CN109475757A - 用于治疗炎症相关疾病和紊乱的亲电子增强的酚类化合物 - Google Patents
用于治疗炎症相关疾病和紊乱的亲电子增强的酚类化合物 Download PDFInfo
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Abstract
治疗性化合物具有通式(I)的修饰酚类化合物其中R、R1、R2、R3和R4中的至少一个为选自卤素、醛、卤代烷、烯烃、丁酰、氟苯酚、磺酰胺、氟苯酚亚砜的亲电子基团，并且剩余的R、R1、R2、R3和R4各自独立地为氢、羟基、烷氧基、芸香糖基团、羧基、色酮、苯并吡喃、鼠李糖基团、取代的烷氧基或取代的酰氧基，其中取代基选自羟基、烷氧基、芳氧基、苯基、卤素和酰胺基。化合物可用于治疗性治疗炎症相关疾病和病况。
Description
相关申请的交叉引用
本申请要求通过引用并入本文的、2016年5月16日提交的美国非临时专利申请系列第15/156,021号的权益。
技术领域
本发明涉及包括但不限于类黄酮化合物的亲电子增强的酚类化合物和这些化合物治疗包括各种紊乱的用途，所述紊乱包括具有炎症性关联的紊乱，包括炎症性相关的疾病和紊乱。
背景技术
生物体的代谢和酶系统已经进化为从植物食品来源吸收在环境中容易获得的酚类化合物、酚酸和类黄酮，而进入每个主要代谢系统的相关生物化学途径。类黄酮不仅仅对于许多代谢系统具有生理学影响，而且它们是这种系统正常运转的固有部分。作为自然进化的一部分，类黄酮结合位点是保守的并且广泛分布在这些途径中。当化学反应过载试剂，比如过多的葡萄糖时，或如果存在代谢组分的损伤，比如蛋白质的变形，则中间体代谢分子积聚至可能导致该途径或相关的途径功能障碍并且表现疾病病况的浓度。类黄酮的主要作用是下调和或上调某些酶，以减少这些中间体的积聚，减轻它们对生物体的不利影响。
因为类黄酮结合位点在数个途径中的分布，类黄酮对于与疾病病况相关的系统中的数个酶具有调节效果。对于疾病病况的大部分其他疗法靶向与疾病相关的一至两个靶酶，而类黄酮靶向数个靶酶。
疾病分类
在六(6)个疾病类别中分布着六十四(64)种关键酶。用于治疗这些疾病的大部分药物下调或上调与这些疾病相关的靶酶。
列举如下了每种主要疾病类别和与这种疾病相关的靶酶。
癌症
靶酶：肌醇1,4,5三磷酸激酶(IP3K)、蛋白激酶CK2、DNA拓扑异构酶II、丝裂原活化蛋白激酶、CYP 181、激酶1(MEK)、MAPK激酶4(MKK4)、乙二醛酶(Glycoxalase)、CYP 1A1、环氧合酶、硫氧还蛋白还原酶、核因子κB(NF-κB)、酪氨酸激酶(MET)、细胞外信号调节激酶(ERK 1-2)、HSP 70腺苷三磷酸酶、黄嘌呤氧化酶、磷脂酰肌醇-3、RAF激酶、基质金属蛋白酶1-18、MRP-1、尿激酶、3-磷酸甘油酸酯激酶、芳香酶(CYP-19)、X蛋白激酶(XK)、鸟氨酸脱羧酶(ODC)和肌醇多磷酸多激酶(IPMK)。
糖尿病和代谢综合症(1型糖尿病、2型糖尿病、妊娠糖尿病、代谢综合症、肥胖、糖原贮积病)
靶酶：丙酮酸羧化酶、脂肪酸合酶、α淀粉酶、丝裂原活化蛋白激酶、MAP K(4)、胆固醇酰基转移酶、肝黄嘌呤氧化酶、葡糖激酶、细胞外调节酶(ERK)、醛糖还原酶、脂肪酶、乙酰辅酶A、激酶(1)、葡糖苷酶、血管紧张素转化酶(ACE)、12-脂肪-加氧酶和HMG-辅酶A激酶(MEK)。
心血管疾病(高胆固醇血症、局部缺血、高血压、心内膜炎、心肌炎、脑血管疾病、血管渗透性、局部缺血)
靶酶：乙酰乙酰基辅酶A、鲨烯合酶、氧鲨烯环化酶、血管紧张素转化酶、乙酰基辅酶A、HMG辅酶A还原酶、HMG辅酶A和胆固醇转移酶。
炎症和疼痛(急性疼痛病、偏头痛、头痛、关节炎、牛皮癣、哮喘、醇毒性、克罗恩病、炎症性肠综合症、结肠炎、易激肠综合症、酒渣鼻)
靶酶：乙二醛酶1、乙二醛酶2、激酶(1)、聚合酶(PARP-1)、丝裂原活化蛋白激酶(MAP K)、核酶聚合酶(ADP核糖)、半胱天冬酶8、MAP K(4)、MKK4、弹性蛋白酶、COX 1和COX2。
神经疾病(阿尔茨海默氏疾病、亨廷顿疾病、精神分裂症、外伤脑损伤、帕金森氏症)
靶酶：酪氨酸激酶、α分泌酶、半胱天冬酶3、蛋白酶、β位点APP切割酶1(BACE-1)、激酶(PLK2)、Tau蛋白激酶、β分泌酶、γ分泌酶、细胞间粘合分子1(ICAM-1)、谷胱甘肽转移酶、M(TOR)、二氢叶酸还原酶、丝氨酸蛋白酶、半胱氨酸蛋白酶、金属蛋白酶和天冬氨酸蛋白酶。
