CN107226810B - Indole derivatives, process for producing the same and anti-influenza virus effect thereof - Google Patents

Indole derivatives, process for producing the same and anti-influenza virus effect thereof Download PDF

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CN107226810B
CN107226810B CN201710454575.4A CN201710454575A CN107226810B CN 107226810 B CN107226810 B CN 107226810B CN 201710454575 A CN201710454575 A CN 201710454575A CN 107226810 B CN107226810 B CN 107226810B
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influenza
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ethyl acetate
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CN107226810A (en
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徐海伟
王振亚
刘宏民
张国臣
王聪聪
胡晓宁
张月影
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Zhengzhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The invention relates to the field of medicinal chemistry, and discloses a compound of general formula I,
Figure DEST_PATH_IMAGE001
、
Figure 48016DEST_PATH_IMAGE002
The novel indole compounds represented by the general formula, the preparation method thereof and the function of resisting influenza virus, particularly show good anti-influenza activity on the aspect of resisting H1N1 influenza virus, have simple synthesis method and high yield, and the total yield reaches more than 67%. Enriches the indole anti-influenza virus compounds and is beneficial to the development of new drugs.

Description

Indole derivatives, process for producing the same and anti-influenza virus effect thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to novel indole compounds, a preparation method thereof and application thereof in resisting influenza viruses, particularly H1N 1.
Background
Influenza is a serious public health problem, with high morbidity in humans, often resulting in massive morbidity and mortality. It is a highly contagious disease that is airborne and causes acute febrile symptoms. General symptoms from mild fatigue to expirationInhalation failure can even cause death. According to the statistics of the world health organization, the average burden of global epidemics is about 10 hundred million every year, and 3-5 million serious diseases and
Figure BDA0001323610810000012
Figure BDA0001323610810000011
ten thousand death cases. Influenza viruses are transmitted annually within the population, often affecting 5-20% of all age groups, and this figure rises to 30% when major infections occur. At age>65 years old or aged<Children 2 years of age, and people of any age who have chronic heart disease, pulmonary, renal, hepatic blood or metabolic disease, or an impaired immune system that increases the risk of influenza complications, have the highest probability of acquiring serious illness and death. Although the number of deaths among children is small, the hospitalization rate of children under 5 years old is 10 ten thousand per year
Figure BDA0001323610810000013
Right and left of the human. The hospitalization rate of children under 2 years of age is comparable to those over 65 years of age. The causative agent of influenza is a mononegavirale RNA virus belonging to the family orthomyxoviridae. Influenza viruses are classified into three types a (a), B (B), and C (C), with influenza a virus being the most common subtype that can be transmitted in mammals and birds. The nomenclature of the influenza A virus subtypes is determined by the type of surface proteins hemagglutinin (H) and neuraminidase (N). There are 18 different hemagglutinins and 11 known neuraminidases. The current seasonal influenza viruses exist in humans primarily as subtypes H1N1 and H3N 2. Influenza B viruses are usually present only in humans and they are not of subtype but can be further subdivided into different strains. Influenza viruses vary widely every year, and both influenza a and B cause seasonal epidemics around the world. Influenza C virus has much milder symptoms and does not cause epidemics.
All three viruses have similar genome structures, and the genome contains 8 segments, encoding 9-11 proteins, depending on the virus type. Influenza a encodes 11 proteins, including the surface proteins Hemagglutinin (HA) and Neuraminidase (NA), the polymerase complex (PA, PB1 and PB2), the Nucleoprotein (NP), the membrane proteins (M1 and M2) and other proteins (NS1, NS2, NEP). Among the three influenza viruses, influenza a has the highest mutation rate, and influenza B evolves slower than a but faster than C. Segmenting the genome allows gene exchange between different virus strains, resulting in the generation of new variants of influenza virus. Influenza viruses can be transmitted in humans by direct contact with infected individuals or viral contaminants. The body can also be reinfected by inhalation of suspended viral droplets, which are produced by coughing, sneezing or speaking in infected individuals. Seasonal influenza is characterized by sudden high fever, coughing (usually dry), headache, muscle and joint pain, severe discomfort (sensory discomfort), sore throat and runny nose. Cough can be severe and can last for more than two weeks, with most people recovering from symptoms such as fever within a week without medical attention. Influenza can cause serious illness or death, particularly in high risk groups.
The time from infection to onset, called latency, is approximately two days. The most effective method for preventing this disease is vaccination. Safe and effective vaccines have been used for over 60 years. In healthy adults, influenza vaccines can provide reasonable protection. However, vaccination has several limitations: first, influenza vaccines are less effective in preventing disease in the elderly, and only reduce the severity of the disease, complications, and incidence of death. Furthermore, influenza vaccination is most effective when the epidemic virus is well matched to the vaccine virus, and the success of the vaccine depends largely on good predictions of the most prevalent virus type. The rapid and continuous evolution of influenza strains coupled with the immune response elicited by the vaccine through antigenic drift makes current influenza vaccines short lived, meaning that seasonal appropriate strains need to be vaccinated for prophylaxis each year.
