CN114507220B - A substituted 4-phenyl-5-position functionalized 1,2,4-triazole derivative and its preparation method and application - Google Patents
A substituted 4-phenyl-5-position functionalized 1,2,4-triazole derivative and its preparation method and application Download PDFInfo
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- CN114507220B CN114507220B CN202210217956.1A CN202210217956A CN114507220B CN 114507220 B CN114507220 B CN 114507220B CN 202210217956 A CN202210217956 A CN 202210217956A CN 114507220 B CN114507220 B CN 114507220B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical class C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims description 70
- 238000006467 substitution reaction Methods 0.000 claims description 48
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 16
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- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 150000002431 hydrogen Chemical group 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 206010022000 influenza Diseases 0.000 claims description 11
- 241000700605 Viruses Species 0.000 claims description 10
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 10
- 238000007363 ring formation reaction Methods 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 6
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 6
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 6
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 6
- -1 cyano, nitro, amino Chemical group 0.000 claims description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 4
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
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- 238000012360 testing method Methods 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
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Abstract
Description
技术领域technical field
本发明涉及医药合成合成技术领域，特别涉及一种取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物及其制备方法和应用。The invention relates to the technical field of pharmaceutical synthesis, in particular to a 1,2,4-triazole derivative substituted with a 4-phenyl-5-position functional group and a preparation method and application thereof.
背景技术Background technique
甲型流感病毒(IAV)是一种单股负链节段RNA病毒，属正粘病毒科。IAV感染是可引起严重呼吸道感染，是呼吸道疾病发病率和死亡率的主要原因之一，曾引起两次世界流感大流行(1918年和2009年)。据估计该流感每年造成29.1万至64.6万人死亡，数百万例重症病例。大多数病例是通过空气传播引起的流感。而新型或重新出现的IAV菌株容易造成了迅速、严重的全球流行，造成数百万人死亡。乙型流感病毒(IBV)几乎只感染人类，比IAV少见，这是因为其基因多样性较少且在早年容易对IBV形成一定程度的免疫。Influenza A virus (IAV) is a single-stranded negative-sense segmental RNA virus belonging to the Orthomyxoviridae family. IAV infection can cause severe respiratory infection and is one of the main causes of respiratory disease morbidity and mortality. It has caused two world influenza pandemics (1918 and 2009). The flu is estimated to cause between 291,000 and 646,000 deaths and millions of severe cases each year. Influenza is airborne in most cases. And new or re-emerging IAV strains are prone to rapid and severe global epidemics, killing millions of people. Influenza B virus (IBV), which infects almost exclusively humans, is less common than IAV because it has less genetic diversity and tends to develop some degree of immunity to IBV in early life.
目前，对于甲型流感病毒和乙型流感病毒，只有两类主要的抗流感病毒药物：M2离子通道抑制剂，主要是金刚烷类(包括金刚烷胺和金刚乙胺)；神经氨酸酶抑制剂(包括奥司他韦和扎那米韦)。然而，绝大多数甲型流感病毒株对金刚烷类具有抗性，并且对奥司他韦和扎那米韦具有抗性的病毒株也在逐渐增加。2018年FDA批准巴洛萨韦用于治疗12岁以上无并发症的急性流感患者，其作用机制为抑制流感病毒中的cap-依赖型核酸内切酶。目前已有对巴洛萨韦耐药性的流感病毒的报道。因此，迫切需要发现开发新的抗流感抗病毒药物。Currently, there are only two main classes of anti-influenza drugs for influenza A and B viruses: M2 ion channel inhibitors, mainly adamantanes (including amantadine and rimantadine); neuraminidase inhibitors agents (including oseltamivir and zanamivir). However, the vast majority of influenza A strains are resistant to adamantanes, and strains resistant to oseltamivir and zanamivir are gradually increasing. In 2018, the FDA approved baloxavir for the treatment of uncomplicated acute influenza patients over 12 years old, and its mechanism of action is to inhibit the cap-dependent endonuclease in influenza virus. Influenza viruses resistant to baloxavir have been reported. Therefore, there is an urgent need to discover and develop new anti-influenza antiviral drugs.
发明内容Contents of the invention
有鉴于此，本发明目的在于提供一种取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物及其制备方法和应用，本发明提供的取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物具有良好的抗流感病毒作用。In view of this, the object of the present invention is to provide a substituted 4-phenyl-5-functionalized 1,2,4-triazole derivative and its preparation method and application. The substituted 4-phenyl The -5-position functionalized 1,2,4-triazole derivatives have good anti-influenza virus effects.
为了实现上述发明目的，本发明提供以下技术方案：In order to achieve the above-mentioned purpose of the invention, the present invention provides the following technical solutions:
本发明提供了一种取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物，具有式1所示结构：The present invention provides a substituted 4-phenyl-5-position functionalized 1,2,4-triazole derivative, which has the structure shown in formula 1:
式1中，R1为氢、C1～C6烷基、C1～C6烷氧基或卤素；In formula 1 , R1 is hydrogen, C1～C6 alkyl, C1～C6 alkoxy or halogen;
R2为氢、C1～C6烷基、C1～C6烷氧基或卤素；R 2 is hydrogen, C1～C6 alkyl, C1～C6 alkoxy or halogen;
R3为氢、卤素、C1～C6烷基、C1～C6烷氧基、三氟甲基、三氟甲氧基、氰基、硝基、氨基或羟基； R3 is hydrogen, halogen, C1～C6 alkyl, C1～C6 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino or hydroxyl;
R4为氢、C1～C6烷氧基或卤素；R 4 is hydrogen, C1～C6 alkoxy or halogen;
所述R3、R4的取代位点独立为一个或多个。The substitution positions of R 3 and R 4 are independently one or more.
优选的，所述C1～C6烷基为C1～C6直链烷基或C3～C6支链烷基；Preferably, the C1-C6 alkyl group is a C1-C6 straight-chain alkyl group or a C3-C6 branched-chain alkyl group;
所述C1～C6烷氧基为C1～C6直链烷氧基或C3～C6支链烷氧基。The C1-C6 alkoxy group is a C1-C6 straight-chain alkoxy group or a C3-C6 branched-chain alkoxy group.
优选的，当所述R3的取代位点为1个时，所述R3的取代位置为2-位，3-位或4-位；Preferably, when the R 3 has one substitution position, the R 3 substitution position is 2-position, 3-position or 4-position;
当所述R3的取代位点为多个时，所述R3的取代位置为2-位至6-位的任意多个位置。When there are multiple substitution positions for R 3 , the substitution positions for R 3 are any number of positions from 2-position to 6-position.
本发明提供了上述取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物的制备方法，包括以下步骤：The present invention provides a preparation method for the substituted 4-phenyl-5-position functionalized 1,2,4-triazole derivatives, comprising the following steps:
具有式a所示结构的化合物与水合肼进行第一取代反应，得到具有式b所示结构的化合物；A compound having a structure shown in formula a is subjected to a first substitution reaction with hydrazine hydrate to obtain a compound having a structure shown in formula b;
具有式c所示化合物与N,N-二甲基硫代甲酰氯进行第二取代反应，得到具有式d所示结构的化合物；performing a second substitution reaction between the compound represented by formula c and N,N-dimethylthioformyl chloride to obtain a compound having the structure represented by formula d;
在碱性条件下，具有式b所示化合物与具有式d所示结构化合物进行成环反应，得到具有式e所示结构的化合物；Under basic conditions, the compound having the structure shown in formula b and the compound having the structure shown in formula d undergo a ring-forming reaction to obtain the compound having the structure shown in formula e;
在碱性条件下，具有式e所示结构的化合物与具有式f所示结构的化合物进行第三取代反应，得到具有式1所示结构的化合物；Under basic conditions, the compound having the structure shown in formula e is subjected to a third substitution reaction with the compound having the structure shown in formula f to obtain the compound having the structure shown in formula 1;
优选的，所述第一取代反应的温度为60～100℃，时间为8～36h。Preferably, the temperature of the first substitution reaction is 60-100° C., and the time is 8-36 hours.
