TW589306B

TW589306B - Antimicrobial quinolones, their compositions and uses

Info

Publication number: TW589306B
Application number: TW87115334A
Authority: TW
Inventors: Benoit Ledoussal; Ji-In Kim Almstead; Jeffrey Lyle Gray; Xiufeng Eric Hu
Original assignee: Procter & Gamble
Priority date: 1997-09-15
Filing date: 1999-02-26
Publication date: 2004-06-01
Also published as: ZA988415B

Abstract

This invention relates to novel antimicrobial compounds of formula; wherein X, R1, R3, R5, R6, and R8 are defined in the claims, and to their optical isomers, diastereomers or enantiomers, as well as pharmaceutically-acceptable salts, hydrates, and biohydrolyzable esters, amides and imides thereof, and to compositions and uses of such compounds. The invention also relates to compounds derived from these compounds having antimicrobial uses.

Description

589306 Λ 7 ___~________ 五、發明説明（1 ) 發明領域本發明係關於新穎抗微生物化合物，其組合物及其用途。交叉參考本案遵照美國法規119(e)，編號35請求1997年9月15 曰提出申請之優先申請案第60/058,891號之優先權。背景化學及醫學參考文獻敘述具有抗微生物作用之化合物亦即了摧毁或抑制微生物如細菌之生長或繁殖。例如此等抗菌劑及其它抗微生物劑述於「疾病防治用抗生素，化聲洛^ —-及柷1-ϋ」(Μ· Grayson編輯，1982年）及Ε· Gale等抗圭素作敬主分子基礎第2版（1981年）。此等抗菌劑之作用機轉不同。但一般相信係以下列一種或多種方式發揮作用：抑制細胞壁合成或修復；改變細胞壁滲透性，·抑制蛋白質合成；或抑制核酸合成。例如内醯胺抗菌劑係經由抑制細菌之必需青黴素結合蛋白質（pBp) 作用，該蛋白質負責細胞壁之合成。舉另一例，喹諾酮至少部分係經由抑制DNA合成發揮作用，如此阻止細胞複經濟部中央標準局員工消費合作社印製製。抗微生物劑之藥理特性及用於特定臨床用途之適合性不同。例如抗微生物劑類別（及類別成員）之下列方面不同： 1)對不同類型微生物之相對效果，2)對發展微生物抗性之敏感度’及3)藥理特性如生物利用率及生物分布。如此，於特定臨床情況選擇適當抗菌劑（或其它抗微生物劑）需要本紙張尺度適用中國國家襟準（CNS ) A4規格（210X297公趁了一~ —-- 589306 經濟部中央標準局員工消費合作社印製 Λ 7 Β7 __五、發明説明（2 ) 分析多種因素，包括相關微生物類別，所需投藥方法，待治療之感染部位及其它考量。但多種嘗試生產改良抗菌劑造成模擬兩可的結果。確實生產少數抗微生物劑其確實就抗微生物活性範圍，避免微生物藥性及藥理方面可爲臨床接受。因此，仍需要有廣效抗微生物劑其對抗藥性微生物有效。某些1，4-二氫喹諾酮，莕啶或相關雜環部分爲業界已知具有抗微生物活性及述於下列參考文獻·· R. Albrecht，Prog, Drug Research. Vol. 21，ρ· 9 (1997); J. Wolfson 等”氟，奎諾酮：結構，作用機轉及抗藥性，及試管試驗活性範圍”，抗微生物劑及化學治療，Vol· 28，p. 581 (1985); G. Klopman等抗微生物劑及化學治療，Vol. 31, p. 1831 (1987); M.P. Wentland et al·，Ann. Rep. Med. Chem·· Vol. 20, p. 145 (1986); J.B. Cornett et al·，Ann· Rep. Med· Chem·· Vol. 21，p. 139 (1986); Ρ·Β· Fernandes et al·，Ann. Rep. Med. Chem., Vol· 22, p. 117 (1987); A. Koga 等”抗菌性 6,7-及 7,8-二取代1-烷基_1，4-二氫-4-氧基喹啉-3_羧酸之結構-活性關係”，J. Med. Chem., Vol. 23. pp. 1358-1363 Π980); J. M. Domagala et al.5 J. Med. Chem.. Vol. 31, p. 991 (1988); T· Rosen et al·，J\ Med. Chem.. Vol· 31，p. 1586 (1988); T. Rosen et al·，L Med. Chem.. Vol. 31，p. 1598 (1988); B. Ledoussal等”非6-氟取代喹諾酮抗菌劑：結構及活性”， Ued二 C_hem·，Vol. 35. p. 198-200 (1992); J. M. Domagala 等含新穎-胺基乙基）-1-p比洛咬基]分支缝之峻請先閱讀背 1¾ 之意事項- 再填寫本頁 % 訂 -5- 本紙張尺度適用中國國家標隼（CNS ) Λ4規格（210X297公簸〉 589306 經濟部中央標準局員工消費合作社印製 Λ7 B7五、發明説明（3 ) 諾酮抗菌劑：1-胺基乙基部分及其立體化學構造對強度及活體試驗效果之影響”，J. Med. Chem·· Vol. 36，pp. 871-882 (1993); Hagen 等”含 7-[3_(l-胺基·1-甲基乙基）-1-吡咯啶基]部分之新穎喹穎喹之合成及抗菌活性。具有絕佳口服活性及低副作用可能之革蘭氏陽性藥劑”，J. Med. Chem“ Vol. 37, ρρ· 733-738 (1994); V. Cecchetti 等” 6-胺基喹諾酮之研究：6-胺基-8-甲基喹諾酮之合成及抗菌評估，，，J. Med· Chem·· Vol. 39，pp. 436-445 (1996); V. Cecchetti等”強力6-去氟-8_甲基喹諾明作爲抗菌化學治療之新穎前導化合物”，J. Med. Chem., VoL 39. pp. 4952-4957 (1996); Hong等”新穎5-胺基-6-甲基喹諾酮抗菌劑：新一類非 _ 6 氟。奎諾酮 ’ ，Bioorg. of Med. Chem. Let.. Vol. 7, pp· 1875-1878 (1997); 1989 年 7 月 4 日頒予 Grohe 之美國專利4,844,902 ; 1991年12月10日頒予Hagen及 Suto之美國專利5,072,001 ; 1994年7月1 2日頒予Demuth 及White之美國專利5,328,908 ; 1995年1 0月1 0日頒予 Bartel等之美國專利5,457，104 ; 1996年9月17日頒予 Philipps等之美國專利5,556,979 ; 1993年12月1日公告之Ube工業公司之歐洲專利申請案572,259 ; 1997年5月 2 8日公告之Toyama化學公司之歐洲專利申請案775,702 ; 1995年3月1日公告之Kyorin藥品公司之日本專利公告案 62/225,482。喳諾酮之結構-活性關係構成詳細研究主題爲時超過1 〇年。由於此等研究結果，業界人士決定某些結構於喹諾酮請先閱讀背之意事項再- 本頁訂 -fi 本紙張尺度適用中國國家榡準（CNS ) A4規格（210X 297公簸） 589306 Λ 7 ----Β7 — _______ 五、發明説明（4 ) ¥上特定位置官能化具有優於其它結構之獨特優點。例如 A· Koga等，”抗菌性6，八及7,8•二取代p燒基-1>4二氫_ 4 -氧基喹啉-3 _羧酸之結構_活性關係”，τ Med. Chem, ν〇1· 23，ρρ· 1358-1363 (1980) (Koga)揭示 6_ 與 8-4諸酮基位置不相等，及6 _喹諾酮基位置取代之重要性。KogL舉例驗證6-氟、8-氫取代優於6-氫、8-氟或_原子取代。或許由於業界之此種早期結構-活性研究工作結果，業界焦點集中於6 -氟化結構提供下一代喹諾酮。儘管於此領域之研究工作’但尚未探勘喹諾酮作爲抗菌劑之完整展望。過去曾報告對抗生素治療有抗性之細菌感染實例；今日構成已開發國家公共衛生的顯著威脅。微生物抗藥性的發展（或許由於長時間密集使用抗菌劑結果）構成醫藥界之憂慮漸增。’抗藥性”定義爲於特定微生物種屬族群中存在有對指定抗菌劑的作用較不敏感的有機體。此種抗藥性於醫院及療養院等環境特別成問題，此處感染比例相當高且常見密集使用抗菌劑。例如參考W· Sanders，Jr.等，，可謗生之β -内醯胺酶：使用較新的頭孢子菌素之臨床及流行病學意義”，傳染病综論830頁（ 1988年）。經濟部中央標準局員工消費合作社印製病原菌已知透過獨特機轉獲得抗藥性，包括藉細菌性酶失活化抗生素（例如β -内醯胺酶水解青黴素及頭孢子菌素）；使用流出唧筒去除抗生素；透過突變及基因重組修改抗生素的標的物（例如***之青黴素抗藥性）；及由外部來源獲得方便轉殖基因而產生抗性標的物（例如金黃葡萄球菌之美西西林（methicillin抗性）。某些革蘭氏陽性病原 589306 經濟部中央標準局員工消費合作社印製 Λ7 ______B7 五、發明説明（5 ) 萬古黴素（vancomycin)抗性糞腸球幾乎對所有市售抗生素皆有抗藥性。因此，目前抗菌劑對於克服抗藥性威脅的能力有限。如此，較佳提供具有有用性質可用於商業上對抗抗藥性微生物之n奎語嗣。發明目的本發明之目的係提供可用於對抗廣泛多種微生物特別細菌之喹諾酮及喹諾酮基抗菌化合物。本發明心又一目的係提供可有效對抗喹諾酮抗藥性微生物之抗微生物劑。發明概沭發明人發現一系列新穎喹諾酮及喹諾酮基化合物可有效對抗抗藥性微生物，及提供優於業界現況之顯著活性優點。此外，發明人發現此等4諾酮及㈣酮基化合物反對業界已經接受的結構/活性關係。本發明係關於下式化合物中其589306 Λ 7 ___ ~ ________ V. Description of the Invention (1) Field of the Invention The present invention relates to novel antimicrobial compounds, their compositions and their uses. Cross Reference This case complies with U.S. regulation 119 (e), number 35, and claims priority of priority application number 60 / 058,891, filed on September 15, 1997. Background Chemical and medical references describe compounds with antimicrobial effects that destroy or inhibit the growth or reproduction of microorganisms such as bacteria. For example, these antibacterial agents and other antimicrobial agents are described in "Antibiotics for the Prevention and Treatment of Diseases, Huashengluo ^-and 柷 1-ϋ" (edited by MG Grayson, 1982), and anti-ghosts such as É Gale. Molecular Basis 2nd Edition (1981). These antibacterial agents work differently. However, it is generally believed to work in one or more of the following ways: inhibit cell wall synthesis or repair; alter cell wall permeability, inhibit protein synthesis; or inhibit nucleic acid synthesis. For example, the linacamide antibacterial agent acts by inhibiting the necessary penicillin-binding protein (pBp) of bacteria, which is responsible for cell wall synthesis. For another example, at least part of quinolone works by inhibiting DNA synthesis, thus preventing the cell from reprinting by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Antimicrobial agents differ in their pharmacological properties and suitability for specific clinical uses. For example, the following categories of antimicrobial agents (and members of the category) differ: 1) the relative effects on different types of microorganisms, 2) the sensitivity to the development of resistance to microorganisms' and 3) pharmacological characteristics such as bioavailability and biodistribution. Therefore, the selection of an appropriate antibacterial agent (or other antimicrobial agent) for a specific clinical situation requires the paper size to be applicable to the Chinese National Standard (CNS) A4 specification (210X297). --- 589306 Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printed Λ 7 Β7 __V. Description of the invention (2) Analyze various factors, including related microorganism types, required drug administration methods, infection sites to be treated, and other considerations. However, many attempts to produce improved antibacterial agents have caused ambiguous results. .It is true that the production of a small number of antimicrobial agents does have a range of antimicrobial activity, which can be clinically acceptable in terms of microbial drug resistance and pharmacology. Therefore, there is still a need for broad-spectrum antimicrobial agents which are effective against drug-resistant microorganisms. Quinolones, pyrimidines or related heterocyclic moieties are known in the industry to have antimicrobial activity and are described in the following references: R. Albrecht, Prog, Drug Research. Vol. 21, ρ · 9 (1997); J. Wolfson et al. " Fluorine, quinolone: structure, mechanism of action and resistance, and test range of test tube activity ", Antimicrobials and Chemotherapy, Vol. 28, p 581 (1985); G. Klopman and other antimicrobial agents and chemotherapy, Vol. 31, p. 1831 (1987); MP Wentland et al., Ann. Rep. Med. Chem. Vol. 20, p. 145 (1986); JB Cornett et al ·, Ann · Rep. Med · Chem ·· Vol. 21, p. 139 (1986); PB Fernandes et al ·, Ann. Rep. Med. Chem., Vol · 22, p. 117 (1987); A. Koga et al. "Antibacterial 6,7- and 7,8-disubstituted 1-alkyl_1,4-dihydro-4-oxyquinoline-3_carboxylic acid Structure-activity relationship ", J. Med. Chem., Vol. 23. pp. 1358-1363 Π980); JM Domagala et al. 5 J. Med. Chem .. Vol. 31, p. 991 (1988); T. Rosen et al., J \ Med. Chem .. Vol. 31, p. 1586 (1988); T. Rosen et al., L Med. Chem .. Vol. 31, p. 1598 (1988); B Ledoussal et al. "Non-6-fluorosubstituted quinolone antibacterial agents: Structure and activity", Ued Di C_hem ·, Vol. 35. p. 198-200 (1992); JM Domagala and others contain novel-aminoethyl) -1- pbilo bite] read the meaning of the back 1¾ of the branch seam-please fill in this page% order-5- this paper size applies to the Chinese national standard (CNS) Λ4 specification (210X297 public dust> 58 9306 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Λ7 B7 V. Description of the invention (3) Norethone antibacterial agent: the effect of the 1-aminoethyl moiety and its stereochemical structure on the strength and the effect of living test ", J. Med Chem ·· Vol. 36, pp. 871-882 (1993); Hagen et al. Novel quinine containing a 7- [3- (l-amino · 1-methylethyl) -1-pyrrolidinyl] moiety Synthesis and antibacterial activity of quinine. Gram-positive agents with excellent oral activity and low potential for side effects ", J. Med. Chem" Vol. 37, ρρ · 733-738 (1994); V. Cecchetti et al. "6-Aminoquinolones Research: 6 -Amino-8-methylquinolone Synthesis and Antibacterial Evaluation, J. Med · Chem ·· Vol. 39, pp. 436-445 (1996); V. Cecchetti et al. Methylquinolamine as a Novel Lead Compound for Antibacterial Chemotherapy ", J. Med. Chem., VoL 39. pp. 4952-4957 (1996); Hong et al." New 5-amino-6-methylquinolone antibacterial agent : A new class of non_6 fluorine. Quinolone ', Bioorg. Of Med. Chem. Let .. Vol. 7, pp. 1875-1878 (1997); US Patent 4,844,902 issued to Grohe on July 4, 1989; issued December 10, 1991 U.S. Patent 5,072,001 to Hagen and Suto; U.S. Patent 5,328,908 to Demuth and White July 12, 1994; U.S. Patent 5,457,104 to Bartel et al. October 10, 1995; September 17, 1996 U.S. Patent 5,556,979 issued to Philipps and others; Ube Industries' European Patent Application 572,259 published on December 1, 1993; Toyama Chemical Company's European Patent Application 775,702 published on May 28, 1997; March 1995 Japanese Patent Publication 62 / 225,482 of Kyorin Pharmaceutical Co., Ltd. announced on 1st. The structure-activity relationship of linoxone constitutes the subject of detailed research for more than 10 years. Due to the results of these studies, the industry has decided that certain structures in quinolone should be read first.-Bookmark this page-fi This paper size is applicable to China National Standard (CNS) A4 (210X 297). 589306 Λ 7 ---- Β7 — _______ 5. Description of the invention (4) The functionalization of a specific position on ¥ has unique advantages over other structures. For example, A. Koga, et al., "Antibacterial properties 6,8 and 7,8 • disubstituted p-alkyl-1 > 4-dihydro-4 -oxyquinoline-3 _structure and activity relationship of carboxylic acids", τ Med. Chem, ν〇1 · 23, ρρ · 1358-1363 (1980) (Koga) revealed that the 6- and 8-4 keto groups are not equal, and the importance of the 6-quinolone position substitution. KogL exemplifies that 6-fluoro, 8-hydrogen substitution is superior to 6-hydrogen, 8-fluoro or _ atom substitution. Perhaps due to the results of such early structure-activity studies in the industry, the industry's focus is on 6-fluorinated structures to provide next-generation quinolone. Despite research work in this area ', the full prospect of quinolone as an antibacterial agent has not yet been explored. Examples of bacterial infections resistant to antibiotic treatment have been reported in the past; today constitutes a significant threat to public health in developed countries. The development of microbial resistance (perhaps due to prolonged intensive use of antimicrobial agents) constitutes growing concern in the medical community. 'Drug resistance' is defined as the existence of organisms that are less sensitive to the effects of specified antibacterial agents in specific microbial species. This type of resistance is particularly problematic in environments such as hospitals and nursing homes, where the infection rate is quite high and is often dense Use of antibacterial agents. For example, refer to W. Sanders, Jr., etc., β-Lactamidase: Clinical and Epidemiological Significance of the Use of Newer Cephalosporins ", Comprehensive Review of Infectious Diseases, page 830 ( 1988). The pathogenic bacteria printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs are known to obtain resistance through unique mechanisms, including the use of bacterial enzymes to deactivate antibiotics (such as β-lactamase hydrolyzing penicillin and cephalosporins); using outflow cartridges Removal of antibiotics; modification of antibiotic targets (such as penicillin resistance of Neisseria gonorrhoeae) through mutation and genetic recombination; and obtaining of resistant targets (such as mecilillin resistance of Staphylococcus aureus) from external sources to facilitate the transgene transfer ). Certain Gram-positive pathogens 589306 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Λ7 ______B7 V. Description of the invention (5) Vancomycin-resistant fecal enterococci are resistant to almost all commercially available antibiotics Therefore, the current ability of antibacterial agents to overcome the threat of resistance is limited. In this way, it is preferred to provide n-killers with useful properties that can be used commercially against drug-resistant microorganisms. Objects of the invention The purpose of the present invention is to provide a variety of agents that can be used against a wide variety Microorganisms, particularly bacterial quinolone and quinolone-based antibacterial compounds. Another object of the present invention is to provide an antimicrobial agent that is effective against quinolone-resistant microorganisms. Summary of the invention The inventors have discovered that a series of novel quinolone and quinolone-based compounds can effectively resist drug-resistant microorganisms and provide significant activity that is superior to the current state of the industry Advantages. In addition, the inventors have found that these 4-northone and fluorenone compounds are opposed to the structure / activity relationships already accepted in the industry. The present invention relates to

選係 X R6Selection X R6

R3 1式本紙張尺度適用中_家標準（CNS 丨_ 21Qxj^^ 06· 3 9 Λ7 B7 1、發明説明（6 )R3 Type 1 This paper is applicable in China _ home standard (CNS 丨 _ 21Qxj ^^ 06 · 3 9 Λ7 B7 1. Description of the invention (6)

