CN114907425A - 一种异喹啉生物碱衍生物及其制备和用途 - Google Patents
一种异喹啉生物碱衍生物及其制备和用途 Download PDFInfo
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Abstract
Description
技术领域
本发明属于天然药物化学领域,涉及一种异喹啉生物碱衍生物的制备方法及其在神经系统疾病预防或治疗中的相关应用。
背景技术
防己科蝙蝠葛属(Menispermum L.)是一个小属,主要分布于亚洲和北美洲东部,包括两种,一种是主要分布于亚洲东部的蝙蝠葛(M.dauricum DC.),另一种是主产于北美洲东部的加拿大蝙蝠葛(M.canadense L.)。蝙蝠葛主要分布在中国东部、西伯利亚、韩国和日本。广泛的研究表明,蝙蝠葛属植物的主要成分是异喹啉生物碱,且表现出广泛的生物活性,如抗菌,抗炎,抗肿瘤等。在药物发现和开发过程中,异喹啉生物碱具有很高的成功机率,比较成功的例子如止痛药吗啡,抗菌小檗碱,止咳药可待因,抗风湿的青藤碱和乙酰胆碱酯酶抑制剂加兰他敏等都是异喹啉生物碱。蝙蝠葛根,又名北豆根,为蝙蝠葛(Menispermum dauricum DC.)的根茎,是传统的中药,2010年被纳入药典,可用于治疗扁桃体炎,风湿性关节炎,腹泻,痢疾,肠胃炎,心血管疾病和血栓形成疾病等。北豆根中的异喹啉生物碱主要包括双苄基异喹啉类、苄基异喹啉类、啊朴啡类、原小檗碱类和吗啡烷类等几个亚类。其中,蝙蝠葛碱和蝙蝠葛苏林碱作为其标志性的成分,其本身以及它们的衍生物具有抗心律失常、降压作用等。除此之外,北豆根中还含有丰富的微量生物碱值得研究和开发。在前期的工作中,已经分离并发现了一些新的生物碱成分,因此,为了继续找到更多有活性的先导化合物,对蝙蝠葛根进行更深入的物质研究是非常有意义的。
发明内容
本发明提供了一种异喹啉生物碱衍生物的制备方法及其在神经系统疾病预防或治疗中的相关应用,所述衍生物的结构通式如下所示:
其中:
R1~R6分别独立地选自为氢、卤素(F、Cl、Br、I中的一种)、羟基、羧基、C1~C6的烷氧基、糖基、C1~C6的烷基、C2~C6的烯基、苯基或带有取代基的苯基,其中所述取代基为C1~C6的烷基、C1~C6的烷氧基、C1~C6的醇羟基、糖基或酯糖基中的一种或几种。
进一步地,化合物1和2的结构如式A2所示
进一步地,R1选自甲基,R2选自羟基,R3选自羟基,R4选自氢,R6选自O-β-D-葡萄糖的衍生物,化合物3结构如式A3所示
进一步地,化合物3的1位的立体构型优选(S)。
进一步地,所述通式B衍生物,R1选自甲氧基,R2选自羟基,R3选自氢,R4选自甲氧基,R5选自O-β-D-葡萄糖,14位的立体构型为S,化合物4如式B1所示
本发明还提供一种制备上述化合物1-4的方法,其特征在于包括以下步骤:
(1)药材提取:北豆根干燥药材1公斤~100公斤,每公斤药材加入6~10L体积分数50%~90%的乙醇浸泡,浸泡1~24h,加热至50℃~90℃回流提取1~3h,过滤得提取液;共回流提取1~5次,合并提取液,所得的提取液浓缩至按每公斤药材计0.3~0.6L,即得北豆根提取液;
(2)总碱制备:在上述北豆根提取液中加入体积浓度0.1%~3%的硫酸调pH至1~4后,加入该酸调后的提取液体积的1~3倍体积的乙酸乙酯萃取,分层,获得乙酸乙酯萃取层和酸水层,共萃取1~5次,再在酸水层中加入弱碱调pH至8~10,接着加入碱调后的样品体积的1~3倍体积的正丁醇萃取,分层,获得正丁醇和碱水层,共萃取1~5次,合并有机层,浓缩,即得北豆根粗碱,然后通过离子交换色谱柱,脱色除杂,即得精制的总碱;
(3)将步骤(2)所得总碱采用C18HCE填料(粒径5~60um)的反相柱进行分离纯化,采用体积比为0:100~100:0的(体积浓度0.01%~5%)甲酸-甲醇/(体积浓度0.01%~5%)甲酸-水溶液洗脱,得到馏分F1~F8;
(4)将步骤(3)所得子馏分F2经过反相制备级HPLC制备,色谱柱为C8CE固定相(5~60μm,20×250~100×250mm),流动相A为(体积分数0.01%~10%的质量浓度为25%~28%的氨水)-甲醇,B为(体积分数0.01%~10%)的(质量浓度为25%氨水)-水,洗脱梯度为0~80分钟,0%A~95%A,共得到11个子馏分,分别为F2-1~F2-10;
(5)将步骤(3)所得子馏分F6经过反相制备级HPLC制备,色谱柱为C18CE固定相(5~60μm,20×250~100×250mm),流动相A为(体积分数0.01%~10%)氨水-甲醇,B为(体积分数0.01%~10%)(质量浓度为25%~28%的氨水)-水,洗脱梯度为0~80分钟,0%A~95%A(V/V),按峰收集,共得到8个子馏分,分别为F6-1~F6-8;