优选的，所述第二取代反应的温度为80～120℃，时间为1～8h。Preferably, the temperature of the second substitution reaction is 80-120° C., and the time is 1-8 hours.
优选的，所述第三取代反应的温度为20～80℃，时间为0.5～2h。Preferably, the temperature of the third substitution reaction is 20-80°C, and the time is 0.5-2h.
优选的，提供所述碱性条件的碱性试剂为碱金属碳酸盐、碱金属氢化物、碱金属氢氧化物中的一种或几种。Preferably, the alkaline reagent providing the alkaline condition is one or more of alkali metal carbonate, alkali metal hydride, and alkali metal hydroxide.
本发明提供了上述取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物在制备抗流感病毒药物中的应用。The invention provides the application of the substituted 4-phenyl-5-position functionalized 1,2,4-triazole derivatives in the preparation of anti-influenza virus drugs.
本发明提供了一种抗流感病毒药物组合物，包括具有式1所示结构的取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物或具有式1所示结构的取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物药学上可接受的盐。The present invention provides an anti-influenza virus pharmaceutical composition, comprising substituted 4-phenyl-5-position functionalized 1,2,4-triazole derivatives having the structure shown in formula 1 or having the structure shown in formula 1 A pharmaceutically acceptable salt of 1,2,4-triazole derivatives substituted at the 4-phenyl-5-position of the structure.
本发明提供了一种取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物，具有式1所示结构。本发明提供的取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物可以抑制流感病毒的RNA依赖性RNA聚合酶，对流感病毒的复制具有明显的抑制活性，初步毒性研究显示其具有良好的成药性，表明该类衍生物作为抗病毒药物具有良好应用前景。实施例结果表明，本发明提供的取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物抗IAV活性EC50为1.20～11.45μM。The present invention provides a substituted 4-phenyl-5-position functionalized 1,2,4-triazole derivative, which has the structure shown in formula 1. The substituted 4-phenyl-5-position functionalized 1,2,4-triazole derivatives provided by the present invention can inhibit the RNA-dependent RNA polymerase of influenza virus, and have obvious inhibitory activity on the replication of influenza virus. Preliminary toxicity studies show that it has good druggability, indicating that this kind of derivatives has good application prospects as antiviral drugs. The results of the examples show that the anti-IAV activity EC 50 of the substituted 4-phenyl-5-position functionalized 1,2,4-triazole derivatives provided by the present invention is 1.20-11.45 μM.
具体实施方式detailed description
本发明提供了一种取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物，具有式1所示结构：The present invention provides a substituted 4-phenyl-5-position functionalized 1,2,4-triazole derivative, which has the structure shown in formula 1:
式1中，R1为氢、C1～C6烷基、C1～C6烷氧基或卤素；在本发明中，所述C1～C6烷基优选为C1～C6直链烷基或C3～C6支链烷基；在本发明中，所述C1～C6直链烷基优选为甲基或乙基，所述C3～C6支链烷基优选为异丙基或叔丁基。In formula 1 , R is hydrogen, C1～C6 alkyl, C1～C6 alkoxy or halogen; in the present invention, the C1～C6 alkyl is preferably C1～C6 straight chain alkyl or C3～C6 branched Chain alkyl group; in the present invention, the C1-C6 straight-chain alkyl group is preferably methyl or ethyl, and the C3-C6 branched-chain alkyl group is preferably isopropyl group or tert-butyl group.
在本发明中，所述C1～C6烷氧基优选为C1～C6直链烷氧基或C3～C6支链烷氧基；在本发明中，所述C1～C6直链烷氧基优选为甲氧基或乙氧基，所述C3～C6支链烷氧基优选为异丙氧基或叔丁氧基。In the present invention, the C1-C6 alkoxy group is preferably a C1-C6 straight-chain alkoxy group or a C3-C6 branched-chain alkoxy group; in the present invention, the C1-C6 straight-chain alkoxy group is preferably Methoxy or ethoxy, the C3-C6 branched alkoxy is preferably isopropoxy or tert-butoxy.
在本发明中，所述卤素优选为氟、氯、溴或碘。In the present invention, the halogen is preferably fluorine, chlorine, bromine or iodine.
式1中，R2为氢、C1～C6烷基、C1～C6烷氧基或卤素；在本发明中，所述C1～C6烷基、C1～C6烷氧基或卤素的优选种类与上文相同，在此不再赘述。In formula 1 , R2 is hydrogen, C1～C6 alkyl, C1～C6 alkoxy or halogen; in the present invention, the preferred species of said C1～C6 alkyl, C1～C6 alkoxy or halogen are the same as above The text is the same and will not be repeated here.
式1中，R3为氢、卤素、C1～C6烷基、C1～C6烷氧基、三氟甲基、三氟甲氧基、氰基、硝基、氨基或羟基。在本发明中，所述卤素优选为氟、氯、溴或碘；在本发明中，所述C1～C6烷基优选为C1～C6直链烷基或C3～C6支链烷基；所述C1～C6烷氧基优选为C1～C6直链烷氧基或C3～C6支链烷氧基。在本发明中，所述C1～C6直链烷基优选为甲基或乙基，所述C3～C6支链烷基优选为异丙基或叔丁基。在本发明中，所述C1～C6直链烷氧基优选为甲氧基或乙氧基，所述C3～C6支链烷氧基优选为异丙氧基或叔丁氧基。In Formula 1, R3 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino or hydroxyl. In the present invention, the halogen is preferably fluorine, chlorine, bromine or iodine; in the present invention, the C1-C6 alkyl is preferably a C1-C6 straight-chain alkyl or a C3-C6 branched-chain alkyl; the The C1-C6 alkoxy group is preferably a C1-C6 straight-chain alkoxy group or a C3-C6 branched-chain alkoxy group. In the present invention, the C1-C6 linear alkyl group is preferably methyl or ethyl, and the C3-C6 branched-chain alkyl group is preferably isopropyl or tert-butyl. In the present invention, the C1-C6 linear alkoxy group is preferably methoxy or ethoxy, and the C3-C6 branched alkoxy group is preferably isopropoxy or tert-butoxy.
式1中，R4为氢、C1～C6烷氧基或者卤素；在本发明中，所述C1～C6烷氧基优选为C1～C6直链烷氧基或C3～C6支链烷氧基；在本发明中，所述C1～C6直链烷氧基优选为甲氧基或乙氧基，所述C3～C6支链烷氧基优选为异丙氧基或叔丁氧基。在本发明中，所述卤素优选为氟、氯、溴或碘。In Formula 1 , R4 is hydrogen, C1-C6 alkoxy or halogen; in the present invention, the C1-C6 alkoxy is preferably C1-C6 straight-chain alkoxy or C3-C6 branched-chain alkoxy ; In the present invention, the C1-C6 linear alkoxy group is preferably methoxy or ethoxy, and the C3-C6 branched alkoxy group is preferably isopropoxy or tert-butoxy. In the present invention, the halogen is preferably fluorine, chlorine, bromine or iodine.
