CN102675299A - 结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物 - Google Patents

结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物 Download PDF

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CN102675299A
CN102675299A CN2012100910385A CN201210091038A CN102675299A CN 102675299 A CN102675299 A CN 102675299A CN 2012100910385 A CN2012100910385 A CN 2012100910385A CN 201210091038 A CN201210091038 A CN 201210091038A CN 102675299 A CN102675299 A CN 102675299A
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野村纯弘
川西英治
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Abstract

本发明涉及结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物。一种新颖的结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物，并具有有利的特性，特征在于其X-射线粉末衍射图谱和/或其红外线图谱。

Description

结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物
本申请是2009年5月21日进入中国的申请号为200780043154.7(PCT/JP2007/073729，国际申请日2007年12月3日)的专利申请“结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物”的分案申请。 
技术领域
本发明涉及可用做钠依赖性葡萄糖转运体(sodium-dependent glucose transporter)抑制剂的结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物、其制备与分离的方法、包含该化合物及医药上可接受的载体的医药组合物、以及治疗的医药方法。 
背景技术
专利WO2005/012326小册子公开为钠依赖性葡萄糖转运体(SGLT)抑制剂的化合物群，及这些化合物对于处理糖尿病、肥胖、糖尿病并发症等的治疗用途。描述于专利WO2005/012326小册子的式(Ⅰ)的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯： 
Figure BDA0000148758110000011
一般而言，为了商业用途，重要的是产物应具备良好的操作性质。另外，亦需要制造纯质与结晶型的该产物，使配方可符合严格的医药上的要求与规格。 
且理想的是该产物应为可易于过滤与容易干燥的型式。另外，经济上理想的是无须特殊保存条件即可在一段延长的时间内为稳定的产物。 
但要从有机溶剂获得式(Ⅰ)化合物的结晶型存在困难。
现已发现可以商业规模可重现的方法产生结晶型式(Ⅰ)化合物的半水合物。 
发明内容
本发明提供式(Ⅰ)化合物的半水合物结晶型做为新颖的材料，特别是以医药上可接受的型式。 
附图说明
图1为式(Ⅰ)化合物的半水合物的结晶的X-射线粉末衍射图谱。 
图2为式(Ⅰ)化合物的半水合物的结晶的红外线图谱。 
具体实施方式
本发明的发明人已发现可从含水的溶剂中结晶出式(Ⅰ)化合物，且该式(Ⅰ)化合物的半水合物的结晶型具备良好的操作性质与特性。 
据此，本发明涉及： 
1.一种结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物。 
2.一种结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯 基)-2-噻吩基甲基]苯半水合物，特征在于粉末X-射线衍射图谱(powder x-ray diffraction pattern)，该图谱包括使用CuKα放射测量的下述2θ值：4.36±0.2、13.54±0.2、16.00±0.2、19.32±0.2及20.80±0.2。 
