淡黃色結晶取得。産率8.2克（90.5¾) ;N H R ( C D C 1 a , 3 0 0 Μ Η ζ ) ί 7 . 2 8 ( d , 1 Η ) , 7 . 1 3 ( m , 1 Η ), 6.86{d, 1Η), 4.20(ra, lfi), 4.13(dd, 1H), 3.37(dd,V. Description of the invention (2fci) The title compound was prepared according to the procedure used in the synthesis of Example 2, using 4, 4'-diamino-benzene-2,2'-disulfonic acid, disodium sulfonium (113 mg, 0.33 mmol) ) And 2-chloro-4,6-bis [4-aminophenyl-H, N-bis (2-aminomethylethyl) sulfoamidoimino] -1,3,5-Sanken ( Example 18) (535 mg, 0.72 mmol) in 25 ml of DHSO-cyclobutane fiS (2: 3, v / v) and diisopropylethylamine (350 ml). The product was a colorless solid (450 mg, obtained at 7 6; melting point> 2 50 0 Γ decomposition; UV (water): 2 9 6 nb (丨〇ge 5.13); MS (ES) (m / z): r2 874.4 MW1794.8. Jiao Li 1 4 2- 氲 -4.β- 二 ('V- 碏醸 Sulfoamido) -1. 3 5-Triple coax-2 ~ 〇υ and mix down A solution of cyanuric cyanide (2.37 g, 12,9 mmol) in propidium (25 ml) was added dropwise to the ointment solution (60 ml, 0.3M, ρΗ7). Within 20 minutes A solution of p-sulfonamide (4.35 g, 25.3 mils) in acetone (30 ml) was added dropwise to the resulting fine suspension, and the pH was maintained at 6.5-7,20 by addition of IN NaOH, and the mixture was stirred for 30 minutes. Minutes (OP, ρΗ7.0) ^ Raise the temperature to 55C. Stir for another 3 hours, on the other hand monitor the completion of the reaction by analytical HPLC (or TLC). Once determined by analytical HPLC (or TLC) Completely, the mixture was cooled to 01C, water (100 liters) was added and the product Shen Yi was filtered, washed with cold water (50 ml), dried on a dishwasher and dissolved in hot acetone (40 ml), Kbenzene (150 Ml) and purified by precipitation. It was washed with propan-2-enzyme (20 ml) and diethyl ether (30 ml), and dried under vacuum at 30¾. Yield, 3.72 g (6U); melting point > 250 It was decomposed; DV ^^^ 1. ^ ^^ 1 ^^^ 1 ^^^ 1 In ϋ— ntnm nn 1. ^ 1. L " i-39 (Please read the precautions on the reverse side before filling out this page) The paper size applies to the Chinese National Standard (CNS) Specification of Λ4 (210 X 29 7 mm) Printed bag A7 B7 of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of invention (W) {N e Ο Η}: 2 7 7 ηι (1 og £ 4.68); CI {ES ) (i / z): MH456.0o Wide plate 丄 5 4, 4 ′-「4,5 -Di「 3-amine M fl Ann (suluhonvlaniido)]-1.3. Amine] -Dimothylene-2. 2'-dioxo .... The dinaline title compound was prepared according to the procedure used in Preparation Example 2 using 4,4'-diaminostilbene-disulfonic acid, di Sodium salt (216 mg, 0.52 mmol) and 2-amino-4,6-bis (3'-amidinoanilide) -1,3,5-triple (Example 1 4) (5 24 mg, U mol) in cyclobutane (15 ml) and diisopropylethylamine (250 ml), and at 4 15 hours at 115 ° C. Cold simmer to 2 (TC, the reaction mixture was diluted with ethyl acetate (10 I) ml) and 1 N MaOH (2.08 ml) was added. After centrifugation, the residue was stirred with propan-2-ol (50 ml) until crystallization was complete. The solid was centrifuged, washed with methanol (2 X .30 mL) and ether (2 X 30 mL), and dried under vacuum at 30 ° C. Yield (570 mg, 923i); melting point > 25Q ° C decomposition; UV (water): 273nm (10 g £ 4.7 6), 350niro (log £ 4.5.2). Example lfi 4,4'- Double "4. 6-bis" 3 ~ amine benzyl chloride sulphnnvlimido l -1,3,5-tristrak-2-ylamino suebenzene-2, disulfonic acid, dinadium lanthanum The title compound was prepared according to the procedure used in Preparation Example 2, using 4, 4'-diaminobiphenyl-2, 2'-disulfonic acid (208 mg, ϋ. 60 mmol) and 2-氱 -4, 6-bis (3′-sulfoamidoanilide) -1,3,5-tritrap (example) 4) (ti (Π mg, 1.3 mmole) in cyclobutane (20 ml ) And diisopropylethylamine (850 ml) and 40 hours at 115 ° C. After cooling to 2 Q ° C, the reaction mixture was diluted with ethyl acetate (50 ml) and 1 NN a 0 fi (2. 4 0 -2 9- This paper size applies to the Chinese National Standard (CNS) Λ4 specification (210X297 mm)-^^^ 1 nt i ^ i ^^^ 1 1 ^ 1 ^^^ 1 ^ ^^ 1 nt (please read the precautions on the back before filling this page) 陛 43 87 9 7 A7 B7 V. Description of the invention (28 ml) added. After centrifugation, the residue was mixed with propan-2-enzyme (50 ml) together Stir Until the crystallization is complete. The solid is washed with Carboxylic Acid (40 ml) and diethyl ether (2 x 20 ml), and dried under vacuum at 30 t: yield (505 mg, 7 2 3; ); Melting point > 2 50 0 Γ decomposition; IH (water): 2 7 6 nm (1se 4. 9 3). G Example 1 7 4.4'-Secondary Moss-2.2'-Dicera A solution of sodium carbonate (8.6 ml, 1.5 M) was added to a suspension of 4,4'-diaminobiphenyl-2,2'-disulfonic acid (4.44 g, 12.9 mF) in water (20 ml) and Warm until a clear solution is obtained. After cooling to 51C, add a solution of sodium nitrite (1.78 g, 12.9 mils) in water (3 ml) to this solution. -5 ~ -21C and mix the resulting solution with stirring A solution of concentrated sulfuric acid (3.8 ml) in water (13 ml) and crushed ice (10 g) were added dropwise. Stirring was continued for 30 minutes and the reaction mixture was warmed to 65TC. The temperature was maintained until nitrogen evolved. The mixture was cooled to IOC and M anhydrous sodium carbonate were neutralized, and the solution was evaporated to a residue. The residue was dried under vacuum at 50, mixed with ethanol (225 ml) and quenched. The mash was evaporated and dried under vacuum at 40 ° F. Yield 3 . 8 8 (8 7 S;). Melting point > 2 5 0 13 Decomposition; UV (0. 0 5 NN a 0 Η): 2 5 0 η Zu (loge 4.16), 311nm (loge 3, 40); MS (ES) (b / z): ( HH) · 1 345,0; MW346.0. Printed and bound by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) Example 1 8 2-Ar-4. 6-Di-4-aminophenyl-N. .Yl.) 1 Temium imine 1-3. 3. The 5-triple title compound was prepared according to the procedure used in Preparation Example 6, using 4-aminophenyl-N, H-bis (aminomethylamidoethyl). ) Sulfoimide (3,3 g, this paper size applies Chinese National Standard (CNS) Λ4 specification (210X 297 mm) 4? 8 7 ρ ^ Α7 Β7 V. Description of the invention (29) 10,5 milligrams Ear) (English_Patent No. 1,194,388; June 10, 1970) and trimeric atmosphere (1.0 g, 5.4 millimolar product 莫 colorless solid (3,5 g, 88! 1! 3;) were obtained; Melting point> 2501 ^ decomposition; 0 (0 »^ 0): 30 3 nm (log e 4.84); MS (CI) (m / z): Μ Η 740 · 1. Rich 锎 1 9 Α" 4.6-two " 3-Amine 茏-MH-訾 (2-Anti-stolen stele-B y) 碏 sugar an imine 1-1.3, 5-trihydrazine-2- a gas group]-Cong Cong-2 .; > , -Difluorene. Di-Nanosalts, 4,4'-Hydroxybenzophenone-2,2 · -dihydroacid (Example 17) (131 mg, 0.34 mmol) and 2 in a sealed thick-walled glass tube -chlorine- 4,6-bis [3-Aminobenzyl-bis (2-aminomethylmethylethyl) sulfonamidoimino] -i, 3,5-triple (Example 6 > (550 mg, 0, 74 mmol) to a suspension of cyclobutane-N, N-dimethylformamidine (15¾ liters, 2: 1 vol / vol) and NaOH (lH, 1.48 ml) was added to 115¾. Keep warming for 50 hours. Department of Printing, Employees Cooperatives, China Standards Bureau, Ministry of Economic Affairs, 1 · ^^^ 1 ^^^ 1 ^^^ 1 ^^^ 1 ^^^ 1 TJ (.Please read the notes on the back first (Fill in this page again) — Once the reaction is judged to be complete by analytical HPLC (or TLC), the mixture is cooled to 20 t: and the product is precipitated by the addition of propan-2-enzyme (70 ml). The yeast (15 ml) was washed and dried under vacuum and 401C. Two solutions of the crude product (about 0-6 g) in deionized water (200 ml) were separately purified by preparative RP-HPLC. The dissociation containing the desired product was combined The organic solvent was evaporated under vacuum (UOanHg) and 30T: and the product was concentrated, removed, and passed through a C18 column (900 g, taken from Burdick & Jackson). The column was separated with water (30橐 liter) washing and product M formase (50 draft) re-extraction 171 mg (28¾) of the product obtained by evaporation of formic acid; melting point > 250,000t: decomposition; UV (water): 272nB (loge4.86); MS (ES) (a / z): Γ 2875, 2; MW1796. 4. This paper size applies Chinese National Standard (CNS) A4 specification (2) 0X297 mm) BO. Ta 12 iS'ii. Annual film ί · ι. Supplementary A7 B7 V. Description of the invention (50) Official example 20 mm -a a · -m 「4.fi-二」 3-Anti-mining HH-Bee (2-m methylphenanthrene-7, some) 碏 captain 1-1 gazing cage-2.V-II碏酹. Disodium triple well-2-a hydrazone 1- compound was prepared according to the procedure used in Preparation Example 2 using 5,5'-dimethyl-4,4'-diaminobiphenyl-2,2 ' -Disulfonic acid, di-nano salt (206 mg, 0.49 mmol) and 2-chloro-4,6-di [3-aminebenzyl- (1, | {-bis (2-amine formamyl) Ethyl) sulfoimino] -1,3,5-triso (Example 6) (805 mg, 1.08 mmol) in 30 ml DMS0-cyclobutane (1: 1, v / v) and Diisopropylethylamine (200 ml) at U5t: 50 hours. The product after HPLC-purification was a colorless solid (191 mg, obtained; melting point > 25) decomposition; UV (water): 27 4nm (l 〇se5.08); MS (ES) (b / z): Η_288δ3.3; MW1822.6. Example 21 short-4.fi-two "3-anti-cage even -NH-qin (2-1? (7, the base) 碏瞌 very defensive 1-1. 3 5-three coax in li r ::. L 衣衣 i. Γ li line (please read the note on the back before filling in this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the People's Republic of China -2 to 013 and stir the polytrichloromethane (135 mg, 0.7 3 mmol) to A solution of dioxane (55 ml) was added dropwise to human phosphate (120 ml, 0.3 M, ρΗ7) and crushed ice (10 g). 3-Aminephenyl-bis (2 -Hydroxyethyl) sulfonyliminomine (365 mg, 1.40 mmol) in N, N-dimethylmethanamine (125 ml) was added dropwise to the resulting fine hydrazone suspension, and the pH was adjusted by adding IN NaOH was maintained at 6.5 to 7.2. The mixture was stirred for 1 hour (0T :, pH7,0) and the temperature was raised to 55 C. The mixture was further stirred for 2.5 hours, and on the other hand, it was analyzed by HPLC (or- 32- This paper standard is applicable to the ten national standards of China (CNS) ΛΊ Regulations (:: 0 credit) Time 43 87 9 7 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (51) TLC) The reaction was monitored for completeness. Once the reaction was judged to be complete by analytical HPLC (or UC), the mixture was cooled to 01, water (160 ml) was added and the product was precipitated. Cooling water (50 ml) and propan-Si (50 mL) and dried under vacuum cleaning 4 0 t. Yield: 395 mg U 9 35); melting point> 2 50 t decomposition; U V (DM S 0): 2 8 4 n b. When 锎 2 ?. H-Zero "4.R-Di-L3-amine Momo-NN-Zero (2-Zen 7, 荜) 碏 Follow a certain Asian defense 1-1. 3.5-Mitsui-2- a defense A 1-Cage-2.2'-diphosphonic acid. This compound was prepared according to the procedure used in Preparation Example 2 using 4,4'-diaminobiphenyl-2,2'-disulfonic acid (28 (Mg, 0.08 mmol) and 115 mg (0.17 mmol) of 2-chloro-4,6-di [3-aminophenyl-N, N-bis (3-hydroxyethyl) sulfosylimino ] -1,3,5-Triple well (Example 21) in acetidine (10 ml) and diisopropylethylamine (25 ml) at UOt: 18 hours. HPLC-purified product as a colorless solid (16 mg, 13¾) obtained; melting point> 2 50 t: decomposition; UV (water): 2 7 2 nm (10 ε 4 8 8); MS (ES) (b / z): M * 2 776.0ϊ HW1534.0 ° Example 9.9-Dioxo-2.7- 螫 "4.6-Di" 3-Antipyridyl- > <. &Gt; < -etc. SI, a certain Asian defense, 1-1. Tris-2-ylamine, 1-Dipyridine, and Prefer-3.fi-Dipyridine, Di-Nitrate. The title compound was prepared according to the procedure used in the preparation example, using trimer chloride. Cyanide (59 mg, 0.32 mmol), 9,9-dioxo-2,7- Diamino-dibenzocarbene-3,6-disulfonic acid (77 mg, 0.16 mmol) and 2- (Please read the precautions on the back before filling this page) The paper size applies to Chinese national standards (CNS) Λ4 specification (210 X 297 mm) Printed by Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (") Ammonia-4, 6-bis [4-aminephenyl-Ν, Ν- Bis (2-Aminomethylethyl) sulfoamidoimino] -1,3,5-tritrap (Example 6) (300 mg, 0.96 mmol) in dioxane (15 ml) and phosphoric acid Solution of salt buffer (2G ml, 0.3M, pH 7) at 1 1 (TC for 18 hours.) PLC-The product was obtained as a colorless solid after purification (64 mg, 1 1 3;); melting point > 2 Decomposed at 50 ° C; HS (ES) (m / ζ): Η 2 9 0 5. 1; MW 1 8 5 8 2 0 Example? 4 H-¥ U-Μ-6 -Di 4-amine -K 1 3 -Amine picking-N. Η -㈧㈧- 跎甲醅一乙乙) 醅醅 a sub 昤 1- 1- 醅醅 1- 彳 3.! ^ Three coax-?-Very amine 1-Difluorene-2. Dioxane. Di-Na salt compound 稂 Prepared according to the procedure used in Preparation Example 2, using 4, 41-diaminostilbene ~ 2, 2'-disulfonic acid (20 mg, D.054 mmol) and 112 mg (0.12 mmol) of 2,4-digas-6- [4-amino 1 '-[3-aminophenyl-N, N-bis ( 2-Metylaminoethyl) sulfoamidoimino] -benzaldehyde amine] -1,3, 5 -Tritrap (Example 26) in cyclobutadiene (20 ml) and diisopropylethylamine (38 ml ) For 18 hours at UQ ° C. HPLC-purified product was a colorless solid (20 mg, obtained from 235Π; melting point > 250 ° C; UV (water): 2 9 5 nm (1 og ε 4. 5 4), 3 5 0 η in (1 ο £ 4.39); HS (ES) (id / z): M 2 7 2 7. 1; HW 1 4 8 2. 2 0 secret 25 in .4'-bis [4,6- [4-amine忖 '-匕-踣栄踣栄-&^; ^ -bis (2-77,）) alkaloids very imine very 1-ronganamine 1-1. .3.5-triple well j-an amine even 1- Dizhu 7.ene-2.2'-dioxoether. The title compound of dina salt was prepared according to the procedure used in Preparation Example 2, using 4, -3 4-This paper is in accordance with the Chinese National Standard (CNS) A4 standard (210 X 297 mm) (Please read the notes on the back before filling out this page)-= " Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, printed kdi > 'A7 B7 V. Invention Description (M) 4'-Diaminodiamine Styrene-2,2, disulfonic acid (20 mg, 0.054 mmol) and 203 mg (0.22 mmol) > 2-chloro-4,6-di [4-amino-N '-[3- Aminophenyl-N, N-bis (2-hydroxyethyl) sulfoimino] -benzenesulfonimide] -1,3,5 -trioxine (Example 27) in cyclobutane (20 ml) And diisopropylethylamine (38 ml 18 hours at 1101. HPLC-purified product was obtained as a colorless solid (30 mg, 2 5 3S); melting point > 2 50 0 Γ decomposition; UV (water): 295na (loge 5.21), 350nai (loge 4.69 ), MS (ES) (a / z): Μ · 2 1 08 9.3; HW22 26. (2-anti-fluorenylethyl) sulfoimino 1-benzyl with amine 1 -1, 3, 5-trioxane-2t: and cyanuric chloride (56 mg, 0.3 mmol) with stirring Ear) in dioxane (U ml) solution was added to acetic acid solution (12 ml, 0.3 Η, Η 7). 4-Amino-fT- [3-aminophenyl-N, N-bis (2 -Amidinoethyl) sulfinoimino] benzamidine (130 mg, 0.3 mmol) in dimethylformamide (2 ml) was added dropwise to the resulting suspension. Maintained at 6.5-7.2 by adding IN NaOH. Hold the ore and stir for 1 hour (0C, PH7.0), add water (20 ml), and immerse the product in cold water (10 ml), acetone (5 Ml) was washed and vacuum dried at 20 ° to obtain 108 mg (62%) of the desired product; melting point > 250C decomposition; UV (DHS0); 285 ηι ° Example 27 2-M -4.fi-two "4-prevent a certain-^-" 3- prevent a certain U-enough (2-筠 7, a certain) fluorenimine benzidine]- 1,3, 5-Tri well-35- binding (please read the precautions on the back before filling this page) This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210X 297 mm) Central Standard Ministry of Economics staff consumption Cooperative printed A7 B7 V. Description of the invention (34) The title compound was prepared according to the procedure used in Preparation Example 6, using 4-amino-N '-[3-hydroxyethyl > sulfosimimine] benzenesulfonium Amine (125 g, 0.31 mmol) and trimeric cyanide (28 mg, 0.15 mmol). The product 取得 colorless solid U05 mg, 74¾) was obtained; melting point > 25〇υ decomposition; ϋV (DMS0): 298ηπ 〇 window example 28 4. two 硪 -2.2. 2'- two-point cage dimethyl dimethyl sulphate 2 2,2'-diphthalic acid (Aldrich, 50.0 g, 206 mmol) was added to 500 ml of 3: 1 90UN03 / H2S04 to keep the temperature below 10C. Stir the stimulating solution in an ice bath for 1 hour, then carefully quench it on about 750 grams of ice. The white solid was isolated by vacuum filtration, which is an isomer in the 2: 1 ratio shown. This mixture was purified by decantation in a 1.5 kg silica gel mixed in 8: 2 isopropion / ammonium hydroxide and dissolved in the same solvent mixture. The product first dissolves from the tube • It actually flows out with the solvent. The Shauri isomer elutes later from the column (see P.R. 232-11). The product fractions were concentrated on a rotary evaporator. The concentrated solution was acidified with (1: 1 to? 111, and filtered to obtain 31.9 g of 4,4'-dinitro-2,2'-diphenyldicarboxylic acid. 30 (^) ^^ 1 ^ (0 « $ 0 (^): 5 7.55 (1H, d, J = 8.7); 8.45UH, dd, J = 2.5, 8, 7); 8.68UH, d, J = 2.5), · 13 (1Η, br s) ° CHN: Theoretical value: C: 48.60 *! H: 2.77S! H: 3.105i. The calculated theoretical value contains 0,75 moles of water, the measured value: C: 48.68! KH: 2.72! «N: 7.42S :. 4.4 '-Dinitromethane-2.2'-Diisocyanic acid-36- lp ^ i > I · ^^^^ 1 ^^^^ 1 ^^^^ 1 nn -Ί (Please read the precautions on the back first (Fill in this page again.) This paper size applies the Chinese Standard for Storehouse (CNS) Λ4 (210 X 297 mm). The Central Consumers Bureau of the Ministry of Economic Affairs, the Consumer Cooperatives of India, Fan ^ 43 87 9 7 A7 B7 V. Description of Invention (35) 4 , 4'-Dinitro-2,2'-diphthalic acid (Example 28, 10.10 g, 30.1 mmol; PR23 2-9) suspended in 90 ml of water and saturated with NaHCO 3 (NaOH can be used ) Titrate to pH 7. Add 10 ¾ M / C (0.5 g; AJdrich) and mix the mixture at 30 psi H2 for 1 hour. The catalyst is removed by quenching and the filtrate is concentrated to about 20 ml. Carefully remove propyl (40 Ml) It was added to the condensed hydrazone solution to precipitate the product dinadium salt. 9.2 g of 4,4'-dinitro-2,2 · -diphenyldiamine was obtained by vacuum collection and vacuum drying. Formic acid. 300MHz NMR (D2 0): 5 4.70 f-NH 2, s); 6.7H1H, dd, J = 2.4, 8.25); 6.79 (1H, d, * 1 = 2.4); 7.00 (1H, d, J = 8.25) aCHN: Theoretical value: C: 49.64 H: 3.72 N: 8.27 (Calculated with 1.25 moles of water >. Measured value: C: 49.5 5 Η: 3. 72 N: 7. 90 «Fen example 30 14 ' -鳔 -U.6-Zero U-"罅-(2- Armor Knee -7. Even)-Anti-Hair 1-¾ Anti-Three Wells 1-艏 -2.2'-Dibismuth Fat. Di-n-naphthalene in a sealed, thick-walled glass tube contains 4,4'-diamine di-n-phthalic acid di-nano salt (Example 2, 9, 66 mg, 0.19 mil) and 2-chloro-4 , 6-bis [3-Aminophenyl-fluorene, N-bis (2-aminomethylamidoethyl) -sulfoamidoimino] -1,3,5-tritrap (Example 6) (300 mg (0.40 moles) was heated to a suspension of cyclodipene (10 ml) and diisopropylethylamine (0.3 ml) to 115 C. Heating was continued for 50 hours. Once the reaction was judged to be complete by analytical Η PLC (or TL C), the mixture was cooled to 20 t, and the product was precipitated by adding propan-2-ol (70 ml) and placed on a vessel. Cold ethanol (15ml) cleaning and I... ^ I policy I order {Please read the precautions on the back before filling this page) This paper size applies the Chinese National Standard (CNS) Α4 size (210X297 mm) A7 Ministry of Economy Printed on B7 of the Consumers' Cooperatives of China Standards Bureau V. Description of Invention (5b) Vacuum drying at 40C. Two solutions of the crude product (about 0.3 g) in deionized water (200 ml) were purified by preparative RP-HPLC, respectively. The fractions containing the desired product were combined, the organic solvent was evaporated under vacuum (10 hi b H g > and 30 t) and the product was concentrated, deionized and passed through a C18 column (900 mg, from Burdick & Jackson} single isolation. The column was washed with water (20 ml) and the product M formate (40 ml) was re-extracted. Methanol was evaporated to obtain 112 mg (34¾) of the desired product; melting point > 2 5 0 1 decomposition; MS ( ES) b / z: M'2 840.2; MW1 724. 4. Real .. Example _. 3) Anti-cages, etc. (2-Shen Ar, some sugar, -Z, etc.); -Aminosulfenilamide (3 g, 17.4 mmol) was dissolved in nitrobenzyl (55 ml). After simmering, the temperature was reduced to 90 ° C, and acrylic acrylic acid was brewed (5 ml. 55.5 mmol). And 1 ′ ″ 丨 1; 〇 [18 (0.4 ml, 40 »: in HeOH) was added. The reaction vessel was equipped with a strong condenser and allowed to operate for 20 hours. TLC showed the reaction was complete. The HC1 solution (30 ml, 1M in two Diethyl ether) was added to the reaction mixture M to produce a viscous oil. This was dissolved in 50 ¾ ethyl acetate / hexane and loaded onto a silica gel column. The desired product hexane was dissolved out. The solvent was evaporated to obtain 3.9 g (65 ¾). Key product; (m / Z): HH 343.2, melting point 59-60 υ. Example 3 2 3-cage-proof-^-zunjia and anti-methylose-7, etc.) Mix 3-aminobenzyl-H, N-bis (2-methoxycarbonyl-ethyl) sulfonamidoimide (Example 31, 0.5 g, 1.45 mmol) with acetic acid (10 ml with gentle stirring). ) Solution to methylamine solution (10ml, S.03H, 33¾ in ^^^ 1 n ^ T ί,-& (Please read the notes on the back before filling this page) This paper size applies to China Standard (CNS) Λ4 specification (210X297 gong) A7 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (B7 V. Invention Description) Ethanol). After 24 hours, TLC showed the reaction was complete. Water was added to the reaction and the compound M Extraction and drying on sodium sulfate (50 mg). Yield: 300 mg (60¾); MS (ES) ra / z: 345.2 (M + H > +.) Example 33 (4-LW 蒈-(?- Shen Mou Anti-Diagram -7. Mou)-Amine medulla 1- 茏 Fat Mou -6-Tweezers-Μ.3.5] Mitsuchi -2- Mou 甚-1- (2- Shenmou pickled formazan-Z-m) -Fangmou 1-N-Shenmou-Triose Fang-mia Tripolychloride (550 mg, 2.98 mmol) The solution in dioxane (4 ml) was added to the gallate solution (15 ml, pH = 7). To the milky mixture was added 3-aminophenyl-N, N-bis- (2-methyl Carbaminyl-ethyl) sulfosylimine (Example 32, 2.0 g, 5.84 mmol) in dimethylformamide (25 ml), on the other hand the pH was adjusted by adding 1N sodium hydroxide solution Maintained within the range of 6.5-7.2. After the addition, the temperature rose to 55 υ for 2 hours, at which time HPLC analysis showed that the reaction was complete. The mixture was diluted with M water (100 ml), saturated with sodium chloride and extracted with ethyl acetate (4 × 150 ml). The combined extracts were concentrated to a viscous oil (3.5 g), which was dissolved in acetonitrile (30 ml) and left in the refrigerator overnight. The gummy precipitate was stirred with diethyl ether (20 ml) until all the precipitate turned into a fine powder, which was isolated by filtration. An amber solid was obtained (1.8 g, 78¾ yield); melting point > 25 ° decomposition; HS (ES) ra / z 795.7 (H + H) +. Window example: U 4.4 · _ beep-"4. β_ etc.-" U-"" Tetamine very 3 — Argon, certain amine, 1 amine, 1 sugar, certain cage, 1 anti-1-1. 5 -三 679-2-A certain antifungal 1 "1.1 '-A certain 1-? · 2 Diacetic acid. Disodium m-ί i —c · —- nn IJ ^^^^ 1 ^^^^ 1 ^^^^ 1 ^^^^ 1 ^^^^ 1 1 V (Please read the precautions on the back before filling out this page) This paper size applies to the Chinese National Standard (CNS) Λ4 specification (2 丨 0〆297) (%) Employees' cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China [A7 B7] 5. Description of the invention (W) Under litre, the 3-[[3- (4- {3- [双-(2- 甲Aminomethylamidino-ethyl) -sulfamoyl] -anilinobu 6-gas- [1,3,5] Triswell-2 -ylamino) -benzenesulfonyl]-(2-methyl N-methylaminomethylethyl-ethylaminomethyl N-methyl-propylamine (Example 33, 200 mg, 0.25 mmol), 4, -diaminobiphenyl-2, 2'-disulfonic acid A mixture of dinaline salt (41 mg, tl.il mmol) and diisopropylethylamine (5G ml, 0.28 mmol) was heated in a mixture of dimethyl sublime (4 ml) for 25 hours. Similar to the above Isolation procedure yielded a white solid (40 mg ^ 19%); melting point> 25 (TC Decomposition; MS (ES) ffi / z 9 3 0. 5 (Μ 2); HW 1 9 0 8. 1 0 4.-(4. β-bis-(. Ί-「bis- (2-methylamine Shen Yingji-Ethyl) -Amine Test 11 Ergai. _Amine_. 1- [Hydroxy, 3,51 tris-2-ylamino)-Congben-2, 2'-dicarboxylic acid, two. 1 salt: in 3-Π3- (4- {3-ίbis- {2-methylaminomethylmethyl-ethyl) -sulfamoylphenylaniline) -6-chloro- [1,3, 5] Tritrap-2-ylamino) -benzenesulfonyl]-(2-methylaminomethylmethyl-ethyl) -amino group N-methyl-propylamine (Example 33, 200 mg, 0.25 millimolar), 4,4'-diaminobiphenyl-2,2'-dicarboxylic acid, dinaline (37 mg, 0.12 millimolar) in dimethylene (4 Ml) was added to a solution of phosphate buffered saline (3 ml, pH = 7). The mixture was heated at 1 1 CTC for 24 hours. After cooling, water (10 Cl ml) was added and the mixture was prepared in preparative HP LC Separation by column. Yield: 60 mg (27¾) white solid; melting point> 25 (TC decomposition; MS (ES) m / z 894.5 {Μ 2); MW1836〇0 -4 0-This paper is in accordance with Chinese national standard (CNS ) A4 size (210X297mm) 1--I ii----I ^ ^^^ 1 ^^^ 1 ^^^ 1 ------- (Please read the notes on the reverse side before filling out this page) Yin Ju, Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 43 87 9 7 A7 B7 V. Description of the invention (59) Glycosides H-zero-U.fi- 謦- Plant 1 "_- (?-Aminomethylammonium-7.even) -Aminomaxyl-1-Mofang some-three-trap-?-A certain fat-)-Cage-2.2'-Dicarboxylase.Dimethyl SN put 2-chloro-4,6-di [3-aminebenzyl-Team ((-bis (2-aminomethylethyl) -sulfoamidoimino] -1) at 1101, 3,5-Tri well (Ranunculus case 6, 200 mg, 0.27 mmol), 4,4'-diamino-2,2'-diphthalate 2 (38 mg, 0.13 mmol) Ear) and diisopropylethylamine (55 ml, 0.31 mmol) were heated for 30 hours. After cooling, add isopropion (50 ml). The precipitate was filtered and washed with K isozyme. Dry solid (190 mg) was purified by HPLC to obtain a white solid (53 mg, 2U yield); melting point> 250ΐ: decomposition; MS (ES) b / z 854.8 (M + 2H) 2t; MW 1707.8 ^ Example of window: Ϊ7 3-Nitrogen in a cage-NH-zun (2 -Hydroxypropylamidine) A fatty acid in diisopropanolamine (50.0 g, 75 mmol) in a stirred solution of water (500 ml) -Nitrobenzenesulfonate (57.1 g, 35 mmol) was added. The mixture was vigorously stirred at room temperature for 25 hours. The obtained 懋 float solution was washed with solid K 固体 2 0 (2 × 40 0 ml) and dried. And recrystallization from a mixture of ethyl acetate / hexane to obtain the desired product of white crystals. Yield 65.8 g (88 black); melting point 114-1161 :; 1 [1-} ^ 1? (〇0 (; 13, 300 ΜΗζ) 5 8. 67 (d, J 5.1Hz, 1H), 8.44 (d, 1H), 8.15 (t, J 6.0Hz, 1H), 7.77 (ffi, 1H). 4.78 (st 2H), 4.18 ( m, 2H), 3.10 (0, J 5.9Hz, 4H), 1.16 (dd, 6H); MS (ES) m / z 319. 5 (M + H) + ^ ^^ 1- ^^^ 1 n it In ^^^ 1 f ml ^ Jt .¾-2-5 (Please read the precautions on the back before filling out this page) This paper size applies to Chinese National Standard (CN'S) Λ4 specification (210X 297 mm) A7 B7 η 8 7 9 7 V. Explanation of the invention (ρ) Examination example μ 3-Amine Rong-HN-Etc. (2-Throwing Propionate) 碏瞌 Chia 踣 on the catalyst (1U Pd / C, 1 gram) Hydrogenation of a solution of 3-nitrophenyl-N, N-bis- (2-hydroxypropyl) sulfonylimine (Example 37, 10.0 g, 31.4 mmol) in methanol UQ (0 ml) 1 5 hours. The resulting mixture was filtered through a Ce] ite pad, the solvent was removed, and the resulting viscous oil was purified by column chromatography on a silica gel, which was then eluted from a 4: 1 mixture of ethyl acetate / hexane. The desired product was obtained as pale yellow crystals. Yield: 8.2 g (90.5¾); NHR (CDC 1 a, 300 M Η ζ) 7. 2 8 (d, 1 Η), 7. 1 3 (m, 1 Η), 6.86 (d, 1Η), 4.20 (ra, lfi), 4.13 (dd, 1H), 3.37 (dd,