在本发明中，所述R3、R4的取代位点独立为一个或多个。In the present invention, the substitution positions of R 3 and R 4 are independently one or more.
在本发明中，当所述R3的取代位点为1个时，所述R3的取代位置优选为2-位，3-位或4-位；In the present invention, when the R3 has one substitution position, the R3 substitution position is preferably 2-position, 3-position or 4-position;
当所述R3的取代位点为多个时，所述R3的取代位置优选为2-位至6-位的任意多个位置。When there are multiple substitution positions for R 3 , the substitution positions for R 3 are preferably any multiple positions from 2-position to 6-position.
作为本发明的具体实施例，所述取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物具有式2～式55所示结构，具体见表1。As a specific example of the present invention, the substituted 4-phenyl-5-position functionalized 1,2,4-triazole derivatives have structures shown in Formula 2 to Formula 55, see Table 1 for details.
表1取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物的结构Table 1 Structures of substituted 4-phenyl-5-functionalized 1,2,4-triazole derivatives
本发明提供了上述取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物的制备方法，包括以下步骤：The present invention provides a preparation method for the substituted 4-phenyl-5-position functionalized 1,2,4-triazole derivatives, comprising the following steps:
具有式a所示结构的化合物与水合肼进行第一取代反应，得到具有式b所示结构的化合物；A compound having a structure shown in formula a is subjected to a first substitution reaction with hydrazine hydrate to obtain a compound having a structure shown in formula b;
具有式c所示化合物与N,N-二甲基硫代甲酰氯进行第二取代反应，得到具有式d所示结构的化合物；performing a second substitution reaction between the compound represented by formula c and N,N-dimethylthioformyl chloride to obtain a compound having the structure represented by formula d;
在碱性条件下，具有式b所示化合物与具有式d所示结构化合物进行成环反应，得到具有式e所示结构的化合物；Under basic conditions, the compound having the structure shown in formula b and the compound having the structure shown in formula d undergo a ring-forming reaction to obtain the compound having the structure shown in formula e;
在碱性条件下，具有式e所示结构的化合物与具有式f所示结构的化合物进行第三取代反应，得到具有式1所示结构的化合物；Under basic conditions, the compound having the structure shown in formula e is subjected to a third substitution reaction with the compound having the structure shown in formula f to obtain the compound having the structure shown in formula 1;
在本发明中，具有式a所示结构的化合物与水合肼进行第一取代反应，得到具有式b所示结构的化合物。In the present invention, the compound having the structure represented by formula a is subjected to the first substitution reaction with hydrazine hydrate to obtain the compound having the structure represented by formula b.
在本发明中，所述具有式a所示的化合物的来源优选为市售或自行制备。当自行制备所述具有式a所示的化合物时，制备方法优选按照文献European Journal of MedicinalChemistry,2020,Volume 186,111861的方法制备。In the present invention, the source of the compound represented by formula a is preferably commercially available or self-prepared. When preparing the compound represented by formula a by yourself, the preparation method is preferably prepared according to the method in the document European Journal of Medicinal Chemistry, 2020, Volume 186, 111861.
在本发明中，所述具有式a所示结构的化合物与水合肼的摩尔比优选为1:3～20，更优选为1:11。在本发明中，所述第一取代反应的溶剂优选为乙醇。In the present invention, the molar ratio of the compound having the structure represented by formula a to hydrazine hydrate is preferably 1:3-20, more preferably 1:11. In the present invention, the solvent for the first substitution reaction is preferably ethanol.
在本发明中，所述第一取代反应的温度优选为95℃，时间优选为24h。In the present invention, the temperature of the first substitution reaction is preferably 95° C., and the time is preferably 24 hours.
所述第一取代反应后，本发明优选对所得第一取代反应液进行后处理，所述后处理优选包括以下步骤：After the first substitution reaction, the present invention preferably carries out post-treatment to the obtained first substitution reaction liquid, and the post-treatment preferably includes the following steps:
对所述第一取代反应液依次进行去除溶剂和反相柱层析，得到具有式b所示结构的化合物纯品。The solvent removal and reverse-phase column chromatography were performed sequentially on the first substitution reaction solution to obtain the pure compound having the structure shown in formula b.
在本发明中，所述去除溶剂的方式优选为蒸干溶剂。在本发明中，所述反相柱层析的固定相优选为C18填料，洗脱相优选为甲醇和水。In the present invention, the method of removing the solvent is preferably to evaporate the solvent to dryness. In the present invention, the stationary phase of the reversed-phase column chromatography is preferably C18 packing, and the elution phase is preferably methanol and water.
在本发明中，具有式c所示化合物与N,N-二甲基硫代甲酰氯进行第二取代反应，得到具有式d所示结构的化合物。In the present invention, the compound represented by formula c is subjected to a second substitution reaction with N,N-dimethylthioformyl chloride to obtain the compound represented by formula d.
在本发明中，所述具有式c所示结构的化合物与N,N-二甲基硫代甲酰氯的摩尔比优选为1:0.8～1.2，更优选为1:1.1。在本发明中，所述第二取代反应的溶剂优选为甲苯。In the present invention, the molar ratio of the compound having the structure represented by formula c to N,N-dimethylthioformyl chloride is preferably 1:0.8-1.2, more preferably 1:1.1. In the present invention, the solvent for the second substitution reaction is preferably toluene.
在本发明中，所述第二取代反应的温度优选为120℃，时间优选为3～8h，更优选为4～6h。In the present invention, the temperature of the second substitution reaction is preferably 120°C, and the time is preferably 3-8 hours, more preferably 4-6 hours.
在本发明中，所述第二取代反应后，本发明优选对所得取代反应液进行后处理，所述后处理优选包括以下步骤：In the present invention, after the second substitution reaction, the present invention preferably performs post-treatment on the obtained substitution reaction solution, and the post-treatment preferably includes the following steps:
对所述第二取代反应液依次进行固液分离，所得液体进行浓缩和柱层析，得到具有式d所示结构的化合物纯品。The second substitution reaction liquid is sequentially subjected to solid-liquid separation, and the obtained liquid is subjected to concentration and column chromatography to obtain a pure compound having a structure represented by formula d.
在本发明中，所述固液分离的方式优选为抽滤，所述浓缩的方式优选为蒸发浓缩。在本发明中，所述柱层析的固定相优选为C18填料，流动相优选为甲醇、水。In the present invention, the method of solid-liquid separation is preferably suction filtration, and the method of concentration is preferably evaporation concentration. In the present invention, the stationary phase of the column chromatography is preferably C18 packing, and the mobile phase is preferably methanol and water.
在本发明中，在碱性条件下，具有式b所示化合物与具有式d所示结构化合物进行成环反应，得到具有式e所示结构的化合物。In the present invention, under basic conditions, the compound represented by formula b and the compound represented by formula d undergo a ring-forming reaction to obtain the compound represented by formula e.
在本发明中，所述具有式b所示化合物与具有式d所示结构化合物的摩尔比优选为1:0.8～1.5，更优选为1:1。在本发明中，所述成环反应的溶剂优选为无水乙醇。In the present invention, the molar ratio of the compound represented by formula b to the compound represented by formula d is preferably 1:0.8-1.5, more preferably 1:1. In the present invention, the solvent for the cyclization reaction is preferably absolute ethanol.
