CN115260100B - 一种用于制备冠状病毒治疗药物的取代酰基胍类化合物和用途 - Google Patents
一种用于制备冠状病毒治疗药物的取代酰基胍类化合物和用途 Download PDFInfo
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Abstract
本发明公开了一种用于制备冠状病毒治疗药物的取代酰基胍类化合物和用途,属于化学医药领域。本发明取代酰基胍类化合物的结构如通式(I)所示,该化合物或其药学上可接受的盐能够治疗冠状病毒感染,包括冠状病毒科超家族的病毒,例如COVID‑19;并且具有较长的代谢半衰期,能够降低医疗剂量和扩大给药时间间隔。
Description
技术领域
本发明属于化学医药领域,涉及一种用于制备冠状病毒治疗药物的取代酰基胍类化合物和用途。
背景技术
新型冠状病毒肺炎(COVID-19),简称“新冠肺炎”,是指2019新型冠状病毒(SARS-CoV-2)感染导致的肺炎,现已证实为一种新型冠状病毒感染引起的急性呼吸道传染病。
目前COVID-19冠状病毒疾病和药物治疗谱总结如下:潜在的治疗药物类别2019冠状病毒疾病包括抗体、抗病毒和抗炎治疗。早期的感染,疾病的严重程度相对较轻,治疗可侧重于病毒的预防进入细胞(抗体疗法)或抑制病毒复制(抗病毒疗法)。当患者肺部感染,在这种情况下,建议增加抗炎治疗,而轻度至中度非住院且为危重病的高风险者可接受抗病毒治疗。当出现肺部感染时,可发展为严重的急性呼吸道感染综合症(SARS),在这种情况下需要补充氧气,包括机械通气或体外膜肺氧合(ECMO)。在这个后来的2019冠状病毒疾病阶段感染,一种压倒性的炎症反应是造成呼吸系统损害的主要原因导致急性呼吸窘迫综合征(ARDS)的系统,需要使用抗炎药疗效数据有限,抗病毒药物疗效证据较少,也没有关于SARS抗体的有效性数据。
目前可用于治疗新冠肺炎的药物很多属于应急用药或同情用药,仍然存在许多不足。例如广谱抗病毒药物对于COVID-19没有明显的活性,许多对症治疗病毒性肺炎的药物效果也较差。还有不少药物虽然可以抑制病毒但存在明显的毒性。辉瑞研发的3CL蛋白酶抑制剂Paxlovid作为首个新冠口服药物正在被全球患者使用,迫于巨大的需求量和成本压力,多元化新冠药物的研发仍然非常重要。
发明内容
为了解决现有技术存在的上述问题,本发明提供了一类新的酰基胍类化合物或其药学上可接受的盐,这类化合物具有更好的抗病毒作用及代谢稳定性,给目前严峻的新冠疫情提供一种新的治疗方式。
本发明首先提供了一种通式(I)所示结构的取代酰基胍类化合物或其药学上可接受的盐,
其中,R选自1-3个氘原子取代的甲基,C3-C6环烷烃,三氟甲基,二氟甲基或三氟乙基。
进一步地,R选自氘代甲基-CD3,环丙基,三氟甲基,二氟甲基或三氟乙基;
进一步地,所述通式(I)所示结构的化合物选自:
在本发明的一种实施方式中,所示化合物中胍基部分的胺基或亚胺基可以用于提供这些化合物的任何常规形式存在。例如,它们可以游离碱、水合物、有机或无机盐或它们的组合存在。
在本发明的一种实施方式中,所述的药学上可接受的盐为无机盐或有机盐;无机盐包括盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐;所述有机盐选自甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、丁二酸盐、戊二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、水杨酸盐、对甲苯磺酸盐、抗坏血酸盐。
更进一步地,所述药学上可接受的盐选自盐酸盐、硫酸盐、琥珀酸盐或甲磺酸盐。
本发明还提供一种药物组合物,包括上述化合物或其药学上可接受的盐,以及药学上可接受载体、赋形剂或稀释剂。
