TW561157B - Antimicrobial cephalosporins, a process for their production and pharmaceutical compositions thereof - Google Patents

Abstract

7-(((5-amino-l,2,4-thiadiazol-3-yl)-(Z)-(fluormethoxyimino)acetyl)amino)-3-(unsubstituted or substituted)imino-l-piperazinylmethyl-(substituted)hydrazono)methyl-3-cephem-4-carboxylic acids and carboxylic acid esters, wherein substituents are selected from alkyl, cycloalkyl, aralkyl, aryl, alkenyl or alkinyl; e.g. in free form and in the form of a salt and/or in the form of a solvate; a process for their production and their use as a pharmaceutical, e.g. as an antibiotic.

Description

561157561157

五、發明説明（i 本發明有關抗微生物性的頭孢素。一 本發明一方面乃在提出下式化合物： h，n N--f•Ο N—OCH,F II 2 •C—CO—NH_- 〇 COOR,V. Description of the Invention (i The present invention relates to antimicrobial cephalosporins. One aspect of the present invention is to propose compounds of the formula: h, n N--f • O N—OCH, F II 2 • C—CO—NH_ -〇COOR,

/ I .〇Η=Ν — I \ / K N n-r3/ I .〇Η = Ν — I \ / K N n-r3

NH 經濟部中夬標準局員工消費合作社印製 其中Ri代表氫或酯基；例如氫；及 I和R3分別代表烷基，例如Cl 0烷基，如Cw烷基；環 烷基、芳烷基，例如芳（Cl·6)烷基；如芳（Ci4)烷基；芳 基；烯基；例如（C2·6)烯基，如（C2·4)烯基；或炔基；及I 可另代表氫；例如R2代表烷基、烯基、或芳烷基；例如 反3代表氫或烷基；例如呈游離型及鹽型及或溶合物型。 I代表氫或酯基。酯基包括烷基，以Ci 6烷基較佳，例 如Cw烷基；芳烷基，例如芊基、烷氧苄基，實例如‘曱氧苄基；茚滿基、酞基、烷氧甲基，例如甲氧曱基；（Cl 6)烷醯氧（c^)烷基、（c〗·6)烷氧基-羰拳_氧_(Ci0)烷基、甘 胺醯氧甲基、苯甘胺醯氧甲基、（甲基1氧el，3H_間二氧雜環戊烯-4-基）曱基；酯基亦包括與c〇〇-基形成生理 上可水解及可接受的酯之酯基，例如在頭孢素領域中已知 可水解的酯基。式I化合物因此可呈生理上可水解及可接 受之酯的形態出現。本文所採用之生理上可水解及可接典 的酯意指該酯中的C00·基被酯化且可在生理條件 *、卞下水解 ___ -4- 本紙張尺度適财_家標準（CNS) A4· ( 21()x297&董) - ------- 11·« I —r··! . . —·- I - - - — .11 - C请先閲讀背N?之注意事項存填寫本貢〕 订 561157 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（2 ) 形成酸，該酸本身可依生理上可耐受之劑量投藥。因此咸 了解此名詞之定義爲一般前驅物形式。酯基以在生理條件 下被水解者較佳。此等酯以口服投藥爲佳。若該酯本身爲 一種活性化合物，或可在血液中水解時，則可以非經腸道 方式投藥。Ri代表氫較佳。 R2代表烷基較佳；如低碳數烷基，例如甲基、乙基， 例如甲基；芳烷基，例如芊基；環烷基；或烯基，例如晞 丙基；如烷基，芳烷基或烯基，例如烷基，如甲基。 及3代表氫或烷基較佳，例如低碳數烷基，如甲基，乙 基。R2和I之烷基定義包括未取代之烷基或經取代之烷 基較佳，例如經β_内醯胺化學中習知的取代基取代，如函 素、輕基；且以未取代較佳。芳烷基包括其苯基未取代或 經取代之芳燒基較佳，例如經β_内醯胺化學中習知的取代 基取代；例如經一個或多個，例如一至三個取代基取代； 例如羥基、烷氧基，如低碳數烷氧基，例如曱氧基。 如典其他定義，本文之燒基包括例如（Ci i2)燒基，如（Ci_ 6)烷基，例如（Cm)烷基。低碳數烷基包括（Cn4)烷基。環 烷基包括例如（C3_8)環烷基，如（C4_7)環烷基，例如（c5_6)環 烷基。烯基包括例如（Cm)烯基，如（C2_6)烯基，例如（C2 4) 晞基。块基包括例如（Cm)炔基，如（c2-6)炔基，例如（c2 4) 块基。芳基包括5苯基或莕基，例如苯基。芳燒基包括芳 (Ci·6)燒基’如芳（(^_4)虎基，例如芊基。碎燒基包括秒垸 基保護基’例如習知的矽烷基保護基，如三烷矽烷基，如 三曱矽烷基。 (請先閲讀背面之注意事項再填寫本頁)Printed by the Consumer Cooperatives of the China Standards Bureau of the Ministry of Economic Affairs, where Ri represents hydrogen or an ester group; for example, hydrogen; and I and R3 represent an alkyl group, for example, Cl 0 alkyl, such as Cw alkyl; cycloalkyl, aralkyl , Such as aryl (Cl · 6) alkyl; such as aryl (Ci4) alkyl; aryl; alkenyl; for example, (C2 · 6) alkenyl, such as (C2 · 4) alkenyl; or alkynyl; and I may Another represents hydrogen; for example, R2 represents an alkyl group, an alkenyl group, or an aralkyl group; for example, trans 3 represents a hydrogen or an alkyl group; for example, it is in a free form and a salt form and / or a solvate form. I represents hydrogen or an ester group. The ester group includes an alkyl group, preferably a Ci 6 alkyl group, such as a Cw alkyl group; an aralkyl group, such as a fluorenyl group, and an alkoxybenzyl group, and examples thereof include a fluorenyl group; an indanyl group, a phthaloyl group, and an alkoxymethyl group; Groups, such as methoxyfluorenyl; (Cl 6) alkoxy (c ^) alkyl, (c] · 6) alkoxy-carbonyl box-oxy_ (Ci0) alkyl, glycinyloxymethyl, Phenylglycinoloxymethyl, (methylloxyel, 3H-m-dioxol-4-yl) fluorenyl; ester groups also include physiologically hydrolyzable and acceptable with the 〇〇- group As the ester group, for example, hydrolyzable ester groups are known in the field of cephalosporins. The compounds of formula I can therefore appear in the form of physiologically hydrolyzable and acceptable esters. The physiologically hydrolyzable and canonical ester used in this article means that the C00 · group in the ester is esterified and can be hydrolyzed under physiological conditions *, -4- ___ This paper is suitable for financial use _ home standard ( CNS) A4 · (21 () x297 & Dong)-------- 11 · «I —r ··!.. — ·-I---— .11-C Please read me first? Precautions should be filled in this tribute] Order 561157 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (2) An acid is formed, and the acid itself can be administered at a physiologically tolerable dose. Therefore, Xian understands the definition of this term as a general precursor. The ester group is preferably hydrolyzed under physiological conditions. These esters are preferably administered orally. If the ester itself is an active compound or is hydrolysable in the blood, it can be administered parenterally. Ri stands for hydrogen. R2 preferably represents an alkyl group; such as a low-carbon alkyl group, such as methyl, ethyl, such as methyl; aralkyl, such as fluorenyl; cycloalkyl; or alkenyl, such as fluorenyl; Aralkyl or alkenyl, such as alkyl, such as methyl. And 3 represents hydrogen or an alkyl group, for example, a lower carbon number alkyl group such as methyl or ethyl. The definition of the alkyl group of R2 and I preferably includes an unsubstituted alkyl group or a substituted alkyl group, for example, substituted with a conventional substituent in β-lactamamine chemistry, such as a halide and a light group; good. Aralkyls preferably include phenyl unsubstituted or substituted aralkyl groups, such as those substituted with conventional substituents in β-lactamamine chemistry; for example, with one or more, such as one to three substituents; For example, hydroxy, alkoxy, such as low-carbon alkoxy, such as fluorenyloxy. As defined elsewhere in the text, alkyl groups herein include, for example, (Ci i2) alkyl groups, such as (Ci-6) alkyl, such as (Cm) alkyl. Low-carbon alkyl includes (Cn4) alkyl. Cycloalkyl includes, for example, (C3_8) cycloalkyl, such as (C4_7) cycloalkyl, such as (c5_6) cycloalkyl. Alkenyl includes, for example, (Cm) alkenyl, such as (C2-6) alkenyl, such as (C2 4) fluorenyl. Bulk groups include, for example, (Cm) alkynyl groups, such as (c2-6) alkynyl groups, such as (c2 4) block groups. Aryl includes 5phenyl or fluorenyl, such as phenyl. Aromatic groups include aryl (Ci · 6) alkyl groups such as aryl ((^ _ 4) Tigeryl groups, such as fluorenyl groups. Crushing groups include second fluorenyl protecting groups, such as conventional silyl protecting groups, such as trialkylsilane Base, such as stilbene silyl (Please read the notes on the back before filling in this page)

561157 Α7 .B7 經濟部中央標準局員工消費合作社印製 五、發明説明（4 ) 式I中Ri代表酯基之化合物。 _ 式I化合物包括任何構形之式I化合物，例如呈任何可 能立體異構型。立體異構型的混合物可以分離，例如以傳 統方式，例如色層分析法，分段結晶法分離。例如-〇1^-〇CH2F中-〇CH2F之構形可爲同側[(Z)]或對側[(E)]，以主 要爲同側[(Z)]構形較佳；例如[(E)]型含量爲0至5°/。，例 如0至2%。通式I化合物可呈3(E)型及3(Z)型的混合物 型式，或可如如：主要呈3(Z)型，例如根據下式561157 Α7 .B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (4) In the formula I, Ri represents an ester-based compound. Compounds of formula I include compounds of formula I in any configuration, for example in any possible stereoisomeric form. Stereoisomeric mixtures can be separated, for example, by conventional means, such as chromatographic analysis, segmented crystallization. For example, the configuration of -〇CH2F in -〇1 ^ -〇CH2F can be ipsilateral [(Z)] or contralateral [(E)], and the main ipsilateral [(Z)] configuration is preferred; for example [ (E)] type content is 0 to 5 ° /. , For example 0 to 2%. The compound of the general formula I may be a mixture of 3 (E) and 3 (Z) type, or may be, for example, mainly 3 (Z) type, for example, according to the following formula

N-R, N—O.CH,F· II 2 C—CO-NHN-R, N—O.CH, F · II 2 C—CO-NH

C〇〇R, 或可例如：主要呈3(E)型，例如根據下式 Η,Ν ΟC〇〇R, or may be, for example: mainly 3 (E) type, for example according to the following formula Η, Ν Ο