在本发明中，提供所述碱性条件的碱性试剂为碱金属碳酸盐、碱金属氢化物、碱金属氢氧化物中的一种或几种；在本发明中，所述碱金属碳酸盐优选为碳酸钾、碳酸铯、碳酸锂和碳酸钠中的一种或几种；所述碱金属氢化物优选为氢化钠；所述碱金属氢氧化物优选为氢氧化钠、氢氧化锂和氢氧化钾中的一种或几种。In the present invention, the alkaline reagent providing the basic condition is one or more of alkali metal carbonate, alkali metal hydride, alkali metal hydroxide; in the present invention, the alkali metal carbon The acid salt is preferably one or more of potassium carbonate, cesium carbonate, lithium carbonate and sodium carbonate; the alkali metal hydride is preferably sodium hydride; the alkali metal hydroxide is preferably sodium hydroxide, lithium hydroxide and one or more of potassium hydroxide.
在本发明中，所述具有式b所示化合物与碱性试剂的摩尔比优选为1:1～5，更优选为1:2。In the present invention, the molar ratio of the compound represented by formula b to the basic reagent is preferably 1:1-5, more preferably 1:2.
本发明优选先将具有式b所示化合物与具有式d所示结构化合物回流混合，再加入碱性试剂进行成环反应。在本发明中，所述回流混合的时间优选为3h。In the present invention, it is preferred to reflux and mix the compound represented by formula b and the compound represented by formula d, and then add a basic reagent to carry out the ring-forming reaction. In the present invention, the reflux mixing time is preferably 3 hours.
在本发明中，所述成环反应的温度优选为回流温度，时间优选为1.5h。In the present invention, the temperature of the ring-forming reaction is preferably reflux temperature, and the time is preferably 1.5 h.
在本发明中，所述成环反应后，本发明优选对所得成环反应液进行固液分离，所得固体为具有式e所示结构的化合物。在本发明中，所述固液分离的方式优选为抽滤。In the present invention, after the cyclization reaction, the present invention preferably performs solid-liquid separation on the obtained cyclization reaction liquid, and the obtained solid is a compound having the structure shown in formula e. In the present invention, the method of solid-liquid separation is preferably suction filtration.
在本发明中，在碱性条件下，具有式e所示结构的化合物与具有式f所示结构的化合物进行第三取代反应，得到具有式1所示结构的化合物。In the present invention, under basic conditions, the compound having the structure represented by formula e is subjected to a third substitution reaction with the compound having the structure represented by formula f to obtain the compound having the structure represented by formula 1.
在本发明中，所述具有式e所示结构的化合物与具有式f所示结构的化合物的摩尔比优选为1:0.8～1:5。In the present invention, the molar ratio of the compound having the structure represented by formula e to the compound having the structure represented by formula f is preferably 1:0.8˜1:5.
在本发明中，提供所述碱性条件的碱性试剂为碱金属碳酸盐、碱金属氢化物、碱金属氢氧化物中的一种或几种；在本发明中，所述碱金属碳酸盐优选为碳酸钾、碳酸铯、碳酸锂和碳酸钠中的一种或几种；所述碱金属氢化物优选为氢化钠；所述碱金属氢氧化物优选为氢氧化钠、氢氧化锂和氢氧化钾中的一种或几种。In the present invention, the alkaline reagent providing the basic condition is one or more of alkali metal carbonate, alkali metal hydride, alkali metal hydroxide; in the present invention, the alkali metal carbon The acid salt is preferably one or more of potassium carbonate, cesium carbonate, lithium carbonate and sodium carbonate; the alkali metal hydride is preferably sodium hydride; the alkali metal hydroxide is preferably sodium hydroxide, lithium hydroxide and one or more of potassium hydroxide.
在本发明中，所述具有式e所示结构的化合物与碱性试剂的摩尔比优选为1:1～5。In the present invention, the molar ratio of the compound having the structure represented by formula e to the basic reagent is preferably 1:1-5.
在本发明中，所述第三取代反应的溶剂优选为N,N-二甲基甲酰胺。In the present invention, the solvent for the third substitution reaction is preferably N,N-dimethylformamide.
在本发明中，所述第三取代反应的温度优选为室温，时间优选为0.5～2h，更优选为1h。In the present invention, the temperature of the third substitution reaction is preferably room temperature, and the time is preferably 0.5-2 hours, more preferably 1 hour.
在本发明中，所述第三取代反应后，本发明优选对所得第三取代反应液进行后处理，所述后处理优选包括：In the present invention, after the third substitution reaction, the present invention preferably performs post-treatment on the obtained third substitution reaction solution, and the post-treatment preferably includes:
将所述第三取代反应液与水混合，对所得混合液进行固液分离，得到具有式1所示结构的化合物固体。The third substitution reaction solution is mixed with water, and the resulting mixed solution is subjected to solid-liquid separation to obtain a solid compound having the structure shown in Formula 1.
在本发明中，所述固液分离的方式优选为抽滤。In the present invention, the method of solid-liquid separation is preferably suction filtration.
在本发明中，所述取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物和合成路线如式A所示：In the present invention, the substituted 4-phenyl-5-position functionalized 1,2,4-triazole derivatives and the synthesis route are shown in Formula A:
本发明提供了上述取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物在制备抗流感病毒药物中的应用。在本发明中，所述流感病毒优选包括甲型流感病毒和/或乙型流感病毒。The invention provides the application of the substituted 4-phenyl-5-position functionalized 1,2,4-triazole derivatives in the preparation of anti-influenza virus drugs. In the present invention, the influenza virus preferably includes influenza A virus and/or influenza B virus.
本发明提供了一种抗流感病毒药物组合物，包括具有式1所示结构的取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物或具有式1所示结构的取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物药学上可接受的盐。The present invention provides an anti-influenza virus pharmaceutical composition, comprising substituted 4-phenyl-5-position functionalized 1,2,4-triazole derivatives having the structure shown in formula 1 or having the structure shown in formula 1 A pharmaceutically acceptable salt of 1,2,4-triazole derivatives substituted at the 4-phenyl-5-position of the structure.
在本发明中，所述药学上可接受的盐优选包括衍生自无机酸、有机酸或无机碱的药学可接受的盐。In the present invention, the pharmaceutically acceptable salt preferably includes a pharmaceutically acceptable salt derived from an inorganic acid, an organic acid or an inorganic base.
在本发明中，所述有机酸优选为盐酸、氢溴酸、硫酸和磷酸中的一种或几种；所述有机酸优选为草酸、马来酸、琥珀酸和柠檬酸中的一种或几种。In the present invention, the organic acid is preferably one or more of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; the organic acid is preferably one or more of oxalic acid, maleic acid, succinic acid and citric acid Several kinds.
在本发明中，所述无机碱优选为金属阳离子的氢氧化物、碳酸盐和碳酸氢盐中的一种或几种；所述金属阳离子中的金属优选为锂、钠、钾、钙、镁和铝中的一种或几种。In the present invention, the inorganic base is preferably one or more of metal cation hydroxide, carbonate and bicarbonate; the metal in the metal cation is preferably lithium, sodium, potassium, calcium, One or more of magnesium and aluminum.
下面结合实施例对本发明提供的取代4-苯基-5-位官能团化的1,2,4-三唑类衍生物及其制备方法和应用进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。The substituted 4-phenyl-5-position functionalized 1,2,4-triazole derivatives provided by the present invention and their preparation methods and applications are described in detail below in conjunction with the examples, but they cannot be understood as a reference to the present invention. Limitation of the scope of protection.
