CN102627642A - Metal complexes of moxifloxacin and pharmaceutical purpose thereof - Google Patents
Metal complexes of moxifloxacin and pharmaceutical purpose thereof Download PDFInfo
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- CN102627642A CN102627642A CN2012100719773A CN201210071977A CN102627642A CN 102627642 A CN102627642 A CN 102627642A CN 2012100719773 A CN2012100719773 A CN 2012100719773A CN 201210071977 A CN201210071977 A CN 201210071977A CN 102627642 A CN102627642 A CN 102627642A
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Abstract
The invention belongs to the field of pharmaceutical chemistry, and relates to novel rare earth metal and platinum group metal complexes of moxifloxacin and their preparation method and pharmaceutical purpose. The novel rare earth metal and platinum group metal complexes of moxifloxacin are superior to moxifloxacin in antibacterial and antineoplastic activity and have application prospects in research and development of antibacterial and antineoplastic drugs.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to anti-infectives Moxifloxacin metal complexes and preparation method, and the pharmaceutical applications of this title complex.
Background technology
Moxifloxacin (moxifloxacin) for Beyer Co., Ltd development the 4th generation fluoroquinolone antibiotics; Chemistry is by name: 1-cyclopropyl-7-{ (S; S)-2,8-diazonium-two ring [4.3.0] nonanal-8-group }-6-fluoro-8-methoxy-1,4-dihydro-4-oxygen-3-quinoline carboxylic acid hydrochloride.Trade(brand)name: visit multiple pleasure.Clinically be used to treat acute sinus gland inflammation, the acute attack of chronic bronchitis, community acquired pneumonia, and uncomplicated skin infections and skin soft-tissue infection.Have broad spectrum antibiotic activity, especially the activity for gram-positive microorganism, chlamydozoan, mycoplasma is superior to levofloxacin greatly.
The Moxifloxacin hydrochloride of clinical use has the structure that is shown below:
The inorganic metal title complex all is an important directions in drug research field all the time, and many metal complexess and inner complex all have the superior efficacy of medicine, in life entity and chemicals, occupies very consequence.3 carboxyls and 4 carbonyls of carbostyril compound can form stable title complex with multiple metals ion.
Biological activitys such as itself has sterilization rare earth metal, and is antitumor, the rare earth metal of existing experiment proof low dosage is inhibited to tumour cell.Rare earth metal can be accumulated in tumour, can form complex compound with nucleic acid, important Ca in the displacement human body, and the Mg ion, this phenomenon is significant in suppressing tumour mechanism.Platinum series antineoplastic medicament is the antitumor drug that a present line uses, and is active powerful, and the platinum metals ion can cause dna structure to change with the DNA covalent attachment.
Forefathers' bibliographical information shows: after quinolone medicine is processed corresponding title complex as part and metals ion; May produce synergy; So have the title complex of quite a few medicine to have, anti-tumor activity better more antibiotic, but also have some and part quite perhaps to be weaker than part than medicine part itself.
Through retrieval, existing open source literature patent report quinolone antibiotic commonly used: norfloxicin, CIPROFLOXACIN USP 24, the metal ion match of Ofloxacine USP 23 etc., and have antibiotic, the report of anti-tumor activity.But never there is open source literature to study the Moxifloxacin rare earth metal and platinum metal complex is antibiotic with flying colors, anti-tumor activity.
Summary of the invention
The invention discloses the structure of Moxifloxacin rare earth metal and platinum metal complex, this compounds has antibiotic with flying colors, anti-tumor activity, and the preparation method of this compounds.
At first, the present invention provides Moxifloxacin rare earth metal and platinum metal complex, has the chemical structure shown in the following formula,
Wherein, M is a rare earth metal, the platinum metals.
Further, metals ion is a kind of in lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), gadolinium (Gd), platinum (Pt), palladium (Pd), osmium (Os), iridium (Ir), ruthenium (Ru), the rhodium (Rh) in above-mentioned Moxifloxacin rare earth metal and the platinum metal complex.
Further, the number of contained crystal water is 0～6 in above-mentioned Moxifloxacin rare earth metal and the platinum metal complex.
It is the method for the metal complexes of part with the Moxifloxacin that the present invention also provides preparation, it is characterized in that, Moxifloxacin or its esters is soluble in water; Heating adds alkali and regulates pH=7～14, is added dropwise to the aqueous hydrochloric acid of above-mentioned metals ion oxide compound or salt; Regulate pH=8～14 with alkaline aqueous solution, deposition is separated out, and filters; Water and ethanol wash respectively, are drying to obtain.
