CN1022324C - 制备无水、结晶型的5-氯-3-(2-噻吩甲酰)-2-羟基吲哚-1-甲酰胺的钠盐的方法 - Google Patents
制备无水、结晶型的5-氯-3-(2-噻吩甲酰)-2-羟基吲哚-1-甲酰胺的钠盐的方法 Download PDFInfo
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- CN1022324C CN1022324C CN88100555A CN88100555A CN1022324C CN 1022324 C CN1022324 C CN 1022324C CN 88100555 A CN88100555 A CN 88100555A CN 88100555 A CN88100555 A CN 88100555A CN 1022324 C CN1022324 C CN 1022324C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
对于止痛剂或消炎剂的配方具有有利的性质的无水、结晶型的5-氯-3-(2-噻吩甲酰)-2-羟基吲哚-1-甲酰胺的钠盐是由搅拌相应的该化合物的水合物与乙腈来制备的。
Description
本发明的目的在于一种对止痛药或消炎药药物配方具有有利的性质的新颖的无水、结晶型5-氯-3-（2-噻吩甲酰）-2-羟基吲哚-1-甲酰胺的钠盐。
Kadin，美国专利4，556，672号已公开了具有下面所示的化学式的上述5-氯-3-（2-噻吩甲酰）-2-羟基吲哚-1-甲酰胺。
（或可做药用的盐）作为一种用作止痛或消炎药的特别优选的化合物。在此公开的专利文献中的式（Ⅰ）化合物的钠盐是以半水合物或水合物分离出来的。进一步的干燥就使一水合物变成无水的化合物。我们现在已确定所形成的几种水合物通常都是具有多种形态（例如无定形的和针状的结晶）的混合物。这些不同的水合物型通常具有造成配方困难的流动性和静电性。我们也已确定在升温和/或减压下由初步干燥所得的无水产物是无定形的和吸湿的。因此很希望能发现一种可克服这些困难的结晶型钠盐。
我们现在已发现一种无水的、结晶型的5-氯-3-（2-噻吩甲酰）-2-羟基吲哚-1-甲酰胺的钠盐，它具有有价值而不显而易见的性质。因此这种盐易于处理及调配成剂量形式如胶囊剂。它不吸湿甚至在相对湿度达90%时仍保持稳定的剂量形式。当将它压成片剂时它比水合的盐溶解得更快。
根据上面引用的、本文作为参考资料的、早先由Kadin公开的专利，通常是将这种有利的结晶盐配制成并用作一种止痛药。
意外的是，在室温时通过搅拌在乙腈中的水合物型的钠盐可简单地制备出本发明的化合物。已经观察到这种转变是在室温时没有其他溶剂存在下进行的，不过在回流的甲苯中亦可以慢慢地进行。
一旦发现，本发明是易于实行的。在此方法中式（Ⅰ）的化合物的钠盐最好首先以它的水合物的形式分离出来，然后在乙腈中简单地搅拌以得到本发明的有用的、无水的、不吸湿的结晶型钠盐。在乙腈中这一转变的温度并不是关键性的，但在室温时易于进行，免去加热或冷冻所需的能量费用。另一方面这种转变可在甲苯的回流温度用迪安-斯达克榻分水器（Dean-Stark trap）共沸除水的情况下在甲苯中进行，但是并不易于进行。由于在此方法中低沸点的苯并不很有效，通常生产的是无定形的无水产物，因此可以认为当应用除乙腈以外的溶剂时，较高的温度对于无水结晶的形成是关键性的。
本发明的结晶盐其特征在于它的如下文所示的特殊物理性质。在上文引用了由Kadin早先公开的这种盐通常的配制和应用。下文举例说明了一种特有的、稳定的并于临床有用的包括本发明的盐的胶囊剂配方。
下面的例子是用于说明本发明而不能被解释为对本发明的限制，在这个范围与其精神实质内可以有许多的变化。