实施例1Example 1
3-(((5-((2-氰基苄基)硫)-4-(2,6-二甲基苯基)-4H-1,2,4-三氮唑-3-基)亚甲基)硫)-1-甲基-1H-吲哚A1的制备3-(((5-((2-cyanobenzyl)thio)-4-(2,6-dimethylphenyl)-4H-1,2,4-triazol-3-yl)ylidene Preparation of methyl)thio)-1-methyl-1H-indole A1
1)化合物2的制备1) Preparation of Compound 2
将化合物1(2.5g，10mmol)(按照文献European Journal of MedicinalChemistry,2020,Volume 186,111861方法制备)溶于30mL乙醇，加入80％水合肼(7mL，110mmol)，95℃回流24h。蒸干溶剂反向柱层析的产物2(2.3g，98％)。Compound 1 (2.5 g, 10 mmol) (prepared according to European Journal of Medicinal Chemistry, 2020, Volume 186, 111861) was dissolved in 30 mL of ethanol, 80% hydrazine hydrate (7 mL, 110 mmol) was added, and refluxed at 95°C for 24 h. The product 2 (2.3 g, 98%) of the reverse column chromatography was evaporated to dryness.
1H NMR(500MHz,DMSO)δ9.00(s,1H),7.61(d,J＝7.9Hz,1H),7.50(s,1H),7.46(d,J＝8.2Hz,1H),7.21(t,J＝1.2Hz,1H),7.13(t,1H),4.17(s,2H),3.77(s,3H),3.22(s,2H). 1 H NMR (500MHz, DMSO) δ9.00(s, 1H), 7.61(d, J=7.9Hz, 1H), 7.50(s, 1H), 7.46(d, J=8.2Hz, 1H), 7.21( t,J=1.2Hz,1H),7.13(t,1H),4.17(s,2H),3.77(s,3H),3.22(s,2H).
2)化合物4的制备2) Preparation of compound 4
将2,6-二甲基苯胺(3.73g，30.86mmol)溶于30mL无水甲苯，加入N,N-二甲基硫代甲酰氯(4.2g，33.95mmol)，120℃回流3h，冷却到室温，抽滤取滤液，浓缩蒸干，柱层析得无色液体为产物4(4.5g，90％)。Dissolve 2,6-dimethylaniline (3.73g, 30.86mmol) in 30mL of anhydrous toluene, add N,N-dimethylthioformyl chloride (4.2g, 33.95mmol), reflux at 120°C for 3h, and cool to At room temperature, the filtrate was collected by suction filtration, concentrated and evaporated to dryness, and the product 4 (4.5 g, 90%) was obtained as a colorless liquid by column chromatography.
3)化合物5的制备3) Preparation of Compound 5
将化合物2(2.88g，12.27mmol)和化合物4(2g，12.27mmol)溶于25mL无水乙醇中，回流3h原料消失，冷却至室温，抽滤取滤液蒸干；加入2N氢氧化钠水溶液20mL，回流1.5mL。冷却至室温，抽滤得产物5(3.8g，82％)。Compound 2 (2.88g, 12.27mmol) and compound 4 (2g, 12.27mmol) were dissolved in 25mL of absolute ethanol, refluxed for 3h, the raw materials disappeared, cooled to room temperature, and the filtrate was taken by suction filtration and evaporated to dryness; adding 2N aqueous sodium hydroxide solution 20mL , reflux 1.5 mL. After cooling to room temperature, the product 5 (3.8 g, 82%) was obtained by suction filtration.
1H NMR(500MHz,DMSO)δ13.83(s,1H),7.47(d,J＝8.2Hz,1H),7.42(s,1H),7.39(t,J＝7.8Hz,1H),7.28(d,J＝7.6Hz,2H),7.24(d,J＝7.9Hz,1H),7.21(t,J＝7.6Hz,1H),7.07(t,J＝7.4Hz,1H),3.76(s,3H),3.53(s,2H),2.04(s,6H). 1 H NMR (500MHz, DMSO) δ13.83(s, 1H), 7.47(d, J=8.2Hz, 1H), 7.42(s, 1H), 7.39(t, J=7.8Hz, 1H), 7.28( d,J=7.6Hz,2H),7.24(d,J=7.9Hz,1H),7.21(t,J=7.6Hz,1H),7.07(t,J=7.4Hz,1H),3.76(s, 3H), 3.53(s, 2H), 2.04(s, 6H).
4)化合物A1的制备4) Preparation of compound A1
将化合物5(100mg，0.26mmol)溶于2mL无水N,N-二甲基甲酰胺，加入碳酸铯(129mg，0.40mmol)和2-氰基溴苄(51mg，0.26mmol)，室温反应1h。将反应液滴到50mL水中，大量白色固体析出抽滤取滤饼为产物A1(111mg，86％)。Compound 5 (100 mg, 0.26 mmol) was dissolved in 2 mL of anhydrous N,N-dimethylformamide, cesium carbonate (129 mg, 0.40 mmol) and 2-cyanobenzyl bromide (51 mg, 0.26 mmol) were added, and reacted at room temperature for 1 h . The reaction solution was dropped into 50 mL of water, a large amount of white solid precipitated out and the filter cake was collected by suction filtration as product A1 (111 mg, 86%).
1H NMR(500MHz,CDCl3)δ7.76(d,J＝7.8Hz,1H),7.62(d,J＝9.4Hz,1H),7.50(t,J＝3.8Hz,1H),7.35(d,J＝6.9,3.0Hz,2H),7.30(d,J＝8.1Hz,2H),7.27–7.20(m,2H),7.19(d,J＝7.6Hz,2H),7.09(t,J＝7.6Hz,2H),7.06(s,1H),4.69(s,2H),3.75(s,3H),3.70(s,2H),1.92(s,6H).13C NMR(101MHz,CDCl3)δ153.30,150.78,140.84,137.24,136.39,134.57,133.04,132.95,130.95,130.60,130.41,129.36,129.20(2C),128.29,122.39,120.27,118.86,117.20,112.70,109.75,102.03,33.98,33.09,30.35,29.74,17.79(2C). 1 H NMR (500MHz, CDCl 3 ) δ7.76(d, J=7.8Hz, 1H), 7.62(d, J=9.4Hz, 1H), 7.50(t, J=3.8Hz, 1H), 7.35(d ,J=6.9,3.0Hz,2H),7.30(d,J=8.1Hz,2H),7.27–7.20(m,2H),7.19(d,J=7.6Hz,2H),7.09(t,J= 7.6Hz,2H),7.06(s,1H),4.69(s,2H),3.75(s,3H),3.70(s,2H),1.92(s,6H). 13 C NMR(101MHz,CDCl3)δ153 .30,150.78,140.84,137.24,136.39,134.57,133.04,132.95,130.95,130.60,130.41,129.36,129.20(2C),128.29,122.39,120.27,118.86,117.20,112.70,109.75,102.03,33.98,33.09,30.35, 29.74,17.79(2C).
实施例2Example 2
3-(((5-((2-氟-6-氯苄基)硫)-4-(2,6-二甲基苯基)-4H-1,2,4-三氮唑-3-基)亚甲基)硫)-1-甲基-1H-吲哚A2的制备3-(((5-((2-fluoro-6-chlorobenzyl)sulfur)-4-(2,6-dimethylphenyl)-4H-1,2,4-triazole-3- Preparation of base)methylene)thio)-1-methyl-1H-indole A2
将实施例1中得到的化合物5(100mg，0.26mmol)溶于2mL无水N,N-二甲基甲酰胺，加入碳酸铯(129mg，0.40mmol)和2-氟-3-氯溴苄(75mg，0.26mmol)，室温反应1h。将反应液滴到50mL水中，大量白色固体析出抽滤取滤饼为产物A1(113mg，83％)。Compound 5 (100 mg, 0.26 mmol) obtained in Example 1 was dissolved in 2 mL of anhydrous N,N-dimethylformamide, cesium carbonate (129 mg, 0.40 mmol) and 2-fluoro-3-chlorobenzyl bromide ( 75mg, 0.26mmol), react at room temperature for 1h. The reaction solution was dropped into 50 mL of water, a large amount of white solid precipitated out and the filter cake was collected by suction filtration as product A1 (113 mg, 83%).
