CN111499676A - 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative and preparation method and application thereof - Google Patents

4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative and preparation method and application thereof Download PDF

Info

Publication number
CN111499676A
CN111499676A CN202010471875.5A CN202010471875A CN111499676A CN 111499676 A CN111499676 A CN 111499676A CN 202010471875 A CN202010471875 A CN 202010471875A CN 111499676 A CN111499676 A CN 111499676A
Authority
CN
China
Prior art keywords
toluenesulfonyl
chloro
nitro
azaindole
stirring
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
CN202010471875.5A
Other languages
Chinese (zh)
Inventor
邓莉平
罗蒙强
沈润溥
徐慧婷
席眉扬
杜奎
程凯
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Shaoxing
Original Assignee
University of Shaoxing
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Shaoxing filed Critical University of Shaoxing
Priority to CN202010471875.5A priority Critical patent/CN111499676A/en
Publication of CN111499676A publication Critical patent/CN111499676A/en
Withdrawn legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • 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
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • 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
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Virology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Pulmonology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative, and a preparation method and application thereof. The invention relates to a 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative which is specifically named as (2S,3S,4R,5S) -2- (hydroxymethyl) -6- (8 b-nitro-4-p-toluenesulfonyl-4, 8 b-dihydro- [1,2,3] triazole pyrrolo (4-chloro) -pyridyl) -tetrahydropyran-3, 4, 5-triol.

