JPH01258666A - Novel substituted quinolinecarboxylic acid and production thereof - Google Patents
Novel substituted quinolinecarboxylic acid and production thereofInfo
- Publication number
- JPH01258666A JPH01258666A JP20538988A JP20538988A JPH01258666A JP H01258666 A JPH01258666 A JP H01258666A JP 20538988 A JP20538988 A JP 20538988A JP 20538988 A JP20538988 A JP 20538988A JP H01258666 A JPH01258666 A JP H01258666A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- tables
- formulas
- general formula
- 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.)
- Granted
Links
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical class C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- -1 piperazino Chemical group 0.000 claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 125000005843 halogen group Chemical group 0.000 claims description 14
- 150000004677 hydrates Chemical class 0.000 claims description 12
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 13
- 125000004193 piperazinyl group Chemical group 0.000 claims 2
- 238000006467 substitution reaction Methods 0.000 claims 1
- 241000894006 Bacteria Species 0.000 abstract description 6
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 125000001153 fluoro group Chemical group F* 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 3
- 150000002367 halogens Chemical group 0.000 abstract 3
- 235000019000 fluorine Nutrition 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000002904 solvent Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 150000007530 organic bases Chemical class 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 229910052684 Cerium Inorganic materials 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- ZMIGMASIKSOYAM-UHFFFAOYSA-N cerium Chemical compound [Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce][Ce] ZMIGMASIKSOYAM-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000002198 insoluble material Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002674 ointment Substances 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
- 239000000047 product Substances 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- CGNYYECYCCAQJV-UHFFFAOYSA-N 1-(2-fluoroethyl)-4-oxoquinoline-3-carboxylic acid Chemical group C1=CC=C2C(=O)C(C(=O)O)=CN(CCF)C2=C1 CGNYYECYCCAQJV-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 239000005973 Carvone Substances 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000282373 Panthera pardus Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- UHCBBWUQDAVSMS-UHFFFAOYSA-N fluoroethane Chemical compound CCF UHCBBWUQDAVSMS-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 208000027096 gram-negative bacterial infections Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 1
- 229960000210 nalidixic acid Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 description 1
- 229960001732 pipemidic acid Drugs 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- RCIMBBZXSXFZBV-UHFFFAOYSA-N piromidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCCC1 RCIMBBZXSXFZBV-UHFFFAOYSA-N 0.000 description 1
- 229960004444 piromidic acid Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
本発明は新規置換キノリンカルボン酸及びその製造法に
関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel substituted quinoline carboxylic acids and processes for their production.
ナリジクス酸、ピロミド酸及びピペミド酸はグラム陰性
菌感染症に有効な安全性の高い合成抗菌剤として臨床的
に広く用いられている。しかしながらこれらの薬剤はグ
ラム陰性菌、あるいは難治性感染症の原因菌の一つであ
り、有効な薬剤が少ない緑膿菌に対して非常に弱い抗菌
力しか有していない。本発明者らは、先に１−（２−フ
ルオロエチル）−１，４−ジヒドロ−４−オキソキノリ
ン−３−カルボン酸の６位にフッ素原子、７位にピペラ
ジン又は置換ピペラジンを有する化合物が緑膿菌を含む
グラム陰性菌並びにグラム陰性菌に対して強い抗菌力を
有することを報告した［日本薬学会第９８年会（昭和５
３年４月、岡山）、講演要旨集、Ｐ、２３３ 、特開昭
５５−４７６５８号］０本発明者らはその後この関連化
合物について、更に検討し、６位及び８位にフッ素原子
、７位にハロゲン原子又はピペラジノ誘導体を同時に有
する６、７゜８−トリ置換体は、６．７−又は７．８−
ジ１換体よりもグラム陰性菌に対してより強い抗菌力を
有することを見出した。Nalidixic acid, pyromidic acid, and pipemidic acid are widely used clinically as highly safe synthetic antibacterial agents effective against Gram-negative bacterial infections. However, these drugs have very weak antibacterial activity against Gram-negative bacteria or Pseudomonas aeruginosa, which is one of the causative agents of refractory infections and for which there are few effective drugs. The present inventors previously discovered that a compound having a fluorine atom at the 6-position and a piperazine or substituted piperazine at the 7-position of 1-(2-fluoroethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid reported that it has strong antibacterial activity against Gram-negative bacteria and Gram-negative bacteria including Pseudomonas aeruginosa [98th Annual Meeting of the Pharmaceutical Society of Japan (1932)]
(April 2003, Okayama), Lecture Abstracts, P, 233, JP-A-55-47658] The present inventors then further investigated this related compound, and found that fluorine atoms at the 6th and 8th positions, and 7th position A 6,7°8-tri-substituted product simultaneously having a halogen atom or a piperazino derivative at the 6,7- or 7.8-
It was found that it has stronger antibacterial activity against Gram-negative bacteria than di-1 conversion.
