CN114081881B - 一种有机酸锂氨基酸盐、晶型、组合物及应用 - Google Patents
一种有机酸锂氨基酸盐、晶型、组合物及应用 Download PDFInfo
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- CN114081881B CN114081881B CN202111392146.1A CN202111392146A CN114081881B CN 114081881 B CN114081881 B CN 114081881B CN 202111392146 A CN202111392146 A CN 202111392146A CN 114081881 B CN114081881 B CN 114081881B
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- amino acid
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- isobutyrate
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Abstract
本发明公开了一种有机酸锂氨基酸盐,所述有机酸锂为异丁酸锂、正丁酸锂、乳酸锂、柠檬酸锂或胆固醇锂中的一种或多种;所述氨基酸为L‑脯氨酸、缬氨酸、赖氨酸或人工合成氨基酸中的一种;所述有机酸锂氨基酸盐为由所述有机酸锂与所述氨基酸形成的盐。本发明同时公开了上述盐的晶型、制备方法及应用。发明的有机酸锂氨基酸盐对双相情感障碍中躁狂、抑郁的反复发作有肯定的疗效和预防作用,可以延缓中枢神经系统退行性病变,使其具有更好的中枢神经系统分布,加强中枢神经系统疾病疗效的同时,降低锂盐的临床用量,避免外周不良反应的发生。
Description
技术领域
本发明属于医药领域,具体涉及一种新型有机酸锂氨基酸盐,晶型、组合物、其制备工艺及其在神经精神疾病领域的应用。
背景技术
锂盐可用于精神疾病领域,对双相情感障碍中躁狂、抑郁的反复发作有良好的疗效和预防作用,而且具有独特的预防自杀风险的效应。最近研究还发现锂盐能够通过作用于GSK-3、WNT、AKT和神经递质来发挥神经保护作用,锂盐对于GSK-3β具有选择活性,锂盐抑制GSK-3β的作用方式主要有2种:(1)作为Mg2+竞争抑制剂直接抑制GSK-3β的活性;(2)通过增高磷酸化AKT、磷酸化GSK-3β(ser9)和MCL-1的表达,间接抑制GSK-3β的活性。这种保护作用对包括阿尔茨海默病在内的神经退行性疾病的防治有潜在用途。目前临床常用的锂盐为碳酸锂、枸橼酸锂、醋酸锂和长效锂盐,其中以碳酸锂最为常用。
目前临床常用的无机锂盐安全范围窄,在治疗精神类疾病时往往需要长期用药,而长期用药造成的潜在肾脏损伤和甲状腺功能损害极大地限制了药物的临床应用。同时,目前临床常用的无机酸锂盐(氯化锂和碳酸锂)长期使用还会导致血液PH值的紊乱,造成代谢性酸中毒、加重肾脏负担。近年来,包括丁酸、异丁酸、丙戊酸和叶酸在内的多种小分子有机酸被发现对于中枢神经系统有重要的影响,能够有效的缓解焦虑抑郁等情绪异常,并且可以延缓中枢神经系统退行性病变。此外,有机酸盐的吸收分布和代谢特点往往与无机酸盐有较大的差异,有望改变现有无机锂盐的体内分布缺陷。因此有机酸锂盐具有更好的新药开发价值和市场前景。
发明内容
解决的技术问题:本发明的目的在于提供一种新型的有机酸锂氨基酸盐,用于解决现有锂制剂的药效不足、毒副作用大的问题。
本发明同时提供了一种有机酸锂-L-脯氨酸盐晶型、组合物。
本发明还提供了一种制备上述有机酸锂氨基酸盐、晶型或组合物的制备方法。
本发明进一步的提供了一种上述有机酸锂氨基酸盐、晶型、组合物在制备神经疾病药物、精神疾病药物中的应用。
