CN103003271A - 新型罗丹宁衍生物及其制备方法,含罗丹宁衍生物为活性成分的预防或治疗aids的药物组合物 - Google Patents
新型罗丹宁衍生物及其制备方法,含罗丹宁衍生物为活性成分的预防或治疗aids的药物组合物 Download PDFInfo
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- thiazolidin
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
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Abstract
本发明涉及新型罗丹宁衍生物,该新型罗丹宁衍生物的制备方法及含有该罗丹宁衍生物作为活性成分的用于预防或治疗AIDS的药物组合物。根据本发明的罗丹宁衍生物抑制HIV的表达,具有抗HIV的高抑制活性,从而可有效地用于AIDS的预防或治疗中。
Description
技术领域
本发明涉及新型罗丹宁衍生物及其制备方法,以及含有所述新型罗丹宁衍生物作为活性成分的用于预防或治疗AIDS的药物组合物。
背景技术
艾滋病(AIDS)临床观察始于1981年,自1984年从AIDS患者中分离HIV(人类免疫缺陷病毒)时,发现HIV导致AIDS。
分类学上,HIV是慢病毒属的一员,是逆转录病毒科的部分。HIV颗粒大致呈球形直径大约10微米。其基因组由两个相同的RNA组成,所述RNA由蛋白质囊(衣壳、核心蛋白)包被,反之,蛋白质囊由磷脂组成的病毒包膜包围,像一般的质膜。HIV基因组编码10个基因,其相对于基因组的总大小太多了。
通过病毒表面的包膜糖蛋白(gp120)与靶细胞上的受体相互作用介导HIV感染。作为受体的细胞表面蛋白分子主要是CD4抗原。这是为什么可在其表面表达CD4的细胞(CD4+细胞),例如巨噬细胞和辅助T细胞,是HIV的主要靶细胞。糖蛋白吸附到受体后,随着HIV基因组和核衣壳释放到细胞中,病毒磷脂包膜与细胞膜融合。进入靶细胞后,病毒RNA基因组由病毒编码的逆转录酶转化为DNA,所述逆转录酶与病毒颗粒中的病毒基因组一起被运输。然后将病毒DNA运输至细胞核并整合到宿主细胞基因组。这个过程是逆转录病毒的独特特征之一。因此,整合的病毒DNA潜伏在宿主细胞中最安全的位点,同时从细胞中提供病毒生长必要的所有机制和资源。此外,HIV保护自身免受免疫系统并生存下来,同时根据周围情况和条件增殖或进入感染的潜伏期。
以两种类型的AIDS病毒为特征:HIV-1和HIV-2。HIV-1发现于全世界的患者中且为全球大多数HIV感染的原因。HIV-2主要限于西非。其核苷酸序列只有55%与HIV-1相同,其与SIV(猿猴免疫缺陷病毒)更相似,被称为猴AIDS病毒。HIV-2比HIV-1毒性较弱。HIV不仅具有高生物变异性,还具有高遗传变异性。HIV的核苷酸序列从一个AIDS患者到另一个患者彼此不同,即使在同一患者中其随着AIDS的进展而不同。更严重的是,HIV的核苷酸序列,在同一时间从同一病人采样时,根据采样组织是不同的。这些HIV序列多态性与病毒的各种生物特征紧密相连。由于不同的核苷酸序列,HIV对靶细胞的感染偏好、病毒粒子生产力、细胞毒性、形成多核巨细胞的能力、潜伏期和活跃期,以及对中和抗体的敏感性不同。关于HIV可变的生物特性和HIV感染的发病机制的关系的更多近期研究表明,早期从患者中分离的大多数AIDS病毒不产生多核巨细胞(不致多核巨细胞(NSI))且优选感染巨噬细胞,然而随着AIDS的进展,HIV更易于产生多核巨细胞(致多核巨细胞(SI)),且优选地在辅助性T细胞复制,表明HIV的生物特性与HIV感染的发病机制之间关系密切。
HIV感染一周后,病毒增殖活跃且可容易地在感染者的血液中检测到,就是说,患者变为病毒血症。然后,病毒在一至两周内迅速降低到低水平以使其不能被分离。在维持一段显著时期的潜伏后,随着AIDS发病HIV积极复制,从而发生病毒血症。最近的PCR研究引起重视,由于其报道HIV在休眠状态时复制。HIV感染后,CD4细胞水平在初始病毒血症期间迅速降低,然后恢复到恒定值(健康的人:500-1000CD4细胞/mm3)。由于这点,CD4细胞的血液水平在几年后逐渐降低。在CD4细胞低于每立方毫米血液200个时,ARC(AIDS相关综合征)或AIDS发作。AIDS患者经历逐渐受损的免疫系统允许威胁生命的机会性感染大量发生的情况,例如卡氏肺孢子虫肺炎。初始病毒血症后HIV水平迅速降低的时期伴随着CD8细胞的激活期。已知CD8T细胞起抑制细胞生长或选择性地杀死病毒感染的细胞的作用。因此,CD8T细胞似乎负责免疫早期感染的病毒。在病毒水平降低后产生抗体。CD8细胞和抗体从感染初期到AIDS发作期间一直存在,但其功能被降低或变性,其甚至促进HIV感染。在感染早期表现明显抗病毒活性的免疫系统怎样失去作用仍是有待解决的问题。由于AIDS的人类特异性,HIV病因的理解处于非常低的水平。尽管科学家对CD4细胞水平降低是免疫缺陷的直接原因的事实达成共识,但对于HIV如何降低CD4细胞水平存在各种不同意见。解释CD4细胞水平降低的建议理论包括形成多核巨细胞,积累非插入式病毒DNA,影响宿主细胞膜结构,诱导程序性细胞死亡,从受感染细胞分泌有毒物质,及自身免疫介导的细胞溶解。然而,迄今为止上述理论中没有一个被证明为事实或显示实践中在体内发生。使用猴AIDS病毒SIV在猴子上进行HIV发病机制的广泛研究,但还没有产生任何新的发现。