Current influenza treatments either use antiviral drugs directly or use other drugs to alleviate symptoms caused by influenza. There are two types of influenza antiviral drugs on the market: neuraminidase inhibitors and M2 channel inhibitors. The neuraminidase inhibitors oseltamivir (tamiflu) or zanamivir are the main antiviral drugs recommended for the prevention and treatment of influenza. These drugs are effective against both influenza a and B viruses. In the treatment of seasonal influenza, resistance to these antiviral drugs, and sporadic 2009 oseltamivir-resistant H1N1 virus, have been found, but the impact on public health has been limited to date. M2 channel inhibitors, such as amantadine and rimantadine, are effective against influenza a strains but not against influenza B strains. The adamantane resistance of influenza a viruses has increased rapidly worldwide during the year 2003-2004. Thus, amantadine and rimantadine are not recommended for antiviral treatment or chemoprevention of currently prevalent influenza a virus strains. In 2009, a novel porcine H1N1 virus strain, which was genetically recombined from human, porcine, avian H1N1 viruses, resulted in an unexpected pandemic of influenza. The pandemic, the continuous epidemic of the highly pathogenic avian influenza H5N1 strain and the recently appeared H7N9 virus are all from avian-derived recombinant strains in China, are related to severe respiratory diseases with 40% mortality, and can possibly cause interpersonal transmission, thereby illustrating the vulnerability of the new influenza virus strain to the humanity. Although vaccination remains the primary prophylactic strategy for controlling influenza infection, a wider choice of anti-influenza drugs is required to compensate for the treatment of severe influenza conditions during the period before a new vaccine is available and to combat viral resistance problems. Thus, the development of new influenza antiviral drugs is again an urgent and unmet medical need.
Disclosure of Invention
The invention aims to provide novel anti-influenza virus indole compounds; another object is to provide a process for the preparation thereof.
The indole compound is shown in the following general formulas I, II and III:
Figure BDA0001323610810000031
r is
Figure BDA0001323610810000032
Ph-、4-F-Ph-、3-F-Ph-、4-CH3-Ph-、3-CH3-Ph-、2-CH3-Ph-、3，5-2CH3-Ph-、2，4，6-3CH3-Ph-、4-C6H5-Ph-、
Figure BDA0001323610810000033
Figure BDA0001323610810000034
And the like, saturated or unsaturated carbocyclic and heterocyclic ring structures.
Preferably:
r is
Figure BDA0001323610810000041
Ph-、4-F-Ph-、3-F-Ph-、4-CH3-Ph-、3-CH3-Ph-、2-CH3-Ph-、3，5-2CH3-Ph-、2，4，6-3CH3-Ph-、4-C6H5-Ph-、
Figure BDA0001323610810000042
Figure BDA0001323610810000043
One kind of (1).
The following compounds are preferred:
Figure BDA0001323610810000044
more preferably: compounds I-2, I-3, I-4.
A process for the preparation of a compound of formula I, II, III:
Figure BDA0001323610810000045
preparation method of compound shown as general formula I
The preparation method of the general formula I comprises two steps: in the first step, 5-chloroindole is used as a raw material and reacts with p-fluorobenzyl chloride in a solvent at room temperature in the presence of alkali to obtain an intermediate 2. Wherein the used alkali is one of sodium hydride, calcium hydride, sodium carbonate, triethylamine, pyridine and the like, and the equivalent ratio of the 5 chloroindole to the alkali is 1: 1 to 1.6; the solvent is one of acetonitrile, tetrahydrofuran, dichloromethane, DMF, etc. The obtained product is separated by column chromatography to obtain an intermediate 2.
And secondly, reacting the intermediate 2 with acyl chloride in a solvent at room temperature in the presence of Lewis acid to prepare the compound shown in the general formula I. Wherein the Lewis acid is one of aluminum trichloride, ferric trichloride, titanium tetrachloride, zinc dichloride, stannic chloride and the like, and the equivalent ratio of the 5-chloroindole to the Lewis acid is 1: 1 to 1.8; the solvent is one of dichloromethane, chloroform, dichloroethane, tetrahydrofuran, etc. The obtained product can be purified by appropriate method such as column chromatography or recrystallization to obtain pure product. The solvent used for recrystallization is one or a mixture of two of ethanol, methanol, acetonitrile, ethyl acetate, dichloromethane and chloroform.
Figure BDA0001323610810000051
Process for the preparation of compounds of the general formula II
A process for preparing a compound of formula II: the compound is obtained by reducing a compound shown as a general formula I in a solvent by sodium borohydride in the presence of a base, wherein the equivalent ratio of a substrate to the reducing agent sodium borohydride is 1: 1 to 3. Wherein the used alkali is one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine and the like, and the equivalent ratio of the substrate to the alkali is 1: 1 to 3. The solvent is one or mixture of methanol, ethanol, propanol, etc. The reaction temperature is 0-90 ℃. The final product can be obtained by column chromatography separation of the obtained product.
Figure BDA0001323610810000052
Process for the preparation of compounds of the general formula III
The preparation of the general formula III is carried out in three steps: in the first step, 5-chloroindole reacts with acetyl chloride in a solvent in the presence of Lewis acid to prepare an intermediate 3. Wherein the Lewis acid is one of aluminum trichloride, ferric trichloride, titanium tetrachloride, zinc dichloride, stannic chloride and the like, and the equivalent ratio of 5-chloroindole to Lewis acid is 1: 1-3; the solvent is one of dichloromethane, chloroform, dichloroethane, toluene, tetrahydrofuran, etc. The reaction temperature is 0-90 ℃. The obtained product can be purified by appropriate method such as column chromatography or recrystallization to obtain pure product. The solvent used for recrystallization is one or two of ethanol, methanol, acetonitrile, ethyl acetate, dichloromethane and chloroform.
And secondly, taking the intermediate 3 as a raw material, and reacting the raw material with p-fluorobenzyl chloride in a solvent at room temperature in the presence of alkali to obtain an intermediate 4. Wherein the used base is one of sodium hydride, calcium hydride, sodium carbonate, triethylamine, pyridine and the like, and the equivalent ratio of the intermediate 3 to the base is 1: 1 to 1.6; the solvent is one of acetonitrile, tetrahydrofuran, dichloromethane, DMF, etc. The obtained product can be purified by appropriate method such as column chromatography or recrystallization to obtain pure product. The solvent used for recrystallization is one or a mixture of two of ethanol, methanol, acetonitrile, ethyl acetate, dichloromethane and chloroform.
And thirdly, taking the intermediate 4 as a raw material, and reacting the raw material with various aldehydes in a solvent in the presence of alkali to obtain the compound in the general formula III. Wherein the used alkali is one of sodium hydride, calcium hydride, sodium carbonate, triethylamine, pyridine, sodium hydroxide and the like, and the equivalent ratio of the intermediate 4 to the alkali is 1: 1 to 2.5; the solvent is one of acetonitrile, tetrahydrofuran, dichloromethane, DMF, methanol, etc. The reaction temperature is 0-90 ℃. And separating the obtained product by column chromatography to obtain a compound III.
The innovation points of the invention are as follows: synthesizes a novel indole derivative which shows good anti-influenza (H1N1) activity, enriches indole anti-influenza virus compounds and is beneficial to the development of new drugs. The synthesis method is simple, the yield is high, and the total yield reaches more than 67%.
Detailed Description
To better illustrate the invention, the following examples are given:
EXAMPLE 1 preparation of intermediate 2 in the Synthesis of Compounds of formula I
Figure BDA0001323610810000061
Taking 5-chloroindole (5mmol) and NaH (15mmol) to a 25mL round-bottom flask, adding 6mL anhydrous acetonitrile, stirring at room temperature for 1h, slowly dropwise adding p-fluorobenzyl chloride (6.5mmol) dissolved by the anhydrous acetonitrile into a reaction system, reacting at room temperature for 5-7h, monitoring the reaction completion by TLC, filtering to remove insoluble solids, concentrating the filtrate under vacuum, and carrying out silica gel column chromatography elution separation, wherein an eluent and the proportion thereof are petroleum ether: ethyl acetate 12:1 as a viscous pale yellow liquid, after lyophilization treatment, the product was 2 as a white solid in 94.6% yield.
Example 2 Synthesis of Compounds of formula I, R-4-CH3C6H5Preparation of-situ I-1
Figure BDA0001323610810000071
Taking AlCl3(2mmol) is added into a beaker, 8mL of anhydrous dichloromethane is added, stirring is carried out at the room temperature of 25 ℃, 4-methylbenzoyl chloride (2mmol) is added, stirring is carried out at the room temperature of 25 ℃ for 1h, compound 2(2mmol,1.5mL of anhydrous dichloromethane is dissolved) is dropwise added into the reaction system, and the reaction is carried out at the room temperature of 25 ℃ for 12 h. TLC to monitor the reaction completion, rotary evaporation under reduced pressure to remove dichloromethane, extraction with water and ethyl acetate, combination of organic phases and drying over anhydrous magnesium sulfate. The magnesium sulfate was removed by suction filtration, and the filtrate was concentrated, petroleum ether: recrystallization from ethyl acetate 4:1 gave I-1 as a pale yellow solid in 89.2% yield. m.p.126.0-129.1 deg.C;1H NMR(400MHz,DMSO)δ8.34(s,1H),8.24(d,J＝2.1Hz,1H),7.73(d,J＝8.0Hz,2H),7.58(d,J＝8.8Hz,1H),7.39–7.32(m,4H),7.28(dd,J＝8.7,1.9Hz,1H),7.13(dd,J＝17.5,8.7Hz,2H),5.53(s,2H),2.40(s,3H)；13C NMR(101MHz,DMSO)δ189.14,162.80,160.38,141.49,139.64,137.20,134.89,129.44,129.03,128.59,128.19,127.15,123.28,120.86,115.60,115.38,113.91,112.93,49.08,21.03.HRMS(ESI):m/z calcdfor C23H17ClFNO(M+H)+，378.1061；found，378.1066.。
example 3 in the synthesis of compounds of general formula I,
Figure BDA0001323610810000072
preparation of intermediate I-2
Figure BDA0001323610810000073
