CN114989178B - Spiro [ beta-lactam-3, 3' -oxindole ] derivative and preparation method and application thereof - Google Patents

Spiro [ beta-lactam-3, 3' -oxindole ] derivative and preparation method and application thereof Download PDF

Info

Publication number
CN114989178B
CN114989178B CN202210578701.8A CN202210578701A CN114989178B CN 114989178 B CN114989178 B CN 114989178B CN 202210578701 A CN202210578701 A CN 202210578701A CN 114989178 B CN114989178 B CN 114989178B
Authority
CN
China
Prior art keywords
spiro
lactam
beta
ring
mmol
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.)
Active
Application number
CN202210578701.8A
Other languages
Chinese (zh)
Other versions
CN114989178A (en
Inventor
周伟
钟先强
熊荟岚
梁玉真
李自豪
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.)
Jinan University
Original Assignee
Jinan University
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 Jinan University filed Critical Jinan University
Priority to CN202210578701.8A priority Critical patent/CN114989178B/en
Publication of CN114989178A publication Critical patent/CN114989178A/en
Application granted granted Critical
Publication of CN114989178B publication Critical patent/CN114989178B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • 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
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention relates to the technical field of pharmaceutical chemistry, and in particular discloses spiro [ beta ] -lactam-3, 3' -oxindole]Derivatives, and preparation method and application thereof are provided. Said spiro [ beta ] -lactam-3, 3' -oxindoles]A derivative, which has a structure shown in a formula I; wherein R is 1 Selected from hydrogen, alkyl, alkoxy, halogen or ester groups; r is R 2 Selected from alkyl, alkenyl or benzyl; r is R 3 Selected from alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring; r is R 4 Selected from alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring. Research shows that the spiro [ beta-lactam-3, 3' -oxindole]The derivative has a certain antiviral effect; in addition, the preparation method can be used for carrying out the reaction under mild conditions, and has the advantages of simple operation, few steps, good functional group compatibility, high yield and high diastereoselectivity; therefore, the method has good application prospect in the medical industrial production.