目前可用的AIDS药物中最普遍的是AZT(齐多夫定),其为HIV逆转录酶抑制剂。今天其仍然广泛使用,并被认为医学史上最具有效的药物之一。这种药物在HIV感染早期临床上是非常有效的,但发现由于其副作用对延长患者生命无积极作用。即,AZT引起骨髓毒性,且可能允许HIV随时间推移变为抗AZT。DDI、DDC和d4T,所有在功能上类似AZT,并由FDA批准,发现其比AZT毒性较弱,但将HIV诱导为对其有抗性的。
已研发了许多抗病毒方法,正在等待药效试验。所述方法的实施例为预防病毒吸附到细胞中,选择性地杀死病毒感染的细胞,使用抗病毒生长中起重要作用的酶的抑制剂(例如,蛋白酶、整合酶、tat抑制剂、rev抑制剂等),细胞因子疗法,注射CD8细胞,及基因疗法。HIV疫苗的研发已取得很大进步,例如使用灭活的病毒,或减弱病毒,其为活着的但不致病,生物工程表达的分离的病毒蛋白(亚单位疫苗),抗独特型抗体,以及直接注射DNA基因。然而,疫苗研发的根本问题在于HIV病毒的过度多样性。例如,观察使用疫苗免疫的人,当遇到与研发疫苗所用的病毒相同的病毒时抑制病毒,但遇到取自不同患者的感染的细胞或病毒时不显示任何免疫保护作用。这种病毒多样性也仍然是一个待解决的问题。
因此,迫切需要解决现有技术中遇到的问题的AIDS药物,所述问题包括传统AIDS治疗中的副作用和耐药性病毒。
发明内容
技术问题
根据本发明,本发明人关于AIDS治疗进行了精细并深入的研究,从而发现了新型罗丹宁衍生物,其具有优越的抑制HIV的活性,而没有副作用也不会诱导耐药性病毒。
技术方案
本发明提供了一种新型罗丹宁衍生物及其制备方法,还提供一种含有所述衍生物作为活性成分的用于预防或治疗AIDS的药物组合物。
有益效果
本发明的罗丹宁衍生物通过抑制HIV表达从而表现出优越的抗HIV活性,从而对于预防或治疗AIDS是有效的。
具体实施方式
根据本发明的一方面,本发明涉及一种选自下组的罗丹宁衍生物:
1)3-(2,4-二甲基-苯基)-5-[5-(3-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
2)5-[5-(4-吗啉-4-基-3-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
3)5-[5-(4-氧代-2-硫代-噻唑烷-5-亚基甲基)-呋喃-2-基]-异吲哚-1,3-二酮,
4)3-(2-甲磺酰基-乙基)-5-[5-(3-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
5)5-[5-(4-溴代-苯基)-呋喃-2-基亚甲基]-3-(3-氧代-丁基)-2-硫代-噻唑烷-4-酮,
6)5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-3-(四氢呋喃-2-基甲基)-2-硫代-噻唑烷-4-酮,
7)3-(4-二乙基氨基-苯基)-5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
8)5-[5-(2,4-二氯代-苯基)-呋喃-2-基亚甲基]-3-(3-氟代-苯基)-2-硫代-噻唑烷-4-酮,
9)3-苯乙基-5-(5-苯基-呋喃-2-基亚甲基)-2-硫代-噻唑烷-4-酮,
10)5-[5-(3-氯代-4-甲基-苯基)-呋喃-2-基亚甲基]-3-乙基-2-硫代-噻唑烷-4-酮,
11)5-(萘-1-基-呋喃-2-基亚甲基)-3-(2-氧代-丙基)-2-硫代-噻唑烷-4-酮,
12)3-环己基-5-[5-(2-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
13)3-(3-氟代-苯基)-5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
14)3-(1,1-二氧代-四氢-噻吩-3-基)-5-[5-(2-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
15)5-[5-(2-硝基-苯基)-呋喃-2-基亚甲基]-3-(4-氧代-戊基)-2-硫代-噻唑烷-4-酮,
16)5-[5-(2-溴代-5-硝基-苯基)-呋喃-2-基亚甲基]-3-(4-碘代-苯基)-2-硫代-噻唑烷-4-酮,
17)5-[5-(2-氯代-4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-3-(3-三氟甲基-苯基)-噻唑烷-4-酮,
18)3-苄基-5-[5-(4-乙氧基-2-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
19){5-[5-(2-甲基-5-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-醋酸,
20){5-[5-(4-乙氧基-2-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-醋酸,
21){5-[5-(4-甲氧基-2-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-醋酸,
22)3-(4-硝基-苯基)-5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,以及
