CN1136844C - β－硝基苯乙烯在制备抗艾滋病药物中的应用 - Google Patents
β－硝基苯乙烯在制备抗艾滋病药物中的应用 Download PDFInfo
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Abstract
一种抗艾滋病的药物组合物，其中含有抗艾滋病有效量的式(I)化合物β-硝基苯乙烯及可药用载体和/或赋形剂。上述药物组合物在制备逆转录酶抑制剂药物中的应用；上述药物组合物在制备抗艾滋病药物中的应用。
Description
本发明属于药物技术领域，具体地说，涉及一种β-硝基苯乙烯在制备逆转录酶抑制剂药物和在制备抗艾滋病药物中的应用。
艾滋病(Acquired Immuno-deficiency Syndrome，AIDS，获得性免疫缺损综合症，简称艾滋病)是当今世界主要威胁人类健康的不可根治的致死疾病之一。导致艾滋病的病原体即人类免疫缺损病毒(Human Immunodeficiency Virus，HIV)，1983年获得分离确证，有两种亚型HIV-1和HIV-2，若干变异株。HIV繁殖过程大致可分九个步骤：吸附、穿入、脱壳、早期蛋白合成、病毒基因组核酸的复制、晚期蛋白合成、核壳体装配、病毒体成熟、释放等。从理论上说，上述过程中的每一个步骤都能作为筛选抗HIV药物的靶点。并且每一步骤都发现了许多相应的抑制剂，不同类型的化合物被相继研究和用于抗艾滋病病毒。然而其中病毒基因组核酸的复制和蛋白质的合成是HIV繁殖最关键的步骤，且需要有某些特异性酶的参与，故抗HIV药物的研制的热点主要集中于寻找这些特异性酶的抑制剂方面，包括逆转录酶(RT)抑制剂(它抑制HIV从mRNA转录DNA)，蛋白质合成酶抑制剂，逆转录启动因子(TAT)抑制剂等。全世界已对约20000个化合物进行了抗HIV的研究，目前已成功地研制出了逆转录酶抑制剂和蛋白酶抑制剂14个抗HIV药物。如逆转录酶抑制剂(AZT，DDC，DDI，D4T，3TC，Nevirapine，Delavirdine，Efavinavir)和蛋白酶抑制剂药物(Sequanavir，Ritonavir，Indinavir，Nelfinavir，Amprenavir)虽然被批准用于临床，客观上延长了艾滋病患者的生命，但同时又带了严重的毒副作用如骨髓抑制和健忘等以及导致抗病毒株的出现。因而临床上急需研制出具有不同化学结构和作用机理的新类型抗HIV病毒的新药物。从中草药中发现天然抗HIV活性化合物或先导物---是目前国内外研究的重要方面和非常活跃的领域。至今发现100多种天然化合物具有HIV活性，分属于倍半萜、二萜、三萜、甾体、黄酮、香豆素、肽类、生物碱，多糖，天花粉蛋白等，其中活性较强的如：甘草甜素，金丝桃素，姜黄素，大豆皂甙，喜树碱，栗精胺，香菇多糖，天花粉蛋白等。
迄今，现有技术中没有含有式(I)化合物β-硝基苯乙烯作为有效成分在抗艾滋病方面的报道，也没有该化合物在制备逆转录酶抑制剂药物中的应用和在制备抗艾滋病药物中的应用的报道。
本发明的目的在于提供式(I)化合物在制备逆转录酶抑制剂药物和在制备抗艾滋病药物中的应用。
为了实现本发明的上述目的，本发明提供了如下的技术方案：
式I化合物在制备逆转录酶抑制剂药物中的应用。
本发明同时提供了式I化合物在制备抗艾滋病药物中的应用。
本发明化合物用作药物时，可以直接使用，或者以药物组合物的形式使用。该药物组合物含有0.1-99％，优选为0.5-90％的本发明化合物，其余为药物学上可接受的，对人和动物无毒和惰性的可药用载体和/或赋形剂。
所述的药用载体或赋形剂是一种或多种选固体、半固体和液体稀释剂、填料以及药物制品辅剂。将本发明的药物组合物以单位体重服用量的形式使用。本发明的药物可经口服和注射(静注、肌注)两种形式给药。
为了更好地理解本发明的实质，下面将用式(I)化合物β-硝基苯乙烯(以下简称KIBL-42)及其与药用载体或赋形剂组成的药物组合物的药理作用结果来说明本发明的实质，但本发明的内容并不局限于此。
1、β-硝基苯乙烯对HIV-1逆转录酶的抑制作用
(1)实验方法
