CN109734723B - Ofloxacin thiazole analogue and preparation method and application thereof - Google Patents
Ofloxacin thiazole analogue and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to an ofloxacin thiazole analogue, a preparation method and application thereof, belonging to the technical field of chemical synthesis, wherein the ofloxacin thiazole analogue and pharmaceutically acceptable salts thereof are shown in a general formula I, and the compounds have certain inhibitory activity on gram-positive bacteria, gram-negative bacteria and fungi and can be used for preparing antibacterial and/or antifungal medicaments, thereby providing more efficient and safe candidate medicaments for clinical antimicrobial treatment and being beneficial to solving 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 easy to obtain, and the synthetic route is short.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to an ofloxacin thiazole analogue, and a preparation method and application thereof.
Background
Quinolone drugs, one of the most important first-line antibacterial drugs, have high oral bioavailability, good pharmacokinetic properties and excellent therapeutic effects, and have been used as effective weapons against morbidity and mortality caused by microbial pathogens. Since the discovery of nalidixic acid in the 60's of the 20 th century, the development of tetrazoquinolones has been successful. Studies on their mechanism of action suggest that such drugs can target DNA gyrase and topoisomerase IV, thereby interfering with DNA replication and ultimately causing bacterial cell death. However, the drug resistance of pathogenic bacteria is becoming more and more serious due to overuse and even abuse of such drugs in clinical treatment, and some side effects such as gastroenteritis, vomiting and cartilage damage are gradually appeared, which brings great challenges to human health, and emphasizes the urgent need for developing novel quinolone derivatives with greater potential and capable of effectively overcoming the side effects and drug resistance. Ofloxacin, one of the most commonly used fluoroquinolones, is now widely used for the treatment of various diseases including pneumonia, urinary tract infection, prostatitis, and some types of infectious diarrhea. Research has shown that carboxyl and carbonyl of ofloxacin are important causes for drug-resistant bacteria and multiple side effects, so modification of carboxyl thereof will have great significance.
Azole is a five-membered nitrogen heterocyclic compound, plays an important role in the field of medicinal chemistry, and particularly plays an important role in azole antibacterial drugs. After azoles are introduced into quinolone, a large number of azole derivatives based on quinolone are found, and the compounds have strong biological activity and high safety. 2-aminothiazole is taken as the most representative azole compound, and because the unique structure of the compound contains nitrogen and sulfur atoms, the derivative of the compound has good binding capacity and is combined with a functional target point of the compound, so that the fragment is widely used for modification and research and development of medicaments by medicinal chemists. The weakly alkaline 2-aminothiazole fragment and the ofloxacin are hybridized to replace the weakly acidic carboxyl group, so that the side effect and the drug resistance of the ofloxacin can be effectively overcome, and a series of novel broad-spectrum antibacterial drugs with high activity are developed.
Disclosure of Invention
In view of the above, it is an object of the present invention to provide ofloxacin thiazole analogues and pharmaceutically acceptable salts thereof; the second purpose is to provide a preparation method of the ofloxacin thiazole analogue and the medicinal salt thereof; the third purpose is to provide the application of the ofloxacin thiazole analogue and the medicinal salt thereof in preparing antibacterial and/or antifungal medicaments;
in order to achieve the purpose, the invention provides the following technical scheme:
1. the structure of the ofloxacin thiazole analogue and the medicinal salt thereof is shown as a general formula I:
in the formula:
R1is amino, hydrazino, hydroxyhydrazino, alkoxyhydrazino, alkyl, benzylidenehydrazino, alkylhydrazino, benzenesulfonylhydrazino or naphthalimide;
R2，R3is hydrogen, trifluoromethyl, cyano, nitroChlorine, fluorine, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl, each of which contains one or more substituents.
Preferably, the first and second liquid crystal materials are,
R1is amino, alkyl, benzylidene hydrazino, alkyl hydrazide, benzenesulfonyl hydrazide or naphthalimide;
R2，R3is hydrogen, trifluoromethyl, chlorine, fluorine, pyrrolidinyl, morpholinyl, piperazinyl or hexahydropyridyl.