23)4-[5-(4-氧代-2-硫代-噻唑烷-5-亚基甲基)-呋喃-2-基]-苯甲酸异丙酯,或其药学上可接受的盐。
本发明的罗丹宁衍生物可以使用本领域已知的典型方法制备成药学上可接受的盐或溶剂化物。
本发明范围内的药学上可接受的盐包括,例如,与药学上可接受的游离酸形成的酸加成盐。根据本发明的化合物的酸加成盐可以使用常规方法制备,例如,通过在水中的过量的酸溶解罗丹宁衍生物,并在与水可混合的有机溶剂中沉淀获得的盐,所述有机溶剂,例如,甲醇、乙醇、丙酮或乙腈。可选地,本发明的罗丹宁衍生物可以在水中与相同摩尔量的酸或乙醇(例如,乙二醇单甲醚)一起加热,然后蒸发混合物,并干燥或抽滤沉淀从而制备酸加成盐。
游离酸可以是无机酸或有机酸。有用的无机游离酸的例子包括盐酸、磷酸、硫酸、硝酸和锡酸。作为有机酸的例子可以使用甲磺酸、对甲苯磺酸、醋酸、三氟醋酸、柠檬酸、马来酸、琥珀酸、草酸、苯甲酸、酒石酸、富马酸、扁桃酸、丙酸、乳酸、乙醇酸、葡糖酸、半乳糖醛酸、谷氨基酸、戊二酸、葡糖醛酸、天门冬酸、抗坏血酸、碳酸、香草酸、氢碘酸。
同样地,与碱基形成的金属盐可落入本发明的化合物的药学上可接受的盐的范围内。可用于本发明的金属盐的例子包括碱金属盐和碱土金属盐。通过实施例,本发明的化合物可以溶解于水中的过量的碱金属氢氧化物或碱土金属氢氧化物中,并且,在溶液过滤后除去非溶解的化合物盐,可以干燥滤液从而提供本发明化合物的药学上可接受的盐。适合用于制药学的是钠盐、钾盐或钙盐。相应的银盐可以通过将碱金属或碱土金属盐与合适的银盐(例如,硝酸银)反应获得。
除非另有说明,本发明的罗丹宁衍生物的药学上可接受的盐包括存在于罗丹宁衍生物上的酸性或碱性基团的盐,例如,药学上可接受的盐包括,羟基基团的钠盐、钙盐或钾盐。对于氨基基团,示意性的例子是氢溴酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐、醋酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、乳酸盐、扁桃酸盐、甲磺酸盐(甲磺酸盐)和对甲苯磺酸盐(甲苯磺酸盐),并且其可以通过本领域典型的已知方法制备。
根据本发明的另一方面,本发明涉及一种罗丹宁衍生物的制备方法,包括:
1)使化学式2的胺化合物与二硫化碳(CS2)和溴乙酸反应从而合成化学式3的化合物,
2)使化学式4的卤化物与5-甲酰-2-呋喃硼酸反应从而合成化学式5的化合物,并且
3)如以下示意性方案1,使步骤1中合成的化学式3的化合物与步骤2中合成的化学式5的化合物反应,以提供化学式1的化合物:
[反应方案1]
其中,
其中
A是(C=O)或SO2,
B是甲基或羟基,
Z是F、I、NO2、CF3或-N(CH2CH3)2,
N是1~3中的整数,以及
M是1或2的整数,
R2和R3,其可以相同或不同,其独立地选自H、NO2、Br、Cl、甲基、甲氧基、乙氧基、-(C=O)-O-CH(CH3)2、或吗啉,或者R2和R3彼此相邻,结合在一起形成:
X是卤原子。
根据本发明的另一方面,本发明提供了一种用于预防或治疗AIDS的药物组合物,其含有选自下组的作为活性成分的罗丹宁衍生物:
1)3-(2,4-二甲基-苯基)-5-[5-(3-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
2)5-[5-(4-吗啉-4-基-3-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
3)5-[5-(4-氧代-2-硫代-噻唑烷-5-亚基甲基)-呋喃-2-基]-异吲哚-1,3-二酮,
4)3-(2-甲磺酰基-乙基)-5-[5-(3-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
5)5-[5-(4-溴代-苯基)-呋喃-2-基亚甲基]-3-(3-氧代-丁基)-2-硫代-噻唑烷-4-酮,
6)5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-3-(四氢呋喃-2-基甲基)-2-硫代-噻唑烷-4-酮,
7)3-(4-二乙基氨基-苯基)-5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
8)5-[5-(2,4-二氯代-苯基)-呋喃-2-基亚甲基]-3-(3-氟代-苯基)-2-硫代-噻唑烷-4-酮,
9)3-苯乙基-5-(5-苯基-呋喃-2-基亚甲基)-2-硫代-噻唑烷-4-酮,
10)5-[5-(3-氯代-4-甲基-苯基)-呋喃-2-基亚甲基]-3-乙基-2-硫代-噻唑烷-4-酮,
11)5-(萘-1-基-呋喃-2-基亚甲基)-3-(2-氧代-丙基)-2-硫代-噻唑烷-4-酮,
12)3-环己基-5-[5-(2-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
13)3-(3-氟代-苯基)-5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
14)3-(1,1-二氧代-四氢-噻吩-3-基)-5-[5-(2-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
15)5-[5-(2-硝基-苯基)-呋喃-2-基亚甲基]-3-(4-氧代-戊基)-2-硫代-噻唑烷-4-酮,
