JPH05112554A - New quinolonecarboxylic acid derivative - Google Patents
New quinolonecarboxylic acid derivativeInfo
- Publication number
- JPH05112554A JPH05112554A JP8135092A JP8135092A JPH05112554A JP H05112554 A JPH05112554 A JP H05112554A JP 8135092 A JP8135092 A JP 8135092A JP 8135092 A JP8135092 A JP 8135092A JP H05112554 A JPH05112554 A JP H05112554A
- Authority
- JP
- Japan
- Prior art keywords
- oxoquinoline
- dihydro
- cyclopropyl
- carboxylic acid
- difluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
(57)【要約】 （修正有）
【目的】新規な６−フルオロ−７−置換−３−キノロン
カルボン酸誘導体を提供する。
【構成】一般式（Ｉ）で表されるキノロンカルボン酸誘
導体。
（式中Ｒ１は、水素原子又はアミノ基を意味し、Ｒ２は
フッ素原子又はメトキシ基を意味し、Ｒ３は水素原子又
は炭素数１〜３の低級アルキル基を意味し、ｎは０又は
１である）
【効果】一般式（Ｉ）のキノロンカルボン酸誘導体は公
知のキノロン系抗菌剤よりも強い抗菌活性を示し、且つ
副作用が少い。(57) [Summary] (Modified) [Objective] To provide a novel 6-fluoro-7-substituted-3-quinolonecarboxylic acid derivative. [Structure] A quinolonecarboxylic acid derivative represented by the general formula (I). (In the formula, R 1 represents a hydrogen atom or an amino group, R 2 represents a fluorine atom or a methoxy group, R 3 represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and n is 0. Or 1) [Effect] The quinolonecarboxylic acid derivative of the general formula (I) exhibits stronger antibacterial activity than known quinolone antibacterial agents and has less side effects.
Description
【０００１】[0001]
【産業上の利用分野】本発明は新規なキノロン系化合物
に関する。本発明の化合物は強い抗菌活性を有し、医薬
として有用である。FIELD OF THE INVENTION The present invention relates to a novel quinolone compound. The compound of the present invention has a strong antibacterial activity and is useful as a medicine.
【０００２】[0002]
【従来技術】キノロン系抗菌剤としては、既販中のもの
を含め、極めて多くの化合物が知られているが、中枢系
に対する副作用を示すものも多く、その使用には極めて
注意を要する等の問題点を有している。また最近、キノ
リン環の６位および８位がフッ素原子で置換された化合
物および６位がフッ素原子、８位がメトキシ基等の低級
アルコキシ基で置換された化合物がその抗菌活性の点で
注目を集めている（米国特許第４５５６６５８号、ヨー
ロッパ特許第１０６４８９号、ヨーロッパ特許公開第２
３０２９５号、ヨーロッパ特許公開第２４１２０６
号）。しかしながらこれらの化合物の中には、前記の副
作用の他に光毒性を有するものも多く、必ずしも抗菌剤
として満足する化合物とは言い得ない面もある。2. Description of the Related Art As quinolone antibacterial agents, a great number of compounds are known, including those already on the market, but many of them show side effects on the central system, and their use requires extreme caution. I have a problem. Further, recently, a compound in which the 6- and 8-positions of the quinoline ring have been substituted with a fluorine atom and a compound in which the 6-position has a fluorine atom and the 8-position has been substituted with a lower alkoxy group such as a methoxy group have attracted attention because of their antibacterial activity. Collected (US Pat. No. 4,556,658, European Patent No. 106489, European Patent Publication No. 2)
30295, European Patent Publication No. 241206
issue). However, among these compounds, many have phototoxicity in addition to the above-mentioned side effects, and there are aspects that cannot necessarily be said to be satisfactory compounds as antibacterial agents.
【０００３】[0003]
【発明が解決しようとする問題点】本発明者等は、前述
の従来から知られているキノロン系抗菌剤の欠点を改良
すべく鋭意研究した結果、キノロン環の７位にピペリジ
ン環の３位にアミノ基、低級アルキルアミノ基、アミノ
メチル基が置換した３−アミノピペリジン−１−イル基
などの３位置換ピペリジン類が置換した下記一般式
（Ｉ）で示される化合物が、公知のキノロン系抗菌剤で
あるＯｆｌｏｘａｃｉｎ、Ｎｏｒｆｌｏｘａｃｉｎより
強い抗菌活性を示し、しかも副作用も少ないことを見い
出した。また本発明の一般式（Ｉ）で示される化合物は
公知の６，８−ジフルオロキノリン系抗菌剤の有してい
る光毒性も低減されている。DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The inventors of the present invention have earnestly studied to improve the above-mentioned drawbacks of the conventionally known quinolone type antibacterial agents, and as a result, the 7th position of the quinolone ring and the 3rd position of the piperidine ring A compound represented by the following general formula (I) in which 3-position piperidines such as 3-aminopiperidin-1-yl group substituted with an amino group, a lower alkylamino group or an aminomethyl group is substituted is a known quinolone compound It has been found that the antibacterial agent has stronger antibacterial activity than Ofloxacin and Norfloxacin and has less side effects. The phototoxicity possessed by the known 6,8-difluoroquinoline antibacterial agent of the compound represented by the general formula (I) of the present invention is also reduced.
【０００４】[0004]
【化２】 （式中Ｒ１は水素原子又はアミノ基を意味し、Ｒ２はフ
ッ素原子又はメトキシ基を意味し、Ｒ３は水素原子又は
炭素数１〜３の低級アルキル基を意味し、ｎは０又は１
である）[Chemical 2] (In the formula, R 1 represents a hydrogen atom or an amino group, R 2 represents a fluorine atom or a methoxy group, R 3 represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and n is 0 or 1
Is)
【０００５】本発明の一般式（Ｉ）で示されるキノロン
系化合物は新規化合物であり、例えば公知化合物であ
る、１−シクロプロピル−６，７，８−トリフルオロ−
１，４−ジヒドロ−４−オキソキノリン−３−カルボン
酸、５−アミノ−１−シクロプロピル−６，７，８−ト
リフルオロ−１，４−ジヒドロ−４−オキソキノリン−
３−カルボン酸またはこれらの化合物の低級アルキルエ
ステルに３−アセトアミドピペリジン類を反応させ、次
いで加水分解することにより８位がフッ素原子の一般式
（Ｉ）で示される化合物が製造される。次いでこの化合
物をナトリウムメトキシドと反応せしめることにより本
発明の一般式（Ｉ）で示される化合物の８位がメトキシ
基である化合物を製造することができる。The quinolone compound represented by the general formula (I) of the present invention is a novel compound, for example, a known compound, 1-cyclopropyl-6,7,8-trifluoro-.