(b) Rl係選自C3至約c5環垸基’ Ci至約C2烷基，c2 至約C3直鏈烯基，C3至約C4分支烷基或烯基，全部烷基或環烷基部分爲無取代或由1至約3個氟取代；及苯基，無取代或以1至約3個氟或以一個羥基取代於4 位置； (c) R3爲氫或羥基； (d) R5係選自氫，羥基，胺基，鹵原子，Ci至約匚2烷基，C2烯基，及甲氧基，全部虎基部分皆爲無取代或以1至約3個氟取代； (e) R6係選自氫，羧基’胺基黢基’溴，氰基’ ^^至約C 2燒基，c 2至約c 4烯基或块基’全部燒基部分皆爲無取代或以1至約3個氟取代’或此等甲基或乙基部分選擇性以一個卑基或一個胺基取代；經濟部中央標準局員工消費合作社印製 (f) R8係選自氯，溴，甲氧基，Ci至約C2烷醯基，c2 至約C 4晞基，全部烷基部分皆爲無取代或以1至約3個氟取代； (g) R 7爲胺基其係附接於X之非毗鄰環氮之環碳，胺基爲無取代或以一或二個Ci至约C3燒基取代；或胺基燒基其係附接於X之任一個環碳及爲Cl至約Cs燒基以一個胺基取代，該胺基爲無取代或以一或二個C1至約C 3 烷基取代；及 _ - 9 - 一— ——~ 本紙張尺度適用中國國家標準（〔奶）/\4規格（210乂 297公梦-) 589306 Λ7 B7 _ ___ 五、發明説明（7 ) (h)各R9分別選自氫，至約c4烷基，C2至約C6缔基或块基’及C 3至約C 6稠合或螺環烷基環，全部烷基郅分皆爲無取代或以1至約3個氟取代； (j)(g)敘述之R7部分及（h)敘述之R9部分可選擇性聯結如此形成（a)所示具有含氮環之稠合或螺環系環，稠合或螺環系環含2至約5個環碳及0或1個環氮，但若此等環爲稠合環，則R8較佳非爲氯或溴；或其光學異構物，非對映異構物或對映異構物；醫藥可接觉性鹽’水合物，或可生物水解酯，醯胺或醯亞胺。此外，合併本發明化合物之化合物，或使用本發明化合物作爲起始物料之化合物意圖也涵蓋於本發明。發現本發明化合物及含有此等化合物之組合物爲對抗廣泛多種病原菌之有效抗微生物劑，具有對微生物抗性之易感度低，毒性低及藥理性質改良等優點。發明説明經濟部中央標準局員工消費合作社印製本發明包括某些化合物，劑型及化合物投予人體或其它動物體之方法。本發明使用之特定化合物及組合物須爲醫藥可接受性。如此處使用，此種”醫藥可接受，，成分爲適用於人類及/或動物而無不當之不良副作用（如毒性，刺激性及過敏反應）可以合理的效益/風險比代償。用語詞彙除非另行規定，否則下列術語用於本案時具有指示意義。 ”統基”爲含1至8個碳原子，較佳1至4個碳原子之 ___ 10-____ 本紙張尺度適用中國國家標準（CNS)A4規格（210ϋ97公藶） '~一 589306 A7 B7 五、發明説明（8 ) 典取代或取代直鏈或分支飽和烴鏈基團。較佳烷基包括（例如）甲基，乙基，丙基，異丙基及丁基。 ’晞基’’爲含2至8個碳原子，較佳含2至4個碳原子’及含至少一個，較佳僅有一個碳-碳雙鍵之無取代或取代直鏈或分支烴鏈基團。块基爲含2至8個後原子，較佳含2至4個碳原子，及含至少一個，較佳僅有一個碳-碳參鍵之無取代或取代直鏈或分支烴鏈基團。除非另行限制僅含其中一或二者或其它限制，否則，，烷基”包括如上定義之烷基，烯基及炔基。烷基用作另一詞之部分時’保有此種意義；舉例如後（例如伸烷基，鹵烷基）。此等字中，烷基可由烷基，烯基或炔基之任一者替代而縮窄用字之定義。伸燒基爲烴基團。較佳伸燒基包括伸乙基及亞甲基。 ’’胺基”爲無取代或取代-NH2。鹵燒基爲垸基含有一或多個鹵原子（氟，氣，溴，碘) 之燒基。如此，氟烷基爲自烷基之亞類之例。經濟部中央標準局員工消費合作社印製雜原子爲氮，硫或氧原子。含一或多個雜原子之基可含不同雜原子。 ’’雜燒基”爲含2至8個成員包含碳原子，及至少一個雜原子之無取代或取代鏈基團。碳環系碳環”爲無取代或取代飽和、未飽和或芳族烴環基團。碳環系環爲單環或稠合、架橋或螺形多環系環 _ — -11- 本紙張尺度適用中國國家榡準（CNS ) A4規格（210X 297公楚")~ " 5的3〇6 Λ7 —.—_____B7 五、發明説明（9 ) 系早衮系環含3至9個礙原子，較佳3至6個碳原子。多壤系壤含7至1 7個碳原子，較佳7至1 3個碳原子。環燒基爲飽和或未飽和但非芳族碳環系環基團。較佳環烷基爲飽和及包括環丙基，環丁基及環戊基，特佳爲環丙基。雜環系環”爲環中包含碳原子及一或多個雜原子之無取代或取代飽和、未飽和或芳族環基團。雜環系環爲單環系或稠合、架橋或螺形多環系環系。單環系環含有3至9 個碳原子及雜原子，較佳3至6個碳及雜原子。多環環系含7至17個碳及雜原子，較佳7至13個碳及雜原子。务基爲操取代或取代芳族碳環系環基團。較佳芳基包括（例如）苯基，2,4-二氟苯基，4-羥苯基，甲苯基，二甲苯基’異丙苯基及莕基。較佳芳基取代基包括氟及羥基。 ’’雜芳基”爲無取代或取代芳族雜環系環基團。較佳雜芳基包括（例如塞吩基，呋喃基，吡咯基，吡啶基，吡啩基，嘍唑基，喹啉基，嘧啶基及四唑基。經濟部中央榡準局員工消費合作社印製 ’’烷氧基”爲含烴鏈取代基之氧基團，此處烴鏈爲烷基 (亦即·〇 -燒基或-〇·燒基）。較佳院氧基爲飽和及包括（例如）甲氧基，乙氧基，丙氧基及烯丙氧基。燒基胺基”爲含1或2個燒基取代基之胺基（例如-NH -烷基）。烷基較佳爲飽和及包括（例如）甲基及乙基。 ”芳基烷基”爲以一個芳基取代之烷基。較佳芳基烷基包括苄基及苯乙基。 _________112J____ 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公摄） 589306 Λ7 B7 五、發明説明（10 ) ’芳基胺基”爲以芳基取代之胺基（例*_NH -苯基）。 ”芳氧基”爲含芳基取代基之氧基圏（例如-〇-苯基）。 ”醯基”或”羧基”爲由幾酸去除羥基形成之基團（例如 n_c(o)_)。較佳基包括例甲醯基，及烷基醯基部分如乙醯基及丙酿基。 ”醯氧基”爲.具有醯基取代基之氧基團（例如醯基例如-o-c(o)-烷基。 ’’醯基胺基”爲含醯基取代基之胺基基團（例如，1醯基）；例如-NH-C(O)-烷基。 ”鹵原子”、”鹵素”或” _陰離子”爲氯、溴、氟或破基團。又此處所述低碳烴邵分（例如”低後”貌基）爲含1 至4，較佳1至2個碳原子之烴鏈。經濟部中央標隼局員工消費合作社印製 ’’醫藥可接受性鹽”爲於本發明化合物之任一個酸性基 (如痠基）形成之陽離子鹽，或於任一個驗性基（如胺基，燒基胺基，二烷基胺基，嗎啉基等）形成的陰離子鹽。因多種本發明化合物爲親兩性離子，故任一種鹽皆可能且可接受。多種鹽爲業界已知。較佳陽離子鹽包括鹼金屬鹽（如鈉及却），驗土金屬鹽（如鎂及鈣），及有機金屬鹽如銨鹽。較佳陰離子鹽包括_化物，續酸鹽，羧酸鹽，嶙酸鹽等。此等鹽明白包括加成鹽其可提供一個光學中心，此處原先並無光學中心。例如光學活性酒石酸鹽可由本發明化合物製備。此定義包括此等光學活性鹽。鹽類意圖於投予生病動物包括哺乳類或人類之用量爲無毒。 -— -13 *_ ·____ 本紙張尺度適用中國國家標隼（CNS ) Α4^Τ21〇χ 297公鳆）"' 589306 Λ7 B7 發明説明（11 ) 本發明化合物具有足夠驗性可形成酸加成鹽。化合物可以自由態驗形式及酸加成鹽形式使用，兩種形式皆屬於本發明之範圍。酸加成鹽於某些情況下爲較爲方便使用形式。實際上，鹽形式使用量超過活性成分之鹼形式之使用。用於製備酸加成鹽之酸較佳包括當合併自由態鹼使用時，可產生醫藥可接受性鹽者。此等鹽爲陰離子鹽，其對動物有機體例如哺乳類於鹽之醫藥劑量時相當無毒，故自由態驗特有之有效性質不會受酸的陰離子之任何副作用所害。經濟部中央標準局員工消費合作社印製適當酸加成鹽範例包括但非限於氫氯酸鹽，氫溴酸鹽 ’氫硪酸鹽’硫酸鹽，硫酸氫鹽，乙酸鹽，三氟乙酸鹽，硝酸鹽，擰檬酸鹽，反丁晞二酸鹽，甲酸鹽，硬脂酸鹽，丁二酸鹽，馬來酸鹽，丙二酸鹽，己二酸鹽，戊二酸鹽，礼酸鹽，丙酸鹽，丁酸鹽，酒石酸鹽，甲烷磺酸鹽，三氟甲烷磺酸鹽，對甲苯磺酸鹽，十二基硫酸鹽，環己烷胺基磺酸鹽等。但屬於本發明範圍之其它適當醫藥可接受性鹽係衍生自其它操機酸及有機酸。驗性化合物之酸加成鹽可藉若干方法製備。例如自由態鹼溶解於含適當酸之醇水溶液，及藉蒸發去除溶液分離鹽。另外，可經由自由態鹼與酸於有機溶劑反應製備，故可直接分離鹽。若鹽之分離困難，則可與第二有機溶劑沉澱，或可藉濃縮溶液獲得。雖然以鹼性化合物之醫藥可接受性鹽爲佳，但全部酸加成鹽皆屬於本發明之範圍。全部酸加成鹽皆可用作自由態鹼形式來源，即使特定鹽本身僅作爲中間產物需求亦: ___ -14- 本紙張尺度適用中國國家標隼（CNS ) A4規格（210X297公漦） 589306 Λ7 ___________B7 五、發明説明（12 ) 一 2例如當生成鹽僅爲了純化或識別用途，或當用作中間 :猎離子交換程序製備醫藥可接受性鹽時，此等鹽顯然構成本發明之一部分。寄主爲適合保有微生物之基質，較佳爲活有機體，更佳爲動物，更佳爲哺乳類，又更佳爲人類。可生物水解醯胺類，，爲本發明化合物之胺基酿基，酿基胺基或其它醯胺類，此處醯胺大致不會干擾，且較佳不會干擾化合物活性，《此處醯胺易於活體内由I主轉變產生活性化合物a 可生物水解醯亞胺類，，爲本發明化合物之醯亞胺類，此處酿亞胺大致不人會干擾，較佳不會干擾化合物活性，或此處醯亞胺易於活體内由寄主轉換產生活性化合物。較佳醯亞胺爲幾醯亞胺。經濟部中央標準局員工消費合作社印製 ”可生物水解酯類”爲本發明化合物之酯類，此處酯大致不會干擾類，較佳不會干擾化合物之抗微生物活性，或此處酯易於寄主轉換產生活性化合物。多種酯爲業界已知，述於1988年1 1月8日頒予Johnston及Mobashery之美國專利4,783,443(併述於此以供參考）。此等酯包括低碳烷基酯，低碳醯氧-烷基酯（如乙醯氧甲基，乙醯氧乙基，胺基羰基氧甲基，特戊醯氧甲基及特戊醯氧乙基酯），内酯基酯（例如酞基及硫酞基酯），低碳烷氧醯氧烷基酯（如甲氧羰氧甲基，乙氧羰氧乙基及異丙氧羰氧乙基酯），烷氧烷基酯，膽鹼酯及烷基醯胺基烷基酯（如乙醯胺基甲基酯）。特疋保漢形式及其它式I化合物衍生物之示例説明絕非 _______-15- 本紙張尺度適用中國國家標準（CNS ) A4規格（2H)X*l97公漦） 589306 Λ7 B7 丨丨"丨丨丨丨丨丨丨丨"" 一……一五、發明説明（13 ) 限制性。其它有用保護基、鹽形式等之應用皆屬於業界人士技巧範圍。 ”光學異構物”，”立體異構物，，及，，非對映異構物，，於此處具有標準業界認知意義（參考HawleVs簡明化輋詞 1，第1 1版）。本發明化合物可具有一或多個光學活性中心。結果可選擇性製備一個光學異構物包括非對映異構物及對映異構物多於另一種異構物，例如經由使用光學活性起始物料，催化劑或溶劑’可製備立體異構物或光學異構物包括同時製備非對映異構物及對映異構物（外消旋混合物）。因本發明化合物呈外消旋混合物，光學異構物混合物，包括非對映異構物及對映異構物或立體異構物存在，故可使用已知方法例如光學活性分割，光學活性層析等分離。此外’ 了解一種光學異構物包括非對映異構物及對映異構物或立體異構物具有優於另一種異構物之有利性質。如此當揭示及請求本發明專利時，揭示一種外消旋混合物時顯然預期兩種光學異構物包括非對映異構物及對映異構物或JL體異構物其大體不含另一者也被揭示及申請專利。經濟部中央標隼局員工消費合作社印製如用於此處，喹諾酮衍生物包括喹諾酮原體或由喹諾酮製備之活性头物。較佳付生物包括内酿胺類（例如Pg吩類，卡巴哂吩類，配念類（penems)，單内醯胺類等）選擇性透過間隔基共價鏈聯至峻諾酮。此等衍生物之製法及用法由本説明書之敎示對業界人士顯然易知。本發明化合物 ____· 16-____ 本紙張尺度適用中國國家標隼（CNS ) A4規格（210X 297公f )一' 589306 Λ7 B7 五、發明説明（14 ) 式1中，X係選自(b) R1 is selected from C3 to about c5 cyclofluorenyl 'Ci to about C2 alkyl, c2 to about C3 linear alkenyl, C3 to about C4 branched alkyl or alkenyl, all alkyl or cycloalkyl moieties Is unsubstituted or substituted with 1 to about 3 fluorines; and phenyl, unsubstituted or substituted at the 4-position with 1 to about 3 fluorines or with a hydroxyl group; (c) R3 is hydrogen or a hydroxyl group; (d) R5 series Selected from the group consisting of hydrogen, hydroxy, amine, halogen, Ci to about 匚 2 alkyl, C2 alkenyl, and methoxy, all tigeryl moieties are unsubstituted or substituted with 1 to about 3 fluorines; (e) R6 is selected from the group consisting of hydrogen, carboxyl'aminomethyl'bromide, cyano 'to about C 2 alkyl, and c 2 to about c 4 alkenyl or bulk. All alkyl groups are unsubstituted or substituted with 1 Up to about 3 fluorine substitutions' or these methyl or ethyl moieties are optionally substituted with one base or one amine group; printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (f) R8 is selected from chlorine, bromine, and A Oxy, Ci to about C2 alkylfluorenyl, c2 to about C4 fluorenyl, all alkyl moieties are unsubstituted or substituted with 1 to about 3 fluorines; (g) R 7 is an amine group which is attached to X is not a ring carbon adjacent to a ring nitrogen, the amine group is unsubstituted or Or two Ci to about C3 alkyl groups are substituted; or an amino alkyl group is attached to any one of the ring carbons of X and is substituted from Cl to about Cs alkyl groups with one amine group, which is unsubstituted or substituted with one Or two C1 to about C 3 alkyl substitutions; and _-9-one — —— ~ This paper size applies to Chinese national standards ([milk] / \ 4 specifications (210 乂 297 public dream-) 589306 Λ7 B7 _ ___ V. Description of the invention (7) (h) Each R9 is selected from hydrogen, to about c4 alkyl, C2 to about C6 alkenyl or bulk group, and C3 to about C6 fused or spirocycloalkyl ring, all The alkyl radicals are all unsubstituted or substituted with 1 to about 3 fluorines; (j) The R7 portion described in (g) and the R9 portion described in (h) can be selectively combined to form (a) nitrogen containing Condensed or spiro ring system ring, the fused or spiro ring system ring contains 2 to about 5 ring carbons and 0 or 1 ring nitrogen, but if these rings are fused rings, R8 is preferably not chlorine Or bromine; or its optical isomers, diastereomers or enantiomers; medically acceptable salts' hydrates, or biohydrolyzable esters, amidines or amidines. In addition, it is intended that the compounds of the compound of the present invention in combination, or the compounds using the compound of the present invention as a starting material, are also encompassed by the present invention. The compounds of the present invention and compositions containing these compounds have been found to be effective antimicrobial agents against a wide variety of pathogenic bacteria, and have the advantages of low susceptibility to microbial resistance, low toxicity, and improved pharmacological properties. Description of the invention Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economics The present invention includes certain compounds, dosage forms, and methods for administering the compounds to humans or other animals. The specific compounds and compositions used in the present invention must be medically acceptable. As used herein, such "medically acceptable" ingredients that are suitable for use in humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic reactions) can be compensated for at reasonable benefit / risk ratios. Glossary of terms unless otherwise specified Stipulated otherwise, the following terms are indicative when used in this case. "Union base" is one containing 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms. ___ 10 -____ This paper size applies Chinese National Standards (CNS) A4 specifications (210ϋ97) 苈 ~~ 589306 A7 B7 V. Description of the invention (8) Canonically substituted or substituted linear or branched saturated hydrocarbon chain groups. Preferred alkyl groups include, for example, methyl, ethyl, propyl , Isopropyl and butyl. 'Fluorenyl' is an unsubstituted group containing 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, and at least one, preferably only one carbon-carbon double bond Or substituted straight or branched hydrocarbon chain groups. Bulk groups are unsubstituted with 2 to 8 post atoms, preferably 2 to 4 carbon atoms, and at least one, preferably only one carbon-carbon parameter bond Or substituted with straight or branched hydrocarbon chain groups. Or other restrictions, or ,, alkyl group "include the above defined alkyl, alkenyl and alkynyl groups. 'Has this meaning when alkyl is used as part of another word; for example, after (e.g., alkylene, haloalkyl). In these words, an alkyl group may be replaced by any one of an alkyl group, an alkenyl group, or an alkynyl group to narrow down the definition of the word. The elongation group is a hydrocarbon group. Preferred elongation groups include ethylenyl and methylene. "Amine" is unsubstituted or substituted -NH2. Haloalkyl is a methyl group containing one or more halogen atoms (fluorine, gas, bromine, iodine). Thus, a fluoroalkyl group is an alkylene group. Heteroatoms printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs are nitrogen, sulfur, or oxygen atoms. The base containing one or more heteroatoms may contain different heteroatoms. The "heterosaturated base" contains 2 to 8 Each member contains a carbon atom and an unsubstituted or substituted chain group of at least one heteroatom. A "carbocyclic carbocyclic ring" is an unsubstituted or substituted saturated, unsaturated, or aromatic hydrocarbon ring group. The carbocyclic ring is a single ring or a fused, bridged, or spiral polycyclic ring _ — -11- Applicable to China National Standard for Standards (CNS) A4 (210X 297 Gong Chu ") ~ " 5 of 3〇6 Λ7 —.—_____ B7 V. Description of the invention (9) The early ring of the system contains 3 to 9 interfering atoms , Preferably 3 to 6 carbon atoms. Multi-lobe soil contains 7 to 17 carbon atoms, preferably 7 to 13 carbon atoms. The cycloalkyl group is a saturated or unsaturated but non-aromatic carbocyclic ring group. The preferred cycloalkyl group is saturated and includes cyclopropyl, cyclobutyl, and cyclopentyl, and particularly preferred is cyclopropyl. A heterocyclic ring is a ring containing carbon atoms and one or more heteroatoms. Substituted or substituted for saturated, unsaturated or aromatic ring groups. The heterocyclic ring is a single ring system or a fused, bridged or spiro polycyclic ring system. A monocyclic ring contains 3 to 9 carbon atoms and heteroatoms, preferably 3 to 6 carbons and heteroatoms. The polycyclic ring system contains 7 to 17 carbons and heteroatoms, preferably 7 to 13 carbons and heteroatoms. The radical is a substituted or substituted aromatic carbocyclic ring group. Preferred aryl groups include, for example, phenyl, 2,4-difluorophenyl, 4-hydroxyphenyl, tolyl, xylyl'cumyl and fluorenyl. Preferred aryl substituents include fluorine and hydroxy. "Heteroaryl" is an unsubstituted or substituted aromatic heterocyclic ring group. Preferred heteroaryls include (e.g., sephenyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, oxazolyl, quine Porphyrinyl, pyrimidinyl, and tetrazolyl. The "Alkoxy" group printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs is an oxy group containing a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl group (i.e. -Benyl or -0 · Benyl). Preferred oxy groups are saturated and include, for example, methoxy, ethoxy, propoxy, and allyloxy. "Branylamino" contains 1 or 2 An amine group (e.g., -NH-alkyl) having an alkyl substituent. The alkyl group is preferably saturated and includes, for example, methyl and ethyl. "Arylalkyl" is an alkyl group substituted with an aryl group. Preferred arylalkyls include benzyl and phenethyl. _________112J____ This paper size is applicable to Chinese National Standard (CNS) A4 specifications (210X 297 public photos) 589306 Λ7 B7 5. Description of the invention (10) 'Arylamine' is An amine group substituted with an aryl group (e.g. * _NH-phenyl). "Aryloxy" is an oxo group containing an aryl substituent (eg -0-phenyl). " "" Or "carboxy" is a group formed by the removal of a hydroxyl group by a few acids (for example, n_c (o) _). Preferred groups include, for example, methylamido, and alkylamido moieties such as ethylamido and propionyl. " "Methoxy" is an oxy group having a fluorenyl substituent (eg, a fluorenyl group such as -oc (o) -alkyl. "" Methylamino "is an amine group containing a fluorenyl substituent (for example, 1 fluorenyl); for example, -NH-C (O) -alkyl. "Halogen", "halogen", or "anion" is a chlorine, bromine, fluorine, or cleavage group. Also, the low-carbon hydrocarbons described herein The points (for example, "low") are hydrocarbon chains containing 1 to 4, preferably 1 to 2 carbon atoms. The "Medical Acceptable Salt" printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs is based on this The cationic salt formed by any acidic group (such as acid group) of the compound of the invention, or the anionic salt formed by any test group (such as amino group, alkylamino group, dialkylamino group, morpholinyl group, etc.). Since many of the compounds of the present invention are zwitterionic, any salt is possible and acceptable. Many salts are known in the industry. Preferred cationic salts include alkali metal salts such as sodium and However), soil metal salts (such as magnesium and calcium), and organometallic salts (such as ammonium salts). Preferred anionic salts include ions, dibasic acid salts, carboxylic acid salts, phosphonium salts, etc. These salts clearly include additions. Salts can provide an optical center, which was originally not present here. For example, optically active tartrate can be prepared from the compounds of the present invention. This definition includes such optically active salts. Salts are intended for administration to sick animals, including mammals or humans. It is non-toxic. ----- -13 * _ · ____ This paper size applies to the Chinese National Standard (CNS) Α4 ^ Τ21〇χ 297 公鳆 " '589306 Λ7 B7 Description of the invention (11) The compound of the present invention has sufficient testability. An acid addition salt is formed. The compounds can be used in free form and acid addition salt forms, both forms falling within the scope of the invention. Acid addition salts are more convenient to use in some cases. In practice, the salt form is used in excess of the base form of the active ingredient. Acids used in the preparation of acid addition salts preferably include those which can produce pharmaceutically acceptable salts when used in combination with a free state base. These salts are anionic salts, which are quite non-toxic to animal organisms such as mammals in the pharmaceutical dosage of salts, so the effective properties peculiar to free state tests are not compromised by any side effects of acid anions. Examples of suitable acid addition salts printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs include, but are not limited to, hydrochloride, hydrobromide 'hydrogallate' sulfate, hydrogen sulfate, acetate, trifluoroacetate, Nitrate, citrate, fumarate, formate, stearate, succinate, maleate, malonate, adipate, glutarate, etiquette Acid salt, propionate, butyrate, tartrate, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, dodecylsulfate, cyclohexaneaminosulfonate, etc. However, other suitable pharmaceutically acceptable salts within the scope of the present invention are derived from other organic acids and organic acids. Acid addition salts of test compounds can be prepared by several methods. For example, the free state base is dissolved in an alcohol-water solution containing a suitable acid, and the salt is separated by removing the solution by evaporation. In addition, it can be prepared by reacting a free state base with an acid in an organic solvent, so the salt can be directly separated. If the separation of the salt is difficult, it can be precipitated with a second organic solvent, or it can be obtained by a concentrated solution. Although pharmaceutically acceptable salts of basic compounds are preferred, all acid addition salts are within the scope of the present invention. All acid addition salts can be used as the source of the free base form, even if the specific salt itself is only required as an intermediate product: ___ -14- This paper size applies to China National Standard (CNS) A4 (210X297) 589306 Λ7 ___________B7 V. Description of the invention (12)-2 For example, when producing salts for purification or identification purposes only, or when used as an intermediate: hunting ion exchange procedure to prepare pharmaceutically acceptable salts, these salts obviously form part of the present invention. The host is a substrate suitable for retaining microorganisms, preferably living organisms, more preferably animals, more preferably mammals, and more preferably humans. Biohydrolyzable amidoamines are amine-based amines, amines or other amines of the compounds of the present invention. Here amines generally do not interfere, and preferably do not interfere with the activity of the compounds. Amine is easy to generate active compound a in vivo from I main conversion. It can biohydrolyze hydrazones, which are the hydrazones of the compounds of the present invention. Here, amines are generally not interfered by people, and preferably do not interfere with the activity of the compounds. Or here the iminoimine is prone to generate active compounds from host conversion in vivo. A more preferred imine is chitosan. The "bio-hydrolyzable esters" printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs are the esters of the compounds of the present invention. The esters here generally do not interfere with the class, preferably they do not interfere with the antimicrobial activity of the compounds, or the esters are easily Host conversion produces active compounds. Various esters are known in the industry and are described in U.S. Patent No. 4,783,443 issued to Johnston and Mobashery on November 8, 1988 (and are incorporated herein by reference). These esters include lower alkyl esters, lower alkyl alkoxy-alkyl esters (such as ethoxymethyl, ethoxyethyl, aminocarbonyloxymethyl, pivaloylmethyl and pivaloyloxy) Ethyl ester), lactone-based esters (such as phthaloyl and thiophthaloyl esters), low-carbon alkoxyalkyloxyalkyl esters (such as methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl, and isopropoxycarbonyloxy) Ethyl esters), alkoxyalkyl esters, choline esters, and alkylamidoalkyl esters (such as ethylamidomethyl esters). Special examples of Baohan form and other derivatives of formula I are by no means _______- 15- This paper size applies to Chinese National Standard (CNS) A4 size (2H) X * l97 male) 589306 Λ7 B7 丨丨 "丨丨丨丨丨丨丨丨 " " " " One ... One Five, Invention Description (13) Restrictive. Other useful protective groups, salt forms, etc. are within the skill of the industry. "Optical isomers", "stereoisomers," and, diastereoisomers, have standard industry-recognized meanings here (see HawleVs Condensed Word 1, Version 11). The present invention Compounds can have one or more optically active centers. As a result, one optical isomer can be selectively prepared including diastereomers and more enantiomers than another isomer, for example by using an optically active starting material The catalyst or solvent can prepare stereoisomers or optical isomers, including the simultaneous preparation of diastereomers and enantiomers (racemic mixtures). Because the compounds of the present invention are racemic mixtures, optical isomers Structure mixtures, including diastereomers and enantiomers or stereoisomers, can be separated using known methods such as optically active segmentation, optically active chromatography, etc. In addition, 'understand an optical isomer Including diastereomers and enantiomers or stereoisomers have advantageous properties over another isomer. So when revealing and claiming a patent for this invention, it is obvious when revealing a racemic mixture Two optical isomers, including diastereomers and enantiomers or JL isomers, which are substantially free of the other are also disclosed and patented. As used herein, quinolone derivatives include protoquinolone or active heads made from quinolone. Preferred by-products include endogenous amines (eg, Pg phenes, carbachols, penems, Monolactams, etc.) are selectively covalently linked to Junodone through a spacer. The preparation method and usage of these derivatives will be apparent to those skilled in the art from the description in this specification. Compounds of the invention ____ · 16- ____ This paper size applies to China National Standard (CNS) A4 (210X 297 male f)-'589306 Λ7 B7 V. Description of the invention (14) In formula 1, X is selected from

