CN1202123C - 晶体形式的1S-[1α(2S<sup>*</sup>,3R<sup>*</sup>),9α]-6,10-二氧代-N-(2-乙氧基-5-氧代-四氢-3-呋喃基)-9-[[1-异喹啉基]羰基]氨基]八氢-6H-哒嗪并[1,2-A][1,2]二氮杂䓬-1-甲酰基 - Google Patents
晶体形式的1S-[1α(2S<sup>*</sup>,3R<sup>*</sup>),9α]-6,10-二氧代-N-(2-乙氧基-5-氧代-四氢-3-呋喃基)-9-[[1-异喹啉基]羰基]氨基]八氢-6H-哒嗪并[1,2-A][1,2]二氮杂䓬-1-甲酰基 Download PDFInfo
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Abstract
本发明涉及新的晶体形式的1S-[1α(2S<sup>*</sup>,3R<sup>*</sup>),9α]-6,10-二氧代-N-(2-乙氧基-5-氧代-四氢-3-呋喃基)-9-[[(1-异喹啉基)羰基]氨基]八氢-6H-哒嗪并[1,2-a][1,2]二氮杂䓬-1-甲酰胺,无水的(A型)和水合的(B型),它们的制备方法,作为药物的应用和含有它们的药物组合物。
Description
本发明的对象是两种新的晶体形式的1S-[1α(2S*,3R*),9α]-6,10-二氧代-N-(2-乙氧基-5-氧代-四氢-3-呋喃基)-9-[[(1-异喹啉基)羰基]氨基]八氢-6H-哒嗪并[1,2-a][1,2]二氮杂-1-甲酰胺(无水的或水合的),它们的制备方法和含有它们的药物组合物。
专利申请WO 9722619描述了作为白细胞介素-1β转化酶的抑制剂的1S-[1α(2S*,3R*),9α]-6,10-二氧代-N-(2-乙氧基-5-氧代-四氢-3-呋喃基)-9-[[(1-异喹啉基)羰基]氨基]八氢-6H-哒嗪并[1,2-a][1,2]二氮杂-1-甲酰胺及其可药用的盐(产物412f:化合物I):
该申请(WO 9722619)中提到和制备的化合物(I)是无定形的。它的主要缺点是吸湿性。
化合物(I)是以下述方式制备的:(1S,9S)9-(异喹啉-1-酰氨基)-6,10-二氧代-1,2,3,4,7,8,9,10-八氢-6H-哒嗪并-[1,2-a][1,2]-二氮杂-1-羧酸和(3S,2S)3-烯丙氧基羰基氨基-2-苄氧基-5-氧代四氢呋喃在二甲基巴比妥酸、四(三苯膦)合钯、1-羟基苯并三唑及1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐存在下,于二氯甲烷、二甲基甲酰胺或这两种溶剂的混合物中进行酰胺化反应。产物用层析法(乙酸乙酯/二氯甲烷)纯化,以得到无定形化合物(I)。
本发明的目的是找到一种或多种没有无定形化合物的缺点的新的晶体形式。
固体形式,特别是药物产物,可以具有一种以上的晶型,这称作同质多晶现象。
相同分子的多晶型形式,一般会显示不同的物理性质,例如溶解度、吸湿性和稳定性。应该指出,目前还不存在使某种多晶型物得以形成的方法,也无法预测它们的物理性质。
获得具有治疗活性的分子的新的多晶型对于药物工业有很大意义,尤其是从它们的工业规模制备、它们在药物组合物中的应用、寻求更好的稳定性和更好的生物利用度来看。(Byrn,S.R.,
药物的固 态化学(Solid-State Chemistry of Drugs),New York,Academ.Press(1982);Kuhnert-Brandstatter,M,
药物分析中的热显微 术(Thermomicroscopy in the Analysis of pharmaceuticals),New York,Pergamon Press(1971);J.Halebian等,
药物科学杂 志(J.Pharm.Science)(1969)58(8),911;J.Halebian等,药物科学杂志(J.Pharm.Science)(1975)
64(8),1269-1288)。
多晶型意味着一种结晶分子的所有的非溶剂化形式,而假多晶型是指所有的溶剂化形式。
分析晶型的方法如下:
热行为:用DSC(示差扫描量热法)测定。将2-5mg待测物质称量到一只透气密封的铝质小皿中。进行分析时用氮气吹洗,以20℃/分的升湿速度由25℃升至350℃。
