CN102002050B - Bisbenzylisoquinoline derivative and preparation and application thereof - Google Patents
Bisbenzylisoquinoline derivative and preparation and application thereof Download PDFInfo
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- CN102002050B CN102002050B CN2010105421047A CN201010542104A CN102002050B CN 102002050 B CN102002050 B CN 102002050B CN 2010105421047 A CN2010105421047 A CN 2010105421047A CN 201010542104 A CN201010542104 A CN 201010542104A CN 102002050 B CN102002050 B CN 102002050B
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Abstract
The invention relates to a bisbenzylisoquinoline derivative and preparation and application thereof. The derivative has high storage stability and is suitable for preparing medicaments for treating or preventing muscle relaxation, hypertension, amebic dysentery, antianaphylaxis, antipyresis, analgesis and the like of people and animals.
Description
Technical field
The present invention relates to medical technical field, specifically provide medicine---Bisbenzylisoquinolinderivative derivative and preparation thereof and the purposes of flaccidity etc.
Background technology
At present, disclosed document has only been reported Bisbenzylisoquinolincompounds compounds Dimethyltetrandrine Iodide (C
40H
48O
6N
2I
2, molecular weight: 906.63), up to the present, still do not have both at home and abroad disclosed bibliographical information to can be used in the medicine of non depolarization class flaccidity etc., i.e. Bisbenzylisoquinolincompounds compounds Dimethyltetrandrine Iodide crystalline hydrate [C
40H
48O
6N
2I
2NH
2O, n=1.0～4.0] and its production and use.
Summary of the invention
Involved in the present invention is Bisbenzylisoquinolinderivative derivative and preparation and purposes, furtherly, relates to the flaccidity medicine---Dimethyltetrandrine Iodide derivative and preparation thereof and purposes, i.e. Dimethyltetrandrine Iodide crystalline hydrate [C
40H
48O
6N
2I
2NH
2O, n=1.0～4.0, n can be 1.0,1.5,1.75,2,2.5,3.0,3.5,4 or the numeral between it] and its production and use.
The Dimethyltetrandrine Iodide that contains crystal water that the present invention obtains, surprisingly, the Dimethyltetrandrine Iodide that contains crystal water draws moist Dimethyltetrandrine Iodide far below containing non-crystallizable water, the Dimethyltetrandrine Iodide hydrate that contains crystal water than do not contain crystal water more can be stable existence, be convenient to store and transportation, and at room temperature have good water-solublely, be easy to make water miscible preparation.In addition, the deliquescence of anhydride is so that want secluding air to prevent adhesion etc. when processing, and hydrate has good sliding, thereby improves the operability of preparation.
Surprisingly, distinctive, has corresponding endotherm(ic)peak under the weightless platform of the heat analysis of hydrate of the present invention (TG-DSC or TG-DTA) collection of illustrative plates, the thermogram spectrum demonstrates the crystalline hydrate of Dimethyltetrandrine Iodide, such as its 1 hydrate, 1.75,2 hydrates, 3,3.5 hydrates etc.
Dimethyltetrandrine Iodide hydrate of the present invention is white or off-white color crystalline powder or plate crystal etc., can stable storage.Draw moist test by the Chinese Pharmacopoeia requirement: get Dimethyltetrandrine Iodide anhydride and the about 5g of hydrate of the present invention, place the watch-glass of dry constant weight, precise weighing, 25 ℃, relative humidity is 75%, respectively at test 0h and 48h sampling, the percentage of wet weightening finish is drawn in calculating, the result shows, anhydride draws moist all more much higher than hydrate of the present invention, the crystalline hydrate of Dimethyltetrandrine Iodide of the present invention is stable storage better, at RH75%, under 40 ℃ of conditions, the anhydride sample of the crystalline hydrate of Dimethyltetrandrine Iodide and Dimethyltetrandrine Iodide is carried out respectively 6 months accelerated stability test, chromatographic condition: chromatographic column: C in airtight and the cillin bottle
18(300mm * 4.6mm, 5 μ m), moving phase: acetonitrile-0.02mol/L ammonium dihydrogen phosphate (65: 35), detect wavelength 280nm, flow velocity 1ml/min measures the amplitude that related substance increases.
Illustrate that Dimethyltetrandrine Iodide hydrate of the present invention has better storage stability.The results are shown in Table 1～3.
Table 1. draws the wet test result
Sample time, (48 hours) were compared with 0 hour, weightening finish %
Dimethyltetrandrine Iodide 3.5 hydrates 0.06
Dimethyltetrandrine Iodide 3 hydrates 0.77
Dimethyltetrandrine Iodide 2 hydrates 1.82
Dimethyltetrandrine Iodide 1 hydrate 3.66
Dimethyltetrandrine Iodide anhydride 5.83
Table 2. accelerated stability test result
Compared with 0 month sample time (June), the multiple of related substance
Dimethyltetrandrine Iodide 3.5 hydrates 0.71
Dimethyltetrandrine Iodide 3 hydrates 0.62
Dimethyltetrandrine Iodide anhydride 1.36
The preparation of Bisbenzylisoquinolinderivative derivative---Dimethyltetrandrine Iodide crystalline hydrate comprises following method:
Method A: with sinomenine in reaction vessel, the low mass molecule alcohol that adds C1-C6, comprising methyl alcohol, ethanol, Virahol etc., the lower ketones of C3-C6, comprising acetone, butanone etc., the lower member ester of C2-C8, comprising N-BUTYL ACETATE, ethyl acetate, ethyl formate etc., the low replacement halohydrocarbon of C1-C6, comprise methylene dichloride, ethylene dichloride, chloroform etc., the rudimentary ether of C2-C6, comprising ether, methyl ethyl ether, isopropyl ether etc., straight or branched alkane or the naphthenic hydrocarbon of C5-C10 comprise pentane, normal hexane, sherwood oil, hexanaphthene etc., the aromatic hydrocarbon of C6-C10, comprise benzene, toluene etc., one or more in waiting, stirring makes dissolving, add methyl iodide, between 30-80 ℃ of the temperature of control, stirring reaction 0.2-5 hour, solvent is taken out in decompression, the residuum water, acetonitrile, the low mass molecule alcohol of C1-C6 comprises methyl alcohol, ethanol, Virahol etc., the lower ketones of C3-C6, comprising acetone, butanone etc., the lower member ester of C2-C8 is comprising N-BUTYL ACETATE, ethyl acetate, ethyl formate etc., the low replacement halohydrocarbon of C1-C6, comprise methylene dichloride, ethylene dichloride, chloroform, the rudimentary ether of C2-C6 comprises ether, methyl ethyl ether, isopropyl ether etc., straight or branched alkane or the naphthenic hydrocarbon of C5-C10, comprise pentane, normal hexane, sherwood oil, hexanaphthene etc., aromatic hydrocarbon, comprising benzene, one or more in the toluene, carry out crystallization, filter, drying gets the Dimethyltetrandrine Iodide crystalline hydrate; Its recrystallization process can carry out once arriving for several times as stated above.
Perhaps method B: Radix Stephaniae Tetrandrae Lorraine alkali in reaction vessel, is added the low mass molecule alcohol of C1-C6, comprise methyl alcohol, ethanol, Virahol etc.; The lower ketones of C3-C6 comprises acetone, butanone etc.; The lower member ester of C2-C8 comprises N-BUTYL ACETATE, ethyl acetate, ethyl formate etc.; The low replacement halohydrocarbon of C1-C6 comprises methylene dichloride, ethylene dichloride, chloroform etc.; The rudimentary ether of C2-C6 comprises ether, methyl ethyl ether, isopropyl ether etc.; Straight or branched alkane or the naphthenic hydrocarbon of C5-C10 comprise pentane, normal hexane, sherwood oil, hexanaphthene etc.; The aromatic hydrocarbon of C6-C10, comprise benzene, in the toluene etc. one or more, stirring makes dissolving, the solution that adds highly basic, the solution of highly basic can be the solution of low mass molecule alcohol of the water of sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood etc. or C1-C6 or low mass molecule alcohol and the mixing solutions of water or one or several of sodium methoxide solution of C1-C6, stir the lower methyl iodide that drips, between 20-80 ℃ of the control temperature, stirring reaction 0.5-6 hour, desolventizing is taken out in decompression, and the low mass molecule alcohol of residuum water, acetonitrile, C1-C6 is comprising methyl alcohol, ethanol, Virahol etc.; The lower ketones of C3-C6 is comprising acetone, butanone etc.; The lower member ester of C2-C8 is comprising N-BUTYL ACETATE, ethyl acetate, ethyl formate etc.; The low replacement halohydrocarbon of C1-C6 is comprising methylene dichloride, ethylene dichloride, chloroform etc.; The rudimentary ether of C2-C6 is comprising ether, methyl ethyl ether, isopropyl ether etc.; Straight or branched alkane or the naphthenic hydrocarbon of C5-C10 are comprising pentane, normal hexane, sherwood oil, hexanaphthene etc.; The aromatic hydrocarbon of C6-C10 comprises benzene, toluene etc., and one or more in waiting are carried out crystallization, filter, and drying gets the Dimethyltetrandrine Iodide crystalline hydrate; Its recrystallization process can carry out once arriving for several times as stated above.
The drying mode of product of the present invention can be in differing temps (such as 20-100 ℃), time of drying (1 hour to a few days) or with under the envrionment conditions of other siccative (comprising silica gel, Vanadium Pentoxide in FLAKES, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate etc.) or use the mode of normal pressure or decompression that last product is carried out drying.Its drying temperature is preferably at 40-60 ℃.
