CN103373959A - Preparation method of cis-benzyl isoquinoline compound and application thereof - Google Patents

Preparation method of cis-benzyl isoquinoline compound and application thereof Download PDF

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Publication number
CN103373959A
CN103373959A CN2013102354716A CN201310235471A CN103373959A CN 103373959 A CN103373959 A CN 103373959A CN 2013102354716 A CN2013102354716 A CN 2013102354716A CN 201310235471 A CN201310235471 A CN 201310235471A CN 103373959 A CN103373959 A CN 103373959A
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cis
compound
compounds
benzylisoquinoline
preparation
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徐奎
陈正晧
魏伟
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ANHUI PIOM PHARMACEUTICAL Co Ltd
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ANHUI PIOM PHARMACEUTICAL Co Ltd
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Priority to PCT/CN2014/076333 priority patent/WO2014198164A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine

Abstract

The invention relates to the field of medicinal chemistry and specifically relates to a cis-benzyl isoquinoline compound, a preparation method thereof, a pharmaceutical preparation containing the cis-benzyl isoquinoline compound and a medicinal application thereof. A neuromuscular blocking agent of the compound disclosed by the invention is high in effect taking speed and also rapid in recovery, and has almost no effect of releasing any histamine.

Description

The preparation method and its usage of cis benzylisoquinoline compounds
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a class cis benzylisoquinoline compounds, its preparation method and comprise its pharmaceutical preparation and medicinal use thereof.
Background technology
Muscle relaxant has vital role in General Anesthesia, the effective and reasonable application of muscle relaxant can not only provide Satisfaction Conditions for operation, and is conducive to breathe management.Muscle relaxant associating GENERAL ANESTHETICS is carried out rapid induction and endotracheal intubation, makes masseter lax, and glottis is opened, and is conducive to the intubate operation.To weaken and obtain satisfied trachea cannula condition be anesthesia critical days to guarding reflex during this period of time due to the general anesthesia induction, and the complication such as anoxic, reflux erroneous aspiration very easily occur, and should shorten as far as possible the general anesthesia induction time, as early as possible trachea cannula control respiratory tract.And the morning and evening of the onset speed of muscle relaxant trachea cannula when determining general anesthesia induction to a great extent, therefore, it is most important to the safety of anesthesia induction phase to accelerate the muscle relaxant onset.
Although sux-cert is to carry out quick-anaesthesia to induce choice drug with endotracheal intubation, but since its numerous untoward reaction make its in many cases (such as severe trauma, glaucoma, hyperkalemia etc.) can not use, and need to use non-depolarizing muscular relaxant.At present, non-depolarizing muscular relaxant is widely used clinically, even but give very high dosage, there is no up to now a kind of non-depolarizing muscular relaxant and can as sux-cert, can in 60 s, provide good Intubation Conditions.Be still one of heat subject that needs to be resolved hurrily so accelerate the onset of non-depolarizing muscular relaxant, scholars have proposed various measures for clinical employing, mainly comprise heavy dose of medication, annotate method, in limited time method, drug combination and development new drug in advance.
Non-depolarizing muscular relaxant belongs to water-soluble quaternary ammonium compounds, its histamine release effect is weaker than tertiary amine class medicine such as morphine, but when fast injecting some heavy dose of non-depolarizing muscular relaxant, can cause obvious histamine release, especially first easier generation during the larger dose fast intravenous injection.If behind the muscle relaxant of quiet notes initial dose, produce slight histamine release and series reaction thereof, then after appending subsequently the muscle relaxant that is no more than initial dose, can not produce again similar reaction.This is an important feature of histamine release.Non-depolarizing muscular relaxant causes that another characteristics of histamine release and series reaction are time length very short (usually after injection in 1～5min), and closely related with dosage and speed.The histamine release effect of non-depolarizing muscular relaxant can by reduce dosage, rate of administration and use histamine H slows down 1And H 2Receptor antagonist is prevented.
