CN112745317B - Purine thiazole compound and preparation method and application thereof - Google Patents

Purine thiazole compound and preparation method and application thereof Download PDF

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CN112745317B
CN112745317B CN202011598159.XA CN202011598159A CN112745317B CN 112745317 B CN112745317 B CN 112745317B CN 202011598159 A CN202011598159 A CN 202011598159A CN 112745317 B CN112745317 B CN 112745317B
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周成合
隋彦斐
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Southwest University
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    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
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Abstract

The invention relates to a purine thiazole compound, a preparation method and application thereof, belonging to the technical field of chemical synthesis. The purine thiazole compounds have certain inhibitory activity on gram-positive bacteria, gram-negative bacteria and fungi, can be used for preparing antibacterial and/or antifungal medicaments, provide more efficient and safe candidate medicaments for clinical antimicrobial treatment and are beneficial to solving the clinical treatment problems of increasingly serious drug resistance, stubborn pathogenic microorganisms, newly-appeared harmful microorganisms and the like. The preparation raw materials are simple, cheap and easily available, the synthetic route is short, and the application in the aspect of infection resistance is of great significance

Description

Purine thiazole compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a purine thiazole compound, and a preparation method and application thereof.
Background
In recent years, with the progress of the problem of antibiotic abuse, the resistance to antibiotics has been gradually increased, resulting in a decrease in the effective rate of treatment for patients with infectious diseases. The emergence of antibiotic resistance has brought serious economic impact on patients, hospitals and society. Antimicrobial drugs, particularly azole drugs, have opened up a new era in microbial drug therapy, and since the first azole antibacterial drug, clotrimazole, was used clinically, azole drugs have attracted extensive attention. With the increasingly widespread use of azole drugs, the problem of microbial drug resistance is becoming more serious, wherein the mechanisms leading to the generation of microbial drug resistance are mainly that the amount of antimicrobial drugs taken in/permeated by microbial cells is reduced, the target enzyme genes of drug action are mutated or over-expressed, the capacity of pumping/transporting drugs out of cells is enhanced, and the microbial drug resistance brings extremely serious challenges to antimicrobial therapy. Therefore, structural modification of existing antimicrobial compounds to reduce toxic side effects and search for highly effective and low toxic antimicrobial drugs acting on new targets have become two major hot spots for antimicrobial drug research in recent years.
The successful marketing of puromycin and cinofungin greatly promotes the development and application of natural and synthetic purine compounds in the field of medicine. A number of structure-activity relationship studies have shown that planar, aromatic structures of purines, which can covalently bind to DNA base pairs via intercalation, minor groove binding or electrostatic interactions, render them DNA-targeting, in addition, purines can disrupt bacterial membrane integrity and mis-localize essential membrane-associated proteins, and purine derivatives can interfere with DNA-dependent enzymes, topoisomerase I/II and telomerase, or other targets such as cyclin-dependent kinases and estrogen receptors, among others. These advantages greatly improve the research and development enthusiasm of researchers for purine multi-target antibacterial drugs. However, the planar rigid structure of purine compounds causes poor solubility of purine compounds, greatly limits further application of purine compounds, and therefore, improving the water solubility and lipophilicity of purine compounds is a key expected to enhance the metabolic stability and biological activity of purine compounds.
Disclosure of Invention
In view of the above, an object of the present invention is to provide purine thiazoles and pharmaceutically acceptable salts thereof; the second object of the present invention is to provide a process for preparing purine thiazole compounds and pharmaceutically acceptable salts thereof; the invention also aims to provide the application of the purine thiazole compound and the medicinal salt thereof in preparing antibacterial and/or antifungal medicaments; the fourth purpose of the invention is to provide a preparation containing the purine thiazole compound and the pharmaceutically acceptable salt thereof.
In order to achieve the purpose, the invention provides the following technical scheme:
1. the structure of the purine thiazole compound and the medicinal salt thereof is shown as the general formula I:
Figure BDA0002870484860000021
in the formula:
x is O, CH2NH or N (CH)2)mR; n is 0 to 5;
the N (CH)2)mIn R, R is hydrogen, halogen, cyano, alkyl, nitro, trifluoromethyl, alkenyl, alkynyl, aryl, hydroxyalkyl, carboxyl, ester group, acyl, sulfydryl or cycloalkyl; m is 0 to 18.
Preferably, n is 1 to 3; r is methyl, allyl, propargyl, ester group, cyano, hydroxyethyl or benzyl; m is 0 to 17.
Preferably, the benzyl group is a 2-chlorobenzyl group, a 4-chlorobenzyl group, a 2-fluorobenzyl group, a 4-nitrobenzyl group or a 4-methylbenzyl group.
Preferably, it is any one of the following compounds:
Figure BDA0002870484860000022
Figure BDA0002870484860000031
preferably, the pharmaceutically acceptable salt is a sodium salt, a sulfate, a hydrochloride, a nitrate or an acetate.
2. The preparation method of the purine thiazole compound and the pharmaceutically acceptable salt thereof comprises the following steps:
a. preparation of intermediate II-1: taking acetylthiazole as a starting material, taking bromine as a brominating agent, and reacting in glacial acetic acid to prepare an intermediate II-1;
Figure BDA0002870484860000032
b. preparation of intermediate III-1: taking the intermediate II-1 as an initial raw material, acetonitrile as a solvent, and potassium carbonate as a base, and reacting with 6-chloropurine to obtain an intermediate III-1;
Figure BDA0002870484860000033
c.I-1 to I-5, and preparation of pharmaceutically acceptable salts thereof: taking the intermediate III-1 as a raw material, taking triethylamine as an alkali and ethanol as a solvent, and respectively carrying out substitution reaction with alicyclic amine to obtain purine thiazole compounds shown as I-1 to I-5 and pharmaceutically acceptable salts thereof;
d.I-6 to I-22, and preparation of pharmaceutically acceptable salts thereof: taking a compound I-5 as a raw material, taking potassium carbonate as alkali and acetonitrile as a solvent, and respectively reacting with a halogenated compound to prepare purine thiazole compounds shown in I-6 to I-22 and pharmaceutically acceptable salts thereof.