Description

4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative, and a preparation method and application thereof.
Background
Chemical name: 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole, the chemical structural formula is as follows:
Figure BDA0002514552110000011
in the process of drug discovery, 7-azaindole is an important structural unit, and many natural compounds with biological activity all contain 7-azaindole structures, and people find that the structural compounds have wide application and can be used for anticancer, antibacterial, antiviral, antidepressant, hypertension treatment and the like.
The alkaloid can be directly extracted from natural animals and plants, and is used as a lead compound to carry out structural modification and modification on the alkaloid, so that a medicament with more ideal curative effect is found by analyzing the structure-activity relationship with a target spot, and the alkaloid is also a good choice.
Disclosure of Invention
The invention aims to provide a 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative and a preparation method and application thereof, and the specific scheme is as follows:
a4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative is specifically named as (2S,3S,4R,5S) -2- (hydroxymethyl) -6- (8 b-nitro-4-p-toluenesulfonyl-4, 8 b-dihydro- [1,2,3] triazole pyrrolo (4-chloro) -pyridyl) -tetrahydropyran-3, 4, 5-triol, wherein the (2S,3S,4R,5S) -2- (hydroxymethyl) -6- (8 b-nitro-4-p-toluenesulfonyl-4, 8 b-dihydro- [1,2,3] triazole pyrrolo (4-chloro) -pyridyl) -tetrahydropyran-3, 4, 5-triol having the following chemical formula:
Figure BDA0002514552110000021
a preparation method of 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivatives comprises the following steps:
(1) synthesizing N-p-toluenesulfonyl-4-chloro-7-azaindole, namely adding 1.52g of 4-chloro-7-azaindole and 10m L DMF into a 50m L round-bottom flask, slowly adding 0.6g of NaH under the ice bath condition, stirring for 10 minutes, adding DMF solution 5m L in which 2.09g of p-toluenesulfonyl chloride is dissolved, stirring at room temperature, monitoring the reaction end point by T L C, after the reaction is finished, adding 20m L water into the reaction solution, extracting by using ethyl acetate 20m L× 3, combining organic layers, and evaporating the solvent to obtain N-p-toluenesulfonyl-4-chloro-7-azaindole;
(2) 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole is synthesized by adding 20m of L acetic anhydride into a 50m L round-bottomed flask, slowly dripping 0.2m of L concentrated nitric acid into the acetic anhydride under ice bath conditions, stirring for 10 minutes, directly dripping the reaction solution into 30m L acetic anhydride solution dissolved with N-p-toluenesulfonyl-4-chloro-7-azaindole, stirring overnight at room temperature after dripping, monitoring the reaction end point by T L C, pouring the reaction solution onto 50g of ice after the reaction is finished, stirring for 1 hour, extracting with ethyl acetate 20m L× 3, combining organic layers, drying with anhydrous sodium sulfate, evaporating the solvent to dryness, and carrying out column chromatography with an eluent to obtain 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole;
(3) introducing galactoside triazole structure, mixing 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole and 1-azido-peracetyl galactose in methanol at room temperature, carrying out [3+2] dipolar cycloaddition reaction, refluxing for about 5 hours, monitoring by T L C until the raw material point disappears, and removing the solvent under reduced pressure until the raw material point is dry to obtain an intermediate compound.
(4) Adding methanol and dichloromethane into an intermediate compound to dissolve the intermediate compound, slowly adding sodium methoxide, after dropwise adding for about half an hour, heating, condensing, refluxing and continuing to react for 3-4 hours, monitoring by T L C until the raw material point disappears, adding cation exchange resin to neutralize while stirring, adjusting the pH to 5-6, filtering, washing the ion exchange resin for a plurality of times by using methanol, decompressing the filtrate to remove the mixed solvent to obtain a yellow solid, purifying by using a column chromatography with V (chloroform) to V (methanol) of 15:1, and drying in vacuum to obtain the 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative.
The amount ratio of the 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole to the 1-azido-peracetylgalactose substance in the step (3) is 1: 1.
In the step (4), the volume ratio of the mixed solvent methanol to the dichloromethane is 3:1, and the mass ratio of the intermediate compound to the sodium methoxide is 1: 2.
And (3) eluting agent in the step (2) is V (petroleum ether) and V (ethyl acetate) which are 5: 1.
The 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative is applied to antitumor drugs.
