CN86104414A - 喹诺酮羧酸衍生物的制备方法 - Google Patents
喹诺酮羧酸衍生物的制备方法 Download PDFInfo
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- CN86104414A CN86104414A CN86104414.2A CN86104414A CN86104414A CN 86104414 A CN86104414 A CN 86104414A CN 86104414 A CN86104414 A CN 86104414A CN 86104414 A CN86104414 A CN 86104414A
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- 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
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- 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
本发明的喹诺酮羧酸衍生物如下式表示:
它们的水合物及可用于药物的盐能作为抗菌剂。
Description
本发明是关于一个如式(Ⅰ)表示的新的喹诺酮羧酸衍生物及它的水合物和盐的制备方法,它们可用作为抗菌剂。
以式(Ⅰ)表示的化合物,由于在7位取代的氨基吡咯烷环的不对称碳原子,因而含有光学异构体,但是所有的光学异构体和它们的混合物均能用分子式方便地表示出来,因此本发明的范围不限止在光学异构体或它们的混合物其中的一个。
喹诺酮羧酸抗菌剂是起始于萘啶酮酸,现已发展成为Piromidic酸,而且还有Pipemidic酸,它们是医学上有用的抗菌剂,治疗因需氧革兰氏阴性菌引起的尿道感染。
最近才被我们发现的Norfloxacin,显示了强抗菌活性,它不仅能抗革兰氏阴性菌,还能抗革兰氏阳性菌;它的能力远远地强于以前的喹诺酮羧酸。Norfloxain在这个领域已成为一个划时代的进展,现在它已非常普遍地用于临床。
喹诺酮羧酸如:Ofloxacin和Ciprofloacin具有类似于Norflo-xacin含有的取代基也不断地发展。
Ciprofl-oxacin比Nofloxacin具有强的抗菌活性,但是它的抗革兰氏阳性菌能力要次于抗革兰氏阴性菌。
另一方面,增加抗革兰氏阳性菌的β-内酰胺抗菌剂,如:甲氧西林和头孢霉素能抗金黄包葡萄球菌、表皮葡萄球菌、粪便杆菌,这在临床范围里有一定的困难。
此外,由于厌氧菌检查的普及,强制厌氧菌在皮肤或粘膜上的作用被证明同机会感染的病原体作用一样,这已作为临床试验技术发展的一个结果。据报导,已发现厌氧菌在有或没有需氧菌时,其在呼吸系统感染、腹膜感染、中耳炎、鼻窦炎、产科与妇科的感染比例为50-80%;厌氧菌与大肠杆菌和其它链球菌结合时感染的比例为95%。由于厌氧菌对原有的有效抗厌氧菌的抗菌剂,如:β-内酰胺抗菌剂或氯洁霉素的耐药性渐渐增加,因而产生了选择化疗剂的一系列问题。
在这些背景下,就需要发展具有强的活性及广谱的新抗菌剂。
我们发现本发明的化合物在动物中有很好的口服吸收,极好的组织分布、满意的生物稳定性和可接受性。
有关本发明化合物的制备方法以下来说明:
上式中R是氢或低级烷基,R1和R2分别是氢、低级烷基、低级烷氧羰基、有取代的苄基、三苯甲基和脂肪族或芳香族磺酰基;X是卤原子。
以式(Ⅲ)表示的化合物与式(Ⅲ)表示的胺反应合成以式(Ⅰ)表示的本发明化合物。式(Ⅱ)化合物与(Ⅲ)化合物的反应最好将反应混合物加热进行,它可以在有溶剂如:水、乙醇、乙腈、二甲基甲酰胺(DMF)、二甲亚砜(DMSO)、六甲基磷三甲酰胺、吡啶、甲基吡啶等中或没有溶剂中进行。适当选择室温-200℃范围内的反应温度,最好为室温-160℃。更详细地说,最好将式(Ⅱ)化合物与1-5倍克分子式(Ⅲ)化合物在2-10倍体积的前述溶剂中,在室温-120℃反应1-几个小时。此时,使用脱酸剂如三乙胺、重氮二环硷和碳酸钾也是需要的。
此外,化合物(Ⅰ′),其中R1或R2是低级酰基、低级烷氧羰基、有取代的苄基,可以按通常方法来提供给本发明化合物,如用硷或酸的水解、催化还原等转化化合物(Ⅰ′)为氨基。
另外,化合物(Ⅰ′),其中R是低级烷基,可以按照通常的方法脱水,酯转化成羧酸来提供。本发明化合物这样在用硷如氢氧化钾或用酸如硫酸,在从室温到溶剂在水中的沸点的温度水解是很容易进行的,其溶剂为如水与乙醇混合液、水与醋酸混合液等。
此外,式(Ⅰ)化合物,如需要可以通过用酸或硷处理转化为可用于药物的铵盐或羧酸金属盐。酸可以是有机酸,也可以是无机酸,如盐酸、硫酸、磷酸、醋酸、甲磺酸、草酸和乳酸。羧酸金属盐可以是钠盐、钾盐、镁盐、钙盐、铝盐、铈盐、铬盐、钴盐、铜盐、铁盐、锌盐、铂盐和银盐。
式(Ⅰ)化合物及它们的水合物和盐可以以药物制备形式作为药物使用,如:片剂、胶囊、粉末、软膏、栓剂、注射剂或眼药水,对于口服的、肠胃外的、肠道的或局部用药都是方便的。
下述例子将进一步阐述本发明,但并不是对本发明的限制。
例1
