JPS60166687A - 5-fluoro-3,4,7,10-tetrahydro-7-oxo-2h-pyrido(3,2-h)-1,4- benzoxazine-8-carboxylic acid derivative - Google Patents
5-fluoro-3,4,7,10-tetrahydro-7-oxo-2h-pyrido(3,2-h)-1,4- benzoxazine-8-carboxylic acid derivativeInfo
- Publication number
- JPS60166687A JPS60166687A JP59021863A JP2186384A JPS60166687A JP S60166687 A JPS60166687 A JP S60166687A JP 59021863 A JP59021863 A JP 59021863A JP 2186384 A JP2186384 A JP 2186384A JP S60166687 A JPS60166687 A JP S60166687A
- Authority
- JP
- Japan
- Prior art keywords
- carboxylic acid
- oxo
- lower alkyl
- tetrahydro
- fluoro
- 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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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は新規な５−フルオロ−３，４，７゜１０−テト
ラヒドロ−７−オキソ−２Ｈ−ピリド［３，２−ｈ）−
１，４−ベンズオキサジン−８−カルボン酸誘導体、及
びその薬理学的に許容しつる塩をこ関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 5-fluoro-3,4,7°10-tetrahydro-7-oxo-2H-pyrido[3,2-h)-
It relates to 1,4-benzoxazine-8-carboxylic acid derivatives and pharmacologically acceptable salts thereof.
（式中、Ｒ１は低級アルキル基を、Ｒ２は低級アルキル
基又は低級アルキｔｖｒｔ換アミノアルキル基を表わす
。）
で示される５−フルオロ−３，４，７，１０−テトラヒ
ドロ−７−オキソ−２Ｈ−ピリド〔３゜２−ｈ）−１，
４−ベンズオキサジン−８−カルボン酸誘導体、及びそ
の薬理学的に許容しうる塩に関するものである。(In the formula, R1 represents a lower alkyl group, and R2 represents a lower alkyl group or a lower alkyl tvrt-substituted aminoalkyl group.) 5-fluoro-3,4,7,10-tetrahydro-7-oxo-2H -pyrid [3゜2-h)-1,
This invention relates to 4-benzoxazine-8-carboxylic acid derivatives and pharmacologically acceptable salts thereof.
本発明の前記一般式（１）中、Ｒ１及びＲ２で示される
低級アルキル基としては、たとえば、メチ／Ｌ／、エチ
）ｖｌ プロピル
チル基等が、又、Ｒ２ で示される低級アルキル１ｄ換
アミノアルキル基としては、たとえば、メチルアミノメ
チル、メチルアミノエチル、メチルアミノプロピル、メ
チルアミノブチル、エチルアミノエチル、ジメチルアミ
ノメチル、ジエチルアミノメチル、ジエチルアミノエチ
／ｌ／、 ジプロピルアミノエチル、ジプロピルアミノ
ブチル基等が挙げられる。In the general formula (1) of the present invention, the lower alkyl group represented by R1 and R2 includes, for example, methyl/L/, ethyl)vl propyltyl group, etc., and the lower alkyl 1d-substituted aminoalkyl group represented by R2. Examples of the group include methylaminomethyl, methylaminoethyl, methylaminopropyl, methylaminobutyl, ethylaminoethyl, dimethylaminomethyl, diethylaminomethyl, diethylaminoethyl/l/, dipropylaminoethyl, dipropylaminobutyl, etc. can be mentioned.
前記一般式（Ｉ）で示される化合物の薬理学的に許容し
うる塩としては、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、硝酸、硫酸、
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ｍ等
（’）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、アンモニウム廖
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 (I) include acid addition salts and alkali addition salts, and examples of acid addition salts include hydrochloric acid, nitric acid, sulfuric 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 , inorganic alkali salts such as potassium, calcium, and ammonium, or ethanolamine, N,
Examples include salts of organic bases such as N-dialkylethanolamine.
本発明の前記一般式（１）で示される新規な５−フルオ
ロ−３，４，７，１０−テトラヒドロ−７−オキソ−２
Ｈ−ピリド［３，２−ｈ’：１−１．４−ペンズオギサ
ジンー８−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Ｏ
即ち、本発明に係わる前記一般式（１）で示される化合
物は、次の一般式（１Ｎ）
（式中、Ｒ１及びＲ２は前述と同意義を表わす。）で示
される６、８−ジフルオロ−１，４−ジヒドロ−７−ヒ
トロキシエチルアミノー４−１ｔ−ソキノリンー３−カ
ルボン酸誘導体を、脱酸剤としての塩基の存在下、溶媒
中で反応させることにより製造することができる。Novel 5-fluoro-3,4,7,10-tetrahydro-7-oxo-2 represented by the above general formula (1) of the present invention
The H-pyrido[3,2-h':1-1,4-penzogisazine-8-carboxylic acid derivative can be produced as follows. ) is a 6,8-difluoro-1,4-dihydro-7-hydroxyethyl compound represented by the following general formula (1N) (wherein R1 and R2 have the same meanings as above). The amino-4-1t-soquinoline-3-carboxylic acid derivative can be produced by reacting it in a solvent in the presence of a base as a deoxidizing agent.
