CN1445211A - New amide ramification of sweetsop as well as its preparing method, its medication composition and usage - Google Patents
New amide ramification of sweetsop as well as its preparing method, its medication composition and usage Download PDFInfo
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Abstract
A novel anonaceamide derivative, its preparing process, the composite medicines containing it, and its medical application in treating Parkinson's disease, dysmnesia, hypomnesia, and Al zheimer's disease are disclosed.
Description
Technical field
The present invention relates to new squqmosamide derivative, its preparation method contains their pharmaceutical composition, and, especially, improve learning memory disorder as the Kang Pajinsenshi disease as medicine, the treatment memory capability go down and Alzheimers disease (Alzheimer ' s disease, purposes AD).
Background technology
Squqmosamide (1) is by a natural product (Acta Pharmaceutica Sinicas 1992 that separation obtains from plant sweetsop such as Inst. of Exploiting of Medical Plant Resource, Chinese Academy of Medical Scienc little rivers of poplar, 27,185-190), about its structure and synthetic by Ji Xiaoshen, Liang Xiaotian in 1993 at Acta Pharmaceutica Sinica (1993,28, report 428-431), squqmosamide that described above-mentioned document is reported mainly is the chemical research aspect about this compound, and does not report the research of the synthetic and relevant pharmacologically active of this compound Mirapexin reason activity and derivative thereof.
The present invention has now found that through studying for a long period of time the new squqmosamide derivative that describes in detail later has good medicinal character.As everyone knows, Parkinson's disease is a kind of chronic progressive external nervous system disorders that is caused by the extrapyramidal system dysfunction, and pathological characters is that substantia nigra striatum dopaminergic neuron cell reduces, and neurotransmitter dopamine and metabolite content thereof significantly reduce.The Mirapexin thing of using only plays the effect of improving symptom at present, can not delay the process of disease, let alone the radical cure Parkinson's disease.L-dopa treats parkinsonian choice drug clinically, but because L-dopa can enter the amount of central nervous system less than 1% of taking dose, week is metabolised to the side effect that Dopamine HCL produces periphery to a large amount of L-dopa outside, prolonged application L-dopa also can produce side reactions such as dyskinesia, altered mental status, and these untoward reactions are the difficult problems that the clinician faces always.People are examining the effect of L-dopa again closely, because the results suggest of increasing fundamental research, this has certain cytotoxicity in external to dopaminergic nerve cell L-dopa, increases the weight of damage thereby the oxidation of L-dopa itself also can make cell be in the oxidative stress state.The proposition of the oxidative stress theory of the Parkinson's disease cause of disease and neuroprotective treatment notion has been opened up new approaches for parkinsonian control and has promptly been sought an effective free-radical scavengers, and neuroprotective unit delays disease process.
The inventor finds; for example The compounds of this invention shifts to an earlier date behavior the have clear improvement effect of administration to the model mice that trembles; and the reduction of Dopamine HCL and meta-bolites thereof in the MPTP induced mice brain there is the raising effect; thereby may be a kind of new compound with neuro-protective effect, probably be developed as a kind of new drug of anti-Parkinson's disease.Especially the sick effect of Kang Pajinsenshi, the effect of being characterized in is obvious, and toxicity is low.
The aging problem of world today's population has caused attracting attention of various countries in addition, elderly population will reach 800,000,000 when estimating the year two thousand fifty, various puzzlements that aging brings and social concern are with even more serious, and preventing and treating or delaying senility becomes the hot subject of life science.Alzheimers disease (AD) claims senile dementia again, is a kind of destructive nerve retrograde affection, and AD sickness rate in elderly population is very high.Clinically, AD is a principal character with progressive cognition dysfunction, finally can develop into the daily basic activity of patient and can't take care of oneself.The notable attribute of cognition dysfunction is the loss of memory, is accompanied by orientation, linguistic function forfeiture, and judgement decline, emotion and behavior are unbalance etc.The cause of disease of AD is diversified, but the pathophysiological change of patient's forebrain is more consistent, shows as the cholinergic nerve regression, and neuron loss cause neurotransmitter acetylcholine (ACh) concentration reduction in the brain, and ACh is inseparable with cognitive function.Therefore, the medicine approach of treatment AD mainly is to strengthen the cholinergic system function at present, for example taking ACh precursor (as choline and LECITHIN) increases the generation of ACh, or reach the purpose of indirect rising ACh concentration with the destruction of reducing synaptic cleft ACh by suppressing Pseudocholinesterase (AChE) active (as tacrine, E2020, Rivastigmine and Physostigmine etc.), also can directly activate postsynaptic cholinocepter.Though it is clinical that these medicines have been applied to, real effectively medicine still very lacks.Because carry out in the property disease at the such nerve of AD, passing in time, these medicines of positive howsoever use can still be reduced gradually by the remaining neurone of ACh excitement, cause result of treatment to reduce gradually.Risen to the 4th cause of death at the AD of developed country, and the AD sickness rate of China rises year by year also.Therefore, developing effective AD control medicine extremely needs.
Compound Wheat Protein of the present invention, and find that this compound can obviously improve the damage in learning and memory of mouse.The compounds of this invention can improve the damage in learning and memory of multiple mouse model, can significantly strengthen memory consolidation, the memory represents of mouse model, strengthen spatial discrimination and the learning capacity of mouse, so this compound has and improves the purposes that memory capability goes down and treats patient's AD cognition dysfunction.