16)5-[5-(2-溴代-5-硝基-苯基)-呋喃-2-基亚甲基]-3-(4-碘代-苯基)-2-硫代-噻唑烷-4-酮,
17)5-[5-(2-氯代-4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-3-(3-三氟甲基-苯基)-噻唑烷-4-酮,
18)3-苄基-5-[5-(4-乙氧基-2-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
19){5-[5-(2-甲基-5-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-醋酸,
20){5-[5-(4-乙氧基-2-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-醋酸,
21){5-[5-(4-甲氧基-2-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-醋酸,
22)3-(4-硝基-苯基)-5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
23)4-[5-(4-氧代-2-硫代-噻唑烷-5-亚基甲基)-呋喃-2-基]-苯甲酸异丙酯,
24)5-[5-(2,5-二氯代-苯基)-呋喃-2-基亚甲基]-3-(1,5-二甲基-3-氧代-2-苯基-2,3-二氢-1H-吡唑-4-基)-2-硫代-噻唑烷-4-酮,
25)5-[5-(1-氧代-1,3-二氢-异苯并呋喃-5-基)-呋喃-2-基亚甲基-2-硫代-噻唑烷-4-酮,
26)3-呋喃-2-基甲基-5-[5-(2-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
27)5-[5-(2-硝基-苯基)-呋喃-2-基亚甲基]-3-苯乙基-2-硫代-噻唑烷-4-酮,
28)3-(3-氯代-苯基)-5-[5-(2,3-二氯代-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
29)2-氯代-5-[5-(4-氧代-2-硫代-噻唑烷-5-亚基甲基)-呋喃-2-基]-苯甲酸丙酯,
30)4-{5-[5-(3,4-二氯代-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-丁酸,
31)2-{5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-琥珀酸,
32)5-[5-(4-氯代-苯基)-呋喃-2-基亚甲基]-3-呋喃-2-基甲基-2-硫代-噻唑烷-4-酮,
33)5-[5-(2,4-二氯代-苯基)-呋喃-2-基亚甲基]-2-硫代-3-(3-三氟甲基-苯基)-噻唑烷-4-酮,
34)3-呋喃-2-基甲基-5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
35)3-{5-[5-(3-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-丙酸,
36)3-{5-[5-(4-氯代-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-丙酸,
37)4-{5-[3-(2,4-二甲基-苯基)-4-氧代-2-硫代-噻唑烷-5-亚基甲基]-呋喃-2-基}-苯甲酸,以及
38){5-[5-(3-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-醋酸。
本发明的化合物通过抑制HIV病毒的表达,显示出了优越的抗HIV的活性。因此,本发明的罗丹宁衍生物可用于预防或治疗AIDS。
除了罗丹宁衍生物外,本发明的组合物还进一步包括至少1种已知的具有抗HIV的抑制活性的活性成分。
为了施用,除了活性成分之外,该药物组合物可进一步包括药学上可接受的载体。药学上可接受的载体的例子包括盐水、无菌水、林格氏溶液、缓冲盐水、葡萄糖溶液、麦芽糖糊精溶液、甘油、乙醇等。任选地,典型的添加剂,例如抗氧化剂、缓冲剂、抗菌剂等,可以添加到本发明的组合物中。制备的药物剂型包括注射剂,例如水溶液、悬浮液和乳剂、药丸、胶囊、颗粒和片剂,该活性成分可以与稀释剂、分散剂、表面活性剂、粘合剂和/或润滑剂混合。关于可以制成合适的药物剂型的药物组合物制剂可以参考文献(Remington’s Pharmaceutical Science(最新版),Mack PublishingCompany,Easton PA)。
本发明的组合物可以通过口服途径或肠道外途径施用(例如,静脉内的、皮下的、腹膜内的、局部的等)。根据本发明的抑制剂的有效剂量取决于各种因素,包括患者的体重、年龄、性别、健康状态、饮食、施用时间、施用途径、排泄率、疾病严重程度等。一般来说,罗丹宁衍生物可以以单剂量施用,并优选地以每天多剂量施用,每日剂量的范围是0.1~50mg/kg,优选2~10mg/kg。
为了有效的预防并治疗AIDS,根据本发明的组合物可以单独施用或与外科手术、激素治疗、药物和/或生物反应调节剂一起组合使用。
通过以下示意性的实施例,将更好的理解本发明,但是其不构成对本发明的限制。
实施例1:3-(2,4-二甲基-苯基)-5-[5-(3-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮的制备