IR(红外),待测物质分散在液体石蜡油中。在傅里叶变换红外(FTIR)分光光度计上从4000到600cm-1进行分析。
XR(粉末X射线衍射):待测物质分布在玻璃样品座的间格里。进行分析时由2°至38°(2θ)扫描,每步0.02°,计数1秒钟。X射线源为铜靶管(45KV,30mA)。
申请人揭示了两种新的晶体形式(A型和B型)。A型是无水的,B型是水合的。晶型A除了上述优点之外,还没有吸湿性(见以下的试验)。
因此,本发明的对象首先是一种新的晶体形式的无水1S-[1α(2S*,3R*),9α]-6,10-二氧代-N-(2-乙氧基-5-氧代-四氢-3-呋喃基)-9-[[(1-异喹啉基)羰基]氨基]八氢-6H-哒嗪并[1,2-a][1,2]二氮杂-1-甲酰胺,它被称为A型。这种A型具有以下特点:
晶系:三斜晶系
a():8.02;b():9.21;c()17.70;α(度):91.38;β(度):93.62;γ(度):90.43;空间群P1;Z2。
本发明的另一对象是一种新的晶体形式的水合1S-[1α(2S*,3R*),9α]-6,10-二氧代-N-(2-乙氧基-5-氧代-四氢-3-呋喃基)-9-[[(1-异喹啉基)羰基]氨基]八氢-6H-哒嗪并[1,2-a][1,2]二氮杂-1-甲酰胺,它被称作B型。
A型有以下特征:
按下述方法之一制备的式(I)的无水化合物具有特定的晶型(A型)。在图1A(DSC)、2A(IR)和3A(XR)中描述了其物理特征。
DSC:吸热的熔融峰,自168℃开始。
IR(Nujol,cm -1 ):3253;1789;1702;1681;1644
XR(d,):17.73;8.87;8.11;7.50;7.17;6.31;6.09;5.81
B型有以下特征:
按下述方法之一制备的式(I)的水合化合物具有特定的晶型(B型)。在图1B(DSC)、2B(IR)和3B(XR)中描述了其物理特征。
DSC:50-110℃和110-130℃的吸热脱水峰。观察到由162℃开始的吸热熔融峰。
IR(Nujol,cm -1 ):3569;3447;3322;1778;1682;1660
XR(d,):11.34;10.80;10.06;7.59;7.16;6.71;6.41;6.11;5.44。
因此,本发明的一个对象是如上定义的A型化合物,它具有至少一个以下特征,优选具有所有以下特征:
a)自168℃开始的吸热熔融峰,
b)红外光谱在大约以下位置具有特征吸收峰(Nujol,cm-1):3253;1789;1702;1681;1644,
c)XR衍射图的特征点阵间距(d,)等于:17.73;8.87;8.11;7.50;7.17;6.31;6.09;5.81。
本发明的更具体的对象是如上定义的A型化合物,它具有基本上与图2A相同的红外光谱和基本上与图3A相同的X射线衍射图。
本发明的另一对象是如上定义的B型化合物,它具有至少一个以下特征,优选具有所有以下特征:
a)50-110℃和110-130℃的吸热脱水峰,和自162℃开始的吸热熔融峰,
b)红外光谱在大约以下位置具有特征吸收峰(Nujol,cm-1):3569;3447;3322;1778;1682;1660,
c)XR衍射图的特征点阵间距(d,)等于:11.34;10.80;10.06;7.59;7.16;6.71;6.41;6.11;5.44。
本发明的另一个更具体的对象是如上定义的B型化合物,它具有与图2B基本相同的红外光谱和与图3B基本相同的XR衍射图。
本发明的对象还包括一种制备A型或B型晶体的方法,其特征在于,将按照上述方法得到的无定形化合物(I)溶于有机溶剂或其混合物中,尤其是在室温下溶解,结晶后得到预期的A型或B型晶体。
A型晶体优选由醇或醚,特别是由异丙醚、丁醇或异丙醇中结晶得到。
A型晶体也可由这些溶剂的混合物,特别是由乙醇/异丙醚混合物中结晶得到。
B型晶体是相当特殊地由甲苯中结晶得到。
如果合适,可以通过向溶液中分别放入少量A型或B型种晶以引发得到预期的A型或B型晶体。
A型或B型晶体的分离是按照本领域技术人员已知的方法进行的。
式(I)化合物的A型或B型晶型与在世界专利申请WO 97/22169和WO 95/35308中所述的无定形的化合物(I)具有相同的治疗活性。
它们具有对ICE(白细胞介素-1β转化酶)的抑制活性,在治疗炎性、自身免疫和神经变性疾病方面特别有用。
