CN1476443A - 新的地洛他定盐、其合成方法及其药物组合物 - Google Patents
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Abstract
本发明涉及新的式I地洛他定盐，其中X是酸残基并且n是1或2，和式II地洛他定盐，其中X是pK＜3.5的酸的残基。本发明还涉及所述盐的合成方法以及含有所述盐的新的抗变应性药物组合物。
Description
本发明涉及新的地洛他定盐、其合成方法以及含有所述盐的新抗变应性药物组合物。
已知，地洛他定(其化学名称：8-氯-6，11-二氢-11-(4-亚哌啶基)-5H-苯并[5，6]环庚[1，2-b]吡啶)是成功的抗变应性药物氯雷他定的活性代谢产物。根据文献，地洛他定的口服活性是氯雷他定的2.5-4倍，并且，其抗组胺活性持续24小时(Arzneim.Forsch./Drug Res.50(1)，Nr.4(345-352)2000)。
根据匈牙利专利194864可知，地洛他定碱可以用两种方法由氯雷他定(化学名称：8-氯-6，11-二氢-11-(1-乙氧羰基-4-亚哌啶基)-5H-苯并[5，6]环庚[1，2-b]吡啶)制得。所述方法如下：
a)通过与氢氧化钠的含水乙醇溶液一起煮沸24小时，使8-氯-6，11-二氢-11-(1-乙氧羰基4-亚哌啶基)-5H-苯并[5，6]环庚[1，2-b]吡啶(氯雷他定)脱乙氧羰基，然后，用乙酸中和溶液，之后，分离出地洛他定乙酸盐。所得粗产物需进行进一步提纯；根据该专利，从苯-己烷混合物中重结晶后，以70％的收率获得地洛他定乙酸盐。对地洛他定乙酸盐进行碱处理，制得地洛他定碱，通过从己烷中重结晶，提纯地洛他定碱。
b)用两个步骤，使8-氯-6，11-二氢-11-(1-甲基-4-亚哌啶基)-5H-苯并[5，6]环庚[1，2-b]吡啶脱甲基：首先，用溴化氰合成1-氰基衍生物，并在乙酸中用浓盐酸溶液水解20小时，蒸发溶剂后，残余物用氢氧化铵溶液中和，得到地洛他定，其熔点为149-151℃。
在上述匈牙利专利中提到，采用药学上可接受的酸(选自盐酸、甲磺酸、硫酸、乙酸、马来酸、富马酸、磷酸)，由地洛他定能够形成地洛他定盐，但是，除了上述乙酸盐外，该专利中并没有给出这些盐的分子式、物理和物化数据以及它们的合成方法。
上文提及的地洛他定合成方法存在一些缺点。在方法a)的完成过程中，发生了大量分解，因此，终产物中存在一些杂质。通过重结晶可以获得所需的地洛他定碱纯度，但是，该过程只能在损失大量物料的条件下完成。从技术的角度考虑，在活性组分的配制中，一个重要的不利因素是地洛他定碱不溶于水。
由于使用有毒的溴化氰试剂并且在两步反应中形成了有毒的溴代甲烷，因此，方法b)本身是不利的。另一方面，采用后一方法获得的地洛他定碱具有和方法a)获得的地洛他定碱相同的缺点。
在本发明的试验中，我们意外地发现，通过用特定的酸处理/加热式III所示的氯雷他定碱，可以获得式I所示的地洛他定酸加成盐，
式I中，X是卤原子，优选氯或溴，或是酸残基，n是1或2。
所制得的酸加成盐是新的，其中地洛他定半硫酸盐尤为有利，因为它可以一步制得，并且纯度和稳定性高。新的酸加成盐的其它特性也是有利的，例如，从药物配制的角度考虑，它们的优良溶解性能是有利的。
根据上述事实，本发明涉及式I的酸加成盐，其中X是酸残基，n是1或2，和式II的酸加成盐，其中X是pK＜3.5的酸的酸残基。
本发明还涉及通过将式III氯雷他定(化学名称：8-氯-6，11-二氢-11-(1-乙氧羰基-4-亚哌啶基)-5H-苯并[5，6]环庚[1，2-b]吡啶)与浓无机酸反应来合成式II酸加成盐的方法。
本发明的另一目的是合成式I酸加成盐的方法，该方法是用碱溶液处理式II酸加成盐或其水溶液，使pH值调整为6.5-7，然后分离出产物，式I中，X是酸残基，n是1或2，式II中，X是pK＜3.5的酸的酸残基。
最后，本发明涉及含有0.1-99.9％式I或II活性组分和0.1-99.9％可药用载体和添加剂的抗变应性药物组合物。方法的详细说明：
在本发明方法中，将氯雷他定与浓无机酸一起加热，从而在数小时内水解氨基甲酸乙酯，并以高收率分离出与两摩尔酸形成的地洛他定盐(参见式II，其中X定义如上所述)。
根据本发明的优选实施方案，在110-120℃，将氯雷他定与60-80重量％硫酸溶液一起加热，从而使氨基甲酸乙酯水解3-6小时。从反应混合物中以高收率(80-95％)分离出地洛他定二硫酸氢盐。
根据本发明的另一优选实施方案，在115℃，将氯雷他定与浓盐酸一起加热，从而使氨基甲酸乙酯水解6小时，并能够从反应混合物中以高收率(90-95％)分离出地洛他定二盐酸盐。
根据本发明的再一实施方案，将氯雷他定与48％氢溴酸溶液一起在110℃加热，使氨基甲酸乙酯在6小时内水解，以高收率(＞95％)分离出地洛他定二氢溴酸盐。
地洛他定复盐不仅能以高收率而且能以高纯度分离出来。
根据本发明，用强碱可以将地洛他定复盐转化为简单盐。