一 IA I

N-FU ΝΗ 式中，1^與112如上述定義，且其中如下構形且 ΝΗ I〆/ -Ν' / Ν ΝΗ 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 丨(Z) ΚΕ) I J ^ ------IT------ (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社印製N-FU ΝΗ In the formula, 1 ^ and 112 are as defined above, and among them the following configuration and ΝΗ I-/ -Ν '/ Ν ΝΗ This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 丨 ( Z) ΚΕ) IJ ^ ------ IT ------ (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

n-〇.ch2f c—c〇一NH 561157 五、發明説明（ ，、在衣系中第一位基的氮上之基團爲例如3⑹盥 或3(Z)型。式1化合物可例如：主要呈型’例如吻 型含量爲0至5%.·，例如〇至2%。 本發明另1面係提出主要呈3•⑹型之式！化合物，例 如7_(((5_胺基切”塞二唾-3.基）_⑸(氟甲氧-亞胺基） 土）胺基）3(E)-((亞胺基_丨_六氫吡啡甲基）甲基亞聯胺 基）甲基-3-喷ρ凡-4*•卷齡，a,， • n 例如呈鹽型，如鹽酸鹽及/或溶 合物型。 、鹽類包括任何可能的鹽，例如酸加成鹽如式！化合物 之鹽酸鹽、内蜂、令扈 皿金屬皿、四級鹽及胺鹽。金屬鹽包括例 域鹽：卸鹽、劈鹽、鎖鹽、鋅鹽、銘鹽，以納鹽或奸鹽 幸^胺鹽包括例如二燒胺鹽、普魯卡因（procaine)、二爷 胺皿及下胺鹽。琢鹽類爲式1化合物之鹽藥上可接受之鹽 較佳。 溶合物包括與有機.溶劑形成的溶合物或與水形成的溶合 杈口物式I化合物的游離型式可轉變爲鹽型且反 之亦然。式1化合物的溶合物型，例如游離型或鹽型，可 轉變成非溶合物型且反之亦然。 本發明另-方面係、提出_種製備如中請專利範圍第一項 中定義的式1化合物的方法，其包括由下式化合物 N—--,— S〆n-〇.ch2f c-c〇-NH 561157 5. Description of the invention (,, the group on the nitrogen of the first group in the clothing system is, for example, 3⑹ or 3 (Z). The compound of formula 1 can be, for example: The main type is, for example, a kiss-type content of 0 to 5% ..., for example, 0 to 2%. The other aspect of the present invention proposes a formula that is mainly 3 •！ type! Compounds such as 7 _ (((5_amino ”Sialisaline-3.yl) _⑸ (fluoromethoxy-imino) soil) amine) 3 (E)-((imine_ 丨 _hexahydropyridinemethyl) methylimine ) Methyl-3-pentinfan-4 * • Volume age, a ,, • n For example, salt type, such as hydrochloride and / or solvate type. Salt includes any possible salt, such as acid addition The salt formation is as follows! The hydrochloride, inner bee, metal dish, quaternary salt, and amine salt of the compound. Metal salts include example salts: unloading salt, split salt, lock salt, zinc salt, Ming salt, to Ammonium salts include amine salts, such as diamine, procaine, diamine, and lower amine salts. Salts that are pharmaceutically acceptable salts of compounds of formula 1 are preferred Solvates include solvates with organic solvents or with water The free form of the compound of formula I can be converted to a salt form and vice versa. The solvate form of the compound of formula 1, such as a free form or a salt form, can be converted to a non-solvate form and vice versa. -Aspects, methods and methods for preparing compounds of formula 1 as defined in the first item of the patent scope, which include compounds of formula N ---,-S〆

I---r---*---------、玎------0 (請先閲讀背面之注意事項再填寫本頁} 561157 A7 B7 五、發明説明（6 )其中， 、 °〇Rb代表羥基且R。和Rd 一起形成化學鍵，或 β) Rd代表氫，酯基或矽烷基，且Rb和& 一起代表氧芙， 例如呈游離型或鹽型及/或溶合物型；例如及/或1其1中反 應基經例如：適當保護基保護的型式，如經習知保護基保 護；與如下式化合物反應 i N-R〇 H2N —N —Cn 2 I R2I --- r --- * ---------, 玎 ------ 0 (Please read the notes on the back before filling out this page} 561157 A7 B7 V. Description of the invention (6) Among them, °° Rb represents a hydroxyl group and R. forms a chemical bond with Rd, or β) Rd represents hydrogen, an ester group or a silane group, and Rb and & together represent an oxygen atom, such as a free form or a salt form and / or Solvate type; for example, and / or 1 in which the reactive group is protected by, for example, a suitable protecting group, such as a conventional protecting group; reacting with a compound of the formula i NR〇H2N —N —Cn 2 I R2

NHNH

III I--Γ--.J----- (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社印製 其中1和r3如上述定義，例如呈游離型或鹽型；及/或溶 合物：例如及/或其中反應基例經例如：冑當保護基保護 的型式，如經習知保護基保護；如 7禾3衣系中第四位置上有 幾酸時，可裂解矽烷基；例如如果 如禾有其他保護基存在，若 需要時，亦可裂解；並分離出式Γ 、 飞1化合物；例如呈游離型 或鹽型及或溶合物型。R定義中乏 d心我甲又酯基可如上述&之定 義。 根據本發明之製法可如下進行： 可由通式II化合物，例如呈游 好離型或鹽型及/或溶合物 型及/或例如反應基，例如接在4 _ 、 ^ 受社1 一唑基環上的胺基，經 適當保護基，如習知保護基保鳟々 休邊〈型式；於在反應條件下 呈鈍性之溶劑中，包括例如水， 八水與低碳數醇或二氧陸圜 燒的混合物，或雙極性非質子性 . 、 丁生/合劑，例如二甲基甲醯胺 或二曱基亞砜，例如與乙醇哎永 吁4水，昆合；例如-20至50 X：溫 本紙張尺纽财賴家鮮（ 、1Τ •9- 經濟部中央標準局員工消費合作社印製 561157 五、發明説明（7 度下，與式IIH匕合物，例如呈游離^或鹽型及/或溶人物 型及/或例如其中反應基，例如接在基或六氫吨^基 氮上的胺基，經適當保護基，如習知保護基保護之型式反 應。以石夕院基保護反應基團時，適合在對料化氧劑不且 活性之溶劑存在下，例如氣化煙，如二氯甲H如^ 腈，醚，如四氫呋喃’雙極性非質子性溶劑，例如N，N- 二甲基甲醯胺;或溶劑系，例如上速之各溶劑的混合物， 進行矽烷基保護技術。 反應混合物的酸鹼値，可藉由添加酸鹼値調節劑調節， 例如有機或無機的酸或鹼，調整至最佳値。式〗化合物， 例如呈鹽型及/或溶合物型，例如主要呈3⑹型；自反 應混合物中，例如以傳統方式，例如：沈澱法，例如在反 性溶劑（anti-Solvent)的存在下，萃取，色層分析，溶劑 法取得或分離。 一 式Π化合物或式m化合物中的保護基，可在式Η化人 物和式III化合物反應期間，於適當反應條件下\例如2 傳統方式分離，或例如有保護基存在，可例如以傳统° = 式，自II化合物或式III化合物反應所得之 、' 裂解保護基而#。 口物上 所得之式I化合物，式中Rl爲氨，例如呈鹽型，可例 如以傳統方法轉變成式中R1爲酯基之化合物，且反之八 然。式I化合物可以傳統方法自反應混合物中分離而=吓 如以過遽，萃取、離心、溶劑蒸發法。游離刑弋I人 物可例如以傳統方式轉換成鹽型及/或溶合物型的弋I匕= (2Ι〇χ297公釐） (請先閲讀背面之注意事項再填寫本頁)III I--Γ-. J ----- (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs, where 1 and r3 are as defined above, such as free-form or Salt type; and / or solvate: for example and / or wherein the reactive group is protected by, for example, a type protected by a protective group, such as protected by a conventional protective group; for example, there are several When acid is present, silane groups can be cleaved; for example, if other protective groups are present, if necessary, it can be cleaved if necessary; and compounds of formula Γ and Fe 1 are isolated; The lack of d in the definition of R may be as defined above &. The preparation method according to the present invention can be carried out as follows: The compound of the general formula II can be, for example, a free form or a salt type and / or a solvate type and / or a reactive group, for example, attached to 4 _, ^ susceptor 1 monoazole The amine group on the base ring is protected by a suitable protecting group, such as the conventional protecting group. The type is in a solvent that is inert under the reaction conditions, including, for example, water, octahydrate, and a lower alcohol or two Oxygenate mixtures, or bipolar aprotic., Butan / mixtures, such as dimethylformamide or dimethylsulfoxide, such as with ethanol, yongyue 4 water, Kunhe; for example -20 to 50 X: Wen Benzhi New York Lai Jiaxian (, 1T • 9- Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 561157 V. Description of the invention (at 7 degrees, it is compound with formula IIH, such as free ^ or Salt type and / or soluble type and / or for example, the reactive group, such as an amine group attached to a radical or a hexahydrotonyl nitrogen, is reacted with a suitable protecting group, such as a conventional protecting group. When protecting the reactive group, it is suitable in the presence of a solvent that is inactive to the oxygenating agent, such as gas. Smoke, such as dichloromethane, such as nitrile, ether, such as tetrahydrofuran 'bipolar aprotic solvent, such as N, N-dimethylformamide; or a solvent system, such as a mixture of various solvents on top Protection technology. The pH of the reaction mixture can be adjusted by adding acid-base pH regulators, such as organic or inorganic acids or bases, to the optimal pH. The type, for example, is mainly 3⑹; from the reaction mixture, for example, in a conventional manner, such as: precipitation, such as extraction in the presence of an anti-Solvent, extraction, chromatography, solvent extraction or separation. A protecting group in a compound of formula II or a compound of formula m can be isolated under the appropriate reaction conditions during the reaction between a compound of formula III and a compound of formula III, for example, 2 in a conventional manner, or if a protective group exists, for example, in traditional ° = A compound of formula I obtained from the reaction of a compound of formula II or a compound of formula III, wherein the cleavage protection group is #. The compound of formula I obtained on the mouthpiece, wherein R1 is ammonia, for example in the form of a salt, can be transformed into R1 in the formula by conventional methods, for example. Ester-based compounds, and vice versa. Compounds of formula I can be separated from the reaction mixture using conventional methods = frightening, extraction, centrifugation, solvent evaporation methods. Free radicals can be converted into salts, for example, in a conventional manner. Type and / or solvate type = (2Ι〇χ297mm) (Please read the precautions on the back before filling this page)

經濟部中央襟準局員工消費合作社印製 561157 A7 ----^_______B7 五、發明説明~~ —~— 合物；且反之亦然。 〜 、、式II化合物和式m化合物爲已知或者或可根據已知方 法’、例如類似方法，或例如根據本發明實例而製得。 式I化合物，下文稱爲”本發明活性化合物"，展現出醫 ^舌性且其毒性是令人㈣地低，因此適用爲醫藥。特定 本發明活性化合物在試管内及活體内均展現抗微生 活陡例如· ·抗好氧性及厭氧性生長細菌。抗細菌活性， 此等細菌如革蘭氏陽性菌及革蘭陰性菌，如腸桿菌屬，例 如陰溝腸桿菌；腸球菌屬，例如糞腸球菌.，屎腸球菌；莫 拉克斯氏桿菌屬，例如卡他性莫拉克斯氏桿菌；嗜血菌 屬，例如流行性感冒嗜血菌；克雷伯氏桿菌屬，例如艾氏 炎克雷伯氏桿菌，肺炎克雷伯氏桿菌；鏈球菌屬，例如釀 膿鏈球菌’·葡萄球菌屬，例如金黃色葡萄球菌mssa (對 二甲氧基苯青黴素感的變種），金黃色葡球菌MRSA (對二 甲氧基苯青黴素有抗性的變種）；艾歇利希氏菌屬，例如 大腸桿菌；變形桿菌屬，例如奇異變形桿菌；沙門氏菌 屬，例如鼠傷寒桿菌；沙雷氏菌屬，例如靈样菌，假單胞 菌屬，例如綠膿桿菌；肺炎雙球菌屬，例如··肺炎肺炎雙 球菌（對盤尼西林敏感且對多種藥物有抗性之變種）。試管 内試驗乃依據國家委員會的臨床實驗室標準…如⑽以Printed by the Consumer Cooperatives of the Central Commission of the Ministry of Economic Affairs 561157 A7 ---- ^ _______ B7 V. Description of Invention ~~ — ~ — Compound; and vice versa. ~, The compound of formula II and the compound of formula m are known or can be prepared according to a known method ', such as a similar method, or for example, according to an example of the present invention. The compound of formula I, hereinafter referred to as "the active compound of the present invention", exhibits medical properties and its toxicity is surprisingly low, so it is suitable for use in medicine. Certain active compounds of the present invention exhibit resistance in vitro and in vivo. Micro life is steep, for example: · Anti-aerobic and anaerobic growth bacteria. Antibacterial activity, such bacteria as Gram-positive and Gram-negative bacteria, such as Enterobacter, such as Enterobacter cloacae; Enterococcus For example, Enterococcus faecalis, Enterococcus faecium; Moraxella genus, such as Moraxella catarrhalis; Haemophilus, such as Haemophilus influenza; Klebsiella, such as Ehrlich Klebsiella pneumoniae, Klebsiella pneumoniae; Streptococcus, such as Streptococcus pyogenes' · Staphylococcus, such as Staphylococcus aureus mssa (p-dimethoxybenzoicin-sensitive variant), golden yellow Staphylococcus MRSA (variants resistant to dimethoxybenzyl penicillin); Escherichia genus, such as E. coli; Proteus, such as Proteus mirabilis; Salmonella, such as Typhoid typhimurium; Serratia Pseudomonas, such as Pseudomonas, Pseudomonas, such as Pseudomonas aeruginosa; Pneumococcus, such as Pneumococcus pneumoniae (variable to penicillin and resistant to multiple drugs). In-vitro tests Based on National Committee's clinical laboratory standards ...

Commitee for Clinical Laboratory Standards，（NCCLS)) 1993 年版 進行細菌之瓊脂稀釋試驗（Agar Dilution Test): -文件-M7-A3第13册，第25號··”好氧性生長細菌的稀 釋性抗微生物敏感度試驗法-第三版，許可標準"；與 ______ -1卜 本紙張尺度適用^國} ------ (請先閱讀背面之注意事項再填寫本頁)Commitee for Clinical Laboratory Standards (NCCLS)) 1993 Edition Performs Agar Dilution Test of Bacteria:-Document-M7-A3 Vol. 13, No. 25 ... "Dilute Antimicrobials for Aerobic Growing Bacteria Sensitivity Test Method-Third Edition, Permissible Standards " and ______ -1 Paper Size Applicable ^ Country} ------ (Please read the precautions on the back before filling this page)

561157 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（9 ) -文件-M11-A3，用於厭氧性細菌 - 試驗濃度爲約0.001至約50微克/毫升（MIC)，例如採用包 括金黃色葡萄球菌（ATCC29213與ATCC9144);糞腸球菌 (ATCC29212);流行性感冒嗜血菌（NTCC49247 和 NCTC11931);大腸样（ATCC25922 和 ATCC35218 );肺炎克 雷伯氏样菌（NCTC11228);艾氏炎克雷伯氏桿菌 (NCTC10896);綠膿桿菌（ATCC27853 和八丁(：025668 )進行試 驗。 活體内實例則根據奥地利衛生局許可’之第159A-5號 (MA58，1995年10月12日第2968/95號）中的方法，以敗血 病老鼠模式進行測試，例如當以0.05至50毫克/公斤體重 的劑量抗藥，如0.1至50毫克/公斤體重（ED5〇値）。例如 以ED95%的金黃色葡萄球菌（ATCC4995)，釀膿鏈球菌 (ATCC2921S)，大腸桿菌（ΔΠΝΠ培養物收集處）感染老 鼠，且在感染後1 ，5 ，24小時後進行治療。ED50%値 由該化合物之投與劑量之普洛比（Probit)分析計算爲約0.2 至50毫克/公斤體重。活性由感染五天後，各種劑量之各 組8隻家鼠的存活隻數決定。 本發明活性化合物展現出令人驚訝之活性範圍。 例如，實例I化合物對抗例如糞腸球菌的MHK (微克/ 毫升）經測定爲約0.1至0.4 ;對抗金黃色葡萄球菌（MSSA) 爲約小於0.125至0.8 ;對抗對二甲氧基苯青黴素有抗性 的金黃色葡萄球菌爲0.8至6.4 ;對抗如有多重抗藥性的 肺炎雙球菌爲0.4。 -12- 本纸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)561157 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (9)-Document-M11-A3 for anaerobic bacteria-Test concentration is about 0.001 to about 50 micrograms / ml (MIC), for example Uses include Staphylococcus aureus (ATCC29213 and ATCC9144); Enterococcus faecalis (ATCC29212); Haemophilus influenzae (NTCC49247 and NCTC11931); Colon-like (ATCC25922 and ATCC35218); Klebsiella pneumoniae (NCTC11228); Klebsiella escherichia (NCTC10896); Pseudomonas aeruginosa (ATCC27853 and octadine (: 025668) were tested. In vivo examples were approved according to the Austrian Health Agency's No. 159A-5 (MA58, October 12, 1995) No. 2968/95), test in septic mouse mode, for example, when the drug is resistant at a dose of 0.05 to 50 mg / kg body weight, such as 0.1 to 50 mg / kg body weight (ED50). For example Rats were infected with ED95% Staphylococcus aureus (ATCC4995), Streptococcus pyogenes (ATCC2921S), and E. coli (ΔΠΝΠ culture collection site), and were treated 1, 5, 24 hours after infection. ED50% was treated by Of the compound Probit analysis with dose was calculated to be about 0.2 to 50 mg / kg body weight. The activity was determined by the number of surviving mice in each group of 8 mice at various doses five days after infection. The active compounds of the present invention showed that Surprising range of activity. For example, the compound of Example I against MHK (micrograms / ml) of, for example, Enterococcus faecalis was determined to be about 0.1 to 0.4; against Staphylococcus aureus (MSSA) was less than about 0.125 to 0.8; Oxypenicillin-resistant Staphylococcus aureus is 0.8 to 6.4; against multi-drug resistant pneumococci is 0.4. -12- This paper size applies to China National Standard (CNS) A4 (210X297 mm) ) (Please read the notes on the back before filling this page)

561157561157

經濟部中央標準局員工消費合作社印製 因此，本發明活性化合物可用於洽療微生物性，例如細 菌性疾病。 ' 以此適應症而言，適合的劑量當然將視例如所採用之式 I化合物、宿主、投藥型式及欲治療之病症的本質及嚴重 程度而足。然而’一般而言，在較大型哺乳類，例如人 類，要得到滿意的結果，其建議的每日劑量範圍爲約〇〇5 至5克，例如（U至2·5克本發明活性化合物，宜例如分 成最多一曰投藥四次。 本發明活性化合物可以任何傳統途徑投.藥，例如以錠劑 或膠囊型式口服，或類似西氟塔斯（Cef〇taxime)的方法，以 注射溶液或懸浮液，依非經腸道式投藥。 7-(((5-胺基-1，2,4”塞二峻_3_基）切_(氣甲氧亞胺基）乙 酷基）胺基）-3-((亞胺基六氫峨p井甲基）甲基亞聯胺基） 曱基-3-啦巩-4-羧酸化合物（實例〗化合物）是本發明中作 爲抗微生物製劑之較佳化合物。例如，實W !化合物（以 鹽酸鹽型式測試）抵抗例如流行性感冒嗜血菌❾mhk (微 克/毫升）已測定爲約小於0.125至〇4，及例如西氣塔斯的 ΜΗΚ (微克/毫升）爲約小於〇125至〇4 。因此表示，可 用於治療微生物疾病，例如細菌疾病，本發明較佳化合物 可以類似於西氟塔斯的投藥模式及投藥劑量，投藥於較大 型哺乳類，例如人類。 ----Ir---费丨^-----1T------0 (請先閱讀背面之注意事項再填寫本頁) 式I化合物可以醫藥上可接受之鹽型投藥，例如酸加成 鹽或驗加成鹽或其相應游離型，若需要時可呈溶合物型。 該等鹽/溶合物展現與游離型相同之活性程度。本發明亦Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Therefore, the active compounds of the present invention can be used to treat microorganisms, such as bacterial diseases. 'For this indication, a suitable dosage will of course depend on, for example, the nature and severity of the compound of formula I employed, the host, the type of administration and the condition to be treated. However, 'in general, in larger mammals, such as humans, to obtain satisfactory results, the recommended daily dose range is about 0.05 to 5 grams, such as (U to 2.5 grams of the active compound of the present invention, preferably For example, divided into a maximum of four administrations. The active compound of the present invention can be administered by any conventional route. For example, oral administration in the form of a tablet or capsule, or a method similar to Cefataxime, by injection of a solution or suspension. , Parenteral administration. 7-((((5-Amino-1,2,4 "serotonin_3_yl) Ce_ (aeromethoxyimino) ethoxy) amino)) -3-(((imino hexahydrop-methyl) methyl) imine) fluorenyl-3-lazon-4-carboxylic acid compound (example compound) is used as an antimicrobial agent in the present invention Preferred compounds. For example, real W! Compounds (tested in the hydrochloride form) against, for example, Haemophilus influenzae hkmhk (μg / ml) have been determined to be less than about 0.125 to 〇4, and for example (Micrograms / ml) is about less than 0125 to 0. Therefore, it is indicated that it can be used to treat microbial diseases such as bacteria Disease, the preferred compounds of the present invention can be administered to larger mammals, such as humans, similar to the dosing mode and dosage of Ciflutas. ---- Ir --- Fei 丨 ^ ----- 1T --- --- 0 (Please read the notes on the back before filling this page) The compound of formula I can be administered in pharmaceutically acceptable salt form, such as acid addition salt or test addition salt or its corresponding free form, if necessary It is a solvate type. These salts / solvates exhibit the same degree of activity as the free type. The present invention also

經濟部中央標準局員工消費合作社印製 561157 五、發明説明（u 提供醫藥組合物，其包括呈醫藥上可—接受之鹽型 i根據申請專利範圍第丨項之 一 ’型 一、 <式1化合物，與至少一錄麗 藥載體或稀釋劑組合。 醫 該等組合物可以傳統方式製造。 單位劑量古可包含例如10毫克至^公克，實例如1〇黑 克至約700 *克，如至約500亳克。 毛 作爲藥物時，根據本發明之活性成分可單獨投盘 典機或有機（醫樂上爲純的賦型劑_起形成合適醫^刑 式投藥。例如可作爲膠囊，注射劑，或輸.注製劑的成分了 其中活性化合物含量足以達到最佳血中濃度，即粒膠囊約 H)至·毫克。在此等應用下，投藥劑量視使用之化合物 與投樂万式’及治療型式而定。對較大型哺乳動物，每曰 投予約〇_…克的劑量時’可得到滿意的結果。如有需 要’孩量可等分成一曰兩次至四次之較小劑量，或持續釋 放的劑型投藥。 本發明另-方面係提供-種式j化合物或含有呈醫藥上 可接受之鹽或游離型之式！化合物，與至少一種醫藥載體 或稀釋劑結合形成之組合物作爲藥物，例如作爲抗生素； 及 以式！化合物或含有呈醫藥上可接受之鹽或游離型之式 !化合物’與至少一種醫藥載體或稀釋劑結合形成之組合 物於作爲藥物上之用途。 -----：~^---—丨 (請先閲讀背面之注意事項再填寫本頁) 訂 本發明另-方面係提供-種治療微生物疾病之方法，例 如由選自下列細菌引起之疾病：綠膿桿菌、腸桿菌 '腸球Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 561157 V. Invention Description (u Provides a pharmaceutical composition, which includes a pharmaceutically acceptable-acceptable salt form i. 1 compound, combined with at least one drug carrier or diluent. These compositions can be made in a conventional manner. A unit dose may include, for example, 10 mg to ^ g, examples such as 10 black grams to about 700 * grams, such as When the hair is used as a medicine, the active ingredient according to the present invention can be separately administered or organic (medical excipients are pure excipients) to form a suitable medical treatment. For example, it can be used as a capsule, Injectables, or infusions. The components of the infusion preparation contain the active compound in an amount sufficient to achieve the optimal blood concentration, i.e., capsules of about H) to · milligrams. In these applications, the dosage depends on the compound used and the Levan formula. Depending on the type of treatment. For larger mammals, a satisfactory result can be obtained when administered at a dose of about 0 .... grams per day. If necessary, the amount can be divided into smaller doses of two to four times a day. Or a sustained release dosage form. Another aspect of the present invention is to provide a compound of formula j or a compound containing a pharmaceutically acceptable salt or free form! A compound formed by combining with at least one pharmaceutical carrier or diluent As a medicament, for example as an antibiotic; and as a medicament using a compound of formula! Or a composition containing a pharmaceutically acceptable salt or free form! Compound 'in combination with at least one pharmaceutical carrier or diluent- ----: ~ ^ ---- 丨 (Please read the notes on the back before filling out this page) Another aspect of the invention is to provide a method for treating microbial diseases, such as diseases caused by bacteria selected from the following : Pseudomonas aeruginosa and Enterobacter's enterosphere

561157 五、發明説明（l2)561157 V. Description of the invention (l2)

菌莫拉兄斯氏桿菌、嗜血菌、克f伯庆浐A 金黃色葡萄玻A 无田伯氏私困、鏈球菌、 、葡匈球囷、艾歇利希氏菌、變形桿菌、沙門氏 =雷氏菌或肺炎.雙球菌’其包括對需該等治療之個體投與 效量式I化合物例如：呈根據本發明醫藥组合物 藥；及 又 、以式I化合物料製備治療微生物疾病之藥物，例如由 ，自了列〈細菌引起之疾病：綠膿桿f、腸桿菌、腸球 囷:莫拉克斯氏桿菌、嗜血菌、克雷伯氏桿菌、鍵球菌、 金頁巴葡萄球菌、艾歇利希氏菌、變形桿菌、沙門氏菌、 沙雷氏菌或肺炎雙球菌。 本發明另一方面係提供下式化合物 N — 〇CH，F II 2 *c — CO一NH 丨B. moraxii, Haemophilus, gram f. Boqing 浐 A, golden yellow grapes A, Botian privacis, streptococcus, 葡, H. esculenta, escherichia, proteus, salmonella = R. reuteri or pneumonia. Diplococcus' which includes administering an effective amount of a compound of formula I to an individual in need of such treatment, for example: taking a pharmaceutical composition according to the invention; and preparing a compound of formula I to treat a microbial disease Drugs, for example, are listed below: Diseases caused by bacteria: Pseudomonas aeruginosa, Enterobacter, Enterococcus: Moraxella, Haemophilus, Klebsiella, Keyococcus, Aureus Cocci, escherichia, proteus, salmonella, serratia or pneumococcus. Another aspect of the present invention is to provide a compound of the formula N — 〇CH, F II 2 * c — CO-NH 丨

NH c請先閲讀背面之注意事項再填寫本頁) H, 〇NH c Please read the notes on the back before filling this page) H, 〇

•CH = M 卞 C COOR, CHn ip 其中 經濟部中央標準局員工消費合作社印製 R1代表氫、酯基或呈游離型之陽離子，或若可能形成之酸 加成鹽、内鹽、四級鹽或水合物。 下列實例更詳細説明本發明範圍，但非限制此範圍，其 (PU中所有溫度單位爲攝氏。1H-NMR ·· 200 ，DMS〇-d6。 實例1 7- ( ( ( 胺基-1，2,4- p塞二唾-3-基）-(Z)-(氟甲氧亞胺基）乙酿 基）胺基）-3-((亞胺基-1-六氫ϊ：比p井甲基）甲基亞聯胺基）甲 -15- 本紙張尺度適用中國國家標準（CNS ) A4規格（21 Οχ297公釐） 經濟部中央標準局員工消費合作社印製 561157 、發明説明（13 ) 基-3-哂叽_4•羧酸 一 a) -3-羥基 _1，7-二氧-3H，7H-乙醯幷（2，l-b) ^I^i3,4-d) (1，3)〇塞畊-6-基）-2- ( 5-胺基 _1·2·4-嘍二唑-(氟甲氧亞胺基）乙醯胺（7- ( ( ( 5-胺基_1，2,4_ P塞二峻基HZH氟甲氧亞胺基）乙醯基）胺基）-3-甲醯 基-3-哂口凡-4-羧酸的經基内酯） 取含10克7-胺基-3-甲醯基-3-哂机-4-幾酸之220毫升氯 甲晞與80毫升乙腈混合物之懸浮液與43毫升N，〇_雙（三 甲石夕燒基）-乙醯胺於0。下攪拌。添加15 7克（5_胺基_ i’2’4· p塞二峻-3-基）-(Z)-2-氟甲氧亞胺基乙醯氣至所得之澄 清溶液中，該反應混合物在約〇。下攪摔1小時。該混合物 以含70毫升水的1250毫升乙腈稀釋。在混合物中添加 12%氨水，將酸鹼値調整至3.5。該混合物以2 5公升水稀 釋後，以乙酸乙酯萃取。乙酸乙酯相脱水及濃縮。該濃縮 物在20。下與1〇〇毫升的乙腈攪摔1小時。仏（1，4，^，6_四 氫-3-經基-l，7-二氧-3H，7H-乙醯幷（2，l-b)呋喃幷（3,心d) (1，3)-4畊冬基）_2· ( 5-胺基-I，2,4-噻二唑_3_基hZ)_2_ (氟甲氧亞 胺基）乙醯胺會呈晶體型式沈澱，再過遽乾燥。 h-NMR-光譜：3.65 (m，2x AB 四裂峰，2H，sc%) · 5 18 (d，J=5 赫兹，1H，β-内酿胺-Η) ; 5.83 (d，J=55 赫兹，2H CH2F) ; 6.03 (dd，J=5 和 8.3 赫茲，1H 卜内醯胺·印；6 % 和 6·30 (s，1H，0-CH-0) ; 8·25 (寬單峰，2H，贿2) ; 9 89 和 9·87 (d5 J=8.3 赫茲，1H，NH)。 -16- 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇X 297公釐） I X ^ -- (請先閲讀背面之注意事項再填寫本頁)• CH = M 卞 C COOR, CHn ip Among them, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, R1 represents hydrogen, ester or free cations, or if possible, acid addition salts, internal salts, and quaternary salts Or hydrate. The following examples illustrate the scope of the invention in more detail, but without limiting the scope, (All temperature units in the PU are Celsius. 1H-NMR · 200, DMS 0-d6. Example 1 7- ((Amine-1, 2 , 4-p-sedialyl-3-yl)-(Z)-(fluoromethoxyimino) ethynyl) amino) -3-((imino-1-hexahydrofluorene: than p well Methyl) methylimido) A-15- This paper size is applicable to Chinese National Standard (CNS) A4 (21 0297 mm) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 561157, Invention Description (13) -3- 哂 叽 _4 • carboxylic acid a) -3-hydroxy_1,7-dioxo-3H, 7H-acetamidine (2, lb) ^ I ^ i3,4-d) (1,3 ) 〇 Sethen-6-yl) -2- (5-Amino-1 · 2 · 4-pyridadiazole- (fluoromethoxyimino) acetamidamine (7-(((5-Amino_ 1,2,4_P-Cycloyl HZH fluoromethoxyimino) ethenyl) amino) -3-methylamido-3-carbophenan-4-carboxylic acid lactone) 10 g of a suspension of a mixture of 7-amino-3-formamyl-3-fluoren-4-yl chloride with 220 ml of chloroformamidine and 80 ml of acetonitrile and 43 ml of N, β-bis (trimethylsulphate )-Acetamide is stirred at 0. Add 15 7 (5-Amine_i'2'4.p-sepund-3-yl)-(Z) -2-fluoromethoxyiminoacetamidine gas to the resulting clear solution, the reaction mixture was at about 0. .Stir down for 1 hour. The mixture was diluted with 1250 ml of acetonitrile containing 70 ml of water. 12% ammonia water was added to the mixture to adjust the pH to 3.5. The mixture was diluted with 25 liters of water and ethyl acetate. Extraction. The ethyl acetate phase was dehydrated and concentrated. The concentrate was stirred with 100 ml of acetonitrile for 1 hour at 20 ° C. (1,4, ^, 6-tetrahydro-3-acyl-1,7 -Dioxo-3H, 7H-acetamidine (2, lb) furan (3, xin d) (1,3) -4crotyl) _2 (5-amino-I, 2,4-thia Diazol_3_ylhZ) _2_ (fluoromethoxyimino) acetamidin will precipitate as a crystal and then be dried over hydrazone. H-NMR-spectrum: 3.65 (m, 2x AB four-split peak, 2H, sc %) · 5 18 (d, J = 5 Hz, 1H, β-lactam-Η); 5.83 (d, J = 55 Hz, 2H CH2F); 6.03 (dd, J = 5 and 8.3 Hz, 1H BU Leptin · India; 6% and 6.30 (s, 1H, 0-CH-0); 8.25 (broad singlet, 2H, bribe 2); 9 89 and 9.87 (d5 J = 8.3 Hz , 1H, NH). -16- Paper Scale applicable Chinese National Standard (CNS) A4 size (297 mm 21〇X) I X ^ - (Please read the Notes on the back to fill out this page)

、1T 經濟部中央標準局員工消費合作社印製 561157 A7 Γ—— —___Β7 __ 五、發明説明（I4 ) b)Zlil(5-胺基-1，2_，4-4二唑-3-基W-ZV(氟甲氧亞胺基）乙 座基）胺基）-3(EM亞胺基-1-六氫吡畊甲基）甲基亞聯胺 基）甲基-3-哂口凡-4-羧酸 將 3.77 克 >1-(1,4,5&，6-四氫-3-羥基-1，7-二氧-311,711-乙醯 幷（2，l-b)呋喃并（3,4-d) (1，3)-嘍畊-6-基）( 5-胺基-1，2,4-嘧 二唑-3-基）-(Z)-2-(氟甲氧亞胺基）乙醯胺懸浮於75毫升乙 腈和11毫升水的混合物中，再以含2克1- ( 1-甲基亞聯胺 基）亞胺曱基）六氫吡畊之二鹽酸鹽的4.5毫升2N的鹽酸 溶液處理。反應混合物在室溫下攪拌約一，天，在攪拌下倒 入600毫升乙腈中。（7- ( ( ( 5-胺基-1，2,4_嘧二唑-3-基）-(Z)-(氟甲氧亞胺基）乙醯基）胺基）-3(E)-(亞胺基-1-六氫吡畊甲 基）甲基亞聯胺基）甲基-3·哂叽-4-羧酸呈三鹽酸鹽的型式 沈澱出，過濾，以乙腈清洗並乾燥。 〇)_7-(((5-胺基-1,2,4-4二唑_3-基）-〇-(氣甲氧亞胺基）乙 醯基）胺基亞胺基-1-六氫吡畊甲基）甲基亞聯胺 基）甲基-3-哂矾-4-羧酸 將得自步驟b)之0.65克呈三鹽酸鹽之粗產物7-(((5-胺 基-1，2,4-遠二峻-3-基）-(Z)-(氟曱氧-亞胺基）乙酿基）胺基）_> 3(E)-(亞胺基-1-六氫吡畊曱基）甲基亞聯胺基）甲基-3-哂口凡 -4-羧酸溶於2毫升水中，且填入含50克RP-18r (LiChroprep RP-18r，顆粒大小爲40至63微米，默克出品） 的管柱内且以水溶離（流速爲20毫升/分鐘）。溶離份以分 析級HPLC檢驗，測定含有單鹽酸鹽型之7- ( ( ( 5-胺基-1，2,4-遠二峻-3-基）-(Z)-(氟甲氧亞胺基）乙酿基）胺基）-3- -17- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） ~ ^-----^ (請先閲讀背面之注意事項再填寫本頁) 、訂 561157、 1T printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 561157 A7 Γ ————___ Β7 __ V. Description of the Invention (I4) b) Zlil (5-Amino-1, 2_, 4-4 Diazol-3-yl W -ZV (fluoromethoxyimino) ethenyl) amine) -3 (EM imino-1-hexahydropyridine methyl) methylimino) methyl-3-methylphenone- 4-carboxylic acid 3.77 g > 1- (1,4,5 &, 6-tetrahydro-3-hydroxy-1,7-dioxo-311,711-acetamidine (2, lb) furo (3, 4-d) (1,3) -Phenox-6-yl) (5-amino-1,2,4-pyrimidazol-3-yl)-(Z) -2- (fluoromethoxyimine Acetylam) was suspended in a mixture of 75 ml of acetonitrile and 11 ml of water, and the mixture containing 2 g of 1- (1-methyliminoimide) imide) hexahydropyridine hydrochloride was added. Treat with 4.5 ml 2N hydrochloric acid. The reaction mixture was stirred at room temperature for about one day, and then poured into 600 ml of acetonitrile with stirring. (7- (((5-Amino-1,2,4-pyrimidazol-3-yl)-(Z)-(fluoromethoxyimino) ethenyl) amino) -3 (E) -(Imino-1-hexahydropyridinemethyl) methyliminoimido) methyl-3 · fluorene-4-carboxylic acid precipitated as a trihydrochloride salt, filtered, washed with acetonitrile and dry. 〇) _7-(((5-amino-1,2,4-4diazol-3-yl) -〇- (airmethoxyimino) ethenyl) aminoimino-1-hexa Hydrogenated methyl) methylimidino) methyl-3-xan-4-carboxylic acid will be obtained from 0.65 g of the crude product 7-(((5-amine -1,2,4-Farabi-3-yl)-(Z)-(Fluorofluorenyl-imino) ethenyl) amino) _ > 3 (E)-(imino-1 -Hexahydropyridyl) methylimidino) methyl-3-carban-4-carboxylic acid is dissolved in 2 ml of water and filled with 50 grams of RP-18r (LiChroprep RP-18r, granules 40 to 63 microns in size, from Merck) and dissolve in water (20 ml / min flow rate). The eluate was analyzed by analytical HPLC to determine the 7- (((5-amino-1,2,4-distoricin-3-yl)-(Z)-(fluoromethoxyoxy) Amine group) Ethyl group) Amine group) -3- -17- This paper size applies to Chinese National Standard (CNS) A4 size (210X 297 mm) ~ ^ ----- ^ (Please read the notes on the back first Fill out this page again), order 561157

A B 經濟部中央標準局員工消費合作社印製 五、發明説明（I5 ) (E)-(亞胺基-1·六氫吡畊曱基）曱基亞聯胺基）甲基-3-哂口凡-4-羧酸之溶離份（HPLC)，合併且冷凍乾燥。 如述於實例1鉍方法，但改用式III化合物，其中R2和 R3如下表1中的定義，得到亦列於下表1中之式I化合 物，其中Ri爲氫，例如呈所指定之鹽型。 表1 實例 R2 r3 鹽 2 c2h5 H HC1 3 ch3 c2h5 HC1 4 -ch2ch=ch2 H 3HC1 5 ch3 ch3 HC1 6 - CH2 ^~^)~ 0CH3 H 3HC1 7 -ch2-"/V-och3 och3 H 3HC1 作爲起始物質之胺基胍可由下法製備：Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the Invention (I5) (E)-(Imine-1 · Hydroxypyridine) Methylideneimine) methyl-3-methyl Fractions of benzo-4-carboxylic acid (HPLC) were combined and lyophilized. As described in the Example 1 bismuth method, but using a compound of formula III, where R2 and R3 are as defined in Table 1 below, a compound of formula I is also listed in Table 1 below, where Ri is hydrogen, for example, as the specified salt type. Table 1 Examples The aminoguanidine of the starting material can be prepared by the following method:

實例A 1-(1-曱基聯胺基）亞胺曱基）六氫吡畊 a) S-甲基-2-甲基-異胺基硫脲 將含239.8克呈氫碘酸鹽型之S-甲基-2-甲基異胺基硫脲 之100毫升水溶液置於.已含1500毫升呈氣化物型式之強鹼 性陰離子交換劑（Amberlite IRA420r)的管柱内，且以水溶 離。取含S-甲基-2-曱基異胺基硫脲鹽酸鹽（HPLC)之溶離 -18 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁)Example A 1- (1-fluorenylhydrazine) iminefluorenyl) hexahydropyridine a) S-methyl-2-methyl-isoaminothiourea will contain 239.8 g of a hydroiodate type A 100 ml aqueous solution of S-methyl-2-methylisoaminothiourea was placed in a column containing 1500 ml of a strong basic anion exchanger (Amberlite IRA420r) in a gaseous form, and was dissolved in water. Take the dissolution-18 containing S-methyl-2-fluorenylisoaminothiourea hydrochloride (HPLC)-This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the back (Please fill in this page again)

II ii 經濟部中央標準局員工消費合作社印製 561157 五、發明説明（16 伤冷凍乾燥。該冷凍乾燥物以***—處理，過濾分離及乾 燥。 ~ 可得白色固體之鹽酸鹽型的s-甲基甲基-異胺基硫 脈。 Μ·Ρ· : 116°(異丙醇） b) 棊-1- ((1- H聯胺基）亞胺-甲某）六氫吡畊的苯 查甲基衍生物 將含40.9克鹽酸鹽型之S_甲基|甲基·異胺基硫脲的 350毫升乙醇溶液與3〇克剛蒸餾出之甲醯.六氫吡畊混合， 且迴流加熱約39小時。反應混合物冷卻至室溫，與26 4 t升苯甲趁混合且授拌約24小時。濾出所得之沈澱物， 以乙醇清洗且乾燥之。即可得鹽酸鹽型之4_曱醯基+ ((1-甲基聯胺基）亞胺甲基）六氫吡畊的苯亞甲基衍生物。 c) ki (1-甲基聯胺基）亞胺甲基）六氪毗畊 使含10克鹽酸鹽型之4-甲醯基-i-((卜甲基聯胺基）亞胺 甲基）六氫吡畊的苯亞甲基衍生物。在添加48毫升2NHC1 下蒸氣蒸餾，以裂解苯甲醛。將所得之水性漿物濃縮，形 成油狀殘餘物，再以煮沸的乙醇處理。乙醇相眞空濃縮， 可得白色固體之二鹽酸鹽型的1-((1_甲基聯胺基）亞胺曱 基）六氫p比17井。II ii Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 561157 V. Description of the invention (16 Injury freeze-drying. The freeze-dried product is treated with ether-, filtered and dried. ~ Hydrochloride type s- Methylmethyl-isoaminosulfide. M · P ·: 116 ° (isopropanol) b) 棊 -1- ((1-H hydrazine) imine-methyl) hexahydropyrine To check the methyl derivative, 350 ml of an ethanol solution containing 40.9 g of S-methyl | methyl · isoaminothiourea in the form of hydrochloride was mixed with 30 g of freshly distilled formamidine, hexahydropyridine, and refluxed. Heat for about 39 hours. The reaction mixture was cooled to room temperature, mixed with 264 t liters of benzyl and allowed to stir for about 24 hours. The resulting precipitate was filtered off, washed with ethanol and dried. A 4-methylene group of the hydrochloride type ((1-methylhydrazine) iminemethyl) hexahydropyridine benzyl derivative can be obtained. c) ki (1-methylhydrazine) iminemethyl) hexamidine, which contains 10 g of 4-methylfluorenyl-i-((buminazine) iminemethyl) in hydrochloride form Benzomethylene derivative of hexahydropigen. Steam distillation with the addition of 48 ml of 2NHC1 to crack the benzaldehyde. The resulting aqueous slurry was concentrated to form an oily residue, which was then treated with boiling ethanol. The ethanol phase was condensed in the air and a white hydrochloride type 1-((1-methylhydrazine) iminefluorenyl) hexahydro p ratio 17 well was obtained.

H-NMR · 3.16 (m，7H, N-CH3 和-CH2-N-CH2-) ; 3.61 (m 4H ’CH2-N+-CH2-) ; 6.0 (寬單峰，3H，N+H3) ; 8.3 (寬單峰， 1H, NH) ； 1〇·〇 (寬單峰，2H,N+H2)。 (請先閱讀背面之注意事項再填寫本頁)H-NMR 3.16 (m, 7H, N-CH3 and -CH2-N-CH2-); 3.61 (m 4H 'CH2-N + -CH2-); 6.0 (broad singlet, 3H, N + H3); 8.3 (Broad singlet, 1H, NH); 10.0 (broad singlet, 2H, N + H2). (Please read the notes on the back before filling this page)