The crystallization of Dimethyltetrandrine Iodide hydrate or recrystallization solvent are selected from the low mass molecule alcohol of water, acetonitrile, C1-C6, comprise methyl alcohol, ethanol, Virahol; The lower ketones of C3-C6 comprises acetone, butanone; The lower member ester of C2-C8 comprises N-BUTYL ACETATE, ethyl acetate, ethyl formate; The low replacement halohydrocarbon of C1-C6 comprises methylene dichloride, ethylene dichloride, chloroform; The rudimentary ether of C2-C6 comprises ether, methyl ethyl ether, isopropyl ether; Straight or branched alkane or the naphthenic hydrocarbon of C5-C10 comprise pentane, normal hexane, sherwood oil, hexanaphthene; The aromatic hydrocarbon of C6-C10 comprises benzene, one or more in the toluene; The crystallization of Dimethyltetrandrine Iodide hydrate or recrystallization solvent, preferably water, methyl alcohol, ethanol, Virahol, one or more in acetone, butanone, ethyl acetate, methylene dichloride, chloroform, ether, isopropyl ether, the benzene.More preferably water, ethanol, Virahol, one or more in acetone, ethyl acetate, chloroform, ether, the isopropyl ether.
Dimethyltetrandrine Iodide crystalline hydrate of the present invention can have different crystal formations, for example, be that the X-ray powder diffraction of the Dimethyltetrandrine Iodide 1,2,3 for preparing of crystallization or recrystallization system, 3.5 hydrates can be different from methanol-water, alcohol-water or acetone-water.Its diffraction angle of Dimethyltetrandrine Iodide 3 hydrates 2 θ utilize the powder ray diffraction method to measure (3-80 °), in its useful range, are included in such as upper/lower positions about 7.35,14.7,18.2,18.8,19.3,20.0,21.2,22.3,24.8,25.4,26.1,27.9,28.4,30.1 35.6,37.1 grades can have corresponding eigenwert.Its diffraction angle of Dimethyltetrandrine Iodide 3.5 hydrates 2 θ utilize the powder ray diffraction method to measure (3-80 °), in its useful range, are included in such as upper/lower positions about 7.35,14.7,18.2,18.8,19.4,20.0,21.1,22.3,24.8,25.4,26.1,27.9,28.4,30.1,31.44 35.6,37.1 grades can have corresponding eigenwert.Its diffraction angle of Dimethyltetrandrine Iodide 1 hydrate 2 θ utilize the powder ray diffraction method to measure (3-80 °), in its useful range, are included in such as upper/lower positions about 7.35,14.8,18.2,18.9,19.3,20.0,21.2,22.3,24.8,25.4,26.1,27.9,28.4,30.1 35.5,37.1 grades can have corresponding eigenwert.The chromatographic retention of the crystalline hydrate among the present invention or the solution of the crystalline hydrate among the embodiment its main peak under same HPLC condition has consistence.
Dimethyltetrandrine Iodide hydrate purposes of the present invention: Dimethyltetrandrine Iodide hydrate of the present invention is for the preparation of injection freeze-dried powder or great transfusion preparation or little water needle injection, through the enterally administering preparation, comprise tablet, capsule, granule, solution etc.
Tablet, capsule, granule for the preparation of through the enterally administering preparation wherein can contain pharmaceutically acceptable weighting agent, such as starch, modified starch, lactose, Microcrystalline Cellulose, cyclodextrin, sorbyl alcohol, N.F,USP MANNITOL, calcium phosphate, amino acid etc.; Pharmaceutically acceptable disintegrating agent is such as starch, modified starch, Microcrystalline Cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, tensio-active agent; Pharmaceutically acceptable wetting agent and tackiness agent are such as gelling starch, methylcellulose gum, Xylo-Mucine, ethyl cellulose, polyvinylpyrrolidone, Lalgine and salt thereof; Pharmaceutically acceptable lubricant and glidant are such as stearic acid, Magnesium Stearate, Macrogol 4000-8000, talcum powder, micropowder silica gel, Stepanol MG etc.; Pharmaceutically acceptable sweeting agent and essence are such as aspartame, Sodium Cyclamate, soluble saccharin, Sucralose, food flavour etc.
Crystalline hydrate of the present invention is different from the deliquescence of anhydride so that want secluding air to prevent adhesion etc. when processing, and crystalline hydrate has good sliding, thereby improves the operability of preparation; And the solid preparation that makes preparation has good dissolving out capability, enters blood circulation so that it is absorbed easily, improves bioavailability, and is conducive to bring into play fast its effect.
