CN112661750B - Ketene-bridged quinazolinone thiazole compound and preparation method and application thereof - Google Patents
Ketene-bridged quinazolinone thiazole compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to an ketene-bridged quinazolinone thiazole compound, and a preparation method and application thereof, and belongs to the technical field of chemical synthesis. The ketene-bridged quinazolinone thiazole compound has a certain inhibitory activity on gram-positive bacteria and gram-negative bacteria, can be used for preparing antibacterial drugs, provides more efficient and safe candidate drugs for clinical antimicrobial therapy, and is beneficial to solving clinical treatment problems such as increasingly severe drug resistance, stubborn pathogenic microorganisms, newly-appeared 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.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to an ketene-bridged quinazolinone thiazole compound as well as a preparation method and application thereof.
Background
The quinazolone is an important heterocyclic molecule existing in natural products and synthetic compounds, has multiple potential biological activities of resisting virus, convulsion, bacteria, inflammation, histamine, cancer and the like, shows huge medicinal potential and development value, attracts a large number of researchers to separate and purify natural alkaloid from various plants or synthesize the quinazolone compound with novel structure and property, and performs biological research and development on new potential medicaments. So far, some quinazolinone drugs, such as mequinone as a hypnotic and anticonvulsant drug, balaglitazone as an antidiabetic drug, etc., have been used clinically. More importantly, the quinazolinone compounds are completely exposed in the aspect of treating microbial infection, and many quinazolinone derivatives not only have excellent antibacterial activity and wider antibacterial spectrum to many drug-resistant strains, but also have good pharmacokinetics. Therefore, the design and development of novel quinazolinone compounds are expected to overcome increasingly serious drug-resistant bacteria.
Thiazole compounds are important five-membered aromatic heterocycles containing nitrogen and sulfur heteroatoms, widely exist in natural products and synthetic molecules, have the characteristic of electron enrichment, and are easy to generate a plurality of weak interactions such as hydrogen bonds, coordination, ion dipoles, hydrophobic interactions, van der waals forces and the like with a plurality of targets in organisms, so that the thiazole compounds not only have double or even multiple drug action mechanisms, but also show wide biological activity. In the thiazole marketed drugs, infectious diseases are the most important application fields of thiazole drugs, in particular to antibacterial drugs, such as antibacterial drugs of sulfathiazole, third and fourth generation cephalosporins and aztreonam; antifungal drugs such as ravuconazole, abafungin, and flulafutizole have been widely used to treat various diseases. In addition, a great deal of research and development are carried out on thiazole compounds with multi-target active molecules, and more thiazole compounds with good tolerance, high activity, broad spectrum, low toxicity, high bioavailability and good pharmacokinetic property are provided for clinical use as antibacterial candidate drugs or drug molecules. Therefore, thiazole shows wide application potential in the development of medicines, and more effective and specific antibacterial compounds are hopeful to be obtained by carrying out medicine development on the thiazole.
Disclosure of Invention
In view of the above, an object of the present invention is to provide ketene-bridged quinazolinone compounds and pharmaceutically acceptable salts thereof; the second purpose of the invention is to provide a preparation method of the ketene-bridged quinazolinone thiazole compound and the pharmaceutically acceptable salt thereof; the invention also aims to provide the application of the ketene-bridged quinazolinone thiazole compound and the pharmaceutically acceptable salt thereof in preparing antibacterial drugs; the fourth purpose of the invention is to provide a preparation containing the ketene-bridged quinazolinone thiazole compound and a pharmaceutically acceptable salt thereof.
In order to achieve the purpose, the invention provides the following technical scheme:
1. the structure of the ketene-bridged quinazolinone thiazole compound and the pharmaceutically acceptable salt thereof is shown as the general formula I:
in the formula, R 1 、R 2 、R 3 And R 4 Is hydrogen, halogen, alkyl, alkoxy, amino, hydroxyl, cyano, carboxyl or nitro; r 5 Is five-membered ring, six-membered ring, benzo heterocycle, condensed ring aromatic hydrocarbon or amine.
Preferably, R 1 、R 2 、R 3 And R 4 Is hydrogen, chlorine or fluorine; r 5 Is a benzene ring, a 4-fluorobenzene ring, a 4-chlorobenzene ring, a 2, 4-dichlorobenzene ring, a 2-chlorobenzene ring, a 3-chlorobenzene ring, a 4-methylbenzene ring, a 4-methoxybenzene ring, a 4-cyanobenzene ring, a 4-nitrobenzene ring, a 4-trifluoromethylbenzene ring, a 2, 4-difluorobenzene ring, a 2, 4-dimethylbenzene ring, a 2-fluoro-4-piperazinene ring, thiophene, furan, pyrrole, imidazole, thiazole, indole, 6-chloroindole, 6-methylindole, 1-ethylindole, benzothiophene, naphthalene or dimethylamine.
Preferably, it is any one of the following compounds:
preferably, the pharmaceutically acceptable salt is hydrochloride, nitrate or acetate.
2. The preparation method of the ketene-bridged quinazolinone thiazole compound and the pharmaceutically acceptable salt thereof comprises the following steps:
a. preparation of intermediate II: carrying out bromination reaction on the 2-acetylthiazole and bromine to obtain an intermediate II;
b. preparation of intermediates III-1 to 3: using anthranilic acid compounds and formamide as starting raw materials, and performing cyclization reaction to obtain intermediates III-1-3;
c. preparation of intermediates IV-1 to 3: respectively carrying out nucleophilic substitution reaction on the intermediates III-1-3 and the intermediate II under the action of alkali to obtain intermediates IV-1-3;
d. preparation of ketene-bridged quinazolines of the general formula I-1-27: respectively carrying out condensation reaction on the intermediates IV-1-3 and aldehyde under the action of alkali to obtain ketene-bridged quinazolinone thiazole compounds shown in general formulas I-1-27;
e. preparation of ketene-bridged quinazolinone compounds of the general formula I-28: and carrying out condensation reaction on the intermediate IV-1 and acetal to obtain the ketene-bridged quinazolinone thiazole compound shown in the general formula I-28.