Taking AlCl3(2mmol) is added into a beaker, 8mL of anhydrous dichloromethane is added, stirring is carried out at the room temperature of 25 ℃, 3-methylthiophene-2-carbonyl chloride (2mmol) is added, stirring is carried out at the room temperature of 25 ℃ for 1h, compound 2(2mmol,1.5mL of anhydrous dichloromethane are dropwise added into the reaction system for dissolving), and the reaction is carried out at the room temperature of 25 ℃ for 12 h. TLC to monitor the reaction completion, rotary evaporation under reduced pressure to remove dichloromethane, extraction with water and ethyl acetate, combination of organic phases and drying over anhydrous magnesium sulfate. The magnesium sulfate was removed by suction filtration, and the filtrate was concentrated, petroleum ether: recrystallization from ethyl acetate 4:1 gave I-2 as a white solid in 92.8% yield. m.p.123.5-125.1 deg.C;1H NMR(400MHz,Acetone)δ8.37(d,J＝2.0Hz,1H),8.32(s,1H),7.62(d,J＝5.0Hz,1H),7.57(d,J＝8.8Hz,1H),7.44–7.38(m,2H),7.28(dd,J＝8.8,2.1Hz,1H),7.13(ddd,J＝10.9,5.9,2.5Hz,2H),7.08(d,J＝5.0Hz,1H),5.63(s,2H),2.49(s,3H)；13C NMR(101MHz,DMSO)δ181.77,162.85,160.42,142.14,138.68,134.93,132.92,131.90,129.52,129.27,127.96,127.16,123.42,120.74,115.64,115.43,112.99,49.03,15.81.HRMS(ESI):m/z calcd forC21H15ClFNOS(M+H)+，384.0625；found，384.0625.。
example 4 in the synthesis of compounds of general formula I,
Figure BDA0001323610810000081
preparation of intermediate I-3
Figure BDA0001323610810000082
Taking ZnCl2(2mmol) in the flaskIn a cup, 8mL of anhydrous tetrahydrofuran is added, stirring is carried out at room temperature of 25 ℃, 5-chloro-2-pyridine carbonyl chloride (2mmol) is added, stirring is carried out at room temperature of 25 ℃ for 1h, compound 2(2mmol,1.5mL of anhydrous tetrahydrofuran is dissolved) is dropwise added into the reaction system, and stirring is carried out at room temperature of 25 ℃ for 12 h. TLC to monitor the reaction is complete, decompression rotary evaporation to remove tetrahydrofuran, water and ethyl acetate extraction, organic phase combination, anhydrous magnesium sulfate drying. The magnesium sulfate was removed by suction filtration, and the filtrate was concentrated, petroleum ether: recrystallization from ethyl acetate 4:1 gave I-3 as a white solid in 67.4% yield. m.p.138.3-141.2 deg.C;1H NMR(400MHz,DMSO)δ8.52(d,J＝2.1Hz,1H),7.94(dd,J＝8.5,2.5Hz,1H),7.70(d,J＝8.5Hz,1H),7.56(d,J＝2.0Hz,1H),7.45(d,J＝8.7Hz,1H),7.40(s,1H),7.29–7.21(m,2H),7.17–7.10(m,2H),7.08(dd,J＝8.7,2.1Hz,1H),6.06(d,J＝4.6Hz,1H),5.95(d,J＝4.3Hz,1H),5.35(s,2H)；13C NMR(101MHz,DMSO)δ184.55,160.40,153.80,147.13,141.90,137.41,134.49,133.86,129.33,128.70,127.58,124.45,123.35,121.04,115.67,115.45,113.01,112.46,49.18.HRMS(ESI):m/z calcd for C21H13Cl2FN2O(M+Na)+，421.0287；found，421.0289。
example 5 in the synthesis of compounds of general formula I,
Figure BDA0001323610810000083
preparation of intermediate I-4
Figure BDA0001323610810000091
Taking TiCl4(2mmol) is added into a beaker, 8mL of anhydrous chloroform is added, stirring is carried out at the room temperature of 25 ℃, 4-pyridine formyl chloride (2mmol) is added, stirring is carried out at the room temperature of 25 ℃ for 1h, compound 2(2mmol,1.5mL of anhydrous chloroform is dissolved) is dropwise added into the reaction system, and stirring is carried out at the room temperature of 25 ℃ for 12 h. TLC to monitor the reaction completion, rotary evaporation under reduced pressure to remove chloroform, extraction with water and ethyl acetate, combination of organic phases and drying over anhydrous magnesium sulfate. The magnesium sulfate was removed by suction filtration, and the filtrate was concentrated, petroleum ether: recrystallization from ethyl acetate 4:1 gave I-4 as a white solid in 72.8% yield. m.p.142.1-144.7 ℃;1H NMR(400MHz,DMSO)δ8.82(dd,J＝4.4,1.5Hz,2H),8.46(s,1H),8.28(d,J＝2.1Hz,1H),7.73(dd,J＝4.4,1.6Hz,2H),7.63(d,J＝8.8Hz,1H),7.42–7.36(m,2H),7.34(dd,J＝8.8,2.2Hz,1H),7.22–7.11(m,2H),5.55(s,2H)；13C NMR(101MHz,DMSO)δ188.02,162.84,160.42,150.24,146.34,140.98,135.06,132.70,129.54,127.68,123.71,122.13,120.79,115.60,115.39,113.30,49.25.HRMS(ESI):m/z calcd for C21H14ClFN2O(M+H)+，465.0857；found，365.0854.。
example 6 in the synthesis of compounds of general formula I,
Figure BDA0001323610810000092
preparation of Compound I-5
Figure BDA0001323610810000093
