JPH04128288A - Quinolonecarboxylic acid derivative and its production - Google Patents
Quinolonecarboxylic acid derivative and its productionInfo
- 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
Links
- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical class C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 title claims description 6
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 8
- 125000002252 acyl group Chemical group 0.000 claims abstract description 5
- 125000003435 aroyl group Chemical group 0.000 claims abstract description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 4
- -1 R_3 and R_4 are H Chemical group 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims 4
- 230000002378 acidificating effect Effects 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract description 12
- 239000002904 solvent Substances 0.000 abstract description 4
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 230000000844 anti-bacterial effect Effects 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000036461 convulsion Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229960001699 ofloxacin Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- KVBNENBFIVLEHO-UHFFFAOYSA-N 1,2-benzoxazine-2-carboxylic acid Chemical compound C1=CC=C2C=CN(C(=O)O)OC2=C1 KVBNENBFIVLEHO-UHFFFAOYSA-N 0.000 description 1
- TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 description 1
- 239000005973 Carvone Substances 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 235000001484 Trigonella foenum graecum Nutrition 0.000 description 1
- 244000250129 Trigonella foenum graecum Species 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000002920 convulsive effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical group FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 229960002549 enoxacin Drugs 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 229960002422 lomefloxacin Drugs 0.000 description 1
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical compound O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
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)
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)
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)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2249340A Pending JPH04128288A (en) | 1990-09-18 | 1990-09-18 | Quinolonecarboxylic acid derivative and its production |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04128288A (en) |
Cited By (6)
| 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 |
-
1990
- 1990-09-18 JP JP2249340A patent/JPH04128288A/en active Pending
Cited By (9)
| 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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