CN1951938A - Penehyclidine quaternary ammonium salt and its derivative - Google Patents
Penehyclidine quaternary ammonium salt and its derivative Download PDFInfo
- Publication number
- CN1951938A CN1951938A CN 200510114293 CN200510114293A CN1951938A CN 1951938 A CN1951938 A CN 1951938A CN 200510114293 CN200510114293 CN 200510114293 CN 200510114293 A CN200510114293 A CN 200510114293A CN 1951938 A CN1951938 A CN 1951938A
- Authority
- CN
- China
- Prior art keywords
- ammonium salt
- quaternary ammonium
- derivative
- ethyl
- alkane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses an ethyl ether quaternary ammonium salt and derivant as Choline-proof compound and preparing method with the following structure, wherein R is C1-C6 paraffin or substituted phenyl C1-C6 paraffin, which is methyl, phenylmethyl, ethyl group, propyl or isopropyl at best; M is halogen, which is F, Cl, Br or I at best. The invention can treat peripheral cholinergic nerve from exciting.
Description
Technical field
The invention provides a kind of cholinolytic compound and preparation method thereof, specifically, is amyl ethyl quin ether (long holder is peaceful) quaternary ammonium salt and derivative thereof, preparation method, and the application in the hyperfunction medicine of preparation treatment peripheral cholinergic nerve.
Background technology
Penequine hydrochloride is the long-acting anticholinergic new drug of China's independent development synthetic country's one class, English name Penehyclidine Hydrochloride Injection, chemistry 3-(2-cyclopentyl-2-hydroxyl-2-phenyl ethoxy) quinuclidine hydrochloride by name, trade name is long holder peaceful (long-acting holder is peaceful), be used for organophosphorus poison (agricultural chemicals) poisoning first-aid treatment and poison later stage or Pseudocholinesterase (ChE) are kept atropinization (atropinization is meant that the organophosphate poisoning patient makes the human body boundary in the maximum physiological tolerance limit of coromegine and the atropinism criticality between the two after using the doses coromegine) after aging, its chemical structure is a tertiary amine salt, can enter in the brain by hemato encephalic barrier, blockage of acetylcholine is to the agonism of M-ChR in the brain (m receptor) and nAChR (n receptor), therefore antagonism organophosphorus poison (agricultural chemicals) the maincenter toxicity symptom of poisoning and causing preferably is as fainting from fear, maincenter respiratory and circulatory failure and dysphoria etc.; Simultaneously the agonism of stronger blockage of acetylcholine to m receptor also arranged in periphery, the malicious alkali sample toxicity symptom that antagonism organophosphorus poison (agricultural chemicals) poisoning equally preferably causes, as bronchial muscular spasm and secretory product increase, perspiration, hydrostomia, miosis and gastrointestinal smooth muscle spasm or contraction etc., can also increase respiratory rate and respiratory flow, because it does not have obvious effect to the M2 acceptor, so heart rate is not had obvious influence; The periphery n receptor there is not obvious antagonistic action.
Rather not only cholinolytic effect is strong in long holder, and effect is comprehensive, longer duration, because it has the selectivity of height to the m receptor hypotype, makes its toxic side effect less, safe, alternative the most frequently used similar medicine coromegine and Scopolamine both at home and abroad, and be widely used in clinical cholinolytic treatment.
Penequine hydrochloride as anticholinergic agent treatment organophosphate poisoning, can also be in order to treatment diseases such as peripheral cholinergic nerve is hyperfunction, be used for microcirculation improvement, lax visceral smooth muscle, treatment is shock for example, chronic obstructive pulmonary disease (COPD), the internal organ spasm, but because of it can pass through hemato encephalic barrier, very easily cause nervus centralis untoward reaction to occur for the COPD gerontal patient who needs the long-term prescription treatment, particularly the present old COPD patient of China is increasing, and the elderly is owing to self secrete the vagusstoff minimizing in the physiological reason body, can might cause senile dementia through the anticholinergic drug of hemato encephalic barrier as life-time service.Though and other traditional anticholinergic drug such as coromegine, Scopolamine etc. can not pass through hemato encephalic barrier, but heart rate all there is considerable influence, more can not long-term prescription, although therefore have the effect of microcirculation improvement expansion bronchus unstriated muscle, still can not be used for the chronic.
How can guarantee that penta second quinoline ether compound in its therapeutic action of performance, can't pass through hemato encephalic barrier, make it not have the maincenter cholinolytic effect, simultaneously the side effect of heart be dropped to minimumly, be the problem that medical circle is endeavoured to solve.