Preferably, the first and second liquid crystal materials are,
in the step a, the molar ratio of the acetyl thiazole to the bromine is 1: 1.1; the temperature of the reaction is 50 ℃;
in the step b, the molar ratio of the intermediate II-1, potassium carbonate and 6-chloropurine is 1.2:1.2: 1; the temperature of the reaction is 50 ℃;
in the step c, the molar ratio of the intermediate III-1 to the triethylamine to the alicyclic amine is 1:1: 1; the temperature of the reaction is 50 ℃;
in the step d, the molar ratio of the compound I-5, the potassium carbonate and the halogenated compound is 1:1.2: 1.2; the temperature of the reaction was 50 ℃.
3. The purine thiazole compound and the medicinal salt thereof are applied to the preparation of antibacterial and/or antifungal medicaments.
Preferably, the bacteria is one or more of methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC 25923, staphylococcus aureus ATCC 29213, klebsiella pneumoniae, acinetobacter baumannii, escherichia coli, pseudomonas aeruginosa ATCC 27853 or escherichia coli ATCC 25922; the fungi is one or more of Candida albicans, Candida tropicalis, Aspergillus fumigatus or Candida parapsilosis ATCC 20019.
4. A preparation containing the purine thiazole compound and a pharmaceutically acceptable salt thereof.
Preferably, the preparation is one or more of tablets, capsules, granules, injections, powder injections, eye drops, liniments, suppositories, ointments or aerosols.
The invention has the beneficial effects that: the invention provides purine thiazole compounds and a preparation method and application thereof, wherein thiazole and purine are combined together by utilizing a drug design split principle to design and synthesize a series of novel purine thiazole compounds, and the compounds have certain inhibitory activity on gram-positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC 25923 and staphylococcus aureus ATCC 29213), gram-negative bacteria (Klebsiella pneumoniae, acinetobacter baumannii, escherichia coli, pseudomonas aeruginosa 27853 and escherichia coli 25922) and fungi (candida albicans, candida tropicalis, aspergillus fumigatus and candida parapsilosis 20019) through in-vitro antimicrobial activity detection, can be used for preparing antibacterial and/or antifungal drugs, and further provide more efficient and 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. The preparation raw materials are simple, cheap and easy to obtain, the synthetic route is short, and the application in the aspect of infection resistance is of great significance.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention. The objectives and other advantages of the invention may be realized and attained by the means of the instrumentalities and combinations particularly pointed out hereinafter.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
Example 1: preparation of intermediate II-1:
Figure BDA0002870484860000051
prepared according to references Y.Y.Hu, J.Wang, T.J.Li, R.R.Y.Bheemanboina, M.F.Anasri, Y.Cheng, C.H.Zhou, An unexpected distributed transmitted nucleic acid as potential MRSA DNA antibodies, Future Med.chem. (2020)12(19), 1709-.
Example 2: preparation of intermediate III-1:
Figure BDA0002870484860000052
after 6-chloropurine (5.000g,32.47mmol), potassium carbonate (5.380g,38.96mmol) and 50mL of acetonitrile were charged into a dry round-bottom flask, and stirred at 50 ℃ for 30 minutes, intermediate II-1(7.990g,38.96mmol) was added, and reacted at 50 ℃ for 12 hours, followed by monitoring the reaction by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/1, V/V), and after completion of the reaction, distillation under reduced pressure was carried out to obtain a crude product, which was subjected to silica gel column chromatography (300-400 mesh) to separate and purify (eluent: dichloromethane/ethyl acetate, 20/1-15/1, V/V) to obtain intermediate III-1(6.90g) as an orange solid, melting point: 167-: 76.2 percent;1H NMR(600MHz,DMSO-d6)δ8.79(s,1H,purine-4-H),8.70(s,1H,purine-9-H),8.41(d,J＝2.9Hz,1H,thiazole-4-H),8.32(d,J＝2.9Hz,1H,thiazole-5-H),6.10(s,2H,CH2)ppm.
example 3: preparation of Compound I-1:
Figure BDA0002870484860000053
a dry round bottom flask was charged with intermediate III-1(50mg,0.18mmol), tetrahydropyrrole (15mg,0.18mmol), triethylamine (17mg,0.18mmol) and 10mL of ethanol, stirred at 50 ℃ for 2 hours, monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), filtered with suction at the end of the reaction and washed with ethanol to give compound I-1 as a white solid (53mg), melting point: > 250 ℃, yield: 93.6 percent;1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝2.8Hz,1H,thiazole-4-H),8.29(d,J＝2.8Hz,1H,thiazole-5-H),8.16(s,1H,purine-4-H),8.12(s,1H,purine-9-H),5.90(s,2H,NCH2),2.50(s,4H,pyrrolidine-2,5-CH2),1.97(d,J＝17.3Hz,4H,pyrrolidine-3,4-CH2)ppm.
example 4: preparation of Compound I-2:
Figure BDA0002870484860000061
a dry round-bottom flask was charged with intermediate III-1(250mg,0.89mmol), piperidine (76mg,0.89mmol), triethylamine (90mg,0.89mmol) and 20mL ethanol, stirred at 50 ℃ for 1 hour, monitored by thin layer chromatography (developing solvent: dichloromethane/ethyl acetate, 5/3, V/V), and after completion of the reaction, distilled under reduced pressure to give compound I-2 as a pink solid (283mg), melting point: 206-: 96.4 percent;1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝2.8Hz,1H,thiazole-4-H),8.29(d,J＝2.8Hz,1H,thiazole-5-H),8.17(s,1H,purine-4-H),8.16(s,1H,purine-9-H),5.91(s,2H,NCH2),4.22(s,4H,piperidine-2,6-CH2),1.69(d,J＝4.8Hz,2H,piperidine-4-CH2),1.60(s,4H,piperidine-3,5-CH2)ppm.
