CN101333181A - 培哚普利特丁胺的新晶形 - Google Patents

培哚普利特丁胺的新晶形 Download PDF

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CN101333181A
CN101333181A CNA2008100912488A CN200810091248A CN101333181A CN 101333181 A CN101333181 A CN 101333181A CN A2008100912488 A CNA2008100912488 A CN A2008100912488A CN 200810091248 A CN200810091248 A CN 200810091248A CN 101333181 A CN101333181 A CN 101333181A
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crystalline form
water
perindopril
methyl ether
butyl methyl
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C·施特雷斯勒
V·勒列科
R·费斯勒
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Laboratoires Servier SAS
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Abstract

本发明公开了培哚普利特丁胺的新晶形，即ε晶形。该晶形适合作为用于治疗心血管疾病、尤其是高血压和心力衰竭的药物的治疗活性物质。ε晶形是通过使培哚普利特丁胺在30至45℃下、优选在34至45℃下从含有1.5至2.5％(v/v)水的MTBE中结晶获得的；所述结晶有利地在搅拌下进行。ε晶形也可以通过在用ε晶形引入晶种的同时将α或β晶形的培哚普利特丁胺于28至35℃下在含有0.9至1.4％(v/v)水的叔丁基甲基醚中搅拌来获得；或者通过将α或β晶形于35至38℃下在含有1.5至2.0％(v/v)水的叔丁基甲基醚中搅拌来获得。