Preferably, the first and second liquid crystal materials are,
in the step a, the molar ratio of the 2-acetylthiazole to the bromine is 1.2; the bromination reaction is specifically carried out for 4 hours at 50 ℃ by taking glacial acetic acid as a solvent;
in the step b, the cyclization reaction is carried out for 8-12h at 130 ℃ by taking formamide as a solvent;
in the step c, the molar ratio of the intermediate III-1-3 to the base to the intermediate II is 1.2; the alkali is potassium carbonate; the nucleophilic substitution reaction is carried out for 2-12h at 50 ℃ by taking acetonitrile or acetone as a solvent;
in the step d, the molar ratio of the intermediate IV-1-3 to aldehyde is 1.2; the base is piperidine; the condensation reaction is specifically to take ethanol as a solvent to react for 20 hours at 65 ℃;
in the step e, the molar ratio of the intermediate IV-1 to the acetal is 1.
3. The ketene-bridged quinazolinone thiazole compound and the medicinal salt thereof are applied to the preparation of antibacterial medicaments.
Preferably, the bacteria are one or more of methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC 25923, staphylococcus aureus ATCC 29213, klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC 27853, escherichia coli ATCC 25922, or acinetobacter baumannii.
4. A preparation containing the ketene-bridged quinazolinone thiazole compound and a pharmaceutically acceptable salt thereof.
Preferably, the preparation is one of tablets, capsules, granules, injections, powder injections, eye drops, liniments, suppositories, ointments or aerosols.
The invention has the beneficial effects that: the invention provides ketene-bridged quinazolinone thiazole compounds, a preparation method and application thereof, wherein a series of novel ketene-bridged quinazolinone thiazole compounds are designed and synthesized by using a medicament design split principle through ketene fragments bridged quinazolinone and thiazole, and are found to have certain inhibitory activity on gram-positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC 25923 and staphylococcus aureus ATCC 29213) and gram-negative bacteria (Klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC 27853, escherichia coli ATCC 25922 and Acinetobacter) through in-vitro antimicrobial activity detection, so that the compounds can be used for preparing antibacterial medicaments, can provide more efficient and safe candidate medicaments for clinical antimicrobial treatment, and are favorable for solving clinical treatment problems of severe drug resistance, stubborn pathogenic microorganisms, newly-occurring 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
Reference is made to the methods described in "Y.Y.Hu, J.Wang, T J.Li, R.R.Y.Bheemanboina, M.F.Ansari, Y.Cheng, C.H.Zhou, an unexpected transformed tissue culture as potential MRSA DNA intermediates. Future Med. Chem.,2020, 12.
Example 2 preparation of intermediates III-1 to 3
The compound is prepared by a method described in the reference' caoquanchen, wanghui, tangdanchu Vijai Kumar Reddy, gopala Lavanya, cai guixin, zhou he.
Example 3 preparation of intermediates IV-1 to 3
The preparation is carried out by the method described in the patents "C.H.Zhou, J.Wang, quinazol kinase compounds, and the prediction method and application in preparation of antibiotic or antibiotic agents. CN 110330487".
Example 4 preparation of Compound I-1
A50 mL round-bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and reacted for a further 20 hours with additional benzaldehyde (83mg, 0.78mmol). Cooled to room temperature, purified by silica gel column chromatography and dried to give I-1 (130 mg) as a white solid, yield: 50.5 percent; melting point: 113-114 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.94(s,1H,quinazolone-2-H),8.25(d,J＝8.5Hz,1H,quinazolone-5-H),7.96(d,J＝3.0Hz,1H,thiazole-5-H),7.80(s,1H,quinazolone-8-H),7.78(d,J＝1.7Hz,1H,quinazolone-6-H),7.70(d,J＝3.0Hz,1H,thiazole-4-H),7.50(dd,J＝8.5,1.9Hz,1H,Ph-4-H),7.39(dd,J＝8.9,4.4Hz,1H,C＝CH),7.34(d,J＝4.3Hz,4H,Ph-2,3,5,6-H)ppm.
Example 5 preparation of Compound I-2
A50 mL round bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and added p-fluorobenzaldehyde (97mg, 0.78mmol) and allowed to react for an additional 20 hours. Cooling to room temperature, purifying by silica gel column chromatography, and drying to obtain yellow solid I-2 (56 mg)Yield, yield: 20.8 percent; melting point: 177-178 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.96(s,1H,quinazolone-2-H),8.25(d,J＝8.5Hz,1H,quinazolone-5-H),7.96(d,J＝2.9Hz,1H,thiazole-5-H),7.80(s,1H,quinazolone-8-H),7.78(s,1H,quinazolone-6-H),7.71(d,J＝2.9Hz,1H,thiazole-4-H),7.50(d,J＝8.5Hz,1H,C＝CH),7.36(dd,J＝8.2,5.4Hz,2H,Ph-2,6-H),7.04(t,J＝8.4Hz,2H,Ph-3,5-H)ppm.