1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-
A compound represented by the general formula (I) having a fluorine atom at the 8-position is produced by reacting 3-carboxylic acid or a lower alkyl ester of these compounds with 3-acetamidopiperidine and then hydrolyzing the same. Then, this compound is reacted with sodium methoxide to produce a compound represented by the general formula (I) of the present invention in which the 8-position is a methoxy group.
【０００６】本発明の一般式（Ｉ）で示される化合物に
は、２種の光学異性体が存在するが、いずれも本発明の
化合物として用い得る。光学活性体の合成は、例えば光
学的に活性なオルニチンを出発物質として製造した３−
アミノピペリジンを用い、以下前述したのと同様な反応
に付すことにより行なわれる。本発明の一般式（Ｉ）で
示される化合物で好ましい例を挙げれば以下の通りであ
る。The compound represented by the general formula (I) of the present invention has two kinds of optical isomers, both of which can be used as the compound of the present invention. The synthesis of the optically active substance is carried out, for example, by using optically active ornithine as a starting material.
It is carried out by using aminopiperidine and subjecting it to the same reaction as described above. Preferred examples of the compound represented by formula (I) of the present invention are as follows.
【０００７】７−（３−アミノピペリジン−１−イル）
−１−シクロプロピル−１，４−ジヒドロ−６，８−ジ
フルオロ−４−オキソキノリン−３−カルボン酸 ７−（３−Ｓ−アミノピペリジン−１−イル）−１−シ
クロプロピル−１，４−ジヒドロ−６，８−ジフルオロ
−４−オキソキノリン−３−カルボン酸 ７−（３−Ｒ−アミノピペリジン−１−イル）−１−シ
クロプロピル−１，４−ジヒドロ−６，８−ジフルオロ
−４−オキソキノリン−３−カルボン酸 ７−（３−アミノピペリジン−１−イル）−１−シクロ
プロピル−６−フルオロ−１，４−ジヒドロ−８−メト
キシ−４−オキソキノリン−３−カルボン酸7- (3-aminopiperidin-1-yl)
-1-Cyclopropyl-1,4-dihydro-6,8-difluoro-4-oxoquinoline-3-carboxylic acid 7- (3-S-aminopiperidin-1-yl) -1-cyclopropyl-1,4 -Dihydro-6,8-difluoro-4-oxoquinoline-3-carboxylic acid 7- (3-R-aminopiperidin-1-yl) -1-cyclopropyl-1,4-dihydro-6,8-difluoro- 4-oxoquinoline-3-carboxylic acid 7- (3-aminopiperidin-1-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid
【０００８】５−アミノ−７−（３−アミノピペリジン
−１−イル）−１−シクロプロピル−１，４−ジヒドロ
−６，８−ジフルオロ−４−オキソキノリン−３−カル
ボン酸 ７−（３−アミノメチルピペリジン−１−イル）−１−
シクロプロピル−６，８−ジフルオロ−１，４−ジヒド
ロ−４−オキソキノリン−３−カルボン酸 １−シクロプロピル−６−フルオロ−１，４−ジヒドロ
−８−メトキシ−７−（３−メチルアミノピペリジン−
１−イル）−４−オキソキノリン−３−カルボン酸5-Amino-7- (3-aminopiperidin-1-yl) -1-cyclopropyl-1,4-dihydro-6,8-difluoro-4-oxoquinoline-3-carboxylic acid 7- (3 -Aminomethylpiperidin-1-yl) -1-
Cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- (3-methylamino Piperidine-
1-yl) -4-oxoquinoline-3-carboxylic acid
【０００９】５−アミノ−１−シクロプロピル−６−フ
ルオロ−１，４−ジヒドロ−８−メトキシ−７−（３−
メチルアミノピペリジン−１−イル）−４−オキソキノ
リン−３−カルボン酸 ７−（３−アミノメチルピペリジン−１−イル）−１−
シクロプロピル−６−フルオロ−１，４−ジヒドロ−８
−メトキシ−４−オキソキノリン−３−カルボン酸5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- (3-
Methylaminopiperidin-1-yl) -4-oxoquinoline-3-carboxylic acid 7- (3-aminomethylpiperidin-1-yl) -1-
Cyclopropyl-6-fluoro-1,4-dihydro-8
-Methoxy-4-oxoquinoline-3-carboxylic acid
【００１０】本発明の化合物は酸と塩を形成する。酸と
しては薬学的に使用し得るものであり、例えば塩酸、硫
酸、硝酸等の無機酸およびシュウ酸、クエン酸、フマル
酸、ｐ−トルエンスルホン酸等の有機酸である。The compounds of the present invention form salts with acids. The acid can be used pharmaceutically, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and organic acids such as oxalic acid, citric acid, fumaric acid and p-toluenesulfonic acid.
【００１１】次に表１に本発明化合物（後記実施例１の
化合物）の抗菌活性を公知のキノロン系抗菌剤であるｏ
ｆｌｏｘａｃｉｎ、ｎｏｒｆｌｏｘａｃｉｎ等と比較し
たＭＩＣ測定結果を示す。なおＭＩＣの測定は常法に従
って行った。Next, the antibacterial activity of the compound of the present invention (compound of Example 1 below) is shown in Table 1 as a known quinolone antibacterial agent.
The MIC measurement result compared with floxacin, norfloxacin, etc. is shown. The MIC was measured according to a conventional method.
【００１２】[0012]
【表１】 表１に示すように、本発明の化合物は公知のキノロン系
抗菌剤より強い活性を有している。本発明の化合物の抗
菌活性はスタフィロコッカス・アウレウス等のグラム陽
性菌において特に強いのが特徴である。[Table 1] As shown in Table 1, the compounds of the present invention have stronger activity than known quinolone antibacterial agents. The antibacterial activity of the compound of the present invention is characterized by being particularly strong in Gram-positive bacteria such as Staphylococcus aureus.
【００１３】本発明の化合物の光毒性に関し、以下に示
す公知の６，８−ジフルオロ−キノリン系化合物と比較
した結果を表２に示す。表２において本発明の化合物と
しては後記実施例１の化合物を用いた。Regarding the phototoxicity of the compound of the present invention, Table 2 shows the results of comparison with the following known 6,8-difluoro-quinoline compounds. In Table 2, the compound of Example 1 described below was used as the compound of the present invention.
