CN111018840A - 3-imidazole substituted isatin alcohol compound and preparation method and medical application thereof - Google Patents

3-imidazole substituted isatin alcohol compound and preparation method and medical application thereof Download PDF

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CN111018840A
CN111018840A CN201911349168.2A CN201911349168A CN111018840A CN 111018840 A CN111018840 A CN 111018840A CN 201911349168 A CN201911349168 A CN 201911349168A CN 111018840 A CN111018840 A CN 111018840A
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isatin
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CN111018840B (en
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周成合
坦咖丹初·维加库玛·瑞迪
张园
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Southwest University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • A61P31/10—Antimycotics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to a 3-imidazole substituted isatinol compound, a preparation method and medical application thereof, wherein the isatinol compound is shown as a general formula V, has certain inhibitory activity on gram-positive bacteria, gram-negative bacteria and fungi, can be used for preparing antibacterial and/or antifungal medicaments, has simple, cheap and easily-obtained preparation raw materials and short synthetic route, and has important significance in application in the aspect of resisting infection.

Description

3-imidazole substituted isatin alcohol compound and preparation method and medical application thereof
Technical Field
The invention belongs to the field of chemical synthesis, and relates to a 3-imidazole substituted isatin azole alcohol compound, a preparation method and medical application of the compound.
Background
Microbial infections have become the greatest threat to human health. To date, a large number of antibiotics and synthetic drugs have been used to treat microbial infections. However, excessive reliance on these antimicrobial drugs has led to the emergence of multi-drug resistant bacteria, such as methicillin-resistant staphylococcus aureus, methicillin-resistant staphylococcus epidermidis, vancomycin-resistant enterococcus faecium, which have rendered many traditional antibiotics and synthetic drugs ineffective. Therefore, the development of antibacterial agents having new structures has become urgent, and particularly, the development of antibacterial agents having high efficacy, low toxicity and low drug resistance has attracted extensive attention.
Isatin is a well-known pharmaceutical agent and is widely found in the brain, nerve endings and other fluid sites of humans and animals as a bioregulator. The versatility of the structure of isatin molecules makes it an ideal substrate in structural modification and structural derivation, and can exhibit a wide range of biological activities, such as antibacterial, antifungal, anticancer, antidepressant, antispasmodic, anti-HIV, anti-inflammatory, etc., by binding non-covalent forces (hydrogen bonding, metal ion coordination, ion-dipole interaction, pi-pi stacking, hydrophobic-hydrophobic interaction, and van der waals forces) to various active targets such as enzymes, receptors, etc., in the organism. Isatin derivative oxindole has been widely used in the synthesis of drug molecules, for example, the oxindole fragment-containing drugs SU-5416 and SU-11248 approved by the U.S. food and drug administration have been used in the treatment of gastrointestinal stromal tumors and advanced kidney cancers. Furthermore, thiazoline, thiazolinone, and the like generated by the cyclization of isatin can increase the antibacterial activity thereof. With the successive appearance of a plurality of drugs containing isatin structural fragments, the synthesis of isatin drug molecules and the research on the biological activity thereof increasingly become hot spots in the field of medicine research and development, mainly through carrying out structural modification on the basic skeleton of the isatin drug molecules and introducing different active groups, and the isatin drug with good pharmacokinetic property, low toxic and side effects and high biological activity is expected to be obtained.
The carfentrazol fragment is an important pharmacodynamic fragment widely existing in bioactive molecules. In recent years, many azolol compounds have been successfully developed and widely used in clinical practice. For example, the triadimenol compounds fluconazole and voriconazole have very good curative effect when being used as first-line medicaments for treating fungal infection when being used for treating candida albicans and neococcal negative bacteria infection. Nitroimidazole azole compounds such as metronidazole, secnidazole and ornidazole have been used for many years to treat infectious diseases caused by anaerobic bacteria. There has been a great deal of interest in the development of antibacterial drugs such as triadimenol. In addition, the unique aromatic nitrogen heterocyclic structure of the azole ring enables the azole derivative to quickly and efficiently react with biological macromolecules such as proteins, enzymes, receptors and the like in organisms to play a good biological activity. Azole compounds have the advantages of high cure rate, good pharmacokinetic properties, high activity, low toxicity, and the like when used for treating infectious diseases. In recent years, the development of new compounds with new targets or multiple modes of action through the combination of oxazolol and other pharmacodynamic fragments has received much attention as hydrogen bond donors capable of hydrogen bonding interactions with active molecules in the organism to enhance the biological activity of drug molecules. Therefore, the modification of isatin molecular structure with the use of an oxazolol fragment in order to obtain an antibacterial drug with high efficacy and low toxicity has attracted our research interest.
Disclosure of Invention
In view of the above, the present invention aims to provide an isatin alcohol compound and a pharmaceutically acceptable salt thereof; the second purpose of the invention is to provide a method for preparing the isatin alcohol compound and the medicinal salt thereof; the third object of the present invention is to provide a preparation containing the isatinozolol compound; the fourth purpose of the invention is to provide the application of the isatin alcohol compound and the medicinal salt thereof in preparing antibacterial and/or antifungal medicaments.
In order to achieve the purpose, the invention provides the following technical scheme:
1. the structure of the 3-imidazole substituted isatin alcohol compound and the pharmaceutically acceptable salt thereof is shown as a general formula V:
Figure BDA0002334239380000021
in the formula, R1Hydrogen, alkyl; r2Hydrogen and nitro; r3Hydrogen and nitro; r6Hydrogen, alkenyl, phenyl, substituted phenyl.
Preferably, R1Hydrogen and methyl; r2Hydrogen and nitro; r3Hydrogen and nitro; r6Hydrogen, vinyl, phenyl, p-fluorophenyl, p-chlorophenyl, 2, 4-dichlorophenyl.
Preferably, it is any one of the following compounds:
Figure BDA0002334239380000022
Figure BDA0002334239380000031
more preferably, the isatin alcohol compounds are V-1, V-2, V-4, V-5, V-6, V-7, V-8, V-9, V-10, V-11 and V-12.
2. The preparation method of the 3-imidazole substituted isatin alcohol compound and the medicinal salt thereof,
preparation of pharmaceutically acceptable salts of isatin alcohol compounds shown as general formula V: dissolving a compound shown as a general formula VIII in an organic solvent, adding different substituted nitroimidazoles, and carrying out a ring-opening reaction under the action of alkali in a reflux process to obtain a medicinal salt of a 3-imidazole substituted isatin alcohol compound shown as a general formula V;
Figure BDA0002334239380000032
preferably, the reaction solvent is acetonitrile; the alkali is potassium carbonate; nitroimidazole and potassium carbonate are added together to react for 0.5h at 60 ℃; the raw materials are added at room temperature and reacted for 10 to 12 hours under reflux.
3. The preparation containing the 3-imidazole substituted isatin alcohol compound and the pharmaceutically acceptable salt thereof.
Preferably, the preparation is tablets, capsules, powder, granules, dripping pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols or transdermal patches.
4. The 3-imidazole substituted isatin alcohol compound and the medicinal salt thereof are applied to the preparation of antibacterial and/or antifungal medicaments.
Preferably, the bacteria is any one or more of methicillin-resistant staphylococcus aureus, enterococcus faecalis, klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa and acinetobacter baumannii; the fungus is any one or more of Candida albicans, Candida tropicalis, Aspergillus fumigatus and Candida parapsilosis.
The invention has the beneficial effects that: the invention utilizes the drug design split principle to introduce the azolol fragment on indole for the first time, designs and synthesizes a series of 3-imidazole substituted isatinol compounds with novel structures, and the compounds are detected by in vitro antimicrobial activity to find that the compounds have certain inhibitory activity on gram-positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923 and staphylococcus aureus ATCC29213), gram-negative bacteria (Klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC27853, escherichia coli 25922 and Acinetobacter baumannii) and fungi (Candida albicans, Candida tropicalis, aspergillus fumigatus, Candida albicans ATCC90023 and Candida parapsilosis ATCC20019), and can be used for preparing antibacterial and/or antifungal drugs, thereby providing more efficient and more efficient antibacterial and/or antifungal drugs for clinical antimicrobial treatment, Safe candidate drugs are helpful for solving clinical treatment problems of increasingly serious drug resistance, stubborn pathogenic microorganisms, newly emerged harmful microorganisms and the like.
Detailed Description
The preferred embodiments of the present invention will be described in detail below.
