CN1944448B - 葛根素衍生物及其药物用途 - Google Patents
葛根素衍生物及其药物用途 Download PDFInfo
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- CN1944448B CN1944448B CN2006100008140A CN200610000814A CN1944448B CN 1944448 B CN1944448 B CN 1944448B CN 2006100008140 A CN2006100008140 A CN 2006100008140A CN 200610000814 A CN200610000814 A CN 200610000814A CN 1944448 B CN1944448 B CN 1944448B
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- Prior art keywords
- puerarin
- substituted
- unsubstituted
- group
- hydrogen
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
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Abstract
本发明公开了通式(I)所示的新葛根素衍生物,其制备方法,含有一个或多个这些化合物成分的药物组合物,和该类化合物在制备与心脑循环有关的疾病,以及视网膜动静脉阻塞,突发性耳聋等疾病和改进记忆,降低血糖的药物中的应用。
Description
技术领域
本发明涉及通式(I)所示的新葛根素衍生物,其制备方法,含有一个或多个这些化合物成分的药物组合物,和该类化合物在制备与心脑循环有关的疾病,以及视网膜动静脉阻塞,突发性耳聋等疾病和改进记忆,降低血糖的药物中的应用。
背景技术
葛根素(puerarin)是从豆科植物野葛(Puerarialobata(Willd.)Ohwi)及甘葛藤(P.thomaonii Benth)的干燥根中提取,分离得到的异黄酮葡萄糖碳苷,化学名为7 4’-二羟基-8-β-D-葡萄糖基异黄酮,是中药葛根中主要活性成分之一,具有较为广泛的药理作用。研究表明葛根素对冠状动脉有扩张作用,能保护全心缺血心肌和心肌缺血再灌注损伤,减少急性心梗面积,降低心肌耗氧量,阻止血小板粘附、聚集和血栓形成;具有疏通视网膜栓塞的作用;并对急性脑缺血有明显的保护作用;而且有改善记忆和降低血糖的功效。
临床上葛根素目前主要用于冠心病、心绞痛、心肌梗塞、缺血性脑血管病和视网膜阻塞等症的治疗。但葛根素的多羟基化学结构决定了它脂溶性差,生物利用度低的缺陷,目前主要以注射形式给药,对于疗程长的心脑血管慢性病长期注射不但给患者带来不便,甚至造成局部组织坏死或感染,增加病人的痛苦。虽然已出现一些片剂、胶囊、颗粒剂,但葛根素口服给药在胃肠道中吸收差,生物利用度低。而且,葛根素的多羟基结构不利于穿越血脑屏障,影响对脑血管疾病的疗效。要从根本上增加葛根素的脂溶性,提高葛根素的生物利用度,改善药效,须对葛根素进行结构修饰与改造。迄今,关于葛根素分子的结构修饰中国药科大学做了部分工作,仅限于对分子的7位、4′位的羟基和11位的羟甲基的修饰,(杨若林,李娜等.中国药科大学学报,1999,30(2):81-85),陕西镇平制药厂对其中的羟乙葛根素作为治疗脑血管病的新药申请了专利(CN1394603A)。本发明在前人的工作之外依据葛根素分子中反应活性不同的各个羟基和苯环上不同的反应位点分别进行了修饰和改造。
本发明的目的在于通过对葛根素分子进行结构修饰与改造,改善其药代动力学性质,提高口服生物利用度,获得性能优良的葛根素衍生物和类似物。
发明内容
本发明的另一目的在于提供制备新型葛根素衍生物方法;
本发明的再一目的在于提供一种含有一个或多个这种化合物的药物组合物;
本发明的又一目的在于提供新型葛根素衍生物在心脑血管相关疾病的药物中的用途。
为了完成本发明之目的,本发明采取如下技术方案:
本发明是涉及具有通式I的新型葛根素衍生物:
其中,
R1和R2分别选自氢,取代或非取代的C1-18烷基,取代或非取代的C3-9环烷基,取代或非取代的芳环、取代或非取代的芳杂环,取代或非取代的C1-18烷酰基、取代或非取代的C1-18烷氧酰基(取代基选自卤素、硝基、羟基、巯基、羧基、酯基、氨基、酰氨基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷酰基、C1-6烷酰氧基、甲磺酰基、氨基甲磺酰基);