(6)将步骤(4)所得子馏分F2-7(1)经过制备级HPLC制备,色谱柱采用C18ME固定相(5~60μm,4.6×250~50×250mm),流动相为乙腈和水(各含体积分数0.01~1%的三氟乙酸),洗脱梯度为0~60分钟,5%A~95%A,所得馏分再经过C18CE(5~60μm,4.6×250~20×250mm),洗脱梯度为0~60分钟,0%A~90%A,所得馏分再继续通过C18HCE固定相(5~60μm,4.6×250~20×250mm),流动相A为体积分数(0.01~1%)甲酸-甲醇,B为体积分数(0.01~1%)甲酸-水,洗脱梯度为0~40分钟,0%A~90%A(V/V),按峰收集,得到化合物2和4;
(7)将步骤(4)所得子馏分F2-7(2)经过制备级HPLC制备,色谱柱采用SCX(5~60μm,4.6×250~20×250mm),流动相为乙腈(A)和水(B)(含体积分数10mM~100mM的三氟乙酸钠)和水(C)(含体积分数10mM~100mM的磷酸二氢钠,加磷酸,调pH至2~5),洗脱梯度为0~60分钟,5%A~95%A,所得馏分再经过C18CE(5~60μm,4.6×250~20×250mm),洗脱梯度为0~60分钟,0%A~90%A,所得馏分通过C18HCE固定相(5~60μm,4.6×250~20×250mm),流动相A为甲醇,B为体积分数(0.01~1%)甲酸-水,洗脱梯度为0~40分钟,0%A~90%A(V/V),所得馏分再继续通过C18HCE固定相(5~60μm,4.6×250~20×250mm),流动相A为乙腈,B为体积分数(0.01~1%)甲酸-水,洗脱梯度为0~40分钟,0%A~90%A(V/V),按峰收集,得到化合物1;
(8)将步骤(5)所得子馏分F6-4经过制备级HPLC制备,色谱柱采用C18ME固定相(5~60μm,4.6×250~50×250mm),流动相为乙腈和水(各含体积分数0.01~1%的三氟乙酸),洗脱梯度为0~60分钟,5%A~95%A,所得馏分再经过C18CE(5~60μm,4.6×250~20×250mm),洗脱梯度为0~60分钟,0%A~90%A,所得馏分再继续通过C18HCE固定相(5~60μm,4.6×250~20×250mm),流动相A为体积分数(0.01~1%)甲酸-甲醇,B为体积分数(0.01~1%)甲酸-水,洗脱梯度为0~40分钟,0%A~90%A(V/V),按峰收集,得到化合物3;
本发明中:所述糖基是指包括但不限于葡萄糖基、葡萄糖醛酸基、甘露糖基、半乳糖基、阿洛糖基、果糖基、山梨糖基、夫糖基、鼠李糖基、鸡纳糖基、阿拉伯糖基、来苏糖基、木糖基、核糖基,以及由上述单糖所形成的各种二糖基及多糖基;所述C1~C6的烷基是指C1、C2、C3、C4、C5、C6的烷基,即具有1~6个碳原子的直链或支链的烷基;C1~C6的烯基是指C1、C2、C3、C4、C5、C6的烷基,即具有1~6个碳原子的直链或支链的烯基,具有1~6个双键的直链或支链的烯基。
本发明的另一个目的是,提供一种新的异喹啉生物碱衍生物,或其晶型、或其异构体或其药学形式上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物作为活性成分,或由所述的任一种或几种作为多巴胺D1受体配体,在制备预防和/或治疗与镇痛、精神分裂症等相关的神经疾病药物开发研究中。
所述疾病包括但不限于镇痛、精神分裂症等。所述与多巴胺受体相关精神疾病包括但不限于疼痛、药物滥用、帕金森、亨廷顿、精神分裂、阿茨海默、抑郁等。
所述药物组合物是指本发明的一种或多种化合物可以彼此联合使用,也可选择将本发明的化合物与任何其它活性试剂结合使用。如果使用的是一组化合物,则可将这些化合物同时、分别或有序地对受试对象进行给药。本发明中药物组合物中活性成分(即本发明化合物)的量可以根据患者的病情、医生诊断的情况特定的加以应用,活性化合物的剂量或浓度在一个较宽的范围内调节,活性化合物的含量范围为药物组合物的1%~90%。
所述化合物经多巴胺D1受体靶点测试表明具有一定的药理活性,可用于制备预防或治疗与D1受体等相关疾病的药物开发中。
显然,根据本发明的上述内容,按照本科领域的普通技术知识和惯用手段,在不脱离本发明的上述基本技术思想前提下,还可以做出其他多种形式的修改、替换或变更。
附图说明
图1化合物1-4的制备流程图
图2化合物1-4的ESI+一级质谱图
图3化合物1-4的1H NMR谱图和13C NMR谱图
图4化合物1-4的1H,1H-COSY和HMBC相关
图5化合物1-4的D1受体拮抗活性测定:在HEK-293-D1细胞上的剂量响应曲线。