Summary of the invention
In order to overcome the weak point of prior art, the object of the present invention is to provide a kind of new squqmosamide derivative;
Another object of the present invention is to provide a kind of preparation method of new squqmosamide derivative;
Another object of the present invention is to provide the application of a kind of new squqmosamide derivative and composition thereof as the Mirapexin thing.
A further object of the present invention is to provide a kind of new squqmosamide derivative at the medicine that improves learning memory disorder or be used for that memory capability goes down and Alzheimers disease (Alzheimer ' s disease, the application of medicine for treatment AD).
So first aspect present invention relates to general formula (I) compound and isomer thereof
It is characterized in that: its A, B ring can be phenyl ring, or contains a heteroatomic fragrant heterocycle; R1 when A, B are phenyl ring, R2, R3, R4 can be positioned at 2,3,4,5 one of A, B ring at the same time or separately, and R1 when A, B are heterocycle, R2, R3, R4 can be positioned at any position of A, B ring at the same time or separately; R1, R2, R3, R7 can be hydrogen C1-C7 straight or branched alkyl, alkoxyl group, nitro, hydroxyl, acyloxy, trihalogenmethyl, halogen at the same time or separately; The same R1 of the definite division of R4, R2, R3, outside the R7, when B ring during for phenyl ring, R4 can directly link to each other by covalent linkage with R5 when being positioned at 2 of B ring; R5 can be hydrogen, C1-7 straight or branched alkyl or directly links to each other with R4 by covalent linkage; R6 can be hydrogen, C1-7 straight or branched alkyl, carboxyl, ester group (R6=-CO2R8, R8 can be C1-7 straight or branched alkyl), the integer of n=1-4.
Further aspect of the present invention relates to pharmaceutical composition, and it comprises carrier commonly used in the compound of the general formula (I) as active ingredient and isomer and the pharmacy field.
What further aspect of the present invention related to is that general formula (I) compound or the pharmaceutical composition that contains it are preventing and/or treating parkinsonian purposes.
What further aspect of the present invention related to is to prevent and/or treat parkinsonian method, and it comprises general formula (I) compound or the pharmaceutical composition that contains it are delivered medicine to the host that need prevent and/or treat.
According to the present invention, general formula of the present invention (I) compound is at the pharmacological testing sick relevant with Kang Pajinsenshi, and is sick active as demonstrating good Kang Pajinsenshi in the mouse pole-jump test.It is sick active that the sick compound exhibits of the Kang Pajinsenshi of general formula (I) goes out good Kang Pajinsenshi, and it is compared with known Mirapexin thing DOPA has effect obviously, the characteristics that mechanism of action difference and toxicity are low.
Specifically, the present invention relates to general formula (I) compound and isomer thereof.
Wherein, its A, B ring can be phenyl ring, or contains a heteroatomic fragrant heterocycle; R1 when A, B are phenyl ring, R2, R3, R4 can be positioned at 2,3,4,5 one of A, B ring at the same time or separately, and R1 when A, B are heterocycle, R2, R3, R4 can be positioned at any position of A, B ring at the same time or separately; R1, R2, R3, R7 can be hydrogen C1-C7 straight or branched alkyl, alkoxyl group, nitro, hydroxyl, acyloxy, trihalogenmethyl, halogen at the same time or separately; The same R1 of the definite division of R4, R2, R3, outside the R7, when B ring during for phenyl ring, R4 can directly link to each other by covalent linkage with R5 when being positioned at 2 of B ring; R5 can be hydrogen, C1-7 straight or branched alkyl or directly links to each other with R4 by covalent linkage; R6 can be hydrogen, C1-7 straight or branched alkyl, carboxyl, ester group (R6=-CO2R8, R8 can be C1-7 straight or branched alkyl), the integer of n=1-4.
According to the present invention, preferred general formula (I) compound includes but not limited to the compound of formula (Ia) expression,
Wherein A, B are phenyl ring R1, R2, R3, the last definition of R4, wherein R7=4 '-OH
According to the present invention, preferred general formula (I) compound includes but not limited to the compound of formula (Ib) expression,
R7=4 '-OH wherein.
According to the present invention, preferred general formula (I) compound includes but not limited to the compound of formula (Ic) expression,
R7=4 '-OH wherein.According to the present invention, preferred general formula (I) compound includes but not limited to the compound of formula (Id) expression,
R7=4 '-OH wherein.According to the present invention, preferred general formula (I) compound includes but not limited to the compound of formula (Ie) expression,
R7=4 '-OH wherein.According to the present invention, preferred general formula (I) compound includes but not limited to the compound of formula (If) expression,
R7=4 '-OH wherein.
Prepare the method for compound of the present invention or its isomer, may further comprise the steps:
With substituted benzaldehyde or contain a heteroatomic heterocycle formaldehyde with substituted phenylacetic acid or contain a heteroatomic substituted heterocycle acetate; condensation obtains 2 in the presence of acid anhydrides; 3-disubstituted benzenes or heterocycle vinylformic acid; again with the aniline condensation that replaces; when containing the substituting group of protection on phenyl ring or the heterocycle; during as acetoxyl group, can obtain the object of deprotection through alkaline hydrolysis.