更优选的R1和R2是烷酰氧亚甲基,烷氧酰基,氨基低级烷基,羟基低级烷基,羧基低级烷基,烷基,-C(=O)(CH2)nCOOH n=2,3,4,
R3和R4分别选自氢;卤素;硝基;取代或非取代的氨基(取代基选自取代或非取代的C1-18烷基、取代或非取代的C3-9环烷基或含有一种或两种杂原子的环烷基、取代或非取代的芳环、取代或非取代的芳杂环、取代或非取代的C1-18烷酰基、取代或非取代的C3-9环烷或含有一种或两种杂原子的环烷酰基、取代或非取代的芳酰基、取代或非取代的杂环芳酰基、取代或非取代的C3-9环烷或含有一种或两种杂原子的环烷酰氧基、取代或非取代的芳酰氧基、取代或非取代的杂环芳酰氧基、取代或非取代的C1-18烷氧酰基、取代或非取代的C1-18烷基磺酰基、取代或非取代的C3-9环烷或含有一种或两种杂原子的环烷基磺酰基、取代或非取代的芳基磺酰基、取代或非取代的杂环芳基磺酰基(取代基选自卤素、硝基、羟基、巯基、羧基、酯基、氨基、酰氨基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷酰基、C1-6烷酰氧基、甲磺酰基、氨基甲磺酰基),磺酰基,);取代或非取代的羟基(取代基选自取代或非取代的C1-18烷基、取代或非取代的C3-9环烷基或含有一种或两种杂原子的环烷基、取代或非取代的芳环、取代或非取代的芳杂环、取代或非取代的C1-18烷酰基、取代或非取代的C3-9环烷或含有一种或两种杂原子的环烷酰基、取代或非取代的芳酰基、取代或非取代的杂环芳酰基、取代或非取代的C3-9环烷或含有一种或两种杂原子的环烷酰氧基、取代或非取代的芳酰氧基、取代或非取代的杂环芳酰氧基、取代或非取代的C1-18烷氧酰基、取代或非取代的C1-18烷基磺酰基、取代或非取代的C3-9环烷或含有一种或两种杂原子的环烷基磺酰基、取代或非取代的芳基磺酰基、取代或非取代的杂环芳基磺酰基(取代基选自卤素、硝基、羟基、巯基、羧基、酯基、氨基、酰氨基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷酰基、C1-6烷酰氧基、甲磺酰基、氨基甲磺酰基));-OSO3H;-OC(=O)(CH2)nCOOH n=2,3,4;-OP(=O)(OH)2。
更优选的R3和R4是氢,硝基,氨基,N-烷基氨基,N,N-二烷基氨基,烷酰胺基,磺酰氨基,烷基磺酰氨基,羟基烷氨基,羧基烷氨基,卤原子,羟基,烷氧基,烷酰氧基,烷氧酰氧基,氨基烷氧基,羟基烷氧基,羧基烷氧基,烷酰氧亚甲氧基,氨基甲酰烷氧基,-OSO3H,-OC(=O)(CH2)nCOOH n=2,3,4,-OP(=O)(OH)2。
R5选自氢,取代或非取代的C1-18烷基、取代或非取代的C3-9环烷基或含有一种或两种杂原子的环烷基、取代或非取代的芳烷基、取代或非取代的芳杂环、取代或非取代的C1-18烷酰基、取代或非取代的C3-9环烷或含有一种或两种杂原子的环烷酰基、取代或非取代的芳酰基、取代或非取代的杂环芳酰基、取代或非取代的C3-9环烷或含有一种或两种杂原子的环烷酰氧基、取代或非取代的芳酰氧基、取代或非取代的杂环芳酰氧基、取代或非取代的C1-18烷氧酰基、取代或非取代的C1 -18烷基磺酰基、取代或非取代的C3-9环烷或含有一种或两种杂原子的环烷基磺酰基、取代或非取代的芳基磺酰基、取代或非取代的杂环芳基磺酰基(取代基选自卤素、硝基、羟基、巯基、羧基、酯基、氨基、酰氨基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷酰基、C1-6烷酰氧基、甲磺酰基、氨基甲磺酰基));-OSO3H;-OC(=O)(CH2)nCOOHn=2,3,4;-OP(=O)(OH)2。
更优选的是R5选自氢,烷基,芳烷基,烷酰基,烷氧甲酰基,烷酰氧亚甲基,-SO3H,-C(=O)(CH2)nCOOH n=2,3,4,-P(=O)(OH)2。
R6,R7和R8分别选自氢,取代或非取代的C1-18烷基,取代或非取代的C3-9环烷基,取代或非取代的芳烷基、取代或非取代的芳杂环,取代或非取代的C1-18烷酰基、取代或非取代的C1-18烷氧酰基(取代基选自卤素、硝基、羟基、巯基、羧基、酯基、氨基、酰氨基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷酰基、C1-6烷酰氧基、甲磺酰基、氨基甲磺酰基);-SO3H,-C(=O)(CH2)nCOOH n=2,3,4,-P(=O)(OH)2。