Taking AlCl3(2mmol) is added into a beaker, 8mL of anhydrous dichloromethane is added, stirring is carried out at the room temperature of 25 ℃, 2-chloropyridine-4-formyl chloride (2mmol) is added, stirring is carried out at the room temperature of 25 ℃ for 1h, compound 2(2mmol,1.5mL of anhydrous dichloromethane is dissolved) is dropwise added into the reaction system, and the reaction is carried out at the room temperature of 25 ℃ for 12 h. TLC to monitor the reaction completion, rotary evaporation under reduced pressure to remove dichloromethane, extraction with water and ethyl acetate, combination of organic phases and drying over anhydrous magnesium sulfate. The magnesium sulfate was removed by suction filtration, and the filtrate was concentrated, petroleum ether: recrystallization from ethyl acetate 4:1 gave I-5 as a pale brown solid in 77.3% yield. m.p.124.6-127.0 ℃;1H NMR(400MHz,Acetone)δ8.58(d,J＝5.0Hz,1H),8.39(d,J＝2.1Hz,1H),8.37(s,1H),7.75(s,1H),7.72(dd,J＝5.0,1.3Hz,1H),7.57(d,J＝8.8Hz,1H),7.40(dd,J＝8.6,5.4Hz,2H),7.32(dd,J＝8.8,2.1Hz,1H),7.14–7.07(m,2H),5.62(s,2H)；13C NMR(101MHz,Acetone)δ187.26,164.51,162.08,152.43,151.37,141.32,136.57,130.27,129.33,124.94,123.61,122.38,116.55,116.33,115.00,113.64,50.89.HRMS(ESI):m/z calcd for C21H13Cl2FN2O(M+Na)+，421.0287；found，421.0288.。
example 7 synthesis of compounds of formula I, R ═ 4-C6H5C6H5Preparation of-situ I-6
Figure BDA0001323610810000101
Taking FeCl3(2mmol) is added into a beaker, 8mL of anhydrous dichloromethane is added, stirring is carried out at the room temperature of 25 ℃, biphenyl-4-formyl chloride (2mmol) is added, stirring is carried out at the room temperature of 25 ℃ for 1h, compound 2(2mmol,1.5mL of anhydrous dichloromethane is dissolved) is dropwise added into the reaction system, and stirring is carried out at the room temperature of 25 ℃ for 12 h. TLC to monitor the reaction completion, rotary evaporation under reduced pressure to remove dichloromethane, extraction with water and ethyl acetate, combination of organic phases and drying over anhydrous magnesium sulfate. The magnesium sulfate was removed by suction filtration, and the filtrate was concentrated, petroleum ether: recrystallization from ethyl acetate 4:1 gave I-6 as a white solid in 98.4% yield. m.p.192.7-194.2 ℃;1H NMR(400MHz,Acetone)δ10.59(s,1H),8.09(s,1H),7.72(dd,J＝7.5,6.7Hz,4H),7.64(d,J＝8.3Hz,2H),7.53–7.46(m,3H),7.41–7.35(m,3H),7.16–7.08(m,4H),5.59(s,2H)；13C NMR(101MHz,Acetone)δ151.20,142.19,141.23,137.82,135.26,134.57,130.42,129.93,129.44,128.46,127.72,127.46,126.10,122.71,122.14,116.45,116.24,112.67,107.89,50.18.HRMS(ESI):m/z calcd for C28H19ClFNO(M+Na)+，462.1037；found，462.1036.
example 8 Synthesis of Compounds of formula I, R is 3-CH3C6H5Preparation of-situ I-7
Figure BDA0001323610810000102
Taking AlCl3(2mmol) is added into a beaker, 8mL of anhydrous dichloromethane is added, stirring is carried out at the room temperature of 25 ℃, 3-methylbenzoyl chloride (2mmol) is added, stirring is carried out at the room temperature of 25 ℃ for 1h, compound 2(2mmol,1.5mL of anhydrous dichloromethane is dissolved) is dropwise added into the reaction system, and the reaction is carried out at the room temperature of 25 ℃ for 12 h. TLC to monitor the reaction completion, rotary evaporation under reduced pressure to remove dichloromethane, extraction with water and ethyl acetate, combination of organic phases and drying over anhydrous magnesium sulfate. Vacuum filtering to remove magnesium sulfate, concentrating the filtrate, and adding petroleumEther: recrystallization from ethyl acetate 4:1 gave I-7 as a yellow solid in 93.4% yield. m.p.122.4-124.7 ℃;1H NMR(400MHz,DMSO)δ8.35(s,1H),8.26(d,J＝2.1Hz,1H),7.64–7.57(m,3H),7.45(dd,J＝8.4,5.0Hz,2H),7.40–7.34(m,2H),7.31(dd,J＝8.8,2.2Hz,1H),5.55(s,2H),2.43(s,3H)；13C NMR(101MHz,DMSO)δ189.56,162.81,160.38,139.90,137.86,134.92,132.00,129.44,128.86,128.35,128.14,127.22,125.66,123.32,120.87,115.60,115.39,113.90,112.97,49.08,20.97.HRMS(ESI):m/z calcd for C23H17ClFNO(M+H)+，378.1061；found，378.1065.。
example 9 Synthesis of Compounds of formula I, R is
Figure BDA0001323610810000111
Preparation of intermediate I-8
Figure BDA0001323610810000112