1H NMR(500MHz,CDCl3)δ7.37(t,J＝7.6Hz,1H),7.33(t,2H),7.28(d,J＝5.4Hz,1H),7.22(d,J＝7.5Hz,3H),7.18(dd,J＝8.3,1.7Hz,1H),7.13(d,J＝7.6Hz,1H),7.10(s,1H),6.99(t,J＝8.1Hz,1H),4.77(s,2H),3.78(s,3H),3.76(s,2H),2.07(s,6H). 1 H NMR (500MHz, CDCl 3 ) δ7.37(t, J=7.6Hz, 1H), 7.33(t, 2H), 7.28(d, J=5.4Hz, 1H), 7.22(d, J=7.5Hz ,3H),7.18(dd,J=8.3,1.7Hz,1H),7.13(d,J=7.6Hz,1H),7.10(s,1H),6.99(t,J=8.1Hz,1H),4.77 (s,2H),3.78(s,3H),3.76(s,2H),2.07(s,6H).
实施例3Example 3
3-(((5-((4-甲氧基苄基)硫)-4-(2,6-二甲基苯基)-4H-1,2,4-三氮唑-3-基)亚甲基)硫)-1-甲基-1H-吲哚A3的制备3-(((5-((4-methoxybenzyl)thio)-4-(2,6-dimethylphenyl)-4H-1,2,4-triazol-3-yl) Preparation of methylene)thio)-1-methyl-1H-indole A3
将实施例1中得到的化合物5(100mg，0.26mmol)溶于2mL无水N,N-二甲基甲酰胺，加入碳酸铯(129mg，0.40mmol)和4-甲氧基溴苄(52mg，0.26mmol)，室温反应1h。将反应液滴到50mL水中，大量白色固体析出抽滤取滤饼为产物A3(122mg，94％)。Compound 5 (100 mg, 0.26 mmol) obtained in Example 1 was dissolved in 2 mL of anhydrous N, N-dimethylformamide, cesium carbonate (129 mg, 0.40 mmol) and 4-methoxybenzyl bromide (52 mg, 0.26mmol), react at room temperature for 1h. The reaction solution was dropped into 50 mL of water, a large amount of white solids precipitated out and the filter cake was extracted by suction filtration as product A3 (122 mg, 94%).
1H NMR(500MHz,DMSO)δ7.45(d,J＝8.1Hz,1H),7.40(t,J＝7.7Hz,1H),7.34(s,1H),7.28(d,J＝2.8Hz,2H),7.26(d,J＝3.6Hz,2H),7.19(t,J＝7.6Hz,1H),7.14(d,J＝7.9Hz,1H),7.03(t,J＝7.4Hz,1H),6.84(d,J＝8.7Hz,2H),4.38(s,2H),3.75(s,3H),3.71(s,3H),3.68(s,2H),1.85(s,6H).13C NMR(101MHz,DMSO)δ159.11,152.53,150.59,137.40,136.36(2C),135.30,131.08,130.76,130.63(2C),129.46,129.41(2C),129.18,122.45,120.39,118.59,114.26(2C),110.90,101.01,55.56,35.38,33.11,30.18,17.68(2C)。 1 H NMR (500MHz, DMSO) δ7.45(d, J=8.1Hz, 1H), 7.40(t, J=7.7Hz, 1H), 7.34(s, 1H), 7.28(d, J=2.8Hz, 2H), 7.26(d, J=3.6Hz, 2H), 7.19(t, J=7.6Hz, 1H), 7.14(d, J=7.9Hz, 1H), 7.03(t, J=7.4Hz, 1H) ,6.84(d,J=8.7Hz,2H),4.38(s,2H),3.75(s,3H),3.71(s,3H),3.68(s,2H),1.85(s,6H) .13C NMR(101MHz,DMSO)δ159.11,152.53,150.59,137.40,136.36(2C),135.30,131.08,130.76,130.63(2C),129.46,129.41(2C),129.18,122.45,120.39,114.5 110.90, 101.01, 55.56, 35.38, 33.11, 30.18, 17.68 (2C).
实施例4Example 4
3-(((5-((3-氯-4-三氟甲氧基苄基)硫)-4-(2,6-二氯苯基)-4H-1,2,4-三氮唑-3-基)亚甲基)硫)-1-甲基-1H-吲哚A21的制备3-(((5-((3-chloro-4-trifluoromethoxybenzyl)sulfur)-4-(2,6-dichlorophenyl)-4H-1,2,4-triazole Preparation of -3-yl)methylene)thio)-1-methyl-1H-indole A21
1)化合物7的制备1) Preparation of Compound 7
将2,6-二氯苯胺(5.0g，30.86mmol)溶于30mL无水甲苯，加入N,N-二甲基硫代甲酰氯(4.2g，33.95mmol)，120℃回流8h，冷却到室温，抽滤取滤液，浓缩蒸干，柱层析得无色液体为产物7(6.3g，64％)。Dissolve 2,6-dichloroaniline (5.0g, 30.86mmol) in 30mL of anhydrous toluene, add N,N-dimethylthioformyl chloride (4.2g, 33.95mmol), reflux at 120°C for 8h, and cool to room temperature , the filtrate was taken by suction filtration, concentrated and evaporated to dryness, and the product 7 (6.3 g, 64%) was obtained as a colorless liquid by column chromatography.
2)化合物8的制备2) Preparation of Compound 8
将化合物2(2.88g，12.27mmol)和化合物7(2.5g，12.27mmol)溶于25mL无水乙醇中，回流6h原料消失，冷却至室温，抽滤取滤液蒸干；加入2N氢氧化钠水溶液20mL，回流1.5mL。冷却至室温，抽滤得产物8(5.1g，76％)。Compound 2 (2.88g, 12.27mmol) and compound 7 (2.5g, 12.27mmol) were dissolved in 25mL of absolute ethanol, refluxed for 6h, the raw materials disappeared, cooled to room temperature, and the filtrate was taken by suction filtration and evaporated to dryness; 2N aqueous sodium hydroxide solution was added 20mL, reflux 1.5mL. After cooling to room temperature, the product 8 (5.1 g, 76%) was obtained by suction filtration.
1H NMR(500MHz,DMSO)δ13.90(s,1H),7.77(d,J＝8.2Hz,2H),7.69–7.63(m,1H),7.47(d,J＝8.2Hz,1H),7.41(s,1H),7.36(d,J＝7.9Hz,1H),7.21(t,J＝7.7Hz,1H),7.09(t,J＝7.5Hz,1H),3.77(s,3H),3.64(s,2H)。 1 H NMR (500MHz, DMSO) δ13.90(s, 1H), 7.77(d, J=8.2Hz, 2H), 7.69–7.63(m, 1H), 7.47(d, J=8.2Hz, 1H), 7.41(s,1H),7.36(d,J=7.9Hz,1H),7.21(t,J=7.7Hz,1H),7.09(t,J=7.5Hz,1H),3.77(s,3H), 3.64(s,2H).