The method of compound of the present invention or its isomer can also may further comprise the steps:
The aniline that substituted benzene replaces after three halogen acetylizes, obtains-substituted benzene ethyl replacement Oxoindole through metallic nickel cyclization under acidic conditions again.Then, be substituted phenyl aldehyde again, or contain a heteroatomic heterocycle formaldehyde condensation, obtain object.The aniline of described replacement can be phenylethylamine, amphetamine, PHENTERMINE.
Specifically, according to the present invention, the present invention can be prepared by reaction scheme I-II by general formula (I) compound of formula (Ia-If) expression:
Reverse route I.
I; Condensation, ii: acidylate, iii: amidation wherein, A can be heterocycle or phenyl ring, B can be heterocycle or phenyl ring.
Reaction scheme II:
I: reduction, ii: three halogen acetylizes, iii: cyclization, iv: condensation wherein, A ring can be phenyl ring or heterocycle, B is a phenyl ring.
In the present invention, term " alkyl " is meant the straight or branched alkyl that contains 1-8 carbon atom, for example ethyl, propyl group, sec.-propyl, normal-butyl.
In the present invention, term " halogen " is meant fluorine, chlorine, bromine, iodine.
According to the present invention, the form that general formula (I) compound can isomer exists, and described usually " the present invention's " compound " comprises the isomer of this compound.
Can there be the cis-trans-isomer of two keys in general formula (I) compound, and asymmetric center has S configuration or R configuration, the present invention includes all possible steric isomer and two or more mixture of isomers.If there is suitable/trans isomer, the present invention relates to the mixture of cis form and trans forms and these forms, single if desired foreign body object can separate according to conventional methods or prepare by three-dimensional selection is synthetic.
According to the present invention, general formula (I) compound and isomer thereof are used for animal, be preferred for Mammals, people particularly, in anti-animal Parkinson's disease, improve learning memory disorder, the treatment memory capability go down and Alzheimers disease (Alzheimer ' s disease demonstrates excellent results in purposes AD).Thereby can be used as Mirapexin or prophylactic treatment learning memory disorder, the treatment memory capability goes down and the drug use of Alzheimers disease.
Therefore the present invention also relates to and containing as at least a general formula (I) compound of the effective dose of active ingredient and/or the pharmaceutical composition of its steric isomer and conventional medicine vehicle or assistant agent.Usually pharmaceutical composition of the present invention contains general formula (I) compound and/or its physiologically acceptable salt of 0.1-90 weight %.
Pharmaceutical composition can prepare according to methods known in the art.When being used for this purpose, if desired, general formula (I) compound and/or steric isomer and one or more solids or liquid medicine vehicle and/or assistant agent can be combined, make and can be used as suitable administration form or the dosage form that people's medicine or veterinary drug use.
General formula of the present invention (I) compound or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc.Form of administration is tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder etc. for example, can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate delivery system.For the unit form of administration is made tablet, can be extensive use of various carrier well known in the art.Example about carrier is, for example thinner and absorption agent are as starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, sucrose, sodium-chlor, glucose, urea, lime carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent are as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent, for example dry starch, alginates, agar powder, laminaran, sodium bicarbonate and Citric Acid, lime carbonate, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; Disintegration inhibitor, for example sucrose, Tristearoylglycerol, theobroma oil, hydrogenation wet goods; Absorption enhancer, for example quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, for example talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, 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 pill is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example thinner and absorption agent are as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.; Tackiness agent, as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice stick with paste or and paste etc.; Disintegrating agent is as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.For suppository is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example the ester of polyoxyethylene glycol, Yelkin TTS, theobroma oil, higher alcohols, higher alcohols, gelatin, semi-synthetic glyceryl ester etc.For capsule is made in the administration unit, effective constituent general formula (I) compound or its steric isomer are mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard gelatine capsule or soft capsule.Also effective constituent general formula (I) compound or its steric isomer can be made microcapsule, be suspended in and form suspensoid in the aqueous medium, in the hard capsule of also can packing into or make injection and use.For injection preparation is made in the administration unit, as solution, emulsion, lyophilized injectable powder and suspensoid, can use this area all thinners commonly used, for example, water, ethanol, polyoxyethylene glycol, 1, the isooctadecanol of ammediol, ethoxylation, the isooctadecanol of polyoxyization, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, ooze injection liquid, can in injection preparation, add proper amount of sodium chloride, glucose or glycerine, in addition, can also add conventional solubility promoter, buffer reagent, pH regulator agent etc. in order to prepare etc.
In addition, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives, sweeting agent or other material.
The dosage of general formula of the present invention (I) compound or its steric isomer depends on many factors, for example to prevent or treat the character and the severity of disease, the sex of patient or animal, age, body weight and individual reaction, used particular compound, route of administration and administration number of times etc.Usually to the about 75 kilograms of patients of body weight, the per daily dose of the general formula of giving (I) compound be 0.001mg/kg body weight-100mg/kg body weight, preferred 0.01mg/kg body weight-20mg/kg body weight.Above-mentioned dosage can the single dose form or be divided into several, for example two, three or four dosage form administrations.
