JPH06500338A - Novel fluoroquinolone, method for producing the same, and pharmaceutical composition containing the same - Google Patents
Novel fluoroquinolone, method for producing the same, and pharmaceutical composition containing the sameInfo
- Publication number
- JPH06500338A JPH06500338A JP4508023A JP50802393A JPH06500338A JP H06500338 A JPH06500338 A JP H06500338A JP 4508023 A JP4508023 A JP 4508023A JP 50802393 A JP50802393 A JP 50802393A JP H06500338 A JPH06500338 A JP H06500338A
- Authority
- JP
- Japan
- Prior art keywords
- compound according
- following formula
- same meaning
- tables
- carboxylic acid
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】 新規なフルオロキノロンと、その製造方法と、それを含む医薬組成や 本発明は新規な弗素化キノロン（ｑｕｉｎｏｌｏｎｅｓ ｆｌｕｏｒｅｅｓ）と その製造方法に関するものである。[Detailed description of the invention] New fluoroquinolones, their production methods, and pharmaceutical compositions containing them The present invention provides novel fluorinated quinolones (quinolones fluorees) and The present invention relates to a manufacturing method thereof.
特に、本発明の対象は７位がピペリジン基で置換された新規なジフルオロキノロ ンにある。In particular, the subject of the invention is a novel difluoroquinolone substituted in the 7-position with a piperidine group. It is located in
特に、本発明は下記一般式（Ｉ）を有する新規なジフルオロキノロン−３−カル ボン酸に関するものである：Ｒは１つまたは複数のハロゲンで置換されていても よいエチル基、フルオロエチル基、アリル基またはベンジル基であり、 Ｒ１は水素、モノまたはポリヒドロキシル化されモノ−またはポリカルボキシ化 された脂肪族、道式または芳香族有機酸から誘導されたアシル残基またはアルキ ルカルボン酸残基であり、 Ｒ２は半極性結合によって結合された酸素を表し、ｎはＯまたは１である） 本発明の他の対象は一般式（１）のキノロン−３−カルボン酸と無機または有機 塩基との塩にある。In particular, the present invention provides a novel difluoroquinolone-3-cal having the general formula (I) below. with respect to bonic acids: R may be substituted with one or more halogens. Good ethyl group, fluoroethyl group, allyl group or benzyl group, R1 is hydrogen, mono- or polyhydroxylated, mono- or polycarboxylated Acyl residues or alkyl residues derived from aliphatic, aromatic or aromatic organic acids carboxylic acid residue, R2 represents oxygen bound by a semipolar bond, n is O or 1) Other objects of the invention are quinolone-3-carboxylic acids of general formula (1) and inorganic or organic In salts with bases.
一般式（１）の化合物の中では、特に１位の窒素が下記の基で置換されたキノロ ンが好ましい： （ａ）エチル基 （ｂ）フルオロエチル基 （ｄ）下記式のベンジル基： Ｚは水素またはハロゲン原子であり、ｎｌは１．２または３である） この場合、一般式（Ｉ）の化合物は下記４つのサブグループに分けることができ る： （１）下記の式（■Ａ）のＮ−エチル化誘導体：（ここで、Ｒ１は上記と同じ意 味を有する）（２）下記の式（１，）のＮ−アリル化誘導体：（ここで、Ｒ１は 上記と同じ意味を有する）（３）下記の式（Ｉｃ ）のＮ−フルオロエチル化誘 導体：（ここで、Ｒ９は上記と同じ意味を有する）（４）下記の式（Ｉｏ）のＮ −ベンジル化誘導体：（ここで、Ｒ５は上記と同じ意味を有し、Ｚは水素または ハロゲン原子であり、Ｎは１．２または３である）アシル化誘導体の中では特に 、琥珀酸、スペリン酸、グルカル酸、グルタミン酸、アスパラギン酸、フタル酸 、テレフタル酸、樟脳酸から誘導されたものおよびそれと類似な誘導体あるいは グルコン酸、ラクトビオン酸、グルコノヘプトン酸、グルコグルコノヘプトン酸 等のヒドロキシカルボン酸から誘導されたものが挙げられる。Among the compounds of general formula (1), quinolones in which the nitrogen at the 1st position is substituted with the following group are particularly preferred. Preferably: (a) Ethyl group (b) Fluoroethyl group (d) Benzyl group of the following formula: Z is a hydrogen or halogen atom, nl is 1.2 or 3) In this case, the compound of general formula (I) can be divided into the following four subgroups. Ru: (1) N-ethylated derivative of the following formula (■A): (Here, R1 has the same meaning as above. (2) N-allylated derivative of the following formula (1,): (where R1 is (3) N-fluoroethylated derivative of the following formula (Ic) Conductor: (where R9 has the same meaning as above) (4) N in the following formula (Io) -benzylated derivatives: (where R5 has the same meaning as above and Z is hydrogen or Among the acylated derivatives (halogen atom, N is 1.2 or 3), especially , succinic acid, speric acid, glucaric acid, glutamic acid, aspartic acid, phthalic acid , terephthalic acid, those derived from camphoric acid and similar derivatives thereof, or Gluconic acid, lactobionic acid, gluconoheptonic acid, glucogluconoheptonic acid Examples include those derived from hydroxycarboxylic acids such as.