1、3-(2,4-二甲基-苯基)-2-硫代-噻唑烷-4-酮的合成
在0°C下,将1g的2,4-二甲基苯胺(8.04mmol)与54mL的0.2M的三乙胺的乙酸乙酯溶液混合,并将0.65mL的二硫化碳(CS2)溶液逐滴加入到混合物中,并缓慢搅拌。加入完成后,继续搅拌额外的12小时。过滤反应混合物,并将过滤物溶于碳酸氢钠(NaHCO3)水溶液中,并与2.2g的溴乙酸(15.83mmol)混合,搅拌2小时。获得的反应混合物用35%的HCl溶液酸化(pH 2),并加热6小时。用二氯甲烷(CH2Cl2)提取后,合并有机层,并用饱和盐水洗涤,在无水硫酸镁上干燥,并真空浓缩。通过硅胶柱层析纯化浓缩物以获得目标化合物。
1-1、3-(2,4-二甲基-苯基)-2-硫代-噻唑烷-4-酮的可替代的合成
向在8.9mL的22%KOH中的1g的2,4-二甲基苯胺(8.04mmol)溶液中,逐滴加入0.81mL的二氧化碳,并搅拌。添加完成后,继续搅拌额外的12小时。溶液与2.78g的溴乙酸(20.01mmol)混合2小时,并搅拌。然后,用硫酸酸化反应混合物,在室温下搅拌12小时,并用水洗涤以获得目标化合物。
2、5-(3-硝基-苯基)-呋喃-2-甲醛的合成
室温下,向1.5g的1-溴代-3-硝基苯(7.42mmol)、1g的5-甲酰-2-呋喃硼酸(7.42mmol)和35mL的饱和碳酸钠(Na2CO3)的0.2M的四氢呋喃溶液的混合物中加入0.2g的四三苯基膦钯[Pd(PPh3)4](0.2mmol),并搅拌。添加完成后,继续将所得混合物加热额外的12小时,冷却至室温,并真空浓缩。用二氯甲烷提取浓缩物。并加入由此形成的有机相,用饱和盐水洗涤,通过无水硫酸镁干燥,并在真空中浓缩。通过硅胶柱层析纯化浓缩物以获得目标化合物。
3、3-(2,4-二甲基-苯基)-5-[5-(3-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-
噻唑烷-4-酮的合成
在4.7mL的0.2M乙醇中溶解上述1中合成的0.1g的3-(2,4-二甲基-苯基)-2-硫代-噻唑烷-4-酮(0.42mmol)。溶液与0.11g的醋酸钠(1.34mmol)和上述2中合成的0.15g的5-(3-硝基-苯基)-呋喃-2-甲醛(0.69mmol)混合,并搅拌,然后加热4小时。获得的反应混合物用乙醇洗涤以获得固体的目标化合物。当没有形成固体时,通过硅胶柱层析进行纯化以获得0.54g的目标化合物(产率:28.6%)。
ESI(m/z):437(M+)
1H NMR(500MHz,DMSO):8.66-8.65(d,J=5Hz,1H),8.30-8.26(m,1H),7.88(t,J=8Hz,1H),7.79-7.77(d,J=10Hz,1H),7.64(t,J=5.3Hz,1H),7.44(t,J=5Hz,1H),7.24-7.15(m,3H),2.35-2.33(d,J=10Hz,3H),2.02-2.00(d,J=10Hz,3H)
实施例:2至23
用反应方案1中的相同的步骤制备实施例2至23的化合物。
在表1中,总结了实施例2至23的化合物的结构式、MS数据和1H NMR数据。
表1
实施例24至38
用实施例1中的相同的步骤制备实施例24至38的化合物。在下表2中,总结了实施例24至38的化合物的结构式。
表2
试验性实施例1:罗丹宁衍生物的抗HIV的抑制活性的分析
对本发明的罗丹宁衍生物对于HIV的抑制活性分析如下。
1、HIV的制备
将携带有HIV基因组的pNL4-3载体转导进293FT细胞中。pNL4-3上的HIV基因组并不感染机体,因为它含有取代nef基因的EGFP基因。将293FT细胞以3.0×105细胞/孔的密度接种于6孔板中,该6孔板含有无抗生素的DMEM,其补充有10%的FBS,并培养48小时。达到90~95%的融合度时,进行转导。
向250μL的低血清培养基Opti-MEM I(GIBCOTM,USA)中加入终浓度为10ng/mL的DNA(pNL4-3),单独地,将4μL的LipofectamineTM 2000(Invitrogen,USA)与250μL的Opti-MEM I(GIBCOTM)混合,并在室温下培养5分钟。DNA(pNL4-3)以1:2的比例与脂质体混合,并在室温下反应20分钟,以形成DNA脂质体复合物。从细胞培养物中去除培养基后,将含有DNA-脂质体复合物的混合物加入到细胞中,并在CO2培养箱中培养4小时。然后,将细胞培养基用新鲜的无抗生素的,补充有10%FBS的DMEM培养基替换,接着再培养48小时。以1,500rpm对HIV感染的细胞培养物离心5分钟,从而产生病毒上清。
以1.0×106细胞/mL的密度将MT-4细胞涂布于6孔板中,该6孔板含有补充有10%FBS的RPMI,并在感染前培养4小时,感染以细胞与病毒上清的比例为1:1进行。细胞在CO2培养箱中培养48小时,之后,培养基用新鲜的培养基更换一次。再次,持续培养72小时以使病毒扩增。在以1,500rpm离心5分钟后,使用Virononstika HIV-1Antigen Microelisa系统试剂盒(bioMerieux,Inc.荷兰)检测获得的病毒上清的病毒密度。
2、抗HIV的抑制活性的分析
将在实施例1至38中制备的罗丹宁衍生物溶解于DMSO中,以制备分别10mM或20mM的原液,并在-20°C下储存。实验开始前,将原液在DMSO中稀释成200μM的初始浓度。