In addition, find compound of the present invention with 37.5,75.0, the 150.0mg/kg oral administration is to the not influence of mouse autonomic activities.Adopt under the condition of the above-mentioned dosage that the mouse autonomic activities is not had an influence, this compound oral administration has the tangible effect that improves learning and memory of little mouse, showing that this compound can significantly improve protein synthesis inhibitor cycloheximide institute inductive mouse memory in the step down test consolidates obstacle, makes mouse jump off the significant prolongation and shorten the time of being shocked by electricity in latent period of safety island for the first time.In the training of water maze method, this compound makes the mouse of sedative hypnotic vetanarcol institute inductive spatial discrimination obstacle recover normal, and errors number is significantly reduced, and swimming time shortens.In darkness avoidance test training, the mouse memory that this compound causes ethanol reproduce obstacle also tool improve significantly, errors number is significantly reduced, the prolongation of latency of being shocked by electricity for the first time.In the training of Morris water maze, this compound can significantly improve the destruction of Scopolamine to learning and memory of little mouse, and the latent period and the total detection range that make mouse arrive safety island obviously shorten; After removing safety island, this compound makes effective detection range of mouse and effectively search time, percentage ratio significantly increased.
Find the oral learning and memory function that can strengthen mouse of compound of the present invention at present.This effect that improves cognitive function shows the following aspects.Compound of the present invention is made suspension in 0.5% Xylo-Mucine (CMC-Na), Kunming mouse is oral administration compound 37.5,75.0 of the present invention respectively, 150.0mg/kg or etc. the 0.5%CMC-Na of capacity.2h, 8h and 24h after administration observe its autonomic activities, get 1 parallel four case putting into the autonomic activities case of mouse respectively for each every group, the movable number of times in the record 10min.The autonomic activities of each dosage group mouse of compound of the present invention in 10min each time point all with give 0.5%CMC-Na control group mice indifference.Show that compound of the present invention does not have remarkable restraining effect to the autonomic activities of mouse.
The acquisition of long-term memory needs the synthetic of specified protein in the brain with consolidating, and is suppressed if the brain internal protein is synthetic, and the ability of consolidating for a long time of memory then can obviously descend.Give mouse oral protein synthetic inhibitor cycloheximide, then can suppress proteinic in the brain and syntheticly bring out learning and memory of little mouse and consolidate obstacle by it.Adopt the training of diving tower method to observe the above-mentioned dosage that does not change the mouse autonomic activities of oral compound of the present invention, the influence of mouse memory being consolidated function.1h before the training, administration group mouse is oral administration each dosage of compound of the present invention or positive control drug piracetam 600mg/kg respectively; Model control group and normal control group all wait capacity 0.5%CMC-Na.30min administration group and the equal abdominal injection cycloheximide of model control group 120mg/kg before the training, capacity distilled water (DW) such as normal control group abdominal injection.With mouse put in the diving tower instrument adapt to 3min after, pass to the 36V alternating-current, mouse is subjected to electric shock to jump onto safety island to hide electric shock.5min of every mouse training.Behind the 24h, directly be put on the safety island animal and energising, record jumps off the latent period of safety island and number of times and the time of being clicked for the first time, compare with the cycloheximide model control group, each dosage group of compound of the present invention all can significantly reduce the number of times that is shocked by electricity in the 5min, prolong the latent period of jumping off safety island for the first time, and can shorten the time of being shocked by electricity.Compare with positive control drug piracetam 600mg/kg group, also shorten the time of being shocked by electricity in compound 150mg/kg energy significant prolongation latent period of the present invention.
The sedative hypnotic vetanarcol can cause the spatial discrimination obstacle, adopt the training of water maze method to observe the influence of compound of the present invention to mouse spatial discrimination obstacle.1h before the training, the administration group is oral compound 37.5,75 of the present invention respectively, 150mg/kg or piracetam 600mg/kg; Capacity 0.5%CMC-Na such as model control group and normal control group are all oral.30min administration group and the equal abdominal injection vetanarcol of model control group 20mg/kg before the training, capacity DW such as normal control group abdominal injection.Training every day of every animal once 2min/ time, was trained 3 days continuously.All administrations as stated above before training every day, the starting point of training is near and far carries out successively.Write down number of times (errors number) and swimming time that every animal enters cecum, the person of not swimming out of is by 120s in the 2min.Tested the 2nd day, tangible space cognitive disorders has appearred in the model control group mouse, significantly reduces for each dosage group mouse wrong times of compound of the present invention, but does not see that swimming time significantly shortens, and piracetam 600mg/kg does not have the improvement effect; Tested the 3rd day, and significantly reduced for each dosage group mouse wrong times of compound of the present invention, compound 75mg/kg of the present invention and 150mg/kg can significantly shorten swimming time, swim out of percentage and obviously improve.Piracetam 600mg/kg is only effective aspect the minimizing errors number, and is not obvious to the effect of other indexs.
Ethanol can cause the memory represents obstacle, adopts the darkness avoidance test training to observe the influence that compound of the present invention reproduces mouse memory.The 1st day, 1h before the training, the administration group is oral compound 37.5,75 of the present invention respectively, 150mg/kg or piracetam 600mg/kg; Capacity 0.5%CMC-Na such as model control group and normal control group are all oral.30min administration group and all oral 40% ethanol 0.1ml/10g body weight of model control group before the training, the oral capacity DW that waits of normal control group.Mouse is put in bright chamber darkroom inlet dorsad, and starts record immediately, when animal enters the darkroom and shocked by electricity back taking-up animal.Behind the 24h, by above-mentioned administration, repetition training, compare with the normal control group, behind the ethanol of mouse oral administration 40%, tangible memory represents obstacle occurs, errors number increases, and shorten latent period.Oral compound 150mg/kg of the present invention of mouse and 75mg/kg can significantly reduce the number of times that is shocked by electricity in the 3min behind the 24h, in the latent period that compound 150mg/kg of the present invention and energy significant prolongation are shocked by electricity for the first time, compound 37.5mg/kg of the present invention does with not obvious.Piracetam 600mg/kg also has obvious effect.