In the context of the present invention, the isatin derivative VI reference "Mehra N V, Hopper M, Patel N, Hall D, Wrischnik L A, Land K M, Kumar V.design and synthesis of β -amino alcohol based β -lactic-acid-iso-matic constructs and expression analysis of in vitro activity against amino acid promoter protein variants. Med.Chem.Commun.2013, 4,1018 1024".
Figure BDA0002334239380000041
VII to VIII are prepared: reference is made to the references "Chouhan M, Senwar K R, Sharma R, Grover V, Nair V A. registration approach for the synthesis of 3-hydroxy-3-aminomethydolindolin-2-one derivative. Green chem.,2011,13, 2553-2560. Senwar K R, Sharma P, Reddy T.S, Jeengar M K, Nayak V.L, Naidu VGM, Kamal A, Shankaiaah N.Spiroxoside-derivative mole-derivative-1, 2, 3-triazoles:" sign, synthesis, cytoxicity and synthesis introduction J.413. C.102, 11. medium J.424; r in the general formulae VII to VIII6Hydrogen, alkyl, alkenyl, phenyl, substituted phenyl. Wherein R in VIII-16Is hydrogen, R in VIII-26Is vinyl, R in VIII-36Is phenyl, R in VIII-46Is p-fluorophenyl, R in VIII-56Is p-chlorophenyl, R in VIII-66Is 2, 4-dichlorophenyl.
In the following examples, the room temperature is 18 to 25 ℃.
Example 1 preparation of Compound I-1
Figure BDA0002334239380000051
A50 mL round-bottomed flask was charged with 2-methyl-5-nitroimidazole (1.90g,15mmol) and potassium carbonate (1.65g,12mmol), stirred at 60 ℃ for 1 hour using 20mL acetonitrile as a solvent, added with isatin derivative VI (2.03g,10mmol), and the reaction was continued at 60 ℃ and followed by thin layer chromatography until the reaction was complete. Distilling under reduced pressure to remove acetonitrile, extracting with water and chloroform, concentrating, recrystallizing, and drying to obtain compound I-1(2.47g) with yield of 74.8%; a yellow solid; melting point: 235 ℃ and 237 ℃.1H NMR(600MHz,DMSO-d6,ppm):δ8.30(s,1H,Im-H-4),7.68(t,J＝7.8Hz,1H,isatin-H-6),7.57(d,J＝6.5Hz,1H,isatin-H-4),7.27(d,J＝8.0Hz,1H,isatin-H-7),7.14(t,J＝7.5Hz,1H,isatin-H-5),5.56(d,J＝4.8Hz,1H,-OH),4.20-4.16(m,1H,CH1a-Im),4.10-4.06(m,1H,OHCH),4.03(dd,J＝13.6,9.1Hz,1H,CH1b-Im),3.75(dd,J＝5.8,1.6Hz,2H,NCH2),2.38(s,3H,CH3-Im)。
Example 2 preparation of Compound I-2
Figure BDA0002334239380000052
A50 mL round-bottom flask was charged with 4-nitroimidazole (1.69g,15mmol) and potassium carbonate (1.65g,12mmol), stirred at 60 ℃ for 1 hour with 20mL acetonitrile as solvent, added with isatin derivative VI (2.03g,10mmol), and the reaction was stirred at 60 ℃ and followed by thin layer chromatography until the reaction was complete. Distilling under reduced pressure to remove acetonitrile, extracting with water and chloroform, concentrating, recrystallizing, and drying to obtain compound I-2(2.50g) with yield of 64.8%; a yellow solid; melting point: 221-223 ℃.1H NMR(600MHz,DMSO-d6,ppm):δ8.35(s,1H,Im-H-5),7.81(s,1H,Im-H-2),7.67(t,J＝7.8Hz,1H,isatin-H-6),7.57(d,J＝8.3Hz,1H,isatin-H-4),7.23(d,J＝8.0Hz,1H,isatin-H-7),7.14(t,J＝7.5Hz,1H,isatin-H-5),5.62(s,1H,-OH),4.31-4.26(m,1H,CH1a-Im),4.09(t,J＝8.5Hz,2H,CH1b-Im,OHCH),3.71(d,J＝4.8Hz,2H,NCH2)。
Example 3 preparation of Compound II-1
Figure BDA0002334239380000053
A50 mL round bottom flask was charged with hydroxylamine hydrochloride (0.04g,0.60mmol) dissolved in 5mL ethanol with catalytic amount of hydrochloric acid, followed by slow dropwise addition of a solution of I-1(0.20g,0.60mmol) in 5mL ethanol at room temperature, stirring the reaction under reflux and thin layer chromatography followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying, etc. to obtain compound II-1(0.17g) with yield of 81.3%; a yellow solid; melting point:>250℃。1H NMR(600MHz,CDCl3,ppm):δ13.39(s,1H,-NOH),8.33(s,1H,Im-H-4),8.00(d,J＝8.3Hz,1H,isatin-H-4),7.44(t,J＝7.2Hz,1H,isatin-H-6),7.21(d,J＝7.9Hz,1H,isatin-H-7),7.09(t,J＝7.3Hz,1H,isatin-H-5),5.53(d,J＝5.5Hz,1H,-OH),4.17(dd,J＝14.0,2.6Hz,1H,CH1a-Im),4.10-4.05(m,1H,OHCH),),3.99(dd,J＝9.0Hz,13.8Hz,1H,CH1b-Im),3.79(dd,J＝13.1,6.3Hz,2H,NCH2),2.38(s,3H,CH3-Im)。
example 4 preparation of Compound II-2
Figure BDA0002334239380000061
A50 mL round bottom flask was charged with hydrazine hydrate (0.04mL,0.90mmol) in 5mL ethanol, and a catalytic amount of hydrochloric acid, followed by slow dropwise addition of a solution of I-1(0.30g,0.90mmol) in 5mL ethanol at room temperature, stirring the reaction under reflux, and thin layer chromatography was followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying to obtain compound II-2(0.21g) with yield of 67.7%; a red solid; melting point:>250℃。1H NMR(600MHz,CDCl3,ppm):δ8.90(s,2H,NNH2),8.33(s,1H,Im-H-4),7.97(d,J＝7.5Hz,1H,isatin-H-4),7.30(t,J＝7.7Hz,1H,isatin-H-6),7.17(d,J＝8.0Hz,1H,isatin-H-7),7.04(t,J＝7.5Hz,1H,isatin-H-5),5.48(d,J＝5.7Hz,1H,-OH),4.15(dd,J＝14.1,2.6Hz,1H,CH1a-Im),4.09-4.05(m,1H,OHCH),3.96(dd,J＝14.1,8.9Hz,1H,CH1b-Im),3.79(d,J＝6.0Hz,2H,NCH2),2.35(s,3H,CH3-Im)。
example 5 preparation of Compound II-3
Figure BDA0002334239380000062
A50 mL round bottom flask was charged with phenylhydrazine (0.12mL,1.21mmol) in 5mL ethanol, and a catalytic amount of hydrochloric acid, followed by slow dropwise addition of a solution of I-1(0.30g,0.90mmol) in 5mL ethanol at room temperature, stirring the reaction under reflux, and thin layer chromatography was followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying to obtain compound II-3(0.28g), with yield of 73.6%; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6,ppm):δ12.69(s,1H,＝NNHAr),8.32(s,1H,Im-H-4),7.61(d,J＝7.4Hz,1H,isatin-H-4),7.46(d,J＝7.8Hz,2H,Ar-H),7.39(t,J＝7.9Hz,2H,Ar-H),7.34(t,J＝7.7Hz,1H,isatin-H-6),7.26(d,J＝7.9Hz,1H,isatin-H-7),7.13(t,J＝7.5Hz,1H,isatin-H-5),7.06(t,J＝7.3Hz,1H,Ar-H),5.56(d,J＝4.8Hz,1H,-OH),4.21(dd,J＝14.1,2.8Hz,1H,CH1a-Im),4.16-4.10(m,1H,OHCH),4.03(dd,J＝14.1,8.9Hz,1H,CH1b-Im),3.90-3.83(m,2H,NCH2),2.38(s,3H,CH3-Im)。
example 6 preparation of Compound II-4
Figure BDA0002334239380000071