Summary of the invention
The present inventor is through a large amount of experiments, a kind of quaternary ammonium salt and derivative thereof have been developed, it is the peaceful quaternary ammonium form of long holder, and this quarternary ammonium salt compound has kept the active function that diseases such as peripheral cholinergic nerve is hyperfunction are rather treated in long holder, has at utmost reduced its side effect simultaneously.
The object of the present invention is to provide amyl ethyl quin ether (long holder is peaceful) quaternary ammonium salt derivative, this derivative (compound) can be hyperfunction as anticholinergic agent treatment peripheral cholinergic nerve, and, therefore avoided Penequine hydrochloride (long holder is peaceful) compound to be easy to cause that the side effect of untoward reaction appears in nervus centralis because the improvement of structure makes it can not see through hemato encephalic barrier.
The invention provides a kind of cholinolytic quaternary ammonium salt and derivative thereof, it is characterized in that, have following structure, wherein, R is C
1-6The C that alkane or phenyl replace
1-6Alkane, M are halogen.
Above-mentioned quaternary ammonium salt of the present invention and derivative thereof are quaternary ammonium salt structure, studies show that this structure can not see through hemato encephalic barrier, avoid producing the side effect of central nervous system, and kept the effect that diseases such as peripheral cholinergic nerve is hyperfunction are rather treated in long holder, made it safer as the medicinal compound that is applied to human body.
The substituting group of above-claimed cpd is preferably methyl, phenmethyl, ethyl, propyl group or sec.-propyl, more preferably methyl; M is F, Cl, Br or I, preferred Cl, Br or I.
Compound its preparation method of the present invention is as follows:
With amyl ethyl quin ether (A) and excessive RM (CH for example
3I, CH
3Cl, CH
3F, CH
5CH
2I, CH
3CH
2I, C
3H
7I, CH
5CH
2Cl, CH
5CH
2Br) add in the reaction flask, add an amount of non-polar solvent that is enough to make material dissolution again, acetonitrile for example, stirring and refluxing then, reaction is (preferred 7-10 days) more than at least 24 hours, and the thin-layer chromatography monitoring reaches balance until reaction; Boil off solvent (also product can be cooled to room temperature and boil off solvent again), residue cleans with ethyl acetate, and ethyl alcohol recrystallization gets target compound, and yield is more than 50%.RM (mole) wherein: raw material A (mole) 〉=1: 1.
Through the proton nmr spectra checking, the synthetic product that obtains is a The compounds of this invention, and wherein, R is C
1-6Alkane or the C that replaces of phenyl
1-6Alkane, M are F, Cl, Br or I, preferred Cl or I.
In a preferred embodiment of the invention, described compound is a methyl amyl ethyl quin ether quaternary ammonium salt compounded of iodine, it is peaceful to be also referred to as the long holder of methyl, it is 3-(2-cyclopentyl-2-hydroxyl-2-phenyl ethoxy) the quinuclidine salt compounded of iodine that connects methyl on the N position, verify through pharmacological evaluation, it has kept the active function that diseases such as peripheral cholinergic nerve is hyperfunction are rather treated in long holder, has at utmost reduced its side effect simultaneously.
The pharmacology pharmacodynamic experiment
1. anti-oxidant tremorine inducing mouse maincenter trembles and the effect of periphery hydrostomia
Animal: ICR mouse (SPF level), male and female half and half;
Agonist: oxotremorine, 0.64mg/kg, subcutaneous injection (sc);
Be subjected to the reagent thing: the compound H of the embodiment of the invention 1-1, the compound H of embodiment 4-2, the compound H of embodiment 2-3;
Positive control drug: coromegine;
Method: behind The compounds of this invention abdominal injection (i.p.) 15min of various dose, sc oxotremorine 0.64mg/kg observes the restraining effect be subjected to the periphery hydrostomia effect that the reagent thing trembles to the mouse maincenter.Oxotremorine can suppress Pseudocholinesterase, it is excessive vagusstoff to occur in the inducing mouse body, produce and twitch and hydrostomia, two kinds of symptoms are all improved behind the injectable drug, illustrate that medicine can enter hemato encephalic barrier maincenter and periphery are all had effect, if can only anti-current saliva, can not improve tic, then this medicine has only peripheral action and can not enter maincenter.The results are shown in following table:
The inhibition effect of anti-oxidant tremorine periphery hydrostomia effect
| Dosage (mg/kg) | Administering mode | The animal subject number | Anti-current saliva number of animals |
| 16.67 | i.p. | 10 | 8 |
| 10.00 | i.p. | 10 | 6 |
| 6.00 | i.p. | 10 | 4 |
| 3.60 | i.p. | 10 | 1 |
The feminine gender and the positive control result of anti-oxidant tremorine periphery hydrostomia effect test
| Medicine | Dosage (mg/kg) | The animal subject number | Anti-current saliva number of animals | Anti-current saliva number of animals |
| Physiological saline | 10 | 0 | 0 | |
| Coromegine | 0.50 | 10 | 8 | 4 |
The result shows: the median effective dose position 8.28mg/kg of the anti-oxidant tremorine inducing mouse of The compounds of this invention (salt compounded of iodine) periphery hydrostomia, its fiducial interval of 95% is 5.57～12.82mg/kg.