Taking AlCl3(2mmol) is added into a beaker, 8mL of anhydrous dichloromethane is added, stirring is carried out at the room temperature of 25 ℃, 2-naphthoyl chloride (2mmol) is added, stirring is carried out at the room temperature of 25 ℃ for 1h, compound 2(2mmol,1.5mL of anhydrous dichloromethane is dissolved) is dropwise added into the reaction system, and stirring is carried out at the room temperature of 25 ℃ for 12 h. TLC to monitor the reaction completion, rotary evaporation under reduced pressure to remove dichloromethane, extraction with water and ethyl acetate, combination of organic phases and drying over anhydrous magnesium sulfate. The magnesium sulfate was removed by suction filtration, and the filtrate was concentrated, petroleum ether: recrystallization from ethyl acetate 4:1 gave I-8 as a white solid in 89.7% yield.1H NMR(400MHz,DMSO)δ8.47(d,J＝15.3Hz,2H),8.31(d,J＝2.0Hz,1H),8.13(d,J＝7.3Hz,1H),8.09(d,J＝8.5Hz,1H),8.04(d,J＝7.4Hz,1H),7.95–7.87(m,1H),7.70–7.60(m,3H),7.40(dd,J＝8.5,5.5Hz,2H),7.33(dd,J＝8.8,2.1Hz,1H),7.15(dd,J＝18.1,9.3Hz,2H),5.56(s,2H).13C NMR(101MHz,DMSO)δ160.41,140.17,137.13,134.99,134.29,132.89,132.13,129.06,128.18,127.83,127.61,127.28,126.73,125.11,123.38,120.90,115.60,115.38,114.10,113.01,49.18.HRMS(ESI):m/z calcd for C26H17ClFNO(M+H)+，414.1061；found，414.1062.。
Example 10 Synthesis of Compound of formula II, R is 3-CH3C6H5Preparation of-situ i.e. II-1
Figure BDA0001323610810000121
Taking the compound I-7(1mmol) synthesized in the series I, adding 10mL of anhydrous methanol, adding sodium carbonate, and gradually adding NaBH for multiple times4(5mmol), the reaction was stirred at 25 ℃ for 12h, TLC monitored for completion, filtered through celite to remove insoluble solids, extracted with water and ethyl acetate, and the combined organic phases were dried over anhydrous magnesium sulfate. Vacuum-filtering to remove magnesium sulfate, concentrating the filtrate under vacuum, and separating by silica gel column chromatography, wherein the eluent and the proportion thereof are petroleum ether: ethyl acetate 8:1 gave II-1 as a viscous liquid in 97.1% yield.1H NMR(400MHz,Acetone)δ7.56(d,J＝1.9Hz,1H),7.38–7.27(m,4H),7.26–7.17(m,3H),7.07(ddd,J＝11.4,5.6,2.9Hz,4H),6.05(d,J＝4.5Hz,1H),5.37(d,J＝20.1Hz,2H),4.62(t,J＝6.2Hz,1H),2.08(s,3H)；13C NMR(101MHz,DMSO)δ162.63,160.22,145.17,136.86,134.71,134.22,129.11,127.90,127.30,126.91,123.40,121.14,119.43,119.07,115.41,115.20,111.74,68.35,48.26,21.13.HRMS(ESI):m/z calcd for C23H19ClFNO(M+Na)+，402.1037；found，402.1038.。
Example 11 Synthesis of a Compound of formula II, R is
Figure BDA0001323610810000122
Preparation of intermediate II-2
Figure BDA0001323610810000123
Taking a compound I-8(1mmol) synthesized in the series I, adding 10mL of anhydrous methanol, adding triethylamine, and gradually adding NaBH for multiple times4(5mmol), the reaction was stirred at 25 ℃ for 12h, TLC monitored for completion, and celite filtered to remove insoluble materialThe solid was extracted with water and ethyl acetate, the organic phases were combined and dried over anhydrous magnesium sulfate. Vacuum-filtering to remove magnesium sulfate, concentrating the filtrate under vacuum, and separating by silica gel column chromatography, wherein the eluent and the proportion thereof are petroleum ether: ethyl acetate 8:1 gave II-2 as a pale yellow solid in 97.1% yield. m.p.48.2-49.1 deg.C;1H NMR(400MHz,DMSO)δ8.03(s,1H),7.91(d,J＝7.3Hz,1H),7.84(dd,J＝10.8,8.1Hz,2H),7.55–7.42(m,5H),7.40(s,1H),7.27–7.21(m,2H),7.16–7.09(m,2H),7.08–7.04(m,1H),6.10(t,J＝7.0Hz,1H),5.87(dd,J＝10.3,4.5Hz,1H),5.36(s,2H)；13C NMR(101MHz,DMSO)δ162.64,160.22,142.74,134.75,134.16,132.80,132.15,129.11,128.23,127.79,127.46,126.01,125.55,125.22,124.14,123.47,121.20,119.11,115.41,115.20,111.79,68.42,48.30.HRMS(ESI):m/zcalcd for C26H19ClFNO(M+Na)+，438.1037；found，438.1035.。
EXAMPLE 12 Synthesis of intermediate 4 in the Synthesis of Compound represented by general formula III
Figure BDA0001323610810000131
Taking SnCl4(20mmol) is added into a flask, 15mL of toluene is added, the mixture is stirred in an ice-water bath, acetyl chloride (20mmol) is added into the system, after the mixture is stirred in the ice-water bath for 0.5h, 2mL of toluene is dissolved in 5-chloroindole (10mmol), the mixture is added into the reaction system dropwise, and the mixture is stirred in the ice-water bath for 2 h. TLC to monitor the reaction is complete, decompression rotary evaporation to remove toluene, water and ethyl acetate extraction, combined organic phase, anhydrous magnesium sulfate drying. The magnesium sulfate was removed by suction filtration, the filtrate was concentrated, and the anhydrous ethanol was recrystallized to obtain compound 3. Taking compound 3(5mmol), NaH (15mmol) and adding 6mL anhydrous acetonitrile into a 25mL