1H) , 3. 0 2 ( d , 2 H) , 2 .8 0 (d d , 1H) ; 1 . 1 6 ( dd , 6H) ; MS {E S)m/z 2 8 9 . 5 (M + H ) + 0 曹例39 2二氛..-4.6---(3-[雙- (2 -萍西..基）-胺磺醯基卜苯胺基卜 [1,2 , ..51 -三哄捸題化合物根據製備實例33之程序製備，使用三聚氮化氰（160毫克，G.87毫莫耳），3 -胺苯基雙（2 -羥丙基）磺醛基亞胺（7 fl G毫克，2 . 0毫莫耳）、二垮烷（3毫升）、磷酸鹽Μ衝液（10毫升，0.3Μ, ρίΠ)、Ν,Ν -二甲基甲醯胺（5毫升）及IN NaOH。以水使産物自冷卻之反應混合物中呈黏性琥珀黃色油沈澱出，以水清洗及在高度真空七乾燥取得64 0毫克（9 3 Si )氣三阱。熔點> 2 5 0 °C分解；MS(ES)m/z 687,7， 689.7(M+H)+ 。 -4 2 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） - - - -I I - - -*-- ^^1 ^^1 -I -I ^^1 穿、v含 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央梯準局員工消費合作社印裝經濟部中夬標準局員工消費合作社印掣 A7 B7五、發明説明（41 ) 實例40 4.4'-簪-(4.6-嗶-{3-「够-(2-择丙某）-防碏醸甚1-笼防某ΐ-「1 .3.M-三哄-2-某防某）-聪茏某-2.2'-二磺辟. 二納锞使2-氛-4,6-雙-〖3-[雙- (2-羥丙基）-胺磺醯基]-苯胺基}-[〗，3,5]-三阱（實例39，3 00毫克，0.44毫莫耳）， 4,4’-二胺基聯苯-2,2'-二磺酸，二鈉鹽（77毫克，0.2 毫莫耳），2毫升D M S 0 , 2毫升磷酸鹽緩衝菠（1 Ν , ρ Η 7 ) 及0.25毫升IN NaOH之混合物暴露於llOt：之微波加熱 (PR0LAB0單位，單式）2小時。冷卻後，將無處理之反應混合物_至¥“ Prodigy C18聚合物管柱上之製備性 HPLC(水/乙腈糸統）。產物呈無色固體（170毫克，50.2 %)取得；熔點 >25〇υ 分解；MS(ES)m/2 822,3 (M-2H)2'; MW1691.9 (MW + 2Ha) ^ 窨例 4.41-替--等-U-「雙- (2 -筠基-丙某）-胺碏瞧基]-笼防某1-「1.3. 51-三肼-2-某防某瞄茏-2.2'-二搿酹. 二納翮在烘箱内加熱密封管中2-氯-4 ,6-雙- (3-[雙- (2-羥基, -丙基）-胺磺醸基卜苯胺基}-[1,3,5]_三阱（實例39, 178毫克，0.25毫莫耳），4,4'-二胺基-2,2'-二聯苯二甲酸二氫氯酸鹽（35毫克，0.11毫莫耳），3牽升DMS0, 0.5毫升磷酸鹽鍰衝液（IN, pH7)及0.5毫升1H NaOH之混合物18小時，陳後不處理而施至製備性HPLC取得90毫克 (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 ) Λ4規格（210X297公釐） Β<3. ΙΟ. 12 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（42 ) (50,5¾)所要產物。熔點>250t：分解；MS(ES)B/z 788,l (M+2H)2f; MW1619‘8(MW+2Na)。宵例42 卜氣-4.fi -尊-Π「雙-肪甲睹甚申甚-胺磺醯基1-¾防甚1 - η . 3. s 1 -三阱標題化合物根據實例33之程序製備，使用三聚氯化m (0.42克，2.27毫莫耳），3-胺苯基-Η,N-雙-胺甲醯基甲基-磺醯基亞胺（CL55675, 1.43克，5.0毫冥耳），二I等烷（2毫升）.磷酸鹽媛衝液（10毫升.0 . 3Κ , ρΗ7) , Ν , Ν -二甲基甲醯胺（4毫升）及IN NaOH。整個程序中反應温合物為非均質的。所胗成之粉紅沈澱經離心，以水清洗數次，再溶於最小量之DKF中及以水再沈澱。最終分離及乾燥取得0.7克U5.U)所要產物；熔點>250 C分解； MS (ES)m/z 6 8 3 . 7 , 685.7 (M + H) + 〇 ^例4 3 雖- M.fi-雙-「3- f唼-胺甲臨某甲甚-胺磺醯基] -¾防某i-M.s.pn三阱某防某ΐ-腊笼甚二硗酴.二纳魏標題化合物根據實例40之程序製備，使用2-氯-4,6-雙- (3-[雙-胺甲瞌基-1-胺磺醯胺基]-苯胺基}-[1,3,5] -三哄（實例42, 500毫克，0.73毫莫耳），4,4*_二胺基聯笨基-2 , 2 '-二磺酸，二納鹽（1 1 4毫克，0 . 2 9毫莫耳） ,2.5毫升0»50,2.5毫升磷酸鹽緩衝液（1»,?1]7)及1.0 毫升IN NaOH。在105¾下持续微波加熱（PR0LAB0單位， -44- 本紙掁尺度適用中國國家標準（CNS ) Λ4規格（210x29〃公徉 (請先閱讀背面之注意事項再填寫本頁) .裝' 經濟部中央標準局貝工消費合作杜印裝暇43 87 9 7 A7 B7 五、發明説明（45 ) 單式）1小時。所得混合物經施至製備性HPLC,取得50 毫克（10.2¾)呈粉紅色固體之產物：熔點>250它分解； HS(ES)m/z 818.2(H-2H)2-； MW1683.7(MW+2Na)〇管例44 4. .41-替-U.R-替-「3-(擊-防田瞌某申_ -胺碛醯基1 -苯胺基1-「1.3,51三阱-2~基防基丨-聯苤-2.2’~二羧醉 . 二納棟標題化合物根據實例40之程序製備，使用2-氯-4,6-雙- (3-[雙-胺甲鹾基甲基-胺磺醯基]-笨胺基）-[1,3, 5卜三阱（茛例42, 500毫克，0.73毫莫耳），4,4·-二胺基-2, 2^二聯笨二甲酸，二氯化氫（100毫克，0.29毫莫耳）.2.5毫升DMS0,2.5毫升磷酸鹽鍰衝液（lH,pH7)及 1.0毫升IN NaOH。在105T：下持續微波加熱（PR0LAB0單位，單式）1小時。將所得混合物經胞至製備性Η P L C , 取得20毫克（4.3¾)圼粉紅色固體之產物；熔點>25〇Ί〇分解；MS(ES)m/Z 784.0(H+2H)2t; HW1619.8(MW+2Na)。官例45 1-π -硝基-¾碏醏某）六am啶u-二羧酸在2 2 P s i下，於1克釕觸媒（5 Si釕於氧化鋁粉末上）使 Parr裝置中3·5 -毗啶二羧酸（3.34克，20毫莫耳）於50毫升水及10毫升湄氫氧化銨之溶液氫化48小時，過洚觸媒及去除溶劑後，粗3, 5 -六氫吡啶二羧酸溶於60毫升1Ν HaOH中及Μ6.6克（30毫莫耳）對-硝基苯磺醯氯處理。反應混合物在室溫下攪拌及pH藉由添加IN NaOH维持在9, 5 -45- 本紙張尺度適用中國囤家標準（CNS ) Λ4規格（210X297公漦） —--------------11------^ (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 i4 3 c' / ： / A7 B7五、發明説明（44 ) 直至其停止掉落。反應混合物再攪拌1.5小時，過滤形成之沈澱及濾液以濃HC1酸化至PH2-3。過漶形成之白色沈澱，K水清洗及在高度真空下乾燥過夜取得5.3克 (74¾}所要產物。1 H-NMR(DMS〇-ds, 300ΜΗζ)δ 8.55 (d, 1H), 8.40(s, 1H), 8.15(d, 1H), 7.95(t, 1H), 3.14Cni, 4H) , 1.65(m, 2H), 1.45(n, 2H)； M S ( E S ) m / z 359(M+H) + ° 奮例 1-(3 -硝某-¾碏醣某）六ffllie啶-二掰醵二申_ 在01下藉由過量重氮甲烷處理1-(3 -硝基-苯磺醢基）六氫吡啶-3,5 -二羧酸（實例45, 3.6克，10毫萁耳）於 THF (200毫升）之懸浮液，並在該溫度攪拌直至懸浮液轉為清激鮮黃色溶液。將反應混合物加溫至室溫，過濾、蒸發及藉由在矽凝膠上進行管柱層析而純化，以氯仿溶離取得2.5克（6U)圼無色晶體之所要產物。1 H-NMR (CDCla , 300 ΗΗζ) δ 8 . 65 (s , 1H), 8.49(d, 1H), 8.11 id, 1H), 7.81(t, 1H), 3.73(s, 6H), 3.40(m, 4H), 2 . 9 5 ( n , 2 H )，2 · 0 5 (t , 2 H ) ; M S ( E S ) b / z 3 8 7 · 2 ( M + H ) +。 IF 例 47 1-( 3-硝某-¾確酺某）六氣毗啶-3. 5 -二狰辭二瞌胺密封1_(3_硝基-苯磺醸基）六氫吡啶_3,5-二羧酸二甲酯（實例46, 2.5克，6,5毫莫耳）於200毫升甲酵（在下Μ氨飽和）之溶液及留置在室溫下7天。將所得黃色溶液濃縮至體積100毫升，過瀘形成之沈澱，Κ甲醇清 nv ^^^^1 ^^^^1 I mu i^i^i ^^^^1 a^m is令-=, (請先閔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 ) Λ4規格（210X 297公釐）經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（45 ) 洗及乾燥取得1.8克（77.7¾)呈淺米色結體之產物。MS (ES)m/z 357.1(M+H) + 。奮例48 1-(3-硪某-笼碏縮某）六S 啶-3.5-二搿酸在25psi下使1-(3 -硝基-笨磺醯基）六氫吡啶-3,5 -二羧酸（實例45, 2.5克，4.2毫莫耳）於150毫升甲醇之溶液在Pa「「裝置中於0.15克鈀觸媒（10¾鈀於碳上）氫化1 小時。過濾觸媒及去除溶劑取得1.8克（79¾)圼白色固體之所要產物。MS(ES)m/z 329.1(M + H)+ 奩例49 1-ί 3-硪某-¾碏魅基）六瓴毗啶-3.5-二搿酸二醢胺在25psi下使1-(3 -硝基-苯磺醚基）六氫吡啶-3,5 -二羧酸（實例47, 1.5克，4.2毫莫耳）於300毫升甲醇之溶液在Parr裝置中於0.1克鈀觸媒（10¾鈀於碳上）氫化1.5 小時。過滤觸媒並去除溶劑取得1.26克（92¾)圼淺灰色固體之所要產物。MS(ES>a/Z 327.1(Μ+ΗΓ 啻例50 2-氧-4.6-饕-「3-(3.5-二防甲醢某-六氩_啶-1-確糖某） -¾防某1-Μ.3.51三哄在0-2 及撹拌下將三聚氯化氰（280毫克，1.5毫莫耳）於二喟烷（5毫升）之溶液加入璘酸鹽鍰衝液（10毫升，0.3M ,pH = 7)中。於所得懸浮液逐滴加人1-(3-胺基-苯磺瞌基）六氫吡啶-3,5 -二羧酸二醯胺（實例49, 1,0克，3.1 毫莫耳）於Κ,Ν-二申基甲醯胺（5毫升）之溶液，pH藉由添 ___1-___^__________T 、v'° (請先閡讀背面之注意事項再填寫本頁〕本紙蒗尺度適用中國國家標準（C'NS ) Λ4規格（2丨0>< 297公釐）經濟部中夬標準局員工消費合作社印裝 4387 9 7 A7 B7五、發明説明（扑）加NaOH維持在6.5-7.2。添加完全後，將反應混合物加潙至50-551C及在該溫度下搅拌2小時（直至HPLC顯示反磨完全），皤後冷卻至室溫，以水稀釋，過濾產物沈溅， Μ冷水（10毫升）、丙嗣（5毫升）清洗及在真空與20C下乾燥取得8 4 5毫克（7 4 . 2 ；Π所要產物；熔點> 2 5 0 t分解； MS(ES)b/z 765·0(Μ+Η), MW764.2。奩例 2~氛一4.fi_等— —斑某一六氣Sft.瞭一1-確随甚）一笼防某1 - Μ . 3 . 5 1三阱標題化合物根據實例50之程序製備，使用三聚氮化氰 (280毫克，1.5毫莫耳），1-(3 -胺基-苯磺醢基）六氫毗 .啶-3,5 -二羧酸（實例48, 1.0克，3.1毫奠耳），二鸣烷 (3毫升），磷酸鹽媛衝液（10毫升，0.3M，ρΗ7), Ν,Ν-二甲基甲釀胺（5牽升）及IN NaOH。反應完全後，將混合物冷卻至室溫，以水稀釋，MHC1酸化至pH5,過濾產物沈澱，Μ冷水（10毫升）清洗及在2〇υ下真空乾烽取得 8 4 5毫克（7 4 . 2 3S)所要產物；熔點2 5 0 1C分解；M S ( E S ) β / ζ 769.0 (Η + Η) , HW767 . 8 ° 窨例52 (R) -2,2 ’ 一Π.2-7,懦二基）雙-等「「3-ΓΓ3.5 —等 (防羰基六氣吡畦基1碏瞌基1茏某]防某-三阱-2-基1胺基〗笼碏醅1二納篇在密封之厚壁玻璃管中將4 ,4'-二胺基二苯乙烯-2,2' -二磺酸，二納鹽（0.41克^ 0.1毫莫耳）及2-氯-4,6-雙--4 8 ~ ________ ^______^4 ! 1 i I ί I i， I I I — ，1Ί (請先閱讀背面之注意事項再填寫本頁) 本纸張尺度適用中國國家標準（CNS ) Λ4規格（2I0X297公釐）經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（47 ) [3-(3,5 -二胺甲醢基-六氫吡啶-1-磺瞌基 >苯胺基]-[1, 3,5]三哄（實例50)(1.62克，0.21毫莫耳）於瑁丁硪（3毫升）及二甲基甲醢胺（5毫升）之懸浮液於二異丙基乙胺 (0 . 0 8毫升）存在下加溫至1 1 5 。持鑛加溫4 0小時。一旦由分析性HPLC(或TLC)判定反應完全，混合物冷卻至 3 0 C，將1 N N a 0 Η ( 0 . 5毫升）加入及產物藉由添加丙-2-酵（50毫升）沈教。過濾沈澱物，以丙_(30毫升）清洗及再溶於最小體横之水中，藉由添加乙醇再沈濺。過瀘後沈澱Μ乙醇（30毫升）清洗，在501下真空乾燥。產率 1,5M(85S!);MS(ES)id/z911.7(M-2H)2，；MW 1 869.9 (2Na) ° 管例53 - (4.6-零-「3-(3·5-二脓甲醃某-六氣卅啶-1-碏瞌某1-笼防某1-「1.3.5 1三阱-2-某防某）-瞄笼-2.2'-二碏酵二納确標題化合物根據實例52之程序製備，使用4,4’-二胺基聯笨基-2,2’-二磺酸，二納鹽（40毫克，0.1毫莫耳）及2-氯-4 ,6-雙-[3-(3,5-二胺甲醢基-六氫吡啶-1-磺醯基）-苯胺基]-[1,3,5]-三阱（實例50)(176毫克，0.23毫莫耳）於60毫升D MS 0-環丁 δ思（1:3,體積/體橫）及二異丙基乙胺（0.08毫升）中。產物圼米色固體（153弯克， 83¾)取得；熔點>250f *W;MS(ES)(m/z)898.3(H-2H)2-；Η¥1843.9(M+2Na) 〇 ^^^^1 ^—^^1 ν^ι^ϋ. n^i 1^^—« 1^1^1 nn I a^l \ ,1 (請先閲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 ) Λ4規格（210X 297公釐）經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（48 ) 實例54 1.2'.1\1”’-「（2.2'-二碏酸某『1.1’-瞄笼1-4.4_-二某） -<»[邸防某-1.：?.5-三哄-朽.？.4-三某等（亞防甚-3.1-伸茉甚碏醣某Ί肆「八六镢PB啶二羧醚標題化合物根據實例52之程序製備，使用4, 4’-二胺基聯苯-2,2’-二磺酸，二納鹽（270毫克，0.68毫莫耳）及2 -氯-4,6 -雙-[3-(3,5 -二羧基-六氮毗啶-1-磺醯基} -笨胺基]-Π,3.5]三阱（實例51)(1.1克，1.43毫莫耳）於60奄升DMS0-環丁硯（1:1,體積/體積）與二異丙基乙胺（1 . 2毫升）中。產物在添加丙-2-酵沈澱後過瀘，Μ丙嗣（30毫升）清洗，乾燥，再溶於最小量之水中，及藉由酸化（HC1)至ρΗΙ-2而再沈澱。所得產物圼米色固體 (1.0 克，80¾)取得；熔點 >2501 分解；HS(ES)U/z) 90 2 ‘ 2 (M-2H) 2—; MW 1 80 7. 8 〇 g M SB 某- Η·Ν-_ (2-撣7』基）碏醣某亞脬將二乙酵胺（Aldrich; 25.0克，0.238毫莫耳）溶於55 牽升9:1二氯甲烷/THF中及冷卻至5T。在10分鐘内將 3-硝基笨磺釀氯（Aldrich; 25.0克，0.113奄莫耳）於35 毫升THF之溶液加入。移除冰浴，反應再攪拌30分後。随後溶劑經汽提、殘渣分配於水（100牽升）及醋酸乙酯 (150毫升）間。水層K三個25毫升份之醋酸乙酯萃取。合併之有機層在MgS〇4上乾燥，通過矽石墊過逋及在真空中濃縮。在此蒸發期間结晶出產物及過濾取得17.4克 -50" _____;______艮______丁 (請先閲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（210X 297公釐）經濟部中央標準局員工消費合作社印製 i43 8 / 9 ( A7 B7五、發明説明（49 ) (53.2SO 白色針狀结晶。熔點 99-10〇υ。MS(ES)m/z 291 . 2 (M + H ) 1+。 g 柳？ifi 使硝基化合物（實例55, 17.2克，59.3毫莫耳）及1.72 克10¾ Pd/C懸浮於170毫升乙酵中。混合物在40psi氫下堪原2小時。將鼸媒遇濾去除及蒸發透明無色漶液至乾取得15.4克（98»；產率）之對應胺基化合物。》^(日$)*/2 261.0(H + H)1+。啻例57 尊「零- (2-锊Z某）-辟碏瞌某1-茉防某Ί-「1.3 .5 1-三阱-2 -某肪某】-瞄笼-2.2'-二搏醚二納at 在0 t：下將三氯三阱U . 5 5克，8 . 4毫莫耳）於2 0毫升二喟烷之溶液加入60毫升pH7媛衝液中。於所得微細懸浮疲中逐滴加人4,4’-二胺基-2,2〜二聯笨二甲酸（P.R.232 -10; 1.55克，4.0毫莫耳）於10毫升水之溶液，M1N HaOH保持pH於6,5-7.丨内。一旦添加完全及pH安定，使反應混合物回至周溫。將二乙酵磺釀胺（2.6克，10毫莫耳）於20奄升二挎烷之溶液及固態碳酸氫钠（0.8 4克，10 毫莫耳）加入及所得混合物在迴流（92υ)下加熱2天。將清澉的黃色溶液冷卻及將二枵烷汽提出。產物自水性溶液中沈澱出及藉由真空過濾收集取得3.16克所要化合物，由HPLC判定約65¾純度，圼白色非晶形固體。熔點 -51- ^^^1 I ^^^1 n I n ^^^1 ^^^1 nn HI—--V 穿-旮 {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（210X 297公釐）經濟部中夬標準局員工消費合作社印製 4^8797 A7 B7五、發明説明（50 ) >250ΐ：分解；MS(ES)U/z)732.5(M + 2H)2t; MW1507.6 (M+2Na卜窖例58 3 -腌茉某-等-Ο鸦丙某）碏醢某亞防在0TC,氮氣及攪拌下將3-胺苯基-Μ,Ν-雙-(2-甲氧基羰基-乙基）磺醢基亞胺（實例31, 150毫克，0,4毫莫耳）於THFU5毫升）之溶液加人LiAlH4 (3毫升，1Μ於THF)中。45分鐘後，TLC顯示反應完全。將氛化銨（15毫升， 1H)溶液加入該溶液中，白色沈澱形成，溶液轉為黃色。變黃之溶液經傾析及白色沈澱Μ醋酸乙®清洗。有機層在硫酸納上乾煉及旋轉式蒸發取得呈黃色油狀之所要產物。產率為 1 1 0 毫克（9 5 . 6 Si) , ( a / z ) : Μ Η 2 8 9 . 2。當例5 9 簪- U.fi-二-「3-防笼某-H等挥而某）-碏醣某茆胺某1-1. 3.5 -三阱某防某）〜聪笼-2.2'-二碏酸 ,二納見標題化合物使用實例1之一般條件製備，其中三聚氯化氰（92毫克，0.50奄莫耳）與4,4’-二胺基聯苯- 2,2’-二磺酸，二納鹽（93毫克，0.24毫莫耳）反應]小時，陲後與3-胺苯基-Ν,Η-雙（3-羥丙基）磺醢基亞胺（708毫克， 2,5毫莫耳）（實例58)反麽。一旦由分析性1^1^(或1^(：) 判定反應完全，混合物冷卻至20C,產物藉由添加丙-2 -醇（40毫升）沈澱，在滹器上Μ冷丙-2-酵（15毫升）清洗，及在40 t下真空乾燥。兩份粗產物（約0.35克）於去齄 -52- (請先閱讀背面之注意事項再填寫本頁) 裝 ,ιτ 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公釐）經濟部中央標隼局員工消費合作社印製 A7 B7五、發明説明（51 ) 子水（200毫升）之溶液藉由製備性ϋΡ-HPLC分別纯化。合併含有所要產物之溶離份，在真空及301下蒸發有櫬溶劑、灑縮產物、除鹽及經由十八基（C18)柱 (900 毫克，取自 Burdick 8< Jackson)單離。柱 Μ 水（40 毫升）清洗及產物Μ甲醇（60毫升）再萃取。蒸發甲酵取得162毫克（40¾)所要產物；熔點>30〇υ分解；MS(ES> (n/z): M_2 822.4; MV1690.8。化合物存病畜畜昼滅少制宙中夕放果化合物使用病毒產量減少測定試驗生物活性。宿主细胞（人類***纖維母细胞稱為HF,及常用之非洲綠猴细胞株稱為vero,於表1及la中）以4X104细胞/井孔載於96井孔盤（0.1毫升/井孔）内含2¾胎牛血清或2¾牛血清之细胞生長培養基中並培育過夜。將化合物加入各別井孔中Μ在二次濃縮步驟中取得經濃度50至0.1撤克 /毫升。1小時後，將病毒加人及持鑛與RSV或CMV — 起培育4天及與HSV —起2天。實驗結束時，定量病毒生長量及計算在化合物不同濃度下之產量減少。此可估計出產生病毒生長50¾減少（IC5D)之化合物濃度。表1及la (生物活性之摘述）摘述化合物在病毒產量減少測定中之活性。化合物存病羞溶菌斑緘少湖[宙中少效果試驗化合物抑制病毒溶菌斑形成之能力。宿主细胞，如表1 , la及2所指出，K106细胞/井孔載於6-井孔盤中並培育過夜。陲後進行二方式之一。在一般（預處 I 策訂 (請先閲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 ) Λ4規格（210X 297公釐） A7 B7 五、發明説明（52 ) 理）方式中，细胞生長培養基Ml毫升含有特定濃度之化合物的培養基取代。1小時後加入病毒（40微升中〜 100個溶菌斑形成軍位）。又1小時後，培養基Μ 4毫升含有試驗濃度之化合物的培養基取代。再培育细胞足夠的時間Μ形成病毒溶菌斑。有時，化合物僅在感染開始後（處理後）添加。此情形下，生長培養基Κ1毫升含有約100個溶菌斑形成單位之培養基取代。1小時後，此以2毫升生長培養基取代。又經表2所界定之時段後 ,又加入2毫升含有化合物者。兩種情形下，在一系列含化合物滬度範圍之井ΪΙ中的溶菌斑數目不含化合物之井孔中的數目相較，IC so藉由將數據晝_及確認產生病毒溶菌斑數目減少50¾之化合物湄度而決定ICbo。表1 , la及2摘述溶菌斑測定中之抗病毒活性。可觀察到實例1及4之標題化合物在約0.1-0.7微克/微升下可對抗所有試驗之RSV菌株。活性亦可由其他病毒屬中特定成員察得（3-2 0微克/毫升範圍内）。此等结果確認及延伸來自產量減少測定之數據，顯示此等化合物為 RSV之強有力且為專一性的抑制劑。 ^^^1 ^^^^1 ^^^^1 ^^^^1 ^^^^1 n^i , I ttnn ί 、、-'a (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作杜印製 -54** 本紙張尺度適用中國國家標準（CNS ) Λ4規格（2)0X 297公釐）五、發明説明（π ) A7 B7 化合物對抗呼吸道合胞病毒、巨细胞病毒及單純疱疹病毒之活體外活性經濟部令央標隼局員工消費合作社印製實例 fb合物生長抑制中之 1C 50 u G/biL 溶菌斑测定中之 ICso ju G/roL RSV/ HF RSV/ VERO CMV/ HF HSV/ HF HSV/ VERO RSV/ VERO CMV/ HF HSV/ VERO 11 10 10 >50 9 <3 0.4 0.3 10 10 <3 0.7 6 >50 >50 >50 1 0.3 0.5 0.3 7 8 4 0.1 0.1 35 20 35 0.1 >30 35 5 0.4 8 7 0.7 1 0.8 10 8 >50 >50 >50 12 8 10 13 8 8 20 10 30 15 7 >8.3 2 1 16 5 ~8·3 3 3 17 >50 >50 >50 19 2 3 12 30 ~50 20 0.5 40 22 0.15 0,25 4 2 23 8 20 24 50 25 301H), 3. 0 2 (d, 2 H), 2. 8 0 (dd, 1H); 1. 16 (dd, 6H); MS (ES) m / z 2 8 9. 5 (M + H ) + 0 Cao Example 39 2 Second atmosphere: -4.6 --- (3- [Bis- (2-Pingxi..yl) -sulfamoylphenylanilide [1,2, .. 