example 5: preparation of Compound I-3:
Figure BDA0002870484860000062
a dry round-bottom flask was charged with intermediate III-1(100mg,0.36mmol), hexamethyleneimine (35mg,0.36mmol), triethylamine (36mg,0.36mmol) and 10mL of ethanol, stirred at 50 ℃ for 1 hour, monitored by thin layer chromatography (developing solvent: dichloromethane/ethyl acetate, 5/3, V/V), and after completion of the reaction, distilled under reduced pressure to give compound I-3(118mg) as a pink solid with a melting point: 214 ℃ and 215 ℃, yield: 96.4 percent;1H NMR(600MHz,CDCl3)δ8.31(s,1H,thiazole-4-H),8.11(d,J＝3.0Hz,1H,thiazole-5-H),7.81(d,J＝2.6Hz,2H,purine-4,9-CH),5.84(s,2H,NH2),3.25–3.22(m,4H,cyclohexanediamine-2,7-CH),1.75–1.72(m,4H,cyclohexanediamine-3,6-CH),1.61(s,4H,cyclohexanediamine-4,5-CH)ppm.
example 6: preparation of Compound I-4:
Figure BDA0002870484860000063
a dry round-bottom flask was charged with intermediate III-1(50mg,0.18mmol), morpholine (15mg,0.18mmol), triethylamine (17mg,0.18mmol) and 10mL ethanol, stirred at 50 ℃ for 2 hours, monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), filtered with suction at the end of the reaction and washed with ethanol to give compound I-4 as a white solid (56mg), melting point: 183 ℃ and 184 ℃, yield: 95.0 percent;1H NMR(600MHz,DMSO-d6)δ8.38(d,J＝2.5Hz,1H,thiazole-4-H),8.30(d,J＝2.0Hz,1H,thiazole-5-H),8.22(s,1H,purine-4-H),8.21(s,1H,purine-9-H),5.93(s,2H,NCH2),3.81–3.78(m,4H,morpholine-3,5-CH2),3.76–3.73(m,4H,morpholine-2,6-CH2)ppm.
example 7: preparation of Compound I-5:
Figure BDA0002870484860000071
a dry round bottom flask was charged with intermediate III-1(50mg,0.18mmol), piperazine (15mg,0.18mmol), triethylamine (17mg,0.18mmol) and 10mL ethanol, stirred at 50 ℃ for 2 hours, monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/4, V/V), suction filtered after the reaction was complete and washed with ethanol to give compound I-5 as a pink solid (56mg), melting point: > 250 ℃, yield: 94.8 percent;1H NMR(600MHz,DMSO-d6)δ8.38(d,J＝2.1Hz,1H,thiazole-4-H),8.30(d,J＝2.1Hz,1H,thiazole-5-H),8.28(s,1H,purine-4-H),8.27(s,1H,purine-9-H),5.95(s,2H,NCH2),3.24(s,4H,piperazine-2,6-CH2),2.51(s,4H,piperazine-3,5-CH2),1.18(t,J＝6.8Hz,1H,NH)ppm.
example 8: preparation of Compound I-6:
Figure BDA0002870484860000072
a dry round-bottom flask was charged with Compound I-5(200mg,0.61mmol), potassium carbonate (101mg,0.73mmol) and 10mL acetonitrile, stirred at 50 ℃ for 30 minutes, then bromoethane (80mg,0.73mmol) was added and reacted at 50 ℃ for 6 hours, the reaction was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), after completion of the reaction, distillation under reduced pressure was carried out to give a crude product, which was subjected to silica gel column chromatography (300-400 mesh) to separate and purify (eluent: dichloromethane/methanol, 40/1-20/1, V/V) to give Compound I-6(162mg) as a yellow solid, melting point: 145-146 ℃, yield: 74.8 percent;1H NMR(600MHz,DMSO-d6)δ8.38(d,J＝3.0Hz,1H,thiazole-4-H),8.30(d,J＝3.0Hz,1H,thiazole-5-H,),8.19(s,1H,purine-4-H),8.18(s,1H,purine-9-H),5.92(s,2H,NCH2),3.33(s,4H,piperazine-2,6-CH2),2.51(s,4H,piperazine-3,5-CH2),2.09(s,2H,NCH2),1.05(t,J＝7.1Hz,3H,CH3)ppm.
example 9: preparation of Compound I-7:
Figure BDA0002870484860000081
a dry round-bottom flask was charged with Compound I-5(250mg,0.76mmol), potassium carbonate (135mg,0.91mmol) and 10mL acetonitrile, stirred at 50 ℃ for 30 minutes, then bromobutane (125mg,0.91mmol) was added and reacted at 50 ℃ for 6 hours, the reaction was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), after the reaction was completed, distillation was carried out under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography (300-400 mesh) to separate and purify (eluent: dichloromethane/methanol, 40/1-20/1, V/V) to obtain Compound I-7(196mg), melting point: 166 ℃ and 167 ℃, yield: 67.0 percent;1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝2.9Hz,1H,thiazole-4-H),8.29(d,J＝2.9Hz,1H,thiazole-5-H),8.19(s,1H,purine-4-H),8.18(s,1H,purine-9-H),5.92(s,2H,NCH2),4.24(s,4H,piperazine-2,6-CH2),2.49(s,4H,piperazine-3,5-CH2),2.32(t,J＝7.1Hz,2H,NCH2),1.45(dt,J＝14.7,7.4Hz,2H,CH2CH2CH2CH3),1.32(dq,J＝14.5,7.2Hz,2H,CH2CH2CH2CH3),0.90(t,J＝7.3Hz,3H,CH3)ppm.