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 ofloxacin thiazole analogue and the pharmaceutically acceptable salt thereof comprises the following steps:
a. preparation of intermediate II: taking triethyl orthoformate as an initial raw material, carrying out nucleophilic substitution and cyclization to obtain a corresponding 3-acetyl quinolone intermediate, and carrying out N-alkylation reaction on the 3-acetyl quinolone intermediate and bromoethanol to carry out ring closure to obtain intermediates II-1 and II-2;
b. preparation of intermediate III: respectively taking the intermediates II-1 and II-2 as initial raw materials, taking glacial acetic acid as a solvent, and brominating to obtain intermediates III-1, III-2 and III-3;
c. preparation of ofloxacin thiazole analogues of formula I: dissolving the intermediate III in a solvent, and reacting with thiourea to obtain the ofloxacin thiazole analogue shown in the general formula I;
d. preparation of a pharmaceutically acceptable salt of an ofloxacin thiazole analog represented by the general formula I: dissolving the ofloxacin thiazole analogue shown in the general formula I in an organic solvent, adding a medicinal acid under the stirring condition, and reacting for 8-12h to obtain the medicinal salt of the ofloxacin thiazole analogue shown in the general formula I.
Preferably, the first and second liquid crystal materials are,
in the step a, the alkali used in the N-alkylation reaction is potassium carbonate, and the molar ratio of the 3-acetyl quinolone intermediate obtained after cyclization to the alkali is 1: 1.2-1.5;
in the step b, the temperature during bromination is 40-60 ℃;
in the step c, the solvent is absolute ethyl alcohol, and the temperature of the thiourea during the reaction is 70-80 ℃;
in the step d, the organic solvent is one or more of ethanol, diethyl ether, tetrahydrofuran and chloroform; the pharmaceutically acceptable acid is one of hydrochloric acid, nitric acid or acetic acid.
3. The ofloxacin thiazole analogue and the medicinal salt thereof are applied to the preparation of antibacterial and/or antifungal medicaments.
Preferably, the bacteria is at least one of staphylococcus aureus, methicillin-resistant staphylococcus aureus, klebsiella pneumoniae, escherichia coli, enterococcus faecalis, acinetobacter baumannii or pseudomonas aeruginosa; the fungus is at least one of Candida tropicalis, Aspergillus fumigatus, Candida albicans or Candida parapsilosis.
The invention has the beneficial effects that: the invention utilizes the principle of drug design split, introduces bioactive fragment aminothiazole at the C-6 position of ofloxacin, synthesizes a series of ofloxacin thiazole analogues with novel structures through different modification designs of amino groups on thiazole rings, and the compounds have certain inhibitory activity on gram-positive bacteria (methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923 and staphylococcus aureus ATCC29213), gram-negative bacteria (Klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC27853, escherichia coli ATCC25922 and acinetobacter baumannii) and fungi (candida albicans, candida tropicalis, aspergillus fumigatus, candida albicans ATCC90023 and candida parapsilosis ATCC20019) through in-vitro antimicrobial activity detection, can be used for preparing antibacterial and/or antifungal drugs, therefore, more efficient and safe candidate drugs are provided for clinical antimicrobial treatment, and the clinical treatment problems of increasingly serious drug resistance, stubborn pathogenic microorganisms, newly appeared harmful microorganisms and the like are solved. The preparation raw materials are simple, cheap and easy to obtain, and the synthetic route is short.
Detailed Description
The preferred embodiments of the present invention will be described in detail below.
Example 1
Preparation of intermediate II
References "Cui, s.f.; addla, d.; zhou, C.H.Novel 3 aminothiazoloquinolones, Design, synthesis, bioactive evaluation, SARs, and preliminary antibiotic mechanisms, J.Med.Chem.2016,59, 4488-4510, "and" Cheng, Y.; avala, s.r.; gao, w.w.; addla, d.; tangadanchu, v.k.r.; zhang, l.; lin, j.m.; zhou, C.H.Multi-targeting amplification of new 2-aminothiazolylones Synthesis, inhibition, interaction with DNA, combination with topoisomase IV and specificity in cells Eur.J.Med.chem.2016,124, 935-945 ".
