CN1026586C - 新的噻唑烷酮衍生物制备方法 - Google Patents
新的噻唑烷酮衍生物制备方法 Download PDFInfo
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- CN1026586C CN1026586C CN90110356A CN90110356A CN1026586C CN 1026586 C CN1026586 C CN 1026586C CN 90110356 A CN90110356 A CN 90110356A CN 90110356 A CN90110356 A CN 90110356A CN 1026586 C CN1026586 C CN 1026586C
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- thiazolidone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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 ring carbon atoms
- C07D277/14—Oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Abstract
本发明是关于新的通式(I)化合物及其制备方法
其中R表示氢或C1-4烷基,Y代表氰基,三氟甲基,芳氧基或芳(C1-4烷基)氧基。
本发明的化合物显示出抑制胃酸分泌的作用,因此它们可用于治疗胃和十二指肠溃疡。此外,它们对例如由消炎痛或含酸乙醇所诱发的胃损伤起着细胞保护作用。
Description
本发明是关于新的通式(Ⅰ)2-噻唑烷酮衍生物以及含有这些化合物的药物组合物,
其中,R表示氢或C1-4烷基;Y代表氰基,三氟甲基,芳氧基或芳(C1-4烷基)氧基。
通式(Ⅰ)化合物具有有效的抑制胃酸分泌的作用。由于患有胃或十二指肠溃疡的病人的数量无论从相对还是绝对意义上都在不断增加,所以这些化合物具有很高的治疗价值。
结构上类似于通式(Ⅰ)并起着类似的抑制胃酸分泌作用的化合物已经公开于匈牙利专利说明书198,915中。由于连在芳核上的它们的取代基的性质使本发明范围内的化合物基本上不同于已知物质。
根据本发明的另一方面,提供了通式(Ⅰ)化合物的制备方法,
其中R表示氢或C1-4烷基;Y代表氰基,三氟甲基,芳氧基或芳(C1-4烷基)氧基,该方法包括使通式(Ⅱ)化合物与2-噻唑烷酮反应,
其中R和Y如上所定义,X代表卤素,甲磺酰氧基或甲苯磺酰氧基。
本发明的方法的反应是在溶剂中,优选在C3-8酮如甲基异丁基酮,或在含水的酮,二甲基甲酰胺或二甲亚砜中,在酸结合剂的存在下,优选的碱金属碳酸盐或碳酸氢盐的存在下进行的。在用水滤出或洗去无机沉淀物之后,由反应所得到的产品经过滤而分离,或除去溶剂之后,将产品通过重结晶或柱色谱法提纯。
用作起始化合物的2-噻唑烷酮为已知的,并且可以按照文献(J.Am.Chem.Soc.,78,5349(1956);和J.Chem.Soc.1952,3094]制备出来。
对于通式(Ⅱ)化合物,含X为卤素的物质是市场上可买到的精细化学药品(参看Aldrich的有关目录单);含X为甲磺酰氧基的物质可以用匈牙利专利说明书163,399中描述的方法由相应的醇来制备。
基于药理学的研究,3-(2-氰基苯基甲基)-2-噻唑烷酮是通式(Ⅰ)这类化合物的一个突出的代表。该化合物对所谓Shay的鼠[Shay:Gastroenterolagy5,43(1945)]显示出抑制胃酸分泌的作用,其口服的ED50值为1.7mg/Kg。该化合物甚至对消炎痛诱发的胃溃疡也是有效的,其口服的ED50值为1.2mg/kg;它对含酸乙醇诱发的胃损伤也是有效的[Robert:Gastroenterology77,761(1979)],即它显示出所谓的细胞保护作用,其口服的ED50值为3.7mg/kg。
基于我们的初步研究,上述本发明的化合物被
预期的人的日剂量为每个病人10-100mg。
本发明的新化合物的制备通过下文所述的一般方法来加以说明:
将0.033mol卤代甲苯或通式(Ⅱ)的苯甲醇甲磺酸酯或甲苯磺酸酯的衍生物加到含有3.09g(0.03mol)的2-噻唑烷酮,11.2g的碳酸钾,1.8g的碳酸氢钾,0.5ml的水和30ml甲基异丁基酮的混合物中,然后在回流下使混合物沸腾,直到起始原料2-噻唑烷酮完全消耗为止,这是通过薄层色谱法(TLC)用10∶3∶1的苯/甲醇/冰醋酸为展开系统来监测的。冷却下来之后用30ml水将反应混合物搅拌30分钟。最后把剩下的不溶部分过滤掉,用水洗,干燥并通过重结晶来纯化。第二代滤液可以用下列方法进行再分离:
在水作用下出现两个清晰的相对,分离出有机相,用30ml水洗,将有机相干燥并蒸发。残余物用柱色谱(用Kieselgel 60,230-400目,用三氯甲烷或乙酸乙酯作洗脱液)或重结晶来纯化。
如上所述制备的化合物及其最重要的特征概括在表Ⅰ中,这些实例对本发明的范围没有任何限制。
在表Ⅰ中所列举的化合物的化学名称如下:
1)3-(2-氰基苯基甲基)-2-噻唑烷酮
2)3-(4-氰基苯基甲基)-2-噻唑烷酮
