CN101412713A - 5-[4-[2-(n-甲基-n-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮马来酸盐的水合物 - Google Patents
5-[4-[2-(n-甲基-n-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮马来酸盐的水合物 Download PDFInfo
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Abstract
5－[4－[2－(N－甲基－N－(2－吡啶基)氨基)乙氧基]苄基]噻唑烷－2，4－二酮，马来酸盐的水合物，其特征在于它：(i)含有0.2－1.1％(w/w)的水；和(ii)提供具有764和579cm－1处峰的红外光谱；和/或(iii)提供基本如同图II提出的X射线粉末衍射(XRPD)图案；制备该化合物的方法，含有该化合物的药用组合物和该化合物或组合物在医学中的用途。
Description
本申请是申请号为98812092.5、申请日为1998年12月14日、同题的申请的分案申请。
本发明涉及新药物，涉及该药物的制备方法和涉及该药物在医学中的用途。
国际专利申请公布号WO94/05659公开了具有降低血糖和降低血脂活性的某些噻唑烷二酮衍生物，包括5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2，4-二酮，马来酸盐(此后也称作“化合物(I)”)。
化合物(I)只是作为无水形式被公开的。现已发现，化合物(I)可以以新的水合物形式存在，该形式特别适合于大批生产和处理。该化合物可通过特别适合于大规模制备的有效的、经济的和可再现的方法制备。
所述新的水合物还具有有用的药学特性，已表明它具体可用于治疗和/或预防糖尿病、与糖尿病有关的疾病及其某些并发症。
因此，本发明提供5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2，4-二酮，马来酸盐的水合物(“水合物”)，其特征在于该水合物：
(i)含有0.2-1.1％(w/w)的水；和
(ii)提供具有764和579cm-1处峰的红外光谱；和/或
(iii)提供基本如同图2提出的X射线粉末衍射(XRPD)图案。
该水合物的水含量适合为0.4-0.9％(w/w)，特别是0.5-0.6(w/w)，例如为0.54(w/w)或0.6(w/w)。
在一个优选的方面，所述水合物提供基本如同根据图1提出的红外光谱。
该水合物可以以某些脱水形式存在，当其与水(液态或水蒸汽形式)接触时，又可逆地转化为水合物。本发明包括所有此类可逆地再水合形式的水合物。
本发明包括以纯净形式分离的水合物或与其它物质，例如已知的化合物I的无水形式、上述可逆地再水合形式或任何其它物质混合的形式。
因此，在一个方面提供分离形式的水合物。
在另一方面，提供纯净形式的水合物。
在又一方面，提供结晶形式的水合物。
本发明还提供制备该水合物的方法，其特征在于5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2，4-二酮，马来酸盐的水合物从链烷醇溶剂(优选含有2.0-2.5％(体积)的水，最优选含有2.0-2.3％如2.1％(体积)的水)中结晶出来。
合适的链烷醇溶剂水溶液包括乙醇水溶液、通常为变性乙醇水溶液和异丙醇水溶液或其混合物。
一般在低温至室温下，例如在0-30℃(如25℃)进行结晶和任何重结晶；或者可在较高温度下，例如在30-60℃(如35℃)引发结晶，然后通过使溶剂温度冷却至室温或低温，例如在0-30℃(如25℃)完成结晶。
所述结晶可通过用该水合物的晶体加晶种来引发，但这并不是必需的。
化合物I可根据已知的方法，例如WO94/05659中公开的方法制备。WO94/05659公开的内容通过引用结合到本文中。
在此所用的术语“预防与糖尿病有关的疾病”包括治疗诸如胰岛素抗性、受损的葡萄糖耐受性、高胰岛素血症和妊娠糖尿病的疾病。
糖尿病优选指II型糖尿病。
与糖尿病有关的疾病包括高血糖和胰岛素抗性，特别是获得性胰岛素抗性和肥胖症。与糖尿病有关的其它疾病包括高血压、心血管疾病(尤其是动脉粥样硬化)、某些饮食紊乱(尤其是患有与饮食过少有关的疾病如神经性厌食症和与饮食过多有关的疾病如肥胖症和神经性贪食症的患者的食欲和食物摄入调节)。与糖尿病有关的其它疾病包括多囊卵巢综合征和类固醇诱导的胰岛素抗性。
与糖尿病有关的疾病的并发症在此包括肾病、尤其是与II型糖尿病的发展有关的肾病包括糖尿病性肾病、肾小球性肾炎、肾小球硬化症、肾变病综合征、高血压性肾硬化和晚期肾病。
在此所用的与给定的溶剂或溶剂混合物有关的“水溶液”指含有提供水合物的足够水，即具有0.2-1.1％(w/w)水的溶剂。
如上所述，本发明化合物具有治疗特性。因而本发明的水合物用作活性治疗物质。
更具体地说，本发明提供用于治疗和/或预防糖尿病、与某些糖尿病有关的疾病及其某些并发症的水合物。
所述水合物可以以其本身或优选作为还含有药学上可接受的载体的药用组合物给予。所述水合物及其剂型的配制一般如国际专利申请公布号WO94/05659中对化合物(I)公开的内容进行。
因此，本发明还提供包含该水合物及其药学上可接受的载体的药用组合物。
该水合物通常以单位剂型给予。