一种有机酸锂氨基酸盐,所述有机酸锂为异丁酸锂、正丁酸锂、乳酸锂、柠檬酸锂或胆固醇锂等有机酸锂中的一种或多种;所述氨基酸为L-脯氨酸、缬氨酸、赖氨酸或其他天然氨基酸或人工合成氨基酸中的一种;所述有机酸锂氨基酸盐为由所述有机酸锂与所述氨基酸形成的盐。
作为优选,所述有机酸锂为异丁酸锂。
作为优选,所述氨基酸为L-脯氨酸。
作为优选,所述机酸锂氨基酸盐为异丁酸锂L-脯氨酸盐。
作为优选,所述的有机酸锂氨基酸盐中异丁酸锂、氨基酸以(0.8~1.2):(0.8~1.2)摩尔比形式进行结合。作为进一步优选,所述机酸锂氨基酸盐为异丁酸锂L-脯氨酸盐。所述的有机酸锂氨基酸盐中异丁酸锂、L-脯氨酸以(0.8~1.2):(0.8~1.2)摩尔比形式进行结合。
作为优选,所述的有机酸锂氨基酸盐中异丁酸锂、L-脯氨酸以1:1摩尔比形式进行结合。作为进一步优选,所述机酸锂氨基酸盐为异丁酸锂L-脯氨酸盐。所述的有机酸锂氨基酸盐中异丁酸锂、L-脯氨酸以1:1摩尔比形式进行结合。
一种有机酸锂氨基酸盐晶型,所述的有机酸锂氨基酸盐中异丁酸锂、L-脯氨酸以1:1摩尔比形式进行结合,其X射线粉末衍射谱图中具有衍射角2θ为8.201°±0.2°、11.735°±0.2°、20.395°±0.2°、23.669°±0.2°、24.930°±0.2°的特征峰。
一种有机酸锂氨基酸盐晶型,所述的有机酸锂氨基酸盐中异丁酸锂、L-脯氨酸以1:1摩尔比形式进行结合,其X射线粉末衍射谱图中具有衍射角2θ为7.909°±0.2°、8.201°±0.2°、11.735°±0.2°、16.525°±0.2°、20.395°±0.2°、23.669°±0.2°、24.930°±0.2°、30.232°±0.2°、31.427°±0.2°、33.451°±0.2°的特征峰。
一种有机酸锂氨基酸盐晶型,所述的有机酸锂氨基酸盐中异丁酸锂、L-脯氨酸以1:1摩尔比形式进行结合,其X射线粉末衍射谱图中具有衍射角2θ为8.255°±0.2°、11.782°±0.2°、16.584°±0.2°、16.811°±0.2°、18.711°±0.2°、18.800°±0.2°、20.451°±0.2°、23.715°±0.2°、25.017°±0.2°、25.040°±0.2°、30.281°±0.2°、31.490°±0.2°、33.537°±0.2°、35.886°±0.2°的特征峰。
本发明同时提供了一种上述任一项技术方案所述的有机酸锂氨基酸盐(优选为异丁酸锂L-脯氨酸盐)或任一项技术方案所述的晶型的制备方法,包括:采用单一溶剂法或混合溶剂法进行制备。
一种上述任一项技术方案所述的有机酸锂氨基酸盐(优选为异丁酸锂L-脯氨酸盐)的制备方法,或一种上述任一项技术方案所述的晶型的制备方法:
在单一溶剂法中,将所述有机酸锂和所述氨基酸中加入适量溶剂,加热回流1-5小时,趁热过滤,自然冷却析晶;
混合溶剂析晶法中,将所述有机酸锂和所述氨基酸中加入适量的良溶剂,加热回流溶解后加入适量不良溶剂析出固体,补加良溶剂使其重新溶解,回流1-5小时,自然冷却析晶。
作为优选,所述的单一溶剂法中,溶剂为正丁醇;所述的混合溶剂析晶法中,良溶剂为乙醇,不良溶剂为四氢呋喃。
在单一溶剂法中,加入的溶剂的量为加热回流下使其恰好溶解;在混合溶剂析晶法中,首先加入良溶剂,使其恰好溶解;然后加入不良溶剂,使其刚好析出,然后补加良溶剂加热溶解,回流1-5小时,自然冷却析晶。
一种有机酸锂氨基酸盐晶型,所述的有机酸锂氨基酸盐中异丁酸锂、L-脯氨酸以1:1摩尔比形式进行结合,其X射线粉末衍射谱图中具有衍射角2θ为7.909°、8.201°、11.735°、16.525°、20.395°、23.669°、24.930°、30.232°、31.427°、33.451°的特征峰。
一种上述晶型的制备方法,包括:将等化学当量的异丁酸锂、L-脯氨酸中加入适量的良溶剂正丁醇,在加热回流下使其恰好溶解并记录溶剂使用量,搅拌约3小时,趁热过滤,自然冷却析晶,过滤固体,真空干燥至恒重得到有机酸锂氨基酸盐晶型固体。