round-bottom flask, stirring at room temperature for 1h, slowly dropwise adding p-fluorobenzyl chloride (6.5mmol) dissolved by the anhydrous acetonitrile into the reaction system, reacting at room temperature for 5-7h, monitoring the reaction completion by TLC, filtering to remove insoluble solids, and concentrating the filtrate under vacuum, adding petroleum ether: recrystallization from a solvent system of 4:1 ethyl acetate gave 4 as a yellow solid in 98.4% yield. m.p.118.2-120.1 deg.C;1H NMR(400MHz,DMSO)δ8.63(s,1H),8.17(d,J＝1.8Hz,1H),7.60(d,J＝8.8Hz,1H),7.37(dd,J＝8.6,5.5Hz,2H),7.26(dd,J＝8.7,2.1Hz,1H),7.17(t,J＝8.9Hz,2H),5.50(s,2H),2.47(s,3H)；13C NMR(101MHz,DMSO)δ192.33,162.84,160.42,138.63,134.91,132.97,129.42,126.99,122.97,120.63,115.62,115.41,112.78,49.08,27.22.HRMS(ESI):m/z calcd for C17H13ClFNO(M+Na)+，324.0567；found，324.0564.。
EXAMPLE 13 preparation of III-1 when R is Ph-in the Synthesis of the Compound of formula III
Figure BDA0001323610810000132
Benzaldehyde (1mmol) was taken in a flask, 2mL of methanol was added, dissolved with stirring at room temperature and 25 ℃, and 30. mu.L of 3mmol of NaOH solution was added, then Compound 4(1mmol) obtained in example 12 was added, stirred at room temperature and 25 ℃, after completion of TLC detection reaction, insoluble solids were removed by filtration, extracted with water and ethyl acetate, the organic phases were combined, and dried over anhydrous magnesium sulfate. Vacuum-filtering to remove magnesium sulfate, concentrating the filtrate, and separating by silica gel column chromatography, wherein the eluent and the proportion thereof are petroleum ether: ethyl acetate 4:1, product III-1 as a white solid in 77.6% yield. m.p.114.5-117.2 ℃;1H NMR(400MHz,DMSO)δ9.03(s,1H),8.34(d,J＝2.1Hz,1H),7.88–7.83(m,2H),7.80(d,J＝15.6Hz,1H),7.69(d,J＝5.6Hz,1H),7.66(s,1H),7.50–7.44(m,3H),7.41(dd,J＝8.7,5.5Hz,2H),7.34–7.27(m,1H),7.22–7.16(m,2H),5.55(s,2H)；13CNMR(101MHz,Acetone)δ182.93,162.70,143.65,136.15,133.93,132.03,130.66,128.53,128.05,127.01,125.41,123.55,122.14,115.24,111.61,52.65.HRMS(ESI):m/z calcd for C24H17ClFNO(M+H)+，390.1061；found，390.1062.。
example 14 Synthesis of a Compound of formula III, R is
Figure BDA0001323610810000141
Preparation of intermediate III-2
Figure BDA0001323610810000142
Adding 2-furan aldehyde (1mmol) into a flask, adding 2mL of acetonitrile, stirring and dissolving at room temperature and 25 ℃, adding 30 mu L of 3mmol of NaOH solution, then adding the compound 3((1mmol) prepared in example 12, stirring at room temperature and 25 ℃, after TLC detection reaction is completed, filtering to remove insoluble solids, extracting with water and ethyl acetate, combining organic phases, drying with anhydrous magnesium sulfate, removing magnesium sulfate by suction filtration, concentrating filtrate, and carrying out silica gel column chromatography elution separation, wherein an eluent comprises petroleum ether, ethyl acetate is 4:1, a product is white solid III-2, and the yield is 68.1%. m.p.107.3-106.8 ℃;1H NMR(400MHz,Acetone)δ8.67(s,1H),8.50(d,J＝2.0Hz,1H),7.71(dd,J＝13.0,2.3Hz,1H),7.56(d,J＝15.3Hz,1H),7.51(d,J＝8.7Hz,1H),7.47–7.35(m,3H),7.24(dd,J＝8.7,2.1Hz,1H),7.17–7.04(m,2H),6.87(t,J＝8.1Hz,1H),6.60(dd,J＝3.3,1.8Hz,1H),5.58(s,2H).13C NMR(101MHz,Acetone)δ183.80,164.51,162.08,152.92,145.64,138.15,136.51,130.33,129.23,128.75,128.11,124.41,122.80,122.19,118.14,116.57,116.35,115.83,113.46,113.17,50.75.HRMS(ESI):m/zcalcd for C22H15ClFNO2(M+Na)+，402.0673；found，402.0672.。
EXAMPLE 15 in vitro antiviral Activity assay of some Compounds of general formulae I, II, III
1. Experimental methods
This experiment determined the in vitro antiviral activity of some compounds of the general formulae I, II, III on H1N 1.
Sample stock solution: a1-3 mg sample was weighed into a 1.5mL EP tube, and then prepared into a 10mM solution with DMSO, stored at 4 ℃ and left, and the laboratory was diluted with DMSO according to the desired concentration.
Cytotoxicity assays CC 50: MDCK 96-well plate with 2.5 × 10 wells45 volume percent of CO2Incubating at 37 ℃; after 24h, removing the culture solution, adding 200 mu L of a drug to be tested prepared by DMEM with 2% FBS by mass into each hole, setting 9 concentrations of 200, 100 and … (mu M/L), repeating the holes for 3 concentrations, and setting a reference; after 48h, cell viability was determined by the MTT method.