According to the difference of chemical structure, non-depolarizing muscular relaxant can be divided into steroid class and benzyl iloquinoline derivative.Pipecuronium bromide, vecuronium bromide, Zemuron, Raplon etc. belong to the steroid class, and tubocurarine, atracurium, cis atracurium, mivacurium etc. belong to the benzyl iloquinoline derivative.Benzyl iloquinoline derivative non-depolarizing muscular relaxant more easily causes obvious histamine release.Research report is arranged, and also with the release of tryptase, and steroid class non-depolarizing muscular relaxant can cause fast histamine release to benzyl iloquinoline derivative non-depolarizing muscular relaxant, the hang-over n. of the tryptase of following when causing the dose-dependently histamine release.
It is of many uses that season is pressed salt compounds, and good development prospect is arranged, especially for pharmaceutical industries as of flaccid muscles oneself extensively paid close attention to by people.The season of clinical existing use is pressed salt compounds, and the overwhelming majority all is stereoisomer mixtures, and the pharmacological action of every kind of single stereoisomers and onset all have a lot of differences, and having caused so clinical use is that onset time and time of recovery are unbalanced.
Biological activity between the enantiomer exists difference, has plenty of enantiomorph identical pharmacologically active is arranged, and has plenty of and only has an enantiomorph that pharmacologically active is arranged, and has plenty of enantiomorph difference or opposite pharmacologically active are arranged.Different stereoisomerisms just because of chiral drug all may there are differences at aspects such as drug effect, medicine generation and toxicitys, therefore medicine generation, drug effect and toxicology character to the pure isomer of optical activity is all stipulated in the research of chiral drug at home and abroad, preferentially carried out clinical study and approval listing.
The benzylisoquinoline class quaternary ammonium compound of clinical use is used for muscle relaxant, all contains four chiralitys, and two chiral carbon and two chirality nitrogen, and what the overwhelming majority was medicinal all is isomer.
Atracurium besylate (atracurium) is the non-depolarizing muscular relaxant of the middle timeliness of classics, in clinical anesthesia, generally use, the clinical medicine that only uses as single stereoisomers, cisatracurium besylate (cisatracurim) is one of ten kinds of isomerss of atracurium besylate, account for 15% of amount of the mixture, it has flesh pine effect and the metabolic way similar to atracurium besylate, but its flesh pine action intensity is about 3 times of atracurium.
The cis atracurium is stronger than atracurium effect, quantity is little, onset time is short.Research in the past thinks that the cis atracurium is without histamine release, without obvious cardiovascular adverse effects.But also have research to think, the cis atracurium also can cause to be similar to and use the clinical adverse that occurs behind the atracurium, as: skin erythema and ypotension etc.
Advantage and great defective based on clinical benzyl iloquinoline derivative non-depolarizing muscular relaxant, the applicant is devoted to study the research of the novel benzyl iloquinoline derivative non-depolarizing muscular relaxant new compound rapid-action, that recovery is fast, side effect is minimum, used reversal of poles etc. medicine principle, a large amount of novel benzyl isoquinoline compounds have been synthesized, wherein, compound of the present invention has beyond thought medicinal effect, has finished the present invention for this reason.
Summary of the invention
The object of the invention is to remedy the deficiencies in the prior art part, and provide the new cis benzylisoquinoline compounds of a class or its pharmacy acceptable salt, technical problem to be solved is to use 3D structure activity relationship and pharmaceutical chemistry reversal of poles principle, filters out a series of new compounds of the novel cis benzylisoquinoline compounds of high-efficiency low-toxicity.
Compound general formula of the present invention is as follows:
Figure DEST_PATH_434887DEST_PATH_IMAGE001
Wherein R is selected from hydrogen atom or methoxyl group,
Figure DEST_PATH_813041DEST_PATH_IMAGE002
Be expressed as the chain hydrocarbon that contains two keys, n is 2 or 4 or 6 or 8 or 10, n more preferably 4 or 6.
The present invention also comprises the cis benzylisoquinoline compounds shown in the general formula (I) or its pharmacy acceptable salt, and the pharmaceutically acceptable acid group that described salt is selected from is muriate, bromide and Phenylsulfonic acid compound salt.