The The compounds of this invention abdominal injection of various dose is after 15 minutes, subcutaneous injection oxotremorine 0.64mg/kg, tried that mouse is trembled to maincenter and the periphery excretory to suppress the result as follows:
The mouse maincenter is trembled and periphery excretory inhibition effect
Presentation of results: H-1～H-3 kind compound all can not enter hemato encephalic barrier, so the nonreactive effect of trembling, but 3 kinds of compounds all have the effect of anti-current saliva, and H-1, H-3 make good use of better tolerance than H-2.This experimental results show that and change the tertiary ammonium salt on the N position of amyl ethyl quin ether into quaternary amine that medicine can keep original peripheral action, can not pass through hemato encephalic barrier, thereby nervus centralis is not had influence.Substituting group carbon potential number is excessive, though can not enter maincenter, influences the effect of anti-current saliva.
This product toxicity is less, mouse LD
50Be 261.7mg/kg (im) that 71.2mg/kg (iv); Rat LD
50450.7mg/kg (im), 71.2mg/kg (iv); Long term toxicity test except that some common cholinolytic reactions occurring, does not see that other are unusual, and intramuscular injection local excitation test is up to specification.Mutagenicity test is negative; Dosage does not have obviously general genotoxicity in being equivalent to 75 times of people's consumptions; In being equivalent to 300 times of people's consumptions, do not see teratogenesis and embryotoxicity, also do not see the behavior teratogenesis.
Description of drawings
Fig. 1-1～1-2: the proton nmr spectra of methyl amyl ethyl quin ether quaternary ammonium salt compounded of iodine;
Fig. 2-1～2-2: the proton nmr spectra of phenmethyl quaternary ammonium salt hydrochlorate.
Embodiment
Further describe the present invention below by embodiment, but be not limited in practical range.
Embodiment 1: methyl amyl ethyl quin ether quaternary ammonium salt compounded of iodine
The preparation method of methyl amyl ethyl quin ether quaternary ammonium salt compounded of iodine:
With raw material amyl ethyl quin ether and excessive CH
3In I, the adding reaction flask, add acetonitrile again and make material dissolution, stir then, back flow reaction 7-10 days, the thin-layer chromatography monitoring reached balance until reaction; Be cooled to room temperature, boil off solvent, residue cleans 2-3 time with ethyl acetate, and ethyl alcohol recrystallization gets target compound, and recording yield is more than 50%.
Through the proton nmr spectra checking, see accompanying drawing 1-1～Fig. 1-2 (the continuous spectrogram of proton nmr spectra), this structure is a methyl amyl ethyl quin ether quaternary ammonium salt compounded of iodine.
Prove that through pharmacodynamic experiment methyl amyl ethyl quin ether quaternary ammonium salt compounded of iodine can not enter hemato encephalic barrier, the nonreactive effect of trembling, but the effect of anti-current saliva is arranged, nervus centralis there is not influence, better tolerance.
Embodiment 2: sec.-propyl amyl ethyl quin ether quaternary ammonium salt compounded of iodine
The preparation method of sec.-propyl amyl ethyl quin ether quaternary ammonium salt compounded of iodine:
With raw material amyl ethyl quin ether and excessive CH
3CH I CH
3, add in the reaction flask, add acetonitrile again and make material dissolution, stir then, back flow reaction 3-7 days, the thin-layer chromatography monitoring reached balance until reaction; Be cooled to room temperature, boil off solvent, residue cleans 2-3 time with ethyl acetate, and ethyl alcohol recrystallization gets target compound, and recording yield is more than 50%.
Through the proton nmr spectra checking, structure is a sec.-propyl amyl ethyl quin ether quaternary ammonium salt compounded of iodine.
Prove that through pharmacodynamic experiment sec.-propyl amyl ethyl quin ether quaternary ammonium salt compounded of iodine can not enter hemato encephalic barrier, the nonreactive effect of trembling, but the effect of anti-current saliva is arranged, nervus centralis there is not influence, better tolerance.