逆转录酶Reverse Transcriptase(RT)测定，非放射性(non-radioactive)试剂盒购自Roche公司。将化合物溶解于DMSO中。取出试剂盒中反应条，每孔滴加20μl HIV-1 RT溶液，13μl裂解缓冲液，7μl溶于DMSO的化合物，20μl含模板和核苷酸的反应缓冲液。化合物的终哝度为210μg/ml。设置Foscarnet阳性对照孔和不含化合物的阴性对照孔。置37℃ 1小时。洗涤5次后，每孔加入200μl抗DIG-POD抗体工作液。37℃温育1小时，洗涤5次。每孔滴加200μl ABTS底物反应液。室温反应15-30分钟。Bio-Tek Elx800酶标仪测定OD值(405/490nm)。以抑制RT活性＞50％的化合物判定为初筛阳性。将初筛阳性化合物用裂解缓冲液进行倍比稀释，每个浓度设二个复孔。按上述方法测定其对RT活性的抑制。计算出抑制HIV-1 RT活性50％的化合物浓度(EC50，50％effective concentration)。
(2)结果(见说明书附图1)
β-硝基苯乙烯对HIV-1RT的抑制活性数据
μg/ml 0.288 1.44 7.2 36 180 EC50
抑制率％ 4.8 17.1 54 94.5 105.56.3μg/ml
2、β-硝基苯乙烯对C8166细胞的毒性测定
(1)测定方法：采用MTT法对样品CC50的测定
样品的制备：将样品用RPMI-1640稀释为1000μg/mL的浓度，用0.22μM膜过滤。
实验操作：
取板每孔+100μL培养基进行2倍梯度稀释+100μL C8166细胞(3×105/mL)，培养72小时(37℃ CO25％)，吸出上清100μL+20μL MTT，继续温育4小时(37℃ CO25％)+100μL，10％SDS放培养箱中过夜(18小时)。
OD值测定：
用Elx-800酶标仪测定OD值波长490nM。
(4)实验结果：(见说明书附图2)计算不同浓度的抑制％率、再算出抑制50％C8166细胞的毒性值(CC50，50％cytoxic concentration)。
β-硝基苯乙烯对C8166细胞的毒性μg/ml 15.6 31.3 62.5 125 500 CC50抑制率％ 25.5 27.7 41.3 35.8 104.4 260.0μg/ml
3、β-硝基苯乙烯对HIV的治疗指数(Selective Index，SI)
SI＝CC50÷EC50＝260μg/ml÷6.3μg/ml＝41
从上述实验结果可以证实：β-硝基苯乙烯对HIV-1逆转录酶具有抑制作用，它对C8166细胞的毒性低，选择指数高，它可用于与逆转录酶有关的疾病如艾滋病等。
图1是β-硝基苯乙烯对HIV-1RT的抑制活性数据图；
图2是β-硝基苯乙烯对C8166细胞的毒性测定图。
下面结合实施例进一步对本发明实质内容进行说明，但本发明的内容并不局限于此。
实施例1：
β-硝基苯乙烯购自美国Aldrich公司
β-硝基苯乙烯结构数据：
结构：如右图所示
分子式：C8H7NO2
分子量：149
mp：56-58℃
性状：黄色针晶
将β-硝基苯乙烯与赋形剂按重量比为9∶1的比例加入赋形剂，制成粉剂。
实施例2：
将β-硝基苯乙烯按其与赋形剂重量比为5∶1的比例加入赋形剂，制成粉剂。
实施例3：
将β-硝基苯乙烯与赋形剂重量比为5∶1的比例加入赋形剂，制粒压片。
实施例4：
将β-硝基苯乙烯溶于无菌注射用水中，搅拌使溶，用无菌抽滤漏斗过滤，再无菌精滤，分装于2ml安瓿中，低温冷冻干燥后无菌熔封得粉针剂。
实施例5：
将β-硝基苯乙烯按常规口服液制法制成口服液。
实施例6：
将β-硝基苯乙烯按常规注射液制备方法加注射用水，精滤，灌封灭菌制成注射液。
实施例7：
将β-硝基苯乙烯按其与赋形剂重量比为5∶1的比例加入赋形剂，制成胶囊。
实施例8：
按β-硝基苯乙烯与赋形剂重量比为3∶1的比例加入赋形剂，制成胶囊。
Claims (2)
1、式I化合物在制备逆转录酶抑制剂药物中的应用。
2、式I化合物在制备抗艾滋病药物中的应用。
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