【００１４】[0014]
【化３】 [Chemical 3]
【表２】 [Table 2]
【００１５】実験の説明 ５週齢のｄｄＹ／Ｃｒｊ雄マウスに検体溶液を経口投与
したのち、各々マウス用保定器に保定した。このマウス
用保定器は尾部のみを器外に出せるものでその尾部を４
０Ｗ ＵＶＡ蛍光燈で４．５〜５．５時間照射した。蛍
光管から尾部までの距離は、１１ｃｍとした。この場合
の照射強度は１．３０〜１．８０ｍＷ／ｃｍ２であっ
た。体部には銀紙でおおい直接ＵＶＡが照射しないよう
にした。Description of Experiments A sample solution was orally administered to 5-week-old male ddY / Crj mice, and each mouse was then retained by a mouse retainer. This mouse restraint has a tail that can be pulled out of the body.
Irradiation was performed with a 0 W UVA fluorescent lamp for 4.5 to 5.5 hours. The distance from the fluorescent tube to the tail was 11 cm. The irradiation intensity in this case was 1.30 to 1.80 mW / cm 2 . The body was covered with silver paper so that it was not directly exposed to UVA.
【００１６】照射後、一定尾根部で尾部を切断し秤量し
たのち、電機乾燥器に移して１１０℃ ３時間乾燥し
た。この乾燥尾部を再秤量して、次式よりＵＶＡ照射部
位の浮腫度を算出した。After the irradiation, the tail portion was cut at a constant ridge portion and weighed, then transferred to an electric dryer and dried at 110 ° C. for 3 hours. The dried tail was re-weighed and the edema degree of the UVA-irradiated site was calculated by the following formula.
【００１７】 また、各々の浮腫度を照射群と比較し、Ｓｔｕｄｅｎｔ
の ｔ ｔｅｓｔ法で有位差検定を行った。[0017] Moreover, each edema degree was compared with the irradiation group, and Student
The difference test was performed by the t test method.
【００１８】表２に示すように本発明の化合物は光毒性
において公知のキノロン系抗菌剤よりも弱いものであ
る。以下に本発明の化合物の合成例を示す。As shown in Table 2, the compounds of the present invention are weaker in phototoxicity than known quinolone antibacterial agents. The synthesis examples of the compound of the present invention are shown below.
【００１９】[0019]
【実施例１】 ａ）１−シクロプロピル−６，７，８−トリフルオロ−
１，４−ジヒドロ−４−オキソキノリン−３−カルボン
酸エチル９３３ｍｇ、３−アセトアミドピペリジン７１
０ｍｇ、トリエチルアミン４００ｍｇ、ジメチルスルホ
キシド１０ｍｌの混合物を攪拌下１００℃で２時間加熱
する。反応後冷却し、氷水を加えクロロホルムで抽出
し、水洗を３回行った後、クロロホルム層を芒硝で乾燥
する。減圧下溶媒を留去し、残渣をシリカゲルカラムク
ロマトグラフィー（クロロホルムーエタノール）に付
し、９３０ｍｇの１−シクロプロピル−６，８−ジフル
オロ−７−（３−アセトアミドピペリジン−１−イル）
−１，４−ジヒドロ−４−オキソキノリン−３−カルボ
ン酸エチルを得る。エタノール−エーテルより再結晶
し、融点２１７〜２１８℃の無色結晶を得る。Example 1 a) 1-Cyclopropyl-6,7,8-trifluoro-
Ethyl 1,4-dihydro-4-oxoquinoline-3-carboxylate 933 mg, 3-acetamidopiperidine 71
A mixture of 0 mg, triethylamine 400 mg and dimethyl sulfoxide 10 ml is heated at 100 ° C. for 2 hours with stirring. After the reaction, the mixture is cooled, ice water is added, the mixture is extracted with chloroform, washed with water three times, and the chloroform layer is dried with sodium sulfate. The solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform-ethanol), and 930 mg of 1-cyclopropyl-6,8-difluoro-7- (3-acetamidopiperidin-1-yl).
Ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate is obtained. Recrystallization from ethanol-ether gives colorless crystals with a melting point of 217-218 ° C.
【００２０】ｂ）前記ａ）で得た１−シクロプロピル−
６，８−ジフルオロ−７−（３−アセトアミドピペリジ
ン−１−イル）−１，４−ジヒドロ−４−オキソキノリ
ン−３−カルボン酸エチル４３３ｍｇを６Ｎ塩酸５ｍｌ
に溶解し、１００℃で２．５時間加熱攪拌する。溶媒を
減圧下留去し、残渣にメタノールを加え不溶物をろ去す
る。溶媒を減圧下留去し、残渣をシリカゲルカラムクロ
マトグラフィー（クロロホルム−メタノール）に付し、
１−シクロプロピル−６，８−ジフルオロ−７−（３−
アミノピペリジン−１−イル）−１，４−ジヒドロ−４
−オキソキノリン−３−カルボン酸の塩酸塩（無色、結
晶性粉末）を得る。B) 1-cyclopropyl-obtained in the above a)
Ethyl 6,8-difluoro-7- (3-acetamidopiperidin-1-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylate 433 mg was added to 6N hydrochloric acid 5 ml.
And is heated and stirred at 100 ° C. for 2.5 hours. The solvent is distilled off under reduced pressure, methanol is added to the residue and the insoluble matter is filtered off. The solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform-methanol),
1-cyclopropyl-6,8-difluoro-7- (3-
Aminopiperidin-1-yl) -1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid hydrochloride (colorless, crystalline powder) is obtained.
【００２１】融点；２７２℃付近より変色し、２８０℃
付近で分解する。 ＩＲ（ＫＢｒ）ｃｍ−１：１７３５、３４５０ ＭＳｍ
／ｅ：３６３（Ｍ＋）、３６２Melting point; discolored from around 272 ° C, 280 ° C
Disassemble in the vicinity. IR (KBr) cm < -1 >: 1735, 3450 MSm
/ E: 363 (M + ), 362
【００２２】[0022]
【実施例２】実施例１で得た１−シクロプロピル−６，
８−ジフルオロ−７−（３−アミノピペリジン−１−イ
ル）−１，４−ジヒドロ−４−オキソキノリン−３−カ
ルボン酸・２Ｈ２Ｏ ７．９８ｇをメタノール：水
（３：１）４００ｍｌに溶解し、ｐ−トルエンスルホン
酸・Ｈ２Ｏ ４．０ｇを水１００ｍｌに溶解した溶液を
加える。反応液を減圧下半分迄濃縮し冷却する。析出し
た結晶を濾過すると１−シクロプロピル−６，８−ジフ
ルオロ−７−（３−アミノピペリジン−１−イル）−
１，４−ジヒドロ−４−オキソキノリン−３−カルボン
酸のｐ−トルエンスルホン酸塩（無色針状晶）を９．７
ｇ得る。融点３００℃以上。Example 2 1-Cyclopropyl-6 obtained in Example 1
8- difluoro-7- (3-amino-piperidin-1-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid · 2H 2 O 7.98 g methanol: water (3: 1) to 400ml A solution prepared by dissolving 4.0 g of p-toluenesulfonic acid.H 2 O in 100 ml of water is added. The reaction mixture is concentrated to half under reduced pressure and cooled. The precipitated crystals were filtered to give 1-cyclopropyl-6,8-difluoro-7- (3-aminopiperidin-1-yl)-
The p-toluenesulfonate salt of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid (colorless needle crystals) was added to 9.7.
get g. Melting point 300 ° C or higher.
