CN106699745A - 一种依匹哌唑甲醇合物、晶型a、及其制备方法和应用 - Google Patents
一种依匹哌唑甲醇合物、晶型a、及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种依匹哌唑甲醇合物、晶型A、及其制备方法和应用。本发明提供了一种依匹哌唑甲醇合物的晶型A,其在通过溴化钾压片法测量的红外吸收光谱中,在3375.1cm‑1、3064.3cm‑1、2942.3cm‑1、2819.0cm‑1、1648.3cm‑1、1625.0cm‑1、1449.7cm‑1、1220.8cm‑1和841.4cm‑1处有特征峰。本发明的制备方法安全简便,且所制得的依匹哌唑甲醇合物或者晶型A溶解性较好,易于解离得到依匹哌唑,缓释效果好,适合药物开发,市场化前景良好。
Description
技术领域
本发明涉及一种依匹哌唑甲醇合物、晶型A、及其制备方法和应用。
背景技术
精神分裂症是一种慢性、严重并令人致残的脑部障碍,它可以导致妄想和幻觉。据研究表明:每年大约有100万人因此而失去生命。随着社会经济的快速发展,人们所承受来自多方面的精神压力不断加大,精神系统的发病率已有增长的趋势。依匹哌唑(英文名brexpiprazole)是由日本大冢制药公司和丹麦灵北制药公司共同研发的首个多巴胺、5-羟色胺调节剂,被认为是继大冢公司开发的畅销药物——阿立哌唑之后的又一重磅品种。基于7项已经完成的临床II和临床III研究,大冢制药和灵北制药已于2014年7月向美国食品药品监督管理局(FDA)提交了依匹唑派的新药申请。该品种于2015年7月11日在美国批准上市,用于精神分裂症的治疗和重度抑郁的辅助治疗。此外,该化合物针对注意力缺陷多动障碍(ADHD)处于Ⅱ期临床阶段,针对阿兹海默症和创伤后应激障碍处于III期临床阶段。
依匹哌唑对多个单胺系统具有广泛的活性。与阿立哌唑相比,本品与多巴胺D2受体(0.295nM)、5-HT2A受体(0.473nM)和5-HT1A受体(0.12nM)表现出更高的亲和力,而对H1、M1受体的亲和力相对较低。本品具有独特的药理学靶向性,针对一系列广泛的精神障碍疾病的治疗均有效果,且安全性和耐受性良好。此外,依匹唑派对各靶点产生的药理作用如下:多巴胺D2受体部分激动作用(改善阳性和阴性症状,认知功能障碍和抑郁症状);5-HT2A受体拮抗作用(改善阴性症状,认知功能障碍,抑郁症状,失眠);肾上腺素α1受体拮抗作用(改善精神分裂症的阳性症状);5-HT摄取/再摄取的抑制作用(改善抑郁症状);5-HT1A受体部分激动作用(改善焦虑和抑郁);5-HT7受体拮抗作用(体温调节,昼夜节律,学习和记忆,睡眠)。
目前,原研公司已经报道了有关依匹哌唑无水物及依匹哌唑二水合物晶型的制备(CN104254530A)。专利制备依匹哌唑二水合物工艺比较繁琐,而依匹哌唑无水物溶解度差,制备较困难。因此,寻找溶解度好、制备工艺简单、适合于工业化生产的依匹哌唑药用晶型是目前急需解决的技术问题。
发明内容
本发明所要解决的技术问题是为了克服现有技术中依匹哌唑药用晶型溶解度差、制备工艺繁琐、不适合于工业化生产等缺陷而提供了一种依匹哌唑甲醇合物、晶型A、及其制备方法和应用。本发明的制备方法安全简便,且所制得的依匹哌唑甲醇合物溶解性较好,易于解离得到依匹哌唑,适合药物开发,市场化前景良好。
本发明提供了一种如式I所示的依匹哌唑甲醇合物,
本发明还提供了所述的如式I所示的依匹哌唑甲醇合物的晶型A,其在通过溴化钾压片法测量的红外吸收光谱中,在3375.1cm-1、3064.3cm-1、2942.3cm-1、2819.0cm-1、1648.3cm-1、1625.0cm-1、1449.7cm-1、1220.8cm-1和841.4cm-1处有特征峰。
本发明还提供了所述的如式I所示的依匹哌唑甲醇合物的晶型A,其在使用辐射源为Cu-Kα的粉末X射线衍射光谱中,在衍射角2θ=10.814,13.247,15.904,16.539,23.723,26.302度处有主要衍射峰,2θ误差范围为±0.2度;