Example 6 preparation of Compound I-3
A50 mL round-bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then charged with p-chlorobenzaldehyde (110mg, 0.78mmol) and allowed to react for 20 hours. Cooled to room temperature, purified by silica gel column chromatography and dried to give I-3 (90 mg) as a white solid. Yield: 32.1 percent; melting point: 171-172 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.92(s,1H,quinazolone-2-H),8.24(d,J＝8.5Hz,1H,quinazolone-5-H),7.96(d,J＝3.0Hz,1H,thiazole-5-H),7.78(d,J＝3.8Hz,2H,quinazolone-6,8-H),7.71(d,J＝3.0Hz,1H,thiazole-4-H),7.50(dd,J＝8.5,1.7Hz,1H,C＝CH),7.32(d,J＝8.6Hz,2H,Ph-2,6-H),7.28(d,J＝8.6Hz,2H,Ph-3,5-H)ppm.
Example 7 preparation of Compound I-4
A50 mL round-bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then charged with 2, 4-dichlorobenzaldehyde (137mg, 0.78mmol) and allowed to react for an additional 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-4 (163 mg) as a yellow solid. Yield: 53.9 percent; . Yield: 207-208 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.95(s,1H,quinazolone-2-H),8.21(d,J＝8.5Hz,1H,quinazolone-5-H),7.96(d,J＝3.0Hz,1H,thiazole-5-H),7.73(d,J＝3.0Hz,1H,thiazole-4-H),7.72(s,1H,quinazolone-8-H),7.69(d,J＝1.3Hz,1H,quinazolone-6-H),7.51(d,J＝1.2Hz,1H,Ph-5-H),7.49(dd,J＝8.6,1.6Hz,1H,Ph-4-H),7.11–7.09(m,2H,Ph-3-H,C＝CH)ppm.
EXAMPLE 8 preparation of Compound I-5
A50 mL round-bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then charged with 2-chlorobenzaldehyde (110mg, 0.78mmol) and allowed to react for a further 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-5 (186 mg) as a white solid. Yield: 66.7 percent; melting point: 116-117 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.99(s,1H,quinazolone-2-H),8.22(d,J＝8.5Hz,1H,quinazolone-5-H),7.96(d,J＝1.2Hz,1H,thiazole-5-H),7.7–7.69(m,3H,thiazole-4-H,quinazolone-6,8-H),7.48(d,J＝7.3Hz,2H,C＝CH,Ph-3-H),7.31(t,J＝7.6Hz,1H,Ph-5-H),7.16(d,J＝7.6Hz,1H,Ph-6-H),7.11(t,J＝7.4Hz,1H,Ph-4-H)ppm.
EXAMPLE 9 preparation of Compound I-6
A50 mL round-bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then charged with 3-chlorobenzaldehyde (110mg, 0.78mmol) and allowed to react for a further 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-6 (43 mg) as a yellow solid. Yield: 15.4 percent; melting point: 112-113 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.88(s,1H,quinazolone-2-H),8.24(d,J＝8.5Hz,1H,quinazolone-5-H),7.96(d,J＝2.9Hz,1H,thiazolone-5-H),7.77(s,2H,quinazolone-6,8-H),7.72(d,J＝2.9Hz,1H,thiazole-4-H),7.50(d,J＝8.5Hz,1H),7.37(d,J＝8.2Hz,2H),7.25(d,J＝7.8Hz,1H),7.17(d,J＝7.8Hz,1H)ppm.
EXAMPLE 10 preparation of Compound I-7
A50 mL round-bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then added with p-tolualdehyde (94mg, 0.78mmol) and allowed to react for further 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-7 (109 mg) as a yellow solid. Yield: 40.9 percent; melting point: 171-172 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.96(s,1H,quinazolone-2-H),8.25(d,J＝8.5Hz,1H,quinazolone-5-H),7.95(d,J＝2.9Hz,1H,thiazole-5-H),7.81(s,1H,quinazolone-8-H),7.78(s,1H,quinazolone-6-H),7.69(d,J＝3.0Hz,1H,thiazole-4-H),7.50(d,J＝8.5Hz,1H,C＝CH),7.23(d,J＝8.0Hz,2H,Ph-3,5-H),7.14(d,J＝7.9Hz,2H,Ph-2,6-H),2.33(s,3H,CH 3 )ppm.
EXAMPLE 11 preparation of Compound I-8
A50 mL round-bottomed flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then added p-methoxybenzaldehyde (107mg, 0.78mmol) and allowed to react for 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-8 (76 mg) as a yellow solid. Yield: 27.4 percent; melting point: 179-180 ℃. 1 H NMR(600MHz,CDCl 3 )δ9.02(s,1H,quinazolone-2-H),8.26(d,J＝8.5Hz,1H,quinazolone-5-H),7.95(s,1H,thiazole-5-H),7.85(s,1H,quinazolone-8-H),7.79(s,1H,quinazolone-6-H),7.68(d,J＝3.0Hz,1H,thiazole-4-H),7.50(d,J＝8.5Hz,1H,C＝CH),7.31(d,J＝8.4Hz,2H,Ph-2,6-H),6.84(d,J＝8.2Hz,2H,Ph-3,5-H),3.80(s,3H,OCH 3 )ppm.
EXAMPLE 12 preparation of Compound I-9
A50 mL round-bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and reacted for a further 20 hours with the addition of p-cyanobenzaldehyde (103mg, 0.78mmol). It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-9 (50 mg) as a white solid. Yield: 18.3 percent; melting point: 182 to 183 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.90(s,1H,quinazolone-2-H),8.22(d,J＝8.5Hz,1H,quinazolone-5-H),7.96(d,J＝3.0Hz,1H,thiazole-5-H),7.77(d,J＝1.5Hz,1H,quinazolone-6-H),7.75(d,J＝3.3Hz,2H,thiazole-4-H,quinazolone-8-H),7.63(d,J＝8.3Hz,2H,Ph-3,5-H),7.51(dd,J＝8.5,1.7Hz,1H,C＝CH),7.44(d,J＝8.2Hz,2H,Ph-2,6-H)ppm.