具体实施方式
以下实施例旨在说明本发明而不是本发明的进一步限定,本发明可以按发明内容所述的任一方式实施。
本发明式(Ⅰ)化合物的制备实施例:
化合物制备
北豆根药材100公斤,
(1)药材提取:称取100kg北豆根药材,加入1000L体积浓度为70%的乙醇,浸泡24h,60℃加热回流提取2h,抽滤后获得提取液1,将过滤后的滤渣再加入1000L体积浓度为70%的乙醇,60℃加热回流提取2h,过滤后获得提取液2,继续将过滤后的滤渣再加入1000L体积浓度为70%的乙醇,60℃加热回流提取2h,过滤后获得提取液3,合并提取液1~3,浓缩至50L,即获得北豆根提取液。
(2)总碱制备:在北豆根提取液中加入体积浓度为1%的稀硫酸调pH至2~3之间,然后加入与该酸调后的提取液相同体积的乙酸乙酯萃取第一次,静置分层,获得乙酸乙酯萃取层1和酸水层1,然后在酸水层1中继续加入体积浓度0.2%的稀硫酸调pH至2~3之间,然后加入与该酸调后的提取液相同体积的乙酸乙酯萃取第二次,即得乙酸乙酯层2和酸水层2,然后在酸水层2中加入体积浓度1%的稀硫酸调pH至2~3之间,然后加入与该酸调后的提取液相同体积的乙酸乙酯萃取第三次,即得乙酸乙酯层3和酸水层3。在酸水层3中加入质量浓度为25%~28%的氨水调pH至9~10之间,加入与碱调后的样品相同体积的正丁醇萃取,静置分层,即得正丁醇层1和碱水层1,然后在碱水层1中加入质量浓度为25%~28%的氨水调pH至9~10之间,然后加入与该碱调后的提取液相同体积的正丁醇萃取第二次,即得正丁醇层2和碱水层2。然后在碱水层2中加入质量浓度为25%~28%的氨水调pH至9~10之间,然后加入与该碱调后的提取液相同体积的正丁醇萃取第三次,即得正丁醇层3和碱水层3,合并正丁醇层1~3并浓缩成浸膏,采用甲醇复溶至12L,取10ml浓缩测固含量约为500g/L,计算即得北豆根粗碱约6.0kg,占药材质量的6.0%。以此计算,取约1L甲醇复溶的粗碱样品,加入1L纯水稀释溶解,离心过滤获得上清液,然后上清液通过琼脂糖凝胶基质的离子交换Q柱,脱色除杂,即得精制的总碱约500g,回收率约97%。
(3)将步骤(2)所得总碱采用反相制备级HPLC制备,色谱柱固定相为C18HCE(粒径10um,直径与高100×250mm)的反相柱进行分离纯化,流速300mL/min,流动相为甲醇(A)和水(B)(它们中分别各含体积浓度0.1%的甲酸),洗脱梯度为0-10min,0%B(体积比);10-20min,10%B;20-35min,20%B;35-45min,25%B;45-60min,30%B;60-75min,90%B洗脱,得到8个馏分分别为F1(RT:0~17min),F2(RT:17~24min),F3(RT:24~28min),F4(RT:28~32.5min),F5(RT:32.5~38.5min),F6(RT:38.5~52min),F7(RT:52~62min),F8(RT:62~74min);
(4)将步骤(3)所得子馏分F2经过反相制备级HPLC制备,色谱柱为C8GE固定相(粒径10μm,直径与高100×250mm),流速300mL/min,流动相为甲醇(A)和水(B,为含体积分数0.01%的质量浓度为25%~28%的氨水),洗脱梯度为0~40min,5%~95%A(线性梯度);40~50min,95%A(体积比),共得到11个子馏分,分别为F2-1(RT:4~6min),F2-2(RT:6~8min),F2-3(RT:8~12min),F2-4(RT:12~15min),F2-5(RT:15~18min),F2-6(RT:18~20min),F2-7(1)(RT:20~25min),F2-7(2)(RT:25~28min),F2-8(RT:28~31min),F2-9(RT:31~33min),F2-10(RT:33~37min);
(5)将步骤(3)所得子馏分F6经过反相制备级HPLC制备,色谱柱为C8GE固定相(粒径10μm,直径与高100×250mm),流速300mL/min,流动相为甲醇(A)和水(B,含体积分数为0.03%的质量浓度为25%~28%的氨水),洗脱梯度为0~30min,10%~95%A(线性梯度),30~40min,95%A(体积比),共得到8个子馏分,分别为F6-1(RT:2~7min),F6-2(RT:7~11min),F6-3(RT:11~13min),F6-4(RT:13~17min),F6-5(RT:17~22min),F6-6(RT:22~27min),F6-7(RT:27~31min),F6-8(RT:31~35min);