Description

Spiro [ beta-lactam-3, 3' -oxindole ] derivative and preparation method and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a spiro [ beta-lactam-3, 3' -oxindole ] derivative, a preparation method and application thereof.
Background
The beta-lactam and spiro oxindole ring system is a core structural unit for forming a plurality of natural products and bioactive molecules, has strong intermolecular force with a plurality of biomacromolecules because of containing hetero atoms with strong electronegativity such as oxygen, nitrogen and the like, is an active compound with special structure, and is known as a dominant structure in drug design and is paid attention to widely.
The marketed drugs penicillin and aztreonam both contain β -lactam building blocks; horsfilline is a chiral spiro compound with oxindole and pyrrole units isolated from Myristicaceae plant, and has analgesic effect; coerulescine and Elaconine are natural products separated from canary grass and elaeagnus pungens respectively, and have good antibacterial activity; spirotryprostatins A is likewise a spiro compound with oxindole and pyrrole units, which is capable of completely inhibiting G2/M phase division in mammalian TsFT210 cells. In recent years, the construction of chiral spiro oxindoles has been receiving increasing attention from pharmaceutical chemists and synthetic chemists.
However, at present, the antiviral effect of the structure of the spiro oxindole compound is less studied; therefore, the spiro oxindole compound with antiviral effect, especially the spiro oxindole compound with excellent antiviral effect, has important application value.
Disclosure of Invention
In order to overcome at least one technical problem in the prior art, the invention provides a spiro [ beta-lactam-3, 3' -oxindole ] derivative with a brand new structure; research shows that the spiro [ beta-lactam-3, 3' -oxindole ] derivative has antiviral effect and can be used for further developing medicaments with antiviral effect.
The technical problems to be solved by the invention are realized by the following technical scheme:
a spiro [ beta-lactam-3, 3' -oxindole ] derivative, which has a structure shown in formula I:
wherein R is 1 Selected from hydrogen, alkyl, alkoxy, halogen or ester groups;
R 2 selected from alkyl, alkenyl or benzyl;
R 3 selected from alkyl, phenyl, substituted phenyl, naphthalene, furan, thiophene or pyridine ringsA ring;
R 4 selected from alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring.
The spiro [ beta-lactam-3, 3' -oxindole ] derivative is characterized in that,
wherein R is 1 Selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen or C 2 -C 6 An ester group;
R 2 selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or benzyl;
R 3 selected from C 1 -C 6 Alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring, or pyridine ring;
R 4 selected from C 1 -C 6 An alkyl group, a phenyl group, a substituted phenyl group, a naphthalene ring, a furan ring, a thiophene ring, or a pyridine ring.
Preferably, R 1 Selected from hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, halogen or C 2 -C 3 An ester group.
Preferably, R 2 Selected from C 1 -C 4 Alkyl or C 2 -C 4 Alkenyl groups.
Preferably, R 3 Selected from phenyl, substituted phenyl, furan or thiophene rings.
Preferably, R 4 Selected from phenyl or substituted phenyl.
Preferably, the spiro [ beta-lactam-3, 3' -oxindole ] derivative is selected from the group consisting of compounds having the following structure:
the invention also provides a preparation method of the spiro [ beta-lactam-3, 3 '-oxindole ] derivative, which comprises the steps of taking propargylamide compounds and nitrone compounds as raw materials, adding monovalent copper salt catalysts, ligands and alkali, reacting in an inert gas atmosphere, and separating target products after the reaction is finished to obtain the spiro [ beta-lactam-3, 3' -oxindole ] derivative.
The invention provides a brand new preparation method of spiro [ beta-lactam-3, 3' -oxindole ] derivatives; the method is innovatively and efficiently constructing the spiro [ beta-lactam-3, 3' -oxindole ] compound by catalyzing continuous Kinugasa reaction/intramolecular carbon-carbon coupling reaction of propargylamide compound and nitrone through monovalent copper. The method takes propargylamide compounds and nitrone as substrates, monovalent copper salt as a catalyst, cyclizes under the action of nitrogen ligand and alkali to obtain spiro [ beta-lactam-3, 3' -oxindole ] compounds, has the advantages of easily available raw materials, cheap and easily available catalyst, simple synthesis conditions, few steps, high diastereoselectivity, high yield, wide substrate application range and the like, and is suitable for mass production and application in medicine and chemical industry.
Preferably, the propargylamide compound has a structure shown in a formula II; the nitrone compound has a structure shown in a formula III;
wherein R in formula II 1 Selected from hydrogen, alkyl, alkoxy, halogen or ester group, R 2 Selected from alkyl, alkenyl or benzyl; r in formula III 3 Selected from alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring, R 4 Selected from alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring or pyridine ring.
Further preferably, R 1 Selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen or C 2 -C 6 An ester group;
R 2 selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or benzyl;
R 3 selected from C 1 -C 6 Alkyl, phenyl, substituted phenyl, naphthalene ring, furan ring, thiophene ring, or pyridine ring;
R 4 selected from C 1 -C 6 An alkyl group, a phenyl group, a substituted phenyl group, a naphthalene ring, a furan ring, a thiophene ring, or a pyridine ring.
Still more preferably, R 1 Selected from hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, halogen or C 2 -C 3 An ester group.
Still more preferably, R 2 Selected from C 1 -C 4 Alkyl or C 2 -C 4 Alkenyl groups.
Still more preferably, R 3 Selected from phenyl, substituted phenyl, furan or thiophene rings.
Still more preferably, R 4 Selected from phenyl or substituted phenyl.
Preferably, the monovalent copper catalyst is cuprous chloride, cuprous bromide, cuprous iodide, tetraacetonitrile copper hexafluorophosphate, tetraacetonitrile copper tetrafluoroborate, cuprous cyanide or copper trifluoromethanesulfonate.
Preferably, the ligand is an amine ligand; the amine ligand is N, N '-dimethyl-1, 2-diphenyl-1, 2-ethylenediamine, 2' -bipyridine or 1, 10-phenanthroline.
Most preferably, the monovalent copper catalyst is selected from the group consisting of cuprous iodide while the amine ligand is selected from the group consisting of 2,2' -bipyridine.
