CN103910674B - Reference compound in analyzing for flupirtine maleate - Google Patents

Reference compound in analyzing for flupirtine maleate Download PDF

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CN103910674B
CN103910674B CN201310733125.0A CN201310733125A CN103910674B CN 103910674 B CN103910674 B CN 103910674B CN 201310733125 A CN201310733125 A CN 201310733125A CN 103910674 B CN103910674 B CN 103910674B
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impurity
reference substance
solution
flupirtine maleate
peak
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CN103910674A (en
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张存彦
韩冬
董凯
孙长海
姚小青
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Tianjin Chase Sun Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N2030/022—Column chromatography characterised by the kind of separation mechanism
    • G01N2030/027—Liquid chromatography

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Physics & Mathematics (AREA)
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  • Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

The invention belongs to medical art, be specifically related to a kind of for impurity compound A, B, C, D, the E in flupirtine maleate analysis and the application in flupirtine maleate pharmaceutical analysis thereof.

Description

Reference compound in analyzing for flupirtine maleate
Technical field
The invention belongs to medical art, be specifically related to a kind of for impurity compound A, B, C, D, the E in flupirtine maleate analysis and the application in flupirtine maleate pharmaceutical analysis thereof.
Background technology
Flupirtine maleate, chemical name 2-amino-3-acetylaminohydroxyphenylarsonic acid 6-(p-fluoroanilino)-pyridine, ethyl-2-amino-6-[(p-fluorophenyl) is amino]-3-pyridine-carboxylamine maleate:
Molecular formula: C 15h 17fN 4o 2c 4h 4o 4, molecular weight: 420.41
Flupirtine maleate is selective neuronal potassium channel openers, is a kind of nonopioid analgesic acting on central nervous system, does not produce dependency and tolerance.Flupirtine maleate is by activating the K of G-protein coupling on neuron membrane +passage .K +resting membrane electric potential is stablized in outflow.Cytolemma activity reduces, thus indirectly inhibits the activation of nmda receptor.Treatment concentration flupirtine maleate not with а 1, а 2, 5-HT 1, 5-HT 2, Dopamine HCL, Benzodiazepine, opium, maincenter M and n receptor combine.
According to pertinent literature, the common untoward reaction relevant to dosage of side effect of flupirtine maleate comprises drowsiness, dizzy, dry and various gastrointestinal symptoms.The reports such as McMahon, 1300 many cases pain patients have carried out double blind random clinical trial in 26 research units of the U.S., and result shows, and the modal reaction of flupirtine is drowsiness reaction (about 10%).The reports such as Herrmann, suffer from the treatment that arthritis chronic pain person carries out 12 months to 200 examples, found that, occur without tolerance, and modal untoward reaction is drowsiness, dizzy, dry and itch, and its incidence is respectively 9%, 11%, 5% and 9%.Herrmann etc. report again, and 191 routine chronic pain persons carry out the multicentre open study of 1 year by a definite date, and result flupirtine can be tolerated preferably by patient, and prolonged application occurs without tolerance and dependency, and Withrawal symptom does not appear in clinical trial.Heusinger etc. also report, 1174 routine pain persons carry out multiple center trial, medication 3d ~ 8 week, and result is compared with pentazocine, and patient can better tolerate.Flupirtine without the breathing caused by opioid drug and cardiovascular inhibition, to the equal apnea restraining effect of patient suffering from pulmonary emphysema, bronchial asthma, pulmonary fibrosis.The advantage place of this new type analgesic flupirtine just, this may be different with opiates from its analgesic mechanism relevant.
Prepared by the method that the many employings of preparation technology's document of flupirtine maleate are reacted with Vinyl chloroformate after ANFP reduction.In current reaction, be all under the condition of high-pressure hydrogenation to the reduction of nitro, pyridine ring can be coupled under elevated pressure conditions, thus causes the generation of side reaction.
The building-up process of flupirtine maleate:
In the standard of flupirtine maleate, the control of the quality standard of impurity is only limited to the content of impurity D14461 and D13085.Do not study other impurity of flupirtine maleate at present, that also openly originates about flupirtine maleate impurity studies report in great detail.
The structural formula of D14461 and D13085 impurity is as follows:
Applicant has also found new impurity A, B, C, D, E in flupirtine maleate preparation and storage process:
In experimentation, we find, flupirtine maleate and instability thereof, and sample is very easy to variable color in put procedure, and then affect the accuracy of sample determination, therefore need to operate under given conditions, as lucifuge, preserve under being stored in the lower condition of the temperature of lucifuge after sample.In long-term and accelerated stability experimentation, the content of related substance increases along with the growth of storage period, and flupirtine maleate is after placement for some time, there will be sensitization and reacts.Therefore, find and control the impurity of flupirtine maleate well and effectively can improve quality and the security of product.
Summary of the invention
The object of the invention is impurity A, B, C, D, E of providing flupirtine maleate, the chemical structural formula of impurity A of the present invention, B, C, D, E, as follows respectively:
Compd A:
Compd B:
Compound C:
Compound C can be hydrochloride, vitriol, maleate, oxalate
Compound D:
Compd E
The present invention also provides the preparation method of impurity A, B, C, D, E.
Impurity compound A preparation process:
Take flupirtine maleate, add anhydrous methanol, heating, stirring and dissolving, column chromatography filters, respectively with methylene dichloride: methyl alcohol mixed liquor carries out wash-out, obtains compd A.
Preferably, the preparation process of impurity compound A in embodiment 1.
The NMR:H chemical shift of compd A: 8.25,7.31,7.05,6.82,5.99,5.04,4.48,4.04,3.39,1.22;
The preparation process of impurity compound B:
Take flupirtine maleate, add anhydrous methanol, heating, stirring and dissolving, column chromatography filters, respectively with methylene dichloride: methyl alcohol mixed liquor carries out wash-out, obtains compd B.
Preferably, the preparation process of impurity compound B in embodiment 1.
The NMR:H chemical shift of compd B: 8.24,7.36,7.29,7.16,7.12,7.11,7.02,6.69,5.71,5.30,4.48,4.37,4.04,1.20,1.11;
The preparation process of impurity compound C:
2-amino-3-nitro-6-NSC 158269 yl pyridines dissolves in anhydrous methanol, adds 5% palladium carbon, under 20 kilograms of pressure, reacts complete, after being spin-dried for, being dissolved in methylene dichloride, adding triethylamine, add methyl-chloroformate at 0 ~ 25 DEG C, be spin-dried for and obtain impurity compound C.
Preferably, the preparation process of impurity compound C in example 2.
The MS(M+1 of Compound C): 291.1180, H chemical shift: 7.38,7.18,6.17,5.80,4.39,3.59.
The preparation process of impurity D:
Weigh Compound C20.0g, adds dimethyl formamide: water (20:1), is heated to 110 DEG C, after stirring and dissolving, keeps temperature 48 hours.Filter, column chromatography, respectively with methylene dichloride: methyl alcohol (100:1) carries out wash-out, obtains impurity D.
Preferably, the preparation process of impurity compound D in embodiment 3.
The MS(M+1 of Compound D): 579.2203, H chemical shift: 7.12,6.15,7.39,5.94,6.48,4.32,4.35,3.68.
The preparation process of impurity E:
Weigh Compound C20.0g, adds dimethyl formamide: water (20:1), is heated to 110 DEG C, after stirring and dissolving, keeps temperature 48 hours, and filter, column chromatography, respectively with methylene dichloride: methyl alcohol (100:1) carries out wash-out, obtains impurity E.
Preferably, the preparation process of impurity compound E is in embodiment 3.
The MS(M+1 of compd E): 579.2202, H chemical shift: 7.12,6.86,7.39,4.35,3.68.
Another object of the present invention is the detection method providing flupirtine maleate.
Impurity A provided by the invention, B, C, D, E can provide reference substance for the qualitative and quantitative analysis of flupirtine maleate, thus improve the quality standard of flupirtine maleate, and the clinical application for flupirtine maleate provides important directive significance.
Specifically, the invention provides impurity A and the impurity B application of product in detection flupirtine maleate medicine in contrast.
Assay of the present invention, comprises the following steps:
The preparation of need testing solution: it is appropriate that precision takes flupirtine maleate, puts in 100ml measuring bottle, solubilizing agent 70ml, ultrasonic and constantly jolting flupirtine maleate is dissolved, let cool, with solvent cut to scale, shake up, filter with the filter membrane of 0.45 μm, subsequent filtrate is as need testing solution;
The preparation of stock solution: precision takes impurity A reference substance and impurity B reference substance is in right amount each, also dilutes the solution made containing 45 μ g in every 1ml, as impurity reference substance stock solution with dissolve with methanol; It is appropriate that precision takes flupirtine maleate reference substance, and solubilizing agent dissolves and dilutes the solution made containing 45 μ g in every 1ml, as flupirtine maleate reference substance stock solution;
