CN1257903C - Quinic compound containing quaternary ammonium group and its preparation and medicina use - Google Patents

Quinic compound containing quaternary ammonium group and its preparation and medicina use Download PDF

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Publication number
CN1257903C
CN1257903C CNB031210317A CN03121031A CN1257903C CN 1257903 C CN1257903 C CN 1257903C CN B031210317 A CNB031210317 A CN B031210317A CN 03121031 A CN03121031 A CN 03121031A CN 1257903 C CN1257903 C CN 1257903C
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compound
quaternary ammonium
preparation
ammonium group
medicine
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CN1532196A (en
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李统威
赵书强
张洁青
陈琨
张强
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YinGu Pharmaceutical Co Ltd
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Cachet Pharmaceutical Co Ltd
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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Abstract

The present invention relates to a quinine compound containing quaternary ammonium groups of the general formula I (disclosed in the specification), a preparation method thereof and a medical composition containing an effective dose of the compound of the general formula I, and in the general formula I, R1 and R2 are stated in the text. The composition can be used for the prevention and the treatment of diseases correlated with blocking choline receptors.

Description

A kind of quinine compounds and method for making and pharmaceutical use that contains quaternary ammonium group
Technical field contains the quinine compounds of quaternary ammonium group, particularly relates to the new compound of general formula I, and preparation method thereof, contain the application in the preparation anticholinergic agents of one or more these compound compositions and this compound.
Technical background vagusstoff (acetylcholine, ACh) be the neurotransmitter that cholinergic nerve tip (comprise Motor nerve fibre, vegetative nerve preganglionic fiber, parasympathetic ganglion after fiber and part sympathetic nerve postganglionic fibers) discharges, having very strong biological activity, is M-ChR (m receptor) and nAChR (n receptor) performance effect by acting on cholinergic receptor.The cholinergic receptor blocking agent medicine that to be a class play a role by the blocking-up cholinocepter is divided into M-cholinocepter blocking agent and N-cholinocepter blocking agent.Cholinocepter on the effector of M-cholinocepter blocking agent energy blocking-up maincenter and joint back cholinergic innervation, show as the plan mentation of nervus centralis and smooth muscle loosening, glandular secretion inhibition, platycoria, the rhythm of the heart speeds etc., has pharmacological action widely and clinical application.
At present, M-cholinocepter blocking agent substantially all is tropine Alkaloid and coromegine synthetic substance.Because its pharmacological action is extensive, use its in a certain respect do the time spent, the effect of others will show as side effect, especially intend the spirituality effect, this has just limited its application clinically, and therefore, anticholinergic should have certain selectivity, promptly keep its cholinolytic effect, reduce its maincenter and intend the spirituality side effect.
In existing document, do not see the report of the present invention's the quinine compounds that contains quaternary ammonium group so far as yet, and it is used to block cholinergic receptor and as the purposes of anticholinergic agents.
Summary of the invention the object of the present invention is to provide a kind of quinine class novel cpd that contains quaternary ammonium group in order to overcome the deficiency of existing medicine and technology.
Another object of the present invention is to provide the method for the quinine compounds that a kind of preparation contains quaternary ammonium group.
Another purpose of the present invention is to provide one or more to contain the pharmaceutical composition of this compound and pharmaceutically acceptable carrier.As: tablet, capsule, aerosol, sprays, injection, sustained release dosage etc.
A further object of the present invention is to provide the purposes of a kind of this compound as anticholinergic relative disease medicine.
In order to realize the present invention's purpose, the present invention takes following technical scheme:
The present invention relates to have the novel cpd of general formula I:
Figure C0312103100041
In the formula, R 1Be cyclopropyl, cyclopentyl or cyclohexyl; R 2It is methyl; X is the halogen ion.。
Be the described compound of preparation general formula I of the present invention, the inventive method comprises, phenylalkyl oxyethane and quinuclidinol are reacted with highly basic in organic solvent, further separates diastereomer with chromatography, reacts with haloalkane again.
Specifically, prepare the method for the described compound of general formula I, comprise the steps:
(A), with 1-phenyl 1-R 1-oxyethane and 3-quinuclidinol react in the organic solvent neutralization bases;
(B), with (A) step products therefrom and haloalkane R 2The X reaction, preparation contains the racemic compound of quaternary ammonium group;
(C), with (A) step products therefrom separate with chromatography, prepare a pair of diastereomeric compound and corresponding pure optical isomer compound;
(D), with (C) step products therefrom respectively with haloalkane R 2The X reaction, preparation contains the steric isomer of quaternary ammonium group;
R wherein 1, R 2, X definition with top identical.
The invention still further relates to a kind of pharmaceutical composition that contains medicine effective dose as described compound of general formula I and pharmaceutically acceptable carrier.
Pharmaceutical research shows that compound of Formula I of the present invention has the activity of blocking-up cholinergic receptor; To cavy specificity allergic asthma, The compounds of this invention has the obvious suppression effect.The more important thing is that The compounds of this invention can not see through hemato encephalic barrier, can not enter central nervous system, do not have maincenter to intend the spirituality side effect.
The compounds of this invention is the cholinergic receptor blocking agent that a class can not enter central nervous system, and it can be used for treating bronchial asthma, chronic obstructive pulmonary disease, flu, rhinitis, peptide ulceration, dysentery, diseases such as irregular pulse.
Select for use pharmaceutical carrier well known to those skilled in the art can make the pharmaceutical composition of the The compounds of this invention that contains effective dosage.
The compounds of this invention or its composition can be with oral methods or the medications of parenteral road.Oral medication can be tablet, capsule, Drug coating, powder, and non-have aerosol, sprays, drops, injection and suppository etc. through the stomach and intestine drug formulation.These preparations are according to the known method preparation of those skilled in the art.For making tablet, capsule, Drug coating, the used dressing of powder is the auxiliary agent of conventional usefulness, starch for example, dextrin, Microcrystalline Cellulose, pregelatinized Starch, gelatin, gum arabic, methylcellulose gum, ethyl cellulose, hydroxypropylcellulose, Xylo-Mucine, silica, polyoxyethylene glycol, the used solvent of liquid dosage form has water, ethanol, propylene glycol, plant oil such as Semen Maydis oil, peanut oil, olive wet goods.Containing in the preparation of The compounds of this invention also can have other auxiliary agent, tensio-active agent for example, lubricant, disintegrating agent, sanitas, correctives, pigment etc.
At tablet, capsule, Drug coating, aerosol, sprays, the dosage that contains formula I compound of the present invention in injection or the suppository is to calculate with the compound amount that exists in the unit dosage form.The general content of formula I compound of the present invention is 1-5000 μ g in unit dosage form.
Be treatment bronchial asthma, chronic obstructive pulmonary disease, flu, rhinitis and other disease, be 1-1000 μ g dosage general every day of the The compounds of this invention that the adult patient spraying gives, and is preferably 1-100 μ g, can be once or the gradation administration;
Embodiment is described further invention below with reference to embodiment, but does not limit the scope of the invention.Determining instrument used herein: the fusing point test micro-fusing point instrument of XRC-1 type, thermometer is not proofreaied and correct; Nuclear magnetic resonance spectrometry Bruker ARX500 type nuclear magnetic resonance analyser, TMS is interior mark; Mass spectroscopy Nicoler FTMS-2000G type instrument.
Embodiment 1 3-quinuclidinyl-(2 '-phenyl-2 '-cyclopentyl-2 '-hydroxyl) preparation of ethyl ether (1)
1-phenyl-1-cyclopentyl oxyethane 9.3g is dissolved among the DMSO.Get quinuclidinol 6.35g, be dissolved among the 64mlDMSO, add sodium hydride 2.5g, stirred 1 hour, be chilled to room temperature, drip benzyl ring amyl group oxyethane-DMSO solution, restir 3 hours.Be chilled to room temperature, ether extraction is extracted the ether layer with 6N HCl, and the sour water layer alkalizes with 20%NaOH, uses ether extraction again, and anhydrous sodium sulfate drying spends the night.Steaming desolventizes, and product is stand-by behind distillation purifying.Yield 54%.
Embodiment 2 3-(N-methyl quinuclidine cyclic group)-(2 '-phenyl-2 '-cyclopentyl-2 '-hydroxyl) preparation of ethyl ether bromide (2)
With embodiment 1 gained compound (1), use anhydrous alcohol solution, feed excessive monobromethane, reaction is spent the night.After steaming desolventizes, use acetone recrystallization, get white solid, yield 75%.Fusing point 166-168 ℃;
1HNMR(CDCl 3)：7.42(d，2H)，7.29(g，2H)，7.20(t，1H)，4.29(m，1H)，3.96(br，1H)，3.85(m，1H)，3.70(m，4H)，3.30(d，1H)，3.22(s，3H)，3.11(m，2H)，2.25(m，2H)，1.96(m，2H)，1.63(m，4H)，1.44(m，4H)，1.26(m，2H)。MS(m/z)：410(M +)；175，726(B)。
Embodiment 3 3-(N-methyl quinuclidine cyclic group)-(2 '-phenyl-2 '-cyclopentyl-2 '-hydroxyl) preparation of ethyl ether bromide I type diastereomer (3)
Get compound (1), separate with the self-control silica-gel plate, developping agent is a chloroform: methyl alcohol: ammoniacal liquor (4: 0.8: 0.15), collect R fBe worth high chromatographic band, products therefrom feeds excessive monobromethane behind wash-out, and reaction is spent the night.After steaming desolventizes, use acetone recrystallization, get white solid, yield 30%.Fusing point 149-151 ℃.
Embodiment 4 3-(N-methyl quinuclidine cyclic group)-(2 '-phenyl-2 '-cyclopentyl-2 '-hydroxyl) preparation of ethyl ether bromide II type diastereomer (4)
Get compound (1), separate with the self-control silica-gel plate, developping agent is a chloroform: methyl alcohol: ammoniacal liquor (4: 0.8: 0.15), collect R fBe worth low chromatographic band, products therefrom feeds excessive monobromethane behind wash-out, and reaction is spent the night.After steaming desolventizes, use acetone recrystallization, get white solid, yield 30%.Fusing point 160-162 ℃;
The external anti-acetylcholine effect of embodiment 5 The compounds of this invention
This test adopts method well known to those skilled in the art to carry out.The stripped ileum sample of preparation hangs among bath Cao (30ml) who is full of tyrode's solution, and nutritive medium passes to 95% O 2And 5%CO 2Mixed gas, keep 37 ℃ of constant temperature, load onto stimulating electrode.With frequency 0.1 time/second, time length is that 1 millisecond square wave stimulates, and for once stimulating, the contraction of one time one mistake property will take place ileum.The Tai Shi that displacement contains different pharmaceutical needs during night to clean three times and do blank the stimulation with tyrode's solution.As a result, containing Tropintran (10 respectively -7G/ml) and The compounds of this invention embodiment 2, embodiment 3 and embodiment 4 (10 -7G/ml) in the tyrode's solution, the ileum contractile response that electricity irritation causes is blocked fully.
The preparation of The compounds of this invention aerosol:
Embodiment 6
The compounds of this invention 0.28g
Propylene glycol 35g
Ethanol 382g
Propellent 983g
Embedding is in the quantitative valve container, and every bottle of 10g, contains The compounds of this invention 20 μ g at every spray 100mg.Propellent is the mixture of Trichloromonofluoromethane, Refrigerant 12, Dichloromonofluoromethane, monochlorodifluoromethane, Dichlorotetrafluoromethane, a chlorine five fluoromethane, chlorodifluoroethane, C2H4F2 C2H4F2 or Perfluorocyclobutane etc. or above-claimed cpd.
Embodiment 7
The compounds of this invention 0.28g
Propylene glycol 42g
Dehydrated alcohol 210g
Refrigerant 12 231g
Dichloro tetrafluoro ethane 971g
Embedding in the quantitative valve container, every bottle of 10g, every spray 100mg contains The compounds of this invention 20 μ g.
Embodiment 8 The compounds of this invention aerosols are to the therapeutic action of cavy specificity allergic asthma
This test adopts method well known to those skilled in the art to carry out.Select for use 30 body weight to test at the healthy guinea pig of 200-220g.Give the oralbumin normal saline solution 1.0ml (oralbumin 100mg) of every guinea pig intraperitoneal injection 10%, be divided into blank group, positive controls [love complete happy (ipratropium bromide aerosol) at random, the 10ml/ bottle, 20 μ g/ spray, vigorous woods Green lattice writing brush (Boehringer lngelheim) company of Germany produces, lot number: 104015, date manufactured: 06 2001, valid until: 06 2004], this compound embodiment 2 aerosol groups, this compound embodiment 3 aerosol groups, this compound embodiment 4 aerosol groups, 10 every group.Began every day once on the 6th day in the injection back through the respiratory tract spray delivery, behind the successive administration 5 days, animal is put separately in the airtight bell jar, with ultrasonic atomizer 0.5% oralbumin normal saline solution is sprayed into 30s in the bell jar equably, observe record also from spraying into the oralbumin normal saline solution, be asthma latent period to producing the time of abdominal muscle between shrinking.The data of surveying through t check comparative group differences.
Result: when giving the guinea pig intraperitoneal injection oralbumin after 10 days, when contacting same antigen once more, antigen antibody reaction just occurred, be referred to as the specificity allergic asthma based on the oedema and the spasm of respiratory tract.Evidence, this compound aerosol has the obvious suppression effect to this specific reaction, and asthma latent period is than blank group significant prolongation, P＜0.01.The results are shown in Table 1.
This compound of table 1. aerosol is to the influence of cavy allergic asthma (s X ± SD)
Group n Dosage gkg -1 Latent period (s)
Blank group positive controls embodiment 2 compound aerosol embodiment 3 compound aerosol embodiment 4 compound aerosols 10 10 10 10 10 - 100μg 100μg 100μg 100μg 124.00±21.66 235.40±45.15** 248.90±38.24** 243.50±42.13** 231.60±37.30**
* * P＜0.01 of comparing with the blank group;
Through above-mentioned test-results, those skilled in the art know, and The compounds of this invention has blocking effect to Mammals M-cholinocepter.And The compounds of this invention comprises in the application of people M cholinergic receptor-blocking agent medicine having good prospect the preparation Mammals.