、1T -19- 561157 A7 經濟部中央標準局員工消費合作社印製 五、發明説明（π 實例Β _ 1- [(1-乙基聯胺基）亞胺甲基]六氫吡畊 a) kl避胺亞胺甲基）六氫吡畊的苯亞甲美拚生物 添加8N氫氧化鈉，將含10.7克鹽酸鹽型之聯胺亞 胺甲基）-六氫吡畊的苯亞曱基衍生物的100亳升水溶液酸 驗値碉整至10 。所得之混合物以乙酸乙酯萃取。乙酸乙 醋相脱水且蒸發溶劑，得到不定形粉末的(聯胺亞胺曱 基）六氫吡啩的苯亞甲基衍生物。 b) ll甲醯基-4- ( 1 -聯胺亞胺曱基）六氫p比p井的笨亞甲基衍生 將i2.7毫升的乙酸酐滴加至42毫升的冰冷之甲酸中， /昆合物檟;摔1小時後，再滴加含克(聯胺亞胺甲基）_ 六氫批畊的苯亞曱基衍生物的42毫升甲酸。該混合物於 〇°下留置2小時使溶劑揮發。殘餘物以水處理且藉由添加 10N鼠氧化舒’將所得混合物酸驗値調整至11 。該混合 物以一氣曱燒萃取。二氯甲娱*相脱水，溶劑點發。可得白 色粉末之1-甲醯基-4- (1-(聯胺亞胺甲基）六氫吡畊的苯亞 甲基衍生物。 c) 】二[(1-乙基聯胺基）亞胺曱基卜4-甲酿六氫咐井的笨亞甲 基衍生物 取經冰冷卻之含2克1-曱醯基-4-(1-聯胺亞胺甲基）六 氫峨畊之苯亞甲基衍生物的40毫升無水四氫吱喃溶液， 以9.3毫升的雙气三甲矽烷基）·胺化鋰（1M四氫呋喃溶液） 處理且於0。下攪拌約1小時。添加2·4克碘乙烷至反應混 -20- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐 ---·,-I·,---豐-----1T------# (請先閲讀背面之注意事項再填寫本頁) 561157 A7 B7 經 濟 部 中 央 準 k 員 工 消 費 合 作 社 印 製 五、發明説明（is 合物中’且該混合物於室溫下攪摔^夜。溶劑蒸發後，殘 餘物以 典水官柱急驟光層析’’（Dry-column-flasli-chromatography)法（溶離液：1.甲醇，2. 90%甲醇/ 10%乙酸） 純化。 合併全1- [( 1-乙基聯胺基）亞胺甲基]-4-曱醯六氫吡畊 之苯亞曱基衍生物之溶離份（以分析級HPLC測知）。溶劑 蒸發後，得到户色粉末之1-[(1-乙基聯胺基）亞胺甲基卜 4-甲醯六氫吡畊的苯亞甲基衍生物。 d) 1-『（1-乙基聯胺基）亞胺甲基1六氫吡畊· 將2.7克1-[(1-乙基聯胺基）亞胺甲基]-4-甲醯六氫吡哨 的苯亞甲基衍生物溶解在11.6毫升2NHC1中，再以蒸氣 蒸餾處理。混合物中之水蒸發，乾燥後可得殘餘物爲白色 固體之二鹽酸鹽型的卜[(1-乙基聯胺基）亞胺甲基]六氫咐 畊。 iH-NMR-光譜：1.22 J=5 赫茲，311，<：113;3.16，1)，411，^ CH2 ; 3.45 q，J=5 赫茲，2H，CH2 ; 3.65, b，4H，N-CH2 ; 10.14, b，2H，NH。 以實例B的相同方法，但使用相應反應物，可得下列化 合物： 1-『（1-烯丙聯胺基）亞胺甲基1六氫吡畊（呈二鹽鹽型） iH-NMR-光譜：3.14, b，4H，N-CH2 ; 3.68, b，4H，N-CH2 ; 3.98-4.18，m5 2H，CH2-C ; 5·16_5·48，m，2H，CH2=C ; 5.80-6.10, m，1H，CH=C ; 10.30, b，2H，NH。 1-[丨1- ( 4-甲氧芊基）聯胺基）亞胺甲基1六氫吡咕丄1二^酸 -21- 本纸張尺度適用中國國家標準（CNS)Α4規格（2丨0x297公楚） ---J---------、玎------0 (請先閱讀背面之注意事項再填寫本頁) 561157 Μ Β7 五、發明説明（19 ) H-NMR-光譜·· 3.19，b，4H，N-CH2 ; 3.67, b，4H，N-CH2 ; 3.77, s，3H，〇-CH3 ; 4.59, s，2H，N-CH2 ; 6.90-7.02ιι· 7.25-7.38, m，每 一個 2H，CH-芳香系；l〇.〇2，b，2H，NH。 ll. [ [ 1- ( 3，4,5二士甲乳字基）聯胺基）亞胺甲基1六氫被呼（呈 二鹽酸鹽琐） h-NMR-光譜：3.20, b，4H，N-CH2 ·，3.67, b，7H，N-CHJ 4H 和 0-CH3 的 3H ; 3.81，s，6H，0-CH3 ; 4.59, s，2H，N-CH2 ; 6.69, s，2H，CH-芳香系；9.96, b，2H，NH。1T -19- 561157 A7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (π Example B _ 1- [(1-ethylhydrazine) iminemethyl] hexahydropyridine a) kl Amineimine methyl) Hexahydropyracine's benzyl medicinal organisms added 8N sodium hydroxide will contain 10.7 g of hydrochloride type hydrazine benzidine) benzamidine The 100 liter aqueous solution of the derivative was adjusted to 10 by acid. The resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was dehydrated and the solvent was evaporated to give a benzidine derivative of (hydrazine) hexahydropyridine as an amorphous powder. b) the methylidene derivative of methyl-4-methyl-4- (1-diaminoiminofluorenyl) hexahydrop-p-p-well was added dropwise i2.7 ml of acetic anhydride to 42 ml of ice-cold formic acid, / Kun compound 槚; After 1 hour, 42 ml of formic acid containing gram of hydrazine-derived phenylimino derivative was added dropwise. The mixture was left at 0 ° for 2 hours to evaporate the solvent. The residue was treated with water and the acidity of the resulting mixture was adjusted to 11 by the addition of 10N muscarinic acid '. The mixture was extracted in a gas burner. Dichloromethane * is dehydrated and the solvent is released. A benzyl derivative of 1-methylfluorenyl-4- (1- (hydrazinemethyl) hexahydropyrrolidine can be obtained as a white powder. C)] Di [(1-ethylhydrazine) The imidene derivative of imine amidinoline 4-methyl hexahydrocarbamate is taken from ice-cooled containing 2 g of 1-amidino-4- (1-diaminoiminemethyl) hexahydrogen A solution of a benzylmethylene derivative in 40 ml of anhydrous tetrahydrofuran was treated with 9.3 ml of digas trimethylsilyl) · lithium amination (1M solution in tetrahydrofuran) and dried at 0 ° C. Stir for about 1 hour. Add 2 · 4 grams of iodoethane to the reaction mixture-20- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm --- ·, -I ·, --- Feng ----- 1T- ----- # (Please read the precautions on the back before filling out this page) 561157 A7 B7 Printed by the Central Consumers Cooperative of the Ministry of Economic Affairs 5. Copies of the invention (is in the compound) and the mixture is stirred at room temperature The solvent was evaporated and the residue was purified by Dry-column-flasli-chromatography (eluent: 1.methanol, 2.90% methanol / 10% acetic acid) Combining the dissociation fractions of all 1-[(1-ethylhydrazine) iminemethyl] -4-hydrazinopyridine's benzylidene derivatives (analytical HPLC). Solvent evaporation After that, 1-[(1-ethylhydrazine) iminemethylbu 4-benzylhexahydropyridine benzyl derivative was obtained. D) 1-[(1-ethyl Hydrazine) imine methyl 1 hexahydropyridine · 2.7 g of benzylidene derivative of 1-[(1-ethylhydrazine) imine methyl] -4-formyl hexahydropyridine Dissolved in 11.6 ml of 2NHC1 and treated with steam distillation. In the mixture The water was evaporated, and the residue was obtained as a dihydrochloride [(1-ethylhydrazine) iminemethyl] hexahydrogenate in the form of a white solid. IH-NMR-spectrum: 1.22 J = 5 Hz, 311, <:113; 3.16, 1), 411, ^ CH2; 3.45 q, J = 5 Hz, 2H, CH2; 3.65, b, 4H, N-CH2; 10.14, b, 2H, NH. In the same manner as in Example B, but using the corresponding reactants, the following compounds were obtained: 1-[(1-allylhydranino) iminemethyl 1 hexahydropyrine (in the form of a di-salt salt) iH-NMR- Spectrum: 3.14, b, 4H, N-CH2; 3.68, b, 4H, N-CH2; 3.98-4.18, m5 2H, CH2-C; 5.16_5 · 48, m, 2H, CH2 = C; 5.80-6.10 , m, 1H, CH = C; 10.30, b, 2H, NH. 1- [丨 1- (4-methoxyfluorenyl) hydrazine) imine methyl 1 hexahydropyrrolidine 1 di ^ acid-21- This paper size applies to China National Standard (CNS) A4 specifications (2丨 0x297 Gongchu) --- J ---------, 玎 ------ 0 (Please read the notes on the back before filling out this page) 561157 Μ Β7 V. Description of the invention (19) H-NMR-spectrum ... 3.19, b, 4H, N-CH2; 3.67, b, 4H, N-CH2; 3.77, s, 3H, 0-CH3; 4.59, s, 2H, N-CH2; 6.90-7.02 ι. 7.25-7.38, m, each 2H, CH-aromatic; 10, 02, b, 2H, NH. ll. [[1- (3,4,5 dimethylformyl) hydrazine) imine methyl 1 hexahydrogen (as dihydrochloride) h-NMR-spectrum: 3.20, b, 4H, N-CH2 ·, 3.67, b, 7H, N-CHJ 4H and 3H of 0-CH3; 3.81, s, 6H, 0-CH3; 4.59, s, 2H, N-CH2; 6.69, s, 2H, CH-aromatic; 9.96, b, 2H, NH.

實例C ^ [ (i-甲基聯胺基）甲基亞胺基）甲基]六氫吡畊 a) U醯基-4-丨麝胺基（甲基亞胺基）甲基1六氪吡畊的苯亞 甲基衍生物 ·， 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 將37克鹽酸鹽型之^甲醯基[聯胺基（曱基亞胺基） 甲基]六氫峨畊溶解於80毫升乙腈和185毫升水的混合物 中’再以30克苯甲醛處理。該混合物在室溫下攪拌約3 小時後再以***萃取。蒸發水相之水。殘餘物以水處理且 以2N氫氧化鈉將該混合物的酸鹼値調整至丨丨。以二氣甲 燒萃取該混合物，有機相脱水，蒸發溶劑，殘餘物乾燥。 可得白色粉末之1-甲醯基聯胺基（甲基亞胺基）曱基） 六氫峨畊的苯亞甲基衍生物。 b) 甲基聯胺基甲某亞胺基）甲基1六氫吡 立的苯至 取含1,62克^甲醯基-4-(聯胺基（甲基亞胺基）甲基）六 ___ -22- E張尺度適用中國國〇χ297公釐） 561157 A7 B7 五、發明説明（2〇 ) 氯哺p井之苯亞甲基衍生物的30毫升-乙腈溶液，以4.56克 甲基破處理，該混合物迴流一夜。蒸發溶劑後，殘餘物於 室溫下與20毫升水及10毫升Amberlite IRA-400 (C1)R (離 子父換樹脂）授拌約1小時。過濾該混合物。水溶液酸鹼 値以2N氫氧化鈉調整至11，以二氯甲烷萃取。有機相脱 水’並蒸發溶劑濃縮。將濃縮物依實例B，c)中的方法純 化。得白色粉末之1-甲醯基甲基聯胺基）（甲基亞 胺基）甲基]六氫吡畊的苯亞甲基衍生物。 c) ilKl:甲基聯胺基U曱某亞胺某）甲基1六氫吡畊 取1.14克1-甲醯基-4-[(l-曱基聯胺基）（甲基亞胺基）曱 基]六氫吡畊的苯亞甲基衍生物溶於6毫升2N HC1中，依 實例B，d)項的方法處理。得到白色固體之二鹽酸鹽型的 甲基聯胺基）（甲基亞胺基）甲基]六氫吡畊。 4-NMR-光譜：2.84, s，3H，CH3 ; 3.18, b，7H，N-CH2 的 4H 和 CH3 的 3H ; 3.63, b，4H，N-CH2 ; 10.13, b，2H，NH。 以實例C的相同方法，但使用相應的反應物，可得到 1^1(1-甲基聯胺基）乙基亞胺某）曱某六·&吡畊（呈二鹽酸 鹽型） iH-NMR-光譜：1.20, t，J=5 赫茲，3Η，CH3 ; 3.19, b，9Η，Ν-CH2 的 4H 和 CH3 的 3H 和 CH2 的 2H，； 3.64, b，4H，N-CH2 ; 10.12，b，2H，NH 〇 實例中化合物的1H-NMR-光譜 1. 3.25 (寬，4H，-CH2-N-CH2) ; 3.3 (s，3H，N-CH3) ; 3.60 和 4·28 (ΑΒ 四裂峰，J=18 赫茲，2Η，SCH2) ; 3.74 (寬，4Η， -23- 本纸張尺度適用中國國家標李（CNS ) A4規格（210x297公瘦） (請先閲讀背面之注意事項再填寫本頁)Example C ^ [(i-methylhydrazine) methylimine) methyl] hexahydropyridine a) U 醯 -4- Pycnogenol's benzylidene derivative · Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page). 37 g of hydrochloride-formamidine (Methinoimino) Methyl] hexahydrogenocene was dissolved in a mixture of 80 ml of acetonitrile and 185 ml of water and then treated with 30 g of benzaldehyde. The mixture was stirred at room temperature for about 3 hours and then extracted with ether. Evaporate the water of the water phase. The residue was treated with water and the pH of the mixture was adjusted to 2 with sodium hydroxide. The mixture was extracted with dichloromethane, the organic phase was dehydrated, the solvent was evaporated and the residue was dried. A white powder of 1-methylfluorenylhydrazine (methylimino) fluorenyl) hexamethylene benzyl derivative can be obtained. b) Methylhydrazine, a certain imino group) methyl 1 hexahydropyridine to 1,62 g of ^ methylamido-4- (hydrazine (methylimino) methyl) 6. ___ -22- E scale is applicable to China ’s 0 × 297 mm) 561157 A7 B7 5. Description of the invention (2) 30 ml of phenylmethylene derivative of chlorinated p-acetonitrile solution, with 4.56 g of formazan After breaking down, the mixture was refluxed overnight. After evaporation of the solvent, the residue was stirred at room temperature with 20 ml of water and 10 ml of Amberlite IRA-400 (C1) R (exchange resin from the father) for about 1 hour. The mixture was filtered. Aqueous acid and base 値 adjusted to 11 with 2N sodium hydroxide and extracted with dichloromethane. The organic phase was dehydrated 'and the solvent was concentrated by evaporation. The concentrate was purified as described in Examples B, c). A white powder of the benzyl derivative of 1-methylamidomethylhydrazine) (methylimino) methyl] hexahydropyridine was obtained. c) ilKl: methyl hydrazine U 曱 some imine some) methyl 1 hexahydropyridine 1.14 g of 1-methylamido-4-[(l-fluorenyl hydrazine) (methyl imino ) Methenyl] hexahydropyridine benzyl derivative was dissolved in 6 ml 2N HC1 and treated as described in Example B, item d). Methylhydrazine) (methylimino) methyl] hexahydropyridine was obtained as the dihydrochloride salt of a white solid. 4-NMR-spectrum: 2.84, s, 3H, CH3; 3.18, b, 7H, 4H of N-CH2 and 3H of CH3; 3.63, b, 4H, N-CH2; 10.13, b, 2H, NH. In the same way as in Example C, but using the corresponding reactants, 1 ^ 1 (1-methylhydrazine) ethylimine)) a certain six · & Pikang (in the form of dihydrochloride) iH-NMR-spectrum: 1.20, t, J = 5 Hz, 3Η, CH3; 3.19, b, 9Η, 4H of N-CH2 and 3H of CH3 and 2H of CH2; 3.64, b, 4H, N-CH2; 10.12, b, 2H, NH 1H-NMR-spectrum of the compounds in the examples 1. 3.25 (broad, 4H, -CH2-N-CH2); 3.3 (s, 3H, N-CH3); 3.60 and 4 · 28 ( ΑB four-split peak, J = 18 Hz, 2Η, SCH2); 3.74 (width, 4Η, -23- This paper size applies to Chinese national standard (CNS) A4 size (210x297 male thin) (please read the note on the back first) (Fill in this page again)