The 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative is applied to the aspect of resisting hepatitis B virus.
The 1,2, 3-triazole compound has various biological activities of resisting bacteria, tumors, tuberculosis, viruses, convulsion and the like. Because the structure of the aromatic biodegradable polyester is aromatic, the biodegradable polyester is not easy to be biodegraded; is rich in electrons, can be tightly combined with biomacromolecules through hydrogen bonds and dipole interaction, and is often used as an effective functional group to be introduced into the structure of the existing medicament so as to improve the physicochemical property and pharmacokinetic parameters of the medicament and improve the biological activity of the medicament. The glucoside compound has good antibacterial and anticancer activities. The introduction of a glucoside structure into the compound can enhance the water solubility and targeting property of the compound and improve the pharmacological property of the compound. The present invention introduces this structure.
The 1, 3-dipolar cycloaddition reaction is the most important method for synthesizing five-membered heterocyclic compounds with good regioselectivity and body selectivity, and is also a more active reaction in heterocyclic pharmaceutical chemistry research. The indole or 7-azaindole becomes an electrophilic reagent with the property similar to that of an electron-deficient olefin after connecting electron-withdrawing groups on the 3-position and the 1-position N, and the research reports on the aspect are relatively less. 7-azaindole, as a member of indole compounds, has important physiological and pharmacological activities, and reports thereof are less than that of indole. Therefore, research on 7-azaindole and in-situ generated 1, 3-dipole dearomatization cycloaddition reaction is carried out, and the construction of polycyclic 7-azaindoline skeleton derivatives is of great significance for enriching the application range of azaindole and constructing compounds with physiological activity.
Meanwhile, drug absorption requires appropriate water solubility and lipid solubility to be able to permeate the lipid bilayer of the biological membrane. The transdermal absorption of the medicine in vitro and the dissolution, absorption, distribution and transportation of the medicine in vivo are all related to the lipid-water distribution coefficient. 7-azaindole and triazole glucoside structures are combined together to obtain a more ideal lipid-water partition coefficient.
The invention provides a 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative, namely (2S,3S,4R,5S) -2- (hydroxymethyl) -6- (8 b-nitro-4-p-toluenesulfonyl-4, 8 b-dihydro- [1,2,3] triazole pyrrolo (4-chloro) -pyridyl) -tetrahydropyran-3, 4, 5-triol and a preparation method and application thereof, the preparation method uses a 1, 3-dipolar cycloaddition method to introduce glycosyl triazazole ring into the chemical structure of 4-chlorine-3-nitryl-1-p-toluenesulfonyl-7-azaindole, thereby finally synthesizing a novel 7-azaindole derivative containing a galactose triazole structure. The (2S,3S,4R,5S) -2- (hydroxymethyl) -6- (8 b-nitro-4-p-toluenesulfonyl-4, 8 b-dihydro- [1,2,3] triazole pyrrolo (4-chloro) -pyridyl) -tetrahydropyran-3, 4, 5-triol prepared by the invention has stronger tumor cell inhibition effect and in-vitro anti-hepatitis B virus activity, and provides a foundation for further application in the medical field.
Drawings
FIG. 1 is a schematic diagram of a chemical structural formula of a 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative.
Detailed Description
The technical solutions of the present invention are further described in detail below with reference to the drawings and examples, which should not be construed as limiting the present invention.
The 7-azaindole derivatives are widely concerned as a useful intermediate and various pharmaceutical activities shown by the intermediates. The general idea of the invention is to skillfully introduce glucoside and 1,2, 3-triazole pharmacodynamic structure with biological activity into the molecular structure of 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole, highly specifically prepare (2S,3S,4R,5S) -2- (hydroxymethyl) -6- (8 b-nitro-4-p-toluenesulfonyl-4, 8 b-dihydro- [1,2,3] triazole pyrrolo (4-chloro) -pyridyl) -tetrahydropyran-3, 4, 5-triol and improve pharmacological activity.
The invention relates to a 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative, namely (2S,3S,4R,5S) -2- (hydroxymethyl) -6- (8 b-nitro-4-p-toluenesulfonyl-4, 8 b-dihydro- [1,2,3] triazole pyrrolo (4-chloro) -pyridyl) -tetrahydropyran-3, 4, 5-triol, the chemical structural formula of which is as follows:
Figure BDA0002514552110000051