Cognitive function is inseparable with the cholinergic nerve of central nervous system, and patient AD is exactly because its cholinergic nerve insufficiency of function has caused its distinctive cognition dysfunction.Scopolamine is a kind of cholinocepter inhibitor of central, can reduce the maincenter choline function, causes cognition dysfunction.The training of Morris water maze is the active learning and memory function method of a kind of internationally recognized observation mouse, can make objective appraisal to the learning and memory process of mouse.Adopt Morris water maze method to observe compound of the present invention causes mouse space learning obstacle to Scopolamine influence.Kunming mouse is divided into normal control group, model group, compound 150mg/kg of the present invention group, 75mg/kg group, 37.5mg/kg group and piracetam 600mg/kg group at random.1h before the training, oral each the dosage compound of compound of the present invention and piracetam group, capacity 0.5%CMC-Na solution such as normal control group and model group are oral.30min before the training, model group, compound group of the present invention and piracetam group abdominal injection Scopolamine 2.5mg/kg, capacity DW such as normal control group abdominal injection.During training safety island is put in the first quartile, animal is from other three quadrants entry, and every day, each was trained once, continuous 5 days.The record animal is found the latent period and the movement locus of platform from following water in 90 seconds, and allows animal stop 5 seconds at platform.Can not find platform in 90 seconds, the main examiner is put in it platform and stops 5s.Tested the 6th day, and removed safety island, mouse is write down the movement locus in 90 seconds from the third quadrant entry.Water maze diameter 120cm, the high 40cm of water is the suspension of milk powder, water temperature 23-25 ℃, safety island places 1cm place under the liquid level.Compare with the model control group mouse, from testing the 3rd day, each dosage group of compound of the present invention can significantly shorten mouse search latent period and total detection range gradually; Mouse is taked orthoscopic and trend formula decision search safety island gradually morely, and the model control group mouse is adopted circulating type and random mode then morely.Tested the 6th day, after removing safety island, each organizes the total detection range there was no significant difference of mouse, but accumulation search time and the accumulation detection range significant prolongation of compound 150mg/kg group of the present invention in the purpose quadrant, in the purpose quadrant in percentage ratio in total search time accumulation search time (effectively search time percentage ratio) and the purpose quadrant percentage ratio (effectively detection range percentage ratio) of accumulation detection range in total detection range all obviously increase, each dosage group mouse of compound of the present invention obviously increases by the number of times of former safety island position.Simultaneously, in whole training process, each organizes the body weight change of mouse does not have significant difference.
Compound of the present invention the medicine that improves learning memory disorder be used for that memory capability goes down and Alzheimers disease (Alzheimer ' s disease, the dosage range that treatment AD) is applied to the people is preferably 75-300mg, is equivalent to 4.5～18mg/kg/ day.
Description of drawings
Fig. 1 causes the influence of mouse movement imbalance model for 22 couples of abdominal injection MPTP of The compounds of this invention:
Wherein, Fig. 1 compound 22 and levodopa are to the improvement effect .-of MPTP model mice motor behavior ◆-: normal control ,-■-: MPTP 50mg/kg ,-▲-: levodopa 75mg; Kg;-x-: compound 22 150mg/kg;-zero-: compound 22 75mg/kg;-●-: compound 22 37.5mg/kg
Fig. 2 represents the compound 15 of various dose, the result of L-dopa and Acreoline contrast, and the time length of wherein trembling is (second).
The compound 15 of Fig. 3 various dose, with the result of L-dopa and oxytremorine contrast, the time length of wherein trembling is (branch).
Fig. 4 is the compound 15 of various dose, contrasts the result who oxotremorine is caused the situation of hiding of trembling with L-dopa and oxytremorine, and its time is second.
Fig. 5 is the influence of compound 20 abdominal injection MPTP. mouse brain mediopelliss, striatum mda (MDA) content, wherein, A: normal control, B:MPTP treatment group, C: compound 22 150mg/kg.*P＜0.05 is compared with normal control ,+P＜0.05 and MPTP treatment group ratio.
Fig. 6 is in Morris water maze training process, and The compounds of this invention 27 oral administrations arrive the preclinical influence of safety island to mouse
Fig. 7 is in Morris water maze training process, and The compounds of this invention 27 oral administrations are to the influence of the total movement locus of mouse.
Fig. 8 is in Morris water maze training process, and The compounds of this invention 27 oral administrations adopt the influence of search strategy to mouse.
Fig. 9 is that compound 27 oral administrations are to the influence of mouse acquisition track, search strategy after removing safety island on the Morris water maze training doomsday.
Figure 10 is 4 kinds of typical search strategies that mouse is adopted in the training of Morris water maze.
Embodiment
The experiment of the following examples and pharmaceutical activity is used for further specifying the present invention, but this and do not mean that any limitation of the invention.
In the present invention, the raw material that uses is as known compound or by the compound that well known to a person skilled in the art the method preparation.Though preparation does not generate compound of the present invention, the useful intermediates of synthetic preparation this general formula (I) compound.