(6)将步骤(4)所得子馏分F2-7(1)经过制备级HPLC制备,色谱柱采用C18ME固定相(粒径7μm,直径与高30×250mm)。流速30mL/min,流动相为乙腈(A)和水(B)(它们中分别各含体积分数0.1%的三氟乙酸),洗脱梯度为0-20min,10%-20%A(线性梯度),20-30min,90%A(体积比)。所得馏分F2-7(1)-4(RT:11~13.5min)再经过C18CE(粒径7μm,直径与高10×250mm),流速3mL/min,流动相为甲醇(A)和水(B)(它们中分别各含体积分数0.05%的乙酸三乙胺(乙酸:三乙胺的体积比为1:3),pH 10.5),洗脱梯度为0-20min,15%-70%A(线性梯度),20-30min,70%-85%A(线性梯度)。所得馏分F2-7(1)-4-6(RT:12~15min)和F2-7(1)-4-8(RT:18.5~19.5min)再分别继续通过C18HCE固定相(粒径7μm,直径与高10×250mm),流动相A和B分别为甲醇和水(含体积分数0.1%甲酸),F2-7(1)-4-6的洗脱梯度为0~15min,8%A(体积比),F2-7(1)-4-8的洗脱梯度为0~15min,7%A(体积比),收集主峰,分别得到化合物2和4;
(7)将步骤(4)所得子馏分F2-7(2)经过制备级HPLC制备,色谱柱采用SCX(粒径7μm,直径与高10×250mm),流动相为乙腈(A)和水(B)(含体积分数100mM的三氟乙酸钠)和水(C)(含体积分数100mM的磷酸二氢钠,加磷酸,调pH 2.8),洗脱梯度为0~40min,40%A,30%B,30%C(体积比);所得馏分F2-7(2)-1(RT:13.0~14.5min)再经过C18HCE(粒径7μm,直径与高10×250mm),流动相A和B分别为甲醇和水(含体积分数0.1%甲酸),洗脱梯度为0~30min,5%A~30%A(体积比);所得馏分F2-7(2)-1-1(RT:15.0~18.5min)再继续通过C18HCE固定相(粒径7μm,直径与高10×250mm),流动相A为乙腈,B为体积分数(0.1%)甲酸-水,洗脱梯度为0~30min,5%A~20%A(V/V),按峰收集,得到化合物1;
(8)将步骤(5)所得子馏分F6-4经过制备级HPLC制备,色谱柱采用C18ME固定相(粒径7μm,直径与高30×250mm)。流速30mL/min,流动相为乙腈(A)和水(B)(各含体积分数0.1%的三氟乙酸),洗脱梯度为0-50min,15%-27.5%A(线性梯度),50-60min,27.5%-40%A,60-70min,95%A(体积比)。所得馏分F6-4-2(RT:12~26min)再经过C18CE(粒径7μm,直径与高10×250mm),流速3mL/min,流动相为甲醇(A)和水(B)(它们中分别各含体积分数0.05%的乙酸三乙胺(乙酸:三乙胺的体积比为1:3,pH 10.5),洗脱梯度为0-20min,30%-85%A(线性梯度),20-30min,85%A(体积比)。所得馏分F6-4-2-6(RT:13.7~15min)再继续通过C18HCE固定相(粒径7μm,直径与高10×250mm),流动相A和B分别为甲醇和水(含体积分数0.1%甲酸),洗脱梯度为0~20min,21%A(体积比),收集主峰收集得到化合物3;
(5)所述化合物1-4,其结构通过紫外、质谱以及核磁表征确定,信息如下:化合物1:20mg,C24H31NO8,MW:461.2050,白色粉末,溶于甲醇。
1H-NMR(CD3OD,600MHz)δ4.44(1H,dd,J=8.2,5.4,H-1),δ3.65(1H,m,H-3α),δ3.33-3.28(1H,overlap,H-3β),δ3.13-3.06(1H,overlap,H-4α),δ2.99(1H,ddd,J=17.4,6.3,3.0,H-4β),δ6.78(1H,s,H-5),δ6.13(1H,s,H-8),δ3.33-3.28(1H,overlap,H-9α),δ3.13-3.06(1H,overlap,H-9β),δ7.10(1H,m,H-10),δ7.06(1H,m,H-11),δ7.06(1H,m,H-13),δ7.10(1H,m,H-14),δ4.90(1H,d,J=7.3,H-1′),δ3.47-3.45(1H,overlap,H-2′),δ3.44-3.42(1H,overlap,H-3′),δ3.40(1H,m,H-4′),δ3.47-3.45(1H,overlap,H-5′),δ3.90(1H,dd,J=12.1,2.3,H-6′α),δ3.69(1H,dd,J=12.0,5.7,H-6′β),δ2.88(3H,s,2-NCH3),δ3.84(3H,s,6-OCH3).