The preparation of reference substance solution: precision measures impurity reference substance stock solution and each 5ml of flupirtine maleate reference substance stock solution respectively, puts in 50ml measuring bottle, with solvent cut to scale, shakes up, in contrast product solution.
Chromatographic condition:
According to China's coastal port two annex VD high effective liquid chromatography for measuring.
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are weighting agent; With ammonium dihydrogen phosphate-acetonitrile for moving phase, column temperature: 40 DEG C, flow velocity is 1.0ml/min; Determined wavelength is 252nm, flow velocity: 1.5ml/min.
Precision measures reference substance solution and each 15 μ l of need testing solution, respectively injection liquid chromatography, and record color atlas is to 12 times of main peak retention time, and flupirtine maleate peak and impurity A peak and the peak-to-peak resolution of impurity B all should be greater than 6.
The present invention also provides impurity C, D, E application of product in detection flupirtine maleate medicine in contrast.
Assay of the present invention, comprises the following steps:
The preparation of need testing solution: it is appropriate that precision takes flupirtine maleate, puts in 100ml measuring bottle, solubilizing agent 70ml, ultrasonic and constantly jolting flupirtine maleate is dissolved, let cool, with solvent cut to scale, shake up, filter with the filter membrane of 0.45 μm, subsequent filtrate is as need testing solution;
The preparation of stock solution: it is in right amount each that precision takes impurity C reference substance, impurity D and impurity E reference substance, also dilutes the solution made containing 45 μ g in every 1ml, as impurity reference substance stock solution with dissolve with methanol; It is appropriate that precision takes flupirtine maleate reference substance, and solubilizing agent dissolves and dilutes the solution made containing 45 μ g in every 1ml, as flupirtine maleate reference substance stock solution;
The preparation of reference substance solution: precision measures impurity reference substance stock solution and each 5ml of flupirtine maleate reference substance stock solution respectively, puts in 50ml measuring bottle, with solvent cut to scale, shakes up, in contrast product solution.
Chromatographic condition:
According to China's coastal port two annex VD high effective liquid chromatography for measuring.
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are weighting agent; With ammonium dihydrogen phosphate-acetonitrile for moving phase, column temperature: 40 DEG C, flow velocity is 1.0ml/min; Determined wavelength is 252nm, flow velocity: 1.5ml/min.
Precision measures reference substance solution and each 15 μ l of need testing solution, respectively injection liquid chromatography, and record color atlas is to 12 times of main peak retention time, and flupirtine maleate peak and impurity C peak, impurity D peak and the peak-to-peak resolution of impurity E all should be greater than 6.
The impurity A that Late Cambrian of the present invention produces in synthesis flupirtine maleate process, B, C, D, E.By the control to this impurity, purity and the content of flupirtine maleate effectively can be improved.In long-term and accelerated stability experimentation, we find that the storage period of impurity A-E longer content is larger, more obvious in sensitization is reacted, therefore, find impurity A, B, C, D, E, and controlled well, effectively can increase Drug safety, reduce anaphylaxis.In addition, the detection method that the present invention is set up by impurity A, B, C, D, E, has the features such as accuracy is high, susceptibility strong, favorable reproducibility.
Accompanying drawing explanation
Fig. 1: in impurity spectrum, each impurity goes out peak position figure.
Fig. 2, impurity A hydrogen spectrogram.
Fig. 3, impurity B hydrogen spectrogram.
Fig. 4, impurity C hydrogen spectrogram.
Fig. 5, impurity D mass spectrum.
Fig. 6, impurity D hydrogen spectrogram.
Fig. 7, impurity E mass spectrum.
Fig. 8, impurity E hydrogen spectrogram.
Embodiment
By following specific embodiment, the present invention is further illustrated, but not as restriction of the present invention.
embodiment 1:
Take flupirtine maleate 20.0g, add 200mL anhydrous methanol, be heated to 80 DEG C, after stirring and dissolving, keep temperature 48 hours.Filter, column chromatography, respectively with methylene dichloride: methyl alcohol 100:1 carries out wash-out, obtains impurity A and impurity B.