病毒/细菌疾病(人鼻病毒、流感、SARS、MERS、埃博拉、登革热、疟疾、MRSA、葡萄球菌、大肠杆菌、HIV)
靶酶：逆转录酶、RNA聚合酶(all)、解旋酶、拓扑异构酶、整合酶、蛋白酶(病毒出芽)、半胱天冬酶(尤其半胱天冬酶8)、尿囊素酶、二氢乳清酸酶、丁酰胆碱酯酶和乙酰基胆碱酯酶。
一种疾病的具体例子：糖尿病
1型糖尿病(之前称为幼年型糖尿病)的特征在于身体不能产生或释放胰岛素。2型糖尿病(也称为成年型糖尿病)的特征在于身体不能对胰岛素进行应答，或胰岛素抗性。两种糖尿病都导致高血糖，通常随后是并发症，比如心血管疾病、视网膜病、神经疾病和肾病。1型糖尿病需要施用外源胰岛素。2型糖尿病可通常最初单独通过膳食来控制，但是通常需要用降糖药治疗。用于控制2型糖尿病的最普遍使用的药物是二甲双胍的盐酸盐，双缩胍。这种化合物通过抑制肝葡萄糖输出(糖异生)和通过刺激葡萄糖转运体4(GLUT4)增加外周组织(比如肌肉)对葡萄糖的吸收而发挥作用。药物和它们的作用模式的列表显示在表1中。
表1
与最广泛使用的抗糖尿病药相关的非依从性的主要原因是胃肠道不适。尤其，α-葡糖苷酶抑制剂和淀粉纤维质类似物通过减缓或抑制复杂的碳水化合物和脂肪转化成容易吸收的更简单分子而发挥作用。这造成富含碳水化合物和脂质的环境，容易为肠道微生物群落所用。结果是常见的腹泻、肠胃气胀、炎症和肠道内层的退化。
类黄酮具有基本结构：
并且根据IUPC(国际纯粹与应用化学联合会)分类为类黄酮(例子包括槲皮素和芸香苷)、异黄酮(例子包括大豆黄素和染料木黄酮)，或新类黄酮(例子包括黄檀素和新黄烷)。
根据1)它们酚醛环上具有的羟基单元的数量、2)分子的平面度，和3)环上单元的位置，类黄酮为有效的酶抑制剂或刺激物。平面度和位置决定对接潜能。一般而言，羟基单元越多，化合物的活性越大。同时，活性的增加表示稳定性的下降。羟基单元的数量越大，作用越直接。较少的单元导致延迟效果。各自具有不同数量羟基单元的类黄酮的制剂可用作引起多种效果的方法。这可通过交替具有不同数量和羟基单元取向的不同类黄酮的比例来实现。
科学文献充满了类黄酮经抑制α-葡糖苷酶、抑制葡萄糖转运体2(从内脏至血流的葡萄糖运输)、刺激葡萄糖转运体4(从血流至肌肉组织的葡萄糖运输)、刺激胰岛素释放、抑制糖异生、抑制脂肪细胞生长和发育、刺激脂分解、抑制脂肪酸合成和增加胰岛素灵敏度而对降低血液葡萄糖的作用。已经报道了类黄酮抑制胃肠道不适的主要贡献者，幽门螺杆菌(helicobacterpylori)，以及胃肠道的数个其他群落的活性。另外，类黄酮显示了抗炎症性活性并且支持肠道内层的愈合。
发明内容
本发明涉及亲电子增强的酚类化合物。亲电子增强的酚类化合物，包括但不限于类黄酮化合物。该化合物可用于治疗各种紊乱，包括具有炎症性关联的紊乱，包括炎症相关疾病和紊乱。一种非限制性例子是亲电子增强杨梅黄素(myricetine)。这种亲电子增强的类黄酮增加了其结合活性，降低了Km，因此增加了其效力。
在一个形式中，组合物包括经共价键合至酚类化合物，比如类黄酮，添加亲电子部分，其引起增加的对接能，增加与六(6)种炎症性相关的疾病类别(本公开下面鉴定的)的酶的上调或下调，和/或增加类黄酮相对于其天然状态的效力。这些化合物有利地有效治疗炎症相关疾病和紊乱。这些紊乱包括上述鉴定的具有炎症性成分、起源或关联的六(6)种疾病类别。亲电子增强的酚类化合物具有通式(I)
其中R、R1、R2、R3和R4中的至少一个为选自卤素、醛、卤代烷、烯烃、丁酰、氟苯酚、磺酰胺、氟苯酚亚砜的亲电子基团并且剩余的R、R1、R2、R3和R4各自独立地为氢、羟基、烷氧基、芸香糖基团、羧基、色酮、苯并吡喃、鼠李糖基团、取代的烷氧基或取代的酰氧基，其中取代基选自羟基、烷氧基、芳氧基、苯基、卤素和酰胺基。在有利的形式中，当施用至需要治疗炎症性疾病或相关紊乱的患者时，亲电子增强的酚类化合物相对于其天然形式具有增加的效力。一个例子是亲电子增强杨梅黄酮，其中杨梅黄酮被一个或多个卤素，比如氯取代。
在一个有利的形式中，R1为具有类黄酮通式(II)和(III)的色酮
其中R、R1、R2、R3、R4、R5和R6中的至少一个为选自卤素、醛、卤代烷、烯烃、丁酰、氟苯酚、磺酰胺、氟苯酚亚砜中的亲电子基团并且剩余的R、R1、R2、R3、R4、R5和R6各自独立地为氢、羟基、烷氧基、芸香糖基团、鼠李糖基团、取代的烷氧基或取代的酰氧基，其中取代基选自羟基、烷氧基、芳氧基、苯基、卤素和酰胺基。在有利的形式中，相对其天然、非亲电子增强的形式，化合物具有增加的效力，其中增强的效力是基于其根据本公开治疗靶疾病和病况的能力。