すなわち、本発明は下記の一般式［１１で表される置換
キノリンカルボン酸
［式中、Ｒ１はハロゲン原子、ピペラジノ基又は４−メ
チルピペラジノ基を表す］
及びその生理学的に許容される塩及び水和物を提供する
ものである。That is, the present invention provides substituted quinoline carboxylic acids represented by the following general formula [11] [wherein R1 represents a halogen atom, a piperazino group, or a 4-methylpiperazino group], and physiologically acceptable salts and hydrates thereof. It is something that provides something.
また、−数式 ［Ｉ］の化合物の塩としてはナトリウム
、カリウム、カルシウム、マグネシウム、アルミニウム
、セリウム、クロム、コバルト、銅、鉄、銀、亜鉛等の
金属塩及び有機塩基の塩、更に塩酸、硫酸、リン酸等の
無機酸塩、酢酸、乳酸、メタンスルホン酸等の有機酸塩
等が例示できる。In addition, salts of the compound of formula [I] include metal salts such as sodium, potassium, calcium, magnesium, aluminum, cerium, chromium, cobalt, copper, iron, silver, and zinc, and salts of organic bases, as well as hydrochloric acid, sulfuric acid, etc. , inorganic acid salts such as phosphoric acid, and organic acid salts such as acetic acid, lactic acid, and methanesulfonic acid.
本出願はまた、本発明化合物の製造法を下記の通り開示
する。すなわち
１）−数式［Ｉ！］
［式中、Ｒは水素原子、又は低級アルキル基を表し、Ｒ
１はハロゲン原子、ピペラジノ基又は４−メチルピペラ
ジノ基を表す］で表される化合物と次の一般式［＋＋１
］ＦＣ８２Ｃ８２Ｘ ［＋１１
］［式中、Ｘはハロゲン原子又は置換スルホニルオキ
シ基等の脱離基を表す］
で表される化合物とを脱酸剤の存在下で反応させ、要す
れば、次いで加水分解することを特徴とする下記の一般
式［Ｉ］
［式中、Ｒ３は前記と同様の意味を有する］
で表される置換キノリンカルボン酸、及びその塩及び水
和物の製造法を提供する。The present application also discloses methods for preparing the compounds of the present invention as described below. That is, 1) - formula [I! ] [In the formula, R represents a hydrogen atom or a lower alkyl group, and R
1 represents a halogen atom, piperazino group or 4-methylpiperazino group] and the following general formula [++1
]FC82C82X [+11
] [In the formula, X represents a leaving group such as a halogen atom or a substituted sulfonyloxy group] is reacted with the compound represented by the following in the presence of an acid absorber, and if necessary, then hydrolyzed. Provided is a method for producing a substituted quinoline carboxylic acid represented by the following general formula [I] [wherein R3 has the same meaning as above], and salts and hydrates thereof.
脱酸剤としては有機及び無機の塩基（例えばトリエチル
アミン、ピリジン、水酸化アルカリ、炭酸アルカリ等）
が用いられる。反応は溶媒（例えば水、ＤＭＦ 、アル
コール、アセトン等）中、又は無溶媒下で行われる。Organic and inorganic bases (e.g. triethylamine, pyridine, alkali hydroxide, alkali carbonate, etc.) can be used as deoxidizing agents.
is used. The reaction is carried out in a solvent (eg water, DMF, alcohol, acetone, etc.) or without solvent.
