CN112979681B - 一种具有神经康复作用的含硫化合物及其应用 - Google Patents
一种具有神经康复作用的含硫化合物及其应用 Download PDFInfo
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Abstract
本发明涉及一种具有神经康复作用的含硫化合物,其对脑中风等脑神经损伤疾病具有很好的治疗与康复作用,与现有药物相比,显示出实质性的科学进步和突出的有益效果。
Description
技术领域
本发明涉及药物化学领域,具体涉及一种具有神经康复作用的含硫化合物,本发明还涉及所述化合物的制备方法、药物组合物及用途。
背景技术
脑出血(intracerebral hemorrhage,ICH)是急性脑血管病的主要病种之一,是神经内、外科的常见病症,具有发病危急、致残率高和致死率高等特点,原发性脑神经损伤通常在出血后数小时内发生,颅内出现血肿后血肿扩散速度极快,若得不到及时治疗,可能出现脑水肿,损害神经功能。由于继发性损伤,大多数病例的神经功能进一步下降。
目前的药物治疗脑卒中引起的脑神经损伤旨在阻断缺血导致的神经元坏死、延长耐受性缺血时间和治疗时间窗,增强神经元生存能力,逆转半暗带,减少梗死体积,促进神经功能恢复。因此,开发和研究具有治疗神经康复活性的新化合物具有重要的临床意义。
Fenazinel dihydrochloride是具有抗局灶性脑卒中作用和对受损脑神经元有保护功能的芳烷甲酰基哌嗪类化合物,动物试验表明,其在大鼠全脑缺血和局灶性脑缺血模型中,口服或静脉注射盐酸非那嗪奈都有效,不仅显著减少梗塞面积,而且能保护受损的脑神经细胞,改善卒中预后,为患者进一步康复治疗赢得宝贵时间。
蛋白质激酶是催化蛋白质中特定残基磷酸化的酶家族,大致可分为酪氨酸激酶和丝氨酸/苏氨酸激酶,由于突变,过度表达或不适当的调节以及生长因子或细胞因子的过量或不足生产引起的激酶活性不正常与神经系统、神经退行性疾病等密切相关。
综上所述,虽然各种化学药和天然药物处于不同研究阶段,但目前上市的预防或治疗脑神经损伤药物中尚未有运用药效团融合等手段将Fenazinel和JAK激酶抑制剂整合在一起的药物。
发明内容
本发明所要解决的技术问题是:
优选地,所述药学上可接受的盐选自:盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、乙酸盐、草酸盐、酒石酸盐;
具体反应步骤如下:
(1)将化合物2用三氟乙酸溶解,升至55℃反应至TLC检测反应结束,将反应液减压浓缩、硅胶柱层析得到化合物3;
(2)将化合物3溶于丙酮中,室温下分别加入化合物4、无机碱和碘化钾,升温至回流反应至TLC检测反应结束,将反应液冷却至室温,抽滤,滤液经减压浓缩、甲醇重结晶制得化合物1。
优选地,步骤(2)所述无机碱选自碳酸钾、碳酸钠、氢氧化钠中的至少一种。
本发明的另一方面提供一种药物组合物,其包含式1所示的化合物或其药学上可接受的盐,以及药学上可接受的载体、赋形剂。
本发明另一方面涉及一种式1所示化合物或其药学上可接受的盐或包含其药物组合物在制备治疗或预防脑神经损伤的药物中的应用;优选地,所述脑神经损伤为脑出血所引起的损伤。
与现有技术相比,本发明的有益效果是:
(1)本发明提供了一类新的具有神经康复作用的含硫化合物,拓宽了现有技术的范围,可作为先导化合物继续优化;
(2)本发明式1所示的化合物在药理试验中,显示出良好的治疗活性,能够用于预防和治疗脑神经损伤。
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。本发明化合物可以用合成领域技术人员熟知的许多方法来制备。式6化合物可以使用下面列出的反应和技术连同合成有机化学领域已知的方法或本领域技术人员所理解的其变体来制备。优选的方法包括但不限于下面描述的那些方法。反应在适用于所用试剂和材料且适用于要实现的转化的溶剂中进行。此外,在下面描述的合成方法中,应理解所有建议的反应条件(包括溶剂、反应气氛、反应温度、实验持续时间和后处理程序的选择)都选择为该反应的标准条件,这应该被有机合成领域技术人员容易确认。并非所有落入给定类别的化合物可以与某些所述方法中需要的某些反应条件相容。对与反应条件相容的取代基的这些限制将对于本领域技术人员而言是显而易见的,并且可使用替代方法。