一种有机酸锂氨基酸盐晶型,所述的有机酸锂氨基酸盐中异丁酸锂、L-脯氨酸以1:1摩尔比形式进行结合,其X射线粉末衍射谱图中具有衍射角2θ为8.255°、11.782°、16.584°、16.811°、18.711°、18.800°、20.451°、23.715°、25.017°、25.040°、30.281°、31.490°、33.537°、35.886°的特征峰。
一种上述晶型的制备方法,包括:将等化学当量的异丁酸锂、L-脯氨酸中加入适量的良溶剂,加热回流使其恰好溶解,而后加入适量不良溶剂至恰好析出固体,补加良溶剂使其重新溶解,回流3小时,自然冷却析晶,过滤固体,真空干燥至恒重得到上述晶型的白色固体。
一种药物组合物,含有上述任一项技术方案所述的有机酸锂氨基酸盐或上述任一技术方案所述的晶型。
一种上述任一项技术方案所述的有机酸锂氨基酸盐或任一项技术方案所述的晶型、或者所述的药物组合物在制备治疗从抑制GSK-3β活性中受益、或从增加β-catenine蛋白表达中受益、或tau蛋白的表达被抑制中受益的疾病的药物中的应用。
作为优选,所述疾病包括神经退行性疾病、精神疾病药物中一种或多种。
作为优选,所述神经退行性疾病为阿尔茨海默病、帕金森病、亨廷顿病、癫痫、肌萎缩性侧索硬化、脊髓小脑共济失调中的一种或多种。
作为优选,所述精神疾病为轻度、中度、重度抑郁症以及双相情感障碍中的一种或多种。
申请人采用单一溶剂法和混合溶剂法,以异丁酸锂和L-脯氨酸作为原料,制备新型的异丁酸锂-L-脯氨酸盐。在单一溶剂法中,将不同化学当量比例的异丁酸锂和L-脯氨酸中加入适量的良溶剂,加热回流1-5小时,趁热过滤,自然冷却析晶。混合溶剂析晶法中,将不同化学当量比的异丁酸锂和L-脯氨酸中加入适量的良溶剂,加热回流溶解后加入适量不良溶剂析出固体,补加良溶剂重新溶解,回流1-5小时,自然冷却析晶。经XRD和氢谱验证为异丁酸锂和L-脯氨酸形成的新型盐。并在此基础上对其抗阿尔茨海默病潜在应用价值和安全性进行了初步评价。
本发明分别对得到的异丁酸锂-L-脯氨酸盐、异丁酸锂、L-脯氨酸分别进行同条件下的核磁氢谱检测,并进行叠加,由叠加图谱可知,单一溶剂条件下析出固体或混合析晶得到的固体与异丁酸锂、L-脯氨酸单一化合物或者两个单一化合物的叠加图谱均不相同,故可判断正丁醇条件下析出固体为不同于两种原料的盐。
本发明使用Mercury软件对单晶晶格内的L-脯氨酸的C-O键键长进行测量,其C-O键键长分别为和1.2 比值为1.028,L-脯氨酸的C-O键键长基本相同,证明复合物中L-脯氨酸明显发生质子转移导致其羧酸根C-O键键长趋于相同,确认制备产物为异丁酸锂-L-脯氨酸盐。
实验结果表明,异丁酸锂-L-脯氨酸盐显著抑制GSK-3β活性,表现为磷酸化GSK-3β(Ser9)的表达剂量依赖性的显著升高,效果显著优于现有临床常用的锂制剂—碳酸锂。同时,异丁酸锂-L-脯氨酸盐显著增加β-catenine蛋白表达,提示其具有促细胞增殖和存活的作用,效果显著优于碳酸锂。SH-SY5Y细胞实验表明,异丁酸锂-L-脯氨酸盐能够显著下调神经元退变相关蛋白tau的表达,提示其具有抑制神经细胞退变的作用,效果显著优于碳酸锂。而且,与碳酸锂相比,异丁酸锂-L-脯氨酸盐的细胞毒性显著降低,在抑制GSK-3β的同时不影响Notch表达。异丁酸锂-L-脯氨酸盐存在下对HEK293细胞的存活情况无明显影响。最后,实验结果进一步证明异丁酸锂-L-脯氨酸盐与碳酸锂相比,具有更高的血锂水平,同时脑中锂元素的水平无明显差别。
本发明具有如下有益效果:本发明对双相情感障碍中躁狂、抑郁的反复发作有肯定的疗效和预防作用,而且具有独特的预防自杀风险的效应,同时能够有效的缓解焦虑抑郁等情绪异常,并且可以延缓中枢神经系统退行性病变,并且有机酸盐的吸收分布和代谢特点往往与无机酸盐有较大的差异,改变了现有无机锂盐的体内分布缺陷,另外,本发明设计开发新型的小分子有机锂盐,在加强中枢神经系统疾病疗效的同时,安全性更好,降低锂盐的临床用量,避免外周不良反应的发生。