51 -tri The compound was prepared according to the procedure of Preparation Example 33 using cyanuric nitride (160 mg, G.87 mmol), 3-aminophenylbis (2-hydroxypropyl) sulfonylimine (7 fl G mg, 2.0 mmol), dipentane (3 ml), phosphate M buffer (10 ml, 0.3 M, ρίΠ), Ν, Ν-dimethylformamide (5 ml), and IN NaOH. The product was precipitated as a viscous amber-yellow oil from the cooled reaction mixture with water, washed with water and dried under high vacuum seven to obtain 64 0 mg (9 3 Si) gas triple trap. Melting point> 2 50 ° C decomposition; MS (ES) m / z 687,7, 689.7 (M + H) +. -4 2-This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)----II-- -*-^^ 1 ^^ 1 -I -I ^^ 1 Wear, v include (please read the precautions on the back before filling this page) The Central Consumer Affairs Bureau of the Ministry of Economic Affairs, the Consumer Cooperatives, printed in the Ministry of Economic Affairs Standard Bureau employee consumer cooperative stamp A7 B7 V. Description of invention (41) Example 40 4.4'- 簪-(4.6-Beep- {3- "Enough- (2-Choose a)) Ϊ́ 「-" 1 .3.M-San coax -2- defend）)-Satoshi--2.2'- Disulfapone. Di Na 锞 2- 2- 氛 -4,6- 双-〖3- [双-(2-Hydroxypropyl) -aminosulfonyl] -aniline}-[3,5] -triple (Example 39,300 mg, 0.44 mmol), 4,4'-diamine Diphenyl-2,2'-disulfonic acid, disodium salt (77 mg, 0.2 mmol), 2 ml DMS 0, 2 ml phosphate buffered spinach (1 Ν, ρ Η 7) and 0.25 ml IN NaOH The mixture was exposed to llOt: microwave heating (PR0LAB0 units, single type) for 2 hours. After cooling, the untreated reaction mixture was subjected to preparative HPLC (water / acetonitrile system) on a Prodigy C18 polymer column. The product was obtained as a colorless solid (170 mg, 50.2%); melting point > 25〇υ decomposition; MS (ES) m / 2 822,3 (M-2H) 2 '; MW1691.9 (MW + 2Ha) ^ 窨Example 4.41-Substitute--wait-U- "bis- (2 -fluorenyl-propanyl) -aminopyridyl] -cage defense 1-" 1.3. 51-trihydrazine-2-protection of a certain target- 2.2'- 二搿酹. Two nanometers in the oven 2-Chloro-4,6-bis- (3- [bis- (2-hydroxy, -propyl) -sulfamoylphenylanilide}-[1,3,5] _triple ( Example 39, 178 mg, 0.25 millimolar), 4,4'-diamino-2,2'-diphthalate dihydrochloride (35 mg, 0.11 millimolar), 3 draft DMS0 , A mixture of 0.5 ml of phosphate rhenium (IN, pH 7) and 0.5 ml of 1H NaOH for 18 hours. After aging, apply preparative HPLC to obtain 90 mg (please read the precautions on the back before filling this page). The scale is applicable to the Chinese National Standard (CNS) Λ4 specification (210X297 mm) Β < 3. ΙΟ. 12 A7 B7 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. The invention product (42) (50, 5¾) is the desired product. Melting point> 250t: Decomposition; MS (ES) B / z 788, l (M + 2H) 2f; MW1619'8 (MW + 2Na). Example 42: Buqi-4.fi-zun-II-bis-fatyl-methyl-amino-sulfanyl-sulfanyl 1-¾and 1-η. 3. s 1-Triple well titled the compound according to the procedure of Example 33 Prepared using tripolymethylene chloride (0.42 g, 2.27 mmol), 3-aminophenyl-fluorene, N-bis-aminomethylmethylmethyl-sulfonylimine (CL55675, 1.43 g, 5.0 mmol) Ginger), Di-I alkane (2 ml). Phosphate solution (10 ml. 0.3K, ρΗ7), Ν, Ν -dimethylformamide (4 ml) and IN NaOH. Reactions throughout the procedure The warm compound is heterogeneous. The resulting pink precipitate is centrifuged, washed several times with water, redissolved in the smallest amount of DKF, and re-precipitated with water. Finally, 0.7 g of U5.U) is obtained as the desired product. ; Melting point> 250 C decomposition; MS (ES) m / z 6 8 3. 7, 685.7 (M + H) + 〇 ^ Example 4 3 Although-M.fi-bis- "3-f 唼 -amine methylpro Some methyl-amine-sulfonyl] -¾ anti-iM.s.pn triple-well anti-a certain hydrazone-wax cage even dihydrazine. The dinawei title compound was prepared according to the procedure of Example 40 using 2-chloro-4 , 6-Bis- (3- [bis-aminomethylamidin-1-aminesulfonamido] -aniline}-[1,3,5] -trioxo (Example 42, 500 mg, 0.73 mmol) ), 4,4 * _diaminobibenzyl-2, 2'-disulfonic acid, dinaline (114 mg, 0.29 mmol), 2.5 ml 0 »50, 2.5 ml phosphoric acid Salt buffer solution (1 »,? 1] 7) and 1.0 ml IN NaOH. Continuous microwave heating at 105¾ (PR0LAB0 units, -44- This paper is sized according to the Chinese National Standard (CNS) Λ4 specification (210x29 〃〃 (please Please read the precautions on the back before filling this page). Install the 'Paperworker's Cooperative Du Duxue of the Central Bureau of Standards of the Ministry of Economy 43 87 9 7 A7 B7 V. Description of the invention (45) Single type) 1 hour. By preparative HPLC, 50 mg (10.2¾) of a pink solid product was obtained: melting point> 250; it decomposes; HS (ES) m / z 818.2 (H-2H) 2-; MW1683.7 (MW + 2Na) 〇Tube Example 44 4. .41-Tie-UR-Tie- "3- (Striking-Ada-Shen Shen-Amine-Amino-1 -Anylamino 1-" 1.3,51 Triple Well-2 ~ Base丨 -Difluorene-2.2 '~ dicarboxyl. The title compound of dinathan was prepared according to the procedure of Example 40 using 2-chloro-4,6-bis- (3- [bis-aminomethylamidomethyl-aminesulfonate Fluorenyl] -benzylamino)-[1,3,5b triple wells (42,500 mg, 0.73 mmol), 4,4 · -diamino-2, 2 ^ United stupid acid, dihydrochloride (100 mg, 0.29 mmol ear Mo) .2.5 ml DMS0,2.5 mL phosphate fines flushing (lH, pH7), and 1.0 mL of IN NaOH. Microwave heating (PR0LAB0 unit, single type) was continued at 105T for 1 hour. The resulting mixture was passed through a preparative ΗPLC to obtain 20 mg (4.3¾) of a product as a pink solid; melting point > 25.0% decomposition; MS (ES) m / Z 784.0 (H + 2H) 2t; HW1619 .8 (MW + 2Na). Official Example 45 1-π-Nitro-¾ 碏醏 a) Hexamidine u-dicarboxylic acid at 2 2 P si in 1 g of ruthenium catalyst (5 Si ruthenium on alumina powder) in Parr device Hydrogenated 3 · 5-pyridinedicarboxylic acid (3.34 g, 20 mmol) in 50 ml of water and 10 ml of ammonium hydroxide solution for 48 hours. After the catalyst and the solvent were removed, the crude 3, 5-6 Hydropyridine dicarboxylic acid was dissolved in 60 ml of 1N HaOH and treated with 6.6 g (30 mmol) of p-nitrobenzenesulfonyl chloride. The reaction mixture was stirred at room temperature and the pH was maintained at 9, 5 -45 by the addition of IN NaOH. This paper size is applicable to the Chinese Standard (CNS) Λ4 specification (210X297 cm) ---------- ----- 11 ------ ^ (Please read the precautions on the back before filling out this page) i4 3 c '/: / A7 B7 printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 44) until it stops falling. The reaction mixture was stirred for another 1.5 hours, the precipitate formed by filtration and the filtrate was acidified with concentrated HC1 to pH 2-3. A white precipitate was formed by washing, washed with K water and dried under high vacuum overnight to obtain 5.3 g (74¾) of the desired product. 1 H-NMR (DMS 0-ds, 300MΗζ) δ 8.55 (d, 1H), 8.40 (s, 1H), 8.15 (d, 1H), 7.95 (t, 1H), 3.14Cni, 4H), 1.65 (m, 2H), 1.45 (n, 2H); MS (ES) m / z 359 (M + H) + ° Fen example 1- (3 -Nitro- ¾ 碏 sugar a) hexa ffllie pyridine-di hydrazine _ 1- (3-nitro-benzenesulfonyl) was treated with excess diazomethane at 01 A suspension of hexahydropyridine-3,5-dicarboxylic acid (Example 45, 3.6 g, 10 mF) in THF (200 ml), and stirred at this temperature until the suspension turned into a clear, bright yellow solution. The reaction mixture was warmed to room temperature, filtered, evaporated, and purified by column chromatography on a silica gel. The desired product was obtained by dissociation with chloroform to obtain 2.5 g (6U) of colorless crystals. 1 H-NMR (CDCla, 300 ΗΗζ) δ 8.65 (s, 1H), 8.49 (d, 1H), 8.11 id, 1H), 7.81 (t, 1H), 3.73 (s, 6H), 3.40 (m , 4H), 2.9 5 (n, 2 H), 2.05 (t, 2H); MS (ES) b / z 3 8 7 · 2 (M + H) +. IF Example 47 1- (3-Nitro- ¾-Confirmed) Hexa-pyridine-3. 5-Dihydrazidine dihydrazine seal 1_ (3_nitro-benzenesulfonyl) hexahydropyridine_3, A solution of dimethyl 5-dicarboxylate (Example 46, 2.5 g, 6,5 mmol) in 200 ml of formic acid (saturated with ammonia at lower pH) and left at room temperature for 7 days. The resulting yellow solution was concentrated to a volume of 100 ml, and the precipitate formed by 泸 was clarified with nv ^^^^ 1 ^^^^ 1 I mu i ^ i ^ i ^^^^ 1 a ^ m is let-=, (Please read the notes on the back of the book before filling in this page) This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (45 ) Wash and dry to obtain 1.8 g (77.7¾) of light beige colored product. MS (ES) m / z 357.1 (M + H) +. Example 48 1- (3- 硪 a-cage-condensed) hexaS-pyridine-3.5-diphosphonic acid enables 1- (3-nitro-benzylsulfonyl) hexahydropyridine-3,5-at 25 psi A solution of a dicarboxylic acid (Example 45, 2.5 g, 4.2 mmol) in 150 ml of methanol was hydrogenated in a Pa "device at 0.15 g of palladium catalyst (10 palladium on carbon) for 1 hour. The catalyst was filtered and the solvent was removed 1.8 g (79¾) of the desired product was obtained as a white solid. MS (ES) m / z 329.1 (M + H) + Example 49 1-ί 3- 硪 some-¾ 碏 meryl) hexapyridine-3.5- Diammonium diacetate was used to make 1- (3-nitro-benzenesulfonyl) hexahydropyridine-3,5-dicarboxylic acid (Example 47, 1.5 g, 4.2 mmol) in 300 ml of methanol at 25 psi. The solution was hydrogenated in a Parr device at 0.1 g of palladium catalyst (10 palladium on carbon) for 1.5 hours. The catalyst was filtered and the solvent was removed to obtain 1.26 g (92 ¾) of the desired product as a pale gray solid. MS (ES > a / Z 327.1 (Μ + ΗΓ 啻 Example 50 2-Oxygen-4.6- 饕-"3- (3.5-Dimethylformate-hexagonal_pyridine-1-contained sugar) -¾Protect 1-M.3.51 Add a solution of cyanuric chloride (280 mg, 1.5 mmol) in dioxane (5 ml) to the osmium osmium solution with 0-2 and mash. 10 ml, 0.3M, pH = 7). To the resulting suspension was added dropwise human 1- (3-amino-benzenesulfonyl) hexahydropyridine-3,5-dicarboxylic acid dioxamine (Example 49 , 1,0 g, 3.1 mmol) in K, N-dishenylformamide (5 ml), pH by adding ___ 1 -___ ^ __________ T, v '° (Please read the back Note: Please fill in this page again.] This paper's standard is applicable to the Chinese National Standard (C'NS) Λ4 specification (2 丨 0 > < 297 mm) Printed by the Consumer Cooperative of the China Standards Bureau of the Ministry of Economic Affairs 4387 9 7 A7 B7 Description of the invention (puff) Add NaOH to maintain at 6.5-7.2. After the addition is complete, add the reaction mixture to 50-551C and stir at this temperature for 2 hours (until HPLC shows complete back-grinding), and then cool to room temperature. Diluted with water, filtered the product to splash, washed with cold water (10 ml), propane (5 ml), and dried under vacuum at 20 C to obtain 8 4 5 mg (7 4.2; Π desired product; melting point> 2 5 0 t decomposition; MS (ES) b / z 765 · 0 (Μ + Η), MW764.2. Example 2 ~ Xiayi 4.fi_etc.-Spot a certain six gas Sft. Yi 1-indeed with Even) a cage against a 1-M. 3. 5 1 triple well standard The compound was prepared according to the procedure of Example 50 using cyanuric nitride (280 mg, 1.5 mmol), 1- (3-amino-benzenesulfonyl) hexahydropyridine-3,5-dicarboxylic acid (Example 48, 1.0 g, 3.1 mil), dioxane (3 ml), phosphate solution (10 ml, 0.3M, ρΗ7), Ν, Ν-dimethylmethanamine (5 drafts) And IN NaOH. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, acidified to pH 5 with MHC1, and the product precipitated was filtered, washed with cold water (10 ml) and dried under vacuum at 20 ° to obtain 8 4 5 mg (7.4 2 3S) desired product; melting point 2 50 0 1C decomposition; MS (ES) β / ζ 769.0 (Η + Η), HW767. 8 ° 52Example 52 (R) -2,2 'a Π.2-7, 懦二Radical) bis-equal "3-ΓΓ3.5 — etc. (anti-carbonyl hexafluoropyridyl 1 fluorenyl 1 碏瞌 1 茏]] anti-tri-trap-2-yl 1 amine〗 cage 碏醅 1 2 Na Na In a sealed, thick-walled glass tube, 4,4'-diaminostilbene-2,2'-disulfonic acid, dinaline (0.41 g ^ 0.1 mmol) and 2-chloro-4,6 -Double--4 8 ~ ________ ^ ______ ^ 4! 1 i I ί I i, III —, 1Ί (Please read the precautions on the back before filling this page) This paper size applies the Chinese National Standard (CNS) Λ4 specification (2I0X297 mm) A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (47) [3- (3,5 -Diaminomethylpyridinyl-hexahydropyridine-1-sulfonyl) > Aniline Base]-[1, 3,5] Three coaxes (Example 50) (1.62 g, 0.21 mmol) in Tintin (3 ml) and two A suspension of methylformamide (5 ml) was warmed to 115 in the presence of diisopropylethylamine (0.08 ml). The ore was warmed for 40 hours. Once analyzed by HPLC (or TLC) judged that the reaction was complete, the mixture was cooled to 30 C, 1 NN a 0 Η (0.5 ml) was added and the product was precipitated by adding propan-2-enzyme (50 ml). The precipitate was filtered to remove (30 ml) was washed and re-dissolved in the water of the smallest body, and then re-spattered by adding ethanol. After washing, the precipitated ethanol (30 ml) was washed and dried under vacuum at 501. Yield 1,5M (85S!) ; MS (ES) id / z911.7 (M-2H) 2; MW 1 869.9 (2Na) ° tube case 53-(4.6-zero- "3- (3 · 5-dipyrazine pickled some-six gas Pyridine-1- 碏瞌 -1-cage-proof 1- "1.3.5 1 triple well-2-some-proof" -Cage-2.2'-dihydrazine dinazol The title compound was prepared according to the procedure of Example 52 , Using 4,4'-diaminobibenzyl-2,2'-disulfonic acid, di-nano salt (40 mg, 0.1 mmol) and 2-chloro-4,6-bis- [3- ( 3,5-diamine formamidine-hexahydropyridine-1-sulfonyl) -anilino]-[1,3,5] -triple (Example 50) (176 mg, 0.23 mmol) at 60 ML D MS 0-Cyclidine δ (1: 3, vol / horizontal) and diisopropylethylamine (0.08 ml). The product was obtained as a beige solid (153 g, 83¾); melting point> 250f * W; MS (ES) (m / z) 898.3 (H-2H) 2-; Η ¥ 1843.9 (M + 2Na) 〇 ^^^ ^ 1 ^ — ^^ 1 ν ^ ι ^ ϋ. N ^ i 1 ^^ — «1 ^ 1 ^ 1 nn I a ^ l \, 1 (Please read the precautions on the back before filling this page) This paper size Applicable to the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (48) Example 54 1.2'.1 \ 1 ”'-“ (2.2'- Diosmic acid "1.1'- Sighting cage 1-4.4_- Ermou"-< »[Di Fangmou-1.:?.5-Three coaxes-decay.?.4-Sanmou etc. -3.1-Dendrobonic acid, "Hexaerythridine PBidine dicarboxy ether The title compound was prepared according to the procedure of Example 52, using 4, 4'-diaminobiphenyl-2,2'-disulfonic acid, Dinadium salt (270 mg, 0.68 mmol) and 2-chloro-4,6-bis- [3- (3,5-dicarboxy-hexaazapyrimidine-1-sulfonyl} -benzylamino] -Π, 3.5] Triple well (Example 51) (1.1 g, 1.43 mmol) at 60 L DMS0-cyclobutane (1: 1, v / v) with diisopropylethylamine (1.2 ml ). The product passed through the addition of propan-2-enzyme precipitation, M propionate 30 ml), washed, dried, redissolved in a minimum amount of water, and reprecipitated by acidification (HC1) to ρΗΙ-2. The obtained product was obtained as a beige solid (1.0 g, 80¾); melting point > 2501 decomposition; HS (ES) U / z) 90 2 '2 (M-2H) 2—; MW 1 80 7. 8 〇g M SB M-Η · N-_ (2- 掸 7 ′ group) Diethylenzyme (Aldrich; 25.0 g, 0.238 mmol) was dissolved in 55 liters of 9: 1 dichloromethane / THF and cooled to 5 T. 3-nitrobenzyl chloride was made in 10 minutes (Aldrich; 25.0 g, 0.113 mol) was added to a solution of 35 ml of THF. The ice bath was removed, and the reaction was stirred for another 30 minutes. The solvent was then stripped, and the residue was partitioned into water (100 drafts) and ethyl acetate (150 Ml). The aqueous layer was extracted with three 25 ml portions of ethyl acetate. The combined organic layers were dried over MgS04, passed through a pad of silica and concentrated in vacuo. The product crystallized during this evaporation and was filtered Get 17.4g-50 "_____; ______ gen______ D (Please read the precautions on the back before filling this page) This paper size applies to Chinese national standards (CNS > A4 size (210X 297mm) Ministry of Economic Affairs Bureau of Standards staff consumer cooperative printed i43 8/9 (A7 B7 five, description of the invention (49) (53.2SO white needles. Melting point 99-10 °. MS (ES) m / z 291.2 (M + H) 1+. g Liu? ifi Suspended the nitro compound (Example 55, 17.2 g, 59.3 mmol) and 1.72 g of 10¾ Pd / C in 170 ml of acetic acid. The mixture was allowed to stand for 2 hours under 40 psi hydrogen. The solvent was removed by filtration and the transparent colorless solution was evaporated to dryness. 15.4 g (98 »; yield) of the corresponding amine compound was obtained. 》 ^ ($) * / 2 261.0 (H + H) 1+. Example 57: "Zero-(2- 锊 Zsome)-Biebusome 1-Mofang-" 1.3 .5 1-Triple well-2-Fatty]-Aiming cage-2.2 '-Second stroke Ether dinatat at 0 t: a solution of trichlorotritrap (U. 55 g, 8.4 mmol) in 20 ml of dioxane was added to 60 ml of pH 7 Yuan rinse. In the resulting fine suspension fatigue A solution of human 4,4'-diamino-2,2 ~ dibenzyl dicarboxylic acid (PR232-10; 1.55 g, 4.0 mmol) in 10 ml of water was added dropwise, and M1N HaOH was maintained at pH 6, 5-7. 丨. Once the addition is complete and the pH is stable, bring the reaction mixture back to ambient temperature. Diethyl sulfonamide (2.6 g, 10 mmol) is dissolved in 20 liters of dioxane solution and solid carbonic acid. Sodium hydride (0.8 4 g, 10 mmol) was added and the resulting mixture was heated under reflux (92 υ) for 2 days. The clear yellow solution was cooled and the dioxane was stripped. The product was precipitated from the aqueous solution and borrowed. 3.16 g of the desired compound was collected by vacuum filtration. The purity was approximately 65¾ by HPLC, and it was a white amorphous solid. Melting point -51- ^^^ 1 I ^^^ 1 n I n ^^^ 1 ^^^ 1 nn HI— --V wear- 旮 (Please read the precautions on the back before filling this page) Paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) Printed by the Consumer Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs 4 ^ 8797 A7 B7 V. Description of the invention (50) > 250ΐ: Decomposition; MS (ES) U / z) 732.5 (M + 2H) 2t; MW1507.6 (M + 2Na) Example 58 3-Pickled Moum-etc.-0 Ya Ping Mou) a certain Asian defense under 0TC, nitrogen and stirring will be 3 -Aminophenyl-M, N-bis- (2-methoxycarbonyl-ethyl) sulfonylimine (Example 31, 150 mg, 0,4 mmol) in 5 mL of THIU) and human LiAlH4 (3 ml, 1M in THF). After 45 minutes, TLC showed the reaction was complete. Aqueous ammonium (15 ml, 1H) solution was added to the solution, a white precipitate formed and the solution turned yellow. The yellowed solution was poured by The organic layer was dried over sodium sulfate and rotary evaporated to obtain the desired product as a yellow oil. The yield was 110 mg (95.6 Si), (a / z ): Μ Η 2 8 9. 2. Example 5 9 簪-U.fi-di- “3-anti-cage-H and other wavers and so on)-carbohydrate and ammonium 1-1. 3.5-triple well A certain prevention) ~ Cong Cang-2.2'-diphosphonic acid Prepared using the general conditions of Example 1, in which cyanuric chloride (92 mg, 0.50 mol) and 4,4'-diaminobiphenyl-2,2'-disulfonic acid, dinaline (93 mg , 0.24 mmol)), and then reacted with 3-aminophenyl-N, pyrene-bis (3-hydroxypropyl) sulfonylimine (708 mg, 2,5 mmol) (Example 58) ) Reverse. Once the reaction was judged to be complete by analytical 1 ^ 1 ^ (or 1 ^ (:), the mixture was cooled to 20C, and the product was precipitated by the addition of propan-2-ol (40 ml), and cold propion-2-fermentation was performed on a vessel. (15 ml) was washed and dried under vacuum at 40 t. Two copies of the crude product (about 0.35 g) were removed from 齄 -52- (please read the precautions on the back before filling this page) Packing, ιτ This paper size is applicable to China National Standard (CNS) Λ4 specification (210X297 mm) A7 B7 printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (51) The solution of water (200 ml) was purified separately by preparative HP-HPLC. The fractions containing the desired product were combined, and the hydrazone solvent, the condensed product, the desalted salt, and the single isolation through a C18 column (900 mg from Burdick 8 < Jackson) were evaporated under vacuum and 301. Column M water (40 ml) was washed and the product M was re-extracted with methanol (60 ml). The formazan was evaporated to obtain 162 mg (40¾) of the desired product; melting point > 30〇υ decomposition; MS (ES > (n / z): M_2 822.4; MV1690 .8. Compounds are stored in diseased animals. The biological activity is determined. Host cells (human foreskin fibroblasts are called HF, and the commonly used African green monkey cell line is called vero, shown in Tables 1 and 1a) are loaded in 96-well plates (0.1 in 4X104 cells / well). Ml / well) in cell growth medium containing 2¾ fetal bovine serum or 2¾ bovine serum and incubated overnight. Compounds were added to the respective wells to obtain a concentration of 50 to 0.1 g / ml in a second concentration step. After 1 hour, the virus was added to humans and held with RSV or CMV for 4 days and HSV for 2 days. At the end of the experiment, the amount of virus growth was quantified and the yield decreased at different concentrations of the compound. This can be estimated The concentration of the compound that produces a 50% reduction in virus growth (IC5D) is shown in Table 1 and 1a (excerpt from biological activity), which summarizes the activity of the compound in the determination of the decrease in virus yield. The ability of the test compound to inhibit the formation of viral plaques. Host cells, as indicated in Tables 1, 1 and 2, K106 cells / wells were loaded in 6-well plates and incubated overnight. One of two methods was performed afterwards. In general (Pre-treatment I (Please read the precautions on the back before filling this page) This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) A7 B7 V. Description of the invention (52) Principle, the cell growth medium Ml ml The medium containing the compound at a specific concentration was replaced. The virus was added after 1 hour (~ 100 plaque formation in 40 microliters). Another 1 hour later, the medium M 4 ml of the medium containing the compound at the test concentration was replaced. The cells are incubated for a sufficient time to form viral plaques. Sometimes, compounds are added only after the onset of infection (after treatment). In this case, the growth medium K1 ml of the medium containing about 100 plaque forming units was replaced. After 1 hour, this was replaced with 2 ml of growth medium. After the period defined in Table 2, 2 ml of the compound was added. In both cases, the number of lysolytic plaques in a series of wells with a range of chemical compounds in the range Ϊ1 was compared to the number of wells without chemical compounds. IC so reduced the number of bacterial plaques by 50 and confirmed that the number of virus The compound Maedo determines ICbo. Tables 1, 1 and 2 summarize the antiviral activity in the plaque assay. It was observed that the title compounds of Examples 1 and 4 were effective against all tested RSV strains at about 0.1-0.7 µg / µl. Activity can also be detected by specific members of other viral genera (in the range of 3-20 μg / ml). These results confirm and extend data from yield reduction assays, showing that these compounds are powerful and specific inhibitors of RSV. ^^^ 1 ^^^^ 1 ^^^^ 1 ^^^^ 1 ^^^^ 1 n ^ i, I ttnn ί,, -'a (Please read the notes on the back before filling this page) Economy Produced by the Central Bureau of Standards for Consumer Consumption Du printed -54 ** This paper size applies to Chinese National Standards (CNS) Λ4 specifications (2) 0X 297 mm) 5. Description of the invention (π) A7 B7 compounds against respiratory syncytial virus, In vitro activity of cytomegalovirus and herpes simplex virus Printed by the Ministry of Economic Affairs, Central Bureau of Labor, Consumer Cooperatives, printed example of 1C 50 u G / biL in growth inhibition, ICso ju G / roL RSV / HF in plaque assay RSV / VERO CMV / HF HSV / HF HSV / VERO RSV / VERO CMV / HF HSV / VERO 11 10 10 > 50 9 < 3 0.4 0.3 10 10 < 3 0.7 6 > 50 > 50 > 50 1 0.3 0.5 0.3 7 8 4 0.1 0.1 35 20 35 0.1 > 30 35 5 0.4 8 7 0.7 1 0.8 10 8 > 50 > 50 > 50 12 8 10 13 8 8 20 10 30 15 7 > 8.3 2 1 16 5 ~ 8 · 3 3 3 17 > 50 > 50 > 50 19 2 3 12 30 ~ 50 20 0.5 40 22 0.15 0,25 4 2 23 8 20 24 50 25 30

少減量 ο -0 U1-1 ， (1定Π)胞制決to细抑述atro 長所(pve 生中VI及 1 文HSF) 表如，(H 用用所所度1ε胞 ild 钿制f母抑MV維丨纖 50),皮之A2包成vf類形RS人斑為為菌株胞溶菌细及毒主 —病宿Decrease by a small amount ο -0 U1-1, (1 fixed Π) cell system must be described in detail atro long (pve middle VI and 1 text HSF), as shown in (H uses 1ε cell ild to control f mother Suppressing MV dimension (Fiber 50), the A2 of the skin into a vf-type RS human plaque is the strain cytolytic bacteria and the poisonous host-sick

本紙張尺度適用中國國家標準（CNS ) Λ4規格（210Χ297公釐） -----：------裝-- (請先閱讀背面之注意事項再填寫本頁) *·1Τ IB43 87 9 7 A7 B7 五、發明説明（55 ) 表2 實例1與4在病毒溶菌斑形成h之效果病毒囷株 IC5Q (微克/毫升） (细胞） ------------------------- 實例1 實例4 前時2 小 ^ι\ 後 4 前時小 /|\ 後 • 2This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210 × 297 mm) -----: ------ install-(Please read the precautions on the back before filling this page) * · 1Τ IB43 87 9 7 A7 B7 V. Description of the invention (55) Table 2 Effect of Examples 1 and 4 on the formation of h in virus plaque virus virus strain IC5Q (μg / ml) (cell) ------------- ------------ Example 1 Example 4 Front 2 hours ^ ι \ Back 4 Front hours / | \ Back • 2