3.一种结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物，其具有与图1所示实质上相同的X-射线粉末衍射图谱。 
4.一种结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物，其具有与图2所示实质上相同的IR图谱(infra-red spectrum)。 
5.一种用以制备结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物的方法，其包括形成1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的溶液，并利用沉淀或再结晶从该溶液结晶该半水合物。 
6.一种医药组合物，包括有效量的结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物及医药上可接受的载体。 
7.一种用于治疗或延缓糖尿病、糖尿病视网膜病变、糖尿病神经病变、糖尿病肾病变、延迟性伤口愈合、胰岛素阻抗性、高血糖症、高胰岛素血症、脂肪酸的血中浓度升高、甘油的血中浓度升高、高血脂症、肥胖、高甘油三酯血症、X症候群(syndrome X)、糖尿病并发症、动脉粥状硬化症或高血压的进展或发病的方法，其包括投药治疗有效量的结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物。 
如所述，本发明包含某些固态结晶型。存在用于表征该型式的多种方法，且本发明不应被所选择的方法、或用来特征化本发明化合物的设备而限制。例如，以X-射线衍射图谱而言， 在实验图谱中，该衍射波峰强度可有所变化，如已知于本技术领域，主要起因于所制备样品的优选定向(该结晶的非任意定向)。因此，熟悉本领域技术的人员可了解，本发明的范畴必须考量到特征的变化度。 
X-射线粉末衍射图谱 
本发明(Ⅰ)的结晶型可通过其X-射线粉末衍射图谱来表征。该化合物(Ⅰ)的半水合物的结晶型的X-射线衍射图谱是以X-射线衍射仪(RINT-TTR，Rigaku，Tokyo，Japan)，使用CuKα放射来测量。X-射线粉末衍射的方法如下： 
扫瞄速度：2.00度/分钟。 
目标：CuKα。 
电压：50仟伏特(kV)。 
电流：300毫安培(mA)。 
扫瞄范围：自3至40.0度。 
取样宽度：0.0200度。 
红外线图谱 
本发明的结晶型在矿物油中的红外线图谱包括下列主要波峰：1626、1600、1549、与1507cm-1。 
结晶型化合物(Ⅰ)的半水合物的红外线图谱，是伴随以纵轴为透射率(％)且横轴为波数(cm-1)的图式而显示。 
热重量分析(thermogravimetric analysis) 
已观察到本发明的结晶型会以半水合物型式而存在。本发明的结晶的理论水含量为1.98％。对于本发明的结晶型的热重量分析显示1.705％的重量损失。 
热重量分析的方法如下：秤重约8毫克的化合物(Ⅰ)的半水合物，并移至TG-50(Shimadzu，Japan)的铝制槽架(cell holder)，接着，以5℃/分钟的加热速率测得结晶型化合物(Ⅰ)半水合物的 热重量(TG)热曲线。典型的测量范围是自环境温度至150℃。 
本发明亦提供化合物(Ⅰ)的半水合物的结晶型的制备方法，其是包括形成化合物(Ⅰ)的溶液并从该溶液沉淀出结晶型。 
典型地，可自以下的混合物获得化合物(Ⅰ)的半水合物的结晶型：式(Ⅰ)的化合物、良溶剂及水、任选含有的不良溶剂。 
有时候，某些杂质会作用为结晶抑制剂，且杂质需以常规方法移除，如硅胶柱层析。然而，该式(Ⅰ)化合物的半水合物的结晶型甚至可自相对不纯的化合物(Ⅰ)获得。 
本发明亦提供包括化合物(Ⅰ)的半水合物的结晶型及医药上可接受的载体的医药组合物。 
本发明的结晶型化合物具有作为钠依赖性葡萄糖转运体抑制剂的活性，并显示极佳的降血糖效果。 
本发明的结晶型预期在以下方面有用：治疗、预防或延缓糖尿病(1型与2型糖尿病等)、糖尿病并发症(如糖尿病视网膜病变、糖尿病神经病变、糖尿病肾病变)、餐后高血糖症、延迟性伤口愈合、胰岛素阻抗性、高血糖症、高胰岛素血症、脂肪酸的血中浓度升高、甘油的血中浓度升高、高血脂症、肥胖、高甘油三酯血症、X症候群、动脉粥状硬化症或高血压的进展或发病。 
