CN101311171A - Compound with dual restraining activities to acetyl cholinesterase and butyryl cholinesterase and use thereof - Google Patents
Compound with dual restraining activities to acetyl cholinesterase and butyryl cholinesterase and use thereof Download PDFInfo
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Abstract
The invention adopts a virtual medicine screening technology and a high-throughput screening technology, assesses the AChE inhibitory activity of more than ten thousand samples in a compound sample library and finds a batch of compounds with higher inhibitory activity by establishing a virtual acetylcholinesterase inhibitor screening method and an AChE activity detection method. Then according to the pathological features of senile dementia, the compounds with higher AChE inhibitory activity are subject to butyryl choline esterase inhibitory activity detection. Research results show that bimolecular 3-piperidyl-ethyl phenyl ketone not only has comparatively high AChE inhibitory activity, but also has very strong BuChE inhibitory activity; the results of animal experiments prove that the bimolecular 3-piperidyl-ethyl phenyl ketone can remarkably improve aphronesia caused by scopolamine and sodium nitrite and can enhance the ability of learning and memory.
Description
Technical field
The present invention relates to a class bimolecular 3-piperidyl-Propiophenone compound, this compounds not only has stronger AChE and suppresses active, also has very strong BuChE simultaneously and suppresses active; And the application of this compounds in treatment learning memory disorder and senile dementia, belong to medical technical field.
Background technology
Senile dementia and age ageing have substantial connection.Along with the world population aging, the sickness rate of senile dementia also increases thereupon.According to statistics, the sickness rate in 65-69 year the elderly every year is 1.4 ‰, and 70-74 year is 3.9 ‰, and 75-79 year is 16.7 ‰, increases to 45.4 ‰ during to 85 years old.Senile dementia is to have a strong impact on life of elderly person quality and healthy disease after the heart trouble, tumour, diabetes.This disease can make memory impaired, and activity of daily living descends, and its function of fading comprises: (1) memory and cognition function--and show hypomnesis, usually forget the name that comprises relatives and friends such as children; Can not resolving time, season, also get lost or the like in the place of being familiar with.(2) behavior mental symptom--comprise illusion, persecutory delusion, easily enrage and attack tendency or the like.(3) activity of daily living--along with PD, patient's activity of daily living is lost gradually, can't participate in public activity, and having a meal wears the clothes acts oddly, even can't take care of oneself.Therefore, not only having the huge social benefit for the research of anti-ageing year dementia medicine, and can obviously alleviate the economical load of country and family, is very necessary.
Senile dementia can be divided into presenile dementia (Alzheimer ' s disease, AD), vascular dementia (vascular dementia, VD) and the two and the mixed type dementia of depositing.AD is more common, also studies manyly.Senile dementia is a kind of comprehensive disease, and its typical pathological change comprises that cortex, hippocampus countless neurofibrillary tangle (NFT) and amyloid-beta (A β) formation of deposits senile plaque (SP) occur in neuron loss, basal forebrain cholinergic function obstacle, the brain widely.According to the pathological characters and the pathogenesis of senile dementia, the treatment approach of taking for the senile dementia patient comprises: (1) improves the medicine of choline system function.(2) correct calcium homeostasis imbalance and oxidation resistant medicine.(3) neurotrophic factor.(4) disturb A β to form and sedimentary medicine.(5) anti-nerve cell apoptosis agent.
Up to the present, cholinergic system is considered to most important neurotransmitter system in the normal cognitive function always, no matter be that (Acetylcholinesterase, AChE) the inhibitor effect still all can improve cognitive function by the effect of M, n receptor agonist by acetylcholinesterase.AD is a kind of disease that relates generally to memory injury, and its cholinergic damages the conclusive key effect of cholinergic system in memory function that proved.
Over past ten years, acetylcholinesterase inhibitor has become the first-line treatment medicine of AD, prove conclusively it and effectively alleviated the status of cognition dysfunction, the sales volume of the product has occupied the lion's share in the antidementia agent, main medicine has tacrine (Tacrine), E2020 (donepezil hydrochloride), sharp this bright (Rivastigmine), lycoremine (Galantamine) and selagine (Huperzine A) etc. have become the representative drugs in this field, thereby have promoted the development process of AD medicine.Tacrine (Tacrine) can effectively improve patient's AD illness clinically, but because it has bigger damage to liver, the use to it at present reduces.The inhibitor toxicity of other several AChE is low, can effectively improve patient's cognition dysfunction, but their clinical validity period is all ofer short duration.Therefore, seek the anti-AD medicine of novel and effective and be still the challenge that the drug research worker faces.