在本发明的一种实施方式中,上述药物组合物制成制剂时,可以系统地或顺序地给予。可以以任何有效的方式完成用于将化合物或药物组合物递送至病毒感染部位。给药方式包括但不限于口服化合物或组合物,通过以下方式局部、经皮、肠外、皮下、静脉、肌肉内、腹腔注射鼻内滴注,通过腔内或膀胱内滴注,眼内,动脉内,病变内或通过应用于粘膜,如鼻、喉和支气管粘膜管。
本发明还提供了上述化合物或其药学上可接受的盐在制备用于抗冠状病毒药物中的应用。
在本发明的一种实施方式中,所述冠状病毒包括:SARS、MERS-CoV、2019冠状病毒SARS-CoV-2。
本发明还提供一种抗新型冠状病毒SARS-CoV-2药物,其特征在于,包括上述化合物或其药学上可接受的盐,以及药用辅料。
在本发明的一种实施方式中,药用辅料包括:包括如下任意一种或多种:溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、絮凝剂与反絮凝剂、助滤剂以及释放阻滞剂。
在本发明的一种实施方式中,药物的剂型包括如下任意一种:注射液、注射用冻干粉针、混悬剂、植入剂、栓塞剂、胶囊剂、片剂、丸剂和口服液。
此外,上述化合物或其药学上可接受的盐与一种抗冠状病毒的组合在制备由冠状病毒感染引起的疾病的药物中的用途,所述抗病毒剂选自以下:
(i)中和抗体药物类药物;
(ii)RdRp抑制剂类药物;
(iii)AR拮抗剂类药物;
(iv)抗冠状病毒siRNA。
本发明有益效果:
本发明通式(I)所示结构的化合物或其药学上可接受的盐可有效治疗由病毒引起的感染,包括冠状病毒科超家族的病毒;并且具有较长的代谢半衰期使得,能够降低医疗剂量和扩大给药时间间隔。
具体实施方式
下列实施例用于说明而非限定通式(I)化合物的合成方法。温度均为摄氏度。如果没有另外说明,所有的蒸发均在减压下进行。如果没有另外说明,否则试剂是自商业供货商购得且未经进一步纯化即使用。终产物、中间体和原料的结构通过标准分析方法确认,例如元素分析、光谱特征分析,例如MS、NMR。使用的缩写是本领域常规缩写。
实施例1:N-氨基脲-5-(1-(甲基-D3)-1H-吡唑-4-基)-2-萘酰胺(1)
第一步:5-(1-(甲基-D3)-1H-吡唑-4-基)-2-萘甲酸的制备
2-萘酸(100mg,39.8mmol)、1-基-D3-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑(101mg,47.8mmol)溶于二氧六环(5mL)中,依次加入2M碳酸钠水溶液(1mL)和四(三苯基膦)钯(46mg,0.04mmol),在氮气保护下将混合物加热回流16小时。反应结束后,反应液冷却至室温,加入1M盐酸水溶液(5mL),然后用乙酸乙酯(3X20 mL)萃取。合并有机层,依次用饱和氯化钠洗涤,无水硫酸钠干燥,减压浓缩得到粗产物。经柱纯化得到5-(1-(甲基-D3)-1H-吡唑-4-基)-2-萘甲酸(45mg,44%),白色固体。MS-ESI(m/z):254[M-l]+。
第二步:N-氨基脲-5-(1-(甲基-D3)-1H-吡唑-4-基)-2-萘酰胺(1)的制备
将5-(1-(甲基-D3)-1H-吡唑-4-基)-2-萘甲酸(45mg,0.17mmol)溶于无水二氯甲烷(5mL)中,加入1滴DMF,冰浴下加入草酰氯(54μL,0.42mmol),该混合物在室温搅拌5小时。40℃加热反应1小时,减压浓缩。将浓缩物悬浮在无水四氢呋喃(5mL)中,将该混合物滴加至盐酸胍(81mg,0.85mmol)的2M氢氧化钠水溶液(5mL)中,然后室温搅拌30分钟。分离有机相,水相乙酸乙酯(2X10 mL)萃取。合并有机层,依次用饱和氯化钠洗涤,无水硫酸钠干燥,减压浓缩得到粗产物。经反相制备得到N-氨基脲-5-(1-(甲基-D3)-1H-吡唑-4-基)-2-萘酰胺(25mg,48%),黄色固体。
MS-ESI(m/z):297[M+l]+。1H NMR(400MHz,DMSO-d6)δ:11.44(s,1H),8.87(d,J=6.8Hz,1H),8.65(s,2H),8.62(s,1H),8.32(d,J=7.8Hz,1H),8.20-8.02(m,3H),7.92-7.68(m,3H).