13C-NMR(CD3OD,150MHz)δ66.0(C-1),δ46.9(C-3),δ23.4(C-4),δ122.2(C-4a),δ112.6(C-5),δ149.5(C-6),δ146.4(C-7),δ115.7(C-8),δ124.1(C-8a),δ40.3(C-9),δ126.9(C-9a),δ131.8(C-10),δ118.1(C-11),δ158.5(C-12),δ118.1(C-13),δ131.8(C-14),δ102.3(C-1′),δ74.9(C-2′),δ78.0(C-3′),δ71.4(C-4′),δ78.2(C-5′),δ62.6(C-6′),δ40.8(2-NCH3),δ56.4(6-OCH3).
化合物2:10mg,C23H29NO8,MW:447.1893,白色粉末,溶于甲醇。
1H-NMR(CD3OD,600MHz)δ4.64(1H,dd,J=6.8,6.8,H-1),δ3.48-3.45(1H,overlap,H-3α),δ3.28(1H,m,H-3β),δ3.85-3.80(2H,overlap,H2-4),δ6.77(1H,s,H-5),δ6.62(1H,s,H-8),δ3.41-3.39(1H,overlap,H-9α),δ3.08-3.05(1H,overlap,H-9β),δ7.24(1H,m,H-10),δ7.11(1H,m,H-11),δ7.11(1H,m,H-13),δ7.24(1H,m,H-14),δ4.91(1H,d,J=7.3,H-1′),δ3.48-3.45(1H,overlap,H-2′),δ3.46-3.45(1H,overlap,H-3′),δ3.40(1H,m,H-4′),δ3.48-3.45(1H,overlap,H-5′),δ3.89(1H,dd,J=12.0,2.3,H-6′α),δ3.69(1H,dd,J=12.0,5.7,H-6′β),δ3.85(3H,s,6-OCH3).
13C-NMR(CD3OD,150MHz)δ57.6(C-1),δ40.8(C-3),δ25.9(C-4),δ123.7(C-4a),δ112.7(C-5),δ149.3(C-6),δ146.8(C-7),δ114.2(C-8),δ125.1(C-8a),δ40.4(C-9),δ130.4(C-9a),δ131.7(C-10),δ118.4(C-11),δ158.7(C-12),δ118.4(C-13),δ131.7(C-14),δ102.3(C-1′),δ74.9(C-2′),δ78.0(C-3′),δ71.4(C-4′),δ78.2(C-5′),δ62.6(C-6′),δ56.4(6-OCH3).
化合物3:2.0mg,C33H39NO13,MW:657.2421,棕色粉末,溶于甲醇。
1H-NMR(CD3OD,600MHz)δ4.14(1H,dd,J=9.0,4.0,H-1),δ3.54-3.52(1H,overlap,H-3α),δ3.24(1H,m,H-3β),δ3.11(1H,m,H-4α),δ2.99(1H,m,H-4β),δ6.75(1H,s,H-5),δ5.97(1H,s,H-8),δ3.11(1H,dd,J=14.0,4.0,H-9α),δ2.85(1H,dd,J=14.0,9.0,H-9β),δ6.57(1H,s,H-10),δ6.94(1H,d,J=8.3,H-13),δ6.10(1H,d,J=7.9,H-14),δ4.79(1H,d,J=7.5,H-1′),δ3.54-3.52(1H,overlap,H-2′),δ3.54-3.52(1H,overlap,H-3′),δ3.43(1H,m,H-4′),δ3.83-3.82(1H,overlap,H-5′),δ4.68(1H,dd,J=11.8,2.4,H-6′α),δ4.54(1H,dd,J=11.8,8.0,H-6′β),δ7.38(1H,s,H-2″),δ7.38(1H,s,H-6″),δ3.83(3H,s,3″-OCH3),δ3.83(2H,s,4″-CH2OH),δ3.83(3H,s,5″-OCH3).