Summary of the invention
The object of the present invention is to provide a kind of bimolecular 3-piperidyl-Propiophenone compound.
A further object of the present invention is to provide the pharmaceutical composition that contains available carrier on bimolecular 3-piperidyl-Propiophenone compound and the pharmacopedics.
Another purpose of the present invention is to provide the application of this bimolecular 3-piperidyl-Propiophenone compound in preparation treatment learning memory disorder medicine and anti senile dementia drug.
Shown in the compound general formula of the present invention (I):
Wherein,
R1, the substituting group that R2, R3 and R4 can be identical or different independently is selected from C
1-10Alkyl;
R1 and R2, R3 and R4 can also form multicomponent heterocycle.
Preferred R1, R2, R3 and R4 independently are selected from CH
3-, C
2H
5-, C
3H
7-, C
4H
9-.
Or substituent R 1, R2 and nitrogen-atoms can form five-ring or six-ring.
Five-ring or six-ring that more preferred substituents R1, R2 and nitrogen-atoms form are selected from
Or substituent R 3, R4 and nitrogen-atoms can form five-ring or six-ring.
Five-ring or six-ring that more preferred substituents R3, R4 and nitrogen-atoms form are selected from
Most preferred including but not limited to
Bimolecular 3-piperidyl Propiophenone (bimolecular bimolecular morpholinyl Propiophenone (bimolecular
3-piperidino propiophenone, compound 1) 3-morpholin propiophenone, compound 2)
Bimolecular 3-diethylamino Propiophenone (bimolecular bimolecular 3-dimethylamino Propiophenone (bimolecular
3-diethylamino propiophenone, compound 3) 3-dimethylamino propiophenone, compound 4)
The contriver finds that compound of the present invention has higher AchE and suppresses active, and further experimental result shows that compound of the present invention has acetylcholinesterase and butyrylcholine esterase dual restraining activities.Compound of the present invention improves the learning and memory of dementia animal model in vivo.
Therefore the present invention also relates to the pharmaceutical composition of The compounds of this invention as active ingredient.This pharmaceutical composition can be according to method preparation well known in the art.Can be by the pharmaceutically acceptable solid of The compounds of this invention and one or more or liquid excipient and/or assistant agent being combined, make any formulation that is suitable for human or animal's use.The content of The compounds of this invention in its pharmaceutical composition is generally 0.1-95 weight %.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For The compounds of this invention is made tablet, can be extensive use of various vehicle well known in the art, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, lime carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet further can also be made coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
For capsule is made in the administration unit, the effective constituent The compounds of this invention can be mixed with thinner, glidant, mixture is directly placed hard capsule or soft capsule.Also the effective constituent The compounds of this invention particle or micropill be can be made with thinner, tamanori, disintegrating agent earlier, hard capsule or soft capsule placed again.Each thinner, tamanori, wetting agent, disintegrating agent, the glidant kind that are used to prepare the The compounds of this invention tablet also can be used for preparing the capsule of The compounds of this invention.
For The compounds of this invention is made injection, can water, ethanol, Virahol, propylene glycol or their mixture as solvent and add an amount of this area solubilizing agent commonly used, solubility promoter, pH and adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepare lyophilized injectable powder, also can add N.F,USP MANNITOL, glucose etc. as propping agent.
In addition, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives or other additive.
For reaching the medication purpose, strengthen result of treatment, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.
The dosage of The compounds of this invention pharmaceutical composition is according to character and the severity that will prevent or treat disease, the individual instances of patient or animal, and route of administration and formulation etc. can have large-scale variation.In general, the suitable dose scope of the every day of The compounds of this invention is the 0.001-150mg/Kg body weight, is preferably the 0.1-100mg/Kg body weight, and more preferably the 1-60mg/Kg body weight most preferably is the 2-30mg/Kg body weight.Above-mentioned dosage can a dose unit or is divided into several dose unit administrations, and this depends on doctor's clinical experience and comprises the dosage regimen of using other treatment means.