Steps A:
Embodiment 1:
196mg (1mmol) 2,5 dimethoxyphenylacetic acids and 225mg (1.5mmol) Vanillin adds the 0.16ml triethylamine under the room temperature in the 1.5ml diacetyl oxide, be warming up to 130-140 ℃, stirred 7 hours, be cooled to 90 ℃, add 5ml water, continue to stir 15 minutes, remove solvent under reduced pressure, resistates dissolves with the 5ml methylene dichloride, the 3ml1NHCl washing, and water layer is used the 5ml dichloromethane extraction again, combining extraction liquid, wash with 3mliNHCl again, anhydrous magnesium sulfate drying, steaming desolventizes, add 0.5ml toluene, refrigeration is placed in the refrigerator, gets required product after the filtration
Productive rate 60%.Mp：177-179℃，
1HNMR(CDCl
3)：2.20(3H，s)，3.44(3H，s)，3.68(3H，s)，3.70(3H，s)，6.66(1H，m)，6.76(1H，s)，6.90(4H，m)，7.76(1H，s).
Embodiment 2:
Is to obtain following compounds under the catalysis of solvent triethylamine with embodiment 1 similar method with the acetic anhydride with toluylic acid and Vanillin:
Productive rate 70%.Mp:203-206 ℃,
1HNMR (CDCl
3): 2.16 (3 Hes are) 3.36 (3 Hes are) 6.64 (1H, d=2.7Hz), 6.84 (1H, d=2.7Hz), 6.85 (1H, s), 7.3 (5H, m), 7.76 (1H, s). embodiment 3
Is to obtain following compounds under the catalysis of solvent triethylamine with embodiment 1 similar method with the acetic anhydride with paranitrophenylacetic acid and Vanillin:
Productive rate 45%.Mp：208-211℃，
1HNMR(CDCl
3)2.20(3H，s)，3.48(3H，s)6.74(1H，d，J＝2.7Hz)，6.8(1H，d，J＝2.7Hz)6.88(1H，s)7.56(2H，d，J＝9Hz)7.92(1H，s)，8.24(2H，d，J＝9Hz).
With 3,4-dimethoxyphenylacetic acid and Vanillin are to obtain following compounds under the catalysis of solvent triethylamine with the acetic anhydride with embodiment 1 similar method:
Productive rate 50%.Mp：177-178℃，
1HNMR(CDCl
3)：2.24(3H，s)3.42(3H，s)3.76(3H，s)3.84(3H，s)，6.60(1H，s)，6.72(1H，s)6.8(4H，m)7.8(1Hs).
Is to obtain following compounds under the catalysis of solvent triethylamine with embodiment 1 similar method with the acetic anhydride with toluylic acid and paranitrobenzaldehyde:
Productive rate 75%.
1HNMR(CDCl
3)：8.0(d，2H，ArH)，7.95(s，1H，CH＝)，7.4(m，3h，ArH)，7.22(d，4H，ArH).
Is to obtain following compounds under the catalysis of solvent triethylamine with embodiment 1 similar method with the acetic anhydride with toluylic acid and 2-chlorobenzaldehyde:
Productive rate 65%
Embodiment 7
With 2,5-dimethoxyphenylacetic acid and 3-methoxyl group, 4-ethoxy-benzaldehyde are to obtain following compounds under the catalysis of solvent triethylamine with the acetic anhydride with embodiment 1 similar method:
Productive rate 35%
Is to obtain following compounds under the catalysis of solvent triethylamine with embodiment 1 similar method with the acetic anhydride with toluylic acid and 2-nitrobenzaldehyde:
Productive rate 50%
Embodiment 9
With 2,5-dimethoxyphenylacetic acid and 2,5-dimethoxy benzaldehyde are to obtain following compounds under the catalysis of solvent triethylamine with the acetic anhydride with embodiment 1 similar method:
Productive rate 48%
1HNMR (CDCl
3): 7.84 (1H, s, CH=), 6.90 (2H, s, ArH), 6.68 (1H, s, ArH), 6.35 (1H, ArH), 6.32 (2H, s, ArH), 3.72 (3H, s, OCH
3), 3.7 (3H, s, OCH
3), 3.56 (3H, s, OCH
3)
With 2,5-dimethoxyphenylacetic acid and 4-isopropyl benzene formaldehyde are to obtain following compounds under the catalysis of solvent triethylamine with the acetic anhydride with embodiment 1 similar method:
Productive rate 70%Oil
1HNMR (CDCl
3): 7.91 (s, 1H, CH=), 7.25-6.66 (m, 7H, ArH), 3.80 (s, 3H, OCH
3), 3.78 (s, 3H, OCH
3), 2.82 (m, 1H, CH), 1.19 (d, 6H, J=6.9Hz, 2*CH
3) .Ms (m/z); 326 (M
+), 178.
