JPH04128288A - Quinolonecarboxylic acid derivative and its production - Google Patents

Quinolonecarboxylic acid derivative and its production

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Publication number
JPH04128288A
JPH04128288A JP2249340A JP24934090A JPH04128288A JP H04128288 A JPH04128288 A JP H04128288A JP 2249340 A JP2249340 A JP 2249340A JP 24934090 A JP24934090 A JP 24934090A JP H04128288 A JPH04128288 A JP H04128288A
Authority
JP
Japan
Prior art keywords
formula
lower alkyl
compound
cyclopropyl
group
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
Application number
JP2249340A
Other languages
Japanese (ja)
Inventor
Akihiko Kitajima
昭彦 北島
Tsutomu Adachi
勉 足立
Osamu Kamota
修 加守田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teikoku Chemical Industry Co Ltd
Original Assignee
Teikoku Chemical Industry Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Teikoku Chemical Industry Co Ltd filed Critical Teikoku Chemical Industry Co Ltd
Priority to JP2249340A priority Critical patent/JPH04128288A/en
Publication of JPH04128288A publication Critical patent/JPH04128288A/en
Pending legal-status Critical Current

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

NEW MATERIAL:The compound of formula I (R1 is lower alkyl or cyclopropyl; R2 is H or lower alkyl; R3 and R4 are H, aralkyl or together form acyl or aroyl). EXAMPLE:(6as)-8-Aminomethyl-4-cyclopropyl-11-fluoro-1,4,6a,7,8,9-hexah ydro-1- oxo-6H-pyrido[3,2-h]pyrrolo[2,1-c][1,4] benzoxazine-2-carboxylic acid. USE:Antibacterial agent. PREPARATION:The objective compound can be produced by reacting a compound of formula II with a compound of formula III usually in a solvent (e.g. acetonitrile) in the presence of 1,8-diazabicyclo[5,4,0]-7-undecene and cyclizing the resultant compound of formula TV.

Description

【発明の詳細な説明】 この発明は、新規なキノロンカルボン酸誘導体を、更に
はその製造方法を提供するものであって。
DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel quinolone carboxylic acid derivative and a method for producing the same.

詳しくは、四環系のキノロンカルボン酸誘導体が提供さ
れ、該化合物は広範且つ特徴ある抗菌スペクトルを持っ
ている新規な抗菌性化合物である。
Specifically, tetracyclic quinolone carboxylic acid derivatives are provided, which are novel antibacterial compounds with a broad and distinctive antibacterial spectrum.

従来、キノロンカルボン酸誘導体のうち、抗菌性を有す
るものとして実用に供されているものは二環乃至二環の
縮合環を持っているものであって。
Conventionally, among quinolone carboxylic acid derivatives, those that have been put to practical use as having antibacterial properties have a bicyclic or bicyclic condensed ring.

例えばエノキサシン、オフロキサシン、ロメフロキサシ
ンなどがあるけれども抗菌スペクトルにおいて不満足で
あったり、多の薬物との併用ができなかったり(例えば
非ステロイド系の抗炎症剤としてよく知られているフエ
ンブフエンと一緒に投与するとケイレンを起し、時には
それが治まらない場合もあると言われている)している
ので、より使い易く且つ安全な合成抗菌剤の創製のため
にテストが繰り返されている実情にある。
For example, there are enoxacin, ofloxacin, and lomefloxacin, but they are unsatisfactory in their antibacterial spectrum, and cannot be used in combination with many drugs (for example, if they are administered together with fuenbufuene, which is well known as a non-steroidal anti-inflammatory agent, (It is said that the disease may sometimes not be cured.) Therefore, repeated tests are being conducted to create synthetic antibacterial agents that are easier to use and safer.

本発明者らは、四環系であるところのキノロンカルボン
酸誘導体が未だ開発極めて少ないことに着目し、抗菌活
性及び安全性の点において優れた物の存在が予測された
ので、検討を重ねた結果、本発明を成すに到ったもので
ある。
The present inventors focused on the fact that there are still very few developed quinolone carboxylic acid derivatives, which are tetracyclic, and predicted the existence of products with excellent antibacterial activity and safety, so they conducted repeated studies. As a result, the present invention has been achieved.

本発明化合物は以下のようにして造られる。即で示され
る化合物とを反応させて、 式 で示される化合物を得る。ここにおいて反応は、アセト
ニトリル、ピリジン、トリエチルアミン、N−メチルピ
ロリドン、ジメチルスルホキシドなど適宜溶媒中、加熱
還流して行う、1,8−ジアザビシクロ[5,4,O]
−7−ウンデセンを共存させると反応が好適に進行する
。(式中R工は低級アルキル又はシクロプロピル基を、
R2はH又は低級アルキル基を、R1、R4はH、アラ
ルキル又は−緒になってアシル、アロイル基を示す)か
くて得られた式(m)で示される化合物は、適宜溶媒中
アルカリ金属塩の存在下加熱し、分子内閉環する。ここ
において用いられる溶媒としてはジメチルホルムアミド
、ジメチルスルホキシドなどであり、アルカリ金属塩と
しては、ナトリウムハイドライド、カリウムハイドライ
ド、リチュウムハイドライド、ナトリウムアミド、炭酸
カリウムなどが挙げられる。かくて式 で示される化合物を得る。(式中R0〜R4は前記と同
じ) かくて得られた式(IV)で示される化合物は、必で示
される化合物へと導かれる。(式中R1,R。
The compound of the present invention is produced as follows. The compound represented by the following formula is reacted with the compound represented by the following formula to obtain the compound represented by the formula. Here, the reaction is carried out in an appropriate solvent such as acetonitrile, pyridine, triethylamine, N-methylpyrrolidone, dimethylsulfoxide, etc. by heating to reflux.
The reaction proceeds suitably when -7-undecene is present. (In the formula, R represents a lower alkyl or cyclopropyl group,
(R2 represents H or a lower alkyl group, R1 and R4 represent H, aralkyl, or together represent an acyl or aroyl group) The thus obtained compound represented by formula (m) is optionally treated with an alkali metal salt in a solvent. Heating in the presence of causes intramolecular ring closure. Examples of the solvent used here include dimethylformamide and dimethyl sulfoxide, and examples of the alkali metal salt include sodium hydride, potassium hydride, lithium hydride, sodium amide, and potassium carbonate. Thus, a compound represented by the formula is obtained. (In the formula, R0 to R4 are the same as above.) The thus obtained compound represented by formula (IV) is led to the compound represented by . (In the formula, R1, R.

は前記と同じ) かくて得られた式(IV) 、  (V)で示される本
発明目的化合物は、広範な抗菌スペクトルを有している
のみならず、非ステロイド系抗炎症薬例えばフエンブフ
エンと併用した場合にもケイレン誘発を詔めないという
優れた性質を有している。
(same as above) The thus obtained compounds of the present invention represented by formulas (IV) and (V) not only have a broad antibacterial spectrum but also can be used in combination with non-steroidal anti-inflammatory drugs such as fenbufuene. It has the excellent property of not being able to induce Keiren even if it does.

実施例1 (2S)−4−(アセチルアミノ)メチル−2−ヒドロ
キシメチルピロリジン0.50gとアセトニトリル7.
5ml、および95%1. 8−ジアザビシクロ[5,
4,0] −7−ウンデセン0゜41gの混合物に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0.7
5gを加え、6.5時間加熱還流した。冷却後、析出物
を濾取し、アセトニトリル、ジエチルエーテルで順次洗
浄を行い、7−[(2S) −4−(アセチルアミノ)
メチル−2−ヒドロキシメチル−1−ピロリジニル]−
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0.65
gを得た。
Example 1 0.50 g of (2S)-4-(acetylamino)methyl-2-hydroxymethylpyrrolidine and 7.0 g of acetonitrile.
5 ml, and 95% 1. 8-diazabicyclo[5,
4,0] 1- to a mixture of 0°41 g of -7-undecene
Cyclopropyl-6,7゜8-trifluoro-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid 0.7
5 g was added and heated under reflux for 6.5 hours. After cooling, the precipitate was collected by filtration and washed sequentially with acetonitrile and diethyl ether to obtain 7-[(2S)-4-(acetylamino).
Methyl-2-hydroxymethyl-1-pyrrolidinyl]-
1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 0.65
I got g.

