CN117157283A - 鞘氨醇-1-磷酸酯受体激动剂的晶体形式 - Google Patents
鞘氨醇-1-磷酸酯受体激动剂的晶体形式 Download PDFInfo
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- CN117157283A CN117157283A CN202280026343.8A CN202280026343A CN117157283A CN 117157283 A CN117157283 A CN 117157283A CN 202280026343 A CN202280026343 A CN 202280026343A CN 117157283 A CN117157283 A CN 117157283A
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Abstract
本发明涉及一种鞘氨醇‑1‑磷酸酯受体激动剂的晶体形式,更具体地,涉及化学式1的1‑[1‑氯‑6‑(3‑氯‑1‑异丙基‑1H‑吲唑‑5‑基甲氧基)‑3,4‑二氢‑萘‑2‑基甲基]‑哌啶‑4‑甲酸或其药学上可接受的盐或溶剂化物的晶体形式。
Description
技术领域
本发明涉及一种鞘氨醇-1-磷酸酯受体激动剂的结晶形式。更具体地,本发明涉及一种下式1的1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或其药学上可接受的盐或溶剂化物的结晶形式:
[式1]
背景技术
鞘氨醇-1-磷酸酯(S1P)通过细胞内神经酰胺途径产生,其中神经酰胺为起始物质。神经酰胺通过两种途径产生,其中第一种途径为从头生物合成途径。神经酰胺还由细胞中的细胞膜成分鞘磷脂降解产生。各个组织中的S1P水平由两种生物合成鞘氨醇激酶(SphK)和两种生物可降解S1P磷酸酶(S1P溶解酶和溶血磷脂磷酸酶)控制。已知通过鞘氨醇激酶导致鞘氨醇磷酸化产生的S1P介导各种细胞应答,如细胞增殖、细胞骨架组织和迁移、粘附和紧密连接组装,以及形态发生。S1P以与血浆蛋白(包括白蛋白)组合的形式以高水平(100-1000nM)存在于血浆中,而它以低水平存在于组织中。
S1P与G蛋白偶联受体S1P受体结合,以显示出各种生物功能。作为S1P受体亚型,迄今已知S1P1至S1P5,分别命名为内皮分化基因(EDG)受体1、5、3、6和8。已知S1P受体参与多种生物功能,如白细胞再循环、神经细胞增殖、形态变化、迁移、内皮功能、血管调节和心血管发育。
同时,研究新药物的物理和化学性质是高效、成功地开发新药物的必要条件。具体地,通过研究药物的多晶型物和伪多晶型物的存在以及相应的多晶型物之间的物理和化学性质差异,可以从药学方面选择药物的优选晶型(Remington's Pharmaceutics,第75章,Preformulation);(Byrn,S.R.,Solid State Chemistry of Drugs,Academic Press,NewYork,1982)。当多晶型物存在于溶液中时,它们在化学上是相同的,但在固体状态下,它们分别具有迥然不同的X射线衍射图,并表现出各种物理和化学性质的差异。具体地,相应的多晶型物可能因溶解速率不同而在生物利用率方面存在差异,并且在热力学稳定性方面表现出意想不到的特性。
当某种药物以多晶型物形式存在时,在制备该药物的过程中,取决于重结晶条件,如重结晶溶剂、药物浓度、加热和冷却速率、温度、搅拌速率等,可以获得具有不同结构的结晶形式。因此,为了获得相同的结晶形式,需要特别注意制造过程的管理。晶体结构的差异可以通过X射线衍射图来区分。由于水合物只在物理性质如结晶度、吸湿性、熔点、溶解度、溶解速率等方面有所改变,而在提供药理作用的化学性质方面没有任何变化,因此它们在药学方面具有非常重要的意义,如多晶型物(Morris,K.R.等,Int.J.Pharm.,108,1994,15-206)。
迄今为止,从与本发明所属的技术领域相关的各种参考文献中了解到的知识是在药物性能,包括药物稳定性、吸湿性等的改善方面没有普遍的趋势。最后,相应化合物的具有最佳药物性能的形式的确定必须通过不断的逐案研究来进行,无法预料并且属于实验范畴,只能通过反复实验来确认。
发明内容
技术问题
本发明旨在提供一种具有优异的药物性能的下式1的1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或其药学上可接受的盐或溶剂化物的结晶形式:
[式1]
技术方案
为了解决上述技术问题,本发明提供了一种1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或其药学上可接受的盐或溶剂化物的结晶形式。
此外,本发明提供了一种药物组合物,所述药物组合物包含作为活性成分的1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或其药学上可接受的盐或溶剂化物的结晶形式,以及药学上可接受的载体。
下文详细描述了本发明。
根据本发明的一个方面,提供了一种1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或其药学上可接受的盐或溶剂化物的结晶形式,所述结晶形式具有选自以下X射线衍射图谱的3个以上、5个以上、7个以上、9个以上、或10个以上特征峰(2θ):6.98±0.2°、11.10±0.2°、12.49±0.2°、13.47±0.2°、14.22±0.2°、15.22±0.2°、19.45±0.2°、19.82±0.2°、20.29±0.2°、20.90±0.2°、22.53±0.2°、24.89±0.2°、25.39±0.2°、25.83±0.2°和26.88±0.2°。在下文中,上述结晶形式称为“结晶形式B”。
在根据本发明的一个实施方式中,所述结晶形式B具有选自以下X射线衍射图谱的3个以上、5个以上、7个以上、9个以上、或10个以上特征峰(2θ):6.98±0.1°、11.10±0.1°、12.49±0.1°、13.47±0.1°、14.22±0.1°、15.22±0.1°、19.45±0.1°、19.82±0.1°、20.29±0.1°、20.90±0.1°、22.53±0.1°、24.89±0.1°、25.39±0.1°、25.83±0.1°和26.88±0.1°。
当使用差示扫描量热法(DSC)分析结晶形式B时,在约91℃观察到宽吸热峰,这对应于热重分析(TGA)的初始失重。再进行加热后,在约142℃(起点)观察到吸热峰。当对结晶形式B进行热载台显微术(HSM)时,在130.2-151.3℃内观察到熔融现象。
在根据本发明的一个实施方式中,所述药学上可接受的盐可以选自盐酸、硫酸、硝酸、磷酸、氢溴酸、氢碘酸、酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、富马酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸和萘磺酸。在根据本发明的一个实施方式中,所述药学上可接受的盐可以是盐酸。
在根据本发明的一个实施方式中,所述溶剂化物可以是水合物。
根据本发明的另一个方面,提供了一种药物组合物,所述药物组合物包含1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或其药学上可接受的盐或溶剂化物的结晶形式B,以及药学上可接受的载体。
在本发明中,除了本发明的活性成分以外,“药物组合物”还可以包括其它组分,如载体、稀释剂、赋形剂等。因此,所述药物组合物在必要时可以包括药学上可接受的载体、稀释剂、赋形剂或其组合。所述药物组合物有助于向体内施用化合物。施用化合物的各种方法包括但不限于口服、注射、气雾剂、肠胃外和局部施用。
在本文中,“载体”意指有助于将化合物加入细胞或组织中的化合物。例如,二甲亚砜(DMSO)是有助于将许多有机化合物施用到活细胞或组织中的常规载体。
在本文中,“稀释剂”意指不仅能稳定生物活性形式而且能稀释在溶解化合物的溶剂中的化合物。在本领域中,将含溶解盐的缓冲液用作稀释剂。一种常规使用的缓冲液是模拟体液中的盐形式的磷酸盐缓冲生理盐水。由于缓冲溶液可以在低浓度下控制溶液的pH,因此缓冲液稀释剂几乎不改变化合物的生物活性。
在本文中,“药学上可接受的”意指不损害化合物的生物活性和物理性质的性质。
根据本发明的化合物可以配制为各种药学施用剂型。在制备本发明的药物组合物时,将活性成分,具体为式1化合物或其药学上可接受的盐或溶剂化物的结晶形式B,与考虑要制备的剂型而选择的药学上可接受的载体混合。例如,本发明的药物组合物在有需要时可以配制为注射液、口服制剂等。
本发明的式1化合物的结晶形式可以通过常规方法使用已知的药物载体和赋形剂配制,并插入单位容器或多单位容器中。所述制剂可以是在油或水性溶剂中的溶液、悬浮液或乳液,并包括常规分散剂、悬浮剂或稳定剂。此外,所述化合物可以为例如在使用前溶解在灭菌无热原水中的干粉形式。本发明的式1化合物的结晶形式可以通过使用常规栓剂基质如可可脂或其它甘油酯配制成栓剂。用于口服施用的固体形式包括胶囊、片剂、丸剂、粉剂和颗粒剂。优选胶囊和片剂。片剂和丸剂优选为肠衣包覆型。固体形式是通过将本发明的式1化合物的结晶形式与选自惰性稀释剂如蔗糖、乳糖或淀粉、润滑剂如硬脂酸镁、崩解剂、粘合剂等的至少一种载体混合来制造。此外,它可以配制为透皮剂型,例如洗液、软膏、凝胶、乳霜、贴剂或喷雾剂。