在仍进一步的形式中，类黄酮选自源自2-苯基色烯-4-酮的化合物。仍此外，在仍另外的实施方式中，类黄酮包括源自3-羟基-2-苯基色烯-4-酮的化合物，比如，但不限于fisiten、高良姜精、橙皮素(hesperitin)、异鼠李素、山奈酚、杨梅黄酮、柚皮苷、槲皮素和芸香苷。
本发明，在其另一形式中，涉及治疗疾病或医学病况(包括但是不限于炎症相关疾病)的方法，所述方法包括向需要其治疗的患者施用治疗有效量的本公开呈现的通式(I)的化合物或任何进一步精选的式(I)的种类。在可选的方法中，治疗可包括施用任何上述的特定形式的通式(I)：包括但不限于fisiten、高良姜精、橙皮素、异鼠李素、山奈酚、杨梅黄酮、柚皮苷、槲皮素和芸香苷的那些。在仍可选的方法中，式(I)(酚类化合物)的化合物是a)杨梅黄酮或b)亲电子增强的、修饰形式的杨梅黄酮，并且化合物进一步与橙皮苷和胡椒碱组合。在一种形式中，杨梅黄酮与橙皮苷和胡椒碱一起配制而形成Equivir。
根据本发明，杨梅黄酮、橙皮苷和胡椒碱的化合物组合形成称为Equivir的组合物。杨梅黄酮可为天然的或亲电子增强的。
Equivir，根据本公开有效治疗根据本公开的各种紊乱，包括但不限于登革热发热/登革热病毒、流感、鼻病毒和埃博拉病毒。
在一个有利的形式中，化合物具有选自由下述组成的组中的式：
化合物可配制成药物组合物，作为常规非侵入性全身性剂型。非侵入性全身性剂型可选自由下述组成的组：胶囊、药丸、片剂、特种片剂(包括含服、舌下和口服崩裂)、薄膜、酏剂、液体溶液或悬液、粉末或晶体。化合物可也并入乳膏、凝胶、擦剂、香脂、洗剂、软膏或皮肤贴剂。
前面提到的三种化合物可用于治疗各种医学病况、紊乱和/或疾病。这些包括但不限于炎症性相关的疾病、癌症疾病病况、糖尿病/代谢综合症疾病病况、心血管疾病病况、炎症性/疼痛疾病病况、神经疾病病况，和病毒/细菌疾病病况。疾病病况可为人的和非人的。
前面提到的三种化合物的药物混合物可包含生理学上可接受的填料、崩裂剂、载体材料、赋形剂、润滑剂、缓冲液、抗菌剂、膨松剂和/或粘合剂和抗氧化剂。崩裂剂可选自由下述组成的组：交联羧甲基纤维素钠、聚维酮、交聚维酮、淀粉乙醇酸钠、玉米淀粉或微晶纤维素。此外，使用脂质体、药物聚合物缀合物、水凝胶、微球或微胶囊，组合物可配制为延时释放剂型。
在一个尤其有利的形式中，组合物包括亲电子增强的、修饰形式的杨梅黄酮，并且化合物进一步与橙皮苷和胡椒碱组合。在一个实施例中，亲电子增强的、修饰形式的杨梅黄酮(例如氯化形式)与橙皮苷和胡椒碱一起配制，而形成Equivir。
附图说明
图1比较MRC-5活力的百分数与浓度的百分数，其中显示了用感染后施加的测试化合物治疗之后，鼻病毒型14的抑制百分数。
图2显示了用感染前施加的测试化合物治疗之后，鼻病毒型14的抑制百分数。
图3是显示用测试化合物治疗之后，MRC-5活力的百分数的图。
图4显示了CPE试验中，在第7天，Equivir在MDCK细胞中的细胞毒性和针对IFVA/Texas/36/91(H1N1)的抑制作用。
图5描绘了CPE试验中，在第7天，Zanamivir IR在MDCK细胞中的毒性和针对IFV A/Texas/36/91(H1N1)的抑制作用。
图6显示了CPE试验中，在第7天，Equivir在MDCK细胞中的细胞毒性和针对IFV A/Perth/265/09的抑制作用。
图7是显示CPE试验中，在第7天，Zanamivir在MDCK细胞中的细胞毒性和针对IFVA/Perth/265/09的抑制作用的图。
图8是显示CPE试验中，在第7天，Equivir在MDCK细胞中的细胞毒性和针对IFV A/HK/1/68(H3N2)的抑制作用的图。
图9是显示CPE试验中，在第7天，Zanamivir在MDCK细胞中的细胞毒性和针对IFVA/HK/1/68(H3N2)的抑制作用的图。
图10是显示树突细胞中DENV-2的抑制的图。
图11包括涉及根据本发明的树突细胞表征的一系列六张图。
图12是显示树突细胞中的细胞因子特征的图。
图13是显示HepG2细胞中，Equivir对野生型埃博拉病毒的感染的作用的图。
图14是显示HepG2细胞中，T-705对野生型埃博拉病毒的感染的作用的图。
图15是显示THP-1细胞中，Equivir对野生型埃博拉病毒的感染的作用的图。