本反応において使用される溶媒としては、反応を阻害し
ない限りいかなるものでもよく、たとえば、ブタノール
、エーテル、テトラヒドロフラン、ジメチルホルムアミ
ド、ジメチルスルホキシド、ベンゼン等が挙げられる。Any solvent may be used in this reaction as long as it does not inhibit the reaction, and examples thereof include butanol, ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, benzene, and the like.
又、本反応において使用される脱酸剤としての塩基とし
ては、たとえば、ナトリウム、ナトリウムアルコラード
、水素化ナトリウム、ブチルリチウム等が挙げられる。Further, examples of the base used as a deoxidizing agent in this reaction include sodium, sodium alcoholade, sodium hydride, butyllithium, and the like.
又、反応は室温から溶媒の加熱還流下において行われる
。Further, the reaction is carried out at room temperature while heating the solvent under reflux.
本発明の製造方法において出発原料となった前記一般式
（ＩＴ）で示される６、８−ジフルオロ−１，４−ジヒ
ドロ−７−ヒトロキシエチルアミノー４−オキソキノリ
ン−６−カルボン酸誘導体は、いずれも新規な物質であ
り、その製造については参考例に記載した。The 6,8-difluoro-1,4-dihydro-7-hydroxyethylamino-4-oxoquinoline-6-carboxylic acid derivative represented by the general formula (IT) that is the starting material in the production method of the present invention is Both are new substances, and their production is described in Reference Examples.
この様にして製造される前記一般式（１）で示される新
規な５−フルオロ−３，４，７，１０−テトラヒドロ−
７−オキソ−２Ｈ−ピリド（３，２−）１：］ −］１
．４−ペンズオ午サジンす８−カルボン酸誘導体及びそ
の薬理学的に許容しつる塩は、ダラム陽性菌、グラム陰
性菌に対１７て強い抗菌作用を有し、医薬として極めて
有用である。The novel 5-fluoro-3,4,7,10-tetrahydro- represented by the general formula (1) produced in this way
7-oxo-2H-pyrido(3,2-)1:] -]1
．． 4-Carboxylic acid derivatives and their pharmacologically acceptable salts have strong antibacterial activity against Durum-positive bacteria and Gram-negative bacteria, and are extremely useful as medicines.
以下、本発明を実施例によって説明する。Hereinafter, the present invention will be explained by examples.
参考例１
１−エチｔＩ／６ ＋ ８−ジフルオロ−１，４−ジヒ
ドロ−７−［（ＩＪ−（２−ヒドロキシエチ／Ｌ／ ）
−Ｎ−メチル〕アミン〕−４−オキソキノリン−６−
カルざン酸
１− エ チ ル− ６．７．８−１− リ ７ ル
オ 口 −４−オキソ−１，４−ジヒドロキノリン−ろ
−カルボン酸３．ＯＯｇ、Ｎ−メチルエタノールアミン
２．５０ｇ及びピリジン３０ ｍｌの混合物を、６０分
間加熱還流する。冷接、ピリジンを留去し、残渣を水に
溶解し、酢酸にて中和する。析出物を戸数Ｌ、エーテル
、イソプロパノ−／Ｌ／）こて順次洗浄する。イソプロ
パノールより再結晶して、融点１８４〜１８５．５°の
淡黄色針状晶２．７０ｇを得る。Reference example 1 1-ethytI/6 + 8-difluoro-1,4-dihydro-7-[(IJ-(2-hydroxyethy/L/)
-N-methyl]amine]-4-oxoquinoline-6-
Carzanic acid 1-ethyl-6.7.8-1-lyl 7
-4-oxo-1,4-dihydroquinoline-ro-carboxylic acid 3. A mixture of OOg, 2.50 g of N-methylethanolamine and 30 ml of pyridine is heated to reflux for 60 minutes. Pyridine is distilled off cold, the residue is dissolved in water and neutralized with acetic acid. The precipitate is sequentially washed with a trowel (L, ether, isopropano/L/). Recrystallization from isopropanol gives 2.70 g of pale yellow needles with a melting point of 184-185.5°.