Compound of the present invention or composition can be taken separately, or merge use with other treatment medicine or symptomatic drugs.When compound of the present invention and other medicine existence synergy, should adjust its dosage according to practical situation.
Description of drawings
The structure of Fig. 1 The compounds of this invention
Fig. 2 The compounds of this invention suppresses the amount effect curve of AChE
Fig. 3 compound suppresses the amount effect curve of BChE
Fig. 4 compound (1) is to Scopolamine model mice diving tower experiment influence
Fig. 5 compound (1) is to Scopolamine model mice diving tower experiment influence
Fig. 6 compound (1) influences Scopolamine model mice water maze laboratory
Fig. 7 compound (1) is kept away dark experiment influence to the Sodium Nitrite model mice
Fig. 8 compound (1) is to Sodium Nitrite model mice diving tower experiment influence
Fig. 9 compound (1) is kept away dark experiment influence to the Sodium Nitrite model mice
Embodiment
Embodiment 1: virtual screening AchE inhibitor.Two compound crystal structures based on E2020 and selagine and AChE, applying virtual screening procedure FlexX and consistent scoring method, result to twice virtual screening carries out adduction, selects the higher compound of score value to amount to 2855 compounds, as testing compound.It predicts the outcome analysis-by-synthesis, therefrom selects part of compounds and carries out the activity detection.
Embodiment 2: to the inhibition activity of AchE.
Set up the AchE inhibitor screening model according to document, the compounds of selecting in 2885 have been carried out active detection, find that compound 1, compound 2, compound 3, compound 4 have higher AChE and suppress active, its activity value sees Table 1.Its IC
50Be 1 μ M～10 μ M.
The AChE vitro inhibition activity of table 1 compound
Annotate: above data are the mean value of 3 experimental datas.
Embodiment 3: to the inhibition activity of butyrylcholine esterase
According to document set up butyrylcholine esterase (Butyrocholinesterase, BChE) inhibitor screening model, by this model detection compound activity,
Experimental result shows that compound (1), (2), (3) and (4) have very strong BChE and suppress active, and its activity value sees Table 2.Its IC
50Be 0.1 μ M～1 μ M.The positive control drug selagine is to BChE unrestraint activity, and the activity that positive drug E2020 (donepezil) suppresses BChE all is lower than active compound (1), (2), (3) and (4).
The BChE vitro inhibition activity of table 2 compound
Annotate: above data are the mean value of 3 experimental datas.
Embodiment 4: compound is to the study of Scopolamine induced mice, amnemonic influence
Build mouse study, dysmnesia model with Scopolamine,, observe the effect of compound (1) with selagine, the positive control drug of E2020.The learning and memory of little mouse function compares the difference between normal control group, model group and the medicine group with study of behaviour indexs such as autonomic activities, hole plate, diving tower, water mazes.The dosage of compound pharmacodynamics evaluation is to determine in conjunction with The acute toxicity tests according to the conventional amount used method of calculation of medicine.Selected middle dosage and low dose for use when compound (1) pharmacodynamics is estimated: middle dosage group is 5mg/kg, and small dose group is 1mg/kg.
90 of laboratory mices are used for the evaluation of dementia animal model pharmacodynamics, and mouse is divided into 6 groups at random, dosage group, compound (1) small dose group in the normal group, model group, selagine group, E2020 group, compound (1), 15 of every group of mouse.
Compound (1) is to the influence of mouse autonomic activities.Behind the experiment mice gastric infusion, compare with normal group, each dosage group mouse autonomic activities number of times does not have obvious change.
Compound (1) is tested influence to mouse hole is firm and hard.Behind the experiment mice gastric infusion, compare with normal group, each dosage group mouse exploratory heading number of times does not have obvious change.