图16是显示THP-1细胞中，T-705对野生型埃博拉病毒的感染的作用的图。
图17是HepG2中，在零小时显示的抗EBOV活性的实验数据的图。
图18是THP-1中，在零小时显示的抗EBOV活性的实验数据的图。
图19是HepG2中，在36小时显示的抗EBOV活性的实验数据的图。
图20是THP-1中，在36小时显示的抗EBOV活性的实验数据图。
图21是HepG2细胞中，在72小时显示的抗EBOV活性的实验数据的图。
图22是THP-1中，在72小时显示的抗EBOV活性的实验数据的图。
具体实施方式
现将结合具体的实施方式和示例性实施例描述本发明，以提供对本化合物和其治疗各种紊乱的用途的进一步了解。
在一个有利的形式中，治疗性化合物具有修饰的通式(I)的酚类化合物
其中R、R1、R2、R3和R4中的至少一个为选自卤素、醛、卤代烷、烯烃、丁酰、氟苯酚、磺酰胺、氟苯酚亚砜中的亲电子基团，并且剩余的R、R1、R2、R3和R4各自独立地为氢、羟基、烷氧基、芸香糖基团、羧基、色酮、苯并吡喃、鼠李糖基团、取代的烷氧基或取代的酰氧基，其中取代基选自羟基、烷氧基、芳氧基、苯基、卤素和酰胺基，所述化合物相对于其天然形式具有增加的效力。
治疗性化合物可用于治疗具有炎症性成分、起源或关联的各种疾病，包括但不限于癌症、糖尿病/代谢综合症疾病病况、心血管疾病、炎症/疼痛、神经疾病，和病毒/生物疾病病况。
治疗性化合物可配制为药学组合物并且可进一步被非侵入性全身性剂型修饰，所述非侵入性全身性剂型包括但是不限于胶囊、药丸、片剂、特种片剂(含服、舌下和口服崩裂)、薄膜、酏剂、液体溶液或悬液、粉末或晶体。
组合物可包含由适当的药物载体携带的药物载体，其包括任何一系列物理形式并且可包括本领域熟知的各种药学上可接受的载体、稀释剂和/或赋形剂。因此，适当的药物载体可包括溶剂、包衣、抗菌剂和抗真菌剂、等渗及和延迟吸收剂等。“药学上可接受的”一般理解为意思是所述载体基本上与组合物或剂型中的活性成分或其他成分相容并且基本上对于经受其治疗的患者无害。适当的载体的一般例子包括碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精、淀粉、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可油等。
取决于本组合物和其剂型的性质，根据本公开的本化合物/组合物可通过跨粘膜的吸收、并入鼻、含服/舌下、阴道、眼睛、直肠(栓剂、灌肠剂)，和吸入(气溶胶、吸入器、喷雾器、汽化器、烟熏)施加而施用。
用于施用根据本公开的通式(I)的化合物和药学组合物的优选剂量是限制出现病况、减少与疾病病况相关的症状，和/或防止出现有限时间的量。本领域普通技术人员将容易认识到，该量将取决于患者的病况的性质而大大变化。根据本公开，“有效量”或“治疗有效量”的通式(I)的化合物或包括通式(I)的化合物的药学组合物旨在意思是产生期望的预防或疗效的任何无毒的但是足够量的化合物、组合物药学组合物等。因此，如本领域普通技术人员容易理解，需要的化合物、药学组合物或具体试剂的精确量在受试者之间不同，取决于患者的物种、受试者的年龄和一般条件、待治疗的病况的严重程度、使用的具体载体或佐剂以及其施用模式等。类似地，也调整给药方案应以适合向其施用组合物的患者，并且再次随着受试者的年龄、体重、代谢等而变化。所以，“有效量”的任何具体化合物、组合物或试剂将基于具体的环境而改变，并且合适的有效量可在每次施加的情况下，由本领域普通技术人员仅仅使用常规实验而确定。
取决于本组合物和其剂型的性质，本化合物可通过跨粘膜的吸收、并入鼻、含服/舌下、阴道、眼睛、直肠(栓剂、灌肠剂)和吸入(气溶胶、吸入器、喷雾器、汽化器、烟熏)施加而施用。
化合物，杨梅黄酮、橙皮苷和胡椒碱的组合形成称为Equivir的组合物。根据本公开的Equivir有效治疗根据本公开的各种紊乱，包括但不限于登革热发热/登革热病毒、流感、鼻病毒和埃博拉病毒。
根据本公开的氯化的类黄酮可并入常规非侵入性全身性剂型，比如胶囊、药丸、片剂、特种片剂(含服、舌下、口服崩裂)、薄膜、酏剂、液体溶液或悬液、粉末或晶体。上述剂型也将包含必要的生理学上可接受的填料、崩裂剂(比如交联羧甲基纤维素钠、聚维酮、交聚维酮、淀粉乙醇酸钠、玉米淀粉或微晶纤维素)、载体材料、赋形剂、润滑剂(比如硬脂酸镁、硬脂酸、棕榈酸、硬脂酸钙、滑石、巴西棕榈蜡)、缓冲液、抗菌剂、膨松剂和/或粘合剂(比如乳糖、糖、金合欢树胶、玉米淀粉、改性的玉米淀粉、聚乙烯吡咯烷酮、甘露醇、山梨糖醇、无机盐，比如碳酸钙和/或纤维素衍生物，比如木质纤维素、微晶纤维素、巴西棕榈蜡、链烷烃、鲸蜡、聚乙烯或微晶蜡)、抗氧化剂(抗坏血酸或亚硫酸氢钠)等。
