CN106380472A - Brominated crebanine compound and preparation method and application thereof - Google Patents
Brominated crebanine compound and preparation method and application thereof Download PDFInfo
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to a brominated crebanine compound and preparation method and an application thereof, which belongs to the technical field of medicine. The invention firstly discloses the synthesis of 3-brominated crebanine and 10, 11-brominated crebanine, through research on effect of chloroform for inducing mice arrhythmia, the research shows that the 3-brominated crebanine and 10, 11-brominated crebanine can antagonize the chloroform-induced ventricular fibrillation, so that the 3-brominated crebanine and 10, 11-brominated crebanine have anti-arrhythmia effect through preliminary determination; the barium chloride-induced rat ventricular rhythm tests confirm that the 3-brominated crebanine and 10, 11-brominated crebanine have good anti-arrhythmia effect, acute toxicity of two brominated crebanine compounds is lower than that of crebanine, LD50 is 65.15+/-1.132 mg/kg of 3-brominated crebanine and 59.62+/-2.610 mg/kg of 10,11-brominated crebanine respectively, and a good base can be established for further deep researches.
Description
Technical field
The invention belongs to pharmaceutical technology field is and in particular to bromo crebanine class compound and preparation method and application.
Background technology
Arrhythmia cordis (cardiac arrhythmia) refers to the frequency of cardiac impulse, the rhythm and pace of moving things, origin position, conduction of velocity
Or the exception of excitement order.Arrhythmia cordis is important one group of disease in angiocardiopathy, and it can individually be fallen ill, also can be with other
Cardiovascular disease occurs together.Its prognosis and the ARR cause of disease, inducement, evolving trend, serious hemodynamic obstacle whether is led to have
Close, can break out and cause to die suddenly, also sustainable involve heart and cause its exhaustion.Although the treatment means such as existing RF ablation,
Antiarrhythmic drug is still its primary treatments or required part.For a long time, people are untiringly devoted to always
Develop and exploitation antiarrhythmic drug, excavating the ergastic medicine recruit of tool from natural products is the important of new drug development
One of means.
At present, the treatment arrhythmia drug clinically commonly used mainly has four kinds, and I class is sodium channel blocking agent；II class is β kidney
Upper parathyrine receptor antagonist；III class is selectively to extend the medicine of process of repolarization；IV class is calcium channel blocker, studies the anti-rhythm of the heart
Arrhythmic agents commonly use test method have chloroform induction mouse ventricular fibrillation method, barium chloride induction rat VA method,
Intravenous injection Aconitine Induced rat ventricular method etc..
Crebanine alleged by the present invention is distributed in menispermaceae Stephania (Stephania) plant, has multiple physiology and lives
Property.Have no with regard to 3- bromo crebanine, being reported in before the present invention completes of 10,11- bromo crebanine antiarrhythmic effect
Report.
3- bromo crebanine (3-Bromocrebanine) and 10,11- bromo crebanine (10,11-
Dibromocrebanine it is) with crebanine (Crebanine) for Material synthesis gained, be all noval chemical compound, have no both at home and abroad
Associated report
Anti-arrhythmia common drug majority in the market is with very important bad reaction, as normal in lidocaine
Show as dizziness, cacesthesia, the nervous system bad reaction such as clouding of consciousness, amiodarone then has first to subtract or hyperthyroidism, lung damage etc.
Bad reaction, if the adjustment of Verapamil dosage is improper, also occurs the bad reaction of the aspects such as angiocarpy, nerve, endocrine,
It is difficult to merely search out all preferable antiarrhythmic drug of each side from natural products again.How to overcome anti-in prior art
The problem of the bad reaction of antiarrhythmic medicament, be currently urgent need to resolve problem.Therefore from by the knot to natural products
Structure is modified and is of great significance to find to have significantly antiarrhythmic new construction type and noval chemical compound and have.
Content of the invention
The invention aims to solution the deficiencies in the prior art, provide bromo crebanine class compound and its preparation side
Method and application.
For achieving the above object, the technical solution used in the present invention is as follows：
Bromo crebanine class compound, shown in structural formula such as formula (I)；
Wherein, X1During for Br, X2、X3It is H；X1During for H, X2、X3It is Br.
The present invention also provides a kind of preparation method of above-mentioned bromo crebanine class compound, and synthetic route is as follows：
Comprise the steps：
Step (1), under condition of ice bath, adds trifluoroacetic acid that crebanine is completely dissolved in crebanine；Then again
It is slowly added to N- bromo-succinimide, the joining day of N- bromo-succinimide is more than 10min；After adding, remove ice bath,
Place reaction liquid into stirring 11-13h under room temperature, rear rotary evaporation, to remove solvent trifluoroacetic acid, obtains concentrate；Crebanine with
The mass volume ratio of trifluoroacetic acid is 0.2：4.9-5.1；Crebanine is 1 with the mol ratio of N- bromo-succinimide：1.1-
1.3；
Step (2), adding in the concentrate obtaining to step (1) is the water of trifluoroacetic acid volume 9.5-10.5 times, then
Use saturation Na2CO3The aqueous solution adjusts pH to 8, then uses CH2Cl2Extracted, extract 2-4 time, extract CH every time2Cl2Usage amount is
/ 5th of water volume, merge organic layer；
Step (3), washes organic layer with the saturated aqueous common salt of organic layer 1/3rd volume, to remove in organic layer
Water, is then dried using anhydrous sodium sulfate, and then rotary evaporation is to remove CH2Cl2, the solid obtaining crosses 200-300 mesh
Silicagel column, first adopts volume ratio to be 200:1 CH2Cl2- MeOH is eluted, until 10,11- bromo crebanine is from silicagel column
After rinsing completely, then it is 100 using volume ratio:1 CH2Cl2- MeOH is eluted, and collects eluent respectively；Entirely cross post mistake
Cheng Caiyong thin-layered chromatography is followed the tracks of, and to no 3- bromo crebanine, stops wash-out.
The volume ratio collected is 200:The eluent of 1 part, after concentration, 39-41 DEG C of vacuum drying 3.9-4.1 hour,
Obtain 10,11- bromo crebanine；The volume ratio collected is 100:The eluent of 1 part, after concentration, 39-41 DEG C of vacuum drying
3.9-4.1 hour, obtains 3- bromo crebanine.