13C-NMR(CD3OD,150MHz)δ65.9(C-1),δ47.0(C-3),δ23.8(C-4),δ122.4(C-4a),δ112.6(C-5),δ149.3(C-6),δ146.1(C-7),δ115.6(C-8),δ124.9(C-8a),δ40.4(C-9),δ132.4(C-9a),δ118.4(C-10),δ148.3(C-11),δ145.8(C-12),δ118.2(C-13),δ121.7(C-14),δ167.7(C-15),δ103.6(C-1′),δ74.8(C-2′),δ77.6(C-3′),δ72.3(C-4′),δ75.7(C-5′),δ65.1(C-6′),δ121.5(C-1″),δ108.7(C-2″),δ149.0(C-3″),δ142.1(C-4″),δ149.0(C-5″),δ108.7(C-6″),δ57.0(3″-OCH3),δ56.3(4″-CH2OH),δ57.0(5″-OCH3).
化合物4:12mg,C25H31NO9,MW:489.1999,白色粉末,溶于甲醇。
1H-NMR(CD3OD,600MHz)δ6.90(1H,s,H-1),δ6.64(1H,s,H-4),δ3.19-3.12(1H,overlap,H-5α),δ2.87(1H,m,H-5β),δ3.56(1H,m,H-6α),δ3.19-3.12(1H,overlap,H-6β),δ4.34(1H,d,J=15.4,H-8α),δ4.21(1H,d,J=15.0,H-8β),δ6.83(1H,s,H-9),δ7.09(1H,s,H-12),δ3.67(1H,dd,J=12.1,5.8,H-13α),δ2.96(1H,dd,J=16.9,11.7,H-13α),δ4.31(1H,dd,J=11.6,4.5,H-14),δ4.90(1H,d,J=7.4,H-1′),δ3.50(1H,q,J=9.0,H-2′),δ3.46(1H,t,J=8.8,H-3′),δ3.37(1H,q,J=10.0,H-4′),δ3.42(1H,m,H-5′),δ3.90-3.87(1H,overlap,H-6′α),δ3.67(1H,dd,J=12.1,5.8,H-6′β),δ7.38(1H,s,H-2″),δ7.38(1H,s,H-6″),δ3.88(3H,s,2-OCH3),δ3.85(3H,s,10-OCH3).
13C-NMR(CD3OD,150MHz)δ109.7(C-1),δ148.5(C-2),δ147.5(C-3),δ116.0(C-4),δ125.6(C-4a),δ27.3(C-5),δ51.7(C-6),δ57.1(C-8),δ124.7(C-8a),δ110.9(C-9),δ149.9(C-10),δ147.7(C-11),δ117.8(C-12),δ125.7(C-12a),δ34.8(C-13),δ61.2(C-14),δ121.8(C-14a),δ102.6(C-1′),δ74.8(C-2′),δ77.9(C-3′),δ71.4(C-4′),δ78.3(C-5′),δ62.5(C-6′),δ56.7(2-OCH3),δ56.6(10-OCH3).
活性试验实施例:
样品制备的新化合物;HEK-293-D1稳转细胞来构建参考文献(Xu,F.F.;Zhou,H.;Liu,X.M.;Zhang,X.L.;Wang,Z.W.;Hou,T.;Wang,J.X.;Qu,L.L.;Zhang,P.Y.;Piao,H.L.;Liang,X.M.,Label-free cell phenotypic study of FFA4 and FFA1 and discovery ofnovel agonists of FFA4 from natural products.Rsc Advances 2019,9(26),15073-15083)(所述D1为多巴胺D1受体);多巴胺(货号:KB712097)分别购于上海思域化工科技有限公司;Calcium-6荧光染料试剂盒(货号:3221567)购于MolecularDevices公司,掩蔽染料Amaranth(货号:A1016-50G)购于Sigma公司,DMEM高糖培养液(货号:C11995500BT)购于ThermoFisher公司,胎牛血清(货号:04000101A)购于沈阳汇佰生物科技有限公司;多聚赖氨酸(货号:P2100)购于北京索莱宝科技有限公司;平衡盐溶液HBSS(货号:14065-056)和HEPES(货号:15630-080)购于Gibco公司;FLIPR专用96孔细胞培养板(货号:655090)购于Greiner公司;检测平台高通量实时荧光检测系统(FLIPRTetra),购于Molecular Devices公司。