TABLE 1 target compound vs influenza virus (H)1N1) in vitro antiviral Activity (EC)50)
Figure BDA0001323610810000151
Figure BDA0001323610810000161
And (3) virus amplification: after MDCK cells are digested, inoculating the MDCK cells into a large culture bottle with the size of 2 multiplied by 75 cm; when the cells grow to a monolayer (about 70 percent), removing the culture medium, and washing with PBS for three times; adding virus solution, and shaking once every 15min for 3 times; after 2h, removing the culture solution, adding 12mL of DMEM with 2% FBS by mass, observing every day, and photographing and recording; toxic materials are collected when 70% -90% of pathological changes occur: placing the culture bottle to-80 deg.C, repeatedly freezing and thawing for 3 times, centrifuging at 4 deg.C and 4500r for 15min, collecting supernatant, subpackaging, labeling, and storing at-80 deg.C for use.
Virus TCID50And (3) determination: MDCK cells were plated in 96-well plates at 2.5X 10/well45 volume percent of CO2Incubating at 37 ℃; after 24h, PBS was washed 3 times, 100. mu.L of virus solution prepared with pure DMEM was added to each well, and diluted to 10-1～10-10Ten gradients, 8 replicates per concentration, and controls were set; after 2h, removing virus liquid, and adding 100 mu L of DMEM with the mass percentage of 2% FBS into each hole; the observation was made daily, and 72 hours later, the measurement was carried out with a Jiemsa staining solution.
Antiviral activity assay EC 50: MDCK 96-well plate with 2.5 × 10 wells4A plurality of; after 24h, the medium was removed, washed 3 times with PBS and 100. mu.L of 100TCID in pure DMEM was added to each well50A viral fluid; after 2h, removing virus liquid, adding 200 mu L of a to-be-detected drug prepared by DMEM with 2% FBS by mass into each hole, setting 6 concentrations (mu M/L) of 50, 25, 12.5, 6.25 and 3.12, and setting 3 compound holes for each concentration; after 48h, the rate of virus inhibition was determined by MTT method.
2. The results of the experiment are shown in table 1.
Experiments show that: most compounds have good inhibitory action on influenza A virus H1N1, particularly in the general formula I,
Figure BDA0001323610810000162
when the compound I-2 is used,
Figure BDA0001323610810000163
When the compound I-3 is used,
Figure BDA0001323610810000164
When the compound is the compound I-4, the activity is better.

Claims (5)

1. Indole derivatives characterized by having a structure represented by formula I, II or III:
Figure FDA0002290694890000011
r is
Figure FDA0002290694890000012
Ph-、4-F-Ph-、3-F-Ph-、4-CH3-Ph-、3-CH3-Ph-、2-CH3-Ph-、3，5-2CH3-Ph-、2，4，6-3CH3-Ph-、4-C6H5-Ph-、
Figure FDA0002290694890000013
Figure FDA0002290694890000014
One kind of (1).
2. The indole derivative of claim 1, selected from the group consisting of:
Figure FDA0002290694890000015
3. the indole derivative of claim 2, selected from the group consisting of:
Figure FDA0002290694890000021
4. use of an indole derivative according to any one of claims 1 to 3 in the manufacture of a medicament for use in the manufacture of a medicament for the treatment of influenza.
5. The use of the indole derivative of claim 4 in the preparation of a medicament, wherein the indole derivative is used in the preparation of an anti-H1N 1 medicament.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1142909C (en) * 1998-03-26 2004-03-24 盐野义制药株式会社 Indole derivatives with antiviral activity
WO2011123719A2 (en) * 2010-03-31 2011-10-06 Ironwood Pharmaceuticals, Inc. Use of faah inhibitors for treating abdominal, visceral and pelvic pain
WO2014176351A1 (en) * 2013-04-23 2014-10-30 The Board Of Trustees Of The University Of Arkansas Polymerase, endonuclease, and helicase inhibitors and methods of using thereof
WO2015042053A1 (en) * 2013-09-17 2015-03-26 Pharmakea, Inc. Vinyl autotaxin inhibitor compounds

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* Cited by examiner, † Cited by third party
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RU2397975C1 (en) * 2008-11-27 2010-08-27 Андрей Александрович Иващенко Substituted 2-(5-hydroxy-2-methyl-1h-indol-3-yl)acetic acids and esters thereof, antiviral agent, pharmaceutical composition, medicinal agent, method of treating viral diseases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1142909C (en) * 1998-03-26 2004-03-24 盐野义制药株式会社 Indole derivatives with antiviral activity
WO2011123719A2 (en) * 2010-03-31 2011-10-06 Ironwood Pharmaceuticals, Inc. Use of faah inhibitors for treating abdominal, visceral and pelvic pain
WO2014176351A1 (en) * 2013-04-23 2014-10-30 The Board Of Trustees Of The University Of Arkansas Polymerase, endonuclease, and helicase inhibitors and methods of using thereof
WO2015042053A1 (en) * 2013-09-17 2015-03-26 Pharmakea, Inc. Vinyl autotaxin inhibitor compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Computational and synthetic approaches for the discovery of HIV-1 integrase inhibitors;Maria Letizia Barreca，等;《Archives of Organic Chemistry》;20061231;第26卷(第7期);第235页方案1 *

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