Further, described preparation method, added alkali is one or more in sodium hydroxide, yellow soda ash, sodium hydrogencarbonate, Pottasium Hydroxide, the salt of wormwood.
Further, control reaction temperature is 20～100 ℃ in the reaction process.
It is the metal complexes of part is used for treating the disease medicament that causes because of bacterium, mycoplasma or choamydiae infection in preparation application with the Moxifloxacin that the present invention also provides above-mentioned.
Further, above-mentioned bacterium is pneumococcus, enterococcus species, intestinal bacteria, moraxelle catarrhalis, suis, Pseudomonas aeruginosa, legionella pneumophilia, klebsiella, enterobacteria, Serratia, staphylococcus, mycetozoan, bacterium morgani, hemophilus influenzae, citric acid fungus, digestion bacterium or fusobacterium.
It is the application of metal complexes in the preparation antitumor drug of part with the Moxifloxacin that the present invention also provides above-mentioned.
Embodiment
The preparation of embodiment 1 Moxifloxacin Gd coordination compound (2)
Take by weighing Moxifloxacin 43.8g (0.1mol), add in the 200ml water, add sodium hydrogencarbonate 8.5g (0.11mol) again and be heated to 30 ℃ under stirring, subsequent use.Other takes by weighing Gd
2O
35.44g (0.015mol), add in the hydrochloric acid of 20ml1mol/L, be added dropwise to after the stirring and dissolving in the aforementioned Moxifloxacin solution; Regulate pH=9～10 with the 1mol/L sodium hydroxide solution, be heated to 50 ℃, stirring reaction 1h; Deposition is separated out, and filters, respectively with water, washing with alcohol; 60 ℃ of forced air drying 2h get Moxifloxacin Gd coordination compound 28.7g.
Ultimate analysis: C
63H
72F
3GdN
9O
12C:55.71% (theoretical value: 55.57%); H:5.61% (theoretical value: 5.33%); N:9.02% (theoretical value: 9.26%); F:3.82% (theoretical value: 4.19%)
Specific conductivity: 43.2Scm
2/ mol
The preparation of embodiment 2 Moxifloxacin lanthanum title complexs (3)
Take by weighing Moxifloxacin 26.9g (0.05mol), add in the 150ml water, add yellow soda ash 6.36g (0.06mol) again and be heated to 55 ℃ under stirring, subsequent use.Other takes by weighing La
2O
32.6g (0.008mol), add in the hydrochloric acid of 15ml3mol/L, be added dropwise to after the stirring and dissolving in the aforementioned Moxifloxacin solution; Regulate pH=8～9 with the 5mol/L sodium hydroxide solution, be heated to 70 ℃, stirring reaction 1.5h; Get sedimentation and filtration; With water, washing with alcohol, 65 ℃ of forced air drying 2h get Moxifloxacin lanthanum title complex 12.5g respectively.
Ultimate analysis: C
63H
72F
3LaN
9O
12C:56.10% (56.33%); H:5.63% (5.40%); N:9.16% (9.39%); F:3.82% (4.24%)
Specific conductivity: 67.4Scm
2/ mol
The preparation of embodiment 3 Moxifloxacin cerium complexes (4)
Take by weighing Moxifloxacin 87.6g (0.2mol), add in the 500ml water, add again to be stirred under sodium hydroxide 10.0g (0.25mol) room temperature entirely and dissolve, subsequent use.Other takes by weighing Ce
2O
316.4g (0.05mol), add in the sulfuric acid of 20ml3mol/L, be added dropwise to after the stirring and dissolving in the aforementioned Moxifloxacin solution; Regulate pH=9～10 with the 1mol/L sodium hydroxide solution, be heated to 60 ℃, stirring reaction 2h; Get sedimentation and filtration; With water, washing with alcohol, 60 ℃ of forced air drying 2h get Moxifloxacin cerium complexes 32.4g respectively.
Ultimate analysis: C
63H
72F
3CeN
9O
12C:56.71% (56.28%); H:5.52% (5.40%); N:9.38% (9.38%); F:3.94% (4.24%)
Specific conductivity: 90.5Scm
2/ mol
The preparation of embodiment 4 Moxifloxacin neodymium title complexs (5)
Take by weighing Moxifloxacin 43.8g (0.1mol), add in the 300ml water, add salt of wormwood 15.18g (0.11mol) stirring at room again to all dissolvings, subsequent use.Other takes by weighing Nd
2O
36.73g (0.02mol), add in the hydrochloric acid of 20ml2mol/L, be added dropwise to after the stirring and dissolving in the aforementioned Moxifloxacin solution; Regulate pH=10 with the 2mol/L potassium hydroxide solution, be heated to 40 ℃, stirring reaction 1.5h; There is deposition to separate out, filters, respectively with water, washing with alcohol; 60 ℃ of forced air drying 3h get Moxifloxacin neodymium title complex 23.4g.