元素分析値 ０１５Ｈ１６Ｆ２Ｎ２０４理論値 Ｃ１５
５，２１ｉ Ｈ，４，９４＋ Ｎ、 ８．５９実験値
０．５５．１６ ｉ Ｈ，５，０４ｉ Ｎ、 ８．４９
実施例１
１０− エ チ ル− ５− フ ル オ ロ −３，
４，７゜１０−テトラヒドロ−４−メチＩｖ −７−オ
キソ−２Ｈ−ピリド［，２−ｈ〕−１，４−ベンズオキ
サジン−８−カルボン酸
参考例１で得た１−エチル−６，８−ジフルオロ−１，
４−ジヒドロ−７−Ｃ［−＜２−ヒドロキシエチル）−
Ｎ−メチル〕アミン〕−４−オキソキノリン−６−カル
ボン酸２．ＯＯｇ。Elemental analysis value 015H16F2N204 Theoretical value C15
5,21i H, 4,94+ N, 8.59 experimental value
0.55.16 i H, 5,04i N, 8.49
Example 1 10-ethyl-5-fluoro-3,
4,7゜10-tetrahydro-4-methyIv-7-oxo-2H-pyrido[,2-h]-1,4-benzoxazine-8-carboxylic acid 1-ethyl-6 obtained in Reference Example 1, 8-difluoro-1,
4-dihydro-7-C[-<2-hydroxyethyl)-
N-methyl]amine]-4-oxoquinoline-6-carboxylic acid2. OOg.
水素化すトリウムｌ］、５８ｇ及びジメチルホルムアミ
ド５０ ｍｌの混合物を、４０分間１６０〜１４０°で
加熱攪拌する。冷接、溶媒を留去し、残渣を水に溶解し
、酢酸にて中和する。析出物なｒ取ｔ、、クロロホルム
に溶解する。クロロホルム層は脱水後、溶媒留去。残渣
をクロロホルム及びエタノールの混液より再結晶して、
融点２５６〜２５７°の黄色針状晶０．７０ｇを得る。A mixture of 58 g of thorium hydride] and 50 ml of dimethylformamide is heated and stirred at 160-140° for 40 minutes. The solvent was distilled off in the cold, the residue was dissolved in water and neutralized with acetic acid. Take the precipitate and dissolve it in chloroform. After dehydrating the chloroform layer, the solvent was distilled off. The residue was recrystallized from a mixture of chloroform and ethanol,
0.70 g of yellow needles with a melting point of 256-257° are obtained.
元素分析値 ０１５Ｊ５ＦＮ２０４
理論値 ａ、 ５Ｂ、８２ ｉＨｌ ４．９４ ｉＮ、
９．１５実験値 ０．５Ｂ、９６ ｉ Ｈ，５，１７
ｉ Ｎ、 ９．０８参考例２
１−エチル−７−［Ｎ−［２−（ジエチルアミノ）エチ
ル］−Ｎ−（２−ヒドロキシェチ）Ｖ）〕〕アミノ］−
６．８−ジフルオロ１，４−ジヒドロ−４−オキソキノ
リン−６−カルボン酸
１− エ チ 、ル＝−６，７，８−ト リ フ ルオ
口 −１゜４−ジヒドロ−４−オキソキノリン−６−
カルボン酸２．００ ｇ＋ ２−（Ｃ２−（ジエチルア
ミノ）エチル〕アミン〕エタノ−）ｖ２．９０ｇ及びピ
リジン２（ｌｌ＋ｌの混合物を、１時間加熱還流する。Elemental analysis value 015J5FN204 Theoretical value a, 5B, 82 iHl 4.94 iN,
9.15 Experimental value 0.5B, 96 i H, 5, 17
i N, 9.08 Reference Example 2 1-ethyl-7-[N-[2-(diethylamino)ethyl]-N-(2-hydroxyethyl)V)]]amino]-
6.8-difluoro1,4-dihydro-4-oxoquinoline-6-carboxylic acid 1-ethyl-6,7,8-trifluoro-1°4-dihydro-4-oxoquinoline -6-
A mixture of 2.00 g of carboxylic acid + 2.90 g of 2-(C2-(diethylamino)ethyl]amine]ethano-) and 2 (11+1) of pyridine is heated to reflux for 1 hour.
冷接、ピリジンを留去し、残渣に水を加え、塩酸水溶液
にて中和する。水層なりロロホルムにて抽出し、クロロ
ホルム層は水洗、脱水。溶媒を留去し、残渣ｅこエーテ
ルを加え、赤褐色粉末１．５０ ｇを得る。Pyridine is distilled off in a cold manner, water is added to the residue, and the mixture is neutralized with an aqueous hydrochloric acid solution. The aqueous layer was extracted with loloform, and the chloroform layer was washed with water and dehydrated. The solvent was distilled off, and ether was added to the residue to obtain 1.50 g of a reddish brown powder.