Claims (9)

1, as the quinine compounds that contains quaternary ammonium group of general formula I:
In the formula: R 1Be cyclopropyl, cyclopentyl or cyclohexyl; R 2It is methyl; X is the halogen ion.
2, compound as claimed in claim 1 is characterized in that R 1Represent cyclopentyl, R 2Represent methylidene, X represents bromide anion.
3, compound as claimed in claim 2 is characterized in that compound structure type is a diastereomer.
4, compound as claimed in claim 2 is characterized in that compound structure type is pure optical isomer.
5, as the synthetic method of the arbitrary described compound of claim 1 to 4, its feature comprises the steps:
(A), with 1-phenyl 1-R 1-oxyethane and 3-quinuclidinol react in the organic solvent neutralization bases;
(B), with (A) step products therefrom and haloalkane R 2The X reaction, preparation contains the racemic compound of quaternary ammonium group;
(C), with (A) step products therefrom separate with chromatography, prepare a pair of diastereomeric compound and corresponding pure optical isomer compound;
(D), with (C) step products therefrom respectively with haloalkane R 2The X reaction, preparation contains the steric isomer of quaternary ammonium group;
R wherein 1, R 2, X definition with claim 1.
6, as the application of the arbitrary described compound of claim 1 to 4 in the medicine of preparation blocking-up cholinergic receptor.
7, application of compound as claimed in claim 6 is characterized in that, is used to prepare the medicine of treatment chronic obstructive pulmonary disease, bronchial asthma, rhinitis and these Mammals respiratory system diseases of flu.
8, application of compound as claimed in claim 6 is characterized in that, is used to prepare the medicine of treatment peptide ulceration, these Mammals digestive system of dysentery.
9, a kind of pharmaceutical composition, it is characterized in that, contain the arbitrary described compound of claim 1 to 4 and the pharmaceutically acceptable carrier of effective dose, described pharmaceutical composition is specially tablet, capsule, aerosol, sprays, injection or sustained release dosage.
CNB031210317A 2003-03-21 2003-03-21 Quinic compound containing quaternary ammonium group and its preparation and medicina use Expired - Lifetime CN1257903C (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101856327B (en) * 2009-04-08 2012-02-22 北京银谷世纪药业有限公司 Aerosol with quantitative inhalation of bencycloquidium bromide and preparation method thereof

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1769286B (en) * 2005-10-20 2010-10-06 嘉事堂药业股份有限公司 Compound and pharmaceutical composition for treating nasal oversecreation and chronic obstructive pulmonary disease
CN101585835B (en) * 2008-05-22 2012-08-22 北京嘉事联博医药科技有限公司 Preparation method and application of bencycloquidium bromide optical isomer and composition of bencycloquidium bromide optical isomer
CN107304206A (en) * 2016-04-18 2017-10-31 银谷制药有限责任公司 Crystal formation I of compound and its production and use
CN107304208A (en) * 2016-04-18 2017-10-31 银谷制药有限责任公司 Crystal formation II of compound and its production and use
CN107304207A (en) * 2016-04-18 2017-10-31 银谷制药有限责任公司 The crystal formation I of compound and the mixing crystal formation of crystal formation II and its production and use
CN107304209A (en) * 2016-04-18 2017-10-31 银谷制药有限责任公司 Compound it is unformed and preparation method thereof
CN111377920B (en) * 2018-12-27 2021-10-26 银谷制药有限责任公司 Method for refining quinine compound containing quaternary ammonium group
CN111689956B (en) * 2019-03-14 2021-12-24 银谷制药有限责任公司 Resolution method of quinine compound containing quaternary ammonium group

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101856327B (en) * 2009-04-08 2012-02-22 北京银谷世纪药业有限公司 Aerosol with quantitative inhalation of bencycloquidium bromide and preparation method thereof

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