Compound (1) is to Scopolamine model mice diving tower experiment influence.Behind the injected in mice Scopolamine, model group compares with blank group, and mouse diving tower avoiding reaction errors number obviously increases (P＜0.05).After the Scopolamine model group mouse electric shock, find the time of diving tower obviously to prolong, behind the 24h, the time on diving tower (latent period) is very short, and compare significant difference (P＜0.05) with blank group latent period.In the compound (1), low dose all can obviously prolong latent period, with model group relatively, significant difference (P＜0.05).(errors number is seen Fig. 4, sees Fig. 5 latent period)
Compound (1) influences Scopolamine model mice water maze laboratory.Behind the injected in mice Scopolamine, model group compares with blank group, and the time that mouse is reached home obviously increases (P＜0.05), and the low dose of compound (1) all can be resisted the learning memory disorder that Scopolamine causes, compare significant difference (P＜0.05) (see figure 6) with model group.
Embodiment 5: compound is to the influence of the study of SODIUMNITRATE induced mice, dysmnesia model
Build mouse study, dysmnesia model with Sodium Nitrite,, observe the effect of compound (1) with selagine, the positive control drug of E2020.90 of laboratory mices are used for the evaluation of dementia animal model pharmacodynamics, and mouse is divided into 6 groups at random, dosage group, compound (1) small dose group in the normal group, model group, selagine group, E2020 group, compound (1), 15 of every group of mouse.The learning and memory of little mouse function with autonomic activities, hole plate, diving tower, keep away study of behaviour indexs such as dark, the difference between normal control group, model group and the medicine group relatively.
Compound (1) is to the influence of mouse autonomic activities.Behind the experiment mice gastric infusion, compare with normal group, dosage group mouse autonomic activities number of times obviously increases (P＜0.05) in the compound (1), and all the other dosage group mouse autonomic activities number of times do not have obvious change.
Compound (1) is tested influence to mouse hole is firm and hard.Behind the experiment mice gastric infusion, compare with normal group, the selagine group exploratory heading number of times of mouse obviously reduces (P＜0.05), and all the other dosage group mouse exploratory heading number of times do not have obvious change.
Compound (1) is to Sodium Nitrite model mice diving tower experiment influence.Behind the injected in mice Sodium Nitrite, model group compares with blank group, mouse diving tower avoiding reaction errors number obviously increases (P＜0.05), the middle dosage of compound (1) can obviously reduce the errors number (see figure 8), can resist the learning memory disorder that Sodium Nitrite causes, compare significant difference (P＜0.05) with model group.After the Sodium Nitrite model group mouse electric shock, find the time of diving tower obviously to prolong, behind the 24h, the time on diving tower is very short, and compare significant difference (P＜0.05) with blank group latent period.The middle dosage of compound (1) all can obviously prolong latent period, compares significant difference (P＜0.05) with model group.
Compound (1) is kept away dark experiment influence to the Sodium Nitrite model mice.Behind the injected in mice Sodium Nitrite, model group is organized relatively with blank, and mouse avoiding reaction errors number increases, and the middle dosage of compound (1) and low dose all can be resisted the learning memory disorder that Sodium Nitrite causes, compare significant difference with model group.Compare significant difference with blank group latent period.In the compound (1), low dose all can obviously prolong the (see figure 7) in latent period, reduces the errors number (see figure 9), with model group relatively, significant difference.
Claims (10)
1, the compound shown in general formula (I):
Wherein,
R1, the substituting group that R2, R3 and R4 can be identical or different independently is selected from C
1-10Alkyl;
R1 and R2, R3 and R4 can also form multicomponent heterocycle.
2, according to the compound of right 1, it is characterized in that, R1, R2, R3 and R4 independently are selected from CH
3-, C
2H
5-, C
3H
7-, C
4H
9-.
3, according to the compound of right 1, it is characterized in that five-ring or six-ring that substituent R 1, R2 and nitrogen-atoms form.
According to the compound of right 3, it is characterized in that 4, five-ring or six-ring that substituent R 1, R2 and nitrogen-atoms form are selected from
5, according to the compound of right 1, it is characterized in that five-ring or six-ring that substituent R 3, R4 and nitrogen-atoms form.
According to the compound of right 5, it is characterized in that 6, five-ring or six-ring that substituent R 3, R4 and nitrogen-atoms form are selected from
According to the compound of right 1, it is characterized in that 7, described compound is selected from
Bimolecular 3-piperidyl Propiophenone bimolecular morpholinyl Propiophenone
Bimolecular 3-diethylamino Propiophenone bimolecular 3-dimethylamino Propiophenone.
