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CN1051312C - 一种噻唑烷衍生物及其制药应用 - Google Patents

一种噻唑烷衍生物及其制药应用 Download PDF

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CN1051312C
CN1051312C CN97122519A CN97122519A CN1051312C CN 1051312 C CN1051312 C CN 1051312C CN 97122519 A CN97122519 A CN 97122519A CN 97122519 A CN97122519 A CN 97122519A CN 1051312 C CN1051312 C CN 1051312C
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C·R·普尔
R·S·罗曼
M·D·布赖特威尔
A·W·特伦帕
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Abstract

本申请提供了5－[4－[2－(N－甲基－N－(2－吡啶基)氨基)乙氧基]苄基]噻唑烷－2，4－二酮马来酸盐或其异构体或互变异构体形式或其药物学上可接受的溶剂化物及其在制备治疗和/或预防高血糖症的药物中的应用。

Description

一种噻唑烷衍生物及其制药应用
本申请是申请日为1993年9月4日、申请号为93119067.3的中国专利申请的分案申请。
本发明公开了某些新的化合物，这些化合物的制备方法，含有这些化合物的药物组合物以及这些化合物和组合物在医学上的应用。公开号为0,306,228的欧洲专利申请，描述了某些具有降血糖和降低血脂质活性(hypoglycaemic and hypolipidaemic activity)的噻唑烷二酮衍生物。
现在惊奇地发现EP-A-0,306,228的式(I)中特定的一组化合物具有显著的作用选择性并因此特别适用于治疗II型糖尿病。还发现这些化合物特别适用于治疗和/或预防包括高脂血症、高血压和心血管疾病，特别是动脉粥样硬化在内的其它疾病。另外，这些化合物被认为可用于治疗某些饮食紊乱，特别是可调节患有与饮食过少有关的疾病如神经性厌食症以及与饮食过多有关的疾病如肥胖症和神经性贪食症患者的食欲和食物摄入。
这些化合物显示出良好的水溶液稳定性和固体形式下良好的稳定性，这些化合物中的某些化合物被认为是特别稳定的。另外这些化合物较相应的游离碱在水中有很高的溶解度。
这些化合物惊人的和显著的稳定性和水溶解度提供了有效制剂和大量使用上的优点。
因此，本发明提供了一种式(I)化合物：
Figure C9712251900031
或其互变异构体和/或其药物上可接受的溶剂化物，其中：
R1表示氢原子，烷基，酰基，芳烷基，其中的芳基部分可被取代或未被取代，或取代或未取代的芳基；A1表示氢或1-4个选自烷基，烷氧基，芳基和卤素的任意取代基或者A1表示在相邻碳原子上的两个取代基，此取代基可与其所连接的碳原子一起形成一个取代或未取代的芳基；A2表示具有1-3个任意取代基的苯环；以及M-表示抗衡离子。
适宜的抗衡离子M-包括由药物上可接受的酸提供的离子。
适宜的抗衡离子M-源是由PKa在0.1-4.5范围内并且特别是在1.75-2.5范围内的药物上可接受的酸所提供。
优选的药物上可接受的酸包括无机酸，例如氢溴酸，盐酸和硫酸，以及有机酸，例如甲磺酸、酒石酸和马来酸，特别是酒石酸和马来酸。
优选的抗衡离子是马来酸根离子HOOC.CH＝CH.COO-。
优选A1是氢。
基团A2的适宜的任意取代基包括至多三个选自卤素、已被取代或被未取代的烷基或烷氧基的取代基。
优选地是，A2表示式(e)基团：其中R2和R3分别表示氢，囟素，已被取代或未被取代的烷基或烷氧基。
较适宜地是，R2和R3分别表示氢、卤素、烷基或烷氧基。
优选地是，R2和R3分别表示氢。
较适宜地是，R1表示氢、烷基、酰基、特别是乙酰基、或苄基。
优选地是，R1表示烷基，例如甲基。
式(I)中基团：
Figure C9712251900051
优选是下式基团：其中A1和R1如上定义。
优选的式(I)化合物是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。