Example 2
Preparation of intermediate III-1
A50 mL round bottom flask was charged with Compound II-1(0.4g, 1.619mmol) and glacial acetic acid (10mL), with Br added at 0 deg.C2(0.125g, 2.429mmol) and the reaction mixture was then held at 60 ℃ for 12 hours. The thin layer chromatography was followed to the end of the reaction. Concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound III-1(150mg) with yield of 28.62%; a brown powder; melting point: 242 ℃ and 244 ℃;1H NMR(600MHz,DMSO-d6)δ8.67(s,1H,quinolone-5-H),7.50(dd,J＝9.1,2.0Hz,1H,quinolone-10-H),7.33(dd,J＝9.4,2.2Hz,1H,quinolone-8-H),4.91(s,2H,CH2Br),4.58–4.55(m,2H,OCH2),4.52–4.46(m,2H,NCH2)ppm。
example 3
Preparation of intermediate III-2
A50 mL round bottom flask was charged with Compound II-1(0.4g, 1.619mmol) and glacial acetic acid (10mL), with Br added at 0 deg.C2(0.125g, 2.429mmol) and the reaction mixture was then held at 60 ℃ for 12 hours. The thin layer chromatography was followed to the end of the reaction. Concentrating, extracting, separating by column chromatography, recrystallizing, drying, etc. to obtain compound III-2(100mg) with yield of 30.72%; a brown powder; melting point: 168-170 ℃;1H NMR(600MHz,DMSO-d6)δ8.81(s,1H,quinolone-5-H),7.84(s,1H,CHBr2),7.53(dd,J＝9.0,2.7Hz,1H,quinolone-10-H),7.37(dd,J＝9.4,2.7Hz,1H,quinolone-8-H),4.63–4.50(m,4H,O-CH2-CH2-N)ppm。
example 4
Preparation of intermediate III-3
In a 150mL round bottom flask was added compound II-2(1.4g, 5.322mmol) and glacial acetic acid (25mL), Br was added at 0 deg.C2(3g, 15.967mmol) and the reaction mixture was then held at 60 ℃ for 12 hours. The thin layer chromatography was followed to the end of the reaction. Concentrating, extracting, and performing column chromatographySeparating, recrystallizing, drying, etc. to obtain compound III-3(1g) with 55% yield; a brown powder; melting point: 230 ℃ to 232 ℃;1H NMR(600MHz,DMSO-d6)δ8.84(s,1H,quinolone-5-H),7.83(s,1H,-CHBr2),7.82(d,J＝8.7Hz,1H,quinolone-8-H),7.58(d,J＝8.7Hz,1H,quinolone-9-H),4.69–4.61(m,2H,O-CH2),4.57–4.50(m,2H,N-CH2)ppm。
example 5
Preparation of Compound I-1
In a 100mL round-bottom flask, reacting compound III-1(0.1g,0.3077mmol), thiourea (0.026g,0.338mmol) and ethanol (30mL) with stirring at 70 ℃ for 4h, cooling to room temperature, tracking by thin layer chromatography until the reaction is finished, and performing post-treatment such as concentration, extraction, column chromatography separation, recrystallization, drying and the like to obtain compound I-1(20mg) with a yield of 21.50%; a yellow powder; melting Point>250℃；1H NMR(600MHz,DMSO-d6)δ8.55(s,1H,quinolone-5-H),7.68(s,1H,thiazole-4-H),7.49(dd,J＝9.3,2.4Hz,1H,quinolone-10-H),7.20(dd,J＝9.3,2.2Hz,1H,quinolone-8-H),6.91(s,2H,Thazole-NH2),4.55(s,2H,C2-OCH2),4.43(d,J＝4.1Hz,2H,C2-NCH2)ppm。
Example 6
Preparation of Compound I-2
In a 100mL round-bottom flask, reacting a compound III-3(1g,2.3874mmol), thiourea (0.181g,2.3874mmol) and ethanol (30mL) by stirring at the temperature of 70 ℃ for 4h, cooling to room temperature, tracking by thin-layer chromatography until the reaction is finished, and performing post-treatment such as concentration, extraction, column chromatographic separation, recrystallization, drying and the like to obtain a compound I-2(0.467g) with the yield of 61.20%; a white powder; melting Point>250℃；1H NMR(600MHz,DMSO-d6)δ8.55(s,1H,quinolone-5-H),7.82(d,J＝8.8Hz,1H,quinolone-8-H),7.68(s,1H,thiazole-4-H),7.40(d,J＝8.8Hz,1H,quinolone-9-H),6.93(s,2H,thiazole-2-NH2),4.65–4.54(m,2H,C2-OCH2),4.47–4.37(m,2H,C3-NCH2)ppm。
Example 7
Preparation of Compound I-3