制备法1
5-氯-3-（2-噻吩甲酰）-2-羟基吲哚-1-甲酰胺的钠盐水合物
根据Kadin，美国专利4，556，672号的实例10制备标题的水合物。用另一种方法，将5-氯-3-（2-噻吩甲酰）-2-羟基吲哚-1-甲酰胺（上述Kadin的实例8;51.2g，0.16mol）在40℃悬浮于400ml乙腈中，同时将碳酸氢钠（14.1g.，0.168mol）溶于200ml水中并热至40℃。在20分钟内将此温热的水溶液加到该温热的乙腈悬浮液中，在此期间有少量泡沫出现。在40℃搅拌所得到的溶液，用5g活性碳脱色，在25℃搅拌30分钟并过滤再用50ml的乙腈：水（1∶1）洗涤。将合并的滤液与洗液在真空下通过蒸气浴浓缩，当用200ml水置换乙腈至最终体积约为500ml时，冷却至25℃通过过滤回收第一批产物。用50ml水洗涤该固体。将合并的母液和洗液气提至400ml生成第二批产品，在空气下干燥后，第一批产品重35.76g（含水6.4%）和第二批产品重16.77g（含水6.2%）经含水量校正的产量为90%。计算一水合物的含水量为5.0%，用差示扫描量热法测定这两批产品显示出4条吸热线（约在110，150，237和255）。
实例1
无水、结晶型的5-氯-3-（2-噻吩甲酰）-2-羟基吲哚-1-甲酰胺的钠盐。
将水合的5-氯-3-（2-噻吩甲酰）-2-羟基吲哚-1-甲酰胺的钠盐（52.5g根据制备法1的另一种方法制备）在52.5ml的乙腈中于室温下搅拌，经过滤回收标题产物，用50ml乙腈洗涤;并在真空中于55℃干燥而得到46.7g（95%）的标题产物;在偏振光显微镜下的结晶体;在50-300℃的范围内用差示扫描量热法测定，显示在255±2℃处有一条单独的清晰的吸热线。
分析计算 C14H8ClN2O3SNa：
C，49.06;H，2.35;N，8.18;S，9.35;Cl，10.34;
硫酸盐灰分，20.72;H2O，O;在100℃于真空中干燥损失，O。
实测值
C，48.85;H，2.39;N，8.22;S，9.54;Cl，10.43;
硫酸盐灰分，20.58;H2O，0.07;在100℃于真空中干燥损失，0.07。
和水合物型形成明显的对照，水合物型是橙色的，而现在的无水钠盐是黄色。
将水合物型的样品（制备法1）和现时的无水型的标题化合物碎成细小颗粒并以2000磅的终压力，在直径为
J<1，2>英寸的模中压成小片。每次压片时，使冲压机移开并用石蜡覆盖压模的底部，以便于对已知的表面区域的单平面进行溶解速率试验。将含有受压药物的模子放入一个按美国药典的带有桨叶的溶解烧瓶底部，使桨叶处于药片曝露面的之上2.5cm处，在水和在0.5M硼酸盐缓冲液（pH9.0）两者之中，就内部的溶解速率（对口服剂型的药效来说这是一个重要的因素）而言，无水型的要比水合物快约三倍。
无水型显示出变为水合物的轻微倾向。甚至在下述胶囊的优选制备所应用的水的湿法制粒作用中，亦不会形成水合物（由没有由黄色变为橙色的颜色改变得到证明）
实例2
含有无水的5-氯-3-（2-噻吩甲酰）-2-羟基吲哚-1-甲酰胺钠盐的口服胶囊剂量型
将下列成份拌合，用875ml水湿粒化，最后用Karl Fischer干燥至含水分5%;
5-氯-3-（2-噻吩甲酰）
-2-羟基吲哚-1-甲
酰胺 600.00g
（561.52g.A＊）
微晶纤维素
（Avicel PH101） 885.75g.
水合的玉米淀粉 236.25g.
Povidone（PVC-30） 105.00g.
（＊A是指游离酸的活度当量）
然后将干的、湿的颗粒粉剂进一步与下列成份拌合，
羟基乙酸淀粉钠
（Explotab） 210.00g.
硬脂酸镁 42.00g.
十二烷基硫酸钠 21.00g.