this example is a method for preparing a 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative, namely (2S,3S,4R,5S) -2- (hydroxymethyl) -6- (8 b-nitro-4-p-toluenesulfonyl-4, 8 b-dihydro- [1,2,3] triazolo (4-chloro) -pyridinyl) -tetrahydropyran-3, 4, 5-triol (compound 6), comprising the steps of:
as shown in figure 1, chemical formula 1 is 7-azaindole (compound 1), chemical formula 2 is N-p-toluenesulfonyl-4-chloro-7-azaindole (compound 2), chemical formula 3 is 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole (compound 3), chemical formula 4 is 1-azido-peracetylgalactose (compound 4), intermediate 5 (compound 5) is generated after dipolar cycloaddition reaction under mild conditions, compound 5 generates compound corresponding to chemical formula 6 after removing acetyl, namely (2S,3S,4R,5S) -2- (hydroxymethyl) -6- (8 b-nitro-4-p-toluenesulfonyl-4), 8 b-dihydro- [1,2,3] triazole pyrrolo (4-chloro) -pyridinyl) -tetrahydropyran-3, 4, 5-triol (compound 6).
The specific preparation method of the compound (6) comprises the following steps:
(1) synthesizing N-p-toluenesulfonyl-4-chloro-7-azaindole, namely adding 1.52g (10mmol) of 4-chloro-7-azaindole (compound 1) and 10m L DMF into a 50m L round-bottom flask, slowly adding 0.6g (25mmol) of NaH under the condition of ice bath, stirring for 10 minutes, adding DMF solution 5m L in which 2.09g (11mmol) of p-toluenesulfonyl chloride is dissolved, stirring at room temperature, monitoring the reaction end point by T L C, after the reaction is finished, adding 20m L water into the reaction solution, extracting with ethyl acetate 20m L× 3, combining organic layers, and evaporating the solvent to dryness to obtain N-p-toluenesulfonyl-4-chloro-7-azaindole (compound 2);
(2) 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole is synthesized by adding 20m L acetic anhydride into a 50m L round-bottomed flask, slowly dripping 0.2m L concentrated nitric acid into the acetic anhydride under ice bath conditions, stirring for 10 minutes, directly dripping the reaction solution into 30m L acetic anhydride solution dissolved with N-p-toluenesulfonyl-4-chloro-7-azaindole, stirring overnight at room temperature after dripping, monitoring the reaction end point by T L C, pouring the reaction solution onto 50g of ice after the reaction is finished, stirring for 1 hour, extracting with ethyl acetate 20m L× 3, combining organic layers, drying with anhydrous sodium sulfate, evaporating the solvent to dryness, and performing column chromatography by using V (petroleum ether) and V (ethyl acetate) as eluent to obtain 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole (compound 3);
(3) introducing galactoside triazole structure, mixing 31.7mg (0.1mmol) of 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole and 37.3mg (0.1mmol) of 1-azido-peracetylgalactose (compound 4) in methanol at room temperature to perform [3+2] dipolar cycloaddition reaction, refluxing for about 5 hours, monitoring by T L C until the raw material point disappears, and removing the solvent under reduced pressure until the solvent is dried to obtain an intermediate compound 5.
(4) Adding 12m L methanol and 3m L dichloromethane into an intermediate compound 5(0.2mmo1) in a reaction bottle for dissolving, slowly adding sodium methoxide (0.98m L, 0.41 mol/L and 0.4mmo1), after dropwise adding for about half an hour, heating, condensing, refluxing and continuing to react for 3-4 hours, monitoring T L C until a raw material point disappears, adding cation exchange resin for neutralization while stirring, adjusting the pH to 5-6, filtering, washing the ion exchange resin for a plurality of times by methanol, removing a mixed solvent from a filtrate under reduced pressure to obtain a yellow solid, purifying by column chromatography with V (chloroform) to V (methanol) of 15:1, and performing vacuum drying to obtain a compound 6.
As shown in fig. 1, the chemical structural formula 6 is triazole glycoside derivative of 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole, namely (2S,3S,4R,5S) -2- (hydroxymethyl) -6- (8 b-nitro-4-p-toluenesulfonyl-4, 8 b-dihydro- [1,2,3] triazole pyrrolo (4-chloro) -pyridyl) -tetrahydropyran-3, 4, 5-triol.
The experimental data are as follows: (2S,3S,4R,5S) -2- (hydroxymethyl) -6- (8 b-nitro-4-p-toluenesulfonyl-4, 8 b-dihydro- [1,2,3] triazolo (4-chloro) -pyridyl) -tetrahydropyran-3, 4, 5-triol (Compound 6) as a white powder in 78.2% yield, m.p.169-170 ℃ melting point, and its nuclear magnetic hydrogen spectrum, infrared spectrum and elemental analysis data are as follows:
1H NMR(DMSO-d6):8.26(d，J＝4.8Hz，1H),7.88(d，J＝8.0Hz，2H),7.17(d，J＝7.2Hz，2H),6.95(dd，J＝7.2，4.8Hz,1H),5.15(dd,J＝6.0,3.6Hz,1H)，4.86-3.40(m,11H,7×GalactosylH,OH),2.37(s，3H)；
IR(KBr)v/cm-13451,3431,2987,1708,1633,1580,1463,1216,1163,1096,757
m/e:556(100.0％)。
Anal.calcd.forC20H21ClN6O9S：C,43.13；H,3.80；N,15.09；found C,43.10；H,3.82；N,15.09；。
in this example, the MTT method is used to determine the in vitro inhibitory effect of compound 6 on different tumor strains, and the results of the determination of the antitumor activity of (2S,3S,4R,5S) -2- (hydroxymethyl) -6- (8 b-nitro-4-p-toluenesulfonyl-4, 8 b-dihydro- [1,2,3] triazole pyrrolo (4-chloro) -pyridyl) -tetrahydropyran-3, 4, 5-triol (compound 6) are as follows:
compound 6 was diluted with DMSO, and tumor cells HepG2 (hepatoma cells), A375 (melanoma cells), SW620 (human colorectal adenocarcinoma cells), A549 (lung adenocarcinoma cells), SGC7901 (gastric cancer cells), SKOV3 (ovarian cancer cells) were seeded in a 96-well plate at 4000/200. mu. L/well, compound 2. mu. L was added to each well to a final concentration of 12.0. mu.M, 6.0. mu.M, 3.0. mu.M, 1.5. mu.M, together at 37 ℃ with 5% CO2The cells were incubated in an incubator for 72 hours with DMSO (1%) as a blank, and after 72 hours MTT was added to a final concentration of 0.25mg/m L and placed at 37 ℃ in 5% CO24 hours in the cell incubator, after which the solvent was blotted dry, 100. mu. L DMSO was added to each well, using an enzyme-linked immunosorbent assay at 570nmThe absorbance (OD value) was measured, and the obtained data was used for calculating IC50The value is obtained. Selecting compounds with high inhibitory activity, and determining the influence of different action times of the compounds at different concentrations on the human tumor cell cycle and apoptosis.
The test compounds of different concentrations were coarse-screened in 96-well plates and IC was calculated from the resulting inhibition50Values, results are given in the table below.
TABLE 1 Compound 6(2S,3S,4R,5S) -2- (hydroxymethyl) -6- (8 b-nitro-4-p-toluenesulfonyl-4, 8 b-dihydro- [1,2,3]IC of triazole pyrrolo (4-chloro) -pyridyl) -tetrahydropyran-3, 4, 5-triol) on six tumor cell strains50Value of
Figure BDA0002514552110000071
In Table 1, (2S,3S,4R,5S) -2- (hydroxymethyl) -6- (8 b-nitro-4-p-toluenesulfonyl-4, 8 b-dihydro- [1,2,3]IC of triazole pyrrolo (4-chloro) -pyridyl) -tetrahydropyran-3, 4, 5-triol (compound 6) on six tumor cell strains50The value shows that the compound 6 has stronger tumor cell inhibition effect on HepG2 (liver cancer cells) and A375 (melanoma cells), and provides a foundation for further application in the medical field.
Taking HepG22.2.15 cells in the logarithmic growth phase, washing the cells for 2 times by 0.02% EDTA, digesting the cells by 0.25% trypsin, uniformly blowing the cells, and counting the number of the cells to 2.5 × 10 (cells)/m L-1And inoculated into 24-well plate at 0.5m L per well, and the administration is started after the cells are attached to the wall, and the samples are prepared into culture solution containing DMSO at 12.5, 25 and 50 mu g/m L-1Adding 3 concentrations of the above components into a 24-well culture plate, wherein each well has a concentration of 0.6m L, each concentration has 2 wells, using a cell with the same amount of DMS0 instead of the liquid medicine as a control group, administering the liquid medicine with the same concentration on the 3 rd day, collecting the cell on the 6 th day, washing with Phosphate Buffer Solution (PBS) for 2 times, extracting with a reagent for extracting virus core particles, determining the content of HBVDNA in the cell by using Taqman probe as fluorescent quantitative PCR, and calculating the percentage of HBVDNA inhibition (control group copy number-administration group copy number)/control group copy number × 100% according to the formulaCompound 6 has inhibition effect on the replication of HBVDNA in HepG22.2.15 cells, and presents a certain dose-effect relationship, and the result can be seen from the table 2 that the compound 6 has the inhibition effect on the replication of HBVDNA at 50 mu g/m L-1The inhibition rate to HBVDNA is 80.44%, and the in vitro anti-HBV activity is better.
TABLE 2 inhibition of HBVDNA cell replication by Compound 6
Figure BDA0002514552110000081
The transdermal absorption of the medicine in vitro, the dissolution, the absorption, the distribution and the transportation of the medicine are related to the lipid-water partition coefficient, the P value of the lipid-water partition coefficient is generally considered to be too low (1ogP < -2) and the compound cannot penetrate through the lipid membrane, on the contrary, the P value is too high (1ogP >3) and the compound is difficult to release from the membrane at the other side of the cell because of strong fat solubility and enters the nearby blood vessel or lymphatic vessel, and the experimental result shows that the L ogP of the n-octanol/water partition coefficient of the compound 6 is 2.57, is more ideal and meets the principle of pharmacy.
The above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and those skilled in the art can make various corresponding changes and modifications according to the present invention without departing from the spirit and the essence of the present invention, but these corresponding changes and modifications should fall within the protection scope of the appended claims.