【００２３】[0023]
【実施例３】１−シクロプロピル−６，７，８−トリフ
ルオロ−１，４−ジヒドロ−４−オキソキノリン−３−
カルボン酸５６６ｍｇ、トリエチルアミン２２０ｍｇ、
３−アセトアミノピペリジン３００ｍｇジメチルスルホ
キシド１０ｍｌの混合物を攪拌下１００℃で２時間加熱
する。反応後溶液を室温まで冷却し、氷水１００ｍｌを
加え、析出する結晶を濾取する。結晶をメタノール−エ
ーテルで洗浄し、５４０ｍｇの１−シクロプロピル−
６，８−ジフルオロ−７−（３−アセトアミドピペリジ
ン−１−イル）−１，４−ジヒドロ−４−オキソキノリ
ン−３−カルボン酸を得る（融点２８０〜２８２℃、メ
タノールより再結晶）。この化合物４０５ｍｇ６Ｎ塩酸
５ｍｌに懸濁し、１００℃で２．５時間加熱攪拌する。
（以下実施例１ｂ）に記載の方法と同様に処理し、１−
シクロプロピル−６，８−ジフルオロ−７−（３−アミ
ノピペリジン−１−イル）−１，４−ジヒドロ−４−オ
キソキノリン−３−カルボン酸の塩酸塩を得る。なおこ
のものは前記実施例１で製造したものとその物性値が一
致した。Example 3 1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-
Carboxylic acid 566 mg, triethylamine 220 mg,
A mixture of 3-acetaminopiperidine 300 mg dimethylsulfoxide 10 ml is heated with stirring at 100 ° C. for 2 hours. After the reaction, the solution is cooled to room temperature, 100 ml of ice water is added, and the precipitated crystals are collected by filtration. The crystals were washed with methanol-ether and 540 mg of 1-cyclopropyl-
6,8-Difluoro-7- (3-acetamidopiperidin-1-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained (melting point 280-282 ° C, recrystallized from methanol). This compound (405 mg) is suspended in 6N hydrochloric acid (5 ml), and the mixture is heated with stirring at 100 ° C. for 2.5 hours.
Treated in the same manner as described in (Example 1b below), 1-
Cyclopropyl-6,8-difluoro-7- (3-aminopiperidin-1-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride is obtained. The physical properties of this product were the same as those produced in Example 1.
【００２４】[0024]
【実施例４】 ａ）Ｌ−オルニチン・１塩酸塩２５ｇのメタノール２０
０ｍｌ懸濁液に氷冷攪拌下、塩化チオニル３２．６ｍｌ
を滴下する。反応混合物を６時間加熱還流後、溶媒を減
圧下留去し、残留物をジイソプロピルエーテル３００ｍ
ｌにて処理し、析出する固型物を濾取すると無色粉末
（吸湿性）のＬ−オルニチンメチル・２塩酸塩３３．０
９ｇを得る。ＮＭＲ（Ｄ２Ｏ）δ：１．８０〜２．６０
（４Ｈ，ｍ）、３．３５（２Ｈ，ｄｉｓｔｏｒｔｅｄ
ｔ，Ｊ＝８Ｈｚ）、４．１３（３Ｈ，ｓ）、４．５１
（１Ｈ，ｔ，Ｊ＝６Ｈｚ）Example 4 a) L-ornithine monohydrochloride 25 g methanol 20
Thionyl chloride (32.6 ml) was added to a 0 ml suspension under stirring with ice cooling.
Is dripped. The reaction mixture was heated under reflux for 6 hours, the solvent was evaporated under reduced pressure, and the residue was diluted with 300 m of diisopropyl ether.
l-Ornithine methyl dihydrochloride of colorless powder (hygroscopic) 33.0
9 g are obtained. NMR (D 2 O) δ: 1.80 to 2.60
(4H, m) 3.35 (2H, distorted
t, J = 8 Hz), 4.13 (3H, s), 4.51
(1H, t, J = 6Hz)
【００２５】ｂ）前記ａ）で得たＬ−オルニチンメチル
・２塩酸塩６２．０ｇの冷水溶液３００ｍｌをアンバー
ライトＩＲＡ−４０（ＯＨ−）イオン交換樹脂充填のカ
ラムクロマトグラフィーに付し、ニンヒドリン呈色陽性
画分を減圧下溶媒留去すると無色粉末（吸湿性）の
（Ｓ）−３−アミノピペリドン４４．５ｇを得る。 B) 62.0 g of L-ornithine methyl dihydrochloride obtained in the above a) 300 ml of a cold aqueous solution was subjected to column chromatography packed with Amberlite IRA-40 (OH − ) ion exchange resin to give ninhydrin. The solvent was distilled off from the color positive fraction under reduced pressure to obtain 44.5 g of colorless powder (hygroscopic) (S) -3-aminopiperidone.
【００２６】Ｃ）水素化アルミニウムリチウム２２．８
ｇのテトラヒドロフラン１０００ｍｌ懸濁液に前記ｂ）
で得た（Ｓ）−３−アミノピペリドン２０．０ｇのテト
ラヒドロフラン３００ｍｌ懸濁液を氷冷攪拌下滴下す
る。反応混合物を６時間加熱還流後、過剰の水素化アル
ミニウムリチウムを氷冷攪拌下１０％水酸化ナトリムウ
ムにて注意深く処理する。析出する無機物を濾別後、テ
トラヒドロフラン溶液を 中固化、吸湿性）の（Ｓ）−３−アミノピペリジン３．
０ｇを得る。C) Lithium aluminum hydride 22.8
g in 1000 ml of a tetrahydrofuran suspension described above in b).