3)3-(3-氰基苯基甲基)-2-噻唑烷酮
4)3-(1-苯基-1-乙基)-2-噻唑烷酮
5)3-(3-苯氧基苯基甲基)-2-噻唑烷酮
6)3-(4-苄氧基苯基甲基)-2-噻唑烷酮
7)3-(4-三氟甲基苯基甲基)-2-噻唑烷酮
8)3-(2-三氟甲基苯基甲基)-2-噻唑烷酮
9)3-(3-三氟甲基苯基甲基)-2-噻唑烷酮
用下述非限制性的实施例对本发明加以详细说明。
实施例1
3-(2-氰基苯基甲基)-2-噻唑烷酮的制备
将含有3.09g(0.03mol)的2-噻唑烷酮,11.2g(0.081mol)的碳酸钾,1.8g(0.018mol)的碳酸氢钾,0.5ml(0.027mol)的水和6.47g(0.033mol)的2-溴甲基苯基氰的混合物在30ml的甲基异丁基酮中回流5小时,然后冷却下来。加入30ml水之后将混合物搅拌30分钟,将不溶的沉淀物滤出,每次用10ml水洗涤两次,并干燥。用20ml乙醇重结晶4.71g粗产物,同时用活性炭纯化后,得到3.39g(51.8%)白色晶状标题化合物,m·p:116-117℃。
实施例2
含有3-(2-氰基苯基甲基)-2-噻唑烷酮作为活性成分的药物组合物的制备
成分: g
3-(2-氰基苯基甲基)-2-噻唑烷酮 40
乳糖 80
淀粉 67
滑石粉 6
聚乙烯吡咯烷酮 4
硬脂酸镁 2
胶体硅酸 1
由上述组合物可以制成1000片直径为8mm每片重量为200mg的药片。
表Ⅰ
化合物 实验式 产率 熔点℃ IR NMR
序号 分子量 % (结晶溶剂) Cm-1ppm
1. C11H10N2OS 52 116-117 2240 3.2-3.9/m,4H,2CH2/
(乙醇) 1665 4.8/s,2H,CH2/
218,26 1250 7.6/m,4H,ArH/
2. C11H10N2OS 45 84-85 2240 3.2-3.8/m,4H,2CH2/
(乙醇) 1665 4.6/s,2H,CH2
218,26 1410 7.6/q,4H,ArH/
3. C11H10N2OS 48 77-78 2240 3.1-3.8/m,4H,2CH2/
(异丙醇) 1670 4.5/s,2H,CH2/
750 7.6/s,4H,ArH/
4. C11H13NOS 44 油*1665 1.5/d,3H,CH3/
1405 2.9-3.7/m,4H,2CH2/
207,28 1240 5.4/q,1H,CH/
788 7.3/s,5H,ArH/
5. C16H15NO2S 42 54-55 1660 3.0-3.7/m,2H,2CH2/
1250 4.5/s,2H,CH2/
285,36 782 6.7-7.5/m,9H,ArH/
6. C17H17NO2S 61 98-99 1660 2.9-3.6/m,4H,2CH2/
1252 4.4/s,2H,CH2/
299,38 788 5.0/s,2H,CH2/
760 7.1/q,4H,ArH/
7.4/s,5H,ArH/
7. C11H10F3NOS 73 41-45 1665 3.0-3.7/m,4H,2CH2/
1330 4.6/s,2H,CH2/
1240 7.5/q,4H,ArH/
8. C11H10F3NOS 56 41-45 1670 3.1-3.7/m,4H,2CH2/
1417 4.7/s,2H,CH2/
1311 7.2-7.8/m,4H,ArH/
9. C11H10F3NOS 61 油*1673 3.1-3.7/m,4H,2CH2/
1408 4.6/s,2H,CH2/
1331 7.6/s,4H,ArH/
*用三氯甲烷作洗脱液通过柱色谱来纯化。
Claims (3)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU896159A HU205092B (en) | 1989-11-24 | 1989-11-24 | Process for producing new thiazolidinone derivatives and pharmaceutical compositions comprising same |
HU6159/89 | 1989-11-24 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1052480A CN1052480A (zh) | 1991-06-26 |
CN1026586C true CN1026586C (zh) | 1994-11-16 |
Family
ID=10971282
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN90110356A Expired - Fee Related CN1026586C (zh) | 1989-11-24 | 1990-11-23 | 新的噻唑烷酮衍生物制备方法 |
Country Status (8)
Country | Link |
---|---|
US (1) | US5169859A (zh) |
EP (1) | EP0455774A1 (zh) |
JP (1) | JPH04503217A (zh) |