example 10: preparation of Compound I-8:
Figure BDA0002870484860000082
a dry round-bottom flask was charged with Compound I-5(250mg,0.76mmol), potassium carbonate (135mg,0.91mmol) and 10mL acetonitrile, stirred at 50 ℃ for 30 minutes, then bromohexane (150mg,0.91mmol) was added and reacted at 50 ℃ for 6 hours, the reaction was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), after completion of the reaction, distillation under reduced pressure was carried out to give a crude product, which was subjected to silica gel column chromatography (300-400 mesh) to separate and purify (eluent: dichloromethane/methanol, 40/1-20/1, V/V) to give Compound I-8(208mg) as a yellow solid, melting point: 148 ℃ and 149 ℃, yield: 71.1 percent;1H NMR(600MHz,DMSO-d6)δ8.39–8.36(m,1H,thiazole-4-H),8.31–8.28(m,1H,thiazole-5-H),8.19(s,1H,purine-4-H),8.18(s,1H,purine-9-H),5.91(s,2H,NCH2),4.23(s,4H,piperazine-2,6-CH2),2.48(s,4H,piperazine-3,5-CH2),2.31(t,J＝7.1Hz,2H,NCH2),1.46(d,J＝6.6Hz,2H,CH2CH2CH2CH2CH2CH3),1.28(s,6H,CH2CH2(CH2)3CH3),0.87(t,J＝6.2Hz,3H,CH3)ppm.
example 11: preparation of Compound I-9:
Figure BDA0002870484860000083
a dry round-bottom flask was charged with Compound I-5(250mg,0.76mmol), potassium carbonate (125mg,0.91mmol) and 10mL acetonitrile, stirred at 50 ℃ for 30 min, then bromooctane (176mg,0.91mmol) was added and reacted at 50 ℃ for 8 h, and the reaction was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), the reactionAfter completion, the crude product was obtained by distillation under reduced pressure, and the obtained crude product was subjected to separation and purification by silica gel column chromatography (300-400 mesh) (eluent: dichloromethane/methanol, 40/1-20/1, V/V) to obtain a yellow solid compound I-9(236mg), melting point: 138 ℃ and 139 ℃, yield: 70.4 percent;1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝3.0Hz,1H,thiazole-4-H),8.29(d,J＝3.0Hz,1H,thiazole-5-H),8.19(s,1H,purine-4-H),8.18(s,1H,purine-9-H),5.91(s,2H,NCH2),4.23(s,4H,piperazine-2,6-CH2),2.48(s,4H,piperazine-3,5-CH2),2.33–2.28(m,2H,NCH2(CH2)6CH3),1.46(d,J＝6.5Hz,2H,CH2CH2(CH2)5CH3),1.31–1.25(m,10H,(CH2)2(CH2)5CH3),0.86(t,J＝6.9Hz,3H,CH3)ppm.
example 12: preparation of Compound I-10:
Figure BDA0002870484860000091
a dry round-bottom flask was charged with Compound I-5(250mg,0.76mmol), potassium carbonate (125mg,0.91mmol) and 10mL acetonitrile, stirred at 50 ℃ for 30 minutes, then bromododecane (227mg,0.91mmol) was added and reacted at 50 ℃ for 8 hours, the reaction was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), after completion of the reaction, distillation under reduced pressure was carried out to give a crude product, which was subjected to silica gel column chromatography (300-400 mesh) to separate and purify (eluent: dichloromethane/methanol, 40/1-20/1, V/V) to give Compound I-10(254mg), melting point: 138 ℃ and 139 ℃, yield: 69.2 percent;1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝2.6Hz,1H,thiazole-4-H),8.29(d,J＝2.7Hz,1H,thiazole-5-H),8.19(s,1H,purine-4-H),8.18(s,1H,purine-9-H),5.91(s,2H,NCH2),4.23(s,4H,piperazine-2,6-CH2),2.49(s,4H,piperazine-3,5-CH2),2.31(t,J＝6.6Hz,2H,CH2(CH2)10CH3),1.46(s,2H,CH2CH2(CH2)9CH3),1.26(d,J＝14.7Hz,18H,(CH2)2(CH2)9CH3),0.85(t,J＝6.8Hz,3H,CH3)ppm.
example 13: preparation of Compound I-11:
Figure BDA0002870484860000092
a dry round-bottom flask was charged with Compound I-5(250mg,0.76mmol), potassium carbonate (125mg,0.91mmol) and 10mL acetonitrile, stirred at 50 ℃ for 30 minutes, then bromooctadecane (304mg,0.91mmol) was added and reacted at 50 ℃ for 12 hours, the reaction was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), after completion of the reaction, distillation under reduced pressure was carried out to give a crude product, which was subjected to silica gel column chromatography (300-400 mesh) to separate and purify (eluent: dichloromethane/methanol, 40/1-20/1, V/V) to give Compound I-11(263mg) as a yellow solid, melting point: 140 ℃ and 141 ℃, yield: 59.5 percent;1H NMR(600MHz,CDCl3)δ8.32(s,1H,thiazole-4-H),8.11(s,1H,thiazole-5-H),7.81(s,1H,purine-4-H),7.80(s,1H,purine-9-H),5.84(s,2H,NCH2),4.36(s,4H,piperazine-2,6-CH2),2.60(s,4H,piperazine-3,5-CH2),2.42–2.38(m,2H,CH2(CH2)16CH3),1.55(s,2H,CH2CH2(CH2)15CH3),1.26(s,30H,CH2CH2(CH2)15CH3),0.88(t,J＝6.8Hz,3H,CH3)ppm.