A50 mL round bottom flask was charged with 2, 4-dinitrophenylhydrazine (0.18mL,0.90mmol) dissolved in 5mL ethanol, and a catalytic amount of hydrochloric acid, followed by slow dropwise addition of a solution of I-1(0.30g,0.90mmol) in 5mL ethanol at room temperature, stirring the reaction under reflux, and thin layer chromatography was followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying to obtain compound II-4(0.32g), with yield of 69.5%; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6,ppm):δ14.44(s,1H,N-NH),8.89(d,J＝2.5Hz,1H,Ar-H),8.51(dd,J＝9.5,2.5Hz,1H,Ar-H),8.31(d,J＝10.6Hz,2H,Im-H-4,Ar-H),7.70(d,J＝7.5Hz,1H,isatin-H-4),7.47(t,J＝7.8Hz,1H,isatin-H-6),7.30(d,J＝7.9Hz,1H,isatin-H-7),7.17(t,J＝7.5Hz,1H,isatin-H-5),5.57(s,1H,-OH),4.22(dd,J＝13.9,2.3Hz,1H,CH1a-Im),4.15-4.11(m,1H,OHCH),4.06(dd,J＝13.9,9.2Hz,1H,CH1b-Im),3.91-3.83(m,2H,NCH2),2.39(s,3H,CH3-Im)。
example 7 preparation of Compound II-5
Figure BDA0002334239380000072
A50 mL round bottom flask was charged with thiosemicarbazide (0.082g,0.90mmol) dissolved in 5mL ethanol and catalytic amount of hydrochloric acid, followed by slow dropwise addition of I-1(0.30g,0.90mmol) at room temperature) 5mL of ethanol, the reaction is stirred under reflux and followed by thin-layer chromatography until the end of the reaction. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying to obtain compound II-5(0.25g) with yield of 69.4%; a red solid; melting point:>250℃。1H NMR(600MHz,CDCl3,ppm):δ12.41(s,1H,＝NNHCSNH2),9.07(s,1H,＝NNHCSNH1a),8.73(s,1H,＝NNHCSNH1b),8.30(s,1H,Im-H-4),7.72(d,J＝7.3Hz,1H,isatin-H-4),7.44(t,J＝7.4Hz,1H,isatin-H-6),7.27(d,J＝7.8Hz,1H,isatin-H-7),7.16(t,J＝7.4Hz,1H,isatin-H-5),5.56(d,J＝4.6Hz,1H,-OH),4.19(d,J＝13.7Hz,1H,CH1a-Im),4.14-4.07(m,1H,OHCH),4.03(dd,J＝13.5,9.6Hz,1H,CH1b-Im),3.88-3.79(m,2H,NCH2),2.37(s,3H,CH3-Im)。
example 8 preparation of Compound II-6
Figure BDA0002334239380000081
A50 mL round-bottomed flask was charged with Compound II-5(0.20g, 0.49mmol) and 40% chloroacetaldehyde in water (0.05g,0.73mmol), 20mL ethanol as a solvent, a catalytic amount of triethylamine was added at room temperature, the reaction was stirred under reflux for 2 to 3 hours, and thin layer chromatography was followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying, and processing to obtain compound II-6(0.17g) with yield of 64.5%; a yellow solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6,ppm):δ13.18(s,1H,＝NNHCSNH2),8.32(s,1H,Im-H-4),7.58(d,J＝7.2Hz,1H,isatin-H-4),7.46-7.40(m,2H,isatin-H-6,thiazole-H-4),7.29(d,J＝7.8Hz,1H,isatin-H-7),7.22(s,1H,thiazole-H-5),7.16(t,J＝7.2Hz,1H,isatin-H-5),5.57(d,J＝4.9Hz,1H,-OH),4.20(d,J＝14.0Hz,1H,CH1a-Im),4.15-4.10(m,1H,OHCH),4.05(d,J＝13.8Hz,1H,CH1b-Im),3.87-3.80(m,2H,NCH2),2.38(s,3H,CH3-Im)。
example 9 preparation of Compound II-7
Figure BDA0002334239380000082
A50 mL round bottom flask was charged with hydroxylamine hydrochloride (0.054g,0.79mmol) dissolved in 5mL ethanol with catalytic amount of hydrochloric acid followed by slow dropwise addition of a solution of I-2(0.25g,0.79mmol) in 5mL ethanol at room temperature, stirring the reaction under reflux and thin layer chromatography followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying to obtain compound II-7(0.21g) with yield of 80.7%; a brown solid; melting point:>250℃。1H NMR(600MHz,DMSO-d6,ppm):δ13.36(s,1H,-NOH),8.38(s,1H,Im-H-5),8.00(d,J＝7.4Hz,1H,isatin-H-4),7.83(s,1H,Im-H-2),7.44(t,J＝8.2Hz,1H,isatin-H-6),7.17(d,J＝7.9Hz,1H,isatin-H-7),7.09(t,J＝7.5Hz,1H,isatin-H-5),5.56(s,1H,-OH),4.28(dd,J＝13.2,2.0Hz,1H,CH1a-Im),4.13-4.06(m,1H,OHCH),4.04(dd,J＝13.3,8.7Hz,1H,CH1a-Im),3.75(d,J＝5.7Hz,2H,NCH2)。
example 10 preparation of Compound II-8
Figure BDA0002334239380000091
A50 mL round bottom flask was charged with hydrazine hydrate (0.039mL,0.79mmol) in 5mL ethanol, and a catalytic amount of hydrochloric acid, followed by slow dropwise addition of a solution of I-2(0.25g,0.79mmol) in 5mL ethanol at room temperature, stirring the reaction under reflux, and thin layer chromatography was followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying to obtain compound II-8(0.17g) with yield of 65.3%; a brown solid; melting point:>250℃；1H NMR(600MHz,DMSO-d6,ppm):δ8.91(s,2H,NNH2),8.39(s,1H,Im-H-5),7.97(d,J＝7.5Hz,1H,isatin-H-4),7.83(s,1H,Im-H-2),7.30(t,J＝7.7Hz,1H,isatin-H-6),7.14(d,J＝7.9Hz,1H,isatin-H-7),7.05(t,J＝7.5Hz,1H,isatin-H-5),5.51(d,J＝5.6Hz,1H,-OH),4.24(dd,J＝13.6,2.3Hz,1H,CH1a-Im),4.10-4.05(m,1H,OHCH),4.01(dd,J＝13.6,8.6Hz,1H,CH1b-Im),3.79-3.72(m,2H,NCH2)。
example 11 preparation of Compound II-9
Figure BDA0002334239380000092
A50 mL round bottom flask was charged with phenylhydrazine (0.07mL,0.63mmol) in 5mL ethanol, and a catalytic amount of hydrochloric acid, followed by slow dropwise addition of a solution of I-2(0.20g,0.63mmol) in 5mL ethanol at room temperature, stirring the reaction under reflux, and thin layer chromatography was followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying, and processing to obtain compound II-9(0.20g) with yield of 80.0%; a yellow solid; melting point:>250℃；1H NMR(600MHz,DMSO-d6,ppm):δ12.68(s,1H,＝NNHAr),8.39(s,1H,Im-H-5),7.85(s,1H,Im-H-2),7.61(d,J＝7.4Hz,1H,isatin-H-4),7.46(d,J＝7.7Hz,2H,Ar-H),7.39(t,J＝7.9Hz,2H,Ar-H),7.34(t,J＝8.2Hz,1H,isatin-H-6),7.22(d,J＝7.9Hz,1H,isatin-H-7),7.13(t,J＝7.6Hz,1H,isatin-H-5),7.06(t,J＝7.3Hz,1H,Ar-H),5.62(d,J＝5.4Hz,1H,-OH),4.31(dd,J＝13.6,2.6Hz,1H,CH1a-Im),4.18-4.13(m,1H,OHCH),4.08(dd,J＝13.7,8.5Hz,1H,CH1b-Im),3.83(d,J＝5.9Hz,2H,NCH2)。
example 12 preparation of Compound II-10
Figure BDA0002334239380000101
A50 mL round bottom flask was charged with 2, 4-dinitrophenylhydrazine (0.12g,0.63mmol) dissolved in 5mL ethanol, and a catalytic amount of hydrochloric acid, followed by slow dropwise addition of a solution of I-2(0.20g,0.63mmol) in 5mL ethanol at room temperature, stirring the reaction under reflux, and thin layer chromatography was followed until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying to obtain compound II-10(0.23g) with yield of 73.4%; an orange solid; melting point:>250℃；1H NMR(600MHz,DMSO-d6,ppm):δ14.40(s,1H,N-NH),8.87(d,J＝2.6Hz,1H,Ar-H),8.50(dd,J＝9.5,2.5Hz,1H,Ar-H),8.37(d,J＝1.2Hz,1H,Im-H-5),8.29(d,J＝9.5Hz,1H,Ar-H),7.83(d,J＝1.2Hz,1H,Im-H-2),7.67(d,J＝7.3Hz,1H,isatin-H-4),7.45(t,J＝7.7Hz,1H,isatin-H-6),7.24(d,J＝7.9Hz,1H,isatin-H-7),7.16(t,J＝7.5Hz,1H,isatin-H-5),5.63(s,1H,-OH),4.32(d,J＝11.3Hz,1H,CH1a-Im),4.16-4.13(m,1H,OHCH),4.12-4.08(m,1H,CH1b-Im),3.82(d,J＝5.8Hz,2H,NCH2)。
