CN105935359A - Virosaine A的哌嗪基和咪唑基衍生物的组合物在抗慢性阻塞性肺病药物中的应用 - Google Patents
Virosaine A的哌嗪基和咪唑基衍生物的组合物在抗慢性阻塞性肺病药物中的应用 Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
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Abstract
本发明涉及有机合成和药物化学领域，具体涉及组合物、制备方法及其在制备抗慢性阻塞性肺病药物上的用途。本发明公开了一种组合物及其制备方法。药理学实验表明，本发明的组合物具有抗慢性阻塞性肺病的作用，具有开发抗慢性阻塞性肺病药物的价值。
Description
技术领域
本发明涉及有机合成和药物化学领域，具体涉及组合物、制备方法及其用途。
背景技术
慢性阻塞性肺疾病(chronic obstructive pulmonary disease，COPD)是一种全球范围内常见的慢性病，目前在全球死亡原因中排名第四，据世界卫生组织预测，到2020年，COPD将在全球疾病发病中排名第五，死亡原因中排名第三。
COPD是一种不完全可逆的气流受限特征的疾病，与肺部对有害气体或有毒颗粒的异常炎症反应有关，其慢性炎症反应遍及气道、肺实质和肺血管。参与COPD的细胞有中性粒细胞、T淋巴细胞和巨噬细胞等炎性细胞，当细胞被激活后释放多种炎性介质，如白三烯B4(LTB4)、白细胞介素8(IL-8)、RANTES、Eotaxin、肿瘤坏死因子α(TNFα)、基质金属蛋白酶9(MMP-9)等，参与肺实质破坏、肺血管等炎症反应。病理变化特征表现为肺泡腔炎性细胞(如巨噬细胞)浸润、小支气管和细支气管周围灶性炎性细胞浸润，肺组织边缘肺泡腔扩张、破坏，肺泡壁变宽，其上皮细胞肿胀、变圆、部分脱落。COPD与慢性支气管炎和肺气肿密切相关，但定义上有所不同，支气管哮喘与特应性***反应有关，其气流受限具可逆性(与慢性气管炎合并时会出现气流受限不完全可逆)。现在尚无药物能遏制COPD病情的进行性发展，其药物治疗的研究进展相当缓慢，目前临床常常将治疗哮喘的药物用于治疗COPD，由于COPD的发病机制不同于哮喘，难以取得满意的疗效。
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I是一个2012年发表(Bing-Xin Zhao et al.,2012.Virosaines A and B,Two New Birdcage-Shaped Securinega Alkaloids with anUnprecedented Skeleton from Flueggea virosa.Organic Letters 14(2012)3096–3099)的化合物，我们对化合物I进行了结构修饰，获得了两个新的衍生物即化合物III和化合物IV，并用化合物III和化合物IV制备了组合物并对该组合物抗慢性阻塞性肺病活性进行了评价，其具有抗慢性阻塞性肺病活性。
发明内容
本发明公开了一个新的组合物，该组合物由化合物III和化合物IV组成，该组合物中化合物III和化合物IV的质量百分数分别为55％和45％。
本发明公开的组合物可以制成药学上可接受的盐或药学上可接受的载体。
长期吸烟是最常见的人类COPD致病因素，我们实验室用香烟诱导模拟小鼠COPD模型，拟研究本发明组合物对香烟诱导的小鼠COPD的缓解作用。
本发明目的在于提供本发明组合物在制备抗COPD疾病药物中的应用。本发明组合物在剂量10mg/kg下灌胃给药，对香烟诱导的COPD小鼠BALF中炎性细胞因子TNFα的生成有抑制作用；对趋化因子RANTES的分泌有抑制作用；对BALF中的炎性细胞的募集有抑制作用。
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Virosaine A的制备
化合物Virosaine A(I)的制备方法参照Bing-Xin Zhao等人发表的文献(Bing-Xin Zhao et al.,2012.Virosaines A and B,Two New Birdcage-ShapedSecurinega Alkaloids with an Unprecedented Skeleton from Flueggea virosa.OrganicLetters 14(2012)3096–3099)的方法。
实施例2 Virosaine A的O-溴乙基衍生物(II)的合成
将化合物I(235mg，1.00mmol)溶于20mL苯，向溶液中加入四丁基溴化铵(TBAB)(0.08g)，1,2-二溴乙烷(3.760g，20.00mmol)和5mL的50％氢氧化钠溶液。混合物在35摄氏度搅拌8h。8h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＝100:1.0，v/v)，收集棕色集中洗脱带并挥去溶剂即得到化合物II的棕色粉末(261mg，78％)。
1H NMR(500MHz,DMSO-d6)δ5.91(s,1H),4.07(s,1H),3.81(s,2H),3.59(s,1H),3.43(s,2H),3.33(s,1H),2.26(s,1H),1.58(d,J＝9.8Hz,3H),1.41(s,2H).