MT-4细胞以4×105细胞的密度悬浮于200μL的RPMI 1640(Gibco,10%FBS)/孔的24孔板中,并用含有2x105pg/mL的200μL的病毒上清感染,从而使总体积为400μL。在罗丹宁衍生物的原液在DMSO中稀释10倍至200μM后,每种2μL稀释液加入到细胞中,以形成1μM或更低的终浓度。对于阳性对照,以终浓度为50nM使用10μM AZT(叠氮胸苷,Sigma,USA),而以0.5%的终浓度的DMSO作为阴性对照。细胞在CO2培养箱(37°C,5%CO2)中培养48小时,并且用RPMI 1640更换培养基,所述培养基含有终浓度为1μM的罗丹宁衍生物,接着再培养48小时。从细胞中通过以1,500rpm离心5分钟,然后13,000rpm离心5分钟分离病毒液。使用Virononstika HIV-1Antigen Microelisa系统试剂盒(bioMerieux,Inc.Netherland)进行p24浓度的ELISA,以检测每种罗丹宁衍生物的抗HIV的抑制活性。
本发明的罗丹宁衍生物的抗HIV的活性(μM)总结于下表3中。
表3
实施例号 | 抑制HIV活性的浓度(μM) |
1 | 0.8 |
5 | 1.0 |
8 | 0.5 |
13 | 0.5 |
16 | 0.5 |
21 | 1.0 |
23 | 0.4 |
29 | 0.5 |
38 | 0.75 |
阳性对照(AZT) | 0.005 |
如表3所示,本发明的罗丹宁衍生物表现出了抗HIV的高抑制活性。
剂型实施例中给出了制备含有本发明组合物的制剂的说明。
剂型实施例1:粉末的制备
本发明的罗丹宁衍生物0.1g
乳糖1.5g
滑石0.5g
将这些成分混合在一起,并装入密封囊中,从而制备粉末。
剂型实施例2:片剂的制备
本发明的罗丹宁衍生物0.1g
乳糖7.9g
结晶纤维素1.5g
硬脂酸镁0.5g
将这些成分混合在一起,并直接压缩成片剂。
剂型实施例3:胶囊的制备
本发明的罗丹宁衍生物0.1g
玉米淀粉5g
羧基纤维素4.9g
将这些成分混合在一起,并且使用合适的装置将这些混合物装入到常规的胶囊中。
制备实施例4:注射剂的制备
本发明的罗丹宁衍生物0.1g
用于注射的无菌水合适的量
pH调节剂合适的量
稳定剂合适的量
使用常规方法,将这些成分放入安瓿(2ml)中,从而制备注射剂。
制备实施例5:药液的制备
本发明的罗丹宁衍生物0.1g
异构化糖10g
甘露糖醇5g
净化水合适的量
每种成分溶解于净化水中,并在混合之前用柠檬调味。将净化水加入到混合物中形成100ml的终体积,然后置于棕色瓶中并灭菌,从而制备药液。
工业应用性
如上所述,本发明的罗丹宁衍生物抑制HIV病毒的表达,从而发现其可以应用于预防或治疗AIDS。
Claims (3)
1.一种罗丹宁衍生物,其选自下列化合物组成的组:
1)3-(2,4-二甲基-苯基)-5-[5-(3-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
2)5-[5-(4-吗啉-4-基-3-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
3)5-[5-(4-氧代-2-硫代-噻唑烷-5-亚基甲基)-呋喃-2-基]-异吲哚-1,3-二酮,
4)3-(2-甲磺酰基-乙基)-5-[5-(3-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
5)5-[5-(4-溴代-苯基)-呋喃-2-基亚甲基]-3-(3-氧代-丁基)-2-硫代-噻唑烷-4-酮,
6)5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-3-(四氢呋喃-2-基甲基)-2-硫代-噻唑烷-4-酮,
7)3-(4-二乙基氨基-苯基)-5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
8)5-[5-(2,4-二氯代-苯基)-呋喃-2-基亚甲基]-3-(3-氟代-苯基)-2-硫代-噻唑烷-4-酮,
9)3-苯乙基-5-(5-苯基-呋喃-2-基亚甲基)-2-硫代-噻唑烷-4-酮,
10)5-[5-(3-氯代-4-甲基-苯基)-呋喃-2-基亚甲基]-3-乙基-2-硫代-噻唑烷-4-酮,
11)5-(萘-1-基-呋喃-2-基亚甲基)-3-(2-氧代-丙基)-2-硫代-噻唑烷-4-酮,
12)3-环己基-5-[5-(2-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
13)3-(3-氟代-苯基)-5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
14)3-(1,1-二氧代-四氢-噻吩-3-基)-5-[5-(2-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
15)5-[5-(2-硝基-苯基)-呋喃-2-基亚甲基]-3-(4-氧代-戊基)-2-硫代-噻唑烷-4-酮,
16)5-[5-(2-溴代-5-硝基-苯基)-呋喃-2-基亚甲基]-3-(4-碘代-苯基)-2-硫代-噻唑烷-4-酮,
17)5-[5-(2-氯代-4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-3-(3-三氟甲基-苯基)-噻唑烷-4-酮,