RSV (VERO) A2 LONG 0.2 3A 9320 2B RSS2 18736 RSV (HF) A2 RSV (SKNSH) A2 RSV (HDBK) A2 HPIV3(VER0) WASH FLt) (MDCK) Al/FM/1/47 A2/HK/8/68 A2/JPN/305/57 A/Texas/36/91 5 A/Beij/32/92 B/Pana/45/90 HCHV (HF) Adl69^ 15 HSV1 (VERO) Patton HSV2(VER0) 333 12 MS 3 5 2 1 ο ο ο ο 4 ο 4 ο 4 ο ο ο ο ο 5 5 5 2 > > > 3 0 11 3 Λν 3 ο 4 ο 8 2 ο 3 > 5 3 2 ο 5 8 8 ΙΑ ϋ ο ο ο ο ο 0 6 2 0 {請先閱讀背面之注意事項再填寫本頁) 、策. .1Τ 經濟部中央標準局員工消費合作社印製 -*57- 本紙張尺度適用中國國家標準（CNS ) Λ4规格（210Χ 297公釐） A7 B7 經濟部中央標準局員工消費合作社印聚五、發明説明（ 56 ) 1 1 預處理方案中 t 6 井孔碟中之滿溢细胞 Μ 各種濃度之 1 1 化合物處理 1 小時〇 Μ 小最將病毒 (〜] 00 p f u ) 加入並在 1 I 培育後 (RS V » C Μ V 及 Η Ρ I V 3 (人類i Sfl流行性感冒病毒類型3 ，—、請 1 先 1 華盛頓菌株 ), 5 -8天 ; 流行性感冒病毒及單純疱疹病閲 1 毒 1 2 天 )計算溶菌斑 a供後處理用，首先感染佃胞1 背 I 之 1 小時及取代培養基 (含未吸附之病毒）〇在感染期结束後注意 I 2 或 24小時將含有各種澹度之化合物的培養基加人〇所項 1 1 再用细胞包括 v e Γ 0 (非洲綠猴细胞） HF (人類***纗維母填 %- 本 m 胞 ) SKHSH (人類交感神經母细胞瘤细胞）， HDBK 頁、· 1 I (Η a 〇 i η -D a r b y 牛腎细胞 )及 MDCK ( Μ a d i η - D a r b y犬臀细胞）。 1 1 作用橢轉 1 | 當實例 1 執行其作用時測定病毒生命周期之時間增 1 訂加作用機轉之了解 0 此藉由在相對於感染之各時間下添 ! 加及去除化合物與評估對病毒蛋白質合成之效果而完成 1 | 0 在冰上感染细胞 1 小時 » 去除未吸附之病 t 再在 37 1 I V 下培育經感染之细 β/τ. 服 18小時 ( 病毒吸附在冰上發生 9 1 1 但不進行融合直至溫度升至 1 8 或更高 ) ◊ 在 37 t：下培 I 育 18小時後 ( 當大部分進行之蛋白質合成由病毒 RN A 引 \ 1 導時 ) ♦ 將彐5 S- 甲碕胺酸加入達 2 小時 » 將细胞溶裂 I i 1 而經標記之蛋白質在 SDS- PAGE 凝膠上分析〇隨後病毒 N , I Ρ 及 Η 蛋白質顯琨〇若在病毒吸附後及在培育溫度升至 1 1 37 V 刖立即將 10微克 / 毫升之實例 1 化合物加入 9 則病 ! 1 毒蛋白質合成完全被防止 0 然而 r 即使是在 37 下僅培 I [ 育 5 分鐘後將實例 1 化合物加入 * 病毒蛋白質生產並未 [ 1 -58- 1 1 1 1 本紙張尺度適用中國國家標準（CNS ) A4規格（2!〇X 297公釐）絵43 8 7 9 7 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（57 ) 受阻〇因此 ϊ 被抑制之過程為融合過程或特定緊密相 m 之步驟 t 其為稍後病毒基因表現所需 0 已知緊密接觸之經 RS V 感染的细胞會融 a 形成合胞且此過程僅依存在病毒 F , SH及G 蛋白質上（H e mi η ν a y B R， Yu \ Ta n a k a Y , Pe ! Γ Γ i η e KG 1 Gu .s t a f S 0 η E , Β e r n s ;t e ί JM T Ga I i n s k i HS . 1 994 . A n a 1 y si S o f Γ e s Pi r a t 0 r y s y n c ：y t ϊ a 1 v ΐ r u S F , G a n d SH Ρ Γ 0 t e i n s i η c e ]1 f u s i on • Vi Γ 0 1 〇 ε y 200 80 1 - 80 5 ) ο 合胞形成不應涉及病毒功能，如不被覆或轉錄 t 其 - 般繼其之後發生及其為稍後病毒基因表琨所需 0 為判定本發明化合物是否抑制融合或後鑛步驟 f 試驗彼等防止先前以 RSV 感染之细胞中合胞形成之能力〇此由 3 次感染 ν e r 〇细 ttfet 胞 1 小時而 7Ό 成 9 随後 Μ 新鲜培着基取代原培養基〇 6 小時培育後 t 將化合物加入 0 在 24及 4 8小時後 1 在顯微鏡下檢視經感染之细胞 Μ 判定合胞形成之程度〇因化合物存在所產生合胞形成程度之差異容易地被確認 » 而化合物可依此測定中之強度輕易地被排序〇由此方法判定之實際 1C 50 為大約值〇化合物 16 及 17 分別為 0 . 3 及 0 . 05微克 / 毫升〇此等化合物抑制合 tUrt 胞肜成之能力證明彼等在病毒生命周期之融合步驟中作用〇筲例 1 及 4 人物於活潲内防 f卜 RS V 牛長棉花鼠以 RS V 感染接著憑藉小顆粒噴霧劑 (SPA) 作藥物傳输，此用以評估化合物於活體内之抗- RSV潛力 (Gilbert BE, Wyde PR, Wilson SZ,及 Meyerson LR. 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公釐） ^^^1· .1·^— —m^^t HR^i I ^nn n^l —^^—t--.、 -¾ Ί (請先閲讀背面之注意事項再填寫本頁) A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（ 58 ) 1 1 1 99 3. s P -30： smi 1 Ρ > a r t 1 C e a e r C S C ] t Γ e e t m e r t of 1 1 | ΐ η f U € η 2 a A v i Γ 1 1 S i r f e c t i ( )η in a i c e a η d r e s f ^ i r ' a t 〇 r y 1 1 s y n c y t i a 1 V r u S ί Γ f € c t i c η i η c otto η r a t s , A r t : viral 請 1 先 1 Re s e a r ch 21 37- 45) D 閲 1 1 本發明之化合物於此系統中試驗 Μ 判定彼等是否可在背 ιέ 1 I 之 1 棉花鼠中抑制 RS V 生長〇實驗 1 (參見表3 ) 中 t 動物 K 注意事 1 RS V A2 (第 0 曰）作典内感染造成呼吸道感染 O 氮唑項再 1 核甙 60 毫克 / 毫升於水中址俄用於噴菝室中及在感染後填寫本袈 I 第 1 » 2 與 3 曰每曰投予二次達 2 小時 0 化合物 16Μ 頁 1 1 4 . 5 毫克 / 毫升 ( 於 25 m V N aHCO 3 中 ) 用於噴霧室中及 \ \ 在感染前投予 4 小時 > 在第 1 t 2 與 3 曰各投予 8 小時 \ 1 Ο 安慰劑依化合物 1 6 之相同用法使用水〇動物在第 4 曰 1 訂時犧牲 t 肺經灌洗並判定灌洗液中 RSV 之力價〇實驗 2 1 中 y 經感染之未處理動物及暴露於 25 mM Ν aHCO 3 之噴霧 1 ! 用作對昭組〇實例 1 及 4 化合物製成 5 毫克 / 毫升於 25 1 I 9 Μ N aHCO 3 〇 —' 組在感染前第 0 曰時 Μ 實例 1 化合物處 1 1 理 4 小時及在第 1 2 及 3 曰 (預防用法）時各處理 8 小 | 時〇一組僅在第 1 > 2 及 3 曰時 (治療用法） >λ 實例 1 化 1 合物各處理 8 小畤 0 最後一組在第 1 τ 2 及 3 曰時 ( 治 1 1 療用法 ) Μ 實例 4 化合物各處理 8 小時〇在第 4 曰時 1 | 所有動物被犧牲 » 肺經灌洗及判定灌洗液中之 RSV 力價 1 I 〇實驗 3 中 > 安慰劑每曰水作鼻内傳輸一次 0 實例 4 1 1 化合物藉由在接種前及其後 1 曰 (第0 及1 日時）典內 1 I 傅輸投藥在接種 * 刖及第 1- 3 曰時 Μ 典内傳輪投 m 及僅 1 1 | "β 0 _ 1 1 1 1 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） A7 B7 五、發明説明（59 ) 在接種後第1-3日時Μ鬓内傳輸投藥而試驗。化合物亦藉由腹膜内投藥而試驗。第4日時，犧牲所有動物，灌洗其肺部並測定灌洗液中之RSV力價。此藉由測定稀釋终點（於ve「o细胞產生细胞病變（CPE))而完成。亦藉由vero细胞上溶菌斑分析而完成。肺部亦經均質化，及藉由將粒吠物質離除（1000 Xg, 10分鐘）與使用溶菌斑分析中上清液之稀釋而測定肺部中病毒之力價。可見實例 1與4化合物在活體内抑制RSV 。 ^^1· ^^^1 tn^ m an— m I Jm - In ^^^1 V. y (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局負工消費合作社印製 "61" 本紙張尺度適用中國國家標準（CNS ) Λ4規格（2I0X 297公釐） H?43 87 9 7 A7 B7 五、發明説明（吣）表3 實例1與4對抗棉花鼠内呼吸道合胞病毒之效果平均力僧實驗斑理處理法 N 樣本/分析loglO/gW SD logT(? 1 H20 噴劑 2x2h/d 5 灌洗液/CPE 4.1 0.27 dl,2,3 三氮唑核或噴劑 n JU /fflh/3 ε 2 2 m < ， ο 1 6 2 d 4 灌洗液/CPE 3.3 0 0.8 實例1 噴劑 4. δικκ/πιΐ 4h uO 8h dl，2,3 r 灌洗液/CPE 2.8 Λ Ο Γ \J * 00 1.0 未處理 4 灌洗液/CPE 3,68 0.48 安慰劑噴劑 4h dO 8h dl,2,3 4 灌洗液/CPE 3.43 0.25 0.25 實例1 噴劑 5ag/«l 4h dO 8h dl,2,3 4 灌洗液/CPE 1.73 1.15 1.95 實例1 噴劑 5ng/is 1 8h dl,2,3 4 灌洗液/CPE 3.43 0.25 0.25 實例4 噴劑 &Blg/ID 1 8h dl,2,3 4 灌洗掖/CPE 2.05 0.5 1.63 d0,1,2,3 Η 2 0鼻内投予實例4 鼻內投予 d0 15ag/k dl 30iBg/k ^^^1 I I» ml »nn ^^^1 ^^^1 I am i \ 1' (請先閱讀背面之注意事項再填寫本頁) 實例4 _ *内投予 dO 15aig/k dl,2,3 30mg/k 經濟部中夾標隼局員工消費合作社印製實例4 #内投予實例4 鼻内投予 30mg/k dl,2,3 30iag/k dl,2,3 4 灌洗液/CPE 灌洗液/溶菌斑肺/溶菌斑 4 灌洗液/CPE 灌洗液/溶菌斑肺/溶菌斑 4灌洗液/CPE 灌洗液/溶菌斑肺/溶菌斑 4灌洗液/CPE 灌洗液/溶菌斑肺/溶菌斑 4灌洗液/CPE 灌洗液/溶菌斑肺/溶菌斑 5 5 5 0 2 2 2 2 2 6 9 7 6 0 3 13 3 3 4 5 13 12 2 12 0.87 0 0 8 5 9 4 6 0 ο ο 1 5 2 7 2 2 9 ο ο ο 2 3 3 5 0 2 2 2 2 3 4 10 3 2 2 2 2 11 0.09 0.26 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公釐） -62-RSV (VERO) A2 LONG 0.2 3A 9320 2B RSS2 18736 RSV (HF) A2 RSV (SKNSH) A2 RSV (HDBK) A2 HPIV3 (VER0) WASH FLt) (MDCK) Al / FM / 1/47 A2 / HK / 8 / 68 A2 / JPN / 305/57 A / Texas / 36/91 5 A / Beij / 32/92 B / Pana / 45/90 HCHV (HF) Adl69 ^ 15 HSV1 (VERO) Patton HSV2 (VER0) 333 12 MS 3 5 2 1 ο ο ο ο 4 ο 4 ο 4 ο ο ο ο ο 5 5 5 2 > > > 3 0 11 3 Λν 3 ο 4 ο 8 2 ο 3 > 5 3 2 ο 5 8 8 ΙΑ ϋ ο ο ο ο ο 0 6 2 0 (Please read the precautions on the back before filling out this page), policies. .1T Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs-* 57- This paper size applies to Chinese national standards ( CNS) Λ4 specification (210 × 297 mm) A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (56) 1 1 Overflowing cells in the well plate at t 6 in the pretreatment scheme. 1 compound treatment for 1 hour 0 μmin. The virus (~) 00 pfu was added and after 1 I incubation (RS V »C MV and HP IV 3 (human i Sfl influenza virus type 3,-, Please 1 first 1 Washington strain), 5-8 days; Influenza virus and herpes simplex disease 1 virus 1 2 days) Calculate plaque a for post-processing, first infect the cells 1 for 1 hour and replace the medium (Contains unadsorbed virus) 〇 After the end of the infection period, pay attention to I 2 or 24 hours. Add the medium containing various compounds to the human body. 0 Item 1 1 Reuse cells include ve Γ 0 (African green monkey cells) HF ( Human foreskin 纗 Vitamin filling%-Ben m cells) SKHSH (human sympathetic neuroblastoma cells), HDBK pages, · 1 I (Η a 〇i η -D arby bovine kidney cells) and MDCK (Μ adi η-D arby canine gluteal cells). 1 1 Action Ellipse 1 | Increase the time to determine the life cycle of the virus when Example 1 performs its action 1 Add to the understanding of the action mechanism 0 This is done by adding at each time relative to the infection! Adding and removing compounds and evaluating The effect of viral protein synthesis is completed 1 | 0 Infect cells on ice for 1 hour »Remove unadsorbed disease t and incubate infected fine β / τ at 37 1 IV. Serve for 18 hours (virus adsorption occurs on ice 9 1 1 but without fusion until the temperature rises to 18 or higher) ◊ at 37 t: after incubation for 18 hours (when most of the protein synthesis is performed by the virus RN A \ 1 guide) ♦ 5 S-formamylic acid was added for 2 hours »The cells were lysed I i 1 and the labeled protein was analyzed on an SDS-PAGE gel. The virus N, IP and β proteins were then displayed. And the incubation temperature rose to 1 1 37 V. Immediately add 10 μg / ml of the compound of Example 1 to 9 and the disease! 1 toxic protein synthesis is completely prevented 0 However r even cultured at 37 I only [After 5 minutes of incubation Example 1 Compound addition * Production of viral proteins is not [1 -58- 1 1 1 1 This paper size is applicable to Chinese National Standard (CNS) A4 specifications (2! 〇X 297 mm) 絵 43 8 7 9 7 A7 B7 Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards 5. Invention Description (57) Obstructed. Therefore, the process of inhibition is the fusion process or the step of a specific close phase, which is required for the later viral gene expression. 0 Known close contact RS V-infected cells will fuse a to form syncytia, and this process depends only on the viral F, SH, and G proteins (H e mi η ν ay BR, Yu \ Tanaka Y, Pe! Γ Γ i η e KG 1 Gu .staf S 0 η E, Β erns; te ί JM T Ga I inski HS. 1 994. A n a 1 y si S of Γ es Pi rat 0 rysync: yt ϊ a 1 v ΐ ru SF, G and SH Ρ Γ 0 teinsi η ce] 1 fusi on • Vi Γ 0 1 〇ε y 200 80 1-80 5) ο syncytia formation should not involve viral function, if it is not covered or transcribed, it-usually occurs after it and it is required for viral gene expression later. 0 To determine whether the compound of the present invention inhibits fusion or post-mine step f test The ability to prevent syncytia formation in cells previously infected with RSV. This was caused by 3 infections of νer. Ttfet cells for 1 hour and 7% to 9% followed by fresh culture medium instead of the original medium. After 6 hours of incubation Add 0 after 24 and 48 hours 1 View the infected cells under a microscope to determine the degree of syncytial formation. 0 The difference in the degree of syncytia formation due to the presence of the compound can be easily confirmed »and the compound can be determined based on this strength Easily sorted. The actual 1C50 determined by this method is approximate. Compounds 16 and 17 are 0.3 and 0.05 micrograms / ml, respectively. The ability of these compounds to inhibit the formation of tUrt cells proves that they are resistant to viruses. The role of the life cycle in the fusion step. Example 1 and 4 characters in the living body to prevent RS V bovine cotton rats infected with RS V followed by small particle spray (SPA) for drug delivery, this is used to evaluate compounds In vivo resistance-RSV potential (Gilbert BE, Wyde PR, Wilson SZ, and Meyerson LR. This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X297 mm) ^^^ 1 · .1 · ^ — — m ^^ t HR ^ i I ^ nn n ^ l — ^^ — t--., -¾ Ί (Please read the notes on the back before filling out this page) A7 B7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the invention (58) 1 1 1 99 3. s P -30: smi 1 ρ > art 1 C eaer CSC] t Γ eetmert of 1 1 | ΐ η f U € η 2 a A vi Γ 1 1 S ir fecti () η in aicea η dresf ^ ir 'at 〇ry 1 1 syncytia 1 V ru S ί Γ f € ctic η i η c otto η rats, A rt: viral please 1 first 1 Re sear ch 21 37- 45) D See 1 1 Compounds of the present invention are tested in this system. M Determine whether they can inhibit RS V growth in cotton 1 I 1 cotton rats. Animal 1 in Experiment 1 (see Table 3) Caution 1 RS V A2 (No. 0) Respiratory tract infection caused by internal infection O Azazole and 1 nucleoside 60 mg / ml in water. Used in spray booths and filled in after the infection. I 1 »2 and 3 Dosing twice a day for 2 hours 0 Compound 16M Page 1 1 4 .5 mg / ml (in 25 m VN aHCO 3) used in the spray chamber and \ 4 hours before infection > on the 1st t 2 and 3 each for 8 hours \ 1 〇 placebo The same usage of substance 16 uses water. Animals are sacrificed at the 4th order. The lungs are lavaged and the power of RSV in the lavage fluid is determined. Experiment 2 1 Infected untreated animals and exposed to 25 mM Ν aHCO 3 Spray 1! Used as a compound for Zhao Group 〇 Example 1 and 4 5 mg / ml at 25 1 I 9 Μ N aHCO 3 〇— 'Group 0 Hour before infection Example 1 Compound 1 1 Treatment for 4 hours and 8 hours each at the 12th and 3rd (preventive usage) | hours. One group only at the 1st > 2 and 3th (therapeutic usage) > λ Example 1 Compound 1 each Treatment 8 一组 0 The last group was at 1 τ 2 and 3 hours (treatment 1 1 therapy) Μ Example 4 Compounds were treated for 8 hours each 〇4 hours 1 | All animals were sacrificed »Lung lavage and Determine the RSV force value in the lavage fluid 1 I 〇 Experiment 3 > Placebo for intranasal delivery of water once per day 0 Example 4 1 1 Compounds were inoculated by vaccination before the inoculation and on the 1st day (on the 0th and the 1st day) 1 I Fu Fu injection * 刖 and the 1st-3rd day on the day M in the canonical transmission m and only 1 1 | " β 0 _ 1 1 1 1 This paper size applies to Chinese National Standards (CNS) A4 specifications (210X297 mm) A7 B7 V. Description of the invention (59) Transmission and administration within Μ 鬓 within 1-3 days after inoculation And experiment. The compounds were also tested by intraperitoneal administration. On the 4th day, all animals were sacrificed, their lungs were lavaged and the RSV force value in the lavage fluid was measured. This was done by measuring the dilution endpoint (producing cytopathic (CPE) on o cells). It was also done by plaque analysis on vero cells. The lungs were also homogenized, and the bark material was removed Divide (1000 Xg, 10 minutes) and use the dilution of the supernatant in the plaque analysis to determine the virus valence in the lungs. It can be seen that the compounds of Examples 1 and 4 inhibit RSV in vivo. ^^ 1 · ^^^ 1 tn ^ m an— m I Jm-In ^^^ 1 V. y (Please read the notes on the back before filling out this page) Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs " 61 " This paper size applies to China Standard (CNS) Λ4 specification (2I0X 297 mm) H? 43 87 9 7 A7 B7 V. Description of the invention (吣) Table 3 Examples 1 and 4 Effect on cotton rat inner respiratory syncytial virus Average effect Monk experimental plaque treatment Method N sample / analysis loglO / gW SD logT (? 1 H20 spray 2x2h / d 5 lavage / CPE 4.1 0.27 dl, 2,3 triazole core or spray n JU / fflh / 3 ε 2 2 m <, Ο 1 6 2 d 4 perfusate / CPE 3.3 0 0.8 Example 1 Spray 4. δικκ / πιΐ 4h uO 8h dl, 2,3 r perfusate / CPE 2.8 Λ Ο Γ \ J * 00 1.0 Untreated 4 lavage solution / CPE 3,68 0.48 placebo spray 4h dO 8h dl, 2,3 4 lavage solution / CPE 3.43 0.25 0.25 Example 1 spray 5ag / «l 4h dO 8h dl, 2, 3 4 Irrigation fluid / CPE 1.73 1.15 1.95 Example 1 Spray 5ng / is 1 8h dl, 2,3 4 Irrigation fluid / CPE 3.43 0.25 0.25 Example 4 Spray & Blg / ID 1 8h dl, 2,3 4 Irrigation 掖 / CPE 2.05 0.5 1.63 d0,1,2,3 Η 2 0 Intranasal administration example 4 Intranasal administration d0 15ag / k dl 30iBg / k ^^^ 1 II »ml» nn ^^^ 1 ^ ^^ 1 I am i \ 1 '(Please read the notes on the back before filling this page) Example 4 _ * Internal investment for dO 15aig / k dl, 2,3 30mg / k Consumption of employees of the Ministry of Economic Affairs Cooperative printed example 4 #internal administration example 4 intranasal administration 30mg / k dl, 2,3 30iag / k dl, 2,3 4 lavage fluid / CPE lavage fluid / bacteriolytic lung / bacteriolytic plaque 4 lavage Liquid / CPE lavage fluid / bacteriolytic lung / bacteriolytic plaque 4 lavage fluid / CPE lavage fluid / bacteriolytic lung / bacteriolytic plaque 4 irrigation fluid / CPE lavage fluid / bacteriolytic lung / bacteriolytic plaque 4 CPE lavage fluid / bacteriolytic lung / bacteriolytic plaque 5 5 5 0 2 2 2 2 2 6 9 7 6 0 3 13 3 3 4 5 13 12 2 12 0.87 0 0 8 5 9 4 6 0 ο ο 1 5 2 7 2 2 9 ο ο ο 2 3 3 5 0 2 2 2 2 3 4 10 3 2 2 2 2 11 0.09 0.26 This paper size applies to the Chinese National Standard (CNS) Λ4 specification (210X297 mm) -62-