example 13 preparation of Compound II-11
Figure BDA0002334239380000102
A50 mL round bottom flask was charged with thiosemicarbazide (0.057g,0.63mmol) in 5mL ethanol, with catalytic amounts of hydrochloric acid, followed by slow dropwise addition of a solution of I-2(0.20g,0.63mmol) in 5mL ethanol at room temperature, the reaction stirred under reflux and followed by thin layer chromatography until the reaction was complete. Distilling under reduced pressure to remove ethanol, diluting with water, filtering, recrystallizing, drying to obtain compound II-11(0.17g) with yield of 69.1%; a yellow solid; melting point:>250℃；1H NMR(600MHz,DMSO-d6,ppm):δ12.40(s,1H,＝NNHCSNH2),9.08(s,1H,＝NNHCSNH1a),8.74(s,1H,＝NNHCSNH1b),8.37(s,1H,Im-H-5),7.82(s,1H,Im-H-2),7.72(d,J＝7.4Hz,1H,isatin-H-4),7.44(t,J＝7.7Hz,1H,isatin-H-6),7.23(d,J＝8.0Hz,1H,isatin-H-7),7.16(t,J＝7.5Hz,1H,isatin-H-5),5.61(d,J＝5.2Hz,1H,-OH),4.29(dd,J＝11.4,1.8Hz,1H,CH1a-Im),4.14-4.11(m,1H,OHCH),4.07(dd,J＝13.2,8.4Hz,1H,CH1b-Im),3.79(d,J＝5.7Hz,2H,NCH2)。
example 14 preparation of Compound III-1
Figure BDA0002334239380000111
Adding compound I-1(0.50g,1.51mmol) and 4-chloroacetophenone (0.19mL,1,51mmol) into a 50mL round-bottom flask, taking 10mL methanol as a solvent, adding diethylamine (0.15mL,1.51mmol) at room temperature, reacting at room temperature, tracking by thin layer chromatography until the reaction is finished, and then carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain compound III-1(0.55g), wherein the yield is 75.3%; white solidA body; melting point: 231 ℃ and 233 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ8.30(s,1H,Im-H-4),7.92(d,J＝8.6Hz,2H,Ar-H),7.56(d,J＝8.5Hz,2H,Ar-H),7.37(d,J＝7.4Hz,1H,isatin-H-4),7.28(t,J＝8.1Hz,1H,isatin-H-6),7.17(d,J＝7.9Hz,1H,isatin-H-7),6.97(t,J＝7.6Hz,1H,isatin-H-5),6.18(s,1H,-OH),5.60(d,J＝4.8Hz,1H,-OH),4.24-4.19(m,1H,CH1a-Im),4.15-4.08(m,3H,CH1b-Im,OHCH,C(OH)CH1aCO),3.86-3.76(m,2H,NCH2),3.69(d,J＝17.7Hz,1H,C(OH)CH1bCO),2.37(s,3H,CH3)。
example 15 preparation of Compound III-2
Figure BDA0002334239380000112
Adding compound I-1(0.50g,1.51mmol) and 4-methylacetophenone (0.20mL,1,51mmol) into a 50mL round-bottom flask, taking 10mL methanol as a solvent, adding diethylamine (0.15mL,1.51mmol) at room temperature, reacting at room temperature, tracking by thin layer chromatography until the reaction is finished, and then carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain compound III-2(0.48g), wherein the yield is 68.5%; a white solid; melting point: 179-181 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ8.34(s,1H,Im-H-4),7.83(d,J＝8.1Hz,2H,Ar-H),7.38(d,J＝7.1Hz,1H,isatin-H-4),7.31(d,J＝8.0Hz,2H,Ar-H),7.28(t,J＝8.1Hz,1H,isatin-H-6),7.18(d,J＝7.9Hz,1H,isatin-H-7),6.96(t,J＝7.5Hz,1H,isatin-H-5),6.17(s,1H,-OH),5.64(d,J＝3.5Hz,1H,-OH),4.22(d,J＝17.8Hz,CH1a-Im),4.14-4.08(m,2H,CH1b-Im,OHCH),3.84-3.77(m,2H,NCH2),3.68(d,J＝17.8Hz,1H,C(OH)CH1aCO),3.17(d,J＝5.2Hz,1H,C(OH)CH1bCO),2.38(s,3H,CH3),2.36(s,3H,Ar-CH3)。
example 16 preparation of Compound III-3
Figure BDA0002334239380000121
In a 50mL round-bottom flask, compound I-1(0.50g,1.51mmol) was charged withAcetophenone (0.17mL,1,51mmol) and 10mL methanol as solvent, adding diethylamine (0.15mL,1.51mmol) at room temperature, reacting at room temperature, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc., to obtain compound III-3(0.51g), with a yield of 74.8%; a white solid; melting point: 207 ℃ and 209 ℃;1H NMR(600MHz,DMSO-d6,ppm):8.33(s,1H,Im H-4),7.93(d,J＝7.5Hz,2H,Ar-H),7.65(t,J＝7.3Hz,1H,Ar-H),7.51(t,J＝7.6Hz,2H,ArH),7.39(d,J＝7.1Hz,1H,isatin-H-4),7.28(t,J＝7.7Hz,1H,isatin-H-6),7.19(d,J＝7.8Hz,1H,isatin-H-7),6.97(t,J＝7.5Hz,1H,isatin-H-5),6.19(s,1H,-OH),5.64(d,J＝3.9Hz,1H,-OH),4.25(d,J＝17.9Hz,1H,CH1a-Im),4.15-4.10(m,3H,CH1b-Im,OHCH,NCH1a),3.83-3.79(m,1H,NCH1b),3.72(d,J＝17.8Hz,1H,C(OH)CH1aCO),3.48-3.41(m,1H,C(OH)CH1bCO),2.38(d,J＝5.8Hz,3H,CH3)。
example 17 preparation of Compound III-4
Figure BDA0002334239380000122
Adding a compound I-2(0.50g,1.58mmol) and 4-chloroacetophenone (0.20mL,1,58mmol) into a 50mL round-bottom flask, taking 10mL methanol as a solvent, adding diethylamine (0.16mL,1.58mmol) at room temperature, reacting at room temperature, tracking by thin layer chromatography until the reaction is finished, and then carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain a compound III-4(0.52g), wherein the yield is 70.2%; a white solid; melting point: 235-237 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ8.35(s,1H,Im-H-5),7.93(d,J＝8.6Hz,2H,Ar-H),7.81(s,1H,Im-H-2),7.57(d,J＝8.6Hz,2H,Ar-H),7.38(d,J＝6.9Hz,1H,isatin-H-4),7.28(t,J＝7.2Hz,1H,isatin-H-6),7.14(d,J＝7.9Hz,1H,isatin-H-7),6.97(t,J＝7.4Hz,1H,isatin-H-5),6.19(s,1H,-OH),5.65(d,J＝4.6Hz,1H,-OH),4.24-4.19(m,2H,CH2-Im),4.13-4.07(m,2H,NCH2),3.76-3.73(m,1H,OHCH),3.68(d,J＝17.7Hz,1H,C(OH)CH1aCO),3.17(d,J＝5.2Hz,1H,C(OH)CH1bCO)。
example 18 preparation of Compound III-5
Figure BDA0002334239380000131
Adding compound I-2(0.50g,1.58mmol) and 4-methylacetophenone (0.21mL,1,58mmol) into a 50mL round-bottom flask, adding diethylamine (0.16mL,1.58mmol) into the flask at room temperature, reacting at room temperature, tracking by thin layer chromatography until the reaction is finished, and then carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain compound III-5(0.46g), wherein the yield is 64.7%; a white solid; melting point: 229 ℃ and 231 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ8.35(s,1H,Im-H-5),7.81(d,J＝8.3Hz,3H,Im H-2,Ar-H),7.38(d,J＝7.2Hz,1H,isatin-H-4),7.31(d,J＝8.0Hz,2H,Ar-H),7.28(t,J＝7.8Hz,1H,isatin-H-6),7.14(d,J＝7.9Hz,1H,isatin-H-7),6.96(t,J＝7.4Hz,1H,isatin-H-5),6.15(s,1H,-OH),5.65(d,J＝4.2Hz,1H,-OH),4.24-4.17(m,2H,CH2-Im),4.13-4.07(m,2H,NCH2),3.79-3.73(m,1H,OHCH),3.66(d,J＝17.7Hz,1H,C(OH)CH1aCO),3.17(d,J＝5.2Hz,1H,C(OH)CH1bCO),2.36(s,3H,ArCH3)。
example 19 preparation of Compound III-6
Figure BDA0002334239380000132