18)3-苄基-5-[5-(4-乙氧基-2-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
19){5-[5-(2-甲基-5-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-醋酸,
20){5-[5-(4-乙氧基-2-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-醋酸,
21){5-[5-(4-甲氧基-2-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-醋酸,
22)3-(4-硝基-苯基)-5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,以及
23)4-[5-(4-氧代-2-硫代-噻唑烷-5-基亚甲基)-呋喃-2-基]-苯甲酸异丙酯,或其药学上可接受的盐。
2.一种罗丹宁衍生物的制备方法,其包括:
1)使化学式2的胺化合物与二硫化碳(CS2)和溴乙酸反应从而合成化学式3的化合物,
2)使化学式4的卤化物与5-甲酰-2-呋喃硼酸反应从而合成化学式5的化合物,并且
3)如以下示意性方案1,使步骤1中合成的化学式3的化合物与步骤2中合成的化学式5的化合物反应,以提供化学式1的化合物:
[反应方案1]
其中,
R1是H、乙基、环己基、-(CH2)n-A-B、-(CH2)m-苯基、2,4-二甲基苯基、
其中
A是(C=O)或SO2,
B是甲基或羟基,
Z是F、I、NO2、CF3或-N(CH2CH3)2,
n是1~3中的整数,以及
m是1或2的整数,
R2和R3,其可以相同或不同,其独立地选自H、NO2、Br、Cl、甲基、甲氧基、乙氧基、-(C=O)-O-CH(CH3)2,或吗啉,或者R2和R3彼此相邻,结合在一起形成以及
X是卤原子。
3.一种用于预防或治疗AIDS的药物组合物,其包含作为活性成分的罗丹宁衍生物,所述衍生物选自以下化合物组成的组:
1)3-(2,4-二甲基-苯基)-5-[5-(3-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
2)5-[5-(4-吗啉-4-基-3-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
3)5-[5-(4-氧代-2-硫代-噻唑烷-5-亚基甲基)-呋喃-2-基]-异吲哚-1,3-二酮,
4)3-(2-甲磺酰基-乙基)-5-[5-(3-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
5)5-[5-(4-溴代-苯基)-呋喃-2-基亚甲基]-3-(3-氧代-丁基)-2-硫代-噻唑烷-4-酮,
6)5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-3-(四氢呋喃-2-基甲基)-2-硫代-噻唑烷-4-酮,
7)3-(4-二乙基氨基-苯基)-5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
8)5-[5-(2,4-二氯代-苯基)-呋喃-2-基亚甲基]-3-(3-氟代-苯基)-2-硫代-噻唑烷-4-酮,
9)3-苯乙基-5-(5-苯基-呋喃-2-基亚甲基)-2-硫代-噻唑烷-4-酮,
10)5-[5-(3-氯代-4-甲基-苯基)-呋喃-2-基亚甲基]-3-乙基-2-硫代-噻唑烷-4-酮,
11)5-(萘-1-基-呋喃-2-基亚甲基)-3-(2-氧代-丙基)-2-硫代-噻唑烷-4-酮,
12)3-环己基-5-[5-(2-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
13)3-(3-氟代-苯基)-5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
14)3-(1,1-二氧代-四氢-噻吩-3-基)-5-[5-(2-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
15)5-[5-(2-硝基-苯基)-呋喃-2-基亚甲基]-3-(4-氧代-戊基)-2-硫代-噻唑烷-4-酮,
16)5-[5-(2-溴代-5-硝基-苯基)-呋喃-2-基亚甲基]-3-(4-碘代-苯基)-2-硫代-噻唑烷-4-酮,
17)5-[5-(2-氯代-4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-3-(3-三氟甲基-苯基)-噻唑烷-4-酮,
18)3-苄基-5-[5-(4-乙氧基-2-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
19){5-[5-(2-甲基-5-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-醋酸,
20){5-[5-(4-乙氧基-2-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-醋酸,
21){5-[5-(4-甲氧基-2-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-醋酸,
