CN111620901B - Fluoroquinolone compound containing siloxane group, preparation method and application thereof - Google Patents

Fluoroquinolone compound containing siloxane group, preparation method and application thereof Download PDF

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CN111620901B
CN111620901B CN202010512038.2A CN202010512038A CN111620901B CN 111620901 B CN111620901 B CN 111620901B CN 202010512038 A CN202010512038 A CN 202010512038A CN 111620901 B CN111620901 B CN 111620901B
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fluoroquinolone
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孙思雨
邢亚群
汪秀秀
吴小祥
李关宝
唐伟
董清清
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Second Affiliated Hospital Of Bengbu Medical College
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Abstract

The invention provides a fluoroquinolone compound containing a siloxane group, which has a general formula I as follows, wherein R is C1-C8 alkoxy, and the alkoxy is: methoxy, ethoxy, propoxy, n-butoxy, n-pentoxy, n-hexoxy, n-heptoxy, n-octoxy. The invention also provides a preparation method of the compound, an application of the compound in the aspect of antibiosis, a temperature-sensitive in-situ gel composition prepared from the compound and a preparation method of the composition.
Figure DDA0002528739220000011

Description

Fluoroquinolone compound containing siloxane group, preparation method and application thereof
Technical Field
The invention relates to a fluoroquinolone compound containing siloxane groups, a preparation method and application thereof, belonging to the field of pharmaceutical chemistry
Background
Since 1962 nalidixic acid (J Med Pharm Chem1962, 5.
Finafloxacin (Finafloxacin) is a pH activated fluoroquinolone, created by bayer corporation, licensed for development by MerLion pharmaceuticals and elconggs. Narfloxacin was developed by MerLion pharmaceutical company for the treatment of severe bacterial infections associated with acidic environments, including: urinary Tract Infections (UTIs) and helicobacter pylori infections. In a slightly acidic environment (pH 5.0-6.0), finafloxacin has the best therapeutic effect, while other fluoroquinolones lose activity in this environment. Finafloxacin is highly selective for bacterial type ii topoisomerases, including: DNA helicase and DNA topoisomerase IV. Topical finafloxacin suspension ear drops were developed by el Kang Gongsi (now a division of nova corporation), and were approved by the FDA in the united states for the treatment of acute otitis externa (age of individuals ≧ 1 year) caused by pseudomonas aeruginosa and staphylococcus aureus susceptible bacteria on 12 months and 17 months 2014, with the exception that nova corporation reported no intent to commercialize finafloxacin suspension ear drops on 1 month 2015. In 2016, 3 months, finafloxacin suspension drops were also approved in canada under the trade name: xtoro. Phase ii clinical trials of oral and intravenous finafloxacin formulations for the treatment of complex UTIs and pyelonephritis were conducted in germany and polish, and clinical trials of oral finafloxacin formulations for the treatment of non-complex UTIs were conducted in germany and singapore. Phase ii clinical trials of finafloxacin oral agents as part of a combination regimen for the treatment of helicobacter pylori infections were conducted in germany. Phase i clinical trials have been completed in switzerland, the uk and the us, with an emphasis on the safety, pharmacokinetics and bactericidal activity in urine, lung tissue of finafloxacin.
The temperature sensitive in-situ gel is a high molecular polymer material, is in a liquid state during storage, forms a semisolid gel after being dropped into eyes under certain conditions, is suitable to be used as a carrier of an eye drug delivery system, prolongs the retention time of a drug in the eyes, delays the release of the drug and improves the bioavailability. But the dosage of poloxamer as the gel matrix is more, generally 10-40% (weight percentage), if the dosage of poloxamer is reduced, the gelation temperature is increased and the gel cannot be formed; and loses the gelling ability after being diluted by tears, and causes discomfort to a human body due to stimulation to sensitive tissues caused by low temperature.
Therefore, it is required to develop a siloxane-containing fluoroquinolone compound having excellent antibacterial activity capable of reducing the amount of poloxamer used and to use it in a temperature sensitive type in situ gel.
Disclosure of Invention
The first object of the present invention is to provide a method for preparing a fluoroquinolone compound containing a siloxane group, which has the following general formula I:
Figure BDA0002528739200000023
the second object of the present invention is to provide a method for preparing a fluoroquinolone compound containing a siloxane group of the following general formula I;
the third object of the present invention is to provide the use of a fluoroquinolone compound having a siloxane group for the preparation of an antibacterial agent;
the fourth purpose of the invention is to provide a temperature-sensitive in-situ gel composition and a preparation method thereof.