Ultimate analysis: C
63H
72F
3NdN
9O
12C:55.71% (56.11%); H:5.61% (5.38%); N:9.02% (9.35%); F:3.82% (4.23%)
Specific conductivity: 22.8Scm
2/ mol
The preparation of embodiment 5 Moxifloxacin platinum complexes (6)
Take by weighing Moxifloxacin 10.95g (0.025mol), add in the 100ml water, add Pottasium Hydroxide 1.4g (0.025mol) stirring at room again to all dissolvings, subsequent use.Other takes by weighing PtO
21.82g (0.008mol), add in the hydrochloric acid of 20ml2mol/L, be added dropwise to after the stirring and dissolving in the aforementioned Moxifloxacin solution; Regulate pH=9～10 with the 1mol/L potassium hydroxide solution, be heated to 55 ℃, stirring reaction 2h; The deposition that filtration is separated out; With water, washing with alcohol, 60 ℃ of forced air drying 2h get Moxifloxacin platinum complex 9.86g respectively.
Ultimate analysis: C
63H
72F
3PtN
9O
12C:53.93% (54.07%); H:5.33% (5.19%); N:9.14% (9.01%); F:3.87% (4.07%)
Specific conductivity: 48.3Scm
2/ mol
The preparation of embodiment 6 Moxifloxacin ruthenium complexees (7)
Take by weighing Moxifloxacin 43.8g (0.1mol), add in the 200ml water, add sodium hydroxide 8.5g (0.11mol) stirring at room again to dissolving, subsequent use.Other takes by weighing RuCl
37.26g (0.035mol), add in the hydrochloric acid of 20ml0.5mol/L, be added dropwise to after the stirring and dissolving in the aforementioned Moxifloxacin solution; Regulate pH=8～9 with the 1mol/L sodium hydroxide solution, be heated to 60 ℃, stirring reaction 1h; Deposition is separated out after-filtration; With water, washing with alcohol, 60 ℃ of forced air drying 2h get Moxifloxacin Gd coordination compound 31.2g respectively.
Ultimate analysis: C
63H
72F
3RuN
9O
12C:57.82% (57.97%); H:5.60% (5.56%); N:9.53% (9.66%); F:4.51% (4.37%)
Specific conductivity: 37.3Scm
2/ mol
The preparation of embodiment 7 Moxifloxacin rhodium complexs (8)
Take by weighing Moxifloxacin 26.9g (0.05mol), add in the 150ml water, add sodium hydroxide 2.4g (0.06mol) stirring at room again to all dissolvings, subsequent use.Other takes by weighing RhCl
33.14g (0.015mol), add in the hydrochloric acid of 20ml1mol/L, be added dropwise to after the stirring and dissolving in the aforementioned Moxifloxacin solution; Regulate pH=9～10 with the 1mol/L sodium hydroxide solution, be heated to 50 ℃, stirring reaction 1h; Deposition is separated out after-filtration; With water, washing with alcohol, 60 ℃ of forced air drying 2h get Moxifloxacin rhodium complex 12.8g respectively.
Ultimate analysis: C
63H
72F
3RhN
9O
12C:57.67% (57.89%); H:5.46% (5.55%); N:9.76% (9.64%); F:4.11% (4.36%)
Specific conductivity: 64.7Scm
2/ mol
Embodiment 8 Moxifloxacin praseodymium title complexs (9), palladium complex (10), osmium title complex (11), complex of iridium (12) preparation method and embodiment 1 said method same operation.
The test of embodiment 9 Moxifloxacin metal complexes anti-microbial activities
Adopt agar dilution to measure minimum inhibitory concentration (MIC); Utilization multiple spot inoculation appearance is in the quantitative inoculated bacteria in agar plate surface that contains medicine series concentration; Bacterium liquid final concentration is 105CFU/ml; Observations behind 35 ℃ of cultivation 18h does not see that the lowest drug concentration of bacterial growth is the minimum inhibitory concentration of this medicine to bacterium.Mensuration result is following:
Table 1 Moxifloxacin and metal complexes thereof are to the vitro antibacterial activity of bacterium
Embodiment 10 Moxifloxacin metal complexes anti-tumor activity tests
1. experiment material: employed cancerous cell line is HL-60 (human leukemia cell), Hepg2 (human liver cancer cell), A549 (human lung carcinoma cell); Perhaps use 1640+10%FBS to cultivate with the DMEM+10%FBS culture medium culturing.