Embodiment 11
Is to obtain following compounds under the catalysis of solvent triethylamine with embodiment 1 similar method with the acetic anhydride with toluylic acid and 2 thiophene carboxaldehyde:
Mp:185-188 ℃
1HNMR (CDCl
3): 8.14 (s, 1H, CH=), 7.50 (m, 3H), 7.3 (m, 3H), 7,25 (m, 1H), 6,95 (m, 1H) Ms (m/z); 230 (M
+), 185,152,113,77. productive rates 80%
Embodiment 12
With 2,5-dimethoxyphenylacetic acid and 2,5-dimethoxy benzaldehyde are to obtain following compounds under the catalysis of solvent triethylamine with the acetic anhydride with embodiment 1 similar method:
Productive rate 55%Mp:177-178 ℃,
1HNMR (CDCl
3): 8.27 (1H, s, CH=), 6.4-6.9 (6H, m, ArH), 3.8,3.73,3.66 and3.32 (each 3H, OCH
3)
Step B:
1.16g the compound 2 that (3.1mmol) makes in the steps A is dissolved among the 8mlDMF, cryosel is bathed and is added the 1.25ml triethylamine down, splash into 450mg (3.3mmol) isobutyl chlorocarbonate in 0-5 ℃, stirred 30 minutes, splash into the DMF solution 5ml (452mg/5ml) of 4-hydroxyphenethylamine, drip off under the room temperature of back and stirred 5 hours.Steaming removes DMF, and resistates adds the methylene dichloride dissolving, water, 1NHCl, water, saturated common salt washing successively, and drying, steaming desolventizes, and silica gel column chromatography gets required product, 1.0g, productive rate 65.4%
Mp:172-173 ℃
1HNMR (CDCl
3): 7.76 (1H, s, CH=C), 7.20-6.50 (10H, m, Ar-H), 5.66 (1H, br, s, NH), 3.68 (3H, s, CH3O), 3.58 (3H, s, CH
3O), 3.42 (5H, s, CH
3O, N-CH
2), 2.68 (2H, t, J=7.2Hz, N-C-CH
2), 2.26 (3H, s, COCH
3). embodiment 14
Is that raw material and the reaction of 4-hydroxyphenethylamine obtain following compounds with embodiment 13 similar methods with compound 3:
Mp.160-166 ℃
1HNMR (CDCl
3): 8.063 (1H, s, CH=C), 7.6-6.68 (12H, m, Ar-H), 5.42 (1H, br, NH), 3.53-3.46 (2H, q, N-CH
2), 2.7-2.65 (2H, t, J=6.9Hz, Ph-CH
2).
Is that raw material and the reaction of 4-hydroxyphenethylamine obtain following compounds 16 with embodiment 13 similar methods with compound 4:
1HNMR (CDCl
3): 7.97 (d, 2H, J=9Hz, ArH), 7.86 (s, 1H, CH=), 7.41 (3H, ArH), 7.1 (d, 4H, J=9Hz, ArH), 6.9 (d, 2H, J=7.8Hz, ArH), 6.72 (d, 2H, J=7.8Hz, ArH), 5.6 (br., 1H, NH), 3.54 (t, 2H, J=6.9Hz ,-NHCH
2), 2.7 (t, 2H, J=6.9Hz ,-NCH
2CH
2).
Embodiment 16
Is that raw material and the reaction of 4-hydroxyphenethylamine obtain following compounds 17 with embodiment 13 similar methods with compound 5:
1HNMR (CDCl
3): 8.0 (s, 1H, CH=), 7.3-6.72 (m, 13H, ArH), 5.6 (br., 1H ,-NH), 1.56 (m, 2H ,-NHCH
2), 2.74 (t, 2H, J=6.6Hz ,-NHCH
2CH
2).
Embodiment 17
Is that raw material and the reaction of 4-hydroxyphenethylamine obtain following compounds 18 with embodiment 13 similar methods with compound 6
1HNMR (CDCl
3): 8.01 (s, 1H, CH=), 7.35-6.63 (m, 13H, ArH), 5.57 (br., 1H ,-NH), 3.54 (m, 2H ,-NHCH
2), 2.72 (t, 2H, J=6.9Hz ,-NHCH
2CH
2).
Embodiment 18
Is that raw material and the reaction of 4-hydroxyphenethylamine obtain following compounds 19 with embodiment 13 similar methods with compound 7:
1HNMR (CDCl
3): 7.77 (s, 1H, CH=), 6.9-6.45 (m, 10H, ArH), 5.58 (br., 1H ,-NH), 4.05 (m, 2H ,-OCH
2), 3.7 (s, 3H ,-OCH
3), 3.6 (s, 3H ,-OCH
3), 3.49 (m, 2H ,-NHCH
2), 3.44 (s, 3H ,-OCH
3), 2.69 (t, 2H, J=6.6Hz ,-NHCH
2CH
2), 1.41 (t, 3H, J=7.2Hz ,-OCH
2CH
3).
Embodiment 19
Is that raw material and the reaction of 4-hydroxyphenethylamine obtain following compounds 20 with embodiment 13 similar methods with compound 8:
1HNMR (CDCl
3): 8.12 (1H, s, CH=), 6.8-6.2 (10H, m, ArH), 3.75,3.72,3.7 and3.3 (each 3H, s, OCH
3), 3.5 (2H, q), 2.63 (2H, t).