附图说明
图1为异丁酸锂单一化合物氢谱;
图2为L-脯氨酸单一化合物氢谱;
图3为异丁酸锂、L-脯氨酸等化学当量物理混合物氢谱;
图4为正丁醇条件下析出固体氢谱;
图5为正丁醇条件下析出固体XRD图;
图6为L-脯氨酸单一化合物XRD图谱;
图7为异丁酸锂单一化合物XRD图谱;
图8为叠加的XRD图谱;
图9为乙醇、四氢呋喃混合溶剂析出固体的氢谱;
图10为乙醇、四氢呋喃混合溶剂析出固体XRD图;
图11为异丁酸锂-L-脯氨酸复合物X-射线单晶衍射图;
图12为异丁酸锂-L-脯氨酸盐对CHO细胞GSK-3β(Ser9)抑制作用实验结果:抑制作用优于碳酸锂和异丁酸锂;
图13为异丁酸锂-L-脯氨酸盐增加CHO细胞β-catenine表达的作用实验结果:优于碳酸锂;
图14为异丁酸锂-L-脯氨酸盐(LisoPro)对SH-SY5Y细胞中tau蛋白表达的抑制作用实验结果:抑制作用优于碳酸锂;
图15为异丁酸锂-L-脯氨酸盐对SH-SY5Y细胞中Notch蛋白表达实验结果:没有抑制作用,优于碳酸锂;
图16为异丁酸锂-L-脯氨酸盐对HEK293细胞的毒性实验结果:显著低于碳酸锂;
图17为异丁酸锂和异丁酸锂-L-脯氨酸盐对HEK293细胞的毒性实验结果:无明显差异;
图18为异丁酸锂-L-脯氨酸盐和碳酸锂对HEK293细胞形态的影响结果:显著优于碳酸锂;
图19为口服异丁酸锂-L-脯氨酸盐和碳酸锂24小时内血浆和脑组织代谢动力学实验结果;
图20为异丁酸锂-L-脯氨酸盐口服后对APP/PS1小鼠脑组织GSK-3β抑制作用结果:优于碳酸锂;
图21为异丁酸锂-L-脯氨酸盐和碳酸锂的经口急性毒性检测结果。
具体实施方式
下面的实施例可使本专业技术人员全面的理解本发明,但不以任何方式限制本发明。本发明中的异丁酸锂可以替换为丁酸锂、乳酸锂、胆固醇锂等其他有机锂中的一种或多种,脯氨酸可替换为缬氨酸、赖氨酸等其他天然必需氨基酸或人工合成氨基酸。
实施例1:单一溶剂析晶法制备异丁酸锂-L-脯氨酸盐
将等化学当量的异丁酸锂(500mg)、L-脯氨酸(612mg)中加入适量的良溶剂正丁醇,在加热回流下使其恰好溶解并记录溶剂使用量(正丁醇加入体积为55ml),搅拌约3h,趁热过滤,自然冷却析晶,过滤固体,真空干燥至恒重得到589.3mg白色固体(单一溶剂析晶法得到的异丁酸锂-L-脯氨酸盐),质量收率为53.06%。进行XRD和氢谱检验(氘代试剂:CD3OD)。
图1~图4分别为异丁酸锂单一化合物氢谱、L-脯氨酸单一化合物氢谱、异丁酸锂、L-脯氨酸等化学当量物理混合物氢谱、本发明采用单一溶剂析晶法得到的异丁酸锂-L-脯氨酸盐的氢谱;
异丁酸锂单一化合物氢谱(图1):1H NMR(400MHz,Methanol-d4)δ2.36(hept,J=6.9Hz,1H),1.10(d,J=7.0Hz,6H).
L-脯氨酸单一化合物氢谱(图2):1H NMR(400MHz,Methanol-d4)δ4.03(dd,J=8.7,6.3Hz,1H),3.43(dt,J=11.5,6.9Hz,1H),3.29(dt,J=11.4,7.3Hz,1H),2.42–2.27(m,1H),2.16(td,J=13.3,6.4Hz,1H),2.07–1.96(m,2H).
异丁酸锂、L-脯氨酸等化学当量物理混合物氢谱(图3):1H NMR(400MHz,Methanol-d4)δ4.02(dd,J=8.7,6.1Hz,1H),3.41(dt,J=11.5,6.9Hz,1H),3.28(dt,J=11.4,7.3Hz,1H),2.47–2.27(m,2H),2.14(td,J=13.3,6.2Hz,1H),2.06–1.92(m,2H),1.13(d,J=7.0Hz,6H).
