CN101987833A - 尼伐地平新晶型及其制备方法 - Google Patents

尼伐地平新晶型及其制备方法 Download PDF

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CN101987833A
CN101987833A CN2009100902955A CN200910090295A CN101987833A CN 101987833 A CN101987833 A CN 101987833A CN 2009100902955 A CN2009100902955 A CN 2009100902955A CN 200910090295 A CN200910090295 A CN 200910090295A CN 101987833 A CN101987833 A CN 101987833A
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nilvadipine
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acetone
crystal formation
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CN101987833B (zh
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姚勇敢
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Jiangsu Furun Pharmaceutical Co.,Ltd.
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BEIJING LILESHENG PHARMACEUTICAL TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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Abstract

本发明公开了抗高血压药物尼伐地平两种新晶型及其制备方法。所述晶型的制备方法采用丙酮、水、乙酸乙酯、石油醚等常用溶剂。

Description

尼伐地平新晶型及其制备方法
技术领域
本发明涉及尼伐地平新晶型及其制备方法。
背景技术
尼伐地平(Nilvadipine)，化学名：6-氰基-5-甲氧基甲酰基-2-甲基-4-(3-硝基苯基)-1，4-二氢吡啶-3-羧酸异丙酯，化学结构式如下：
Figure B2009100902955D0000011
尼伐地平为二氢吡啶类钙拮抗剂类抗高血压药，其钙拮抗作用和与膜特异性结合作用比硝苯地平强10倍，作用持续时间长2～3倍。作用特点是对血管的作用比对心脏的作用强；对椎动脉和冠动脉的扩张作用比对其它动脉强；能明显改善因血压升高所伴有的静脉伸展性低下，从而降低前负荷；还具有抗心绞痛和抗动脉硬化的作用。1989年在日本首次上市，临床可应用于轻、中、重度原发性高血压的治疗。
在文献GB2036722中提到了使用乙醇进行重结晶，本发明人在研究结晶的过程中，发现了两种稳定的新晶型，命名为I型、II型。
发明内容
本发明的目的提供了2种尼伐地平的新晶型。
本发明的第一种尼伐地平的新晶型，该晶型定名为I型，其X-射线粉末衍射图在反射角2θ约为10.7，21.5，21.7，28.3处有特征吸收峰。
本发明的第二种尼伐地平的新晶型，该晶型定名为II型，其X-射线粉末衍射图在反射角2θ约为13.5，18.3，20.6，21.4，23.4，27.2处有特征吸收峰。
本发明中，2θ值的测定使用CuKα光源，精度为±0.2°，因此，上述“X-射线粉末衍射图特征吸收峰反射角2θ约为”中的“约”应定义为2θ±0.2°，代表上述所取的2θ值允许有一定合理的误差范围，其误差范围为±0.2°。
本发明的另一目的是公开了尼伐地平新晶型的制备方法。
本发明的尼伐地平晶型I的制备方法，其过程包括：将尼伐地平用乙酸乙酯溶解，必要时可以加热，加入石油醚，振摇后静置析晶。其特征在于，乙酸乙酯的用量为尼伐地平重量的5～50倍，石油醚用量为乙酸乙酯用量的0.5～5倍。
本发明的尼伐地平晶型II的制备方法，其过程包括：将尼伐地平用丙酮溶解，必要时可以加热，加入水，搅拌析晶。其特征在于，丙酮的用量为尼伐地平重量的1～10倍，水的用量为丙酮用量的0.1～1倍。
具体实施方式
通过下面的实施例可以对本发明进行进一步的描述，然而，本发明的发明并不限于下面的实施例，这些实施例不以任何方式限制本发明的范围。本领域的技术人员在权利要求的范围内所作出的某些改变和调整也应认为属于本发明的范围。
实施例1 晶I的制备
尼伐地平4g悬浮于40ml乙酸乙酯中，加热溶解，趁热加入80ml石油醚，室温静置析晶，抽滤，45℃真空干燥。
实施例2 晶II的制备
尼伐地平4g，加入10ml丙酮，50℃水浴加热使完全溶解，加入4ml水，室温下搅拌析晶。抽滤，45℃真空干燥。
实施例3 尼伐地平新晶型物理特性的测定
通过X-射线衍射方法将新晶型的尼伐地平粉末置于粉末衍射仪上，以8度/分的扫描速率在2.6～40度2θ角之间进行扫描，使用Cu-Ka 40Kv～100mAX射线辐射。
附图1 晶型I的X-射线粉末衍射图谱
附图2 晶型II的X-射线粉末衍射图谱
实施例4药效评价实验
1.实验方法：取健康雄性SD大鼠30只，适应性喂养1周后.以RBP一1大鼠血压仪测基础血压。术前晚禁食12h，次晨造模。造模4w后凡血压比处理前高2.66kPa(大于正常血压3个标准差值)以上，且高于15.30kPa者确定为高血压疾病模型形成。将造模成功的大鼠随机分成：尼伐地平组、尼伐地平晶型I组、尼伐地平晶型II组及空白模型组，另取健康SD大鼠10只，设正常对照组。给药方法为：尼伐地平(或其晶型)1.2mg/kg，灌胃给予，灌胃容积为1ml/100g体重。正常对照组和空白模型组以1ml/100g体重生理盐水灌胃，连续给药4周。在干燥、通风、安静的环境中，RBP一1大鼠血压仪预热后，将大鼠置恒温加热箱中预热10～15min后，测取收缩压，每个时点测3次，取均数。血压测定在以下时点进行：手术前、给药后第1、2、3、4周末。给药后的血压测定应在给药后2h开始进行。
2.统计学处理：采用SPSS软件进行统计学分析，实验结果均用元x±s表示，多组均数比较采用ANOVA方差分析，组间比较用q检验。P≤0.05为差异有显著性意义。
3结果
术后4周，空白模型组血压明显升高，与其相比较，各给药组均具有明显的降压效果(P≤0.01)，与尼伐地平组比较，尼伐地平的晶型组降压作用较显著(P≤0.05)，灌胃1周后，血压开始下降至连续给药4周末，见表1。
表1对肾性高血压大鼠血压的影响
Figure B2009100902955D0000031
Figure B2009100902955D0000032