KR (1) | KR920701185A (zh) |
CN (1) | CN1026586C (zh) |
BG (1) | BG60536B2 (zh) |
HU (1) | HU205092B (zh) |
WO (1) | WO1991008203A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100369902C (zh) * | 2004-12-21 | 2008-02-20 | 浙江工业大学 | N-烃氧羰基-2-噻唑烷酮衍生物、制备方法及其用途 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU210789B (en) * | 1992-12-23 | 1995-07-28 | Richter Gedeon Vegyeszet | Process for preparing new thiazolidinone derivatives and pharmaceutical preparations containing them |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE81123T1 (de) * | 1987-11-20 | 1992-10-15 | Hoechst Roussel Pharma | 3-(4(1-substituierte-4-piperazinyl)butyl>-4thiazolidinone, verfahren zu deren herstellung und ihre anwendung als arzneimittel. |
HU198915B (en) * | 1987-12-14 | 1989-12-28 | Richter Gedeon Vegyeszet | Process for producing new 2-thiazolidinone derivatives and pharmaceutical compositions containing them |
CA2002245A1 (en) * | 1988-12-01 | 1990-06-01 | Lawrence I. Kruse | Dopamine-.beta.-hydroxylase inhibitors |
-
1989
- 1989-11-24 HU HU896159A patent/HU205092B/hu not_active IP Right Cessation
-
1990
- 1990-11-23 US US07/730,922 patent/US5169859A/en not_active Expired - Fee Related
- 1990-11-23 CN CN90110356A patent/CN1026586C/zh not_active Expired - Fee Related
- 1990-11-23 EP EP90917264A patent/EP0455774A1/en not_active Ceased
- 1990-11-23 JP JP3500262A patent/JPH04503217A/ja active Pending
- 1990-11-23 WO PCT/HU1990/000077 patent/WO1991008203A1/en not_active Application Discontinuation
- 1990-11-23 KR KR1019910700773A patent/KR920701185A/ko not_active Application Discontinuation
-
1994
- 1994-02-22 BG BG098520A patent/BG60536B2/bg unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100369902C (zh) * | 2004-12-21 | 2008-02-20 | 浙江工业大学 | N-烃氧羰基-2-噻唑烷酮衍生物、制备方法及其用途 |
Also Published As
Publication number | Publication date |
---|---|
HU205092B (en) | 1992-03-30 |
WO1991008203A1 (en) | 1991-06-13 |
EP0455774A1 (en) | 1991-11-13 |
HUT57196A (en) | 1991-11-28 |
JPH04503217A (ja) | 1992-06-11 |
CN1052480A (zh) | 1991-06-26 |
HU896159D0 (en) | 1990-02-28 |
US5169859A (en) | 1992-12-08 |
KR920701185A (ko) | 1992-08-11 |
BG60536B2 (bg) | 1995-07-28 |
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