Claims

难43 A8 B8 ! CS D8 申請專利範圍第8 6 1 0 1 8 1 8號「有效用作抗病毒劑之含陰離子化合物之三畊」專利案（90年3年修正） A申請專利範圍：極下式化合物： N -N U'W' 其中： XDifficulty 43 A8 B8! CS D8 Patent Application Range No. 8 6 1 0 1 8 1 8 "The Three Cultivations Containing Anionic Compounds Effectively Used as Antiviral Agents" (Amended in 1990 and 3 years) A Patent Application Range: Extreme Compound of the formula: N -N U'W 'where: X

U'Wr (請先閱讀背面之注意事項再填寫本頁) 為選自下列之基圑： C,U'Wr (please read the notes on the back before filling out this page) is based on the following: C,

C C' 普Q- 反C C 'General Q- Anti

經濟部智慧財產局員工消費合作社印製 C’選自-S〇3H 或-C00H; B ·為-NH 或 0 ; X為Cl, F ,或下式基圈：本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）圍範利專請申 ABCD 其中 u·選自-so 2 ; V選自下列基團： ΊPrinted by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, C 'is selected from -S〇3H or -C00H; B · is -NH or 0; X is Cl, F, or the following formula: The paper size applies the Chinese national standard ( CNS) A4 specification (210 X 297 mm) Fan Li specially applies for ABCD where u · is selected from -so 2; V is selected from the following groups: Ί

Y- / -Ν Υ、 Υ 為-（CH2 )η η為0至6 ; m為0至2 ; Z 選自 Η ，-CH2 〇H, -C00 11，或-COHR2 R2 ; R 2各分別選自Η或（Ci -Ce )低碳院基；或其睽槩容許鹽或（C】-C6)烷基醋。如申諳専利範圓第〗項之化合物，其中Λ為下式基@Y- / -N Υ and Υ are-(CH2) η η is 0 to 6; m is 0 to 2; Z is selected from Η, -CH2 OH, -C00 11, or -COHR2 R2; R 2 is selected separately It is self-hydraulic or (Ci-Ce) low-carbon radical; or its ammonium tolerant salt or (C) -C6) alkyl vinegar. For example, the compound of Shen Yuanli Fan Yuan, where Λ is the following formula @

經^-部纪^財吒^肖工垆費合作社印®; -2- 為-S 0 3 H ; 為-ΝΗ : 為下式基團本紙張尺度適用中國國家標準（CNS ) Α4現格（210Χ 公蝥）楷43 87 9 7 經濟部中央標準局負工消資合作社印裝六、申請專利範圍^-部纪 ^ 财吒 ^ 肖工垆费合作合印印 ®; -2- is -S 0 3 H; is -NΗ: is the group of the following formula This paper standard applies Chinese National Standard (CNS) Α4 is present ( 210 × Public address) Kai 43 87 9 7 Printed by the Central Standards Bureau of the Ministry of Economy

為及鹽圍 , 許範 Y容利 X’槃埠 , 兹諝 υρφ 或如第中圍其 0 。，利 as 物 ¥基合請烷化 Φ6)之 H1-C® C 義定之項團基式下為For the Yanwei, Xu Fan Y Rongli X ’槃 bu, 谞 υρφ or as 0 in the middle. The formula for the definition of the term H1-C® C defined by the following formula is as follows:

Β Η 團基 3 ; ο Η 式 s Ν , 1 - 下為為為 c Β V 為及 (請先W讀背面之注意事項再填寫本頁) X,槩專 ,0 請 U 其申或如及申 Ρ 女Β 团 group 3; ο Η formula s Ν, 1-the following is c Β V is Shen P Female

