CN108948085A - 一类新的化合物及其用途 - Google Patents
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Abstract
本发明涉及一类新的化合物及其用途,或其立体异构体,其药学上可接受的盐和/或水合物、溶剂合物或晶型,其特征在于,其结构通式为:通式A1:
Description
技术领域
本发明涉及一类新的化合物及其用途,还涉及该类化合物在制备抗病毒药物等方面的应用。
背景技术
HBV(乙型肝炎病毒)简称乙肝病毒。是一种DNA病毒,属于嗜肝DNA病毒科(hepadnaviridae)。根据目前所知,HBV就只对人和猩猩有易感性,引发乙型病毒性肝炎疾病。完整的乙肝病毒成颗粒状,也会被称为丹娜颗粒(Dane)。1965年由丹娜发现。直径为42纳米。颗粒分为外壳和核心两部分。
我国的乙肝病毒感染率约60%-70%;乙肝表面抗原携带率约占总人口的7.18%,以此计算,全国约有9300万人携带乙肝病毒,其中慢性乙型肝炎患者约2000万例。
人类免疫缺陷病毒(Human Immunodeficiency Virus;abbr:HIV),即艾滋病(AIDS,获得性免疫缺陷综合征)病毒,是造成人类免疫系统缺陷的一种病毒。1981年,人类免疫缺陷病毒在美国首次发现。它是一种感染人类免疫系统细胞的慢病毒(Lentivirus),属逆转录病毒的一种。
HIV通过破坏人体的T淋巴细胞,进而阻断细胞免疫和体液免疫过程,导致免疫系统瘫痪,从而致使各种疾病在人体内蔓延,最终导致艾滋病。由于HIV的变异极其迅速,难以生产特异性疫苗,至今无有效治疗方法,对人类健康造成极大威胁。
HBV和HIV-1药物的研发一直以来都是药物研发的重点和热点之一。
发明内容
本发明的发明人在研制新的抗HBV和HIV-1抗病毒药物的过程中,意外地发现一类新化合物,该类化合物出人意料地具有优异的抗HBV和HIV-1病毒活性。
为了完成本发明的目的,本发明提供一类新的化合物及其用途,经过药理实验发现,该类新化合物在抗病毒药理实验中,效果显著。现有技术中未见对该类化合物的报道。
该类新化合物为通式A1的化合物,或其立体异构体,其药学上可接受的盐和/或水合物、溶剂合物或晶型,其结构通式如下:
通式A1:
其中X为氢或卤素;
R1为WQ1ZQ2;
R2为OH、SH、
X为卤素;X、Z各自分别为S或O;
Q1为亚烷基或取代亚烷基;
Q2为烷基或亚烷基;
R3、R6、R8各自分别为亚烷基或取代亚烷基;
R4、R5、R7、R9各自分别为烷基或取代烷基。
进一步优化为通式A2或A3:
通式A2:
或者A3:
其中X为氢或卤素;
m、n分别为1-40的整数。
通过进一步优化,可以优化为表1中各化合物,其结构式如下:
表1:
以上本发明各结构通式及结构式的详细描述,不应被认为是对本发明的限制。
本发明还提供上述新的化合物在制备抗病毒药物中的应用。特别的,该化合物用于制备抗乙肝病毒和/或抗艾滋病病毒的药物中。
本发明采用细胞培养法测定了本发明化合物M1、M4、M11、M15的体外抗病毒活性,结果表明,本发明各化合物对HBV和HIV-1的抑制作用均较强。各化合物的抗HBV和抗HIV-1药理活性均强于恩替卡韦。
具体实施方式
下面以实施例的方式对本发明做进一步的详细说明,给出本发明的实施细节,但是不应被认为是对本发明的限制。
本发明的化合物抗病毒活性检测:
实施例1:HIV活性测试
将293T细胞按每孔6×104的密度加到24孔板上,用DMSO溶解待测化合物,并配制不同的浓度,于感染前15分钟加入细胞培养液中,DMSO溶剂作空白对照,再加入0.5ml病毒液(根据p24浓度将病毒原液稀释至0.1-0.5ng p24/ml)。感染后48小时,去除上清液,每孔中加入50μl细胞裂解液(Promega)裂解细胞,再将20μl细胞裂解产物加入至30μl荧光素酶底物中(Promega),用FB15荧光检测器(Sirius)仪器测定细胞荧光素酶的相对活性,以DMSO作对照,计算化合物对野生型HIV-1复制的半数抑制浓度。
将对数生长期的293T细胞按8000~10000个/孔的细胞密度接种至96孔板中,每孔100ul,37℃,5%CO2培养箱中培养24h后,加入待测化合物,并以DMSO为空白对照(终浓度为0.1%),37℃,5%CO2培养箱中继续培养44小时。向每孔中加入20μlMTS/PMS现配的混合液,37℃,5%CO2培养箱中继续培养4小时后显色。在酶联检测仪上,波长490nm和650nm处检测各孔的光吸收值(OD),在Victor3V1420多标记记数器(Perkin Elmer)中检测板的突光,应用Microsoft Excel和XLfit4.1软件求出CC50值。