活性化合物可以经任何合适的途径给予，但通常经口服或胃肠外途径给予。为此种使用，该化合物通常以与药用载体、稀释剂和/或赋形剂一起的药用组合物的形式使用，尽管该组合物的准确形式自然取决于给药方式。
组合物通过混合制备并适宜用于口服、胃肠外或局部给予，这样可以为片剂、胶囊、口服液制剂、散剂、颗粒剂、糖锭、锭剂、可重新配制粉末、可注射和可输注溶液或悬浮液、栓剂和透皮装置。优选可口服给予的组合物，特别是成形的口服组合物，因为它们对于普通使用更为方便。
用于口服给药的片剂和胶囊通常以单位剂量存在，并含有常规赋形剂，例如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和润湿剂。根据本领域熟知的方法可对片剂进行包衣。
使用的合适填充剂包括纤维素、甘露醇、乳糖和其它类似的物质。合适的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物如羟基乙酸淀粉钠。合适的润滑剂包括，例如硬脂酸镁。合适的药学上可接受的润湿剂包括十二烷基硫酸钠。
通过混合、填充、压片等常规方法可以制备固体口服组合物。重复混合操作可用于使活性剂充分分布于使用大量填充剂的这些组合物中。这样的操作在本领域中当然是常规的。
口服液体制剂可以为，例如，水性或油性悬浮液、溶液、乳液、糖浆或酏剂的形式，或可以作为使用前用水或其它合适的溶媒重新配制的干产品存在。此类液体制剂可含有常规的添加剂如悬浮剂，例如，山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪，乳化剂如卵磷脂、脱水山梨醇一油酸酯或阿拉伯胶；非水溶媒(它可包括食用油)如杏仁油、分级椰子油、油性酯如甘油、丙二醇或乙醇的酯；防腐剂如对羟基苯甲酸甲酯或丙酯，或山梨酸的甲酯或丙酯，如果需要，还可含有常规的调味剂或着色剂。
对于胃肠外给药，可配制为含有本发明化合物和无菌溶媒的液体单位剂量形式。根据溶媒和浓度，所述化合物可以被悬浮或溶解。胃肠外溶液通常通过将活性化合物溶解于溶媒中并过滤灭菌，然后填充至合适的管制瓶或安瓿中并密封来制备。为有利，辅助剂如局部麻醉剂、防腐剂和缓冲剂也可溶于溶媒中。为增加稳定性，所述组合物可在填充入管制瓶并真空除去水份后进行冷冻。
胃肠外悬浮液可用基本相同的方式制备，但活性化合物是悬浮而非溶解于溶媒中，并在悬浮于无菌溶媒之前经接触环氧乙烷而灭菌。表面活性剂或润湿剂可有利地包括在组合物中，以促使活性化合物的均匀分布。
此外，此类组合物还可含有活性剂，例如抗高血压剂和利尿剂。
按照常规做法，该组合物一般附有用于涉及医学治疗的书写或印刷的使用说明书。
如在此所用的术语“药学上可接受的”包括人和兽医使用的化合物、组合物和组分：例如，术语“药学上可接受的盐”包括兽医可接受的盐。
本发明还提供在人或非人哺乳动物中治疗和/或预防糖尿病、与糖尿病有关的疾病及其某些并发症的方法，该方法包括给予有此需要的人或非人哺乳动物有效、无毒量的水合物。
活性成分可以方便地作为上述的药用组合物给予，这形成本发明的具体方面。
在糖尿病、与糖尿病有关的疾病及其某些并发症的治疗和/或预防中，水合物可以采用如上所述的剂型给予。
类似的剂量方案适合于非人哺乳动物的治疗和/或预防。
在另一方面，本发明提供水合物在治疗和/或预防糖尿病、与糖尿病有关的疾病及其某些并发症的药物生产中的用途。
本发明化合物在上述治疗中未表明有不利的毒性作用。
下列实施例说明本发明，但不以任何方式限制本发明。
实施例1：5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2，4-二酮，马来酸盐的水合物的制备
将5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2，4-二酮游离碱(4.0g)和马来酸(1.40g，1.05摩尔量)在含有另外水(0.51g，即总水量约2.1％(v/v))的变性乙醇(40ml)中加热至60℃并维持该温度30分钟，在此期间获得一溶液。过滤该溶液，再加热至50℃，然后以1度/分钟的速率冷却，在35℃生成晶体。将生成的悬浮液冷却至25℃并搅拌2小时。过滤该产物，用99％的变性乙醇(8ml)洗涤，于50℃真空干燥24小时，得到标题化合物(4.38g，82％)。产物的水含量为0.54％w/w特征数据：对该水合物产生下列特征数据：
A 红外
用Nicolet710FT-IR分光计于2cm-1分辨率获得该水合物的矿物油分散体的红外吸收光谱。按1cm-1间隔将数据数字化。获得的光谱示于图1中。峰位置如下：3129、2776、1756、1747、1706、1641、1617、1586、1542、1512、1413、1351、1331、1290、1264、1246、1210、1182、1163、1108、1078、1064、1031、1005、975、955、926、865、764、738、719、662、619、579、557、532、525和508cm-1。
B X射线粉末衍射(XRPD)
该水合物的XRPD图案如下示于图2中。该水合物的XRPD角度和计算的点阵间距特征在表1中给出。
采用下列取数条件，使用PW1710X射线粉末衍射仪(Cu X射线源)以生成光谱：
管阳极： Cu
发生器电压： 40kV
发生器电流： 30mA
起始角度： 3.5°2θ
结束角度： 35.0°2θ
步长： 0.02O
每步时间： 4.55O秒
表1
该水合物的X射线粉末衍射角度和计算的点阵间距特征。