EXAMPLE 13 preparation of Compound I-10
A50 mL round-bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and reacted for a further 20 hours with further p-nitrobenzaldehyde (119mg, 0.78mmol). It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-10 (89 mg) as a yellow solid. Yield: 31.0 percent; melting point: 128-129 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.95(s,1H,quinazolone-2-H),8.23(d,J＝8.5Hz,1H,quinazolone-5-H),8.20(s,1H,quinazolone-8-H),8.19(s,1H,quinazolone-6-H),7.97(d,J＝3.0Hz,1H,thiazole-5-H),7.75(dd,J＝7.7,4.6Hz,3H,thiazole-4-H,Ph-3,5-H),7.52(d,J＝8.5Hz,3H,C＝CH,Ph-2,6-H)ppm.
EXAMPLE 14 preparation of Compound I-11
Adding the intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL) into a 50mL round-bottom flask, heating to 65 ℃ for half an hour for reaction, and then addingP-trifluoromethylbenzaldehyde (137mg, 0.78mmol) was added thereto and the reaction was continued for 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give white solid I-11 (68 mg). Yield: 22.5 percent; melting point: 170-171 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.93(s,1H,quinazolone-2-H),8.23(d,J＝8.5Hz,1H,quinazolone-5-H),7.96(d,J＝3.0Hz,1H,thiazole-5-H),7.78–7.74(m,2H,quinazolone-6,8-H),7.73(d,J＝3.0Hz,1H,thiazole-4-H),7.60(d,J＝8.2Hz,2H,Ph-2,6-H),7.50(dd,J＝8.5,1.8Hz,1H,C＝CH),7.46(d,J＝8.1Hz,2H,Ph-3,5-H)ppm.
EXAMPLE 15 preparation of Compound I-12
A50 mL round-bottomed flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then added with 2, 4-difluorobenzaldehyde (112mg, 0.78mmol) and allowed to react for further 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-12 (74 mg) as a yellow solid. Yield: 26.3 percent; the melting point is 190-191 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.94(s,1H,quinazolone-2-H),8.23(d,J＝8.5Hz,1H,quinazolone-5-H),7.96(d,J＝2.7Hz,1H,thiazole-5-H),7.76(d,J＝11.2Hz,2H,quinazolone-6,8-H),7.72(d,J＝2.8Hz,1H,thiazole-4-H),7.49(d,J＝8.5Hz,1H,C＝CH),7.18(dd,J＝14.7,8.1Hz,1H,Ph-6-H),6.90(dd,J＝13.4,5.0Hz,1H,Ph-5-H),6.80(t,J＝7.7Hz,1H,Ph-3-H)ppm.
EXAMPLE 16 preparation of Compound I-13
A50 mL round bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then added with 2, 4-dimethylbenzaldehyde (105mg, 0.78mmol) and allowed to react for an additional 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-13 (34 mg) as a yellow solid. Yield: 12.3 percent; melting point:154–155℃。 1 H NMR(600MHz,CDCl 3 )δ9.09(s,1H,quinazolone-2-H),8.23(d,J＝8.5Hz,1H,quinazolone-5-H),7.94(d,J＝2.9Hz,1H,thiazole-5-H),7.70(t,J＝7.5Hz,3H,thiazole-4-H,quinazolone-6,8-H),7.47(d,J＝8.5Hz,1H,C＝CH),7.08(s,1H,Ph-3-H),6.96(d,J＝7.9Hz,1H,Ph-6-H),6.82(d,J＝7.9Hz,1H,Ph-5-H),2.43(s,3H,Ph-2-CH 3 ),2.27(s,3H,Ph-4-CH 3 )ppm.
EXAMPLE 17 preparation of Compound I-14
A50 mL round-bottomed flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then added with 2, 4-difluorobenzaldehyde (112mg, 0.78mmol) and allowed to react for further 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-14 (75 mg) as a red solid. Yield: 23.2 percent; melting point: 141-142 ℃. 1 H NMR(600MHz,CDCl 3 )δ9.25(s,1H,quinazolone-2-H),8.27(d,J＝8.5Hz,1H,quinazolone-5-H),7.96(s,1H,thiazole-5-H),7.87(s,1H,quinazolone-8-H),7.78(s,1H,thiazole-4-H),7.67–7.62(m,1H,quinazolone-6-H),7.48(d,J＝8.4Hz,1H,Ph-6-H),6.92(t,J＝8.6Hz,1H,C＝CH),6.51(d,J＝14.4Hz,1H,Ph-5-H),6.45–6.40(m,1H,Ph-3-H),3.31(s,4H,piperidine-2,6-H),1.63(s,6H,piperidine-3,4,5-H)ppm.
EXAMPLE 18 preparation of Compound I-15
A50 mL round bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then added 2-thiophenecarboxaldehyde (88mg, 0.78mmol) and allowed to react for an additional 20 hours. Cooled to room temperature, purified by silica gel column chromatography and dried to give I-15 (224 mg) as a yellow solid, yield: 85.6 percent; melting point: 232-233 ℃. 1 H NMR(600MHz,CDCl 3 )δ9.61(s,1H,quinazolone-2-H),8.27(d,J＝8.5Hz,1H,quinazolone-5-H),8.01(d,J＝3.0Hz,1H,thiazole-5-H),7.86(s,1H,quinazolone-8-H),7.84(d,J＝1.5Hz,1H,quinazolone-6-H),7.71(d,J＝3.1Hz,1H,thiazole-4-H),7.61(d,J＝3.6Hz,1H,thiophene-5-H),7.55(d,J＝5.0Hz,1H,thiophene-4-H),7.50(dd,J＝8.5,1.8Hz,1H,thiophene-3-H),7.16–7.13(m,1H,C＝CH)ppm.