更优选的是R6,R7和R8分别选自氢,烷基,芳烷基,烷酰基,烷氧酰基,烷酰氧亚甲基,-SO3H,-C(=O)(CH2)nCOOH n=2,3,4,-P(=O)(OH)2。
最优选的是
R1和R2选自氢、乙酰基、新戊酰基、苯甲酰基、甲氧甲酰基、新戊酰氧亚甲基;
R3和R4选自氢、3′-硝基、3′-氨基、N,N-二甲氨基;
R5、R6、R7和R8选自氢、乙酰基、新戊酰基、苯甲酰基、甲氧甲酰基、新戊酰氧亚甲基、苯甲叉、丙叉。
但是
R1、R2、R3、R4、R5、R6,、R7和R8不能同时为氢,不能同时为乙酰基。
R3、R4、R5、R6,、R7和R8同时为氢时,R1和R2不能同时为羟乙基、。
R1、R2、R3、R4、R6、R7和R8同时为氢时,R5不能为三苯甲基和苯甲酰基。
本发明中的“烷“基一般包括直链或支链或环状的脂肪烷基,其中可包含一个或两个杂原子(N,O,S,),卤素取代或不取代;还包括取代或不取代的芳香烷烃(芳环或芳香杂环),其中取代基(单取代或多取代)可为卤素,硝基,烷氧基,酯基,酰氨基,烷基,甲磺酰基,氨基甲磺酰基)。
本发明中的低级烷基一般指取代或不取代的1~5个碳的直链烷基,取代基可为脂肪烷基或芳香烷烃。
本发明的R3可是3′位或5′位单取代,其中R3可与R1合并为一个取代基;R3也可是3′位与5′位,或3′位与6′位,或5′位与2′位的双取代。R4可是6位的单取代,也可是5位与6位的双取代。
本发明的R5,R2,R6,R7,R8中某两个可合并为一个取代基,如12-O,15-O-丙叉葛根素,12-O,15-O-苯甲叉葛根素。
为制备本发明通式I所述的化合物,本发明方法包括:
在碱性介质中,选择性地对酚羟基进行酰化或烷基化,并依据两个酚羟基的空间位阻和反应性能的不同,选择适宜的反应条件分别对葛根素分子的7位酚羟基和4′位酚羟基进行酰化和烷基化。可选的无机碱包括:无水碳酸钠,无水碳酸钾,氢氧化钠,氢氧化钾,氢氧化锂,氢化钠等;可选的有机碱包括胺类,含氮杂环类,弱酸强碱盐类及碱式离子交换树脂等。可选的溶剂包括极性质子溶剂和极性非质子溶剂,如丙酮,N,N-二甲基甲酰胺,二甲亚砜,六甲基磷酰胺,异丙醇,乙醇,叔丁醇,四氢呋喃,吡啶,三乙胺等。
在酸性环境中,可选择性的对醇羟基进行酰化或烷基化,并依据伯醇羟基和仲醇羟基的反应活性不同,选择适宜的反应条件分别对葛根素分子中伯醇羟基和仲醇羟基进行酰化或烷基化。可选的无机酸包括:三氟化硼,三氯化铝,二氯化锌等路易氏酸,盐酸,硫酸,磷酸,草酸等质子酸及氯化铵等强酸弱碱盐和酸式盐;可选的有机酸包括:甲酸,乙酸,苯甲酸等羧酸类,甲磺酸,对甲苯磺酸等磺酸类,酚类和有机碱强酸盐类及酸式离子交换树脂类。可选的溶剂包括极性质子溶剂和极性非质子溶剂,如丙酮,N,N-二甲基甲酰胺,二甲亚砜,六甲基磷酰胺,异丙醇,乙醇,叔丁醇,四氢呋喃,乙酸乙酯,氯仿等。
通过保护和脱保护策略可分别对葛根素分子的酚羟基和醇羟基进行酰化或烷基化。如可先用氯甲醚在碱性环境下保护酚羟基,再进行醇羟基的酰化,然后在酸性条件下脱去甲醚保护基。
也可先对葛根素酚羟基和醇羟基进行全部酰化或烷基化,然后选择适当的反应条件进行选择性的脱除,从而获得所需要的结构修饰产物。
葛根素分子中两个苯环的修饰可通过选择合适的硝化剂并控制适当的反应条件进行有选择性的硝化,进一步还原成氨基,对氨基进行烷基化或酰基化,并可对苯环进一步进行硝化,氨基也可进一步重氮化,从而发生重氮盐的取代反应,得到一系列的苯环取代产物。硝化试剂可选自:HNO3/AcOH,HNO3/Ac2O,HNO3/BF3,CH3ONO2/BF3,NH4NO3/HNO3/Ac2O,硝酸苯甲酰,硝酸乙酰等。
本发明还涉及一种含有药物有效剂量的如通式I所述的化合物和药学上可接受的载体的药物组合物。
本发明的通式I化合物中,当R1、R2、R5、R6、R7、R8为酰基或部分为酰基其余为氢时,这些化合物应为葛根素的前药,在生物介质中,在酯酶或磷酸酯酶的作用下应容易水解转变成原药葛根素,而这些酯化的化合物的脂溶性、生物利用度有很大提高。并且这些酯化化合物的用途应该包括目前已知的和以后发现的葛根素的用途。
在本发明的通式I化合物中,R1、R2、R5、R6、R7、R8为烷基或部分为烷基其余为氢时,以及R3、R4不为氢或部分不为氢时,这些葛根素衍生物作为新的活性成分其生物活性在某些方面优于或相当于葛根素。药理研究发现,这些葛根素衍生物中部分化合物在对离体大鼠心脏再灌注损伤和垂体后叶素诱发大鼠心肌缺血的作用模型中在减轻心肌组织缺血损伤方面都显示出相当或优于葛根素的活性。
