CN104800222A - 闭花木酮的o-(苯并咪唑基)乙基衍生物在制备抗红细胞低下性贫血药物中的应用 - Google Patents
闭花木酮的o-(苯并咪唑基)乙基衍生物在制备抗红细胞低下性贫血药物中的应用 Download PDFInfo
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Abstract
本发明涉及有机合成和药物化学领域，具体涉及闭花木酮Cleistanone衍生物、制备方法及其在制备抗红细胞低下性贫血药物上的用途。本发明合成了一个新的闭花木酮Cleistanone衍生物，并公开了其制备方法。药理学实验表明，本发明的闭花木酮Cleistanone衍生物具有抗红细胞低下性贫血的作用，具有开发抗红细胞低下性贫血药物的价值。
Description
技术领域
本发明涉及有机合成和药物化学领域，具体涉及闭花木酮Cleistanone衍生物、制备方法及其用途。
背景技术
基于不同的临床特点，贫血有不同的分类。如：按贫血进展速度分急、慢性贫血；按骨髓红系增生情况分增生性贫血(如溶血性贫血、缺铁性贫血、巨幼细胞贫血等)和增生低下性贫血(如再生障碍性贫血)。
临床上常从贫血发病机制和病因的分类：
1.红细胞生成减少性贫血
造血细胞、骨髓造血微环境和造血原料的异常影响红细胞生成，可形成红细胞生成减少性贫血。
(1)造血干祖细胞异常所致贫血
1)再生障碍性贫血(AA)AA是一种骨髓造血功能衰竭症，与原发和继发的造血干祖细胞损害有关。部分全血细胞减少症的发病机制与B细胞产生抗骨髓细胞自身抗体，进而破坏或抑制骨髓造血细胞有关。
2)纯红细胞再生障碍贫血(PRCA)PRCA是指骨髓红系造血干祖细胞受到损害，进而引起贫血。依据病因，该病可分为先天性和后天性两类。先天性PRCA即Diamond-Blackfan综合征，系遗传所致；后天性PRCA包括原发、继发两类。有学者发现部分原发性PRCA患者血清中有自身EPO或幼红细胞抗体。继发性PRCA主要有药物相关型、感染相关型(细菌和病毒，如微小病毒B19、肝炎病毒等)、自身免疫病相关型、淋巴细胞增殖性疾病相关型(如胸腺瘤、淋巴瘤、浆细胞病和淋巴细胞白血病等)以及急性再生障碍危象等。
3)先天性红细胞生成异常性贫血(CDA)CDA是一类遗传性红系干祖细胞良性克隆异常所致的、以红系无效造血和形态异常为特征的难治性贫血。根据遗传方式，该病可分为常染色体隐陛遗传型和显性遗传型。
4)造血系统恶性克隆性疾病这些疾病造血干祖细胞发生了质的异常，包括骨髓增生异常综合征及各类造血系统肿瘤性疾病如白血病等。前者因为病态造血，高增生，高凋亡，出现原位溶血；后者肿瘤性增生、低凋亡和低分化，造血调节也受到影响，从而使正常成熟红细胞减少而发生贫血。
(2)造血微环境异常所致贫血
造血微环境包括骨髓基质，基质细胞和细胞因子。
1)骨髓基质和基质细胞受损所致贫血骨髓坏死、骨髓纤维化、骨髓硬化症、大理石病、各种髓外肿瘤性疾病的骨髓转移以及各种感染或非感染性骨髓炎，均可因损伤骨髓基质和基质细胞，造血微环境发生异常而影响血细胞生成。
2)造血调节因子水平异常所致贫血干细胞因子(SCF)、白细胞介素(IL)、粒-单系集落刺激因子(GM-CSF)、粒系集落刺激因子(G-CSF)、红细胞生成素(EPO)、血小板生成素(TPO)、血小板生长因子(TGF)、肿瘤坏死因子(TNF)和干扰素(IFN)等均具有正负调控造血作用。肾功能不全、肝病和垂体或甲状腺功能低下等时产生EPO不足；肿瘤性疾病或某些病毒感染会诱导机体产生较多的造血负调控因子如TNF、IFN、炎症因子等，均可导致慢性病性贫血(ACD)。
(3)造血原料不足或利用障碍所致贫血
造血原料是指造血细胞增殖、分化、代谢所必需的物质，如蛋白质、脂类、维生素(叶酸、维生素B12等)、微量元素(铁、铜、锌等)等。任一种造血原料不足或利用障碍都可能导致红细胞生成减少。
1)叶酸或维生素B12缺乏或利用障碍所致贫血由于各种生理或病理因素导致机体叶酸或维生素B12绝对或相对缺乏或利用障碍可引起的巨幼细胞贫血。
2)缺铁和铁利用障碍性贫血这是临床上最常见的贫血。缺铁和铁利用障碍影响血红素合成，有称该类贫血为血红素合成异常性贫血。该类贫血的红细胞形态变小，中央淡染区扩大，属于小细胞低色素性贫血。
2.溶血性贫血(HA)
即红细胞破坏过多性贫血。
3.失血性贫血