本发明的结晶型或其医药上可接受的盐类可以口服或非肠道投药，并可以适当的医药制剂型式而使用。对于口服投药的适当医药制剂包含，例如，固态制剂如片剂、粒剂、胶囊、及粉末，或液态制剂、悬浮制剂、乳化制剂等。对于非肠道投药的适当医药制剂包含，例如，栓剂；注射制剂或静脉点滴制剂，利用注射用蒸馏水、生理食盐水溶液或葡萄糖水溶液；及吸入制剂。 
此处的医药组合物将于每剂量单位，即片剂、胶囊、粉末、 注射剂、栓剂、一茶匙量(teaspoonful)等，包含活性成分自约0.01毫克/千克至约100毫克/千克体重(优选自约0.01毫克/千克至约50毫克/千克；且更优选自约0.01毫克/千克至约30毫克/千克)，且可给予剂量自约0.01毫克/千克/天至约100毫克/千克/天(优选自约0.01毫克/千克/天至约50毫克/千克/天，且更优选自约0.01毫克/千克/天至约30毫克/千克/天)。治疗描述于本发明的病症的方法也可使用包括如此处定义的结晶型及医药上可接受的载体的医药组合物而实施。该剂量型将包含活性成分自约0.01毫克/千克至约100毫克/千克(优选自约0.01毫克/千克至约50毫克/千克，且更优选自约0.01毫克/千克至约30毫克/千克)，并可构成适合所选择的投药模式的任何型式。然而，该剂量可依投药途径、个体的需求、欲治疗症状的严重度、及所使用的化合物而不同。可采用于每日投药或后周期性用药(po st-periodic dosing)的用法。 
若需要时，本发明结晶型可与一种或多种的其他抗糖尿病剂、抗高血糖剂、和/或其他疾病治疗剂组合使用。本发明化合物与该其他治疗剂可以相同剂型、或分开的口服剂型或注射投药。 
该治疗剂的剂量可依，例如，年龄、体重、病患症状、投药途径、与剂量型式而不同。 
该医药组合物可以口服投药至哺乳类，包含人类、猿、狗，以例如片剂、胶囊、粒剂、或粉末，或非肠道投药的注射剂型、或鼻内投药、或皮肤贴剂型的剂量型式。 
可自以下的混合物制备该式(I)化合物的半水合物的结晶型：该化合物(I)、良溶剂与水、任选含有的不良溶剂。 
已发现为适当的良溶剂的实例包含酮类(如丙酮、2-丁酮)、酯类(如乙酸乙酯、乙酸甲酯)、醇类(如甲醇、乙醇、异丙醇)， 与该溶剂的混合物。不良溶剂的实例包含烷类(如己烷、庚烷)、芳族烃类(如苯、甲苯)、醚类(如乙醚、二甲基醚、二异丙基醚)与这些溶剂的混合物。 
该式(I)化合物的半水合物的结晶型的一个优选制剂，典型地，包括使依据专利WO2005/012326小册子所描述的方法所制备的式(I)的粗产物或非晶形化合物溶解于良溶剂中(如酮类或酯类)，并加入水及不良溶剂(如烷类或醚类)至该所得溶液，接着过滤。 
在可溶于水的良溶剂的情况中，无须使用不良溶剂，且可将水加入该式(I)化合物于良溶剂中的溶液，依此，可降低该式(I)化合物在该溶液中的溶解性。 
在使用不良溶剂的情况中，水的优选用量是对该式(I)化合物为1至10摩尔当量(molar equivalent)，良溶剂的优选用量是水的体积的10至100倍，且该不良溶剂的优选用量是该良溶剂的体积的0.1至10倍。 
形成该式(I)化合物的半水合物的结晶型的精确条件可依经验而决定。 
在该条件下，优选可在降低的、常温的、或升高的温度下进行结晶作用。 
该式(I)化合物的半水合物的结晶型明显较非晶型化合物容易分离，且可在冷却后从该结晶作用的基质过滤、并洗涤和干燥。此外，本发明的结晶型较式(I)化合物的非晶型更为稳定。 
实施例
实施例1：结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物
依描述于WO 2005/012326中的相似方法制备1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯。 
Figure BDA0000148758110000081
在氩气气氛中、于-67至-70℃，将正-丁基锂(1.6M己烷溶液，50.0毫升)滴入5-溴-1-[5-(4-氟苯基)-2-噻吩基甲基]-2-甲基苯(1，28.9克)于四氢呋喃(480毫升)与甲苯(480毫升)的溶液中，且将该混合物于相同温度搅拌20分钟。将2(34.0克)于甲苯(240毫升)的溶液于相同温度滴入，且将混合物于相同温度进一步搅拌1小时。接着，将甲基磺酸(21.0克)于甲醇(480毫升)的溶液滴入，并将所得混合物回温至室温并搅拌17小时。混合物于冰-水冷却中放凉，并加入饱和碳酸氢钠水溶液。混合物以乙酸乙酯萃取，并以浓盐水洗涤合并的有机层并以硫酸镁干燥。滤除不溶物并减压挥发溶剂。残余物以甲苯(100毫升)-己烷(400毫升)磨碎，获得1-(1-甲氧基吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯(3)(31.6克)。APCI-Mass m/z 492(M+NH4)。 