Adding the compound I-2(0.50g,1.58mmol) and acetophenone (0.18mL,1,58mmol) into a 50mL round-bottom flask, adding the diethylamine (0.16mL,1.58mmol) into the flask at room temperature by using 10mL of methanol as a solvent, reacting at room temperature, tracking the reaction by using a thin layer chromatography until the reaction is finished, and carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain the compound III-6(0.53g), wherein the yield is 77.9%; a white solid; melting point: 225 ℃ and 227 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ8.36(s,1H,Im-H-5),7.92(d,J＝7.5Hz,2H,Ar-H),7.81(s,1H,Im-H-2),7.64(t,J＝7.4Hz,1H,Ar-H),7.51(t,J＝7.7Hz,2H,Ar-H),7.39(d,J＝7.2Hz,1H,isatin-H-4),7.28(t,J＝7.6Hz,1H,isatin-H-6),7.15(d,J＝7.9Hz,1H,isatin-H-7),6.97(t,J＝7.4Hz,1H,isatin-H-5),6.18(s,1H,-OH),5.66(d,J＝4.3Hz,1H,-OH),4.27-4.20(m,2H,CH2-Im),4.12(d,J＝8.5Hz,2H,NCH2),3.79-3.75(m,1H,OHCH),3.70(d,J＝17.8Hz,1H,C(OH)CH1aCO),3.18(d,J＝5.3Hz,1H,C(OH)CH1bCO)。
example 20 preparation of Compound IV-1
Figure BDA0002334239380000141
Adding compound III-1(0.24g, 0.50mmol) into a 50mL round-bottom flask, adding 10mL ethanol as a solvent, adding 37% hydrochloric acid (0.25mL) and glacial acetic acid (0.75mL) at room temperature, controlling the temperature to react at 120 ℃, tracking by thin layer chromatography until the reaction is finished, adding a saturated sodium bicarbonate solution for neutralization, and carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain compound IV-1(0.22g), wherein the yield is 92.1%; an orange solid; melting point: 211-213 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ8.35(s,1H,Im-H-4),8.10(d,J＝8.2Hz,2H,Ar-H),8.03(d,J＝7.6Hz,1H,isatin-H-4),7.78(s,1H,CHalkene),7.68(d,J＝7.4Hz,2H,Ar-H),7.45(t,J＝7.6Hz,1H,isatin-H-6),7.21(d,J＝7.9Hz,1H,isatin-H-7),7.04(t,J＝7.6Hz,1H,isatin-H-5),5.57(s,1H,-OH),4.20(d,J＝15.9Hz,1H,CH1a-Im),4.16-4.07(br m,1H,OHCH),4.03(dd,J＝13.9,9.0Hz,1H,CH1b-Im),3.85-3.80(m,2H,NCH2),2.39(s,3H,CH3)。
example 21 preparation of Compound IV-2
Figure BDA0002334239380000142
Adding a compound III-2(0.23g, 0.50mmol) into a 50mL round-bottom flask, using 10mL ethanol as a solvent, adding 37% hydrochloric acid (0.25mL) and glacial acetic acid (0.75mL) at room temperature, controlling the temperature to react at 120 ℃, tracking by using a thin layer chromatography until the reaction is finished, adding a saturated sodium bicarbonate solution for neutralization, and carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain a compound IV-2(0.20g), wherein the yield is 91.5%; an orange solid; melting point: 216 ℃ and 218 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ8.35(s,1H,Im-H-4),7.99-7.95(m,3H,Ar-H,isatin-H-4),7.78(s,1H,CHalkene),7.42(d,J＝7.6Hz,3H,Ar-H,isatin-H-6),7.21(d,J＝7.9Hz,1H,isatin-H-7),7.02(t,J＝7.6Hz,1H,isatin-H-5),5.57(s,1H,-OH),4.20(d,J＝13.8Hz,1H,CH1a-Im),4.15-4.08(m,1H,OHCH),4.03(dd,J＝13.9,9.0Hz,1H,CH1b-Im),3.86-3.79(m,2H,NCH2),2.42(s,3H,Ar-CH3),2.39(s,3H,CH3)。
example 22 preparation of Compound IV-3
Figure BDA0002334239380000151
Adding a compound III-3(0.23g, 0.50mmol) into a 50mL round-bottom flask, using 10mL ethanol as a solvent, adding 37% hydrochloric acid (0.25mL) and glacial acetic acid (0.75mL) at room temperature, controlling the temperature to react at 120 ℃, tracking by using a thin layer chromatography until the reaction is finished, adding a saturated sodium bicarbonate solution for neutralization, and carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain a compound IV-3(0.20g), wherein the yield is 93.5%; an orange solid; melting point: 173-175 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ8.35(s,1H,Im-H-4),8.08(d,J＝7.4Hz,2H,Ar-H),7.99(d,J＝7.6Hz,1H,Ar-H),7.81(s,1H,CHalkene),7.74(t,J＝7.4Hz,1H,isatin-H-4),7.62(t,J＝7.7Hz,2H,Ar-H),7.44(t,J＝7.7Hz,1H,isatin-H-6),7.21(d,J＝7.9Hz,1H,isatin-H-7),7.03(t,J＝7.6Hz,1H,isatin-H-5),5.57(d,J＝5.5Hz,1H,-OH),4.20(d,J＝13.9Hz,1H,CH1a-Im),4.16-4.10(m,1H,OHCH),4.03(dd,J＝14.0,9.0Hz,1H,CH1b-Im),3.85-3.80(d,J＝28.6Hz,2H,NCH2),2.41(d,J＝18.1Hz,3H,CH3)。
example 23 preparation of Compound IV-4
Figure BDA0002334239380000152
Adding compound III-4(0.24g, 0.50mmol) and 10mL ethanol as solvent into a 50mL round bottom flask, adding 37% hydrochloric acid (0.25mL) and glacial acetic acid (0.75mL) at room temperature, reacting at 120 deg.C, tracking by thin layer chromatography until the reaction is finished, adding saturated solutionNeutralizing with sodium bicarbonate solution, concentrating, extracting, separating by column chromatography, recrystallizing, drying to obtain compound IV-4(0.21g) with yield of 91.5%; an orange solid; melting point: 131 ℃ and 133 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ8.40(s,1H,Im-H-5),8.10(d,J＝8.5Hz,2H,Ar-H),8.02(d,J＝7.6Hz,1H,isatin-H-4),7.85(s,1H,CHalkene),7.78(s,1H,Im-H-2),7.68(d,J＝8.5Hz,2H,Ar-H),7.44(t,J＝7.7Hz,1H,isatin-H-6),7.19(d,J＝7.9Hz,1H,isatin-H-7),7.03(t,J＝7.6Hz,1H,isatin-H-5),4.94(s,1H,-OH),4.31(d,J＝14.7Hz,1H,CH1a-Im),4.14-4.06(m,2H,NCH2),3.79(d,J＝5.6Hz,2H,CH1b-Im,OHCH)。
example 24 preparation of Compound IV-5
Figure BDA0002334239380000161
Adding compound III-5(0.23g, 0.50mmol) into a 50mL round-bottom flask, adding 10mL ethanol as a solvent, adding 37% hydrochloric acid (0.25mL) and glacial acetic acid (0.75mL) at room temperature, controlling the temperature to react at 120 ℃, tracking by thin layer chromatography until the reaction is finished, adding a saturated sodium bicarbonate solution for neutralization, and carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain compound IV-5(0.20g), wherein the yield is 93.1%; an orange solid; melting point: 117 ℃ and 119 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ8.40(d,J＝1.0Hz,1H,Im-H-5),7.99(d,J＝8.1Hz,2H,Ar-H),7.95(d,J＝7.6Hz,1H,isatin-H-4),7.85(d,J＝1.0Hz,1H,CHalkene),7.79(s,1H,Im-H-2),7.42(dd,J＝7.1,4.9Hz,3H,Ar-H,isatin-H-6),7.19(d,J＝7.9Hz,1H,isatin-H-7),7.02(t,J＝7.6Hz,1H,isatin-H-5),4.76(brs,1H,-OH),4.30(d,J＝14.9Hz,1H,CH1a-Im),4.13-4.06(m,2H,NCH2),3.79(d,J＝5.7Hz,2H,CH1b-Im,OHCH),2.42(s,3H,Ar-CH3)。
example 25 preparation of Compound IV-6
Figure BDA0002334239380000162