example 14: preparation of Compound I-12:
Figure BDA0002870484860000101
a dry round-bottom flask was charged with Compound I-5(250mg,0.76mmol), potassium carbonate (125mg,0.91mmol) and 10mL acetonitrile, stirred at 50 ℃ for 30 min, then bromopropene (110mg,0.91mmol) was added and reacted at 50 ℃ for 2 h, and the reaction was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), reverseAfter completion of the reaction, the crude product was obtained by distillation under reduced pressure, and the obtained crude product was subjected to separation and purification by silica gel column chromatography (300-400 mesh) (eluent: dichloromethane/methanol, 40/1-20/1, V/V) to obtain a yellow solid compound I-12(198mg), melting point: 196 ℃ and 197 ℃, yield: 70.7 percent;1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝3.0Hz,1H,thiazole-4-H),8.29(d,J＝3.0Hz,1H,thiazole-5-H),8.19(s,1H,purine-4-H),8.18(s,1H,purine-9-H),5.92(s,2H,NCH2),5.88–5.81(m,1H,CH2＝CH),5.21(d,J＝17.2Hz,1H,CHH＝CH),5.16(d,J＝10.1Hz,1H,CHH＝CH),4.24(s,4H,piperazine-2,6-CH2),3.00(d,J＝6.3Hz,2H,CH2CH＝CH2),2.51–2.49(m,4H,piperazine-3,5-CH2)ppm.
example 15: preparation of Compound I-13:
Figure BDA0002870484860000102
a dry round-bottom flask was charged with Compound I-5(250mg,0.76mmol), potassium carbonate (125mg,0.91mmol) and 10mL acetonitrile, stirred at 50 ℃ for 30 minutes, then bromopropyne (108mg,0.91mmol) was added and reacted at 50 ℃ for 2 hours, the reaction was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), after completion of the reaction, distillation under reduced pressure was carried out to give a crude product, which was subjected to silica gel column chromatography (300-400 mesh) to separate and purify (eluent: dichloromethane/methanol, 40/1-20/1, V/V) to give Compound I-13(203mg) as a yellow solid, melting point: 180 ℃ and 190 ℃, yield: 72.8 percent;1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝2.7Hz,1H,thiazole-4-H),8.29(d,J＝2.8Hz,1H,thiazole-5-H),8.21(s,1H,purine-4-H),8.20(s,1H,purine-9-H),5.92(s,2H,NCH2),4.27(s,4H,piperazine-2,6-CH2),3.36(s,2H,CH2CCH),3.15(s,1H,CCH),2.60(d,J＝4.2Hz,4H,piperazine-3,5-CH2)ppm.
example 16: preparation of Compound I-14:
Figure BDA0002870484860000111
a dry round-bottom flask was charged with Compound I-5(250mg,0.76mmol), potassium carbonate (125mg,0.91mmol) and 10mL acetonitrile, stirred at 50 ℃ for 30 minutes, then added with ethyl bromoacetate (152mg,0.91mmol) and reacted at 50 ℃ for 1 hour, the reaction was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), after completion of the reaction, distillation under reduced pressure was carried out to give a crude product, which was subjected to silica gel column chromatography (300-400 mesh) to separate and purify (eluent: dichloromethane/methanol, 40/1-20/1, V/V) to give Compound I-14(201mg) as a yellow solid, melting point: 136 ℃ and 137 ℃, yield: 63.7 percent;1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝3.0Hz,1H,thiazole-4-H),8.29(d,J＝3.0Hz,1H,thiazole-5-H),8.20(s,1H,purine-4-H),8.19(s,1H,purine-9-H),5.92(s,2H,NCH2),4.25(s,4H,piperazine-2,6-CH2),4.12–4.08(m,2H,OCH2CH3),3.31(s,2H,CH2COOC2H5),2.68–2.64(m,4H,piperazine-3,5-CH2),1.20(t,J＝7.1Hz,3H,CH2CH3)ppm.
example 17: preparation of Compound I-15:
Figure BDA0002870484860000112
a dry round-bottom flask was charged with Compound I-5(250mg,0.76mmol), potassium carbonate (125mg,0.91mmol) and 10mL acetonitrile, stirred at 50 ℃ for 30 minutes, then chloroacetonitrile (69mg,0.91mmol) was added and reacted at 50 ℃ for 6 hours, the reaction was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), after completion of the reaction, distillation under reduced pressure was carried out to give a crude product, which was subjected to silica gel column chromatography (300-400 mesh) to separate and purify (eluent: dichloromethane/methanol, 40/1-20/1, V/V) to give Compound I-15(210mg) as a yellow solid, melting point: 222 ℃ and 223 ℃, yield: 75.1 percent;1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝2.9Hz,1H,thiazole-4-H),8.30(d,J＝3.0Hz,1H,thiazole-5-H),8.23(s,1H,purine-9-H),8.22(s,1H,purine-4-H),5.93(s,2H,NCH2),4.30(s,4H,piperazine-2,6-CH2),3.82(s,2H,CH2CN),2.64–2.60(m,4H,piperazine-3,5-CH2)ppm.
example 18: preparation of Compound I-16:
Figure BDA0002870484860000121
a dry round-bottom flask was charged with Compound I-5(250mg,0.76mmol), potassium carbonate (125mg,0.91mmol) and 10mL acetonitrile, stirred at 50 ℃ for 30 minutes, then bromoethanol (95mg,0.91mmol) was added and reacted at 50 ℃ for 8 hours, the reaction was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), after completion of the reaction, distillation under reduced pressure was carried out to give a crude product, which was subjected to silica gel column chromatography (300-400 mesh) to separate and purify (eluent: dichloromethane/methanol, 40/1-20/1, V/V) to give Compound I-16(198mg), melting point: > 250 ℃, yield: 69.9 percent;1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝3.0Hz,1H,thiazole-4-H),8.29(d,J＝3.0Hz,1H,thiazole-5-H),8.19(s,1H,purine-4-H),8.18(s,1H,purine-9-H),5.91(s,2H,NCH2),4.43(s,1H,OH),4.23(s,4H,piperazine-2,6-CH2),3.56(d,J＝5.0Hz,2H,CH2CH2OH),2.56(s,4H,piperazine-3,5-CH2),2.45(t,J＝6.1Hz,2H,CH2CH2OH)ppm.