异丁酸锂-L-脯氨酸盐的氢谱(图4):1H NMR(400MHz,Methanol-d4)δ4.01(dd,J=8.7,6.1Hz,1H),3.41(dt,J=11.5,6.9Hz,1H),3.27(dt,J=11.4,7.3Hz,1H),2.47–2.26(m,2H),2.14(dq,J=13.1,6.3Hz,1H),1.99(pt,J=7.3,4.3Hz,2H),1.13(d,J=7.0Hz,6H).
由图1~图4可知,实施例1正丁醇条件下析出固体中的异丁酸锂、L-脯氨酸的化学当量比为1:1;鉴于异丁酸锂、L-脯氨酸在正丁醇下的溶解度有较大差异,析出化合物并非单纯物理混合物,而是二者的盐,且盐中异丁酸锂、L-脯氨酸以1:1形式进行结合。
图5为实施例1得到的异丁酸锂-L-脯氨酸盐的XRD图谱;以正丁醇作为单一溶剂析出的固体2θ特征峰值为:7.909°、8.201°、11.735°、16.525°、20.395°、23.669°、24.930°、30.232°、31.427°、33.451°。
图6为L-脯氨酸单一化合物的XRD图谱;L-脯氨酸单一化合物2θ特征峰值为:8.564°、12.295°、15.110°、18.001°、18.390°、19.100°、19.518°、22.682°、24.770°、30.528°、32.120°、36.517°、37.602°、39.750°。
图7为异丁酸锂单一化合物的XRD图谱;异丁酸锂单一化合物2θ特征峰值为:7.169°、8.489°、14.377°、17.056°、18.945°、20.329°、21.291°、21.802°、24.123°、25.713°、26.395°、27.819°、29.003°、29.577°、29.866°、33.101°、39.219°。
图8为叠加的XRD图谱(自上而下分别为:异丁酸锂单一化合物、实施例2采用混合溶剂得到的异丁酸锂L-脯氨酸盐、L-脯氨酸单一化合物、实施例1采用单一溶剂得到的异丁酸锂L-脯氨酸盐)。
由叠加图谱可知,实施例1中正丁醇条件下析出的固体与异丁酸锂、L-脯氨酸单一化合物或者两个单一化合物的叠加图谱均不相同,故可判断正丁醇条件下析出固体为不同于单一的异丁酸锂或L-脯氨酸。结合核磁谱图,进一步证明本发明实施例1得到的固体为1:1的异丁酸锂L-脯氨酸盐。
实施例2:混合溶剂析晶法制备异丁酸锂-L-脯氨酸盐
将等化学当量的异丁酸锂(500mg)、L-脯氨酸(612mg)中加入适量50ml的良溶剂(乙醇),加热回流使其恰好溶解,而后加入适量30ml不良溶剂(四氢呋喃)至恰好析出固体,补加良溶剂(7ml)使其重新溶解,回流3h,自然冷却析晶,过滤固体,真空干燥至恒重得到374.8mg白色固体(混合溶剂析晶法制备得到的异丁酸锂-L-脯氨酸盐),质量收率为33.75%。分别进行XRD和氢谱(氘代试剂:CD3OD)检验。
图9为实施例2乙醇、四氢呋喃混合溶剂析出固体的氢谱。
综合图9和图1、2、3分析可知:实施例2乙醇、四氢呋喃混合溶剂析出固体中的异丁酸锂、L-脯氨酸的化学当量比为1:1;鉴于异丁酸锂、L-脯氨酸在乙醇、四氢呋喃下的溶解度均有较大差异,析出化合物并非单纯物理混合物,而是盐,且盐中异丁酸锂、L-脯氨酸以1:1形式进行结合。
图10为实施例2中乙醇、四氢呋喃混合溶剂析出的固体的XRD图。以乙醇、四氢呋喃混合溶剂析出盐的2θ特征峰值为:8.255°、11.782°、16.584°、16.811°、18.711°、18.800°、20.451°、23.715°、25.017°、25.040°、30.281°、31.490°、33.537°、35.886°。
由叠加图谱可知,实施例2中乙醇、四氢呋喃混合溶剂条件下析出固体与异丁酸锂、L-脯氨酸单一化合物或者两个单一化合物的叠加图谱均不相同,故可判断乙醇、四氢呋喃混合溶剂条件下为不同于两种原料的盐。由乙醇、四氢呋喃混合溶剂条件下析出固体的XRD和正丁醇单一溶剂条件下析出固体的XRD图可看出,两者的2θ特征峰值在±0.2偏差范围内,且峰强特征相同,可判定两者为同一种盐的同一种晶型。