A suspension of 20.0 g of the (S) -3-aminopiperidone obtained in 1 above in 300 ml of tetrahydrofuran is added dropwise under stirring with ice cooling. After the reaction mixture is heated under reflux for 6 hours, excess lithium aluminum hydride is carefully treated with 10% sodium hydroxide under ice cooling with stirring. After separating the precipitated inorganic matter by filtration, a tetrahydrofuran solution was added. Medium solidified, hygroscopic (S) -3-aminopiperidine 3.
Get 0 g.
【００２７】ｄ）前記ｃ）で得た（Ｓ）−３−アミノピ
ペリジン４．０ｇ、１−シクロプロピル−１，４−ジヒ
ドロ−６，７，８−トリフルオロ−４−オキソキノリン
−３−カルボン酸１１．４ｇおよびトリエチルアミン
８．４ｇのアセトニトリル２５０ｍｌ懸濁液を攪拌下３
時間加熱還流する。冷後析出する粉末を濾取し、エタノ
ール５５０ｍｌと水２５０ｍｌの混合液により処理する
と融点２４７．８℃（分解）の７−（３−Ｓ−アミノピ
ペリジン−１−イル）−１−シクロプロピル−１，４−
ジヒドロ−６，８−ジフルオロ−４−オキソキノリン−
３−カルボン酸の無色針状晶１１．６ｇを得る。〔α〕
Ｄ２０＝＋１９．９°（Ｃ＝１．００２、０ Ｒ（ＣＤＣｌ３）δ：１．１０〜１．４０（４Ｈ，ｍ）
２．９０〜３．６０（９Ｈ，ｍ）、３．９５〜４．０５
（１Ｈ，ｍ）、７．８３（１Ｈ，ｄｄ，Ｊ＝１２Ｈｚ，
Ｊ＝２Ｈｚ）、９．７８（１Ｈ，ｓ）D) 4.0 g of (S) -3-aminopiperidine obtained in the above c), 1-cyclopropyl-1,4-dihydro-6,7,8-trifluoro-4-oxoquinoline-3- A suspension of 11.4 g of carboxylic acid and 8.4 g of triethylamine in 250 ml of acetonitrile was stirred 3
Heat to reflux for hours. The powder precipitated after cooling was collected by filtration and treated with a mixed solution of 550 ml of ethanol and 250 ml of water to give 7- (3-S-aminopiperidin-1-yl) -1-cyclopropyl-having a melting point of 247.8 ° C. (decomposition). 1,4-
Dihydro-6,8-difluoro-4-oxoquinoline-
11.6 g of colorless needles of 3-carboxylic acid are obtained. [Α]
D 20 = + 19.9 ° (C = 1.002,0 R (CDCl 3 ) δ: 1.10 to 1.40 (4H, m)
2.90-3.60 (9H, m), 3.95-4.05
(1H, m), 7.83 (1H, dd, J = 12Hz,
J = 2 Hz), 9.78 (1H, s)
【００２８】[0028]
【実施例５】Ｄ−オルニチン・１塩酸塩を出発物質と
し、以下実施例４ａ〜ｃ）に記載の方法と同様に処理し
て得た（Ｒ）−３−アミノピペリジンに１−シクロプロ
ピル−１，４−ジヒドロ−６，７，８−トリフルオロ−
４−オキソキノリン−３−カルボン酸を反応させ、以下
実施例４ｄ）に記載の方法と同様に処理し、７−（３−
Ｒ−アミノピペリジン−１−イル）−１−シクロプロピ
ル−１，４−ジヒドロ−６，８−ジフルオロ−４−オキ
ソキノリン−３−カルボン酸を得る。融点２５２．３℃
（分解）、〔α〕Ｄ２０＝−１５．５℃（Ｃ＝０．９９
１，０．１Ｎ ＣＤＣ１３）δ：１．１０〜１．４０（４Ｈ，ｍ）、
２．９０〜３．６０（９Ｈ，ｍ）、３．９０〜４．１０
（１Ｈ，ｍ）、７．８６（１Ｈ，ｄｄ，Ｊ＝１２Ｈｚ，
Ｊ＝２Ｈｚ）、８．７６（１Ｈ，ｓ）。[Example 5] (R) -3-Aminopiperidine obtained by treating D-ornithine monohydrochloride as a starting material in the same manner as in Examples 4a to 4c below was treated with 1-cyclopropyl-. 1,4-dihydro-6,7,8-trifluoro-
4-oxoquinoline-3-carboxylic acid was reacted and treated as described in Example 4d) below to give 7- (3-
R-aminopiperidin-1-yl) -1-cyclopropyl-1,4-dihydro-6,8-difluoro-4-oxoquinoline-3-carboxylic acid is obtained. Melting point 252.3 ° C
(Decomposition), [α] D 20 = −15.5 ° C. (C = 0.99
1,0.1N CDC1 3 ) δ: 1.10 to 1.40 (4H, m),
2.90-3.60 (9H, m), 3.90-4.10.
(1H, m), 7.86 (1H, dd, J = 12Hz,
J = 2 Hz), 8.76 (1H, s).
【００２９】[0029]
【実施例６】 ａ）１−シクロプロピル−６，８−ジフロオロ−７−
（３−アセトアミドピペリジン−１−イル）−１，４−
ジヒドロ−４−オキソキノリン−３−カルボン酸４．０
５ｇ、ナトリウムメトキシド２．１６ｇおよびジメチル
ホルムアミド１２０ｍｌの混合物を１００〜１４０℃で
２時間攪拌する。反応混合物を減圧下濃縮し残渣に水を
加え、１Ｎ−ＨＣｌで中和し、次いで反応混合物を濃縮
して残渣をシリカゲルカラムクロマトグラフィー（クロ
ロホルム：メタノール）に付すと７−（３−アセトアミ
ドピペリジン−１−イル）−１−シクロプロピル−６−
フルオロ−１，４−ジヒドロ−８−メトキシ−４−オキ
ソキノリン−３−カルボン酸を得る。融点２４８〜２５
０℃。Example 6 a) 1-Cyclopropyl-6,8-difluoro-7-
(3-acetamidopiperidin-1-yl) -1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 4.0
A mixture of 5 g, 2.16 g of sodium methoxide and 120 ml of dimethylformamide is stirred at 100-140 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, the mixture was neutralized with 1N-HCl, the reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography (chloroform: methanol) to give 7- (3-acetamidopiperidine- 1-yl) -1-cyclopropyl-6-
Fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid is obtained. Melting point 248-25
0 ° C.