之第中圍其範。 * 利 gg 物 ®基Θ 請烷化C- 義定之項團基式下為 B 本紙張尺度適用中Κ阀萆戊肀f ΓΝί； ) A4it格（2Ι0Χ 297公铎） q 7 A6 B8 C8 D8 々、申請專利範圍 C ’ 為-S 0 3 Η ； B，為-N II ; * W '為下式基團： / \ ι r -Ur 广1 Π Ρ Π . ϊ (¾ - t η Ί U ί1 2 -， Ζ 為-CO Ν Η 2 ;及 U ’， X , Υ , η及ιπ如申請專利範圍第1項之定義；或其醫槩容許鹽或（CVC6)烷基酯。 5 .如申請專利範圍第1項之化合物，其中其险餒容許鹽為二納鹽。 6 .如申請爯利範圍第1項之化合物，其為4 , 4 '-雙[4 , 6 - 二[3-胺苯基-Η,Ν -雙（2-胺甲醯基-乙基）磺酵基亞胺基]-1,3, 5 -三阱-2-基胺基]-二笨乙烯-2,2’-二磺酸或其餒槩容許鹽。 7.如申請專利範圍第1項之化合物，其為4, 4’-雙[4,6-二[3-胺苯基-N,H -雙（2-胺甲醯基-乙基）磺醯基亞胺基]-1,3, 5 -三阱-2-基胺基]-聯笨-2, 2'-二磺酸或其 61藥容許鹽。 8 .如申請專利盹圍第1項之化合物，其為4 , 4〜雙[4 , 6 -二[3 -胺笨基- H,N -雙（2 -羥乙基）碌醯基亞胺基]-1,3, 5 -三阱-2-基胺基]-二笨乙烯- 2,2’ -二磺酸或其ϋ藥容許IS。本紙張尺度述用中國®家橾準（CNS ) Λ4現格（2丨0X297公釐） (請先M讀背面之注意事項再填寫本頁) 訂經濟部中央標準局貝工消費合作社印裝、申請專利範圍 9 .如申諳椁利輯圍第1項之化合物，其為4 - [4 , 6 -二[3 -胺苯基U -雙（2 -胺甲臨基乙基）磺醢S亞胺基]-1.3 ,5-三阱-2-基胺基]-4'-〔4-氯-6〜[3-胺苯基1,卜雙 (2 -胺甲醯基乙基）磺醯基亞胺基]-1,3,5 -三阱-2 -基胺基]-二苯乙烯-2,2’-二磺酸或其鞺槃容許鹽。 1 0 ,如申諳玛利輅圍第1項之化合物，其為Ί , 4 ’ -雙[4 -氯-6-[3-胺苯基- Κ,Η -雙（2-胺甲醯基乙基）磺隨基亞肢基]_1,3,5·*三哄-2-基胺基]-二笨乙羯二碌酸或其鬍藥容許鹽。 - 1 1 .如申請専利範圍Β 1項之化合物，其為4 - [ 4 , 6 -二[ 3 -胺笨甚- Ν,Ν-雙（2~胺甲醯基乙基）磺醯基亞胺基]-1 ,3,5-三畊-2-基胺基]-4'-[4-[3-胺苯基-丨彳，1雙（2-胺甲醯基乙基）磺睦基亞胺驻]_6-[3-肢笨基_!彳-(2_胺甲醯基乙基）-Κ’-(3-丙酸）]-1,3,5_三阱-2-基胺基卜二苯乙烯-2,2'-二磺酸或其H藥容許鹽。經濟部中央標华局貝工消費合作社印裝 (請先閱讀背面之注意事項再填寫本頁) 12.如申請専利範圍第1項之化合物，其為4-[4,6-二[ 3-胺笨基-Η,Ν-雙（2-胺甲_基乙基）磺醯基亞胺基]-1 ,3,5-三阱-2-基胺基]-4’-[4-[3-胺苯基-«,«-雙（2-胺甲醯基乙基）磺醯基亞胺基]-6-[3 -胺笨基-Ν,Η -雙 (3 -丙酸）]-1,3, 5-二哄-2-基胺基]-二笨乙陆-2，2'-二磺酸或其轻槩容許鹽。 1 3 .如申請專利範圍第1項之化合物，其為4 , 4 ’ -雙[4 , 6-二[3-胺苯基- Η,Κ-雙（2-胺甲鹺基-乙基）磺醢基亞胺基卜1,3, 5-三阱_2_基胺基]-雙苄- 2,2’-二磺酸或本紙張尺度適用中国國家標準（CNS ) Α4現格（210χ Μ7公螫） ABCD 經濟部中央摞準局貝工消費合作社印裝六、申請專利範圍其羟橥容許鹽。 1 4 .如申諳專利紐函第1項之化合物，其為4 , 4 '-雙μ , G -二[4 -胺笨基H -雙（2 -胺甲醛甚-乙基）磺陸基亞胺基1 - 1 , 3 , 5 -三阱-2 -基胺基]-二苯乙烯-2 , 2 '-二磺酸或其睦藥容許鹽。 1 5 .如申諾奪利範圆第1項之化合物，其為Ί , 4 '-雙丨4 , 6 -二[4 -肢苯丛-Ν , Ν -雙（2 -胺φ酸基-乙基）磺醇基亞胺练1 - 1 , 3 , 5 -三Gjf - 2 -基胺基j -聯苯-2，2、二磺酸或其醫藥容許鹽。 _ 16.如申請專利範圍第1項之化合物，其為4 , 4 '-雙[4 , 6 -二[3 -胺苯基處酷基胺基（aniido)]-l,3,5 -三附-基胺基j -二苯乙烯-2，2 _ -二磺酸或其醫藥容'許鹽。 ί 7 .如申請專利範圍第1.項之化合物，其為4，4 1 -雙[4， 6 -二[3 -胺苯惩磺醯基亞胺基1 - 1 , 3，5 -三阱-2 -基胺基] -聯苯-2，2 '-二磺酸或其醫藥容許鹽。 1 8 .如申請專利範圍第1項之化合物，其為4 , 4 1 -雙[4 , 6-二丨3-胺笨基-Ν,卜雙（2 -胺甲醛基-乙基）磺醯基亞胺基i - i , 3 , 5 -三阱-2 -基氣基]-聯苯-2 , 2匕二磺酸或其醫藥容許鹽。 1 S .如申請專利範圍第1項之化合物，其為5 , 5 '-二甲基- 4,4、雙{4,6 -二[3 -胺苯基U -雙（2 -胺甲醯基-乙基）磺醯基亞胺垫1-1,3,5 -三哄-2-基胺基卜聯苯-2,2' -二磺酸或其醫藥容許鹽。本紙ft尺度適用中國國家標华（CNS ) Λ4現格（210X297公釐）請先閲讀背面之注意事項再填寫本页) 訂 4 A8 B8 CS D8 1^43 87 9 7 六、申請專利範圍 2 0 .如申請取利範圃第1項之化合物，其為4 , 4 ’ -雙[4 . 6-二[3-胺笨基- Ν,Ν-雙（2-羥乙Ιί )磺醯基亞胺基]-1, (請先閲讀背而之注意事項再填寫本頁) 3 , 5 -三卩并-2 -盔胺基]-聯苯-2 , 2 ’ -二磺酸或其S槩容許鹽。 2 1 .如申請®利盹函第1項之化合物，其為9 , 9 -二氣基 -2 , 7 -雙[4 , 6 -二[3 -胺笨站-Ν , Ν -雙（2 -胺甲醯基乙基）磺睦基亞胺基]-1 , 3 , 5 -三阱-2 -基胺基]-二笨並咕吩- 3.6 -二磺酸或其趦藥容許鹽。 2 2 .如申請谆利範圍第]項之化合物，其為4，-4 '-雙[4 -氯-6- [4- 胺基- Κ·-[3 -胺笨基- Ν,Ν -雙（2 -胺甲酲基乙基）磺醯基亞胺基]-笨甲醯胺]-1,3, 5 -三阱-2 -基胺基]-二笨乙烯-2,2' -二磺酸或其醫藥容許鹽。 2 3 .如申請專利範圍第1項之化合物，其為4 , 4 雙[4 -胺基-1Τ-[3_胺笨基- N,H -雙（2 -羥乙基）磺醛基亞胺基] -1,3, 5-三阱-2-基胺基]-二笨乙烯-2, 2'-二磺酸或其駐槩容許鹽。經濟部中央標牟局貝工消费合作社印11 2 4 .如申請專利範圍第1項之化合物，其為4 , 4 ’ -雙-(4 , 6-雙{3-[雙-（2-胺甲臨基-乙基）_胺磺醯基]-笨胺基） -1,3,5 -三阱-2 -基胺基卜聯苯-2,2'-二羧酸，二納IS。 2 5 .如申請專利範圍第1項之化合物，其為4 , 4 '-雙-([, 4.6 -雙-[[3-[[雙-（3-(甲胺 )-3 -氧基丙基]胺基]磺臨基]苯基]胺基]-1,3, 5 -三畊-2-基]胺基]聯笨]-2 . 2 ’ -二碳酸，二納鹽。 2 6 .如申請專利範圍第1項之化合物.其為4 , 4 ’ -雙-(4 , 本紙張尺度適用中國國家標华（CNS ) ΛΊ说格（210X297公釐} 經濟部中央標準局貝工消费合作社印策 4 3 I D8 六、申請專利範圍 6-雙{3-[雙- (2 -甲基H安甲醯基-乙基）-胺磺醯基卜苯胺基} - Π , 3 , 5 ]三阱-2 -基胺基卜聯苯-2 , 2 ‘ -二羧酸，二納鹽。 2 7 .如申請專利範圍第1項之化合物，其為4，4 (-雙（4， G -雙U - f 5!—（ 2 -胺甲醯基-乙基）-胺磺陸基卜苯胺甚} -[1 , 3 , 5 1三畊-2 -基胺基卜聯苯-2，2 1 -二菝酸二甲酯或其醫藥容許鹽= 2 8 .如申請專利範函第1項之化合物，其為4 , ^ -雙（4， 6 -雙{ 3 -丨雙-(2 -羥丙基）-胺磺醯基]-苯胺基丨-[1，3 , 5 ] 三阱-2 -基胺基]-聯苯-2 , 2 ^二羧酸，二鈉鹽。 2 9 ·如申請專利範圍第]項之化合物，其為4 , 4 ’ -雙（4， 6 -雙丨3 -[雙-(2 -羥丙基）-胺磺醯基]-苯胺基} - [ 1 , 3 , 5 ] 三哄-2 -基胺基]-聯苯-2 , ^ -二菝酸，二鈉鹽。 3 0 .如申請專利菇圍第1項之化合物，其為4 , 4 _ -雙{ 4 , 6 -雙（3 -雙-胺甲醯基甲基-胺磺醯基）-苯胺基] -[1 , 3 , 5 ]三阱-2 -基胺基卜聯苯-2 , 2 1 -二磺酸，二鈉鹽。 3 1 .如申請專利範圍第1項之化合物，其為4，4 1 -雙{ 4 , 6-雙（3-雙-胺甲醯基甲基·胺磺醯基）-苯胺基]· [1 , 3 , 5 i三阱-2 -基胺基卜聯苯-2 , 2 '-二羧酸，二納鹽。 3 2 .如申諳專利範圍第1項之化合物，其為^)-2,2-(1，2 -乙烯二甚）雙[5 - [ [ 4，6 -雙Π 3 - [ [ 3 , 5 -雙（胺基羰基）-1 -六氮吡啶基i磺.醒基]苯基I胺基]-1 , 3 , 5 -三阱-2 -基j胺基]苯磺酸]，二鈉鹽。本杈依尺度通用中囷國家標华（CNS ) Λ4见格（210X 297公楚} (請先閱讀背面之注意事項再填寫本哲) 訂 f ί 六、申請專利範圍 3 3 .如申請攻利範郾第1項之化合物，其為4. , 4〜雙-{ 4 , (¾先閱請背*之注"事項再Μ:Η本两) (5 -雙-[3 - ( 3 J -二胺甲醯基-六氫咄啶-1 -磺醛基）-苯胺雄]-[1,3, 5]三阱-2 -基胺驻）-聯笨-2, 2'-二磺酸，二納®。 3 4 .如中請辟利範圍第1項之化合物，其為1 , 2 ’，1 ”，1… -[(2，2 ’ -二磺基[1 , 1 ^聯苯]-4 , 4 '-二基）雙[亞胺基- 1.3.5 -三阱-6, 2, 4-三基雙（亞胺基-3,1-伸笨基磺醯基）]肆[3 , 5〜六氮吡啶二羧酸或其超藥容許鹽。 3 5 .如申請専利範圍第1項之化合物，其為4 , 4 ’ -雙-(4 , 6 -雙-[3-[雙- (2-羥乙基卜胺磺醯基]-笨胺基}-[1，3, 5] -三阱_2_基胺基]聯苯-2, 2'-二梭酸，二納鹽。 3 6.如申請専利範圍第〗項之化合物，其為4 , 4 '-雙[4 , 6 -二[3 -胺苯基-Η,Ν-雙（3-羥丙基）-磺醯基亞胺基]- 1.3.5 -三哄-2 -基胺基]-聯苯-2,2，-二磺酸，二納鹽。 37. —種用於治療哺乳類病毒感染之醫藥組成物，包含將有效量之如申請專利範圍第1項之化合物作爲活性成分，以及醫藥可容許載體。經"部智慧"4^3(工消費合作杜印製 38. 如申請專利範圍第37項之醫藥組成物|其中有效量為自10毫克/公斤至約500毫克/公斤之劑量》 3 9 .如申請專利範圍第3 7項之醫藥組成物，其中病毒感染爲呼吸道合胞病毒感染。 40.如申請專利範圍第37項之醫藥組成物，其中病毒感染爲單純疱疹病毒感染。本紙张尺度適用中國國家標窣（CNS ) Α4規格（210Χ297公犛、 ®43 87 9 7 8 8 8 8 ABCD 六圍範利專請中 4 7 3 第圍範利專請串如不疫免類人爲染感毒物成組藥。醫染之感項毒病全病中其 2 4 專請中如第園範病胞細巨爲染感毒物成組藥醫之項。 7 染 3 感毒病 ΤΓ 其 -7.T 經濟邓钇慧財是局员工消費合作社印製 ο 木紙浪尺度適用中國國家標窣（CNS ) A4規格（2l〇x 2<>7公犛） BO. ta 12 iS'ii. 年片ί·ι .補无 A7 B7 五、發明説明（50 ) 官例20 m m -a . a· -m 「4.fi -二「3-防采甚一H.H -嗶(2-m 甲瞌基-7,某）碏皚甚亞防基1-1 瞪笼-2.V-二碏酹.二钠闊三阱-2-某踣甚1- 化合物根據製備實例2所用程序製備，使用5,5’-二甲基-4,4'-二胺基聯苯-2,2'-二磺酸，二納鹽（206毫克 ,〇.49毫莫耳）及2-氯-4,6-二[3-胺笨基-(1,|{-雙（2-胺甲醯基乙基）磺醯基亞胺基]-1,3,5 -三畊（實例6 )(805 毫克，1.08毫冥耳）於30毫升DMS0 -環丁硪（1:1,體積/ 體積）及二異丙基乙胺（200毫升）中在U5t：下50小時。 HPLC-純化後之產物呈無色固體（191毫克，取得；熔點 >25〇υ 分解；UV (水）：27 4nm(l〇se5.08); MS(ES) (b/z): Η_288δ3.3; MW1822.6。實.例21 短-4.fi -二「3-防笼甚-N.H-琴（2-1? 7,基）碏瞌甚亞防甚1 - 1 . 3 5 -三哄 i n li r::.L 奸衣 i. Γ 訂 li 線 (請先閱讀背面之注意事碩再填寫本頁) 經濟部中央標準局員工消費合作社印裝 -2至013及攪拌下將三聚氯化氣（135毫克，0.7 3毫莫耳）於二枵烷（55毫升）之溶液逐滴加人磷酸Μ媛衝疲 (120毫升，0.3Μ, ρΗ7)及碎冰（10克）中。在20分鐘内將 3-胺苯基- 雙（2-羥乙基）磺醯基亞胺（365毫克， 1.40毫莫耳）於Ν,Ν -二甲基甲醒胺（125毫升）之溶液逐滴加入所得微细愍浮液中，pH藉由添加IN NaOH維持在6.5 -7.2。再持缜搜拌1小時（0T：, pH7,0)及將溫度升至55 C。再持编探拌2.5小時，另一方面藉由分析性HPLC(或 -32- 本紙張尺度適用十國國家標华（CNS ) ΛΊ规栴（：：〇公兑）难43 A8 B8 ! CS D8 申請專利範圍第8 6 1 0 1 8 1 8號「有效用作抗病毒劑之含陰離子化合物之三畊」專利案（90年3年修正） A申請專利範圍：極下式化合物： N -N U'W' 其中： XIn the middle of its range. * Gg 物物基基 Θ Please alkylate the C-defined term. The radical formula is B. The paper size is applicable to the K-valve valence; f ΓΝί;) A4it grid (2Ι0 × 297); 2. The scope of patent application C 'is -S 0 3 Η; B is -N II; * W' is a group of the formula: / \ ι r -Ur 广 1 Π Π Π. Ϊ (¾-t η Ί U ί1 2-, Z is -CO Ν Η 2; and U ', X, Υ, η, and ιπ are as defined in the scope of patent application; or their medically acceptable salts or (CVC6) alkyl esters. 5. If applied The compound of item 1 of the patent scope, wherein the permissible salt is a dinaline salt. 6. The compound of item 1 of the patent scope, which is 4, 4'-bis [4, 6-di [3-amine Phenyl-fluorene, N-bis (2-aminomethylmethyl-ethyl) sulfonylimino] -1,3, 5-tritriptra-2-ylamino] -dibenzyl-2,2 '-Disulfonic acid or its permissive salt. 7. The compound according to item 1 of the scope of patent application, which is 4, 4'-bis [4,6-bis [3-aminephenyl-N, H -bis (2-Aminomethylamidino-ethyl) sulfoamidoimino] -1,3,5-tritrap-2-ylamino] -biben-2,2'-disulfonic acid or its 61 drugs allow 8. The compound according to item 1 of the patent application, which is 4, 4 to bis [4, 6-bis [3-aminebenzyl-H, N-bis (2-hydroxyethyl) pyridine) Amine] -1,3, 5 -Tritrap-2-ylamino] -dibenzylethylene-2,2'-disulfonic acid or its peony permit IS. This paper is described in China® furniture standard ( CNS) Λ4 is now (2 丨 0X297 mm) (Please read the notes on the back before filling out this page) Order the printed and applied for patent scope of the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. The compound around item 1, which is 4- [4, 6-bis [3-aminophenyl U-bis (2-aminomethylphenylethyl) sulfonamidoSimino] -1.3,5-tris 2-ylamino] -4 '-[4-chloro-6 ~ [3-aminophenyl1, bubis (2-aminomethylethyl) sulfoamidoimino] -1,3, 5 -Tristrap-2-ylamino] -stilbene-2,2'-disulfonic acid or its permissible salt. 1 0, such as the compound in item 1 of Shenyang Marie, which is Ί , 4'-bis [4-chloro-6- [3-aminophenyl-K, Η-bis (2-aminomethylmethylethyl) sulfoacidylidene] -1,3,5 · * 2-Aminoamino] -dibenzylacetic acid or its edible salt. -1 1. If the compound in the scope of claim B 1 of the application, it is 4-[4, 6-bis [3 -aminobenzyl-Ν, Ν-bis (2 ~ amine methyl ethyl) sulfonyl) Amine] -1,3,5-trigen-2-ylamino] -4 '-[4- [3-aminophenyl- 丨彳, 1bis (2-aminomethylmethylethyl) sulfonium Imidene] _6- [3-limylbenzyl_! 彳-(2_aminomethylmethylethyl) -K '-(3-propionic acid)]-1,3,5_triswell-2- Aminostilbene stilbene-2,2'-disulfonic acid or its H-tolerant salt. Printed by the Shell Standard Consumer Cooperative of the Central Bureau of Standardization of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 12. If you apply for the compound of item 1 in the profit scope, it is 4- [4,6- 二 [3- Aminobenzyl-fluorene, N-bis (2-aminomethyl-ethyl) sulfoamidoimino] -1,3,5-triple-2-ylamino] -4 '-[4- [ 3-aminophenyl-«,«-bis (2-aminomethylmethylethyl) sulfonamidoimino] -6- [3-aminobenzyl-N, fluorene-bis (3-propionic acid)] -1,3,5-Dioxo-2-ylamino] -dibenzyl-2,2'-disulfonic acid or a lightly acceptable salt thereof. 1 3. The compound according to item 1 of the scope of patent application, which is 4, 4'-bis [4, 6-bis [3-aminophenyl-fluorene, K-bis (2-aminemethylmethyl-ethyl) Sulfonylimine group 1,3, 5-triple_2_ylamino] -bisbenzyl-2,2'-disulfonic acid or this paper size applies Chinese National Standard (CNS) A4 (210χ Ｍ7 公螫) Printed by the ABCD Central Consumers' Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives. 6. The scope of patent applications for its hydroxyl salt allows. 14. The compound as described in item 1 of Shenyang Patent New Letter, which is 4, 4′-bisμ, G-bis [4-aminebenzyl H-bis (2-amine formaldehyde and even ethyl) sulfolandyl Imine 1-1, 3, 5-triple-trap-2-ylamino] -stilbene-2, 2'-disulfonic acid or a pharmaceutically acceptable salt thereof. 1 5. The compound as claimed in claim 1, which is Ί, 4'-bis 丨 4, 6-bis [4-limbenzyl-N, Ν-bis (2-amine φ acid group-B Sulfonylimine 1-1, 3, 5-trigjf-2-ylamino j-biphenyl-2, 2, disulfonic acid or a pharmaceutically acceptable salt thereof. _ 16. The compound according to item 1 of the scope of patent application, which is 4, 4′-bis [4, 6-bis [3-aminophenylanilide] -l, 3,5 -tris E-aminoamino j-stilbene-2,2_-disulfonic acid or its medicinal salt. ί 7. The compound according to item 1. in the scope of patent application, which is 4,4 1 -bis [4, 6 -bis [3 -aminobenzenesulfonimidoimino 1-1, 3,5-triple well -2-aminoamino] -biphenyl-2,2'-disulfonic acid or a pharmaceutically acceptable salt thereof. 18. The compound according to item 1 of the scope of patent application, which is 4, 4 1-bis [4, 6-di 丨 3-aminebenzyl-N, bis (2-aminoformyl-ethyl) sulfonium Imino i-i, 3, 5 -triple-2 -ylamino] -biphenyl-2,2-disulfonic acid or a pharmaceutically acceptable salt thereof. 1 S. The compound according to item 1 of the scope of patent application, which is 5, 5'-dimethyl-4,4, bis {4,6-bis [3-aminophenyl U-bis (2-amine formamidine) -Ethyl) sulfoamidoimine pad 1-1,3,5-trisamino-2-ylaminobiphenyl-2,2'-disulfonic acid or a pharmaceutically acceptable salt thereof. The ft scale of this paper is applicable to China National Standardization (CNS) Λ4 grid (210X297 mm) Please read the precautions on the back before filling in this page) Order 4 A8 B8 CS D8 1 ^ 43 87 9 7 VI. Patent Application Scope 2 0 . If the compound of claim 1 is applied, it is 4, 4'-bis [4. 6-bis [3-aminebenzyl-N, N-bis (2-hydroxyethyl Ιί)) sulfonimide Phenyl] -1, (please read the precautions before filling this page) 3, 5 -Tripyrido-2 -Hexylamino] -biphenyl-2, 2 '-disulfonic acid salt. 2 1. The compound according to item 1 of the application letter, which is 9, 9-dioxo-2, 7-bis [4, 6-bis [3-aminobenzyl-N, Ν-bis (2 -Aminomethylethyl) sulfamoimino] -1, 3, 5-tritrap-2-ylamino] -dibenzopyridine-3.6-disulfonic acid or its peony permissible salt. 2 2. The compound according to item [1] in the scope of application, which is 4, -4′-bis [4-chloro-6- [4-amino-K ·-[3-aminebenzyl-N, N- Bis (2-aminomethylamidoethyl) sulfoamidoimino] -benzidinemethylamine] -1,3, 5 -Triswell-2 -ylamino] -dibenzylethylene-2,2 '- Disulfonic acid or a pharmaceutically acceptable salt thereof. 2 3. The compound according to item 1 of the scope of patent application, which is 4, 4 bis [4-amino-1T- [3-aminebenzyl-N, H-bis (2-hydroxyethyl) sulfonyl Amine] -1,3,5-Tritrap-2-ylamino] -dibenzyl-2,2'-disulfonic acid or its permissible salt. Printed by the Central Bureau of Standards, the Ministry of Economic Affairs, Shellfish Consumer Cooperative, 11 2 4. If the compound in the scope of patent application for item 1 is 4, 4 '-bis- (4, 6-bis {3- [bis- (2-amine Methyl-ethyl) -aminosulfanyl] -benzylamino) -1,3,5-triswell-2 -ylaminobiphenyl-2,2'-dicarboxylic acid, dinaline IS. 25. The compound according to item 1 of the scope of patent application, which is 4, 4'-bis-([, 4.6 -bis-[[3-[[bis- (3- (methylamine) -3 -oxypropyl [Amino] amino] sulfonyl] phenyl] amino] -1,3,5-trigen-2-yl] amino] bibenzyl] -2. 2'-dicarbonic acid, di-nano salt. 2 6 .If the compound in the scope of the application for the first item of the patent, it is 4, 4 '-double- (4, this paper size is applicable to China National Standards (CNS) Ί Ί 格 (210X297 mm) Central Bureau of Standards of the Ministry of Economics consumption of shellfish Cooperative cooperative policy 4 3 I D8 6. Scope of patent application 6-Bis {3- [bis- (2-methylH-carboxamyl-ethyl) -sulfamoylphenylaniline}-Π, 3, 5 ] Tritrap-2-aminoaminobiphenyl-2, 2'-dicarboxylic acid, di-nano salt. 2 7. The compound according to item 1 of the scope of patent application, which is 4,4 (-bis (4, G -bisU-f 5! — (2-aminomethylamidino-ethyl) -sulfanilbiphenylaniline}-[1, 3, 5 1Sangen-2 -ylaminobiphenyl-2 , 2 1-Dimethyl diacetate or a pharmaceutically acceptable salt thereof = 2 8. As for the compound of the first item of the patent application letter, it is 4, ^ -bis (4, 6-bis {3-丨 bis- ( 2 -Hydroxypropyl) -sulfamoyl] -aniline -[1,3,5] Triple well-2 -ylamino] -biphenyl-2, 2 ^ dicarboxylic acid, disodium salt. 2 9 · The compound according to item [Scope of the patent application], which is 4, 4 '-bis (4, 6 -bis 丨 3-[bis- (2-hydroxypropyl) -aminosulfonyl] -aniline}-[1, 3, 5] tris-2-ylamino] -Biphenyl-2, ^ -diphosphonic acid, disodium salt. 30. The compound according to item 1 of the patent application, which is 4, 4 _-bis {4, 6-bis (3-bis-amine Formamylmethyl-aminosulfonyl) -anilino]-[1, 3, 5] Triple well-2 -ylaminobiphenyl-2, 2 1 -disulfonic acid, disodium salt. 3 1 The compound as claimed in item 1 of the scope of patent application, which is 4,4 1-bis {4, 6-bis (3-bis-aminomethylaminomethyl · sulfamoyl) -aniline]. [1, 3, 5 i triple well-2 -ylaminobiphenyl-2, 2'-dicarboxylic acid, di-nano salt. 3 2. As the compound of the scope of the patent claim 1, it is ^)-2, 2- (1,2-Ethylenedieven) bis [5-[[4,6 -bisΠ 3-[[3, 5 -bis (aminocarbonyl) -1 -hexaaziridinyl i-sulfonyl.pentyl] Phenyl Iamino] -1,3,5-tritrap-2-yljamino] benzenesulfonic acid], disodium salt. According to the standard, China National Standards Corporation (CNS) Λ4 sees the standard (210X 297). (Please read the notes on the back before filling in this philosophy.) Order f ί 6. Application for patent scope 3 3. If you apply for profit化合物 The compound of item 1, which is 4., 4 ~ bi- {4, (¾ Please read the note of * before reading the matter and then M: two copies of this) (5-双-[3-(3 J- Diamine formamidine-hexahydropyridine-1 -sulfonaldehyde) -anisole]-[1,3, 5] Tritrap-2 -ylamine) -bibenzyl-2, 2'-disulfonic acid ，二纳 ®. 3 4. The compound of item 1 in the claim range, which is 1, 2 ', 1 ”, 1 ...-[(2, 2'-disulfo [1, 1 ^ biphenyl ] -4, 4 '-diyl) bis [imino-1.3.5-triple-6, 2,4-triylbis (imino-3,1-benzylsulfonyl)]] [3, 5 ~ hexaazapyridine dicarboxylic acid or its superdrug-accepting salt. 3 5. If the compound in the scope of claim 1 is applied, it is 4, 4'-bis- (4, 6-bis- [3- [Bis- (2-Hydroxyethylammoniumsulfonyl) -benzylamino}-[1,3,5] -Tristrak-2-ylamino] biphenyl-2, 2'-bisoteric acid, 2 Na salt. 6. If the compound in the item of the scope of the claim is applied, it is 4, 4 '-bis [4, 6-二 [3 -Aminephenyl-fluorene, N-bis (3-hydroxypropyl) -sulfoamidoimino]-1.3.5 -trioxo-2-ylamino] -biphenyl-2,2, -disulfo 37. —A pharmaceutical composition for treating mammalian viral infections, comprising an effective amount of a compound such as the one in the scope of patent application as the active ingredient, and a pharmaceutically acceptable carrier. Ministry of Wisdom " 4 ^ 3 (industrial-consumer cooperation Du printed 38. For example, the pharmaceutical composition in the 37th scope of the patent application | where the effective amount is a dose from 10 mg / kg to about 500 mg / kg "3 9. The pharmaceutical composition of scope item 37, wherein the viral infection is a respiratory syncytial virus infection. 40. For example, the pharmaceutical composition of scope item 37 of the patent application, wherein the viral infection is herpes simplex virus infection. This paper standard applies to Chinese national standards窣 (CNS) Α4 specification (210 × 297 male, ® 43 87 9 7 8 8 8 8 ABCD Of the 2 to 4 diseases of the medically infected disease, please refer to the first The size of the cells of the Yuanfan disease is a group of medicines that are infected with the poison. 7 Dyed 3 Toxic Diseases ΓΓ Its -7.T Economy Deng Yenghuicai is printed by the Bureau ’s Consumer Cooperatives ο Wood Paper Wave Standard Applicable to China National Standard (CNS) A4 Specification (2l0x 2 < > 7g) ta 12 iS'ii. Annual film ί · ι. Supplement without A7 B7 V. Description of invention (50) Official example 20 mm -a. a · -m 「4.fi-二」 3-Anti-mining HH- Beep (2-m formamyl-7, a certain) cyttriol 1-1 gazing cage-2.V-difluorene. Disodium triple wells 2-some fluorene 1- compounds according to the preparation examples 2 The procedure used was prepared using 5,5'-dimethyl-4,4'-diaminobiphenyl-2,2'-disulfonic acid, di-nano salt (206 mg, 0.49 mmol) and 2-chloro-4,6-di [3-aminebenzyl- (1, | {-bis (2-aminomethylmethylethyl) sulfoamidoimino] -1,3,5 -Sangen ( Example 6) (805 mg, 1.08 mmol) in 30 ml of DMS0-cyclobutane (1: 1, v / v) and diisopropylethylamine (200 ml) at U5t: 50 hours. HPLC- The purified product was a colorless solid (191 mg, obtained; melting point > 25〇υ decomposition; UV (water): 27 4nm (10se5.08); MS (ES) (b / z): Η_288δ3.3; MW1822.6. Real. Example 21 Short-4.f i-二「3-Fang cage even-NH-Qin (2-1? 7, base) 碏瞌亚 Fang Fang 1-1. 3 5-Three coax in li r ::. L 衣衣 i. Γ Order li line (please read the note on the back before filling in this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs of the People's Republic of China -2 to 013 and stir the polytrichloromethane (135 mg, 0.7 3 mmol) under stirring. A solution of dioxane (55 ml) was added dropwise to human phosphate (120 ml, 0.3 M, ρΗ7) and crushed ice (10 g). 3-Aminephenyl-bis (2 -Hydroxyethyl) sulfonyliminomine (365 mg, 1.40 mmol) in N, N-dimethylmethanamine (125 ml) was added dropwise to the resulting fine hydrazone suspension, and the pH was adjusted by adding IN NaOH was maintained at 6.5 to 7.2. The mixture was stirred for 1 hour (0T :, pH7,0) and the temperature was raised to 55 C. The mixture was further stirred for 2.5 hours, and on the other hand, it was analyzed by HPLC (or- 32- The size of this paper is applicable to the ten national standards of China (CNS) ΛΊ Regulations (:: 0 credit) Difficulty 43 A8 B8! CS D8 Patent Application No. 8 6 1 0 1 8 1 8 Patent of “Three Cultivations of Poisonous Anionic Compounds” (9 (Revised 0,3 years) A Scope of patent application: Compound of extreme formula: N -N U'W 'where: X

C C' 普Q- 反C C 'General Q- Anti

經濟部智慧財產局員工消費合作社印製 C’選自-S〇3H 或-C00H; B ·為-NH 或 0 ; X為Cl, F ,或下式基圈：本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy, C 'is selected from -S〇3H or -C00H; B · is -NH or 0; X is Cl, F, or the following formula: CNS) A4 size (210 X 297 mm)