Dimethyltetrandrine Iodide hydrate injection, its preparation method is:
The preparation method of freeze-dried powder is: get the Dimethyltetrandrine Iodide hydrate, can add pharmaceutically acceptable solubility promoter, frozen-dried supporting agent or auxiliary shape agent, stablizer, water for injection, stir and make dissolving, if need, available pharmaceutically acceptable acid-alkali accommodation pH is 4.0～7.5, adds activated carbon 0.005～0.5% (W/V) and stirs 15～45min, filters, moisturizing, sterile filtration is by 10～80mg/ bottle (in main ingredient) packing, lyophilize, tamponade gets finished product.
Dimethyltetrandrine Iodide hydrate injection with small volume and preparation technology thereof: the Dimethyltetrandrine Iodide hydrate injects water and pharmaceutically acceptable additives, for example: pharmaceutically acceptable pH adjusting agent, pharmaceutically acceptable oxidation inhibitor, rare gas element, the sterilization injection with small volume is made in filtration, degerming, and its pH value is between 3.7～7.5.
Its pharmaceutically acceptable pH adjusting agent can be pharmaceutically acceptable mineral acid or organic acid, mineral alkali or organic bases, also can be Lewis acid or the alkali of broad sense, can contain one or several, can be hydrochloric acid, phosphoric acid, propionic acid, acetic acid and acetate, such as sodium-acetate etc., lactic acid and lactic acid pharmaceutical salts, the Citric Acid pharmaceutical salts, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, phosphoric acid salt, tartrate and pharmaceutical salts thereof, borax, boric acid, Succinic Acid, caproic acid, hexanodioic acid, FUMARIC ACID TECH GRADE, maleic acid, the trihydroxy-aminomethane, diethanolamine, thanomin, α-amino isopropyl alcohol, diisopropanolamine (DIPA), 2-amino-2-(methylol) 1, ammediol amine, 1, the 2-hexanediamine, N-methyl grape amine, Diisopropylamine and their salt, multi-hydroxy carboxy acid and pharmaceutical salts are such as glucuronic acid, gluconic acid, lactobionic acid, oxysuccinic acid, threonic acid, glucoheptonic acid, in amino acid and the amino acid salts etc. one or several.
Its pharmaceutically acceptable oxidation inhibitor and stablizer can be sulfurous acid, sulphite, hydrosulphite, pyrosulfite, hyposulfite, thiosulphate, organosulfur compound thiocarbamide, gsh, dimercaprol dimercaptopropanol, Thiovanic acid and salt, thiolactic acid and salt, thio-2 acid and salt, phenol compound, such as gallic acid and salt, coffic acid, caffeiate, forulic acid, ferulate, di-t-butyl Pyrogentisinic Acid, 2,5-resorcylic acid, DHB salt, phenol or derivatives thereof, Whitfield's ointment or its salt; Amino acid with and salt; Xitix and ascorbate salt, saccharosonic acid and erythorbate, niacinamide, tartrate, nitrate, phosphoric acid salt, acetic acid pharmaceutical salts, Citrate trianion, EDTA and edta salt, such as in EDETATE SODIUM, EDTA four sodium, N-two (2-hydroxyethyl) glycine etc. one or several.
Its pharmaceutically acceptable solubility promoter can be glucose, Xylitol, sorbyl alcohol, N.F,USP MANNITOL, niacinamide, N-methyl grape amine, N-ethyl grape amine, phosphoric acid and pharmaceutically acceptable phosphoric acid salt (can be SODIUM PHOSPHATE, MONOBASIC, Sodium phosphate dibasic, sodium phosphate, potassium primary phosphate etc.), lactic acid, Sodium.alpha.-hydroxypropionate, Citric Acid, Sodium Citrate, multi-hydroxy carboxy acid and pharmaceutical salts are (such as glucuronic acid, gluconic acid, lactobionic acid, oxysuccinic acid, threonic acid, glucoheptonic acid etc. or its pharmaceutical salts), amino acid and amino acid salts (can be arginine, arginine hydrochloride, lysine hydrochloride etc.), hydrochloric acid, sulfuric acid, tartrate, polysorbas20-80, poloxamer (comprises Pluronic/Lutrol F 44,188,237,338,407 etc.), Macrogol 200-2000, ethanol, ethylene glycol, glycerol, glucosyl-cyclodextrin (G
1-CYD), (((SBE-β-CD) is such as (SBE for 3-HP-β-CYD), sulfobutyl ether-beta-cyclodextrin for 2-HP-β-CYD), 3-hydroxypropylβ-cyclodextrin for malt sugar group-beta-cyclodextrin, hydroxypropylβ-cyclodextrin, 2-hydroxypropylβ-cyclodextrin
7-β-CD), SBE
4In-β-CD etc. and the water etc. one or several.
Its pharmaceutically acceptable isotonic regulator can be one or more in glucose, fructose, Xylitol, sorbyl alcohol, N.F,USP MANNITOL, Nulomoline, maltose, dextran, sodium-chlor, Repone K, the Sodium.alpha.-hydroxypropionate etc.