所述的依匹哌唑甲醇合物的晶型A,其在使用辐射源为Cu-Kα的粉末X射线衍射光谱中,在衍射角2θ=5.389,8.870,10.814,13.247,15.904,16.539,17.667,19.812,23.723,26.302,28.672,30.896,32.046,34.832,38.975度处有主要衍射峰,2θ误差范围为±0.2度。
所述的依匹哌唑甲醇合物的晶型A,其在使用辐射源为Cu-Kα的粉末X射线衍射光谱中,在衍射角2θ=5.389,8.870,10.814,12.137,12.725,13.247,13.580,13.669,15.904,16.539,16.893,17.667,18.351,19.426,19.812,20.624,21.884,23.070,23.723,24.505,25.593,26.302,27.607,28.083,28.672,29.284,30.489,30.896,31.575,32.046,34.832,35.814,38.975,39.586度处有衍射峰,2θ误差范围为±0.2度。
所述的依匹哌唑甲醇合物的晶型A,其在使用辐射源为Cu-Kα的粉末X射线衍射光谱如图1所示。
本发明中,所述的如式I所示的依匹哌唑甲醇合物的晶型A,差热分析图谱(DSC)在75.16~93.50℃处有解离吸收热76.19J/g;在182.43~184.30℃处有熔化吸收热峰102.50J/g。
本发明中,所述的如式I所示的依匹哌唑甲醇合物的晶型A,其DSC-TGA迹线在80℃~150℃处有6.53%-7.64%的失重。
本发明还提供了所述的如式I所示的依匹哌唑甲醇合物的晶型A的制备方法,其包括以下步骤:向依匹哌唑、甲醇与非质子有机溶剂形成的溶液中,加入甲醇、析晶,得到如式I所示的依匹哌唑甲醇合物的晶型A即可。
所述的如式I所示的依匹哌唑甲醇合物的晶型A的制备方法中,所述的非质子有机溶剂优选卤代烃类溶剂和/或芳烃类溶剂;所述的卤代烃类溶剂优选氯代烃类溶剂;所述的氯代烃类溶剂优选二氯甲烷;所述的芳烃类溶剂优选甲苯。
所述的如式I所示的依匹哌唑甲醇合物的晶型A的制备方法中,所述的“依匹哌唑、甲醇与非质子有机溶剂形成的溶液中”所述的非质子有机溶剂与所述的甲醇的体积比值优选2~15,进一步优选2~10,例如5。
所述的如式I所示的依匹哌唑甲醇合物的晶型A的制备方法中,所述的“依匹哌唑、甲醇与非质子有机溶剂形成的溶液中”,所述的“甲醇和非质子有机溶剂”与所述的依匹哌唑的体积质量比值优选1mL/g~10mL/g,进一步优选3mL/g~8mL/g,例如6mL/g。
所述的如式I所示的依匹哌唑甲醇合物的晶型A的制备方法中,所述的“依匹哌唑、甲醇与非质子有机溶剂形成的溶液”,优选将依匹哌唑加热溶解于甲醇与非质子有机溶剂的混合溶剂中。所述的加热的温度以依匹哌唑溶解为准。
所述的如式I所示的依匹哌唑甲醇合物的晶型A的制备方法中,所述的“加入甲醇”的温度优选0~10℃。
所述的如式I所示的依匹哌唑甲醇合物的晶型A的制备方法中,所述的“加入甲醇”的方式优选滴加,所述的滴加的速度以维持体系温度不超过10℃为准,优选0~10℃。
所述的如式I所示的依匹哌唑甲醇合物的晶型A的制备方法中,所述的加入的甲醇与所述的依匹哌唑的体积质量比值优选1mL/g~50mL/g,进一步优选8mL/g~30mL/g,例如6mL/g、9mL/g、10mL/g或30mL/g。
所述的如式I所示的依匹哌唑甲醇合物的晶型A的制备方法中,所述的依匹哌唑可以为依匹哌唑无水物或二水合物。
所述的如式I所示的依匹哌唑甲醇合物的晶型A的制备方法中,所述的析晶的温度优选0~30℃,进一步优选0~10℃。
所述的如式I所示的依匹哌唑甲醇合物的晶型A的制备方法中,所述的析晶的时间优选1小时~5小时,优选2小时~3小时,例如2小时。
所述的如式I所示的依匹哌唑甲醇合物的晶型A的制备方法中,所述的析晶的方式优选搅拌析晶,所述的搅拌的速度优选30转/分~3000转/分,例如30转/分、120转/分、1000转/分、1500转/分、2000转/分或3000转/分。
所述的如式I所示的依匹哌唑甲醇合物的晶型A的制备方法优选包括以下后处理步骤:析晶后过滤、干燥,得到纯化后的依匹哌唑甲醇合物的晶型A。
所述的过滤、干燥可以采用本领域中该类操作的常规方法,所述的干燥的方式优选真空干燥。所述的真空干燥的温度优选45℃~55℃。所述的真空干燥的时间优选1小时~10小时,进一步优选3小时~8小时,例如4小时~5小时。所述的真空干燥的压强优选-0.08MPa~-0.01MPa。
本发明还提供了所述的依匹哌唑甲醇合物的晶型A的制备方法制得的依匹哌唑甲醇合物的晶型A。
本发明还提供了一种药物组合物,其特征在于包含所述的依匹哌唑甲醇合物或者所述的依匹哌唑甲醇合物的晶型A。
所述的药物组合物优选进一步包含药学上可接受的载体。
本发明还提供了所述的药物组合物在制备预防和/或治疗神经系统疾病的药物中的应用。
本发明还提供了所述的依匹哌唑甲醇合物和/或所述的依匹哌唑甲醇合物的晶型A在制备预防和/或治疗神经系统疾病的药物中的应用。
所述的中枢神经系统疾病选自精神分裂症、情绪紊乱、精神障碍、情感障碍、双向障碍、躁狂症、抑郁症、心境恶劣障碍、焦虑性障碍、躯体形式障碍、造作性障碍、分离性障碍、性功能障碍、进食障碍、睡眠障碍、适应障碍、物质滥用障碍、兴趣缺失、谵妄、认知损害、伴随阿尔茨海默病的认知损害、帕金森病和其他神经变性疾病、认知损害引起的痴呆行为和精神症状、呕吐、晕动病、肥胖症、偏头痛、疼痛、智力低下、孤独症、图雷特综合症、抽动障碍、注意缺陷多动障碍、品行障碍,以及唐氏综合症。所述的精神分裂症选自治疗耐受的、顽固及慢性的精神分裂症。所述的抑郁症选自内因性抑郁症、重型抑郁症、忧郁及治疗耐受型抑郁症。所述的情感障碍选自循环型情感障碍。所述认知损害选自精神分裂症中的认知损害和治疗耐受的、顽固或慢性的精神分裂症引起的认知损害。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明提供的依匹哌唑甲醇合物制备方法操作安全简便、环境和友好、适合于工业化生产。本发明制得的如式I所示的依匹哌唑甲醇合物及其晶型A溶解性较好、易于解离得到依匹哌唑,缓释效果好,适合药物开发,市场化前景良好。
附图说明
图1为实施例1制得的依匹哌唑甲醇合物的晶型A的Cu-Kα的粉末X射线衍射光谱谱图(XRPD);
图2为实施例1制得的依匹哌唑甲醇合物的晶型A的差热分析谱图(DSC);
图3为实施例1制得的依匹哌唑甲醇合物的晶型A的DSC-TGA迹线谱图。
图4为实施例1制得的依匹哌唑甲醇合物的晶型A的红外光谱谱图。
图5为实施例1制得的依匹哌唑甲醇合物的晶型A与参比制剂在3%SDSpH6.8磷酸盐缓冲液中溶出曲线对比图;
表示实施例1制得的依匹哌唑甲醇合物的晶型A在3%SDSpH6.8
磷酸盐缓冲液中溶出曲线;
表示参比制剂(大冢制药的依匹哌唑甲醇无水物)在3%SDSpH6.8
磷酸盐缓冲液中溶出曲线。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1
50L的反应釜中,将1.8kg依匹哌唑原料药(无水物)加热溶于9L二氯甲烷和1.8L的甲醇中,温度降至0~10℃,缓慢滴加甲醇18L,滴加完毕后,保持0~10℃以120转/分速率搅拌2小时析晶,过滤得白色固体滤饼。45~55℃真空(-0.08MPa~-0.01MPa)干燥4~5小时,得依匹哌唑甲醇合物的晶型A1.68kg,收率86.9%,HPLC纯度99.82%。测定其XRPD,DSC,DSC-TGA和红外谱图,其XRPD谱图如图1所示;其DSC谱图如图2所示;其DSC-TGA谱图如图3所示;其红外谱图如图4所示;实施例1制得的依匹哌唑甲醇合物的晶型A与参比制剂(otsukapharmaceutical.co.,即大冢制药生产的依匹哌唑无水物)在3%SDSpH6.8磷酸盐缓冲液中溶出曲线对比图如图5所示(所述的%是重量体积百分比;具体是指十二烷基硫酸钠的重量与SDSpH6.8磷酸盐缓冲液体积的百分比);实施例1制得的依匹哌唑甲醇合物的晶型A与依匹哌唑无水物的溶解度对比见表1;实施例1制得的依匹哌唑甲醇合物的晶型A与依匹哌唑无水物的溶出度对比见表2。
图1可见,依匹哌唑甲醇合物的晶型A,其在使用辐射源为Cu-Kα的粉末X射线衍射光谱中,在衍射角2θ=5.389,8.870,10.814,12.137,12.725,13.247,13.580,13.669,15.904,16.539,16.893,17.667,18.351,19.426,19.812,20.624,21.884,23.070,23.723,24.505,25.593,26.302,27.607,28.083,28.672,29.284,30.489,30.896,31.575,32.046,34.832,35.814,38.975,39.586度处有衍射峰,2θ误差范围为±0.2。
图2可见,所述的依匹哌唑甲醇合物的晶型A,差热分析图谱(DSC)在75.16℃~93.50℃处有解离吸收热76.19J/g;在182.43℃~184.30℃处有熔化吸收热峰102.5J/g。本发明的依匹哌唑甲醇合物的晶型A更容易解离。
图3可见,所述的依匹哌唑甲醇合物的晶型A的DSC-TGA迹线在80℃~150℃处有6.53%-7.64%的失重。
图4可见,所述的依匹哌唑甲醇合物的晶型A其在通过溴化钾压片法测量的红外吸收光谱中,在3375.1cm-1、3064.3cm-1、2942.3cm-1、2819.0cm-1、1648.3cm-1、1625.0cm-1、1449.7cm-1、1220.8cm-1和841.4cm-1处有特征峰。
表1实施例1制得的依匹哌唑甲醇合物的晶型A与依匹哌唑无水物的溶解度对比表
由表1可见,本发明的如式I所示的依匹哌唑甲醇合物的晶型A具有与依匹哌唑无水物相当的溶解度。
表2实施例1制得的依匹哌唑甲醇合物的晶型A与依匹哌唑无水物的累积溶出度对比表
由表2可见,本发明的如式I所示的依匹哌唑甲醇合物的晶型A与原研依匹哌唑无水物相比溶出时间更长,具有缓释作用,更适合做缓释药物。
实施例2
500mL的反应瓶中,将18g依匹哌唑原料药(二水合物)加热溶于90mL二氯甲烷和18mL的甲醇中,温度降至0~10℃,缓慢滴加甲醇180mL,滴加完毕后,保持0~10℃以30转/分速率搅拌2小时析晶,过滤得白色固体滤饼。45~55℃真空(-0.08MPa~-0.01MPa)干燥4小时~5小时得依匹哌唑甲醇合物的晶型A 16.1g,收率83.3%,HPLC纯度99.74%。
实施例3
500mL的反应瓶中,将18g依匹哌唑原料药(无水物)加热溶于90mL甲苯中和18mL的甲醇中,温度降至0~10℃,缓慢滴加甲醇180mL,滴加完毕后,保持0~10℃以3000转/分速率搅拌2小时析晶,过滤得白色固体滤饼。45~55℃真空干燥(-0.08MPa~-0.01MPa)4小时~5小时得依匹哌唑甲醇合物的晶型A 16.5g,收率85.3%,HPLC纯度99.89%。
实施例4
500mL的反应瓶中,将18g依匹哌唑原料药(二水物)加热溶于90mL甲苯和18mL甲醇中,温度降至0~10℃,缓慢滴加甲醇180mL,滴加完毕后,保持0~10℃以1500转/分速率搅拌2小时析晶,过滤得白色固体滤饼。45~55℃真空(-0.08MPa~-0.01MPa)干燥4小时~5小时得依匹哌唑甲醇合物的晶型A 13.5g,收率69.8%,HPLC纯度99.92%。
实施例5
500mL的反应瓶中,将9g依匹哌唑原料药(无水物)加热溶于45mL二氯甲烷和9mL的甲醇中,温度降至0~10℃,缓慢滴加甲醇90mL,滴加完毕后,保持0~10℃以2000转/分速率搅拌2小时析晶,过滤得白色固体滤饼。45~55℃真空(-0.08MPa~-0.01MPa)干燥4小时~5小时得依匹哌唑甲醇合物的晶型A 17.1g,收率88.5%,HPLC纯度99.69%。