Another object of the present invention provides implements optimised form compound of the present invention:
Compound I 1:
Compound I 3:
Figure 257704DEST_PATH_IMAGE003
Compound I 4:
Compound I 5:
Figure 961404DEST_PATH_IMAGE005
Compound I 6:
Figure 542558DEST_PATH_IMAGE006
The invention also discloses the cis benzylisoquinoline compounds shown in the general formula (I) or the preparation method of its pharmacy acceptable salt.
Cis benzylisoquinoline compounds shown in the general formula (I) or the preparation method of its pharmacy acceptable salt comprise:
Figure 877724DEST_PATH_IMAGE007
Figure 793597DEST_PATH_IMAGE008
R wherein 1And the definition of n is with claim 1.
The preparation method of other pharmacy acceptable salt of cis benzylisoquinoline compounds shown in the general formula (I) such as chloride salt and bromide salt, adopts substitution method, comprising:
Figure 872411DEST_PATH_IMAGE009
A further object of the present invention is that described cis benzylisoquinoline compounds or its pharmacy acceptable salt and pharmaceutically acceptable carrier are made common pharmaceutical preparation, such as injection liquid, freeze-drying and aseptic subpackaged powder, can add the common medicinal supplementary material such as fungistat, pH adjusting agent, weighting agent, isotonic regulator, glidant.
The clinical used dosage of compound of the present invention is 0.01mg～1000mg/ days, also can depart from this scope according to the weight of the state of an illness or the difference of dosage.
Another purpose of the present invention provides described cis benzylisoquinoline compounds or its pharmacy acceptable salt is preparing the purposes for the treatment of the neuromuscular blocking agents medicine.
Main points of the present invention are:
New compound of the present invention has less onset time, less time of recovery with respect to contrast medicine mivacurium chloride and benzene sulphur along atracurium and almost without any the histamine release effect, has good social benefit and wide market uses prospect.
Four, embodiment
The following examples can conduct further description the present invention, yet these embodiment should be as limitation of the scope of the invention.
Embodiment 1Compound I 1 Preparation
Figure 79718DEST_PATH_IMAGE011
R-tetrahydrochysene opium poppy alkali-N-ethanoyl-leucine salt (300g) is added in the l0L reactor, in reactor, add water (1000ml).Ammoniacal liquor with 25% is regulated pH to 9～10, adds toluene (3000ml) in reaction flask, tells organic phase.℃ be evaporated to (600ml) in temperature＜90, in reactor, add methyl acrylate (83g), add Glacial acetic acid (14ml) and be warming up to 80 ℃～85 ℃.(15～18h), HPLC detects, and reaction is cooled to 20 ℃～25 ℃ after finishing in 80 ℃～85 ℃ stirrings.In reactor, add acetone (4000ml), in reactor, add oxalic acid (157g) again.In reactor, add ethyl acetate (5000ml) (a large amount of solids are separated out).In 20～30 ℃ of stirrings (15～18h), filter, filter cake washes (500～1000ml) with ethyl acetate.Material obtains faint yellow solid (1) 253g in temperature＜45 ℃ decompression drying), yield is 95%.
Methylene dichloride (2000ml) is packed in the 10L reactor, add salt of wormwood (924g), add methyl alcohol (150g), lentamente benzene sulfonyl chloride (1300ml) is added by the constant pressure dropping funnel, obvious exothermic phenomenon is arranged.Drip and finish the rear stirring 20～30in that continues, TLC follows the tracks of detection, the raw material completely consumed, new dot generation is arranged simultaneously, filter, ℃ be evaporated to dried in temperature＜45, add ethyl acetate (5000ml) dissolving, water (3000ml) is washed Phenylsulfonic acid off, tell organic, anhydrous sodium sulfate drying 30min, after the filtration, ℃ be evaporated to driedly in temperature＜45, obtain at last yellow oily methyl benzenesulfonate (2), yield is 85%.
The oxalate (240g) of compound (1) is added in the 10L reactor, to wherein adding entry (2000ml), be stirred to whole dissolvings, then slowly add 25%NaOH solution, regulate pH to 8～9, add methylene dichloride (2000ml) and tell organic phase, stir 5min, water uses methylene dichloride (2x400ml) to extract again.Merge organic phase, ℃ be evaporated to dried in temperature＜35.Resistates adds second eyeball (3000ml), is stirred to whole dissolvings, changes the 10L reactor over to, adds methyl benzenesulfonate (202g).(15～18h), HPLC detects in 20～30 ℃ of stirrings of temperature.Reaction adds methylene dichloride (450ml) after finishing in reactor.Add simultaneously t-butyl methyl ether (800ml), in 20～30 ℃ of stirrings of temperature (15～18h), filter, the mixed solvent of filter cake methylene dichloride: t-butyl methyl ether=3:4 carries out washing leaching cake in temperature＜45 ℃ decompression drying.Obtained white solid (3) 256g, yield is 93%.
Suitable back mixing compound (ratio 3:1) 250g of compound (3) is added in the 10L reactor, then add acetone (2500ml), in 30 ℃ of lower 72h that stir, filter, obtain white solid (4) 185g, yield is 74%.
Compound (4) 180g is added in the 10L reactor, then add methyl alcohol (4000ml), (totally ten times) add sodium borohydride 210g in batches under 20 ℃～25 ℃, add complete, stirring at room 4h,＜35 ℃ are evaporated to dried, add ethyl acetate 5000ml dissolving, water (2 * 400ml) washings, anhydrous sodium sulfate drying removes by filter siccative,＜35 ℃ are evaporated to dried, resistates adds methyl alcohol 2000ml, adds the 50ml methanol solution of 50g Phenylsulfonic acid, stirring at room 5h, filter, filtrate is used methanol wash, obtains white solid (5) 131g, and yield is 82%.
(E)-and Xin-4-alkene-1,8-diacid 400g adds in the 2000ml there-necked flask of dried and clean, adds DMF 10ml, slowly splash into thionyl chloride 700ml, temperature maintains 40 ℃～45 ℃, splash into complete, stirring reaction 10h under this temperature, react complete, be concentrated into dried, for subsequent use.
Compound (5) 130g is added in the 10L reactor, then add methylene dichloride (3000ml) and triethylamine 400ml, under 20 ℃～25 ℃, splash into upper step (E)-Xin-4-alkene-1, the 300ml dichloromethane solution of 8-diacid chloride 75g, stirring at room 15h adds entry 600ml, stir 20min, separate organic layer water 2 * 300ml washing, anhydrous sodium sulfate drying, filter, it is dried that filtrate＜35 ℃ are evaporated to, and resistates adds acetone 3500ml, and 40 ℃～45 ℃ are slowly stirred 5h, 0 ℃～-5 ℃ lower 1h that stir of what, filter, filtrate is with cold washing with acetone, dry must the white powder solid chemical compound I 1 107g.Yield 51%, mp:76～78 ℃, HPLC content 98.9%.
Figure 992674DEST_PATH_IMAGE015
?[0030]? 1H—NMR（500MHz,CDCl 3/TMS，ppm）:
δ 2.01～2.23(4H, m, 2CH 3C H 2 CH 2); δ 2.36～2.42(4H, m, 2CH 3C H 2 CH=); δ 2.59(4H, t, J=5.7Hz, 2COC H 2 CH 2); δ 3.21(4H, d, J=9.6Hz, C H 2 ); δ 3.39(6H, s, 2NC H 3 ); δ 3.42(4H, t, J=5.7Hz,, 2NC H 2 CH 2); δ 3.96(24H, s, 2OC H 3 ); δ 4.26(4H, t, J=5.7Hz,, 2CH 2C H 2 CO); δ 5.98(2H, t, J=7.6Hz, 2C H=CH); δ 3.04～4.63(10H, m, piperidines on the tetrahydroquinoline); δ 6.82(2H, s, phenyl ring on the tetrahydroquinoline); δ 6.93～7.45(6H, m, phenyl ring);
MS：m/z?（M +）1126.5（100%）
Embodiment 2Compound I 2 Preparation
Figure DEST_PATH_697821DEST_PATH_IMAGE004
With reference to the preparation method of embodiment 1, replace R-tetrahydrochysene opium poppy alkali-N-ethanoyl-leucine salt to do initial raw material, make target compound with R-tetrahydrochysene methoxyl group opium poppy alkali-N-ethanoyl-leucine salt I 2 , white crystalline powder, mp:, 112～114 ℃, yield 47%, its purity is 98.3%, (HPLC method).