3)化合物A21的制备3) Preparation of Compound A21
将化合物8(110mg，0.26mmol)溶于2mL无水N,N-二甲基甲酰胺，加入碳酸铯(129mg，0.40mmol)和2-氯-4-三氟甲氧基溴苄(75mg，0.26mmol)，室温反应1h。将反应液滴到50mL水中，大量白色固体析出抽滤取滤饼为产物A21(134mg，82％)。Compound 8 (110 mg, 0.26 mmol) was dissolved in 2 mL of anhydrous N, N-dimethylformamide, cesium carbonate (129 mg, 0.40 mmol) and 2-chloro-4-trifluoromethoxybenzyl bromide (75 mg, 0.26mmol), react at room temperature for 1h. The reaction solution was dropped into 50 mL of water, a large amount of white solid precipitated out and the filter cake was collected by suction filtration as the product A21 (134 mg, 82%).
1H NMR(500MHz,DMSO)δ7.74(d,J＝8.2Hz,2H),7.66(t,1H),7.62(s,1H),7.46(dd,J＝12.5,8.3Hz,2H),7.40(d,J＝7.7Hz,1H),7.29(d,J＝3.0Hz,1H),7.26(d,J＝7.8Hz,1H),7.20(t,J＝7.6Hz,1H),7.05(t,J＝7.5Hz,1H),4.41(s,2H),3.78(s,2H),3.74(s,3H).13C NMR(101MHz,DMSO)δ153.14,150.39,143.61,143.59,139.56,137.44,135.51,133.94(2C),133.63,131.60,130.04(2C),129.91,129.14,128.37,126.16,123.49,122.43,120.39,118.51,110.94,100.39,35.32,33.11,30.18。 1 H NMR (500MHz, DMSO) δ7.74 (d, J = 8.2Hz, 2H), 7.66 (t, 1H), 7.62 (s, 1H), 7.46 (dd, J = 12.5, 8.3Hz, 2H), 7.40(d, J=7.7Hz, 1H), 7.29(d, J=3.0Hz, 1H), 7.26(d, J=7.8Hz, 1H), 7.20(t, J=7.6Hz, 1H), 7.05( t,J＝7.5Hz,1H),4.41(s,2H),3.78(s,2H),3.74(s,3H). 13 C NMR(101MHz,DMSO)δ153.14,150.39,143.61,143.59,139.56,137.44 .
实施例5Example 5
3-(((5-((2-三氟甲基-4-氯苄基)硫)-4-(2,6-二氯苯基)-4H-1,2,4-三氮唑-3-基)亚甲基)硫)-1-甲基-1H-吲哚A23的制备3-(((5-((2-trifluoromethyl-4-chlorobenzyl)sulfur)-4-(2,6-dichlorophenyl)-4H-1,2,4-triazole- Preparation of 3-yl)methylene)thio)-1-methyl-1H-indole A23
将实施例4中得到的化合物8(110mg，0.26mmol)溶于2mL无水N,N-二甲基甲酰胺，加入碳酸铯(129mg，0.40mmol)和2-三氟甲基-4-氯溴苄(71mg，0.26mmol)，室温反应1h。将反应液滴到50mL水中，大量白色固体析出抽滤取滤饼为产物A23(129mg，81％)。Compound 8 (110 mg, 0.26 mmol) obtained in Example 4 was dissolved in 2 mL of anhydrous N, N-dimethylformamide, cesium carbonate (129 mg, 0.40 mmol) and 2-trifluoromethyl-4-chloro Benzyl bromide (71 mg, 0.26 mmol) was reacted at room temperature for 1 h. The reaction solution was dropped into 50 mL of water, a large amount of white solid precipitated out and the filter cake was collected by suction filtration as the product A23 (129 mg, 81%).
1H NMR(500MHz,DMSO)δ7.77(d,J＝2.6Hz,2H),7.75(s,1H),7.72(dd,J＝8.2,2.2Hz,1H),7.67(d,J＝7.4Hz,1H),7.64(t,J＝6.5Hz,1H),7.45(d,J＝8.2Hz,1H),7.32(s,1H),7.27(d,J＝7.9Hz,1H),7.20(t,J＝7.6Hz,1H),7.06(t,J＝7.5Hz,1H),4.52(s,2H),3.81(s,2H),3.75(s,3H).13C NMR(101MHz,DMSO)δ153.36,150.04,137.44,135.57,134.41,134.39,134.33,133.92,133.68,133.53,133.21,130.07(2C),129.15,128.28,126.75,126.69,125.07,122.44,120.40,118.51,110.95,100.33,33.40,33.12,30.17. 1 H NMR (500MHz, DMSO) δ7.77(d, J=2.6Hz, 2H), 7.75(s, 1H), 7.72(dd, J=8.2, 2.2Hz, 1H), 7.67(d, J=7.4 Hz, 1H), 7.64(t, J=6.5Hz, 1H), 7.45(d, J=8.2Hz, 1H), 7.32(s, 1H), 7.27(d, J=7.9Hz, 1H), 7.20( t, J=7.6Hz, 1H), 7.06(t, J=7.5Hz, 1H), 4.52(s, 2H), 3.81(s, 2H), 3.75(s, 3H). 13 C NMR (101MHz, DMSO )δ153.36,150.04,137.44,135.57,134.41,134.39,134.33,133.92,133.68,133.53,133.21,130.07(2C),129.15,128.28,126.75,126.69,125.07,122.44,120.40,118.51,110.95,100.33,33.40, 33.12, 30.17.
实施例6Example 6
3-(((5-((2-三氟甲氧基苄基)硫)-4-苯基-4H-1,2,4-三氮唑-3-基)亚甲基)硫)-1-甲基-1H-吲哚A64的制备3-(((5-((2-trifluoromethoxybenzyl)sulfur)-4-phenyl-4H-1,2,4-triazol-3-yl)methylene)sulfur)- Preparation of 1-methyl-1H-indole A64
1)化合物10的制备1) Preparation of Compound 10
将苯胺(2.9g，30.86mmol)溶于30mL无水甲苯，加入N,N-二甲基硫代甲酰氯(4.2g，33.95mmol)，120℃回流4h，冷却到室温，抽滤取滤液，浓缩蒸干，柱层析得无色液体为产物4(3.5g，83％)。Dissolve aniline (2.9g, 30.86mmol) in 30mL of anhydrous toluene, add N,N-dimethylthioformyl chloride (4.2g, 33.95mmol), reflux at 120°C for 4h, cool to room temperature, and filter the filtrate. Concentrated and evaporated to dryness, the product 4 (3.5 g, 83%) was obtained as a colorless liquid by column chromatography.
2)化合物11的制备2) Preparation of compound 11
将化合物2(2.9g，12.27mmol)和化合物7(1.7g，12.27mmol)溶于25mL无水乙醇中，回流5h原料消失，冷却至室温，抽滤取滤液蒸干；加入2N氢氧化钠水溶液20mL，回流1.5mL。冷却至室温，抽滤得产物11(3.5g，81％)。Compound 2 (2.9g, 12.27mmol) and compound 7 (1.7g, 12.27mmol) were dissolved in 25mL of absolute ethanol, refluxed for 5h, the raw materials disappeared, cooled to room temperature, and the filtrate was taken by suction filtration and evaporated to dryness; adding 2N aqueous sodium hydroxide solution 20mL, reflux 1.5mL. After cooling to room temperature, the product 11 was obtained by suction filtration (3.5 g, 81%).
