CN113563273B - 一种抗病毒的吡嗪酰胺衍生物及其制备方法 - Google Patents
一种抗病毒的吡嗪酰胺衍生物及其制备方法 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A—HUMAN NECESSITIES
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本发明涉及一种抗病毒的吡嗪酰胺衍生物及其制备方法,尤其是一种抗病毒的3‑羟基‑2‑吡嗪甲酰胺衍生物及其制备方法。本发明所涉及的化合物及其组合物和衍生物具有抗病毒作用,与原型药物T‑1105或T‑705相比,本发明的通式I化合物及其组合物和衍生物具有合成简单,体内作用时间长等明显优点。
Description
技术领域
本发明属于医药化工领域,涉及一种吡嗪酰胺衍生物的制备方法及其抗病毒用途。
背景技术
以6-氟-3-羟基-2-吡嗪甲酰胺(T-705)和3-羟基-2-吡嗪甲酰胺(T-1105)(见下式)为代表的吡嗪酰胺类化合物是一类病毒RNA聚合酶抑制剂,具有较好的抗病毒作用。
据文献报道,T-705(商品名为“法匹拉韦”、“favipiravir”)为新型RNA聚合酶选择性抑制剂,具有广谱抗RNA病毒活性,对流感病毒、埃博拉病毒、黄热病病毒、沙粒病毒、布尼亚病毒、西尼罗病毒等RNA病毒均具有抗病毒作用。2014年3月在日本已批准上市用于新发或再发型流感病毒感染(但仅限于对其他抗流感病毒药物无效或效果不明显的情况)的治疗(参见Antimicrobial Agents and Chemotherapy,2007,Vol.51,No.3,845-851;Antimicrobial Agents and Chemotherapy,2010,p.126133,专利WO2000010569);T-1105在体内和体外模型中表现出较好的抗口蹄疫病毒的活性(参见专利WO20071139081)。
T-1105和T-705具有类似的结构和作用机制,在体内都可以转化为相应的核苷三磷酸的形式,通过模拟三磷酸鸟苷(GTP)竞争性地抑制病毒RNA聚合酶而发挥抗病毒作用(参见ANTIMICROBIAL AGENTS AND CHEMOTHERAPY,2005,Vol.49,No.3,p.981-986)。
虽然T-705和T-1105在体内外模型中有很好的抗病毒作用,但是这两个化合物都存在一些不良的药代动力学性质,不利于药效的发挥。例如T-1105的口服吸收很差,体内消除也很快;而T-705的口服吸收很好,但是消除较快,存在半衰期短的问题,导致其用药剂量较大,每天口服剂量达800mg-2400mg。因此,有必要对这些化合物进行改进。
发明内容
为了克服3-羟基-2-吡嗪甲酰胺类化合物T-1105和T-705存在的半衰期短等不良的药代动力学性质,本发明提供了具有通式I结构的6-R-3-羟基-2-吡嗪甲酰胺类化合物,此类化合物在体内可转化为可以转化为相应的核苷三磷酸的形式而发挥抗病毒的作用。
本发明的第一方面涉及具有通式I结构的化合物、其可药用的盐或溶剂化物,
其中R选自:烷基;烷氧基取代的烷基;环烃基;芳香基取代的烷基或带有取代基团的芳基取代的烷基,所述取代基选自烷氧基、烷基、环烃基、卤素、硝基、腈基、羟基或氨基等,优选烷氧基;苯基或取代的苯基,所述取代基选自烷氧基、烷基、环烃基、卤素、硝基、腈基、羟基或氨基等,优选烷氧基;
所述烷基为C1-10烷基,是具有1-10个碳原子的直链或支链烷基,例如为C1-6烷基,所述烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、正戊基、异戊基、正己基、正辛基等;
所述环烃基是指饱和或不饱和的、但是非芳香族的具有3至12个碳原子且具有一个或多个环的环状烷基,例如为C3-6环烃基,所述环烃基包括例如金刚烷基、环丙基、环丁基、环戊基、环辛基、环己烯基等,优选环戊基和环己基;
所述烷氧基是指“烷基-O-”,所述烷基的定义如上所述,其中包括例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基等,优选甲氧基和乙氧基;