Source and the degerming mode of reducing phlegm and internal heat can be the gac that adds dosing amount 0.005～3% source of reducing phlegm and internal heat, and millipore filtration degerming and pressure sterilizing also can adopt heat sterilization, the source of reducing phlegm and internal heat.In the hyperfiltration process, that ultra-fine filter can be selected is flat, rolling, tubular type, tubular fibre formula or circle boxlike etc., preferred rolling and tubular fibre formula ultra-fine filter, it is after 50,000 to 300,000 filter membrane is removed most of heat generation material and bacterium that relative molecular mass is held back in employing, adopt again the ultra-filtration membrane of holding back relative molecular mass 4000～30000 to remove the residue thermal source, the ultra-filtration membrane of preferred relative molecular mass 6000～30000.
Dimethyltetrandrine Iodide hydrate of the present invention, fundamental characteristics with Dibenzylisoquinolinealkaloids compound is applicable to prepare the application in the medicine of the needle anaesthesia, inflammation, neuropathic pain, hypertension, amebic dysentery, antianaphylaxis of muscle relaxant, Chinese drug anesthesia and the abdominal operation of humans and animals, analgesic, analgesic treatment or prevention.
The consumption usage: generally speaking, in the adult, each 0.3-1mg/kg does intravenous injection or instillation; Through gastrointestinal administration consumption usage: the human or animal of 10～70kg body weight, 10～100mg/ days generally speaking, minute 1-3 administration; Children's amount of reducing by half is above to be used.
Description of drawings
Fig. 1 is the thermogram spectrum of Dimethyltetrandrine Iodide 3 hydrates.
Fig. 2 is the thermogram spectrum of Dimethyltetrandrine Iodide 3.5 hydrates.
Fig. 3 is the thermogram spectrum of Dimethyltetrandrine Iodide 1 hydrate.
Test condition: the Setsys of Setaram company 16, NETZSCH STA449C, about sample size 5mg, heat-up rate: 10K/min, N
2Flow velocity: 50ml/min, temperature: be generally about room temperature～400 ℃.
Embodiment
The preparation of embodiment 1 Dimethyltetrandrine Iodide 3 hydrates restrains sinomenine 3 in the eggplant type flask of 250ml, adds chloroform 100ml, heating, stirs and makes dissolving, add methyl iodide 15ml, between 30-80 ℃ of the temperature of control, stirring reaction 0.2-3 hour, desolventizing is taken out in decompression, residuum carries out crystallization with ethanol 100ml, acetone 5ml, water 10ml, is cooled to below 15 ℃, places, treat that solid fully separates out, suction filtration, drying gets the Dimethyltetrandrine Iodide crystalline hydrate; With ethanol 100ml, acetone 5ml, water 10ml recrystallization, be cooled to below 15 ℃, place, treat that solid fully separates out suction filtration, dry, Dimethyltetrandrine Iodide 3 hydrates, about 60 ℃ of solids about dry 4-5 hour get off-white color crystallization 2.1g, fusing point: 235 ℃ of decomposition (not proofreading and correct), [α]
D 25:+179.5 ° of (CH
3OH, 25mg (dry product meter)/ml); Get the saturated aqueous solution of this product, add 2 of bismuth potassium iodide test solutions, produce orange precipitation; Drip the Tetraphenyl sodium borate test solution and produce white precipitate; Get this product 4mg and add water and make moltenly, add chloroform 2ml and hydrogen peroxide test solution number droplet, jolting, water layer produces yellow muddy, continues to add about hydrogen peroxide test solution 15ml, violent jolting, chloroform layer is rose; Ultraviolet: get this product, be dissolved in water and quantitatively dilution make the solution that contains 60 μ g among every 1ml, according to spectrophotometry, at the wavelength place of 224nm and 280nm maximum absorption is arranged, at the wavelength place of 258nm minimal absorption is arranged.Infrared spectra: ν
KBr MaxCm
-13446 (wide), 3002,2935,2837,2034,1611,1585,1509,1451,1422,1359,1322,1270,1238,1122,1077,1045,1019,979,923,839,811,528; ESI-MS:m/z:906; It is 6.06% that the Ka Shi method is measured moisture, and heat is analyzed: platform is weightless about 5.58%, and result's (theoretical value 5.63%) that this and sample contain 3 crystal water (sees accompanying drawing 1) in limit of error, ultimate analysis theoretical value: C 50.01%, H5.67%, I26.42%, N2.92%; Measured value: C 50.14%, H5.77%, I26.25%, N2.79%.Behind the present embodiment solid suction filtration, but the solid that takes a morsel gets its anhydride in vacuum-drying more than 80 ℃, in the presence of the Vanadium Pentoxide in FLAKES more than 48 hours.