将处于对数生长期的HEK-293-D1细胞,接种于用多聚赖氨酸(poly-D-lysine,简称PDL)涂层的FLIPR专用96细胞培养板中,每孔的培养液(组成:DMEM+10%胎牛血清(FBS)(v/v))体积为100μL,细胞接种密度为8.0×104个/孔,将接种好的96孔细胞板置于细胞培养箱中37℃培养20~24h,至细胞融合度达95%左右,进行活性检测。将培养好的细胞除去培养基并于每孔中加入100μL荧光染料溶液(Calcium-6)在37℃下恒温孵育1h;除去染料溶液并于每孔加入100μL Amaranth(0.5mg/mL),室温孵育5min;
将化合物1~4分别加入到接种HEK293-D1细胞的微孔板中,化合物1~4配制8个终浓度分别为100μM、25μM、6.25μM、1.56μM、0.39μM、0.097μM、0.024μM、0.006μM,平行3次,溶剂为含20mM HEPES的HBSS缓冲液,置于96孔药物板,记为药物板A;将D1激动剂多巴胺固定终浓度为50nM(溶剂为含20mM HEPES的HBSS缓冲液)置于96孔药物板,记为药物板B;在HEK-293-D1细胞上,采用FLIPR进行化合物1~4拮抗活性表征,将药物板A和B中的样品自动加样到FLIPR细胞板上,每孔加入2个样品的体积各为50μL,在520nm和488nm波长下进行钙流荧光信号检测。检测结果如图5所示,化合物1~4能剂量依赖地拮抗多巴胺的钙流荧光信号,且曲线是单相“S”型,其IC50值分别为0.32±0.06μM,0.97±0.17μM,3.04±1.19μM,3.05±1.9μM,说明化合物1~4具有D1的拮抗活性。
目前的研究表明多巴胺D1受体与精神分裂症、疼痛、抑郁、焦虑、阿兹海默症相关。本发明的化合物对精神分裂症、疼痛、抑郁、焦虑、便秘、肠易激综合症及阿兹海默症等疾病有重要的临床应用。
Claims (10)
5.根据权利要求4所述的衍生物,其特征在于,化合物3的1位的立体构型优选(S)。
7.一种权利要求1-6任一所述的衍生物的制备方法,包括以下步骤:
(1)药材提取:北豆根干燥药材1公斤~100公斤,每公斤药材加入6~10L体积分数50%~90%的乙醇浸泡,浸泡1~24h,加热至50℃~90℃回流提取1~3h,过滤得提取液;共回流提取1~5次,合并提取液,所得的提取液浓缩至按每公斤药材计0.3~0.6L,即得北豆根提取液;
(2)总碱制备:在上述北豆根提取液中加入体积浓度0.1%~3%的硫酸调pH至1~4后,加入该酸调后的提取液体积的1~3倍体积的乙酸乙酯萃取,分层,获得乙酸乙酯萃取层和酸水层,共萃取1~5次(即酸水层再萃取0~4次),再在酸水层中加入弱碱调pH至8~10,接着加入碱调后的样品体积的1~3倍体积的正丁醇萃取,分层,获得正丁醇层和碱水层,共萃取1~5次(即碱水层再萃取0~4次),合并正丁醇层,浓缩,即得北豆根粗碱,然后通过离子交换色谱柱,脱色除杂,即得精制的总碱;
(3)将步骤(2)所得总碱采用C18HCE填料(粒径5~60um)的反相柱进行分离纯化,采用体积比为0:100~100:0的(体积浓度0.01%~5%)甲酸-甲醇/(体积浓度0.01%~5%)甲酸-水溶液洗脱,得到馏分F1~F8;洗脱梯度为0-10min,0%B(体积比);10-20min,10%B;20-35min,20%B;35-45min,25%B;45-60min,30%B;60-75min,90%B洗脱,得到8个馏分分别为F1(RT:0~17min),F2(RT:17~24min),F3(RT:24~28min),F4(RT:28~32.5min),F5(RT:32.5~38.5min),F6(RT:38.5~52min),F7(RT:52~62min),F8(RT:62~74min);
(4)将步骤(3)所得子馏分F2经过反相制备级HPLC制备,色谱柱为C8CE固定相(5~60μm,20×250~100×250mm),流动相A为(体积分数0.01%~10%)的(质量浓度为25%~28%的氨水)-甲醇,B为(体积分数0.01%~10%)的(质量浓度为25%~28%氨水)-水,洗脱梯度为0~80分钟,0%A~95%A,共得到11个子馏分,分别为F2-1~F2-10;洗脱梯度为0~40min,5%~95%A(线性梯度);40~50min,95%A(体积比),共得到11个子馏分,分别为F2-1(RT:4~6min),F2-2(RT:6~8min),F2-3(RT:8~12min),F2-4(RT:12~15min),F2-5(RT:15~18min),F2-6(RT:18~20min),F2-7(1)(RT:20~25min),F2-7(2)(RT:25~28min),F2-8(RT:28~31min),F2-9(RT:31~33min),F2-10(RT:33~37min);