8, a kind of pharmaceutical composition comprises available carrier at least a compound of claim 1-8 and the pharmacopedics.
9, the application of arbitrary described compound in preparation treatment learning memory disorder medicine among the claim 1-8.
10, the application of arbitrary described compound in the preparation anti senile dementia drug among the claim 1-8.
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| Application Number | Priority Date | Filing Date | Title |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101797223B (en) * | 2009-02-06 | 2012-05-23 | 上海交通大学医学院 | Huperzine A preparations for eyes and application thereof |
| CN103420941A (en) * | 2013-08-26 | 2013-12-04 | 浙江大学 | 2-methoxyphenyl-dimethylamino formic ether derivative and preparation method and application thereof |
| CN103420942A (en) * | 2012-05-23 | 2013-12-04 | 中国医学科学院药物研究所 | Compound with dual inhibitory activities to acetylcholine esterase and cholinesterase |
| CN105348221A (en) * | 2014-08-21 | 2016-02-24 | 中国医学科学院药物研究所 | Bimolecular 3- piperidyl-propiophenone hydrochloride crystal form II substance, preparation method and composition thereof, and uses of bimolecular 3-piperidyl-propiophenone hydrochloride crystal form II substance and composition |
| CN105461658A (en) * | 2014-08-21 | 2016-04-06 | 中国医学科学院药物研究所 | Dimolecular 3-piperidyl-propiophenone hydrochloride I crystal form substance, and preparation method, composition and use thereof |
| CN105461657A (en) * | 2014-08-21 | 2016-04-06 | 中国医学科学院药物研究所 | Dimolecular 3-piperidyl-propiophenone hydrochloride III crystal form substance, and preparation method, composition and use thereof |
| CN109665988A (en) * | 2017-10-16 | 2019-04-23 | 中国医学科学院药物研究所 | The biphenyl dione compounds and application thereof that bipiperidine replaces |
-
2007
- 2007-05-22 CN CN2007101076046A patent/CN101311171B/en active Active
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101797223B (en) * | 2009-02-06 | 2012-05-23 | 上海交通大学医学院 | Huperzine A preparations for eyes and application thereof |
| CN103420942A (en) * | 2012-05-23 | 2013-12-04 | 中国医学科学院药物研究所 | Compound with dual inhibitory activities to acetylcholine esterase and cholinesterase |
| CN103420942B (en) * | 2012-05-23 | 2016-12-14 | 中国医学科学院药物研究所 | Second, butyrylcholine esterase had dual restraining activities compound |
| CN103420941A (en) * | 2013-08-26 | 2013-12-04 | 浙江大学 | 2-methoxyphenyl-dimethylamino formic ether derivative and preparation method and application thereof |
| CN103420941B (en) * | 2013-08-26 | 2015-09-23 | 浙江大学 | 2-p-methoxy-phenyl-dimethylin carbamate derivatives and preparation and purposes |
| CN105348221A (en) * | 2014-08-21 | 2016-02-24 | 中国医学科学院药物研究所 | Bimolecular 3- piperidyl-propiophenone hydrochloride crystal form II substance, preparation method and composition thereof, and uses of bimolecular 3-piperidyl-propiophenone hydrochloride crystal form II substance and composition |
| CN105461658A (en) * | 2014-08-21 | 2016-04-06 | 中国医学科学院药物研究所 | Dimolecular 3-piperidyl-propiophenone hydrochloride I crystal form substance, and preparation method, composition and use thereof |
| CN105461657A (en) * | 2014-08-21 | 2016-04-06 | 中国医学科学院药物研究所 | Dimolecular 3-piperidyl-propiophenone hydrochloride III crystal form substance, and preparation method, composition and use thereof |
| CN109665988A (en) * | 2017-10-16 | 2019-04-23 | 中国医学科学院药物研究所 | The biphenyl dione compounds and application thereof that bipiperidine replaces |
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| CN101311171B (en) | 2011-09-28 |
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Address after: 100050 No. 2 Nanwei Road, Xicheng District, Beijing Patentee after: Institute of Materia Medica of Chinese Academy of Medical Sciences Address before: 100050 Beijing city Xuanwu District Xiannongtan Street No. 1 Patentee before: Institute of Materia Medica of Chinese Academy of Medical Sciences |