EXAMPLE 19 preparation of Compound I-16
A50 mL round-bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and reacted for a further 20 hours with the addition of furfural (75mg, 0.78mmol). Cooled to room temperature, purified by silica gel column chromatography and dried to give I-16 (89 mg) as a yellow solid, yield: 35.5 percent; melting point: 174-175 ℃. 1 H NMR(600MHz,CDCl 3 )δ9.13(s,1H,quinazolone-2-H),8.25(d,J＝8.5Hz,1H,quinazolone-5-H),7.99(d,J＝3.0Hz,1H,thiazole-5-H),7.94(s,1H,quinazolone-8-H),7.81(d,J＝1.8Hz,1H,quinazolone-6-H),7.70(d,J＝3.1Hz,1H,thiazole-4-H),7.48(dd,J＝8.5,1.9Hz,1H,furan-4-H),7.46(d,J＝0.8Hz,1H,furan-5-H),6.87(d,J＝3.5Hz,1H,furan-3-H),6.52(dd,J＝3.5,1.6Hz,1H,C＝CH)ppm.
EXAMPLE 20 preparation of Compound I-17
A50 mL round-bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then charged with 2-pyrrolecarboxaldehyde (75mg, 0.78mmol) and allowed to react for an additional 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-17 (106 mg) as a yellow solid. Yield: 42.3 percent; melting point:>250℃。 1 H NMR(600MHz,DMSO-d 6 )δ12.16(s,1H,NH),9.14(s,1H,quinazolone-2-H),8.30(d,J＝1.3Hz,1H,quinazolone-5-H),8.23(s,1H),8.21–8.13(m,2H),7.90(s,1H),7.66(d,J＝8.3Hz,1H),7.32(s,1H),6.25(s,1H),5.91(s,1H)ppm.
EXAMPLE 21 preparation of Compound I-18
A50 mL round bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then added 2-imidazolecarboxaldehyde (75mg, 0.78mmol) and allowed to react for an additional 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-18 (229 mg) as a yellow solid. Yield: 91.2 percent; melting point:>250℃。 1 H NMR(600MHz,DMSO-d 6 )δ13.28(s,1H,NH),8.93(s,1H,quinazolone-2-H),8.30(d,J＝2.8Hz,1H,thiazole-5-H),8.26(d,J＝2.1Hz,1H,quinazolone-5-H),8.20(d,J＝2.8Hz,1H,thiazole-4-H),8.12(dd,J＝8.4,1.4Hz,1H,quinazolone-6-H),7.85(s,1H,quinazolone-8-H),7.61(dd,J＝8.5,1.8Hz,1H,C＝CH),7.53(s,1H,Im-5-H),7.15(s,1H,Im-4-H)ppm.
EXAMPLE 22 preparation of Compound I-19
A50 mL round bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then added 2-thiazolecarboxaldehyde (89mg, 0.78mmol) and allowed to react for an additional 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-19 (140 mg) as a yellow solid. Yield: 53.4 percent; melting point: 202-203 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ9.36(s,1H,quinazolone-2-H),8.43(s,1H,quinazolone-8-H),8.36(d,J＝2.5Hz,1H,CH-thiazole-4-H),8.25(d,J＝2.5Hz,1H,thiazole-5-H),8.18(d,J＝8.5Hz,1H,quinazolone-5-H),8.14(d,J＝2.5Hz,1H,CH-thiazole-5-H),8.10(d,J＝2.3Hz,1H,thiazole-4-H),7.93(s,1H,C＝CH),7.68(d,J＝8.3Hz,1H,quinazolone-6-H)ppm.
EXAMPLE 23 preparation of Compound I-20
A50 mL round-bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then 3-indolecarboxaldehyde (114mg, 0.78mmol) was added and the reaction was continued for 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-20 (136 mg) as a yellow solid. Yield: 48.0 percent; melting point:>250℃。H NMR(600MHz,DMSO-d 6 )δ12.05(s,1H,NH),9.68(s,1H,quinazolone-2-H),8.36(s,1H,quinazolone-5-H),8.25(d,J＝6.6Hz,2H,thiazole-5-H,quinazolone-6-H,),8.22(d,J＝8.5Hz,1H,thiazole-4-H),7.92(s,1H,quinazolone-8-H),7.76(d,J＝7.6Hz,1H,indole-2-H),7.68(d,J＝7.3Hz,1H,indole-2-H),7.53(d,J＝7.8Hz,1H,indole-7-H),7.29–7.23(m,2H,indole-5,6-H),7.21(s,1H,C＝CH)ppm.
EXAMPLE 24 preparation of Compound I-21
A50 mL round-bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then charged with 6-chloro-3-indolecarboxaldehyde (141mg, 0.78mmol) and allowed to react for an additional 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-21 (75 mg) as a red solid. Yield: 24.5 percent; melting point:>250℃。 1 H NMR(600MHz,DMSO-d 6 )δ12.05(s,1H,NH),9.58(s,1H,quinazolone-2-H),8.35(s,1H,quinazolone-5-H),8.24(d,J＝19.9Hz,3H,thiazole-4,5-H,quinazolone-6-H),7.92(s,1H,quinazolone-8-H),7.77(d,J＝6.9Hz,1H,indole-4-H),7.68(d,J＝6.3Hz,1H,indole-5-H),7.59(s,1H,indole-2-H),7.26(s,2H,indole-7-H,C＝CH)ppm.