22)3-(4-硝基-苯基)-5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
23)4-[5-(4-氧代-2-硫代-噻唑烷-5-基亚甲基)-呋喃-2-基]-苯甲酸异丙酯,
24)5-[5-(2,5-二氯代-苯基)-呋喃-2-基亚甲基]-3-(1,5-二甲基-3-氧代-2-苯基-2,3-二氢-1H-吡唑-4-基)-2-硫代-噻唑烷-4-酮,
25)5-[5-(1-氧代-1,3-二氢-异苯并呋喃-5-基)-呋喃-2-基亚甲基-2-硫代-噻唑烷-4-酮,
26)3-呋喃-2-基甲基-5-[5-(2-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
27)5-[5-(2-硝基-苯基)-呋喃-2-基亚甲基]-3-苯乙基-2-硫代-噻唑烷-4-酮,
28)3-(3-氯代-苯基)-5-[5-(2,3-二氯代-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
29)2-氯代-5-[5-(4-氧代-2-硫代-噻唑烷-5-基亚甲基)-呋喃-2-基]-苯甲酸丙酯,
30)4-{5-[5-(3,4-二氯代-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-丁酸,
31)2-{5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-琥珀酸,
32)5-[5-(4-氯代-苯基)-呋喃-2-基亚甲基]-3-呋喃-2-基甲基-2-硫代-噻唑烷-4-酮,
33)5-[5-(2,4-二氯代-苯基)-呋喃-2-基亚甲基]-2-硫代-3-(3-三氟甲基-苯基)-噻唑烷-4-酮,
34)3-呋喃-2-基甲基-5-[5-(4-硝基-苯基)-呋喃-2-基亚甲基]-2-硫代-噻唑烷-4-酮,
35)3-{5-[5-(3-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-丙酸,
36)3-{5-[5-(4-氯代-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-丙酸,
37)4-{5-[3-(2,4-二甲基-苯基)-4-氧代-2-硫代-噻唑烷-5-亚基甲基]-呋喃-2-基}-苯甲酸,以及
38){5-[5-(3-硝基-苯基)-呋喃-2-基亚甲基]-4-氧代-2-硫代-噻唑烷-3-基}-醋酸。
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- 2011-06-17 JP JP2013515269A patent/JP2013528646A/ja active Pending
- 2011-06-17 US US13/805,326 patent/US8759536B2/en active Active
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CN109111408A (zh) * | 2017-06-26 | 2019-01-01 | 中国科学技术大学 | 噻唑啉酮杂环化合物、其制备方法、药用组合物及应用 |
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CN111303070A (zh) * | 2017-06-26 | 2020-06-19 | 中国科学技术大学 | 噻唑啉酮杂环化合物、其制备方法以及药用组合物 |
CN109111408B (zh) * | 2017-06-26 | 2021-03-09 | 中国科学技术大学 | 噻唑啉酮杂环化合物、其制备方法、药用组合物及应用 |
CN111303070B (zh) * | 2017-06-26 | 2024-02-23 | 中国科学技术大学 | 噻唑啉酮杂环化合物、其制备方法以及药用组合物 |
CN112203655A (zh) * | 2018-05-16 | 2021-01-08 | 爱维斯健有限公司 | 用于预防或治疗aids的含有罗丹宁衍生物的药学组合物 |
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CN111995622A (zh) * | 2020-08-20 | 2020-11-27 | 复旦大学 | 化合物及其用途 |
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WO2011159129A3 (ko) | 2012-04-26 |
EP2583969A2 (en) | 2013-04-24 |
KR20110137939A (ko) | 2011-12-26 |
WO2011159129A2 (ko) | 2011-12-22 |
US8759536B2 (en) | 2014-06-24 |
KR101159000B1 (ko) | 2012-06-21 |
US20130096125A1 (en) | 2013-04-18 |
EP2583969A4 (en) | 2013-10-23 |
JP2013528646A (ja) | 2013-07-11 |
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