表2:合成化合物的抗HIV活性评价:
序号 | 测试化合物 | EC50(nM) | CC50(nM) |
1 | M1 | 5.1 | 〉100 |
2 | M4 | 5.3 | 〉100 |
3 | M11 | 5.2 | 〉100 |
4 | M15 | 5.4 | 〉100 |
5 | 恩替卡韦 | 6.5 | 〉100 |
实验结果显示,新化合物都有很强的抗HIV活性。和恩替卡韦的抗HIV活性对比,化合物M1、M4、M11、M15都显示了更高的活性,其中M1活性表现最好。
实施例2:合成化合物的抗HBV活性评价:
HepG2 2.2.15细胞(SELLS,PNAS,1987andSELLS,JV,1988)的染色体整合有完整的HBV基因组,并稳定表达病毒RNA,cccDNA和病毒蛋白质。此外,该细胞还向培养基中分泌成熟的乙肝病毒颗粒。通过qPCR量化病毒粒子DNA的方法可以测量病毒的复制。待测化合物用DMSO溶解为30mM的储存液并保存在-20℃。在96孔细胞培养板中加入每孔10,000个HepG22.2.15细胞,每孔200μL细胞培养基,在37℃,5%CO2细胞培养箱中培养3天至细胞长满。弃掉旧的培养基并加入200μL新鲜的检测培养基(5%FBS)。加入100%DMSO稀释的化合物1μL:稀释为不同的指定的测试浓度,在CO2培养箱中孵育10天,每隔一天(第2,4,6,8,10天)换一次液(5%FBS),并加入新鲜配制浓度的化合物。在第11天每孔取150μL上清提取病毒DNA。细胞毒性检测板也进行类似处理:最高浓度是150μM。病毒基因组DNA的提取试剂盒为QIAamp96DNA Blood Kit。经过常规的离心和QPCR过程。用包含HBV基因组的质粒(病毒拷贝数:2*10E6,2*10E5,2*10E4,2*10E3)做标准曲线,并以标准曲线来计算病毒拷贝数。抑制率的计算公式如下:抗病毒的抑制率=100-(检测值-HPE平均值)/(ZPE平均值-HPE平均值)*100(ZPE:最低浓度化合物孔平均值,HPE:最高浓度化合物孔平均值)。抑制率数据通过Graphpad Prism 5软件处理并绘制曲线,EC50和EC90通过四参数非线性回归模型计算。细胞毒性%=100-(检测值/DMSO对照孔平均值*100)。细胞毒性%数据通过Graphpad Prism 5软件处理并绘制曲线,CC50通过四参数非线性回归模型计算。
表3:化合物的抗HBV活性评价:
序号 | 测试化合物 | EC50(nM) | CC50(nM) |
1 | M1 | 7.2 | 〉100 |
2 | M4 | 7.3 | 〉100 |
3 | M11 | 7.5 | 〉100 |
4 | M15 | 7.5 | 〉100 |
5 | 恩替卡韦 | 16.1 | 〉100 |
实验结果显示,所有的新化合物都有很强的抗HBV活性。和恩替卡韦比较,新化合物M1、M4、M11、M15都显示了更优秀的活性。
Claims (5)
1.一类新的化合物,或其立体异构体,其药学上可接受的盐和/或水合物、溶剂合物或晶型,其特征在于,其结构通式为:
通式A1:
其中X为氢或卤素;
R1为WQ1ZQ2;
R2为OH、SH、-NR3R4COOR5 -OR6OCOOR7 或-OR8OCOR9
X为卤素;X、Z各自分别为S或O;
Q1为亚烷基或取代亚烷基;
Q2为烷基或亚烷基;
R3、R6、R8各自分别为亚烷基或取代亚烷基;
R4、R5、R7、R9各自分别为烷基或取代烷基。
2.根据权利要求1所述的化合物,或其立体异构体,其药学上可接受的盐和/或水合物、溶剂合物或晶型,其特征在于,其结构通式为:
通式A2:
或者A3:
其中X为氢、卤素;
m、n各自分别为1-40的整数。
3.根据权利要求1-2的化合物,或其立体异构体,其药学上可接受的盐和/或水合物、溶剂合物或晶型,其特征在于,其结构通式为下述通式中的任一种:
4.应用权利要求1-3任一项所述的化合物,或其立体异构体,其药学上可接受的盐和/或水合物、溶剂合物或晶型,其特征在于,该化合物用于制备抗病毒的药物。
5.根据权利要求4所述的药物,或其立体异构体,其药学上可接受的盐和/或水合物、溶剂合物或晶型,其特征在于,该药物用于制备抗艾滋病病毒和/或抗乙肝病毒的药物。
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