根据本发明的药物组合物适合于预防或治疗与鞘氨醇-1-磷酸酯受体相关的疾病。在根据本发明的一个实施方式中,所述药物组合物可用于治疗自身免疫性疾病,包括多发性硬化症。在根据本发明的一个实施方式中,所述药物组合物可用于预防或治疗由与鞘氨醇-1-磷酸酯相关的不希望的淋巴细胞浸润引起的疾病。在根据本发明的一个实施方式中,所述药物组合物可用于预防或治疗免疫调节病症。在根据本发明的一个实施方式中,所述免疫调节病症的实例可以是选自全身性红斑狼疮、慢性类风湿性关节炎、炎性肠病、多发性硬化症、肌萎缩性侧索硬化症(ALS)、动脉硬化症、动脉粥样硬化症、硬皮病和自身免疫性肝炎的自身免疫性疾病或慢性炎性疾病,但不限于此。
在本文中,术语“预防”是指降低或消除感染疾病的可能性。
在本文中,术语“治疗”用于指在表现出疾病症状的受试者中阻止、延迟或改善疾病进展。
发明效果
1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或其药学上可接受的盐或溶剂化物的结晶形式B具有作为鞘氨醇-1-磷酸酯受体激动剂的药理活性,同时具有优异的药物性能,如稳定性,例如热稳定性和储存稳定性。
附图说明
图1是结晶形式B的X射线粉末衍射(XRPD)图谱。
图2是结晶形式B的热重分析(TGA)/差示扫描量热(DSC)分析的结果。
图3是结晶形式B的热载台显微术结果。
图4是比较结晶形式B在浆液化前后的X射线粉末衍射(XRPD)图谱的结果。
具体实施方式
下文利用以下实施例更详细地说明本发明。然而,必须理解本发明的保护范围不局限于所述实施例。
制备例1:1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基
甲基]-哌啶-4-甲酸盐酸盐的合成
根据国际公开号WO 2014/129796 A1的制备例153-1所述的方法来合成1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸乙酯,利用NaOH使所述酯水解,用HCl酸化,然后进行结晶,得到盐酸盐形式(下文称为“化合物1”)。
制备例2:基本结晶形式的制备
将化合物1(226g,0.46mol)、乙醇(1.13L,5倍)、水(0.57L,2.5倍)和NaOH(32g,0.80mol)加入到反应器中。在45℃的内部温度下加热60分钟后,将内部温度冷却到28℃。向反应混合物中加入二氯甲烷(DCM)(340mL,1.5倍)后,在50分钟内缓慢滴加6N HCl(167ml,1.00mol)以便将溶液的pH酸化至2.5,然后加入乙酸乙酯(EtOAc)(0.23L,1倍)以进行结晶。内部温度冷却至5℃后,将所得产物保持30分钟,过滤并用水(1.13L,5倍)洗涤两次,用甲基叔丁基醚(MTBE)(0.50L,3倍)洗涤一次,得到具有表1的下列XRPD(X射线粉末衍射)图的化合物1的结晶形式(下文称为“结晶形式A”)(156g,两步产率:69.0%)。
[表1]
实施例1:结晶形式B的制备通过以下三(3)种方法制备结晶形式B。
(1)将结晶形式A溶解在乙醇与水的混合溶剂(50:50)中后,所得溶液通过0.2μm尼龙过滤器过滤到玻璃小瓶中。在小瓶开放的情况下室温蒸发后,得到结晶白色固体。
(2)将结晶形式A溶解在四氢呋喃与水的混合溶剂(5:1)中制成溶液,然后向其中缓慢加入反溶剂环己烷。此时,四氢呋喃/水混合溶剂与环己烷以1:20的比率使用。在室温下搅拌1天后,将混合物冷藏3天。如果形成了沉淀物,则将它滤过0.45μm PVDF过滤器。
(3)将结晶形式A溶解在甲醇与甲基叔丁基醚的混合溶剂(70:30)中后,将所得溶液短暂加热至35℃。此时大部分固体被溶解。将所得溶液滤过预热的0.2μm尼龙过滤器,并放入在相同温度下预热的洁净小瓶中。然后从热板取下溶液,并允许冷却至室温。由于小瓶中没有形成固体,因此在小瓶打开的同时在室温下蒸发小瓶,然后得到结晶白色固体。
实施例2:结晶形式B的分析
(1)XRPD(x射线粉末衍射)
通过使用PANalytical Xpert Pro MPD衍射仪进行XRPD分析,其中入射束为Cu辐射。在玻璃样品容器上将约20-30mg样品压实使其具有平坦表面后,将设备的发生器设为45kV(加速电压)和40mA(灯丝发射),然后以反射模式(不自旋)进行测量。在步长为0.026°和每步时间为51秒的条件下,在4°至40°的范围内测量布拉格角(2θ)。使用HighScore Plus2.2c软件对XRPD图案进行分类和处理,结果如图1和表2所示。