In a 100mL round-bottom flask, controlling the temperature of compound I-1(0.3g,0.990mmol), 1-Boc-piperazine (0.6g,2.976mmol) and DMSO (5mL), stirring and reacting for 12h at 80 ℃, cooling to room temperature, tracking by thin layer chromatography until the reaction is finished, and then carrying out post-treatment such as concentration, extraction, column chromatography separation, recrystallization and drying to obtain compound I-3(0.06g), wherein the yield is 12.93%; a yellow powder; melting point 176 and 178 ℃;1H NMR(600MHz,DMSO-d6)δ8.31(s,1H,quinolone-5-H),8.10(s,1H,thiazole-4H),7.43(d,J＝8.3Hz,1H,quinolone-10-H),7.21(d,J＝8.5Hz,1H,quinolone-8-H),6.72(s,2H,thiazole-2-NH2),4.56–4.51(m,2H,C2-OCH2),4.36(s,2H,C3-NCH2),3.39(s,2H,piperidine-CH2),3.26(s,2H,piperidine-CH2),2.28(s,4H,piperidine-2CH2),1.37(s,9H,N-Boc-3CH3)ppm。
example 8
Preparation of Compound I-4
In a 100mL round-bottom flask, controlling the temperature of a compound III-1(0.25g,0.769mmol), a 2-acethydrazide-1-thiocarbamide (0.102g,0.769mmol) and ethanol (5mL), stirring and reacting for 3h at 80 ℃, cooling to room temperature, tracking by thin layer chromatography until the reaction is finished, and then carrying out concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain a compound I-4(0.06g), wherein the yield is 21.73%; a yellow powder; melting Point>250℃；1H NMR(600MHz,DMSO-d6)δ10.16(s,1H,CO-NH),9.27(s,1H,thiazole-2-NH),8.57(s,1H,quinolone-5-H),7.84(s,1H,thiazole-4-H),7.50(dd,J＝9.3,2.6Hz,1H,quinolone-10-H),7.22(dd,J＝9.4,2.7Hz,1H,quinolone-8-H),4.63–4.52(m,2H,C2OCH2),4.49–4.39(m,2H,C3-NCH2),1.92(s,3H,-CH3)ppm。
Example 9
Preparation of Compound I-5
In a 100mL round-bottom flask, compound III-1(0.15g,0.461mmol), (E/Z) -2-benzylidenehydrazine-1-thiocarboxamide (0.082g,0.461mmol) and ethanol (10mL) are stirred and reacted for 3h at the temperature of 70 ℃, the reaction is cooled to room temperature, thin layer chromatography is carried out until the reaction is finished, and then after concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments, compound I-5(0.09g) is obtained, the yield is 48.12%; a yellow powder; melting Point>250℃；1H NMR(600MHz,DMSO-d6)δ12.06(s,1H,thiazole-2-NH),8.59(s,1H,quionolone-5-H),8.08(s,1H,imine-CH),7.91(s,1H,thiazole-4-H),7.67(d,J＝7.7Hz,2H,phenyl-2,6-H),7.52(dd,J＝9.2,2.0Hz,1H,quinolone-10-H),7.44(t,J＝7.4Hz,2H,phenyl-3,5-H),7.39(t,J＝7.1Hz,1H,quinolone-8-H),7.26–7.20(m,1H,phenyl-4-H),4.57(d,J＝4.4Hz,2H,C2-OCH2),4.46(d,J＝4.3Hz,2H,C3-NCH2)ppm。
Example 10
Preparation of Compound I-6
In a 100mL round-bottom flask, compound III-1(0.5g,1.5389mmol), 2-benzenesulfonylhydrazide-1-thiocarboxamide (0.37g, 1.53894 mmol) and ethanol (10mL) are stirred and reacted for 3h at the temperature of 70 ℃, cooled to room temperature, followed by thin layer chromatography until the reaction is finished, and then subjected to concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain compound I-6(0.35g) with the yield of 49.17%; a yellow powder; melting Point>250℃；1H NMR(600MHz,DMSO-d6)δ10.27(s,1H,SO2-NH),9.73(s,1H,thiazole-NH),8.55(s,1H,quinolone-5-H),7.80(s,1H,thiazole-4-H),7.76(d,J＝7.6Hz,2H,phenyl 2-H,6-H),7.50(d,J＝9.0Hz,1H,quinolone-10-H),7.44(d,J＝7.8Hz,2H,phenyl 3-H,5-H),7.24(d,J＝9.2Hz,1H,quinolone-8-H),4.56(s,2H,C2-OCH2),4.43(s,2H,C3-NCH2),2.40(s,3H,-CH3)。
Example 11
Preparation of Compound I-7
