CN1213033C - 二[(e)－7－[4－(4－氟苯基)－6－异丙基－2－[甲基(甲基磺酰基)氨基]嘧啶－5－基](3r,5s)－3,5－二羟基庚－6－烯酸]钙盐晶体 - Google Patents

二[(e)－7－[4－(4－氟苯基)－6－异丙基－2－[甲基(甲基磺酰基)氨基]嘧啶－5－基](3r,5s)－3,5－二羟基庚－6－烯酸]钙盐晶体 Download PDF

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CN1213033C
CN1213033C CNB998155047A CN99815504A CN1213033C CN 1213033 C CN1213033 C CN 1213033C CN B998155047 A CNB998155047 A CN B998155047A CN 99815504 A CN99815504 A CN 99815504A CN 1213033 C CN1213033 C CN 1213033C
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

本发明涉及化合物二[(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基](3R，5S)-3，5-二羟基庚-6-烯酸]钙盐的晶体，其制备方法和含有该晶体的药物组合物，该晶体可用作药物活性剂来治疗高脂血、高胆固醇血和动脉粥样硬。

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二[(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基] 嘧啶-5-基](3R，5S)-3，5-二羟基庚-6-烯酸]钙盐晶体
本发明涉及新的化合物晶体，特别是二[(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基](3R，5S)-3，5-二羟基庚-6-烯酸]钙盐(该化合物在下文中称为“该活性剂”，并且其结构如式I所示)的新晶形，该化合物是酶-3-羟基-3-甲基戊二酸单酰辅酶A还原酶(HMG CoA还原酶)的抑制剂，并且可用作药物活性剂来治疗例如高脂血、高胆固醇血和动脉粥样硬化，以及涉及HMG CoA还原酶的其它疾病或病症。本发明还涉及制备该晶形的方法、包含该晶形的药物组合物、以及该晶形在医疗中的应用。
第521471号欧洲专利申请出版物(下文中称为EPA 521471，该文献引入本发明以作参考)公开了该活性剂的非晶体(粉末)形式，其是通过将相应的钠盐溶于水中，加入氯化钙，并经过滤收集所形成的沉淀而制得的。
打算药用的非晶形化合物可能会带来生产方面的问题，因此需要鉴定出具有下述特征的此化合物的晶体形式：该晶体形式具有与非晶体形式不同的物理特征，在该化合物的生产和配制过程中有助于达到药品管理机构所要求的纯度水平和均匀性。此化合物的晶体形式还可能具有改进的药理学特征，例如改善的生物利用度。
我们现在已经惊奇并且出乎意料地发现，该活性剂可以以晶体形式制得。
本发明提供了该活性剂及其水合物的晶体形式，该晶体形式的X-射线粉末衍射图案在下述2θ角有特异峰：4.92、11.50、6.93、9.35、23.12和18.76°(在下文中称为晶形A)。
X-射线粉末衍射光谱是如下测定的：将该晶形样本固定在Siemans单晶硅(SSC)片封固器上，借助于显微镜载物片将样本铺开以形成薄层。将样本以30转/分钟的速度旋转(以改善计数统计学)，并用X-射线照射，该X-射线是由在40kV和40mA运转的铜长细聚焦管产生的，并且波长为1.5406埃。使校准的X-射线源通过设定为V20(20mm通路长度)的自动可变发散狭缝，并使反射的照射通过2mm抗散射狭缝和0.2mm检测器狭缝。在2-40°的2-θ角范围内，以θ-θ方式，以4秒/0.02°2-θ增加的速度照射样本(连续扫描方式)。运行时间为2小时6分40秒。该装置安装着闪烁计数器作为检测器。通过用Diffrac AT(Socabim)软件运行的DECpc LPv 433sx个人电脑捕获对照和数据。
晶形A典型样本的X-射线粉末衍射光谱如附图1所示。应当理解，从一台机器到另一台机器，或者从一个晶形A样本到另一个晶形A样本，X-射线粉末衍射图案的2-θ值可能会有轻微改变，因此所引用的2-θ值不是绝对的。
晶形A一般是以水合形式，例如水分含量约为7％w/w的水合形式获得的。
另一方面，本发明提供了制备晶形A的方法，其中是在该活性剂、水和一种或多种有机溶剂的混合物中结晶出晶形A。为了获得晶形A，该混合物中有机溶剂与水的最佳比例取决于所用有机溶剂的特征和所采用的操作条件。精确的条件可凭经验确定。例如，晶形A可这样获得：将非晶体形式的该活性剂悬浮在含有共溶剂例如乙腈、丙酮或甲醇与甲基叔丁基醚(MTBE)的混合物的水中，将该混合物温热以获得完全溶液，然后将该溶液冷却，之后分离出晶形A，例如通过过滤分离出晶形A。水与共溶剂的合适混合物包括例如1∶1水/乙腈、1∶1水/丙酮和1∶1∶1水/甲醇/MTBE，其中所述比例是体积比。用作制备晶形A的原料是该活性剂的非晶体形式，它可通过例如在EPA 521471中描述的方法制得。
本发明化合物的实用性可通过标准测试和临床实验、包括在EPA521471中描述的那些来证实。
依据本发明的另一特征，本发明提供了治疗其中可受益于抑制HMG CoA还原酶的病症的方法，包括给温血哺乳动物施用有效量的该活性剂。本发明还涉及晶形A在制备用于治疗病症的药物中的应用。
可将本发明化合物以常规药物组合物的形式施用给需要治疗涉及HMG CoA还原酶的疾病的温血动物、特别是人。因此，另一方面，本发明提供了含有晶形A和可药用载体的药物组合物。
对于希望治疗的病症，可以以标准方式施用本发明组合物，例如通过口服、局部、非胃肠道、颊、鼻、阴道或直肠给药或通过吸入来施用。为了以这些方式给药，可通过本领域已知方法将该活性剂配制成剂型，例如片剂、胶囊、水或油溶液、悬浮剂、乳剂、霜剂、软膏剂、凝胶剂、鼻用喷雾剂、栓剂、细分散粉剂或吸入用气雾剂，和非胃肠道给药用(包括静脉内注射、肌内注射或输注)的无菌水或油溶液或悬浮剂或无菌乳剂。优选的给药途径是口服。该活性剂可以以日剂量，例如在EPA 521471中提出的日剂量施用给人。可按照需要将日剂量分成均分剂量施用，并且根据本领域已知原则，该活性剂的精确给药剂量和给药途径取决于所治疗患者的体重、年龄和性别，以及所治疗的特定病症。
依据本发明另一特征，本发明提供了制备含有晶形A作为活性组分的药物组合物的方法，包括将晶形A与可药用载体混合在一起。
通过下述非限制性实施例举例说明本发明。
实施例1
在15℃，将非晶体形式的该活性剂(465mg)加到水(5ml)与乙腈(5ml)的混合物中。将该混合物温热至40℃以获得完全溶液。将该混合物缓慢地冷却至室温，并搅拌16小时。通过在室温过滤分离出结晶产物，并在50℃真空干燥，获得了晶形A(337mg)，为白色晶体。
X-射线粉末衍射(XRD)：
峰号    2θ              d-间距    计数/秒    相对的强度(＞20％)
1       4.92     17.945    820.25         100
2       11.50    7.686     258.75         31.55
3       6.93     12.750    230.25         28.07
4       9.35     9.455     213.75         26.06
5       23.12    3.843     212.75         25.94
6       18.76    4.726     177.5          21.64
水分含量：7.1％w/w
1H NMR(d6-DMSO)δ：7.7(2H，t)，7.3(2H，t)，6.5(1H，d)，5.5(1H，dd)，4.2(1H，m)，3.8(1H，m)，3.5(3H，s)，1.9-2.1(2H，dd)，1.3-1.5(2H，m)，1.2(6H，d)
质谱：MH+482.3
式I