R7V R9 R9R7V R9 R9

R3 式备. 經濟部中央標準局員工消費合作社印製較佳X包括前述吡咯啶環或六氫吡啶環或吖丁啶環；更佳爲吨洛淀環。式1中’ R1包括某些烷基，環烷基，及芳基部分。環烷基部分於環中包括約3至約5個碳原子，較佳包括3 個碇原子於環。R1環烷基部分較佳爲飽和或未飽和具有一個雙鍵；更佳R1環烷基爲飽和（環烷基）。R1直鏈烷基含有1至約2個碳原子；以甲基及乙基爲佳，特佳爲乙基。R1直鏈烯基含有2至約3個碳原子；以乙烯基爲佳。R1分支烷基及烯基含有3至約4個碳原子；以分支烷基爲佳；以異丙基，異丙烯基，異丁基，異丁晞基及第三丁基又更佳。本段前文敘述之全部烷基（烷基，晞基及炔基）或環烷基部分爲無取代或以1至約3個氟部分取代。 R1芳基部分包括苯基，無取代或以1至約3個氟取代，或以一個輕基取代於4位置；以取代苯基爲佳。較佳R1係選自環丙基，乙基，以1至3個氟取代之苯基，及4 -羥苯 -17 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公梦-) 589306 經濟部中央標隼局員工消費合作社印製 Λ 7 ----------Β7 ___ 五、發明説明（15 ) 基’·更佳爲2,4 -二氟苯基及特佳爲環丙基或乙基。式1中’ R3爲氫或經基；較佳R3爲輕基。當R3爲經基時’其及其附接之羰基爲羧酸部分。如此，構成形成本化合物之醫藥可接受性鹽之點，及如此處所述之生物可水解醋類’胺基醯基類及醯胺類。r3位置有此種變化之化合物含括於本發明。式1中’ R5包括氫，胺基，鹵原子，羥基，甲氧基及某些燒基。R5烷基部分含i至約2個碳原子，較佳1個碳原子。R5晞基部分較佳含2個碳原子。全部R5烷基及甲氧基邵分皆爲無取代或以1至約3個氟部分取代。較佳R5 係選自氫，羥基，氣，溴，胺基，甲基，一氟甲基，二氟甲基’及三氟甲基。更佳R5係選自氫，羥基，胺基及甲基，特別氫。式1中’ R6包括氬，羥基，胺基羰基，溴，氰基及某些燒基。R6烷基部分含丨至約2個碳原子；較佳爲甲基及乙基；更佳爲甲基。R6烯基及決基部分含有2至約4個碳原子’較佳2個碳原子，附有一個雙键或參键，較佳雙鍵；以乙晞基爲佳。全部r6燒基部分皆爲無取代或以1 至約3個氟取代。R6甲基或乙基部分選擇性以一個羥基部分或一個胺基部分取代。較佳R6係選自氫，羥基，甲基，一氟甲基，二氟甲基及三氟甲基。更佳R6爲氫。式1中’ R8包括氣，溴，甲氧基，甲硫基及某些燒基。 R8烷基部分含有1至約2個碳原子；以甲基爲佳。R8烯基邵分含有2至約4個碳原子；以乙晞基爲佳。全部r 8 -18 - 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐1 " ' 589306 五經濟部中央標隼局員工消費合作社印裝 Λ7 B7 、發明説明（16 ) 燒基部分皆爲無取代或以1至約3個氟部分取代。較佳R 8 係選自氣，甲基，甲氧基，甲硫基，一氟曱基，二氟甲基’三氟甲基，一氟甲氧基’二氟甲氧基及三氟甲氧基。更佳R8係選自以1至約3個氟，甲氧基，甲硫基及氯取代之甲基，·特佳爲甲氧基或甲硫基或氣。式1之X中，R 7包括胺基’其附接於非βτ比鄰環氮之環碳。此種R7胺基爲無取代或以一或二個含1至約3個後原子之烷基取代，較佳甲基或乙基，更佳甲基；較佳胺基 R7爲無取代或以一個燒基部分取代。當X包含六氫^比咬基環時，R7較佳爲無取代或取代胺基部分。更佳R7，特別當X包含六氫吡啶基環時爲胺基或甲基胺基。 R7亦包括胺基烷基，該烷基含有1至約3個碳原子，較佳甲基，乙基或異丙基，燒基以一個胺基取代，此胺基可爲無取代或以一或二個，較佳一個含有1至約3個凌原子之烷基，特別乙基或特別甲基取代。此種胺基烷基附接於 X環之任一個碳；較佳附接於非毗鄰環氮之碳。r7較佳爲胺基烷基，特別若R 8爲任何無取代烷基，又特別若χ 包含吡咯啶環。較佳R7，特別當X包含吡咯啶環時係選自胺基甲基，甲基胺基甲基，1_胺基乙基，1-甲基胺基乙基，1-胺基-1-甲基乙基及1_甲基胺基_1_甲基乙基；更佳爲胺基甲基，及特別1-胺基乙基。 R7胺基部分爲可能形成本化合物之醫藥可接受性陰離子鹽之破，此等鹽含括於本發明化合物。較佳鹽爲與例如 HC1，CH3S03H，HCOOH 或 CF3COOH 生成之酸加成鹽。 ___-19- 本紙張尺度適用中國國家標隼（（：1^)/、4規格（210\ 297公簸） 589306 經濟部中央標準局員工消費合作社印製 Λ7 ____ B7五、發明説明（17 ) — 式1之X中’ R9表示所示X之六氫峨啶，吡洛啶及口丫丁淀環之環碳上非爲R7之全部部分；此等部分包括氫或某些烷基。非氫R9於R7未附接之各個環碳原子可爲一取代基或二取代基，或於R7附接之環碳可爲一取代基（亦即各個X環碳有兩個氫，一個氫及R7 ，一個氫及一個燒基，一個烷基及R7，或兩個烷基键結於其上）。較佳不多於兩個環碳有烷基R9取代基；更佳僅有一個環碳具有烷基R9取代基，·又較佳全部R9皆爲氫。燒基R9，特別二烷基R9較佳附接於X環之毗鄰環氮之環碳，特別X構成吡咯啶環時。非氫r 9包含直鏈、分支垸或環狀烷基，較佳直鏈或分支，更佳直鏈，含1至4個碳原子；以甲基及乙基爲佳；以甲基爲更佳。非氫r9包括直鏈、分支或環狀烯基及块基，較佳直鏈或分支，更佳直鏈，含2至約6個碳原子，較佳2至約4個碳原子；以乙烯基爲佳。兩個烷基R9可共同附接，如此與X之含氮環共同形成稠合或螺環烷基環，稠合環或螺環含有約3至約6個碳原子。此種稠合或螺環烷基環較佳爲飽和或未飽和含一個雙鍵，更佳飽和。以螺環丙基環爲特佳。全部R 9烷基部分皆爲無取代或以1至約3個氟部分取代，較佳無取代。更佳R9係選自氫，甲基，二甲基，螺環丙基及乙基；更佳爲乙基，二甲基及螺環丙基；及特佳爲氫。選擇性地，R9可聯結至R7如此與X之含氮環形成稠合 ___-20-_____ 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公籍） 589306 Λ7 Β7 五、發明説明（18 ) 環或螺環，稠合環或螺環含2至約5個環碳原子及〇或1 個環氮原子（得自R7)。此種稠合環或嫘環可爲含胺基或胺基烷基取代基之烴環，該胺基係得自R7 ;或可爲雜環系環具有R7胺基氮作爲環氮。此種環可含一或二個烷基取代基。此種稠合環或螺環較佳爲飽和或未飽和含一個雙鍵 ;更佳爲飽和。若此種環爲稠合，則R 8非爲氯，較佳非爲氣及溴，更佳爲甲氧基或甲硫基或甲基，又更佳爲甲氧基或甲硫基，特佳爲甲氧基。含R7或R9螺環之化合物係根據如下編號系統命名：編號始於較小環，繞過構成螺接合的較大環完成，例如當較小環爲環丙基時，於碳3完成如下例：Formula R3. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Preferably X includes the aforementioned pyrrolidine ring or hexahydropyridine ring or azetidine ring; more preferably a tonidine ring. 'R1 in Formula 1 includes certain alkyl, cycloalkyl, and aryl moieties. A cycloalkyl moiety includes about 3 to about 5 carbon atoms in the ring, preferably 3 fluorene atoms in the ring. The R1 cycloalkyl moiety is preferably saturated or unsaturated with one double bond; more preferably, R1 cycloalkyl is saturated (cycloalkyl). R1 straight-chain alkyl contains 1 to about 2 carbon atoms; methyl and ethyl are preferred, and ethyl is particularly preferred. R1 linear alkenyl contains 2 to about 3 carbon atoms; vinyl is preferred. R1 branched alkyl and alkenyl contain 3 to about 4 carbon atoms; branched alkyl is preferred; isopropyl, isopropenyl, isobutyl, isobutylfluorenyl, and third butyl are more preferred. All alkyl (alkyl, fluorenyl, and alkynyl) or cycloalkyl moieties described earlier in this paragraph are unsubstituted or substituted with 1 to about 3 fluoro moieties. The aryl portion of R1 includes a phenyl group, which is unsubstituted or substituted with 1 to about 3 fluorines, or substituted at a 4-position with a light group; preferably a substituted phenyl group. Preferably R1 is selected from cyclopropyl, ethyl, phenyl substituted with 1 to 3 fluorines, and 4-hydroxybenzene-17-This paper size is applicable to China National Standard (CNS) A4 (210X297 public dream-) 589306 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Λ 7 ---------- Β7 ___ V. Description of the invention (15) The best is 2,4-difluorophenyl and especially good Cyclopropyl or ethyl. In Formula 1, 'R3 is hydrogen or meridian; preferably R3 is light. When R3 is a radical, its and its attached carbonyl are carboxylic acid moieties. In this way, the point of forming a pharmaceutically acceptable salt of the present compound, and the biodegradable vinegars' aminoamidos and amidos as described herein are constituted. Compounds having such a change in the r3 position are included in the present invention. 'R5 in formula 1 includes hydrogen, an amine group, a halogen atom, a hydroxyl group, a methoxy group and some alkyl groups. The R5 alkyl moiety contains i to about 2 carbon atoms, preferably 1 carbon atom. The R5 fluorenyl moiety preferably contains 2 carbon atoms. All R5 alkyl and methoxy groups are unsubstituted or substituted with 1 to about 3 fluorine moieties. Preferably, R5 is selected from the group consisting of hydrogen, hydroxyl, gas, bromine, amine, methyl, monofluoromethyl, difluoromethyl 'and trifluoromethyl. More preferably, R5 is selected from the group consisting of hydrogen, hydroxyl, amine and methyl, especially hydrogen. 'R6 in formula 1 includes argon, hydroxyl, aminocarbonyl, bromine, cyano and some alkyl groups. The R6 alkyl moiety contains from 1 to about 2 carbon atoms; methyl and ethyl are preferred; and methyl is more preferred. The alkenyl and decanyl moiety of R6 contains 2 to about 4 carbon atoms', preferably 2 carbon atoms, and is attached with a double bond or a para-bond, preferably a double bond; ethenyl is preferred. All r6 alkyl groups are unsubstituted or substituted with 1 to about 3 fluorines. The R6 methyl or ethyl moiety is optionally substituted with a hydroxyl moiety or an amine moiety. Preferably R6 is selected from hydrogen, hydroxy, methyl, monofluoromethyl, difluoromethyl and trifluoromethyl. More preferably R6 is hydrogen. 'R8 in formula 1 includes gas, bromine, methoxy, methylthio and some alkyl groups. The R8 alkyl moiety contains from 1 to about 2 carbon atoms; methyl is preferred. R8 alkenyl contains 2 to about 4 carbon atoms; ethenyl is preferred. All r 8 -18-This paper size applies Chinese National Standard (CNS) Λ4 specification (210X 297 mm1 " '589306 5th Central Economic Bureau of the Ministry of Economic Affairs of the People's Republic of China Consumer Co-operative Printing Λ7 B7, invention description (16) Burning base The moieties are all unsubstituted or substituted with 1 to about 3 fluorine moieties. Preferably R 8 is selected from the group consisting of gas, methyl, methoxy, methylthio, monofluoromethyl, difluoromethyl'trifluoromethyl , Monofluoromethoxy'difluoromethoxy and trifluoromethoxy. More preferably R8 is selected from methyl substituted with 1 to about 3 fluorine, methoxy, methylthio and chlorine. Is a methoxy group or a methylthio group or a gas. In X of Formula 1, R 7 includes an amine group, which is attached to a ring carbon other than βτ adjacent ring nitrogen. Such R7 amine groups are unsubstituted or substituted with one or two Alkyl substituted with 1 to about 3 back atoms, preferably methyl or ethyl, more preferably methyl; preferably amine R7 is unsubstituted or substituted with one alkyl group. When X contains hexahydro In the case of a basic ring, R7 is preferably an unsubstituted or substituted amino moiety. More preferably R7, especially when X contains a hexahydropyridyl ring, is an amino group or a methylamino group. R7 also includes an aminoalkyl group, and the alkyl group Contains 1 Up to about 3 carbon atoms, preferably methyl, ethyl or isopropyl, and the alkyl group is substituted with an amine group. This amine group may be unsubstituted or with one or two, preferably one containing from 1 to about 3 The alkyl group of the lyn atom is substituted by an ethyl group or a special methyl group. This amino alkyl group is attached to any carbon of the X ring; preferably attached to a carbon not adjacent to the ring nitrogen. R7 is preferably an amino alkyl group. Group, especially if R 8 is any unsubstituted alkyl group, and especially if χ contains a pyrrolidine ring. Preferred R 7, especially when X contains a pyrrolidine ring, is selected from aminomethyl, methylaminomethyl, 1 _Aminoethyl, 1-methylaminoethyl, 1-amino-1-methylethyl and 1_methylamino_1_methylethyl; more preferably aminemethyl, and Particularly 1-aminoethyl. The R7 amine moiety is the breakdown of the pharmaceutically acceptable anionic salts that may form the compound. These salts are included in the compounds of the present invention. Preferred salts are, for example, HC1, CH3S03H, HCOOH or CF3COOH. The generated acid addition salt. ___- 19- This paper size is applicable to Chinese national standard ((: 1 ^) /, 4 specifications (210 \ 297)) 589306 Employees' Cooperatives, Central Standards Bureau, Ministry of Economic Affairs Preparation Λ7 ____ B7 V. Description of the invention (17) — In X of Formula 1, 'R9 represents the hexahydroeridine, pyrrolidine, and oxalidine ring ring carbon of the indicated X, but not all parts of R7; these parts Including hydrogen or certain alkyl groups. Non-hydrogen R9 at each ring carbon atom to which R7 is not attached may be a substituent or a di-substituent, or the ring carbon attached to R7 may be a substituent (that is, each X ring Carbon has two hydrogens, one hydrogen and R7, one hydrogen and one alkyl group, one alkyl and R7, or two alkyl groups bonded to it. It is preferred that no more than two ring carbons be substituted with alkyl R9 More preferably only one ring carbon has an alkyl R9 substituent, and still more preferably all R9 are hydrogen. The alkyl group R9, especially the dialkyl R9 is preferably attached to the ring carbon adjacent to the ring nitrogen of the X ring, especially when X forms a pyrrolidine ring. Non-hydrogen r 9 contains a linear, branched fluorene or cyclic alkyl group, preferably straight or branched, more preferably straight chain, containing 1 to 4 carbon atoms; methyl and ethyl are preferred; methyl is more preferred good. Non-hydrogen r9 includes linear, branched or cyclic alkenyl and bulk groups, preferably straight or branched, more preferably straight chain, containing 2 to about 6 carbon atoms, preferably 2 to about 4 carbon atoms; ethylene Base is better. The two alkyl groups R9 may be attached together to form a fused or spirocycloalkyl ring together with the nitrogen-containing ring of X. The fused or spiro ring contains about 3 to about 6 carbon atoms. Such a fused or spirocycloalkyl ring is preferably saturated or unsaturated and contains a double bond, more preferably saturated. Spirocyclopropyl ring is particularly preferred. All R 9 alkyl moieties are unsubstituted or substituted with 1 to about 3 fluoro moieties, preferably unsubstituted. More preferably R9 is selected from the group consisting of hydrogen, methyl, dimethyl, spirocyclopropyl and ethyl; more preferably ethyl, dimethyl and spiropropyl; and particularly preferably hydrogen. Optionally, R9 can be connected to R7 so that it is fused with the nitrogen-containing ring of X ___- 20 -_____ This paper size applies to the Chinese National Standard (CNS) Λ4 specification (210X 297 citizenship) 589306 Λ7 Β7 V. Description of the invention (18) A ring or spiro ring, a fused ring or a spiro ring containing 2 to about 5 ring carbon atoms and 0 or 1 ring nitrogen atom (from R7). Such a fused ring or fluorene ring may be a hydrocarbon ring containing an amine group or an amine alkyl substituent, the amine group being derived from R7; or it may be a heterocyclic ring having an R7 amine nitrogen as the ring nitrogen. Such a ring may contain one or two alkyl substituents. Such a fused or spiro ring is preferably saturated or unsaturated and contains a double bond; more preferably, it is saturated. If such a ring is fused, R 8 is not chlorine, preferably gas and bromine, more preferably methoxy or methylthio or methyl, and still more preferably methoxy or methylthio. Preferred is methoxy. Compounds containing R7 or R9 spiro rings are named according to the following numbering system: Numbering starts with the smaller ring and bypasses the larger ring that forms the spiro junction. For example, when the smaller ring is cyclopropyl, complete the following example on carbon 3. :

經濟部中央標準局員工消費合作社印裝此處使用吖命名遵照習知命名，且爲環氮附於喹諾酮核位置。如此處使用每次使用時各基團係獨立選擇（例如定義本發明之指定化合物時’ R1及R5於各次出現時無需相同）。本發明化合物含有光學中心，如此任一種化合物包括及意圖包含各光學異構物’非對映異構物或對映異構物呈純化或大致純化形式，及其混合物包括外消旋混合物。後文範例化合物係使用此處所述程序，及其變化程序完成屬於業界人士技巧範圍。下列實例並非限制本發明，反 _____-21 - 本紙度適用中關家標準（CNS ) Α4規格（210X297公籍) 一~一一一 589306 Λ7 ________B7____ 五、發明説明（19 ) 而係用於示例説明本發明之若干具體例。具有式2結構式之本發明喹諾酮之較佳例提供於下表：Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The name of acridine is used here following the conventional name, and the ring nitrogen is attached to the quinolone nuclear site. As used herein, each group is independently selected for each use (for example, when defining a designated compound of the present invention, 'R1 and R5 need not be the same at each occurrence). The compounds of the present invention contain optical centers, and any such compound includes and is intended to contain the individual optical isomers' diastereomers or enantiomers in a purified or substantially purified form, and mixtures thereof include racemic mixtures. Exemplary compounds described below use the procedures described here, and their completion is within the skill of the industry. The following examples do not limit the present invention, but _____- 21-This paper applies the Zhongguanjia Standard (CNS) A4 specification (210X297 citizenship). One to one by one 589306 Λ7 ________B7____ V. Description of the invention (19) is used for examples Some specific examples of the present invention will be described. Preferred examples of the quinolone of the present invention having the structural formula of Formula 2 are provided in the following table:

式2 經濟部中央標準局員工消費合作社印製下列實例中’ R1爲環丙基，R3爲羥，及z表示附接於吡咯啶環之R7基團之較佳光學活性，但也包括其它光學活〇 R7 〇爲 _ch(ch3)nh2 之化合物中，較佳基圏構造爲實例 R5 E6 R7 m 1 _nh2 H -nh2 Cl 2 _nh2 H 垂 ch2nh2 Cl 3 -NH2 H -CH(CH3)NH2 Cl 4 F H -nh2 Cl 5 F H (h2nh2 Cl 6 F H -CH(CH3)NH2 Cl 7 -och3 H -nh2 Cl 8 H H -ch2nh2 ch3 實例 R5 R6 R7 EB 9 H H •ch(ch3)nh2 ch3 -22- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 589306 五、發明説明（2〇 ) 經濟部中央標準局員工消費合作社印製 ΡκΊ Β7Formula 2 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs In the following example, 'R1 is cyclopropyl, R3 is hydroxyl, and z represents the preferred optical activity of the R7 group attached to the pyrrolidine ring, but other optical properties are also included Among the compounds where 〇R7 〇 is ch (ch3) nh2, the preferred structure is R5 E6 R7 m 1 _nh2 H -nh2 Cl 2 _nh2 H ch2nh2 Cl 3 -NH2 H -CH (CH3) NH2 Cl 4 FH -nh2 Cl 5 FH (h2nh2 Cl 6 FH -CH (CH3) NH2 Cl 7 -och3 H -nh2 Cl 8 HH -ch2nh2 ch3 Example R5 R6 R7 EB 9 HH • ch (ch3) nh2 ch3 -22- This paper standard Applicable to China National Standard (CNS) A4 specification (210X 297 mm) 589306 V. Description of invention (20) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs κκΒ7

10 OH Η _nh2 Cl s 11 OH Η -CH2NH2 Cl s 12 -OH Η _ch(ch3)nh2 Cl R 13 Η Η _nh2 Cl s 14 Η Η -CH2NH2 Cl s 15 Η Η -CH(CH3)NH2 Cl R 16 Η Η -nh2 COCH3 s 17 Η Η -CH2NH2 COCH3 s 18 Η Η -CH(CH3)NH2 COCH3 R 19 Η Βγ nh2 Cl s 20 Η Βγ -ch2nh2 Cl s 21 Η Βγ -ch(ch3)nh2 Cl R 22 Η -ch3 _nh2 Cl s 23 Η 麵ch3 ch2nh2 Cl s 24 Η -CH3 -CH(CH3)NH2 Cl R 25 Η -chch2 _nh2 Cl s 26 Η -chch2 -CH2NH2 Cl s 27 Η -chch2 -ch(ch3)nh2 Cl R 28 Η -OH _nh2 Cl s 29 Η -OH -CH2NH2 Cl s 30 Η OH -CH(CH3)NH2 Cl R 31 Η 麵CN _nh2 Cl s 32 Η _CN -CH2NH2 Cl s 33 Η CN -CH(CH3)NH2 Cl R _-23- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 589306 Λ 7 Β7 五、發明説明（21 ) 經濟部中央標準局員工消費合作社印製 34 Η -CH2OH -nh2 Cl s 35 Η -ch2oh -ch2nh2 Cl s 36 Η -ch2oh ^CH(CH3)NH2 Cl R 37 Η ch2nh2 _nh2 Cl s 38 Η ch2nh2 -ch2nh2 Cl s 39 Η -ch2nh2 -ch(ch3)nh2 Cl R 40 Η -CONH2 _nh2 Cl s 41 Η -conh2 -ch2nh2 Cl s 42 Η conh2 -CH(CH3)NH2 Cl R 43 Η H c(ch3)2nh2 Cl R 44 Η H c(ch3)2nh2 och3 R 實例 R5 M R2 R8 z 45 Η H -ch(ch3)nhch3 och3 R 46 Η H C(CH3)2NHCH3 och3 R 47 Η H -C(CH3)2NH2 och3 R 48 Η H _c(ch3)2nh2 Cl R 49 Η H -ch(ch3)nhch3 Cl R 50 Η H C(CH3)2NHCH3 Cl R 51 Η H -CH(CH3)NH2 sch3 R 52 Η H -c(ch3)2nh2 sch3 R 53 Η H -ch2nh2 sch3 R 54 Η H -nh2 sch3 S 具式i結構式之本發明化合物喹諾酮及較佳實例提供於 (請先閱讀背面之注意事項再填寫本頁) -24- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 589306 Λ 7 Β7 五、發明説明（22 下表10 OH _ _nh2 Cl s 11 OH Η -CH2NH2 Cl s 12 -OH Η _ch (ch3) nh2 Cl R 13 Η _nh2 Cl s 14 Η CH -CH2NH2 Cl s 15 Η CH -CH (CH3) NH2 Cl R 16 Η Η -nh2 COCH3 s 17 Η Η -CH2NH2 COCH3 s 18 Η Η -CH (CH3) NH2 COCH3 R 19 Η Βγ nh2 Cl s 20 Η Βγ -ch2nh2 Cl s 21 Η Βγ -ch (ch3) nh2 Cl R 22 Η- ch3 _nh2 Cl s 23 Η surface ch3 ch2nh2 Cl s 24 Η -CH3 -CH (CH3) NH2 Cl R 25 Η -chch2 _nh2 Cl s 26 Η -chch2 -CH2NH2 Cl s 27 Η -chch2 -ch (ch3) nh2 Cl R 28 Η -OH _nh2 Cl s 29 Η -OH -CH2NH2 Cl s 30 Η OH -CH (CH3) NH2 Cl R 31 面 Surface CN _nh2 Cl s 32 Η _CN -CH2NH2 Cl s 33 Η CN -CH (CH3) NH2 Cl R _-23- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X 297 mm) 589306 Λ7 Β7 V. Description of the invention (21) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economics 34 Η -CH2OH -nh2 Cl s 35 Η -ch2oh -ch2nh2 Cl s 36 Η -ch2oh ^ CH (CH3) NH2 Cl R 37 Η ch2nh2 _nh2 Cl s 38 Η ch2nh2 -ch2nh2 Cl s 39 Η -ch2nh2 -ch (ch3) nh2 Cl R 40 Η- CONH2 _nh2 Cl s 41 Η -conh2 -ch2nh2 Cl s 42 Η co nh2 -CH (CH3) NH2 Cl R 43 Η H c (ch3) 2nh2 Cl R 44 Η H c (ch3) 2nh2 och3 R Example R5 M R2 R8 z 45 Η H -ch (ch3) nhch3 och3 R 46 Η HC ( CH3) 2NHCH3 och3 R 47 Η H -C (CH3) 2NH2 och3 R 48 Η H _c (ch3) 2nh2 Cl R 49 Η H -ch (ch3) nhch3 Cl R 50 Η HC (CH3) 2NHCH3 Cl R 51 Η H- CH (CH3) NH2 sch3 R 52 Η H -c (ch3) 2nh2 sch3 R 53 Η H -ch2nh2 sch3 R 54 Η H -nh2 sch3 S The compound quinolone of the present invention having the formula i and the preferred examples are provided in (Please Read the notes on the back before filling in this page) -24- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 589306 Λ 7 Β7 V. Description of the invention (22 Table below

式1下列實例中，R 3爲羥基，R 5及R 6皆爲氫，及z表示R 7 基團附接於吡咯啶環或六氫吡啶環之較佳光學活性（若有），但也包括其它光學活性。實例 Μ 55 -och3 56 -Cl 57 -0CH3 58 -Cl 59 -0CH3 60 -ClIn the following examples of formula 1, R 3 is a hydroxyl group, R 5 and R 6 are both hydrogen, and z represents a preferred optical activity (if any) of the R 7 group attached to a pyrrolidine ring or a hexahydropyridine ring, but also Includes other optical activities. Example Μ 55 -och3 56 -Cl 57 -0CH3 58 -Cl 59 -0CH3 60 -Cl

HoN Ζ 請先閱讀背 \δ 之注- 意事項再填寫本頁經濟部中央標隼局員工消費合作社印製 25 本紙張尺度適用中國國家標準（CNS ) A4規格（21QX 297公t )HoN ZZ Please read back the note of \ δ-the item of interest and then fill in this page. This page is printed by the Consumers' Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. 25 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (21QX 297 g)

589306 Λ7 B7 經濟部中央標隼局員工消費合作社印製589306 Λ7 B7 Printed by the Staff Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs

589306 經濟部中央標举局員工消費合作社印製589306 Printed by the Consumer Cooperatives of the Central Bureau of the Ministry of Economic Affairs

本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 589306 Λ7 B7 五、發明説明（ 25The size of this paper applies to Chinese National Standard (CNS) A4 (210X 297 mm) 589306 Λ7 B7 V. Description of the invention (25

Example R8 91 92 OCH] -ClExample R8 91 92 OCH] -Cl

RV HORV HO

XIXI

R R 93 -〇ch3 CH3CH2- 94 -Cl CH3CH2- 95 -SCH3 CH3CH2- 96 -OCH3 CH3CH2- 97 -Cl CH3CH2- 98 -〇CH3 CH3- 99 -Cl CHy nh2R R 93 -〇ch3 CH3CH2- 94 -Cl CH3CH2- 95 -SCH3 CH3CH2- 96 -OCH3 CH3CH2- 97 -Cl CH3CH2- 98 -〇CH3 CH3- 99 -Cl CHy nh2

nh2nh2

h2nh2n

R R RR R R

R RR R

R R 100 101 -och3 -ClR R 100 101 -och3 -Cl

n—n—

S S 經濟部中央標準局員工消费合作社印製 102 103 -OCH3 -Cl [>S S Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 102 103 -OCH3 -Cl [>

S S -28- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公t ) r589306 Λ7 B7 五、發明説明（26 ) Example 104 105 m -OCH] -ClS S -28- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297g t) r589306 Λ7 B7 V. Description of the invention (26) Example 104 105 m -OCH] -Cl

EH Σ1EH Σ1

R R 106 107 -OCH3 -ClR R 106 107 -OCH3 -Cl

R R 108 109 -OCH3 -Cl CFH2CH2- cfh2ch2-R R 108 109 -OCH3 -Cl CFH2CH2- cfh2ch2-

nh2nh2

R R 110 111 〇CH] -ClR R 110 111 〇CH] -Cl

R R 經濟部中央標準局員工消費合作社印製 *本攔説明之各結構概略係關於其所屬之二或三個不同實例0 此外，須了解爲了純化、投藥等，常使用前述化合物之鹽及其它衍生物。如此，醫藥可接受性鹽，水合物或生物可水解酯、醯胺或醯亞胺意圖及含括作爲本發明之一部分0 前述本發明化合物亦爲式Q-L-B化合物之有用前驅物 ’其中Q爲式1化合物，L爲聯結部分，及B爲含内醯胺 29 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） ^89306 Λ 7 Β7 五、發明説明（27 ) 部分。此式包括光學異構物，非對映異構物或對映異構物；醫藥可接受性鹽，水合物或生物可水解酯，醯胺及醯亞胺。此等合。此等化合物及其使用揭示於1993年i月 19日獲頒之美國專利5，180,719 ; 1995年2月7日獲頒之美國專利5,387,748 ; 1996年2月13日獲頒之美^專利 5,491，139 ; 1996年6月25日獲頒之美國專利5 53〇116 ,· 及1990年5月2日公告之EPO公告案0366189，及1990年 5月2日公告之0366640，全部併述於此以供參考。至於組合物及用法，式Q-L-B化合物可以式丄化合物之相同方式使用。故可於此處之組合物實例中交換。經濟部中央標準局員工消費合作社印製本發明化合物之生物活性可與赛普洛辛（cipr〇fl〇xaein)及其它已知抗微生物喹諾酮化合物比較。本發明化合物比較赛普洛辛及某些先前技術化合物對某些4諾酮抗藥性細菌提供更佳抗菌性質。當對喹諾酮抗性菌如金黃葡萄球菌0 aureus)，腐生葡萄球菌sapr〇phytieus)，糞腸葡萄球菌 (E. faecalis)，釀膿鏈球菌（s py〇genes)，肺炎球菌（s pneumoniae)，綠色鏈球菌（s viddans)，大腸桿菌（E c〇li)，綠膿样菌（P. aeruginosa)，奇異變形菌（p. mirablllS) ’肺炎克氏样菌（K· pneumoniae)，陰溝腸桿菌（E. cloacae)試驗時，發現某些本發明化合物具有MIC値（微克/ 毫升）比赛普洛辛低抵約5〇〇倍。化合物製法製造本發明化合物時，可改變合成步驟順序，俾提高所需化合物產率。此外，業界人士也了解適當選擇反應物、 ---一 - 30 -_ _____ 本紙張尺度適财關家縣（CNS ) M規格（21QX 297公楚） 589306 經濟部中央標準局員工消費合作社印製 Λ 7 --—-------- 一 Β7___ 五、發明説明（2β ) ^ ^知丨及/m度爲成功合成之重要組成分。雖然最佳條件等之 $定爲例行公事，但須了解多種化合物可使用如下反應圖指導而以類似方式產生。、可用於製備本發明化合物之起始物料爲已知，藉已知方法製備或市面可得作爲起始物料。有機化學業界人士了解可無需進一步指導易對有機化合物進行標準操作；換言之，此等操作係屬於業界人士技巧及實務範圍。此等包括但非限於羰基化合物還原成其對應醇類’氧化’醯化，芳族取代包括親電子及親核取代，醚化、§旨化及包化等。操作範例討論於標準參考書例如 March患進有機化Kwiiey)，Carey及Sundberg先進有機化 i(第2卷），Fieser & Feiser有機合成反應劑（第16卷）， L. Paquette 成反應劑百科（第8卷），Frost &Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs * The structure of this description is about two or three different examples. In addition, it must be understood that for purification, drug administration, etc., the salts of the aforementioned compounds and other derivatives are often used Thing. Thus, pharmaceutically acceptable salts, hydrates or biohydrolyzable esters, amidines or amidines are intended and included as part of the present invention. 0 The aforementioned compounds of the invention are also useful precursors for compounds of formula QLB, where Q is the formula 1 compound, L is the linking part, and B is the lactam-containing 29. This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) ^ 89306 Λ 7 B7 V. Description of the invention (27). This formula includes optical isomers, diastereomers, or enantiomers; pharmaceutically acceptable salts, hydrates or biohydrolyzable esters, amidines and amidines. All together. These compounds and their use are disclosed in U.S. Patent 5,180,719, issued on January 19, 1993; U.S. Patent 5,387,748, issued on February 7, 1995; U.S. Patent 5,491,139, issued on February 13, 1996 ; U.S. Patent 5,53,116,116, issued on June 25, 1996, and EPO Announcement 0366189, published on May 2, 1990, and 0366640, published on May 2, 1990, all of which are hereby incorporated herein by reference. reference. As for the composition and usage, the compound of the formula Q-L-B can be used in the same manner as the compound of the formula VII. Therefore, it can be exchanged in the composition examples here. Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs The biological activity of the compound of the present invention can be compared with that of ciprfloxaein and other known antimicrobial quinolone compounds. The compounds of the present invention provide better antibacterial properties against certain 4-nordone-resistant bacteria compared to cyproxine and certain prior art compounds. When resistant to quinolones such as Staphylococcus aureus), Staphylococcus saprophytaus, E. faecalis, S. pyogenes, pneumoniae, S. viddans, E. coli, E. coli, P. aeruginosa, p. MirablllS, 'K. pneumoniae, Enterobacter cloacae (E. cloacae) In the test, it was found that some of the compounds of the present invention have a MIC (R) (micrograms / ml) that is about 500 times lower than that of promethine. Compound production method When the compound of the present invention is produced, the order of the synthetic steps can be changed to increase the yield of the desired compound. In addition, the industry also knows the appropriate choice of reactants, --- a- 30 -_ _____ This paper size is suitable for Guancai County (CNS) M specifications (21QX 297) Chu 589306 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Λ 7 ----------- Β7 ___ V. Description of the invention (2β) ^ ^ Knowing and / m degrees are important components of successful synthesis. Although optimal conditions are routinely determined, it is important to understand that multiple compounds can be generated in a similar manner using the following reaction map guidance. The starting materials that can be used to prepare the compounds of the present invention are known and can be prepared by known methods or available on the market as starting materials. The organic chemistry industry understands that standard operations on organic compounds can be easily performed without further guidance; in other words, these operations are within the skill and practice of the industry. These include, but are not limited to, reduction of carbonyl compounds to their corresponding alcohols, 'oxidation', halogenation, aromatic substitutions include electrophilic and nucleophilic substitutions, etherification, stentification, and encapsulation. Examples of operations are discussed in standard reference books such as March with Organic Kwiiey), Carey and Sundberg Advanced Organics i (Vol. 2), Fieser & Feiser Organic Synthesis Reactants (vol. 16), L. Paquette Reagent Encyclopedia (Volume 8), Frost &