Figure DEST_PATH_27171DEST_PATH_IMAGE005
1H—NMR（500MHz,CDCl 3/TMS，ppm）:
δ 2.13～2.31(4H, m, 2CH 3C H 2 CH 2); δ 2.43～2.49(4H,, m, 2CH 3C H 2 CH=); δ 2.65(4H, t, J=9.6Hz, 2COC H 2 CH 2); δ 3.36(4H, d, J=12.4Hz, C H 2 ); δ 3.52(6H, s, 2NC H 3 ); δ 3.67(4H,, t, J=5,7Hz, 2NC H 2 CH 2); δ 4.15(30H, s, 2OC H 3 ); δ 4.43(4H, t, J=5,7Hz, 2CH 2C H 2 CO); δ 5.99(2H, t, J=7.6Hz, 2C H=CH); δ 3.14～4.87(10H, m, piperidines on the tetrahydroquinoline); δ 7.03(2H, s, phenyl ring on the tetrahydroquinoline); δ 7.18～7.67(6H, m, phenyl ring);
MS：m/z?（M +）1186.6（100%）
Embodiment 3Compound I 3 Preparation
With reference to the preparation method of embodiment 1, with (E)-own-3-alkene-1,6-two acid substitutions (E)-Xin-4-alkene-1, the 8-diacid is done initial raw material, makes target compound I 3 , white crystalline powder, mp:55～59 ℃, yield, 41%, its purity is 99.2%, (HPLC method).
Figure 612694DEST_PATH_IMAGE021
?[0032]?MS：m/z?（M +）1098.6（100%）
Embodiment 4Compound I 4 Preparation
Preparation method with reference to embodiment 2 and embodiment 3 makes target compound I 4 , white crystalline powder, mp:103～105 ℃, yield, 37%, its purity is 98.4%, (HPLC method).
Figure 46529DEST_PATH_IMAGE023
?[0033]?MS：m/z?（M +）1158.7（100%）
Embodiment 5Compound I 5 Preparation
Figure 30357DEST_PATH_IMAGE012
With reference to the preparation method of embodiment 1, replace (E)-Xin-4-alkene-1 with pentanedioic acid, the 8-diacid is done initial raw material, makes target compound I 3 , white crystalline powder, mp:97～99 ℃, yield, 56%, its purity is 99.0%, (HPLC method).
Figure 378470DEST_PATH_IMAGE025
?[0034]?MS：m/z?（M +）1086.5（100%）
Embodiment 6Compound I 6 Preparation
Embodiment 1 compound I 1 45gPlace the 2000ml there-necked flask of dried and clean, room temperature, add the 900ml anhydrous acetonitrile, be stirred to entirely moltenly, add lithiumbromide 24g, vigorous stirring 1.5h, remove by filter the Phenylsulfonic acid lithium of generation, solid merges acetonitrile,＜40 ℃ of concentrating under reduced pressure 100ml with the washing of 3 * 50ml acetonitrile, this resistates is at room temperature splashed in the acetone (2500ml) of stirring, splash into completely, room temperature continue to stir 1h, filters, solid is pulled an oar in 600ml acetone, filter, solid is with 3 * 30ml washing with acetone, and 70 ℃ in vacuum is dry must the white powder compounds I 6 33g, yield 76%, mp:173～177 ℃, its purity is 99.3%, (HPLC method).