In a 100mL round-bottom flask, a compound I-1(0.25g,0.769mmol), 1- (6-bromo-1, 3-dioxo-1H-benzisoquinoline-2 (3H) -yl) thiourea (0.267g,0.767mmol) and ethanol (10mL) are stirred and reacted for 4 hours at the temperature of 80 ℃, cooled to room temperature, followed by thin-layer chromatography till the reaction is finished, and then subjected to concentration, extraction, column chromatography separation, recrystallization, drying and other post-treatments to obtain a compound I-7(44mg), wherein the yield is 10.0%; a yellow powder; melting Point>250℃；1H NMR(600MHz,DMSO-d6)δ10.35(s,1H,thiazole-NH),8.71–8.65(m,2H,naphthalene-4,9-H),8.46(d,J＝7.8Hz,1H,naphthalene-7-H),8.35(s,1H,quinolone-5-H),8.33–8.29(m,1H,naphthalene-8-H),8.08(dd,J＝8.4,7.4Hz,1H,naphthalene-5-H),7.97(s,1H,thiazole-4-H),7.48(dd,J＝9.4,2.8Hz,1H,quinolone-10-H),7.19(dd,J＝9.4,2.8Hz,1H,quinolone-8-H),4.46–4.43(m,2H,C2-OCH2),4.28–4.25(m,2H,C3-NCH2)ppm。
Example 12
In vitro antimicrobial activity of ofloxacin thiazole analogues
The ofloxacin thiazole analogues prepared in example 1, intermediates II-1 and II-2 prepared in example 2-4, III-1, III-2, III-3 prepared in example 2-4, and examples 5-11 were tested for their Minimal Inhibitory Concentrations (MIC) against gram-positive bacteria (methicillin-resistant Staphylococcus aureus, enterococcus faecalis, Staphylococcus aureus ATCC25923, Staphylococcus aureus ATCC29213), gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa ATCC 85273, Escherichia coli ATCC25922, Acinetobacter baumannii) and fungi (Candida albicans, Aspergillus fumigatus, Candida albicans ATCC90023, Candida parapsilosis ATCC20019) using a 96-well microdilution method in accordance with the Clinical Laboratory Standards Institute (CLSI) set by the national Committee, dissolving the compound to be tested with a small amount of dimethyl sulfoxide, diluting with water to obtain a solution with a concentration of 1.28mg/mL, diluting with the culture solution to 128 μ g/mL, culturing at 35 deg.C for 24-72 hr, shaking the culture plate on a shaker, and determining MIC at 490nm wavelength, the results are shown in tables 1-3.
TABLE 1 in vitro gram-positive activity data (MIC, μ g/mL) for intermediates prepared in examples 1-11 and ofloxacin thiazole analogs
TABLE 2 in vitro gram-negative activity data (MIC, μ g/mL) for intermediates prepared in examples 1-11 and ofloxacin thiazole analogs
As can be seen from tables 1 and 2, the intermediates prepared in examples 1 to 11 and the ofloxacin thiazole analogue showed certain inhibitory effect on the tested bacteria, wherein the ofloxacin thiazole analogue I-1 showed good biological activity on Staphylococcus aureus and MRSA, and the MIC values were 32 and 64 mug/mL respectively. Surprisingly, the intermediate oxyfluorsaxacin analogues III-2 and III-3 also show higher antibacterial activity, and the antibacterial activity on MRSA and Klebsiella pneumoniae is particularly outstanding. Other compounds also exhibit varying degrees of antimicrobial activity.
TABLE 3 in vitro antifungal Activity data (MIC, μ g/mL) for intermediates prepared in examples 1-11 and for ofloxacin thiazole analogs
As can be seen from Table 3, the intermediates prepared in examples 1 to 11 and the ofloxacin thiazole analogues showed a certain inhibitory effect on the fungi tested, wherein the antibacterial MIC values of the ofloxacin thiazole analogues I-1 to Candida albicans ATCC90023 and Candida parapsilosis ATCC20019 are 64 μ g/mL. In addition, the ofloxacin thiazole analogue I-6 also shows good biological activity to candida tropicalis, and the MIC values are all 32 mu g/mL. The intermediate of the ofloxacin analogue has good antifungal activity, and the biological activity of the intermediate is comparable to or even stronger than that of a reference drug fluconazole.