Fleming塁解有機合成f繁9卷）等。業界人士了解當分子之其它官能基被遮蔽或保護時，最佳進行某些反應，如此避免任何非期望之副反應及/或提高反應產率。經常業界人士利用保護基來完成增高產率或避免非期望之反應。此等反應可參考參考文獻也屬於業界人士技巧範圍。多種操作實例例如參考T. Greene有機合成保簠棊。當然用作起始物料之具有反應性分支鏈之胺基酸較佳被封阻以防非期望之副反應。製備本發明化合物時可用於製備喳諾酮部分之概略程序説明於下列參考文獻，全部併述於此以供參考（包括此等參考文獻中列舉之文件）；藥物研究進展，Vol. 21，pp. 9-104 ——__________________ -31 - 本紙張尺度適用中國國家標準（CNS ) A4規格(210'乂297公簸) 一一 (請先閱讀背面之注意事項再填寫本頁) «衣 589306 Λ7 B7 經濟部中央標準局員工消費合作社印裝五、發明説明（29) (1997); J. Med·_ Chem·, Vol. 23, pp. 1358-1363 (1980); L Med. Chem.. Vol. 29, pp. 2363-2369 (1986); J. Med. Chem.. Vol. 31, pp. 503 (1988); J. Med. Chem·· Vol. 31, pp. 503-506 (1988); J. Med· Chem·· Vol· 31，pp. 983-991 (1988); J. Med. Chem·, Vol. 31，pp. 991-1001 (1988); J. Med. Chem.. Vol· 31， pp. 1586-1590 (1988); J. Med. Chem·· Vol. 31, pp. 1598-1611 (1988); J. Med. Chem., Vol· 32, pp· 537-542 (1989); J. Med. Chem·· Vol· 32, pp· 1313 (1989); J. Med· Chem.· Vol. 32, pp. 1313-13 18 (1989); Drugs Exptl. Clin. Res·· Vol· 14，pp· 379-383 (1988); J. Pharm. Sci·· Vol. 78, pp. 585-588 (1989); L Het. Chem., Vol. 24, pp. 181-185 (1987); J. Het· Chem.· Vol. 25, pp. 479-485 (1988); Chem. Pharm. Bull.. Vol. 35, pp. 2281-2285 (1987); Chem. Pharm. Bull.. Vol. 36, pp. 1223-1228 (1988);美國專利 4,594,347，1986 年 6 月 10 日；美國專利4,599,334 ， 1986年7月8日；美國專利 4,687,770，1987 年 8 月 1 日；美國專利 4,689,325，1987 年8月25日；美國專利4,767,762，1988年8月30日；美國專利4,771，055 ， 1988年9月13日；美國專利 4,795,751 ’ 1989 年 1 月 3 日；美國專利 4,822,801，1989 年4月18日；美國專利4,839,355，1989年6月13日；美國專利4,851，418 ， 1989年7月25日；美國專利 4,886,810，1989 年 12 月 12 日；美國專利 4,920，120， 1990年4月24日；美國專利4,923,879，1990年5月8 日；美國專利4,954,507 ， 1990年9月4日；美國專利 __— _-32^___ 本紙張尺度適用中國國家標隼（CNS ) A4規格（210X 297公楚） 589306 Λ 7 Β7 五、發明説明（30 ) 4,956,465，1990 年 9 月 1 1 日；美國專利 4,977，154，1990 年12月1 1日，·美國專利4,980,470，1990年12月25 日’·美國專利5,013,841 ，1991年5月7日，·美國專利 5,045,549，1991 年 9 月 3 日；美國專利 5,290,934，1994 年3月1曰·，美國專利5 328，9〇8，1994年7月12日；美國專利5,430,152，1995年7月4日；歐洲專利公告案 172,651 ’ 1986年2月26日；歐洲專利公告案230,053， 1987年7月29日；歐洲專利公告案23〇 946，1987年8月 5日；歐洲專利公告案247,464，1987年12月2日；歐洲專利公告案284,935，1988年10月5日；歐洲專利公告案 3〇9,789，1989年4月5日；歐洲專利公告案332 〇33， 1989年9月13日，·歐洲專利公告案342,649，1989年1 1 月23日，及日本專利公告案〇9/67,3〇4 (μ”年）。法==係藉前述參考文獻揭示之方法製備。較佳方 “I備；7位置具有適當離去基之喹諾基以雜環-X置拖柞塗县‘ 系離去置換作A最末步驟。此等方法舉例如下。 :發明之㈣嗣化合物可以多種方式製備。提〇物〈多種万法顯示於如下反應圖I ·· 經濟部中央標準局員工消費合作社印製Fleming's Decomposition of Organic Synthesis (f. 9 volumes) and so on. Those in the industry understand that when other functional groups of the molecule are masked or protected, certain reactions are best performed, so as to avoid any undesired side reactions and / or increase the reaction yield. Often the industry uses protecting groups to achieve higher yields or to avoid undesired reactions. These reactions can refer to the reference and also belong to the skill of the industry. For various operation examples, see, for example, T. Greene Organic Synthesis. Of course, the amino acids with reactive branches used as starting materials are better blocked to prevent undesired side reactions. The general procedures that can be used to prepare the linoxone moiety when preparing the compounds of the present invention are described in the following references, all of which are hereby incorporated by reference (including documents listed in these references); Progress in Pharmaceutical Research, Vol. 21, pp 9-104 ——__________________ -31-This paper size is applicable to Chinese National Standard (CNS) A4 specifications (210 '乂 297 mm). One by one (please read the precautions on the back before filling this page) «衣 589306 Λ7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs V. Invention Description (29) (1997); J. Med · _Chem ·, Vol. 23, pp. 1358-1363 (1980); L Med. Chem .. Vol. 29, pp. 2363-2369 (1986); J. Med. Chem .. Vol. 31, pp. 503 (1988); J. Med. Chem. Vol. 31, pp. 503-506 (1988); J Med · Chem ·· Vol 31, pp. 983-991 (1988); J. Med. Chem ·, Vol. 31, pp. 991-1001 (1988); J. Med. Chem .. Vol · 31, pp. 1586-1590 (1988); J. Med. Chem. Vol. 31, pp. 1598-1611 (1988); J. Med. Chem., Vol. 32, pp. 537-542 (1989); J Med. Chem. Vol. 32, pp. 1313 (1989); J. Med. Chem. Vol. 32, pp. 1313-13 18 (1989); Drugs Exptl. Clin. Res. Vol. 14, pp. 379-383 (1988); J. Pharm. Sci .. Vol. 78, pp. 585-588 (1989); L Het. Chem. , Vol. 24, pp. 181-185 (1987); J. Het · Chem. · Vol. 25, pp. 479-485 (1988); Chem. Pharm. Bull .. Vol. 35, pp. 2281-2285 (1987); Chem. Pharm. Bull .. Vol. 36, pp. 1223-1228 (1988); US Patent 4,594,347, June 10, 1986; US Patent 4,599,334, July 8, 1986; US Patent 4,687,770, August 1, 1987; US Patent 4,689,325, August 25, 1987; US Patent 4,767,762, August 30, 1988; US Patent 4,771,055, September 13, 1988; US Patent 4,795,751 'January 1989 3; US Patent 4,822,801, April 18, 1989; US Patent 4,839,355, June 13, 1989; US Patent 4,851,418, July 25, 1989; US Patent 4,886,810, December 12, 1989; United States Patent 4,920,120, April 24, 1990; U.S. Patent 4,923,879, May 8, 1990; U.S. Patent 4,954,507, Sept. 4, 1990; U.S. Patent ___ _-32 ^ ___ This paper is suitable for China National Standards (CNS) A4 specification (210X 297 Gongchu) 589306 Λ 7 Β7 V. Description of the invention (30) 4,956,465, September 1, 1990; US patent 4,977,154, December 11, 1990, US Patent 4,980,470, December 25, 1990 'US Patent 5,013,841, May 7, 1991, US Patent 5,045,549, September 3, 1991; US Patent 5,290,934, March 1, 1994, US Patent 5 328, 908, July 12, 1994; U.S. Patent 5,430,152, July 4, 1995; European Patent Publication 172,651 'February 26, 1986; European Patent Publication 230,053, July 29, 1987 ; European Patent Bulletin 23〇946, August 5, 1987; European Patent Bulletin 247,464, December 2, 1987; European Patent Bulletin 284,935, October 5, 1988; European Patent Bulletin 309,789, April 5, 1989; European Patent Publication No. 332 033, September 13, 1989, European Patent Publication No. 342,649, November 23, 1989, and Japanese Patent Publication No. 09 / 67,304 (μ "years). Method == Prepared by the method disclosed in the aforementioned reference. The preferred method is "I; the quinolyl group with a suitable leaving group at the 7 position is substituted with heterocyclic-X to Tutu County" as the last step of A. Examples of these methods are as follows: Compounds can be prepared in a variety of ways. Extracts (multiple methods are shown in the following reaction diagram I ·· Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

反應圖IReaction diagram I

(210x 297公釐） 589306 Λ7 經濟部中央標準局員工消費合作社印製(210x 297 mm) 589306 Λ7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

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 $ S 事項再填寫本頁 589306 A7 B? 五、發明説明（32 R5 R6This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm). Please read the back $ S item first and then fill out this page. 589306 A7 B? V. Description of the invention (32 R5 R6

COOH R3 (C〇CI)2COOH R3 (C〇CI) 2

or SOCU R5 R6or SOCU R5 R6

COCI R8 (i) CH2(C〇〇BI)2, Mg (ii) PTSA H2〇 T RS 9 ^ (i)HC(〇Et)3, Ac2〇 ^00COCI R8 (i) CH2 (C〇〇BI) 2, Mg (ii) PTSA H2〇 T RS 9 ^ (i) HC (〇Et) 3, Ac2〇 ^ 00

(ii) 脱保護 R8 R1(ii) Deprotection R8 R1

o oo o

R8 R1R8 R1

NH R9NH R9

B\KB \ K

請先閱讀背面之注· 意事項. 再本頁訂 I ά 經濟部中央標準局員工消費合作社印製 Β 1 =封阻基。製備反應圖I及11之苯甲酸前驅物之較佳方法敘1及舉例説明如後。苯甲酸衍生物具有下式·· ι -35- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X29?公釐） 589306 Λ7 _ B7 五、發明説明（33 ) R5Please read the notes and notices on the back first, and then make this page. I ά Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Β 1 = Blocking base. A preferred method for preparing the benzoic acid precursors in Reaction Schemes I and 11 is described in Example 1 and described below. The benzoic acid derivative has the following formula: -35- The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X29? Mm) 589306 Λ7 _ B7 V. Description of the invention (33) R5

RS^J^COOH R8 此種方法中，2，4 -二氟-溴苯：RS ^ J ^ COOH R8 In this method, 2,4-difluoro-bromobenzene:

經濟部中央標準局員工消費合作社印製以強非親核鹼處理。此種鹼可爲任一種可用於排列氫·金屬交換之鹼。較佳鹼包括鋰貳二異丙醯胺（LDA)，鋰 2,2,6,6_四甲基六氫吡啶（LiTMP)，鋰貳（三甲基矽烷基）醯胺（LTSA)，第三丁氧化物或其它用於此用途之已知鹼。適當鹼爲業界已知，且於常見參考文獻發現爲非親核鹼。最佳爲LDA，其產生中間物可穩定歷一段時間及溫度範圍。較佳此種反應溫度爲約-8 0 °C至約4 0 °C，更佳至約室溫，最佳至約-40 °C。溫度隨使用之鹼改變，例如最佳反應溫度爲使用LDA爲約·65 Ό。反應時間可長達約24 小時，較佳約2小時，最佳該方法係於所得苯衍生物可能於製程中前進之次一步驟時繼續進行。也較佳此種反應係於惰性氣氛下進行。於鹼已經與1-溴-2,4·氟苯反應後，親電子反應劑可獲得所需R8取代基，或可轉成所需R8取代基之官能基，如此產生下式化合物： __ _36- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） 589306 Λ7 B7 五、發明说明（34 )Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. This base can be any base that can be used for hydrogen / metal exchange. Preferred bases include lithium ammonium diisopropylamidine (LDA), lithium 2,2,6,6-tetramethylhexahydropyridine (LiTMP), lithium ammonium (trimethylsilyl) ammonium amine (LTSA), and Tributoxide or other known bases used for this purpose. Suitable bases are known in the art and are found in common references as non-nucleophilic bases. The best is LDA, which produces intermediates that are stable over time and temperature ranges. The reaction temperature is preferably about -8 ° C to about 40 ° C, more preferably about room temperature, and most preferably about -40 ° C. The temperature varies depending on the base used. For example, the optimal reaction temperature is about · 65 ° C using LDA. The reaction time may be up to about 24 hours, preferably about 2 hours. The best method is that the benzene derivative obtained may be continued in the next step of the process. It is also preferred that this reaction is carried out under an inert atmosphere. After the base has reacted with 1-bromo-2,4 · fluorobenzene, the electrophilic reactant can obtain the desired R8 substituent, or a functional group that can be converted into the required R8 substituent, thus producing a compound of the formula: __ _36 -This paper size applies to Chinese National Standard (CNS) Α4 size (210X297 mm) 589306 Λ7 B7 V. Description of invention (34)

R8 適用於此種反應之溶劑典型爲質子惰性溶劑。較佳溶劑可與前述步驟使用之鹼相容。更佳溶劑包括醚及乙二醇醚，最佳爲四氫呋喃（THF)。此等溶劑爲業界已知，適當取代係依據驗，親電子基團，及反應物及所得化合物之極性及溶解度特性而定。經濟部中央標準局員工消費合作社印製此種3-R8-2,4-二氟-溴苯化合物可用於製造對應苯甲酸，及相關中間物最終合成本發明之喹諾酮或峻諾酮衍生物。苯甲酸之製備係經由使用可用於排列卣原子-金屬交換反應劑相當物處理如述R 8 ·苯化合物製備。較佳反應劑包括正丁基鐘，錢，經或其它已知用於此用途之反應劑。適當反應劑爲參考文獻已知，出現於常見參考文獻。最佳驗爲正丁基鋰，其產生可於某一時間及溫度範園合理穩定之中間物。較佳反應溫度爲至少-8 0 °C至約4 0 °C ,更佳至約室溫，最佳至約-40 °C。溫度可隨使用之鹼改變，例如最佳iaiL度使用正丁基鐘時爲約-7 0 C。反應時間可長達約2 4 小時，較佳約1 5分鐘，最佳方法係於一旦顯示所得中間物衍生物可能前進至製程之次一步驟時進行。亦較佳此種反應係於惰性氣氛進行。由如述反應所传中間物以二氧化峻或N，N -二甲基甲醯胺 (DMF)處理，最佳爲二氧化碳。常見此種反應爲放熱，故較佳藉冷卻反應維持溫度以防副反應等。若使用二氧化碳，則所得苯甲酸化合物經典型後續處理後無需進一步純 _ -37- 本紙張尺度適用中國國家標隼（CNS ) A4規格（210X 297公釐) 顧 - 589306 Λ7 B7 五、發明説明（35 化即可使用：R8 Solvents suitable for this reaction are typically aprotic solvents. Preferred solvents are compatible with the base used in the previous steps. More preferred solvents include ethers and glycol ethers, most preferably tetrahydrofuran (THF). These solvents are known in the industry, and appropriate substitutions are based on the polarity, solubility characteristics of the reactants and the resulting compounds, as well as the electrophilic groups. Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs This 3-R8-2,4-difluoro-bromobenzene compound can be used to make the corresponding benzoic acid and related intermediates to finally synthesize the quinolone or junodone derivative of the present invention. The benzoic acid is prepared by treating R 8 · benzene compounds as described above with the equivalent of a fluorene atom-metal exchange reactant. Preferred reactants include n-butyl bell, europium, or other reactants known for this purpose. Appropriate reactants are known in the literature and appear in common references. The best test is n-butyllithium, which produces intermediates that are reasonably stable at a certain time and temperature. The preferred reaction temperature is at least -8 0 ° C to about 40 ° C, more preferably to about room temperature, and most preferably to about -40 ° C. The temperature may vary with the base used, for example, the optimal iaiL degree is about -7 0 C when using n-butyl clock. The reaction time may be as long as about 24 hours, preferably about 15 minutes. The best method is to perform it once it is shown that the obtained intermediate derivative may proceed to the next step in the process. It is also preferred that the reaction is performed in an inert atmosphere. The intermediates passed from the reaction described above are treated with sulphur dioxide or N, N-dimethylformamide (DMF), preferably carbon dioxide. This reaction is usually exothermic, so it is better to maintain the temperature by cooling the reaction to prevent side reactions. If carbon dioxide is used, the obtained benzoic acid compound does not need to be further purified after subsequent treatment. -37- This paper size applies to China National Standard (CNS) A4 (210X 297 mm) Gu-589306 Λ7 B7 V. Description of the invention ( 35 seconds to use:

COOH 厂丫、F R8 若使用D M F或類似甲醯化化合物，則所得苯甲_化合物透過氧化被氧化成對應苯甲酸。此種反應可於空氣存在下或使用任何其它已知氧化劑進行。所得苯甲酸化合物同樣可於典型後續處理後，無需進一步純化即供使用。藉前述方法製備之甲苯酸化合物也適合汉6位置衍生。若需要衍生此位置，則反應之選擇依據所需官能度而定，例如鹵化反應：COOH plant, F R8 If D M F or a similar formazan compound is used, the resulting benzoyl compound is oxidized to the corresponding benzoic acid through oxidation. This reaction can be performed in the presence of air or using any other known oxidant. The resulting benzoic acid compound can also be used after typical subsequent processing without further purification. The toluic acid compound prepared by the aforementioned method is also suitable for the 6-position derivatization. If this position needs to be derived, the choice of reaction depends on the required functionality, such as a halogenation reaction:

COOH r 丫、f R8 Z2/HhCOOH r y, f R8 Z2 / Hh

COOH F R8 此處Z爲自化物’較佳溴。反應係發生於酸性條件，例如乙酸，較佳使用鹵化物活化劑如銀劑（如A g N 〇 3 )。確化經濟部中央標準局員工消費合作社印製COOH F R8 Here Z is a self-product ', preferably bromine. The reaction occurs under acidic conditions, such as acetic acid, preferably using a halide activator such as a silver agent (such as AgNO3). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

COOH Να F Y'F HN〇3/H2S〇4 R8COOH Να F Y'F HN〇3 / H2S〇4 R8

FF

R8R8

COOH 硝化反應係透過以活化確酸處理’例如於確酸與硫酸之;昆合物進行。確基化合物還4原成爲對應胺可透過任何適當 38 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐） 589306 Λ7 B7 五、發明説明（36 ) 還原法進行。醯化：〇The COOH nitration reaction is carried out by treatment with activated acid, e.g., between acid and sulfuric acid; The authentic compound can also be converted into the corresponding amine by any appropriate 38 paper size applicable to the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) 589306 Λ7 B7 V. Description of the invention (36) reduction method. Alchemy: 〇

經濟部中央標準局員工消費合作社印製醯基化合物之製備可藉引進醯化劑例如R’COCl(此處R’ 爲烷基或芳基），較佳於路易士酸如A1C13存在下完成。結果所得化合物適合拜耳·威利格（Baeyei:-Villiger)化學而提供R6羥基其可選擇性經醚化。 R5可使用R6之類似方法衍生。供示例説明，提供下列製造苯甲酸前驅物實例；此等實例非爲限制性。The production of fluorenyl compounds by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs can be accomplished by the introduction of fluorinating agents such as R'COCl (where R 'is alkyl or aryl), preferably in the presence of a Lewis acid such as A1C13. As a result, the obtained compound was suitable for Baeyei: -Villiger chemistry to provide R6 hydroxyl group, which could be selectively etherified. R5 can be derived using a similar method to R6. By way of illustration, the following examples of making benzoic acid precursors are provided; these examples are not limiting.

前驅物實例A 3 -氣-2,4 -二氟溴笨於19愛升（0.135莫耳）二異丙基胺於125毫升四氫咬喃 (THF)於_20eC冷卻之溶液内加入80毫升正丁基鋰（1.61^於己烷）。溫度提高至0 °C歷5分鐘，及下降至-78 Ό。然後加入25克（0.129莫耳）2,4_二氟·溴苯，反應於-65 °C攪拌 2小時。然後加入25毫升（0.164莫耳）六氣丙酮，及溶液溫熱至室溫。蒸發去除溶劑後，殘餘物經眞空蒸餾獲得所需產物。 3 -氯-2，4 -二氟苯甲醢於21.5克(0.0945莫耳）3-氣_2,4_二氟_溴苯於22〇亳升 -39- 589306 Λ7 B7 五、發明説明（37) 於-78 C之溶液内加入5 9亳升ι·6Μ正丁基鋰稀釋於60毫升醚，溫度維持低於-70 °C。1 5分鐘後，反應内通入二氧化碳氣體，維持溫度低於-70 °C。溫熱至室溫後，加水及鹽酸，及有機相經分離，乾燥。去除溶劑獲得所需產物。Examples of precursors A 3 -Ga-2,4-difluorobromobenzylbenzene is less than 19 liters (0.135 moles) of diisopropylamine in 125 ml of tetrahydrofuran (THF) in a solution cooled at -20eC and 80 ml is added. N-butyllithium (1.61 ^ in hexane). The temperature increased to 0 ° C for 5 minutes, and decreased to -78 ° C. Then, 25 g (0.129 mole) of 2,4-difluoro · bromobenzene was added, and the reaction was stirred at -65 ° C for 2 hours. Then 25 ml (0.164 mole) of hexagas acetone was added and the solution was allowed to warm to room temperature. After removing the solvent by evaporation, the residue was subjected to vacuum distillation to obtain the desired product. 3-Chloro-2,4-difluorobenzidine in 21.5 g (0.0945 moles) of 3-gas_2,4_difluoro_bromobenzene in 22 liters-39-589306 Λ7 B7 V. Description of the invention ( 37) Into a solution of -78 C, add 5 9 liters of 6M n-butyllithium to dilute in 60 ml of ether, and maintain the temperature below -70 ° C. After 15 minutes, carbon dioxide gas was passed into the reaction to maintain the temperature below -70 ° C. After warming to room temperature, water and hydrochloric acid were added, and the organic phase was separated and dried. Removal of the solvent gave the desired product.

前驅物膏例R 3 -甲基-2,4·二氟·溪笨二異丙基胺（11.9毫升，85毫莫耳）溶解於5〇毫升無水 THF及於乾冰/丙酮浴冷卻，逐滴加入正丁基鐘（34毫升， 2.5M於己烷類溶液，85毫莫耳）。15分鐘後，以可維持溫度低於-65 °C之速率加入1-溴-2,4-二氟苯（16克，83毫莫耳）於8亳升THF之溶液。反應攪拌2.5小時，然後碘甲烷（10.3毫升，166毫莫耳）於8毫升THF之溶液添加至反應。去除冰浴，及任反應溫熱至室溫。2小時後，反應以水及1 N鹽酸淬熄。水層以醚萃取兩次。合併有機層以鹽水洗滌，及以硫酸鈉脱水。去除溶劑獲得所需產物。 3-甲基-2,4-二氟苯甲酸經濟部中央標準局員工消費合作社印製 3 -甲基-2,4 -二氟漠苯（16.07克，77.6毫莫耳）溶解於 120毫升無水醚及於乾冰/丙酮冷卻。以可維持溫度低於_65 °C之速率逐滴加入丁基Ιϊ(20·5亳升，2.5M於己貌類溶液，76.2毫莫耳）於1 5毫升醚之溶液。4 5分鐘後，二氧化碳通氣通過溶液，維持溫度低於-65 °C，溫度穩定後持續通入二氧化碳氣體任反應溫熱至室溫。混合物以3 〇毫升水淬熄，及以1N鹽酸酸化至pH 2。分離各層，及水層以醚 .萃取。合併有機層以鹽水及飽和碳酸氫鈉洗滌。然後碳酸 ______:40-____ 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公t ) " 589306 Λ7 ____ B7 五、發明説明（38 ) 氫鹽層以IN鹽酸酸化至pH 3。所得固體經過濾，以水洗滌' 及眞空脱水。Precursor paste example R 3 -methyl-2,4 · difluoro · xiben diisopropylamine (11.9 ml, 85 mmol) was dissolved in 50 ml of anhydrous THF and cooled in a dry ice / acetone bath, dropwise Add n-butyl bell (34 ml, 2.5 M in hexane, 85 mmol). After 15 minutes, a solution of 1-bromo-2,4-difluorobenzene (16 g, 83 mmol) in 8 ml of THF was added at a rate capable of maintaining the temperature below -65 ° C. The reaction was stirred for 2.5 hours, and then a solution of iodomethane (10.3 ml, 166 mmol) in 8 ml of THF was added to the reaction. Remove the ice bath and allow the reaction to warm to room temperature. After 2 hours, the reaction was quenched with water and 1 N hydrochloric acid. The aqueous layer was extracted twice with ether. The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent gave the desired product. 3-Methyl-2,4-difluorobenzoic acid Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, 3-methyl-2,4-difluorobenzyl (16.07 g, 77.6 mmol) dissolved in 120 ml of anhydrous Ether and cooled on dry ice / acetone. A solution of butyl 1ϊ (20 · 5 liters, 2.5 M in a solution of 7 ml, 76.2 mmol) in 15 ml of ether was added dropwise at a rate capable of maintaining the temperature below -65 ° C. After 5 minutes, carbon dioxide was passed through the solution to maintain the temperature below -65 ° C. After the temperature was stable, carbon dioxide gas was continuously passed in and the reaction was allowed to warm to room temperature. The mixture was quenched with 30 ml of water and acidified to pH 2 with 1N hydrochloric acid. The layers were separated, and the aqueous layer was extracted with ether. The combined organic layers were washed with brine and saturated sodium bicarbonate. Then carbonic acid ______: 40 -____ This paper size applies Chinese National Standard (CNS) A4 specification (210X 297g t) " 589306 Λ7 ____ B7 V. Description of the invention (38) The hydrogen salt layer is acidified to pH 3 with IN hydrochloric acid. The solid obtained was filtered, washed with water and dehydrated.