EXAMPLE 25 preparation of Compound I-22
A50 mL round-bottomed flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then added with 6-methyl-3-indolecarboxaldehyde (125mg, 0.78mmol) and allowed to react for another 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-22 (103 mg) as a red solid. Yield: 35.2 percent; melting point:>250℃。 1 H NMR(600MHz,DMSO-d 6 )δ11.94(s,1H,NH),9.64(s,1H,quinazolone-2-H),8.34(s,1H,quinazolone-5-H),8.25–8.20(m,3H,thiazole-4,5-H,quinazolone-6-H),7.92(s,1H,quinazolone-8-H),7.68(d,J＝8.0Hz,1H,indole-4-H),7.60(d,J＝7.8Hz,1H,indole-5-H),7.30(s,1H,indole-2-H),7.13(s,1H,C＝CH),7.06(d,J＝7.7Hz,1H,indole-7-H),2.41(s,3H,CH 3 )ppm.
EXAMPLE 26 preparation of Compound I-23
A50 mL round-bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then charged with 1-ethyl-3-indolecarboxaldehyde (136mg, 0.78mmol) and allowed to react for an additional 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-23 (152 mg) as a yellow solid. Yield: 50.4 percent; melting point: 165-166 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ9.63(s,1H,quinazolone-2-H),8.32(s,1H,quinazolone-5-H),8.27–8.16(m,3H,thiazole-4,5-H,quinazolone-6-H),7.91(s,1H,quinazolone-8-H),7.75(d,J＝7.6Hz,1H,indole-4-H),7.67(d,J＝8.1Hz,1H,indole-7-H),7.63(d,J＝7.9Hz,1H,C＝CH),7.38(s,1H,indole-2-H),7.35–7.30(m,1H,indole-6-H),7.27(t,J＝6.9Hz,1H,indole-5-H),4.20(d,J＝6.9Hz,2H,CH 2 ),1.21(t,J＝6.7Hz,3H,CH 3 )ppm.
EXAMPLE 27 preparation of Compound I-24
In a 50mL round bottom flaskAdding intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), heating to 65 ℃ for half an hour for reaction, adding 3-benzothiophene aldehyde (127mg, 0.78mmol), and continuing the reaction for 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-24 (179 mg) as a yellow solid. Yield: 60.8 percent; melting point: 237-238 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ9.40(s,1H,quinazolone-2-H),8.36–8.30(m,2H,thiazole-5-H,quinazolone-5-H),8.24(s,1H,quinazolone-8-H),8.19(d,J＝8.4Hz,1H,thiazole-4-H),8.09(dd,J＝16.0,7.9Hz,2H,quinazolone-6-H,benzothiophene-2-H),7.88(s,1H,benzothiophene-4-H),7.85(s,1H,benzothiophene-7-H),7.68(d,J＝8.1Hz,1H,benzothiophene-6-H),7.57(t,J＝7.3Hz,1H,benzothiophene-5-H),7.51(t,J＝7.2Hz,1H,C＝CH)ppm.
EXAMPLE 28 preparation of Compound I-25
A50 mL round-bottom flask was charged with intermediate IV-1 (200mg, 0.65mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then charged with 2-naphthaldehyde (123mg, 0.78mmol) and allowed to react for an additional 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-25 (89 mg) as a yellow solid. Yield: 30.1 percent; melting point: 128-129 ℃. 1 H NMR(600MHz,CDCl 3 )δ9.14(s,1H,quinazolone-2-H),8.28(d,J＝8.5Hz,1H,quinazolone-5-H),7.98(d,J＝3.0Hz,1H,thiazole-5-H),7.96(s,1H,naphthalene-1-H),7.84(s,1H,quinazolone-8-H),7.78(dd,J＝4.7,2.8Hz,2H,quinazolone-6-H,naphthalene-8-H),7.74(d,J＝8.0Hz,1H,naphthalene-5-H),7.73–7.70(m,2H,thiazole-4-H,naphthalene-4-H),7.54(t,J＝7.2Hz,1H,naphthalene-3-H),7.52–7.49(m,2H,naphthalene-6,7-H),7.28(dd,J＝8.6,1.1Hz,1H,C＝CH)ppm.
EXAMPLE 29 preparation of Compound I-26
A50 mL round-bottom flask was charged with intermediate IV-2 (200mg, 0.69mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then added with p-trifluoromethylbenzaldehyde (144mg, 0.83mmol) and allowed to react for further 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-26 (89 mg) as a yellow solid. Yield: 28.9 percent; melting point: 188-189 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.94(s,1H,quinazolone-2-H),8.32(dd,J＝8.6,6.1Hz,1H),7.97(d,J＝2.8Hz,1H,thiazole-5-H),7.76(s,1H),7.74(d,J＝2.3Hz,1H,thiazole-4-H),7.61(d,J＝8.0Hz,2H,Ph-2,6-H),7.47(d,J＝8.0Hz,2H,Ph-3,5-H),7.43–7.40(m,1H),7.26(d,J＝6.6Hz,1H,C＝CH)ppm.
EXAMPLE 30 preparation of Compound I-27
A50 mL round bottom flask was charged with intermediate IV-3 (200mg, 0.59mmol), piperidine and ethanol (20 mL), warmed to 65 ℃ for half an hour, and then added with p-trifluoromethylbenzaldehyde (123mg, 0.71mmol) and allowed to react for 20 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-27 (53 mg) as a yellow solid. Yield: 18.2 percent; melting point: 99-100 ℃. 1 H NMR(600MHz,CDCl 3 )δ8.99(s,1H,quinazolone-2-H),8.19(d,J＝2.2Hz,1H,quinazolone-4-H),7.98(d,J＝3.0Hz,1H,thiazole-5-H),7.89(d,J＝2.3Hz,1H,quinazolone-5-H),7.85(s,1H,C＝CH),7.75(d,J＝3.0Hz,1H,thiazole-4-H),7.62(d,J＝8.1Hz,2H,Ph-2,6-H),7.45(d,J＝8.1Hz,2H,Ph-3,5-H)ppm.