、1T Φ 經濟部中央標準局員工消費合作社印製 56!157 A7 B7 五、發明説明（2l ) (請先閲讀背面之注意事項再填寫本頁) -CIK-NH^CI^-) ; 5.28 (d，J=5 赫茲、1H，β-内醯胺-Η); 5.78 (d, J=55 赫茲，2Η，CH2F) ; 5·91 (dd，J=5 和 8·3 赫茲， 1氏0-内醯胺-11);8.1(3，111，€11=11);9.〇4(寬單峰，111， ΝΗ) ; 9·35 (寬單峰，1Η，ΝΗ) ; 9.81 (d，J=8.3 赫茲，1Η， NH) ; 9.9 (寬單峰，2H，NH2)。 2. 1.17, t，J=5 赫茲，3H，CH3 ; 3.28, b，4H，N-CH2 ; 3.60 和 4.21，AB 四裂峰，J=18 赫茲，211，8-(：112);3.67，13,411，；^-CH2 ; 3.91，m，2H，CH2 ; 5.22, d，J=5 赫茲，1Η，β·内醯胺-Η ; 5.82 d，J=55 赫茲，2H，CH2F ; 5.85, dd，J=5 赫茲和 8 赫茲，1H，β-内醯胺-Η ; 8.35, b，3H，1H CH=H 和 9.78 d， J=8 赫茲，1H，NH。 3· 1.18, t，J=5 赫茲，3H，CH3 ; 3.30, b，9H，NCH2 的 4H 和 CH2 的 2H 和 CH3 的 3H ; 3.70, m，5H，NCH2 的 4H，C-SH2 的 1H ; 4.10 部分的 AB 四裂峰，J=18 赫茲，1H，SCH2 ; 5.32, d， 赫茲，1H，β-内醯胺-H ; 5.82 d，J=55 赫茲，2H， CH2F ; 5.95, dd，J=5 赫茲和 8 赫茲，1H，β-内醯胺-Η ; 8.08, s，1Η CH=N ; 8.32, b，1H，NH ; 9.82, d，J=8 赫茲， 經濟部中央標準局員工消費合作社印製 1H，NH 〇 4. 3.30, b，4H，NCH2 ; 3.58 和 4.25 部分的 AB 四裂峰，J=18 赫茲，2H，S-CH2) ; 3.73, b, 4H, N-CH2 ； 4.30, m, 2H? N-CH2 ; 5.26, m，3H，1H β-内醯胺-H 和 CH2=C 的 2H ; 5.64,部 分的雙裂峰，1H，CH2F ; 5.90, m，4H，CH2-F 的 1H，和 CH:C 的 1H 和 1Η，β:内醯胺-Η ; 8.11，s, 1H，CH=N ; 9.81， d，J=8 赫茲，1H，NH。 -24- 本纸張尺度適用中國國家標準（CNS ) A4g ( 210X297公釐） 561157 A7 B7 五、發明説明（22 ) 5. 2.9 和 3.03, 2s (2:1), 3H，C-3-CH3 ; 3.33, b，7H，N-CH2 的 4H 和 N-2-CH3 ; 3.64, b，5H，N-CH2 的 4H 和 S-CH2 的 1H ; 4.15, 部分的AB四裂峰，J=18赫茲，1H，S-CH2 ; 5.21，d， J=5 赫茲 1H，β-内醯胺-H ; 5.81，d，J=55 赫茲，2H， CH2F ; 5.83, dd，J=5 赫茲和 8 赫茲，1Η，β·内醯胺-Η ; 8.32, 3Η，CH=N 的 1Η 和 2Η ; 9.79, d，J=8 赫茲，1Η，ΝΗ。 6. 3.31, b，4Η，N-CH2 ; 3.52 和 4.18, ΑΒ 四裂峰，J=18 赫 茲，2H，S-CH2 ; 3.72, b，7H，N-CH2 的 4H 和 OCH3 的 3H ; 4.95, AB 四裂峰，J=17 赫茲；2H，CH2 ; 5.14, d，4H，J=5 赫 茲，1Η，β-内醯胺-Η ; 5.78, d，J=55 赫茲 2H，CH2F ; 5.77, dd，J=5 赫兹和 8 赫兹’ 1H，β-内酿胺-Η ; 6.86-6.91，m， 2Η, CH-arom. ; 7.15-7.19, m3 2H, CH-arom. ; 8.26, b, 2H, CH-N 和 NH ; 8.40, b，1H，NH ; 9.74, d，J=8 赫茲，1H，NH。 7· 3.34, b，4H，N-CH2 ; 3·57 和 4.23, AB 四裂峰，J=18 赫 茲，2H，S-CH2 ; 3:64, s，3H，OCH3 ; 3.79, b，10H，N-CH2 的 4H 和 OCH3 的 6H ; 5.03, AB 四裂峰，J=17 赫茲；2H， 經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) CH2 ; 5.27, d，J=5 赫茲，1H，β-内醯胺-Η ; 5.81，d，J=55 赫茲2H，CH2F ; 5.92, dd，J=5赫茲和8赫茲，1Η，β-内醯 胺-Η ; 6.53, s，2Η，CH-arom· ; 8.14, s，1Η，CH=N ; 8.30, b, 2H，NH ; 9.83, d，J=8 赫茲，1H，NH。 -25- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）1T Φ 56! 157 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (2l) (Please read the precautions on the back before filling this page) -CIK-NH ^ CI ^-); 5.28 ( d, J = 5 Hz, 1H, β-lactamamine-Η); 5.78 (d, J = 55 Hz, 2Η, CH2F); 5.91 (dd, J = 5 and 8.3 Hz, 1 ° 0 -Lactam-11); 8.1 (3,111, € 11 = 11); 9.04 (broad singlet, 111, ΝΗ); 9.35 (broad singlet, 1Η, ΝΗ); 9.81 (d , J = 8.3 Hz, 1Η, NH); 9.9 (broad singlet, 2H, NH2). 2. 1.17, t, J = 5 Hz, 3H, CH3; 3.28, b, 4H, N-CH2; 3.60 and 4.21, AB four-split peak, J = 18 Hz, 211.8-(: 112); 3.67, 13,411 ,; ^ -CH2; 3.91, m, 2H, CH2; 5.22, d, J = 5 Hz, 1Η, β · lactam-Η; 5.82 d, J = 55 Hz, 2H, CH2F; 5.85, dd, J = 5 Hz and 8 Hz, 1H, β-lactamamine-Η; 8.35, b, 3H, 1H CH = H and 9.78 d, J = 8 Hz, 1H, NH. 3.1.18, t, J = 5 Hz, 3H, CH3; 3.30, b, 9H, 4H of NCH2 and 2H of CH2 and 3H of CH3; 3.70, m, 5H, 4H of NCH2, 1H of C-SH2; 4.10 Partial AB splitting peak, J = 18 Hz, 1H, SCH2; 5.32, d, Hz, 1H, β-lactam-H; 5.82 d, J = 55 Hz, 2H, CH2F; 5.95, dd, J = 5 Hz and 8 Hz, 1H, β-lactamamine-Η; 8.08, s, 1Η CH = N; 8.32, b, 1H, NH; 9.82, d, J = 8 hertz, Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs Printed 1H, NH 〇4. 3.30, b, 4H, NCH2; AB four-split peaks in sections 3.58 and 4.25, J = 18 Hz, 2H, S-CH2); 3.73, b, 4H, N-CH2; 4.30, m, 2H? N-CH2; 5.26, m, 3H, 1H β-lactamamine-H and 2H of CH2 = C; 5.64, partial double-split peak, 1H, CH2F; 5.90, m, 4H, CH2-F 1H, and 1H and 1Η of CH: C, β: endoamine-Η; 8.11, s, 1H, CH = N; 9.81, d, J = 8 Hz, 1H, NH. -24- This paper size applies to Chinese National Standard (CNS) A4g (210X297mm) 561157 A7 B7 V. Description of Invention (22) 5. 2.9 and 3.03, 2s (2: 1), 3H, C-3-CH3 ; 3.33, b, 7H, 4H and N-2-CH3 of N-CH2; 3.64, b, 5H, 4H of N-CH2 and 1H of S-CH2; 4.15, partial AB splitting peak, J = 18 Hz , 1H, S-CH2; 5.21, d, J = 5 Hz 1H, β-lactamamine-H; 5.81, d, J = 55 Hz, 2H, CH2F; 5.83, dd, J = 5 Hz and 8 Hz, 1Η, β · lactamamine-Η; 8.32, 3Η, CH = N 1Η and 2Η; 9.79, d, J = 8 Hz, 1Η, ΝΗ. 6. 3.31, b, 4Η, N-CH2; 3.52 and 4.18, ABA quadruple peak, J = 18 Hz, 2H, S-CH2; 3.72, b, 7H, 4H of N-CH2 and 3H of OCH3; 4.95, AB four-split peak, J = 17 Hz; 2H, CH2; 5.14, d, 4H, J = 5 Hz, 1Η, β-lactamamine-Η; 5.78, d, J = 55 Hz 2H, CH2F; 5.77, dd , J = 5 Hz and 8 Hz '1H, β-lactam- 酿; 6.86-6.91, m, 2Η, CH-arom .; 7.15-7.19, m3 2H, CH-arom .; 8.26, b, 2H, CH-N and NH; 8.40, b, 1H, NH; 9.74, d, J = 8 Hz, 1H, NH. 7. · 34, b, 4H, N-CH2; 3.57 and 4.23, AB four-split peak, J = 18 Hz, 2H, S-CH2; 3:64, s, 3H, OCH3; 3.79, b, 10H, 4H of N-CH2 and 6H of OCH3; 5.03, AB four-split peak, J = 17 Hz; 2H, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) CH2; 5.27 , d, J = 5 Hz, 1H, β-lactamamine-Η; 5.81, d, J = 55 Hz 2H, CH2F; 5.92, dd, J = 5 Hz and 8 Hz, 1Η, β-lactamamine- Η; 6.53, s, 2Η, CH-arom ·; 8.14, s, 1Η, CH = N; 8.30, b, 2H, NH; 9.83, d, J = 8 Hz, 1H, NH. -25- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm)