前驅物實例C 二氟蘭溴笨足量40.2耄升2.0M鋰二異丙基胺（LDA)於-78 °C溶解於 8〇耄升丁1^，及加入15.4克2,4-二氟溴苯維持溫度低於-65 C。反應於_65乇攪拌2小時，及加入6·6毫升6M無水第二丁基過氧氫。溫熱至室溫後，加入100毫升水及混合物經酸化。蒸發去除溶劑，及水層以醚萃取。萃出物經脱水，然後濃縮獲得所需產物。氧-2,4-二氣-溴 1 定量3.7克3 -羥·2,4_二氟-溴苯溶解於25毫升丙酮及加入2.5克碳酸钾，接著加入2.2毫升甲基碘。混合物於20 C攪拌歷6小時，及蒸發去除溶劑。加入二氣甲烷後，懸浮液經過濾。蒸發去除溶劑獲得所需產物。 - 2，4 _ 二氟苽甲 _ 使用類似製備3-氣-2，4-二氟苯甲酸之程序，但始於3-甲氧-2,4_二氟-溴苯。經濟部中央標準局員工消費合作社印製Precursor Example C Difluoro blue bromide 40.2 liters 2.0M lithium diisopropylamine (LDA) at -78 ° C dissolved in 80 liters butane 1 ^, and 15.4 g 2,4-difluoro Bromobenzene maintains a temperature below -65 C. The reaction was stirred at -65 ° F for 2 hours, and 6.6 ml of 6M anhydrous second butyl hydroperoxide was added. After warming to room temperature, 100 ml of water was added and the mixture was acidified. The solvent was removed by evaporation, and the aqueous layer was extracted with ether. The extract is dehydrated and concentrated to obtain the desired product. Oxy-2,4-digas-bromo 1 Quantitative 3.7 g of 3-hydroxy · 2,4-difluoro-bromobenzene was dissolved in 25 ml of acetone and 2.5 g of potassium carbonate was added, followed by 2.2 ml of methyl iodide. The mixture was stirred at 20 C for 6 hours, and the solvent was removed by evaporation. After the addition of methane, the suspension was filtered. The solvent was removed by evaporation to obtain the desired product. -2,4 _ difluoropyrene _ uses a similar procedure for the preparation of 3-gas-2,4-difluorobenzoic acid, but starts with 3-methoxy-2,4_difluoro-bromobenzene. Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs

前驅物實例D h溴_3-氣_2.4 -二氟苯甲酸於50¾升乙酸，1〇毫升水及13毫升硝酸之混合物溶解 2克（0.014莫耳）3-氣-2,4-二氟苯甲酸及3.64毫升（0.028 莫耳）溴。然後缓慢加入3·52克（0.0208莫耳）硝酸銀於1〇毫升水之溶液。於20 °C經14小時後，過濾沉澱及以醚清 ___-41 __ 本紙張尺度適用中國國家標準（CNS ) A4规格（210X297公簸） 589306 Λ 7 Β7 五發明説明（ 39 洗。有機相以亞硫酸氫鈉洗滌，然後以水洗滌及脱水。去除溶劑獲得所需產物。請閱讀背面 >王意事項《再填< 寫本頁Examples of precursors D h Bromine_3-gas_2.4-difluorobenzoic acid was dissolved in 50 g of acetic acid, 10 ml of water and 13 ml of nitric acid to dissolve 2 g (0.014 mol) of 3-gas-2,4-difluoro Benzoic acid and 3.64 ml (0.028 moles) of bromine. Then slowly add a solution of 3.52 g (0.0208 mol) of silver nitrate in 10 ml of water. After 14 hours at 20 ° C, filter the precipitate and use ethereal ___- 41 __ This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 male dust) 589306 Λ 7 Β7 Description of the five inventions (39 Wash. Organic phase Wash with sodium bisulfite, then wash with water and dehydrate. Remove the solvent to get the desired product. Please read the back > Wang Yi Matter "Fill Again" & write this page

前驅物實例E ^1^-3-氯-2,4-二氟笨甲醢定量1克3-氯-2,4-二氟苯甲酸添加至1毫升發煙硝酸與亳升硫酸於0 °C之混合物。然後懸浮液於室溫攪拌30 分鐘，及倒至冰上。過濾獲得所需產物。以下爲如上反應圖I説明之喹諾酮之官能化實例。前驅物實例F •氣-2,4-二氣苯甲醯氳訂 5.2克5-溴-3-氣-2,4_二氟苯甲酸懸浮於30毫升二氣甲境，然後加入2·92克草醯氣，及3滴無水DMF。混合物於至溫攪拌3小時，及蒸發去除溶劑後分離所需化合物。經濟部中夬標準局員工消費合作社印製，4 -二氟-3-氣-苯甲醯基乙酸乙酯 —份0.475克鎂懸浮於1.5毫升乙醇及加入〇·ΐ6毫升四氣化碳。逐滴加入3毫升丙二酸二乙酯於15毫升乙醇之溶液’及混合物於60 °C攪拌至鍰完全溶解。混合物於_ 5 X：冷卻’及逐滴加入5·5克5 -溴-3 ·氣-2，4 _二氟苯甲醯氣。處合物於室溫攪拌1小時，及加入50毫升***，2〇毫升水；然後混合物以濃鹽酸酸化。分離有機相及去除溶劑後，殘餘物懸浮於40毫升水，及加入〇·1克PTSA。懸浮液回流2小時，於室溫冷卻及以***萃取。所需產物係於蒸發去除溶劑後獲得。酸 -if裒丙基胺基- 2- (5 -溪-2,4_二氟_3_氣-笨甲締基）丙矯 -42 589306 Λ7 B7 五、發明説明（4G ) 乙酉旨一份ό·2克5·溴-2,4-二氟-3 -氯-苯甲醯基乙酸乙酯溶解於4.4亳升乙酐與4·5毫升原甲酸三乙酯混合物。回流2小時後，蒸發去除過量反應劑，殘餘物溶解於2 〇毫升乙醇，及所得溶液於0。(：冷卻。加入一份2毫升環丙基胺，及經 3〇分鐘後藉過濾分離所需產物及風乾。臭_ 1 _環丙基_ 1，4 -二氫-7 -氟-8 -氣-4 -氧基-喹啉 3 -勒酸乙酯一份2.48克3-環丙基胺基讎2-(5-溴賴2,4·二氟麵3-氣-苯甲醯基）丙烯酸乙酯溶解於15毫升THF，及逐份加入0.27 克60%氫化鈉。於室溫經1小時後，懸浮液倒入1〇〇亳升水中’及所需產物藉過濾分離及風乾。二氫·7-氣-8-氣-6 -甲基-4-氧基喹啉-3-淼酸乙酯經濟部中央標準局員工消費合作社印製 6漠8 -乳- i-j辰丙基-氟二氫·4 -氧基u奎琳_3·幾酸醋（100毫克，〇·26毫莫耳），氣化鋰（0.033克，〇·77亳莫耳）’參（二亞苄基丙酮）二飽（〇)(〇 024克，0.026亳莫耳），四甲基錫（〇〇93克，〇·52毫莫耳）及5毫克丁基化羥甲苯（2,6_二·第三丁基_4-甲基-酚·ΒΗΤ)合併於8亳升二甲基甲醯胺（DMF)及加熱至70-75 Τ：歷18小時。然後眞空去除溶劑。殘餘物以己烷類研製，然後以1 %甲醇於氣仿於矽氧層析獲得所需產物。下列爲如反應圖π説明之本發明曱氧及队氣喹諾酮 ^典型合成實例。末二步驟允許使用不同胺於R7變化。 ---；--- -43-___ 紙尺度適用中國國家榡準（cns ) Μ規格（no〆 297公廢） 589306 Λ7 B7 五、發明説明（41 ) 實例G ·· 製備：Precursor Example E ^ 1 ^ -3-Chloro-2,4-difluorobenzidine Quantitatively 1 g of 3-chloro-2,4-difluorobenzoic acid was added to 1 ml of fuming nitric acid and sulphuric acid at 0 ° C mixture. The suspension was then stirred at room temperature for 30 minutes and poured onto ice. The desired product was obtained by filtration. The following is an example of the functionalization of quinolone as illustrated in Reaction Scheme I above. Precursor example F • Gas-2,4-digas benzamidine 5.2 g of 5-bromo-3-gas-2,4_difluorobenzoic acid was suspended in 30 ml of digas formaldehyde, then 2.92 was added Gram grass gas, and 3 drops of anhydrous DMF. The mixture was stirred at room temperature for 3 hours, and the desired compound was isolated after removing the solvent by evaporation. Printed by the Consumer Cooperative of the China Standards Bureau of the Ministry of Economic Affairs. 4-Difluoro-3-gas-benzylidene ethyl acetate—a portion of 0.475 g of magnesium was suspended in 1.5 ml of ethanol and 0.6 ml of carbon tetracarbonate was added. A solution of 3 ml of diethyl malonate in 15 ml of ethanol was added dropwise and the mixture was stirred at 60 ° C until the mash was completely dissolved. The mixture was cooled at _5X: ' and 5.5 grams of 5-bromo-3.gas-2,4-difluorobenzidine gas was added dropwise. The mixture was stirred at room temperature for 1 hour, and 50 ml of diethyl ether and 20 ml of water were added; the mixture was then acidified with concentrated hydrochloric acid. After the organic phase was separated and the solvent was removed, the residue was suspended in 40 ml of water, and 0.1 g of PTSA was added. The suspension was refluxed for 2 hours, cooled at room temperature and extracted with ether. The desired product was obtained after evaporation of the solvent. Acid-if-propylamino- 2- (5 -Xi-2,4_difluoro_3_qi-benzylidene) propane-42 589306 Λ7 B7 V. Description of the invention (4G) 2 g of 5-bromo-2,4-difluoro-3-chloro-benzylidene ethyl acetate was dissolved in a mixture of 4.4 ml of acetic anhydride and 4.5 ml of triethyl orthoformate. After refluxing for 2 hours, the excess reactant was removed by evaporation, the residue was dissolved in 20 ml of ethanol, and the resulting solution was dissolved in 0%. (: Cool. Add 2 ml of cyclopropylamine, and after 30 minutes isolate the desired product by filtration and air-dry. Odor_ 1_cyclopropyl_ 1,4-dihydro-7 -fluoro-8- GA-4 -oxy-quinoline 3-ethyl oleate 2.48 g of 3-cyclopropylaminofluorenyl 2- (5-bromolysene 2,4-difluoromethane 3-gas-benzylidene) Ethyl acrylate was dissolved in 15 ml of THF, and 0.27 g of 60% sodium hydride was added in portions. After 1 hour at room temperature, the suspension was poured into 100 liters of water 'and the desired product was isolated by filtration and air-dried. Hydrogen · 7-Gas-8-Gas-6-methyl-4-oxyquinoline-3-miaonate ethyl ester Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Dihydro · 4-oxyu quinine_3 · chinic acid vinegar (100 mg, 0.26 mol), lithium gasification (0.033 g, 0.77 mol), ginseng (dibenzylideneacetone) ) Disaturated (0) (0.024 g, 0.026 mol), tetramethyltin (0.093 g, 0.52 mol) and 5 mg of butylated hydroxytoluene (2,6-di · Tributyl 4-methyl-phenol (BHT) was combined in 8 liters of dimethylformamide (DMF) and heated to 70-75 Τ: over 18 hours. Then 眞The solvent was removed. The residue was triturated with hexanes, and the desired product was obtained by silica gel chromatography using 1% methanol in gas. The following is a typical synthesis example of the oxygen and quinolone of the present invention as illustrated in the reaction chart. The last two steps allow the use of different amines to vary in R7. ---; --- -43 -___ The paper size applies to the Chinese National Standard (cns) M specification (no〆297 public waste) 589306 Λ7 B7 V. Description of the invention (41 ) Example G Preparation:

經濟部中央標準局員工消費合作社印製 3-甲氧-2,4-二氟苯甲醯氲一份43.9克3-甲氧_2,4-二氟苯甲酸懸浮於3〇〇毫升二氣甲燒及加入25毫升草醯氣’接著加入4滴無水DMF。混合物於室溫攪拌6小時，及蒸發去除溶劑獲得所需產物。 2,4 -二氟-3-甲氧苯甲酿基乙酸乙酉旨一份26.4克丙二酸一乙酯溶解於700毫升thf。溶液於-50 °C冷卻，及加入160亳升2.5M正丁基鋰，及維持溫度低於 -50 I。溫度初步升高至〇 X：，及冷卻回_5〇 °c。加入一份 20.6克3·甲氧_2,4·二氟苯甲醯氣，維持溫度於_5〇 π，然後反應混合物溫熱至室溫。加入鹽酸至ρ Η變成酸性。有機相以碳酸氫鈉洗滌及脱水，蒸發去除溶劑獲得所需產物。 3-壤—ϋ胺基-2-(2,4-二氟-3 _甲氧疆苯甲醯基巧烯酸乙酯於50耄升乙酐及50亳升原甲酸三乙酯之混合物内加入 52.94克2,4 -二氟-3 -甲氧-苯甲醯基乙酸乙酯。混合物回流2小時，然後冷卻至室溫。過量反應劑藉蒸發去除獲得稠厚油，其落解於15G毫升乙醇。然後加入一份171克環 —__-_— -44 ,_ 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公f ) -- 589306 Λ 7 〜一________一五、發明説明（42 ) - 丙基胺，同時維持溫度於約2〇 °c。所需產物藉過遽分離及風乾。 ll·^丙基-1，土^二氫_7_氟_8 -甲氧-4-氣基-邊淋·3_羧酸乙3-Methoxy-2,4-difluorobenzidine printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 43.9 g of 3-methoxy-2,4-difluorobenzoic acid suspended in 300 ml of digas Scallop and add 25 ml of grasshopper gas' followed by 4 drops of anhydrous DMF. The mixture was stirred at room temperature for 6 hours, and the solvent was removed by evaporation to obtain the desired product. Ethyl 2,4-difluoro-3-methoxybenzylacetate A portion of 26.4 g of monoethyl malonate was dissolved in 700 ml of thf. The solution was cooled at -50 ° C, and 160 liters of 2.5M n-butyllithium was added, and the temperature was maintained below -50 ° C. The temperature initially rose to 0x :, and cooled back to -50 ° C. A 20.6 g portion of 3 · methoxy-2,4 · difluorobenzidine gas was added, the temperature was maintained at -50 π, and the reaction mixture was allowed to warm to room temperature. Add hydrochloric acid until ρ ρ becomes acidic. The organic phase was washed with sodium bicarbonate and dehydrated, and the solvent was evaporated to obtain the desired product. 3-soil-fluorenylamino-2- (2,4-difluoro-3_methoxybenzylbenzoic acid ethyl ester in a mixture of 50 liters of acetic anhydride and 50 liters of triethyl orthoformate 52.94 g of ethyl 2,4-difluoro-3 -methoxy-benzylidene ethyl acetate was added. The mixture was refluxed for 2 hours and then cooled to room temperature. The excess reactant was removed by evaporation to obtain a thick oil, which disintegrated at 15G Ml of ethanol. Then add a portion of 171 grams of ring — __-_— -44, _ This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 male f)-589306 Λ 7 ～一 ________ Description of the invention (42)-propylamine, while maintaining the temperature at about 20 ° C. The desired product is separated by tritium and air-dried. Ll ^ propyl-1, ^ dihydro_7_fluoro_8 -formyl Oxy-4-amino group-side leaching · 3_carboxylic acid ethyl

II 伤30.3克3-5衣丙基胺基_2-(2,4_二氟-3-甲氧_苯甲酿基) 丙缔酸乙酯添加至230亳升無水THF。逐份加入4.1克量之6 0%氫化鈉於油，同時維持溫度低於4〇Ό。溶液於室溫攪拌2小時，然後倒入1.5升水。所需產物藉過濾分離及風乾。 hA,否基-1，4_二氫-7-氟-8-甲氣-4-氳某-喽啉-3-羧酸一份28.6克1-環丙基-L4-二氫_7_氟-8-甲氧-4-氧基-喹琳-3-羧酸乙酯及300亳升乙酸，水，硫酸（8/6/1)之混合物回流2小時。反應混合物於〇冷卻，藉過濾收集所得產物。 h環丙基-1,4二氫-7-氟-8-甲氣-4-氫基-喹啉-3-羧齡^ 氟化硼錯合物經濟部中央標準局員工消費合作社印製一份1.0克1_環丙基-1，4-二氫-7-氟-8-甲氧-4-氧基-喹琳蠢3-羧酸溶解於10毫升THF，及加入1.76毫升三氟化硼鍵酸鹽。混合物於60 °C攪拌2小時，然後冷卻至室溫。所需產物藉過濾收集及風乾。II. 30.3 grams of 3-5 islamido-2-(2,4-difluoro-3-methoxy-benzyl) propionate were added to 230 liters of anhydrous THF. Add 4.1 grams of 60% sodium hydride to the oil in portions while maintaining the temperature below 40 ° F. The solution was stirred at room temperature for 2 hours and then poured into 1.5 liters of water. The desired product is isolated by filtration and air-dried. hA, Nyl-1,4-dihydro-7-fluoro-8-methyl-4-methyl-pyridin-3-carboxylic acid 28.6 g 1-cyclopropyl-L4-dihydro_7_ A mixture of fluoro-8-methoxy-4-oxy-quinolin-3-carboxylic acid ethyl ester and 300 ml of acetic acid, water, sulfuric acid (8/6/1) was refluxed for 2 hours. The reaction mixture was cooled at 0 and the resulting product was collected by filtration. h Cyclopropyl-1,4 dihydro-7-fluoro-8-methyl-4-hydro-quinoline-3-carboxyl ^ Boron fluoride complex Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 1.0 g of 1-cyclopropyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxy-quinolinol 3-carboxylic acid was dissolved in 10 ml of THF, and 1.76 ml of trifluoride was added Boron bond salt. The mixture was stirred at 60 ° C for 2 hours and then cooled to room temperature. The desired product was collected by filtration and air-dried.

ZdX3 R) - (is -第三丁氧羰基胺基乙基）-ΐ·吡咯啶基μ 生基-8-甲氧_1,4-二氫-4-氧基-喹啉-3-羧酸一伤〇·1克1-環丙基-1，4 -二氨-7-氣-8-甲氧·4 -氧基-唆琳 -3-羧酸二氟化硼錯合物溶解於2毫升乙腈，·然後加入〇16 -45 - 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X29*7公釐） 589306 Λ7 B7 43 五、發明説明（亳升二異丙基乙基胺及0.08克3 R-(1S-第三丁氧羰基胺基乙基）被哈淀。混合物於60 °C攪拌2 4小時，然後蒸發去除溶劑。殘餘物溶解於5毫升乙醇及2毫升三乙基胺。溶液於80 °C攪拌4小時，然後蒸發至乾。所需化合物藉柱式層析分離。 [ (3 R) - (1S ·胺基乙基）-1_吡咯啶基卜1-環丙基_8_甲擎 li4 -二氫氧基淋-3-瘦酸鹽酸鹽一份54毫克7-[(3R)-(lS·第三丁氧羰基胺基乙基卜丨^比咯啶基]-1-環丙基-8 -甲氧-1，4-二氫-4-氧基-喹啉-3-羧酸溶解於2毫升乙醇及〇 · 5亳升濃鹽酸。於室溫經半小時後，混合物於冰浴冷卻過濾收集所需化合物。實例Η 製備：請先閱讀背面之注· 意事項，再填寫本頁 % 訂 ΟZdX3 R)-(is -Third-butoxycarbonylaminoethyl) -fluorene · pyrrolidinyl μ Biosin-8-methoxy_1,4-dihydro-4-oxy-quinoline-3-carboxy 0.1 mg of 1-cyclopropyl-1,4-diamino-7-gas-8-methoxy · 4-oxo-Lin-3-carboxylic acid boron difluoride complex dissolved in acid 2 ml of acetonitrile, and then add 〇16 -45-This paper size applies the Chinese National Standard (CNS) A4 specification (210X29 * 7 mm) 589306 Λ7 B7 43 V. Description of the invention (亳 liter of diisopropylethylamine and 0.08 g of 3 R- (1S-tert-butoxycarbonylaminoethyl) was deposited. The mixture was stirred at 60 ° C for 2 4 hours, and then the solvent was removed by evaporation. The residue was dissolved in 5 ml of ethanol and 2 ml of triethyl Amine. The solution was stirred at 80 ° C for 4 hours and then evaporated to dryness. The desired compound was separated by column chromatography. [(3 R)-(1S · aminoethyl) -1 -pyrrolidinyl 1-ring Propyl_8_methine li4 -dihydroxyline-3-leptoate, 54 mg 7-[(3R)-(1S · third butoxycarbonylaminoethyl) Pyridyl] -1-cyclopropyl-8-methoxy-1,4-dihydro-4-oxy-quinoline-3-carboxylic acid was dissolved in 2 ml of ethanol and 0.5 ml of concentrated hydrochloric acid. After half an hour temperature, the mixture in an ice bath to cool the preparation of the desired compound were collected by filtration instance Η:. Please first read the back of the note read CAUTIONS · item, and then fill in this page order Ο%

COOH C1H 八 Η,Ν. ά 經濟部中央標準局員工消費合作社印製 -46 - ^ _=_ I 2氟苯甲酿翥. 一份6.0克3-氣-2,4_二氟苯甲酸懸浮於2〇毫升二氣甲烷。然後加入一份2.99毫升草醯氣及2滴DMF。懸浮液於室溫卿隔夜，及蒸發去除溶劑後收騎需產物。苯甲醯基乙齡一份0.728克鎂懸浮於5毫升乙醇，及加人Q i毫升四氣化本紙張尺度適财關家標準（CNS )八4規格（2ι〇χ297公楚 Λ 7 Β7 五、發明説明（44) 碳。加入4.6毫升丙二酸二乙酯於20亳升乙醇之溶液，及反應於60 °C攪捽至鎂完全溶解。然後加入6· 1克3 _氯-2,4 -二氟苯甲醯氯，及反應攪拌隔夜。蒸發去除溶劑後，殘餘物以鹽酸處理，及有機相藉乙酸乙酯萃取。蒸發去除溶劑後’反應物懸洋於5 G毫升水，及加入iq〇毫克 PTSA。懸浮液回流4小時，然後冷卻至室溫。所需化合物以乙酸乙酯萃取，及藉蒸發去除溶劑回收。 3 -環丙基胺基-2-(2，4·二氟-3-氯·笨甲醯某）丙晞酸乙酯於7.03毫升原甲酸三乙酯及6.65亳升乙肝之混合物内加入 7 · 6克2，4 - 氣-3 -風|甲酿基乙乙g旨。溶液回流4小時，及蒸發去除過量反應劑。殘餘稠厚油溶解於1〇亳升乙醇及2毫升***之混合物，及於冰浴冷卻。然後加入環丙基胺（1.3毫升）。於室溫經30分鐘後，過濾分離所需產物。經濟部中央標準局員工消費合作社印製 1-環丙基-1，4-二氫-7-氟-8-氯-4-氧基〇奎琳_3-瘦酸乙酉§ 一份2.8克3 -環丙基胺基- 2- (2，4 -二氟_3_氣-苯甲醯基）丙晞酸乙醋溶解於25毫升THF，及逐份加入0.37克60% 氳化鈉。3 0分鐘後，蒸發去除溶劑；殘餘物再溶解於乙酸乙酯及以水洗滌。所需產物藉去除溶劑收集。 j - $衣丙基一鼠-7-鼠-8-氣-4-氧基- π奎琳-3·叛酸一份1.93克1_環丙基-1，4-二氫-7-氟-8-氯-4·氧基-喳啉_ 3-羧酸乙酯溶解於30亳升乙酸，水及硫酸（8/6/1)之混合物。混合物回流3小時，及冷卻至室溫。所需化合物藉過濾收集及風乾。 ____ -47-__ 本紙張尺度適用中國國家標準（CNS )八4規格（210X29*/公趁〉 Λ7 B7 45 五、發明説明（ ? - [ (M) - (1 s -第三丁氧羰基胺基乙基）_丨·吡咯啶基卜丨-$ 丙基甲氧-1,4-二氫-4-氧基-喹啉-3-#_ i刀〇·1克1-ί衣丙基-1，4_二氮-7·氣_8_氯-4 -氧基-峻琳_ 3 -獲故二氟化硼錯合物溶解於2毫升乙腈；然後加入〇 16 囊升二異丙基乙基胺及〇·〇8克3R-(1S -第三丁氧羰基胺基乙基）响洛啶。混合物於60 °C攪拌2 4小時，然後蒸發去除溶劑。殘餘物溶解於5毫升乙醇及2毫升三乙基胺。溶液於80 °C攪拌4小時，然後蒸發至乾。藉柱式層析分離所需化合物。 l，4-i氫-4 -氧某淋-3_瘦酸鹽酸鹽一份54耄克7-[(3R)-(lS-第三丁氧羰基胺基乙基卜^吡咯哫基]-1-環丙基_8_甲氧_1,4 -二氫-4 -氧基·喹啉-3·羧酸落解於2耄升乙醇及〇·5毫升濃鹽酸。於室溫經半小時後，混合物於冰浴冷卻，所需化合物藉過濾收集。COOH C1H Hachiman, Ν.ά Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -46-^ _ = _ I 2 Fluorobenzoic acid. One 6.0g 3-Gas-2,4_difluorobenzoic acid suspension In 20 ml of digas methane. Then add a 2.99 ml portion of grasshopper gas and 2 drops of DMF. The suspension was left overnight at room temperature, and the desired product was collected after evaporation of the solvent. A 0.728 g portion of benzamidine ethyl acetate is suspended in 5 ml of ethanol, and added with 4 ml of Q i ml. Gasification of this paper. Standards for Financial Standards (CNS) 8 4 Specification (2ιχ × 297 Gong Chu Λ 7 Β7 5 Explanation of the invention (44) carbon. Add 4.6 ml of a solution of diethyl malonate in 20 liters of ethanol, and stir at 60 ° C until the magnesium is completely dissolved. Then add 6.1 g of 3_chloro-2, 4-Difluorobenzyl chloride, and the reaction was stirred overnight. After removing the solvent by evaporation, the residue was treated with hydrochloric acid, and the organic phase was extracted with ethyl acetate. After removing the solvent by evaporation, the reaction was suspended in 5 G ml of water, and Iq. 0 mg of PTSA was added. The suspension was refluxed for 4 hours and then cooled to room temperature. The desired compound was extracted with ethyl acetate and recovered by evaporation to remove the solvent. 3-Cyclopropylamino-2- (2,4 · Di Fluoro-3-chloro · benzylformate) Ethyl propionate was added to a mixture of 7.03 ml of triethyl orthoformate and 6.65 ml of Hepatitis B. 7.6 g of 2,4 -qi-3 -feng | methyl The solution is refluxed for 4 hours, and the excess reactant is removed by evaporation. The remaining thick oil is dissolved in 10 liters of ethanol and 2 ml of ether. And cooled in an ice bath. Then cyclopropylamine (1.3 ml) was added. After 30 minutes at room temperature, the desired product was separated by filtration. Printed by the Consumers Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, 1-cyclopropyl-1 4,4-dihydro-7-fluoro-8-chloro-4-oxy〇quinine_3-Leptanoic acid § 2.8 g of 3-cyclopropylamino-2- (2,4-difluoro_ 3-Gas-benzylidene) Ethyl propionate was dissolved in 25 ml of THF, and 0.37 g of 60% sodium trioxide was added in portions. After 30 minutes, the solvent was removed by evaporation; the residue was redissolved in ethyl acetate and Washed with water. The desired product was collected by removing the solvent. J-$ Isopropyl-mouse-7-mouse-8-gas-4-oxy-π-Quulin-3 · A portion of acid 1.1.9 g Ethyl-1,4-dihydro-7-fluoro-8-chloro-4 · oxy-fluoroline-3-carboxylic acid ethyl ester dissolved in 30 liters of a mixture of acetic acid, water and sulfuric acid (8/6/1) The mixture is refluxed for 3 hours, and cooled to room temperature. The required compounds are collected by filtration and air-dried. ____ -47 -__ This paper size is applicable to China National Standard (CNS) 8 4 specifications (210X29 * / common) Λ7 B7 45 5 Description of the invention (?-[(M)-(1 s -Third butoxycarbonylaminoethyl) _ 丨 · Pyridinyl ---- propyl methoxy-1,4-dihydro-4-oxy-quinoline-3-# _ i knife 0.1 g 1-I-propyl-1,4-diazine -7 · Ga_8_chloro-4 -oxy-Junlin_ 3 -The obtained boron difluoride complex was dissolved in 2 ml of acetonitrile; then 016 capsules of diisopropylethylamine and 〇 · 〇8g of 3R- (1S-third butoxycarbonylaminoethyl) ringoline. The mixture was stirred at 60 ° C for 2 4 hours, and then the solvent was removed by evaporation. The residue was dissolved in 5 ml of ethanol and 2 ml of triethylamine. The solution was stirred at 80 ° C for 4 hours and then evaporated to dryness. The required compounds are separated by column chromatography. 1,4-ihydro-4 -oxo-3 -leptonate 1 part 54 g 7-[(3R)-(1S-third butoxycarbonylaminoethyl ethyl pyrrolidinyl] The -1-cyclopropyl_8_methoxy_1,4-dihydro-4 -oxy · quinoline-3 · carboxylic acid was decomposed in 2 ml of ethanol and 0.5 ml of concentrated hydrochloric acid. After half an hour, the mixture was cooled in an ice bath and the desired compound was collected by filtration.