2. experimental technique and interpretation of result:
2.1 cell inoculation is in 96 orifice plates, inoculum size is 1500/hole, 190 μ l/ holes, 37 ℃ 5% CO
2The incubator overnight cultures;
2.2 every hole adds the different compounds of 10 μ l, final concentration is 10
-5～10
-10M; 37 ℃, 5% CO
2Incubator was hatched 72 hours;
2.3 every hole adds the MTT of 20 μ l 5mg/ml, 37 ℃ 5% CO
2Incubator was hatched 4 hours;
2.4 supernatant discarded, every hole adds the DMSO of 100 μ l, vibration;
2.5 in the 570nm reading, calculate cell survival rate, get median effective dose (IC
50), it is following to measure the result:
Table 2 Moxifloxacin and metal complexes anti tumor activity in vitro thereof
Need to prove; The above is merely part embodiment of the present invention; And being not used in qualification scope of the present invention, all any modifications of within spirit of the present invention and principle, having done, the replacement that is equal to and improvement etc. all should be included within protection scope of the present invention.
Claims (9)
1. one kind is the metal complexes of part with the Moxifloxacin, has the chemical structure shown in the following formula,
Wherein, M is a metals ion.
2. according to claim 1 is the metal complexes of part with the Moxifloxacin, it is characterized in that, M is a rare earth metal, the platinum metals.
3. according to claim 1 is the metal complexes of part with the Moxifloxacin; It is characterized in that M is a kind of in lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), gadolinium (Gd), platinum (Pt), palladium (Pd), osmium (Os), iridium (Ir), ruthenium (Ru), the rhodium (Rh).
4. according to claim 1 is the metal complexes of part with the Moxifloxacin, it is characterized in that number n=0～6 of crystal water.
5. be the preparation method of the metal complexes of part with the Moxifloxacin, it is characterized in that, Moxifloxacin or its esters is soluble in water; Heating adds alkali and regulates pH >=7, is added dropwise to the aqueous hydrochloric acid of above-mentioned metals ion oxide compound or salt; Regulate pH >=8 with alkaline aqueous solution, deposition is separated out, and filters; Water and ethanol wash respectively, are drying to obtain.
6. preparation method according to claim 5, added alkali is one or more in sodium hydroxide, yellow soda ash, sodium hydrogencarbonate, Pottasium Hydroxide, the salt of wormwood.
7. preparation method according to claim 5, control reaction temperature is 20～100 ℃ in the reaction process.
8. claim 1～4 is said is the purposes of metal complexes in treatment bacterium, chlamydozoan, the caused disease of mycoplasma infection of part with the Moxifloxacin.
9. claim 1～4 is said is the purposes of the metal complexes of part as anti-tumor medicine with the Moxifloxacin.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102924527A (en) * | 2012-10-29 | 2013-02-13 | 山西大学 | Ru(II) complex with anticancer activity and preparation method of complex |
| CN103804393A (en) * | 2014-01-28 | 2014-05-21 | 广西师范大学 | Marbofloxacin rare-earth chelates as well as synthetic method and application thereof |
| CN114315911A (en) * | 2021-12-21 | 2022-04-12 | 南方海洋科学与工程广东省实验室(湛江) | Preparation method and application of pazufloxacin iridium complex |
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| WO2000066126A2 (en) * | 1999-04-29 | 2000-11-09 | Alza Corporation | Liposome compositions for improved drug retention |
| CN101747382A (en) * | 2009-12-29 | 2010-06-23 | 广东药学院 | Ruthenium polypyridyl complex using quinolones compound as ligand, preparation method and application thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102924527A (en) * | 2012-10-29 | 2013-02-13 | 山西大学 | Ru(II) complex with anticancer activity and preparation method of complex |
| CN103804393A (en) * | 2014-01-28 | 2014-05-21 | 广西师范大学 | Marbofloxacin rare-earth chelates as well as synthetic method and application thereof |
| CN114315911A (en) * | 2021-12-21 | 2022-04-12 | 南方海洋科学与工程广东省实验室(湛江) | Preparation method and application of pazufloxacin iridium complex |
| CN114315911B (en) * | 2021-12-21 | 2024-03-26 | 南方海洋科学与工程广东省实验室(湛江) | Preparation method and application of pazufloxacin iridium complex |
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Application publication date: 20120808 |