In the present invention, more preferred compound I may be of any of the following structures:
Figure BDA0002528739200000022
Figure BDA0002528739200000031
the invention also provides a synthesis method of the compound of the formula I, which comprises the following steps:
1) Weighing a certain amount of a compound 1, potassium carbonate and chlorotrialkoxysilane 2, taking acetonitrile as a solvent, heating in an oil bath at 80 ℃, and stirring for reflux reaction for 12h; adding a proper amount of deionized water into the reaction system for dissolving, and using CH 2 Cl 2 Extracting, combining organic phases, drying with anhydrous magnesium sulfate, filtering, and rotary steamingFrom CH 2 Cl 2 /CH 3 Performing column chromatography purification on OH to obtain a white oily substance which is a compound II;
2) Weighing a certain amount of a compound II, dissolving the compound II in methanol, adding sodium bicarbonate, dropwise adding a solution of a compound shown as a compound 4 in dichloromethane, heating and refluxing for 4 hours, cooling, adding 50ml of water, and separating out an organic phase; evaporating the organic phase to dryness to obtain a compound I,
the reaction synthetic route is as follows:
Figure BDA0002528739200000032
among them, compound 1 can be obtained by any known method, for example, refer to: "finafloxacin synthesis scheme", li Jiang et al, world Notes on Antibiotics, vol 36, vol 5, p 228-231, 2015; compound 4 can be referred to: "finafloxacin synthesis scheme", li Jiang et al, world Notes on Antibiotics, vol 36, 5 th, p 228-231, 2015; CN101522662a, published: 09 month 02 in 2009.
The invention also provides an antibacterial composition taking the compound with the structure shown in the formula I as an effective component, and the compound can be mixed with medicinal auxiliary materials such as excipient, diluent and the like to prepare tablets, capsules, granules, powder, gel and other dosage forms.
The antibacterial composition, i.e., the pharmaceutical preparation, can be prepared by a conventional method. The adjuvants may include excipients such as lactose, sucrose, glucose, mannitol, and sorbitol; corn starch, potato starch, dextrin and carboxymethyl starch; crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose; acacia gum; dextran; magnesium aluminum metasilicate; calcium phosphate; calcium carbonate; binders such as gelatin, polyvinylpyrrolidone and polyethylene glycol; disintegrants such as sodium carboxymethyl cellulose and polyvinylpyrrolidone; lubricants such as talc, calcium stearate, magnesium stearate, spermaceti, boric acid, sodium benzoate, leucine; stabilizers such as methyl p-hydroxybenzoate, propyl p-hydroxybenzoate and the like; taste-modifying agents such as conventional sweeteners, acidulants, flavors, etc., diluents and solvents for injection such as water, ethanol, glycerin, etc.; temperature sensitive gel matrix such as poloxamer 407 and poloxamer 188.
Further preferably prepared into a temperature-sensitive in-situ gel composition.
The temperature-sensitive in-situ gel composition comprises the following raw materials in percentage by weight: 0.1 to 1% of the oxosilane group-containing fluoroquinolone compound according to any one of claims 1 to 2, 0.1 to 5% of a temperature sensitive gel matrix, 0.1 to 5% of a permeation enhancer, 0.1 to 5% of a pH adjuster, and the balance of water; the temperature-sensitive gel matrix is poloxamer; the penetration enhancer is polyethylene glycol; the pH regulator is sodium hydroxide.
Compared with the prior art, the fluoroquinolone compound containing the siloxane group is a quinolone compound with a novel structure, has high-efficiency antibacterial activity, is easy to synthesize by a synthesis method, can be prepared into a temperature-sensitive in-situ gel composition, greatly reduces the consumption of poloxamer in the composition, and can form gel when the gelling temperature rises; the gelation ability is not obviously weakened after the simulated tears are diluted, the gelation temperature is close to the body surface temperature of human bodies, and no stimulation is caused to sensitive tissues.