実施例２
１０− エ チル−４−［２−（ジ エ チ ルア ミ
力エ チ ル ］ −５−フ ル オ 口 −３，４，
７，１０−テトラヒドロ−７−オキソ−２Ｈ−ピリド〔
６゜２−ｈ〕−１，４−ベンズオキサジン−８−カルボ
ン酸・塩酸塩
参考例２で得た１−エチｔｖ−７−（（Ｎ−［２−（ジ
エチルアミノ）エチル）−Ｎ−（２−ヒドロキシエチ）
ｖ）〕アミノ）−６，ｓ−ジフルオロ−１，４−ジヒド
ロ−４−オキソキノリン−６−カルボン酸１．４０ ｇ
、水素化ナトリウム０．５４ｇ及びジメチルホルムア
ミド５０ｇ／の混合物を、１５分間加熱還流する。冷接
、溶媒を留去し、残渣に水を加え、塩酸水溶液にて中和
スる。水層をクロロホルムにて抽出し、クロロホルム層
は水洗、脱水。残渣を熱ベンゼンに溶解し、不溶物をｐ
去する。Ｐ液を濃縮し、エタノール性塩酸にて塩酸塩と
なす。析出物を戸数し、エタノール及びエーテルの混液
より再結晶して、融点２５０〜２５５°（分解）の褐色
針状晶０．４０ ｇを得る。Example 2 10-ethyl-4-[2-(diethyl ethyl]-5-fluoride-3,4,
7,10-tetrahydro-7-oxo-2H-pyrido [
6゜2-h]-1,4-benzoxazine-8-carboxylic acid hydrochloride 1-ethytv-7-((N-[2-(diethylamino)ethyl)-N-( 2-hydroxyethyl)
v)] 1.40 g of [amino)-6,s-difluoro-1,4-dihydro-4-oxoquinoline-6-carboxylic acid
, 0.54 g of sodium hydride and 50 g of dimethylformamide are heated under reflux for 15 minutes. After cold welding, the solvent was distilled off, water was added to the residue, and the mixture was neutralized with an aqueous hydrochloric acid solution. The aqueous layer was extracted with chloroform, and the chloroform layer was washed with water and dehydrated. Dissolve the residue in hot benzene and remove the insoluble matter
leave Concentrate the P solution and make the hydrochloride with ethanolic hydrochloric acid. The precipitate was separated and recrystallized from a mixture of ethanol and ether to obtain 0.40 g of brown needles with a melting point of 250-255° (decomposed).
元素分析値 ０２０Ｈ１９ＦＮ３０４− ＨＯＩ理論値
０，５６．１４１．６．３６；Ｎ＋ ９．８２実験値
０．５５．９０ ｉ Ｈ，６，４２ｉ Ｎ、 ９．８
５特許出顆人 北陸製薬株式会社Elemental analysis value 020H19FN304- HOI theoretical value 0,56.141.6.36; N+ 9.82 Experimental value 0.55.90 i H, 6,42i N, 9.8
5 Patent author Hokuriku Pharmaceutical Co., Ltd.
Claims (1)
基又は低級アルキル置換アミノアルキｐ基を表わす。） で示される５−フルオロ−３，４，７，１０−テトラヒ
ドロ−７−オキソ−２Ｈ−ヒ°リド〔６゜２−ｈ）−１
，４−ベンズオキサジン−８−カルボン酸誘導体、及び
その薬理学的に許容しうる塩。[Scope of Claims] 5-fluoro-3,4,7,10-tetrahydro- (wherein R1 represents a lower alkyl group, and R2 represents a lower alkyl group or a lower alkyl-substituted aminoalkyl p group) 7-oxo-2H-hydride [6゜2-h)-1
, 4-benzoxazine-8-carboxylic acid derivatives, and pharmacologically acceptable salts thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59021863A JPS60166687A (en) | 1984-02-10 | 1984-02-10 | 5-fluoro-3,4,7,10-tetrahydro-7-oxo-2h-pyrido(3,2-h)-1,4- benzoxazine-8-carboxylic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59021863A JPS60166687A (en) | 1984-02-10 | 1984-02-10 | 5-fluoro-3,4,7,10-tetrahydro-7-oxo-2h-pyrido(3,2-h)-1,4- benzoxazine-8-carboxylic acid derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS60166687A true JPS60166687A (en) | 1985-08-29 |
Family
ID=12066955
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59021863A Pending JPS60166687A (en) | 1984-02-10 | 1984-02-10 | 5-fluoro-3,4,7,10-tetrahydro-7-oxo-2h-pyrido(3,2-h)-1,4- benzoxazine-8-carboxylic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60166687A (en) |
-
1984
- 1984-02-10 JP JP59021863A patent/JPS60166687A/en active Pending
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