Claims (7)

1. A4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative is specifically named as (2S,3S,4R,5S) -2- (hydroxymethyl) -6- (8 b-nitro-4-p-toluenesulfonyl-4, 8 b-dihydro- [1,2,3] triazolo (4-chloro) -pyridyl) -tetrahydropyran-3, 4, 5-triol and is characterized in that the (2S,3S,4R,5S) -2- (hydroxymethyl) -6- (8 b-nitro-4-p-toluenesulfonyl-4, 8 b-dihydro- [1,2,3] triazolo (4-chloro) -pyridyl) -tetrahydropyran-3, 4, 5-triol having the following chemical formula:
Figure FDA0002514552100000011
2. a process for the preparation of 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivatives as claimed in claim 1, comprising the steps of:
(1) synthesizing N-p-toluenesulfonyl-4-chloro-7-azaindole, namely adding 1.52g of 4-chloro-7-azaindole and 10m L DMF into a 50m L round-bottom flask, slowly adding 0.6g of NaH under the ice bath condition, stirring for 10 minutes, adding DMF solution 5m L in which 2.09g of p-toluenesulfonyl chloride is dissolved, stirring at room temperature, monitoring the reaction end point by T L C, after the reaction is finished, adding 20m L water into the reaction solution, extracting by using ethyl acetate 20m L× 3, combining organic layers, and evaporating the solvent to obtain N-p-toluenesulfonyl-4-chloro-7-azaindole;
(2) 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole is synthesized by adding 20m of L acetic anhydride into a 50m L round-bottomed flask, slowly dripping 0.2m of L concentrated nitric acid into the acetic anhydride under ice bath conditions, stirring for 10 minutes, directly dripping the reaction solution into 30m L acetic anhydride solution dissolved with N-p-toluenesulfonyl-4-chloro-7-azaindole, stirring overnight at room temperature after dripping, monitoring the reaction end point by T L C, pouring the reaction solution onto 50g of ice after the reaction is finished, stirring for 1 hour, extracting with ethyl acetate 20m L× 3, combining organic layers, drying with anhydrous sodium sulfate, evaporating the solvent to dryness, and carrying out column chromatography with an eluent to obtain 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole;
(3) introducing a galactoside triazole structure, namely mixing 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole and 1-azido-peracetyl galactose in methanol at room temperature to perform [3+2] dipolar cycloaddition reaction, refluxing for about 5 hours, monitoring by T L C until the raw material point disappears, and removing the solvent under reduced pressure until the raw material point is dry to obtain an intermediate compound;
(4) adding methanol and dichloromethane into an intermediate compound to dissolve the intermediate compound, slowly adding sodium methoxide, after dropwise adding for about half an hour, heating, condensing, refluxing and continuing to react for 3-4 hours, monitoring by T L C until the raw material point disappears, adding cation exchange resin to neutralize while stirring, adjusting the pH to 5-6, filtering, washing the ion exchange resin for a plurality of times by using methanol, decompressing the filtrate to remove the mixed solvent to obtain a yellow solid, purifying by using a column chromatography with V (chloroform) to V (methanol) of 15:1, and drying in vacuum to obtain the 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative.
3. The process for preparing 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivatives according to claim 2, wherein: the amount ratio of the 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole to the 1-azido-peracetylgalactose substance in the step (3) is 1: 1.
4. The process for preparing 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivatives according to claim 2, wherein: in the step (4), the volume ratio of the mixed solvent methanol to the dichloromethane is 3:1, and the mass ratio of the intermediate compound to the sodium methoxide is 1: 2.
5. The process for preparing 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivatives according to claim 2, wherein: and (3) eluting agent in the step (2) is V (petroleum ether) and V (ethyl acetate) which are 5: 1.
6. The use of the 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative according to claim 1 in the preparation of an antitumor agent.
7. The use of the 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative according to claim 1 for inhibiting hepatitis b virus.
CN202010471875.5A 2020-05-29 2020-05-29 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative and preparation method and application thereof Withdrawn CN111499676A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010471875.5A CN111499676A (en) 2020-05-29 2020-05-29 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010471875.5A CN111499676A (en) 2020-05-29 2020-05-29 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative and preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN111499676A true CN111499676A (en) 2020-08-07