一般式（Ｉ）のカルボン誘導体は無機塩基または有機塩基を付加して塩にするこ とができる。使用可能な主要な塩としてはアルカリ金属塩、アルカリ土類金属塩 、アンモニウム塩、鉄塩、アルミニウム塩、アルキルアミン塩、ヒドロキシアル キルアミン塩、フェニルアルキルアミン塩、ピリジルアルキルアミン塩、シクラ ニルアミン塩、ジシクラニルアルキルアミン塩等がある。The carboxyl derivative of general formula (I) can be converted into a salt by adding an inorganic base or an organic base. I can do it. The main salts that can be used are alkali metal salts and alkaline earth metal salts. , ammonium salts, iron salts, aluminum salts, alkylamine salts, hydroxyalkyl Kylamine salt, phenylalkylamine salt, pyridylalkylamine salt, cycra There are nylamine salts, dicyclanylalkylamine salts, etc.
これらの塩の中では、ナトリウム塩、リチウム塩、Ｎ−メチルグルカミン塩およ びトロメタノール塩が好ましい。Among these salts, the sodium salt, lithium salt, N-methylglucamine salt and Bitromethanol salts are preferred.
これらの誘導体は、水および生理学的媒体への可溶性がピペリジン誘導体の可溶 性よりもわずかに良いＮ−酸化物（Ｎ−ｏｘｙｄｅ）形で存在してもよい。ピペ リジン誘導体は第３窒素の塩基度が低過ぎるので無機酸または有機酸で塩化する ことはできない。These derivatives are soluble in water and physiological media, but the solubility of piperidine derivatives is It may also exist in the N-oxide form, which has slightly better properties. Pipe Lysine derivatives have too low basicity of tertiary nitrogen, so they are salted with inorganic or organic acids. It is not possible.
Ｒ，が有機ジカルボン酸のアシル残基である場合には遊離カルボキシル残基との 塩、特にアルカリ無機塩基またはアルカリ土類無機塩基との塩にすることができ る。When R is an acyl residue of an organic dicarboxylic acid, the relationship between the free carboxyl residue and Can be made into salts, especially salts with alkali inorganic bases or alkaline earth inorganic bases. Ru.
本発明化合物は極めて大きな抗菌（ａｎｔ １ｂａｃｔｅｒ １ｅｎｎｅ）特性 、特にダラム陽性菌に対する抗菌特性を示す。従って、ダラム陽性またはグラム 陰性細菌による外部または内部細菌感染症の治療医薬の有効成分として使用する ことができる。The compound of the present invention has extremely strong antibacterial (ant1bacter1enne) properties. , exhibiting antibacterial properties, especially against Durham-positive bacteria. Therefore, Durham positive or Gram Use as an active ingredient in medicines for the treatment of external or internal bacterial infections caused by negative bacteria be able to.
この場合、本発明化合物は非経口、経口、直腸、経粘膜または局部投与用の医薬 組成物の形で使用される。この医薬組成物は薬理学上許容される無毒な不活性賦 形剤またはビヒクルに有効成分として少なくとも１つの一般式（Ｉ）の化合物ま たはそ−の無機塩基または有機塩基付加塩を添加または混合して得られる。In this case, the compound of the invention is a pharmaceutical for parenteral, oral, rectal, transmucosal or local administration. Used in the form of compositions. This pharmaceutical composition contains pharmacologically acceptable non-toxic, inert excipients. The form or vehicle contains at least one compound of general formula (I) as an active ingredient. or by adding or mixing an inorganic base or an organic base addition salt thereof.
考えられる医薬形態の中で最も適当なものは注射溶液または注射懸濁液であり、 これらはアンプル、フラスコまたは自動注射用アンプル等に貯蔵される。経口用 で最も適当なものは無糖衣錠または糖衣錠、糖衣錠、カプセル、柔カプセル、錠 剤、粉末薬または顆粒等の乾燥形態のものである。局部投与用では鼻用滴剤、耳 用滴剤および眼用調製物が最も適した投与形態である。The most suitable of the possible pharmaceutical forms are injection solutions or suspensions; These are stored in ampoules, flasks, autoinjector ampoules, and the like. oral The most suitable ones are unsweetened tablets, sugar-coated tablets, sugar-coated tablets, capsules, soft capsules, and tablets. It is in dry form, such as a drug, powder, or granules. For local administration, nasal drops and ear drops are available. Drops and ophthalmic preparations are the most suitable dosage forms.
単位投与量は化合物によって異なるが一般に１００〜５００ｍｇ。The unit dose varies depending on the compound, but is generally 100-500 mg.
１−Ｒ−１，４−ジヒドロキシリノン−３−カルボン酸の場合は２００〜４００ ｍｇの範囲が好ましい。１日当りの投与量は治療上の指示と、感染症の原因微生 物株の感度および投与経路とによって変るが、非経口、経口または直腸投与の場 合の１日当りの薬用量は１００〜１０００ｍｇの範囲であり、経粘膜または局部 投与の場合の１日当りの薬用量は皮膚または粘膜の浸透パーセントと生体内での 拡散度に応じて決定される。200 to 400 in the case of 1-R-1,4-dihydroxylinone-3-carboxylic acid A range of mg is preferred. The daily dosage depends on the treatment instructions and the microorganism that causes the infection. For parenteral, oral or rectal administration, depending on the sensitivity of the strain and the route of administration. The daily dosage ranges from 100 to 1000 mg, and can be administered transmucosally or locally. In the case of administration, the daily dosage depends on the skin or mucosal penetration percentage and the in vivo Determined according to the degree of diffusion.
本発明はさらに一般式（１）の化合物の製造方法を提供する。The present invention further provides a method for producing the compound of general formula (1).
本発明の製造方法では、下記の式（■）：（ここで、Ｒは上記と同じ意味を有す る）の６，７．８−１−リフルオロ−１−Ｒ−１，４−ジヒドロキルイン−４− オン−３−カルボン酸を、塩基性媒体中で３−ヒドロキシメチルピペリジンと反 応させ、得られた下記の式（■）＝（ここで、Ｒは上記と同じ意味を有する）の ６，８−ジフルオロ−７−（３−ヒドロキシメチルピペリジニル−１）＝１．４ −ジヒドロキルイン−４−オン−３−カルボン酸をカルボン酸の官能性誘導体を 用いてアシル化するか、アルキルクロロクロメートを用いてカーボネート化する か、無機塩基または有機塩基を付加して塩化するか、無機また有機ヒドロペルオ キシドを反応させてＮ−酸化する。とができることからなる。In the production method of the present invention, the following formula (■): (where R has the same meaning as above) 6,7.8-1-Refluoro-1-R-1,4-dihydrokylyne-4- 1-3-carboxylic acid is reacted with 3-hydroxymethylpiperidine in basic medium. The following formula (■) = (where R has the same meaning as above) 6,8-difluoro-7-(3-hydroxymethylpiperidinyl-1) = 1.4 -dihydrokylyn-4-one-3-carboxylic acid as a functional derivative of carboxylic acid or carbonate with an alkyl chlorochromate. salt by adding an inorganic or organic base, or by addition of an inorganic or organic hydroperoxide. The oxide is reacted to undergo N-oxidation. It consists of being able to.
以下、本発明の実施例を示すが、本発明が下記実施例に限定されるものではない 。Examples of the present invention are shown below, but the present invention is not limited to the following examples. .
実施例１ ７− （３−ヒドロキシメチルピペリジニル−１）−６，８−ジフルオロ−１− エチル−４−オキソ−１，４−ジヒドロキルイニル−３−カルボ酸く化合物１） ３−ヒドロキシメチルピペリジン１．４５ｇを添加したジメチルホルムアミド１ ０ｄ中に、６．７．８− トリフルオロ−１−エチル−４−オキソ−１，４−ジ ヒドロキルイニル−３−カルボン酸１．２５ｇを溶解させる。反応混合物を１４ ０℃で４時間加熱した後、常温に冷却し、結晶化が始まるまで水に希釈する。１ 時間放置した後、結晶を分離し、水分を除去し、水、次に、エタノールで洗浄し 、最後に、減圧乾燥する。Example 1 7-(3-hydroxymethylpiperidinyl-1)-6,8-difluoro-1- Ethyl-4-oxo-1,4-dihydrokylynyl-3-carboxylic acid compound 1) Dimethylformamide 1 with addition of 1.45 g of 3-hydroxymethylpiperidine 0d, 6.7.8-trifluoro-1-ethyl-4-oxo-1,4-di 1.25 g of hydroxylinyl-3-carboxylic acid are dissolved. The reaction mixture was After heating at 0° C. for 4 hours, cool to room temperature and dilute in water until crystallization begins. 1 After standing for an hour, separate the crystals, remove the moisture, and wash with water and then ethanol. , Finally, dry under reduced pressure.
こうしてピペリジン誘導体１．４ｇを回収する。これをジメチルホルムアミドを 数滴添加したエタノールから再結晶して分析しブこ。1.4 g of piperidine derivative are thus recovered. Add dimethylformamide to this Recrystallize from a few drops of ethanol and analyze.
その結果、１７１℃で溶融する（コフラー（Ｋｏｆ Ｉｅｒ）プロ・ツク）純粋 な生成物０．９ｇが回収された。As a result, the pure 0.9 g of product was recovered.
ＴＲスペクトルは上記構造と一致していた。The TR spectrum was consistent with the above structure.
溶離剤としてクロロホルム−メタノール（８：２）混合物を用いたＴＬＣ分析の 結果、螢光で単一点を示す生成物（ｐｒｏｄｕｉｔ ｍｏｎｏｔａｃｈｅ）の存 在を示す。TLC analysis using chloroform-methanol (8:2) mixture as eluent. As a result, there is a product monotache that shows a single point in fluorescence. Indicates presence.
同様にして以下も化合物を合成した。The following compounds were also synthesized in the same manner.
７−（３−ヒドロキシメチルピペリジニル−１）−６，８−ジフルオロ−１−フ ルオロエチル−４−オキソ−１，４−ジヒドロキルイニル−３−カルボン酸を６ ．７．８−１−リフルオロ−１−フルオロエチル−４−オキソ−１，４−ジヒド ロキルイニル−３−カルボン酸から合成した。この化合物は２３０℃で溶融する （化合物２）。7-(3-hydroxymethylpiperidinyl-1)-6,8-difluoro-1-ph 6 fluoroethyl-4-oxo-1,4-dihydrokylynyl-3-carboxylic acid ．． 7.8-1-Lifluoro-1-fluoroethyl-4-oxo-1,4-dihyde Synthesized from lokiruinyl-3-carboxylic acid. This compound melts at 230℃ (Compound 2).
７− （３−ヒドロキシメチルピペリジニル−１）−６，８−ジフルオロ−１− （ｐ−フルオロベンジル）−４−オキソ−１，４−ジヒドロキルイニル−３−カ ルボン酸を６．７．８−）リフルオロ−１−（ｐ−フルオロベンジル）−４−オ キソ−１，４−ジヒドロキルイニル−３−カルボン酸から合成した。この化合物 は２２５℃で溶融する（化合物３）。7-(3-hydroxymethylpiperidinyl-1)-6,8-difluoro-1- (p-fluorobenzyl)-4-oxo-1,4-dihydrokylynyl-3-carboxylate 6.7.8-)lifluoro-1-(p-fluorobenzyl)-4-o It was synthesized from xo-1,4-dihydrokylinyl-3-carboxylic acid. this compound melts at 225°C (compound 3).
７−（３−ヒドロキシメチルピペリジニル−１）−６． ８−ジフルオロ＝１ー アリルー４ーオキソ−１．４−ジヒドロキルイニル−−カルボン酸も同様にして 得られる。これは１７３℃で溶融する（化合物４）。7-(3-hydroxymethylpiperidinyl-1)-6. 8-difluoro=1- Similarly, aryl-4-oxo-1,4-dihydrokylynyl-carboxylic acid can get. It melts at 173°C (compound 4).
７− （３−ヒドロキシメチルピペリジニル−１）−６． ８−ジフルオロ− １ − （ｏ−フルオロベンジル）−４−オキソ−１． ４−ジヒドロキルイニ ル−３−カルボン酸を６．７．８−４リフルオロ−１−（叶フルオロベンジル） −５−オキソ−１，４−ジヒドロキルイニル−３−カルボン酸から合成した。こ の化合物は１８６℃で溶融する （化合物１１）。7-(3-hydroxymethylpiperidinyl-1)-6. 8-difluoro- 1-(o-fluorobenzyl)-4-oxo-1. 4-dihydrokylini 6.7.8-4 Refluoro-1-(fluorofluorobenzyl) It was synthesized from -5-oxo-1,4-dihydrokylinyl-3-carboxylic acid. child The compound melts at 186°C (compound 11).
常温でジメチルホルムアミド１２１ｎｌ中に７−（３−ヒドロキシメチルピペリ ジニル−１）−６． ８−ジフルオロ−１−エチル−４−オキソ−１．４−ジヒ ドロキルイニル−３−カルボン酸１．４６ｇを溶解させる。次いで、攪拌しなが らフェニルイソシアネート１．１蔵を徐々に添加する。常温で２時間放置して反 応を進行させる。7-(3-hydroxymethylpiperi) in 121 nl of dimethylformamide at room temperature. Dinyl-1)-6. 8-difluoro-1-ethyl-4-oxo-1,4-dihy 1.46 g of dolokylinyl-3-carboxylic acid are dissolved. Then, while stirring Then gradually add 1.1 volumes of phenyl isocyanate. Leave it at room temperature for 2 hours and then proceed with the response.
次いで、エタノールで媒体を希釈し、過剰な反応体を破壊する。The medium is then diluted with ethanol to destroy excess reactants.
アロファナートが沈澱する。結晶を分離し、水分を除去した後に洗浄し、乾燥す ると、１８７℃で溶融する粗生成物０．６ｇが回収される。Allophanate precipitates. Separate the crystals, remove water, wash and dry. 0.6 g of crude product, which melts at 187° C., is recovered.
濾液を濃縮し、エタノールで回収すると重さ０．５ｇの第２の粗生成物（Ｊｅｔ ）が得られる。The filtrate was concentrated and recovered with ethanol to yield a second crude product weighing 0.5 g (Jet ) is obtained.
２つの粗生成物を合わせて、エタノール−ジメチルホルムアミド混合物で再結晶 化させると１９９〜２００℃で溶融する純粋な生成物０．８ｇを得る。The two crude products were combined and recrystallized from an ethanol-dimethylformamide mixture. 0.8 g of pure product melting at 199-200 DEG C. is obtained.
溶離剤としてメチレン−メタノール（８：２＞混合物を用いたＣＣＭの結果、単 一点を示す生成物の存在を示す（Ｒｆ＝０．２８）。CCM using methylene-methanol (8:2> mixture) as eluent resulted in a simple One point indicates the presence of the product (Rf=0.28).
ＴＲスペクトルは上記構造と一致とする。The TR spectrum is consistent with the above structure.
生成物は温めたＩＮソーダに可溶性である。The product is soluble in warm IN soda.
同様にして、融点が１３５℃の１−アリル化誘導体（化合物６）を得た。Similarly, a 1-allylated derivative (compound 6) having a melting point of 135°C was obtained.
実施例３ ７−（３−フタロイルオキシメチルピペリジニＪレ−１）−６，８−ジフルオロ −１−エチル−４−オキソ−１，４−ジヒドロキルイニル−３−カルボン酸く化 合物７）ジメチルスルホキシド４９ｒｄ中で、無水フタル酸２ ｇ （０，０１ ４５Ｍ〉と−緒に７−（３−ヒドロキシメチルピペリジニルフルオロ−１−エチ ル−４−オキソ−１．４−ジヒドロキルイニル−３−カルボン酸を１３０℃で８ 時間加熱する。冷却後、反応混合物を水に注ぎ、生成した沈澱物を分離し、水分 を除去し、次に、ジメチルホルムアミドとエタノールとの混合物中で再結晶化さ せる。Example 3 7-(3-phthaloyloxymethylpiperidini-1)-6,8-difluoro -1-ethyl-4-oxo-1,4-dihydrokylynyl-3-carboxylic acid oxidation Compound 7) 2 g of phthalic anhydride (0,01 45M> and 7-(3-hydroxymethylpiperidinylfluoro-1-ethyl -4-oxo-1,4-dihydrokylynyl-3-carboxylic acid at 130°C. Heat for an hour. After cooling, pour the reaction mixture into water, separate the formed precipitate, and drain the water. and then recrystallized in a mixture of dimethylformamide and ethanol. let
２２３℃で溶融するクリーム色の結晶１，５ｇを分離する。ＩＲスペクトルおよ び元素分析は上記構造と一致してしする。1.5 g of cream-colored crystals melting at 223° C. are separated. IR spectrum and and elemental analysis are consistent with the above structure.
同様にして、１８８℃で溶融する１−アＩＪ ）し化誘導体（化合物８）を調製 した。In the same manner, a 1-A IJ) derivative (compound 8) that melts at 188°C was prepared. did.
実施例４ 世と玉む区立す土乙ゴ土虞江Ｚヨ但＝Ｊヒシフルオローｌ−エチル−４−オキソ −１．４−ジヒドロキルイニル−３−カルボン酸（化合物９）ジメチルスルホキ シド１５ｄとピリジン１．５ｄとの混合物中（こ６、 ８−ジフルオロ−７−（ ３−ヒドロキシメチルピペリジニル）−ｌ−エチル−４−オキソ−１．４−ジヒ ドロキルイニクレー３ーカルボン酸１．５ｇを溶解させる。Example 4 World and Tamamu Ward Togo Togoe Z Yotan = J Hishifluoro l-ethyl-4-oxo -1,4-dihydrokylynyl-3-carboxylic acid (compound 9) dimethylsulfoxy In a mixture of side 15d and pyridine 1.5d (6,8-difluoro-7-( 3-Hydroxymethylpiperidinyl)-l-ethyl-4-oxo-1,4-dihy 1.5 g of dolokylinicle 3-carboxylic acid is dissolved.
次に、予めジメチルスルホキシド１０ｍ１２中に溶解した無水琥珀酸１．８ｇを 添加し、混合物を１１０〜１１５℃で３時間加熱した後、放置して常温に戻す。Next, 1.8 g of succinic anhydride previously dissolved in 10 ml of dimethyl sulfoxide was added. and the mixture is heated at 110-115° C. for 3 hours, then left to return to room temperature.
次に、氷水中に溶液を注ぎ、１時間の間結晶化させる。生成した沈澱物を分離し 、水分を除去した後、水およびエタノールで洗浄し、真空乾燥する。エタノール から生成物を再結晶化する。The solution is then poured into ice water and allowed to crystallize for 1 hour. Separate the formed precipitate After removing moisture, wash with water and ethanol, and vacuum dry. ethanol Recrystallize the product from
１４０℃で溶融する無色の結晶１．１ｇが回収される。1.1 g of colorless crystals melting at 140° C. are recovered.
ＩＲスペクトルおよび元素分析は上記構造と一致する。IR spectrum and elemental analysis are consistent with the above structure.
同様にして、１３０℃で溶融する７−（３−スクシノイルオキシメチルビペリジ ニル−１）−６． ８−ジフルオロ−１−アリル−４−オキソ−１．４−ジヒド ロキルイニル−３−カルボン酸（化合物１０）が得られる。Similarly, 7-(3-succinoyloxymethylbiperidi Nil-1)-6. 8-difluoro-1-allyl-4-oxo-1,4-dihyde Lokiruinyl-3-carboxylic acid (compound 10) is obtained.
上記各生成物を下記６つの参照株についてテストした：（１）３種のダラム陽性 菌 枯草菌（Ｂａｃｉｌｌｕｓ ｓｕｂｔｉｌｉｓ） ＡＴＣＣ ９３７２黄色ブド ウ球菌（Ｓｔａｐｈｙｌｏｃｏｃｃｕｓ ａｕｒｅｕｓ） ＡＴＣＣ ２５９２ ３ストレプトコツカス ファエ力リス（Ｓｔｒｅｐｔｏｃｏｃｃｕｓｆａｅｃａ ｌｉｓ） ＡＴＣＣ ８０４３（２）３種のグラム陰性菌 大腸菌（Ｅｓｃｈｅｒｉｃｈｉａ ｃｏｌｉ） ＡＴＣＣ ２５９２２シユード モナス アエルギノーザ（Ｐｓｅｕｄｏｍｏｎａｓａｅｒｕｇｉｎｏｓａ） Ａ ＴＣＣ ２２８５３アシネトバクタ− 力ルコアセチクス変種アニタラタム（Ａ ｃｉｎｅｔｏｂａｃｔｅｒ ｃａｌｃｏａｃｅｔｉｃｕｓ ｖａｒｉｅｔｅａｎ ｔｉｔｒａｔｕｍ） ＡＴＣＣ １７９０３阻害最小濃度は、滴定値が５１２ｍ ｇ／ （ｌの抗生母溶液から調製した濃度範囲１２８〜０． ０６ｍｇ／ １の １００μｌ容量の液体培地（ミューラーーヒントン（Ｍｕｅｌｌｅｒ−Ｈｉｎｔ ｏｎ）ブイヨン）でミクロ希釈法（ダイナチック（Ｄｙｎａｔｅｃｈ）のミクロ プレートと接種器）を用いて測定した。母溶液の調製法は可溶性に応じて分子に 従って変えた。Each of the above products was tested against the following six reference strains: (1) three Durham positive strains; fungus Bacillus subtilis ATCC 9372 yellow bud Staphylococcus aureus ATCC 2592 3 Streptococcus faeca lis) ATCC 8043 (2) 3 types of Gram-negative bacteria Escherichia coli ATCC 25922 Monas aeruginosa (Pseudomonasaeruginosa) A TCC 22853 Acinetobacter Acinetobacter var. Anitaratum (A cinetobacter calcoaceticus varietean titratum) ATCC 17903 minimum inhibitory concentration is a titration value of 512 m g/(l) of antibiotic mother solution with a concentration range of 128 to 0.06 mg/1 100 μl volume of liquid medium (Mueller-Hint using the micro dilution method (Dynatech's micro dilution method (on) broth) (plate and inoculator). The preparation method of the mother solution depends on the solubility of the molecules. So I changed it.
各カプセルに１８時間齢の心ＩＩ／脳ブイヨンの生理食塩水の希釈液１０μβを 添加して、各カプセルが約１０６菌／ｒｎｌを含むように接種する。Add 10μβ of 18-hour old heart II/brain broth diluted in saline to each capsule. to inoculate each capsule to contain approximately 10 6 bacteria/rnl.
阻害最小濃度は、３７℃で１８時間培養した後に顕微鏡で見た時に成長（ｃｕｌ ｔｕｒｅ）が見られない最初の抗生物質濃度である。The minimum inhibitory concentration is the growth (cul) observed microscopically after 18 hours of incubation at 37°C. ture) is the first antibiotic concentration at which no trace is observed.
国際調査報告 フロントページの続き （８１）指定国 ＥＰ（ＡＴ、ＢＥ、ＣＨ，ＤＥ。international search report Continuation of front page (81) Designated countries EP (AT, BE, CH, DE.
ＤＫ、ＥＳ、ＦＲ，ＧＢ、ＧＲ，ＩＴ、ＬＵ、ＭＣ，ＮＬ、ＳＥ）、０Ａ（ＢＦ 、ＢＪ、ＣＦ、ＣＧ、ＣＩ、ＣＭ、 ＧＡ、 ＧＮ、 ＭＬ、 Ｌ・ＩＲ，ＳＮ 、ＴＤ、ＴＧ）、ＡＴ、 ＡＵ、 ＣＡ、 ＣＨ，ＤＥ、 ＤＫ、 ＥＳ、 Ｆ Ｌ ＧＢ。DK, ES, FR, GB, GR, IT, LU, MC, NL, SE), 0A (BF , BJ, CF, CG, CI, CM, GA, GN, ML, L・IR, SN , TD, TG), AT, AU, CA, CH, DE, DK, ES, F LGB.
ＨＵ、ＪＰ、 ＫＲ，ＬＵ、 ＮＬ、 ＲＵ、 ＳＥ、 ＵＳHU, JP, KR, LU, NL, RU, SE, US
Claims (10)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR91/03421 | 1991-03-19 | ||
| FR9103421A FR2674247B1 (en) | 1991-03-19 | 1991-03-19 | NOVEL FLUORINATED QUINOLONES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06500338A true JPH06500338A (en) | 1994-01-13 |
Family
ID=9410967
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4508023A Pending JPH06500338A (en) | 1991-03-19 | 1992-03-18 | Novel fluoroquinolone, method for producing the same, and pharmaceutical composition containing the same |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0530355A1 (en) |
| JP (1) | JPH06500338A (en) |
| AU (1) | AU1645992A (en) |
| FI (1) | FI925240A (en) |
| FR (1) | FR2674247B1 (en) |
| WO (1) | WO1992016521A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW301607B (en) * | 1993-03-09 | 1997-04-01 | Takeda Pharm Industry Co Ltd | |
| WO2005026145A2 (en) * | 2003-09-12 | 2005-03-24 | Warner-Lambert Company Llc | Quinolone antibacterial agents |
| CA2631917A1 (en) | 2005-12-05 | 2007-06-14 | Merck & Co., Inc. | Quinolone m1 receptor positive allosteric modulators |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3940608A (en) * | 1974-02-04 | 1976-02-24 | Mechanical Technology Incorporated | Fiber optic displacement measuring apparatus |
| US4656866A (en) * | 1984-04-11 | 1987-04-14 | Douwe Egberts Koninklijke Tabaksfabriek-Koffiebranderijen-Theehandel N.V. | Method of measuring the pressure in a vacuum package |
| US4771630A (en) * | 1985-12-20 | 1988-09-20 | Warner-Lambert Company | Method and apparatus for testing hermetic seal integrity of sealed packages and containers |
| JPH02186232A (en) * | 1989-01-13 | 1990-07-20 | Ueno Hiroshi | Method and apparatus for inspecting leakage of sealed container |
| JPH03218429A (en) * | 1989-11-07 | 1991-09-26 | Yamamura Glass Co Ltd | Method for inspecting degree of vacuum in sealed container |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3606698A1 (en) * | 1986-03-01 | 1987-09-03 | Bayer Ag | 7- (1-PYRROLIDINYL) -CHINOLONCARBONIC ACID DERIVATIVES |
| DK164287A (en) * | 1986-03-31 | 1987-10-01 | Sankyo Co | QUINOLIN-3-CARBOXYLIC ACID DERIVATIVES AND PROCEDURES FOR PREPARING THEREOF AND THEIR USE |
-
1991
- 1991-03-19 FR FR9103421A patent/FR2674247B1/en not_active Expired - Fee Related
-
1992
- 1992-03-18 EP EP92908914A patent/EP0530355A1/en not_active Withdrawn
- 1992-03-18 AU AU16459/92A patent/AU1645992A/en not_active Abandoned
- 1992-03-18 JP JP4508023A patent/JPH06500338A/en active Pending
- 1992-03-18 WO PCT/FR1992/000243 patent/WO1992016521A1/en not_active Application Discontinuation
- 1992-11-18 FI FI925240A patent/FI925240A/en not_active Application Discontinuation