Claims (7)

1.式I所示二[(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲基磺酰基)氨基]嘧啶-5-基](3R，5S)-3，5-二羟基庚-6-烯酸]钙盐化合物的结晶水合物形式的晶体
其中所述晶体在下述2θ角有特异峰：4.92、11.50、6.93、9.35、23.12和18.76°。
2.含有权利要求1的结晶水合物形式的晶体和可药用载体的药物组合物。
3.制备权利要求1的结晶水合物形式的晶体的方法，包括从式I化合物和(i)体积比为1∶1的水和乙腈；(ii)体积比为1∶1的水和丙酮；或(iii)体积比为1∶1∶1的水、甲醇和甲基叔丁基醚的混合物中形成晶体。
4.制备权利要求2的药物组合物的方法，包括将权利要求1的结晶水合物形式的晶体与可药用载体混合在一起。
5.用作药物的权利要求1的结晶水合物形式的晶体。
6.权利要求1的结晶水合物形式的晶体在制备药物中的用途。
7.权利要求6的用途，其中所述药物用于治疗高胆固醇血症、高血脂症或动脉硬化。
CNB998155047A 1999-01-09 1999-12-23 二[(e)－7－[4－(4－氟苯基)－6－异丙基－2－[甲基(甲基磺酰基)氨基]嘧啶－5－基](3r,5s)－3,5－二羟基庚－6－烯酸]钙盐晶体 Expired - Lifetime CN1213033C (zh)

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