实施例6
500mL的反应瓶中,将9g依匹哌唑原料药(二水物)加热溶于45mL甲苯和9mL甲醇中,温度降至0~10℃,缓慢滴加甲醇90mL,滴加完毕后,保持0~10℃以1000转/分速率搅拌2小时析晶,过滤得白色固体滤饼。45~55℃真空(-0.08MPa~-0.01MPa)干燥得依匹哌唑甲醇合物的晶型A 12.6g,收率65.2%,HPLC纯度99.90%。
Claims (10)
1.一种如式I所示的依匹哌唑甲醇合物,
2.如权利要求1所述的如式I所示的依匹哌唑甲醇合物的晶型A,其特征在于:其在通过溴化钾压片法测量的红外吸收光谱中,在3375.1cm-1、3064.3cm-1、2942.3cm-1、2819.0cm-1、1648.3cm-1、1625.0cm-1、1449.7cm-1、1220.8cm-1和841.4cm-1处有特征峰。
3.如权利要求1所述的如式I所示的依匹哌唑甲醇合物的晶型A,其特征在于:其在使用辐射源为Cu-Kα的粉末X射线衍射光谱中,在衍射角2θ=10.814,13.247,15.904,16.539,23.723,26.302度处有主要衍射峰,2θ误差范围为±0.2度;
4.如权利要求3所述的如式I所示的依匹哌唑甲醇合物的晶型A,其特征在于:其在使用辐射源为Cu-Kα的粉末X射线衍射光谱中,在衍射角2θ=5.389,8.870,10.814,13.247,15.904,16.539,17.667,19.812,23.723,26.302,28.672,30.896,32.046,34.832,38.975度处有主要衍射峰,2θ误差范围为±0.2度。
5.如权利要求4所述的如式I所示的依匹哌唑甲醇合物的晶型A,其特征在于:其在使用辐射源为Cu-Kα的粉末X射线衍射光谱中,在衍射角2θ=5.389,8.870,10.814,12.137,12.725,13.247,13.580,13.669,15.904,16.539,16.893,17.667,18.351,19.426,19.812,20.624,21.884,23.070,23.723,24.505,25.593,26.302,27.607,28.083,28.672,29.284,30.489,30.896,31.575,32.046,34.832,35.814,38.975,39.586度处有衍射峰,2θ误差范围为±0.2度。
6.如权利要求1所述的如式I所示的依匹哌唑甲醇合物的晶型A,其特征在于:所述的如式I所示的依匹哌唑甲醇合物的晶型A,其在使用辐射源为Cu-Kα的粉末X射线衍射光谱如图1所示;
和/或,
所述的如式I所示的依匹哌唑甲醇合物的晶型A,差热分析图谱在75.16~93.50℃处有解离吸收热76.19J/g;在182.43~184.30℃处有熔化吸收热峰102.5J/g;
和/或,
所述的如式I所示的依匹哌唑甲醇合物的晶型A,其DSC-TGA迹线在80℃~150℃处有6.53-7.64%的失重。
7.如权利要求1~6任一项所述的如式I所示的依匹哌唑甲醇合物的晶型A的制备方法,其特征在于包括以下步骤:向依匹哌唑、甲醇与非质子有机溶剂形成的溶液中,加入甲醇、析晶,得到如式I所示的依匹哌唑甲醇合物的晶型A即可。
8.一种药物组合物,其特征在于包含如权利要求2~6任一项所述的依匹哌唑甲醇合物的晶型A和/或如权利要求1所述的依匹哌唑甲醇合物。
9.如权利要求8所述的药物组合物,其特征在于:其进一步包含药学上可接受的载体。
10.如权利要求1所述的依匹哌唑甲醇合物和/或如权利要求2~6任一项所述的依匹哌唑甲醇合物的晶型A和/或如权利要求8或9所述的药物组合物在制备预防和/或治疗神经系统疾病的药物中的应用。
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