式(I)化合物是盐。本发明涉及此盐的所有形式包括成盐氢与分子的所有可能成盐部分缔合形成的盐并且特别是与吡啶上的氮缔合形成的盐。
如上所述，式(I)化合物可以以几种互变异构体形式的一种形式存在，所有这些互变异构体均包括在本发明内。可以理解地是本发明包括式(I)化合物的所有异构体形式及其药物上可接受的盐，包括以单一异构体或构体混合物形式的任何立体异构体。
此处所用术语“芳基”包括被至多5个，优选至多3个取代基任意取代的苯基和萘基，取代基选自卤素、烷基、苯基、烷氧基、卤代烷基、羟基、硝基、烷氧羰基、烷氧羰基烷基、烷基羰氧基或烷基羰基。
此处所用术语“卤素”指氟、氯、溴和碘；优选氯。
包括烷基本身和其它基团的烷基部分(如烷氧基)的适宜烷基为直链或支链的C1-C12烷基，特别是C1-C6烷基，例如甲基、乙基，正丙基，异丙基，正丁基，异丁基或叔丁基。
对任一烷基适宜的取代基包括上述与术语“芳基”有关的取代基。
适宜的酰基包括烷基羰基。
适宜的药物上可接受的溶剂化物包括水合物。
另外，本发明还提供了式(I)化合物或其互变异构体，和/或其药物上可接受的溶剂化物的制备方法，此方法包括将式(II)化合物：
Figure C9712251900061
其中R1、A1和A2如式(I)中定义，与上述定义的抗衡离子M-源反应，此后如果需要，制备其药物上可接受的溶剂化物。
适宜的抗衡离子M-源是药物上可接受的酸。
适宜的抗衡离子M-源包括PKa在1.5-4.5范围内，特别是在1.75-2.5范围内的药物上可接受的酸。
优选的药物上可接受的酸包括无机酸如氢溴酸，盐酸和硫酸，以及有机酸如甲磺酸，酒石酸和马来酸。
优选的抗衡离子源是马来酸。
式(I)化合物与抗衡离子M-源之间的反应通常是在常规成盐条件下进行，例如，在溶剂中通常为C1-C4链烷醇溶剂如乙醇，于可提供生成所需化合物的适宜速率的任意温度下，通常于升高的温度例如溶剂的回流温度下，较适宜地是以约等摩尔量但优选用稍过量的抗衡离子M-源的情况下将式(I)化合物与抗衡离子M-源混合并然后结晶出所需产物。
式(I)化合物的药物上可接受的溶剂化物可以用常规的化学方法制备。
式(II)化合物可根据EP-A-0306228所述方法制备。
适宜的抗衡离子源是公知的在商业上可获得的，例如马来酸，或者可以根据已知方法制备所需的抗衡离子源。
式(I)化合物和其药物上可接受的盐的适宜的异构体形式可用常规化学方法以单一异构体形式制得。
本发明化合物的稳定性可以用常规定量分析法测定；例如固体形式的化合物稳定性可用加速的稳定性试验来测定，例如差示扫描量热法(DSC)，热解重量分析法(TGA)和于升温下的等温线试验。此试验包括常规贮藏试验。(其中在公知期间内于温度和湿度控制条件下贮藏试验化合物)。试验化合物的定量分析是在贮藏期之前、贮藏期间或贮藏期之后。相对于适宜的参考标准测定试验化合物的稳定性。
如上所述，本发明化合物与相应的游离碱相比在水中有显著的溶解性。这样测定本发明化合物于水溶液中的稳定性的常规方法包括在已知的温度条件和已知的期间内测定由试验化合物的水溶液中沉淀出母体游离碱的程度，我们发现式(I)化合物显示出良好的水溶液稳定性。特别是其中M-表示马来酸根或酒石酸根的式(I)化合物在水溶液中特别稳定，更惊奇地是，其中M-表示马来酸根离子。HOOC.CH＝CH.COO-的式(I)化合物在水溶液中异常地稳定。
上述试验化合物定量分析试验可以用常规方法，通常用色谱法例如高压液相色谱法进行。
如上所述，本发明的化合物具有实用的治疗活性。
因此，本发明提供了用作治疗活性物质的式(I)化合物和/或其药物上可接受的溶剂化物。
这样，本发明提供了用于治疗和/或预防高血糖症的式(I)化合物或其互变异构体和/或其药物上可接受的溶剂化物。
另外，本发明还提供了用于治疗和/或预防高脂血症的式(I)化合物或其互变异构体和/或其药物上可接受的溶剂化物。
如上所述，本发明还提供了用于治疗高血压、心血管疾病和某些饮食紊乱的式(I)化合物或其互变异构体和/或其药物上可接受的溶剂化物。
心血管疾病特别是包括动脉粥样硬化。
某些饮食紊乱特别是包括调节患有与饮食过少有关的疾病如神经性厌食症以及与饮食过多有关的疾病如肥胖症和神经性贪食症患者的食欲和食物摄入。
式(I)化合物或其互变异构体和/或其药物上可接受的溶剂化物可以以其自身的形式施用，优选地是也可以含有药物上可接受的载体的药物组合物的形式施用。
因此，本发明还提供了一种含有式(I)化合物或其互变异构体或其药物上可接受的溶剂化物和药物上可接受的载体的药物组合物。