13C NMR(125MHz,DMSO-d6)δ171.81(s),106.71(s),79.95(s),74.33(s),69.81(s),66.68(s),44.21(s),35.56(s),33.28(s),25.85(s),21.88(s).
HRMS(ESI)m/z[M+H]+calcd for C14H17BrNO4:342.0341；found 342.0343.
实施例3 Virosaine A的O-(哌嗪基)乙基衍生物(III)的合成
将化合物II(171mg，0.5mmol)溶于20mL乙腈当中，向其中加入无水碳酸钾(690mg，5.0mmol)，碘化钾(168mg，1.0mmol)和无水哌嗪(3446mg，40mmol)，混合物加热回流3h。反应结束后将反应液倒入冰水中，用等量二氯甲烷萃取2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＝100:1.0，v/v)，收集棕色集中洗脱带并挥去溶剂即得到化合物III的淡棕色固体(123.2mg,71％)。
1H NMR(500MHz,DMSO-d6)δ5.90(s,1H),4.04(s,1H),3.59(s,1H),3.50(s,2H),3.40(d,J＝65.9Hz,1H),2.64(s,4H),2.54(s,2H),2.31(s,4H),2.22(s,1H),1.62(s,2H),1.56(s,1H),1.43(s,2H),0.97(s,1H).
13C NMR(125MHz,DMSO-d6)δ171.84(s),106.72(s),79.94(s),74.33(s),66.72(d,J＝9.2Hz),54.45(s),54.16(s),45.25(s),44.20(s),35.56(s),25.86(s),21.87(s).
HRMS(ESI):m/z[M+H]+calcd for C18H26N3O4:348.1923；found:348.1927。
实施例4 Virosaine A的O-(咪唑基)乙基衍生物(IV)的合成
将化合物II(171mg，0.5mmol)溶于25mL乙腈当中，向其中加入无水碳酸钾(690mg，5.0mmol)，碘化钾(252mg，1.5mmol)和咪唑(870mg，10mmol)，混合物加热回流2h。反应结束后将反应液倒入25mL冰水中，用等量二氯甲烷萃取3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＝100:0.3，v/v)，收集棕色集中洗脱带并挥去溶剂即得到化合物IV的淡棕色固体(144.1mg,71％)。
1H NMR(500MHz,DMSO-d6)δ7.86(s,1H),7.12(s,1H),6.71(s,1H),5.99(s,1H),4.09(s,1H),3.89(d,J＝16.4Hz,2H),3.80(s,2H),3.58(s,1H),3.35(s,1H),2.31(s,1H),1.68(s,1H),1.58(s,2H),1.44(s,2H).
13C NMR(125MHz,DMSO-d6)13C NMR(125MHz,Common NMR Solvents)δ171.82(s),139.64(s),128.67(s),119.31(s),106.70(s),79.92(s),74.31(s),67.61(s),66.66(s),44.20(s),43.75(s),35.52(s),25.85(s),21.86(s).