特别优选，通过加入强碱，例如，加入25％氢氧化四甲基铵溶液，将pH值调节至6.8，使地洛他定二硫酸氢盐(disulfate)形成地洛他定半硫酸盐，并分离出地洛他定半硫酸盐。
本发明新的地洛他定半硫酸盐可以作为新的非镇静H1-拮抗药物组合物的活性组分。
本发明化合物的原料是氯雷他定(化学名称：8-氯-6，11-二氢-11-(1-乙氧羰基-4-亚哌啶基)-5H-苯并[5，6]环庚[1，2-b]吡啶)。在US4282233中详细描述了氯雷他定的合成(其同族专利为匈牙利专利186774)。
本发明通过下述非限制性实施例加以说明。
实施例1地洛他定二硫酸氢盐
在115℃，将19.5g(50mmol)氯雷他定和40g 72重量％硫酸的混合物搅拌6小时。反应混合物冷却至室温，加入100ml甲醇，然后将混合物冷却至0℃，并在该温度下搅拌3小时。滤出沉淀的晶形物，用冰冷甲醇洗涤。干燥后，得到20.95g(84％)标题化合物。熔点：244-246℃。
采用HPLC检测，产物纯度大于99.5％。
用滴定分析法测定：
将地洛他定二硫酸氢盐溶解在80％丙酮中，采用电位滴定法，用0.1N氢氧化钠溶液进行滴定。滴定曲线具有两个拐点，两个硫酸氢根阴离子和吡啶氮上的质子被滴定直至出现第一个拐点，而哌啶氮上的质子在两个拐点之间被滴定。两个面积的比值为3/1。
实施例2地洛他定二盐酸盐
在115℃，将5.0g(13mmol)氯雷他定(固体)和50ml浓盐酸的混合物搅拌6小时。蒸发过量的盐酸，残余物用30ml丙酮进行结晶。在0℃下搅拌晶体悬浮物5小时，过滤并用丙酮洗涤，得到4.7g(94％)标题化合物。熔点：210-220℃。
实施例3地洛他定二氢溴酸盐
在115℃，将3.83g(10mmol)氯雷他定和30ml 48％氢溴酸的混合物搅拌6小时。蒸发过量的氢溴酸，残余物溶解在20ml热乙醇中。冷却后，结晶沉淀出标题化合物。在0℃下搅拌晶体悬浮物3小时，过滤并用冰冷乙醇洗涤，得到4.7g(99％)标题化合物。熔点：247-250℃。
实施例4地洛他定半硫酸盐
将3.04g(6mmol)地洛他定二硫酸氢盐(由实施例1制得)溶解在5ml水和2ml乙醇的混合物中，然后冷却至0℃，加入25％氢氧化四甲基铵溶液，调节pH至6.8。蒸发溶剂，残余物与50ml乙醇一起在0℃搅拌5小时，过滤并用冰冷乙醇洗涤，得到1.64g(74％)标题化合物。熔点：279-280℃。
用滴定分析法测定：
将地洛他定半硫酸盐溶解在80％丙酮中，采用电位滴定法，用0.1N氢氧化钠溶液进行滴定。仅观察到一个拐点，该拐点是哌啶氮上的质子的等当量滴定终点。
实施例5制备式I盐的一般方法
将5.07g(10mmol)地洛他定二硫酸氢盐溶解在50ml二氯甲烷中，并加入4N氢氧化钠溶液。剧烈搅拌后，溶液澄清。分离有机层，用10ml饱和氯化钠溶液洗涤，在无水硫酸镁上干燥。将10mmol式HX酸加入到二氯甲烷溶液中。冷却后，产物从溶液中结晶沉淀出来。制得下列式I盐：
实施例6制备药物组合物
对于100mg片剂，需要下列组分(对每一片剂)：
地洛他定半硫酸盐 5.0mg
(根据实施例4制备)
乳糖 47.0mg
玉米淀粉 47.0mg
硬脂酸镁 1.0mg
均化后，立即将粉末混合物压制成片剂。
实施例7制备药物组合物
对于100mg片剂，需要下列组分(对每一片剂)：
地洛他定半硫酸盐 5.0mg
(根据实施例4制备)
乳糖 25.0mg
玉米淀粉 69.0mg
硬脂酸镁 1.0mg
均化后，立即将粉末混合物压制成片剂。
实施例8制备药物组合物
对于100mg片剂，需要下列组分(对每一片剂)：
地洛他定半硫酸盐 5.0mg
(根据实施例4制备)
乳糖 69.0mg
玉米淀粉 25.0mg
硬脂酸镁 1.0mg
均化后，立即将粉末混合物压制成片剂。
Claims (5)
1.式I的酸加成盐
其中，X是酸残基，n是1或2。
2.式II的酸加成盐
其中，X是pK＜3.5的酸的残基。
3.合成式II酸加成盐的方法，其特征在于，将式III氯雷他定(化学名称：8-氯-6，11-二氢-11-(1-乙氧羰基-4-亚哌啶基)-5H-苯并[5，6]环庚[1，2-b]吡啶)与浓无机酸反应。
4.合成式I酸加成盐的方法，式I中，X是酸残基，n是1或2，其特征在于，用碱溶液处理式II酸加成盐或其水溶液，使pH值调整为6.5-7，然后分离出产物，式II中，X是pK＜3.5的酸的残基。
5.一种抗变应性药物组合物，其特征在于，含有0.1-99.9％式I或II活性组分和0.1-99.9％可药用载体和添加剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP0004701 | 2000-11-23 | ||