ＦＣＨ２Ｃ８２Ｘ又は脱酸剤が液体の場合は溶媒を兼ね
させてもよい。When FCH2C82X or the deoxidizing agent is liquid, it may also serve as a solvent.
２）−数式［ＩＶ］
［式中、Ｘはハロゲン原子を表す］
で表される化合物と次の一般式 ［Ｖ］Ｒ２Ｈ［Ｖ ］
［式中、Ｒ２はピペラジノ基又は４−メチルピペラジノ
基を表す］
で表される化合物とを反応させることを特徴とする下記
の一般式［Ｖ１］
［式中、Ｒ２は前記と同様の意味を有する］
で表される置換キノリンカルボン酸、及びその塩及び水
和物の製造法を提供する。2) - A compound represented by the formula [IV] [wherein, X represents a halogen atom] and the following general formula [V]R2H[V] [wherein, R2 represents a piperazino group or a 4-methylpiperazino group] ] A substituted quinoline carboxylic acid represented by the following general formula [V1] [wherein R2 has the same meaning as above], and its salt and water Provides a method for manufacturing Japanese products.
本反応は、溶媒中又は無溶媒下、脱酸剤の存在下反応さ
せるのが望ましいが、Ｒ２Ｈを過剰に用いて脱酸剤ある
いは溶媒を兼ねさせてもよい。This reaction is preferably carried out in a solvent or without a solvent in the presence of a deoxidizing agent, but R2H may be used in excess to serve as a deoxidizing agent or a solvent.
３）−数式［■］
［式中、Ｒ１は前記と同様の意味を有する］
で表される化合物と次の一般式［■］
Ｒ５０ＣＨ−Ｃ（ＣＯＯＲｓ） ２
［■］［式中、Ｒ３は低級アルキル基を表すコで表され
る化合物とを反応させ一般式 ［ＩＸ］［式中、Ｒ２及
びＲ５は前記と同様の意味を有する］
で表される化合物を得、次いで閉環剤（ポリリン酸、ポ
リリン酸エステル、オキシ塩化リン、無水酢酸、硫酸等
）を作用させ、次いで、要すれば、加水分解することを
特徴とする下記の一般式［１１
［式中、Ｒ，は前記と同様の意味を有する〕
で表される＠換ギノリンヵルボン酸、及びその塩及び水
和物の製造法を提供する。3) - Compound represented by the formula [■] [In the formula, R1 has the same meaning as above] and the following general formula [■] R50CH-C(COORs) 2
[■] [In the formula, R3 represents a lower alkyl group] A compound represented by the general formula [IX] [In the formula, R2 and R5 have the same meanings as above] The following general formula [11 [Formula wherein R has the same meaning as defined above] Provided is a method for producing @-substituted ginoline carboxylic acid, and salts and hydrates thereof.
４）−数式［Ｘ］
［式中、Ｒ，及びＲ３は前記と同様の意味を有する］
で表される化合物を加水分解することを特徴とする下記
の一般式［１］
［式中、Ｒ３は前記と同様の意味を有する］
で表される置換キノリンカルボン酸、及びその塩及び水
和物の製造法を提供する。4) - The following general formula [1] [wherein R3 is characterized by hydrolyzing the compound represented by the formula [X] [wherein R and R3 have the same meanings as above] has the same meaning as above] Provided are substituted quinoline carboxylic acids represented by the following, and methods for producing salts and hydrates thereof.
５）式［ＸＩ］
で表される化合物に還元剤（蟻酸、水素化ホウ素ナトリ
ウム、接触還元剤等）の存在下、ホルムアルデヒドを反
応させることを特徴とする式［刈］
で表される置換キノリンカルボン酸、及びその塩及び水
和物の製造法を提供する。5) Substituted quinoline represented by the formula [Kari] characterized by reacting formaldehyde with the compound represented by the formula [XI] in the presence of a reducing agent (formic acid, sodium borohydride, catalytic reducing agent, etc.) Provided are methods for producing carboxylic acids, salts and hydrates thereof.