HRMS(ESI):m/z[M+H]+calcd for C17H20N3O4:330.1454；found:330.1458。
实施例5组合物抗慢性阻塞性肺病实验
方法：SPF级雌性BALB/c小鼠，18-20g，随机分为正常对照组、模型对照组、药物处理组(组合物、化合物III和化合物IV 10mg/kg，灌胃给药)，每组10只。将小鼠置于4L容器内，每日烟熏(南京牌香烟—红壳，焦油含量小于16mg)，一周五次，连续四周，每日烟熏前1小时灌胃给药，小鼠在末次烟熏后1小时，以***钠麻醉，用0.6mL预冷的PBS缓冲液(pH7.0)肺部灌流，冲洗3次，吸出支气管肺泡灌洗液(BALF)，250×g离心10min，上清用于分析TNFα、RANTES的含量。细胞用PBS缓冲液重悬，计数，细胞涂片后用瑞氏-吉姆萨染色，分析BALF中炎性细胞的变化。
组合物的制备：将研磨之后过200目网的55mg化合物III的粉末和研磨之后过200目网的45mg化合物IV的粉末装入带盖的小管中并用涡轮搅拌仪混合即得到100mg组合物，使用时用水溶解这100mg的组合物即得到组合物的溶液。
实验例1组合物对COPD小鼠支气管肺泡灌洗液(BALF)中炎症介质生成抑制作用
(1)组合物对COPD小鼠BALF中TNFα生成抑制作用
前炎性细胞因子TNFα是COPD的发病过程中的启动因子。COPD患者的TNFα水平高于正常人，培养的支气管上皮细胞与香烟的烟雾接触可分泌TNFα。TNFα可促使中性粒细胞脱颗粒，诱导起到粘膜细胞增生和高分泌，增加上皮细胞IL-8生成，增加巨噬细胞基质金属蛋白酶生成，促进气道高反应性。本实验目的在于考察组合物对COPD小鼠BALF中TNFα生成的影响，结果见表1.
表1组合物对COPD小鼠BALF中TNFα生成的影响
注：*P<0.05，与模型对照组相比；#P<0.05，与正常对照组相比。n＝10。
结果：组合物在10mg/kg下对COPD模型小鼠灌胃给药，可显著降低小鼠BALF中TNFα的生成，而化合物III和化合物IV无此作用。
(2)组合物对COPD小鼠BALF中RANTES分泌抑制作用
炎症细胞的迁移受到趋化因子的调节，各种结构细胞核炎性细胞均可分泌这些小分子蛋白，COPD发病过程中RANTES分泌增加，趋化单核/巨噬细胞，T淋巴细胞，嗜酸性细胞。本实验目的在于考察组合物对COPD小鼠BALF中RANTES分泌的影响，结果见表2。
表2组合物对COPD小鼠BALF中RANTES分泌的影响
注：*P<0.05，与模型对照组相比；#P<0.01，与正常对照组相比。n＝10。
结果：组合物在10mg/kg下对COPD模型小鼠灌胃给药，可降低小鼠BALF中RANTES的分泌，而化合物III和化合物IV无此作用。
实验例2组合物对COPD小鼠BALF中炎性细胞募集的抑制作用
(1)组合物对COPD小鼠BALF中中性粒细胞募集的抑制作用
中性粒细胞在COPD发病中具有重要作用，它可以释放两种丝氨酸蛋白酶，弹性蛋白酶和半胱氨酰蛋白酶-3，诱导动物产生人类肺气肿样的病理变化。中性粒细胞生命短暂，它循环招募到气道以及穿越间隙腔的过程十分迅速。病理研究证明有些COPD患者支气管组织内中性粒细胞数目增加与气流阻塞的程度有关。吸烟的COPD患者气道内中性粒细胞数目增加，特别是那些伴有慢性支气管炎的患者。影响COPD患者肺内中性粒细胞募集的主要因素为IL-8趋化活性增强。本实验目的在于考察组合物对COPD小鼠BALF中中性粒细胞募集的影响，结果见表3。