(5)将步骤(3)所得子馏分F6经过反相制备级HPLC制备,色谱柱为C18CE固定相(5~60μm,20×250~100×250mm),流动相A为(体积分数0.01%~10%)氨水-甲醇,B为(体积分数0.01%~10%)(质量浓度为25%~28%的氨水)-水,洗脱梯度为0~80分钟,0%A~95%A(V/V),按峰收集,共得到8个子馏分,分别为F6-1~F6-8;洗脱梯度为0~30min,10%~95%A(线性梯度),30~40min,95%A(体积比),共得到8个子馏分,分别为F6-1(RT:2~7min),F6-2(RT:7~11min),F6-3(RT:11~13min),F6-4(RT:13~17min),F6-5(RT:17~22min),F6-6(RT:22~27min),F6-7(RT:27~31min),F6-8(RT:31~35min);
(6)将步骤(4)所得子馏分F2-7(1)经过制备级HPLC制备,色谱柱采用C18ME固定相(5~60μm,4.6×250~50×250mm),流动相为乙腈和水(各含体积分数0.01~1%的三氟乙酸),洗脱梯度为0~60分钟,5%A~95%A,所得馏分再经过C18CE(5~60μm,4.6×250~20×250mm),洗脱梯度为0~60分钟,0%A~90%A,所得馏分再继续通过C18HCE固定相(5~60μm,4.6×250~20×250mm),流动相A为体积分数(0.01~1%)甲酸-甲醇,B为体积分数(0.01~1%)甲酸-水,洗脱梯度为0~40分钟,0%A~90%A(V/V),按峰收集,得到化合物2和4;
(7)将步骤(4)所得子馏分F2-7(2)经过制备级HPLC制备,色谱柱采用SCX(5~60μm,4.6×250~20×250mm),流动相为乙腈(A)和水(B)(含体积分数10mM~100mM的三氟乙酸钠)和水(C)(含体积分数10mM~100mM的磷酸二氢钠,加磷酸,调pH至2~5),洗脱梯度为0~60分钟,5%A~95%A,所得馏分再经过C18CE(5~60μm,4.6×250~20×250mm),洗脱梯度为0~60分钟,0%A~90%A,所得馏分通过C18HCE固定相(5~60μm,4.6×250~20×250mm),流动相A为甲醇,B为体积分数(0.01~1%)甲酸-水,洗脱梯度为0~40分钟,0%A~90%A(V/V),所得馏分再继续通过C18HCE固定相(5~60μm,4.6×250~20×250mm),流动相A为乙腈,B为体积分数(0.01~1%)甲酸-水,洗脱梯度为0~40分钟,0%A~90%A(V/V),按峰收集,得到化合物1;
(8)将步骤(5)所得子馏分F6-4经过制备级HPLC制备,色谱柱采用C18ME固定相(5~60μm,4.6×250~50×250mm),流动相为乙腈和水(各含体积分数0.01~1%的三氟乙酸),洗脱梯度为0~60分钟,5%A~95%A,所得馏分再经过C18CE(5~60μm,4.6×250~20×250mm),洗脱梯度为0~60分钟,0%A~90%A,所得馏分再继续通过C18HCE固定相(5~60μm,4.6×250~20×250mm),流动相A为体积分数(0.01~1%)甲酸-甲醇,B为体积分数(0.01~1%)甲酸-水,洗脱梯度为0~40分钟,0%A~90%A(V/V),按峰收集,得到化合物3。
8.根据权利要求7所述的衍生物的制备方法,其特征在于,
步骤(1)中回流提取2~5次时,将上次回流提取过程的物料过滤,过滤后的滤渣再按每公斤药材加入6~10L体积分数50%~90%的乙醇,加热至50℃~90℃回流提取1~3h,过滤得提取液;合并提取液;
步骤(2)中乙酸乙酯萃取2~5次时,首先采用体积浓度0.1%~3%的硫酸将上次分层的酸水层调pH至1~4,于酸水层中加入其体积的1~3倍体积的乙酸乙酯萃取,分层,获得乙酸乙酯萃取层和酸水层;
弱碱为质量浓度为10~25%的氨水;
正丁醇萃取2~5次时,首先采用弱碱将上次分层的碱水层调pH至8~10,于碱水层中加入其体积的1~3倍体积的正丁醇萃取分层,获得正丁醇和碱水层。
9.一种权利要求1~6任一项所述化合物1-4,或其晶型、或其异构体、或其糖苷、或其药学形式上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物中的一种或二种以上在制备预防和/或治疗疼痛、药物滥用、帕金森、亨廷顿、精神分裂、阿茨海默、抑郁、焦虑、便秘、肠易激综合症、溃疡、痉挛、慢阻肺、哮喘、膀胱过度活动症等疾病药物中的一种或二种以上中的应用。
10.根据权利要求9所述的药物组合物,其特征在于,其中添加有药学上可接受的辅料制备而成的制剂。
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