實例J 製備：Example J Preparation:

COOHCOOH

CH3S〇3H 經濟部中央標隼局員工消費合作社印製 U^ R) ( 1 S -甲棊胺基乙基）-1 _ p比洛咬基卜1 _環丙某-8 _ m，4_·二氫_4·氧基〇奎啉_3·卷酩甲烷磺酸鹽一伤1.775克1-環丙基.ls4-二氣_7ϋ甲氧本氧基"奎 -48 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公楚） 589306 Λ7 B7 五、發明说明（46 ) 啉_3_羧酸二氟化硼酯溶解於12毫升二甲 τ卷甲醯胺；然後加入3.35毫升三乙基胺及1.050克3R-(iS-甲1，、"甲基胺基乙基）-1-吡咯啶。混合物於50 °C攪拌18小時，發去除溶劑。殘餘物再溶解於20毫升乙醇及7蒼弁：, 毛开—乙基胺。溶液於80 °C回流24小時’然後蒸發至乾。所需物料經由由異丙醇及甲醇再結晶分離。此物料懸浮於15薹毛开乙醇及略爲溫熱。懸浮液以〇·3毫升甲烷磺酸處理，及於室溫擺摔2 小時。混合物於冰浴冷卻，及過濾收集所需化合物。實例Κ 製備： 0CH3S〇3H Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (U ^ R) (1 S -methylaminoethyl) -1 _ p Billot bite 1 _ cyclopropyl-8 _ m, 4_ · Dihydro_4 · oxy〇quinoline_3 · coil methane sulfonate 1.775 g of 1-cyclopropyl. Ls4-digas_7ϋmethoxybenzoxy " Kui-48 This paper is applicable to China National Standard (CNS) Λ4 Specification (210X297 Gongchu) 589306 Λ7 B7 V. Description of the Invention (46) Boroline difluoride _3_ carboxylic acid difluoride is dissolved in 12 ml of dimethyl τ roll formamide; then 3.35 ml of Ethylamine and 1.050 g of 3R- (iS-methyl-1, " methylaminoethyl) -1-pyrrolidine. The mixture was stirred at 50 ° C for 18 hours, and the solvent was removed. The residue was re-dissolved in 20 ml of ethanol and 7 Zanthoxylum :, Maokai-ethylamine. The solution was refluxed at 80 ° C for 24 hours' and then evaporated to dryness. The required material was separated by recrystallization from isopropanol and methanol. This material was suspended in 15 薹 of ethanol and slightly warm. The suspension was treated with 0.3 ml of methanesulfonic acid and shaken at room temperature for 2 hours. The mixture was cooled in an ice bath, and the desired compound was collected by filtration. Example KK Preparation: 0

經濟部中央標準局員工消費合作社印製 1-芊基-4R-(1S-第三丁氣羰基胺基乙基）-2-毗i唉酮氫化鈉（60%於礦油分散液，1.06克，26.4亳莫耳）懸浮於〇]\^。4尺-(18-第三丁氧黢基胺基乙基）-2-咐哈咬酮（5.04 克，22.0毫莫耳）呈於DMF之溶液以5分鐘時間添加。任溶液攪拌1小時，隨後加入芊基溴（3.76克，22.0毫莫耳），及任溶液攪拌隔夜。於減壓下去除DMF，及剩餘固體分配於水與乙酸乙酯。移出有機層，及水層以乙酸乙酯萃取兩次。合併有機層以鹽水洗一次，以硫酸鈉脱水及蒸發獲得白色固體。 -49- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公楚） 589306 Λ 7 Β7 五、發明説明（47 ) 苄基-4R-HS-胺基乙基）-2-吡咯啶酮 1_爷基- 4R-(1S-第三丁氧窥基胺基乙基比洛淀酮 (6.57克，20·6毫莫耳）溶解於40毫升絕對乙醇，及加入 10亳升12Ν鹽酸伴以攪拌。溶液攪拌2小時，此時溶液藉加入氫氧化铵調整至大於pH 12。溶液以300毫升二氯甲垸萃取三次。有機部分以硫酸鈉脱水及蒸發獲得琥珀色油。基-4-(2’，2’，5’，5’_四甲基_2，，5’-二矽烷-1，·# 環戊基）乙基- 2-g比洛淀嗣 1-芊基- 4R-(1S -胺基乙基）-2 -峨略淀酮（2.47克，11.3毫莫耳）溶解於25亳升二氣甲烷及12毫升二異丙基乙基胺。加入武（氣二甲基碎娱:基）乙燒（4.88克，22.6毫莫耳），及反應於氬下攪拌3小時。反應藉加入飽和氣化铵淬熄，及以水洗兩次。去除二氣甲烷及殘餘物再溶解於醚，過濾去除任何固體。醚經眞空去除獲得紅色油。 1^节基_6-(2’，2’，5’，5，-四甲基_2\5，-二矽忮-1，_吖環戌某）乙基-4-叶螺|~2.4〗庚垸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) 160耄升THF及38毫升1M溴化乙基鎂於THF (38 〇毫莫耳）之混合物調整至-70 °C。快速加入異丙氧化鈦（4 85克， 17.1笔莫耳）’溶液轉成淺橙色。2分鐘後，逐滴加入1· 卞基-4_(2’，2’，5’，5’_四甲基_2’，5、二矽烷-1，_吖環戊基）乙基吡咯哫酮（3·85克，1〇·7毫莫耳）於THF。所得混合物於-70 C攪拌15分鐘，然後任其溫熱至室溫歷2小時。反應藉加入200毫升半飽和氣化銨淬熄；所得漿液經 -50- 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X297公釐） 589306 Λ 7 _________ _ Β7 五、發明説明（48 ) 過濾。濾液以150毫升醚萃取三次。合併有機層以鹽水洗條’以硫酸鈉脱水及蒸發獲得淺黃色油。Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs , 26.4 mol) suspended in 0] \ ^. A solution of 4 ft- (18-tertiary butoxyfluorenylaminoethyl) -2-halidone (5.04 g, 22.0 mmol) in DMF was added over 5 minutes. The solution was stirred for 1 hour, then fluorenyl bromide (3.76 g, 22.0 mmol) was added, and the solution was stirred overnight. DMF was removed under reduced pressure, and the remaining solids were partitioned between water and ethyl acetate. The organic layer was removed, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed once with brine, dried over sodium sulfate and evaporated to give a white solid. -49- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 Gongchu) 589306 Λ 7 B7 V. Description of the invention (47) Benzyl-4R-HS-aminoethyl) -2-pyrrolidone 1_Epiyl-4R- (1S-tertiary butoxyaminoamino ethyl bilodolide (6.57 g, 20.6 mmol) was dissolved in 40 ml of absolute ethanol, and 10 ml of 12N hydrochloric acid was added. The solution was stirred for 2 hours, at which time the solution was adjusted to a pH greater than 12 by adding ammonium hydroxide. The solution was extracted three times with 300 ml of dichloromethane. The organic portion was dehydrated with sodium sulfate and evaporated to obtain an amber oil. (2 ', 2', 5 ', 5'_tetramethyl_2,, 5'-disila-1, · # cyclopentyl) ethyl- 2-g Biloxinium 1-fluorenyl-4R -(1S -Aminoethyl) -2 -Eleudonone (2.47 g, 11.3 mmol) was dissolved in 25 liters of digas methane and 12 ml of diisopropylethylamine. Base crushing: base) Ethyl alcohol (4.88 g, 22.6 mmol), and the reaction was stirred under argon for 3 hours. The reaction was quenched by the addition of saturated ammonium gasification, and washed twice with water. The methane and the residue were removed Redissolved in ether, filtered off Remove any solids. The ether is removed by emptying to obtain a red oil. 1 ^ benzyl_6- (2 ', 2', 5 ', 5, -tetramethyl_2 \ 5, -disilazone-1, _azepine戌 a) Ethyl-4-leaf snail | ~ 2.4 〖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) 160 liters of THF and 38 ml of 1M ethyl bromide The mixture of methyl magnesium in THF (38 mM) was adjusted to -70 ° C. Titanium isopropoxide (4 85 g, 17.1 mol) was quickly added and the solution turned light orange. After 2 minutes, add dropwise 1 · Amidino-4_ (2 ', 2', 5 ', 5'_tetramethyl_2', 5, disila-1, _acylcyclopentyl) ethylpyrrolidone (3.85 g, 10.7 mmol) in THF. The resulting mixture was stirred at -70 C for 15 minutes, and then allowed to warm to room temperature for 2 hours. The reaction was quenched by the addition of 200 ml of semi-saturated ammonium vaporization; 50- This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X297 mm) 589306 Λ 7 _________ _ B7 V. Description of the invention (48) Filtration. The filtrate is extracted three times with 150 ml of ether. The combined organic layers are washed with brine. Sodium sulfate and evaporated to give a pale yellow oil.

(請先閱讀背面之注意事項再填寫本頁) 私苄基·6_(2，，2，，5,55，_四甲基-2，，5’-二矽烷_1，_吖環戊基) 乙基-4-吖螺[2·4]庚烷（0·89克，2·4毫莫耳）溶解於1〇毫升絕對乙醇及5毫升冰醋酸。攪拌1小時後，眞空去除溶劑’樣本再溶於乙醇及以二碳酸二第三丁酯（1〇5克，48 毫莫耳）及三乙基胺（〇·49克，4.8毫莫耳）處理。任混合物攪拌隔夜。蒸發去除溶劑及過量三乙基胺，殘餘物接受急速層析（3·· 2己烷/乙酸乙酯Wv)獲得所需化合物。 1 S_第三丁氳羰基胺基乙基）-5 -乙基吡咯啶 4 -苄基- 6R-(1S_第三丁氧羰基胺基乙基）-4_吖螺[2.4]庚貌（〇·31克，0.9毫莫耳）溶解於5毫升甲醇，與氫氧化鈀/ 後（〇·1〇克）及免/活性碳（0.05克）混合。混合物置於44 psi 之氩氣氛下及振搖隔夜。然後溶液過濾去除催化劑，濾液經濃縮獲得3 -第三丁氧羰基胺基乙基-5-乙基吡咯啶呈澄清油。經濟部中央標準局員工消費合作社印製 7-『（3尺）-(18_篱三丁氧羰基胺基乙基）-5-乙基-1-吡咯啶基卜1 -環丙某-1，4 二氫-8 -甲氣-4 氣基-3 -喹淋羧酸，二氣化硼酯 3R-(1S-第三丁氧羰基胺基乙基）-5-乙基吡咯啶（〇·17克， 0.7毫莫耳）溶解於DMF及於1-環丙基_7-氟-1，4·二氫-8· 甲氧-4-氧基-3·喹啉羧酸，二氟化硼酯（〇·13克，〇·4毫莫 ^紙張用中國國家標準（CNS〉A4規格（210X 297公釐) -51 _ __ 589306 Λ 7 Β7 49 五、發明說明（耳）及三乙基胺存在下於40。(：攪拌數小時至反應完成。眞空去除溶劑，及殘餘物以水研製獲得目標化合物呈固體。 __丁氧羰i胺基乙甚in爷^-a忒啶蓋J·1·環丙基=I_dL·二氫氧_啐咁盎齡 7-[(3R)-(lS_第三丁氧羰基胺基乙基）-5_乙基吡咯啶基]-1-環丙基-1，4 -二氫_8_甲氧-4-氧基-3-喹琳羧酸，二氟化硼酯（0·20克，0.4毫莫耳）於1: t乙醇/三乙基胺溶液攪拌數小時至二羥硼酸酿之去除完全。眞空蒸發去除溶劑，及殘餘物以水研製獲得所需產物。 2^1 (3R)-(1S -胺基乙基）-5 -乙基- l_g比洛唉基ι_ι_環丙基_ 氫-8-甲氧-4_氣基-3_喹啉羧酸鹽_唾 7-[(3R)-(lS-第三丁氧羰基胺基乙基）·5 -乙基-1-吡咯淀基]_1-ί哀丙基-1，4 -二氮-8-甲乳·4_氧基_3 -峻琳叛酸（〇18 克，0.4亳莫耳）於乙醇及濃鹽酸之1:1混合物攪拌至反應完成。眞空去除溶劑，及殘餘物由乙醇再結晶純化。(Please read the precautions on the back before filling this page) Private benzyl 6_ (2, 2, 2, 5, 55, _tetramethyl-2 ,, 5'-disilaline_1, _ acyclopentyl ) Ethyl-4-acrylo [2 · 4] heptane (0.89 g, 2.4 mmol) was dissolved in 10 ml of absolute ethanol and 5 ml of glacial acetic acid. After stirring for 1 hour, the solvent was removed and the sample was redissolved in ethanol and di-tert-butyl dicarbonate (105 g, 48 mmol) and triethylamine (0.49 g, 4.8 mmol). deal with. Let the mixture stir overnight. The solvent and excess triethylamine were removed by evaporation, and the residue was subjected to flash chromatography (3. 2 hexane / ethyl acetate Wv) to obtain the desired compound. 1 S_Third-butyl fluorenylcarbonylaminoethyl) -5 -ethylpyrrolidine 4-Benzyl-6R- (1S_Third-butoxycarbonylaminoethyl) -4_acridyl [2.4] heptyl (0.31 g, 0.9 mmol) was dissolved in 5 ml of methanol, and mixed with palladium hydroxide / post (0.10 g) and free / activated carbon (0.05 g). The mixture was placed under an argon atmosphere at 44 psi and shaken overnight. The solution was then filtered to remove the catalyst, and the filtrate was concentrated to obtain 3-tert-butoxycarbonylaminoethyl-5-ethylpyrrolidine as a clear oil. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China , 4 dihydro-8-methyl-4 gas-based 3-quinolinecarboxylic acid, boron ester of digas 3R- (1S-third butoxycarbonylaminoethyl) -5-ethylpyrrolidine (〇 · 17g, 0.7mmol) dissolved in DMF and 1-cyclopropyl_7-fluoro-1,4 · dihydro-8 · methoxy-4-oxy-3 · quinolinecarboxylic acid, difluoro Boronate (0.13 g, 0.4 mmol) ^ Chinese National Standard for Paper (CNS> A4 Specification (210X 297 mm) -51 _ _ 589306 Λ 7 Β7 49 49 5. Description of the Invention (Ear) and Triethyl In the presence of amines at 40. (: Stir for several hours until the reaction is complete. Remove the solvent by emptying, and the residue is triturated with water to obtain the target compound as a solid. J · 1 · Cyclopropyl = I_dL · Dihydroxide_Age age 7-[(3R)-(1S_Third butoxycarbonylaminoethyl) -5_ethylpyrrolidyl] -1- Cyclopropyl-1,4-dihydro-8-methoxy-4-oxy-3-quininecarboxylic acid, boron difluoride (0.20 g, 0.4 mmol) at 1: t ethanol / Triethylamine solution Stir for several hours until the removal of dihydroxyboronic acid is complete. The solvent is removed by evaporation and the residue is triturated with water to obtain the desired product. 2 ^ 1 (3R)-(1S-aminoethyl) -5 -ethyl-l_g Biloximyl ι_ι_cyclopropyl_ hydrogen-8-methoxy-4_airyl-3_quinolinecarboxylate_sialo 7-[(3R)-(lS-tert-butoxycarbonylaminoethyl ) · 5-Ethyl-1-pyrrolidinyl] _1-Alanyl-1,4-diazine-8-methyl milk · 4-oxy_3-Junlin acid (0,18 g, 0.4 亳) Mol) was stirred in a 1: 1 mixture of ethanol and concentrated hydrochloric acid until the reaction was completed. The solvent was removed by emptying, and the residue was purified by recrystallization from ethanol.

實例L 製備：〇Example L Preparation: 〇

C〇〇H 經濟部中央標準局員工消費合作衽印製基-4 -甲某六备毗啶 —份5.0克3-硝基-4_甲基毗啶，〇·5克氧化釕，〇.5克鍺/ 鋁氧，及0.5克氧化鉑懸浮於2〇毫升氨溶液及亳升甲 52- 本紙張尺度適用帽_標準（CNS ) Α4規格（2丨〇><州公慶 589306 Λ 7 ____Β7 五、發明説明（50 ) 醇。混合物置於高溫及高壓氫氣下。所需產物藉水液後續處理獲得。 7 - [ 3 -胺基-4 -甲基六氫吡啶基卜1 _環丙基_ i 4 -二氫_ 8 -甲氧氧基-喳啉-3-羧酸二氟化硼錯合物一份2·62克1-環丙基_1，4_二氫_7_氟-8-甲氧-4-氧基啉-3-羧酸二氟化硼錯合物及ι·38克3-胺基-4_甲基六氫峨啶溶解於48.0毫升二甲基甲醯胺及4·50毫升三乙基胺。於室溫隔夜後，溶液蒸發至乾。所需產物藉再結晶分離。 [3_胺基-4-曱基六氫？比淀基卜1-環丙基-1,4 -二氫_8·甲氧-4-氧基-4啉-3-羧酸一份0.263克7-[3-胺基_4_甲基六氫吡啶基]-1-環丙基_ 1，4_二氫-8-甲氧-4-氧基奎琳-3-叛酸二氟化硼錯合物溶解於6毫升乙醇，及加入ι·75毫升三乙基胺。溶液加熱至回流歷2小時，然後冷卻至室溫。溶液蒸發至乾，所需產物藉再結晶分離。 Z~[3 -胺基-4_甲基六氫峨淀基1-1_環丙基- ΐ，4 -二氫-8-甲里l - 4 -氧基_喹嗾_3_羧酸鹽酸鹽經濟部中央標準局員工消費合作社印11 一份0·20克7_[3-胺基-4-甲基六氫吡啶基]-1-環丙基_ 1，4-二氫-8-甲氧-4_氧基-喹啉-3-羧酸懸浮於1.0亳升乙醇。pH以氣化氫調整至2 ，而於蒸發去除溶劑後獲得所需產物。 _—_ _-53- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公趁） 589306 Λ 7 Β7 五、發明説明（51 ) HClCoHH Consumer cooperation with the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China. Imprinting base-4-a certain hexabipyridine-5.0 grams of 3-nitro-4-methylpyridine, 0.5 grams of ruthenium oxide, 〇. 5 grams of germanium / aluminum oxide, and 0.5 grams of platinum oxide suspended in 20 milliliters of ammonia solution and hydrazine A 52- This paper size applies to the cap_standard (CNS) A4 specification (2 丨〇> < State Gongqing 589306 Λ 7 ____ Β7 V. Description of the invention (50) Alcohol. The mixture is placed under high temperature and high pressure hydrogen. The desired product is obtained by subsequent treatment with water. 7-[3 -Amino-4 -methylhexahydropyridyl bu 1 _ ring Propyl_i 4 -dihydro_ 8 -methoxyoxy-pyridin-3-carboxylic acid boron difluoride complex 2.62 g 1-cyclopropyl_1,4_dihydro_7 _Fluoro-8-methoxy-4-oxoline-3-carboxylic acid boron difluoride complex and ι · 38 g of 3-amino-4-methylhexahydroeridine were dissolved in 48.0 ml of dimethyl Formamidine and 4.50 ml of triethylamine. After overnight at room temperature, the solution was evaporated to dryness. The desired product was isolated by recrystallization. [3-Amino-4-fluorenylhexahydro? -Cyclopropyl-1,4-dihydro-8 · methoxy-4-oxy-4line-3-carboxylic acid 0.263 g 7- [3-amino_4-methylhexahydropyridyl] -1 -Cyclopropyl_ 1,4_dihydro-8-methoxy-4-oxyquinine-3-metanoic acid boron difluoride complex was dissolved in 6 ml of ethanol, and ι · 75 ml of triethyl was added Amine. The solution was heated to reflux for 2 hours, and then cooled to room temperature. The solution was evaporated to dryness, and the desired product was isolated by recrystallization. Z ~ [3-Amine-4_methylhexahydroeodoyl 1-1_ Cyclopropyl-hydrazone, 4-dihydro-8-methyl-l-4-oxy-quinoline_3_carboxylic acid hydrochloride, Central Standards Bureau, Ministry of Economic Affairs, Consumer Consumption Cooperative, 11 copies, 0.20 g 7_ [ 3-Amino-4-methylhexahydropyridyl] -1-cyclopropyl-1,4-dihydro-8-methoxy-4_oxy-quinoline-3-carboxylic acid suspended in 1.0 liter Ethanol. The pH is adjusted to 2 with hydrogenated hydrogen, and the desired product is obtained after removing the solvent by evaporation. ___ _-53- This paper size applies to China National Standard (CNS) A4 (210X 297) while 589306 Λ 7 Β7 5. Description of the invention (51) HCl

COOH OMe Et 經濟部中央標準局員工消費合作社印製 K2,4·二氧苯甲酿基基胺基包遂酸乙酯於3.7毫升乙酐及4·3毫升原甲酸三乙基酯（26亳莫耳）之混合物内加入4.15克2,4_二氟-3_甲氧苯甲醯基乙酸乙酯（16 亳莫耳）。混合物回流4小時，冷卻至室溫及減壓去除過量反應劑獲得稠厚油。產物溶解於12毫升絕對乙醇，未經進一步純化即供使用。然後於〇加入一份8亳升乙基胺 (2·0Μ於THF溶液），及於室溫攪捽隔夜。所需產物藉過濾分離，及以冷乙醇洗滌。 1_-乙基-1-二氫_ 7 -氟-8 ·甲氣_ 4 -氧基-3 _喹啉#醴乙酯 2-(2,4_二氟-3-甲氧苯甲醯基）-3_乙基胺基丙晞酸乙酯 (1·75克，5·6毫莫耳）於氮氣氛下加至無水THF。混合物於冰浴冷卻至〇 °C。以2分鐘時間逐份加入氫化鈉（335毫克，8.3毫莫耳）同時維持反應溫度低於1〇 °C。反應溫熱至室溫’及又揽摔5 0分鐘及冷卻至〇 t。小心加入水泮媳反應，反應以二氣甲烷萃取。有機層以鹽水洗滌，以硫酸鎂脱水，及減壓濃縮獲得所需化合物呈固體。 1-乙基-1，4-二氫-7-氟-8_甲1-4-氫基_3_喹啉羧酸 1-乙基-1，4_二氫·7_氟-8 -甲氧-4 -氧基-3-喹啉羧酸乙酯 (1.37克，4.7毫莫耳）懸浮於乙酸：水：硫酸（8:6: 1)之混合物。混合物回流3小時，然後冷卻至室溫。晶體經過濾本纸張尺度適用中國國家標準（CNS ) Α4規格（2丨0 X 297公t ) (請先閱讀背面之注意事項再填寫本頁)COOH OMe Et Printed K2,4 · dioxobenzoylamino-coated ethanoic acid ethyl ester in 3.7 ml of acetic anhydride and 4.3 ml of triethyl orthoformate (26 亳4.15 g of ethyl 2,4_difluoro-3_methoxybenzylacetate (16 mol) was added to the mixture. The mixture was refluxed for 4 hours, cooled to room temperature and the excess reagent was removed under reduced pressure to obtain a thick oil. The product was dissolved in 12 ml of absolute ethanol and used without further purification. Then add 8 liters of ethylamine (2.0 M in THF solution) at 0 and stir overnight at room temperature. The desired product was isolated by filtration and washed with cold ethanol. 1_-Ethyl-1-dihydro-7-fluoro-8-methyl- 4-oxy-3_quinoline # fluorenylethyl 2- (2,4-difluoro-3-methoxybenzyl) ) Ethyl 3-ethylaminopropionate (1.75 g, 5.6 mmol) was added to anhydrous THF under a nitrogen atmosphere. The mixture was cooled to 0 ° C in an ice bath. Sodium hydride (335 mg, 8.3 mmol) was added in portions over 2 minutes while maintaining the reaction temperature below 10 ° C. The reaction was warmed to room temperature 'and allowed to fall for another 50 minutes and cooled to 0 t. Carefully add the leech reaction, and the reaction is extracted with methane. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain the desired compound as a solid. 1-ethyl-1,4-dihydro-7-fluoro-8-methyl1-4-hydroyl_3-quinolinecarboxylic acid 1-ethyl-1,4_dihydro · 7_fluoro-8- Methoxy-4-oxy-3-quinolinecarboxylic acid ethyl ester (1.37 g, 4.7 mmol) was suspended in a mixture of acetic acid: water: sulfuric acid (8: 6: 1). The mixture was refluxed for 3 hours and then cooled to room temperature. Crystals are filtered This paper size is in accordance with Chinese National Standard (CNS) Α4 size (2 丨 0 X 297g t) (Please read the precautions on the back before filling this page)

、1T 589306 Λ 7 B? 經濟部中央標準局員工消費合作社印製五、發明説明（52 出及以冷水清洗。酸，二氣化硼酯 -- ，匕乙基十4:二氫_7_氟.8_甲氧氧基奎琳幾酸 (985 ¾克’ 3·7爱莫耳）容解於無水THF〇〇毫升）加入三化硼醚酸鹽（940毫升，7·4毫莫耳）。混合物加熱至65ς歷 4小時，及任其冷卻至室溫隔夜。過遽出之晶體以己^ 洗滌獲得所需產物。 ~^~~ 一丁氧窥基胺基乙基）-1 -峨吃唉基匕 i - 8 -甲氧· 1，4 -二氫-4 _氣某-喹啉_ 3 -卷_ 1-乙基-1，4-二氫-7·氟-8·甲氧_4•氧基_3_喹啉羧酸，二氟化硼酯（0.17克，〇·5毫莫耳），3R-(1S_第三丁氧羰基胺基乙基）_吡咯啶（0.11克，〇·5毫莫耳）及三乙基胺（〇 3毫升，2.0¾莫耳）溶解於5毫升DMF。混合物於60 °C攪拌 24小時，於減壓下去除溶劑。過濾所得固體以小量水洗，及以1毫升三乙基胺再溶解於5毫升甲醇。溶液於70 °C加熱6小時，然後蒸發至乾獲得所需產物。 7-[3?1-(18-胺基乙基）-1_毗咯啶某1_1-乙基-8 -甲氧-1，4· 二氫-4-氧基-3-喹啉羧酸鹽酸鹽一份110毫克7-[(3R)-(lS-第三丁氧羰基胺基乙基）-1-口比嘻淀基]-1 -乙基-8-甲氧-1，4 -二氯-4-氧基-p奎琳-3 -竣溶解於2毫升乙醇及2亳升濃鹽酸。於室溫經2小時後，於蒸發去除溶劑及於乙醇再結晶後獲得固體。1T 589306 Λ 7 B? Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (52 out and washed with cold water. Acid, boron dicarbonate-, ethyl 4: dihydro_7_ Fluoride. 8-methoxyquinolinic acid (985 ¾ g '3.7 Emole) was dissolved in anhydrous THF (00 ml) and boron trioxide (940 ml, 7.4 mmol) was added. ). The mixture was heated to 65 ° C for 4 hours, and allowed to cool to room temperature overnight. The decanted crystals were washed with hexane to obtain the desired product. ~ ^ ~~ 1-Butoxyaminoaminoethyl) -1 -Ethenyl dagger i-8 -methoxy · 1,4-dihydro-4 _ 气某 -quinoline_ 3 -Volume_ 1- Ethyl-1,4-dihydro-7 · fluoro-8 · methoxy_4 · oxy_3_quinolinecarboxylic acid, boron difluoride ester (0.17 g, 0.5 mmol), 3R- (1S-third butoxycarbonylaminoethyl) -pyrrolidine (0.11 g, 0.5 mmol) and triethylamine (0.3 ml, 2.0¾ Mol) were dissolved in 5 ml of DMF. The mixture was stirred at 60 ° C for 24 hours, and the solvent was removed under reduced pressure. The solid obtained by filtration was washed with a small amount of water, and redissolved in 1 ml of triethylamine in 5 ml of methanol. The solution was heated at 70 ° C for 6 hours and then evaporated to dryness to obtain the desired product. 7- [3? 1- (18-aminoethyl) -1_pyrrolidine 1_1-ethyl-8-methoxy-1,4 · dihydro-4-oxy-3-quinolinecarboxylic acid 110 mg portion of hydrochloride 7-[(3R)-(lS-Third-butoxycarbonylaminoethyl) -1-oxopyridyl] -1 -ethyl-8-methoxy-1,4 -Dichloro-4-oxy-p-quelin-3-was dissolved in 2 ml of ethanol and 2 ml of concentrated hydrochloric acid. After 2 hours at room temperature, the solvent was removed by evaporation and a solid was obtained after recrystallization from ethanol.