【００３０】ｂ）前記ａ）で得た７−（３−アセトアミ
ドピペリジン−１−イル）−１−シクロプロピル−６−
フルオロ−１，４−ジヒドロ−８−メトキシ−４−オキ
ソキノリン−３−カルボン酸１．２５ｇを６Ｎ塩酸３０
ｍｌ、エタノール５ｍｌに懸濁し３時間、１００℃で加
熱する。反応混合物を減圧下濃縮し、残渣をシリカゲル
カラムクマトグラフィー（クロロホルム：メタノール：
水酸化アンモニウム＝１００：３０：５）に付し、７−
（３−アミノピペリジン−１−イル）−１−シクロプロ
ピル−６−フルオロ−１，４−ジヒドロ−８−メトキシ
−４−オキソキノリン−３−カルボン酸を得る。融点１
７６〜１７７℃。B) 7- (3-acetamidopiperidin-1-yl) -1-cyclopropyl-6-obtained in the above a)
Fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (1.25 g) was added to 6N hydrochloric acid (30 g).
ml and 5 ml of ethanol, and heat at 100 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol:
Ammonium hydroxide = 100: 30: 5), 7-
(3-Aminopiperidin-1-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid is obtained. Melting point 1
76-177 ° C.
【００３１】[0031]
【実施例７】実施例１のｂ）で得た１−シクロプロピル
−６，８−ジフルオロ−７−（３−アミノピペリジン−
１−イル）−１，４−ジヒドロ−４−オキソキノリン−
３−カルボン酸１．２１ｇ、ナトリウムメトキシド１．
２ｇおよびジメチルホルムアミド４０ｍｌの混合物を１
２０〜１４０℃で２時間攪拌する。反応混合物を減圧下
濃縮し、残渣に水を加え、１Ｎ塩酸で中和し、次いで反
応混合物を減圧下濃縮してシリカゲルカラムクロマトグ
ラフィー（クロロホルム：メタノール：水酸化アンモニ
ウム＝１００：３０：５）に付し、７−（３−アミノピ
ペリジン−１−イル）−１−シクロプロピル−６−フル
オロ−１，４−ジヒドロ−８−メトキシ−４−オキソキ
ノリン−３−カルボン酸を得る。このものは前記実施例
６で製造したものとその物性値が一致した。Example 7 1-Cyclopropyl-6,8-difluoro-7- (3-aminopiperidine-obtained in b) of Example 1
1-yl) -1,4-dihydro-4-oxoquinoline-
1.21 g of 3-carboxylic acid, sodium methoxide 1.
1 g of a mixture of 2 g and 40 ml of dimethylformamide.
Stir at 20-140 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue and neutralized with 1N hydrochloric acid, and then the reaction mixture was concentrated under reduced pressure and subjected to silica gel column chromatography (chloroform: methanol: ammonium hydroxide = 100: 30: 5). Then, 7- (3-aminopiperidin-1-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid is obtained. This product had the same physical properties as those produced in Example 6 above.
【００３２】[0032]
【実施例８】前記実施例６または７で得られた７−（３
−アミノピペリジン−１−イル）−１−シクロプロピル
−６−フルオロ−１，４−ジヒドロ−８−メトキシ−４
−オキソキノリン−３−カルボン酸をクロロホルム：メ
タノール（１：１）に懸濁し、メタノール−塩酸を滴下
し、以下常法に従い処理すると７−（３−アミノピペリ
ジン−１−イル）−１−シクロプロピル−６−フルオロ
−１，４−ジヒドロ−８−メトキシ−４−オキソキノリ
ン−３−カルボン酸の塩酸塩を得る。融点１８８〜１９
０℃（分解）。Example 8 7- (3 obtained in Example 6 or 7
-Aminopiperidin-1-yl) -1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4
-Oxoquinoline-3-carboxylic acid was suspended in chloroform: methanol (1: 1), methanol-hydrochloric acid was added dropwise, and the following treatment was carried out according to a conventional method to give 7- (3-aminopiperidin-1-yl) -1-cyclo. The hydrochloride salt of propyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid is obtained. Melting point 188-19
0 ° C (decomposition).
【００３３】[0033]
【実施例９】５−アミノ−１−シクロプロピル−６，
７，８−トリフルオロ−１，４−ジヒドロ−４−オキソ
キノリン−３−カルボン酸１．３ｇ、３−アミノピペリ
ジン塩酸塩０．９０５ｇ、トリエチルアミン３ｇおよび
４０ｍｌのアセトニトリルとからなる懸濁液を５時間還
流する。反応混合物を室温に冷却し、溶媒を減圧下濃縮
後、シリカゲルカラムクロマトグラフィー（クロロホル
ム：メタノール：水酸化アンモニウム＝１５：５：１）
に付し黄色結晶を得る〔マススペクトルｍ／ｅ：３７８
（Ｍ＋）〕得られた結晶をイソプロパノールに懸濁し、
１０％塩酸でｐＨを約１〜２に調整し析出する結晶を濾
取し、エタノールより再結晶すると５−アミノ−７−
（３−アミノピペリジン−１−イル）−１−シクロプロ
ピル−６，８−ジフルオロ−１，４−ジヒドロ−４−オ
キソキノリン−３−カルボン酸の塩酸塩０．６ｇを得
る。融点２６５℃（分解）。Example 9 5-Amino-1-cyclopropyl-6,
A suspension consisting of 1.3 g of 7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.905 g of 3-aminopiperidine hydrochloride, 3 g of triethylamine and 40 ml of acetonitrile was added to 5 Reflux for an hour. The reaction mixture was cooled to room temperature and the solvent was concentrated under reduced pressure, followed by silica gel column chromatography (chloroform: methanol: ammonium hydroxide = 15: 5: 1).
To give yellow crystals (mass spectrum m / e: 378
(M + )] The obtained crystals were suspended in isopropanol,
The pH was adjusted to about 1-2 with 10% hydrochloric acid, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 5-amino-7-
0.6 g of the hydrochloride of (3-aminopiperidin-1-yl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained. Melting point 265 [deg.] C (decomposition).