根据失血速度分急性和慢性，慢性失血性贫血往往合并缺铁性贫血。可分为出凝血性疾病(如特发性血小板减少性紫癜、血友病和严重肝病等)所致和非出凝血性疾病(如外伤、肿瘤、结核、支气管扩张、消化性溃疡、痔和妇科疾病等)所致两类。
从天然产物中寻找化合物或先导化合物并进行结构修饰获得其衍生物，从而得到高效低毒的潜在药物最有重要价值。
本发明涉及的化合物闭花木酮Cleistanone是一个2011年发表(Van Trinh ThiThanh et al.,2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensis witha New Carbon Skeleton.Volume 2011,Issue 22,pages 4108–4111,August 2011)的化合物，我们对化合物闭花木酮Cleistanone进行了结构修饰，获得了一个新的闭花木酮Cleistanone衍生物，并对其抗红细胞低下性贫血活性进行了评价，其具有抗红细胞低下性贫血活性。
发明内容
本发明公开了一个闭花木酮Cleistanone衍生物，其结构为：
本发明闭花木酮Cleistanone衍生物(III)可通过下面方法制备：
(1)闭花木酮Cleistanone(I)与1,2-二溴乙烷反应得到闭花木酮Cleistanone的O-溴乙基衍生物(II)；
(2)闭花木酮Cleistanone的O-溴乙基衍生物(II)与苯并咪唑发生取代反应制得闭花木酮Cleistanone衍生物(III)。
进一步的闭花木酮Cleistanone衍生物(III)的制备方法为：
(1)将440mg化合物闭花木酮Cleistanone(I)溶于10mL苯，向溶液中加入0.04g的四丁基溴化铵，3.760g的1,2-二溴乙烷和6mL的50％氢氧化钠溶液；混合物在25摄氏度搅拌24h；24h之后将反应液倒入冰水中，立即用二氯甲烷萃取两次，合并有机相溶液；然后对有机相溶液依次用水和饱和食盐水洗涤3次，再用无水硫酸钠干燥，最后减压浓缩去除溶剂得到产物粗品；产物粗品用硅胶柱层析纯化，流动相为：石油醚/丙酮＝100:1，v/v，收集黄色集中洗脱带即得到闭花木酮Cleistanone的O-溴乙基衍生物(II)的黄色固体。
(2)将273mg的闭花木酮Cleistanone的O-溴乙基衍生物溶于15mL乙腈当中，向其中加入345mg的无水碳酸钾，84mg的碘化钾和1180mg的苯并咪唑，混合物加热回流5h；反应结束后将反应液倒入冰水中，用等量二氯甲烷萃取三次，合并有机相；依次用水和饱和食盐水洗涤合并之后的有机相，再用无水硫酸钠干燥，减压浓缩去除溶剂得到产物粗品；产物粗品用硅胶柱层析纯化，流动相为：石油醚/丙酮＝100:1.5，v/v，收集棕色集中洗脱带即得到闭花木酮Cleistanone衍生物(III)的棕色固体。
本发明公开的化合物可以制成药学上可接受的盐或药学上可接受的载体。
本发明的目的在于提供本发明化合物在制药领域中的新的应用。
本发明涉及本发明化合物作为制备治疗红细胞低下性贫血药物中的应用。
以下通过实施例对本发明作进一步详细的说明，但本发明的保护范围不受具体实施例的任何限制，而是由权利要求加以限定。
具体实施方式
实施例1化合物闭花木酮Cleistanone的制备
化合物闭花木酮Cleistanone(I)的制备方法参照Van Trinh Thi Thanh等人发表的文献(Van Trinh Thi Thanh et al.,2011.Cleistanone:A Triterpenoid fromCleistanthus indochinensis with a New Carbon Skeleton.Volume 2011,Issue 22,pages 4108–4111,August 2011)的方法。
实施例2闭花木酮Cleistanone的O-溴乙基衍生物(II)的合成
将化合物I(440mg，1.00mmol)溶于10mL苯，向溶液中加入四丁基溴化铵(TBAB)(0.04g)，1,2-二溴乙烷(3.760g，20.00mmol)和6mL的50％氢氧化钠溶液。混合物在25摄氏度搅拌24h。24h之后将反应液倒入冰水中，立即用二氯甲烷萃取两次，合并有机相溶液。然后对有机相溶液依次用水和饱和食盐水洗涤3次，再用无水硫酸钠干燥，最后减压浓缩去除溶剂得到产物粗品。产物粗品用硅胶柱层析纯化(流动相为：石油醚/丙酮＝100:1，v/v)，收集黄色集中洗脱带即得到化合物II的黄色固体(344mg，63％)。