mp、約211℃ I R(Nu j o 1) cm−’:3299.1
70B、1674,1624NMR(NaOD−D20
.DSS)δ(ppm):    8.  45(IH
,s     、   2 位メブシ)7、  64(
IH,dd   、   5  位メチン)4、  3
3  (IH,m     、   ヒ@0リソ′ン環
のメチン)3、  94(IH,m     、   
シフ0ブ0」ビン環のメチン)3、  5 9  (2
H,A B  X、   ヒ)−o4ンメfll(7)
メチシン)3、  55(IH,m     、   
七″0リシ゛ン環のメチシン)3、  43  (IH
,m     、   ヒ@Dリソ“ン環のメチレジ)
3、  33  (2H,ABX、   ?tf117
ミノメff1(7)メチシン)2、  48  (IH
,m     、   七″0リシーン環のメチジ)2
、  28(IH,ddd、   ヒ0ロリシーン環の
メゾしシ)2、  03(3H,s     、   
?セチルのメチル)1、  53(IH,ddd、  
 ピロリシーン環のメチレン)1、  3〜0.  9
  (4H,m、   シクロフ″0ハロン環のメチ[
ン) 実施例2 ?−[(2S)−4−(アセチルアミノ)メチル−2−
ヒドロキシメチル−1−ビロリジニルコー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*0.10gをN、  
N−ジメチルホルムアミド2.2mlに懸濁させ、60
%水素化ナトリウム計15.0mgを5回に分けて添加
し、それぞれ室温で1時間攪拌した後、140℃で3時
間攪拌した。冷却後、反応液を濃縮し、残渣に水10m
1を加え、希塩酸で中和した。析出物を濾取して(6a
S)−8−アセチルアミノメチル−4−シクロプロピル
−11−フルオロ−1,4,6a。
mp, approximately 211°C IR (Nuj o 1) cm-': 3299.1
70B, 1674, 1624NMR (NaOD-D20
.. DSS) δ (ppm): 8. 45 (IH
, s, 2nd place Mebushi) 7, 64 (
IH, dd, 5-position methine) 4, 3
3 (IH,m, methine of H@0 litho ring) 3, 94 (IH,m,
Schif0bu0” Bin ring methine) 3, 5 9 (2
H, AB
methicin) 3, 55 (IH, m,
7″0 lysine ring methicine) 3, 43 (IH
,m, methylation of the D-lison ring)
3, 33 (2H, ABX, ?tf117
Minome ff1 (7) methicin) 2, 48 (IH
, m, 7″0 rescene ring) 2
, 28 (IH, ddd, mesoshishi of the heroic scene ring) 2, 03 (3H, s,
? Methyl of cetyl) 1, 53 (IH, ddd,
Methylene of pyrrolicine ring) 1, 3-0. 9
(4H, m, cycloph″0 halon ring methi[
) Example 2? -[(2S)-4-(acetylamino)methyl-2-
Hydroxymethyl-1-pyrrolidinyl-1-cyclopropyl-6,8-difluoro-1゜4-dihydro-4-
Oxoquinoline-3-carvone*0.10g N,
Suspend in 2.2 ml of N-dimethylformamide,
A total of 15.0 mg of % sodium hydride was added in 5 portions, each of which was stirred at room temperature for 1 hour and then at 140° C. for 3 hours. After cooling, concentrate the reaction solution and add 10ml of water to the residue.
1 was added and neutralized with dilute hydrochloric acid. Collect the precipitate by filtration (6a
S)-8-acetylaminomethyl-4-cyclopropyl-11-fluoro-1,4,6a.

7、 8. 9−ヘキサヒドロ−1−オキソ−6[■−
ピリド[3,2−h]ピロロ[2,1−cl  [1゜
4]ベンゾオキサジン−2−カルボン酸の黄土色結晶0
.07gを得た。
7, 8. 9-hexahydro-1-oxo-6 [■-
Ocher crystals of pyrido[3,2-h]pyrrolo[2,1-cl [1゜4]benzoxazine-2-carboxylic acid 0
.. 07g was obtained.

I R(Nu j o 1) cm”:3272.1?
15,1660.1624NMR(CD30D、TMS
)δ(ppm):8−  7(IH,s   、   
3 位のメチジ)7.7(IH,d  、12位のメチ
ジ)2、 0(3H,s   、   7セチhのメチ
ル)実施例3 (6aS)−8−アセチルアミノメチル−4−シクロプ
ロピル−11−フルオロ−1,4,6a。
I R (Nu j o 1) cm”: 3272.1?
15,1660.1624NMR (CD30D, TMS
) δ (ppm): 8-7 (IH,s,
3-position methyl) 7.7 (IH, d, 12-position methyl) 2, 0 (3H, s, 7-set methyl) Example 3 (6aS)-8-acetylaminomethyl-4-cyclopropyl- 11-Fluoro-1,4,6a.