(2)在氩气气氛中，利用干冰-丙酮浴冷却3(63.1克)与三乙基硅烷(46.4克)在二氯甲烷(660毫升)中的溶液，并向其中滴入三氟化硼·乙醚的复合物(50.0毫升)，且于相同温度搅拌混合物。将混合物回温至0℃并搅拌2小时。于相同温度下，加入饱和碳酸氢钠水溶液(800毫升)，并搅拌混合物30分钟。减压挥发有机溶剂，并将残余物注入水中并以乙酸乙酯萃取两次。有机层以 水洗涤两次，以硫酸镁干燥并以活性碳处理。滤除不溶物并减压挥发溶剂。残余物溶解于乙酸乙酯(300毫升)中，并加入二乙醚(600毫升)与H2O(6毫升)。混合物于室温搅拌过夜，并收集沉淀物，以乙酸乙酯-二乙醚(1∶4)洗涤，并于室温减压干燥以获得1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物(33.5克)的无色结晶。mp 98-100℃。APCI-Mass m/z 462(M+NH4)。 
1H-NMR(DMSO-d6)δ2.26(3H，s)，3.13-3.28(4H，m)，3.44(1H，m)，3.69(1H，m)，3.96(1H，d，J＝9.3Hz)，4.10，4.15(each 1H，d，J＝16.0Hz)，4.43(1H，t，J＝5.8Hz)，4.72(1H，d，J＝5.6Hz)，4.92(2H，d，J＝4.8Hz)，6.80(1H，d，J＝3.5Hz)，7.11-7.15(2H，m)，7.18-7.25(3H，m)，7.28(1H，d，J＝3.5Hz)，7.59(2H，dd，J＝8.8，5.4Hz).Anal.Calcd.for C24H25FO5S·0.5H2O：C，63.56；H，5.78；F，4.19；S，7.07.Found：C，63.52；H，5.72；F，4.08；S，7.00. 
实施例2
1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的非晶型粉末(1.62克)溶于丙酮(15毫升)中，并于其中加入H2O(30毫升)及晶种。混合物于室温搅拌18小时，并收集沉淀物，以丙酮-H2O(1∶4，30毫升)洗涤，并在室温减压干燥以获得1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物(1.52克)的无色结晶。mp 97-100℃。 

Claims (6)

1.一种结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物，其具有与图1所示实质上相同的X-射线衍射图谱。
2.根据权利要求1所述的结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物，其中所述结晶型在矿物油中的IR图谱包括下列主要波峰：1626、1600、1549、与1507cm-1。
3.根据权利要求1所述的结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物，其具有与图2所示实质上相同的IR图谱。
4.一种用以制备根据权利要求1、2或3所述的结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物的方法，其包括形成1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的溶液，并利用沉淀或再结晶将该半水合物从该溶液结晶。
5.一种医药组合物，其包括有效量的根据权利要求1、2或3所述的结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物及医药上可接受的载体。
6.根据权利要求1、2或3所述的结晶型1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物用于制备以下药物的用途，所述药物用于治疗或延缓糖尿病、糖尿病视网膜病变、糖尿病神经病变、糖尿病肾病变、延迟性伤口愈合、胰岛素阻抗性、高血糖症、高胰岛素血症、脂肪酸的血中浓度升高、甘油的血中浓度升高、高血脂症、肥胖、高甘油三酯血症、X症候群、糖尿病并发症、动脉粥状硬化症或高血压的进展或发病。
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