所述芳香基是指具有6至12个碳原子且具有单个环(例如苯基)或多个稠环(例如萘基或蒽基)的单价芳香族碳环基团,其中稠环可以是芳香族的或者可以是非芳香族的(例如2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等),前提是连接点是芳基,芳香基优选苯基。
本发明的第二方面涉及药物组合物,其包含本发明第一方面任一项所述的化合物或其可药用的盐或溶剂化物,以及药学上可接受的载体。
根据本发明第二方面的药物组合物,其可制成以下制剂固体制剂,注射剂,外用制剂,喷剂,液体制剂或复方制剂等。
本发明的第三方面涉及本发明第一方面任一项所述的化合物、其可药用的盐或溶剂化物或本发明第二方面任一项所述的药物组合物在制备抗病毒药物中的用途或者在制备预防和/或治疗病毒感染所致疾病的药物中的用途。其中所述药物可用于哺乳动物,例如人或偶蹄动物,所述偶蹄动物可以为猪、牛或羊等。
根据本发明第三方面的用途,其中所述的病毒主要包括各种类型的RNA病毒,其包括但不限于以下病毒:流感病毒(Influenza Virus),丙肝病毒(Hepatitis C Virus),布尼亚病毒(Bunyavirus),口蹄疫病毒(Foot and Mouth Disease Virus),西尼罗病毒(WestNile virus),沙粒病毒(Arenavirus),或黄热病病毒(Yellow Fever Virus)等。其中病毒感染所致疾病例如为流感、丙型肝炎、登革热、出血热、口蹄疫、西尼罗病毒病、拉沙热、阿根廷出血热、玻利维亚出血热、和黄热病等。
本发明第四方面涉及本发明的第一方面任一项所述的化合物、其可药用的盐或溶剂化物在制备预防和/或治疗哺乳动物口蹄疫的药物的用途。所述哺乳动物例如为人或偶蹄动物,所述偶蹄动物可以为猪、牛或羊等。
本发明的第五方面涉及本发明的第一方面任一项所述的化合物的制备方法,其包括:
6-X-3-羟基-2-吡嗪甲酰胺与ROH反应得到6-R-3-羟基-2-吡嗪甲酰胺,
其中R定义如前所述,X为卤素,包括氟、氯、溴或碘;
其中6-X-3-羟基-2-吡嗪甲酰胺可以直接与ROH反应,也可以在无水非质子及有机溶剂存在下反应;可选择的无水非质子及有机溶剂包括但不限于甲苯、乙腈、THF、苯。6-X-3-羟基-2-吡嗪甲酰胺直接与ROH的反应或在无水非质子及有机溶剂存在下反应,进一步可选的在酰氯存在下反应;酰氯进一步可选自二氯亚砜
本发明还涉及预防和/或治疗病毒感染所致疾病的方法,所述方法包括给有需要的个体以预防和/或治疗有效量的本发明第一方面任一项所述的化合物、其可药用的盐或溶剂化物或本发明的药物组合物。其中所述的病毒主要包括各种类型的RNA病毒,其包括但不限于以下病毒:流感病毒(Influenza Virus),丙肝病毒(Hepatitis C Virus),布尼亚病毒(Bunyavirus),口蹄疫病毒(Foot and Mouth Disease Virus),西尼罗病毒(West Nilevirus),沙粒病毒(Arenavirus),或黄热病病毒(Yellow Fever Virus)等。其中病毒感染所致疾病例如为流感、丙型肝炎、登革热、出血热、口蹄疫、西尼罗病毒病、拉沙热、阿根廷出血热、玻利维亚出血热、和黄热病等。其中所述的有需要的个体可以为哺乳动物,如人或偶蹄动物,所述偶蹄动物可以为猪、牛或羊等。
本发明所涉及的化合物及其组合物和衍生物具有抗病毒作用,与原型药物T-1105或T-705相比,本发明的通式I化合物及其组合物和衍生物具有合成简单,体内作用时间长等明显优点。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
实施例1 6-甲氧基-3-羟基-2-吡嗪甲酰胺的制备
在干燥的、带有温度计、冷凝管和干燥管的三口瓶中,加入无水甲醇20mL,加入6-氟-3-羟基-2-吡嗪甲酰胺1g,室温下缓缓滴加二氯亚砜1ml,滴完后升温至50℃,反应3h,冷却至室温后,减压浓缩至干。甲醇重结晶得到目标化合物0.88g。
1H NMR(600MHz,DMSO-d6)δ12.78(s,1H),8.52(s,1H),8.37(s,1H),8.15(s,1H),3.92(s,4H).