Example 12
Pharmaceutical application of ofloxacin thiazole analogue
According to the antimicrobial activity detection result, the ofloxacin thiazole analogue has better antibacterial and antifungal activity, and can be prepared into antibacterial and antifungal medicaments for clinical use. The medicaments can be single-ingredient preparations, for example, the medicaments are prepared from ofloxacin thiazole analogues with one structure and pharmaceutically acceptable auxiliary materials; or a compound preparation, for example, prepared by ofloxacin thiazole analogues with one structure, existing antibacterial and antifungal active ingredients (such as sulfamethoxazole, fluconazole, phosphorus fluconazole, itraconazole and the like) and pharmaceutically acceptable auxiliary materials, or prepared by a plurality of ofloxacin thiazole analogues with different structures and pharmaceutically acceptable auxiliary materials. The preparation types include, but are not limited to, tablets, capsules, powders, granules, dripping pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal patches and other dosage forms, and various sustained-release and controlled-release preparations and nano preparations.
1. Preparation of Compound I-1 tablets
Prescription: the tablet is prepared from compound I-110 g, lactose 187g, corn starch 50g, magnesium stearate 3.0g, and ethanol solution with volume percentage concentration of 70% in a proper amount, and is prepared into 1000 tablets.
The preparation method comprises the following steps: drying corn starch at 105 deg.C for 5 hr; mixing compound I-1 with lactose and corn starch, making soft mass with 70% ethanol solution, sieving to obtain wet granule, adding magnesium stearate, and tabletting; each tablet weighs 250mg, and the content of active ingredients is 10 mg.
2. Preparation of Compound I-1 capsules
Prescription: the formula comprises, by weight, compound I-125 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 the granules are prepared into 1000 granules.
The preparation method comprises the following steps: micronizing compound I-1, 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-4 granules
Prescription: compound I-426 g, dextrin 120g and sucrose 280 g.
The preparation method comprises the following steps: mixing compound I-4, dextrin and sucrose uniformly, granulating by wet method, drying at 60 deg.C, and packaging.
4. Preparation of Compound I-4 injection
Prescription: 1000mL of the compound I-410 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-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-4 powder injection
The preparation method comprises the following steps: and subpackaging the sterile powder of the compound I-4 under the sterile condition to obtain the compound I-4.
6. Preparation of Compound I-6 eye drops
Prescription: compound I-63.78 g, sodium chloride 0.9g, phenethyl alcohol 3g, appropriate amount of boric acid buffer solution, and distilled water to 1000 mL.
The preparation method comprises the following steps: weighing the compound I-6 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-6 Liniment
Prescription: compound I-64 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-6, 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-6
Prescription: compound I-64 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-6, stirring, pouring into vaginal suppository mold when it is nearly solidified, and cooling to solidify.
9. Preparation of Compound I-6 ointment
Prescription: 60.5-2 g of compound I, 6-8 g of hexadecanol, 8-10 g of white vaseline, 8-19 g of liquid paraffin, 2-5 g of monoglyceride, 2-5 g of polyoxyethylene (40) stearate, 5-10 g 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-6, stirring, and cooling.
10. Preparation of intermediate III-2 and fluconazole compound powder injection
Prescription: and preparing 100 bottles of the intermediate III-250 g, the fluconazole 50g and the sodium benzoate 1 g.
The preparation method comprises the following steps: taking the intermediate III-2, the fluconazole and the sodium benzoate according to the prescription amount, uniformly mixing in a sterile state, and subpackaging 100 bottles to obtain the final product.
11. Preparation of intermediate III-3 Aerosol
Prescription: intermediate III-32.5 g, Span 203 g, talcum powder (100 mesh) 4g, trichlorofluoromethane added to appropriate amount.
The preparation method comprises the following steps: and respectively drying the intermediate III-3, 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, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (6)
1. The ofloxacin thiazole analogue and the medicinal salt thereof are characterized by being any one of the following compounds:
2. the ofloxacin thiazole analog and pharmaceutically acceptable salts thereof of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride, a nitrate or an acetate.