此处所用术语“药物上可接受的”包括对人和兽医两者使用的化合物、组合物和组分，例如，术语“药物上可接受的盐”包括兽医上可接受的盐。
如果需要，组合物可以进行包装，上面附有书写或印制的使用说明。
尽管组合物也可以经其它途径例如注射和经皮吸收施用，但本发明药物组合物通常采用口服。
特别适宜的口服药物组合物是单位剂型的组合物例如片剂和胶囊，也可以使用其它混合的单位剂型如在小药囊中的粉剂。
根据常规的药物上的惯例，载体可包括稀释剂、填充剂、崩解剂、润湿剂、润滑剂、着色剂、调味剂或其它常规添加剂。
典型的载体包括例如微晶纤维素、淀粉、淀粉乙醇酸钠、聚乙烯吡咯烷酮、聚乙烯聚吡咯烷酮、硬脂酸镁或十二烷基磺酸钠。
最适宜的组合物是配制成单位剂型。此单位剂型通常含有0.1-1000mg，通常为0.1-500mg，更具体的是0.1-250mg范围内的活性成分。
本发明还提供了一种治疗和/或预防人或非人的哺乳动物高血糖症的方法，此方法包括给所需治疗的高血糖症患者或非人的哺乳动物施用无毒而有效量的式(I)化合物或其互变异构体和/或其药物上可接受的溶剂化物。
本发明进一步提供了一种治疗人或非人的哺乳动物的高脂血症的方法，此方法包括给所需治疗的高脂血症患者或非人的哺乳动物施用无毒而有效量的式(I)化合物或其互变异构体和/或其药物上可接受的溶剂化物。
通常，活性成分可以以上述的药物组合物形式施用并构成了本发明特殊的一个方面。
在治疗和/或预防高血糖症患者，和/或治疗和/或预防高脂血症患者时，可以例如以如上所述的剂量服用式(I)化合物或其互变异构体和/或其药物上可接受的溶剂化物，对70kg成年人每日一至六次服用的总日剂量通常在0.1-6000mg，更通常为1-1500mg的范围内。
在治疗和/或预防高血糖症的非人哺乳动物，特别是狗时，通常可以以每日一次或两次并以约0.025mg/kg-25mg/kg的量，例如0.1mg/kg-20mg/kg口服活性成分。相似的剂量也适用于治疗和/或预防非人哺乳动物的高脂血症。
治疗高血压，心血管疾病和饮食紊乱的剂量通常如上述高血糖症中所述。
本发明进一步提供了式(I)化合物或其互变异构体和/或其药物上可接受的溶剂化物在生产治疗和/或预防高血糖症的药物中的应用。
本发明还提供了式(I)化合物或其互变异构体和/或其药物上可接受的溶剂化物在生产治疗和/或预防高脂血症、高血压、心血管疾病或某些饮食紊乱的药物中的应用。
下列实施例用于说明本发明，但没有任何限制作用。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。
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(470g)和马来酸(137g)溶于沸腾的乙醇(4l)中。此热溶液经硅藻土过滤，然后于温和搅拌下缓慢冷却，于0-5℃的冰箱中静置数小时，滤出马来酸盐，用乙醇洗涤并于50°真空中干燥，得446g(73％)产物，m.p.120-121℃。
1HNMR δ(d6-DMSO)：3.0-3.35(2H，多重峰)；3.10(3H，单峰)；3.95(2H，三重峰)；4.15(2H，三重峰)；4.85(1H，多重峰)；6.20(2H，单峰)；6.65(1H，三重峰)；6.85(3H，多重峰)；7.15(2H，双峰)；7.65(1H，三重峰)；8.05(1H，多重峰)；11.85-12.1(1H，宽峰，用D2O交换)。
在2-5ppm范围内可察到一个很宽的信号它被认为是溶剂中残存的水和可交换的羧酸质子。实施例2
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。
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(294.6g，0.825M)和马来酸(95.8g，0.825M)于回流的乙醇(2.7l)中搅拌直至固体全部溶解。加入脱色碳并将此热溶液经塞力特硅藻土过滤，搅拌下令其冷至室温。于0-5℃冰箱中静置数小时，将标题化合物过滤，将集并于50℃真空干燥过夜，得364.1g(87％)产物，m.p.119-119.5℃。
1HNMR谱如实施例1。

Claims (2)

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。
2.权利要求1的化合物在制备治疗和/或预防高血糖症的药物中的应用。
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