1H NMR(500MHz,DMSO)δ13.65(s,1H),7.50(td,J＝5.2,1.8Hz,3H),7.46(d,J＝8.2Hz,1H),7.38(s,1H),7.31(t,2H),7.25(d,J＝7.9Hz,1H),7.20(t,J＝7.6Hz,1H),7.07(t,J＝7.5Hz,1H),3.75(s,3H),3.71(s,2H)。 1 H NMR (500MHz, DMSO) δ13.65(s, 1H), 7.50(td, J=5.2, 1.8Hz, 3H), 7.46(d, J=8.2Hz, 1H), 7.38(s, 1H), 7.31(t,2H),7.25(d,J=7.9Hz,1H),7.20(t,J=7.6Hz,1H),7.07(t,J=7.5Hz,1H),3.75(s,3H), 3.71(s,2H).
3)化合物A64的制备3) Preparation of Compound A64
将化合物11(92mg，0.26mmol)溶于2mL无水N,N-二甲基甲酰胺，加入碳酸铯(129mg，0.40mmol)和2-三氟甲氧基溴苄(66mg，0.26mmol)，室温反应1h。将反应液滴到50mL水中，大量白色固体析出抽滤取滤饼为产物A64(129mg，81％)。Compound 11 (92 mg, 0.26 mmol) was dissolved in 2 mL of anhydrous N,N-dimethylformamide, cesium carbonate (129 mg, 0.40 mmol) and 2-trifluoromethoxybenzyl bromide (66 mg, 0.26 mmol) were added, Reaction at room temperature for 1h. The reaction solution was dropped into 50 mL of water, a large amount of white solid precipitated out and the filter cake was extracted by suction filtration as the product A64 (129 mg, 81%).
1H NMR(500MHz,DMSO)δ7.49(t,J＝8.3Hz,2H),7.45(d,2H),7.42(d,J＝7.6Hz,2H),7.33(t,J＝7.8Hz,2H),7.28(s,1H),7.19(t,J＝7.6Hz,1H),7.11(d,J＝7.9Hz,1H),7.03(t,J＝7.6Hz,2H),6.99(d,J＝7.5Hz,1H),4.33(s,2H),3.84(s,2H),3.72(s,3H).13CNMR(101MHz,DMSO)δ153.97,149.93,147.10,137.37,135.64,133.02,132.04,130.21,130.13,129.97(2C),129.69,129.64,127.88,127.44(2C),122.36,120.74,120.35,119.24,118.53,110.80,100.54,33.05,31.34,30.44。 1 H NMR (500MHz, DMSO) δ7.49(t, J=8.3Hz, 2H), 7.45(d, 2H), 7.42(d, J=7.6Hz, 2H), 7.33(t, J=7.8Hz, 2H), 7.28(s, 1H), 7.19(t, J=7.6Hz, 1H), 7.11(d, J=7.9Hz, 1H), 7.03(t, J=7.6Hz, 2H), 6.99(d, J＝7.5Hz,1H),4.33(s,2H),3.84(s,2H),3.72(s,3H). 13 CNMR(101MHz,DMSO)δ153.97,149.93,147.10,137.37,135.64,133.02,132.04, 130.21, 130.13, 129.97(2C), 129.69, 129.64, 127.88, 127.44(2C), 122.36, 120.74, 120.35, 119.24, 118.53, 110.80, 100.54, 33.05, 31.34, 30.44.
性能测试Performance Testing
体外抗病毒活性的评价及细胞毒性实验Evaluation of Antiviral Activity in Vitro and Cytotoxicity Experiment
以293T-GLUC细胞为病毒宿主，测定样品抑制甲型流感病毒携带报告基因荧光素酶活性。Using 293T-GLUC cells as the virus host, the samples were determined to inhibit the luciferase activity of the reporter gene carried by influenza A virus.
病毒株：感染MDCK细胞获得IAV(滴度107)，-80℃保存。Virus strain: Infect MDCK cells to obtain IAV (titer 10 7 ), and store at -80°C.
样品处理：样品溶于DMSO配成适宜初始浓度，再用培养液稀释，各5个稀释度。Sample treatment: The sample was dissolved in DMSO to make an appropriate initial concentration, and then diluted with culture medium, each with 5 dilutions.
测试方法：293T-GLUC细胞接种96孔培养板，置5％CO2，37℃培养24小时。预先加入药物孵育2小时，然后将病毒原毒稀释以MOI＝0.3接种病毒。培养24小时后，测定感染细胞中荧光素酶活性，计算各样品的抑制率和EC50。实验重复三次，所得结果见表2。Test method: 293T-GLUC cells were inoculated in a 96-well culture plate, placed in 5% CO 2 , and cultured at 37°C for 24 hours. Drugs were added in advance to incubate for 2 hours, and then the original virus was diluted to inoculate the virus at MOI=0.3. After culturing for 24 hours, the luciferase activity in the infected cells was measured, and the inhibition rate and EC 50 of each sample were calculated. The experiment was repeated three times, and the results are shown in Table 2.
采用CCK-8(CellCountingKit-8)试剂盒进行检测。HEK293T细胞接种于96孔板，每孔2.5×104个细胞，于100μL含10％FBS的DMEM培养液中培养。细胞铺板24h后每孔加入1μL梯度稀释的待测化合物，37℃孵育24h。每孔加入10μLCCK-8试剂，37℃继续孵育1～2个小时后，使用Enspire2300多功能酶标仪检测各孔在450nm波长处的光吸收值，用以计算半数细胞毒性浓度CC50(指致使50％细胞死亡的药物浓度)。实验重复三次，所得结果见表2。CCK-8 (CellCountingKit-8) kit was used for detection. HEK293T cells were seeded in a 96-well plate with 2.5×104 cells per well and cultured in 100 μL of DMEM medium containing 10 % FBS. 24 hours after the cells were plated, 1 μL of the compound to be tested was added to each well and incubated at 37°C for 24 hours. Add 10μLCCK-8 reagent to each well, and continue to incubate at 37°C for 1 to 2 hours. Use the Enspire2300 multifunctional microplate reader to detect the light absorption value of each well at a wavelength of 450nm, and use it to calculate the half cytotoxic concentration CC 50 (referring to causing drug concentration for 50% cell death). The experiment was repeated three times, and the results are shown in Table 2.
表2中列出了本发明的式1中部分衍生物对甲型流感病毒的抑制作用和毒性。其中阳性对照药物利巴韦林(ribavirin)作为对比例。Table 2 lists the inhibitory effect and toxicity of some derivatives in formula 1 of the present invention on influenza A virus. Wherein the positive control drug ribavirin (ribavirin) was used as a comparative example.
表2部分衍生物的体外抗流感病毒活性和细胞毒作用Table 2 In vitro anti-influenza virus activity and cytotoxicity of some derivatives
实验结果表明，表1中所有测试化合物均对甲型流感病毒有显著抑制作用，大多数化合物在细胞水平上活性优于阳性对照药物利巴韦林，这说明该类结构具有进一步研究价值。The experimental results showed that all the tested compounds in Table 1 had a significant inhibitory effect on influenza A virus, and most of the compounds were more active than the positive control drug ribavirin at the cellular level, which indicated that this type of structure had further research value.
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。The above is only a preferred embodiment of the present invention, it should be pointed out that, for those of ordinary skill in the art, without departing from the principle of the present invention, some improvements and modifications can also be made, and these improvements and modifications can also be made. It should be regarded as the protection scope of the present invention.
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| CN1930132A (en) * | 2004-03-08 | 2007-03-14 | 惠氏公司 | Ion channel modulators |
| WO2009011850A2 (en) * | 2007-07-16 | 2009-01-22 | Abbott Laboratories | Novel therapeutic compounds |
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