实施例3:盐结构的表征
根据XRD和氢谱结果,选择正丙醇、正丁醇体系进行单晶培养,确定所形成的固体产物结构。最终正丁醇条件下析出晶体质量符合测试要求,其单晶结构如图11所示:
使用Mercury软件对单晶晶格内的L-脯氨酸的C-O键键长进行测量,其C-O键键长分别为和比值为1.028。L-脯氨酸的C-O键键长基本相同,证明固体产物中L-脯氨酸明显发生质子转移导致其羧酸根C-O键键长趋于相同,确认制备产物为异丁酸锂-L-脯氨酸盐。
实施例4:异丁酸锂-L-脯氨酸盐对CHO细胞GSK-3β的抑制作用明显优于碳酸锂和异丁酸锂
CHO细胞常规培养条件下,以0、0.78、1.56、3.13、6.25、12.5、25和50mM(mmol/L)浓度的异丁酸锂或异丁酸锂-L-脯氨酸盐处理2小时(或0、5、10、20、40、60和90mM浓度的碳酸锂或异丁酸锂-L-脯氨酸盐处理2小时),PBS洗三次,每次5分钟。细胞继续用含蛋白酶抑制剂的RIPA缓冲液裂解后进行Western blot检测,所用抗体为磷酸化GSK-3β(Ser9)或总GSK-3β抗体。GAPDH(甘油醛-3-磷酸脱氢酶)为内参蛋白。实验结果见图12,实验结果表明,异丁酸锂-L-脯氨酸盐(LisoPro)、碳酸锂(Li2CO3)和异丁酸锂(LiIB)均能够抑制GSK-3β活性,表现为磷酸化GSK-3β(Ser9)升高。其中异丁酸锂-L-脯氨酸盐表现出剂量依赖性的GSK-3β抑制作用,且抑制作用稳定;而异丁酸锂在>12.5mM浓度后抑制作用明显减弱,碳酸锂对GSK-3β抑制作用明显弱于异丁酸锂-L-脯氨酸盐。因此异丁酸锂-L-脯氨酸盐的效果显著优于异丁酸锂和碳酸锂。
异丁酸锂-L-脯氨酸盐具有更优的促细胞存活作用
实施例5:异丁酸锂-L-脯氨酸盐对CHO细胞中细胞存活相关蛋白β-catenine表达的上调作用优于碳酸锂
CHO细胞常规培养条件下,以0、0.78、1.56、3.13、6.25、12.5、25和50mM浓度的碳酸锂或异丁酸锂-L-脯氨酸盐处理2小时,PBS洗三次,每次5分钟。细胞继续用含蛋白酶抑制剂的RIPA缓冲液裂解后进行Western blot检测,所用抗体为β-catenine抗体。GAPDH为内参蛋白。实验结果见图13,实验结果表明,异丁酸锂-L-脯氨酸盐剂量依赖性显著增加细胞存活相关蛋白β-catenine的表达,提示其具有促细胞存活的作用,且β-catenine表达的上调作用显著优于碳酸锂。
实施例6:异丁酸锂-L-脯氨酸盐对SH-SY5Y细胞中神经元退变相关蛋白tau表达的下调作用优于碳酸锂
SH-SY5Y细胞常规培养条件下,以0、3.125、6.25、12.5、25和50mM浓度的碳酸锂或异丁酸锂-L-脯氨酸盐处理3小时,PBS洗三次,每次5分钟。细胞继续用含蛋白酶抑制剂的RIPA缓冲液裂解后进行Western blot检测,所用抗体为总tau蛋白抗体。GAPDH为内参蛋白。实验结果见图14,实验结果表明,异丁酸锂-L-脯氨酸盐能够浓度依赖性显著降低总tau蛋白的表达,在3.125mM浓度即可起效,而碳酸锂在6.25mM才起效,提示异丁酸锂-L-脯氨酸盐具有抑制神经细胞退变的作用,且效果显著优于碳酸锂。
实施例7:异丁酸锂-L-脯氨酸盐对SH-SY5Y细胞中Notch蛋白的表达没有影响
SH-SY5Y细胞常规培养条件下,以0、3.125、6.25、12.5、25和50mM浓度的碳酸锂或异丁酸锂-L-脯氨酸盐处理3小时,PBS洗三次,每次5分钟。细胞继续用含蛋白酶抑制剂的RIPA缓冲液裂解后进行Western blot检测,所用抗体为Notch蛋白抗体。GAPDH为内参蛋白。Notch蛋白是GSK-3下游重要信号分子,对细胞存活和增殖具有重要调控的正向作用。实验结果见图15,实验结果表明,异丁酸锂-L-脯氨酸盐在低于50mM浓度条件下不影响Notch的表达,因此不影响神经细胞的增殖和存活。与异丁酸锂-L-脯氨酸盐相比,临床常用的锂制剂碳酸锂对Notch蛋白的表达有明显抑制作用。上述结果表明异丁酸锂-L-脯氨酸盐对SH-SY5Y细胞的保护作用优于碳酸锂。