Studies have shown that the catalytic activity of copper iodide in combination with 2,2' -bipyridine is best.
Preferably, the base is K 2 CO 3 、Cs 2 CO 3 、K 3 PO 4 NaOH, KOH, CSOH, csF or tBuOLi.
Most preferably, the base is tBuOLi.
Most preferably, the inert gas environment is a nitrogen environment or an argon environment.
The cyclization reaction is carried out in an inert gas atmosphere, an oxygen-free environment is provided, and side reactions are reduced, so that the yield is effectively improved.
Preferably, the molar ratio of the nitrogen ligand to the propargylamide compound is 0.1-0.2: 1.
more preferably, the molar ratio of amine ligand to amide compound is 0.1:1.
preferably, the dosage of the monovalent copper catalyst is 5-10% of the molar weight of propargylamide compounds.
More preferably, the monovalent copper catalyst is used in an amount of 10% of the molar amount of propargylamide-based compounds.
Preferably, the molar ratio of the alkali to the propargylamide compound is 1.5-4.5: 1.
more preferably, the molar ratio of the base to propargylamide is 2:1.
preferably, the molar ratio of the propargylamide compound to nitrone is 1-2: 1.
preferably, the solvent is acetonitrile.
Preferably, the reaction temperature is 15 to 30 ℃.
Most preferably, the preparation method of the spiro [ beta-lactam-3, 3' -oxindole ] derivative comprises the following steps: dissolving propargylamide compounds and nitrone compounds in an organic solvent, adding a monovalent copper catalyst, a nitrogen ligand and alkali, reacting for 8 hours in an inert gas atmosphere, and separating by column chromatography to obtain the spiro [ beta-lactam-3, 3' -oxindole ] compounds 3.
The invention also provides application of the spiro [ beta-lactam-3, 3' -oxindole ] derivative in preparing medicaments with antiviral effect.
Preferably, the virus is a herpes simplex virus.
The beneficial effects are that:
(1) The invention provides a spiro [ beta-lactam-3, 3 '-oxindole ] derivative with a brand new structure, and researches show that the spiro [ beta-lactam-3, 3' -oxindole ] derivative has a certain anti-herpes simplex disease effect.
(2) The inventors have found in the study that in the spiro [ beta ] -lactam-3, 3' -oxindoles described in the present invention]In the parent nucleus structure of the derivative, R 1 、R 2 、R 3 、R 4 The compounds obtained after substitution by different groups have a great difference in anti-herpes simplex effect; wherein R is 1 The compound obtained after being substituted by alkyl, alkoxy, ester or halogen has better anti-herpes simplex virus effect compared with R 1 Unsubstituted compounds with significantly improved anti-herpes simplex virus effect. The inventors have surprisingly found in further studies that R 3 The compound obtained after the group is replaced by the heterocyclic group has very excellent anti-herpes simplex virus effect; compared with the compound obtained after being substituted by other groups, the anti-herpes simplex virus effect of the compound is greatly improved. In conclusion, the spiro [ beta ] -lactam-3, 3' -oxindole according to the invention]The derivative is used for developing medicines with anti-herpes simplex virus and has wide application prospect.
(3) In addition, the invention also provides a brand-new, efficient and simple preparation method of the spiro [ beta-lactam-3, 3' -oxindole ] compound; the method adopts cheaper and easily available monovalent copper as a catalyst, and the reaction is carried out under mild conditions, so that the method is simple and convenient to operate, few in steps, good in functional group compatibility, high in yield and high in diastereoselectivity; therefore, the method has good application prospect in the medical industrial production.
Drawings
FIG. 1 is a synthetic route diagram of spiro [ beta-lactam-3, 3' -oxindole ] derivatives according to the invention.
Detailed Description
The present invention is further illustrated below with reference to specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art. Reagents and materials used in the following examples are commercially available unless otherwise specified.
Example 1 preparation of Compounds 1 and 2
The starting compound 1 of the present invention is a reported compound, which is synthesized by a method reported in the literature (Yan, j. Et al. Org. Lett.2012,14,1262) and is produced by a condensation reaction of an aromatic amine compound with propiolic acid. The specific synthesis method is as follows: to a reaction flask containing aromatic amine compound (5 mmol) and propargylic acid (5 mmol) were added 25mL of dried dichloromethane and Dicyclohexylcarbodiimide (DCC) (5 mmol), respectively, in this order. The reaction solution was stirred at 25℃for 24 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give the white solid product of formula (I) (yield 74 to 80%) as shown below:
the starting compound 2 of the present invention is a reported compound, which is synthesized by the method reported in the literature (Biswas, p.k.et al. Synth. Commun.2011,41,1146), and is prepared by reacting hydroxylamine compounds with aldehydes. The specific synthesis method is as follows: to each of the reaction bottles containing hydroxylamine compound (5 mmol) and aldehyde (5 mmol) was successively added 25mL of methanol. The reaction solution was stirred at 25℃for 4 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give the white solid product of formula (I) (yield 85-95%) as shown below:
EXAMPLE 2 Synthesis of Compound 3aa
The synthetic reaction formula for compound 3aa is shown below:
to a reaction flask containing propargylamide 1a (59.0 mg,0.2 mmol), nitrone 2a (40.0 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium tert-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The reaction solution was stirred at 25℃for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give 3aa (54 mg, yield 76%) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.43(d,J＝7.2Hz,1H),7.41-7.29(m,10H),7.15(m,2H),6.84(d,J＝8.0Hz,1H),5.50(s,1H),3.04(s,3H). 13 C NMR(100MHz,CDCl 3 )δ168.6,161.3,144.4,136.8,131.7,129.9,129.1,129.0,128.2,127.6,124.6,124.1,123.2,122.9,117.7,108.6,68.4,65.6,26.4.HRMS calcd for C 23 H 19 N 2 O 2 + (M+H) + 355.1442,found 355.1444.
EXAMPLE 3 Synthesis of Compound 3ba
The synthetic reaction formula for compound 3ba is shown below:
to a reaction flask containing propargylamide 1b (62.0 mg,0.2 mmol), nitrone 2a (40.0 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium tert-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The above reaction solution was stirred at 25℃for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give a white solid product 3ba (56 mg, yield 73%).