embodiment 2:
20gANFP(2-amino-3-nitro-6-NSC 158269 yl pyridines) dissolve in anhydrous methanol, add 5% palladium carbon, under 20 kilograms of pressure, react complete, after being spin-dried for, be dissolved in methylene dichloride, add 13mL triethylamine, add methyl-chloroformate at 0 ~ 25 DEG C, be spin-dried for and obtain Compound C.
embodiment 3:
Weigh Compound C20.0g, adds 200mL dimethyl formamide: water (20:1), is heated to 110 DEG C, after stirring and dissolving, keeps temperature 48 hours.Filter, column chromatography, respectively with methylene dichloride: methyl alcohol 100:1 carries out wash-out, obtains impurity D and impurity E.
embodiment 4:
Impurity A and impurity B are detecting the application in flupirtine maleate medicine as reference substance.
The preparation of need testing solution: it is appropriate that precision takes flupirtine maleate, puts in 100ml measuring bottle, solubilizing agent 70ml, ultrasonic and constantly jolting flupirtine maleate is dissolved, let cool, with solvent cut to scale, shake up, filter with the filter membrane of 0.45 μm, subsequent filtrate is as need testing solution;
The preparation of stock solution: precision takes impurity A reference substance and impurity B reference substance is in right amount each, also dilutes the solution made containing 45 μ g in every 1ml, as impurity reference substance stock solution with dissolve with methanol; It is appropriate that precision takes flupirtine maleate reference substance, and solubilizing agent dissolves and dilutes the solution made containing 45 μ g in every 1ml, as flupirtine maleate reference substance stock solution;
The preparation of reference substance solution: precision measures impurity reference substance stock solution and each 5ml of flupirtine maleate reference substance stock solution respectively, puts in 50ml measuring bottle, with solvent cut to scale, shakes up, in contrast product solution.
Chromatographic condition:
Measure according to high performance liquid chromatography (China's coastal port two annex VD).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are weighting agent; With 0.02mol/L ammonium dihydrogen phosphate-acetonitrile (600:470), mixing is rear is 5.4 ~ 5.5 by phosphoric acid adjust ph) be moving phase, column temperature: 40 DEG C, flow velocity is 1.0ml/min; Determined wavelength is 252nm.
Flow velocity: 1.5ml/min.
Precision measures reference substance solution and each 15 μ l of need testing solution, respectively injection liquid chromatography, and record color atlas is to 12 times of main peak retention time, and flupirtine maleate peak and impurity A peak and the peak-to-peak resolution of impurity B all should be greater than 6.
embodiment 5:
Impurity C, D and impurity E are detecting the application in flupirtine maleate medicine as reference substance.
The preparation of need testing solution: it is appropriate that precision takes flupirtine maleate, puts in 100ml measuring bottle, solubilizing agent 70ml, ultrasonic and constantly jolting flupirtine maleate is dissolved, let cool, with solvent cut to scale, shake up, filter with the filter membrane of 0.45 μm, subsequent filtrate is as need testing solution;
The preparation of stock solution: it is in right amount each that precision takes impurity C reference substance, impurity D and impurity E reference substance, also dilutes the solution made containing 45 μ g in every 1ml, as impurity reference substance stock solution with dissolve with methanol; It is appropriate that precision takes flupirtine maleate reference substance, and solubilizing agent dissolves and dilutes the solution made containing 45 μ g in every 1ml, product stock solution in contrast;
The preparation of reference substance solution: precision measures impurity reference substance stock solution and each 5ml of flupirtine maleate reference substance stock solution respectively, puts in 50ml measuring bottle, with solvent cut to scale, shakes up, in contrast product solution;
Chromatographic condition:
Measure according to high performance liquid chromatography (China's coastal port two annex VD).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are weighting agent; With 0.02mol/L ammonium dihydrogen phosphate-acetonitrile (600:470), mixing is rear is 5.4 ~ 5.5 by phosphoric acid adjust ph) be moving phase, column temperature: 40 DEG C, flow velocity is 1.0ml/min; Determined wavelength is 252nm, flow velocity: 1.5ml/min.
Precision measures reference substance solution and each 15 μ l of need testing solution, respectively injection liquid chromatography, and record color atlas is to 12 times of main peak retention time, and flupirtine maleate peak and impurity C peak, impurity D peak and the peak-to-peak resolution of impurity E all should be greater than 6.

Claims (3)

1. the impurity A of flupirtine maleate, B, D, its chemical structure is as follows:
Compd A
Compd B
Compound D
2. a detection method for flupirtine maleate, is characterized in that, with impurity A and impurity B product in contrast, comprises the following steps:
The preparation of need testing solution: it is appropriate that precision takes flupirtine maleate, puts in 100ml measuring bottle, solubilizing agent 70ml, ultrasonic and constantly jolting flupirtine maleate is dissolved, let cool, with solvent cut to scale, shake up, filter with the filter membrane of 0.45 μm, subsequent filtrate is as need testing solution;
The preparation of stock solution: precision takes impurity A reference substance and impurity B reference substance is in right amount each, also dilutes the solution made containing 45 μ g in every 1ml, as impurity reference substance stock solution with dissolve with methanol; It is appropriate that precision takes flupirtine maleate reference substance, and solubilizing agent dissolves and dilutes the solution made containing 45 μ g in every 1ml, as flupirtine maleate reference substance stock solution;
The preparation of reference substance solution: precision measures impurity reference substance stock solution and each 5ml of flupirtine maleate reference substance stock solution respectively, puts in 50ml measuring bottle, with solvent cut to scale, shakes up, in contrast product solution;
Chromatographic condition: according to China's coastal port two annex VD high effective liquid chromatography for measuring
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are weighting agent; With ammonium dihydrogen phosphate-acetonitrile for moving phase, column temperature: 40 DEG C, flow velocity is 1.0ml/min; Determined wavelength is 252nm, flow velocity: 1.5ml/min;
Precision measures reference substance solution and each 15 μ l of need testing solution, respectively injection liquid chromatography, and record color atlas is to 12 times of main peak retention time, and flupirtine maleate peak and impurity A peak and the peak-to-peak resolution of impurity B all should be greater than 6
Wherein, compd A
Compd B
3. a detection method for flupirtine maleate, is characterized in that, with impurity D product in contrast, comprises the following steps:
The preparation of need testing solution: it is appropriate that precision takes flupirtine maleate, puts in 100ml measuring bottle, solubilizing agent 70ml, ultrasonic and constantly jolting flupirtine maleate is dissolved, let cool, with solvent cut to scale, shake up, filter with the filter membrane of 0.45 μm, subsequent filtrate is as need testing solution;
The preparation of stock solution: it is appropriate that precision takes impurity D reference substance, also dilutes the solution made containing 45 μ g in every 1ml, as impurity reference substance stock solution with dissolve with methanol; It is appropriate that precision takes flupirtine maleate reference substance, and solubilizing agent dissolves and dilutes the solution made containing 45 μ g in every 1ml, as flupirtine maleate reference substance stock solution;
The preparation of reference substance solution: precision measures impurity reference substance stock solution and each 5ml of flupirtine maleate reference substance stock solution respectively, puts in 50ml measuring bottle, with solvent cut to scale, shakes up, in contrast product solution;
Chromatographic condition: according to China's coastal port two annex VD high effective liquid chromatography for measuring
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are weighting agent; With ammonium dihydrogen phosphate-acetonitrile for moving phase, column temperature: 40 DEG C, flow velocity is 1.0ml/min; Determined wavelength is 252nm, flow velocity: 1.5ml/min;
Precision measures reference substance solution and each 15 μ l of need testing solution, respectively injection liquid chromatography, and record color atlas is to 12 times of main peak retention time, and flupirtine maleate peak and the peak-to-peak resolution of impurity D should be greater than 6
Wherein Compound D
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CN104974087A (en) * 2015-01-30 2015-10-14 吉林修正药业新药开发有限公司 Synthesis method of flupirtine dimer
CN105541705B (en) * 2015-12-31 2019-08-06 山东罗欣药业集团恒欣药业有限公司 A kind of synthetic method of flupirtine maleate compound
CN110317166A (en) * 2018-03-29 2019-10-11 北京盈科瑞药物安全有效性研究有限公司 A kind of Flupirtine conjugate and its preparation method and application