根据本公开的氯化的类黄酮可通过并入乳膏、凝胶、擦剂、香脂、洗剂、软膏或皮肤贴剂而施用。
根据本公开的氯化的类黄酮可通过跨粘膜的吸收、并入鼻的、含服/舌下、阴道(冲洗器、阴道栓剂)、眼睛、直肠(栓剂、灌肠剂)，和吸入(气溶胶、吸入器、喷雾器、汽化器、烟熏)施加而施用。
根据本公开的氯化的类黄酮可通过皮内、皮下、肌内、骨内、腹膜内或静脉内注射而施用。
根据本公开的氯化的类黄酮可通过并入脂质体、药物聚合物缀合物、水凝胶或微球的延时释放剂型而施用。
示例性实施例
提供下述实施例为了示例性目的，以加强对本组合物和治疗的理解。从实施例，人们可推断根据本公开的化合物、治疗性组合物和治疗性治疗。
实施例1
根据本公开，一种或多种类黄酮，比如例如杨梅黄酮是氯化的。可单独采用化合物，或可组合在单个剂型中，例如作为胶囊、液体溶液或悬液、糖浆剂、片剂、粉末以及控制释放剂型。
在优选的实施方式中，以胶囊形式口服施用1至1000mg的氯化的类黄酮。
实施例2
根据本公开的氯化的类黄酮可施用至需要这种治疗的各种哺乳物种，比如家养动物、马、母牛、绵羊、猪、狗、猫、人等。
下述实施例的名称为“一种测试化合物用于针对鼻病毒14的抗病毒活性的非GLP评估”。
如下制备测试产品：将0.312g的测试产品溶于10mL的DMSO，以获得100mM浓度的测试产品；以维持培养基中，制备1/1000稀释的100μM测试产品，以获得100uM的浓度；随后使用2.15的渐变因子，在维持培养基中进行连续稀释。评估培养基中，1/1000稀释的DMSO的细胞毒性。总计评估八个不同浓度的测试产品对于鼻病毒型14株1059(ATCC#VR-284)的抗病毒特性。评估测试产品的感染后和感染前抗病毒活性。一式六份进行铺平板，一式两份进行测试。
测试方法：
测试产品：测试产品描述提供在表2中。在DMSO中制备初始测试产品并且随后在细胞培养基中浓缩。
表2
病毒：
人鼻病毒型14株1059(ATCC#VR-284)。病毒剂量：0.1MOI。
宿主细胞：
MRC-5(人肺成纤维细胞，ATCC 11CCL-171)。
培养基：
维持培养基-具有2％胎牛血清的EMEM(ATCC)(Atlas)和抗-抗(青霉素-链霉素-两性霉素B[Gibco])。
MTT细胞增殖试验：ATCC#30-1010K。
方法：使用基于致细胞病变作用(CPE)的试验，评估抗病毒特性和细胞毒性。使用MTT细胞增殖试验确定CPE。
感染后抗病毒活性：用PBS冲洗约90％的汇合细胞。将100ul等分试样的0.1MOI测试病毒(用于细胞毒性测试的培养基)添加至细胞并且在33℃±2℃下，在CO2培养箱中温育1小时，用于病毒吸附。温育之后，去除病毒接种体；用PBS冲洗感染的细胞并且覆盖100μl的测试产品浓度。将平板在CO2培养箱中温育72小时。当完成温育时，使用MTT试验，评估平板的CPE抑制：用PBS冲洗细胞；将100μl的培养基和10μl的MTT试剂添加至平板的每个孔；将平板返回至培养箱并且在37℃±2℃下温育4小时；温育之后，去除培养基并且添加100μl的DMSO，以溶解紫色甲臜。
感染前抗病毒活性：用PBS冲洗约90％的汇合细胞。将100μl等分试样的测试产品浓度添加至细胞并且在37℃±2℃下，CO2培养箱中温育1小时。温育之后，添加100μl等分试样的0.1MOI测试病毒并且在33℃±2℃下，CO2培养箱中温育72小时。当完成温育时，使用MTT试验平板评估CPE抑制：用PBS冲洗细胞；将100μl的培养基和10μl的MTT试剂添加至平板的每个孔；将平板返回至培养箱并且在37℃±2℃下温育4小时；温育之后，去除培养基并且添加100μl的DMSO，以溶解紫色甲臜。
使用“VERSAmax”可调微板阅读器(具有PRO软件)设置在570nm，具有空白孔，测定样品的光密度。结果计算为CPE的抑制百分数，其中100％CPE的抑制近似等于细胞对照的平均数。IC50值以μM浓度呈现并且使用非线性回归分析，GraphPad Prism 5.0软件计算。
表3呈现了抑制浓度的总结。
表3
测试产品对鼻病毒型14的抑制浓度和对于MRC-5细胞毒性浓度的总结
表4和5，以及图1呈现了感染后施加测试产品的抑制浓度(IC)。