實例N _ _-55-_______ 本紙張尺度適用中國國家標準(CNS ) A4規格（21〇Χ297公t ) (請先閱讀背面之注意事項再填寫本頁) 訂 589306 Λ7 B7 五、發明説明（53 ) 製備：Example N _ _-55 -_______ This paper size applies the Chinese National Standard (CNS) A4 specification (21〇 × 297 metric t) (Please read the notes on the back before filling this page) Order 589306 Λ7 B7 V. Description of the invention (53 ) Preparation:

nh2 7_『3-賒基六氤毗啶基卜1-環丙基二氫-8·甲氣-4-氲基嗾-3-羧酸二氟化硼錯合物_ 一份2.62克1-環丙基-1，4 -二氮氟-8-甲氧-4-氧基-峻啉_3-羧酸二氟化硼錯合物及2.08克3-胺基六氫吡啶二鹽酸鹽混合於48.0毫升二甲基甲醯胺及4.50毫升三乙基胺。於室溫攪拌隔夜後，溶液經冷卻及過濾獲得所需產物。 ?_『3 -胺某六氫吡啶基卜1 ·環丙基-L4_二氫-8 -甲氣-4- g 基-g奎淋·3·叛酸一份0.253克7-[3_胺基六氫吡啶基]-1-環丙基-ΐ，4-二氫_ 8 -甲氧_4_氧基-4,林-3-幾酸二氟化硼錯合物溶解於6毫升乙醇，及加入1.75亳升三乙基胺。溶液加熱至回流歷2小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) 時，及混合物於減壓下蒸發至乾。所需產物藉再結晶分離。 Ζ__[ 3 -胺基六氫吡啶基1 -1 -環丙基-1,4 -二氤-8 -甲氣-4 _ i 基奎淋-3-痠酸二鹽酸鹽一份o.l9克7_[3_胺基六氫吡啶基卜b環丙基-14-二氫_ 8-甲氧-4-氧基-喹啉-3_羧酸懸浮於1〇毫升乙醇。溶液 pH藉加入氣化氫調整至2。蒸發去除溶劑獲得所需產物。 ___-56- 本紙張尺度通用中國國家標準（CNS ) Λ4規格（210X 297公釐） 589306 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（54 ) 主發明组本發明組合物包含： (a)安全且有效量之本發明化合物㈨醫藥可接受性賦形劑。也選擇性包含其它抗微生物劑或其它活性物質，其可或可未與本發明化合物發揮協同效果。 ”安全有效量”之邊諾蜗爲可有效抑制寄主待治療感染邵位之微生物生長之量，不會造成不當之不良副作用（例如毒性，刺激性或過敏反應）當以本發明之方式使用時可補償合理效益/風險比。特定”安全有效量，，將隨多種因素而異例如接受治療之特定病情，病人健康狀況，治療持續時間，合併治療性質（若有），使用之特定劑型，使用之賦形劑，喹諾酮溶解度，及組合物所需用法用量。本發明組合物較佳呈單位劑型提供。如此處使用一”單位劑型”冑本發明組合物含有定量4諾酮，其適合根據優良製藥規範以單一劑量投予人體或低等動物體。此等組合物較佳含有約3 0耄克，更佳約5 〇毫克，又更佳約ι〇〇亳克，較佳至約20,000亳克，更佳至約7〇〇〇毫克又更佳至約1，000毫克，最佳至約5〇〇毫克喹諾酮。本發明組合物可呈適合（例如）經口、經直腸、局部或腸外投藥之多種劑型之任一種。依據所需特定投藥途徑而定，可使用業界眾所周知之多種醫藥可接受性賦形劑。包括固體或液體填充劑，稀釋劑，親水劑，界面活性劑及包膠物質。可包括選擇性醫藥活性物質，其大致不會干擾喹 - ------------------------ Of · 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公楚） (請先閱讀背面之注意事項再填寫本頁) 訂 589306 經濟部中央標隼局員工消费合作社印製 A 7 B7 五、發明説明（55 ) 諾酮之抗微生物活性。合併喹諾酮使用之賦形劑用量係足夠提供每單位劑量喹諾酮之物質實際投藥量。製造本發明有用之劑型之技術及組合物述於下列參考文獻，全部併述於此以供參考··近傲藥物，第7卷，第9及1〇章（Banker 及Rhodes編輯，1979年）；Lieberman等醫藥劑型：4全;^丨 (1981年）；及Ansel查藥劑型導論篇2版（1 976年）〇特別系統性投藥用之醫藥可接受性賦形劑包括糖類，殿粉，纖維素及其衍生物，麥芽糖，明膠，滑石，硫酸舞，植物油，合成油，多元醇，褐藻酸，磷酸緩衝液，乳化劑，等張鹽水及無熱原水。較佳腸外投藥賦形劑包括丙二醇，油酸乙酯，吡咯啶酮，乙醇及芝麻油。較佳醫藥可接受性賦形劑於腸外投藥組合物係占總組合物至少約90%重量比。此外，注射劑型可以乾燥或凍乾形式製備。此等劑型可以水或鹽水重新調製，依據劑型之製備而定。此等劑型可包裝爲個別劑量或多劑量供方便處理。若使用凍乾或乾燥劑型，則重新調製劑型較佳爲等張及生理相容性pH。可使用多種口服劑型包括固體劑型如錠劑，膠囊劑，粒劑及散裝粉劑。口服劑型包括安全有效量，通常至少約 5 /ί) ’及較佳約2 5 %至約5 0 %峻語酮。鍵劑可經塵縮，研製錠，包腸衣，包糖衣，包膜衣，或多重壓縮，含有適當黏結劑，潤滑劑，稀釋劑，崩散劑，著色劑，矯味劑，流動劑，及熔化劑。液體口服劑型包括水溶液劑，乳液劑，懸浮液劑’由非發泡粒劑重新調製之溶液及/或懸浮液，及 -58- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X 297公釐） (請先閱讀背面之注意事項再填寫本頁) -θ 589306 經濟部中央榡準局員工消費合作社印製 Λ 7 ______Β7__________ 五、發明説明（56 ) 由發泡粒劑重新調製之發泡製劑，含有適當溶劑，保藏劑’乳化劑，懸浮液劑，稀釋劑，甜味劑，熔化劑，著色劑及矯味劑如業界人士眾所周知。較佳口服投藥賦形劑包括明膠，丙二醇，棉籽油及芝麻油。本發明組合物也可局部投予個體，亦即直接舖層或展開組合物於病人上皮或表皮组織。此種組合物包括例如洗劑’乳膏劑，溶液劑，膠漿劑及固體劑型。局部用組合物較佳包含安全有效量通常至少约0.iy◎，及較佳約1%至約 5%喹諾酮。適當局部投藥用賦形劑較佳於皮膚維持呈連續膜，可對抗被汗水或浸泡於水中去除。通常賦形劑屬於有機性質，及可分散或溶解喹諾酮。賦形劑包括醫藥可接受性款化劑，乳化劑，增稠劑及溶劑等；此等爲業界人士眾所周知。化合物用法本發明也提供經由投予安全有效量喹諾酮至人體或其它動物體治療或預防傳染病症之方法。此處使用”傳染病症”爲任一種以微生物感染存在爲特徵的病症。較佳本發明方法係用於治療細菌性感染。此等傳染病症包括（例如）中樞神經系統感染，外耳感染，中耳感染（如急性中耳炎），顱竇感染，眼感染，口腔感染（如牙齒、牙齦及黏膜感染），上呼吸道感染，下呼謂㈣，包㈣炎，生殖泌尿道感染，胃腸道感染，婦科感染，敗血病壞死，腹膜炎，骨與關節感染，皮膚與皮膚結構感染，細菌性心内膜炎’燒傷’手術之抗菌預防，及手術後病人或免疫受抑制 ___ - 59 - 本紙張尺度適用中國國家標準（CNS)A4規格（210x 297公t) (請先閲讀背面之注意事項再填寫本頁} 衣. 、11 589306 Λ7 _____ B7 _____ 五、發明説明（57 ) 病人（例如接受癌症化學治療或器官移植病人）之抗菌預防。本發明之喹諾酮衍生物及組合物可局部或系統性投藥。系統性施用包括任一種將喹諾酮引進身體組織之方法例如鞘内’硬膜外，肌肉，經皮，靜脈，腹内，皮下，舌下’直腸及經口投藥。待投藥之抗微生物劑之特定劑量與治療持續時間有交互關係。劑量及治療計畫也依據下列因素而定例如使用之特定喹諾酮，感染有機體對使用之喹諾晒足抗藥性類型，喹諾酮於感染部位達到最低抑制濃度之能力’其它感染（若有）之性質及程度，病人個人之屬性（如體重），對治療計畫之順從性，病人年齡及健康狀況，及是否存在有治療副作用及嚴重程度。典型用於成人（體重約70千克）每日投予約75毫克，更佳約200毫克，最佳約500亳克至約30 00〇毫克，更佳至約10,000毫克，最佳至約3,500毫克喹諾酮。典型用法用量較佳時間持續約1 ’較佳約3至約5 6日，較佳至約2 0 日。預防用法用量（例如避免免疫受損病人出現伺機性感染）則依據醫療實務而定可長達6個月或更久。經濟部中央標準局員工消費合作社印裂更佳腸外投藥方法係透過靜脈注射。如業界已知及實務，全部腸外投藥配方須爲無菌。用於哺乳類特別人類（假定體重約70千克），可接受個別劑量約1〇〇毫克，較佳約 500毫克至約7,000毫克，更佳至約3 5〇〇毫克。某些病例例如全面性系統性感染或免疫受損病人，本發明可採靜脈投藥。.劑型通常爲等張性及於生理pH。劑量 ___ ___-60- _ 本紙張尺度適用中國國家標隼（CNS ) A4規格（21〇x 297公t ) 589306 Λ7 Β7 五、發明説明（58) 將隨病人及病情嚴重程度，以及其它常見考慮參數而定。劑量之決定屬於執業醫師使用本説明書給予指導之實務範圍内。、較佳系統性投藥方法爲經口投藥。個別劑量爲約20毫克，更佳約100亳克至約2 500亳克，更佳至約500毫克。局部投藥可用於系統性輸送喹諾酮或治療局部感染。局部投藥喹諾酮量依據下列因素而定例如皮膚敏感程度，待治療之組織類別及所在部位，投藥組合物及賦形劑（若有），待投藥之特定喹諾酮，及待治療之特定病症，及所需系統性（與局部區別）效果程度。下列非限制性實例示例説明本發明化合物、組合物、方法及用法。組合物實例P 根據本發明之口服投藥用錠劑組合物製備成包含·_ 經濟部中央標準局員工消費合作社印製成分數量實例15化合物 150毫克乳糖 120毫克玉米澱粉 70毫克滑石 4毫克硬脂酸鎂 1毫克其i具有根據式i結構式之化合物可使用而獲得大致類似效果。組合物實例〇 __—_-61 -_ 本紙張尺度適财關( CNS ) ( 21〇χ 29) 589306 Λ 7 Β7 五、發明説明（ 59 根據本發明之口服投藥用之含200毫克活性成分之膠囊劑製備成包含·· 成分數量(％ w/w) 實例18化合物 10% 含水乳糖 43% 微晶纖維素 33% 克羅斯普維隆(Crosspovidone) 3.3% 硬脂酸鎂 5.7% 果果 (請先閱讀背面之注意事項再填寫本頁) 衣· 經濟部中央標準局員工消費合作社印製其它具有式1結構式之化合物可使用而獲得大致類似結組合物實例R 根據本發明供眼用之基於鹽水之組合物製備成包含：成分數量（％ w/w) 實例6 3化合物 1 〇 0/。鹽水 · 9 0% 其它具有式1結構式之化合物可使用而獲得大致類似結组合物實例S 根據本發明之局部投藥用鼻内組合物製備成包含：成分實例24化合物氣化苄烷鑌組成(％ w/w) 0.20 0.02 -62- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公t ) 589306 Λ7 B7 五、發明説明（60 經濟部中央標準局員工消費合作社印製 EDTA 0.05 甘油 2.0 PEG 1450 2.0 芳族化合物 0.075 純水適量其它具有式1結構式之化合物可使用而獲得大致組合物實例T 根據本發明之吸入氣霧劑組合物製備成包含：成分組成(％ w/w) 實例84化合物 5.0 抗壞血酸 0.1 薄荷醇 0.1 沙卡林鈉 0.2 推進劑(F12，F114) 適量其它具有式1結構式之化合物可使用而獲得大致组合物實例U 根據本發明之局部眼用組合物製備成包含：成分組成(％ w/w) 實例47化合物 0.10 氯化苄烷鑌 0.01 EDTA 0.05 羥乙基纖維素 0.5 -63 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210X 297公釐） ._ 裝訂 (請先閱讀背面之注意事項再填寫本頁) 589306 經濟部中央標準局員工消費合作社印製 B7 五、發明説明（61 ) 乙酸 0.20 偏亞硫鼠鋼 0.10 氯化鈉(0.9%) 適量其它具有式1結構式之化合物可使用而獲得大致類似結組合物實例V 根據本發明之腸外投藥用抗微生物組合物製備成包含：成分數量實例9 3化合物 30毫克/毫升賦形劑賦形劑： 50 mM磷酸鹽緩衝液以即磷脂緩衝pH 5 0.48% 羧甲基纖維素 0.53 普維隆 0.50 對羥苯甲酸甲酯 0.11 對羥苯甲酸丙酯 0.011 前述成分經混合，形成懸浮液。於2.0毫升懸浮液經肌肉注射系統性投予患有下呼吸道感染存在有肺炎鏈球菌病人。劑量每日重複投藥2次約經 14日。4日後，疾病症狀消失，表示病原菌大體被清除。其它具有式1結構式之化合物也可使用而獲得大致類似結果。組合物實例W 根據本發明之腸衣抗微生物組合物製備成包含下列芯鍵： -64- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 589306 Λ7 B7 五、發明説明（62 ) 數量(毫克) 實例17化合物 350.0 麥芽糖糊精 30.0 硬脂酸鎂 5.0 微晶纖維素 100.0 膠體二氧化碎 2.5 普維隆 12.5 各成分混合成爲散裝混合物。使用業界已知打鍵方法形成壓製錠。然後錠劑包衣甲基丙晞酸/甲基丙晞酸酯聚合物於異丙醇/丙酮之懸浮液。患有泌尿道感染存在有大腸桿菌之病人每8小時投予2錠，延續4日。隨後疾病症狀消失，指示病原菌大致清除。其它具有式i結構式之化合物也可使用而有大致類似結果。此處所述全部參考文獻皆併述於此以供參考。經濟部中央標準局員工消費合作社印製雖然已經描述本發明之特定具體例，但業界人士顯然易知可對本發明作出多種變化及修改而未悖離本發明之精髓及範圍。隨附之申請專利範圍意圖涵蓋全部落入本發明範圍内之修改。 -65- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 9a 3.30nh2 7_ "3-Crylhexamidinepyrimidinyl 1-cyclopropyldihydro-8 · methyl-4-methylfluorenyl-3-carboxylic acid boron difluoride complex_ One serving 2.62 g 1- Cyclopropyl-1,4-diazafluoro-8-methoxy-4-oxy-junline_3-carboxylic acid boron difluoride complex and 2.08 g of 3-aminohexahydropyridine dihydrochloride Mix in 48.0 ml of dimethylformamide and 4.50 ml of triethylamine. After stirring at room temperature overnight, the solution was cooled and filtered to obtain the desired product. ? _ "3-Amine hexahydropyridyl bu 1 · cyclopropyl-L4_dihydro-8 -methyl-4-g-yl-g querin · 3 · refusible acid 0.253 g 7- [3_ Amine hexahydropyridyl] -1-cyclopropyl-fluorene, 4-dihydro-8-methoxy-4_oxy-4, lin-3-chinic acid boron difluoride complex dissolved in 6 ml Ethanol, and 1.75 milliliters of triethylamine were added. The solution is heated to reflux for 2 hours. When 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), and the mixture is evaporated to dryness under reduced pressure. The desired product is isolated by recrystallization. Z __ [3-aminohexahydropyridyl 1 -1 -cyclopropyl-1,4-difluorene-8 -methyl gas-4 _ i quiquine-3-acid dihydrochloride 1 part o.l9 G of 7- [3-Aminohexahydropyridylb b cyclopropyl-14-dihydro-8-methoxy-4-oxy-quinoline-3_carboxylic acid was suspended in 10 ml of ethanol. The pH of the solution was adjusted to 2 by adding hydrogenated hydrogen. The solvent was removed by evaporation to obtain the desired product. ___- 56- The paper size is in accordance with the Chinese National Standard (CNS) Λ4 specification (210X 297 mm) 589306 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A 7 ~ ....... ._ B7 V. Description of the invention (54) The main invention group The composition of the present invention comprises: (a) a safe and effective amount of the compound of the present invention, a pharmaceutically acceptable excipient. Other antimicrobial agents or other active substances are also optionally included, which may or may not work synergistically with the compounds of the invention. A "safe and effective amount" of Ponorella is an amount that can effectively inhibit the growth of microorganisms in the host to be treated for infection, without causing undesired adverse side effects (such as toxicity, irritation or allergic reactions). When used in the manner of the present invention Can compensate for reasonable benefit / risk ratio. The "specific" safe and effective amount will vary depending on a variety of factors such as the particular condition being treated, the patient's health, the duration of the treatment, the nature of the combined treatment (if any), the particular dosage form used, the excipient used, the solubility of the quinolone, And the required dosage of the composition. The composition of the present invention is preferably provided in a unit dosage form. For example, a "unit dosage form" is used herein. The composition of the present invention contains a quantitative amount of 4 nordone, which is suitable for being administered to the human body in a single dose in accordance with good pharmaceutical practice. Or lower animal body. These compositions preferably contain about 30 g, more preferably about 50 mg, and still more preferably about 500,000 g, more preferably about 20,000 g, more preferably about 70. 0.00mg and more preferably about 1,000 mg, most preferably about 500 mg of quinolone. The composition of the present invention may be in any of a variety of dosage forms suitable for, for example, oral, rectal, topical, or parenteral administration. Depending on the particular route of administration required, a variety of pharmaceutically acceptable excipients well known in the industry can be used, including solid or liquid fillers, diluents, hydrophilic agents, surfactants and packages Gum material. It can include selective medicinal active substance, which will not interfere with quine.------------------------- Of Standard (CNS) A4 specification (210X297). (Please read the notes on the back before filling out this page.) Order 589306 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A 7 B7 5. Description of the invention (55) Antimicrobial activity. The amount of excipients used in combination with quinolone is sufficient to provide the actual dosage of the substance per unit dose of quinolone. Techniques and compositions for making useful dosage forms of the present invention are described in the following references, all of which are hereby incorporated by reference · Jinao Medicine, Volume 7, Chapters 9 and 10 (Edited by Banker and Rhodes, 1979); Lieberman et al. Pharmaceutical Formulations: 4 Quan; ^ 丨 (1981); and Ansel's Introduction to Pharmaceutical Formulations, 2nd Edition (1976). Specially acceptable pharmaceutical acceptable excipients for systemic administration include sugars, powder, cellulose and its derivatives, maltose, gelatin, talc, sulphuric acid dance, vegetable oils, synthetic oils, polyols, brown algae Acid, phosphate buffer, emulsifier, isotonic Water and pyrogen-free water. Preferred parenteral excipients include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferred pharmaceutical acceptable excipients account for the total composition in parenteral administration At least about 90% by weight. In addition, injection dosage forms can be prepared in a dry or lyophilized form. These dosage forms can be reconstituted in water or saline, depending on the preparation of the dosage form. These dosage forms can be packaged as individual doses or multiple doses for convenient handling If lyophilized or dried dosage forms are used, the reconstituted dosage form is preferably isotonic and physiologically compatible pH. A variety of oral dosage forms can be used including solid dosage forms such as lozenges, capsules, granules, and bulk powders. Oral dosage forms include safety An effective amount is usually at least about 5 / L) 'and preferably about 25% to about 50%. Bonding agents can be dust-contracted, developed tablets, casings, sugar-coated, film-coated, or multiple compression, containing appropriate binders, lubricants, diluents, disintegrating agents, colorants, flavoring agents, flow agents, and melting agents . Liquid oral dosage forms include aqueous solutions, emulsions, suspensions' solutions and / or suspensions reconstituted from non-foaming granules, and -58- This paper size applies to China National Standard (CNS) A4 specifications (210X 297 public (%) (Please read the precautions on the back before filling this page)-θ 589306 Printed by the Central Consumers Association of the Ministry of Economic Affairs, Consumer Cooperative Λ 7 ______ Β7 __________ 5. Description of the invention (56) Foaming preparation reconstituted by foaming granules Contains appropriate solvents, preservatives, emulsifiers, suspensions, diluents, sweeteners, melting agents, colorants and flavoring agents as well known in the industry. Preferred oral administration excipients include gelatin, propylene glycol, cottonseed oil and sesame oil. The composition of the present invention can also be administered topically to an individual, that is, the composition is directly laminated or spread on the patient's epithelium or epidermal tissue. Such compositions include, for example, lotions ' creams, solutions, pastes, and solid dosage forms. The topical composition preferably comprises a safe and effective amount, usually at least about 0.1%, and preferably about 1% to about 5% quinolone. Appropriate topical excipients are preferred to maintain a continuous film on the skin, which can resist removal by sweat or immersion in water. Excipients are usually organic in nature and disperse or dissolve quinolone. Excipients include pharmaceutically acceptable formulation agents, emulsifiers, thickeners, and solvents; these are well known to those in the industry. Use of Compounds The present invention also provides methods for treating or preventing infectious conditions by administering a safe and effective amount of quinolone to the human or other animal body. As used herein, "infectious disease" is any condition characterized by the presence of a microbial infection. Preferably, the method of the invention is used to treat a bacterial infection. These infectious conditions include, for example, central nervous system infections, external ear infections, middle ear infections (such as acute otitis media), cranial sinus infections, eye infections, oral infections (such as teeth, gums, and mucosal infections), upper respiratory tract infections, lower exhalations Antibiotics, bursitis, genitourinary tract infections, gastrointestinal infections, gynecological infections, septicaemia and necrosis, peritonitis, bone and joint infections, skin and skin structure infections, antibacterial prevention of bacterial endocarditis 'burn' surgery , And patients or immune suppression after surgery ___-59-This paper size applies the Chinese National Standard (CNS) A4 size (210x 297 g t) (Please read the precautions on the back before filling in this page} Clothing, 11 589306 Λ7 _____ B7 _____ V. Description of the invention (57) Antibacterial prevention of patients (such as patients receiving cancer chemotherapy or organ transplantation). The quinolone derivatives and compositions of the present invention can be administered topically or systemically. Systemic administration includes either Methods for the introduction of quinolone into body tissues such as intrathecal 'epidural, intramuscular, transdermal, intravenous, intraabdominal, subcutaneous, sublingual' rectal and Oral administration. The specific dose of antimicrobial agent to be administered has an interactive relationship with the duration of treatment. The dose and treatment plan also depend on the following factors, such as the specific quinolone used, the type of quinoline resistance used by the infected organism, Ability of quinolone to reach the minimum inhibitory concentration at the site of infection 'The nature and extent of other infections (if any), the patient's personal attributes (such as weight), compliance with the treatment plan, the patient's age and health status, and the presence of treatment Side effects and severity. Typical for adults (approximately 70 kg), about 75 mg per day, more preferably about 200 mg, most preferably about 500 g to about 30,000 mg, more preferably to about 10,000 mg, best To about 3,500 mg of quinolone. Typical usage and dosage is preferably for about 1 ', preferably from about 3 to about 5 to 6 days, and preferably to about 20 days. Preventive dosage (for example, to prevent opportunistic infections in immunocompromised patients) It can be as long as 6 months or more depending on medical practice. The Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs have better printed parenteral administration methods through static Injection. If known and practiced in the industry, all parenteral formulations must be sterile. For mammals, particularly humans (assuming body weight of about 70 kg), individual doses of about 100 mg, preferably about 500 mg to about 7,000 mg , More preferably to about 3500 mg. In some cases such as generalized systemic infections or immunocompromised patients, the present invention can be administered intravenously .. The dosage form is usually isotonic and at physiological pH. Dose ___ ___- 60- _ This paper size is in accordance with Chinese National Standard (CNS) A4 specification (21 × 297 mm) 589306 Λ7 Β7 V. Description of the invention (58) It will depend on the severity of the patient and the disease, and other common considerations. The decision on the dosage is within the scope of the practice given by the practitioner using the instructions. The preferred method of systemic administration is oral administration. Individual doses are about 20 mg, more preferably about 100 mg to about 2 500 mg, and even more preferably about 500 mg. Topical administration can be used to systemically deliver quinolone or to treat local infections. The amount of quinolone to be administered topically depends on factors such as the degree of skin sensitivity, the type and location of the tissue to be treated, the composition and excipients (if any), the specific quinolone to be administered, and the specific condition to be treated, and the Systematic (different from local) effects are required. The following non-limiting examples illustrate the compounds, compositions, methods, and uses of the invention. Composition Example P The orally administered lozenge composition according to the present invention is prepared to contain the amount printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Example 15 Compound 150 mg lactose 120 mg corn starch 70 mg talc 4 mg stearic acid 1 mg of magnesium whose compound i has a structural formula according to formula i can be used to obtain approximately similar effects. Composition Example 〇 __—_- 61 -_ This paper size is suitable for financial affairs (CNS) (21〇χ 29) 589306 Λ 7 Β7 V. Description of the invention (59 Oral administration according to the present invention containing 200 mg of active ingredient The capsules were prepared to contain the number of ingredients (% w / w). Example 18 Compound 10% Aqueous lactose 43% Microcrystalline cellulose 33% Crosspovidone 3.3% Magnesium Stearate 5.7% Fruit ( Please read the notes on the back before filling this page.) Other compounds with the structural formula 1 printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs and Clothing can be used to obtain a roughly similar composition. Example R According to the present invention for ophthalmic use A salt water-based composition was prepared to include: Number of ingredients (% w / w) Example 6 3 Compound 100 /. Brine · 90% Other compounds having the structural formula 1 can be used to obtain a composition similar to Example S The intranasal composition for topical administration according to the present invention is prepared to include: Ingredient Example 24 Compound vaporized benzane hydrazone composition (% w / w) 0.20 0.02 -62- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 public t) 589306 Λ7 B7 V. Description of the invention (60 Printed by EDTA, Consumer Cooperative of Central Standard Bureau of the Ministry of Economic Affairs, 0.05 EDTA, glycerol 2.0, PEG 1450 2.0, aromatic compound 0.075 pure water, suitable amount of other compounds having the formula 1 can be used to obtain the approximate composition Example T An inhalation aerosol composition according to the present invention is prepared to include: Composition of ingredients (% w / w) Example 84 Compound 5.0 Ascorbic acid 0.1 Menthol 0.1 Sacarbin sodium 0.2 Propellant (F12, F114) An appropriate amount of others having formula 1 Compounds of structural formula can be used to obtain approximate compositions. Example U A topical ophthalmic composition according to the invention is prepared to include: Composition (% w / w) Example 47 Compound 0.10 Benzyl chloride 镔 0.01 EDTA 0.05 Hydroxyethyl fiber Prime 0.5 -63 This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X 297 mm). _ Binding (Please read the precautions on the back before filling this page) 589306 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the invention (61) Acetic acid 0.20 Metathionite steel 0.10 Sodium chloride (0.9%) Appropriate amount 1 A compound of the formula can be used to obtain a composition similar to that of Example V. A parenteral pharmaceutical antimicrobial composition according to the present invention is prepared to contain: Number of ingredients Example 9 3 Compound 30 mg / ml Excipient Excipient: 50 mM phosphate buffer solution is phospholipid buffered pH 5 0.48% carboxymethyl cellulose 0.53 proviron 0.50 methyl paraben 0.11 propyl paraben 0.011 The above ingredients are mixed to form a suspension. Systemic administration of 2.0 ml of suspension to a patient with lower respiratory tract infection and strep pneumoniae by intramuscular injection. The dose was repeated twice daily for about 14 days. After 4 days, the symptoms of the disease disappeared, indicating that the pathogenic bacteria were largely eliminated. Other compounds having the structural formula 1 can also be used to obtain approximately similar results. Composition example W The casing antimicrobial composition according to the present invention is prepared to include the following core keys: -64- This paper size is applicable to China National Standard (CNS) A4 specifications (210X 297 mm) (Please read the precautions on the back before (Fill in this page) 589306 Λ7 B7 V. Description of the invention (62) Amount (mg) Example 17 Compound 350.0 Maltodextrin 30.0 Magnesium stearate 5.0 Microcrystalline cellulose 100.0 Colloidal comminuted 2.5 Proviron 12.5 The ingredients are mixed into bulk mixture. Pressed ingots are formed using keying methods known in the industry. The lozenges are then coated with a suspension of the methylpropionate / methylpropionate polymer in isopropanol / acetone. Patients with urinary tract infection and E. coli are given 2 tablets every 8 hours for 4 days. Symptoms of the disease subsequently disappeared, indicating that the pathogenic bacteria were substantially cleared. Other compounds having the formula i may also be used with substantially similar results. All references mentioned herein are hereby incorporated by reference. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Although specific specific examples of the present invention have been described, it will be apparent to those skilled in the art that various changes and modifications can be made to the present invention without departing from the spirit and scope of the invention. The scope of the accompanying patent application is intended to cover all modifications that fall within the scope of the invention. -65- This paper size applies to China National Standard (CNS) A4 (210X297mm) 9a 3.30

申請曰期初、、-4 · 案號 87115334 類別 A4 C4 589306 中文說明書替換頁(93年3月） % J專利説明書中文 «名稱抗微生物喹啉，其組合物及用途英文Application Date Beginning, -4 · Case No. 87115334 Category A4 C4 589306 Chinese Manual Replacement Page (March 1993)% J Patent Specification Chinese «Name Antimicrobial Quinoline, Its Composition and Use English

ANTIMICROBIAL QUINOLONES, THEIR COMPOSITIONS AND USES 姓名國籍 1. 畢諾特里度司歐 2. 傑英金歐密斯提 3·傑佛瑞里利格瑞 4.胡佑峰艾瑞克發明創作/ 住、居所姓名 (名稱）國籍 1.法國 2,3-均美國4.中國大陸 1.美國俄亥俄州馬森市印第安木大道6569號 2·美國俄亥俄州愛地市特爾瑞吉街6348號 3·美國俄亥俄州愛地市英耶特路11313號 4·美國俄亥俄州辛辛那提市印第安木路10678號美商寶鹼公司美國裝訂三、申請人美國俄亥俄州辛辛那提市寶鹼廣場1號傑可巴斯.西·雷瑟本紙張尺度邊用中國國家榡準(CNS) Α4規格(21〇 X 297公釐）ANTIMICROBIAL QUINOLONES, THEIR COMPOSITIONS AND USES Name Nationality 1. Binot Tridosi 2. Jayin King Omisty 3. Jeffrey Liliger 4. Hu Youfeng Eric's invention / name of residence and residence (name ) Nationality 1. France 2, 3-both U.S. 4. Mainland China 1. No. 6569 Indian Wood Avenue, Masson, Ohio, USA 2 6348 Terrige Street, Love Land, Ohio, USA 3 Love Land, Ohio, USA No. 11313 Yingyite Road, Shanghai 4 · 10678 Indian Wood Road, Cincinnati, Ohio, United States of America Breguet Company III. Applicant Jacobas West Reeseburn, No. 1 Breguet Plaza, Cincinnati, Ohio, USA Paper size is in accordance with China National Standards (CNS) Α4 (21〇X 297mm)

Claims

589306 ，陳弟087115334號專利申請案中文申請專利範圍替換本(93年3月）589306, Chen Di Patent Application No. 087115334 Patent Application for Chinese Patent Replacement (March 1993)

A BCD >Γ 1· 一種化合物，其具有下式 R5 〇A BCD > Γ 1. A compound having the formula R5.