example 19: preparation of Compound I-17:
Figure BDA0002870484860000122
adding compound I-5(250mg,0.76mmol), potassium carbonate (125mg,0.91mmol) and 10mL of acetonitrile into a dry round-bottom flask, stirring at 50 ℃ for 30 minutes, adding 2-chlorobenzyl chloride (146mg,0.91mmol) to react at 50 ℃ for 2 hours, monitoring the reaction by thin layer chromatography (developing agent: dichloromethane/methanol, 15/2, V/V), after the reaction is finished, distilling under reduced pressure to obtain a crude product, separating and purifying the obtained crude product by silica gel column chromatography (300-400 meshes) (eluent: dichloromethane/methanol, 40/1-20/1, V/V) to obtain a yellow solid compoundSubstance I-17(226mg), melting Point: 203 ℃ and 204 ℃, yield: 65.6 percent;1H NMR(600MHz,CDCl3)δ8.32(s,1H,thiazole-4-H),8.10(d,J＝2.8Hz,1H，thiazole-5-H),7.81–7.79(m,2H,purine-4,9-CH),7.53(d,J＝7.3Hz,1H,benzene-3-CH),7.37(d,J＝7.9Hz,1H,benzene-4-CH),7.27(d,J＝7.2Hz,1H,benzene-6-CH),7.21(t,J＝7.6Hz,1H,benzene-5-CH),5.84(s,2H,NCH2),4.36(s,4H,piperazine-2,6-CH2),3.70(s,2H,(piperazine)CH2),2.68(s,4H,piperazine-3,5-CH2)ppm.
example 20: preparation of Compound I-18:
Figure BDA0002870484860000123
a dry round-bottom flask was charged with Compound I-5(250mg,0.76mmol), potassium carbonate (125mg,0.91mmol) and 10mL acetonitrile, stirred at 50 ℃ for 30 minutes, then reacted with 4-chlorobenzyl chloride (146mg,0.91mmol) at 50 ℃ for 2 hours, the reaction was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), after completion of the reaction, distillation under reduced pressure was carried out to give a crude product, which was subjected to silica gel column chromatography (300-400 mesh) to separate and purify (eluent: dichloromethane/methanol, 40/1-20/1, V/V) to give Compound I-18(246mg), melting point: 166 ℃ and 167 ℃, yield: 71.4 percent;1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝3.0Hz,1H,thiazole-4-H),8.29(d,J＝3.0Hz,1H,thiazole-5-H),8.19(s,1H,purine-4-H),8.18(s,1H,purine-9-H),7.40(d,J＝8.2Hz,2H,benzene-3,5-CH),7.38(d,J＝8.3Hz,2H,benzene-2,6-CH),5.91(s,2H,NCH2),4.25(s,4H,piperazine-2,6-CH2),3.53(s,2H,(piperazine)CH2),2.50(s,4H,piperazine-3,5-CH2)ppm.
example 21: preparation of Compound I-19:
Figure BDA0002870484860000131
a dry round bottom flask was charged with Compound I-5(250mg,0.76mmol), potassium carbonate (125)mg,0.91mmol) and 10mL acetonitrile, stirring at 50 ℃ for 30 minutes, adding 2-fluorobenzyl chloride (132mg,0.91mmol) to react at 50 ℃ for 2 hours, and monitoring the reaction by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), after the reaction is finished, carrying out reduced pressure distillation to obtain a crude product, and separating and purifying the obtained crude product by silica gel column chromatography (300-400 meshes) (eluent: dichloromethane/methanol, 40/1-20/1, V/V) gave compound I-19(238mg) as a yellow solid, melting point: 155 ℃ and 156 ℃, yield: 71.7 percent;1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝2.9Hz,1H,thiazole-4-H),8.29(d,J＝2.8Hz,1H,thiazole-5-H),8.19(s,1H,purine-4-H),8.18(s,1H,purine-9-H),7.46(t,J＝7.3Hz,1H,benzene-4-CH),7.34(dd,J＝13.1,6.3Hz,1H,benzene-3-CH),7.19(dd,J＝13.5,6.1Hz,2H,benzene-5,6-CH),5.92(s,2H,NCH2),4.25(s,4H,piperazine-2,6-CH2),3.60(s,2H,(piperazine)CH2),2.54(s,4H,piperazine-3,5-CH2)ppm.
example 22: preparation of Compound I-20:
Figure BDA0002870484860000132
a dry round-bottom flask was charged with Compound I-5(250mg,0.76mmol), potassium carbonate (125mg,0.91mmol) and 10mL acetonitrile, stirred at 50 ℃ for 30 minutes, then reacted with 4-fluorobenzyl chloride (132mg,0.91mmol) at 50 ℃ for 2 hours, the reaction was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), after completion of the reaction, distillation under reduced pressure was carried out to give a crude product, which was subjected to silica gel column chromatography (300-400 mesh) to separate and purify (eluent: dichloromethane/methanol, 40/1-20/1, V/V) to give Compound I-20(236mg), melting point: 166 ℃ and 167 ℃, yield: 71.1 percent;1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝2.0Hz,1H,thiazole-4-H),8.29(d,J＝2.8Hz,1H,thiazole-5-H),8.19(s,1H,purine-4-H),8.18(s,1H,purine-9-H),7.38(t,J＝6.7Hz,2H,benzene-2,6-CH),7.16(t,J＝8.7Hz,2H,benzene-3,5-CH),5.92(s,2H,NCH2),4.25(s,4H,piperazine-2,6-CH2),3.52(s,2H,(piperazine)CH2),2.50(d,J＝1.6Hz,4H,piperazine-3,5-CH2)ppm.