In a 50mL round-bottom flask was added compound III-6 (0)22g, 0.50mmol) and 10mL of ethanol are taken as a solvent, 37 percent hydrochloric acid (0.25mL) and glacial acetic acid (0.75mL) are added at room temperature, the temperature is controlled at 120 ℃ for reaction, the thin-layer chromatography is carried out until the reaction is finished, saturated sodium bicarbonate solution is added for neutralization, and then the compound IV-6(0.19g) is obtained after concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments, and the yield is 94.7 percent; an orange solid; melting point: 99-101 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ8.40(s,1H,Im-H-5),8.09(d,J＝7.2Hz,2H,Ar-H),7.98(d,J＝7.6Hz,1H,isatin-H-4),7.85(s,1H,CHalkene),7.81(s,1H,Im-H-2),7.74(t,J＝7.4Hz,1H,Ar-H),7.62(t,J＝7.8Hz,2H,Ar-H),7.43(t,J＝8.1Hz,1H,isatin-H-6),7.19(d,J＝7.9Hz,1H,isatin-H-7),7.02(t,J＝7.5Hz,1H,isatin-H-5),4.88(br s,1H,-OH),4.31(dd,J＝13.2,2.1Hz,1H,CH1a-Im),4.15-4.05(m,2H,CH1b-Im,OHCH),3.80(d,J＝5.7Hz,2H,NCH2)。
example 26 preparation of Compound V-1
Figure BDA0002334239380000171
A50 mL round-bottom flask was charged with the compound 2-methyl-5-nitroimidazole (0.95g, 7.5mmol), potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-1(0.94g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-1(1.12g) with yield of 71.3%; a white solid; melting point: 201-203 ℃;1HNMR(600MHz,DMSO-d6,ppm):δ7.83(s,1H,Im-H-4),7.37(t,J＝7.7Hz,1H,isatin-H-6),7.10-7.04(m,2H,isatin-H-4,5),6.96(d,J＝6.9Hz,1H,isatin-H-7),6.68(s,1H,-OH),4.33(q,J＝14.5Hz,2H,NCH2),3.66(dd,J＝33.3,14.1,7.1Hz,2H,CH2-Im),2.07(s,3H,CH3-Im),1.08(t,J＝7.2Hz,3H,NCH2CH3)。
example 27 preparation of Compound V-2
Figure BDA0002334239380000172
A50 mL round-bottom flask was charged with the compound 2-methyl-5-nitroimidazole (0.95g, 7.5mmol), potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-2(1.0g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-2(1.24g), with 75.6% yield; a white solid; melting point: 169 ℃ and 171 ℃;1HNMR(600MHz,DMSO-d6,ppm):δ7.89(s,1H,Im-H-4),7.35(t,J＝7.7Hz,1H,isatin-H-6),7.06(t,J＝7.5Hz,1H,isatin-H-4),6.96(dd,J＝13.5,7.6Hz,2H,isatin-H-5,7),6.76(s,1H,-OH),5.81-5.75(m,1H,CH＝CH2),5.13-5.09(m,2H,CH＝CH2),4.40-4.33(m,2H,CH2-Im),4.32-4.22(m,2H,NCH2),2.07(s,3H,CH3-Im)。
example 28 preparation of Compound V-3
Figure BDA0002334239380000173
A50 mL round-bottom flask was charged with the compound 2-methyl-5-nitroimidazole (0.95g, 7.5mmol), potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-3(1.25g,5.0mmol), reacting under reflux, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-3(1.51g) with 79.8% yield; a white solid; melting point: 115 ℃ and 117 ℃;1HNMR(600MHz,DMSO-d6,ppm):δ7.85(s,1H,Im-H-4),7.29(t,J＝7.8Hz,3H,isatin-H-6,Ar-H),7.25(d,J＝7.1Hz,1H,isatin-H-4),7.21(d,J＝7.6Hz,2H,Ar-H),7.05(t,J＝7.4Hz,1H,isatin-H-5),7.02(d,J＝6.5Hz,1H,Ar-H),6.89(d,J＝7.8Hz,1H,isatin-H-7),6.86(d,J＝4.0Hz,1H,-OH),4.87(s,2H,CH2-Im),4.47-4.39(m,2H,NCH2),2.09(s,3H,CH3-Im)。
example 29 preparation of Compound V-4
Figure BDA0002334239380000181
A50 mL round-bottom flask was charged with the compound 2-methyl-5-nitroimidazole (0.95g, 7.5mmol), potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-4(1.34g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-4(1.54g) with 77.7% yield; a white solid; melting point: 228 ℃ and 230 ℃;1HNMR(600MHz,DMSO-d6,ppm):δ7.83(s,1H,Im-H-4),7.32-7.27(m,3H,isatin-H-6,Ar-H),7.12(t,J＝8.9Hz,2H,Ar-H),7.06(t,J＝7.3Hz,1H,isatin-H-5),7.01(d,J＝7.3Hz,1H,isatin-H-4),6.93(d,J＝7.8Hz,1H,isatin-H-7),6.83(s,1H,-OH),4.85(d,J＝6.2Hz,2H,CH2-Im),4.41(d,J＝6.7Hz,2H,NCH2),2.09(s,3H,CH3-Im)。
example 30 preparation of Compound V-5
Figure BDA0002334239380000182
A50 mL round-bottom flask was charged with the compound 2-methyl-5-nitroimidazole (0.95g, 7.5mmol), potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-5(1.42g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-5(1.79g), with 86.8% yield; a white solid; melting point: 231 ℃ and 233 ℃;1HNMR(600MHz,DMSO-d6,ppm):δ7.83(s,1H,Im-H-4),7.35(d,J＝8.5Hz,2H,Ar-H),7.31(t,J＝7.7Hz,1H,isatin-H-6),7.25(d,J＝8.4Hz,2H,Ar-H),7.06(t,J＝7.4Hz,1H,isatin-H-5),7.02(d,J＝7.3Hz,1H,isatin-H-4),6.91(d,J＝7.9Hz,1H,isatin-H-7),6.83(s,1H,-OH),4.86(s,2H,NCH2),4.45-4.39(m,2H,CH2-Im),2.09(s,3H,CH3-Im)。
example 31 preparation of Compound V-6
Figure BDA0002334239380000191
A50 mL round-bottom flask was charged with the compound 2-methyl-5-nitroimidazole (0.95g, 7.5mmol), potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-6(1.59g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-6(1.85g) with 82.9% yield; a white solid; melting point: 118 ℃ and 120 ℃;1HNMR(600MHz,DMSO-d6,ppm):δ7.90(s,1H,Im-H-4),7.70(s,1H,Ar-H),7.32(dd,J＝17.2,8.2Hz,2H,isatin-H-6,Ar-H),7.09(t,J＝7.3Hz,1H,isatin-H-5),7.02(d,J＝7.0Hz,1H,isatin-H-4),6.96(d,J＝8.3Hz,1H,Ar-H),6.89(s,1H,-OH),6.86(d,J＝7.8Hz,1H,isatin-H-7),4.91(s,2H,NCH2),4.47-4.40(m,2H,CH2-Im),2.08(s,3H,CH3-Im)。
example 32 preparation of Compound V-7
Figure BDA0002334239380000192
A50 mL round bottom flask was charged with the compound 4-nitroimidazole (0.84g, 7.5mmol) and potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent, and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-1(0.94g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-7(1.18g) with yield of 78.6%; a white solid; melting point: 188-190 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ7.98(s,1H,Im-H-5),7.52(s,1H,Im-H-2),7.36(t,J＝7.7Hz,1H,isatin-H-6),7.05(dd,J＝8.5,5.8Hz,2H,isatin-H-4,5),6.97(d,J＝7.2Hz,1H,isatin-H-7),6.74(s,1H,-OH),4.44(q,J＝13.9Hz,2H,NCH2),3.68(dd,J＝14.1,7.1Hz,1H,CH1a-Im),3.61(dd,J＝14.1,7.1Hz,1H,CH1b-Im),1.06(t,J＝7.1Hz,3H,NCH2CH3)。
example 33 preparation of Compound V-8
Figure BDA0002334239380000201
A50 mL round bottom flask was charged with the compound 4-nitroimidazole (0.84g, 7.5mmol) and potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent, and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-2(1.0g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-8(1.24g) with yield of 78.9%; a white solid; melting point: 180 ℃ and 182 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ8.02(s,1H,Im-H-5),7.55(s,1H,Im-H-2),7.34(t,J＝7.8Hz,1H,isatin-H-6),7.05(d,J＝7.5Hz,1H,isatin-H-4),6.96(d,J＝8.4Hz,2H,isatin-H-5,7),6.80(s,1H,-OH),5.78-5.73(m,1H,CH＝CH2),5.11(dd,J＝12.5,10.5Hz,2H,CH＝CH2),4.51-4.44(m,2H,CH2-Im),4.31-4.21(m,2H,NCH2)。
example 34 preparation of Compound V-9
Figure BDA0002334239380000202