表4
感染后产品施加的抑制浓度50％(1050)(GraphPad Prism 5.0log(抑制剂)对应答--变斜率(四个参数))
表5
感染后产品施加的抑制浓度90％(IC90)(GraphPad Prism 5.0)
表6和7，以及图2呈现了感染前施加测试产品的抑制浓度(IC)。
表6
感染前产品施加的抑制浓度50％(IC50)(GraphPad Prism 5.0log(抑制剂)对应答--变斜率(四个参数))
表7
感染前产品施加的抑制浓度90％(IC90)(GraphPad Prism 5.0)
表8和图3呈现MRC-5细胞的毒性浓度50％(TC50)。
表8
MRC-5细胞的毒性浓度50％(TC50)
实施例3
分析Equivir抗流感病毒和登革热病毒
下述实施例和实验具有下述目标：
·CPE试验中，确定Equivir抗三种甲型流感病毒的抗病毒活性：
—A/TX/36/91(H1N1)
—A/Perth/265/09(H1N1)和
—A/HK/1/68(H3N2)；
·确定第7天MDCK细胞中的细胞毒性；
·确定树突细胞中，抗DENV-2新几内亚C的抗病毒活性(产量减少试验)；和
·确定感染之后树突细胞中的细胞因子特征(IFN-γ、IL-1β、IL-2、IL-4、IL-6、IL-8、IL-10、IL-12p70、IL-13和TNF-α)(MSD)。
表9：效力概述
EC50[μM]
影响MDCK细胞中的病毒的数据。
与MDCK细胞中流感病毒相关的数据显示在图4-8中。
基于CPE的EC50试验。
如下进行下述实验：
将细胞接种在96孔板中并且温育过夜。
第二天，在培养基中，制备测试品(50μM开始，2倍稀释)以及对照化合物的连续稀释。
从细胞吸去生长培养基并且添加化合物稀释一小时温育时间。
然后，以0.01MOI添加病毒并且将细胞温育7天。
接着，将细胞固定并且用结晶紫在戊二醛溶液中染色。测定光密度并且使用OD的4-PL曲线拟合计算EC50，使用未感染的对照(仅仅细胞)作为0％CPE并且没有化合物的对照(仅仅病毒)作为100％CPE。
细胞毒性试验
如下测试细胞毒性。将细胞接种在黑壁96孔板中并且温育过夜。第二天，制备测试品的连续稀释。从细胞吸去生长培养基并且添加化合物稀释。仅仅用培养基温育的细胞用于0％细胞毒性数据。吸去培养基并且使用Promega的CelltiterGlo试剂盒将细胞裂解用于评估ATP含量(MDCK细胞：第7天)。量化所得荧光素酶荧光并且用于使用4-PL曲线拟合计算CC50。
树突细胞中的登革热病毒
在下述实验中，测定树突细胞中的登革热病毒，数据显示在图10中。
下面总结了进行的实验。
单核细胞的分化
从一个供体接受纯化、冷冻的单核细胞。用GM-CSF和IL-4在三个烧瓶中启动分化。7天之后，进行收获、感染和表征。
树突细胞表征
进行下述表征，结果显示在图11的图A-F中。
·非粘附细胞(树突细胞)计数为7.0x106
·回收的树突细胞显示特征性曲线
用DENV-2感染树突细胞
如下进行下述实验：
·在37℃下，用DENV-2新几内亚C，以1.0M01感染5x105个新鲜收获的细胞2小时。
·感染之后，冲洗细胞并且一式两份添加化合物稀释(50、25、5和1μM)。
·2天之后，收获上清液并且滴定免疫噬斑试验。
免疫噬斑试验。
如下进行下述实验：
·以每孔1x105个细胞，将Vero细胞接种在24孔板中并且使得粘附过夜。
·开始以1:100，将上清液稀释10倍。
·感染Vero细胞并且在37℃下，温育1小时
·温育之后，将1ml的0.8％甲基纤维素添加至每个孔。
·将细胞固定并且4天之后，检测噬斑。
·温育时间之后，去除覆盖并且用甲醇/乙醇将细胞固定。
·用抗DENV E蛋白的抗体检测感染灶并且用HRP底物染色。
·对噬斑计数并且基于4-PL曲线拟合计算EC50。
细胞因子特征
为了确定细胞因子特征，进行下述。
MSD
下述表征了如下用于MSD的实验：
·1:5和1:50稀释来自树突细胞的上清液，并且使用MSD人促炎试剂盒1平板，分析IFN-γ、IL-10、IL-2、IβL-4、IL-6、IL-8、IL-10、IL-12p70、IL-13和TNF-α的水平。
·将数据针对Equivir的浓度绘图。
树突细胞中的细胞因子特征显示在图12的图中。
现鉴于包括实验和实施例的下述公开显而易见，包括Equivir的本化合物从治疗包括但不限于流感、登革热病毒和埃博拉的炎症性疾病的效力角度，具有增强的特性。本化合物这种增强的特性是相对于之前已知的化合物，包括之前已知的类黄酮。