Embodiment 3: ethyl quaternary ammonium salt hydrochlorate
The preparation method of ethyl quaternary ammonium salt hydrochlorate:
With raw material amyl ethyl quin ether and excessive CH
3CH
2In Cl, the adding reaction flask, add acetonitrile again and make material dissolution, stir then, back flow reaction 5-7 days, the thin-layer chromatography monitoring reached balance until reaction; Boil off solvent, residue cleans 2-3 time with ethyl acetate, and ethyl alcohol recrystallization gets target compound, and recording yield is more than 50%.
Through the proton nmr spectra checking, structure is an ethyl quaternary ammonium salt hydrochlorate.
Prove that through pharmacodynamic experiment ethyl quaternary ammonium salt hydrochlorate can not enter hemato encephalic barrier, the nonreactive effect of trembling, but the effect of anti-current saliva is arranged, nervus centralis there is not influence, better tolerance.
Embodiment 4: phenmethyl quaternary ammonium salt hydrochlorate
The preparation method of phenmethyl quaternary ammonium salt hydrochlorate:
With raw material amyl ethyl quin ether and excessive C
6H
5CH
2In Cl, the adding reaction flask, add acetonitrile again and make material dissolution, stir then, normal-temperature reaction is more than 7 days, and the thin-layer chromatography monitoring reaches balance until reaction, boils off solvent, residue cleans 2-3 time with ethyl acetate, and ethyl alcohol recrystallization gets target compound, and recording yield is more than 50%.
Through the proton nmr spectra checking, see accompanying drawing 2-1～Fig. 2-2 (the continuous spectrogram of proton nmr spectra), this structure is a phenmethyl quaternary ammonium salt hydrochlorate.
Claims (10)
1, quaternary ammonium salt and derivative thereof have following structure,
Wherein, R is C
1-C
6The C that alkane or phenyl replace
1-C
6Alkane; M is a halogen.
2, described quaternary ammonium salt of claim 1 and derivative thereof, wherein R is methyl, phenmethyl, ethyl, propyl group or sec.-propyl.
3, described quaternary ammonium salt of claim 1 and derivative thereof, wherein M is F, Cl, Br or I.
4, described quaternary ammonium salt of claim 2 and derivative thereof, wherein R is methyl, phenmethyl, ethyl.
5, described quaternary ammonium salt of claim 3 and derivative thereof, wherein M is Cl or I.
6, described quaternary ammonium salt of claim 1 and derivative thereof, wherein R is a methyl; M is Cl or I.
7, the method for preparing described quaternary ammonium salt of claim 1 and derivative thereof, comprising back flow reaction is until reaching molecular balance in acetonitrile with amyl ethyl quin ether and excessive RM, wherein, R is C
1-6The C that alkane or phenyl replace
1-6Alkane; M is F, Cl, Br or I.
8, the described preparation method of claim 7, wherein also comprise molecular balance after, boil off solvent, residue cleans with ethyl acetate, the step of ethyl alcohol recrystallization.
9, the described preparation method of claim 8 behind the wherein said molecular balance, comprises the product cooling, boils off the step of solvent again.
10, described quaternary ammonium salt of claim 1 and derivative thereof the application in the hyperfunction medicine of preparation treatment peripheral cholinergic nerve.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510114293 CN1951938A (en) | 2005-10-21 | 2005-10-21 | Penehyclidine quaternary ammonium salt and its derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510114293 CN1951938A (en) | 2005-10-21 | 2005-10-21 | Penehyclidine quaternary ammonium salt and its derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1951938A true CN1951938A (en) | 2007-04-25 |
Family
ID=38058514
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510114293 Pending CN1951938A (en) | 2005-10-21 | 2005-10-21 | Penehyclidine quaternary ammonium salt and its derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1951938A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070631A (en) * | 2009-11-20 | 2011-05-25 | 中国人民解放军军事医学科学院毒物药物研究所 | Quaternary ammonium salt of penehyclidine optical isomer, medicinal composition and medical application thereof |
| CN102993125A (en) * | 2012-09-25 | 2013-03-27 | 中国人民解放军第四军医大学 | New kappa-opiate receptor stimulant having protection function on ischemia heart |
| CN104603108A (en) * | 2012-08-09 | 2015-05-06 | 才思制药公司 | Piperidinium quaternary salts |