Description

培哚普利特丁胺的新晶形
本申请为2004年6月18日提交的申请号为PCT/CH2004/000374、发明名称为“培哚普利特丁胺的新晶形”的国际申请的分案申请，该申请于2005年12月26日进入中国国家阶段，申请号为200480017867.2。
技术领域
本发明涉及培哚普利特丁胺的两种新晶形。
背景技术
培哚普利((2S，3aS，7aS)-1-[2-(1-乙氧基羰基-(S)-丁基氨基)-(S)-丙酰基]-八氢吲哚-2-甲酸)具有以下式(I)的结构：
Figure A20081009124800041
培哚普利特丁胺是培哚普利的叔丁基胺盐。
培哚普利是ACE抑制剂(ACE＝血管紧张素转化酶)，用于治疗心血管疾病，尤其是治疗高血压和心力衰竭。
合成培哚普利的方法在EP 49658、US 4,508,729、EP 308341和US4,914,214中有记载，在EP 1256590和WO 01/58868中也有记载。
在WO 01/87835、WO 01/87836和WO 01/83439中记载了使培哚普利特丁胺从乙酸乙酯中(WO 01/87835)、从二氯甲烷或乙酸乙酯(WO01/87836)和从氯仿中(WO 01/83439)结晶的方法以及在那些方法中获得的α(WO 01/87835)、β(WO 01/87836)和γ(WO 01/83439)晶形。
发明内容
现已发现通过使任一晶形的培哚普利特丁胺从含有0.9至2.5％v/v水的叔丁基甲基醚中结晶或者通过在含有0.9至2.5％v/v水的叔丁基甲基醚中对培哚普利特丁胺的α或β晶形进行转化，可能获得两种其它的晶形，即δ和ε晶形，这取决于精确的条件。这些新的δ和ε晶形通过以下的X-射线衍射数据进行表征(参见下面的表1和表2)：
表1：培哚普利特丁胺δ晶形的X-射线衍射数据(由通过CuKα照射得到的粉末图谱获得相对强度)
Figure A20081009124800051
Figure A20081009124800061
注：众所周知强度可能由于结构影响而变化。
表2：培哚普利特丁胺ε晶形的X-射线衍射数据(由通过CuKα照射得到的粉末图谱获得相对强度)
Figure A20081009124800071
注：众所周知强度可能由于结构影响而变化。
根据本发明，ε晶形是通过使任一晶形的培哚普利特丁胺在30至45℃下、优选在34至45℃下从含有1.5至2.5％v/v水的叔丁基甲基醚(MTBE)中结晶获得的；所述结晶有利地在搅拌下进行。如果之后除去水，有利地通过共沸蒸馏除去，优选在35至37℃下进行，然后在30至45℃下、优选在35至37℃下继续搅拌至少15小时，则ε晶形转化为δ晶形。
另外，通过在33至38℃下、优选在35至37℃下在含有0.9至1.4％v/v水、优选含有1.0至1.1％v/v水的叔丁基甲基醚(MTBE)中进行搅拌并用δ晶形引入晶种可将已知的培哚普利特丁胺的α和β晶形转化为δ晶形。
在含有0.9至1.4％v/v水、优选含有1.0至1.1％v/v水的叔丁基甲基醚(MTBE)中，通过用ε晶形引入晶种可以在28至35℃下、优选在31至33℃下将已知的α和β晶形转化为ε晶形。
不引入晶种也可以进行这些转化，但是在边缘区域当然无法确定地预测获得的是δ晶形、ε晶形还是这些晶形的混合物。
α和β晶形向ε晶形的转化也可以于35至38℃下在含有1.5至2.0％v/v水的叔丁基甲基醚(MTBE)中进行。
培哚普利特丁胺的δ和ε晶形均是新晶形并且是本发明所涉及的内容。
根据本发明，它们可以用作治疗活性物质，并且可与可药用的载体材料一起被加工成药物。所述药物则可以用于治疗心血管疾病，尤其是治疗高血压和心力衰竭。
用于制备药物的可药用载体材料是通常已知的，并且对本领域技术人员而言是熟悉的。
由于药学活性物质的不同形式例如新的结晶形式通常表现出不同的生物利用度、溶解性和溶出速率，所以它们可能对相关的病人非常有利，因为它们使得降低剂量或延长给药间隔并最终减少用药花费成为可能。
具体实施方式
以下实施例用于对本发明进行举例说明，但不以任何方式限制本发明的范围及其应用：
在Philips ADP1700粉末衍射仪上使用Kα1＝0.15406nm和Kα2＝0.15444的Cu照射和40kV的电压测定X-射线衍射谱。
实施例1：培哚普利特丁胺的ε晶形
将5.00g培哚普利特丁胺混悬在50ml MTBE中，加入0.95ml水。在搅拌下将所得混悬液加热至48℃，形成澄清的溶液。在搅拌下将该溶液冷却至41℃。在该温度下引入晶种，之后开始结晶。在40至41℃下搅拌30分钟，然后在1小时期间将混合物冷却至34℃。将所得的沉淀物滤出，用10ml MTBE洗涤。干燥后，获得1.85gε晶形的培哚普利特丁胺。
实施例2：培哚普利特丁胺的δ晶形
将11.09g培哚普利特丁胺混悬在130ml MTBE中，加入2ml水。在搅拌下将所得混悬液加热至51℃，形成澄清的溶液。在搅拌下于120分钟期间将溶液冷却至35℃。在44℃下引入晶种，之后开始结晶。在35至37℃下于45分钟期间减压蒸馏除去50ml MTBE。同时也通过共沸除去了水。然后再加入50ml MTBE并在35至37℃下于60分钟期间再次减压蒸馏除去50ml MTBE。在35至37℃下继续搅拌15小时，然后将所得的沉淀物滤出，用10ml MTBE洗涤。干燥后，获得8.42gδ晶形的培哚普利特丁胺。
实施例3：α晶形向δ晶形的转化
将8.50gα晶形的培哚普利特丁胺混悬在85ml MTBE中，在搅拌下将该混悬液加热至35至37℃。向其中加入0.85ml水，随后加入0.17gδ晶形的晶种。将所得混悬液在35至37℃下搅拌23小时，然后将沉淀物滤出。干燥后，获得7.00gδ晶形。
实施例4：α晶形向ε晶形的转化
将21.66gα晶形的培哚普利特丁胺混悬在216ml MTBE中，在搅拌下将该混悬液加热至33至35℃。向其中加入2.16ml水，将混悬液在33至35℃下搅拌14小时。将沉淀物滤出并干燥后，获得18.68gε晶形。
实施例5：β晶形向δ晶形的转化
将4.00gβ晶形的培哚普利特丁胺混悬在40ml MTBE中，加入0.36ml水。将所得混悬液加热至35至37℃，在35至37℃下搅拌20小时。将沉淀物滤出并干燥后，获得δ晶形。
实施例6：α晶形向ε晶形的转化
将7.55gα晶形的培哚普利特丁胺混悬在75ml MTBE中，在搅拌下将该混悬液加热至35至37℃。向其中加入1.32ml水，将所得混悬液在35至37℃下搅拌20小时。将沉淀物滤出并干燥后，获得2.31gε晶形。

