CN85108940A - 氨磺酰苯甲酸衍生物的制备方法 - Google Patents
氨磺酰苯甲酸衍生物的制备方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/28—Nitrogen atoms
- C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/66—Nitrogen atoms not forming part of a nitro radical
Abstract
本发明涉及新的和有用的氨磺酰苯甲酸衍生物，它具有利尿和促尿酸尿的作用。
Description
本发明涉及某些新型的氨磺酰苯甲酸（SVLFAMOYLBENZOIC ACID）衍生物及其制备方法。这些衍生物具有有效的排盐利尿作用，促尿酸尿作用以及降血压作用。因此，本发明的化合物构成了一类有价值的药剂，它们可用耒对伴有肝病或心脏病特别是伴有心力衰竭的水肿进行药疗，以及用耒治疗高血压、血尿酸过多等疾病
本发明之更详细的内容是，它涉及一些新的氨磺酰苯甲酸衍生物，其化学式为
其中的R1是氯原子或苯氧基团，R2是氢原子、囟素原子、低级烷基、低级烷氧基或亚甲二氧基团，本发明还涉及这些衍生物的制备方法。
本发明的化合物（Ⅰ）可通过使氨磺酰苯甲酸（Ⅱ）或它们的活性衍生物与哌嗪衍生物（Ⅲ）在缩合剂存在下进行反应而被制备出耒。
这里的R1和R2具有如上所述的意义。
氨磺酰苯甲酸衍生物（Ⅱ）与哌嗪衍生物（Ⅲ）的反应是在缩合剂的存在下进行的，这类缩合剂有N，N-双环己基碳化二亚胺（N，N′-dicyclohexylcarbodiimide）、NN′-碳酰二咪唑（N、N′-carbonyldiimidazole）等等。
这一反应是通过把缩合剂加入到化合物（Ⅱ）和（Ⅲ）的混合物中而进行的。对缩合耒说也方便的是在缩合剂的存在下化合物（Ⅱ）首先转化成它的酸酐，然后该酸酐与化合物（Ⅲ）进行反应，适合这一反应的溶剂是一类对质子有惰性的溶剂，例如氯仿、四氢呋喃、二甲基甲酰胺等等。
在把氨磺酰苯甲酸（Ⅱ）的活性衍生物与哌嗪衍生物（Ⅲ）进行反应的情况下，该酸的氯化物或溴化物是用作活性衍生物的。在这种情况下，三乙胺、啶、碳酸钠、碳酸钾或者其它这类物质被用作缩合剂，而苯、甲苯、甲酰胺、二氯甲烷、四氢呋喃或其它这类物质则被用作溶剂。
为了使本发明能被充分理解，现给出以下实施例。
实施例1 4-氯-N-[4-（2-甲氧基苯基）-1-哌嗪基]-3-氨磺酰苯甲酰胺
在室温且搅拌的条件下，把处在20毫升四氢呋喃中的2.1克4-氯-3-氨磺酰苯甲酸溶液加入到5毫升四氢呋喃中的1.8克N，N′-双环己基碳化二亚胺溶液中。完全加入之后，该混合物就在室温下进行20分钟的搅拌，然后加入0.83克的1-氨基-4-（2-甲氧基苯基）哌嗪，此后，该反应混合物再被搅拌5小时。接着，再加入5毫升10%的盐酸并在室温下搅拌10分钟。又加入250毫升2%的氢氧化钠溶液并把不溶物质过滤掉。之后，又采用2%的氢氧化纳溶液对滤液进行碱化从而获得白色的沉淀。所生成的沉淀物被过滤出耒并用水冲洗，最后从乙醇中再沽晶出耒，于是就获得了如本文标题所述的化合物，其生成量为0.84克（49%），这是一种无色的晶体，熔点为232～235℃。
对C18H21CN4O4S进行分析（%），计算的（括号中为实测的为：C，50、88（51，06）;H，4.98（5.02）;N，13，19（13.19）。
实施例2 4-氯-N-[4-（2-甲氧基苯基）-1-哌嗪基]-3-氨磺酰苯甲酰胺
在室温且搅拌的条件下，把1.25克的4-氯-3-氨磺酰苯甲酰氯加入到1克1-氨基-4-（2-甲氧基苯基）哌嗪和1毫升三乙胺的混合物中。然后，在室温下对该反应混合物进行9小时的搅拌。接着，所生成的沉淀物被过滤出耒并用水冲洗，最后从乙醇中再结晶出耒，于是就获得了如本文标题所述的化合物，其生成量为1.20克（60%）这是一种无色的针状晶体，熔点为231～233℃。
对C18H21ClN4O4S进行分析，计算的（括号中为实测的）为：C，50，88（50，58）;H，4.98（5.19）;N，13.19（13.15）。
表1列出了用与实施例2中相同的程序而制备的其它的新化合物。
采用一些大约重300克的雄性Wistar系老鼠。每一组由5只老鼠组成。经过18小时的断粮断水之后，就把本发明的化合物和参照药物从口中引入到鼠的机体中。其结果如表2所示。实施例1和6的化合物是有效的利尿剂，并显示出自然的排盐利尿性能。
表2
利尿和排盐利尿的效果
Na+K+：钠和钾的总排泄量（毫克当量/公斤）。
UV：尿体积（毫升/公斤）
Behyd：苄基氢氯噻嗪类
HCT：氢氯噻嗪类
＊，＊＊：不同于对照物，分别为P＜0.05，P＜0.01
实验2 促尿酸尿效果
在出生后11～14个星期的雄性Wistar系老鼠上进行清除实验。每一组由5只老鼠组成。根据清除率（尿酸的清除/菊粉的清除）对促尿酸尿活性进行了评价。其结果如图1所示。显然，实施例1的化合物要比被称为促尿酸尿剂的丙磺舒（Probrnecid）具有更有效的促尿酸尿效果。
实验3 在剧烈地载有尿酸的老鼠中显示的降尿酸血Hypouricemic）的效果。