Claims (6)

1.一种尼伐地平的晶型I，其特征在于该晶体的X-射线粉末衍射图在反射角2θ约为10.7，21.5，21.7，28.3处有特征吸收峰。
2.一种尼伐地平的晶型II，其特征在于该晶体的X-射线粉末衍射图在反射角2θ约为13.5，18.3，20.6，21.4，23.4，27.2处有特征吸收峰。
3.权利要求1所述晶型，其特征在于其制备方法，通过将尼伐地平用乙酸乙酯溶解，加热，加入石油醚，振摇后静置析晶。
4.权利要求3所述的制备方法，其特征在于，乙酸乙酯的用量为尼伐地平重量的5～50倍，石油醚用量为乙酸乙酯用量的0.5～5倍。
5.权利要求2所述晶型，其特征在于其制备方法，通过将尼伐地平用丙酮溶解，加热，加入水，搅拌析晶。
6.权利要求5所述的制备方法，其特征在于，丙酮的用量为尼伐地平重量的1～10倍，水的用量为丙酮用量的0.1～1倍。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2036722A (en) * 1978-10-10 1980-07-02 Fujisawa Pharmaceutical Co 2-Methyl-dihydropyridines
GB1591089A (en) * 1976-12-17 1981-06-10 Fujisawa Pharmaceutical Co 1,4-dihydropyridine derivatives and process for preparation thereof
US5508413A (en) * 1987-08-27 1996-04-16 Fujisawa Pharmaceutical Co., Ltd. (+)-5-isopropyl 3-methyl 2-cyano-6 methyl-4-(3-nitrophenyl)-1, 4-dihydropyridine-3, 5-dicarboxylate

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993006082A1 (en) * 1991-09-13 1993-04-01 Merck & Co., Inc. Process for the preparation of 4-substituted-1,4-dihydropyridines
IT1301759B1 (it) * 1998-06-19 2000-07-07 Nicox Sa Sali nitrati di farmaci antiipertensivi

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1591089A (en) * 1976-12-17 1981-06-10 Fujisawa Pharmaceutical Co 1,4-dihydropyridine derivatives and process for preparation thereof
GB2036722A (en) * 1978-10-10 1980-07-02 Fujisawa Pharmaceutical Co 2-Methyl-dihydropyridines
US5508413A (en) * 1987-08-27 1996-04-16 Fujisawa Pharmaceutical Co., Ltd. (+)-5-isopropyl 3-methyl 2-cyano-6 methyl-4-(3-nitrophenyl)-1, 4-dihydropyridine-3, 5-dicarboxylate

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
YOSHINARI SATOH,等: "Studies on nilvadipine.Ⅰ. Synthesis and structure-activity relationships of l,4-dihydropyridines containing novel substituents at the 2-position", 《CHEM. PHARM. BULL.》 *
岳步星: "新型钙通道拮抗剂及伐地平", 《国外医药.合成药.生化药.制剂分册》 *
常宏宏,等: "新型钙离子拮抗剂尼伐地平", 《精细与专用化学品》 *
常宏宏: "新型钙拮抗剂尼伐地平的合成研究", 《太原理工大学硕士学位论文》 *

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