7-(3-氨基-1-吡咯烷基)-8-溴-1-环丙基-6-氟-1,4-二氢-4-氧-3-喹啉羧酸
将200毫克8-溴-1-环丙基-6,7-二氟-1,4-二氢-4-氧代-3-喹啉羧酸、3毫升无水乙腈、95毫克1,8-二氮并环〔5,4,0〕-7-+-碳烯和280毫克3-叔丁氧羰酰氨基吡咯烷混合后,搅拌回流1小时,将反应混合物在室温再搅拌4小时后浓缩,向残余物中加入冷的浓盐酸-甲醇混合液(1∶1)4毫升,在冰浴中搅拌45分钟,将反应混合物用浓氨水中和,过滤收集沉淀物,用水洗后,以氯仿一甲醇重结晶得到标题化合物80毫克,淡黄色棱形结晶,熔点207-210℃(分解)
分析(%)C17H17BrFN3O3,2H2O计算值(实验值):C,45.75(45.88);H,4.74(4.25);N,9.42(9.24)
实验1 抗菌谱
按日本化疗会志介绍的方法测定其最低抑菌浓度,结果见表1。
表1-1 在体外的抗菌活性(标准菌株)
表1-2 在体外的抗菌活性(标准菌株)
CPFX:ciprofloxacin
Claims (1)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP146413/85 | 1985-07-03 | ||
JPSHO60-146413 | 1985-07-03 | ||
JP60146413A JPS6236377A (ja) | 1985-07-03 | 1985-07-03 | キノロンカルボン酸誘導体 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN86104414A true CN86104414A (zh) | 1987-02-04 |
CN1009830B CN1009830B (zh) | 1990-10-03 |
Family
ID=15407131
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN86104414A Expired CN1009830B (zh) | 1985-07-03 | 1986-07-02 | 喹诺酮羧酸衍生物的制备方法 |
Country Status (12)
Country | Link |
---|---|
EP (1) | EP0207497A3 (zh) |
JP (1) | JPS6236377A (zh) |
KR (1) | KR870001191A (zh) |
CN (1) | CN1009830B (zh) |
CA (1) | CA1289961C (zh) |
DK (1) | DK161457C (zh) |
ES (1) | ES2001852A6 (zh) |
FI (1) | FI82935C (zh) |
HU (1) | HU196785B (zh) |
MX (1) | MX163074B (zh) |
NO (1) | NO167456C (zh) |
PT (1) | PT82903B (zh) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4791225A (en) * | 1986-01-20 | 1988-12-13 | Kyorin Pharmaceutical Co., Ltd. | Halogenobenzoic acid derivatives and their preparation |
CA1332605C (en) * | 1988-10-03 | 1994-10-18 | Yasuhiro Nishitani | Pyridonecarboxylic acids |
JPH0821527B2 (ja) * | 1990-05-23 | 1996-03-04 | ルビコン株式会社 | 電解コンデンサ |
KR950014567B1 (ko) * | 1991-08-01 | 1995-12-08 | 주식회사대웅제약 | 신규한 퀴놀론 카르복실산 유도체 |
JP2804006B2 (ja) * | 1995-06-23 | 1998-09-24 | ルビコン株式会社 | 電解コンデンサ |
PL339408A1 (en) * | 1997-09-15 | 2000-12-18 | Procter & Gamble | Antimicrobial quinolones, agents containing them and their applications |
US6387928B1 (en) | 1997-09-15 | 2002-05-14 | The Procter & Gamble Co. | Antimicrobial quinolones, their compositions and uses |
WO2007110836A1 (en) | 2006-03-28 | 2007-10-04 | The Procter & Gamble Company | A hydride reduction process for preparing quinolone intermediates |