發明 新型 中 文 抗微生物之頭孢素，其製法及醫藥組合物 名稱 英 文 姓 名 國 發明 創作>Invention of a new type of Chinese antimicrobial cephalosporin, its preparation method and pharmaceutical composition Name English Name Last Name Country Invention >

A PR0CESS F0R THEIR RODUCTION AND PHARMACEUTICAL COMPOSITIONS THEREOF M_ 1. 卓德奥斯契 2. 喬瑟夫魏思爾 3. 麥克史桂茲 4. 瓊那斯露易思契爾 5. 瓊那斯易德布蘭特 均奥地利 裝 住、居所 訂 1·奥地利坎德市黛斯特費德街3,6250號 2.奥地利柏爾林市塞格費德街95,6403號 3·奥地利韋恩市柏格哈德凱斯街7/丨8,丨2〇〇號 4·奥地利布里頓貝契市克林索爾街1〇1，6252號 5.奥地利歐林郝森市羅儉特凱斯街12,2512號 三、申請人 姓 名 (名稱） 國 籍 住、居所 (事務所） 代表人 姓 名 奥地利商拜歐開勵公司 奥地利 奥地利坎德市A-6250號 珍·克拉瑪 喬治斯·葛瑞里尼 線 本紙張尺度適用中國國家榡準（CNS ) A4規格（2ΐ〇χ297公釐） 561157 #正補充 第87103843專利申計案年月 中文說明書修正頁(8;年8月）A PR0CESS F0R THEIR RODUCTION AND PHARMACEUTICAL COMPOSITIONS THEREOF M_ 1. Zhuo De Oschi 2. Joseph Weisser 3. Mike Schweizer 4. Jonas Luis Kiel 5. Jonas Luis Cler 5. Specially furnished, domiciled in Austria1. 3,6250 Destfelder Street, Kander, Austria 2. 95,6403 Segfelder Street, Berlin, Austria 3. Berghard, Wayne, Austria Case Street 7 / 丨 8, 丨 200 4 # 101, 6252 Klinsall Street, Brittenbach, Austria 5. Roessert Case Street 12, 2512, Olchinghausen, Austria No. 3. Name of the applicant (name) Nationality residence, domicile (office) Name of representative Austrian Bio-Keli Company Austrian K-6, Kant, Austria K-6, Jan Klamath Georges Grellini Thread Paper Size Applicable China National Standards (CNS) A4 Specification (2 × 〇297mm) 561157 # is supplementing the 87103843 Patent Application Date and the Chinese Manual Amendment Page (8; August)

任何上述定義之基團例如：未取代或例如：經卜内醯胺 化學中習知的基團取代。 較佳化合物包括例如7-(((5-胺基十2,4-噻二唑_3_基）_ (ZM氟甲氧亞胺基）乙醯基）胺基）冬（（亞胺基小六氫吡畊 甲基）甲基亞肼基）甲基哂叽冰羧酸；7_ (以5_胺基· 1，2,4-噻一唑-3-基）-(Z)-(氟甲氧亞胺基）乙醯基）胺基卜3_ ((亞胺基小六氫吡畊甲基）乙基亞胼基）甲基嗎叽_4_羧 酸；'(((5·胺基-U，“塞二峻|基）_(ZH氟η·亞胺基） 乙醯基）胺基）-3-((亞胺基-丨-六氫吡畊甲基）烯丙基亞肼基） 甲基·3-哂叽-4-羧酸；7-(((5_胺基β1，2,4_噻二唑基）_(z)_ (氟甲氧亞胺基）乙醯基）胺基）_3-((亞胺基+六氫吡畊曱 基）（4-甲氧+基）甲基-亞月井基）甲基p西叹冰幾酸；7_ 經濟部中央標準局員工消費合作社印製 (((5-胺基-1，2,4-噻二唑-3-基）-(Z)-(氟甲氧亞胺基）乙醯基） 胺基）-3-((亞胺基-1-六氫吡畊甲基）（3,4,5-甲氧苯基）_甲基 亞胼基）甲基-3-哂叽-4-羧酸；7-(((5-胺基-1，2,4-嘧二唑-3-基）-(Z)-(氟甲氧亞胺基）乙醯基）胺基）|(((义甲基-亞 胺基-1-六氫吡畊甲基）甲基亞肼基）甲基_3-哂叽羧酸； 及7-((( 5-胺基-1，2,4-嘍二唑-3-基）-(Z)-(氟甲氧亞胺基）乙 醯基）胺基）-3-(( N-乙基-亞胺基-1-六氫p比p井甲基）_甲基亞 月井基）甲基-3-哺p凡-4-複酸。 本發明另一個方面係提供7-((( 5-胺基-1，2,4-嘍二唑-3-基）-(ZH氟甲氧基-亞胺基）乙醯基）胺基亞胺基-丨-六 氫吡畊甲基）甲基亞胼基）甲基-3-哂叽-4-羧酸化合物，例 如呈鹽型式，如鹽酸鹽形式；例如及/或呈酯型式，例如 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐）Any of the above-defined groups is, for example, unsubstituted or substituted with groups conventionally known in blinamine chemistry. Preferred compounds include, for example, 7-(((5-Aminododecyl-2,4-thiadiazol_3_yl) _ (ZM fluoromethoxyimino) ethenyl) amino) dong ((imine Hexahydropyroxymethyl) methyl hydrazino) methyl glacial carboxylic acid; 7- (with 5-amino group · 1,2,4-thiatriazol-3-yl)-(Z)-( Fluoromethoxyimino) ethenyl) amino group 3-(((imino- small hexahydropyridinemethyl) ethylamido)) methyl? 4-carboxylic acid; '(((5 · Amine-U, "Secretium | yl" _ (ZHfluoroη · imine) ethynyl) amino) -3-((imino- 丨 -hexahydropyridinemethyl) allyl Hydrazinyl) methyl · 3-fluoren-4-carboxylic acid; 7-(((5-amino β1,2,4_thiadiazolyl) _ (z) _ (fluoromethoxyimino) Ethylamido) amino) _3-((imine + hexahydropyridyl) (4-methoxy + yl) methyl-yieldyl) methyl piracetic acid; 7_ Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards (((5-amino-1,2,4-thiadiazol-3-yl)-(Z)-(fluoromethoxyimino) ethenyl) amine) -3-((imino-1-hexahydropyridinemethyl) (3,4,5-methoxyphenyl) _methylamidino) methyl-3-fluorene-4-carboxylic acid; 7-(((Amino-1, 2,4-pyrimidazol-3-yl)-(Z)-(fluoromethoxyimino) ethenyl) amino) | (((Methyl-imino-1-hexahydropyridine) Methyl) methylhydrazinyl) methyl-3-fluorenecarboxylic acid; and 7-(((5-amino-1,2,4-fluorenediazol-3-yl)-(Z)-( Fluoromethoxyimino) ethenyl) amino) -3-((N-ethyl-imino-1-hexahydro p ratio p well methyl) _methyl sulfenyl) methyl- 3-Pyridyl-4- complex acid. Another aspect of the present invention provides 7-(((5-amino-1,2,4-fluorenediazol-3-yl)-(ZHfluoromethoxy- Imino) ethynyl) aminoimino- 丨 -hexahydropyridine methyl) methylimino) methyl-3-fluorene-4-carboxylic acid compound, for example in the form of a salt, such as a salt Acid salt form; for example, and / or in the form of an ester, for example, this paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm)

Claims (1)

561157 第087103843專利申請案 中文申請專利範圍替換本(92年8月) 女.、申請專利範圍 一 公告561157 Patent Application No. 087103843 Chinese Application for Replacement of Patent Scope (August 1992) Female. Scope of Patent Application Announcement A8 B8 C8 D8 式I化合名A8 B8 C8 D8 Formula I compound name 式中 R!代表氫； R2代表甲基；及 R3代表氫，其係呈游離型、鹽型及/或溶合物型。 2·根據申請專利範圍第1項之化合物，其為7_ ((( 5-胺 基-1，2,4-噻二唑-3-基）-(Z)-(氟甲氧亞胺基）乙醯基）胺 基）-3-((亞胺基-1-六氫吡畊甲基卜甲基亞聯胺基）甲基_ 3- 口西吼（cephem) -4-痩酸。 3·根據申請專利範圍第1或2項之化合物，其係呈鹽型 及/或溶合物型。 4·根據申請專利範圍第1或2項之化合物，其主要為3(E) 異構物。 5. —種製造如申請專利範圍第1項所定義之式I化合 物，其包括由下式化合物In the formula, R! Represents hydrogen; R2 represents methyl; and R3 represents hydrogen, which are in a free form, a salt form, and / or a solvate form. 2. The compound according to item 1 of the scope of patent application, which is 7 _ (((5-amino-1,2,4-thiadiazol-3-yl)-(Z)-(fluoromethoxyimino)) Ethylamido) amino) -3-((imino-1-hexahydropyridinemethylp-methylimidino) methyl_ 3-cephem-4-acetic acid. 3 · According to The compounds in scope 1 or 2 of the patent application are in the form of salts and / or solvates. 4. The compounds in scope 1 or 2 of the patent application are mainly 3 (E) isomers. 5 . — A compound of formula I as defined in item 1 of the scope of patent application, which comprises a compound of the formula 其中， a) Rb代表經基且Rc和Rd —起形成化學鍵，或 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) ^01157申請專利範圍 A8 B8 C8 D8 氫或㈣㈣’且&和1起代表氧基， 二式化合物於-20至5〇t溫度下及溶劑中反應，該 ^係選自以下所組成之群：水、水與（CM)醇之混 ;物、水與二氧陸園之混合物、雙極性非質子性溶 :早雙極性非質子性溶劑與水之混合物以及雙極性非 貝子性溶劑與醇之混合物； KjN— N — C I \ > 111 /、中R3如申請專利範圍第1項之定義，自環 弟四位置㈣酸根上裂解單料基，並分離式！化 物0 6·:種用於治療微生物疾病之醫藥組合物，其包含呈 藥上可接受之鹽或游離型之根據中請專㈣圍第' 之式1化合物，及至少—種醫藥載體或稀釋劑。 7·根據申請專利範圍第1項之化合物，其係作為抗微 物藥物。 8· —種下式化合物， 合 醫 項 生Among them, a) Rb represents a radical and Rc and Rd together form a chemical bond, or this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ^ 01157 patent application scope A8 B8 C8 D8 hydrogen or ㈣㈣ 'and & amp And 1 represents an oxy group, and the compound of formula 2 is reacted in a solvent at a temperature of -20 to 50 t, the ^ is selected from the group consisting of: a mixture of water, water and (CM) alcohol; Mixture with dioxin garden, bipolar aprotic solvent: mixture of early bipolar aprotic solvent and water, and bipolar non-shellfish solvent and alcohol; KjN—N — CI \ > 111 /, Medium R3 is as defined in item 1 of the scope of patent application, and the single material base is cleaved from the ring four-position phosphonate and separated! Compound 06: A pharmaceutical composition for treating a microbial disease, which comprises a compound of formula 1 in the form of a pharmaceutically acceptable salt or free form, and at least one pharmaceutical carrier or dilution Agent. 7. The compound according to item 1 of the scope of patent application, which is used as an anti-microbial drug. 8 · — A compound of the formula Ri代表陽離子。 -2- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)Ri stands for cation. -2- This paper size applies to China National Standard (CNS) A4 (210X 297 mm)