EXAMPLE 31 preparation of Compound I-28
A50 mL round-bottomed flask was charged with intermediate IV-1 (200mg, 0.65mmol) and N, N-dimethylformamide dimethyl acetal (156mg, 1.31mmol) and acetonitrile (20 mL) and reacted at 80 ℃ for 4 hours. It was cooled to room temperature, purified by silica gel column chromatography and dried to give I-28 (117 mg) as a yellow solid. Yield of:49.6 percent; melting point: 207-208 ℃. 1 H NMR(600MHz,DMSO-d 6 )δ9.41(s,1H,quinazolone-2-H),8.25(s,1H,quinazolone-5-H),8.19(d,J＝8.0Hz,1H,thiazole-5-H),8.10(s,1H,quinazolone-8-H),8.07(s,1H,quinazolone-6-H),7.82(s,1H,C＝CH),7.63(d,J＝7.7Hz,1H,thiazole-4-H),3.27(s,3H,CH 3 ),2.74(s,3H,CH 3 )ppm.
Example 32 in vitro antimicrobial Activity of ketene-bridged quinazolinone thiazoles
The Minimal Inhibitory Concentrations (MIC) of ketene-bridged quinazolinone thiazole compounds prepared in examples 4-31 against gram-positive bacteria (methicillin-resistant Staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC 25923, staphylococcus aureus ATCC 29213) and gram-negative bacteria (Klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC 27853, escherichia coli ATCC 25922, acinetobacter baumannii) were determined by a 96-well microdilution method in accordance with Clinical Laboratory Standards (CLSI) set by the national Committee of the United states, and the MIC results were determined at 490nm after 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, further diluted with a culture solution to 128. Mu.g/mL, cultured at 35 ℃ for 24-72 hours, the culture plates were sufficiently shaken on a shaker.
TABLE 1 in vitro gram Positive Activity data (MIC, μ g/mL) for enone-bridged quinazolinone compounds prepared in examples 4-31
As can be seen from Table 1, the ketene-bridged quinazolinone thiazole compounds prepared in examples 4-31 of the invention show certain inhibitory effects on tested gram-positive bacteria, and particularly, the minimum inhibitory concentration of compounds I-1, I-9 and I-11 on MRSA is 4 μ g/mL, which is better than that of the reference drug norfloxacin.
TABLE 2 in vitro gram negative activity data (MIC, μ g/mL) for ketene-bridged quinazolinone compounds prepared in examples 4-31
As can be seen from Table 2, the ketene-bridged quinazolinone thiazole compounds prepared in examples 4-31 of the invention show certain inhibitory effect on tested gram-negative bacteria, and especially the minimum inhibitory concentration of the compound I-11 on drug-resistant Pseudomonas aeruginosa, escherichia coli and Acinetobacter baumannii is 1 mug/mL, which is better than that of the reference drug norfloxacin.
EXAMPLE 33 pharmaceutical use of ketene-bridged quinazolinone Compounds
According to the antimicrobial activity detection result, the ketene-bridged quinazolinone thiazole compound has good antibacterial activity and can be prepared into antibacterial drugs for clinical use. The medicines can be single preparations, for example, the medicines are prepared by ketene-bridged quinazolinone thiazole compounds with a structure and pharmaceutically acceptable auxiliary materials; or a compound preparation, for example, the compound preparation is prepared by ketene-bridged quinazolinone thiazole compound with one structure, the existing antibacterial active ingredients (such as sulfamethoxazole, cefixime and the like) and pharmaceutically acceptable auxiliary materials, or is prepared by a plurality of ketene-bridged quinazolinone thiazole compounds with different structures and pharmaceutically acceptable auxiliary materials. The preparation types include but are not limited to tablets, capsules, powder, 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-5 tablets
Prescription: compound I-5-10 g, corn starch 50g, lactose 187g, magnesium stearate 3.0g, and a proper amount of ethanol solution with the volume percentage concentration of 70 percent, and the total amount 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-5 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 10mg.
2. Preparation of Compound I-4 capsules
Prescription: 25g of compound I-4, 12.5g of modified starch (120 meshes), 7.5g of microcrystalline cellulose (100 meshes), 2.5g of low-substituted hydroxypropyl cellulose (100 meshes), 2.0g of talcum powder (100 meshes), 1.25g of sweetener, 0.25g of orange essence, a proper amount of pigment and a proper amount of water, and the granules are prepared into 1000 granules.
The preparation method comprises the following steps: micronizing compound I-4 into superfine powder, 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 25mg.
3. Preparation of Compound I-5 granules
Prescription: 26g of compound I-5, 120g of dextrin and 280g of sucrose.
The preparation method comprises the following steps: mixing compound I-5, dextrin and sucrose uniformly, granulating by wet method, drying at 60 deg.C, and packaging.
4. Preparation of Compound I-4 injection
Prescription: compound I-4 (10 g), propylene glycol (500 mL), and water for injection (500 mL) were prepared in a total volume of 1000mL.
The preparation method comprises the following steps: weighing the compound I-4, 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-4.
5. Preparation of compound I-1 powder injection
The preparation method comprises the following steps: and subpackaging the sterile powder of the compound I-1 under the aseptic condition to obtain the compound I-1.
6. Preparation of Compound I-5 eye drops
Prescription: 3.78g of compound I-5, 0.9g of sodium chloride, a proper amount of boric acid buffer solution and distilled water are added to 1000mL.
The preparation method comprises the following steps: weighing the compound I-5 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, bottling, sealing, and sterilizing with 100 deg.C flowing steam for 1 hr.
7. Preparation of Compound I-3 Liniment
Prescription: compound I-3 g, potassium soap 7.5g, camphor 5g, distilled water added to 100mL.
The preparation method comprises the following steps: dissolving camphor with 95% ethanol solution by volume percentage concentration for later use; heating potassium soap to liquefy, weighing compound I-3, 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-5
Prescription: compound I-5 g, gelatin 14g, glycerin 70g, distilled water to 100mL, metric 100.
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-5, stirring, pouring into vaginal suppository mold when it is nearly solidified, and cooling to solidify.
9. Preparation of Compound I-4 ointment
Prescription: 0.5-2g 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 which is added to 100g.
The preparation method comprises the following steps: heating cetyl alcohol, white vaseline, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate to completely melt, 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-4, stirring, and cooling.
10. Preparation of compound I-5 and fluconazole compound powder injection
Prescription: 5 50g of compound I, 50g of norfloxacin and 1g of sodium benzoate, and 100 bottles are prepared.
The preparation method comprises the following steps: taking the compound I-5, the norfloxacin and the sodium benzoate according to the prescription amount, uniformly mixing in a sterile state, and subpackaging 100 bottles to obtain the norfloxacin and sodium benzoate injection.
11. Preparation of Compound I-5 Aerosol
Prescription: compound I-5.5 g, span20 g, talc (100 mesh) 4g, trichlorofluoromethane to appropriate amount.
The preparation method comprises the following steps: respectively placing the compound I-5, the Span20 and the talcum powder in a vacuum drying oven for drying for several 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, 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 (10)
1. The ketene-bridged quinazolinone thiazole compound or the pharmaceutically acceptable salt thereof is characterized in that the structure is shown as the general formula I:
in the formula, R 1 、R 2 、R 3 And R 4 Is hydrogen, chlorine or fluorine; r 5 Is a benzene ring, a 4-fluorobenzene ring, a 4-chlorobenzene ring, a 2, 4-dichlorobenzene ring, a 2-chlorobenzene ring, a 3-chlorobenzene ring, a 4-methylbenzene ring, a 4-methoxybenzene ring, a 4-cyanobenzene ring, a 4-nitrobenzene ring, a 4-trifluoromethylbenzene ring, a 2, 4-difluorobenzene ring, a 2, 4-dimethylbenzene ringA ring, a 2-fluoro-4-piperazine benzene ring, thiophene, furan, pyrrole, imidazole, thiazole, indole, 6-chloroindole, 6-methylindole, 1-ethylindole, benzothiophene, naphthalene or dimethylamine.
2. An enone-bridged quinazolinone thiazole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized by being any one of the following compounds:
3. an enone-bridged quinazolinone thiazole compound, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein said pharmaceutically acceptable salt is the hydrochloride, nitrate or acetate salt.
4. A process for the preparation of an enone-bridged quinazolinone thiazole compound according to claim 2, characterized in that the process comprises:
a. preparation of intermediate II: carrying out bromination reaction on the 2-acetylthiazole and bromine to obtain an intermediate II;
b. preparation of intermediates III-1 to 3: performing cyclization reaction on an anthranilic acid compound and formamide serving as initial raw materials to obtain an intermediate III-1-3;
c. preparation of intermediates IV-1 to 3: respectively carrying out nucleophilic substitution reaction on the intermediates III-1-3 and the intermediate II under the action of alkali to obtain intermediates IV-1-3;
d. preparation of ketene-bridged quinazolines of the general formula I-1-27: respectively carrying out condensation reaction on the intermediates IV-1-3 and aldehyde under the action of alkali to obtain ketene-bridged quinazolinone thiazole compounds shown in general formulas I-1-27;
e. preparation of enone-bridged quinazolinone thiazole compounds of the general formula I-28: and carrying out condensation reaction on the intermediate IV-1 and acetal to obtain the ketene-bridged quinazolinone thiazole compound shown in the general formula I-28.
5. The method according to claim 4,
in the step a, the molar ratio of the 2-acetylthiazole to the bromine is 1.2; the bromination reaction is specifically carried out for 4 hours at 55 ℃ by taking glacial acetic acid as a solvent;
in the step b, the cyclization reaction is specifically carried out for 8-12h at 135 ℃ by taking formamide as a solvent;
in the step c, the molar ratio of the intermediate III-1-3 to the base to the intermediate II is 1.2; the alkali is potassium carbonate; the nucleophilic substitution reaction is carried out for 2-12h at 55 ℃ by taking acetonitrile or acetone as a solvent;
in the step d, the molar ratio of the intermediate IV-1-3 to aldehyde is 1.2; the base is piperidine; the condensation reaction is specifically to take ethanol as a solvent to react for 25 hours at 65 ℃;
in the step e, the molar ratio of the intermediate IV-1 to the acetal is 1.
6. Use of an enone bridged quinazolinone thiazole compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for the preparation of an antibacterial agent.
7. The use of claim 6, wherein the bacteria is one or more of enterococcus faecalis, staphylococcus aureus, klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa or acinetobacter baumannii.
8. The use of claim 7, wherein the bacteria is one or more of methicillin-resistant staphylococcus aureus, staphylococcus aureus ATCC 25923, staphylococcus aureus ATCC 29213, pseudomonas aeruginosa ATCC 27853, or escherichia coli ATCC 25922.
9. A formulation comprising an enone bridged quinazolinone compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
10. The formulation of claim 9, wherein the formulation is one of a tablet, a capsule, a granule, an injection, an eye drop, a liniment, a suppository, an ointment, or an aerosol.
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