A50 mL round bottom flask was charged with the compound 4-nitroimidazole (0.84g, 7.5mmol) and potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent, and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-3(1.25g,5.0mmol), reacting under reflux, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-9(1.60g) with yield of 87.9%; a white solid; melting point: 103-105 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ8.02(s,1H,Im-H-5),7.58(s,1H,Im-H-2),7.29-7.25(m,4H,isatin-H-6,Ar-H),7.21(d,J＝7.4Hz,2H,Ar-H),7.05(t,J＝7.4Hz,1H,isatin-H-5),7.01(d,J＝7.3Hz,1H,isatin-H-4),6.90(s,1H,-OH),6.88(d,J＝7.9Hz,1H,isatin-H-7),4.89-4.82(m,2H,NCH2),4.57-4.49(m,2H,CH2-Im)。
example 35 preparation of Compound V-10
Figure BDA0002334239380000211
A50 mL round bottom flask was charged with the compound 4-nitroimidazole (0.84g, 7.5mmol) and potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent, and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-4(1.34g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-10(1.39g) with yield of 72.7%; a white solid; melting point: 220 ℃ and 222 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ8.00(d,J＝1.3Hz,1H,Im-H-5),7.57(d,J＝1.3Hz,1H,Im-H-2),7.31-7.28(m,3H,isatin-H-6,Ar-H),7.11(t,J＝8.9Hz,2H,Ar-H),7.05(d,J＝7.4Hz,1H,isatin-H-4),7.00(d,J＝7.3Hz,1H,Ar-H,isatin-H-5),6.92(d,J＝7.8Hz,1H,Ar-H,isatin-H-7),6.87(s,1H,-OH),4.84(s,2H,CH2-Im),4.55-4.48(m,2H,NCH2)。
example 36 preparation of Compound V-11
Figure BDA0002334239380000212
A50 mL round bottom flask was charged with the compound 4-nitroimidazole (0.84g, 7.5mmol) and potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent, and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-5(1.42g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-11(1.69g) with yield of 84.9%; a white solid; melting point: 216 ℃ and 218 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ8.01(s,1H,Im-H-5),7.57(s,1H,Im-H-2),7.35(d,J＝8.5Hz,2H,Ar-H),7.29(t,J＝7.1Hz,1H,isatin-H-6),7.26(d,J＝8.5Hz,2H,Ar-H),7.06(t,J＝7.5Hz,1H,isatin-H-5),7.01(d,J＝7.2Hz,1H,isatin-H-4),6.90(d,J＝7.9Hz,1H,isatin-H-7),6.88(s,1H,-OH),4.85(s,2H,NCH2),4.56-4.49(m,2H,CH2-Im)。
example 37 preparation of Compound V-12
Figure BDA0002334239380000221
A50 mL round bottom flask was charged with the compound 4-nitroimidazole (0.84g, 7.5mmol) and potassium carbonate (0.82g,6.0mmol), 15mL acetonitrile as solvent, and stirred at 60 ℃ for 1.5 h. Cooling to room temperature, adding compound VIII-6(1.59g,5.0mmol), refluxing for reaction, tracking by thin layer chromatography until the reaction is finished, concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound V-12(1.57g) with yield of 72.6%; a white solid; melting point: 110-112 ℃;1H NMR(600MHz,DMSO-d6,ppm):δ8.05(s,1H,Im-H-5),7.69(d,J＝2.0Hz,1H,Ar-H),7.59(s,1H,Im-H-2),7.33-7.28(m,2H,isatin-H-6,Ar-H),7.10(t,J＝7.5Hz,1H,isatin-H-5),7.03(d,J＝7.2Hz,1H,isatin-H-4),6.96(d,J＝8.4Hz,1H,Ar-H),6.94(s,1H,-OH),6.85(d,J＝7.8Hz,1H,isatin-H-7),4.89(t,J＝11.5Hz,2H,NCH2),4.53(q,J＝14.0Hz,2H,CH2-Im)。
note: im is imidazole, and Ar is a benzene ring.
Example 38 in vitro antimicrobial Activity of isatinol Compounds
The isazoyl alcohol compounds prepared in examples 1 to 37 were examined for the Minimal Inhibitory Concentrations (MIC) of gram-positive bacteria (methicillin-resistant Staphylococcus aureus, enterococcus faecalis, Staphylococcus aureus ATCC25923, Staphylococcus aureus ATCC29213), gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922, Acinetobacter baumannii) and fungi (Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida albicans ATCC90023, Candida parapsilosis ATCC20019) by a 96-well microdilution method in accordance with the Clinical Laboratory Standards (CLSI) set by the national Committee of the United states of America, and the like, and the test compounds were dissolved in a small amount of dimethyl sulfoxide, diluted with water to a solution having a concentration of 1.28mg/mL, and then diluted to 128. mu.g/mL with the culture medium, after incubation at 35 ℃ for 24-72 hours, the plates were shaken well on a shaker and MIC was measured at 490nm, the results are shown in tables 1 and 2.
TABLE 1 in vitro antibacterial Activity data (MIC, μ g/mL) of isatinozolol Compounds I-1-V-12
Figure BDA0002334239380000222
Figure BDA0002334239380000231
Figure BDA0002334239380000241
As can be seen from Table 1, the compounds I-1-V-12 prepared in examples 1-37 of the present invention showed certain inhibitory effect on the tested bacteria, and more importantly, the antibacterial activity of some compounds was comparable to or even stronger than that of norfloxacin, the reference drug.
TABLE 2 in vitro antifungal Activity data (MIC, μ g/mL) for Inidazool Compounds I-1-V-12
Figure BDA0002334239380000242
Figure BDA0002334239380000251
As can be seen from Table 2, the compounds I-1 to V-12 prepared in examples 1 to 37 of the present invention exhibited certain inhibitory effects on the fungi tested, and more importantly, some of the compounds exhibited antibacterial activities comparable to, or even stronger than, that of the reference drug fluconazole.
Example 39 pharmaceutical use of isatin alcohol Compounds
According to the antimicrobial activity detection result, the isatin alcohol compound has good antibacterial and antifungal activity, and can be prepared into antibacterial and antifungal medicines for clinical use. The medicines can be single-component preparations, for example, the medicines are prepared from isatin alcohol compounds with one structure and pharmaceutically acceptable auxiliary materials; or a compound preparation, for example, the compound preparation is prepared by the isatin alcohol compound with one structure, the existing antibacterial and antifungal active ingredients (such as norfloxacin, ciprofloxacin, sulfamethoxazole, fluconazole, phosphorus fluconazole, itraconazole and the like) and pharmaceutically acceptable auxiliary materials, or is prepared by a plurality of isatin alcohol compounds with different structures and pharmaceutically acceptable auxiliary materials. The preparation types include, but are not limited to, tablets, capsules, powders, granules, dripping pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal patches and other dosage forms, and various sustained-release and controlled-release preparations and nano preparations.