1 H NMR(400MHz,CDCl 3 )δ7.47-7.30(m,11H),7.14(q,J＝7.2Hz,2H),6.82(d,J＝7.6Hz,1H),5.70-5.58(m,1H),5.51(s,1H),5.13-4.95(m,2H),4.31-4.21(m,1H),4.06-4.00(m,1H). 13 C NMR(100MHz,CDCl 3 )δ168.4,161.2,143.5,136.9,131.7,130.7,129.8,129.2,128.9,128.2,127.4,124.6,124.1,123.3,122.9,117.6,117.2,109.4,68.5,65.7,42.3.HRMS calcd for C 25 H 21 N 2 O 2 + (M+H) + 381.1598,found 351.1600.
EXAMPLE 4 Synthesis of Compound 3ca
The synthetic reaction formula of compound 3ca is shown below:
to a reaction flask containing propargylamide 1c (72.0 mg,0.2 mmol), nitrone 2a (40.0 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium tert-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The above reaction solution was stirred at 25℃for 8 hours, then the solvent was removed by concentration under reduced pressure, and the residue was separated by column chromatography to give a white solid product 3ca (61 mg, yield 71%).
1 H NMR(400MHz,CDCl 3 )δ7.48-7.41(m,3H),7.39-7.32(m,7H),7.27-7.20(m,5H),7.17(t,J＝7.2Hz,1H),7.13-7.07(m,1H),6.96-6.90(m,2H),6.71(d,J＝7.6Hz,1H),5.52(s,1H),4.97(d,J＝15.6Hz,1H),4.45(d,J＝15.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ169.0,161.2,143.4,136.9,135.2,131.7,129.8,129.2,129.0,128.6,128.2,127.5,127.4,127.1,124.6,124.1,123.4,123.0,117.7,109.5,68.7,65.9,43.7.HRMS calcd for C 29 H 23 N 2 O 2 + (M+H) + 431.1755,found 431.1754.
EXAMPLE 5 Synthesis of Compound 3cb
The synthetic reaction formula of compound 3cb is shown below:
to a reaction flask containing propargylamide 1c (72.0 mg,0.2 mmol), nitrone 2b (43.0 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium tert-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The above reaction solution was stirred at 25℃for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give a white solid product 3cb (65 mg, yield 72%).
1 H NMR(400MHz,CDCl 3 )δ7.45-7.40(m,3H),7.38-7.33(m,4H),7.29–7.22(m,4H),7.20-7.15(m,1H),7.13-7.01(m,3H),6.99-6.96(m,2H),6.73(d,J＝8.0Hz,1H),5.50(s,1H),4.95(d,J＝15.6Hz,1H),4.49(d,J＝15.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ169.0,163.0(d,J＝247.0Hz),161.0,143.4,136.7,135.2,129.9,129.4(d,J＝9.0Hz),129.2,128.6,127.6,127.4(d,J＝3.0Hz),127.1,124.8,123.9,123.4,123.1,117.6,115.3(d,J＝22.0Hz),109.5,68.8,65.3,43.7.HRMS calcd for C 29 H 22 FN 2 O 2 + (M+H) + 449.1660,found 449.1663.
EXAMPLE 6 Synthesis of Compound 3cc
The synthetic reaction formula for compound 3cc is shown below:
to a reaction flask containing propargylamide 1c (72.0 mg,0.2 mmol), nitrone 2c (43.0 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium t-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The above reaction solution was stirred at 25℃for 8 hours, then the solvent was removed by concentration under reduced pressure, and the residue was separated by column chromatography to give 3cc (65 mg, yield 70%) of a white solid product.
1 H NMR(400MHz,CDCl 3 )δ7.46-7.26(m,10H),7.24-7.21(m,3H),7.19-7.15(m,1H),7.13-7.06(m,1H),7.00-6.95(m,2H),6.74(d,J＝8.0Hz,1H),5.47(s,1H),4.95(d,J＝15.6Hz,1H),4.49(d,J＝15.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ168.9,160.9,143.4,136.7,135.2,134.9,130.3,13.0,129.3,128.9,128.6,128.5,127.7,127.2,124.8,123.8,123.4,123.1,117.6,109.5,68.7,65.2,43.8.HRMS calcd for C 29 H 22 ClN 2 O 2 + (M+H) + 465.1365,found 465.1360.
EXAMPLE 7 Synthesis of Compound 3cd
The synthetic reaction formula of compound 3cd is shown below:
to a reaction flask containing propargylamide 1c (72.0 mg,0.2 mmol), nitrone 2d (55.0 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium tert-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The above reaction solution was stirred at 25℃for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give a white solid product 3cd (74 mg, yield 73%).
1 H NMR(400MHz,CDCl 3 )δ7.48(d,J＝8.4Hz,2H),7.43-7.39(m,3H),7.38-7.32(m,2H),7.29-7.21(m,6H),7.19-7.15(m,1H),7.11-7.07(m,1H),6.97-6.90(m,2H),6.74(d,J＝7.8Hz,1H),5.45(s,1H),4.95(d,J＝15.6Hz,1H),4.48(d,J＝15.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ168.9,160.9,143.4,136.7,135.2,131.5,130.8,130.0,129.3,129.2,128.7,127.7,127.2,124.8,123.7,123.4,123.2,123.1,117.6,109.5,68.7,65.3,43.8.HRMS calcd for C 29 H 22 BrN 2 O 2 + (M+H) + 509.0860,found 509.0865.
EXAMPLE 8 Synthesis of Compound 3ce
The synthesis reaction of compound 3ce is shown below:
to a reaction flask containing propargylamide 1c (72.0 mg,0.2 mmol), nitrone 2e (45.0 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium tert-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The above reaction solution was stirred at 25℃for 8 hours, then the solvent was removed by concentration under reduced pressure, and the residue was separated by column chromatography to give 3ce (61 mg, yield 66%) of a white solid product.
1 H NMR(400MHz,CDCl 3 )δ10.01(s,1H),7.86(d,J＝8.4Hz,2H),7.51(d,J＝8.0Hz,2H),7.48-7.33(m,5H),7.29-7.25(m,1H),7.22-7.16(m,4H),7.11(td,J＝7.6,0.8Hz,1H),6.956-6.93(m,2H),6.75(d,J＝7.8Hz,1H),5.58(s,1H),4.91(d,J＝15.6Hz,1H),4.48(d,J＝15.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ191.6,168.7,160.7,143.4,138.6,136.6,136.5,135.0,130.1,129.6,129.3,128.7,128.1,127.7,127.1,125.0,123.5,123.4,123.2,117.5,109.7,68.7,65.0,43.8.HRMS calcd for C 30 H 23 N 2 O 3 + (M+H) + 459.1704,found 459.1700.
EXAMPLE 9 Synthesis of Compound 3cf
The synthetic reaction formula for compound 3cf is shown below:
to a reaction flask containing propargylamide 1c (72.0 mg,0.2 mmol), nitrone 2f (42.2 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium tert-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The above reaction solution was stirred at 25℃for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give 3cf (64 mg, yield 72%) of a white solid product.
1 H NMR(400MHz,CDCl 3 )δ7.44(t,J＝7.6Hz,3H),7.35(t,J＝8.0Hz,2H),7.28(s,1H),7.26-7.13(m,8H),7.09(t,J＝7.6Hz,1H),6.98-6.95(m,2H),6.71(d,J＝7.8Hz,1H),5.50(s,1H),4.96(d,J＝15.6Hz,1H),4.49(d,J＝15.6Hz,1H),2.37(s,3H). 13 C NMR(100MHz,CDCl 3 )δ169.1,161.2,143.4,138.8,137.0,135.3,129.7,129.1,128.2,128.6,128.5,127.5,127.4,127.1,124.6,124.2,123.3,122.9,117.7,109.4,68.8,66.0,43.7,21.3.HRMS calcd for C 30 H 25 N 2 O 2 + (M+H) + 445.1911,found 445.1908.
EXAMPLE 10 Synthesis of Compound 3cg
The synthetic reaction formula of compound 3cg is shown below:
to a reaction flask containing propargylamide 1c (72.0 mg,0.2 mmol), nitrone 2g (45.4 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium t-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The above reaction solution was stirred at 25℃for 8 hours, then the solvent was removed by concentration under reduced pressure, and the residue was separated by column chromatography to give 3cg (68 mg, yield 74%) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.46-7.40(m,3H),7.38-7.29(m,4H),7.26-7.19(m,4H),7.17-7.13(m,1H),7.10(td,J＝7.6,0.8Hz,1H),6.97-6.95(m,2H),6.89(d,J＝8.8Hz,2H),6.70(d,J＝8.0Hz,1H),5.47(s,1H),4.97(d,J＝15.6Hz,1H),4.48(d,J＝15.6Hz,1H),3.80(s,3H). 13 C NMR(100MHz,CDCl 3 )δ169.2,161.3,160.1,143.4,137.0,135.3,129.7,129.1,128.9,128.61,127.5,127.1,124.6,124.2,123.4,123.3,123.0,117.7,113.6,109.4,68.9,65.9,55.2,43.7.HRMS calcd for C 30 H 25 N 2 O 3 + (M+H) + 461.1860,found 461.1862.