表3组合物对COPD小鼠BALF中中性粒细胞募集的影响
注：*P<0.05；#P<0.01，与正常对照组相比。n＝10。
结果：组合物在10mg/kg下对COPD模型小鼠灌胃给药，可降低小鼠BALF中中性粒细胞的募集，而化合物III和化合物IV无此作用。
(2)组合物对COPD小鼠BALF中巨噬细胞募集的抑制作用
吸烟者和COPD患者肺内巨噬细胞较正常人群水平增加，多聚集在肺泡、细支气管和小气道。肺泡壁巨噬细胞数目和轻中度肺气肿以及COPD患者的小气道疾病程度呈正相关。组织病变和损伤部位可见到COPD缓慢进展和慢性病变与巨噬细胞长期增加平行。巨噬细胞可能通过释放基质金属蛋白酶导致弹性组织降解能力异常增高，诱发肺气肿的发生。本实验目的在于考察组合物对COPD小鼠BALF中巨噬细胞募集的影响，结果见表4。
表4组合物对COPD小鼠BALF中巨噬细胞募集的影响
注：*P<0.05，与模型对照组相比；#P<0.01，与正常对照组相比。n＝10。
结果：组合物在10mg/kg下对COPD模型小鼠灌胃给药，可显著降低小鼠BALF中巨噬细胞的募集，而化合物III和化合物IV无此显著作用。
结论：组合物在10mg/kg下灌胃给药，对香烟诱导的小鼠慢性阻塞性肺病过程中的炎性介质的生成和趋化因子的分泌有显著抑制作用，对炎性细胞的浸润有显著的抑制，对慢性阻塞性肺病有显著的治疗作用。而化合物III和化合物IV在10mg/kg下灌胃给药，对香烟诱导的小鼠慢性阻塞性肺病过程中的炎性介质的生成和趋化因子的分泌无显著抑制作用，对炎性细胞的浸润无显著抑制，对慢性阻塞性肺病无任何治疗作用。
实施例6本发明所涉及组合物片剂的制备
取2克组合物，加入制备片剂的常规辅料18克，混匀，常规压片机制成100片。
实施例7本发明所涉及组合物胶囊的制备
取2克组合物，加入制备胶囊剂的常规辅料如淀粉18克，混匀，装胶囊制成100粒。
Claims (10)
1.一种组合物，其特征为该组合物由化合物III和化合物IV组成，该组合物中化合物III和化合物IV的质量百分数分别为55％和45％，
2.如权利要求1所述的组合物的制备方法，其特征为：将化合物III的粉末和化合物IV的粉末按照质量百分数分别为55％和45％充分混合。
3.一种如权利要求1所述的组合物在治疗慢性阻塞性肺病药物中的应用。
4.如权利要求3所述的组合物在治疗慢性阻塞性肺病药物中的应用，其特征为：所述慢性阻塞性肺病是由吸烟引起的。
5.如权利要求3所述的组合物在治疗慢性阻塞性肺病药物中的应用，其特征为：所述组合物抑制慢性阻塞性肺病过程中炎性介质的释放。
6.如权利要求5所述的组合物在治疗慢性阻塞性肺病药物中的应用，其特征为：所述炎性介质为TNFα。
7.如权利要求3所述的组合物在治疗慢性阻塞性肺病药物中的应用，其特征为：所述组合物抑制慢性阻塞性肺病过程中趋化因子的分泌。
8.如权利要求7所述的组合物在治疗慢性阻塞性肺病药物中的应用，其特征为：所述趋化因子为RANTES。
9.如权利要求3所述的组合物在治疗慢性阻塞性肺病药物中的应用，其特征为：所述组合物抑制炎性细胞的募集。
10.如权利要求9所述的组合物在治疗慢性阻塞性肺病药物中的应用，其特征为：所述炎性细胞为中性粒细胞或者巨噬细胞。
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