Drawings
FIG. 1 is a compound of formula I;
FIG. 2 is a nuclear magnetic spectrum of Compound I1;
FIG. 3 is a NMR spectrum of Compound I2;
FIG. 4 is a NMR spectrum of Compound I3.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the scope of the present invention is not limited thereto.
Example 1: II1
Figure BDA0002528739200000051
Weighing a certain amount of 0.05mol of compound 1,3.2g of potassium carbonate and 0.045mol of chlorotrimethoxysilane, and 500ml of acetonitrile as solventHeating in oil bath at 80 ℃, stirring and refluxing for reaction for 12h; adding a proper amount of deionized water into the reaction system for dissolving, and using CH 2 Cl 2 Extracting, combining organic phases, drying with anhydrous magnesium sulfate, filtering, rotary evaporating, and using CH 2 Cl 2 /CH 3 Performing column chromatography purification on OH to obtain 3.65g of white oily matter with the yield of 32.7%; ESI-HRMS (M/z) [ M + H ]] + :C 9 H 20 N 2 O 4 Si:249.12。
Example 2: compound I1
Figure BDA0002528739200000052
Weighing 0.01mol of compound II1, dissolving in 250ml of methanol, adding 1g of sodium bicarbonate, dropwise adding 200ml of dichloromethane solution containing 0.01mol of compound 4, heating and refluxing for 4h, cooling, adding 50ml of water, and separating out an organic phase; evaporating the organic phase to dryness to obtain 1.48g of white solid with the yield of 27.14%; ESI-HRMS (M/z) [ M + H ]] + :C 24 H 27 FN 4 O 8 Si:547.18； 1 H NMR(500MHz,Chloroform)δ8.34(s,1H),8.14(s,1H),4.24(s,1H),3.94(s,1H),3.72–3.47(m,11H),3.33(dd,J＝20.4,5.4Hz,4H),3.08(d,J＝25.0Hz,2H),2.92(s,2H),1.39–1.20(m,2H),1.11–0.84(m,2H)。
Example 3: II2
Figure BDA0002528739200000053
Weighing 0.05mol of compound 1,3.3g of potassium carbonate and 0.045mol of chlorotriethoxysilane, taking 500 acetonitrile as a solvent, heating in an oil bath at 80 ℃, and stirring and refluxing for reaction for 12 hours; adding a proper amount of deionized water into the reaction system for dissolving, and using CH 2 Cl 2 Extracting, combining organic phases, drying by using anhydrous magnesium sulfate, filtering, carrying out rotary evaporation, and carrying out column chromatography purification by using CH2Cl2/CH3OH to obtain 4.12g of white oily matter with the yield of 31.57%; ESI-HRMS (M/z) [ M + H ]] + :C 12 H 26 N 2 O 4 Si:291.17。
Example 4: compound I2
Figure BDA0002528739200000061
Weighing 0.01mol of compound II2, dissolving in 250ml of methanol, adding 1g of sodium bicarbonate, dropwise adding 200ml of dichloromethane solution containing 0.01mol of compound 4, heating and refluxing for 4h, cooling, adding 50ml of water, and separating out an organic phase; evaporating the organic phase to dryness to obtain 1.06g of white solid with the yield of 18.05 percent; ESI-HRMS (M/z) [ M + H ]] + :C 27 H 33 FN 4 O 8 Si:589.21； 1 H NMR(500MHz,Chloroform)δ8.33(s,1H),8.12(s,1H),4.22(s,1H),4.00–3.78(m,6H),3.64(d,J＝3.3Hz,2H),3.52(d,J＝19.7Hz,2H),3.41–3.22(m,3H),3.08(d,J＝25.0Hz,2H),2.92(s,2H),1.44–1.17(m,11H),1.09–0.79(m,2H)。
Example 5: II3
Figure BDA0002528739200000062
Weighing 0.05mol of compound 1,3.2g potassium carbonate and 0.045mol of chloro tripropoxysilane, taking 500 acetonitrile as a solvent, heating in an oil bath at 80 ℃, and stirring and refluxing for reaction for 12 hours; adding a proper amount of deionized water into the reaction system for dissolving, and using CH 2 Cl 2 Extracting, combining organic phases, drying with anhydrous magnesium sulfate, filtering, rotary evaporating, and using CH 2 Cl 2 /CH 3 Performing column chromatography purification on OH to obtain 3.15g of white oily matter with the yield of 21.08%; ESI-HRMS (M/z) [ M + Na ]] + :C 15 H 32 N 2 O 4 Si:332.21。
Example 6: compound I3
Figure BDA0002528739200000063