1H NMR(500MHz,DMSO-d6)δ5.04(s,1H),4.82(s,1H),3.94(d,J＝26.5Hz,1H),3.87(d,J＝26.5Hz,2H),3.57(s,2H),2.40(d,J＝14.0Hz,1H),2.39(d,J＝14.0Hz,1H),2.27(s,1H),2.21(s,1H),2.15(s,1H),1.82(s,1H),1.62(s,2H),1.57(d,J＝3.3Hz,1H),1.54(d,J＝3.3Hz,1H),1.50(d,J＝1.2Hz,1H),1.47(d,J＝1.2Hz,1H),1.39(d,J＝15.3Hz,2H),1.34(d,J＝15.3Hz,1H),1.26(dd,J＝32.6,13.7Hz,4H),1.13(d,J＝18.0Hz,2H),1.05(s,6H),0.98(s,1H),0.88(s,12H),0.78(s,3H),0.74(s,1H)。
13C NMR(125MHz,DMSO-d6)δ216.59(s),154.50(s),105.23(s),74.63(s),69.85(s),59.71(s),52.55(s),51.21(s),47.92(s),44.10(s),42.25(s),41.73(s),40.64(s),40.16(s),38.88(s),38.65(s),37.21(s),36.23(s),33.34(d,J＝1.1Hz),32.96(s),29.91(s),27.18(s),26.03(s),24.23(s),23.96(s),20.77(s),18.48(s),17.98(s),16.93(s)。
HRMS(ESI)m/z[M+H]+calcd for C32H52BrO2:547.3151；found 547.3159.
实施例3闭花木酮Cleistanone的O-(苯并咪唑基)乙基衍生物(III)的合成
将化合物II(273mg，0.5mmol)溶于15mL乙腈当中，向其中加入无水碳酸钾(345mg，2.5mmol)，碘化钾(84mg，0.5mmol)和苯并咪唑(1180mg，10mmol)，混合物加热回流5h。反应结束后将反应液倒入冰水中，用等量二氯甲烷萃取三次，合并有机相。依次用水和饱和食盐水洗涤合并之后的有机相，再用无水硫酸钠干燥，减压浓缩去除溶剂得到产物粗品。产物粗品用硅胶柱层析纯化(流动相为：石油醚/丙酮＝100:1.5，v/v)，收集棕色集中洗脱带，浓缩即得到化合物III的棕色固体(105.2mg,36％)。
1H NMR(500MHz,DMSO-d6)δ8.27(s,1H),7.68(d,J＝25.0Hz,2H),7.31(s,1H),7.21(s,1H),4.65(s,1H),4.56(s,1H),4.14(d,J＝7.9Hz,2H),4.05(s,1H),3.93(s,2H),2.51(d,J＝127.9Hz,1H),2.37(s,1H),2.28(d,J＝15.8Hz,2H),2.22(s,1H),1.90(s,2H),1.83(s,1H),1.66(s,2H),1.62–1.49(m,4H),1.29(t,J＝17.7Hz,3H),1.19(d,J＝14.3Hz,2H),1.11(d,J＝7.6Hz,7H),1.02(dd,J＝42.5,9.8Hz,13H),0.88(s,3H),0.80(s,1H),0.63(s,1H).
13C NMR(125MHz,DMSO-d6)δ216.57(s),154.46(s),146.57(s),139.24(s),134.35(s),124.01(s),123.47(s),118.67(s),110.97(s),105.19(s),74.62(s),67.84(s),59.73(s),52.52(s),51.17(s),47.88(s),45.48(s),44.08(s),42.26(s),41.75(s),40.61(s),40.13(s),38.83(s),38.62(s),37.22(s),36.24(s),33.30(s),32.92(s),29.86(s),27.16(s),26.04(s),24.24(s),23.92(s),20.75(s),18.43(s),17.97(s),16.93(s).