Family

ID=71873644

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010471875.5A Withdrawn CN111499676A (en) 2020-05-29 2020-05-29 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN111499676A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113429445A (en) * 2021-05-13 2021-09-24 绍兴文理学院元培学院 Isoxazole derivative containing arabinose triazole structure and preparation method and application thereof
CN113429446A (en) * 2021-05-13 2021-09-24 绍兴文理学院元培学院 Isoxazole derivative containing xylose triazole structure and preparation method and application thereof
CN113444133A (en) * 2021-05-13 2021-09-28 绍兴文理学院元培学院 Isoxazole derivative containing glucose triazole structure and preparation method and application thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113429445A (en) * 2021-05-13 2021-09-24 绍兴文理学院元培学院 Isoxazole derivative containing arabinose triazole structure and preparation method and application thereof
CN113429446A (en) * 2021-05-13 2021-09-24 绍兴文理学院元培学院 Isoxazole derivative containing xylose triazole structure and preparation method and application thereof
CN113444133A (en) * 2021-05-13 2021-09-28 绍兴文理学院元培学院 Isoxazole derivative containing glucose triazole structure and preparation method and application thereof

Similar Documents

Publication Publication Date Title
CN112110969B (en) Triazole glucoside derivative of 3-nitro-1-ethyl formate-7-azaindole, and preparation method and application thereof
CN111499676A (en) 4-chloro-3-nitro-1-p-toluenesulfonyl-7-azaindole derivative and preparation method and application thereof
CN111454313A (en) Triazole glucoside derivative of 3-nitro-1-benzenesulfonyl-7-azaindole, and preparation method and application thereof
CN109053731B (en) P-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof
CN101323591A (en) 5- or 6-substited naphthoyl imines compounds and antineoplastic application
CN105399757A (en) Acid-sensitive camptothecin-site 20 norcantharidate derivative and antineoplastic application thereof
CN106749513A (en) Bifunctional molecule and its preparation and application based on the induction BET degradeds of VHL parts
CN106632043A (en) Licochalcone A pyrazoline derivatives with antitumor activity and synthesis method thereof
CN107573327A (en) Indazolecarboxamides Pyridione derivatives and its production and use
CN105646546A (en) Acid-sensitive camptothecin-20-position ester derivative and antineoplastic application thereof
CN109824664A (en) One group of antitumor indoles alkaloid compound and its preparation method and application
CN106478692A (en) Copper-nitrate complex and its synthetic method and application with 1 (2 pyridine) 9 benzyl β carboline as part
CN109232570B (en) Pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof
CN110092789B (en) Indolo [2,3-b ] carbazole derivative and application thereof
CN112645957A (en) Pyridazinone structure-containing spiropyrazole-pyrrolizine derivative and preparation method and application thereof
CN106397407A (en) Novel anti-tumor drug AZD9291 derivative and its preparation method and use
CN109053732B (en) Para-fluorine substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof
CN101407515A (en) Chinoline polycyclic compounds as CDK inhibitors
CN104098524A (en) 1-m-methoxy benzoyl-3-phenyl-1, 4-dihydro-1,2,4,5-tetrazine and preparation and application thereof
CN109180675B (en) P-methoxy substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof
CN109180676B (en) 3,4, 5-trimethoxy substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method thereof
CN113444133A (en) Isoxazole derivative containing glucose triazole structure and preparation method and application thereof
CN109232571B (en) P-methylmercapto-substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof
CN109232572B (en) P-methyl-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof
CN103923082B (en) 4-methoxyl-5-hydroxy canthinone ramification

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WW01 Invention patent application withdrawn after publication

Application publication date: 20200807

WW01 Invention patent application withdrawn after publication