Claims (10)
1.一种5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2，4-二酮，马来酸盐的结晶水合物，所述水合物特征在于：
(i)具有0.2-1.1％w/w的含水量；
以及还具有以下特征：
(ii)提供764和579cm-1处峰的红外光谱；
或
(iii)提供基本如同图2的X射线粉末衍射图案。
2.权利要求1的水合物，其中所述乙醇是变性乙醇。
3.权利要求1或2的水合物，其中所述水合物的水含量是0.5-0.6％重量。
4.权利要求1-3中任一项的水合物，其中所述水合物的红外光谱基本如同图1。
5.权利要求1-4中任一项的水合物，其中所述水合物的X射线粉末衍射图案基本如同图2。
6.权利要求1-5中任一项的水合物，其中所述水合物由一种方法得到，所述方法包括：
将5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2，4-二酮，马来酸盐溶解于含有2-2.5％体积水的含水乙醇中，并且将所述水合物从所述含水溶液中结晶出来。
7.权利要求6的水合物，其中所述水合物以纯化形式分离或以与其他物质的混合物形式获得。
8.根据权利要求7的水合物，其中水合物以与无水5-[4-[2-(N-甲基-N-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2，4-二酮，马来酸盐的混合物形式获得。
9.用于治疗和/或预防人类糖尿病、与糖尿病相关的症状以及糖尿病并发症的药用组合物，含有有效、无毒量的权利要求1-8中任一项的水合物和其药学上可接受的载体。
10.根据权利要求1-8中任一项的水合物在用于治疗和/或预防人类和动物糖尿病、与糖尿病相关的症状以及糖尿病并发症的药物生产中的用途。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9726568.0 | 1997-12-16 | ||
| GBGB9726568.0A GB9726568D0 (en) | 1997-12-16 | 1997-12-16 | Novel pharmaceutical |
Related Parent Applications (1)
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|---|---|---|---|
| CN98812092A Division CN1281454A (zh) | 1997-12-16 | 1998-12-14 | 5－[4－[2－(n－甲基－n－(2－吡啶基)氨基)乙氧基]苄基]噻唑烷－2,4－二酮马来酸盐的水合物 |
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| CN101412713A true CN101412713A (zh) | 2009-04-22 |
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| CN98812092A Pending CN1281454A (zh) | 1997-12-16 | 1998-12-14 | 5－[4－[2－(n－甲基－n－(2－吡啶基)氨基)乙氧基]苄基]噻唑烷－2,4－二酮马来酸盐的水合物 |
| CNA2008100930575A Pending CN101412714A (zh) | 1997-12-16 | 1998-12-14 | 5-[4-[2-(n-甲基-n-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮马来酸盐的水合物 |
| CNA2008100930560A Pending CN101412713A (zh) | 1997-12-16 | 1998-12-14 | 5-[4-[2-(n-甲基-n-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮马来酸盐的水合物 |
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| CN98812092A Pending CN1281454A (zh) | 1997-12-16 | 1998-12-14 | 5－[4－[2－(n－甲基－n－(2－吡啶基)氨基)乙氧基]苄基]噻唑烷－2,4－二酮马来酸盐的水合物 |
| CNA2008100930575A Pending CN101412714A (zh) | 1997-12-16 | 1998-12-14 | 5-[4-[2-(n-甲基-n-(2-吡啶基)氨基)乙氧基]苄基]噻唑烷-2,4-二酮马来酸盐的水合物 |
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| GB9909041D0 (en) * | 1999-04-20 | 1999-06-16 | Smithkline Beecham Plc | Novel pharmaceutical |
| AP1607A (en) * | 1999-04-23 | 2006-05-03 | Smithkline Beecham Plc | Thiazolidinedione derivative and its use as antidiabetic. |