The preparation of embodiment 2 Dimethyltetrandrine Iodides 3.5 hydrates with hanfangchin B 3g in the round-bottomed flask of 500ml, add methylene dichloride 100ml, heating, stirring makes dissolving, stir lower about 38% the aqueous solution that adds 0.35g potassium hydroxide, stir the lower methyl iodide 35ml that drips, between 20-70 ℃ of the control temperature, stirring reaction 2-5 hour, desolventizing, residuum methyl alcohol 30ml are taken out in decompression, water 100ml, ethyl acetate 2ml carries out crystallization, reactant is cooled to below 15 ℃, place, treat that solid fully separates out suction filtration, with crystallization methyl alcohol 30ml, ether 1ml, water 100-200ml carries out recrystallization, be cooled to below 15 ℃, place, treat that solid fully separates out, suction filtration, the crystallization of gained gets Dimethyltetrandrine Iodide 3.5 crystalline hydrate 1.5g, fusing point: 234 ℃ of decomposition (ELECTROTHERMAL MELTING POINT APPARATUS drying about 40 ℃ about 4 hours, do not proofread and correct), [α]
D 25:+180.6 ° of (CH
3OH, 25mg (dry product meter)/ml), UV spectrum: λ
H2O Min258nm, λ
H2O Max280nm; Infrared spectra: ν
KBr MaxCm
-13445 (wide), 3001,2935,2837,2034,1610,1584,1509,1450,1422,1359,1322,1270,1238,1122,1077,1045,1019,979,923,839,811,528; ESI-MS:m/z 906; It is 6.83% that the Ka Shi method is measured moisture, and heat is analyzed: platform is weightless about 6.36%, and result's (theoretical value 6.50%) that this and sample contain 3.5 crystal water (sees accompanying drawing 2) in limit of error, ultimate analysis theoretical value: C 49.54%, H5.72%, I26.17%, N2.89%; Measured value: C 49.36%, H5.62%, I26.35%, N2.97%.
The preparation of embodiment 3 Dimethyltetrandrine Iodides 1 hydrate in the eggplant type flask of 5g 500ml, adds methyl alcohol 100ml, methylene dichloride 100ml with sinomenine, heating, stirring makes dissolving, adds methyl iodide 25ml, between 30-66 ℃ of the temperature of control, stirring reaction 0.5-4 hour, desolventizing was taken out in decompression, and residuum carries out crystallization with methyl alcohol, isopropyl alcohol and water, be cooled to below 15 ℃, place, treat that solid fully separates out suction filtration, drying gets the Dimethyltetrandrine Iodide crystalline hydrate; With methyl alcohol, isopropyl alcohol and water recrystallization, be cooled to below 15 ℃, place, treat that solid fully separates out, suction filtration, gained solid be 60 ℃ of vacuum-dryings in the presence of Vanadium Pentoxide in FLAKES, get Dimethyltetrandrine Iodide 1 hydrate 3.1 grams, it is 2.29% that the Ka Shi method is measured moisture, and heat is analyzed: platform is weightless about 2.15%, and result's (theoretical value 1.95%) that this and sample contain 1 crystal water (sees accompanying drawing 3) in limit of error; [α]
D 25:+181.2 ° of (CH
3OH, 25mg/ml); UV spectrum: λ
H2O Min258nm, λ
H2O Max224nm, 280nm, (E
1% 1cm280nm is about 73.3); Infrared spectra: ν
KBr MaxCm
-13447 (wide), 3002,2935,2837,2034,1612,1586,1509,1452,1423,1359,1322,1270,1238,1122,1077,1045,1019,979,924,839,812,528; ESI-MS:m/z:906; Ultimate analysis: theoretical value: C 51.96%, H5.45%, I27.45%, N3.03%; Measured value: C 51.74%, H5.77%, I27.21%, N2.86%.
Embodiment 4 gets Dimethyltetrandrine Iodide hydrate 3g, with N.F,USP MANNITOL 5g, niacinamide 6g, EDETATE SODIUM 0.01g, add about 40-80 ℃ of water for injection 800ml, stirring makes molten, regulating pH with the citric acid about 1-5M and disodium phosphate soln is 4.0～7.8, adds activated carbon 0.01～0.5% (W/V) and stirs 15-30min, filters, add Sodium Pyrosulfite 0.8g, hold back the ultrafiltration membrance filter of relative molecular mass 6000～20000 with 0.22 micron filtering with microporous membrane or employing, by 10mg/ bottle or 30mg/ bottle or 60mg/ bottle (by anhydride) packing, vacuum lyophilization, tamponade gets finished product.