本发明的通式I化合物,对冠状动脉有扩张作用,能保护全心缺血心肌和心肌缺血再灌注损伤,减少急性心梗面积,降低心肌耗氧量,阻止血小板粘附、聚集和血栓形成,并且具有疏通视网膜栓塞的作用,对急性脑缺血有明显的保护作用,并有改善记忆和降低血糖的功效。临床上,可用于冠心病、心绞痛、心肌梗塞、缺血性脑血管病和视网膜阻塞等症的治疗。
本发明化合物可用口服方法或非肠胃道用药。口服用药可以是片剂、颗粒剂、胶囊剂、软胶囊剂;非经肠用药剂型有注射剂和栓剂等。这些制剂是按照本领域的技术人员所熟知的方法制备的。为制造片剂、颗粒剂、胶囊剂、软胶囊剂所用的辅料是常规用的助剂,例如淀粉,乳糖,明胶,糖浆、甘油、蜂蜡、***胶,微粉硅胶,滑石粉,聚乙二醇。液体剂型所用的溶剂例如有水,乙醇,丙二醇,植物油类如玉米油,花生油,橄榄油等。含有本发明化合物的制剂中还可有其他助剂,例如表面活性剂,润滑剂,抗氧化剂,崩解剂,防腐剂,矫味剂,色素等。
在片剂、颗粒剂、胶囊剂、软胶囊剂,注射剂或栓剂中含有本发明式I化合物的剂量是以单元剂型中存在的化合物量计算的。在单元剂型中本发明式I化合物一般含量为10-50mg,优选的单元剂型含有20-100mg。
具体实施方式
以下将结合实施例对发明作进一步说明,但并不限制本发明的范围。
测定仪器:熔点用Yanaco显微熔点仪,核磁共振光谱用VaariaanMercury 300型核磁共振仪。质谱用ZAD-2F和VG300质谱仪。
实施例1.7-O-新戊酰基葛根素
将葛根素0.416克(1毫摩尔)溶于50毫升丙酮中,加入无水碳酸钾0.414克(3毫摩尔),室温搅拌下分批滴加1毫摩尔的新戊酰氯,TLC跟踪反应,室温搅拌至原料点消失,旋去大部分溶剂后加入乙酸乙酯萃取,水洗,无水硫酸钠干燥,旋去溶剂,柱层析(乙酸乙酯∶甲醇=10∶1)得到白色固体产物0.345克,熔点:216-218℃,产率69%。
1H NMR(300MHZ,CD3OD),δ:8.261(S,3/7H,H2),8.246(S,4/7H,H2),8.17(d,1H,H5),7.35(d,2H,H2′6′),7.165(d,3/7H,H6),7.095(d,4/7H,H6),6.80(d,2H,H3′5′),1.37(S,9H,-CH3),5.05(d,4/7H,H9),4.66(d,3/7H,H9),4.16(t,3/7H,H14),3.94(t,4/7H,H14),3.83(d,1H,H15),3.64(dd,3/7H,H15),3.54(dd,4/7H,H15),3.22-3.52(m,3H,H11,H12,H13)。
MS(FAB):M+1=501。
实施例2.7-O-乙酰基葛根素
将葛根素0.416克(1毫摩尔)溶于50毫升丙酮中,加入无水碳酸钾0.414克(3毫摩尔),室温搅拌下分批滴加1毫摩尔的乙酰氯,TLC跟踪反应,室温搅拌至原料点消失,旋去大部分溶剂后加入乙酸乙酯萃取,水洗,无水硫酸钠干燥,旋去溶剂,柱层析(乙酸乙酯∶甲醇=10∶1)得到白色固体产物0.289克。熔点:194-196℃,产率63%。
1H NMR(300MHz,CD3OD),δ:8.278(S,2/5H,H2),8.246(S,3/5H,H2),8.18(d,1H,H5),7.36(d,2H,H2′6′),7.175(d,2/5H,H6),7.15(d,3/5H,H6),6.80(d,2H,H3′5′),1.37(S,9H,-CH3),5.05(d,3/5H,H9),4.67(d,2/5H,H9),4.15(t,2/5H,H14),3.93(t,3/5H,H14),3.83(d,1H,H15),3.64(dd,2/5H,H15),3.54(dd,3/5H,H15),3.3-3.5(m,3H,H11,H12,H13)。
MS(FAB):M+1=459.3。
实施例3.7-O,4′-O-二新戊酰基葛根素
将葛根素0.416克(1毫摩尔)溶于50毫升丙酮中,加入无水碳酸钾0.414克(3毫摩尔),室温搅拌下分批滴加两毫摩尔的新戊酰氯,TLC跟踪反应,室温搅拌至原料点消失,旋去大部分溶剂后加入乙酸乙酯萃取,水洗,无水硫酸钠干燥,旋去溶剂,柱层析(乙酸乙酯∶甲醇=10∶1)得到白色固体产物0.42克。熔点:163-165℃,产率71%。
1H NMR(300MHz,CDCl3),δ:8.01(S,2/3H,H2),7.99(S,1/3H,H2),8.31(d,1H,H5),7.41(d,2/3H,H2′6′),7.39(d,4/3H,H2′6′),7.11(d,1/3H,H6),7.02(d,2/3H,H6),6.85(d,2H,H3′5′),5.28(d,2/3H,H9),4.83(d,1/3H,H9),5.62(dd,1/3H,H14),5.39(dd,2/3H,H14),3.40-4.20(m,5H,H11,H12,H13,H15).0.80-1.50(m,18H,CH3)。
MS(FAB):M+1=585.2。
实施例4.7-O,4′-O,15-O-三新戊酰基葛根素
将葛根素0.416克(1毫摩尔)溶于50毫升丙酮中,加入无水碳酸钾0.414克(3毫摩尔),室温搅拌下分批滴加3毫摩尔的新戊酰氯,TLC跟踪反应,室温搅拌至原料点消失,旋去大部分溶剂后加入乙酸乙酯萃取,水洗,无水硫酸钠干燥,旋去溶剂,柱层析(乙酸乙酯∶甲醇=10∶1)得到白色固体产物0.32克。熔点:142-144℃,产率47%。
1H NMR(300MHz,CDCl3),δ:8.10(S,4/9H,H2),8.09(S,5/9H,H2),8.27(d,5/9H,H5),8.21(dd,4/9H,H5),7.55(d,10/9H,H2′6′),7.51(dd,8/9H,H2′6′),7.05(dd,4/9H,H6),7.00(d,5/9H,H6),7.12(d,10/9H,H3′5′),7.07(dd,8/9H,H3′5′),5.18(d,4/9H,H9),4.77(d,5/9H,J=9.9Hz,H9),5.64(dd,4/9H,H14),5.44(dd,5/9H,H14),3.38-3.93(m,5H,H11,H12,H13,H15),0.82-1.42(m,27H,CH3)。
MS(FAB):M+1=669.2。
实施例5.7-O,4′-O-二苯甲酰基葛根素
将葛根素0.416克(1毫摩尔)溶于50毫升丙酮中,加入无水碳酸钾0.414克(3毫摩尔),室温搅拌下分批滴加两毫摩尔的苯甲酰氯,TLC跟踪反应,室温搅拌至原料点消失,旋去大部分溶剂后加入乙酸乙酯萃取,水洗,无水硫酸钠干燥,旋去溶剂,柱层析(乙酸乙酯∶甲醇=10∶1)得到白色固体产物0.18克。熔点:169-171℃,产率29%。
1H NMR(300MHZ,CD3COCD3),δ:8.52(S,1H,H2),8.17(d,1H,H5),7.81(d,2H,H2′6′),7.65(d,2H,H3′5′),6.90(d,1H,H6),8.31(m,2H,ArH),7.3-7.9(m,8H,ArH),5.87(dd,1H,H14),5.43(d,1H,H9),3.0-5.0(m,5H,H15,H11,H12,H13)。
MS(FAB):M+1=625.1。
实施例6.12-O,13-O,14-O-三乙酰基葛根素
将葛根素0.416克(1毫摩尔)溶于50毫升丙酮中,冰水浴下,滴加0.2毫升三氟化硼***溶液和乙酸酐酰化剂5毫摩尔,TLC跟踪反应,室温搅拌至原料点消失,加入5毫升乙醇再搅拌1小时,滴加饱和碳酸氢钠溶液终止反应,旋去大部分溶剂,乙酸乙酯萃取,饱和碳酸氢钠溶液洗涤,无水硫酸钠干燥,旋去溶剂后柱层析(乙酸乙酯∶甲醇=10∶1)得到黄色固体0.17克,熔点:141-143℃,产率31%。
1H NMR(300MHz,CD3OD),δ:8.24(S,1H,H2),7.98(d,1H,H5),7.34(d,2H),6.90(d,1H,H6),6.79(d,2H,H3′5′),5.81(w,1H,H9),5.28(w,1H,H14),5.22(dd,1H,H13),3.97(dd,1H,H12),3.84(m,2H,H15),3.54(m,1H,H11),1.96(S,3H,COCH3),1,49(S,3H,COCH3),1.32(S,3H,COCH3)。
MS(FAB):M+1=541。
实施例7.12-O,13-O,14-O,4′-O-四乙酰基葛根素
将葛根素0.416克(1毫摩尔)溶于50毫升丙酮中,冰水浴下,滴加0.2毫升三氟化硼***溶液和乙酸酐酰化剂5毫摩尔,TLC跟踪反应,室温搅拌至原料点消失,加入5毫升乙醇再搅拌1小时,滴加饱和碳酸氢钠溶液终止反应,旋去大部分溶剂,乙酸乙酯萃取,饱和碳酸氢钠溶液洗涤,无水硫酸钠干燥,旋去溶剂后柱层析(乙酸乙酯∶甲醇=10∶1)得到黄色固体0.26克。熔点:126-128℃,产率45%。
1H NMR(300MHz,CD3OD),δ:8.34(S,1H,H2),7.99(d,1H,H5),7.55(d,2H,H2′6′),6.92(d,1H,H6),7.12(d,2H,H3′5′),5.80(w,1H,H9),5.31(w,1H,H14),5.25(t,1H,H13),3.98(t,1H,H12),3.84(m,2H,H15),3.54(m,1H,H11),2.23(S,3H,COCH3),1.96(S,3H,COCH3),1,49(S,3H,COCH3),1.32(S,3H,COCH3)。