【００３４】[0034]
【実施例１０】５−アミノ−１−シクロプロピル−６，
７−ジフルオロ−８−メトキシ−１，４−ジヒドロ−４
−オキソキノリン−３−カルボン酸１．０３９ｇ、３−
メチルアミノピペリジン塩酸塩１．５ｇ、トリエチルア
ミン２．５ｇ、アセトニトリル３０ｍｌ、ジメチルホル
ムアミド１０ｍｌからなる懸濁液を一夜還流する。反応
混合物を減圧下濃縮し、シリカゲルクロマトグラフィー
（クロロホルム：メタノール：水酸化アンモニウム＝１
５：５：１）に付し黄色結晶を得る〔マススペクトルｍ
／ｅ：４０４（Ｍ＋）〕。得られた結晶をエタノールよ
り再結晶すると黄色針状晶の５−アミノ−１−シクロプ
ロピル−６−フルオロ−１，４−ジヒドロ−７−（３−
メチルアミノピペリジン−１−イル）−８−メトキシ−
４−オキソキノリン−３−カルボン酸４００ｍｇを得
る。融点２６５〜２７５℃（分解）。Example 10 5-amino-1-cyclopropyl-6
7-difluoro-8-methoxy-1,4-dihydro-4
-Oxoquinoline-3-carboxylic acid 1.039 g, 3-
A suspension consisting of 1.5 g of methylaminopiperidine hydrochloride, 2.5 g of triethylamine, 30 ml of acetonitrile and 10 ml of dimethylformamide is refluxed overnight. The reaction mixture was concentrated under reduced pressure and subjected to silica gel chromatography (chloroform: methanol: ammonium hydroxide = 1.
5: 5: 1) to give yellow crystals [mass spectrum m
/ E: 404 (M + )]. When the obtained crystals were recrystallized from ethanol, yellow needle crystals of 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-7- (3-
Methylaminopiperidin-1-yl) -8-methoxy-
400 mg of 4-oxoquinoline-3-carboxylic acid are obtained. Melting point 265-275 [deg.] C (decomposition).
【００３５】[0035]
【実施例１１】１−シクロプロピル−６，７−ジフロオ
ロ−８−メトキシ−１，４−ジヒドロ−４−オキソキノ
リン−３−カルボン酸１．４８ｇ、３−アミノメチルピ
ペリジン１．１４ｇ、トリエチルアミン１．５ｇ、アセ
トニトリル２０ｍｌ、ジメチルホルムアミド１０ｍｌと
からなる懸濁液を一夜還流する。反応混合物を減圧下濃
縮し、残渣をシリカゲルカラムクロマトグラフィー（ク
ロロホルム：メタノール：水酸化アンモニウム＝１５：
５：１）に付し、１−シクロプロピル−６−フルオロ−
１，４−ジヒドロ−７−（３−アミノメチルピペリジン
−１−イル）−８−メトキシ−４−オキソキノリン−３
−カルボン酸を得る。イソプロパノール−水より再結晶
すると黄色プリズム晶を得る。融点１９２〜１９３℃。
マススペクトルｍ／ｅ：３８９（Ｍ＋）。Example 11 1-Cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1.48 g, 3-aminomethylpiperidine 1.14 g, triethylamine 1 A suspension consisting of 0.5 g, 20 ml acetonitrile and 10 ml dimethylformamide is refluxed overnight. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: methanol: ammonium hydroxide = 15:
5: 1), 1-cyclopropyl-6-fluoro-
1,4-Dihydro-7- (3-aminomethylpiperidin-1-yl) -8-methoxy-4-oxoquinoline-3
-Obtaining a carboxylic acid. Recrystallization from isopropanol-water gives yellow prism crystals. Melting point 192-193 [deg.] C.
Mass spectrum m / e: 389 (M + ).
【００３６】[0036]
【実施例１２】１−シクロプロピル−６，７，８−トリ
フルオロ−１，４−ジヒドロ−４−オキソキノリン−３
−カルボン酸２．８３ｇ，３−アセトアミドピペリジン
１．８７ｇ，トリエチルアミン１．５ｇ，アセトニトリ
ル６０ｍｌよりなる混合物を攪拌下６時間還流する。残
渣をろ取すると粗製の７−（３−アセトアミドピペリジ
ン−１−イル）−１−シクロプロピル−６，８−ジフル
オロ−１，４−ジヒドロ−４−オキソキノリン−３−カ
ルボン酸３．５ｇを得る。この化合物３．０ｇを６Ｎ塩
酸５０ｍｌに懸濁し、攪拌下１００℃で５時間加熱す
る。反応混合物を減圧下濃縮し、残渣を氷冷下２０ｍｌ
のアンモニア水に溶解する。溶媒を除去した後、残渣を
シリカゲルカラムクロマトグラフィー（クロロホルム：
メタノール：水酸化アンモニウム＝１５：５：１）に付
すと、７−（３−アミノメチルピペリジン−１−イル）
−１−シクロプロピル−６，８−ジフルオロ−１，４−
ジヒドロ−４−オキソキノリン−３−カルボン酸１．６
ｇを得る。メタノール−水から再結晶すると融点２４２
〜２４３℃の無色プリズム晶を得る。マススペクトルｍ
／ｅ：３３７（Ｍ＋）。Example 12 1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3
A mixture of -2.83 g of carboxylic acid, 1.87 g of 3-acetamidopiperidine, 1.5 g of triethylamine and 60 ml of acetonitrile is refluxed with stirring for 6 hours. The residue was collected by filtration to obtain 3.5 g of crude 7- (3-acetamidopiperidin-1-yl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. obtain. 3.0 g of this compound is suspended in 50 ml of 6N hydrochloric acid, and heated at 100 ° C. for 5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was cooled with ice to 20 ml.
Dissolved in ammonia water. After removing the solvent, the residue was subjected to silica gel column chromatography (chloroform:
Methanol: ammonium hydroxide = 15: 5: 1) gives 7- (3-aminomethylpiperidin-1-yl).
-1-Cyclopropyl-6,8-difluoro-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 1.6
get g. Recrystallized from methanol-water, melting point 242
Colorless prism crystals of ˜243 ° C. are obtained. Mass spectrum m
/ E: 337 (M <+> ).
【００３７】[0037]
【実施例１３】１−シクロプロピル−６，７−ジフルオ
ロ−１，４−ジヒドロ−８−メトキシ−４−オキソキノ
リン−３−カルボン酸２．９５ｇ，３−メチルアミノピ
ペリジン６．６９ｇ，トリエチルアミン１０ｇ，アセト
ニトリル５０ｍｌよりなる混合物を１２時間還流する。
反応混合物を減圧下濃縮し、残渣をクロロホルムで抽出
する。抽出物を飽和食塩水で洗滌後、減圧下濃縮し、残
渣をシリカゲルカラムクロマトグラフィー（クロロホル
ム：メタノール：水酸化アンモニウム＝１５：５：１）
に付すと１−シクロプロピル−６−フルオロ−１，４−
ジヒドロ−８−メトキシ−７−（３−メチルアミノピペ
リジン−１−イル）−４−オキソキノリン−３−カルボ
ン酸１．２８ｇを入る。このものはアセトニトリルから
再結晶すると融点１３４〜１３５℃の無色針状晶を得
る。EXAMPLE 13 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid 2.95 g, 3-methylaminopiperidine 6.69 g, triethylamine 10 g. A mixture of 50 ml of acetonitrile is refluxed for 12 hours.