The preparation of embodiment 6 Dimethyltetrandrine Iodide hydrate injection liquids takes by weighing glucose 300g and adds in the water for injection, stirs and makes dissolve complete, adds the gac of dosing amount 0.5%, heats about 10-30 minute, through the sand stick filtering decarbonization; Dimethyltetrandrine Iodide hydrate (in Dimethyltetrandrine Iodide) 9g and above-mentioned filtrate are mixed, add biphosphate sodium 10g, hydrochloric acid Cys 1g, S-WAT 1g, EDETATE SODIUM 0.1g, behind the dissolve complete, inject water to 3000ml, regulate the pH value in the scope of 3.7-6.0 with 1-3M hydrochloric acid or lactic acid or citric acid and sodium citrate solution, the gac that adds dosing amount 0.05%, about heated and stirred 10-30 minute, filtering decarbonization, hold back the ultrafiltration membrance filter one of relative molecular mass 6000～30000 to twice through the smart filter of 0.22um millipore filtration or employing again, the logical high pure nitrogen of solution is saturated, check work in-process content, pH value and clarity etc., qualified rear solution is by 10,30mg or 60mg/ prop up embedding, sterilization is packed and be get final product.
The preparation of embodiment 7 Dimethyltetrandrine Iodide hydrate sodium-chlor transfusion: with Dimethyltetrandrine Iodide hydrate (by anhydride) 10g, sodium-chlor 425g, Sodium Pyrosulfite 5g, EDETATE SODIUM 0.6g, add in the water for injection, stirring makes dissolve complete, the logical high pure nitrogen of solution is saturated, regulate the pH value in the scope of 4.0-6.5 with citric acid soln and liquor sodii citratis, inject water to 50000ml, the gac that adds dosing amount 0.05%, about heated and stirred 10-30 minute, filtering decarbonization, the ultrafiltration membrance filter of holding back relative molecular mass 6000～20000 through the filter of film essence or the employing of 0.22um again through the work in-process chemical examination, is treated its content, after pH value and clarity are qualified, under high pure nitrogen, can is in 50ml or 100ml bottle or plastics bag, and sterilization is packed and be get final product.
Embodiment 8 Dimethyltetrandrine Iodides, 3 hydrate sheets or capsule (30mg/ grain)
Prescription: Dimethyltetrandrine Iodide 3 hydrate 30g
Microcrystalline Cellulose 65g
Sodium starch glycolate 5g
5%PVP-K30 (50% aqueous ethanolic solution) is an amount of
Magnesium Stearate 2g
Dimethyltetrandrine Iodide 3 hydrates, Microcrystalline Cellulose, sodium starch glycolate are crossed 100 mesh sieves, mixing, 50% aqueous ethanolic solution with 5%PVP-K30 is tackiness agent softwood processed in right amount, crossing the 18-24 mesh sieve granulates, dry, after crossing the whole grain of 14-20 mesh sieve, add Magnesium Stearate and mix compressing tablet or can capsule.
Embodiment 9 Dimethyltetrandrine Iodides, 1 hydrate sheets (30mg/ sheet)
Prescription: Dimethyltetrandrine Iodide 1 hydrate 30g
Lactose 165g
Sodium starch glycolate 5g
5% Vltra tears is an amount of
Magnesium Stearate 2g
Dimethyltetrandrine Iodide 3 hydrates, lactose, sodium starch glycolate are crossed 100 mesh sieves, mixing, 50% aqueous ethanolic solution with 5% Vltra tears is tackiness agent softwood processed in right amount, crossing the 18-24 mesh sieve granulates, dry, after crossing the whole grain of 14-20 mesh sieve, add Magnesium Stearate and mix compressing tablet.
Prescription: Dimethyltetrandrine Iodide hydrate 50g (in anhydride)
N.F,USP MANNITOL 155g
Lactose 20g
Sodium starch glycolate 5g
Solid edible essence 1g
5% Vltra tears is an amount of
Dimethyltetrandrine Iodide hydrate, N.F,USP MANNITOL, lactose, sodium starch glycolate, food flavour are crossed 100 mesh sieves, mixing, 50% aqueous ethanolic solution of the Vltra tears with 5% is tackiness agent softwood processed in right amount, crossing the 18-24 mesh sieve granulates, dry below 60 ℃, after crossing the whole grain of 14-20 mesh sieve, minute packing.
Embodiment 11
Pharmacology test is as follows:
Rabbit head-dropping tests: get 6 of rabbit, quiet notes Dimethyltetrandrine Iodide 3 hydrates of the present invention or Dimethyltetrandrine Iodide 3.5 hydrates or Dimethyltetrandrine Iodide 2 hydrates or Dimethyltetrandrine Iodide 1 hydrate 1-1.5mg/kg, all namely hung one's head in visible 30 seconds to 1 minute, four limbs are that abdominal muscles is lax, recover about average ten minutes, enliven as usual.