用生后十个星期的雄性Wistar系老鼠进行这一实验。在把药物引入老鼠机体之前先在30分钟之内以200毫克/公斤的剂量把尿酸引入到老鼠的腹膜内。实施例1的化合物和丙磺舒被引入到鼠的腹膜。30分钟之后，通过驱血法把这些老鼠弄死。把血收集起耒然后测定出血清尿酸的含口量。表3已表明，实施例1的化合物也具有降尿酸血（Hypouricemic）的活性。表3 剧烈被载有尿酸的老鼠中的血清尿酸含量
实施例4 降血压作用
以100毫克/公斤的剂量每天口服实施例1的化合物达四天之后就降低了原耒就有高血压病症的老鼠的收缩（血）压。数据列在表4中。
表4 降血压效果
实施例5 急性毒性
以2.500毫克/公斤的剂量让老鼠口服实施例1的化合物以后，没有一只ICR系的老鼠死亡。
图1显示了实施例1的化合物和其它药物的促尿酸尿活性。纵坐标表示了促尿酸尿活性随含盐基团对照物的变化而发生的百分比变化。横坐标表示了服药后的时间（分钟）。
Claims (1)
- 一种制备化学式为
的氨磺酰苯甲酸衍生物的方法，其中的R是一氯原子或苯氧基团，R是氢原子、卤素原子、低级烷基团、低级烷氧基团或亚甲二氧基团，该方法包括采用缩合剂耒使化学式为
酰苯甲酸衍生物与化学式为的氨磺哌嗪衍生物进行反应。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP59256877A JPS61134382A (ja) | 1984-12-04 | 1984-12-04 | 新規なスルファモイル安息香酸誘導体およびその製造法 |
| JP59-256877 | 1984-12-04 | ||
| JP256877/84 | 1984-12-04 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85108940A true CN85108940A (zh) | 1986-10-22 |
| CN1012642B CN1012642B (zh) | 1991-05-22 |
Family
ID=17298651
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN85108940A Expired CN1012642B (zh) | 1984-12-04 | 1985-12-03 | 氨磺酰苯甲酸衍生物的制备方法 |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4650871A (zh) |
| EP (1) | EP0186796B1 (zh) |
| JP (1) | JPS61134382A (zh) |
| KR (1) | KR900003371B1 (zh) |
| CN (1) | CN1012642B (zh) |
| AU (1) | AU569812B2 (zh) |
| CA (1) | CA1241960A (zh) |
| DE (1) | DE3573253D1 (zh) |
| DK (1) | DK167760B1 (zh) |
| ES (1) | ES8702394A1 (zh) |
| FI (1) | FI80686C (zh) |
| HU (1) | HU194200B (zh) |
| NO (1) | NO168245C (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2027898A6 (es) * | 1991-01-24 | 1992-06-16 | Espanola Prod Quimicos | Procedimiento de preparacion de nuevos derivados de la 2-metoxifenilpiperacina. |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2663707A (en) * | 1951-06-22 | 1953-12-22 | American Cyanamid Co | Amino piperazines and methods of preparing the same |
| FR1448711A (fr) * | 1960-11-09 | 1966-03-18 | Sandoz Sa | Nouveaux dérivés de l'hydrazine et leur préparation |
| US3200121A (en) * | 1964-08-05 | 1965-08-10 | Searle & Co | Disubstituted-alkanoyl hydrazides of 1-aminopiperazines |
| FR2104930B1 (zh) * | 1970-09-08 | 1974-08-30 | Ferlux | |