| HU0004701A HU226998B1 (en) | 2000-11-23 | 2000-11-23 | Desloratadine hemisulphate, process for the preparation thereof and pharmaceutical compositions containing the same |
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| Publication Number | Publication Date |
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| CN1476443A true CN1476443A (zh) | 2004-02-18 |
| CN1199968C CN1199968C (zh) | 2005-05-04 |
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| US (1) | US7196195B2 (zh) |
| EP (1) | EP1347965B1 (zh) |
| JP (1) | JP4427249B2 (zh) |
| CN (1) | CN1199968C (zh) |
| AT (1) | ATE316525T1 (zh) |
| AU (1) | AU2002218422A1 (zh) |
| CA (1) | CA2425422C (zh) |
| CY (1) | CY1105595T1 (zh) |
| CZ (1) | CZ304694B6 (zh) |
| DE (1) | DE60116902T2 (zh) |
| DK (1) | DK1347965T3 (zh) |
| ES (1) | ES2257467T3 (zh) |
| HU (1) | HU226998B1 (zh) |
| NO (1) | NO325155B1 (zh) |
| PL (1) | PL206973B1 (zh) |
| RU (1) | RU2285001C2 (zh) |
| SK (1) | SK285715B6 (zh) |
| UA (1) | UA74858C2 (zh) |
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| AU2003262141A1 (en) * | 2002-04-15 | 2003-10-27 | Sun Pharmaceutical Industries Limited | Preperation of desloratatine |
| AU2003251974C1 (en) * | 2002-08-05 | 2006-09-14 | Sandoz Ag | Novel salt and polymorphs of desloratadine hemifumarate |
| JP4501015B2 (ja) | 2004-03-17 | 2010-07-14 | 味の素株式会社 | アミノピリミジン化合物の製造方法 |
| WO2006003479A2 (en) * | 2004-07-07 | 2006-01-12 | EGIS Gyógyszergyár Rt. | New pseudopolymorph of desloratadine formed with carbon dioxide |
| CA2541045A1 (en) * | 2006-03-24 | 2007-09-24 | Pharmascience Inc. | A descarbonylethoxyloratadine containing pharmaceutical composition |
| EP2837631A1 (en) * | 2013-08-14 | 2015-02-18 | Merck & Cie | New stable salt of 5,10-methylene-(6R)-tetrahydrofolic acid |
| KR102567448B1 (ko) * | 2019-10-31 | 2023-08-17 | (주)제이디바이오사이언스 | 삼환식 화합물 및 이의 약학적 용도 |
| CN115785065A (zh) * | 2022-12-02 | 2023-03-14 | 山东达因海洋生物制药股份有限公司 | 一种地氯雷他定共晶及其制备方法与应用 |
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| US4282233B1 (en) * | 1980-06-19 | 2000-09-05 | Schering Corp | Antihistaminic 11-(4-piperidylidene)-5h-benzoÄ5,6Ü-cyclohepta-Ä1,2Ü-pyridines |