13C NMR(151MHz,DMSO-d6)δ54.08,120.36,137.91,153.30,157.11,169.90.
HRMS ESI-m/z 168.0415(M–H)-.
实施例2 6-乙氧基-3-羟基-2-吡嗪甲酰胺的制备
在干燥的,带有温度计、冷凝管和干燥管的三口瓶中,加入无水乙醇20mL,加入6-氟-3-羟基-2-吡嗪甲酰胺1g,室温下缓缓滴加二氯亚砜1ml,滴完后升温至50℃,反应3h,冷却至室温后,减压浓缩至干。甲醇重结晶得到目标化合物0.76g。
1H NMR(600MHz,Chloroform-d)δ11.88(s,1H),8.10(s,1H),7.41(d,J=7.7Hz,1H),5.86(s,1H),4.30(q,J=7.1Hz,2H),1.41(d,J=7.2Hz,3H).
13C NMR(151MHz,Chloroform-d)δ14.32,62.70,119.51,139.79,153.43,157.62,169.99.
HRMS ESI-m/z 182.0571(M–H)-.
实施例3 6-丙氧基-3-羟基-2-吡嗪甲酰胺的制备
在干燥的、带有温度计、冷凝管和干燥管的三口瓶中,加入无水丙醇20mL,加入6-氟-3-羟基-2-吡嗪甲酰胺1g,室温下缓缓滴加二氯亚砜1ml,滴完后升温至50℃,反应3h,冷却至室温后,减压浓缩至干。甲醇重结晶得到目标化合物0.82g。
1H NMR(600MHz,Chloroform-d)δ11.91(s,1H),8.09(s,1H),7.45(s,1H),6.52(s,1H),4.17(d,J=6.6Hz,2H),1.84–1.74(m,2H),1.01(d,J=7.2Hz,3H).
13C NMR(151MHz,Chloroform-d)δ10.41,22.04,68.49,119.56,139.63,153.62,157.49,170.24.
HRMS ESI-m/z 196.0728(M–H)-.
实施例4 6-丁氧基-3-羟基-2-吡嗪甲酰胺的制备
在干燥的、带有温度计、冷凝管和干燥管的三口瓶中,加入无水正丁醇20mL,加入6-氟-3-羟基-2-吡嗪甲酰胺1g,室温下缓缓滴加二氯亚砜1ml,滴完后升温至50℃,反应3h,冷却至室温后,减压浓缩至干。甲醇重结晶得到目标化合物0.70g。
1H NMR(600MHz,Chloroform-d)δ11.92(s,1H),8.05(s,1H),7.48(s,1H),6.85(s,1H),4.20(t,J=6.6Hz,2H),1.75–1.67(m,2H),1.47–1.38(m,2H),0.92(t,J=7.4Hz,3H).
13C NMR(151MHz,Chloroform-d)δ13.69,19.09,30.69,66.68,119.58,139.54,153.60,157.42,170.30.
HRMS ESI-m/z 210.0884(M–H)-.
实施例5 6-异丙氧基-3-羟基-2-吡嗪甲酰胺的制备
在干燥的、带有温度计、冷凝管和干燥管的三口瓶中,加入无水异丙醇20mL,加入6-氟-3-羟基-2-吡嗪甲酰胺1g,室温下缓缓滴加二氯亚砜1ml,滴完后升温至50℃,反应3h,冷却至室温后,减压浓缩至干。甲醇重结晶得到目标化合物0.75g。
1H NMR(600MHz,Chloroform-d)δ11.88(s,1H),8.04(s,1H),7.41(s,1H),6.46(s,1H),5.25–4.85(m,1H),1.34(d,J=6.2Hz,6H).
13C NMR(151MHz,Chloroform-d)δ21.70,69.69,119.53,140.16,152.95,157.29,170.30.
HRMS ESI-m/z 196.0728(M–H)-.
实施例6 6-正戊氧基-3-羟基-2-吡嗪甲酰胺的制备
在干燥的、带有温度计、冷凝管和干燥管的三口瓶中,加入无水正戊醇20mL,加入6-氟-3-羟基-2-吡嗪甲酰胺1g,室温下缓缓滴加二氯亚砜1ml,滴完后升温至50℃,反应3h,冷却至室温后,减压浓缩至干。甲醇重结晶得到目标化合物0.68g。
1H NMR(600MHz,Chloroform-d)δ11.89(s,1H),8.08(s,1H),7.44(s,1H),6.48(s,1H),4.21(t,J=6.6Hz,2H),1.79–1.72(m,2H),1.44–1.31(m,4H),0.90(d,J=7.2Hz,3H).