Figure 273931DEST_PATH_IMAGE027
MS：m/z?（M +）1049.8（100%）
Embodiment 7The injection compound I 1 Preparation
Prescription:
The embodiment compound I 1 5g
Lactose 20g
Aqueous solution of citric acid is an amount of
Water for injection 4000ml
1000
Preparation technology:
Get the water for injection of prescription total amount about 80%, water temperature is controlled at 25 ℃ ± 5 ℃, and add precision and take by weighing lactose 20g, and the embodiment compound I 1 5g, be stirred well to whole dissolvings, measure the pH value, drip aqueous solution of citric acid, control pH value be about 3.8 adding waters for injection to full dose, add 0.1% needle-use activated carbon, 25 ℃ ± 5 ℃ are stirred 30min, with 0.22 μ m millipore filtration Sterile Filtration, solution is sub-packed in the cillin bottle of 10m1 specification, and every bottled amount is 4ml.
With the can embodiment compound for preparing I 1 Cillin bottle put into freeze drying box, then the freeze-drying built-in temperature is reduced in 2h below one 40 ℃, make its quick freezing.Vacuumize, make in 30min that normal atmosphere reaches 2. 66pa in the case.Pressing board temperature-40 ℃ is raised to 30 ℃ start program and heats up dry.Jump a queue, roll lid after drying is complete and obtain the embodiment compound I 1 Freeze-dried powder.
Embodiment 8Compound I 6 The preparation of injection liquid
Prescription:
The embodiment compound I 6 5g
Sodium-chlor 9g
Water for injection 4000ml
1000
Preparation technology:
Get the water for injection of prescription total amount about 80%, water temperature is controlled at 25 ℃ ± 5 ℃, adds the accurate embodiment compound that takes by weighing I 6 5g and sodium-chlor 9g are stirred well to whole dissolvings, add water for injection to full dose, add 0.1% needle-use activated carbon, 25 ℃ ± 5 ℃ are stirred 30min, with 0.22 μ m millipore filtration Sterile Filtration, aseptic subpackaged in the cillin bottle of 5m1 specification, every bottled amount is 4ml, namely gets compound I 6 Injection liquid.
Embodiment 9Pharmacological testing
One, the onset time of neuromuscular blocking agents and action time
The rabbit head-dropping tests:
Get 16 of rabbit, quiet notes the compounds of this invention and contrast medicine benzene sulphur is along atracurium and mivacurium chloride, observes that rabbit hangs one's head and four limbs belly time of relaxation and return to the active time as before, and the result is as follows:
Figure 626415DEST_PATH_IMAGE028
Conclusion: compound of the present invention is rapid-action, recovers also slightly fast, can be used as the rapid-action medicine of needs of minor operation, simultaneously can be as the medicine of major operation continuous infusion.
Two, histamine release Experiment on Function
1, anesthesia induction and keeping: 16 rabbit are divided into 8 groups, 30min intramuscular injection Pethidine 1.0mg before the rabbit art, and coromegine 0.05mg, then pipe is put in the parallel internal jugular vein puncture of open ulnar vein, and all medicines all inject through ulnar vein.Anesthesia induction midazolam 0.01～0.05mg/kg, etomidate 0.2～0.3mg/kg enables flesh pine detector after mind disappears, after calibration reaches 5min, give respectively compound and contrast medicines that 8 groups of injections are invented.
2, the mensuration of histamine concentration:
1., the extraction of sample and preparation: distinguish the neuromuscular blocking agents of what intravenous injection the compounds of this invention and contrast before the medicine and 2min, 5min after the administration, with the heparinization syringe through the internal jugular vein 5ml that takes a blood sample, centrifugation goes out blood plasma, gets upper plasma 2ml and places in vitro, and is stand-by.
2., histamine concentration determination: adopt fluorophotometer to send out, with histamine content and its relative intensity of fluorescence of histamine reference liquid, set up the typical curve of histamine content with the method for straight-line regression, calculate the histamine content in each sample.Unit: ng/ml
Figure 631280DEST_PATH_IMAGE029
Conclusion: the compound of this compound does not all have the histamine release effect substantially, and namely clinical do not have cardiovascular side effect substantially, and tool has a broad prospect of the use.