MX2008012328A (es) | 2006-03-28 | 2008-10-09 | Procter & Gamble | Sales de malato, y polimorfos de acido (3s,5s)-7-[3-amino-5-metil- piperidinil]-1-ciclopropil-1,4-dihidro-8-metoxi-4-oxo-3-quinolinc arboxilico. |
JP2009531418A (ja) | 2006-03-28 | 2009-09-03 | ザ プロクター アンド ギャンブル カンパニー | キノロン中間体調製のためのカップリング方法 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4665079A (en) * | 1984-02-17 | 1987-05-12 | Warner-Lambert Company | Antibacterial agents |
-
1985
- 1985-07-03 JP JP60146413A patent/JPS6236377A/ja active Pending
-
1986
- 1986-06-27 HU HU862711A patent/HU196785B/hu not_active IP Right Cessation
- 1986-07-01 EP EP86108949A patent/EP0207497A3/en not_active Withdrawn
- 1986-07-02 FI FI862822A patent/FI82935C/fi not_active IP Right Cessation
- 1986-07-02 NO NO862687A patent/NO167456C/no not_active IP Right Cessation
- 1986-07-02 CN CN86104414A patent/CN1009830B/zh not_active Expired
- 1986-07-02 KR KR1019860005353A patent/KR870001191A/ko not_active Application Discontinuation
- 1986-07-02 DK DK314386A patent/DK161457C/da not_active IP Right Cessation
- 1986-07-02 CA CA000512913A patent/CA1289961C/en not_active Expired - Lifetime
- 1986-07-02 PT PT82903A patent/PT82903B/pt not_active IP Right Cessation
- 1986-07-02 MX MX3006A patent/MX163074B/es unknown
- 1986-07-03 ES ES8600105A patent/ES2001852A6/es not_active Expired
Also Published As
Publication number | Publication date |
---|---|
PT82903A (en) | 1986-08-01 |
CA1289961C (en) | 1991-10-01 |
FI82935B (fi) | 1991-01-31 |
ES2001852A6 (es) | 1988-07-01 |
NO862687L (no) | 1987-01-05 |
CN1009830B (zh) | 1990-10-03 |
NO167456B (no) | 1991-07-29 |
FI862822A0 (fi) | 1986-07-02 |
EP0207497A2 (en) | 1987-01-07 |
PT82903B (pt) | 1988-05-27 |
DK314386D0 (da) | 1986-07-02 |
DK314386A (da) | 1987-01-04 |
NO167456C (no) | 1991-11-06 |
DK161457C (da) | 1991-12-16 |
HUT43580A (en) | 1987-11-30 |
EP0207497A3 (en) | 1988-05-18 |
JPS6236377A (ja) | 1987-02-17 |
FI82935C (fi) | 1991-05-10 |
HU196785B (en) | 1989-01-30 |
KR870001191A (ko) | 1987-03-12 |
NO862687D0 (no) | 1986-07-02 |
DK161457B (da) | 1991-07-08 |
MX163074B (es) | 1991-08-05 |
FI862822A (fi) | 1987-01-04 |
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