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3481943A (en) * 1966-05-12 1969-12-02 Degussa Benzyl and pyridylmethyl substituted amido amino pyridines
US4673666A (en) * 1984-05-05 1987-06-16 Degussa Aktiengesellschaft 2-amino-3-ethoxycarbonylamino-6-(p-fluoro-benzylamino)-pyridine gluconate and pharmaceutical preparations containing it
WO2012004391A1 (en) * 2010-07-09 2012-01-12 K.H.S. Pharma Holding Gmbh Process for the preparation of flupirtine maleate
CN102850265A (en) * 2011-06-29 2013-01-02 陈小花 Flupirtine conjugate and preparation method and use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3481943A (en) * 1966-05-12 1969-12-02 Degussa Benzyl and pyridylmethyl substituted amido amino pyridines
US4673666A (en) * 1984-05-05 1987-06-16 Degussa Aktiengesellschaft 2-amino-3-ethoxycarbonylamino-6-(p-fluoro-benzylamino)-pyridine gluconate and pharmaceutical preparations containing it
WO2012004391A1 (en) * 2010-07-09 2012-01-12 K.H.S. Pharma Holding Gmbh Process for the preparation of flupirtine maleate
CN102850265A (en) * 2011-06-29 2013-01-02 陈小花 Flupirtine conjugate and preparation method and use thereof

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Investigation of the in vitro metabolism of the analgesic flupirtine;Karen Methling，等;《Drug Metabolism and Disposition》;20091231;第37卷(第3期);第479-493页 *
Isolation, identification and characterization of novel process-related impurities in flupirtine maleate;Dengfeng Zhang，等;《Journal of Pharmaceutical and Biological Analysis》;20131127;第90卷;第27-34页 *
Isolation, structure, synthesis and cytotoxicity of an unprecedented flupirtine dimer;Rene Csuk，等;《Zeitschrift fur naturforschung section B-A journal of chemical》;20121231;第67卷(第12期);第1297-1304页 *
Synthesis and Quantitative Structure-Activity Relationships of Anticonvulsant 2,3,6-Triaminopyridines;Joachim K. Seydel，等;《Journal of Medicinal Chemistry》;19941231;第37卷(第19期);第3016-3022页 *
第90卷.Isolation, identification and characterization of novel process-related impurities in flupirtine maleate.《Journal of Pharmaceutical and Biological Analysis》.2013,第90卷第27-34页. *

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