异丁酸锂-L-脯氨酸盐具有比碳酸锂更低的细胞毒性
实施例8:异丁酸锂-L-脯氨酸盐对HEK293细胞的毒性明显低于碳酸锂
HEK293细胞常规培养条件下,以0,0.7,1.56,3.12,6.25,12.5,25和50mM浓度的碳酸锂(黑色虚线)或异丁酸锂-L-脯氨酸盐(黑色实线)处理12和24小时,以CCK-8实验检测细胞毒性。酶标仪在450nm处读取吸光值(结果以平均值±标准误表示)。实验结果见图16,实验结果表明,与碳酸锂相比,异丁酸锂-L-脯氨酸盐的细胞毒性显著降低。
实施例9:异丁酸锂-L-脯氨酸盐和异丁酸锂细胞毒性无差异
HEK293细胞常规培养条件下,以0,0.7,1.56,3.12,6.25,12.5,25和50mM的异丁酸锂(黑色虚线)或异丁酸锂-L-脯氨酸盐(黑色实线)处理12小时和24小时,以CCK-8实验检测细胞毒性。酶标仪在450nm处读取吸光值(结果以平均值±标准误表示)。实验结果见图17,实验结果表明,与异丁酸锂相比,异丁酸锂-L-脯氨酸盐处理后细胞存活情况无明显差异。
实施例10:异丁酸锂-L-脯氨酸盐对HEK293细胞形态的影响
5mM异丁酸锂-L-脯氨酸盐和碳酸锂分别处理HEK293细胞4小时,然后加入5μg/mL小麦胚芽凝集素和Alexa Fluor 488偶联物细胞膜染料,37℃孵育10分钟,PBS洗两次,共聚焦显微镜下观察。实验结果(图18)表明,碳酸锂处理4小时后,HEK293细胞出现明显形态学变化,表现为细胞变小、漂浮;而异丁酸锂-L-脯氨酸盐处理的细胞未见明显形态变化,提示无明显细胞毒性。
异丁酸锂-L-脯氨酸盐具有比碳酸锂更佳的体内药代动力学、脑组织GSK-3抑制活性和安全性
实施例11:异丁酸锂-L-脯氨酸盐具有比碳酸锂更高的血锂水平
选取38只雄性SD大鼠灌胃给予碳酸锂或异丁酸锂-L-脯氨酸盐(0.08mmol锂/只,溶于400μL双蒸水)。给药后不同时间点(0,0.5,1,4,8,12和24小时),处死大鼠(0时间点处死1只,其他时间点各处死3只),迅速取血和脑组织,分离血浆并制备脑组织匀浆,以ICP-MS法检测血浆和脑组织中的锂元素含量(结果以平均值±标准误表示)。实验结果见图19,实验结果表明,异丁酸锂-L-脯氨酸盐与碳酸锂相比,具有更高的血锂水平,同时脑中锂元素的水平无明显差别。
实施例12:异丁酸锂-L-脯氨酸盐口服后对APP/PS1转基因AD模型小鼠脑组织磷酸化GSK-3β(Ser9)表达的影响优于碳酸锂
APP/PS1转基因AD模型小鼠口服异丁酸锂-L-脯氨酸盐和碳酸锂(灌胃0.02,0.08和0.16mmol/只,每组3只),4小时后处死冰上取脑,制备脑组织匀浆。用western blot法检测脑组织中的磷酸化GSK-3β(Ser9)表达,以β-actin蛋白作为内参。实验结果见图20,实验结果表明,异丁酸锂-L-脯氨酸盐在0.02和0.08mmol/只剂量条件下作用显著优于碳酸锂。
实施例13:异丁酸锂-L-脯氨酸盐的小鼠经口急性毒性显著低于碳酸锂