其中： (a) X係選自 R7, N—— R9 R9 R7心- (b) R 1係選自c 3至C 5環烷基，c i至c 2烷基，c 2至 C3直鏈烯基，C3至C4分支烷基或烯基，全部烷基或環烷基部分為無取代或由丨至3個氟取代；及苯基，無取代或以1至3個氟或以一個經基取代於4位置； (OR3為氫或羥基； (d) R 5係選自氫’ |空基，胺基，鹵原子，c 1至c 2境基，C 2晞基，及甲氧基，全部烷基部分皆為無取代或以 1至3個氟取代； (e) R6係選自氫，羥基，胺基羰基，氰基，Cl至c 燒基’ C 2至C 4缔基或块基，全部燒基部分皆為無取代戈以1至3個氟取代，或此等甲基或乙基部分選擇性以— 個羥基或一個胺基取代；本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）Where: (a) X is selected from R7, N——R9 R9 R7 heart-(b) R1 is selected from c 3 to C 5 cycloalkyl, ci to c 2 alkyl, c 2 to C3 straight alkene Radicals, C3 to C4 branched alkyl or alkenyl radicals, all alkyl or cycloalkyl moieties are unsubstituted or substituted with 1 to 3 fluorines; and phenyl, unsubstituted or substituted with 1 to 3 fluorines or 1 substituted Substituted at the 4 position; (OR3 is hydrogen or hydroxyl; (d) R 5 is selected from hydrogen ′ | empty, amine, halogen atom, c 1 to c 2 alkyl, C 2 fluorenyl, and methoxy, All alkyl moieties are unsubstituted or substituted with 1 to 3 fluorines; (e) R6 is selected from hydrogen, hydroxyl, aminocarbonyl, cyano, Cl to c, alkyl, or C 2 to C 4 groups or blocks. All radicals are unsubstituted and substituted with 1 to 3 fluorines, or these methyl or ethyl moieties are optionally substituted with-one hydroxyl group or one amine group; Chinese paper standard (CNS) applies to this paper A4 size (210 X 297 mm)

A8 B8 C8 -------- D8 申請專利範圍 s (f)R8係選自氯，溴，〒氧基，至c2烷驢基，c2 至C4烯基，全部烷基部分皆為無取代或以〗至3個氟取代； (g) R7為胺基其係附接於χ之非毗鄰環氮之環碳，胺基為無取代或以一或二個Ci j C3烷基取代；或胺基 C u C 2烷基其係附接於χ之任一個環碳及為c 1至c 3烷 ^ 個胺基取代，戎胺基為無取代或以一或二個C i至基取代，其限制條件為f χ包含<咯㈣時，R7 不為胺基；（h) 各R9分別選自氫，C!至c4烷基，c2至c6烯基或炔基，及C3至c6稠合或螺環烷基環，全部烷基部分皆為無取代或以1至3個氟取代；及 (j)(g)敘述之R7部分及（h)敘述之R9部分可選擇性聯結如此形成（a)所示具有含氮環之稠合或螺環系環，稠合或螺環系環含2 i 5個環碳及〇 < !個環氮，但若此等環為稠合環，則R8較佳非為氯或溴；或其光學異構物，非對映異構物或對映異構物；醫藥可接受性鹽。 2.如申請專利範圍第丨項之化合物，其中R3為羥基。 3·如申請專利範圍第2項之化合物，其中： (a)X 為A8 B8 C8 -------- D8 Patent application scope s (f) R8 is selected from chlorine, bromine, fluorenyl, to c2 alkyl, c2 to C4 alkenyl, and all alkyl parts are Substituted or substituted with 3 to 3 fluorines; (g) R7 is an amine group which is a ring carbon attached to a non-adjacent ring nitrogen of χ, the amine group is unsubstituted or substituted with one or two Ci j C3 alkyl groups; Or an amine C u C 2 alkyl group which is attached to any one of the ring carbons of χ and is substituted with c 1 to c 3 alkyl groups, and the amine group is unsubstituted or substituted with one or two Ci groups Substitution, with the limitation that when f χ contains < pyro, R7 is not an amine group; (h) each R9 is selected from hydrogen, C! To c4 alkyl, c2 to c6 alkenyl or alkynyl, and C3 to c6 fused or spirocycloalkyl ring, all alkyl moieties are unsubstituted or substituted with 1 to 3 fluorines; and (j) (g) the R7 part and (h) the R9 part can be selectively connected Thus, a fused or spiro ring system ring having a nitrogen-containing ring as shown in (a) is formed. The fused or spiro ring system contains 2 i 5 ring carbons and 0 <! ring nitrogens, but if these rings are thick Ring, then R8 is preferably not chlorine or bromine; or its optical isomer, diastereomer or Enantiomers; medically acceptable salts. 2. The compound according to the first item of the patent application, wherein R3 is a hydroxyl group. 3. The compound as claimed in item 2 of the patent application, wherein: (a) X is

-2- 申請專利範圍 (b) Rl係選自包括C3至q環烷基，曱基，乙基，乙烯基，異丙基，異丙烯基，異丁基，異丁烯基，第三丁基’全部此等燒基或環烷基部分為無取代或以1至3個氟取代；及苯基，其為無取代或以丨至3個氟取代，或以一個备基取代於4位置； (c) R 5係選自包括氫，羥基，胺基，氟，氯，溴及甲基’甲基為無取代或以1至3個氟取代； (d) R6係選自包括氫，羥基，胺基羰基，氰基，甲基及乙晞基，乙烯基為無取代或以1至3個氟取代，甲基為無取代或以一個羥基或胺基或1至3個氟取代； (e) R 8係選自包括氯，溴，甲氧基或甲硫基其為無取代或以1至3個氟取代，及甲基為無取代或以丨至3個氟取代； (f) R 7係附接於X之未w比鄰環氮之環碳；及 (g) X之環碳具有非氫r9’附接其上者不多於兩個。 4·如申請專利範圍第3項之化合物，其中若r 8為無取代烷基，則R7為胺基烷基。 5·如申請專利範圍第3項之化合物，其中r7為胺基其為無取代或以一個C i至C 3烷基或兩個甲基取代，或胺基垸基其為甲基或乙基或異丙基以一個胺基取代，而該胺基為無取代或以一個甲基或乙基或二甲基取代；及任何非氮 R9為甲基或乙基。 6·如申請專利範圍第5項之化合物，其中R 1係選自包括環丙基，乙基，以1至3個氟取代之苯基，及4·經苯基。 -3- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 589306 A8 B8 C8 D8 申請專利範圍 7·如申請專利範圍第6項之化合物，其中： (a) R5係選自包括氫，羥基，氯，溴，胺基及甲基，甲基為無取代或以1至3個氟取代；及 (b) R6係選自包括氳，羥基及甲基，甲基為無取代或以1至3個氟取代。 8·如申請專利範圍第7項之化合物，其中R8係選自包括氯’甲氧基’甲硫基，一氟甲基，二氟甲基，及三氟甲基。 9.如申請專利範圍第7項之化合物，其中R7係選自包括胺基’甲基胺基，胺基甲基，甲基胺基甲基，丨_胺基乙基’ 1-甲基胺基乙基，胺基甲基乙基及基胺基-1-甲基乙基。 1〇.如申凊專利範圍第9項之化合物，其中R 1為環丙基或乙基’其為無取代或以丨至3個氟取代。 11. 如申凊專利範圍第8項之化合物，其中r 8為甲氧基或甲硫基。 12. 如申凊專利範圍第1 1項之化合物，其中R 5係選自包括氫，羥基，胺基及甲基。 11如申請專利範圍第1 2項之化合物，其中R6為氫。 14. 如申請專利範圍第13項之化合物，其中以丨為環丙基。 15. 如申請專利範圍第13項之化合物，其中ri*乙基。 16. 如申請專利範圍第1 5項之化合物，其中R5為氮。 Π.如申請專利範圍第3、9、14或15項中任一項之化合物，其中R8為曱氧基。 -4- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) ^9306 A8-2- Application scope (b) Rl is selected from the group consisting of C3 to q cycloalkyl, fluorenyl, ethyl, vinyl, isopropyl, isopropenyl, isobutyl, isobutenyl, third butyl ' All of these alkyl or cycloalkyl moieties are unsubstituted or substituted with 1 to 3 fluorines; and phenyl is unsubstituted or substituted with 1 to 3 fluorines, or substituted at the 4 position with a backup group; ( c) R 5 is selected from the group consisting of hydrogen, hydroxy, amine, fluorine, chlorine, bromine and methyl'methyl is unsubstituted or substituted with 1 to 3 fluorines; (d) R 6 is selected from the group consisting of hydrogen, hydroxyl, Aminocarbonyl, cyano, methyl and ethenyl, vinyl is unsubstituted or substituted with 1 to 3 fluorines, methyl is unsubstituted or substituted with one hydroxyl or amine or 1 to 3 fluorines; (e R 8 is selected from the group consisting of chlorine, bromine, methoxy or methylthio which is unsubstituted or substituted with 1 to 3 fluorines, and methyl is unsubstituted or substituted with 1 to 3 fluorines; (f) R 7 is a ring carbon attached to X that is adjacent to a ring nitrogen; and (g) no more than two ring carbons of X have a non-hydrogen r9 'attached to it. 4. The compound according to item 3 of the scope of patent application, wherein if r 8 is an unsubstituted alkyl group, then R 7 is an amino alkyl group. 5. The compound as claimed in claim 3, wherein r7 is an amine group which is unsubstituted or substituted with one C i to C 3 alkyl group or two methyl groups, or an amino fluorenyl group which is methyl or ethyl Or isopropyl is substituted with an amine group which is unsubstituted or substituted with a methyl or ethyl or dimethyl group; and any non-nitrogen R9 is methyl or ethyl. 6. The compound according to claim 5 in which R 1 is selected from the group consisting of cyclopropyl, ethyl, phenyl substituted with 1 to 3 fluorines, and 4. phenyl via phenyl. -3- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 589306 A8 B8 C8 D8 Patent application scope 7 · As for the compound in the sixth scope of patent application, where: (a) R5 is selected from the group consisting of Hydrogen, hydroxyl, chlorine, bromine, amine and methyl, methyl is unsubstituted or substituted with 1 to 3 fluorines; and (b) R6 is selected from the group consisting of hydrazone, hydroxyl and methyl, and methyl is unsubstituted or Substituted with 1 to 3 fluorine. 8. The compound according to item 7 of the scope of patent application, wherein R8 is selected from the group consisting of chloro'methoxy 'methylthio, monofluoromethyl, difluoromethyl, and trifluoromethyl. 9. The compound according to item 7 of the scope of patent application, wherein R7 is selected from the group consisting of amino'methylamino, aminomethyl, methylaminomethyl, and aminoamino'1-methylamine. Ethylethyl, aminomethylethyl and aminoamino-1-methylethyl. 10. The compound according to item 9 of the patent application, wherein R 1 is cyclopropyl or ethyl 'which is unsubstituted or substituted with 1 to 3 fluorines. 11. A compound as claimed in claim 8 wherein r 8 is methoxy or methylthio. 12. The compound as claimed in item 11 of the patent application, wherein R 5 is selected from the group consisting of hydrogen, hydroxyl, amine and methyl. 11 The compound according to item 12 of the scope of patent application, wherein R6 is hydrogen. 14. The compound as claimed in claim 13 wherein 丨 is cyclopropyl. 15. The compound as claimed in claim 13 wherein ri * ethyl. 16. A compound as claimed in item 15 in which R5 is nitrogen. Π. The compound according to any one of claims 3, 9, 14 or 15, wherein R8 is fluorenyloxy. -4- This paper size applies to China National Standard (CNS) A4 (210X 297 mm) ^ 9306 A8

队如申請專利範圍第3、9、14或15項中任一項之化合物，其中X包含p比嘻咬基環。以如申請專利範圍第3、9、14或15項中任一項之化合物，其中X包含吡咯啶基環，及R7係選自包括胺基甲基，甲基胺基甲基，1-胺基乙基，卜甲基胺基乙基，丨_胺基甲基乙基及1-甲基胺基-1-甲基乙基。 2〇·如申請專利範圍第3、9、1 4或1 5項中任一項之化合物，其中X包含六氫P比咬基環。 21·如申請專利範圍第3、9、1 4或1 5項中任一項之化合物，其中X包含六氫吡啶基環，及R7為胺基或甲基胺基。 22. 如申請專利範圍第3、9、1 4或1 5項中任一項之化合物，其中全部R9皆為氫’或僅有一個X之環碳具有非氫，此種非氫R 9係選自包括甲基，乙基，二甲基及螺環丙基。 23. 如申請專利範圍第3、9、1 4或丨5項中任一項之化合物，其中X包含吡咯啶基環，及R9包含烷基或二烷基於吡咯啶基環之毗鄰環氮之環碳上。 24. 如申請專利範圍第1項之化合物，其係選自下列所組成之群：了-^尺气“-胺基乙基吡咯啶基”-^乙基-^-二氫· 8 -甲氧-4-氧基- 3-0奎琳幾酸； 7-[3R-(lS-胺基乙基吡嘻啶基）_ι_(2 -氟乙基）]_ 1，4 -二氫-8 -甲氧-4 -氧基-3 -喳啉羧酸； 7-[3R-(lS-胺基乙基吡咯啶基）]·ΐ -環丙基“，斗-二 -5- 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 589306 A BCD 申請專利範圍氫-8 -甲氧-4 -氧基-3 -喹啉羧酸； 7 - [ 3 R- ( 1 S -甲基胺基乙基吡咯啶基）]-1 -環丙基-1，4 -二氫-8-甲氧-4-氧基- 3- p奎啦複酸； 7-[3R-(l -胺基-甲基乙基？比p各淀基）]-1-琢丙基-1，4-二氫-8-甲氧-4 -氧基-3-峻琳幾酸； 7-[3R-( 1 -甲基胺基-甲基乙基吡咯啶基）]-卜環丙基-1，4 -二氫-8-甲氧-4-氧基-3-峻琳幾酸； 7-[3R-(lS-胺基乙基-5 -甲基-p比?各淀基）]-1_環丙基-1，4 -二氫-8 -甲氧-4 -氧基-3 -喹啉羧酸； 7-[3R-(lS-胺基乙基-5,5 -二甲基-p比咯淀基）]-l -環丙基-1，4 -二氫-8-甲氧-4-氧基-3-峻淋叛酸； 7-[3R-(l-胺基甲基乙基-5,5-二甲基-吡咯啶基）]-1_ 環丙基-1，4 -二氫-8-甲氧-4-氧基-3-p奎淋叛酸； 7 - [ 3 R - (1 S -甲基胺基乙基-5，5 _二甲基_吡哈啶基）]_ 1 -環丙基-1，4 -二氫-8 -甲氧-4 -氧基-3 -峻淋致酸； 7-[311-(1-甲基胺基甲基乙基-5,5-二甲基-17比嘻咬基）]-1 -環丙基-1，4 -二氫-8 -甲氧乂 4 -氧基_ 3 -喹啉幾酸； 7-[3R-(l S-胺基乙基-5-乙基-吡咯啶基）]_〖_環丙基_ 1，4 -二氫-8-甲氧-4-氧基- 3-0奎淋幾酸； 7-[3R-(l-胺基甲基乙基-5 -乙基_吡咯啶基）]-:卜環丙基-1，4 -二氫-8-甲氧-4-氧基- 3-4琳幾酸· 7-[3R-(lS-甲基胺基乙基-5-乙基-吡咯啶基環丙基-1，4 -二氫-8-甲氧-4-氧基-3-唆琳幾酸· -6 - D8 、申請專利範圍 7-[3R-(卜甲基胺基甲基乙基_5_乙基-吡咯啶基）]-1-環丙基-1，4 -二氫-8 -甲氧-4 -氧基-3 -喳啉羧酸； 7 ·[ 3 R-(卜胺基-1 -環丙基-甲基吡咯啶基）]· 1 -環丙基-1，4-二氫-8-甲氧-4-氧基-3-喳啉羧酸； 7-[6R-(lS -胺基乙基）·4 -吖螺[2.4]庚基卜1-環丙基-1，4-二氫-8-甲氧-4-氧基-3-喹啉羧酸； 7-[6R-(lS -甲基胺基乙基）-4 -吖螺[2.4]庚基]-1-環丙基-1，4 -二氫-8-甲氧-4 -氧基- 3- 4淋叛酸； 7-[6R-(l S-胺基-甲基乙基）-4 -吖螺[2·4]庚基]-1-環丙基-1，4 -二氫-8 -甲氧-4 -氧基-3 -峻淋複酸； 7-[611-(18-甲基胺基-甲基乙基）-4-吖螺[2.4]庚基]-1-環丙基-1，4 -二氫-8 -甲氧-4-氧基-3-峻淋瘦酸；或其醫藥可接受性鹽。 25·如申請專利範圍第1項之化合物，其係選自下列所組成之群： 7-[3 -胺基六氫吡啶基]-卜環丙基-1，4 -二氫-8-曱氧-4 -氧基-3 - ρ奎淋叛酸； 7-[3 -甲基胺基六氫吡啶基]-卜環丙基-1，4 -二氫-8-甲氧-4-氧基-3-喳啉羧酸； 7-[3 -胺基-4-曱基-六氫吡啶基]-1-環丙基-1，4 -二氫-8-甲氧-4-氧基-3-喹啉羧酸； 7-[3-胺基-4 -乙基-六氫吡啶基]-1-環丙基-1，4 -二氫-8-甲氧-4-氧基-3-喹啉羧酸； 7-[3 -胺基-6,6 -二甲基-六氫π比淀基]-1-¾丙基-1，4- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 589306 A B c D 六、申請專利範圍二鼠-8 -甲氧-4·氧基-3-p奎淋致酸， 7 - [ 3 -胺基-6-甲基-7T氮ρ比症基]-1 -琢丙基-1，4 -二風_ 8 -甲氧-4 -氧基-3 -喹啉羧酸； 7 - [ 6 -胺基-4-叶螺[2.5] -辛基]-1-5募丙基-1，4-二氮-8 -甲氧-4-氧基-3 _喹啉羧酸； 7 - [ 7 -胺基-5-叶螺[2.5]-辛基]-l-¾>丙基-l，4-二氮-8-甲氧-4-氧基-3-喹啉羧酸； 7-[4-胺基-6-吖螺[2.5] -辛基]-1 -環丙基-1，4 -二氫-8 -甲氧-4 -氧基-3 -喹啉羧酸；或其醫藥可接受性鹽。 26. —種用於預防或治療微生物感染之醫藥組合物，其包含·· (a)安全且有效量之如申請專利範圍第3、9、14、 1 5、2 4或2 5項中任一項之化合物；及 (b )醫藥可接受性賦形.劑。本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)For example, a compound of any one of claims 3, 9, 14, or 15 in which X includes a p-bite ring. A compound as in any one of claims 3, 9, 14, or 15 in which the scope of the patent application, wherein X comprises a pyrrolidinyl ring, and R7 is selected from the group consisting of aminomethyl, methylaminomethyl, 1-amine Ethyl, ethylmethylaminoethyl, aminomethylethyl and 1-methylamino-1-methylethyl. 20. The compound according to any one of claims 3, 9, 14 or 15 in the scope of the application for a patent, wherein X comprises a hexahydro P ring. 21. The compound according to any one of claims 3, 9, 14 or 15 in the scope of the application for a patent, wherein X comprises a hexahydropyridyl ring, and R7 is an amine group or a methylamine group. 22. If the compound in any one of claims 3, 9, 14 or 15 of the scope of patent application, wherein all R9 are hydrogen 'or only one ring carbon of X has non-hydrogen, such non-hydrogen R 9 series It is selected from the group consisting of methyl, ethyl, dimethyl and spirocyclopropyl. 23. A compound as claimed in any one of claims 3, 9, 14 or 5 in which X contains a pyrrolidinyl ring and R9 contains an alkyl or dialkyl group adjacent to the ring nitrogen of the pyrrolidinyl ring Ring carbon. 24. The compound according to item 1 of the scope of the patent application, which is selected from the group consisting of: ^ ^ "qi-amino ethyl pyrrolidinyl"-^ ethyl-^-dihydro · 8-methyl Oxy-4-oxy-3-0 quinolinic acid; 7- [3R- (lS-aminoethylpyridinyl) _ι_ (2-fluoroethyl)] _ 1,4-dihydro-8 -Methoxy-4 -oxy-3 -pyridinocarboxylic acid; 7- [3R- (lS-aminoethylpyrrolidinyl)] · ΐ-cyclopropyl ", bucket-di-5- This paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 589306 A BCD Application for patent scope Hydrogen-8-methoxy-4-oxy-3-quinolinecarboxylic acid; 7-[3 R- (1 S -Methylaminoethylpyrrolidinyl)]-1 -cyclopropyl-1,4-dihydro-8-methoxy-4-oxy-3 -p-quinarate; 7- [3R- ( l-Amino-methylethyl? than p-Hydroxyl)]-1-Chloro-1,4-dihydro-8-methoxy-4 -oxy-3-junlin chinoic acid; 7- [3R- (1 -methylamino-methylethylpyrrolidinyl)]-cyclopropyl-1,4-dihydro-8-methoxy-4-oxy-3-junlinic acid; 7- [3R- (1S-aminoethyl-5 -methyl-p ratio to each phenyl group)]-1_cyclopropyl-1,4-dihydro-8-methoxy-4-oxy- 3 -quinolinecarboxylic acid; 7- [3R- (lS-aminoethyl-5,5-dimethyl-p-pyridyl)]-l-cyclopropyl-1,4-dihydro-8-methoxy-4-oxy-3-jun Lysamic acid; 7- [3R- (l-aminomethylethyl-5,5-dimethyl-pyrrolidinyl)]-1_ cyclopropyl-1,4-dihydro-8-methoxy- 4-oxy-3-p quinucronate; 7-[3 R-(1 S -methylaminoethyl-5,5- dimethyl_pyhalidinyl)] _ 1 -cyclopropyl -1,4 -dihydro-8 -methoxy-4 -oxy-3 -caproic acid; 7- [311- (1-methylaminomethylethyl-5,5-dimethyl- 17-Bee group)]-1 -cyclopropyl-1,4-dihydro-8 -methoxymethoxy 4-oxy-3 -quinolinoline acid; 7- [3R- (l S-aminoethyl --5-ethyl-pyrrolidinyl)] _ 〖_ cyclopropyl_ 1,4-dihydro-8-methoxy-4-oxy-3-0 quinacic acid; 7- [3R- ( l-Aminomethylethyl-5 -ethyl_pyrrolidinyl)]-: Bucyclopropyl-1,4-dihydro-8-methoxy-4-oxy-3-4 Lindaic acid · 7- [3R- (lS-methylaminoethyl-5-ethyl-pyrrolidinylcyclopropyl-1,4-dihydro-8-methoxy-4-oxy-3-carboximine · -6-D8, the scope of patent application 7- [3R- (bumethylaminomethylethyl-5_ethyl-pyrrolidinyl)]-1-cyclopropyl-1,4-dihydro-8-methyl Oxygen-4- -3 -pyridinocarboxylic acid; 7 · [3 R- (ramino-1 -cyclopropyl-methylpyrrolidinyl)] · 1 -cyclopropyl-1,4-dihydro-8-formyl Oxy-4-oxy-3-fluorinoline carboxylic acid; 7- [6R- (lS-aminoethyl) · 4-aspiro [2.4] heptyl-1-cyclopropyl-1,4-dihydro -8-methoxy-4-oxy-3-quinolinecarboxylic acid; 7- [6R- (lS-methylaminoethyl) -4-acylspiro [2.4] heptyl] -1-cyclopropyl -1,4-dihydro-8-methoxy-4 -oxy-3-4 lysinic acid; 7- [6R- (l S-amino-methylethyl) -4 -acrido [2 · 4] heptyl] -1-cyclopropyl-1,4-dihydro-8-methoxy-4 -oxy-3 -junlinate; 7- [611- (18-methylamino-methyl Ethyl) -4-acylspiro [2.4] heptyl] -1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxy-3-junleic acid; Acceptable salt. 25. The compound according to item 1 of the scope of patent application, which is selected from the group consisting of: 7- [3-aminohexahydropyridyl] -bucyclopropyl-1,4-dihydro-8-fluorene Oxy-4 -oxy-3 -p-quinolinate; 7- [3-methylaminohexahydropyridyl] -bucyclopropyl-1,4-dihydro-8-methoxy-4-oxo 3-Methinolinecarboxylic acid; 7- [3-Amino-4-amidino-hexahydropyridyl] -1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxy 3-quinolinecarboxylic acid; 7- [3-amino-4 -ethyl-hexahydropyridyl] -1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxy- 3-quinoline carboxylic acid; 7- [3-amino-6,6-dimethyl-hexahydroπ-pyridyl] -1-¾propyl-1,4- This paper is sized to the Chinese National Standard (CNS ) A4 specification (210X 297 mm) 589306 AB c D 6. Application scope of patents 2 mouse-8-methoxy-4 · oxy-3-p quinacid, 7-[3 -amino-6-formaldehyde -7T nitrogen ρ ratio group] -1 -Cyclopropyl-1,4-difluoro_ 8-methoxy-4 -oxy-3 -quinolinecarboxylic acid; 7-[6 -amino-4- Snail [2.5] -octyl] -1-5trispropyl-1,4-diazine-8-methoxy-4-oxy-3 quinolinecarboxylic acid; 7-[7 -amino-5 -Snail [2.5] -octyl] -l-¾ > propyl-l, 4-diaza-8- Oxo-4-oxy-3-quinolinecarboxylic acid; 7- [4-amino-6-acrylo [2.5] -octyl] -1 -cyclopropyl-1,4-dihydro-8 -formyl Oxy-4 -oxy-3 -quinolinecarboxylic acid; or a pharmaceutically acceptable salt thereof. 26. A pharmaceutical composition for preventing or treating microbial infections, comprising: (a) a safe and effective amount of any of the items 3, 9, 14, 15, 2, 4 or 25 of the scope of patent application A compound of one; and (b) a pharmaceutically acceptable excipient. This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)