MS(FAB):M+1=583。
实施例8.14-O-甲氧甲酰基葛根素
将葛根素0.416克(1毫摩尔)溶于50毫升丙酮中,加入无水碳酸钾0.414克(3毫摩尔),室温搅拌下分批滴加两毫摩尔的甲氧基甲酰氯,TLC跟踪反应,室温搅拌至原料点消失,旋去大部分溶剂后加入乙酸乙酯萃取,水洗,无水硫酸钠干燥,旋去溶剂,柱层析(乙酸乙酯∶甲醇=10∶1)得到白色固体产物0.25克。熔点:180-182℃,59%。
1H NMR(300MHz,CD3OD),δ:8.16(S,1H,H2),7.98(d,1H,H5),7.33(d,2H,H2′6′),6.89(d,1H,H6),6.78(d,2H,H3′5′),5.38(dd,1H,H14),5.15(d,H,H9),3.85(dd,1H,H15),3.67(dd,1H,H15),3.63(dd,1H,H13),3.52(t,1H,H12),3.42(dd,1H,H11),3.39(S,3H,-OCH3)。
MS(FAB):M+1=475.1
实施例9.7-O,4′-O,12-O,14-O-四乙酰基葛根素
将葛根素0.416克(1毫摩尔)溶于50毫升丙酮中,冰水浴下,滴加0.2毫升三氟化硼***溶液和乙酸酐酰化剂5毫摩尔,TLC跟踪反应,室温搅拌至原料点消失,加入5毫升乙醇再搅拌1小时,滴加饱和碳酸氢钠溶液终止反应,旋去大部分溶剂,乙酸乙酯萃取,饱和碳酸氢钠溶液洗涤,无水硫酸钠干燥,旋去溶剂后柱层析(乙酸乙酯∶甲醇=10∶1)得到黄色固体0.12克,熔点:134-136℃,产率21%。
1H NMR(300MHz,CD3OD),δ:8.35(S,1H,H2),8.14(d,1H,H5),7.57(d,2H,H2′6′),7.07(d,1H,H6),7.15(d,2H,H3′5′),4.81(d,1H,H9),4.39(dd,1H,H14),5.11(dd,1H,H12),3.85(dd,1H,H15),3.63(m,3H,H11,H13,H15),2.24(S,3H,COCH3),2.10(S,3H,COCH3),1.54(S,3H,COCH3).1.20(S,3H,COCH3)。
MS(FAB):M+1=585
实施例10.12-O,15-O-苯甲叉葛根素
将葛根素0.416克(1毫摩尔)溶于50毫升丙酮中,加入两粒对甲苯磺酸,冰水浴下滴加1.2毫摩尔苯甲醛,TLC跟踪反应,室温搅拌至原料点消失,加入几滴饱和碳酸钠溶液终止反应,旋去大部分溶剂,乙酸乙酯萃取,水洗,饱和碳酸氢钠溶液洗涤,无水硫酸钠干燥,旋去溶剂,柱层析(乙酸乙酯∶甲醇=10∶1)分离,得到白色固体产品0.24克。熔点:199-201℃,产率48%。
1H NMR(300MHZ,CD3OD),δ:8.16(S,1H,H2),8.00(d,1H,H5),7.48(m,2H,H17),7.31(d,2H,H2′6′),6.95(d,1H,H6),7.29(m,3H,H18),6.79(d,2H,H3′5′),5.59(S,1H,H16),4.32(dd,1H,H14),5.15(d,1H,H9),4.22(dd,1H,H15),3.76(dd,1H,H15),3.69(dd,1H,H13),3.63(dd,1H,H12),3.57(m,1H,H11)。
MS(FAB):M+1=505。
实施例11.12-O,15-O-丙叉葛根素
将葛根素0.416克(1毫摩尔)溶于50毫升丙酮中,加入两粒对甲苯磺酸,冰水浴下滴加1.2毫摩尔2-甲氧基丙烯,TLC跟踪反应,搅拌至原料点消失,加入几滴饱和碳酸钠溶液终止反应,旋去大部分溶剂,乙酸乙酯萃取,水洗,饱和碳酸氢钠溶液洗涤,无水硫酸钠干燥,旋去溶剂,柱层析(乙酸乙酯∶甲醇=10∶1)分离,得到白色固体产品0.27克。熔点:230-232℃,产率59%。
1H NMR(300MHZ,CD3OD),δ:8.16(S,1H,H2),8.01(d,1H,H5),7.33(d,2H,H2′6′),6.94(d,1H,H6),6.79(d,2H,H3′5′),4.26(t,1H,H14),5.06(d,1H,H9),3.80(m,2H,H15),3.69(dd,1H,H13),3.54(dd,1H,H12),3.39(m,1H,H11),1.51(S,3H,CH3),1.36(S,3H,CH3)。
MS(FAB),M+1=457。
实施例12.7-O-新戊酰氧亚甲基葛根素