The reaction mixture is concentrated under reduced pressure and the residue is extracted with chloroform. The extract was washed with saturated brine and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: methanol: ammonium hydroxide = 15: 5: 1).
When attached to 1-cyclopropyl-6-fluoro-1,4-
Charge 1.28 g of dihydro-8-methoxy-7- (3-methylaminopiperidin-1-yl) -4-oxoquinoline-3-carboxylic acid. This product is recrystallized from acetonitrile to obtain colorless needle crystals having a melting point of 134 to 135 ° C.
Claims (10)
ッ素原子又はメトキシ基を意味し、Ｒ３は水素原子又は
炭素数１〜３の低級アルキル基を意味し、ｎは０又は１
である）化合物およびその塩。1. A compound represented by the general formula (I): (In the formula, R 1 represents a hydrogen atom or an amino group, R 2 represents a fluorine atom or a methoxy group, R 3 represents a hydrogen atom or a lower alkyl group having 1 to 3 carbon atoms, and n is 0 or 1
And the salts thereof.
−１−シクロプロピル−１，４−ジヒドロ−６，８−ジ
フルオロ−４−オキソキノリン−３−カルボン酸2. 7- (3-Aminopiperidin-1-yl)
-1-Cyclopropyl-1,4-dihydro-6,8-difluoro-4-oxoquinoline-3-carboxylic acid
ル）−１−シクロプロピル−１，４−ジヒドロ−６，８
−ジフルオロ−４−オキソキノリン−３−カルボン酸3. 7- (3-S-Aminopiperidin-1-yl) -1-cyclopropyl-1,4-dihydro-6,8
-Difluoro-4-oxoquinoline-3-carboxylic acid
ル）−１−シクロプロピル−１，４−ジヒドロ−６，８
−ジフルオロ−４−オキソキノリン−３−カルボン酸4. 7- (3-R-Aminopiperidin-1-yl) -1-cyclopropyl-1,4-dihydro-6,8
-Difluoro-4-oxoquinoline-3-carboxylic acid
−１−シクロプロピル−６−フルオロ−１，４−ジヒド
ロ−８−メトキシ−４−オキソキノリン−３−カルボン
酸5. 7- (3-Aminopiperidin-1-yl)
-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid
−１−イル）−１−シクロプロピル−１，４−ジヒドロ
−６，８−ジフルオロ−４−オキソキノリン−３−カル
ボン酸6. Amino-5- (3-aminopiperidin-1-yl) -1-cyclopropyl-1,4-dihydro-6,8-difluoro-4-oxoquinoline-3-carboxylic acid
イル）−１−シクロプロピル−６，８−ジフルオロ−
１，４−ジヒドロ−４−オキソキノリン−３−カルボン
酸7. 7- (3-Aminomethylpiperidine-1-
Yl) -1-cyclopropyl-6,8-difluoro-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid
４−ジヒドロ−８−メトキシ−７−（３−メチルアミノ
ピペリジン−１−イル）−４−オキソキノリン−３−カ
ルボン酸8. 1-Cyclopropyl-6-fluoro-1,
4-dihydro-8-methoxy-7- (3-methylaminopiperidin-1-yl) -4-oxoquinoline-3-carboxylic acid
ルオロ−１，４−ジヒドロ−８−メトキシ−７−（３−
メチルアミノピペリジン−１−イル）−４−オキソキノ
リン−３−カルボン酸9. 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- (3-
Methylaminopiperidin-1-yl) -4-oxoquinoline-3-carboxylic acid
−イル）−１−シクロプロピル−６−フルオロ−１，４
−ジヒドロ−８−メトキシ−４−オキソキノリン−３−
カルボン酸10. 7- (3-Aminomethylpiperidine-1
-Yl) -1-cyclopropyl-6-fluoro-1,4
-Dihydro-8-methoxy-4-oxoquinoline-3-
carboxylic acid
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8135092A JPH05112554A (en) | 1992-02-19 | 1992-02-19 | New quinolonecarboxylic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8135092A JPH05112554A (en) | 1992-02-19 | 1992-02-19 | New quinolonecarboxylic acid derivative |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1125093A Division JPH0395177A (en) | 1988-05-19 | 1989-05-18 | Novel quinolone carboxylic acid derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH05112554A true JPH05112554A (en) | 1993-05-07 |
Family
ID=13743921
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8135092A Pending JPH05112554A (en) | 1992-02-19 | 1992-02-19 | New quinolonecarboxylic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH05112554A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996001260A1 (en) * | 1994-07-01 | 1996-01-18 | Dainippon Pharmaceutical Co., Ltd. | Pyridonecarboxylic acid derivative, ester thereof, salt thereof, and intermediate for synthesis of these compounds |
| KR19980066915A (en) * | 1997-01-29 | 1998-10-15 | 이웅열 | Novel quinolone carboxylic acid derivatives and preparation method thereof |
| US6645981B2 (en) * | 2000-12-14 | 2003-11-11 | The Procter & Gamble Company | Antimicrobial quinolones, their compositions and uses |
| US7868021B2 (en) | 1997-09-15 | 2011-01-11 | Warner Chilcott Company, Llc | Antimicrobial quinolones, their compositions and uses |
-
1992
- 1992-02-19 JP JP8135092A patent/JPH05112554A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996001260A1 (en) * | 1994-07-01 | 1996-01-18 | Dainippon Pharmaceutical Co., Ltd. | Pyridonecarboxylic acid derivative, ester thereof, salt thereof, and intermediate for synthesis of these compounds |
| KR19980066915A (en) * | 1997-01-29 | 1998-10-15 | 이웅열 | Novel quinolone carboxylic acid derivatives and preparation method thereof |
| US7868021B2 (en) | 1997-09-15 | 2011-01-11 | Warner Chilcott Company, Llc | Antimicrobial quinolones, their compositions and uses |
| US6645981B2 (en) * | 2000-12-14 | 2003-11-11 | The Procter & Gamble Company | Antimicrobial quinolones, their compositions and uses |
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