7、 8. 9−へキサヒトロー1−オキソ−6H−ピ
リド[3,2−hコピロロ[2,1−cl  [1゜4
]ベンゾオキサジン−2−カルボン酸0.10gを6N
塩酸3mlに懸濁させ、90℃で7時間加熱した。冷却
後、反応液を濃縮し、残渣をジエチルエーテルで洗浄し
て黄褐色粉末0.11gを得た。このものにメタノール
3mlを加えて不溶物を濾別した。メタノール溶液をI
j2酸水素ナトリウム水溶液で中和して、シリカゲルカ
ラムクロマトおよびイオン交換カラムクロマトを用いて
精製し、黄色粉末状の(6aS)−8−アミノメチル−
4−シクロプロピル−11−フルオロ−1,4゜6a、
  7. 8. 9−ヘキサヒドロ−1−オキソ−6H
−ピリド[3,2−h]ピロロ[2,1−cl[l、4
コベンゾオキサジン−2−カルボン酸・塩酸塩63mg
を得た。
7, 8. 9-hexahitrow 1-oxo-6H-pyrido[3,2-hcopyrrolo[2,1-cl [1゜4
] 0.10 g of benzoxazine-2-carboxylic acid 6N
It was suspended in 3 ml of hydrochloric acid and heated at 90°C for 7 hours. After cooling, the reaction solution was concentrated, and the residue was washed with diethyl ether to obtain 0.11 g of a yellowish brown powder. 3 ml of methanol was added to this, and insoluble matter was filtered off. methanol solution I
It was neutralized with an aqueous solution of sodium hydrogen oxide and purified using silica gel column chromatography and ion exchange column chromatography to obtain (6aS)-8-aminomethyl- as a yellow powder.
4-cyclopropyl-11-fluoro-1,4゜6a,
7. 8. 9-hexahydro-1-oxo-6H
-pyrido[3,2-h]pyrrolo[2,1-cl[l,4
Cobenzoxazine-2-carboxylic acid hydrochloride 63mg
I got it.

MS:  374 (M+H)” [発明の効果] つぎに、本発明化合物についての薬理作用を示す。MS: 374 (M+H)” [Effect of the invention] Next, the pharmacological effects of the compounds of the present invention will be shown.

1、抗菌作用 試験方法 日本化学療法学会標準法(Chemotherapy 
29 : 76〜791981 )に準じて最小発育阻
止濃度(MIC)を測定した。
1. Antibacterial activity test method Japanese Society of Chemotherapy standard method (Chemotherapy
29:76-791981), the minimum inhibitory concentration (MIC) was measured.

その結果を表−1に示す、参考のためオフロキサシン(
OFLX)のMICを同表に示す。
The results are shown in Table 1. For reference, ofloxacin (
The MIC of OFLX) is shown in the same table.

2、痙撃誘発作用 試験方法 1群4匹のddY系雄性マウス(体重;19〜23g)
に非ステロイド系抗炎症薬であるフエンブフエンを 1
00璽g/kgで経口投与し、5分後に被検化合物を経
口投与し、痙章および致死の有無を調べた。
2. Convulsive induction effect test method 1 group of 4 ddY male mice (body weight: 19-23 g)
Fuenbufuen, a non-steroidal anti-inflammatory drug, was added to
After 5 minutes, the test compound was orally administered at a dose of 0.00 g/kg, and the presence or absence of convulsions and mortality was examined.

その結果、実施例2および3の化合物は1000■g/
kgにおいて、痙撃誘発を認めなかった。
As a result, the compounds of Examples 2 and 3 were obtained at 1000 g/
kg, no convulsion induction was observed.

表 発育阻止濃度 (μg/■I)table Inhibitory concentration (μg/■I)

Claims (1)