６）式［ＸＩ］
で表される化合物に次の一般式 ［−］ＣＨ３Ｙ
［ＸＩＩＩ ］［式中、Ｙは
ハロゲン原子、アシルオキシ基、置換スルボニルオキシ
基等の脱離基を表す］
で表される化合物を反応させることを特徴とする下記の
式［Ｘ［１］
で表される置換キノリンカルボン酸、及びその塩及び水
和物の製造法を提供する６
本反応は、反応中生成する）ＩＹを補足するための脱酸
剤の存在下で行うのが望ましい。反応は一般に溶媒中（
水、アルコール、アセトン、エーテル、ＤＭＦ％ＤＭＳ
Ｏ等）で行うのが好ましいが、Ｃ）１３Ｙあるいは脱酸
剤を過剰に用いて溶媒を兼ねさせる場合もある。6) The compound represented by formula [XI] has the following general formula [-]CH3Y
[XIII] [wherein Y represents a leaving group such as a halogen atom, an acyloxy group, or a substituted sulfonyloxy group] This reaction is preferably carried out in the presence of a deoxidizing agent to capture IY (formed during the reaction). The reaction is generally carried out in a solvent (
Water, alcohol, acetone, ether, DMF%DMS
It is preferable to use C) 13Y or an excess of a deoxidizer to serve as a solvent.
次に本発明は本発明化合物を活性成分として含有する製
薬組成物にもある。The invention also resides in pharmaceutical compositions containing the compounds of the invention as active ingredients.
本発明化合物の人及び動物（魚類を含む）の治療及び予
防のためには一般の薬学的な投与形式が用いられる。明
確な投与形式及び投与基準は治療又は予防する個体の状
況に応じて適宜選択する事ができる。Common pharmaceutical modes of administration are used for the treatment and prophylaxis of humans and animals (including fish) with the compounds of this invention. The precise administration format and administration standards can be appropriately selected depending on the circumstances of the individual to be treated or prevented.
剤型の代表的なものとして錠剤、丸剤、散剤、液剤、懸
濁剤、乳剤、顆粒剤、カプセル剤、坐剤、注射剤、軟膏
剤等を例示する事ができる。Typical dosage forms include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections, and ointments.
軟膏剤等の有機基剤を用いる製剤においては本発明化合
物中の銀、亜鉛、セリウム等の金属塩の使用も好ましく
、有機基剤との親和性にも優れている。In preparations using organic bases such as ointments, it is also preferable to use metal salts such as silver, zinc, and cerium in the compounds of the present invention, which have excellent affinity with organic bases.
本発明の内容を更に具体的に説明するため、以下の実施
例を述べる。In order to explain the contents of the present invention more specifically, the following examples will be described.
実施例１
６．７．８−１−リフルオロ−１，４−ジヒドロ−４−
オキソキノリン−３−カルボン酸エチルエステルＯ，ａ
、；、無水炭酸カリウム２．２ｇ、 １−ブロム−２
−フルオロエタン３．８ｇ及びヨウ化ナトリウム４．５
８をＤＭＦ ３０ｍ１に加え９０〜１００ ℃で１０時
間攪拌した。Example 1 6.7.8-1-Refluoro-1,4-dihydro-4-
Oxoquinoline-3-carboxylic acid ethyl ester O,a
,;, 2.2 g of anhydrous potassium carbonate, 1-bromo-2
-3.8 g of fluoroethane and 4.5 g of sodium iodide
8 was added to 30ml of DMF and stirred at 90-100°C for 10 hours.
次いで溶媒を留去し残漬に水を加えて塩化メチレンで抽
出し、水洗、乾燥の後溶媒を留去した。Next, the solvent was distilled off, water was added to the residue, extracted with methylene chloride, washed with water, dried, and then the solvent was distilled off.
この残渣に１８％塩酸１４ｍ１及びエタノールＬ４ａ＋
ｌ及び水１４ｍＱを加え水冷し、析出結晶を濾取し、Ｄ
ＭＦ−エタノール混合溶媒（１：２）より再結晶し、１
−（２−フルオロエチル）−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
ン酸を白色粉末として０．３４ｇを得た。Add 14 ml of 18% hydrochloric acid and ethanol L4a+ to this residue.
1 and 14 mQ of water were added, cooled with water, and the precipitated crystals were collected by filtration.
Recrystallized from MF-ethanol mixed solvent (1:2), 1
0.34 g of -(2-fluoroethyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained as a white powder.
ｍｐ ： ２Ｇ８〜２１．０℃
分析値 Ｃｌ２８７ＮＯ３Ｆ４
ＣＨＮ
計算値（Ｘ） ４９．８４ ２．４４ ４．８４実
測値鴎） ４９．８６ ２．３７ ５．０１実施例
２
ｌ−（２−フルオロエチル）−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Ｑ！ｔＯ，２ｇ及び無水ピペラジン０．３ｇをピリ
ジン５ｍｉに加え油浴上１４０℃で６時間還流した。mp: 2G8~21.0°C Analysis value Cl287NO3F4 CHN Calculated value (X) 49.84 2.44 4.84 Actual value 49.86 2.37 5.01 Example 2 l-(2-fluoroethyl) -6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carvone Q! 2 g of tO and 0.3 g of anhydrous piperazine were added to 5 ml of pyridine, and the mixture was refluxed on an oil bath at 140° C. for 6 hours.
次いで溶媒を留去し酢酸でｐＨを４にし、熱時不溶物を
濾去した。この濾液に塩酸を加えｐｕを１にし、析出結
晶を濾取し水から再結晶した。Then, the solvent was distilled off, the pH was adjusted to 4 with acetic acid, and insoluble materials were filtered off when heated. Hydrochloric acid was added to this filtrate to bring the pu to 1, and the precipitated crystals were collected by filtration and recrystallized from water.
６．８−ジフルオロ−１−（２−フルオロエチル）−１
，４−ジヒドロ−４−オキソ−７−（１−ピペラジニル
）−キノリン−３−カルボン酸塩酸塩を無色板状晶とし
てｏ、ｏｑｇ得た。6.8-difluoro-1-(2-fluoroethyl)-1
, 4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic hydrochloride hydrochloride was obtained as colorless plate crystals in an oqg amount.
ｍｐ ： ２９１〜２９４℃（分解）
分析値 Ｃｌ８１１１６Ｎ３０３Ｆ３・ＨＣＩＣＨＮ
計算値（豹 ４９．０５ ４．３７ １０．７３実測値
（６４） ４９．０４ ４．３６ １０．６８実施例
３
ｌ−（２−フルオロエチル）−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０．１２ｇ及び１−メチルビペラジン０．３４ｇ
をピリジン３ｍ、Ｑに加え油浴上１４０℃で６時間還流
した。mp: 291-294°C (decomposition) Analysis value Cl81116N303F3・HCICHN Calculated value (Leopard 49.05 4.37 10.73 Actual value (64) 49.04 4.36 10.68 Example 3 l-(2-fluoro 0.12 g of ethyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 0.34 g of 1-methylbiperazine
was added to 3M of pyridine and Q, and the mixture was refluxed on an oil bath at 140°C for 6 hours.
次いで溶媒を留去し酢酸でｐＨを４にし、熱時不溶物を
濾去した。この濾液に塩酸を加えｐＨを１にし、析出結
晶を濾取し、水から再結晶した。Then, the solvent was distilled off, the pH was adjusted to 4 with acetic acid, and insoluble materials were filtered off when hot. Hydrochloric acid was added to this filtrate to adjust the pH to 1, and the precipitated crystals were collected by filtration and recrystallized from water.
６．８−ジフルオロ−１−（２−フルオロエチル）−１
，４−ジヒドロ−４−オキソ−７−（４−メチル−１−
ピペラジニル）−キノリン−３−カルボン酸塩酸塩を黄
色針状晶として０．０８ｇ得た。6.8-difluoro-1-(2-fluoroethyl)-1
,4-dihydro-4-oxo-7-(4-methyl-1-
0.08 g of yellow needle-like crystals of (piperazinyl)-quinoline-3-carboxylic hydrochloride was obtained.
ｍｐ ： ２６９〜２７１℃（分解）
分析値 Ｃ＋７）１＋ａＮｓ０３Ｆ３・ｌ＋ｃｌＣＨＮ
計算値鴎） ５０．３２ ４．７２ １０．３６実測
値鴎） ５０．１２ ４．９７ １０．２４試験例１
実施例で得た化合物について抗菌試験を行った。その結
果は第１表に示す通りである。試験方法は日本化学療法
学会指定の方法［日木化学療法学会編：最少発育阻止濃
度（ＭＩＧ）測定法改定について、日本化学療法学会雑
誌、２２巻６号、１１２６〜１１２８頁 （１９７４年
）］に準じた。mp: 269-271°C (decomposition) Analysis value C+7) 1+aNs03F3・l+clCHN Calculated value 50.32 4.72 10.36 Actual value 50.12 4.97 10.24 Test example 1 Obtained in Example Antibacterial tests were conducted on the compounds. The results are shown in Table 1. The test method is the method specified by the Japanese Chemotherapy Society [edited by the Japan Chemotherapy Society: Revision of the minimum inhibitory concentration (MIG) measurement method, Journal of the Japanese Chemotherapy Society, Vol. 22, No. 6, pp. 1126-1128 (1974)] According to.
本発明化合物は第１表に示したようにグラム陰性菌に対
し極めて強い抗菌活性を示すと同時にグラム陽性菌の中
でもブドウ球菌に対し強い活性を示した。As shown in Table 1, the compounds of the present invention exhibited extremely strong antibacterial activity against Gram-negative bacteria, and also exhibited strong activity against Staphylococcus among Gram-positive bacteria.
第１表Table 1
Claims (1)
メチルピペラジノ基を表す］で表される置換キノリンカ
ルボン酸及びその生理学的に許容される塩及び水和物。 ２ 一般式 ▲数式、化学式、表等があります▼ ［式中、Ｒは水素原子又は低級アルキル基を表し、Ｒ＿
１はハロゲン原子、ピペラジノ基又は４−メチルピペラ
ジノ基を表す］で表される化合物と次の一般式 ＦＣＨ＿２ＣＨ＿２Ｘ ［式中、Ｘはハロゲン原子又は置換スルホニルオキシ基
等の脱離基を表す］で表される化合物とを脱酸剤の存在
下で反応させ、要すれば、次いで加水分解することを特
徴とする下記一般式 ▲数式、化学式、表等があります▼ ［式中、Ｒ＿１はハロゲン原子、ピペラジノ基又は４−
メチルピペラジノ基を表す］で表される置換キノリンカ
ルボン酸、及びその塩及び水和物の製造法。 ３ 一般式 ▲数式、化学式、表等があります▼ ［式中、Ｘはハロゲン原子を表す］で表される化合物と
次の一般式 Ｒ＿２Ｈ ［式中、Ｒ＿２はピペラジノ基又は４−メチルピペラジ
ノ基を表す］で表される化合物とを反応させることを特
徴とする下記の一般式 ▲数式、化学式、表等があります▼ ［式中、Ｒ＿２はピペラジノ基又は４−メチルピペラジ
ノ基を表す］で表される置換キノリンカルボン酸、及び
その塩及び水和物の製造法。 ４ 一般式 ▲数式、化学式、表等があります▼ ［式中、Ｒ＿１はハロゲン原子、ピペラジノ基又は４−
メチルピペラジノ基を表す］で表される化合物と次の一
般式 Ｒ＿３ＯＣＨ＝Ｃ（ＣＯＯＲ＿３）＿２ ［式中、Ｒ＿３は低級アルキル基を表す］で表される化
合物とを反応させ、次いで閉環剤と反応させ、要すれば
、次いで加水分解することを特徴とする下記の一般式 ▲数式、化学式、表等があります▼ ［式中、Ｒ＿１はハロゲン原子、ピペラジノ基又は４−
メチルピペラジノ基を表す］で表される置換キノリンカ
ルボン酸、及びその塩及び水和物の製造法。 ５ 一般式 ▲数式、化学式、表等があります▼ ［式中、Ｒ＿１はハロゲン原子、ピペラジノ基又は４−
メチルピペラジノ基を表し、Ｒ＿３は低級アルキル基を
表す］で表される化合物を加水分解することを特徴とす
る下記一般式 ▲数式、化学式、表等があります▼ ［式中、Ｒ＿１はハロゲン原子、ピペラジノ基又は４−
メチルピペラジノ基を表す］で表される置換キノリンカ
ルボン酸、及びその塩及び水和物の製造法。 ６ 式 ▲数式、化学式、表等があります▼ で表される化合物に還元剤の存在下、ホルムアルデヒド
を反応させることを特徴とする下記の式 ▲数式、化学式、表等があります▼ で表される置換キノリンカルボン酸、及びその塩及び水
和物の製造法。 ７ 式 ▲数式、化学式、表等があります▼ で表される化合物に次の一般式 ＣＨ＿３Ｙ ［式中、Ｙはハロゲン原子、アシルオキシ 基、置換スルホニルオキシ基等の脱離基を表す］で表さ
れる化合物を反応させることを特徴とする下記の式 ▲数式、化学式、表等があります▼ で表される置換キノリンカルボン酸、及びその塩及び水
和物の製造法。[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 is a halogen atom, a piperazino group, or a 4-
Substituted quinoline carboxylic acid represented by the following formula: methylpiperazino group, and its physiologically acceptable salts and hydrates. 2 General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R represents a hydrogen atom or a lower alkyl group, and R_
1 represents a halogen atom, a piperazino group, or a 4-methylpiperazino group] and the following general formula FCH_2CH_2X [wherein, X represents a halogen atom or a leaving group such as a substituted sulfonyloxy group] The following general formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is a halogen atom, a piperazine atom, etc.] group or 4-
A method for producing a substituted quinoline carboxylic acid represented by methylpiperazino group, and salts and hydrates thereof. 3. Compounds represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. Substitution represented by the following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_2 represents a piperazino group or 4-methylpiperazino group] A method for producing quinolinecarboxylic acid and its salts and hydrates. 4 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is a halogen atom, a piperazino group, or a 4-
methylpiperazino group] and a compound represented by the following general formula R_3OCH=C(COOR_3)_2 [wherein R_3 represents a lower alkyl group], and then reacted with a ring-closing agent. , if necessary, is then hydrolyzed by the following general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 is a halogen atom, a piperazino group, or a 4-
A method for producing a substituted quinoline carboxylic acid represented by methylpiperazino group, and salts and hydrates thereof. 5 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is a halogen atom, a piperazino group, or a 4-
Represents a methylpiperazino group, R_3 represents a lower alkyl group] The following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is a halogen atom, piperazine group or 4-
A method for producing a substituted quinoline carboxylic acid represented by methylpiperazino group, and salts and hydrates thereof. 6 Formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Represented by the following formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ characterized by reacting formaldehyde in the presence of a reducing agent with the compound represented by Method for producing substituted quinoline carboxylic acid, salts and hydrates thereof. 7 The compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. A method for producing a substituted quinoline carboxylic acid, and its salts and hydrates, represented by the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20538988A JPH01258666A (en) | 1988-08-18 | 1988-08-18 | Novel substituted quinolinecarboxylic acid and production thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20538988A JPH01258666A (en) | 1988-08-18 | 1988-08-18 | Novel substituted quinolinecarboxylic acid and production thereof |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP675990A Division JPH02231477A (en) | 1990-01-16 | 1990-01-16 | Production of novel substituted qunolinecarboxylic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01258666A true JPH01258666A (en) | 1989-10-16 |
| JPH0250108B2 JPH0250108B2 (en) | 1990-11-01 |
Family
ID=16506013
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20538988A Granted JPH01258666A (en) | 1988-08-18 | 1988-08-18 | Novel substituted quinolinecarboxylic acid and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01258666A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2275141A1 (en) | 1999-03-17 | 2011-01-19 | Daiichi Pharmaceutical Co., Ltd. | Tastemasked pharmaceutical compositions |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5547658A (en) * | 1978-09-29 | 1980-04-04 | Kyorin Pharmaceut Co Ltd | Substituted quinolinecarboxylic acid derivative |
-
1988
- 1988-08-18 JP JP20538988A patent/JPH01258666A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5547658A (en) * | 1978-09-29 | 1980-04-04 | Kyorin Pharmaceut Co Ltd | Substituted quinolinecarboxylic acid derivative |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2275141A1 (en) | 1999-03-17 | 2011-01-19 | Daiichi Pharmaceutical Co., Ltd. | Tastemasked pharmaceutical compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0250108B2 (en) | 1990-11-01 |
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