| DE2611705A1 (de) * | 1976-03-18 | 1977-09-22 | Josef Dipl Chem Dr Rer N Klosa | N-5-(nitrofurfuryliden-)-1-amino- hydantoin enthaltende kristalloesungsmittel |
| CA1082181A (en) * | 1976-06-03 | 1980-07-22 | Eric A. Watts | Benzamide derivatives |
| GB8303946D0 (en) * | 1983-02-12 | 1983-03-16 | Recordati Chem Pharm | Antihypertensive n-piperazinylalkanoylanilides |
-
1984
- 1984-12-04 JP JP59256877A patent/JPS61134382A/ja active Granted
-
1985
- 1985-11-27 AU AU50431/85A patent/AU569812B2/en not_active Ceased
- 1985-11-29 FI FI854745A patent/FI80686C/fi not_active IP Right Cessation
- 1985-12-02 CA CA000496626A patent/CA1241960A/en not_active Expired
- 1985-12-03 KR KR1019850009043A patent/KR900003371B1/ko not_active IP Right Cessation
- 1985-12-03 CN CN85108940A patent/CN1012642B/zh not_active Expired
- 1985-12-03 DK DK559185A patent/DK167760B1/da not_active IP Right Cessation
- 1985-12-03 EP EP85115296A patent/EP0186796B1/en not_active Expired
- 1985-12-03 DE DE8585115296T patent/DE3573253D1/de not_active Expired
- 1985-12-03 US US06/804,123 patent/US4650871A/en not_active Expired - Fee Related
- 1985-12-03 NO NO854872A patent/NO168245C/no unknown
- 1985-12-04 HU HU854643A patent/HU194200B/hu not_active IP Right Cessation
- 1985-12-04 ES ES549559A patent/ES8702394A1/es not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| KR900003371B1 (ko) | 1990-05-16 |
| KR860004864A (ko) | 1986-07-14 |
| CN1012642B (zh) | 1991-05-22 |
| EP0186796A1 (en) | 1986-07-09 |
| JPS61134382A (ja) | 1986-06-21 |
| FI854745A (fi) | 1986-06-05 |
| HU194200B (en) | 1988-01-28 |
| FI80686B (fi) | 1990-03-30 |
| AU5043185A (en) | 1986-06-12 |
| ES8702394A1 (es) | 1987-01-01 |
| NO168245B (no) | 1991-10-21 |
| DK559185D0 (da) | 1985-12-03 |
| AU569812B2 (en) | 1988-02-18 |
| DK167760B1 (da) | 1993-12-13 |
| US4650871A (en) | 1987-03-17 |
| CA1241960A (en) | 1988-09-13 |
| ES549559A0 (es) | 1987-01-01 |
| JPH0434997B2 (zh) | 1992-06-09 |
| NO854872L (no) | 1986-06-05 |
| NO168245C (no) | 1992-01-29 |
| EP0186796B1 (en) | 1989-09-27 |
| DE3573253D1 (en) | 1989-11-02 |
| HUT40428A (en) | 1986-12-28 |
| DK559185A (da) | 1986-06-05 |
| FI80686C (fi) | 1990-07-10 |
| FI854745A0 (fi) | 1985-11-29 |
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