Weighing 0.01mol of compound II2, dissolving in 250ml of methanol, adding 1g of sodium bicarbonate, dropwise adding 200ml of dichloromethane solution containing 0.01mol of compound 4, heating and refluxing for 4h, cooling, adding 50ml of water, and separating out an organic phase; the organic phase was evaporated to dryness to give 1.17g of a white oil in 18.59% yield; ESI-HRMS (M/z) [ M + H ]] + :C 30 H 39 FN 4 O 8 Si:631.25； 1 H NMR(500MHz,Chloroform)δ8.39(s,1H),8.12(s,1H),4.20(s,1H),4.09(s,1H),3.82–3.78(m,7H),3.64(s,1H),3.54(s,1H),3.49–3.29(m,4H),3.13–3.04(m,4H),2.92(s,1H),1.71–1.67(m,2H),1.31–1.27(m,2H),1.08–1.02(m,13H)。
Example 7: MIC assay for Compounds
1. The experimental method comprises the following steps: the compound is subjected to Minimum Inhibitory Concentration (MIC) measurement by adopting a standard plate double dilution method of NCCL, and the antibacterial activity and selectivity of the compound are judged.
2. Test samples: finafloxacin as a control drug; test samples I1-3.
3. The test strains were:
bacillus subtilis 168 (B.subtilis 168)
Staphylococcus aureus USA300 (S. Aureus USA 300)
Escherichia coli DH5a (E. Coli DH5 a)
Pseudomonas aeruginosa PAO1 (P.aer μ ginosa PAO 1)
Acinetobacter baumannii ATCC19606 (A. Baumann ni ATCC 19606)
4. The experimental steps are as follows:
test bacteria were inoculated in normal nutrient broth (10 mL/tube), incubated at 37 ℃ for 18h, and diluted to 10 the next day 6 the/Cuf was used as the experimental bacterial concentration. LB medium (100. Mu.L per well) was added to a sterilized 96-well plate. Let 3 wells be healthy bacteria control, 3 wells be blank control, 3 wells be solvent control with 0.4mL DMSO added, and 50mM compound solution in DMSO added sequentially from low to high concentration in the remaining wells (3 wells are repeated); the concentration of the compound in each hole is (0.39,0.78,1.56,3.13,6.25, 12.5, 25, 50, 100, 200) mu mol/L; then 5. Mu.L of the bacterial liquid which grows fresh in LB culture solution on the day and has an absorbance of 0.6-1.0 is added into each well. The plates were covered and sealed with gummed paper, incubated for 18h at 37 ℃ using a plate reader (BMG labech fluosarcoptima), and the 96-well plates were shaken up and down at a distance of 7mm, rested every 10 minutes and absorbance read at 600nm, and the minimum inhibitory concentration (MIC/. Mu. Mol/L) was calculated.
5. The test results are shown in table 1 below:
TABLE 1 MIC (. Mu. Mol/L) of the novel compounds I1-3 of the present invention
Figure BDA0002528739200000071
6. Results and discussion
Most of the compounds tested had better antibacterial activity against 5 strains tested:
(1) The compound I1-3 has a good bacteriostatic action on drug-resistant bacteria S.aureus USA 300. The antibacterial activity of the I1 and the I3 is 3 times stronger than that of finafloxacin;
(2) The compound I1-3 has a good bacteriostatic action on drug-resistant bacteria P.aer mu ginosa PAO1, and the antibacterial activity of the compound I3 is similar to that of finafloxacin.
In conclusion, the compound with the structure shown in the formula I, which is prepared by the method, has an antibacterial effect and can be used for preparing antibacterial drugs.
Example 8 temperature sensitive in situ gel composition
1. The preparation method comprises the following steps:
the compound I1 temperature-sensitive in-situ gel composition comprises the following raw materials in percentage by weight: the compound is 1 percent of I1, 4 percent of poloxamer 407, 1 percent of polyethylene glycol, 5 percent of NaOH and the balance of water.
Comparative experiment:
the finafloxacin temperature-sensitive in-situ gel composition comprises the following raw materials in percentage by weight: finafloxacin 1%, poloxamer 407 4%, polyethylene glycol 1%, naOH 5%, and the balance water.