| US20040248945A1 (en) | 1999-04-23 | 2004-12-09 | Smithkline Beecham P.L.C. | Thiazolidinedione derivative and its use as antidiabetic |
| EA004534B1 (ru) * | 1999-04-23 | 2004-06-24 | Смитклайн Бичам Плс | Новый фармацевтический препарат |
| GB0014005D0 (en) * | 2000-06-08 | 2000-08-02 | Smithkline Beecham Plc | Novel pharmaceutical |
| GB0021784D0 (en) * | 2000-09-05 | 2000-10-18 | Smithkline Beecham Plc | Novel pharmaceutical |
| GB0021978D0 (en) * | 2000-09-07 | 2000-10-25 | Smithkline Beecham Plc | Novel pharmaceutical |
| AU2002350965A1 (en) * | 2001-12-13 | 2003-06-23 | Smithkline Beecham Plc | Toluenesulfonate hydrates of a thiazolidinedione derivative |
| WO2003050116A1 (en) * | 2001-12-13 | 2003-06-19 | Smithkline Beecham Plc | A 5(-4-(2-(n-methyl-n-(2-pyridil)amino)ethoxy)benzyl)thiazolidine-2,4-dione (i) 10-camphorsulphonic acid salt and use against diabetes mellitus |
| GB0129876D0 (en) * | 2001-12-13 | 2002-02-06 | Smithkline Beecham Plc | Novel pharmaceutical |
| GB0130511D0 (en) * | 2001-12-20 | 2002-02-06 | Smithkline Beecham Plc | Novel pharmaceutical |
| WO2003053962A1 (en) * | 2001-12-20 | 2003-07-03 | Smithkline Beecham Plc | 5- (4- (2- (n-methyl-n- (2-pyridyl) amino) ethoxy) benzyl) thiazolidine-2, 4-dione malic acid salt and use against diabetes mellitus |
| GB2405403A (en) * | 2003-08-29 | 2005-03-02 | Cipla Ltd | Rosiglitazone maleate of particular polymorphic forms and methods of preparing rosiglitazone free base |
| ITMI20041537A1 (it) * | 2004-07-28 | 2004-10-28 | Chemi Spa | Nuova forma polimorfa del rosiglitazone maleato |
| CZ298424B6 (cs) * | 2005-05-24 | 2007-09-26 | Zentiva, A. S. | Zpusob krystalizace rosiglitazonu a jeho derivátuze smesných rozpouštedel |
| EP2184055A1 (en) | 2008-11-07 | 2010-05-12 | LEK Pharmaceuticals d.d. | Process for preparing solid dosage forms of rosiglitazone maleate |
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| AR240698A1 (es) * | 1985-01-19 | 1990-09-28 | Takeda Chemical Industries Ltd | Procedimiento para preparar compuestos de 5-(4-(2-(5-etil-2-piridil)-etoxi)benzil)-2,4-tiazolidindiona y sus sales |
| US4812570A (en) * | 1986-07-24 | 1989-03-14 | Takeda Chemical Industries, Ltd. | Method for producing thiazolidinedione derivatives |