3. The process for preparing ofloxacin thiazole analogues I-1 to 2 and pharmaceutically acceptable salts thereof according to claim 1 or 2, wherein the process comprises the steps of:
a. preparation of intermediate II: taking triethyl orthoformate as an initial raw material, carrying out nucleophilic substitution and cyclization to obtain a corresponding 3-acetyl quinolone intermediate, and carrying out N-alkylation reaction on the 3-acetyl quinolone intermediate and bromoethanol to carry out ring closure to obtain intermediates II-1 and II-2;
b. preparation of intermediate III: respectively taking the intermediates II-1 and II-2 as initial raw materials, taking glacial acetic acid as a solvent, and brominating to obtain intermediates III-1, III-2 and III-3;
c. preparation of ofloxacin thiazole analogues I-1-2: dissolving the intermediate III-1 or III-3 in a solvent, and reacting with thiourea to obtain ofloxacin thiazole analogues I-1-2;
d. preparation of pharmaceutically acceptable salts of ofloxacin thiazole analogues I-1-2: dissolving the ofloxacin thiazole analogue I-1-2 in an organic solvent, adding a pharmaceutically acceptable acid under the stirring condition, and reacting for 8-12h to obtain the pharmaceutically acceptable salt of the ofloxacin thiazole analogue I-1-2.
4. The method of claim 3,
in the step a, the alkali used in the N-alkylation reaction is potassium carbonate, and the molar ratio of the 3-acetyl quinolone intermediate obtained after cyclization to the alkali is 1: 1.2-1.5;
in the step b, the temperature during bromination is 40-60 ℃;
in the step c, the solvent is absolute ethyl alcohol, and the temperature of the thiourea during the reaction is 70-80 ℃;
in the step d, the organic solvent is one or more of ethanol, diethyl ether, tetrahydrofuran and chloroform; the pharmaceutically acceptable acid is one of hydrochloric acid, nitric acid or acetic acid.
5. Use of the ofloxacin thiazole analogues according to claim 1 or 2, and pharmaceutically acceptable salts thereof, for the preparation of antibacterial and/or antifungal medicaments.
6. The use of claim 5, wherein the bacteria is at least one of Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, enterococcus faecalis, Acinetobacter baumannii, or Pseudomonas aeruginosa; the fungus is at least one of Candida tropicalis, Aspergillus fumigatus, Candida albicans or Candida parapsilosis.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2049652B1 (en) * | 1992-09-16 | 1994-10-01 | Genesis Para La Investigacion | PROCEDURE FOR THE PREPARATION OF A QUINOLIN CARBOXILIC ACID. |
| CN104530034A (en) * | 2014-12-31 | 2015-04-22 | 西南大学 | Quinolone thiazole compound and preparation method and application thereof |
| CN108440518A (en) * | 2018-04-19 | 2018-08-24 | 西南大学 | 3- (thiazolamine) -7- substituted-piperazinyl class quinolone compounds and its preparation method and application |
-
2018
- 2018-12-29 CN CN201811647894.8A patent/CN109734723B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2049652B1 (en) * | 1992-09-16 | 1994-10-01 | Genesis Para La Investigacion | PROCEDURE FOR THE PREPARATION OF A QUINOLIN CARBOXILIC ACID. |
| CN104530034A (en) * | 2014-12-31 | 2015-04-22 | 西南大学 | Quinolone thiazole compound and preparation method and application thereof |
| CN108440518A (en) * | 2018-04-19 | 2018-08-24 | 西南大学 | 3- (thiazolamine) -7- substituted-piperazinyl class quinolone compounds and its preparation method and application |
Non-Patent Citations (2)
| Title |
|---|
| Design, synthesis, and docking studies of novel ofloxacin analogues as antimicrobial agents;Jubie, S. et al.;《Medicinal Chemistry Research》;20110511;第27卷(第7期);第1404页Scheme 1，第1405页左栏第3段，第1408页左栏第3段 * |
| Novel 3‑Aminothiazolquinolones: Design, Synthesis, Bioactive Evaluation, SARs, and Preliminary Antibacterial Mechanism;Sheng-Feng Cui et al.;《Journal of Medicinal Chemistry》;20160426;第59卷;第4489-4490页图1-3 * |
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