按与实施例1基本操作相似的操作合成实施例2-4(参见表1),得到期望的产物。
表1实施例2-4的结构和数据
比较例1(BIT225):
N-(氨基亚胺甲基)-5-(1-甲基-1H-吡唑-4-基)-2-萘甲酰胺通过商业化途径获得。
实施例6:SARS-CoV-2-E蛋白磷脂双层抑制试验
1)将含有表达SARS-CoV-2-E(分离物HXB2)和N末端谷胱甘肽S-转移酶(GST)标签的质粒p2GEX-E的细胞在30℃下生长至约250Klett单位,然后在收获前用IPTG(异丙基硫代半乳糖苷,0.01mM)再诱导4h。在渗透破坏和离心后,制备组合细胞碎片和膜组分。在MTPBS-DTT(6mM Na2HPO4,4mM NaH2PO4,150mM NaCl,1mM二硫苏糖醇,pH 7.3)中存在CHAPS(3-[3-(胆酰胺丙基)二甲氨基]丙磺酸内盐)洗涤剂(2%wt/vol)和甘油(20%wt/vol)的情况下,在冰上搅拌1h,重新悬浮颗粒并溶解GST-E。不溶性物质在400000×g的转速下离心1小时去除。上清液应用于谷胱甘肽琼脂糖色谱柱,彻底清洗后,用人凝血酶(100U/mL:37℃,1小时)处理树脂,以洗脱融合蛋白的E部分。该E组分可通过阴离子交换和免疫层析进一步纯化至均一。
2)纯化的E蛋白通过透析重新组成磷脂囊泡。在N2气流下,将氯仿中棕榈酰油酰基磷酰乙醇胺(PE)、棕榈酰-油酰基磷酰胆碱(PC)和棕榈酰油酰基磷酰丝氨酸(PS)(7:2:1,5mg总脂)的混合物蒸发至干燥,并重新悬浮在100μL的CHAPS溶液(400mg/ml)中。将E(1μg)添加到400μL的含有CHAPS(0.5%)、甘油(5%)、DTT(1mM)和Tris(50mM),pH 7.5的缓冲液中的脂质悬浮液中。在浴式超声仪中超声处理10分钟后,将混合物注入1mL玻片裂解器(Pierce)中,并用两个500mL体积的MES(2-吗啉乙磺酸,10mM)/NaCl(200mM)(pH 7.2)透析过夜。生成的蛋白质脂质体悬浮液第二天用于双层实验,或在4℃下储存。
使用正癸烷中7:2:1的PE:PC:PS的脂质混合物涂在Delrin塑料壁上的一个小圆孔(直径约100μm)上,以分离顺式和反式室,两个腔室最初包含10mM MES、50mM NaCl、10mMCaCl2,pH 7.2。将代表10-50ng E的等量E蛋白脂质体添加到CIS室中并搅拌2分钟,以帮助蛋白脂质体与平面脂质双层发生碰撞。然后将CIS室中的NaCl浓度调整为500mM,并继续搅拌,直到检测到E通道活性。CIS室接地,跨室保持在+100mV和-100mV之间的各种保持电位。使用Axopatch 200放大器记录电流,并使用Vetter PCM记录仪以1kHz的采样率直接记录到录像带中。为了进一步分析,原始数据以0.5kHz数字化。计算通道活动连续段(5-80s持续时间)的平均电流。平均电导的计算方法是将平均电流除以保持电位减去电流的反转电位。500/50mM NaCl浓度下的反转电位梯度为31±1.2mV。
试验结果分析:
根据加入纯化重组的E蛋白后,所观察到的离子通道活性来评价药物对该靶点的抑制效果。具体测定结果见表2。
表2各实施例对离子通道的电导率的影响
从表2可以看出,经过加药前后对比,各实施例可以显著降低电导率,达到了良好的离子通道抑制效果。
实施例7:SARS COV 2病毒感染hACE2小鼠实验模型构建方法
1、随机选择4~12周龄,体重在23~35g的K18hACE2小鼠为实验动物,雌雄兼用。
2、所有的小鼠都要在生物安全柜内进行感染。将hACE2转基因小鼠分为正常组(不感染)、SARS CoV 2感染组(模型组)、SARS CoV 2感染+实施例药物干预组,每组10只。用异氟烷麻醉,将塑料干燥器置于生物安全柜内,向塑料干燥器内加入异氟烷;将小鼠置于干燥器内进行麻醉,观察小鼠呼吸,直至达到麻醉效果。每组设置3个重复。
3、稀释SARS CoV 2病毒:从80℃冰箱取出装有SARS CoV 2病毒的冻存管,并登记。用移液器量取病毒至含有适量PBS或DMEM的冻存管中进行稀释,得到滴度107PFU/mL的病毒液。
4、取出麻醉好小鼠,鼻腔滴注50μL稀释好的病毒,除正常组滴鼻给予PBS之外,其它各组小鼠滴鼻感染病毒。感染后2小时,药物干预组小鼠灌胃给予实施例化合物,实施例化合物的给药量为50mg/kg,连续给药5日,1次/日。
5、等待小鼠从麻醉中恢复,并将其放入无菌的鼠笼中以降低可能的笼内污染。
上述过程均为在武汉病毒所中进行的合规操作。
实施例8:
比较实施例6制备的SARS CoV 2感染组小鼠模型和正常组小鼠及药物干预组小鼠感染第五天的死亡率。
统计感染5天时,模型组、正常组以及药物干预组的小鼠死亡情况。结果如下表3所示,与空白组比较,感染SARS COV 2新冠病毒的K18hACE2小鼠模型的死亡率显著升高(p<0.001),药物干预治疗后显著降低,具有较好的死亡保护作用。
表3各组小鼠感染后5天的死亡率统计结果
实施例9:
比较感染SARS CoV 2新冠病毒的K18hACE2小鼠模型、正常组小鼠及药物干预组小鼠的第三天和第五天肺匀浆液病毒滴度TCID50值。用Karber法计算TCID50值,统计学处理。
结果如下表4所示,与空白组小鼠比较,感染SARS CoV 2新冠病毒的K18hACE2小鼠肺组织匀浆病毒滴度显著升高(p<0.001),药物干预治疗后,肺病毒滴度显著降低。
表4各组小鼠感染后3天和5天的肺匀浆液的活病毒滴度的TCID50值
实施例10:使用人体肝脏微粒体进行化合物稳定性的评价
将实施例化合物的肝微粒体酶稳定性与BIT225进行比较。
测定系统:本发明化合物的代谢稳定性利用由男女混合的肝脏微粒体用1mMNADPH进行试验。样品使用质谱仪进行分析。将HRMS用于确定峰面积响应比率(对应于试验化合物或对照物的峰面积除以分析内标的峰面积)而不运行标准曲线。为了检测到所有的可能代谢物,在适当的m/z范围内进行HRMS扫描。
测定条件:该测定用一次孵育(N=1)进行。将试验化合物在37℃下在含有0.5毫克/毫升肝脏微粒体蛋白的缓冲液中孵育。通过加入辅因子引发反应,并于0、2、4、8、16、24、36、48小时取样,平行孵育阳性对照物(5μM睾丸素)并于0、2、4、8、16、24、36、48小时取样。
测定质量控制:平行进行对照化合物睾丸素以证实(肝脏)微粒体的酶活性。最终时间点后,利用荧光测定法来确认NADPH添加到反应混合物中。对照物的T1/2满足可接受的内标。
分析方法:
液相色谱柱:Thermo BDS Hypersil C18 30X2.0mm,3μm,具有保护柱M.P.,缓冲液:25mM甲酸接缓冲液,pH 3.5;
水相(A):90%水,10%缓冲液;
有机相(B):90%乙腈,10%缓冲液;
流速:300微升/分钟
自动进样器:注射体积10微升
梯度程序参见表5。
表5梯度程序
通过使用人体肝微粒体,实施例对代谢半衰期进行评价,如本发明中所述,实施例1-5均表现为10-15小时代谢半衰期,均远大于BIT225的5小时代谢半衰期。结果显示,相对较长的代谢半衰期使得它们具有降低医疗剂量和扩大给药时间间隔的潜能。
由实施例1-5的化合物小鼠实验结果和人体肝脏微粒体酶稳定性可知,对于通式(I)的化合物而言,取代基团R基团对于化合物的药效学性能和代谢稳定性有着重要的影响。
尽管本发明通过之前的特定实施例说明,但不应将其解释为受此限制;而是本发明涵盖之前公开的一般方面。可在不背离本发明的精神和范围下进行多种修饰并具有多种实施方案。
Claims (6)
1.通式(I)所示结构的取代酰基胍类化合物或其药学上可接受的盐在制备用于抗冠状病毒药物中的应用,
,
其中,R选自1-3个氘原子取代的甲基,C3-C6环烷烃,三氟甲基,二氟甲基或三氟乙基。
2.根据权利要求1所述的应用,其特征在于,R选自氘代甲基-CD3,环丙基,三氟甲基,二氟甲基或三氟乙基。
3.根据权利要求1所述的应用,其特征在于,化合物选自:
。
4.根据权利要求1所述的应用,其特征在于,所述的药学上可接受的盐为无机盐或有机盐;无机盐包括盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐;所述有机盐选自甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、丁二酸盐、戊二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、水杨酸盐、对甲苯磺酸盐、抗坏血酸盐。
5.根据权利要求1所述的应用,其特征在于,所述冠状病毒包括:SARS、MERS-CoV、2019冠状病毒SARS-CoV-2。
6.根据权利要求1所述的应用,其特征在于,与其他抗病毒剂联用,所述抗病毒剂选自以下一种或多种:
(i)中和抗体药物类药物;
(ii)RdRp抑制剂类药物;
(iii)AR拮抗剂类药物;
(iv)抗冠状病毒siRNA。
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