It is further preferred that described use saturated aqueous common salt water-washing step (2) obtain organic layer when, washing times are
3 times.
The present invention also provides a kind of above-mentioned bromine bromo crebanine class compound and its pharmaceutically acceptable salt and solvation
Thing is as the application preparing antiarrhythmic drug.
Described the pharmaceutically acceptable salt including but not limited to acetate of formula (I), acrylates, benzene sulfonate, benzene
Formates is (as chloro-benzoate, methyl benzoic acid salt, dinitro-benzoate, hydroxy benzoate and methoxy benzoic acid
Salt), bicarbonate, disulfate, bisulfites, biatrate, borate, bromide, butine-Isosorbide-5-Nitrae-diacid salt, second
Ethylenediamine tetraacetic acid (EDTA) calcium salt, camsilate, carbonate, chloride, caproate, caprylate, Clavulanate
(clavulanate), citrate, caprate, dihydrochloride, dihydric phosphate, edetate, ethanedisulphonate
(edislyate), Estolate (estolate), esilate, ethylsuccinate, formates, rich horse
Hydrochlorate, gluceptate, gluconate, glutamate, glycollate, hydroxyl acetyl arsanilate
(glycollylarsanilate), enanthate, hexin -1,6- diacid salt, hexyl resorcin salt
(hexylresorcinate), Hai Baming salt (hydrabamine), hydrobromate, hydrochloride, y- hydroxybutyric acid salt, iodide,
Isobutyrate, different thiosulfate (isothionate), lactate, Lactobionate, laruate, malate, maleic acid
Salt, malonate, mandelate, mesylate, metaphosphate, methane sulfonates, Methylsulfate, dibasic alkaliine
(monohydrogenphosphate), mucic acid salt, naphthalene sulfonate, naphthalene -1- sulfonate, naphthalene-2-sulfonic acid salt, nitrate, oleic acid
Salt, oxalates, pamoate (embonate), palmitate, pantothenate, phenyl acetate salt, PB, phenylpropionic acid
Salt, phthalate, phosphate, diphosphate, Polygalacturonate, propane sulfonate, propionate, propiolate, Jiao
Phosphate, pyrosulfate, salicylate, stearate, basic acetate, suberate, succinate, sulfate, sulfonate,
Sulphite, tannate, tartrate, chloro theophylline salt (teoclate), toluene fulfonate, plus draw salt compounded of iodine
(triethiodode), valerate.
The solvent that described acceptable solvates adopt is water, isopropanol, ethanol, methyl alcohol, dimethyl sulfoxide, ethyl acetate,
The composition of one or more in acetic acid and monoethanolamine.
It is further preferred that described pharmaceutical dosage form is oral formulations, ejection preparation, suppository or preparation capable of permeating skin.Oral
Preparation is selected from any one of tablet, capsule, granule, pill, dripping pill, oral liquid；Ejection preparation is selected from
In injection, powder pin etc..
It is further preferred that according to weight/mass percentage composition meter, described medicine contains the acceptable excipients of 1%-99%
Agent, balance of bromo crebanine class compound, bromo crebanine class compound pharmaceutically acceptable salt and bromo crebanine class
The combination of one or more in the solvate of compound.
It is further preferred that according to weight/mass percentage composition meter, described medicine contains the acceptable excipients of 20%-70%
Agent, balance of bromo crebanine class compound, bromo crebanine class compound pharmaceutically acceptable salt and bromo crebanine class
The combination of one or more in the solvate of compound.
It is further preferred that according to weight/mass percentage composition meter, described medicine contains the acceptable excipients of 30%-40%
Agent, balance of bromo crebanine class compound, bromo crebanine class compound pharmaceutically acceptable salt and bromo crebanine class
The combination of one or more in the solvate of compound.
Pharmaceutical excipient of the present invention, in addition to including common excipient, can also include the medicine of other compatibilities
Thing.
It is further preferred that described medicine is granule, including following component in parts by weight：Bromo gram
Class peaceful class compound 50-250 part, Icing Sugar 20-90 part, dextrin 5-20 part；Described bromo crebanine class compound is 3- bromo
Crebanine, 10,11- bromo crebanine, its pharmaceutically acceptable salt and solvate.
It is further preferred that described medicine is tablet, including following component in parts by weight：Bromo gram class
Peaceful class compound 50-250 part, amylum pregelatinisatum 20-90 part, sodium carboxymethylcellulose 1-5 part, magnesium stearate 0.3-1 part；Described
Bromo crebanine class compound be 3- bromo crebanine, 10,11- bromo crebanine, its pharmaceutically acceptable salt and solvent
The combination of one or more in compound.
It is further preferred that described medicine is dripping pill, including following component in parts by weight：Bromo gram class
Peaceful class compound 50-250 part, Macrogol 6000 50-500 part；Described bromo crebanine class compound is 3- bromo gram class
Rather, 10,11- bromo crebanine, its pharmaceutically acceptable salt and one or more combine in solvate.
It is further preferred that described medicine is syrup, including following component in parts by weight：Bromo gram
Class peaceful class compound 50-250 part, solubilizer 1-10 part, ethyl hydroxy benzoate 0.05-0.15 part, sucrose 4800-5200 part, add water to
Gross weight is 10000 parts；Described bromo crebanine class compound is 3- bromo crebanine, 10,11- bromo crebanine, its medicine
Acceptable salt and one or more combine in solvate on.
It is further preferred that described medicine is suppository, including following component in parts by weight：Bromo gram class
Peaceful class compound 50-400 part, semi-synthetic fatty glyceride 1000-2000 part；Described bromo crebanine class compound is 3-
Bromo crebanine, 10,11- bromo crebanine, its pharmaceutically acceptable salt and one or more combine in solvate.
It is further preferred that described medicine is injection, including following component in parts by weight：Bromo gram
Class peaceful class compound 25-125 part, solubilizer 5-10 part, water for injection 1000-2000 part；Described bromo crebanine class chemical combination
Thing is one or more in 3- bromo crebanine, 10,11- bromo crebanine, its pharmaceutically acceptable salt and solvate
Combination.
It is equipped with pharmaceutically acceptable various carrier and additives in the medicine of the present invention, various formulations can be made,
Including ordinary preparation and sustained-release preparation, such as tablet, capsule, granule, oral liquid, injection, suppository, patch etc..Institute
State pharmaceutically acceptable carrier and additives refer to the conventional carrier of pharmacy and additives, such as filler, adhesive, wetting
Agent, disintegrant, solvent, stabilizer, flavouring, matrix etc..Its preparation illustrates in a specific embodiment.In medicine of the present invention
The medicine of other compatibilities refers to the 3- bromo crebanine of effective dose, 10,11- bromo crebanine and its pharmaceutically can connect
The salt being subject to and solvate are certain medicine material, more other Chinese medicine or the chemicals that can allow to share of compatibility.
Following pharmacological evaluation confirms that 3- bromo crebanine, 10,11- bromo crebanine have anti-arrhythmia pharmacology and live
Property：
1st, experiment material：
Kunming mouse, cleaning grade, body weight 18-22g, it is purchased from Hunan SJA Laboratory Animal Co. ， Ltd, qualified
Card number is SCXK (Hunan) 2011-0003, quality certification number：43004700023323.SD rat, cleaning grade, body weight 120-150g, purchase
In Hunan SJA Laboratory Animal Co. ， Ltd, quality certification number is SCXK (Hunan) 2011-00034, quality certification number：
43004700022638.
2nd, experimental technique and result：
(1) chloroform causes the property fibrillation test of induction mouse room
Take healthy Kunming mouse 40, be randomly divided into 4 groups, respectively：1. model group, 2. positive (Verapamil) group
(4mg/kg), 3. 3- bromo crebanine (7.5mg/kg), 4. 10,11- bromo crebanine
(7.5mg/kg), every group each 10, male and female half and half.It is gradually quiet in mouse tail that each group presses 0.1ml/10g administered volume
Arteries and veins injection gives the medicine of corresponding group, and model group gives equal-volume physiological saline.After 2min, put it into the cotton balls of chloroform containing 4ml
In 500ml beaker, after mouse breathing stops, taking out from beaker immediately, quickly cut its thoracic cavity open, expose mouse heart, meat
Whether eye examination mouse ventricular fibrillation occurs, and record result simultaneously compares, and result is as shown in table 1.
Table 1 3- bromo crebanine, 10,11- bromo crebanine induce the impact (n=of mouse ventricular fibrillation model to chloroform
10,)
| Dosage (mg/kg) | Number of mice (n) | Quiver number of mice in room | Quiver incidence % in room | |
| Model group | —— | 10 | 10 | 100 |
| Positive group | 4 | 10 | 1 | 10** |
| 3- bromo crebanine | 7.5 | 10 | 5 | 50** |
| 10,11- bromo crebanine | 7.5 | 10 | 5 | 50** |
Note：Compare with model group：*P<0.05, * * P<0.01.
Result：From table 1 and Fig. 1, with physiological saline group contrast, 3- bromo crebanine, 10,11- bromo crebanine are equal
Room can substantially be reduced quiver incidence (P ＜ 0.01).
(2) barium chloride induction rat VA method test
Take SD rat 32, male and female half and half, body weight 250～300g, be randomly divided into 4 groups, respectively physiological saline group is (negative
Control group), lidocaine group (positive controls, 5mg/kg), 3- bromo crebanine (7.5mg/kg), 10,11- bromo crebanine
(7.5mg/kg), each 4 of every group of male and female.Lumbar injection mass percent 10% chloraldurate 300mg/kg anaesthetizes, and back of the body position is fixed,
Connect Physiological Signal Acquiring System, record one section of normal II lead electrocardiogram.Lingual vessels inject BaCl2(aq) 4mg/kg, treats
After arrhythmia cordis 3min occurs, negative control group sublingual vein injecting normal saline (4ml/kg), positive controls intravenous injection
Lidocaine injection (5mg/kg), 2 administration group sublingual injection 3- bromo crebanine (7.5mg/kg), 10,11- bromos respectively
Crebanine (7.5mg/kg) parenteral solution, observes the situation that each group rat recovers sinus rhythm, and record each group in detail recovers hole
The mouse number of the rhythm of the heart, recover the time needed for sinus rhythm and hold time after recovering sinus rhythm >=mouse of 5min and >=20min
Number.Result is as shown in table 2.
The impact to the rat ventricular that BaCl2 induces for the 2 three kinds of compounds of table (n=8,)
Note：Through Chi-square Test, compare with physiological saline group, * * P ＜ 0.01；In experiment, physiological saline group sublingual vein is given
Give BaCl2(aq), after, occur there is not recovery in the 30min that arrhythmia cordis is observed.
As shown in Table 2, compare with physiological saline group, to barium chloride induce rat VA, 3- bromo crebanine,
10,11- bromo crebanine all can dramatically increase the rat quantity (P recovering sinus rhythm<0.01), shorten recover required for when
Between (P<0.01), and can increase recovery normal cardiac rhythm hold time>Rat quantity (the P of 5min<0.01), wherein recover normal
The rhythm of the heart holds time >=and the number of rats of 20min is also significantly increased (P ＜ 0.05).
The mechanism of action of bromo crebanine class compound of the present invention：Barium chloride induction the rat ventricular mechanism of action with
Ca2+Similar, lead to rat to produce on VPB, Ventricular Tachycardia and ventricular fibrillation, with cell membrane after intravenous administration
Ca2+Interior stream relevant；It may also is that suppression K+Outflow, thus increase by the four phase gradients, improve atrium conductive tissue and room
The self-disciplining of the fast responsive cellses such as room bundle-Pu hectare Ye Shi fiber is relevant.In this experiment, 3- bromo crebanine and 10,11- bromo gram
Class rather has good inhibitory action thus it is speculated that effect may suppress Ca with it to the rat ventricular of barium chloride induction2+Interior stream
Or K+Outflow is relevant.
(4) median lethal dose test
Kunming mouse, SPF level, male and female half and half, body weight 20 ± 2g is purchased from Chengdu Da Shuo bio tech ltd, raw
Produce licensing：SYXK(Dian)K 2011-0011.
1. trial test determines the value of compound Dm and Dn
First set a metering experiment, after mouse tail vein injection administration, close observation administration mouse reacts and dead feelings
Condition, moves up and down the gear examination of dosage by geometric progression, so carry out 10～20 tests find out cause mouse 0% (Dn) and
100% (Dm) dead dosage.
Experiment draws 3- bromo crebanine：Dm=69.39mg/kg, Dn=62.72mg/kg；10,11- bromo crebanine：
Dm=66.50mg/kg, Dn=54.20mg/kg；
2. formal test determines the LD of compound50
Using the test of upper laxative remedy.List each test dose and logarithm value, group sequence (d), stoichiometric number (death toll, a), ad,
ad2, by approximately LD50Dosage give the 1st mouse, if this mouse survival.2nd mouse gives high one grade of dosage,
If death, give low one grade of dosage.It is necessary to clearly go up a mouse test before determining to the dosage of next mouse
Result.
After off-test, calculate dead animal number (a) of each group sequence, the summation (N) of dead animal number, dead animal number
With the product (ad) of group sequence, the summation (A) of ad.Then the following LD calculating test mice50.
Calculate by formula below：
LD50=lg-1[X0+i(A/N-0.5)
LD50Standard error SX50=i/ √ N { [1.46 (NB-A2)/N2]+0.167}
LD5095% average fiducial limit=LD50±4.5*LD50*SX50
3. experimental result：
a：3- bromo crebanine LD50Measurement result
LD50=lg-1[1.8150+0.0088 (3/8-0.5)]=lg-11.8139=65.15mg/kg
SX50=0.0088/ √ 8 { [1.46 (8*7-32)/82]+0.167=0.00386
LD5095% average fiducial limit=65.15 ± 4.5*65.15*0.00386=65.15 ± 1.132mg/kg
b：10,11- bromo crebanine LD50Measurement result
LD50=lg-1[1.7782+0.0222 (3/8-0.5)]=lg-11.7754=59.62mg/kg
SX50=0.0222/ √ 8 { [1.46 (8*7-32)/82]+0.167=0.00973
LD5095% average fiducial limit=59.62 ± 4.5*59.62*0.00973=59.62 ± 2.610mg/kg
It can be found that its effective dose is far low by the effective dose and its median lethal dose contrasting two kinds of bromo crebanines
In its median lethal dose, illustrate that both Drug safety are high, patent medicine possibility is big.
Compared with prior art, its advantage is the present invention：
The present invention is first public to have synthesized 3- bromo crebanine and 10,11- bromo crebanine, is then passed through chloroform is induced
The research of mouse Arrhythmia, research shows that 3- bromo crebanine and 10,11- bromo crebanine being capable of the inductions of antagonism chloroform
The effect of room property fibrillation, preliminary assert that it has antiarrhythmic effect；Through carrying out the barium chloride induction rat room property heart further
Rule test is it was demonstrated that 3- bromo crebanine and 10,11- bromo crebanine have good antiarrhythmic effect, and 2 bromos gram
The peaceful acute toxicity of class is all a lot of than crebanine (LD50) reduces, (LD50) be respectively 3- bromo crebanine 65.15 ±
1.132mg/kg, 10,11- bromo crebanine 59.62 ± 2.610mg/kg, its security greatly improves, and reaches Synergy and attenuation
Purpose, and this research speculates its drug action mechanism, for next by multiple anti-arrhythmia model test Comparative result
Good basis is laid in step further investigation.
3- bromo crebanine of the present invention, 10,11- bromo crebanine are distributed in menispermaceae Stephania (Stephania) and plant
In thing, there are multiple physiologically actives, the anti-arrhythmia medicine being prepared into various formulations can be researched and developed, and absent cardiovascular, lung, god
The bad reaction of the aspects such as warp, endocrine.
Brief description
Fig. 1 is the 1H NMR spectra of 3- bromo crebanine；
Fig. 2 is the MS spectrogram of 3- bromo crebanine；
Fig. 3 is the 1H NMR spectra of 10,11- bromo crebanine；
Fig. 4 is the MS spectrogram of 10,11- bromo crebanine.
Specific embodiment
With reference to embodiment, the present invention is described in further detail.
It will be understood to those of skill in the art that the following example is merely to illustrate the present invention, and should not be regarded as limiting this
Bright scope.Unreceipted particular technique or condition person in embodiment, according to the technology described by document in the art or condition
Or carry out according to product description.Agents useful for same or the unreceipted production firm person of instrument, are and can pass through what purchase obtain
Conventional products.
Preparation method embodiment 1
Step (1), under condition of ice bath, adds trifluoroacetic acid that crebanine is completely dissolved in crebanine；Then again
It is slowly added to N- bromo-succinimide, the joining day of N- bromo-succinimide is more than 10min；After adding, remove ice bath,
Place reaction liquid into stirring 11h under room temperature, rear rotary evaporation, to remove solvent trifluoroacetic acid, obtains concentrate；
Crebanine is 0.2 with the mass volume ratio of trifluoroacetic acid：4.9；Crebanine and N- bromo-succinimide mole
Than for 1：1.1；
Step (2), adding in the concentrate obtaining to step (1) is the water of 9.5 times of trifluoroacetic acid volume, then uses saturation
Na2CO3The aqueous solution adjusts pH to 8, then uses CH2Cl2Extracted, extract 2 times, extract CH every time2Cl2Usage amount is water volume
1/5th, merge organic layer；
Step (3), washes organic layer with the saturated aqueous common salt of organic layer 1/3rd volume, to remove in organic layer
Water, is then dried using anhydrous sodium sulfate, and then rotary evaporation is to remove CH2Cl2, the solid obtaining crosses 200-300 mesh silicon
Glue post, first adopts volume ratio to be 200:1 CH2Cl2- MeOH is eluted, until 10,11- bromo crebanine rushes from silicagel column
After washing entirely, then it is 100 using volume ratio:1 CH2Cl2- MeOH is eluted, and collects eluent respectively；Entirely cross post process
Followed the tracks of using thin-layered chromatography, to no 3- bromo crebanine, stop wash-out.
The volume ratio collected is 200:The eluent of 1 part, after concentration, 39 DEG C are vacuum dried 3.9 hours, obtain 10,
11- bromo crebanine；The volume ratio collected is 100:The eluent of 1 part, after concentration, 41 DEG C are vacuum dried 3.9 hours, obtain
To 3- bromo crebanine.
Preparation method embodiment 2
Step (1), under condition of ice bath, adds trifluoroacetic acid that crebanine is completely dissolved in crebanine；Then again
It is slowly added to N- bromo-succinimide, the joining day of N- bromo-succinimide is more than 10min；After adding, remove ice bath,
Place reaction liquid into stirring 13h under room temperature, rear rotary evaporation, to remove solvent trifluoroacetic acid, obtains concentrate；
Crebanine is 0.2 with the mass volume ratio of trifluoroacetic acid：5.1；Crebanine and N- bromo-succinimide mole
Than for 1：1.3；
Step (2), adding in the concentrate obtaining to step (1) is the water of 10.5 times of trifluoroacetic acid volume, then with satisfying
And Na2CO3The aqueous solution adjusts pH to 8, then uses CH2Cl2Extracted, extract 4 times, extract CH every time2Cl2Usage amount is water volume
1/5th, merge organic layer；
Step (3), washes organic layer with the saturated aqueous common salt of organic layer 1/3rd volume, to remove in organic layer
Water, is then dried using anhydrous sodium sulfate, and then rotary evaporation is to remove CH2Cl2, the solid obtaining crosses 200-300 mesh silicon
Glue post, first adopts volume ratio to be 200:1 CH2Cl2- MeOH is eluted, until 10,11- bromo crebanine rushes from silicagel column
After washing entirely, then it is 100 using volume ratio:1 CH2Cl2- MeOH is eluted, and collects eluent respectively；Entirely cross post process
Followed the tracks of using thin-layered chromatography, to no 3- bromo crebanine, stop wash-out.
The volume ratio collected is 200:The eluent of 1 part, after concentration, 41 DEG C are vacuum dried 4.1 hours, obtain 10,
11- bromo crebanine；The volume ratio collected is 100:The eluent of 1 part, after concentration, 41 DEG C are vacuum dried 4.1 hours, obtain
To 3- bromo crebanine.
Preparation method embodiment 3
Step (1), under condition of ice bath, adds trifluoroacetic acid that crebanine is completely dissolved in crebanine；Then again
It is slowly added to N- bromo-succinimide, the joining day of N- bromo-succinimide is more than 10min；After adding, remove ice bath,
Place reaction liquid into stirring 12h under room temperature, rear rotary evaporation, to remove solvent trifluoroacetic acid, obtains concentrate；
Crebanine is 0.2 with the mass volume ratio of trifluoroacetic acid：5；Crebanine and the mol ratio of N- bromo-succinimide
For 1：1.2；
Step (2), adding in the concentrate obtaining to step (1) is the water of 10 times of trifluoroacetic acid volume, then uses saturation
Na2CO3The aqueous solution adjusts pH to 8, then uses CH2Cl2Extracted, extract 3 times, extract CH every time2Cl2Usage amount is water volume
1/5th, merge organic layer；
Step (3), washes organic layer with the saturated aqueous common salt of organic layer 1/3rd volume, washs 3 times, organic to remove
Water in layer, is then dried using anhydrous sodium sulfate, then rotary evaporation is to remove CH2Cl2, the solid obtaining crosses 200-
300 mesh silicagel columns, first adopt volume ratio to be 200:1 CH2Cl2- MeOH is eluted, until 10,11- bromo crebanine is from silicon
After rinsing completely on glue post, then it is 100 using volume ratio:1 CH2Cl2- MeOH is eluted, and collects eluent respectively；Entirely
Crossing post process adopts thin-layered chromatography to follow the tracks of, and to no 3- bromo crebanine, stops wash-out.
The volume ratio collected is 200:The eluent of 1 part, after concentration, 40 DEG C are vacuum dried 4 hours, obtain 10,11-
Bromo crebanine；The volume ratio collected is 100:The eluent of 1 part, after concentration, 40 DEG C are vacuum dried 4 hours, obtain 3-
Bromo crebanine.
Preparation method embodiment 4
White solid crebanine (200mg, 0.59mmol) is added in 50ml single necked round bottom flask, adds three under ice bath
Fluoroacetic acid (5ml) is dissolved, then is slowly added to N- bromo-succinimide (126.37 mg, 0.72mmol) by several times and exceedes
10min, after adding, removes ice bath, places reaction liquid into stirring 12h under room temperature.Sample point plate, observes still there be a small amount of gram of class
Peaceful but reaction is not being carried out, and reactant liquor is spin-dried for, and the 50ml that adds water dissolves, and uses saturation Na2CO3The aqueous solution adjusts its pH=8.Use again
CH2Cl2Extraction, extracts three times, each 10ml every time, merges organic layer.Organic layer and the comparison of water layer each sample point plate, aqueous phase is in purple
Under outer 254nm, find no product point, then with saturated aqueous common salt washing organic layer 3 times, aqueous phase discarded, organic layer is again with anhydrous
Sodium sulphate is dried 15min, and rotation is evaporated organic layer, obtains white solid, mixes sample, crosses 200-300 mesh silicagel column, uses CH2Cl2-MeOH
(200:1) elute, obtain target product faint yellow solid 10,11- bromo crebanine (50mg, yield 20%)；Use CH2Cl2-MeOH
(100:1) elute, obtain target product white solid 3- bromo crebanine (80mg, yield 27%).
Collection of illustrative plates and data：
(1) 10,11- bromo crebanine 1H NMR, MS compose, as shown in Figure 3 and Figure 4.
Positive ESI-MS m/z:497.9.[M+H]+.1H NMR(400MHZ,CDCl3):δ7.13(s,1H,3-H),
6.14(s,1H,-OCH2O-),6.05(s,1H,-OCH2O-),3.89(s,3H,8-OCH3),3.79(s,3H,9-OCH3),
3.61-3.57(m,1H,6a-H),3.11-3.07(m,1H,7-Ha),2.97-2.87(m,2H,5-Ha,7-Hb),2.80-2.66
(m,1H,5-Hb),2.56(s,3H,-NCH3), 2.52-2.47 (m, 1H, 4-Ha), 2.11-2.04 (t, J=13.6HZ,1H,4-
Hb).
(2) 3- bromo crebanine 1H NMR, MS spectrum, as shown in Figures 2 and 3.
Positive ESI-MS m/z:418[M]+,420.0[M+2]+.1H NMR(400MHZ,CDCl3):δ7.76(d,J
=8.8HZ, 1H, 11-H), 6.90 (d, J=8.8HZ,1H,10-H),6.22(s,1H,-OCH2O-),6.07(s,1H,-
OCH2O-),3.91(s,3H,8-OCH3),3.84(s,3H,9-OCH3),3.82-3.80(m,1H,6a-H),3.09-3.04(m,
2H,5-Ha,7-Hb),2.90-2.82(m,2H,5-Ha,7-Hb),2.17(s,3H,-NCH3),1.95-1.87(m,1H,4-
Ha),1.79-1.72(m,1H,4-Hb).
Embodiment 1
A kind of antiarrhythmic drug, including following component in parts by weight：Bromo crebanine class compound 50
Bromo crebanine class compound described in part, 20 parts of Icing Sugar, 20 parts of dextrin is 3- bromo crebanine or 10,11- bromo crebanine
And its pharmaceutically acceptable salt.
By said ratio, bromo crebanine class compound, microcrystalline cellulose and starch are mixed, add appropriate volume percentage
Suitable softwood made by several 50% ethanol, crosses 20 mesh sieves and pelletizes, 80 DEG C of dryings 2 hours, and dry particle whole grain of sieving adds stearic acid
Magnesium, mixes, obtains final product granule.
Described bromo crebanine class compound is 3- bromo crebanine.
Embodiment 2
A kind of antiarrhythmic drug, including following component in parts by weight：Bromo crebanine class compound 250
Part, 60 parts of Icing Sugar, 5 parts of dextrin；Described bromo crebanine class compound is 3- bromo crebanine or 10,11- bromo crebanine
And its pharmaceutically acceptable salt.Described bromo crebanine class compound is 10,11- bromo crebanine.
Preparation method is same as Example 1.
Embodiment 3
A kind of antiarrhythmic drug, including following component in parts by weight：Bromo crebanine class compound 120
Part, 90 parts of Icing Sugar, 10 parts of dextrin；Described bromo crebanine class compound is 3- bromo crebanine or 10,11- bromo crebanine
And its pharmaceutically acceptable salt.
Described bromo crebanine class compound is the pharmaceutically acceptable salt of 3- bromo crebanine.
Preparation method is same as Example 1.
Embodiment 4
A kind of antiarrhythmic drug, including following component in parts by weight：Bromo crebanine class compound 50
Part, 20 parts of amylum pregelatinisatum, 1 part of sodium carboxymethylcellulose, 1 part of magnesium stearate；
Described bromo crebanine class compound is 3- bromo crebanine pharmaceutically acceptable salt.
By said ratio, bromo crebanine class compound, amylum pregelatinisatum and sodium carboxymethylcellulose are mixed, add suitable
Suitable softwood made by amount percentage by volume 50% ethanol, crosses 20 mesh sieves and pelletizes, 80 degrees Celsius of dryings 2 hours, and dry particle is sieved
Add magnesium stearate after whole grain, mix, compressing tablet, obtain final product tablet.
Embodiment 5
A kind of antiarrhythmic drug, including following component in parts by weight：Bromo crebanine class compound 250
Part, 90 parts of amylum pregelatinisatum, 5 parts of sodium carboxymethylcellulose, 0.3 part of magnesium stearate；
Described bromo crebanine class compound is 3- bromo crebanine.
Preparation method is same as Example 4.
Embodiment 6
A kind of antiarrhythmic drug, including following component in parts by weight：Bromo crebanine class compound 120
Part, 60 parts of amylum pregelatinisatum, 3 parts of sodium carboxymethylcellulose, 0.7 part of magnesium stearate；
Described bromo crebanine class compound is 10,11- bromo crebanine.
Preparation method is same as Example 4.
Embodiment 7
A kind of antiarrhythmic drug, including following component in parts by weight：Bromo crebanine class compound 50
Part, 50 parts of Macrogol 6000；
Described bromo crebanine class compound is the solvate of 3- bromo crebanine.
By said ratio, bromo crebanine class compound is mixed with Macrogol 6000, heating stirring (100 DEG C about),
After all melting, instill quick under 85 DEG C about heat-retaining conditions for feed liquid in condensate liquid, be condensed into dripping pill.
Embodiment 8
A kind of antiarrhythmic drug, including following component in parts by weight：Bromo crebanine class compound 250
Part, 500 parts of Macrogol 6000；
Described bromo crebanine class compound is the solvate of 10,11- bromo crebanine.
Preparation method is same as Example 7.
Embodiment 9
A kind of antiarrhythmic drug, including following component in parts by weight：Bromo crebanine class compound 120
Part, 240 parts of Macrogol 6000；
Described bromo crebanine class compound is the pharmaceutically acceptable salt of 10,11- bromo crebanine.
Preparation method is same as Example 7.
Embodiment 10
A kind of antiarrhythmic drug, including following component in parts by weight：
50 parts of bromo crebanine class compound, 1 part of solubilizer, 0.05 part of ethyl hydroxy benzoate, 4800 parts of sucrose, add water to gross weight
Measure as 10000 parts；
Described bromo crebanine class compound is 3- bromo crebanine pharmaceutically acceptable salt.
By said ratio, bromo crebanine class compound and ethyl hydroxy benzoate are added after appropriate water dissolves.Separately take sucrose, add water
Boil, after dissolving, filter, concentrate the syrup of system, mix with aforesaid liquid, after letting cool, add solubilizer, be diluted with water to complete
Amount, obtains final product syrup.
Embodiment 11
A kind of antiarrhythmic drug, including following component in parts by weight：
250 parts of bromo crebanine class compound, 10 parts of solubilizer, 0.15 part of ethyl hydroxy benzoate, 5200 parts of sucrose, add water to total
Weight is 10000 parts；
Described bromo crebanine class compound is 3- bromo crebanine or 10,11- bromo crebanine.
Preparation method is same as in Example 10.
Embodiment 12
A kind of antiarrhythmic drug, including following component in parts by weight：
150 parts of bromo crebanine class compound, 8 parts of solubilizer, 0.1 part of ethyl hydroxy benzoate, 5000 parts of sucrose, add water to total
Weight is 10000 parts；
Described bromo crebanine class compound is 3- bromo crebanine or 10,11- bromo crebanine.
Preparation method is same as in Example 10.
Embodiment 13
A kind of antiarrhythmic drug, including following component in parts by weight：
25 parts of bromo crebanine class compound, 5 parts of solubilizer, 1000 parts of water for injection；
Described bromo crebanine class compound is 3- bromo crebanine, 10,11- bromo crebanine, it pharmaceutically can connect
The salt being subject to and one or more combine in solvate.
By said ratio, bromo crebanine class compound and solubilizer are first mixed and add the nearly full dose of water for injection afterwards, be allowed to molten
Solution, plus pH adjusting agent tune pH to 7 about, add to the full amount of water for injection, filtration, embedding, and 100 degrees Celsius of flowing steam sterilizations obtain final product
Parenteral solution.
Embodiment 14
A kind of antiarrhythmic drug, including following component in parts by weight：
125 parts of bromo crebanine class compound, 10 parts of solubilizer, 2000 parts of water for injection；
Described bromo crebanine class compound is 3- bromo crebanine, 10,11- bromo crebanine, it pharmaceutically can connect
The salt being subject to and one or more combine in solvate.
Preparation method is identical with embodiment 13.
Embodiment 15
A kind of antiarrhythmic drug, including following component in parts by weight：
60 parts of bromo crebanine class compound, 6 parts of solubilizer, water for injection 1500；
Described bromo crebanine class compound is 3- bromo crebanine, 10,11- bromo crebanine, it pharmaceutically can connect
The salt being subject to and one or more combine in solvate.
Preparation method is identical with embodiment 13.
Embodiment 16
A kind of antiarrhythmic drug, including following component in parts by weight：
50 parts of bromo crebanine class compound, 1000 parts of semi-synthetic fatty glyceride；
Described bromo crebanine class compound is 3- bromo crebanine, 10,11- bromo crebanine, it pharmaceutically can connect
The salt being subject to and one or more combine in solvate.
By said ratio, semi-synthetic fatty acid ester is heated fusing, insulation, at 40 DEG C about, adds bromo crebanine class
Compound, mixes, injection molding, and cooling obtains final product suppository.
Embodiment 17
A kind of antiarrhythmic drug, including following component in parts by weight：
400 parts of bromo crebanine class compound, 2000 parts of semi-synthetic fatty glyceride；
Described bromo crebanine class compound is 3- bromo crebanine, 10,11- bromo crebanine, it pharmaceutically can connect
The salt being subject to and one or more combine in solvate.
Preparation method is identical with embodiment 16.
Embodiment 18
A kind of antiarrhythmic drug, including following component in parts by weight：
200 parts of bromo crebanine class compound, 1500 parts of semi-synthetic fatty acid ester；
Described bromo crebanine class compound is 3- bromo crebanine, 10,11- bromo crebanine, it pharmaceutically can connect
The salt being subject to and one or more combine in solvate.
Preparation method is identical with embodiment 16.
Embodiment 19
A kind of antiarrhythmic drug, according to weight/mass percentage composition meter, described medicine contains 1%3- bromo crebanine
Solvate and 99% pharmaceutical excipient.
Embodiment 20
A kind of antiarrhythmic drug, according to weight/mass percentage composition meter, described medicine contain 49%3- bromo crebanine,
The solvate of 50% stephanine and 1% pharmaceutical excipient.
Embodiment 21
A kind of antiarrhythmic drug, according to weight/mass percentage composition meter, described medicine contains 30%3- bromo crebanine
With 70% pharmaceutical excipient.
Embodiment 22
A kind of antiarrhythmic drug, according to weight/mass percentage composition meter, described medicine contains 40%10,11- bromo gram
Class is peaceful, 40%10,11- bromo crebanine pharmaceutically acceptable salt and 20% pharmaceutical excipient.
Embodiment 23
A kind of antiarrhythmic drug, according to weight/mass percentage composition meter, described medicine contains 60%10,11- bromo gram
Class's peace 40% pharmaceutical excipient.
Embodiment 24
A kind of antiarrhythmic drug, according to weight/mass percentage composition meter, described medicine contains 70%10,11- bromo gram
The peaceful pharmaceutically acceptable salt of class and 30% pharmaceutical excipient.
Embodiment 25
A kind of antiarrhythmic drug, it is pharmaceutically acceptable that described medicine contains 65%10,11- bromo crebanine
Salt and 35% pharmaceutical excipient.
General principle, principal character and the advantages of the present invention of the present invention have been shown and described above.The technology of the industry
, it should be appreciated that the present invention is not restricted to the described embodiments, the simply explanation described in above-described embodiment and specification is originally for personnel
The principle of invention, without departing from the spirit and scope of the present invention, the present invention also has various changes and modifications, these changes
Change and improvement both falls within scope of the claimed invention.Claimed scope by appending claims and its
Equivalent thereof.
Claims (10)
1. bromo crebanine class compound, structural formula such as formula（Ⅰ）Shown；
, formula（Ⅰ）；
Wherein, X1During for Br, X2、X3It is H；X1During for H, X2、X3It is Br.
2. the preparation method of the bromo crebanine class compound described in claim 1 is it is characterised in that comprise the steps：
Step（1）, under condition of ice bath, add trifluoroacetic acid that crebanine is completely dissolved in crebanine；Then slow again
Add N- bromo-succinimide, the joining day of N- bromo-succinimide is more than 10min；After adding, remove ice bath, will be anti-
Liquid is answered to put stirring 11-13h at room temperature, rear rotary evaporation, to remove solvent trifluoroacetic acid, obtains concentrate；
Crebanine is 0.2 with the mass volume ratio of trifluoroacetic acid：4.9-5.1；Crebanine and N- bromo-succinimide mole
Than for 1：1.1-1.3；
Step（2）, to step（1）Adding in the concentrate obtaining is the water of trifluoroacetic acid volume 9.5-10.5 times, then with satisfying
And Na2CO3The aqueous solution adjusts pH to 8, then uses CH2Cl2Extracted, extract 2-4 time, extract CH every time2Cl2Usage amount is water body
Long-pending 1/5th, merge organic layer；
Step（3）, wash organic layer with the saturated aqueous common salt of organic layer 1/3rd volume, to remove the water in organic layer, so
It is dried using anhydrous sodium sulfate afterwards, then rotary evaporation is to remove CH2Cl2, the solid obtaining crosses 200-300 mesh silicagel column,
Volume ratio is first adopted to be 200:1 CH2Cl2- MeOH is eluted, and thin-layered chromatography traces into 10,11- bromo crebanine from silicon
After rinsing completely on glue post, then it is 100 using volume ratio:1 CH2Cl2- MeOH is eluted, and collects eluent respectively；Thin layer
Chromatography is followed the tracks of, and to no 3- bromo crebanine, stops wash-out；
The volume ratio collected is 200:The eluent of 1 part, after concentration, 39-41 DEG C of vacuum drying 3.9-4.1 hour, obtain
10,11- bromo crebanine；The volume ratio collected is 100:The eluent of 1 part, after concentration, 39-41 DEG C of vacuum drying 3.9-
4.1 hours, obtain 3- bromo crebanine.
3. the preparation method of bromo crebanine class compound according to claim 2 is it is characterised in that described uses saturation
Saline solution water-washing step（2）During the organic layer obtaining, washing times are 3 times.
4. the bromo crebanine class compound described in claim 1 and its pharmaceutically acceptable salt and solvate are as preparation
The application of antiarrhythmic drug.
5. bromo crebanine class compound according to claim 4 and its pharmaceutically acceptable salt and solvate conduct
The application preparing antiarrhythmic drug is it is characterised in that described pharmaceutically acceptable salt includes but is not limited to formula（Ⅰ）'s
Acetate, acrylates, benzene sulfonate, benzoate, bicarbonate, disulfate, bisulfites, biatrate, boron
Hydrochlorate, bromide, butine-Isosorbide-5-Nitrae-diacid salt, Ca-EDTA salt, camsilate, carbonate, chloride, caproate,
Caprylate, Clavulanate, citrate, caprate, dihydrochloride, dihydric phosphate, edetate, ethionic acid
Salt, Estolate, esilate, ethylsuccinate, formates, fumarate, gluceptate, glucose
Hydrochlorate, glutamate, glycollate, hydroxyl acetyl arsanilate, enanthate, hexin -1,6- diacid salt, hexylresorcinol two
Phenates, Hai Baming salt, hydrobromate, hydrochloride, y- hydroxybutyric acid salt, iodide, isobutyrate, different thiosulfate, lactic acid
Salt, Lactobionate, laruate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, first
Alkyl sulfonate, Methylsulfate, dibasic alkaliine, mucic acid salt, naphthalene sulfonate, naphthalene -1- sulfonate, naphthalene-2-sulfonic acid salt, nitric acid
Salt, oleate, oxalates, pamoate, palmitate, pantothenate, phenyl acetate salt, PB, phenylpropionic acid salt, adjacent benzene
Diformate, phosphate, diphosphate, Polygalacturonate, propane sulfonate, propionate, propiolate, pyrophosphate,
Pyrosulfate, salicylate, stearate, basic acetate, suberate, succinate, sulfate, sulfonate, sulfurous acid
Salt, tannate, tartrate, chloro theophylline salt, toluene fulfonate, plus draw salt compounded of iodine, valerate.
6. bromo crebanine class compound according to claim 4 and its pharmaceutically acceptable salt and solvate conduct
Prepare the application of antiarrhythmic drug it is characterised in that the solvent that described acceptable solvates adopt be water, isopropanol,
The composition of one or more in ethanol, methyl alcohol, dimethyl sulfoxide, ethyl acetate, acetic acid and monoethanolamine.
7. bromo crebanine class compound according to claim 4 and its pharmaceutically acceptable salt and solvate conduct
Prepare the application of antiarrhythmic drug it is characterised in that described pharmaceutical dosage form be oral formulations, ejection preparation, suppository or
Preparation capable of permeating skin.
8. bromo crebanine class compound according to claim 4 and its pharmaceutically acceptable salt and solvate conduct
Prepare the application of antiarrhythmic drug it is characterised in that according to weight/mass percentage composition meter, described medicine contains 1%-99%'s
Pharmaceutical excipient, balance of bromo crebanine class compound, bromo crebanine class compound pharmaceutically acceptable salt and bromo
The combination of one or more in the solvate of crebanine class compound.
9. bromo crebanine class compound according to claim 4 and its pharmaceutically acceptable salt and solvate conduct
Prepare the application of antiarrhythmic drug it is characterised in that according to weight/mass percentage composition meter, described medicine contains 20%-70%
Pharmaceutical excipient, balance of bromo crebanine class compound, bromo crebanine class compound pharmaceutically acceptable salt and bromine
For the combination of one or more in the solvate of crebanine class compound.
10. bromo crebanine class compound according to claim 4 and its pharmaceutically acceptable salt are made with solvate
For preparing the application of antiarrhythmic drug it is characterised in that according to weight/mass percentage composition meter, described medicine contains 30%-
40% pharmaceutical excipient, balance of bromo crebanine class compound, bromo crebanine class compound pharmaceutically acceptable salt and
The combination of one or more in the solvate of bromo crebanine class compound.
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| 淤泽溥，等: "克班宁的抗心律失常作用", 《中国中药杂志》 * |
| 马云淑，等: "克班宁急性毒性与抗心律失常活性的初步研究", 《中国现代应用药学杂志》 * |
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