example 23: preparation of Compound I-21:
Figure BDA0002870484860000141
a dry round-bottom flask was charged with Compound I-5(250mg,0.76mmol), potassium carbonate (125mg,0.91mmol) and 10mL acetonitrile, stirred at 50 ℃ for 30 minutes, then reacted with 4-nitrobenzyl chloride (156mg,0.91mmol) at 50 ℃ for 2 hours, the reaction was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), after completion of the reaction, distillation under reduced pressure was carried out to give a crude product, which was subjected to silica gel column chromatography (300-400 mesh) to separate and purify (eluent: dichloromethane/methanol, 40/1-20/1, V/V) to give Compound I-21(245mg), melting point: 216 ℃ and 217 ℃, yield: 69.5 percent;1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝2.9Hz,1H,thiazole-4-H),8.30(d,J＝3.0Hz,1H,thiazole-5-H),8.22(s,1H,purine-4-H),8.21(s,1H,purine-9-H),8.20(d,J＝5.1Hz,2H,benzene-2,6-CH),7.65(d,J＝8.2Hz,2H,benzene-3,5-CH),5.92(s,2H,NCH2),4.28(s,4H,piperazine-2,6-CH2),3.68(s,2H,(piperazine)CH2),2.55(s,4H,piperazine-3,5-CH2)ppm.
example 24: preparation of Compound I-22:
Figure BDA0002870484860000142
a dry round-bottom flask was charged with Compound I-5(250mg,0.76mmol), potassium carbonate (125mg,0.91mmol) and 10mL acetonitrile, stirred at 50 ℃ for 30 minutes, then reacted with 4-methylbenzyl chloride (128mg,0.91mmol) at 50 ℃ for 6 hours, the reaction was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol, 15/2, V/V), after completion of the reaction, distillation under reduced pressure was carried out to give a crude product, which was subjected to silica gel column chromatography (300-400 mesh) to separate and purify (eluent: dichloromethane/methanol, 40/1-20/1, V/V) to give Compound I-22(224mg), melting point: 153 ℃ and 154 ℃, yield: 68.1 percent;1H NMR(600MHz,DMSO-d6)δ8.37(d,J＝2.9Hz,1H,thiazole-4-H),8.29(d,J＝3.0Hz,1H,thiazole-5-H),8.19(s,1H,purine-4-H),8.18(s,1H,purine-9-H),7.22(d,J＝7.7Hz,2H,benzene-2,6-CH),7.14(d,J＝7.7Hz,2H,benzene-3,5-CH),5.91(s,2H,NCH2),4.24(s,4H,piperazine-2,6-CH2),3.48(s,2H,(piperazine)CH2),2.49(d,J＝5.3Hz,4H,piperazine-3,5-CH2),2.29(s,3H,CH3)ppm.
example 25: in vitro antimicrobial activity of purine thiazole compounds
The Minimal Inhibitory Concentration (MIC) of the purine thiazole compounds and the intermediate III-1 in example 3-24 against gram-positive bacteria (methicillin-resistant Staphylococcus aureus, enterococcus faecalis, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213), gram-negative bacteria (Klebsiella pneumoniae, Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa 27853, Escherichia coli 25922) and fungi (Candida albicans, Candida tropicalis, Aspergillus fumigatus, Candida parapsilosis 20019) is detected by a 96-well microdilution method meeting the Clinical Laboratory Standards (NCCLS) set by the National Committee of the 1993 National Committee, the test compounds are dissolved in a small amount of dimethyl sulfoxide, diluted with water to a solution with the concentration of 1.28mg/mL, and diluted to 128. mu.g/mL with a culture solution, 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 1-3.
TABLE 1 in vitro gram Positive Activity data (MIC, μ g/mL) for purine thiazoles I-1 through I-22 and intermediate III-1
Figure BDA0002870484860000151
As can be seen from Table 1, the compounds I-10 of the present invention showed a certain inhibitory effect on the gram-positive bacteria tested, especially the MIC value for enterococcus faecalis was 4 μ g/mL, which is comparable to the activity of the reference drug norfloxacin.
TABLE 2 in vitro gram-negative activity data (MIC, μ g/mL) for purothiazole compounds I-1 to I-22 and intermediate III-1
Figure BDA0002870484860000161
As can be seen from Table 2, some of the compounds of the present invention showed good inhibitory effect on tested gram-negative bacteria, and in particular, the MIC value of compound I-10 to Acinetobacter baumannii was 1. mu.g/mL, which is 8 times of the norfloxacin activity.
TABLE 3 in vitro antifungal Activity data (MIC, μ g/mL) for purine thiazoles I-1 to I-22 and intermediate III-1
Figure BDA0002870484860000162
Figure BDA0002870484860000171
As can be seen from Table 3, the compounds I-1 to I-22 and the intermediate III-1 of the invention all show certain inhibitory action on the tested fungi, particularly the compound I-14 shows higher antibacterial activity on Candida albicans, and the MIC value is 1 mug/mL, which is 4 times that of the clinical drug fluconazole.
Example 26: pharmaceutical application of purine thiazole compounds
According to the antimicrobial activity detection result, the purine thiazole compound has better antibacterial and antifungal activity, and can be prepared into antibacterial and antifungal medicines for clinical use. The medicines can be single preparations, for example, prepared by purine thiazole compounds with one structure and pharmaceutically acceptable auxiliary materials; or a compound preparation, for example, the compound preparation is prepared by the purine thiazole compounds with one structure, the existing antibacterial and antifungal active components (such as norfloxacin, ciprofloxacin, sulfamethoxazole, fluconazole, phosphorus fluconazole, itraconazole and the like) and pharmaceutically acceptable auxiliary materials, or is prepared by a plurality of purine thiazole 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-6 tablets
Prescription: the tablet is prepared from compound I-610 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-6 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 I-7 capsules
Prescription: compound I-725 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 I-7, mixing with modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, pulvis Talci, sweetener, orange essence and pigment, granulating with water, sieving 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 I-8 granules
Prescription: compound I-826 g, dextrin 120g and sucrose 280 g.
The preparation method comprises the following steps: mixing compound I-8, dextrin and sucrose uniformly, granulating by wet method, drying at 60 deg.C, and packaging.