Rabbit is tested at the body tibialis anterior: get 6 of rabbit, anaesthetize with urethane respectively, it is front neural to isolate shin, with neural before the rectangular pulse stimulator super-strong stimulus shin, per minute 6 times, ripple is wide 0.2 millisecond, record tibialis anterior meat shrinkage curve, find quiet notes Dimethyltetrandrine Iodide 3 hydrates of the present invention or Dimethyltetrandrine Iodide 3.5 hydrates or Dimethyltetrandrine Iodide 2 hydrates or Dimethyltetrandrine Iodide 1 hydrate 6mg/kg, its tibialis anterior shrinks fully and suppresses, and continues recovery in about 40 minutes.
Be appreciated that from this professional angle the variation of a lot of details is possible, therefore this do not limit the scope of the invention and spirit, and the present invention is not limited to above-described embodiment.
Claims (7)
1. Bisbenzylisoquinolinderivative derivative, it is characterized in that: Bisbenzylisoquinolinderivative derivative is the Dimethyltetrandrine Iodide hydrate, its molecular formula is C
40H
48O
6N
2I
2NH
2O, n=1.0,3.0,3.5.
2. Bisbenzylisoquinolinderivative derivative claimed in claim 1, it is characterized in that: Bisbenzylisoquinolinderivative derivative is Dimethyltetrandrine Iodide 3 hydrates.
3. Bisbenzylisoquinolinderivative derivative claimed in claim 1, it is characterized in that: Bisbenzylisoquinolinderivative derivative is Dimethyltetrandrine Iodide 3.5 hydrates.
4. Bisbenzylisoquinolinderivative derivative claimed in claim 1, it is characterized in that: Bisbenzylisoquinolinderivative derivative is Dimethyltetrandrine Iodide 1 hydrate.
5. the preparation method of Bisbenzylisoquinolinderivative derivative claimed in claim 1, it is characterized in that: the preparation method comprises:
Method A: with sinomenine in reaction vessel, the low mass molecule alcohol of adding C1-C6, the low replacement halogen of C1-C6 replace one or more in the hydrocarbon, stir and make dissolving, add methyl iodide, between 30-80 ℃ of the control temperature, stirring reaction 0.2-5 hour, solvent was taken out in decompression, and residuum adds one or more in the rudimentary ether of lower member ester, C2-C6 of lower ketones, the C2-C8 of low mass molecule alcohol, the C3-C6 of entry, C1-C6, carry out crystallization, filter, drying gets the Dimethyltetrandrine Iodide crystalline hydrate; Its recrystallization process can carry out once arriving for several times as stated above;
Perhaps method B: with hanfangchin B in reaction vessel, the low mass molecule alcohol that adds C1-C6, the low replacement halogen of C1-C6 replaces one or more in the hydrocarbon, stirring makes dissolving, the solution that adds highly basic, the solution of highly basic is sodium hydroxide, potassium hydroxide, yellow soda ash, the mixing solutions of the solution of the water of salt of wormwood or the low mass molecule alcohol of C1-C6 or the low mass molecule alcohol of C1-C6 and water, or one or several of sodium methoxide solution, stir the lower methyl iodide that drips, between 20-80 ℃ of the control temperature, stirring reaction 0.5-6 hour, desolventizing is taken out in decompression, the residuum water, the low mass molecule alcohol of C1-C6, the lower ketones of C3-C6, the lower member ester of C2-C8, in the rudimentary ether of C2-C6 one or more, carry out crystallization, filter, drying gets the Dimethyltetrandrine Iodide crystalline hydrate; One or more recrystallizations in the lower member ester of the low mass molecule alcohol of gained solid water, acetonitrile, C1-C6, the lower ketones of C3-C6, C2-C8, the rudimentary ether of C2-C6 filter, and drying gets the Dimethyltetrandrine Iodide hydrate.
6. the purposes of Bisbenzylisoquinolinderivative derivative claimed in claim 1 is characterized in that: for the preparation of injection freeze-dried powder or great transfusion preparation or little water needle injection or through the application of gastrointestinal administration preparation.
7. the purposes of Bisbenzylisoquinolinderivative derivative claimed in claim 1 is characterized in that: the medicine that is applicable to prepare the needle anaesthesia of muscle relaxant, Chinese drug anesthesia and the abdominal operation of humans and animals, hypertensive treatment or prevention.
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| CN2010105421047A CN102002050B (en) | 2009-11-02 | 2010-11-02 | Bisbenzylisoquinoline derivative and preparation and application thereof |
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Non-Patent Citations (2)
| Title |
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| 应诗达等.汉肌松持续控制性降压期的血流动力及呼吸动力的观察.《山东医科大学学报》.1991,第29卷(第3期),222-226. * |
| 张灿等.双苄基异喹啉季铵类化合物的合成及肌肉松弛活性.《中国药科大学学报》.2001,第32卷(第6期),403-407. * |
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