| WO1985003707A1 (en) * | 1984-02-15 | 1985-08-29 | Schering Corporation | 8-CHLORO-6,11-DIHYDRO-11-(4-PIPERIDYLIDENE)-5H-BENZO AD5,6 BDCYCLOHEPTA AD1,2-b BDPYRIDINE AND ITS SALTS, PROCESSES FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS |
| DE3677842D1 (de) * | 1985-05-13 | 1991-04-11 | Schering Corp | Verfahren zur herstellung von piperidyliden-dihydrodibenzo(a,d)zykloheptenen und deren azoderivate, so hergestellte verbindungen und ihre anwendung zur vorbereitung von heilmitteln. |
| PT656348E (pt) * | 1993-12-03 | 2000-10-31 | Hoffmann La Roche | Derivados do acido acetico como medicamentos |
| GB9709945D0 (en) * | 1997-05-17 | 1997-07-09 | Glaxo Group Ltd | A novel salt |
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- 2001-11-14 RU RU2003118425/04A patent/RU2285001C2/ru active
- 2001-11-14 DE DE60116902T patent/DE60116902T2/de not_active Expired - Lifetime
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Also Published As
| Publication number | Publication date |
|---|---|
| PL206973B1 (pl) | 2010-10-29 |
| US20050203116A1 (en) | 2005-09-15 |
| DK1347965T3 (da) | 2006-06-06 |
| JP2004514675A (ja) | 2004-05-20 |
| SK285715B6 (sk) | 2007-06-07 |
| US7196195B2 (en) | 2007-03-27 |
| CA2425422A1 (en) | 2002-05-30 |
| EP1347965B1 (en) | 2006-01-25 |
| CZ20031321A3 (cs) | 2003-08-13 |
| CZ304694B6 (cs) | 2014-09-03 |
| CY1105595T1 (el) | 2010-07-28 |
| CN1199968C (zh) | 2005-05-04 |
| UA74858C2 (en) | 2006-02-15 |
| NO325155B1 (no) | 2008-02-11 |
| DE60116902T2 (de) | 2006-08-24 |
| PL362126A1 (en) | 2004-10-18 |
| NO20032314D0 (no) | 2003-05-22 |
| RU2285001C2 (ru) | 2006-10-10 |
| NO20032314L (no) | 2003-07-18 |
| SK5662003A3 (en) | 2003-10-07 |
| DE60116902D1 (de) | 2006-04-13 |
| AU2002218422A1 (en) | 2002-06-03 |
| WO2002042290A1 (en) | 2002-05-30 |
| HU0004701D0 (zh) | 2001-02-28 |
| EP1347965A1 (en) | 2003-10-01 |
| HUP0004701A2 (hu) | 2002-11-28 |
| JP4427249B2 (ja) | 2010-03-03 |
| ATE316525T1 (de) | 2006-02-15 |
| ES2257467T3 (es) | 2006-08-01 |
| CA2425422C (en) | 2009-11-10 |
| HU226998B1 (en) | 2010-04-28 |
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