根据预实验结果,分别采用限量试验法和霍恩氏法,对异丁酸锂-L-脯氨酸盐和碳酸锂的经口急性毒性进行检测。限量试验中,20只昆明种小鼠(体重19.6~22克,雌雄各半),经口一次性给予5000mg/kg异丁酸锂-L-脯氨酸盐;霍恩氏法中,40只昆明种小鼠(体重19.8~22克,雌雄各半),分为四组,按照2.15等比设定464、1000、2150和4640mg/kg四个剂量组(一次性经口给药,每组10只,雌雄各半)。给药后0.5,2,4小时观察,24小时后每日观察实验动物中毒症状、出现时间和死亡时间,观察期14天。死亡动物和14天内为死亡动物处死,进行大体解剖,若有肉眼可见大体病理改变,则进行病理检查。实验结果见图21,实验结果表明,异丁酸锂-L-脯氨酸盐给药后14天内,实验动物未出现死亡,大体解剖无异常,LD50>5000mg/kg;碳酸锂2150和4640mg/kg剂量组实验动物在给药后24小时内出现体位异常症状,并全部死亡,464和1000mg/kg剂量组未见异常,各组实验动物大体解剖未见异常,LD50=1470mg/kg(文献报道的碳酸锂的LD50为530mg/kg)。上述结果表明,异丁酸锂-L-脯氨酸盐与碳酸锂相比,经口毒性显著降低。
Claims (12)
1.一种有机酸锂氨基酸盐,其特征在于,所述有机酸锂为异丁酸锂;所述氨基酸为L-脯氨酸;所述有机酸锂氨基酸盐为由所述有机酸锂与所述氨基酸形成的盐。
2.根据权利要求1所述的有机酸锂氨基酸盐,其特征在于,所述的有机酸锂氨基酸盐中异丁酸锂、氨基酸以1:1摩尔比形式进行结合。
3.一种有机酸锂氨基酸盐晶型,其特征在于,所述的有机酸锂氨基酸盐中异丁酸锂、L-脯氨酸以1:1摩尔比形式进行结合,其X射线粉末衍射谱图中具有衍射角2θ为8.201°±0.2°、11.735°±0.2°、20.395°±0.2°、23.669°±0.2°、24.930°±0.2°的特征峰。
4.根据权利要求3所述的有机酸锂氨基酸盐晶型,其特征在于,其X射线粉末衍射谱图中具有衍射角2θ为7.909°±0.2°、8.201°±0.2°、11.735°±0.2°、16.525°±0.2°、20.395°±0.2°、23.669°±0.2°、24.930°±0.2°、30.232°±0.2°、31.427°±0.2°、33.451°±0.2°的特征峰。
5.根据权利要求3所述的有机酸锂氨基酸盐晶型,其特征在于,其X射线粉末衍射谱图中具有衍射角2θ为7.909°、8.201、11.735°、16.525°、20.395°、23.669°、24.930°、30.232°、31.427°、33.451°的特征峰;或者其X射线粉末衍射谱图中具有衍射角2θ为8.255°、11.782°、16.584°、16.811°、18.711°、18.800°、20.451°、23.715°、25.017°、25.040°、30.281°、31.490°、33.537°、35.886°的特征峰。
6.一种权利要求1~2任一项所述的有机酸锂氨基酸盐或权利要求3~5任一项所述的晶型的制备方法,其特征在于,采用单一溶剂法或混合溶剂析晶法进行制备。
7.根据权利要求6所述的制备方法,其特征在于:
单一溶剂法中,将所述有机酸锂和所述氨基酸中加入适量溶剂,加热回流1-5小时,趁热过滤,自然冷却析晶;
混合溶剂析晶法中,将所述有机酸锂和所述氨基酸中加入适量的良溶剂,加热回流溶解后加入适量不良溶剂析出固体,补加良溶剂重新溶解,回流1-5小时,自然冷却析晶。
8.根据权利要求6或7所述的制备方法,其特征在于:所述的单一溶剂法中,溶剂为正丁醇;所述的混合溶剂析晶法中,良溶剂为乙醇,不良溶剂为四氢呋喃。
9.一种药物组合物,其特征在于,含有权利要求1~2任一项所述的有机酸锂氨基酸盐或权利要求3~5任一项所述的晶型。
10.一种权利要求1~2任一项所述的有机酸锂氨基酸盐或权利要求3~5任一项所述的晶型、权利要求9所述的药物组合物在制备治疗神经退行性疾病或精神疾病的药物中的应用。
11.根据权利要求10所述的应用,其特征在于,所述神经退行性疾病为阿尔茨海默病、帕金森病、亨廷顿病、癫痫、肌萎缩性侧索硬化、脊髓小脑共济失调中的一种或多种。
12.根据权利要求10所述的应用,其特征在于,所述精神疾病为轻度、中度、重度抑郁症以及双相情感障碍中的一种或多种。
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