实施例4：埃博拉病毒筛选试验
下述实验表明了治疗埃博拉的效力。
这些实验的目的是在HepG2和THP-1细胞中，评估一(1)全球研究和发现组化合物，Equivir对埃博拉病毒(EBOV)的抗病毒效力、细胞毒性和细胞因子应答的作用。
药物制备
作为预先溶解的原料制备Equivir。将溶解的原料储存在4℃下，直到试验当天。在实验设置的当天，将原料在室温下融解并且用于产生在试验中使用的工作药物稀释。在试验中使用4个不同的测试浓度(50μM、25μM、5μM和2μM)评估化合物。EBOV抑制剂T-705用作阳性对照，使用400μM高测试浓度以及5个另外连续半对数稀释(浓度范围＝1.26μM至400μM)。
通过产量减少试验的EBOV抗病毒的测试的描述
对于产量减少试验，将HepG2和THP-1细胞保持在改良的Eagle培养基(MEM)，具有10％的胎牛血清(FBS)，并且将1X GlutaMax平铺在24孔板中。在37℃下用0.1MOI的EBOV感染汇合单层1小时，每15分钟振荡一次。感染之后，去除包含病毒的培养基并且用PBS冲洗平板三次，以去除残留的病毒。冲洗之后，在培养基中添加4个浓度的测试品，一式两份并且将平板在37℃下温育72小时。在感染后的0、36和72小时收集培养基，用于通过实时RT-PCR评估，以确定与病毒RNA标准相比的EBOV基因组当量。另外，使用ProcartaPlex免疫试验试剂盒(货号EPX180-12165-901，eBioscience，San Diego，CA)评估对细胞因子应答的作用。EBOV抑制剂T-705用作阳性对照并且包括仅培养基的阴性对照(无病毒)和仅病毒的对照(无化合物)。
细胞制备
HepG2和THP-1细胞获得自ATCC并且基于供应商提供的说明书，使用标准组织培养技术，在T-75烧瓶中常规传代。在试验前头一天，将细胞1:2分离，以确保它们在感染时，处在指数生长期。使用血细胞计数器和苔酚蓝排斥，进行总细胞数量和活力百分数测定。对于试验中使用的细胞，细胞活力必须大于95％。对于产量减少试验，将细胞以100μL的体积添加至24孔板。对于细胞毒性试验，在试验的前一天，将细胞以100μL的体积，添加至96孔板。
病毒制备
用于该试验的病毒是扎伊尔埃博拉病毒株199510621。对于每个试验，从冰箱(-80℃)取出预先滴定的等分试样的病毒并且使得在BSL-4实验室的生物安全性橱柜中缓慢融化至室温。将病毒在组织培养基中稀释并且将100lit添加至每个孔(约0.1MOI)。
细胞毒性分析
将测试品以4个浓度一式两份添加至细胞，并且将平板在37℃下温育36小时和/或72小时。毒性平板也包含细胞对照孔(仅仅细胞)和药物比色对照孔(仅仅药物)。在试验结束时，将试验平板用基于可溶性四唑的染料MTS(96试剂，Promega)染色，以确定细胞活力并且量化化合物毒性。MTS被代谢活性细胞的线粒体酶代谢，而产生可溶性甲臜产物，使得快速定量分析细胞活力和化合物细胞毒性。该试剂是稳定的、单个溶液，其不需要在使用之前制备。在试验结束时，将10μl至25μl的MTS试剂添加至每个孔(基于体积，10％的终浓度)并且将微滴定板在37℃，5％CO2下温育4小时至6小时，以评估细胞活力。使用粘合板密封材料，代替盖子，将密封板颠倒数次，以将可溶性甲臜产物混合，并且在490/650nm下，用分子设备SpectraMax i3平板阅读器分光光度法读取平板。
细胞因子分析
使用ProcartaPlex免疫试验试剂盒(货号EPX180-12165-901，eBioscience，SanDiego，CA)根据制造商的指导，评估对细胞因子应答的作用。该试验检测下述抗原：IL-12、IL-23、IL-27、GM-CSF、IFNγ、IL-1β、IL-10、IL-13、IL-17A、IL-18、IL-2、IL-21、IL-22、IL-4、IL-5、IL-6、IL-9和TNFα。无化合物对照(仅仅病毒)和仅仅培养基(无病毒)对照包括在分析中，用于比较。在Luminex工具上读取试验，并且用ProcartaPlex Analyst软件1.0分析结果。
结果
来自进行的实验的结果的总结提供在下面表10和11中，并且数据显示在图13-22中。