Five, description of drawings
Fig. 1 is embodiment 1 compound I 1 The HPLC color atlas
Fig. 2 is embodiment 1 compound I 2 The HPLC color atlas
Fig. 3 is embodiment 1 compound I 3 The HPLC color atlas
Fig. 4 is embodiment 1 compound I 4 The HPLC color atlas
Fig. 5 is embodiment 1 compound I 5 The HPLC color atlas
Fig. 6 is embodiment 1 compound I 6 The HPLC color atlas

Claims (8)

1. the cis benzylisoquinoline compounds shown in the general formula (I) or its pharmacy acceptable salt:
Figure DEST_PATH_FDA0000352445070000011
Wherein R is selected from hydrogen atom or methoxyl group, Be expressed as the chain hydrocarbon or the singly-bound chain hydrocarbon that contain two keys, n is 2 or 4 or 6 or 8 or 10.
2. cis benzylisoquinoline compounds claimed in claim 1 or its pharmacy acceptable salt, it is characterized in that: n is 4 or 6.
3. claim 1～2 described cis benzylisoquinoline compounds or its pharmacy acceptable salt, it is characterized in that: the pharmaceutically acceptable acid group that this compound is selected from is muriate, bromide and Phenylsulfonic acid compound salt.
4. according to claim 1～3 described cis benzylisoquinoline compounds or its pharmacy acceptable salt is characterized in that: the preferred following structure of described compound:
Figure DEST_PATH_FDA0000352445070000013
Figure DEST_PATH_FDA0000352445070000021
Figure DEST_PATH_FDA0000352445070000031
5. the preparation method of the cis benzylisoquinoline compounds of claim 1 general formula (I) comprising:
Figure DEST_PATH_FDA0000352445070000032
R wherein 1And the definition of n is with claim 1.
6. a pharmaceutical composition wherein contains claim 1～4 described cis benzylisoquinoline compounds or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
7. cis benzylisoquinoline compounds claimed in claim 1 is for the preparation of the purposes for the treatment of neuromuscular blocking agents medicine.
8. purposes claimed in claim 7 comprises anesthetic,general surgical operation therapy step.
CN2013102354716A 2013-06-14 2013-06-14 Preparation method of cis-benzyl isoquinoline compound and application thereof Pending CN103373959A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014198164A1 (en) * 2013-06-14 2014-12-18 安徽省先锋制药有限公司 Cis-benzylisoquinoline compound, preparation method therefor and uses thereof
CN111662230A (en) * 2019-03-06 2020-09-15 四川道珍科技有限公司 Benzyl isoquinoline compound, preparation method and application

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1257483A (en) * 1997-03-25 2000-06-21 葛兰素集团有限公司 Substituted isoquinolines as ultra short acting neuromuscular blockers
US20120095041A1 (en) * 2009-03-17 2012-04-19 Cornell University Reversible nondepolarizing neuromuscular blockade agents and methods for their use

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8418303D0 (en) * 1984-07-18 1984-08-22 Wellcome Found Compounds
WO2013021398A2 (en) * 2011-08-05 2013-02-14 Sequent Scientific Limited A process for preparation of mivacurium chloride
CN103373959A (en) * 2013-06-14 2013-10-30 安徽省先锋制药有限公司 Preparation method of cis-benzyl isoquinoline compound and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1257483A (en) * 1997-03-25 2000-06-21 葛兰素集团有限公司 Substituted isoquinolines as ultra short acting neuromuscular blockers
EP1380573A2 (en) * 1997-03-25 2004-01-14 Avera Pharmaceuticals, Inc. Isoquinolines and preparation thereof
US20120095041A1 (en) * 2009-03-17 2012-04-19 Cornell University Reversible nondepolarizing neuromuscular blockade agents and methods for their use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ERIC E. BOROS等: "Neuromuscular Blocking Activity and Therapeutic Potential of Mixed-Tetrahydroisoquinolinium Halofumarates and Halosuccinates in Rhesus Monkeys", 《J. MED. CHEM.》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014198164A1 (en) * 2013-06-14 2014-12-18 安徽省先锋制药有限公司 Cis-benzylisoquinoline compound, preparation method therefor and uses thereof
CN111662230A (en) * 2019-03-06 2020-09-15 四川道珍科技有限公司 Benzyl isoquinoline compound, preparation method and application

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