将新戊酰氧亚甲基氯(6.8毫摩尔)和无水碘化钠1.02克(6.8毫摩尔)溶于15毫升无水丙酮中密封过夜,然后加入到无水碳酸钾1.9克(13.6毫摩尔)和葛根素1.4克(6.8毫摩尔)的150毫升丙酮溶液中搅拌,TLC跟踪反应至反应完全,旋去大部分溶剂后加入150毫升乙酸乙酯稀释,过滤,减压浓缩后柱层析分离得到白色固体0.19克,熔点:183-185℃,产率37%。
1H NMR(300MHZ,CD3OD),δ:8.17(S,1H,H2),8.21(d,1H,H5),7.34(d,2H,H2′6′),5.90(dd,2H,-OCH2O-),7.34(d,1H,H6),6.80(d,2H,H3’5’),1.16(S,9H,-CH3),5.02(d,2/5H,H9),4.96(d,3/5H,H9),4.17(t,1H,H14),3.82(dd,1H,H15),3.64(dd,1H,H15),3.25-3.45(m,3H,H11,H12,H13)。
MS(FAB):M+1=531
实施例13.7-O,4′-O-二新戊酰氧亚甲基葛根素
将新戊酰氧亚甲基氯2.04克(13.6毫摩尔)和无水碘化钠2.04克(13.6毫摩尔)溶于30毫升无水丙酮中密封过夜,然后加入到无水碳酸钾1.9克(13.6毫摩尔)和葛根素1.4克(6.8毫摩尔)的150毫升丙酮溶液中搅拌,TLC跟踪反应至反应完全,旋去大部分溶剂后加入150毫升乙酸乙酯稀释,过滤,减压浓缩后柱层析(乙酸乙酯∶甲醇=10∶1)分离得到白色固体0.37克。熔点:176-178℃,产率58%。
1H NMR(300MHZ,CD3OD),δ:8.19(S,1H,H2),8.21(d,1H,H5),7.36(d,2H,H2′6′),6.01(S,2H,-OCH2O-),7.38(d,1H,H6),5.90(dd,2H,-OCH2O-),6.80(d,2H,H3′5′),1.10(S,9H,-CH3),1.16(S,9H,-CH3),5.02(d,2/5H,H9),4.96(d,3/5H,H9),4.17(t,1H,H14),3.82(dd,1H,H15),3.64(dd,1H,H15),3.25-3.45(m,3H,H11,H12,H13)。
MS(FAB):M+1=645
实施例14.3′-硝基葛根素
将葛根素3克溶于30毫升水和30毫升乙酸的混合液中,冰水浴下缓慢滴加36毫升乙酸和24毫升浓硝酸的混合溶液,TLC跟踪反应,搅拌至原料点消失后,过滤,水洗,烘干得到产品黄色固体2.18克,熔点237-239℃,产率65%。
1H NMR(300MHz,CD3OD),δ:8.33(S,1H,H2),8.02(d,1H,H5),8.31(d,1H,H6′),7.78(dd,1H,H2′),6.96(d,1H,H6),7.17(d,1H,H3′),5.04(d,1H,H9),4.06(t,1H,H14),3.84(dd,1H,H15),3.69(dd,1H,H15),3.45(m,3H,H11,H13,H12)。
MS(FAB):M+1=462
实施例15.3′-氨基葛根素
将0.5克上面所得硝基化合物溶于20毫升溶剂中,加入Raney-Ni0.05克,常压氢化至原料点消失,滤出Raney-Ni,旋干滤液,乙醇重结晶得到产品白色固体0.5克,260℃碳化,产率95%。
1H NMR(300MHz,CD3OD),δ:8.08(S,1H,H2),7.99(d,1H,H5),8.31(d,1H,H6′),6.70(S,2H,H2′,H6′),6.92(d,1H,H6),6.88(S,1H,H3′),5.03(d,1H,H9),4.05(w,1H,H14),3.83(dd,1H,H15),3.69(dd,1H,H15),3.39-3.50(m,3H,H11,H13,H12)。
MS(FAB):M+1=432.2
实施例16.3′-N,N-二甲氨基葛根素
将0.5克上面所得硝基化合物和0.07毫升36%的甲醛水溶液溶于50毫升溶剂中,加入0.05克Raney-Ni,常压氢化至原料点消失,滤出Raney-Ni,旋干滤液,乙醇重结晶得到产品0.51克。熔点:180-182℃,产率95%。
1H NMR(300MHz,CD3COCD3),δ:8.19(S,1H,H2),8.03(d,1H,J=9,H5),7.41(S,1H,H2’),7.11(d,H,J=7.8,H6’)6.94(d,1H,J=9,H6),6.85(d,1H,J=7.8,H5’),5.18(d,1H,J=9.9,H9),3.89(w,1H,H14),3.81(dd,1H,H15),3.69(dd,1H,H15),3.39-3.50(m,3H,H11,H13,H12),2.69(S,6H,2N-CH3).
MS(FAB):M+1=460.2.