13C NMR(151MHz,Chloroform-d)δ13.91,22.35,28.08,28.38,67.01,119.56,139.66,153.62,157.50,170.24.
HRMS ESI-m/z 224.1041(M–H)-.
实施例7 6-正辛氧基-3-羟基-2-吡嗪甲酰胺的制备
在干燥的、带有温度计、冷凝管和干燥管的三口瓶中,加入无水正辛醇20mL,加入6-氟-3-羟基-2-吡嗪甲酰胺1g,室温下缓缓滴加二氯亚砜1ml,滴完后升温至50℃,反应3h,冷却至室温后,减压浓缩至干。甲醇重结晶得到目标化合物0.86g。
1H NMR(600MHz,Chloroform-d)δ11.88(s,1H),8.10(s,1H),7.41(s,1H),5.90(s,1H),4.21(t,J=6.6Hz,2H),1.92–1.61(m,2H),1.54–1.13(m,10H),0.87(t,J=7.0Hz,3H).
13C NMR(151MHz,Chloroform-d)δ14.06,22.63,25.99,28.74,29.18,29.29,31.77,67.06,119.51,139.78,153.62,157.58,170.04.
HRMS ESI-m/z 266.1510(M–H)-.
实施例8 6-(2-甲氧基)乙氧基-3-羟基-2-吡嗪甲酰胺的制备
在干燥的、带有温度计、冷凝管和干燥管的三口瓶中,加入无水乙二醇独甲醚20mL,加入6-氟-3-羟基-2-吡嗪甲酰胺1g,室温下缓缓滴加二氯亚砜1ml,滴完后升温至50℃,反应3h,冷却至室温后,减压浓缩至干。甲醇重结晶得到目标化合物0.68g。
1H NMR(600MHz,Chloroform-d)δ11.91(s,1H),8.17(s,1H),7.38(s,1H),5.82(s,1H),4.46–4.23(m,2H),3.74(t,J=4.2Hz,2H),3.43(s,3H).
13C NMR(151MHz,Chloroform-d)δ59.22,65.99,70.49,119.43,139.90,153.14,157.85,169.89.
HRMS ESI-m/z 212.0677(M–H)-.
实施例9抗流感病毒活性评价
化合物对细胞的最大无毒浓度(TC0)
采用十倍稀释的方法设定6个浓度梯度,每个浓度设3个副孔。将长成单层细胞的96孔板取出,弃去孔中的培养液,除最大浓度的3个副孔外,每孔加180μl细胞维持液。将母液用细胞维持液稀释100倍为最大实验浓度,最大浓度的3个副孔每孔加200μl的100μg/ml的化合物溶液。从最大浓度的孔中吸取20μl液体至第二个浓度的孔中,混合均匀;再从第二个浓度孔中吸取20μl液体至第三个浓度的孔中,依次类推完成浓度的十倍递减稀释,并设细胞对照组。将96孔板置于37℃,5%CO2的细胞培养箱中培养72h。利用中性红染色法测定各孔细胞的OD值。将达到实验终点的96孔板取出,弃去孔中原有的液体,加入中性红染液,100μl/孔,置于37℃,5%CO2的细胞培养箱中孵育。1h后取出孔板,弃去中性红染液,并用PBS溶液将孔中的中性红荡洗2-3次,弃去PBS,加入醋酸乙醇溶液显色,100μl/孔。利用酶标仪在波长为544nm处测定OD值。判定结果参考:实验组的OD值≥90%对照组的OD值,判定是最大无毒浓度TC0值。
化合物CC50值测定
实验设定阳性对照组、阴性对照组、空白背景组以及实验组,实验组采用对倍稀释的方法分成5个浓度梯度,每个浓度设3个副孔。将长成单层细胞的96孔板取出,弃去孔中的培养液,除最大浓度的3个副孔外,每孔加100μl细胞维持液。将母液用细胞维持液稀释100倍,为最大实验浓度,最大浓度的3个副孔每孔加200μl的100μg/ml的化合物溶液。从最大浓度的孔中吸取100μl液体至第二个浓度的孔中,混合均匀;再从第二个浓度孔中吸取100μl液体至第三个浓度的孔中,依次类推完成浓度的对倍递减稀释,并设细胞对照孔。将96孔板置于37℃,5%CO2的细胞培养箱中培养,每天于显微镜下观察,直至不再出现新的细胞病变,为实验终点。