1. Preparation of Compound I-1 tablets
Prescription: the tablet is prepared from compound I-110 g, lactose 187g, corn starch 50g, magnesium stearate 3.0g, and ethanol solution with volume percentage concentration of 70% in a proper amount, and is prepared into 1000 tablets.
The preparation method comprises the following steps: drying corn starch at 105 deg.C for 5 hr; mixing compound I-1 with lactose and corn starch, making soft mass with 70% ethanol solution, sieving to obtain wet granule, adding magnesium stearate, and tabletting; each tablet weighs 250mg, and the content of active ingredients is 10 mg.
2. Preparation of Compound II-2 Capsule
Prescription: compound II-225 g, modified starch (120 meshes) 12.5g, microcrystalline cellulose (100 meshes) 7.5g, low-substituted hydroxypropyl cellulose (100 meshes) 2.5g, talcum powder (100 meshes) 2g, sweetening agent 1.25g, orange essence 0.25g, proper amount of pigment and water, and prepared into 1000 granules.
The preparation method comprises the following steps: micronizing compound II-2 into superfine powder, mixing with modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, pulvis Talci, sweetener, orange essence and pigment, making into soft material with water, granulating with 12-14 mesh sieve, drying at 40-50 deg.C, sieving, grading, and making into capsule; each tablet weighs 50mg, and the content of active ingredient is 25 mg.
3. Preparation of Compound III-1 granules
Prescription: compound III-126 g, dextrin 120g and sucrose 280 g.
The preparation method comprises the following steps: mixing compound III-1, dextrin and sucrose uniformly, granulating by wet method, drying at 60 deg.C, and packaging.
4. Preparation of compound IV-2 injection
Prescription: 1000mL of the compound IV-210 g, 500mL of propylene glycol and 500mL of water for injection.
The preparation method comprises the following steps: weighing the compound IV-2, adding propylene glycol and injection water, stirring for dissolving, adding 1g of activated carbon, fully stirring, standing for 15 minutes, filtering with a 5-micron titanium rod for decarbonization, sequentially fine-filtering with microporous filter membranes with the pore diameters of 0.45 micron and 0.22 micron, finally encapsulating in a 10mL ampoule, and sterilizing with 100 ℃ circulating steam for 45 minutes to obtain the compound IV-2.
5. Preparation of compound V-1 powder injection
The preparation method comprises the following steps: and subpackaging the compound V-1 sterile powder under the aseptic condition to obtain the compound V-1.
6. Preparation of Compound V-4 eye drops
Prescription: 43.78 g of compound V, 0.9g of sodium chloride, 3g of phenethyl alcohol, a proper amount of boric acid buffer solution and distilled water are added to 1000 mL.
The preparation method comprises the following steps: weighing the compound V-4 and sodium chloride, adding into 500mL of distilled water, dissolving completely, adjusting pH to 6.5 with boric acid buffer solution, adding distilled water to 1000mL, stirring well, filtering with microporous membrane, filling, sealing, and sterilizing with 100 deg.C flowing steam for 1 hr.
7. Preparation of compound V-6 liniment
Prescription: compound V-64 g, potassium soap 7.5g, camphor 5g, distilled water added to 100 mL.
The preparation method comprises the following steps: dissolving camphor with 95 percent ethanol solution by volume percentage for later use; heating potassium soap to liquefy, weighing compound V-6, adding potassium soap solution and camphorethanol solution under stirring, gradually adding distilled water, emulsifying, and adding distilled water to full volume.
8. Preparation of compound V-8 suppository
Prescription: 100 metric copies of compound V-84 g, gelatin 14g, glycerol 70g and distilled water to 100 mL.
The preparation method comprises the following steps: weighing gelatin and glycerol, adding distilled water to 100mL, heating in water bath at 60 deg.C to melt into paste, adding compound V-8, stirring, pouring into vaginal suppository mold when it is nearly solidified, and cooling to solidify.
9. Preparation of Compound V-9 ointment
Prescription: the compound V-90.5-2 g, cetyl alcohol 6-8 g, white vaseline 8-10 g, liquid paraffin 8-19 g, monoglyceride 2-5 g, polyoxyethylene (40) stearate 2-5 g, glycerol 5-10 g, ethylparaben 0.1g, and distilled water added to 100 g.
The preparation method comprises the following steps: heating cetyl alcohol, white vaseline, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate to completely dissolve, mixing, and keeping the temperature at 80 deg.C to obtain oil phase; adding ethylparaben into glycerol and distilled water, heating to 85 deg.C for dissolving, adding oil phase under stirring, emulsifying, adding compound V-9, stirring, and cooling.
10. Preparation of compound V-11 and fluconazole compound powder injection
Prescription: the compound V-1150 g, fluconazole 50g and sodium benzoate 1g are prepared into 100 bottles.
The preparation method comprises the following steps: taking the compound V-11, the fluconazole and the sodium benzoate according to the prescription amount, uniformly mixing in a sterile state, and subpackaging 100 bottles to obtain the compound.
11. Preparation of Compound II-4 Aerosol
Prescription: 42.5 g of compound II, 203 g, 4g of talcum powder (100 meshes) and trichlorofluoromethane added in a proper amount.
The preparation method comprises the following steps: respectively placing the compound II-4, the Span20 and the talcum powder in a vacuum drying oven for drying for a plurality of hours, placing in a dryer for cooling to room temperature, crushing into micro powder by using an airflow crusher, uniformly mixing according to the prescription amount, filling into a closed container, and adding trichloromonofluoromethane to a specified amount to obtain the trichloromonofluoromethane.
Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.

Claims (10)

1.3-imidazole substituted isatin azole alcohol compounds and pharmaceutically acceptable salts thereof, which are characterized in that: the structure is shown as the general formula V:
Figure FDA0002334239370000011
in the formula, R1Hydrogen, alkyl; r2Hydrogen and nitro; r3Hydrogen and nitro; r6Hydrogen, alkenyl, phenyl, substituted phenyl.
2. The 3-imidazole-substituted isatinozolol compounds and pharmaceutically acceptable salts thereof according to claim 1, wherein: r1Hydrogen and methyl; r2Hydrogen and nitro; r3Hydrogen and nitro; r6Hydrogen, vinyl, phenyl, p-fluorophenyl, p-chlorophenyl, 2, 4-dichlorophenyl.
3. The 3-imidazole-substituted isatinozolol compounds and pharmaceutically acceptable salts thereof according to claim 2, which are any one of the following compounds:
Figure FDA0002334239370000012
Figure FDA0002334239370000021
4. the 3-imidazole-substituted isatinozolol compounds and pharmaceutically acceptable salts thereof according to claim 3, wherein: the isatin azole alcohol compounds are V-1, V-2, V-4, V-5, V-6, V-7, V-8, V-9, V-10, V-11 and V-12.
5. The process for preparing 3-imidazole-substituted isatinozolol compounds and pharmaceutically acceptable salts thereof according to any one of claims 1 to 4, characterized in that: preparation of pharmaceutically acceptable salts of isatin alcohol compounds shown as general formula V: dissolving a compound shown as a general formula VIII in an organic solvent, adding nitroimidazole, refluxing under the action of alkali to perform a ring-opening reaction to obtain a pharmaceutically acceptable salt of the 3-imidazole-substituted isatin alcohol compound shown as a general formula V;
Figure FDA0002334239370000022
6. the process for preparing 3-imidazole-substituted isatinozolol compounds and pharmaceutically acceptable salts thereof according to claim 5, wherein: the reaction solvent is acetonitrile; the alkali is potassium carbonate; nitroimidazole and potassium carbonate are added together to react for 0.5h at 60 ℃; the raw materials are added at room temperature and reacted for 10 to 12 hours under reflux.
7. A preparation containing the 3-imidazole-substituted isatinozolol compound according to any one of claims 1 to 4 and a pharmaceutically acceptable salt thereof.
8. The formulation of claim 7, wherein: the preparation is tablet, capsule, powder, granule, dripping pill, injection, powder for injection, solution, suspension, emulsion, suppository, ointment, gel, pellicle, aerosol or transdermal patch.
9. Use of the 3-imidazole-substituted isatinozolol compounds according to any one of claims 1 to 4 and their pharmaceutically acceptable salts for the preparation of antibacterial and/or antifungal medicaments.
10. The use according to claim 9, wherein the bacteria is any one or more of methicillin-resistant staphylococcus aureus, enterococcus faecalis, klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa, acinetobacter baumannii; the fungus is any one or more of Candida albicans, Candida tropicalis, Aspergillus fumigatus and Candida parapsilosis.
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