CN105566316A - Dibenzo quinolizine compound entity and application thereof - Google Patents
Dibenzo quinolizine compound entity and application thereof Download PDFInfo
- Publication number
- CN105566316A CN105566316A CN201410553630.1A CN201410553630A CN105566316A CN 105566316 A CN105566316 A CN 105566316A CN 201410553630 A CN201410553630 A CN 201410553630A CN 105566316 A CN105566316 A CN 105566316A
- Authority
- CN
- China
- Prior art keywords
- rotundine
- hydrochloride
- dibenzoquinolizine
- hydrate
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Dibenzo quinolizine compound entity has relatively low hygroscopicity and relatively high storage stability, and is applicable to preparation of analgesic, sedative, hypnotic and tranquillizing medicines, medicines for treating hypertension, arrhythmia and functional dyspepsia, stopping cough, resisting schizophrenia and heroin and other drug dependence, reversing tumor cell drug resistance and delaying or reducing myocardial ischemia reperfusion injury, calcium antagonists, and medicines for protecting the liver and preventing visceral implicated reaction and other effects, which are applied to humans or animals.
Description
Technical field
The present invention relates to medical art, be specifically to provide and there is analgesia, calmness, hypnosis, stable, treatment hypertension, anti-arrhythmia, functional dyspepsia, cough-relieving, antipsychotic, drug rehabilitation, reversing tumor cellular drug resistance, delay or the dibenzoquinolizine alkaloid compound entity alleviating the effects such as myocardial ischemia-reperfusion injury and uses thereof---rotundine hydrochloride crystalline hydrate and preparation thereof and purposes.
Background technology
The polymorphic of chemicals has critical role in drug research.In field of pharmacology, the research range that scientific and technological key special subjects formulated by country's 12 great new drugs has been listed in the research work of drug crystal forms and drug hydrate or drug solvent compound.The solvated compounds of compound comprises hydrate many being produced and applying in medicine very early, the antitumor drug endoxan normal temperature that for example American Pharmacopeia 36 editions, European Pharmacopoeia 6.1 editions and Chinese Pharmacopoeia 2010 editions record exists with monohydrate form at solid, this chemical entities just starts to lose crystal water at about 40 DEG C, and about 72 DEG C just lose whole crystal water.Since nearest two more than ten years, be not only the crystal formation with same molecular formula medicine and be constantly found, and there is same parent but the research of differing molecular formula drug solvent compound also constantly obtains new progress.Even adjustment hypoglycemic medicament dapagliflozin is all the pharmaceutical preparation of core with dapagliflozin propylene glycol hydrate in research, and this antidiabetic medicine dapagliflozin not only containing water, but also contains organic solvent propylene glycol.This is a solvated compounds containing two molecule organic solvents, although the toxicity of propylene glycol is greater than water.
Heat analysis method has important value and status in Materials science, chemistry or pharmaceutical analysis etc., can be used for separately the change (Li Zengyu of crystal formation in the polymorphic of detection compound or process, " thermal analyses ", press of Tsing-Hua University, in August, 1987 first version).Differential thermal analysis (DTA) is the analytical procedure comparatively commonly used, and it both can be used for the qualitative identification of material, also can be used for quantitative analysis, in the international thermal analyses meeting of Second Committee of nineteen sixty-eight, is just used for identifying unknown compound by Barta etc.The pharmacopeia of external many countries records differential thermal analysis already, and the method especially has unique advantage for the discriminating of the same compound of tool different crystal forms.Before more than ten years, differential thermal analysis is not only just widely applied in chemical industry, pharmacy system in China, and also starts to apply (Zhang Hanming in the identification of Chinese materia medica of complexity, Deng, the differential thermal analysis research of pearl powder and adulterant thereof, Chinese patent medicine, 1999,21 (4): 173-175).In crystal formation research, differential scanning (DSC) can complete multinomial research (application of Zhu Bing, Liu Ji great waves .DSC in pharmaceutical analysis, the process industries such as pharmaceutical purity assessment, discriminating, polycrystalline state analysis, 2008,15:64-66), (Lin Kejiang, Chen Wei, You Qidong. DETECTION OF CRYSTAL POLYMORPHS OF NATEGLINIDE BY DSC, Acta Pharmaceutica Sinica, 2002,37 (1): 46-49).And the polymorphic of medicine not could be prepared in rare or expensive solvent, can the polymorphic (Du Qing of unexpected acquisition compound by conventional solvent, temperature, time etc. or other trickle change, its energy flat. the polymorphic research of Travin, China Medicine University's journal, 2000,31 (2): 102-104).In thermal analyses field, the coupling of TG-DTA or TG-DSC brings more facility to especially the analysis of compound.
Rotundine hydrochloride system dibenzoquinolizine alkaloid compound, rotundine hydrochloride has analgesia, calmness, hypnosis, stabilizes, treats drug dependence, drug rehabilitation, the reversing tumor cellular drug resistance such as hypertension, anti-arrhythmia, functional dyspepsia, cough-relieving, antipsychotic, treatment heroine, delays or alleviate myocardial ischemia-reperfusion injury, calcium antagonist, hepatoprotective effect, prevents internal organ from involving the effects such as reaction.At present disclosed document only reports the pharmacology of rotundine hydrochloride and parent compound Rotundine and clinical application situation etc., as reference: document 1, Min Qing, etc., left-handed Tetrahydropalmatine to the effect of Experimental Hepatic Injuries, and Pharmacology and Clinics of Chinese Materia Medica 2006; 22 (3,4) 99; Document 2, Du Yuandong, Zhao Yuzhen, the pharmacological action of Rotundine and clinical application research progress, northwest pharmaceutical journal, 2012,27 (1): 91-93; Document 3, Zhao Na, etc., the applied research progress of rotundin in treatment of drug addiction, Chinese Journal of Drug Dependence, 2011,20 (1): 8-12; Document 4, Pang Jun, Zhou Xin, the Therapeutic effect of Rotundin treating cough in children, special journal is cured in Heze, and 1999,11 (3): 39; Document 5, Wang Yunjiao, etc., the experimental study of Rotundine Tablet analgesia, sedative effect, Chinese medicinal materials, the 29th volume the 7th phase in 2006, p713-714; Document 6, Sun Liaodong, Sun Yingguo, Rotundine treatment tachyarrhythmia 76 example, Chinese Journal of New Drugs and Clinical Remedies, 1999,18 (3): 185-186; Deng.But up to the present, still there is no disclosed bibliographical information rotundine hydrochloride crystalline hydrate of the present invention and its production and use both at home and abroad.
Summary of the invention
Involved in the present invention is has the drug dependence such as analgesia, calmness, hypnosis, stable, treatment hypertension, anti-arrhythmia, functional dyspepsia, cough-relieving, antipsychotic, treatment heroine, drug rehabilitation, reversing tumor cellular drug resistance, delays or alleviates myocardial ischemia-reperfusion injury, calcium antagonist, hepatoprotective effect, the dibenzoquinolizine alkaloid compound that prevents from internal organ from involving reaction etc. acting on, i.e. rotundine hydrochloride crystalline hydrate and preparation thereof and purposes, its molecular formula is C
21h
25nO
4hClnH
2o, wherein, n=0.50,0.75 etc.
The rotundine hydrochloride crystalline hydrate that the present invention obtains, surprisingly, drawing of rotundine hydrochloride containing crystal water is moist far below rotundine hydrochloride anhydride, rotundine hydrochloride hydrate containing crystal water more can be stable than rotundine hydrochloride anhydride existence, be convenient to store and transport, be easy to make preparation.In addition, the deliquescence of anhydride makes will to completely cut off air when processing and prevents adhesion etc., and crystalline hydrate has good sliding, thus improves the operability of preparation.Moreover crystalline solid has chemical stability higher than amorphous form and low-crystallinity form and physical stability, they also can show as the water absorbability of raising, bulk properties and or mobility.
Surprisingly, distinctive, thermal analyses (TG-DSC or the TG-DTA etc.) collection of illustrative plates of crystalline hydrate of the present invention demonstrates the endotherm(ic)peak that weightless platform has strong correspondence, and thermal analyses collection of illustrative plates demonstrates rotundine hydrochloride crystalline hydrate [C
21h
25nO
4hCl0.5H
2o, C
21h
25nO
4hCl0.75H
2o] etc., match by Karl_Fischer method mensuration moisture result and thermal analyses result.
Even if the preparation of the different crystal forms of same compound or acquisition, pharmacology all has the potential or following meaning of reality or value, say nothing of be the acquisition of the different crystalline hydrate of same medicine to pharmacology all having the potential or following meaning of reality or value, the research range that scientific and technological key special subjects formulated by country's 12 great new drugs has been listed in the work of related drugs crystal and drug crystallization hydrate.The discovery of the useful compound on the medicine of new crystal provides new chance once improving the action characteristic of medicament production, it expands the storehouse of formulation science man design example as the pharmaceutical dosage form and the material obtained with the medicine of targeted release profile or other desired characteristic, the construction in the storehouse of the compound of medicine is extremely important, be not only comparative study to use, the crystalline hydrate that this area needs rotundine hydrochloride new or its new crystalline form.
Rotundine hydrochloride crystalline hydrate of the present invention, for off-white color or or yellowish crystallization, can stable storage.Rotundine hydrochloride crystalline hydrate and anhydride sample are carried out drawing moist test: get rotundine hydrochloride anhydride and hydrate of the present invention is about 2g, be placed in the watch-glass of dry constant weight, precise weighing, 25 DEG C, relative humidity is 65%, respectively at test 0h and 12h sampling, calculate the percentage drawing wet weightening finish, result shows, anhydride draws and moistly has significant difference than crystalline hydrate of the present invention, and rotundine hydrochloride crystalline hydrate of the present invention stable storage can the results are shown in Table 1 better.As can be seen here, rotundine hydrochloride crystalline hydrate of the present invention, can stable storage.Above-mentioned rotundine hydrochloride crystalline hydrate matter sample is enclosed within the cillin bottle of shading the accelerated stability test carried out 6 months respectively, with reference to the content assaying method of 2010 editions Chinese Pharmacopoeias two of rotundine hydrochloride, the rotundine hydrochloride crystalline hydrate that mensuration various embodiments of the invention 1, embodiment 3 legal system are standby, have been surprisingly found that, before and after experiment, the content of rotundine hydrochloride crystalline hydrate of the present invention does not have considerable change (40 DEG C, RH75%).
Table 1. draws wet test result
Dibenzoquinolizine alkaloid compound---rotundine hydrochloride crystalline hydrate is preparation method comprise:
Method A. takes Rotundine or Rotundine solvate, and (weight unit gram, g) is added in a reaction vessel, adds water, the C of 2-20 times amount (envelope-bulk to weight ratio=ml:g)
1-C
6low mass molecule alcohol in one or more in in reaction vessel, add hydrochloric acid soln or logical hydrogen chloride gas under stirring, stir, below regulator solution pH to 4.0, place, cooling, abundant precipitation to be precipitated, filtration, by the cold C of gained solid
1-C
6low mass molecule alcohol, C
2-c
6low molecule nitrile, C
3-C
8low molecule ketone, C
2-C
8low molecule ether, C
2-C
8one or more washing gained solids in low molecule ester, filter, dry, obtain isoquinoline compound of the present invention---rotundine hydrochloride crystalline hydrate.
Or by Rotundine or Rotundine solvate, (weight unit gram, g) is added in a reaction vessel method B., adds water, the C of 2-20 times amount (envelope-bulk to weight ratio=ml:g) wherein
1-C
6low mass molecule alcohol in one or more, add hydrochloric acid soln or logical hydrogen chloride gas under stirring, be stirred to dissolve, make below solution ph to 4.0, in filtrate, add C
1-C
6low mass molecule alcohol, C
2-C
6low molecule nitrile, C
3-C
8low molecule ketone, C
2-C
8low molecule ether, C
2-C
8in low molecule ester one or more, place, cooling, crystallization is fully separated out, filter, with cold C
1-C
6low mass molecule alcohol, C
2-C
8low molecule ether in one or more washing solids, filter, obtain solid, by gained solid water and C
1-C
6low mass molecule alcohol, C
2-c
6low molecule nitrile, C
3-C
8low molecule ketone, C
2-C
8low molecule ether, C
2-C
8one or more in low molecule ester, carry out one or many recrystallization, filter, and washing is dry, obtains dibenzoquinolizine compounds of the present invention---rotundine hydrochloride crystalline hydrate.
One or more preferably in: water and methyl alcohol, ethanol, Virahol, acetonitrile, ether, isopropyl ether, acetone, hexone, ethyl acetate of the crystallization of product of the present invention or recrystallization solvent.
Lower alcohol in the present invention or the carbonatoms of low mass molecule alcohol are defined as C
1-C
6(that is: the alcohol of 1-6 carbon atom), as methyl alcohol, ethanol, Virahol, butanols etc.; The carbonatoms of the rudimentary nitrile of 2-6 carbon atom is defined as C
2-C
6, as acetonitrile, propionitrile etc.; The low molecule ketone of the ketone of 3-8 carbon atom is defined as C
3-C
8, comprise acetone, butanone, pentanone, hexanone, hexone etc.; Rudimentary ether or the low molecule ether of 2-8 carbon atom are defined as C
2-C
8, as ether, isopropyl ether, butyl ether etc.; The low molecule ester of 2-8 carbon atom is defined as C
2-C
8, as ethyl acetate, propyl acetate, butylacetate etc.; Be described as " low molecule ", " rudimentary " as long as the marking method of the amount of carbon atom of compound occurs once in the text of the application about any class, other any unmarked carbonatoms being described as the similar compound of " low molecule " is consistent with the quantity indicated herein.
The drying mode of product of the present invention can be differing temps (as 10-60 DEG C), time of drying (as, 0.5 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 to carry out drying to last product.Its drying temperature preferably 60 DEG C or within, more preferably at about 35-50 DEG C.
The preparation of rotundine hydrochloride anhydride can be obtained through different drying meanss by crystalline hydrate of the present invention, its preparation can in differing temps (as 25-100 DEG C, preferred 40-80 DEG C), time of drying (a few hours are to a few days), or (comprise silica gel with other siccative, molecular sieve, Vanadium Pentoxide in FLAKES, sodium hydroxide, anhydrous sodium carbonate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous magnesium sulfate etc.) envrionment conditions under, or and use the mode of normal pressure or decompression to carry out drying to last product, also first the method for placing a few days process or distillation band water can be mixed by dry-out benzene, and obtain in conjunction with after other drying means drying described herein.
The assay of rotundine hydrochloride with reference to 2010 editions Chinese Pharmacopoeias two the content assaying method of rotundine hydrochloride.The moisture determination of compound of the present invention adopts Karl_Fischer method, uses methyl alcohol and methane amide etc. to be solvent.