Equivir在THP-1细胞中在感染后0小时，并且在HepG2细胞中在感染后72小时，显示抗EBOV的最强的抗病毒活性。总体化合物在HepG2或THP-1细胞中无毒性。T-705对照如预期在HepG2细胞中起作用，但是不如在THP-1细胞中有活性。大部分细胞因子评估低于试验的定量的下限，并且所以结果的解释是非结论性的。
表10.He G2细胞中GRDG化合物抗EBOV的活性
ND-未进行
表11.THP-1细胞中GRDG化合物抗EBOV的活性
ND-未进行
讨论
HepG2和THP-1细胞中，评估Equivir抗EBOV的抗病毒效力。从这些试验获得的实验数据和图形结果包括在图13-22中。在THP-1细胞中，在感染后0小时，并且在HepG2细胞中，在感染后72小时，Equivir有抗EBOV的活性。在THP-1细胞中，Equivir在早期时间点具有即时抗病毒作用，但是随着病毒复制，该作用消失。相反，在HepG2细胞中，在稍后的时间点，Equivir有抗EBOV的活性。在两个细胞系中，对于评估的所有浓度都观察到了该活性。总体上，这些结果提供了Equivir有抗EBOV活性的证据。应完成进一步的测试，以确认这些结果和确定剂量响应。
对照化合物T-705验证了总体试验表现，其在使用HepG2细胞的试验中展示了预期水平的抗病毒活性。但是，在THP-1细胞中，对照化合物不如预期的有活性。THP-1细胞不是用于该试验的标准细胞系，并且这些结果指示需要对照化合物的进一步优化。评估的大部分细胞因子低于试验的定量的下限，并且所以结果的解释是非结论性的。
本领域普通技术人员将认识到，在不背离本公开主题教导的情况下，另外实施方式也是可能的。给出该详述的说明书，和尤其本文公开的示例性实施方式的具体细节，主要用于使理解清晰，并且从其理解中没有不必要的限制，因为当阅读了本公开之后，修饰对于本领域技术人员将是显而易见的，并且可在不背离本公开主题的精神和范围的情况下进行修饰。
Claims (19)
1.一种具有选自由下述组成的组中的式的化合物：
2.一种包含权利要求1所述的化合物的药物组合物，所述化合物并入常规非侵入性全身性剂型。
3.根据权利要求2所述的药物组合物，其中所述非侵入性全身性剂型选自由下述组成的组：胶囊；药丸；片剂；包括含服、舌下和口服崩裂的特种片剂；薄膜；酏剂；液体溶液或悬液；粉末；或晶体。
4.根据权利要求1所述的化合物，其并入乳膏、凝胶、擦剂、香脂、洗剂、软膏或皮肤贴剂。
5.一种治疗炎症相关疾病的方法，所述方法包括向需要其的受试者施用治疗有效量的权利要求1所述的化合物。
6.一种治疗癌疾病病况的方法，所述方法包括向需要其治疗的患者施用治疗有效量的权利要求1所述的化合物。
7.一种治疗糖尿病/代谢综合症疾病病况的方法，所述方法包括向需要其治疗的患者施用治疗有效量的权利要求1所述的化合物。
8.一种治疗心血管疾病病况的方法，所述方法包括向需要其治疗的患者施用治疗有效量的权利要求1所述的化合物。
9.一种治疗炎症/疼痛疾病病况的方法，所述方法包括向需要其治疗的患者施用治疗有效量的权利要求1所述的化合物。
10.一种治疗神经疾病病况的方法，所述方法包括向需要其治疗的患者施用治疗有效量的权利要求1所述的化合物。
11.一种治疗病毒/细菌疾病病况的方法，所述方法包括向需要其治疗的患者施用治疗有效量的权利要求1所述的化合物。
12.一种治疗非人哺乳动物物种中疾病病况的方法，所述方法包括向需要治疗的所述哺乳动物物种施用权利要求1所述的化合物。
13.根据权利要求12所述的方法，其中所述非人哺乳动物物种选自由下述组成的组：家养动物、马、母牛、绵羊、猪、狗和猫。
14.一种治疗性方法，所述方法包括向需要其治疗的患者施用治疗有效量的权利要求2所述的药物化合物。
15.根据权利要求14所述的治疗性方法，其中所述药物化合物包含生理学上可接受的填料、崩裂剂、载体材料、赋形剂、润滑剂、缓冲液、抗菌剂、膨松剂和/或粘合剂、以及抗氧化剂。
16.根据权利要求15所述的方法，其中所述崩裂剂选自由下述组成的组：交联羧甲基纤维素钠、聚维酮、交聚维酮、淀粉乙醇酸钠、玉米淀粉或微晶纤维素。
17.根据权利要求2所述的组合物，其使用脂质体、药物聚合物缀合物、水凝胶、微球或微胶囊配制为延时释放剂型。
18.根据权利要求5所述的方法，其中所述化合物进一步与橙皮苷和胡椒碱组合。
19.根据权利要求18所述的方法，其中杨梅黄酮与橙皮苷和胡椒碱配制，而形成Equivir。
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