在一通常使用的胶囊填充机上应用填充重量为375mg的制成的混合物制备含有100mg.A的软凝胶胶囊。当对狗口服投药时，与以口服溶液投药比较，由血液水平显示出有89%的高生物利用度，因此这类胶囊表现出有极优良的生物利用度。
Claims (1)
1、一种制备无水、结晶型的5-氯-3-(2-噻吩甲酰)-2-羟基吲哚-1-甲酰胺的钠盐的方法，其特征在于将相应的该化合物的水合物与乙腈一起搅拌。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1987/000201 WO1988005656A1 (en) | 1987-02-02 | 1987-02-02 | Anhydrous, crystalline sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide |
| USPCT/US87/00201 | 1987-02-02 | ||
| USPCT/US87/000201 | 1987-02-02 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN88100555A CN88100555A (zh) | 1988-08-17 |
| CN1022324C true CN1022324C (zh) | 1993-10-06 |
Family
ID=22202263
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN88100555A Expired - Fee Related CN1022324C (zh) | 1987-02-02 | 1988-02-02 | 制备无水、结晶型的5-氯-3-(2-噻吩甲酰)-2-羟基吲哚-1-甲酰胺的钠盐的方法 |
Country Status (42)
| Country | Link |
|---|---|
| US (1) | US5036099A (zh) |
| EP (1) | EP0277738B1 (zh) |
| JP (1) | JPS63201184A (zh) |
| KR (1) | KR900001422B1 (zh) |
| CN (1) | CN1022324C (zh) |
| AP (1) | AP52A (zh) |
| AR (1) | AR243182A1 (zh) |
| AT (1) | ATE73800T1 (zh) |
| AU (1) | AU587736B2 (zh) |
| BG (1) | BG51042A3 (zh) |
| CA (1) | CA1335590C (zh) |
| CS (2) | CS265250B2 (zh) |
| CY (1) | CY1775A (zh) |
| DD (1) | DD267490A5 (zh) |
| DE (1) | DE3869149D1 (zh) |
| DK (1) | DK44888A (zh) |
| EC (1) | ECSP941082A (zh) |
| ES (1) | ES2032955T3 (zh) |
| FI (1) | FI89598C (zh) |
| GR (1) | GR3004200T3 (zh) |
| HK (1) | HK132695A (zh) |
| IE (1) | IE60000B1 (zh) |
| IL (1) | IL85277A (zh) |
| IN (1) | IN171799B (zh) |
| IS (1) | IS1533B (zh) |
| LV (1) | LV10252B (zh) |
| MA (1) | MA21171A1 (zh) |
| MY (1) | MY102737A (zh) |
| NO (1) | NO170581C (zh) |
| NZ (1) | NZ223373A (zh) |
| OA (1) | OA08710A (zh) |
| PH (1) | PH26545A (zh) |
| PL (1) | PL149550B1 (zh) |
| PT (1) | PT86675B (zh) |
| RO (1) | RO105052B1 (zh) |
| RU (1) | RU2011381C1 (zh) |
| SG (1) | SG27994G (zh) |
| SI (1) | SI8810183A8 (zh) |
| UA (1) | UA25898A1 (zh) |
| WO (1) | WO1988005656A1 (zh) |
| YU (1) | YU46766B (zh) |
| ZA (1) | ZA88679B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4853409A (en) * | 1988-04-13 | 1989-08-01 | Pfizer Inc. | 3-substituted-2-oxindole-1-carboxamides for suppressing T-cell function |
| US4861794A (en) * | 1988-04-13 | 1989-08-29 | Pfizer Inc. | 3-substituted-2-oxindole-1-carboxamides as inhibitors of interleukin-1 biosynthesis |
| EP0365194B1 (en) * | 1988-10-18 | 1995-08-02 | Pfizer Inc. | Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides |
| MX18021A (es) * | 1988-10-18 | 1993-11-01 | Pfizer | Pro-farmacos de la 3-acil-2-oxindol-1-carboxamidasanti-inflamatorias |
| US5059693A (en) * | 1989-10-06 | 1991-10-22 | Pfizer Inc. | Process for making 3-aroyl-2-oxindole-1-carboxamides |
| US5008283A (en) * | 1990-03-19 | 1991-04-16 | Pfizer Inc. | Use of tenidap to inhibit activation of collagenase and to inhibit the activity of myeloperoxidase |
| US5006547A (en) * | 1990-03-19 | 1991-04-09 | Pfizer Inc. | Tenidap as an inhibitor of the release of elastase by neutrophils |