EXAMPLE 11 Synthesis of Compound 3ch
The synthesis reaction formula of compound 3ch is shown below:
/>
to a reaction flask containing propargylamide 1c (72.0 mg,0.2 mmol), nitrone 2h (54.8 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium tert-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in sequence, under nitrogen. The above reaction solution was stirred at 25℃for 8 hours, then the solvent was removed by concentration under reduced pressure, and the residue was separated by column chromatography to give a white solid product 3ch (80 mg, yield 78%).
1 H NMR(400MHz,CDCl 3 )δ7.57-7.51(m,2H),7.47-7.43(m,3H),7.40-7.36(m,2H),7.34-7.30(m,1H),7.30-7.17(m,6H),7.15-7.07(m,3H),6.72(d,J＝8.0Hz,1H),5.83(s,1H),4.98(d,J＝15.6Hz,1H),4.57(d,J＝15.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ168.6,161.2,143.5,136.7,135.1,132.5,132.1,130.3,130.0,129.6,129.3,128.5,127.5,127.2,126.9,124.8,124.7,123.0,123.9,121.9,117.6,109.5,68.1,64.2,43.9.HRMS calcd for C 29 H 22 BrN 2 O 2 + (M+H) + 509.0860,found 509.0863.
EXAMPLE 12 Synthesis of Compound 3ci
The synthetic reaction formula of compound 3ci is shown below:
to a reaction flask containing propargylamide 1c (72.0 mg,0.2 mmol), nitrone 2i (44.6 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium tert-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The above reaction solution was stirred at 25℃for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give the product 3ci (68 mg, yield 74%) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.58(dd,J＝8.4,1.0Hz,2H),7.47-7.45(m,2H),7.39-7.30(m,6H),7.24-6.98(m,9H),6.84(d,J＝16.0Hz,1H),6.72(d,J＝8.0Hz,1H),5.08(d,J＝15.6Hz,1H),5.00(d,J＝9.2Hz,1H),4.70(d,J＝15.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ170.2,160.6,143.5,137.6,136.9,135.5,135.1,129.8,129.2,128.7,127.6,127.1,127.0,124.7,123.8,123.8,123.4,123.1,117.4,109.5,69.2,64.4,43.9.HRMS calcd for C 31 H 25 N 2 O 2 + (M+H) + 457.1911,found 457.1910.
EXAMPLE 13 Synthesis of Compound 3cj
The synthetic reaction formula for compound 3cj is shown below:
to a reaction flask containing propargylamide 1c (72.0 mg,0.2 mmol), nitrone 2j (52.8 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium tert-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The above reaction solution was stirred at 25℃for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give a white solid product 3cj (72 mg, yield 72%).
1 H NMR(400MHz,CDCl 3 )δ7.45(d,J＝8.0Hz,2H),7.40-7.31(m,5H),7.27-7.15(m,5H),7.10(t,J＝7.6Hz,1H),6.73(d,J＝7.6Hz,1H),6.59(d,J＝3.2Hz,1H),6.34(d,J＝3.2Hz,1H),5.49(s,1H),5.10(d,J＝15.6Hz,1H),4.62(d,J＝15.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ168.5,160.5,147.7,143.4,136.2,135.0,130.1,129.3,128.9,127.7,127.0,125.0,123.3,123.2,123.1,122.3,117.6,114.3,112.9,109.8,68.0,58.7,43.9.HRMS calcd for C 27 H 20 BrN 2 O 3 + (M+H) + 499.0654,found 499.0650.
EXAMPLE 14 Synthesis of Compound 3ck
The synthetic reaction formula of compound 3ck is shown below:
to a reaction flask containing propargylamide 1c (72.0 mg,0.2 mmol), nitrone 2k (40.6 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium tert-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The reaction solution was stirred at 25℃for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give 3ck (65.4 mg, yield 75%) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.48-7.45(m,2H),7.41-7.32(m,4H),7.29-7.21(m,6H),7.17(t,J＝7.6Hz,1H),7.12-7.01(m,4H),6.72(d,J＝8.0Hz,1H),5.71(s,1H),5.00(d,J＝15.6Hz,1H),4.58(d,J＝15.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ168.7,160.8,143.4,136.5,135.1,133.7,129.9,129.1,128.6,128.5,127.5,127.2,127.1,126.4,124.8,123.7,123.3,123.0,117.7,109.6,69.1,61.8,43.8.HRMS calcd for C 27 H 21 N 2 O 2 S + (M+H) + 437.1319,found 437.1316.
EXAMPLE 15 Synthesis of Compound 3cl
The synthetic reaction formula of compound 3cl is shown below:
to a reaction flask containing propargylamide 1c (72.0 mg,0.2 mmol), nitrone 2l (46.0 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium tert-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The reaction solution was stirred at 25℃for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give a white solid product 3cl (73 mg, yield 78%).
1 H NMR(400MHz,CDCl 3 )δ7.44(d,J＝7.2Hz,1H),7.42-7.17(m,13H),7.10(t,J＝7.6Hz,1H),6.95-6.92(m,2H),6.71(d,J＝7.6Hz,1H),5.50(s,1H),4.96(d,J＝15.6Hz,1H),4.44(d,J＝15.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ168.8,161.1,143.4,135.4,135.1,131.2,129.9,129.8,129.3,129.1,128.6,128.3,127.5,127.4,127.1,123.8,123.4,123.0,118.9,109.5,69.0,66.1,43.7.HRMS calcd for C 29 H 21 ClN 2 O 2 + (M+H) + 465.1365,found 465.1361.
EXAMPLE 16 Synthesis of Compound 3cm
The synthesis reaction formula of 3cm of the compound is shown as follows:
to a reaction flask containing propargylamide 1c (72.0 mg,0.2 mmol), nitrone 2m (45.0 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium tert-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The reaction solution was stirred at 25℃for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give a white solid product (3 cm, 68mg, yield 74%).
1 H NMR(400MHz,CDCl 3 )δ7.44(d,J＝6.8Hz,1H),7.42-7.33(m,7H),7.27-7.17(m,4H),7.11-1.07(m,1H),6.96-6.93(m,2H),6.91-6.85(m,2H),6.70(d,J＝7.6Hz,1H),5.49(s,1H),4.96(d,J＝15.6Hz,1H),4.45(d,J＝15.6Hz,1H),3.79(s,3H). 13 C NMR(100MHz,CDCl 3 )δ169.1,160.6,156.5,143.4,135.2,131.8,130.4,129.7,128.9,128.6,128.2,127.5,127.1,124.1,123.4,123.0,119.0,114.4,109.4,68.7,65.9,55.4,43.6.HRMS calcd for C 30 H 25 N 2 O 3 + (M+H) + 461.1860,found 461.1858.
EXAMPLE 17 Synthesis of Compound 3da
The synthetic reaction formula of compound 3da is shown below:
to a reaction flask containing propargylamide 1d (87.6 mg,0.2 mmol), nitrone 2a (40.0 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium t-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The above reaction solution was stirred at 25℃for 8 hours, then the solvent was removed by concentration under reduced pressure, and the residue was separated by column chromatography to give a white solid product 3da (73 mg, yield 72%).
1 H NMR(400MHz,CDCl 3 )δ7.57(d,J＝1.2Hz,1H),7.44-7.33(m,10H),7.25-7.14(m,4H),6.98-6.87(m,2H),6.58(d,J＝8.4Hz,1H),5.51(s,1H),4.94(d,J＝15.6Hz,1H),4.44(d,J＝15.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ168.4,160.3,142.4,136.7,134.7,132.6,131.3,129.2,129.1,128.7,127.7,127.5,127.1,126.6,126.0,124.9,117.7,115.6,110.9,68.5,65.8,43.8.HRMS calcd for C 29 H 22 BrN 2 O 2 + (M+H) + 509.0860,found 509.0862.