| CN105431432A (en) * | 2013-07-13 | 2016-03-23 | 北京嘉事联博医药科技有限公司 | Quinine compounds, and optical isomers, preparation method and medical use thereof |
| CN111377920A (en) * | 2018-12-27 | 2020-07-07 | 银谷制药有限责任公司 | Method for refining quinine compound containing quaternary ammonium group |
-
2005
- 2005-10-21 CN CN 200510114293 patent/CN1951938A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070631A (en) * | 2009-11-20 | 2011-05-25 | 中国人民解放军军事医学科学院毒物药物研究所 | Quaternary ammonium salt of penehyclidine optical isomer, medicinal composition and medical application thereof |
| CN102070631B (en) * | 2009-11-20 | 2016-09-07 | 中国人民解放军军事医学科学院毒物药物研究所 | The quaternary ammonium salt of optical isomer of penehyclidine, pharmaceutical composition and medical usage thereof |
| CN104603108A (en) * | 2012-08-09 | 2015-05-06 | 才思制药公司 | Piperidinium quaternary salts |
| CN108658842A (en) * | 2012-08-09 | 2018-10-16 | 才思制药公司 | Piperidines quaternary salt |
| CN102993125A (en) * | 2012-09-25 | 2013-03-27 | 中国人民解放军第四军医大学 | New kappa-opiate receptor stimulant having protection function on ischemia heart |
| CN105431432A (en) * | 2013-07-13 | 2016-03-23 | 北京嘉事联博医药科技有限公司 | Quinine compounds, and optical isomers, preparation method and medical use thereof |
| JP2016528199A (en) * | 2013-07-13 | 2016-09-15 | ベイジン エフエスウェルカム テクノロジー ディベロップメント カンパニー リミテッド | Kinin compounds, optical isomers thereof, production methods thereof, and pharmaceutical uses |
| AU2014292722B2 (en) * | 2013-07-13 | 2017-03-09 | Beijing Showby Pharmaceutical Co., Ltd. | Quinine compounds, and optical isomers, preparation method and medical use thereof |
| US9751875B2 (en) | 2013-07-13 | 2017-09-05 | Beijing Fswelcome Technology Development Co., Ltd. | Quinine compounds, and optical isomers, preparation method and medical use thereof |
| CN105431432B (en) * | 2013-07-13 | 2018-01-09 | 北京硕佰医药科技有限责任公司 | Quinine class compound, its optical isomer and preparation method thereof and medical usage |
| CN111377920A (en) * | 2018-12-27 | 2020-07-07 | 银谷制药有限责任公司 | Method for refining quinine compound containing quaternary ammonium group |
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20220017459A1 (en) | Compositions, methods, and systems for the synthesis and use of imaging agents | |
| US10513525B2 (en) | Methods and compositions for studying, imaging, and treating pain | |
| CN101248041B (en) | Sphingosine kinase inhibitors | |
| CN105026360B (en) | S1P conditioning agents | |
| Hikino et al. | Antiinflammatory principle of Ephedra herbs | |
| US20120046246A1 (en) | Methods for treating osteoclast-related disease, compounds and compositions thereof | |
| WO2014111004A1 (en) | Flavone alkylamine compound, preparation method and use thereof | |
| CN1951938A (en) | Penehyclidine quaternary ammonium salt and its derivative | |
| WO2011034860A1 (en) | Treatment methods using triaryl methane compounds | |
| AU2021215274A1 (en) | Targeted drug rescue with novel compositions, combinations, and methods thereof | |
| EP3638239A1 (en) | Methods of treating rbp4 related diseases with triazolopyridines | |
| HUE032235T2 (en) | Azetidinyloxyphenylpyrrolidine compounds | |
| JP2022166027A (en) | SMALL MOLECULE DRUGS AND RELATED METHODS FOR TREATMENT OF DISEASES RELATED TO Aβ42 OLIGOMER FORMATION | |
| TW201904967A (en) | Method for treating metabolic diseases by fused bicyclic pyrazole | |
| JP2024063076A (en) | Cyclobenzaprine analogs and amitriptyline analogs | |
| EP3091982B1 (en) | Organic compounds | |
| US9968592B2 (en) | Dyslipidemia therapeutic agent | |
| CN103826622B (en) | For preventing or treat hydrocinnamamide or the phenylallene acid amides of the N-replacement of affective disorder | |
| US9126989B2 (en) | Compound and methods for treating long QT syndrome | |
| JP2009509926A (en) | Lysophylline analogs and methods of use | |
| US20120190743A1 (en) | Compounds for treating disorders or diseases associated with neurokinin 2 receptor activity | |
| CN107586281A (en) | Aralkyl heterocyclic derivative and its application in Mutiple Targets depression | |
| US20200369674A1 (en) | Anti-pain compound and preparation method thereof | |
| CN110240549A (en) | A kind of amine alkoxy chalcone compound and its preparation method and application | |
| CN104177352B (en) | Water solublity benzothiazole slaine of anti-cell proliferative disorder and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |