JPS60190777A - Optical active 6,8-difluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxylic acid derivative - Google Patents
Optical active 6,8-difluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxylic acid derivativeInfo
- Publication number
- JPS60190777A JPS60190777A JP4566484A JP4566484A JPS60190777A JP S60190777 A JPS60190777 A JP S60190777A JP 4566484 A JP4566484 A JP 4566484A JP 4566484 A JP4566484 A JP 4566484A JP S60190777 A JPS60190777 A JP S60190777A
- Authority
- JP
- Japan
- Prior art keywords
- dihydro
- carboxylic acid
- formula
- difluoro
- oxo
- 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
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Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は強い抗菌作用を有する新規な光学活性６．８−
ジフルオロ−１，４−ジヒドロ−４ン酸誘導体、及びそ
の薬理学的に許容しつる塩に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel optically active 6.8-
This invention relates to difluoro-1,4-dihydro-quaternic acid derivatives and pharmacologically acceptable salts thereof.
更に詳しく言えば、本発明は式（１）
（式中、※印が付いている炭素原子は、Ｒ又はＳの絶対
配置を有する不整炭素原子を表わす。）で示される新規
な光学活性６，８−ジフルＡロー１，４−ンヒドロ−４
−オキシー７−置換ピペラジニルキ／リン−５−カルボ
ン酸誘導体、及びその曇理学的６て許容しつる塩に関す
るものである。More specifically, the present invention provides novel optical activity 6, represented by formula (1) (in the formula, carbon atoms marked with * represent asymmetric carbon atoms having an absolute configuration of R or S). 8-diflu A rho 1,4-onehydro-4
-oxy-7-substituted piperazinyl/phosphorus-5-carboxylic acid derivatives and their ambiguously acceptable salts.
前記一般式（＋）で示される化合物の薬理学的に許容し
つる塩としては、酸付加塩又はアルカリ付加塩が挙げら
れ、酸付加塩としては、たとえば、塩酸、硫酸、硝酸、
臭化水素酸、ヨウ化水素酸、燐酸等の鉱酸塩、あるいは
酢酸・マレイン酸、フマール酸、クエン酸、酒石酸等の
有機酸塩が、アルカリ付加塩としては、たとえば、ナト
リウム、カリウム、カルシウム、アンモニウム塩等の無
機アルカリ塩、あるいはエタノールアミン、Ｎ、Ｎ−ジ
アルキルエタノールアミン等の有機塩基の塩等が挙げら
れる。Examples of pharmacologically acceptable salts of the compound represented by the general formula (+) include acid addition salts and alkali addition salts. Examples of acid addition salts include hydrochloric acid, sulfuric acid, nitric acid,
Mineral acid salts such as hydrobromic acid, hydroiodic acid, phosphoric acid, etc., or organic acid salts such as acetic acid/maleic acid, fumaric acid, citric acid, tartaric acid, etc. are used as alkali addition salts such as sodium, potassium, calcium, etc. , inorganic alkali salts such as ammonium salts, and salts of organic bases such as ethanolamine and N,N-dialkylethanolamine.
本発明の前記式（１）で示される新規な光学活性６．ｓ
−ジフルオロ−１，４−ジヒドロ−４−オキソ−７−置
換ピペラジニルキノリン−６−カルボン酸誘導体は、以
下の様にして製造することができる。Novel optical activity represented by the above formula (1) of the present invention 6. s
-Difluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-6-carboxylic acid derivative can be produced as follows.
即ち、前記式（１）で示される化合物は、次の式（１１
）
で示される６、７．８−）リフルオロ−１，４−ジヒド
ロ−４−オキソキノリン−６−カルボン酸誘導体と、次
の式（ＩＩＩ）
（式中、※印が付いている炭素原子は前述と同意義を表
わす。）
で示される光学活性なピペラジン誘導体とを、熱溶媒ド
あるいは溶媒Ｆにおいて反応させることにより製造する
ことができる。That is, the compound represented by the formula (1) is represented by the following formula (11
) 6,7.8-)lifluoro-1,4-dihydro-4-oxoquinoline-6-carboxylic acid derivative represented by the following formula (III) (wherein, the carbon atoms marked with It can be produced by reacting an optically active piperazine derivative represented by (has the same meaning as above) in a hot solvent or solvent F.
本反応において使用される溶媒としては、たとえば、水
、ブタノール、５−メトキシブタメール、イソアミルア
ルコール等のアルコール類、エチレングリコールジメチ
ルエーテル（モノグライム）、ジエチレングリコールジ
メチルエーテル（ジグライム）、トリエチレングリコー
ルジメチルエーテル（トリグライム）等のエーテル類、
ジメチルホルムアミド、ジメチルスルホキシド、ヘキサ
メチル７オスフオリツクトリアミド等の非プロトン性極
性溶媒、ヘンセン、トルエン等の芳香族炭化水素系溶媒
、あるいは、ピリジン、ビフリン、ルチジン、フリジン
、トリエチルアミン等の有機塩基が挙げられる。Examples of the solvent used in this reaction include water, alcohols such as butanol, 5-methoxybutamel, and isoamyl alcohol, ethylene glycol dimethyl ether (monoglyme), diethylene glycol dimethyl ether (diglyme), triethylene glycol dimethyl ether (triglyme), etc. ethers,
Examples include aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide, and hexamethyl heptophoric triamide, aromatic hydrocarbon solvents such as Hensen and toluene, and organic bases such as pyridine, bifrin, lutidine, furizine, and triethylamine. It will be done.
又、反応は室温から２００°の範囲で行なわれ、好まし
くは１００〜１８０°の範囲で適宜選択される。Further, the reaction is carried out at a temperature ranging from room temperature to 200°, preferably appropriately selected from a range of 100 to 180°.
本発明の製造方法において出発原料となった前記式（１
１）で示される６、７．８−）リフ用５５−４フ６５８
号、特開昭５６−３０９６４号等に既に開示されている
公知の物質である０又、前記式（ＩＩＩ ）で示される
′ＩＣＩＣ性などペラジン誘導体も公知の物質であり、
たとえば、ジャーナル・オブ・ケミカル・リサーチ、シ
ップ’／ ス（Ｊｏｕｒｎａｌ ｏｆ Ｃｈｅｍｉｃａ
ｌ Ｒｅ５ｅａｒｃｈ 。The formula (1) used as the starting material in the production method of the present invention
1) 6, 7.8-) 55-4 for riff 658
Perazine derivatives such as 'ICIC' represented by the above formula (III) are also known substances.
For example, Journal of Chemical Research, Ship'/S.
lRe5earch.
５ｙｒ１ｏｐＳｉＳ ）、１９８’０ （４） 、１３
３． ジャーナル オブ・ザ・ケミカル・ソサエティ、
ケミカル・コミュニケーションズ（Ｊｏｕｒｎａｌ○ｆ
ｔｈｅＣｈｅｍｉｃａｌ ５ｏｃｉｅｔｙ 、 Ｃｈ
ｅｍｉｃａｌ Ｃｏｎｙｎｕｎｉｃａｔｉｏｎｓ ）＋
１９８０ （８）、３３４等に既に開示されている０
この様にして製造される前記式（１）で示される新規な
６，８−ジフルオロ−１，４−ジヒドロ−４−オキソ−
７−置換ピペラジニルキノリン−６−カルボン酸誘導体
、及びその薬理学的に許容しうる塩は、ダラム陽性菌、
グラム陰性菌に対し広い抗菌作用を有し、医薬とし′Ｃ
極めて有用である。5yr1opSiS), 198'0 (4), 13
3. Journal of the Chemical Society,
Chemical Communications (Journal○f
theChemical 5ociety, Ch.
chemical communications)+
1980 (8), 334 etc. Novel 6,8-difluoro-1,4-dihydro-4-oxo-
7-substituted piperazinylquinoline-6-carboxylic acid derivatives and pharmacologically acceptable salts thereof
It has a wide range of antibacterial effects against Gram-negative bacteria and is used as a medicine.
Extremely useful.
以下、本発明を実施例によって説明する０実施例１
（Ｒ）−（＋）−１−エチル−６，８−ジフルオロ−１
，４−ジヒドロ−７−（６−メチル−１−ピペラジニル
）−４〜オキソキノリン−６−カルボン酸
１−エチル−６，７，８−）リフルオロ−１゜４−ジヒ
ドロ−４−オキソキノリン−６−カルボン酸２．００＃
、（Ｒ）−（−）−２−メチルビイラジ−，／（〔ワ）
２１−．６．４° ＜Ｃ＝１．エタメール））１．５
０．９及びピリジン１５ｙ＋ｔの混合物を１５分間加熱
還流する。反応後溶媒を留去する。得られた残渣を１０
％塩酸水溶液に溶解し、Ｗコ啼−炭酸水素す） ＩＪウ
ム水溶液を加えて中和する。析出物をｐ取し乾燥後、ク
ロロホルム及びメタノールの混液に溶解する。溶液にエ
タノール性塩酸を加え酸性となし、析出物を戸数する。EXAMPLE 1 (R)-(+)-1-Ethyl-6,8-difluoro-1
,4-dihydro-7-(6-methyl-1-piperazinyl)-4-oxoquinoline-6-carboxylic acid 1-ethyl-6,7,8-)lifluoro-1°4-dihydro-4-oxoquinoline- 6-carboxylic acid 2.00#
, (R)-(-)-2-methylbiyradi-,/([wa)
21-. 6.4° <C=1. Eta mail)) 1.5
A mixture of 0.9 and pyridine 15y+t is heated to reflux for 15 minutes. After the reaction, the solvent is distilled off. The obtained residue was
% hydrochloric acid aqueous solution and neutralize by adding an IJum aqueous solution. The precipitate is separated, dried, and then dissolved in a mixed solution of chloroform and methanol. Add ethanolic hydrochloric acid to the solution to make it acidic, and count the precipitate.
戸数物を水に溶かし、炭酸水素ナトリウム水溶液で中和
する。析出結晶を戸数し、無色結晶１．７２５’を得る
。クロロホルム及びエタノールの混液から再結晶して、
融点２４４．５〜２４５、５°の無色針状晶を得る。Dissolve the tofu in water and neutralize it with an aqueous sodium bicarbonate solution. The precipitated crystals were separated to obtain 1.725' of colorless crystals. Recrystallized from a mixture of chloroform and ethanol,
Colorless needle crystals with a melting point of 244.5-245, 5° are obtained.
〔α）％” ＋５９．５°（Ｃ＝１ 、クロロホルム）
元素分析値 Ｃ１７Ｈ１９Ｆ″２Ｎ３０．３理、倫ｆ直
Ｃ，５８，１１ｉＨ，５，４５ｉ Ｎ、１ １．９６
実験値 Ｃ，５８，１２；Ｈ，５，７２；Ｎ、 １２．
０７実施例２
（Ｓ）−（−）ｌ−エチル−６，８−ジフルオロ−１＋
４−ジヒドロ−７−（３−メチル−１−ピペラジニル
）−４−オキソキノリン−５−カルボン酸
１−エチル−６，７，１３−）リフルオロ−１゜４−ジ
ヒドロ−４−オキソキノリン−５−カルボン酸２．００
，９．（Ｓ）−（＋）−２−メチルビペラシア（〔７〕
甘＋６．８０（Ｃ＝１．エタノール））１．５０．９及
びピリジン２０ｍ１の混合物を２０分間加熱還流する。[α)%” +59.5° (C=1, chloroform)
Elemental analysis value C17H19F''2N30.3 Logic, ethics C, 58, 11iH, 5, 45i N, 1 1.96
Experimental value C, 58,12; H, 5,72; N, 12.
07 Example 2 (S)-(-)l-ethyl-6,8-difluoro-1+
4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxoquinoline-5-carboxylic acid 1-ethyl-6,7,13-)lifluoro-1°4-dihydro-4-oxoquinoline-5 -carboxylic acid 2.00
,9. (S)-(+)-2-methylbiperacea ([7]
A mixture of 1.50.9 (C=1.ethanol) and 20 ml of pyridine is heated under reflux for 20 minutes.
以下、実施例１と′同様に処理し、無色結晶１．２５Ｆ
を得る。クロロホルム及びエタノールの混液から再結晶
して、融点２４２．５〜２．４３．５°の無色針状晶を
得る。Hereinafter, the treatment was carried out in the same manner as in Example 1, and colorless crystals of 1.25F were obtained.
get. Recrystallization from a mixture of chloroform and ethanol gives colorless needles with a melting point of 242.5-2.43.5°.
〔α）Ｄ−３４，Ｔｏ＜ｃ＝１．クロロホルム）元素分
析値 Ｃ１７Ｈ１９Ｆ２Ｎ３０３理論値 Ｃ，５，８，
１１ｉＨ，５，４５；Ｎ、 １１．９６実験値 Ｃ，５
８，０１；Ｈ，５，６４ｉＮ、 １１．７７特許出願人
北陸製薬株式会社[α) D-34, To<c=1. Chloroform) Elemental analysis value C17H19F2N303 Theoretical value C, 5, 8,
11iH, 5, 45; N, 11.96 experimental value C, 5
8,01;H,5,64iN, 11.77 Patent applicant Hokuriku Pharmaceutical Co., Ltd.
Claims (1)
対配置を有する不整炭素原子を表わす。）で示される光
学活性な６，８−ジフル珂ＩＪ−１゜４−ジヒドロ−４
−オキソ−７−置換ビペラジニルキ／リン−６−カルボ
ン酸誘導体、及びその薬理学的に許容しつる塩。(In the formula, a carbon atom marked with an asterisk represents an asymmetric carbon atom having an absolute configuration of IR or S.)
-oxo-7-substituted biperazinyl-6-carboxylic acid derivatives and pharmacologically acceptable salts thereof.
Priority Applications (18)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4566484A JPS60190777A (en) | 1984-03-12 | 1984-03-12 | Optical active 6,8-difluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxylic acid derivative |
| AU32984/84A AU553415B2 (en) | 1983-09-19 | 1984-09-12 | 6-fluoro-1-4-dihydro-4-oxo-7-substituted piperazinyl- quinoline-3-carboxylic acids |
| KR1019840005625A KR870001016B1 (en) | 1983-09-19 | 1984-09-15 | Process for preparing 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxylic acid derivatives |
| AT84111035T ATE34573T1 (en) | 1983-09-19 | 1984-09-15 | A 6-FLUORO-1,4-DIHYDRO-4-OXO-7 SUBSTITUTED PIPERAZINYLQUINOLINE-3-CARBONIC ACID DERIVATIVE AND PROCESS FOR ITS PREPARATION. |
| DE19843433924 DE3433924A1 (en) | 1983-09-19 | 1984-09-15 | 6-FLUORO-1,4-DIHYDRO-4-OXO-7-SUBSTITUTED PIPERAZINYL-CHINOLINE-3-CARBONIC ACID DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
| EP84111035A EP0140116B1 (en) | 1983-09-19 | 1984-09-15 | A 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinyl-quinoline-3-carboxylic acid derivative and the method for preparing the same |
| FI843620A FI80033C (en) | 1983-09-19 | 1984-09-17 | Process for the preparation of pharmacologically valuable 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxyl derivative |
| US06/651,423 US4528287A (en) | 1983-09-19 | 1984-09-17 | 6-Fluoro-1, 4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxylic acids and the method for preparing the same |
| FR8414294A FR2555584B1 (en) | 1983-09-19 | 1984-09-18 | FLUORO-6-DIHYDRO-1,4-OXO-4-PIPERAZINYL SUBSTITUE-7-QUINOLINE-CARBOXYLIC-3 ACID DERIVATIVES AND PROCESS FOR THEIR PREPARATION AND ANTI-BACTERIAL-BASED PHARMACEUTICAL COMPOSITIONS |
| ES536004A ES8604565A1 (en) | 1983-09-19 | 1984-09-18 | A 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinyl-quinoline-3-carboxylic acid derivative and the method for preparing the same. |
| SI8411603A SI8411603A8 (en) | 1983-09-19 | 1984-09-18 | Process for obtaining derivatives of 6-fluoro-1,4-dihydro-4-oxo-7- substituted piperazinyl-quinoline-3-carboxylic acids |
| HU843498A HU193226B (en) | 1983-09-19 | 1984-09-18 | Process for preparing 6-fluoro-1,4-dihydro-4-oxo-7-substituted-piperazinyl-quinoline-3-carboxylic acid derivatives |
| DK445084A DK157997C (en) | 1983-09-19 | 1984-09-18 | 6-FLUOR-1,4-DIHYDRO-4-OXO-7-SUBSTITUTED PIPERAZINYLQUINOLINE-3-CARBOXYLIC ACID DERIVATIVES AND THEIR PHARMACOLOGICAL ACCEPTABLE SALTS AND PHARMACEUTICAL COMPOSITIONS FOR TREATMENT |
| YU1603/84A YU45204B (en) | 1983-09-19 | 1984-09-18 | Process for making derivatives of 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinyle-quinoline-3-carboxilic acid |
| CA000463652A CA1238638A (en) | 1983-09-19 | 1984-09-19 | 6-fluoro-1, 4-dihydro-4-oxo-7-substituted piperazinyl- quinoline-3-carboxylic acid derivative and the method for preparing the same |
| ES545756A ES8609303A1 (en) | 1983-09-19 | 1985-07-31 | A 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinyl-quinoline-3-carboxylic acid derivative and the method for preparing the same. |
| HK621/91A HK62191A (en) | 1983-09-19 | 1991-08-08 | A 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinyl-quinoline-3-carboxylic acid derivative and the method for preparing the same |
| HRP-1603/84A HRP930651B1 (en) | 1983-09-19 | 1993-04-01 | Process for the preparation of 6-fluoro-1,4-dihydro-4-oxo-7-substituted piperazinyl-quinoline-3-carboxylic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4566484A JPS60190777A (en) | 1984-03-12 | 1984-03-12 | Optical active 6,8-difluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxylic acid derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS60190777A true JPS60190777A (en) | 1985-09-28 |
Family
ID=12725648
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4566484A Pending JPS60190777A (en) | 1983-09-19 | 1984-03-12 | Optical active 6,8-difluoro-1,4-dihydro-4-oxo-7-substituted piperazinylquinoline-3-carboxylic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60190777A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0661974A4 (en) * | 1991-11-27 | 1994-08-29 | Sepracor Inc | Methods and compositions for treating infection using optically pure (r)-lomefloxacin. |
| EP0614364A1 (en) * | 1991-11-27 | 1994-09-14 | Sepracor, Inc. | Methods and compositions for treating infection using optically pure (s)-lomefloxacin |
| JP2007112559A (en) * | 2005-10-19 | 2007-05-10 | Hitachi Ltd | Elevator device |
-
1984
- 1984-03-12 JP JP4566484A patent/JPS60190777A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0661974A4 (en) * | 1991-11-27 | 1994-08-29 | Sepracor Inc | Methods and compositions for treating infection using optically pure (r)-lomefloxacin. |
| EP0614364A1 (en) * | 1991-11-27 | 1994-09-14 | Sepracor, Inc. | Methods and compositions for treating infection using optically pure (s)-lomefloxacin |
| EP0614364A4 (en) * | 1991-11-27 | 1994-10-19 | Sepracor Inc | Methods and compositions for treating infection using optically pure (s)-lomefloxacin. |
| EP0661974A1 (en) * | 1991-11-27 | 1995-07-12 | Sepracor, Inc. | Methods and compositions for treating infection using optically pure (r)-lomefloxacin |
| JP2007112559A (en) * | 2005-10-19 | 2007-05-10 | Hitachi Ltd | Elevator device |
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