Claims (6)

1.培哚普利特丁胺的ε晶形，其用以下X-射线衍射数据(用CuKα照射在粉末衍射仪上测定)表征：
Figure A2008100912480003C1
2.用作治疗活性物质的权利要求1的培哚普利特丁胺的晶形。
3.含有权利要求1的培哚普利特丁胺的晶形的药物。
4.权利要求1的培哚普利特丁胺的晶形在治疗心血管疾病中和在制备相应药物中的用途。
5.权利要求4的用途，其中所述的心血管疾病是高血压和心力衰竭。
6.制备权利要求1的ε晶形的培哚普利特丁胺的方法，其特征在于：
a)使任一晶形的培哚普利特丁胺在30至45℃下从含有1.5至2.5％(v/v)水的叔丁基甲基醚中重结晶；或者
b)将α或β晶形的培哚普利特丁胺于28至35℃下在含有0.9至1.4％(v/v)水的叔丁基甲基醚中进行搅拌，同时用ε晶形引入晶种；或者
c)将α或β晶形的培哚普利特丁胺于35至38℃下在含有1.5至2.0％(v/v)水的叔丁基甲基醚中进行搅拌。
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FR2827860B1 (fr) 2001-07-24 2004-12-10 Servier Lab Nouveau procede de synthese de derives de l'acide (2s, 3as, 7as)-1-[(s)-alanyl]-octahydro-1h-indole-2-carboxyline et application a la synthese du perindopril
GB2395195A (en) * 2002-11-18 2004-05-19 Cipla Ltd Preparation of perindopril from carboxy-protected precursor, & perindopril monohydrates for use as angiotensin converting enzyme (ACE) inhibitors
EP1973523A2 (en) * 2005-12-15 2008-10-01 Acusphere, Inc. Processes for making particle-based pharmaceutical formulations for pulmonary or nasal administration

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WO2004113293A1 (de) 2004-12-29
EP1636185A1 (de) 2006-03-22
US20100160404A1 (en) 2010-06-24
SI1636185T1 (sl) 2012-06-29
US7981921B2 (en) 2011-07-19
DK1636185T3 (da) 2012-05-07
BRPI0411966A (pt) 2006-08-29
US7705046B2 (en) 2010-04-27
ES2382171T3 (es) 2012-06-06
ZA200600655B (en) 2007-05-30
US20070135512A1 (en) 2007-06-14
AU2004249345B8 (en) 2009-06-25
MXPA05013811A (es) 2006-06-27
AU2004249345B2 (en) 2009-02-26
ATE540924T1 (de) 2012-01-15
CY1112597T1 (el) 2016-02-10
PL1636185T3 (pl) 2012-12-31
AU2004249345A1 (en) 2004-12-29
NO20060256L (no) 2006-01-18
CN100395235C (zh) 2008-06-18
CA2530550A1 (en) 2004-12-08
NZ544160A (en) 2008-07-31
CN1812971A (zh) 2006-08-02
EA008603B1 (ru) 2007-06-29
KR20060035636A (ko) 2006-04-26
PT1636185E (pt) 2012-04-16
HK1093984A1 (en) 2007-03-16
EP1636185B1 (de) 2012-01-11
EA200501859A1 (ru) 2006-06-30
CA2530550C (en) 2017-04-04
JP2007507418A (ja) 2007-03-29

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