(2)TGA/DSC组合(热重分析/差示扫描量热法)
使用Mettler-Toledo TGA/DSC3+分析仪进行TGA/DSC组合分析。将样品放在开放的铝锅中,将锅密封,将锅盖打孔并插入TG炉中,在氮气下以10℃/min的速率从30℃加热到最高250℃。结果示于图2中。
(3)HSM(热载台显微术)
使用Leica DM LP显微镜上的Linkman热载台(型号FTIR 600)和TMS93控制器进行热载台显微术。使用λ波片和交叉偏振器在10×0.22或20×0.40倍放大下观察样品。将样品放在盖玻片上,并将另一个盖玻片放在样品上。在加热载台时目视观察样品。为了研究气体逸出,在一些情况下可以向样品加入一滴矿物油。通过使用SPOT软件v.4.5.9和SPOTInsight彩色数码相机来拍摄图像(图3)。
(4)结果
作为XRPD分析的结果,证实了所述化合物是结晶形式,具体值示于下表2中。
[表2]
作为DSC的结果,在约91℃观察到宽吸热峰,这对应于TGA的初始失重。额外加热后,在约142℃(起点)观察到吸热,基于HSM观察结果,这很可能是由于脱水固体熔融所致。结晶形式B很可能是结晶形式A的水合物,并且TGA的初始失重对应于约2.3摩尔H2O。
作为HSM的结果,在130.2-151.3℃内观察到熔融现象。
使用结晶形式B作为晶种,并与结晶形式A一起在50:50EtOH/H2O(获得结晶形式B的溶剂条件,制备方法是快速蒸发)中室温搅拌9天,所分离的固体对应于结晶形式A。
Claims (9)
1.一种1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或其药学上可接受的盐或溶剂化物的结晶形式,所述结晶形式具有选自以下X射线衍射图谱的3个以上特征峰(2θ):
6.98±0.2°、11.10±0.2°、12.49±0.2°、13.47±0.2°、14.22±0.2°、15.22±0.2°、19.45±0.2°、19.82±0.2°、20.29±0.2°、20.90±0.2°、22.53±0.2°、24.89±0.2°、25.39±0.2°、25.83±0.2°和26.88±0.2°。
2.根据权利要求1所述的结晶形式,所述结晶形式具有选自以下X射线衍射图谱的3个以上特征峰(2θ):
6.98±0.1°、11.10±0.1°、12.49±0.1°、13.47±0.1°、14.22±0.1°、15.22±0.1°、19.45±0.1°、19.82±0.1°、20.29±0.1°、20.90±0.1°、22.53±0.1°、24.89±0.1°、25.39±0.1°、25.83±0.1°和26.88±0.1°。
3.根据权利要求1所述的结晶形式,其中所述药学上可接受的盐选自盐酸、硫酸、硝酸、磷酸、氢溴酸、氢碘酸、酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、富马酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸和萘磺酸。
4.根据权利要求3所述的结晶形式,其中所述药学上可接受的盐是盐酸。
5.根据权利要求1所述的结晶形式,其中所述溶剂化物是水合物。
6.一种药物组合物,所述药物组合物用于治疗自身免疫性疾病,包括多发性硬化症,所述药物组合物包含如权利要求1中定义的1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或其药学上可接受的盐或溶剂化物的结晶形式,以及药学上可接受的载体。
7.一种药物组合物,所述药物组合物用于预防或治疗由与鞘氨醇-1-磷酸酯相关的不希望的淋巴细胞浸润引起的疾病,所述药物组合物包含如权利要求1中定义的1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或其药学上可接受的盐或溶剂化物的结晶形式,以及药学上可接受的载体。
8.一种药物组合物,所述药物组合物用于预防或治疗免疫调节病症,所述药物组合物包含如权利要求1中定义的1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或其药学上可接受的盐或溶剂化物的结晶形式,以及药学上可接受的载体。
9.根据权利要求8所述的药物组合物,其中所述免疫调节病症是选自全身性红斑狼疮、慢性类风湿性关节炎、炎性肠病、多发性硬化症、肌萎缩性侧索硬化症(ALS)、动脉硬化症、动脉粥样硬化症、硬皮病和自身免疫性肝炎的自身免疫性疾病或慢性炎性疾病。
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