因此,本发明的一个对象是作为药物的上述A型或B型晶体。
晶型A或B的式(I)化合物可以通过口服、非肠道、局部施用、吸入或植入等方式使用。它们可以以按照常用方法制备的普通或糖衣药片、明胶胶囊、粒剂、栓剂、阴道药栓、注射制剂、膏剂、霜剂、凝胶、微球、植入剂、贴剂等形式使用。
A或B型的晶态式(I)化合物可以与用于制备药物组合物的赋形剂、稀释剂和本领域技术人员了解的所有载体混合。作为常用于这些药物组合物中的赋形剂实例,可以提到以下物质:滑石,阿拉伯树胶、乳糖,淀粉,硬脂酸镁,可可脂,水基或非水载液,动物或植物来源的脂肪类物质,石蜡衍生物,二醇类,各种润湿剂、分散剂或乳化剂,防腐剂。
因此,本发明扩展到药物组合物,其中含有作为活性组分的至少一种如上定义的A型或B型式(I)化合物和一种或多种可药用的赋形剂、稀释剂或载体。
本发明的又一对象是如上定义的A或B型晶态式(I)化合物在制备用于抑制ICE(白细胞介素-1β转化酶)活性的药物中的应用。
以下实施例示例说明了本发明而并非是对它的限制。
实施例1:利用自正丁醇中结晶得到A型晶体。
将1.5ml正丁醇加到300mg无定形化合物I(按照专利申请WO9722619中所述方法得到)中,在环境温度下将反应介质搅拌2小时15分。观察到产物结晶,将该产物分离并在20℃和4毫巴下干燥。得到160mg无水的式(I)化合物(A型)。
实施例2:利用自异丙醇中结晶得到A型晶体。
将1.5ml异丙醇加到300mg无定形化合物I(按照专利申请WO9722619中所述方法得到)中,将反应介质在环境温度下搅拌16小时,观察到产物结晶,分离出该产物并在20℃和4毫巴下干燥。得到166mg无水的式(I)化合物(A型)。
实施例3:利用自甲苯中结晶得到B型晶体。
将1.5ml甲苯加到300mg无定形化合物I(按照专利申请WO9722619中所述的方法得到)中,将反应介质在环境温度下搅拌16小时。观察到产物结晶,分离出该产物并在20℃和4毫巴下干燥。得到水合的式(I)化合物(B型)。
实施例4:利用自异丙醚/乙醇混合物中结晶得到A型晶体。
在氮气和搅拌下将23.8ml无水乙醇加到11.9g无定形化合物(I)中,将该悬浮液加热至60±2℃以得到溶液。将该溶液冷却到40±2℃,此时开始结晶并使溶液保持此温度1小时。然后在40±2℃下于15分钟内加入119ml异丙醚并使反应介质保持此温度15分钟,随后于15分钟内冷却到20±2℃,在这些条件下保持1小时,然后在15分钟内再冷却到0~+5℃,保持2小时。分离出反应介质,用异丙醚洗,在20℃下减压干燥12小时,得到11.3g无水的式(I)化合物(A型)。
吸湿性曲线(或水吸收等温线)
吸水等温线是用DVS 1型动态蒸汽吸收装置(SurfaceMeasurement System Ltd)在恒温和或多或少含水的氮气氛下得到的。气氛的相对湿度(RH)分步调节。当待分析的样品的重量已达到恒值时由某一步进行到下一步。
相对湿度(%) | 无定型 | 无水的A型 | 水合的B型 | |||
吸收 | 解吸 | 吸收 | 解吸 | 吸收 | 解吸 | |
0.012.021.032.043.051.057.066.075.080.090.096.0 | 0.000.670.971.291.601.832.032.372.903.715.115.93 | -0.201.482.092.582.943.193.353.613.904.124.945.93 | 0.000.030.050.070.090.110.130.140.140.160.140.06 | 0.110.120.140.190.210.220.210.210.210.210.190.06 | 0.001.412.363.233.884.264.534.925.275.455.936.86 | -0.111.422.333.143.754.134.404.755.085.305.966.86 |
在吸收循环期间A型不吸水(<0.2%)。将样品在相对湿度96%(温度32℃)的隔室内放置7天,证实了这种不吸湿性。观察到水吸收率约为0.15%。水合型(B型)在同样条件下具较高的吸湿性(7%水)。这与无定形的情形相同。
Claims (18)
1.A型晶体形式的无水的1S-[1α(2S*,3R*),9α]-6,10-二氧代-N-(2-乙氧基-5-氧代-四氢-3-呋喃基)-9-[[(1-异喹啉基)羰基]氨基]八氢-6H-哒嗪并[1,2-a][1,2]二氮杂-1-甲酰胺。