EXAMPLE 18 Synthesis of Compound 3ea
The synthetic reaction formula of compound 3ea is shown below:
to a reaction flask containing propargylamide 1e (84.0 mg,0.2 mmol), nitrone 2a (40.0 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium tert-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The above reaction solution was stirred at 25℃for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give a white solid product 3ea (74 mg, yield 76%).
1 H NMR(400MHz,CDCl 3 )δ7.57(d,J＝1.2Hz,1H),7.44-7.33(m,10H),7.25-7.14(m,4H),6.98-6.87(m,2H),6.58(d,J＝8.4Hz,1H),5.51(s,1H),4.94(d,J＝15.6Hz,1H),4.44(d,J＝15.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ168.4,160.3,142.4,136.7,134.7,132.6,131.3,129.2,129.1,128.7,127.7,127.5,127.1,126.6,126.0,124.9,117.7,115.6,110.9,68.5,65.8,43.8.HRMS calcd for C 29 H 22 BrN 2 O 2 + (M+H) + 509.0860,found 509.0862.
EXAMPLE 19 Synthesis of Compound 3fa
The synthetic reaction formula of the compound 3fa is shown as follows:
to a reaction flask containing propargylamide 1f (78.0 mg,0.2 mmol), nitrone 2a (40.0 mg,0.2 mmol) and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dry acetonitrile, lithium tert-butoxide (34 mg,0.4 mmol) and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in that order, under a nitrogen atmosphere. The above reaction solution was stirred at 25℃for 8 hours, then the solvent was removed by concentration under reduced pressure, and the residue was separated by column chromatography to give 3fa (69 mg, yield 78%) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.45(d,J＝7.6Hz,2H),7.40-7.31(m,7H),7.25-7.14(m,4H),7.05(d,J＝2.4Hz,1H),6.95-6.93(m,2H),6.77(dd,J＝8.4,2.4Hz,1H),6.60(d,J＝8.4Hz,1H),5.51(s,1H),4.94(d,J＝15.6Hz,1H),4.42(d,J＝15.6Hz,1H),3.77(s,3H). 13 C NMR(100MHz,CDCl 3 )δ168.7,161.1,156.3,136.9,136.8,135.3,131.7,129.2,129.0,128.6,128.2,127.4,127.1,125.1,124.6,117.7,114.5,110.4,110.0,69.1,66.0,55.9,43.7.HRMS calcd for C 30 H 25 N 2 O 3 + (M+H) + 461.1860,found 461.1857.
EXAMPLE 20 Synthesis of Compound 3ga
The synthesis reaction of compound 3ga is shown below:
to a reaction flask containing 1g (65.0 mg,0.2 mmol) of propargylamide, 2a (40.0 mg,0.2 mmol) of nitrone, and cuprous iodide (3.8 mg,0.02 mmol) were added 2mL of dried acetonitrile, lithium tert-butoxide (34 mg,0.4 mmol), and 2,2' -bipyridine (3.1 mg,0.02 mmol), respectively, in this order, under nitrogen atmosphere. The above reaction solution was stirred at 25℃for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give 3ga (60 mg, yield 68%) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.46(dd,J＝8.4,0.8Hz,2H),7.39-7.32(m,7H),7.21-7.12(m,5H),6.92-6.85(m,3H),6.55(d,J＝8.0Hz,1H),5.66(s,1H),5.01(d,J＝15.6Hz,1H),4.30(d,J＝15.6Hz,1H),2.36(s,3H). 13 C NMR(100MHz,CDCl 3 )δ169.1,160.9,143.7,137.1,135.4,134.9,131.8,129.7,129.3,128.8,128.5,128.2,127.6,127.4,127.1,125.0,124.7,121.7,117.5,107.1,69.2,62.5,43.6,17.9.HRMS calcd for C 30 H 25 N 2 O 2 + (M+H) + 445.1911,found 445.1910.
Experimental example 1 antiviral Activity test of the spiro [ beta-lactam-3, 3' -oxindole ] derivatives of the present invention
Placing MDCK cells into a 96-hole cell culture plate, and cleaning with Eagle's liquid after the cells grow to be full of a single layer; after washing, the supernatant was discarded, and 80. Mu.L of 100TCID was added to each well of a 96-well cell culture plate 50 Type I herpes simplex virus (SM 44 strain), then 80. Mu.L of test compound diluted with MEM-fold ratio is added to each well; after the completion of the dosing, the cell culture plates were placed in an incubator at 37℃with 5% CO 2 Incubating for 48h under saturated humidity; after incubation, old solution in 96-well plates was discarded, and then 10 μl of CCK8 solution was added per well; continuing to incubate for 1h, and then testing the absorbance at 450nm by adopting an enzyme-labeled instrument; and calculate IC 50 A value; the experiment is provided with a virus control group and a cell control group at the same time; the test results are shown in Table 1.
The drug concentration is taken as the X axis, the cell survival rate is taken as the Y axis, and the drug concentration corresponding to 50% of the cell survival rate is obtained by plotting on Origin, and then the drug concentration is taken as IC 50 ；
Cell viability = (dosing well OD value-virus control OD value)/(cell control OD value-virus control OD value) ×100%.
TABLE 1 antiviral Activity of spiro [ beta-lactam-3, 3' -oxindole ] derivatives
/>
/>
/>
As can be seen from the experimental data in Table 1, the spiro [ beta-lactam-3, 3' -oxindole ] derivatives prepared in examples 2 to 20 of the present invention all show anti-herpes simplex disease activity; the spiro [ beta-lactam-3, 3' -oxindole ] derivative has a certain anti-herpes simplex effect.
Furthermore, it can be seen from the experimental data in Table 1 that in the spiro [ beta ] -lactam-3, 3' -oxindole according to the invention]In the parent nucleus structure of the derivative, R 1 、R 2 、R 3 、R 4 The compounds obtained after substitution by different groups have a great difference in anti-herpes simplex effect; wherein R is 1 The compounds of examples 17-20 obtained after being substituted by alkyl, alkoxy, ester or halogen have IC50 values of less than 10 mu M and have better anti-herpes simplex virus effect; r as compared with that prepared in example 4 1 The IC50 value of the unsubstituted compound is significantly reduced. This illustrates: spiro [ beta-lactam-3, 3' -oxindoles described in the present invention]In the parent nucleus structure of the derivative, R 1 Compounds obtained by substitution with alkyl, alkoxy, ester or halogen, relative to R 1 Unsubstituted compounds have significantly improved anti-herpes simplex virus effects.
Furthermore, it can be seen from the experimental data of Table 1 that R is prepared in examples 13 and 14 3 Is a compound substituted by heterocyclic groups, has IC50 values of less than 1 mu M, is greatly reduced compared with other compounds, and has excellent anti-herpes simplex virus effect. This illustrates: spiro [ beta-lactam-3, 3' -oxindoles described in the present invention]In the parent nucleus structure of the derivative, R 3 Compared with the compound obtained by substituting other groups, the compound obtained by substituting the heterocyclic groups has the advantages that the anti-herpes simplex virus effect is greatly improved, and the compound has very excellent anti-herpes simplex virus effect. Especially when R 3 The IC50 value of the compound obtained after the group is replaced by the thiophene ring reaches 0.27 mu M, and the compound has the optimal anti-herpes simplex virus effect.