【特許請求の範囲】 1 式 ▲数式、化学式、表等があります▼ (式中R_1は低級アルキル又はシクロプロピル基を、
R_2はH又は低級アルキル基を、R_3、R_4はH
、アラルキル、又は一緒になってアシル、アロイル基を
示す) で示されるキノロンカルボン酸誘導体 2 式 ▲数式、化学式、表等があります▼ で示される化合物を閉環反応に付し、式 ▲数式、化学式、表等があります▼ で示される化合物を得、場合によっては、酸性条件下で
R_3、R_4を除くことを特徴とする式 ▲数式、化学式、表等があります▼ で示されるキノロンカルボン酸誘導体の製造方法(式中
R_1は低級アルキル又はシクロプロピル基を、R_2
はH又は低級アルキル基を、R_3、R_4はアラルキ
ル、又は一緒になってアシル、アロイル基をR_5、R
_6はH又はアラルキル又は一緒になってアシル、アロ
イル基を示す)
[Claims] 1 Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 is a lower alkyl or cyclopropyl group,
R_2 is H or a lower alkyl group, R_3 and R_4 are H
, aralkyl, or together represent an acyl or aroyl group) Quinolonecarboxylic acid derivative 2 Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ The compound represented by the formula ▼ is subjected to a ring-closing reaction, and the compound represented by the formula ▲ mathematical formula, chemical formula There are formulas, tables, etc. ▼ to obtain the compound shown by, and in some cases, R_3 and R_4 are removed under acidic conditions ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Production method (in the formula, R_1 is a lower alkyl or cyclopropyl group, R_2 is
represents H or a lower alkyl group, R_3 and R_4 represent aralkyl, or together represent an acyl or aroyl group, R_5 and R
_6 represents H or aralkyl, or together represents an acyl or aroyl group)
JP2249340A 1990-09-18 1990-09-18 Quinolonecarboxylic acid derivative and its production Pending JPH04128288A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2249340A JPH04128288A (en) 1990-09-18 1990-09-18 Quinolonecarboxylic acid derivative and its production

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP2249340A JPH04128288A (en) 1990-09-18 1990-09-18 Quinolonecarboxylic acid derivative and its production

Publications (1)

Publication Number Publication Date
JPH04128288A true JPH04128288A (en) 1992-04-28

Family

ID=17191565

Family Applications (1)

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Country Status (1)

Country Link
JP (1) JPH04128288A (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR19980066915A (en) * 1997-01-29 1998-10-15 이웅열 Novel quinolone carboxylic acid derivatives and preparation method thereof
WO2007017828A3 (en) * 2005-08-08 2007-07-19 Actelion Pharmaceuticals Ltd Oxazolidinone-quinolone hybrids as antibacterial compounds
WO2008062379A3 (en) * 2006-11-24 2008-07-17 Actelion Pharmaceuticals Ltd 4- (2-oxo-oxazolidin-3yl)-phenoxymethyle derivativeas as antibacterials
WO2011031744A1 (en) * 2009-09-09 2011-03-17 Achaogen, Inc. Antibacterial fluoroquinolone analogs
US8124623B2 (en) 2006-11-10 2012-02-28 Actelion Pharmaceuticals Ltd. 5-hydroxymethyl-oxazolidin-2-one-derivatives and their uses as antibacterials
US10087171B2 (en) 2016-12-19 2018-10-02 Actelion Pharmaceuticals Ltd Crystalline forms of cadazolid

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR19980066915A (en) * 1997-01-29 1998-10-15 이웅열 Novel quinolone carboxylic acid derivatives and preparation method thereof
WO2007017828A3 (en) * 2005-08-08 2007-07-19 Actelion Pharmaceuticals Ltd Oxazolidinone-quinolone hybrids as antibacterial compounds
EP2256120A1 (en) * 2005-08-08 2010-12-01 Actelion Pharmaceuticals Ltd. Oxazolidinone-quinolone hybrids as antibacterial compounds
US8124623B2 (en) 2006-11-10 2012-02-28 Actelion Pharmaceuticals Ltd. 5-hydroxymethyl-oxazolidin-2-one-derivatives and their uses as antibacterials
WO2008062379A3 (en) * 2006-11-24 2008-07-17 Actelion Pharmaceuticals Ltd 4- (2-oxo-oxazolidin-3yl)-phenoxymethyle derivativeas as antibacterials
JP2010510977A (en) * 2006-11-24 2010-04-08 アクテリオン ファーマシューティカルズ リミテッド 4- (2-Oxo-oxazolidine-3-yl) -phenoxymethyl derivatives as antibacterial agents
US8039466B2 (en) 2006-11-24 2011-10-18 Actelion Pharmaceutical Ltd. 5-hydroxymethyl-oxazolidin-2-one antibacterials
WO2011031744A1 (en) * 2009-09-09 2011-03-17 Achaogen, Inc. Antibacterial fluoroquinolone analogs
US10087171B2 (en) 2016-12-19 2018-10-02 Actelion Pharmaceuticals Ltd Crystalline forms of cadazolid

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