4. Preparation of Compound I-9 injection
Prescription: 1000mL of the compound I-910 g, 500mL of propylene glycol and 500mL of water for injection were prepared in total.
The preparation method comprises the following steps: weighing the compound I-9, 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 I-9.
5. Preparation of compound I-10 powder injection
The preparation method comprises the following steps: and subpackaging the sterile powder of the compound I-10 under the sterile condition to obtain the compound I-10.
6. Preparation of eye drops of Compound I-11
Prescription: compound I-113.78 g, sodium chloride 0.9g, appropriate amount of boric acid buffer solution, and distilled water to 1000 mL.
The preparation method comprises the following steps: weighing the compound I-8 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 I-12 Liniment
Prescription: compound I-124 g, potassium soap 7.5g, camphor 5g, distilled water 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 I-12, adding potassium soap solution and Camphora ethanol solution under stirring, gradually adding distilled water, emulsifying completely, and adding distilled water to full volume.
8. Preparation of suppository of compound I-13
Prescription: 100 metric pills of compound I-134 g, 14g of gelatin, 70g of glycerol and 100mL of distilled water.
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 I-13, stirring, pouring into vaginal suppository mold when it is nearly solidified, and cooling to solidify.
9. Preparation of Compound I-14 ointment
Prescription: 140.5-2 g of compound I, 6-8g of hexadecanol, 8-10g of white vaseline, 8-19g of liquid paraffin, 2-5g of monoglyceride, 2-5g of polyoxyethylene (40) stearate, 5-10g of glycerol, 0.1g of ethylparaben 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 I-14, stirring, and cooling.
10. Preparation of compound I-15 and fluconazole compound powder injection
Prescription: compound I-1550 g, fluconazole 50g and sodium benzoate 1g, and 100 bottles are prepared.
The preparation method comprises the following steps: taking the compound V-15, 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 I-16 Aerosol
Prescription: compound I-162.5 g, Span 203 g, talc (100 mesh) 4g, trichlorofluoromethane added to appropriate amount.
The preparation method comprises the following steps: respectively drying the compound I-16, the Span20 and the talcum powder in a vacuum drying oven for several hours, cooling in a drier 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, the above embodiments are only intended to illustrate the technical solutions of the present invention and not to limit the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions, and all of them should be covered by the claims of the present invention.

Claims (8)

1. Purine thiazole compounds and pharmaceutically acceptable salts thereof, which are characterized by being any one of the following compounds:
Figure FDA0003267607130000011
2. the purine thiazole compound and the pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is sodium salt, sulfate, hydrochloride, nitrate or acetate.
3. A process for preparing a purine thiazole compound and a pharmaceutically acceptable salt thereof according to claim 1, which comprises the following steps:
a. preparation of intermediate II-1: taking acetylthiazole as a starting material, taking bromine as a brominating agent, and reacting in glacial acetic acid to prepare an intermediate II-1;
Figure FDA0003267607130000021
b. preparation of intermediate III-1: taking the intermediate II-1 as an initial raw material, acetonitrile as a solvent, and potassium carbonate as a base, and reacting with 6-chloropurine to obtain an intermediate III-1;
Figure FDA0003267607130000022
c.I-1 to I-5, and preparation of pharmaceutically acceptable salts thereof: taking the intermediate III-1 as a raw material, taking triethylamine as an alkali and ethanol as a solvent, and respectively carrying out substitution reaction with alicyclic amine to obtain purine thiazole compounds shown as I-1 to I-5 and pharmaceutically acceptable salts thereof; the alicyclic amine is pyrrolidine, piperidine, hexamethyleneimine, morpholine or piperazine;
d.I-6 to I-22, and preparation of pharmaceutically acceptable salts thereof: taking a compound I-5 as a raw material, taking potassium carbonate as alkali and acetonitrile as a solvent, and respectively reacting with halogenated compounds to prepare purine thiazole compounds shown as I-6 to I-22 and pharmaceutically acceptable salts thereof; the halogenated compound is bromoethane, bromobutane, bromohexane, bromooctane, bromododecane, bromooctadecane, bromopropene, bromopropyne, ethyl bromoacetate, chloroacetonitrile, bromoethanol, 2-chlorobenzyl chloride, 4-chlorobenzyl chloride, 2-fluorobenzyl chloride, 4-nitrobenzyl chloride or 4-methylbenzyl chloride.
4. The method of claim 3,
in the step a, the molar ratio of the acetyl thiazole to the bromine is 1: 1.1; the temperature of the reaction is 50 ℃;
in the step b, the molar ratio of the intermediate II-1, potassium carbonate and 6-chloropurine is 1.2:1.2: 1; the temperature of the reaction is 50 ℃;
in the step c, the molar ratio of the intermediate III-1 to the triethylamine to the alicyclic amine is 1:1: 1; the temperature of the reaction is 50 ℃;
in the step d, the molar ratio of the compound I-5, the potassium carbonate and the halogenated compound is 1:1.2: 1.2; the temperature of the reaction was 50 ℃.
5. Use of the purine thiazole compound and the pharmaceutically acceptable salt thereof according to claim 1 or 2 for the preparation of antibacterial and/or antifungal agents.
6. The use of claim 5, wherein the bacteria is one or more of methicillin-resistant Staphylococcus aureus, enterococcus faecalis, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 29213, Klebsiella pneumoniae, Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa ATCC 27853, or Escherichia coli ATCC 25922; the fungi is one or more of Candida albicans, Candida tropicalis, Aspergillus fumigatus or Candida parapsilosis ATCC 20019.
7. A preparation comprising the purine thiazole compound according to claim 1 or 2 and a pharmaceutically acceptable salt thereof.
8. The preparation of claim 7, wherein the preparation is one or more of a tablet, a capsule, a granule, an injection, a powder injection, an eye drop, a liniment, a suppository, an ointment or an aerosol.
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