Claims (8)

1. A spiro [ beta-lactam-3, 3' -oxindole ] derivative is characterized by having a structure shown in a formula I:
；
wherein,,
R 1 selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen or C 2 -C 6 An ester group;
R 2 selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or benzyl;
R 3 selected from C 1 -C 6 An alkyl group, a phenyl group, a naphthalene ring, a furan ring, a thiophene ring, or a pyridine ring;
R 4 selected from C 1 -C 6 An alkyl group, a phenyl group, a naphthalene ring, a furan ring, a thiophene ring, or a pyridine ring.
2. A spiro [ beta ] -lactam-3, 3' -oxindole according to claim 1]A derivative, characterized in that R 1 Selected from hydrogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, halogen or C 2 -C 3 An ester group.
3. A spiro [ beta ] -lactam-3, 3' -oxindole according to claim 1]A derivative, characterized in that R 2 Selected from C 1 -C 4 Alkyl or C 2 -C 4 Alkenyl groups.
4. A spiro [ beta ] -lactam-3, 3' -oxindole according to claim 1]A derivative, characterized in that R 3 Selected from phenyl, furan or thiophene rings.
5. A spiro [ beta ] -lactam-3, 3' -oxindole according to claim 1]A derivative, characterized in that R 4 Selected from phenyl groups.
6. The process for producing a spiro [ beta-lactam-3, 3' -oxindole ] derivative according to any one of claims 1 to 5, characterized in that,
propargylamide compounds and nitrone compounds are used as raw materials, then monovalent copper salt catalysts, ligands and alkali are added to react in an inert gas atmosphere, and after the reaction is finished, target products are separated to obtain the spiro [ beta-lactam-3, 3' -oxindole ] derivatives;
the propargylamide compound has a structure shown in a formula II; the nitrone compound has a structure shown in a formula III;
；
wherein R in formula II 1 Selected from hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, halogen or C 2 -C 6 Ester group, R 2 Selected from C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl or benzyl; r in formula III 3 Selected from C 1 -C 6 Alkyl, phenyl, naphthalene, furan, thiophene or pyridine rings, R 4 Selected from C 1 -C 6 An alkyl group, a phenyl group, a naphthalene ring, a furan ring, a thiophene ring, or a pyridine ring.
7. The use of the spiro [ beta-lactam-3, 3' -oxindole ] derivative according to any one of claims 1-5 in the preparation of a medicament having an antiviral effect.
8. The use according to claim 7, wherein the virus is a herpes simplex virus.
CN202210578701.8A 2022-05-26 2022-05-26 Spiro [ beta-lactam-3, 3' -oxindole ] derivative and preparation method and application thereof Active CN114989178B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210578701.8A CN114989178B (en) 2022-05-26 2022-05-26 Spiro [ beta-lactam-3, 3' -oxindole ] derivative and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210578701.8A CN114989178B (en) 2022-05-26 2022-05-26 Spiro [ beta-lactam-3, 3' -oxindole ] derivative and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN114989178A CN114989178A (en) 2022-09-02
CN114989178B true CN114989178B (en) 2023-09-01