| US5122534A (en) * | 1991-02-08 | 1992-06-16 | Pfizer Inc. | Use of tenidap to reduce total serum cholesterol, ldl cholesterol and triglycerides |
| DE4111305C2 (de) * | 1991-04-08 | 1994-12-01 | Mack Chem Pharm | Pharmazeutische Zubereitung zur rektalen Applikation, die ein 2-Oxindol-l-carboxamid-derivat enthält |
| TW438798B (en) * | 1992-10-07 | 2001-06-07 | Pfizer | 3-substituted 2-oxindole-1-carboxamide pharmaceutical compositions |
| US5270331A (en) * | 1993-01-26 | 1993-12-14 | Pfizer, Inc. | Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides |
| AU7503496A (en) * | 1995-12-19 | 1997-07-14 | Pfizer Inc. | Stable, long acting salts of indole derivatives for the treatment of joint diseases |
| EP0826685A1 (en) * | 1996-08-21 | 1998-03-04 | Pfizer Inc. | Stable, long acting salts of carboxamides for the treatment of joint disease |
| DE19854355A1 (de) * | 1998-11-25 | 2000-05-31 | Bayer Ag | Kristallmodifikation B von 8-Cyan-1-cyclopropyl-7-(1S, 6S-2,8-diazabicyclo-/4.3.O/nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
| US7407195B2 (en) | 2004-04-14 | 2008-08-05 | William Berson | Label for receiving indicia having variable spectral emissivity values |
| US7651031B2 (en) * | 2004-10-25 | 2010-01-26 | William Berson | Systems and methods for reading indicium |
| US7931413B2 (en) * | 2005-01-14 | 2011-04-26 | William Berson | Printing system ribbon including print transferable circuitry and elements |
| US7619520B2 (en) * | 2005-01-14 | 2009-11-17 | William Berson | Radio frequency identification labels and systems and methods for making the same |
| US7728726B2 (en) * | 2005-01-14 | 2010-06-01 | William Berson | Radio frequency identification labels |
| US7621451B2 (en) * | 2005-01-14 | 2009-11-24 | William Berson | Radio frequency identification labels and systems and methods for making the same |
| EP3703583B1 (en) | 2017-11-02 | 2025-10-15 | Accurate Medical Therapeutics Ltd. | Embolization catheter with integral filter |
| EP3972500B1 (en) | 2019-05-23 | 2025-04-30 | Accurate Medical Therapeutics Ltd. | Embolization catheter for reflux free delivery of microspheres |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3767653A (en) * | 1971-06-28 | 1973-10-23 | Squibb & Sons Inc | Thiazines |
| GB1532413A (en) * | 1974-12-23 | 1978-11-15 | Union International Co Ltd | Chenodeoxycholic acid |
| DE2613346C3 (de) * | 1976-03-29 | 1981-07-23 | Diamalt AG, 8000 München | Monoklin kristalline Chenodesoxycholsäure und Verfahren zu ihrer Herstellung |
| DE3582890D1 (de) * | 1984-02-07 | 1991-06-20 | Pfizer | 2-oxindolzwischenprodukte. |
| US4556672A (en) * | 1984-03-19 | 1985-12-03 | Pfizer Inc. | 3-Substituted 2-oxindole-1-carboxamides as analgesic and anti-inflammatory agents |
| DE3579716D1 (de) * | 1984-03-19 | 1990-10-25 | Pfizer | Verfahren zur herstellung von 2-oxindole-1-carboxamiden und deren zwischenprodukte. |
| US4569942A (en) * | 1984-05-04 | 1986-02-11 | Pfizer Inc. | N,3-Disubstituted 2-oxindole-1-carboxamides as analgesic and antiinflammatory agents |