2.根据权利要求1的A型晶体形式的无水1S-[1α(2S*,3R*),9α]-6,10-二氧代-N-(2-乙氧基-5-氧代-四氢-3-呋喃基)-9-[[(1-异喹啉基)羰基]氨基]八氢-6H-哒嗪并[1,2-a][1,2]二氮杂-1-甲酰胺,它具有以下特征:
a)自168℃开始的吸热熔融峰,
b)红外光谱在以下位置有以Nujol,cm-1表示的特征吸收:3253;1789;1702;1681;1644,
c)以d,表示的XR衍射图的特征点阵间距等于:17.73;8.87;8.11;7.50;7.17;6.31;6.09;5.81。
3.B型晶体形式的水合的1S-[1α(2S*,3R*),9α]-6,10-二氧代-N-(2-乙氧基-5-氧代-四氢-3-呋喃基)-9-[[(1-异喹啉基)羰基]氨基]八氢-6H-哒嗪并[1,2-a][1,2]二氮杂-1-甲酰胺。
4.根据权利要求3的B型晶体形式的水合1S-[1α(2S*,3R*),9α]-6,10-二氧代-N-(2-乙氧基-5-氧代-四氢-3-呋喃基)-9-[[(1-异喹啉基)羰基]氨基]八氢-6H-哒嗪并[1,2-a][1,2]二氮杂-1-甲酰胺,它具有以下特征:
a)在50至110℃之间和110至130℃之间吸热脱水和自162℃开始的吸热熔化,
b)红外光谱在以下位置有以Nujol,cm-1表示的特征吸收:3569;3447;3322;1778;1682;1660,
c)以d,表示的特征点阵间距如下的B型XR衍射图:11.34;10.80;10.06;7.59;7.16;6.71;6.41;6.11;5.44。
5.制备权利要求1或2定义的A型晶体的方法,其特征在于,将无定形的1S-[1α(2S*,3R*),9α]-6,10-二氧代-N-(2-乙氧基-5-氧代-四氢-3-呋喃基)-9-[[(1-异喹啉基)羰基]氨基]八氢-6H-哒嗪并[1,2-a][1,2]二氮杂-1-甲酰胺在合适的有机溶剂或其混合物中混合,结晶后得到预期的A型晶体。
6.权利要求5的方法,其中混合在环境温度下进行。
7.根据权利要求5的制备A型晶体的方法,其特征在于,溶剂是醚。
8.权利要求7的方法,其中醚是异丙醚。
9.根据权利要求5的制备A型晶体的方法,其特征在于,溶剂是醇。
10.权利要求9的方法,其中醇是正丁醇或异丙醇。
11.根据权利要求5的制备A型晶体的方法,其特征在于,在醇和醚的混合物中进行结晶。
12.权利要求11的方法,其特征在于在乙醇/异丙醚混合物中进行结晶。
13.制备权利要求3或4定义的B型晶体的方法,其特征在于,将无定形的1S-[1α(2S*,3R*),9α]-6,10-二氧代-N-(2-乙氧基-5-氧代-四氢-3-呋喃基)-9-[[(1-异喹啉基)羰基]氨基]八氢-6H-哒嗪并[1,2-a][1,2]二氮杂-1-甲酰胺在合适的有机溶剂或其混合物中混合,结晶后得到预期的B型晶体。
14.权利要求13的方法,其中混合在环境温度下进行。
15.根据权利要求13的制备B型晶体的方法,其特征在于,溶剂是甲苯。
16.权利要求1-4中任一项定义的A型或B型晶体在制备药物中的用途。
17.含有至少一种权利要求1-4中任一项定义的A型或B型晶体和一种或多种可药用的赋形剂、稀释剂或载体的药物组合物。
18.权利要求1-4中任一项中定义的晶体形式在制备用于抑制ICE活性的药物中的应用。
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FR9804367A FR2777279B1 (fr) | 1998-04-08 | 1998-04-08 | Nouvelles formes cristallines du 1s-[1alpha(2s*,3r*), 9 alpha] 6,10-dioxo-n-(2-ethoxy-5-oxo-tetrahydro-3-furanyl) -9[[(1-isoquinolyl)carbonyl]amino]octohydro-6h-pyridazino [1,2-a][1,2]diazepine-1-carboxamide |
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