实施例1:化合物1的合成
(1)将化合物2(0.1mol)用三氟乙酸80mL溶解,油浴升温至55℃反应至TLC检测反应结束,将反应液冷却至室温,减压浓缩、反相柱层析梯度洗脱(乙腈:水=0-100%)得到淡黄色油状物化合物3,收率45%,HPLC纯度97.3%;
(2)将0.05mol化合物3溶于50mL丙酮中,室温下分别加入0.05mol化合物4、0.1mol碳酸钾和5.0mmol碘化钾,升温至回流反应至TLC检测反应结束,将反应液冷却至室温,抽滤,滤液经减压浓缩、甲醇重结晶制得白色晶体状化合物1,收率86%,HPLC纯度99.6%。
分子式:C22H25N3O2S;ESI-MS:396.61[M+H]+
1H NMR(400MHz,CDCl3):δ2.23-2.60(m,4H),2.69-2.95(m,3H),3.26(s,2H),3.61(m,3H),4.32(s,2H),7.19-7.30(m,5H),7.55-7.70(m,3H),8.15(m,2H)。
实施例2:式1所示化合物谷氨酸诱导的神经元兴奋作用的药效学筛选研究
在细胞模型上观察谷氨酸诱发的神经元损伤以及目标受试化合物可能的神经保护作用,并与阳性受试品比较。
1、动物及材料
化合物1,自制,HPLC纯度99.0%;DW-2000 脑立体定位仪(成都泰盟软件有限公司); 阳性对照品Fenazinel dihydrochloride,购自上海医药工业研究院;无菌PBS购自上海远慕生物科技有限公司;SH-SY5Y人神经母细胞癌细胞购自上海酶联生物科技有限公司。
2、实验方法
2.1 细胞培养
SY5Y细胞培养在含有10%胎牛血清的DMEM培养基中进行,37℃,5%CO2,每3天换液1次,细胞生长至第3-4代,待其融合80%时,用0.25@的胰酶消化,并收集计数,调整细胞密度为2*104个/mL,每孔100μL加入96孔板内,经24h贴壁,给药处理。
2.2 谷氨酸处理
细胞分为正常培养组、模型组、给药组合阳性对照组,细胞经药物处理后,除正常组和模型组外,各给药组先给予不同浓度受试物预处理0.5h后,再与100nM谷氨酸孵育24h。24h后做MTT分析,测定细胞存活率。具体地,每孔加入5mg/mL MTT溶液,使其终浓度为0.5mg/mL,在培养箱内继续培养4h,然后丢弃培液,每孔加入200μL DMSO,在酶标仪上读取光密度OD值(测定波长570nm)。细胞存活率(%)=【(给药组OD值-调零孔OD值)/(正常组OD值-调零孔OD值)】*100%。
3、实验结果
试验结果表明:化合物1具有一定的对抗谷氨酸诱发的神经元兴奋毒性的保护作用,与同剂量的Fenazinel dihydrochloride相比,神经元保护活性更强。
表1 化合物1对谷氨酸引起的神经元损伤模型的影响
以上描述了本发明优选实施方式,然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。
Claims (6)
2.根据权利要求1所述的式1化合物或其药学上可接受的盐,所述药学上可接受的盐选自:盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、乙酸盐、草酸盐、酒石酸盐。
4.一种药物组合物,其包含权利要求1-2任一项所述式1所示化合物或其药学上可接受的盐,以及药学上可接受的载体。
5.权利要求1-2任一项所述的式1所示的化合物或其药学上可接受的盐或权利要求4所述药物组合物在制备治疗或预防脑神经损伤的药物中的应用。
6.根据权利要求5所述的应用,其特征在于,所述脑神经损伤为脑出血所引起的神经损伤。
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芳甲酰烷基哌嗪类化合物的合成及抗脑缺氧缺血活性;李建其 等;《中国药物化学杂志》;20060228;第16卷(第1期);第6-14页 * |
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