Family

ID=83029544

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210578701.8A Active CN114989178B (en) 2022-05-26 2022-05-26 Spiro [ beta-lactam-3, 3' -oxindole ] derivative and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN114989178B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115304507A (en) * 2022-09-19 2022-11-08 兰州石化职业技术大学 Synthesis method of N-substituted aryl formamide

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107652296A (en) * 2016-07-26 2018-02-02 南开大学 Loop coil Oxoindole acyl hydrazone derivative and preparation method thereof and the application in terms of preventing and treating plant virus, sterilization, desinsection
CN112430236A (en) * 2020-11-27 2021-03-02 暨南大学 Synthesis method of chiral spiro [ pyrrolidone-3, 3 '-oxindole ] ring system and application of chiral spiro [ pyrrolidone-3, 3' -oxindole ] ring system in synthesis of natural product
CN114105978A (en) * 2021-11-04 2022-03-01 江西师范大学 Oxindole compound and preparation method and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107652296A (en) * 2016-07-26 2018-02-02 南开大学 Loop coil Oxoindole acyl hydrazone derivative and preparation method thereof and the application in terms of preventing and treating plant virus, sterilization, desinsection
CN112430236A (en) * 2020-11-27 2021-03-02 暨南大学 Synthesis method of chiral spiro [ pyrrolidone-3, 3 '-oxindole ] ring system and application of chiral spiro [ pyrrolidone-3, 3' -oxindole ] ring system in synthesis of natural product
CN114105978A (en) * 2021-11-04 2022-03-01 江西师范大学 Oxindole compound and preparation method and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Hai-Jun Leng,等.Diastereoselective [3 + 1] Cyclization Reaction of Oxindolyl Azaoxyallyl Cations with Sulfur Ylides: Assembly of 3,3′-Spiro[β-lactam]-oxindoles.Org. Lett..2021,第1451−1456页. *

Also Published As

Publication number Publication date
CN114989178A (en) 2022-09-02

Similar Documents

Publication Publication Date Title
US9656256B2 (en) N-heterocyclic carbene type palladium catalyst and its preparation method as well as applications
CN110724164B (en) Preparation method and application of 3-substituted chiral spiro aminophosphine ligand on pyridine ring
CN109232265B (en) Method for preparing benzyl amine compound
CN109320434B (en) Application of ionic iron (III) complex as catalyst in preparation of benzyl amine compounds
CN114989178B (en) Spiro [ beta-lactam-3, 3' -oxindole ] derivative and preparation method and application thereof
CN109265475B (en) Preparation method of polysubstituted aryl ethylene boronic acid pinacol ester derivative
US11890602B2 (en) Application of the ionic iron (III) complex as catalyst in preparation of benzylamine compound
CN112661764B (en) Tetrahydrofuran indole compound and preparation method and application thereof
Swingle et al. Enantioselective conjugate addition, part V. Synthesis and testing of scalemic tetraamines as chiral cuprate ligands.
CN109400611B (en) Synthesis method of 1-vinyl-4, 5-dihydropyrrole [1,2-a ] quinoxaline compound
CN111763197A (en) Synthesis method of novel chiral indole compound
FI90541B (en) Process for the preparation of thiophene derivatives substituted in the position by a bromine atom
CN113234061B (en) Synthesis method of disubstituted spiro aromatic hydrocarbon
CN110256349B (en) Polysubstituted pyrazoles and process for their preparation
CN113200980B (en) Method for synthesizing indolizine compound under catalysis of silver
CN113861238B (en) Method for synthesizing phosphine chiral center secondary/tertiary phosphine oxide compound through palladium/chiral ligand catalysis
CN113234083B (en) Tetrahydroquinoline pyran compound and preparation method and application thereof
CN111808045B (en) Method for synthesizing chiral seven-element cyclic sulfonamide through organic catalysis
CN112125843B (en) Preparation method of 3-hydroxymethyl-4-phenyl-3, 4-dihydroquinolinone compound
CN113461690B (en) Synthesis method of chiral 4,6-dioxooctahydropyrrolo [3,4-c ] pyrrole-1-carboxylate compound
CN110804007B (en) Polysubstituted pyrrole derivative and preparation method thereof
CN109796372B (en) Method for preparing polysubstituted alkenyl amidine
CN108997089B (en) Method for catalyzing arylation of benzyl alcohol compound
CN108101758B (en) Method for preparing chiral propargylated aliphatic six-membered carbocyclic ring compound
CN116120193A (en) Novel method for synthesizing chiral triphenylmethane compounds

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
GR01 Patent grant
GR01 Patent grant