2. The related temperature and the viscosity of the gel are measured as follows:
the gelation temperature was determined by tube inversion and magnetic stirring. Placing a penicillin bottle containing 5mL of solution into a refrigerator at 4 ℃, taking out after a period of time, placing a magnetic stirrer, inserting a thermometer with the precision of 0.1 ℃, and taking care that the mercury balls are completely immersed in the gel solution to ensure that the water bath liquid level is higher than the gel solution in the penicillin bottle. Starting the magnetic stirrer, heating from 4 deg.C, and maintaining the heating rate at 1 deg.C/1-2 min. And (3) when the stirrer does not rotate any more and the stirring is inverted by 180 degrees and the temperature of the stirring does not flow in 10s is the gelling temperature of the solution. Each sample solution was measured 3 times and averaged. The gel temperature was measured in the same manner as above after diluting and mixing with Simulated Tear Fluid (STF) at a ratio of 40: 7.
Viscosity: the measurement was carried out with reference to viscometry (third method of the fourth general rule 0633 of the edition of the Chinese pharmacopoeia 2015). The results are shown in Table 2 below.
TABLE 2 gelation temperature (n = 3) of gels of the invention and their viscosity
Figure BDA0002528739200000081
In contrast, no gelation was observed in the finafloxacin temperature sensitive in situ gel composition of the comparative experiment.
From the above experiments, it can be found that the siloxane fluoroquinolone compound of the present invention can be prepared into a temperature-sensitive in-situ gel composition, wherein the dosage of poloxamer in the composition is greatly reduced, but the gelling ability is weakened, and the gelling ability is not obviously weakened after the composition is diluted with a simulated tear fluid; the irritation to sensitive tissues is reduced. Reason analysis: it is possible that during this process the siloxane undergoes hydrolysis to form polysiloxane, which interacts with the poloxamer to form a gel.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims (6)

1. A fluoroquinolone compound containing a siloxane group, having the following general formula I:
Figure FDA0002528739190000011
wherein R is C1-C8 alkoxy; the alkoxy is: methoxy, ethoxy, propoxy, n-butoxy, n-pentoxy, n-hexoxy, n-heptoxy, n-octoxy.
2. The oxoalkyl-containing fluoroquinolone compound according to claim 1, wherein the alkoxy group is: methoxy, ethoxy, propoxy.
3. The method for preparing a fluoroquinolone compound having a siloxane group according to any one of claims 1 to 2, comprising the steps of: 1) Weighing a certain amount of a compound 1, potassium carbonate and chlorotrialkoxysilane 2, taking acetonitrile as a solvent, heating in an oil bath at 80 ℃, and stirring for reflux reaction for 12h; adding a proper amount of deionized water into the reaction system for dissolving, and using CH 2 Cl 2 Extracting, combining organic phases, drying with anhydrous magnesium sulfate, filtering, rotary evaporating, and using CH 2 Cl 2 /CH 3 Performing column chromatography purification on OH to obtain a white oily substance which is a compound II;
the reaction synthetic route is as follows:
Figure FDA0002528739190000012
2) Weighing a certain amount of a compound II, dissolving the compound II in methanol, adding sodium bicarbonate, dropwise adding a solution of a compound 4 dissolved in dichloromethane, heating and refluxing for 4 hours, cooling, adding water, and separating an organic phase; evaporating the organic phase to dryness to obtain a compound I;
the reaction synthetic route is as follows:
Figure FDA0002528739190000013
4. use of the oxosilane group-containing fluoroquinolone compound according to any one of claims 1 to 2 for preparing an antibacterial agent.
5. An antibacterial composition comprising the fluoroquinolone compound having a siloxane group according to any one of claims 1 to 2.
6. The temperature-sensitive in-situ gel composition comprises the following raw materials in percentage by weight: 0.1 to 1% of the oxosilane group-containing fluoroquinolone compound according to any one of claims 1 to 2, 0.1 to 5% of a temperature sensitive gel matrix, 0.1 to 5% of a permeation enhancer, 0.1 to 5% of a pH adjuster, and the balance of water; the temperature-sensitive gel matrix is poloxamer; the penetration enhancer is polyethylene glycol; the pH regulator is sodium hydroxide.
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