| ATE186724T1 (de) | 1987-09-04 | 1999-12-15 | Beecham Group Plc | Substituierte thiazolidindionderivate |
| GB8820389D0 (en) * | 1988-08-26 | 1988-09-28 | Beecham Group Plc | Novel compounds |
| GB9124513D0 (en) | 1991-11-19 | 1992-01-08 | Smithkline Beecham Plc | Novel process |
| CA2142708A1 (en) | 1992-08-28 | 1994-03-17 | Frank Dininno | Cationic-2-heteroarylphenyl-carbapenem antibacterial agents |
| GB9218830D0 (en) | 1992-09-05 | 1992-10-21 | Smithkline Beecham Plc | Novel compounds |
| US5741803A (en) | 1992-09-05 | 1998-04-21 | Smithkline Beecham Plc | Substituted thiazolidinedionle derivatives |
| TW245716B (zh) * | 1992-12-28 | 1995-04-21 | Takeda Pharm Industry Co | |
| DE4404198A1 (de) | 1994-02-10 | 1995-08-17 | Henkel Kgaa | 2-Fluor-6-nitroaniline |
| GB9726563D0 (en) | 1997-12-16 | 1998-02-11 | Smithkline Beecham Plc | Novel pharmaceutical |
| US20020137940A1 (en) | 1997-12-16 | 2002-09-26 | Smithkline Beecham P.L.C. | 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2, 4-dione, maleic acid salt, hydrate as pharmaceutical |
| GB9726566D0 (en) | 1997-12-16 | 1998-02-11 | Smithkline Beecham Plc | Novel pharmaceutical |
| US6664278B2 (en) * | 1997-12-16 | 2003-12-16 | Smithkline Beecham P.L.C. | Hydrate of 5-[4-[2-(N-methyl-N-(2-pyridil)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt |
| CZ432299A3 (cs) * | 1998-06-02 | 2000-08-16 | Smithkline Beecham Plc | Kompozice obsahující 5-[4-[2-(N-methyl-N-(2- pyridyI)amino)ethoxy]benzyl]thiazolidin-2,4-dion |
| EA004534B1 (ru) | 1999-04-23 | 2004-06-24 | Смитклайн Бичам Плс | Новый фармацевтический препарат |
| AP1607A (en) | 1999-04-23 | 2006-05-03 | Smithkline Beecham Plc | Thiazolidinedione derivative and its use as antidiabetic. |
| JP2002543077A (ja) | 1999-04-23 | 2002-12-17 | スミスクライン ビーチャム パブリック リミテッド カンパニー | ５−［４−［２−（ｎ−メチル−ｎ−（２−ピリジル）アミノ）エトキシ］ベンジル］チアゾリジン−２，４−ジオン，マレイン酸塩の多形体 |
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1997
- 1997-12-16 GB GBGB9726568.0A patent/GB9726568D0/en not_active Ceased
-
1998
- 1998-12-14 KR KR1020007006517A patent/KR100549143B1/ko not_active Expired - Fee Related
- 1998-12-14 NZ NZ504704A patent/NZ504704A/xx unknown
- 1998-12-14 CA CA002314965A patent/CA2314965A1/en not_active Abandoned
- 1998-12-14 CN CN98812092A patent/CN1281454A/zh active Pending
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