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3940608A (en) * | 1974-02-04 | 1976-02-24 | Mechanical Technology Incorporated | Fiber optic displacement measuring apparatus |
| US4656866A (en) * | 1984-04-11 | 1987-04-14 | Douwe Egberts Koninklijke Tabaksfabriek-Koffiebranderijen-Theehandel N.V. | Method of measuring the pressure in a vacuum package |
| US4771630A (en) * | 1985-12-20 | 1988-09-20 | Warner-Lambert Company | Method and apparatus for testing hermetic seal integrity of sealed packages and containers |
| JPH02186232A (en) * | 1989-01-13 | 1990-07-20 | Ueno Hiroshi | Method and apparatus for inspecting leakage of sealed container |
| JPH03218429A (en) * | 1989-11-07 | 1991-09-26 | Yamamura Glass Co Ltd | Method for inspecting degree of vacuum in sealed container |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0530355A1 (en) | 1993-03-10 |
| FI925240A0 (en) | 1992-11-18 |
| FR2674247B1 (en) | 1993-07-16 |
| WO1992016521A1 (en) | 1992-10-01 |
| FI925240A (en) | 1992-11-18 |
| FR2674247A1 (en) | 1992-09-25 |
| AU1645992A (en) | 1992-10-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0221463B1 (en) | Quinoline derivatives and processes for preparation thereof | |
| US4886810A (en) | Quinoline derivatives, pharmaceutical composition and method of use | |
| HU188181B (en) | Process for producing salts of naphtiridine and quinoline compounds of antimicrobial activity | |
| US5527910A (en) | Pyridone carboxylic acid compounds and their uses for treating infectious diseases caused by bacteria | |
| CN101298452A (en) | Preparing methods and uses of S-(-)-nadifloxacin and water soluble salt thereof | |
| JPS62187459A (en) | 5-amino and 5-hydroxy-6,8-difluoroquinolone compound | |
| JPS62129273A (en) | 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acids | |
| CA2013136C (en) | (s)-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid | |
| JPH04502317A (en) | Antibacterial quinolone compounds | |
| JPS60126284A (en) | Pyridonecarboxylic acid derivative and salt thereof | |
| JPH06500338A (en) | Novel fluoroquinolone, method for producing the same, and pharmaceutical composition containing the same | |
| HU196785B (en) | Process for production of quinoline-carbonic acid derivatives and medical compositions containing them | |
| HU204521B (en) | Process for producing quinoline derivatives and pharmaceutical compositions containing them | |
| JPH02290870A (en) | Enantiomerically pure 7-(3-amino-1- pyrrolidinyl)-quinolone- and naphthyridonecarboxylic acid | |
| JPS6089480A (en) | Pyridonecarboxylic acid derivative | |
| PT88431B (en) | PROCESS FOR THE PREPARATION OF USEFUL 4-OXO-3-KINOLINOCARBOXYL ACID ACIDS AS ANTI-BACTERIAL AGENTS | |
| US4698350A (en) | 1-ethyl-6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid and antibacterial use thereof | |
| JPH05508170A (en) | Novel difluoroquinolones, their synthesis methods, and pharmaceuticals containing them | |
| JPS62108878A (en) | Quinolonecarboxylic acid derivative and production thereof | |
| JPS6028978A (en) | 1,8-naphthyridine derivative | |
| CA1250846A (en) | 6-fluoro-1,4-dihydro-4-oxo-7-(4-pyridyl)-1,8- naphthyridine-3 carboxylic acid compounds | |
| JPH0637489B2 (en) | Quinolonecarboxylic acid derivative and method for producing the same | |
| US5478841A (en) | Fluorinated quinolones, process for their preparation and pharmaceutical preparations containing same | |
| KR100234546B1 (en) | Pyridonecarboxylic acid derivatives and their preparation | |
| JP2621204B2 (en) | Antibacterial compound |