-
1987
- 1987-02-02 US US07/460,137 patent/US5036099A/en not_active Expired - Lifetime
- 1987-02-02 UA UA4614718A patent/UA25898A1/uk unknown
- 1987-02-02 RO RO140907A patent/RO105052B1/ro unknown
- 1987-02-02 WO PCT/US1987/000201 patent/WO1988005656A1/en not_active Ceased
-
1988
- 1988-01-25 EP EP88300561A patent/EP0277738B1/en not_active Expired - Lifetime
- 1988-01-25 ES ES88300561T patent/ES2032955T3/es not_active Expired - Lifetime
- 1988-01-25 DE DE8888300561T patent/DE3869149D1/de not_active Expired - Lifetime
- 1988-01-25 AT AT88300561T patent/ATE73800T1/de not_active IP Right Cessation
- 1988-01-27 IN IN67/DEL/88A patent/IN171799B/en unknown
- 1988-01-28 AP APAP/P/1988/000081A patent/AP52A/en active
- 1988-01-29 DK DK044888A patent/DK44888A/da not_active Application Discontinuation
- 1988-01-29 CA CA000557662A patent/CA1335590C/en not_active Expired - Fee Related
- 1988-02-01 DD DD88312599A patent/DD267490A5/de not_active IP Right Cessation
- 1988-02-01 KR KR1019880000876A patent/KR900001422B1/ko not_active Expired
- 1988-02-01 AU AU11160/88A patent/AU587736B2/en not_active Ceased
- 1988-02-01 SI SI8810183A patent/SI8810183A8/sl not_active IP Right Cessation
- 1988-02-01 PT PT86675A patent/PT86675B/pt not_active IP Right Cessation
- 1988-02-01 YU YU18388A patent/YU46766B/sh unknown
- 1988-02-01 MA MA21408A patent/MA21171A1/fr unknown
- 1988-02-01 AR AR88309983A patent/AR243182A1/es active
- 1988-02-01 PL PL1988270415A patent/PL149550B1/pl unknown
- 1988-02-01 ZA ZA88679A patent/ZA88679B/xx unknown
- 1988-02-01 IL IL8527788A patent/IL85277A/en not_active IP Right Cessation
- 1988-02-01 BG BG082816A patent/BG51042A3/bg unknown
- 1988-02-01 NZ NZ223373A patent/NZ223373A/xx unknown
- 1988-02-01 OA OA59273A patent/OA08710A/xx unknown
- 1988-02-01 PH PH36441A patent/PH26545A/en unknown
- 1988-02-02 JP JP63022675A patent/JPS63201184A/ja active Granted
- 1988-02-02 MY MYPI88000091A patent/MY102737A/en unknown
- 1988-02-02 CS CS88648A patent/CS265250B2/cs unknown
- 1988-02-02 CN CN88100555A patent/CN1022324C/zh not_active Expired - Fee Related
- 1988-02-02 IS IS3309A patent/IS1533B/is unknown
- 1988-09-29 NO NO88884329A patent/NO170581C/no not_active IP Right Cessation
-
1989
- 1989-07-18 IE IE26988A patent/IE60000B1/en not_active IP Right Cessation
- 1989-08-01 FI FI893647A patent/FI89598C/fi not_active IP Right Cessation
- 1989-08-01 RU SU894614718A patent/RU2011381C1/ru not_active IP Right Cessation
-
1991
- 1991-11-22 CS CS913541A patent/CS354191A3/cs unknown
-
1992
- 1992-03-31 GR GR920400571T patent/GR3004200T3/el unknown
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1993
- 1993-11-15 LV LVP-93-1225A patent/LV10252B/xx unknown
-
1994
- 1994-02-22 SG SG27994A patent/SG27994G/en unknown
- 1994-05-05 EC EC1994001082A patent/ECSP941082A/es unknown
-
1995
- 1995-08-24 HK HK132695A patent/HK132695A/en not_active IP Right Cessation
-
1996
- 1996-04-05 CY CY177596A patent/CY1775A/xx unknown
Also Published As
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