实施例17.7-O,4′-O,12-O,13-O,14-O,15-O-六乙酰基-3′-N,N-二甲胺基葛根素
将3′-N,N-二甲胺基葛根素0.23克(0.5毫摩尔)置于30毫升圆底烧瓶中,加入2毫升醋酐和2毫升吡啶,室温搅拌2小时后倾入20毫升水中,用乙酸乙酯萃取,水洗3次后无水硫酸钠干燥,减压除去溶剂后得到白色固体0.35克,熔点78-80℃,产率98%。
1H NMR(300MHz,CD3COCD3),δ:8.66(S,1H,H2),8.24(d,1H,J=9,H5),7.38(S,1H,H2’),7.28(d,H,J=8.1,H6’),7.28(d,1H,J=9,H6),7.07(d,1H,J=8.1,H5’),5.8~4.0(m,7H,H9,H11,H13,H12,2H15,H14),2.79(S,6H,2N-CH3),1,68~2.44(6S,18H,COCH3).
MS(FAB):M+1=712.2
实施例18.7-O,4′-O-二新戊酰基-3′-N,N-二甲胺基葛根素,
将3′-N,N-二甲胺基葛根素0.23克(0.5毫摩尔)溶于60毫升丙酮中,加入无水碳酸钾0.414克(3毫摩尔),室温搅拌下分批滴加两毫摩尔的特戊酰氯,室温搅拌至原料点消失,旋去大部分溶剂后加入乙酸乙酯萃取,水洗,无水硫酸钠干燥,旋去溶剂,柱层析得到白色固体产物0.21克。熔点:136~138℃,产率66%。
1H NMR(300MHz,CD3COCD3),δ:8.49(S,2/3H,H2),8.39(S,1/3H,H2),8.26(d,2/3H,J=9,H5),8.24(d,1/3H,J=9,H5),7.25~7.44(m,3H,H2′H6′H6),7.16(d,2/3H,J=8.1,H5′),6.90(d,1/3H,J=8.1,H5′),5.20~5.38(m,1H,H9),2.80(S,6H,2N-CH3),2.0~4.0(6S,18H,CH3),3.4~3.9(m,5H,H14,H11,H12,H13,H15).
MS(FAB):M+1=628.2.
活性评价实验
实验例1.葛根素衍生物对离体大鼠心脏再灌注损伤模型的影响
模型制备采用SD大鼠,制备Langendorff离体心脏。实验分为模型组,空白对照组和给药组。观察指标是测定灌流心脏流出液中LDH活性。统计方法是将各给药组分别与模型组进行比较,采用studentt test进行显著性检验。结果见下表:
表1.葛根素衍生物对离体大鼠心脏再灌注损伤模型的影响
*P<0.05,**P<0.01vs缺血模型。阳性对照——葛根素
结果表明:受试样品实施例1和实施例15可使Langendorff离体心脏缺血再灌注损伤模型的复灌后/缺血前LDH活性比值显著降低,明显减轻心肌细胞损伤。
实验例2.葛根素衍生物垂体后叶素诱发SD大鼠心肌缺血模型的影响
模型制备采用SD大鼠,预先将大鼠麻醉,记录大鼠正常心电图II导联,然后静脉注射垂体后叶素,并连续记录大鼠心电图5分钟。观察大鼠心电图ST段的变化。受试样品组大鼠预先分别皮下注射受试样品20mg/kg和40mg/kg,每天给药一次,连续7天,在末次给药后30分钟静脉注射垂体后叶素0.5U/kg诱发心肌缺血模型。观察指标是测定心电图ST波的抬高程度。实验结果见下表:
表2.葛根素衍生物(20mg/kg皮下注射7天)对垂体后叶素诱发SD大鼠心肌缺血模型心电图ST段的影响
*P<0.05,**P<0.01VS空白对照组
表3.葛根素衍生物(40mg/kg皮下注射7天)对垂体后叶素诱发SD大鼠心肌缺血模型心电图ST段的影响
*P<0.05,**P<0.01VS空白对照组
结果表明:受试样品实施例1、实施例12和实施例15,不论20mg/kg剂量组还是40mg/kg剂量组大鼠注射垂体后叶素后心电图ST段的升高程度较模型组显著降低,说明受试样品能明显减轻心肌组织缺血损。
Claims (5)
1.通式(I)所示的葛根素衍生物:
其中,
R1和R2选自氢,C1-5烷酰氧亚甲基,C1-5烷氧酰基,C1-5烷酰基;
R3和R4选自氢,硝基,氨基,N-C1-5烷基氨基,N,N-二C1-5烷基氨基;
R5、R6,R7和R8分别选自氢,C1-5烷基,苯基取代C1-5烷基,C1-5烷酰基,C1-5烷氧酰基,C1-5烷酰氧亚甲基;
但是
R1、R2、R3、R4、R5、R6,、R7和R8不能同时为氢;并且不包括如下化合物:
2.通式(I)所示的葛根素衍生物:
其中,
R1和R2选自氢、乙酰基、新戊酰基、苯甲酰基、甲氧甲酰基、新戊酰氧亚甲基;
R3和R4选自氢、3′-硝基、3′-氨基、N,N-二甲氨基;
R5、R6、R7和R8选自氢、乙酰基、新戊酰基、甲氧甲酰基、新戊酰氧亚甲基、苯甲叉基、丙叉基。
4.一种药物组合物,其特征在于,含有权利要求1-3中任一项所述的任一化合物及药用载体。
5.权利要求1-3中任一项所述的化合物制备治疗心脑循环有关疾病药物的应用。
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