利用中性红染色法[33]测定各孔细胞的OD值。将达到实验终点的96孔板取出,弃去孔中原有的液体,加入中性红染液,100μl/孔,置于37℃,5%CO2的细胞培养箱中孵育。1h后取出孔板,甩出中性红染液,并用PBS溶液将孔中的中性红荡洗2-3次,弃去PBS,加入醋酸乙醇溶液显色,100μl/孔。利用酶标仪在波长为544nm处测定OD值。
测得OD值后计算细胞存活率,公式如下:
细胞存活率(%)=(受试孔OD544值/细胞对照孔的平均OD544值)×100%
用GraphPad Prism 5.0计算药物的半数细胞毒性浓度(CC50值)。实验平行操作3次及以上,实验结果用表示,采用GraphPad Prism 5.0统计软件对数据进行统计分析,并验证实验组与阴性对照组间采用两独立样本的t检验,P<0.05认为差异有统计学意义,P>0.05为尚不能认为差异有统计学意义。
化合物体外抗流感病毒实验(IC50)
将病毒原液用细胞维持液稀释成10-100TCID50。
准备长成单层细胞的96孔板,弃去板中原有的完全培养液,实验设定阳性对照组、阴性对照组、空白背景组以及实验组,实验组和阴性对照组用稀释的病毒液感染细胞,100μl/孔。然后向对照孔中加入细胞维持液,100μl/孔;向样品实验组中加入以选用的TC0浓度为终浓度的样品溶液对倍稀释,向下稀释四个浓度梯度,100μl/孔,即实验组5个浓度梯度进行实验;向阳性对照孔中加入细胞维持液,200μl/孔。对照组均设有5个副孔。
将96孔板置于37℃,5%CO2培养箱中培养。每日在倒置显微镜下观察并记录细胞病变情况。直到病毒对照孔出现4个“+”细胞病变时为实验终点。用中性红染色,醋酸乙醇溶液显色后在波长544nm出测定各孔细胞的OD值,计算抑制率。公式如下:
抑制率(%)=(受试孔OD544值—病毒对照孔平均OD544值)/(细胞对照孔平均OD544值—病毒对照孔平均OD544值)×100%
用GraphPad Prism 5.0软件计算药物半数抑制浓度(IC50值)。实验平行操作3次及以上,实验结果用表示,采用GraphPad Prism 5.0统计软件对数据进行统计分析,实验组与阴性对照组间采用两独立样本的t检验,P<0.05认为差异有统计学意义,P>0.05为尚不能认为差异有统计学意义。
a:81.2TCID50;b:73.2TCID50;n=3,P<0.05。
Claims (2)
1.一种通式I所示的吡嗪酰胺类化合物或其可药用的盐在制备预防和/或治疗病毒感染所致疾病的药物中的用途,其特征在于,病毒为H3N2;
通式I所示的吡嗪酰胺类化合物选自
6-甲氧基-3-羟基-2-吡嗪甲酰胺、
6-乙氧基-3-羟基-2-吡嗪甲酰胺、
6-(2-甲氧基)乙氧基-3-羟基-2-吡嗪甲酰胺。
2.根据权利要求1所述的通式I所示的吡嗪酰胺类化合物或其可药用的盐在制备预防和/或治疗病毒感染所致疾病的药物中的用途,其特征在于,所述的吡嗪酰胺类化合物的制备方法,
包括6-X-3-羟基-2-吡嗪甲酰胺与ROH反应得到6-RO-3-羟基-2-吡嗪甲酰胺,其中X为卤素,R的定义如权利要求1中所述,其中6-X-3-羟基-2-吡嗪甲酰胺直接与ROH反应,或6-X-3-羟基-2-吡嗪甲酰胺与ROH在无水非质子的有机溶剂存在下反应;
无水非质子的有机溶剂包括甲苯、乙腈、THF、苯;
6-X-3-羟基-2-吡嗪甲酰胺与ROH的反应中,加入酰氯,酰氯为二氯亚砜。
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