Powder X-ray diffraction can be used to characterize and/or differentiate polymorph usually, for powder X-ray diffraction when characterizing and/or differentiate, before report peak value, uses modifier " about ".In view of the intrinsic change of peak value, this is the practice of solid-state chemical arts.The usual accuracy of the 2 θ x-axle values at powder collection of illustrative plates peak in ± 0.2 ° of 2 θ rank, therefore, so that " the powder X-ray diffraction peak that about 8.0 ° of 2 θ occurs means when measuring on most of x-ray diffractometer, and peak may between 7.8 ° of 2 θ and 8.2 ° of 2 θ.The change of peak intensity is each crystal result relative to external X-ray source how orientation in sampling receptacle, and orientation effect does not provide the structural information about crystal.
The present invention on the one hand, provides different crystalline hydrates or the polymorphic of rotundine hydrochloride.
The present invention on the one hand, provides the different new crystal of rotundine hydrochloride crystalline hydrate.
The present invention on the other hand, the preparation method of the crystalline hydrate providing rotundine hydrochloride different.
The present invention provides a kind of medicinal compositions on the other hand, comprising any one or the multiple rotundine hydrochloride hydrate prepared by method of the present invention, and the acceptable vehicle of one or more pharmacy, diluent or carrier composition.
The crystalline hydrate of rotundine hydrochloride prepared by the embodiment of the present invention 1 and embodiment 2 is thinner powder, and the crystalline hydrate of rotundine hydrochloride prepared by embodiment 3 and embodiment 4 is particulate state, respectively have feature at different aspects such as mobility, the preparation research for future provides more selection.
The present invention further provides the method for useful in preparing drug formulations, comprising the merging of any one or the multiple rotundine hydrochloride hydrate prepared by method of the present invention and at least one or the acceptable vehicle of pharmacy.
The present invention further provides rotundine hydrochloride hydrate, for the preparation for the treatment of people or mammiferous analgesia, calmness, hypnosis, stable, treatment hypertension, anti-arrhythmia, functional dyspepsia, cough-relieving, antipsychotic, drug rehabilitation, reversing tumor cellular drug resistance, delay or alleviate the purposes in the pharmaceutical composition of the treatments such as myocardial ischemia-reperfusion injury or prevention.The defect that the relative human body of rotundine hydrochloride hydrate of the present invention absorbs Rotundine, advantageously.
Rotundine hydrochloride crystalline hydrate of the present invention, its purposes is, for the preparation of the application on the medicinal compositions containing rotundine hydrochloride crystalline hydrate, this medicinal compositions contains the vehicle, the diluent or carrier that pharmaceutically accept; This medicinal compositions can show as on pharmaceutical dosage forms, in preparation injection freeze-dried powder or little water needle injection, great transfusion preparation, application on gastrointestinal administration preparation, dosing eyes preparation, solid preparation or be selected from tablet, capsule, granule, pill, soft capsule through gastrointestinal administration preparation, dosing eyes preparation comprises eye drop and gel for eye use etc.
The solid preparation of rotundine hydrochloride hydrate of the present invention comprises tablet, capsule, granule, pill etc.; Tablet (comprising ordinary tablet, buccal tablet, fast disintegrating tablet, effervescent tablet etc.), capsule (comprising capsule for vagina), granule, wherein can contain pharmaceutically acceptable weighting agent, as starch, modified starch, lactose, Microcrystalline Cellulose, cyclodextrin, sorbyl alcohol, N.F,USP MANNITOL, calcium phosphate, amino acid etc.; Pharmaceutically acceptable disintegrating agent, as starch, modified starch, Microcrystalline Cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, tensio-active agent (sodium lauryl sulphate etc.); Pharmaceutically acceptable wetting agent and tackiness agent, as gelling starch, methylcellulose gum, Xylo-Mucine, ethyl cellulose, polyvinylpyrrolidone, Lalgine and salt thereof; Pharmaceutically acceptable lubricant and glidant, as stearic acid, Magnesium Stearate, Macrogol 4000-8000, talcum powder, micropowder silica gel, Stepanol MG etc.; Pharmaceutically acceptable sweeting agent and essence, as aspartame, Sodium Cyclamate, soluble saccharin, Sucralose, food flavour etc.
Obtaining composition for the preparation of tablet or capsule filling can by wet granulation in preparation, in wet-granulation process, the activeconstituents of some or all or the vehicle of powder type mixed, and then mix further under the existence of liquid, this causes powder grumeleuse to become particle.This particle is sieved and or grinding, dry, then sieve, to the granularity expected, then this particle can make tablet, or before preparation, add other vehicle, such as glidant and/or lubricant.The tablet, capsule, granule, pill, soft capsule etc. of product of the present invention, the weight ratio of its main ingredient and auxiliary material can be the auxiliary material composition of 1 part of main ingredient and 0.5-10 part weight.
The composition being prepared into tablet can be prepared by being dry mixed usually.Such as, the composition after activeconstituents and mixed with excipients can be compacted into as small pieces or thin slice, and be then ground into the particle of compacting, the particle of this compacting can be suppressed into tablet subsequently.
Substituting as dry granular method, mixed composition can dry method direct compression, direct compression obtain evenly tablet.The vehicle being particularly suitable for direct compression comprises Microcrystalline Cellulose, spray-dired lactose calcium phosphate and colloid silica.These and other vehicle is proper use of in direct compression is be known to the technician in this area with experience and technical ability.Country's 2010 editions standards of pharmacopoeia with reference to rotundine hydrochloride sheet measure the content of the rotundine hydrochloride in embodiment 8 and embodiment 9, find its content all between the 90-110% of the labelled amount shown in embodiment.
Capsule filling of the present invention can comprise any above-mentioned mixture and particle or particle, and it describes with reference to being prepared into tablet, but they do not carry out the last step being prepared into tablet.
Prepared by pill: be dissolved in by the product of the present invention of 1 part of weight in the pharmaceutically acceptable matrix of the melting of 1-10 part weight, fully stir evenly, prepare dripping pill with dropping method in refrigerant, throw away the refrigerant, be drying to obtain dripping pill.Pharmaceutically acceptable matrix of the present invention comprises and is singly not limited to poloxamer, glycogelatin, S40, stearic acid, stearyl alcohol, hexadecanol, single stearic acid glycerine lipoprotein, polyethylene glycol 6000, Macrogol 4000 etc.; Refrigerant includes but not limited to dimethyl silicone oil, vegetables oil, whiteruss, ethanol, water etc.
The deliquescence that crystalline hydrate of the present invention is different from anhydride makes will to completely cut off air when processing and prevents adhesion etc., and crystalline hydrate has good sliding, thus improves the operability of preparation; Rotundine hydrochloride hydrate than the good water solubility of Rotundine, and makes the solid preparation of preparation be conducive to having good dissolving out capability, makes it easily be rapidly absorbed into blood circulation, improves bioavailability, and is conducive to its effect of fast onset.
Its preparation method can be: added by rotundine hydrochloride hydrate in appropriate water for injection, stir, make dissolving, add oxidation inhibitor, sanitas, osmotic pressure regulator, stablizer, pH adjusting agent, water, stir, become solution shape, make pH=3.0-7.0, filter in the mode such as millipore filtration or ultrafiltration, detect, aseptic subpackaged in sterilized clean plastics eyedrops bottle and get final product.
Rotundine hydrochloride hydrate injection, its preparation method is:
Rotundine hydrochloride hydrate injection with small volume and preparation technology thereof: rotundine hydrochloride hydrate injects with water and pharmaceutically acceptable additives, such as: pharmaceutically acceptable pH adjusting agent, pharmaceutically acceptable oxidation inhibitor, rare gas element, filter, degermingly make sterilizing injection with small volume, its pH value is between 3.0 ~ 7.0.
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, one or several can be contained, can be hydrochloric acid, phosphoric acid, acetic acid and acetate, as sodium-acetate etc., lactic acid and lactic acid pharmaceutical salts, Citric Acid pharmaceutical salts, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, phosphoric acid salt, tartrate and pharmaceutical salts thereof, borax, boric acid, succinic acid, caproic acid, hexanodioic acid, trans or maleic acid, trihydroxy-aminomethane, diethanolamine, thanomin, diisopropanolamine (DIPA), 2-amino-2-(methylol) 1, ammediol amine, 1, 2-hexanediamine, N-methyl glucose amine, Diisopropylamine and their salt, multi-hydroxy carboxy acid and pharmaceutical salts, as glucuronic acid, gluconic acid, lactobionic acid, oxysuccinic acid, threonic acid, glucoheptonic acid, one or several in amino acid and amino acid salts etc.
Pharmaceutically acceptable oxidation inhibitor in pharmaceutical compositions of the present invention and stablizer can be sulfurous acid and salt thereof, hydrosulphite, pyrosulfite, hyposulfite, thiosulphate, organosulfur compound thiocarbamide, gsh, dimercaprol dimercaptopropanol, Thiovanic acid and pharmaceutical salts thereof, thiolactic acid and pharmaceutical salts thereof, thio-2 acid and salt, phenol compound, as gallic acid and pharmaceutical salts thereof, coffic acid and pharmaceutical salts thereof, forulic acid and pharmaceutical salts thereof, di-t-butyl Pyrogentisinic Acid, 2, 5-resorcylic acid and pharmaceutical salts thereof, Whitfield's ointment or its pharmaceutical salts, amino acid and its pharmaceutical salts, xitix and pharmaceutical salts, saccharosonic acid and pharmaceutical salts thereof, niacinamide, tartrate, nitrate, phosphoric acid salt, acetic acid pharmaceutical salts, Citrate trianion, EDTA and edta salt, as one or several in EDETATE SODIUM, EDTA tetra-sodium, N-bis-(2-hydroxyethyl) glycine etc., the salt of above-mentioned substance all selects its pharmacy acceptable salt.
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, Sodium.alpha.-hydroxypropionate etc.
Source and the degerming mode of reducing phlegm and internal heat can be that the gac adding dosing amount 0.005 ~ 3% reduces phlegm and internal heat source, and the degerming and pressure sterilizing of millipore filtration, also can adopt heat sterilization, source of reducing phlegm and internal heat.In hyperfiltration process, ultra-fine filter can select flat, rolling, tubular type, hollow fiber form or circle boxlike etc., preferred rolling and hollow fiber form ultra-fine filter, adopt retain relative molecular mass be 5 ten thousand to 30 ten thousand filter membrane remove most of heat generation material and bacterium after, adopt the ultra-filtration membrane removing residue thermal source retaining relative molecular mass 3000 ~ 60000 again, the ultra-filtration membrane of preferred relative molecular mass 3000 ~ 20000.
Rotundine hydrochloride crystalline hydrate of the present invention, be applicable to prepare following to people or mammiferous analgesia, calmness, hypnosis, stable, treatment hypertension, anti-arrhythmia, functional dyspepsia, cough-relieving, antipsychotic, drug rehabilitation, reversing tumor cellular drug resistance, delay or alleviate the application of medicine aspect of the treatments such as myocardial ischemia-reperfusion injury or prevention aspect.
Consumption usage: generally, in adult, the little liquid drugs injection getting rotundine hydrochloride hydrate of the present invention 10 ~ 100mg, in 0.9% sodium-chlor or 5 ~ 10% glucose 20 ~ 500 milliliters, does intravenous injection or instillation, every day 1 ~ 2 time; Intramuscularly: get the little aqueous injection of medicine 10 ~ 100mg of the present invention, carry out intramuscularly, every day 1 ~ 2 time; More than children's amount of reducing by half use.Through the dosage of gastrointestinal administration preparation, be generally oral: analgesia, 50mg/ sheet, be grown up one time 2 ~ 4; Sleeping, be grown up one time 1 ~ 3; 3 times on the one, more than children's amount of reducing by half use.
Accompanying drawing explanation
Fig. 1 is the thermal analyses collection of illustrative plates (embodiment 1) of rotundine hydrochloride 0.5 hydrate;
Fig. 2 is the X powder diffraction collection of illustrative plates (embodiment 1) of rotundine hydrochloride 0.5 hydrate;
Fig. 3 is the thermal analyses collection of illustrative plates (embodiment 3) of rotundine hydrochloride 0.75 hydrate;
Fig. 4 is the X powder diffraction collection of illustrative plates (embodiment 3) of rotundine hydrochloride 0.75 hydrate
Fig. 5 is the X powder diffraction collection of illustrative plates (embodiment 3) of rotundine hydrochloride 0.75 hydrate
Embodiment
During except there being instruction in an embodiment and separately, in specification sheets and claims, all numerical value used should be understood to be in all examples and modify with term " about ", therefore, unless the contrary indication, numerical parameter given in this specification sheets and appending claims is approximation, it can change according to by character required for sought by present disclosure, at least, and not the application being intended to limit doctrine of equivalents right, each numerical parameter should consider that the number of significant figure and the routine method of rounding up are explained.
Although numerical range and the parameter of the wide region of setting disclosure are approximations.But numerical value given in a particular embodiment is as far as possible accurately reported, any number comprises some error certainly led to by the standard deviation found in their respective tests in essence.
Unless it is pointed out that in literary composition and illustrated in addition clearly, the singulative " " used in this specification and the appended claims, " one " and " being somebody's turn to do " comprise the plural form referring to thing, so, such as.If comprise the mixture of two or more compounds when mentioning the composition containing " a kind of compound ", unless it should be noted that in addition and illustrate in addition clearly herein, term "or" generally includes "and/or".
As used herein, term " obtains " referring to that valuable content or purity level are separated the compound obtained, and described content and purity level include but not limited to the content and the purity level that are greater than 90%, 95%, 96%, 97%, 98% and 99%.Described content or purity level can by about the volumetry specified in the national drug standards of rotundine hydrochloride or ultraviolet spectrophotometry or high-performance liquid chromatogram determinations.Adopt Fourier transformation infrared spectrometer working sample ir data, the instrument used comprises the intelligent Fourier transformation infrared spectrometer of Nexus (ThermoNicolet) etc.
This " solvate " refers to the crystal formation of molecule, atom and/or the ion also comprising the solvent molecule penetrated in crystalline structure herein, the solvent molecule of solvate can be in regularly arranged and/or lack of alignment, and solvate of the present invention is aqueous solvent compound.
Polymorphic refers to have identical chemical constitution but form the different crystal of the spatial disposition of the molecule of crystal, atom and/or ion herein.
Pharmaceutical composition: " pharmaceutical composition " used herein refers to the composition of medicine, described pharmaceutical composition can contain the pharmaceutically acceptable carrier of at least one.
" pharmaceutically acceptable vehicle " used herein refers to the pharmaceutical carrier or solvent that are applicable to the compound administration occasionally provided herein, it comprises any examples of such carriers that well known to a person skilled in the art and be applicable to specific administration mode, such as, sterile diluent (such as, water for injection, salts solution, non-volatile wet goods) can be comprised for the solution of parenteral, intradermal, subcutaneous or topical application or suspension agent; The fatty solvent (such as, polyoxyethylene glycol, glycerine, propylene glycol etc.) of synthesis; Antiseptic-germicide (such as, benzylalcohol, to hydroxyl third methyl-formiate, to hydroxyl third ethyl formate etc.); Antioxidant (such as, xitix, sodium bisulfite etc.); Sequestrant (such as, EDTA etc.); Buffer reagent (phosphoric acid salt, Citrate trianion etc.); With or for tonicity-adjusting substances (e.g., sodium-chlor, glucose etc.), or their mixture.Other example comprises, and when intravenous administration, suitable carrier comprises physiological saline, phosphate buffered saline buffer and the solution containing thickening material, such as glucose, polyoxyethylene glycol etc. and their mixture.
As non-limiting example, rotundine hydrochloride crystalline hydrate can optionally and one or more pharmaceutically acceptable mixed with excipients, and can with following form oral administration: tablet, capsule, dispersible powder, granule or the suspensoid containing such as about 0.05-5% suspending agent, pill, ophthalmic preparation, or with the form parenteral admin of sterile solution agent or suspensoid, the suspending agent of described suspensoid also containing 0.05-5% in isotonic medium, these pharmaceutical preparations can contain activeconstituents and the carrier of such as about 25% to about 90%, active ingredient more generally containing 5% to 60% (weight).
In order to understand the present invention further; below in conjunction with embodiment, the preferred embodiment of the invention is described; but be to be understood that; these describe just as further illustrating the features and advantages of the present invention or effect; instead of limiting to the claimed invention, protection scope of the present invention is not limited by the following examples.
Infrared spectra: pressing potassium bromide troche, working sample ir data, the instrument used comprises power & light company of U.S. NICOLET5700FTIRSpectrometer, the intelligent Fourier transformation infrared spectrometer of Nexus (ThermoNicolet) etc.
Heat analysis method
Thermal analyses test condition: Setaram company Setsys16, about sample size 3-10mg, heat-up rate: 10K/min, N
2flow velocity: 50ml/min, temperature: about room temperature ~ 400 DEG C.
In the present invention, surprisingly, distinctive, there is under the weightless platform of thermal analyses (TG-DTA or the TG-DSC) collection of illustrative plates of hydrate of the present invention corresponding endotherm(ic)peak, under the weightless platform of its thermal analyses collection of illustrative plates between 30-125 DEG C, correspondence shows obvious endotherm(ic)peak, the obvious platform of performance before weightless, thermal analyses collection of illustrative plates demonstrates rotundine hydrochloride crystalline hydrate, and this weightlessness of Karl_Fischer method test evidence is water molecules.
Powder X-ray diffraction approach
Utilize D/MX-III AX x ray diffractometer x, voltage: 30-60kv, electric current: about 30-100mA, sweep velocity: 10 °/min, step-length: 0.02 °/step; Copper target, monochromator: graphite monochromator; Wavelength wavelength
: 1.54, diffraction angle 2 θ, sweep limit 3-60 °, determine the x-ray diffractogram of powder of rotundine hydrochloride crystalline hydrate, and whole peak position is in ± 0.2 ° of 2 θ; Or utilize the D8AdvanceX x ray diffractometer x of German Bruker company, wavelength
: 1.54, diffraction angle 2 θ, sweep limit 3-60 °, other (index such as voltage, electric current) is approximately the same, measures sample.Each accompanying drawing in this specification sheets and the data in embodiment are proved (collection of illustrative plates and data that Fig. 4, Fig. 5 are embodiment 3) each other.
Specific embodiment
The preparation of embodiment 1 rotundine hydrochloride 0.5 hydrate gets the fine powder 6.22g of Rotundine in 250ml flask, add water 50ml, stir, heating, add the hydrochloric acid soln of appropriate 4M, stir, control below pH value of solution=1.5, continue stirring 4 hours, filter, after decompression is slightly concentrated, place, slowly be cooled to about 0 DEG C, place, abundant precipitation to be precipitated, filter, gained solids icy water and ice-cold on a small quantity washing with alcohol three times, suction filtration, gained crystallization is made thinner, about 25 DEG C forced air dryings 3 hours, about 50 DEG C dry 5 hours again, obtain off-white color solid 5.53 grams, differentiate: 1) get product 10mg prepared by the present embodiment, add 2ml water and make it dissolve, add potassium bichromate test solution 1, namely produce yellow mercury oxide, (2) get product 10mg prepared by the present embodiment, add 2ml water dissolution, add rare iron potassuim cyanide test liquid 1, namely produce yellow mercury oxide, become green gradually, a little heat, become blue gradually, (3) specific optical rotation gets product prepared by the present embodiment, accurately weighed, be dissolved in water and quantitatively dilute the solution made containing 10mg (calculating by anhydride) in every 1ml, measure 25 DEG C time (Chinese Pharmacopoeia version in 2010 two annex VI E), specific optical rotation is more than-232 ° in accordance with the law, it is 2.56% that Ka Shi method measures moisture, thermal analyses TG-DTA: platform weightlessness about 2.495%, and this and sample contain the result (theoretical value 2.33%) (see accompanying drawing 1) in limit of error of 0.5 crystal water, infrared spectra: ν
kBr maxcm
-13620.9,3559.6,3434.6,3000.5,2938.9,2840.1,2686.6,2534.4,1615.3,1518.8,1496.1,1462.7,1428.0,1396.6,1359.4,1339.3,1282.8,1262.0,1235.6,1128.4,1090.7,1061.6,1036.5,1019.0,991.8,948.6,902.6,859.6,810.3, X-ray powder diffraction (see accompanying drawing 2) about etc. has characteristic peak 6.77 in the position of following 2 θ values, 7.84, 10.01, 12.87, 14.00, 14.79, 15.12, 15.46, 15.78, 16.27, 16.85, 19.32, 19.62, 20.12, 20.41, 20.99, 21.71, 23.28, 23.79, 24.33, 24.67, 25.27, 25.79, 26.38, 27.00, 27.55, 28.51, 28.67, 29.19, 29.38, 29.83, 30.13, 30.61, 31.46, 32.34, 32.90, 35.12, 35.59, 37.63, 38.11, 39.26, 40.11, 41.53, 42.23, 49.07, ultimate analysis, theoretical value: C62.92%, H6.79%, N3.49%, Cl8.84%, measured value: C62.81%, H6.69%, N3.40%, Cl8.91%.
The preparation of embodiment 2 rotundine hydrochloride 0.5 hydrate gets fine powder 5.36g, the ethanol 5ml of Rotundine, water 50ml in 250ml flask, stir, heating, pass into hydrogen chloride gas, stir, control below pH value of solution=1.5, continue stirring 4 hours, slowly be cooled to about-5 DEG C, place, abundant precipitation to be precipitated, filter, ice-cold ethanol is washed, suction filtration, makes thinner gained crystallization, about 28 DEG C forced air dryings 6 hours, about 40 DEG C dry 2 hours (vacuum tightness is approximately about 0.08MPa) of vacuum chamber, obtain off-white color solid 2.47 grams again; Differentiate: 1) get product 10mg prepared by the present embodiment, add 2ml water dissolution, add potassium bichromate test solution 1, namely produce yellow mercury oxide; (2) get product 10mg prepared by the present embodiment, add 2ml water dissolution, add rare iron potassuim cyanide test liquid 1, namely produce yellow mercury oxide, become green gradually, a little heat, become blue gradually; (3) specific optical rotation gets product prepared by the present embodiment, accurately weighed, be dissolved in water and quantitatively dilute the solution made containing 10mg (calculating by anhydride) in every 1ml, measure 25 DEG C time (Chinese Pharmacopoeia version in 2010 two annex VI E), specific optical rotation is more than-232 ° in accordance with the law; It is 2.25% that Ka Shi method measures moisture, thermal analyses TG-DTA: platform weightlessness about 1.904%, and this and sample contain the result (theoretical value 2.33%) of 0.5 crystal water in limit of error; Ultimate analysis, theoretical value: C62.92%, H6.79%, N3.49%, Cl8.84%; Measured value: C62.78%, H6.71%, N3.39%, Cl8.75%.
The fine powder 5.36g of Rotundine is got in the preparation of embodiment 3 rotundine hydrochloride 0.75 hydrate, add ethanol 50ml in 250ml flask, stir, heating makes dissolving, add the hydrochloric acid soln of appropriate 6M, stir, control below pH value of solution=1.5, stir about 30 minutes, after decompression is slightly concentrated, place, slowly be cooled to about-20 DEG C, placement is spent the night, abundant precipitation to be precipitated, filter, ice-cold ethanol is washed, suction filtration, gained solids is placed in flask, add water 2ml, add 90% ethanol of appropriate volume again and heat about 78 DEG C and make dissolving, carry out recrystallization operation, to less than 0 DEG C, place, abundant precipitation to be crystallized, suction filtration, gained crystallization is made thinner, about 28 DEG C forced air dryings 3 hours, about 60 DEG C dry 2 hours again, obtain micro-yellow crystal 3.23 grams, differentiate: 1) get product 10mg prepared by the present embodiment, add 2ml water dissolution, add potassium bichromate test solution 1, namely produce yellow mercury oxide, (2) get product 10mg prepared by the present embodiment, add 2ml water dissolution, add rare iron potassuim cyanide test liquid 1, namely produce yellow mercury oxide, become green gradually, a little heat, become blue gradually, (3) specific optical rotation gets product prepared by the present embodiment, accurately weighed, be dissolved in water and quantitatively dilute the solution made containing 10mg (calculating by anhydride) in every 1ml, measure 25 DEG C time (Chinese Pharmacopoeia version in 2010 two annex VI E), specific optical rotation is more than-232 ° in accordance with the law, it is 3.35% that Ka Shi method measures moisture, thermal analyses TG-DTA: platform weightlessness about 3.37% (see accompanying drawing 3), and this and sample contain the result (theoretical value 3.33%) of 0.75 crystal water in limit of error, infrared spectra: ν
kBr maxcm
-13621.2,3559.6,3403.9,3203.2,3000.6,2939.0,2840.5,2686.4,2518.8,1614.9,1518.3,1496.0,1462.3,1428,1396.6,1359.2,1339.2,1282.6,1262.0,1235.6,1128.3,1090.8,1061.6,1036.8,1019.3,991.8,948.6,902.8,860.3,810.4, X-ray powder diffraction is (see accompanying drawing 4, 5) about etc. characteristic peak is had in the position of following 2 θ values: 6.79, 10.01, 12.90, 13.57, 14.00, 14.82, 15.12, 15.45, 15.84, 16.29, 16.85, 19.32, 19.63, 20.12, 20.43, 20.98, 21.73, 23.29, 24.35, 25.29, 26.41, 27.05, 27.36, 27.60, 28.35, 28.69, 29.21, 29.37, 30.16, 31.24, 31.42, 32.36, 32.92, 34.38, 35.18, 35.61, 37.62, 38.79, 40.02, 41.55, 42.25, 45.60, 49.52, 56.42, ultimate analysis, theoretical value: C62.22%, H6.84%, N3.46%, Cl8.75%, measured value: C62.13%, H6.95%, N3.53%, Cl8.82%.
The fine powder 4.01g of Rotundine is got in the preparation of embodiment 4 rotundine hydrochloride 0.75 hydrate, add ethanol 50ml and acetone 5ml in 100ml flask, stir, heating makes dissolving, add the hydrochloric acid soln of appropriate 3M, stir, control below pH value of solution=1.5, stir about 30 minutes, after pressure reducing and steaming about 1/3rd solvent concentration, place, slowly be cooled to about-20 DEG C, placement is spent the night, abundant precipitation to be precipitated, filter, ice-cold ethanol washing, suction filtration, gained solids is placed in flask, add water 2ml and acetonitrile, ether, the each 0.5ml of acetone, add 95% ethanol of appropriate volume again, and heating makes dissolving, carry out recrystallization operation, spend the night to-4 ~-10 DEG C of placements, abundant precipitation to be crystallized, suction filtration, gained crystallization is made thinner, about 28 DEG C forced air dryings 3 hours, about 50 DEG C dry 3 hours again, obtain micro-yellow crystal 2.27 grams, differentiate: 1) get product 10mg prepared by the present embodiment, add 2ml water dissolution, add potassium bichromate test solution 1, namely produce yellow mercury oxide, (2) get product 10mg prepared by the present embodiment, add 2ml water dissolution, add rare iron potassuim cyanide test liquid 1, namely produce yellow mercury oxide, become green gradually, a little heat, become blue gradually, (3) specific optical rotation gets product prepared by the present embodiment, accurately weighed, be dissolved in water and quantitatively dilute the solution made containing 10mg (calculating by anhydride) in every 1ml, measure 25 DEG C time (Chinese Pharmacopoeia version in 2010 two annex VI E), specific optical rotation is more than-232 ° in accordance with the law, it is 3.31% that Ka Shi method measures moisture, and thermal analyses TG-DTA: platform weightlessness about 3.42%, this and sample contain the result (theoretical value 3.33%) of 0.75 crystal water in limit of error.
The little hydro-acupuncture preparation of embodiment 5 prepare rotundine hydrochloride hydrate 5.08g (by embodiment 1 legal system standby or embodiment 2 method or embodiment 3 legal system standby), add cysteine hydrochloride 0.8g, EDETATE SODIUM 0.1g, inject and use water 800ml, 2M lactic acid and Sodium.alpha.-hydroxypropionate regulate pH to be 3.0 ~ 5.0, be stirred to dissolve, add activated carbon 0.01% (W/V) and stir 15 ~ 45min, filter, moisturizing is to 1000ml, retain the ultrafiltration membrance filter of relative molecular mass 5000-10000 with 0.22 micrometer Millipore membrane filtration or employing, by the packing of 5ml/ bottle, sterilizing obtains finished product.
The preparation of embodiment 6 high-capacity injection takes glucose 500g and adds in water for injection, is stirred to dissolve completely, adds the gac of dosing amount 0.05%, heat about 10-30 minute, let cool, through sand stick filtering decarbonization; By rotundine hydrochloride hydrate (by embodiment 1 legal system standby or embodiment 2 legal system is standby) 0.51g, after dissolving with the water for injection of appropriate 50-70 DEG C, mix with above-mentioned filtrate, add L-cysteine hydrochloride 1g, EDETATE SODIUM 0.2g, by 1M lactic acid solution adjust ph in the scope of 3.0-5.0, inject water to 5000ml, add the gac of dosing amount 0.03%, about heated and stirred 10-30 minute, filtering decarbonization, again through the filter of 0.22um millipore filtration essence, embedding is in the vial of 50ml or 100ml or 200ml, and sterilizing, packs and get final product.
The preparation of embodiment 7 rotundine hydrochloride hydrate sodium-chlor transfusion: by rotundine hydrochloride hydrate 2g (by embodiment 1 legal system standby or embodiment 2 method or embodiment 3 legal system standby), sodium-chlor 85g, Sodium Pyrosulfite 1.1g, EDETATE SODIUM 0.2g, add in 8000m water for injection, by the Citric Acid of 1M and liquor sodii citratis adjust ph in the scope of 4.0-6.0, be stirred to dissolve completely, inject water to 10000ml, add the gac of dosing amount 0.05%, about heated and stirred 10-30 minute, filtering decarbonization, the ultrafiltration membrance filter of relative molecular mass 3000-20000 is retained again through the filter of 0.22um millipore filtration essence or employing, embedding is in the vial of 50ml or 100ml or 200ml, sterilizing, pack and get final product.
Embodiment 8 rotundine hydrochloride hydrate tablet (30mg/ sheet)
By rotundine hydrochloride crystalline hydrate (by embodiment 1 method or embodiment 3 legal system standby), Microcrystalline Cellulose, sodium starch glycolate cross 100 mesh sieves, with PVP K-30 ethanol water (7:3) the solution softwood processed in right amount of 10%, cross 18-24 mesh sieve to granulate, dry, after crossing the whole grain of 14-20 mesh sieve, add micropowder silica gel mixing, compressing tablet, inspection, packaging.
Embodiment 9 rotundine hydrochloride hydrate tablet (50mg/ sheet)
Get recipe quantity rotundine hydrochloride crystalline hydrate raw material (by embodiment 1 method or embodiment 2 legal system standby) pulverized 100 mesh sieves, mix with the pregelatinized Starch of mistake 100 mesh sieve of recipe quantity, Microcrystalline Cellulose, low-substituted hydroxypropyl methylcellulose gum, the thin rectangular dry plate of 2mm is pressed into dry-pressing formula rubber mixing machine, cross the whole grain of 14 mesh sieve, add the micropowder silica gel of recipe quantity, mixing, detects the drug content of particle, compressing tablet, inspection, packaging.
Embodiment 10 rotundine hydrochloride hydrate capsule (15mg/ grain)
Rotundine hydrochloride hydrate (embodiment 1 legal system standby or embodiment 2 method), Microcrystalline Cellulose, lactose are crossed 100 mesh sieves, and the gelling starch with 10% is softwood processed in right amount, crosses the granulation of 18-24 mesh sieve, dry, after crossing the whole grain of 14-20 mesh sieve, add Magnesium Stearate mixing, filling capsule.
Embodiment 11 rotundine hydrochloride hydrate capsule (50mg/ grain)
The rotundine hydrochloride crystalline hydrate raw material pulverizing of getting recipe quantity crosses 100 mesh sieves, mix with the pregelatinized Starch of mistake 100 mesh sieve of recipe quantity, Microcrystalline Cellulose, low-substituted hydroxypropyl methylcellulose gum, the thin rectangular dry plate of 2mm is pressed into dry-pressing formula rubber mixing machine, cross the whole grain of 20 mesh sieve, add the micropowder silica gel of recipe quantity, mixing, detects the drug content of particle, filling capsule, inspection, packaging.
The granule (30mg/ bag) of embodiment 12 rotundine hydrochloride hydrate
Rotundine hydrochloride 0.5 hydrate (by embodiment 1 legal system standby or embodiment 2 legal system is standby), N.F,USP MANNITOL, lactose, Sodium Cyclamate, food flavour are crossed 100 mesh sieves, PVP K-30 aqueous ethanolic solution with 8% softwood processed in right amount, cross 18-24 mesh sieve to granulate, less than 60 DEG C dry, added the xanthan gum of 100 mesh sieves, after crossing the whole grain of 14-20 mesh sieve, mixing, added the xanthan gum of 100 mesh sieves, point packaging.
The preparation (10000) of embodiment 13 rotundine hydrochloride hydrate dripping pill
Prescription: rotundine hydrochloride hydrate 30g
Poloxamer 20g
Polyethylene glycol 6000 60g
After the rotundine hydrochloride hydrate of recipe quantity (embodiment 1 method or embodiment 3 method or embodiment 4 legal system standby) is crossed 100 mesh sieves, be added in the poloxamer of melting, polyethylene glycol 6000 matrix, fully stir evenly, take dimethyl silicone oil as refrigerant, dropping method pill, dry, packaging.
Industrial applicibility etc. and explanation etc. thereof:
Below through the specific embodiment and the embodiment to invention has been detailed description; but should understand; these explanations do not form any restriction to scope of the present invention; person skilled obviously can in the case of without departing from the spirit and scope of protection of the present invention; multiple modification, improvement and replacement and combination can be carried out to technical solutions and their implementation methods of the present invention; realize the technology of the present invention, these are all because falling within the scope of protection of the present invention.Special needs to be pointed out is, be appreciated that the change of a lot of details is possible, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in spirit of the present invention, scope and content, and the present invention is not limited to above-described embodiment.
Claims (9)
1. dibenzoquinolizine compounds entity, is characterized in that: dibenzoquinolizine compounds entity is rotundine hydrochloride crystalline hydrate, and its molecular formula is C
21h
25nO
4hClnH
2o, wherein n=0.5,0.75.
2. dibenzoquinolizine compounds entity according to claim 1, is characterized in that: dibenzoquinolizine compounds entity is rotundine hydrochloride 0.5 hydrate, and its molecular formula is C
21h
25nO
4hCl0.5H
2o.
3. rotundine hydrochloride 0.5 hydrate according to claim 2, it is characterized in that: utilize powder X-ray diffractometry to measure, in the useful range of 3-60 ° of diffraction angle 2 θ, in the position of following 2 θ values, there is corresponding eigenwert: 6.77, 7.84, 10.01, 12.87, 14.00, 14.79, 15.12, 15.46, 15.78, 16.27, 16.85, 19.32, 19.62, 20.12, 20.41, 20.99, 21.71, 23.28, 23.79, 24.33, 24.67, 25.27, 25.79, 26.38, 27.00, 27.55, 28.51, 28.67, 29.19, 29.38, 29.83, 30.13, 30.61, 31.46, 32.34, 32.90, 35.12, 35.59, 37.63, 38.11, 39.26, 40.11, 41.53, 42.23, 49.07.
4. dibenzoquinolizine compounds entity according to claim 1, is characterized in that: dibenzoquinolizine compounds entity is rotundine hydrochloride 0.75 hydrate, and its molecular formula is C
21h
25nO
4hCl0.75H
2o.
5. rotundine hydrochloride 0.75 hydrate according to claim 4, it is characterized in that: utilize powder X-ray diffractometry to measure, in the useful range of 3-60 ° of diffraction angle 2 θ, in the position of following 2 θ values, there is corresponding eigenwert: 6.79, 10.01, 12.90, 13.57, 14.00, 14.82, 15.12, 15.45, 15.84, 16.29, 16.85, 19.32, 19.63, 20.12, 20.43, 20.98, 21.73, 23.29, 24.35, 25.29, 26.41, 27.05, 27.36, 27.60, 28.35, 28.69, 29.21, 29.37, 30.16, 31.24, 31.42, 32.36, 32.92, 34.38, 35.18, 35.61, 37.62, 38.79, 40.02, 41.55, 42.25, 45.60, 49.52, 56.42.
6. dibenzoquinolizine compounds entity according to claim 1, it is characterized in that, its preparation method is selected from:
Method A. takes Rotundine or Rotundine solvate joins in reaction vessel, adds the water of 2-12 times amount, C
1-C
6low mass molecule alcohol in one or more in reaction vessel, add hydrochloric acid soln or logical hydrogen chloride gas under stirring, make below pH value of solution to 4.0, stir, filter, obtain solid, use C
1-C
6low mass molecule alcohol, C
2-c
6low molecule nitrile, C
3-C
8low molecule ketone, C
2-C
8low molecule ether, C
2-C
8one or more washing gained solids in low molecule ester, filter, obtain solid, by gained solid drying, obtain dibenzoquinolizine compounds entity of the present invention;
Or Rotundine or Rotundine solvate join in reaction vessel by method B., add the water of 2-12 times amount, C
1-C
6low mass molecule alcohol, C
3-C
8low molecule ketone in one or more in reaction vessel, add hydrochloric acid soln or logical hydrogen chloride gas, be stirred to dissolve, below adjust ph to 4.0, stir, add C
1-C
6low mass molecule alcohol, C
2-C
6low molecule nitrile, C
3-C
8low molecule ketone, C
2-C
8low molecule ether, C
2-C
8in low molecule ester one or more, cooling, makes crystallization fully separate out, and filters, dry, obtains dibenzoquinolizine compounds entity of the present invention.
7. rotundine hydrochloride compounds process for production thereof according to claim 6, it is characterized in that, described crystallization or recrystallization solvent are selected from: one or more in water and methyl alcohol, ethanol, Virahol, acetonitrile, ether, isopropyl ether, acetone, hexone, ethyl acetate.
8. dibenzoquinolizine compounds entity according to claim 1, it is characterized in that: its purposes is for the preparation of the application on the medicinal compositions containing rotundine hydrochloride compound, this medicinal compositions contains the vehicle, the diluent or carrier that pharmaceutically accept; This medicinal compositions shows as on pharmaceutical dosage forms, injection, solid preparation or through gastrointestinal agent, wherein, and solid preparation or be selected from tablet, capsule, granule, pill, soft capsule through gastrointestinal agent.
9. dibenzoquinolizine compounds entity according to claim 1, it is characterized in that: its purposes is, be applicable to preparation following to the application in the caused treatment of humans and animals disease or the medicine of prevention: for the preparation of analgesia, calmness, hypnosis, stabilize, treat hypertension, anti-arrhythmia, functional dyspepsia, cough-relieving, schizophrenia, drug rehabilitation, reversing tumor cellular drug resistance, delay or alleviate the application in the treatment of myocardial ischemia-reperfusion injury or the medicine of prevention.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410553630.1A CN105566316A (en) | 2014-10-17 | 2014-10-17 | Dibenzo quinolizine compound entity and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410553630.1A CN105566316A (en) | 2014-10-17 | 2014-10-17 | Dibenzo quinolizine compound entity and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105566316A true CN105566316A (en) | 2016-05-11 |
Family
ID=55877006
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410553630.1A Pending CN105566316A (en) | 2014-10-17 | 2014-10-17 | Dibenzo quinolizine compound entity and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105566316A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107586293A (en) * | 2016-07-06 | 2018-01-16 | 胡梨芳 | Sulfur-bearing dibenzothiazine alkaloid compound and application thereof |
| CN111100122A (en) * | 2018-10-26 | 2020-05-05 | 刘力 | Novel levo-tetrahydropalmatine compound |
| JP2022509701A (en) * | 2018-11-29 | 2022-01-21 | ヤン、チェン | Crystalline salt of coridalmin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100467494C (en) * | 2002-05-10 | 2009-03-11 | 刘云清 | Organic medicine and betacyclodextrin derivative and preparation process thereof |
| CN102796096A (en) * | 2011-05-27 | 2012-11-28 | 中国科学院上海药物研究所 | Hexahydro dibenzo [a,g] quinolizidine compound and preparation method, medicinal composition and application thereof |
-
2014
- 2014-10-17 CN CN201410553630.1A patent/CN105566316A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100467494C (en) * | 2002-05-10 | 2009-03-11 | 刘云清 | Organic medicine and betacyclodextrin derivative and preparation process thereof |
| CN102796096A (en) * | 2011-05-27 | 2012-11-28 | 中国科学院上海药物研究所 | Hexahydro dibenzo [a,g] quinolizidine compound and preparation method, medicinal composition and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 霍立等: "罗通定的合成", 《中国医药工业杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107586293A (en) * | 2016-07-06 | 2018-01-16 | 胡梨芳 | Sulfur-bearing dibenzothiazine alkaloid compound and application thereof |
| CN111100122A (en) * | 2018-10-26 | 2020-05-05 | 刘力 | Novel levo-tetrahydropalmatine compound |
| JP2022509701A (en) * | 2018-11-29 | 2022-01-21 | ヤン、チェン | Crystalline salt of coridalmin |
| JP7194828B2 (en) | 2018-11-29 | 2022-12-22 | ヤン、チェン | crystalline salt of corridarmin |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104736526B (en) | Fertile for western spit of fland salt and crystal thereof, their preparation method, pharmaceutical composition and purposes | |
| ES2652187T3 (en) | L-Ornithine Phenylacetate and methods to make it | |
| ES2691395T3 (en) | Chidamide crystalline form, preparation procedure and use thereof | |
| CN104628796A (en) | Gastrodin medicine, and composition and use thereof | |
| JP2016527242A (en) | Crystalline form of dasatinib salt | |
| CN104761492A (en) | Crystal form of sorafenib tosylate, and preparation method thereof | |
| CN105017060A (en) | Novel polymorph of safinamide and preparation method therefor | |
| CN105566316A (en) | Dibenzo quinolizine compound entity and application thereof | |
| US20220002306A1 (en) | Crystal form of upadacitinib and preparation method and use thereof | |
| AU2018215687A1 (en) | Tebipenem pivoxil crystalline forms, compositions including the same, methods of manufacture, and methods of use | |
| CN102659880B (en) | Erythromycin ethylsuccinate crystalline hydrate and preparation method and application thereof | |
| KR20140111044A (en) | Aildenafil citrate crystal form O, preparation method and use thereof | |
| EP3453384B1 (en) | Pharmaceutical tablet composition comprising bilastine | |
| EP3135666B1 (en) | (s)-oxiracetam crystal form iii, preparation method therefor, and application thereof | |
| CN104447771A (en) | Stable asenapine maleate sublingual compound | |
| CN111205290B (en) | Crystal form of JAK kinase inhibitor and preparation method thereof | |
| CN105461713A (en) | New benzonaphthyridine compound, and composition and use thereof | |
| CN114644642B (en) | Crystal form A of thienopyridine compound, preparation method and pharmaceutical composition thereof | |
| CN105837646A (en) | Flavonoid new chemical entity, composition and use | |
| CN102746183B (en) | Tigecycline crystalline hydrate, preparation method thereof and uses thereof | |
| CN102046621A (en) | Antiviral salts | |
| CN102911226B (en) | Erythromycin octadecanoate compounds thing entity and uses thereof | |
| CN103690499B (en) | Stable crystalline form I agomelatine tablets and preparation method thereof | |
| CN110551038B (en) | Novel antitumor compounds and uses thereof | |
| US20160120825A1 (en) | Stable crystal x-form agomelatine tablet and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160511 |