HRMS(ESI):m/z[M+H]+calcd for C39H57N2O2:585.4420；found:585.4416。
实施例4化合物III抗红细胞低下性贫血实验
实验1化合物III对失血小鼠的治疗作用
ICR小鼠30只，♀♂各半，均分成3组(n＝10)。除生理盐水组外，其它组每只小鼠从眼眶静脉放血0.5ml，24h后再取血测全部各组指标，然后连续灌胃给药1周且给药之后每天放血0.5ml，末次给药1h后，从眼眶静脉丛取血用F-800全血小板分析仪进行红细胞计数(1012/L)。
表1化合物III对因失血所致红细胞减少的治疗作用
与模型组比较：*p<0.05
结果表明，放血小鼠经服用化合物III治疗7天后，与模型组比较，其红细胞显著高于模型组，接近生理盐水组。
二、化合物III对环磷酰胺致红细胞减少的治疗作用
对小鼠骨髓造血功能损伤的防治作用ICR小鼠30只，♀♂兼用，均分成3组(n＝10)，即生理盐水组、造模组、化合物III 1.2mg/kg组，口服给药，每天1次。第0、5、10日除生理盐水组外，其它各组小鼠分别腹腔注射环磷酸胺80mg/kg，然后继续给药3天。于末次给药后1h，从眼眶静脉丛取血，测红细胞数(1012/L)。
表2化合物III对环磷酰胺所致红细胞的影响
与模型组比较：**p<0.01
结果表明，与生理盐水组比较，环磷酸胺能使小鼠骨髓损伤，造成外周血细胞下降，化合物III组与模型组比较，可明显对抗环磷酸胺所致小鼠红细胞下降。
三、化合物III对苯所致红细胞减少的治疗作用
对再生障碍性贫血小鼠的影响：昆明种小鼠30只，♀♂兼用，均分成3组(n＝10)，除生理盐水组外，其它组小鼠皮下注射苯0.5ml/kg，连续12天，造模的当日，同时口服给药，每天1次，共18天，末次给药后1h，眼眶静脉丛取血，测红细胞。
表3化合物III对苯所致红细胞减少的治疗作用
与模型组比较：**p<0.01
结果表明，给药组与模型组比较，可明显对抗苯所致再生障碍性贫血小鼠红细胞的下降。
结论：化合物III能够显著升高红细胞，可以用来制备治疗贫血的药物。
实施例5本发明所涉及化合物III片剂的制备
取20克化合物III或者其药学上可接受的盐当中的一种，加入制备片剂的常规辅料180克，混匀，常规压片机制成1000片。
实施例6本发明所涉及化合物III胶囊的制备
取20克化合物III或者其药学上可接受的盐当中的一种，加入制备胶囊剂的常规辅料如淀粉180克，混匀，装胶囊制成1000粒。
Claims (5)
1.一种具有式III所示结构的闭花木酮Cleistanone衍生物(III)及其药学上可接受的盐在治疗红细胞低下性贫血药物中的应用：
2.如权利要求1所述的一种具有式III所示结构的闭花木酮Cleistanone衍生物(III)及其药学上可接受的盐在治疗红细胞低下性贫血药物中的应用，其特征为：所述红细胞低下性贫血是由失血所引起的。
3.如权利要求1所述的一种具有式III所示结构的闭花木酮Cleistanone衍生物(III)及其药学上可接受的盐在治疗红细胞低下性贫血药物中的应用，其特征为：所述红细胞低下性贫血是由化学物质所引起的红细胞低下。
4.如权利要求3所述的一种具有式III所示结构的闭花木酮Cleistanone衍生物(III)及其药学上可接受的盐在治疗红细胞低下性贫血药物中的应用，其特征为：所述化学物质为苯，所述红细胞低下性贫血是由苯所致的再生障碍性贫血。
5.如权利要求3所述的一种具有式III所示结构的闭花木酮Cleistanone衍生物(III)及其药学上可接受的盐在治疗红细胞低下性贫血药物中的应用，其特征为：所述化学物质为环磷酸胺，所述红细胞低下性贫血是由环磷酸胺所致红细胞下降。
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| CN106038552A (zh) * | 2016-06-13 | 2016-10-26 | 南京广康协生物医药技术有限公司 | Schiglautone A衍生物的组合物用于制备抗缺氧药物 |
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