Embodiment 21
Is that raw material and the reaction of 4-hydroxyphenethylamine obtain following compounds 24:Oil with embodiment 13 similar methods with compound 10:
1HNMR (CDCl
3): 8.08 (1H, s, CH=C), 7.2-6.59 (10H, m, Ar-H), and 5.61-5.58 (1H, t, J=6Hz, NH), 3.77 (3H, s, OCH3), 3.66 (3H, s, OCH3), 3.53-4.66 (2H, q, J=, N-CH2), and 2.9-2.78 (1H, m, CH), 1.81-1.16 (6H, D, J=7.5Hz, 2*CH3). embodiment 22
Is that raw material and L-Tyrosine methyl ester reaction obtain following compounds 23 with embodiment 13 similar methods with compound 2:
1HNMR (CDCl
3): 7.76 (1H, s, CH=), 6.91-6.6 (10H, m, ArH), 6.14 (1H, d, NH), 2.87 (1H, q ,-NHCH), 3.68 (6H,, s, 2*OCH
3), 3.62 (3H, s, OCH
3), 3.42 (3H, s, OCH
3), 3.06 (2H, q, MeCHCH
2)
Embodiment 23
Is that raw material and the reaction of 4-hydroxyphenethylamine obtain following compounds 28 with embodiment 13 similar methods with compound 13
1HNMR (CDCl
3): 7.76 (1H, s, CH=), 6.9-6.21 (10H, m, ArH), 5.69 (1H, t, NH), 3.69 (3H, s, OCH
3), 3.6 (3H, s, OCH
3), 3.53-3.48 (8H, 2*OCH
3+ NCH
2), 2.68 (2H, t, J=6.6Hz)
Step C:
Embodiment 24
7.8g (15.9mmol) add 110ml methyl alcohol and 185ml14% solution of potassium carbonate in the compound 14 that makes among the step B, refluxed 7 hours, steam and remove methyl alcohol, transfer PH to be about 3, ethyl acetate extraction, drying with 10% hydrochloric acid, steaming desolventizes, with 30ml chloroform recrystallization, must about 7g product compound 12, productive rate 98.2%
Mp:125-127 ℃
1HNMR (CD
3COCD
3); 2.64 (2H, t, J=7.2Hz, N-C-CH
2), 3.36 (2H, t, J=7.2Hz, N-CH
2), 3.42 (3H, s, CH
3O), 3.64 (3H, s, CH
3O) 3.68 (3H, s, CH
3O), 6.16 (1H, br, OH), 6.64 (1H, s, NH), 6.52-6.8 (5H, m) 6.8-7.04 (5H, m), 7.58 (1H, s, CH=C) .MSm/z; 449 (M
+) 328,313,298,270,137.
Embodiment 25
With embodiment 24 similar methods, be to obtain the reaction of following compounds 11 and 4-hydroxyphenethylamine under the catalysis of solvent triethylamine to obtain product with the acetic anhydride with paranitrophenylacetic acid and Vanillin, through the hydrolysis of methyl alcohol wet chemical, obtain following compounds 25:
Oil
1HNMR (CD
3COCD
3): 8.30-7.40 (5H, m, Ar-H, CH=C), 7.24-6.40 (8H, m, Ar-H, NH), 3.44 (3H, s, CH
3O), 3.20 (2H, br, s, N-CH
2), 2.68 (2H, t, J=7.2Hz, N-C-CH
2) .Ms:m/z (%) 434 (M
+), 315 (100), 270 (4), 271 (5), 153 (10), 120 (45), 57 (18).
Embodiment 26
With embodiment 24 similar methods, with 3,4-dimethoxyphenylacetic acid and Vanillin are to obtain the reaction of following compounds 12 and 4-hydroxyphenethylamine under the catalysis of solvent triethylamine to obtain product and obtain following compounds 26 through the hydrolysis of methyl alcohol wet chemical with the acetic anhydride
Mp.197-198 ℃
1HNMR (CD
3COCD
3): 7.60 (1H, s, CH=C), 7.04 (2H, d, J=8Hz, Ar-H), 6.90 (2H, s, Ar-H), 6.74 (3H, s, Ar-H), 6.68 (3H, s, Ar-H), 6.48 (1H, s, NH), 3.86 (3H, s, OCH
3), 3.76 (3H, s, CH
3O), 3.44 (3H, s, CH
3O), 3.40 (2H, t, J=7.2Hz, N-CH2), 2.68 (2H, t, J=7.2Hz, N-C-CH2) .Ms:m/z (%): 449 (M
+, 40), 329 (80), 328 (100), 313 (22), 285 (90), 272 (8), 152 (13), 120 (17), 107 (28), 77 (10).
With embodiment 24 similar methods, obtain following compounds through the hydrolysis of methyl alcohol wet chemical with compound 21:
Mp.90-91 ℃
1HNMR (CDCl
3): 7.72 (1H, s, CH=C), 7.44-7.0 (8H, m, Ar-H), 6.88-6.56 (6H, m, Ar-H), 6.22 (1H, s, NH), 3.44 (2H, t, J=7.2Hz, N-CH
2), 3.36 (3H, s, CH
3O), 2.62 (2H, t, J=7.2Hz, N-C-CH2) .Ms:m/z (%): 389 (M
+, 55), 270 (64), 268 (100), 253 (65), 225 (72), 193 (18), 165 (30), 152 (20), 120 (22), 91 (15), 73 (25).
Next, further adopt following examples to describe the present invention in detail.
Steps A:
Embodiment 28
2.6g (7.8mmol) N-(4 ' p-methoxy-phenyl)-4-benzyloxy phenylethylamine, 2.54g (15.6mmol) trichoroacetic acid(TCA) are in the 120ml methylene dichloride, ice bath stirred 20 minutes down, added 3.24gDCC, continued to stir 6 hours.Filter, filtrate is used 0.5%HCl successively, saturated sodium bicarbonate, and water, the saturated common salt washing, drying, steaming desolventizes, and silica gel column chromatography gets the 2.42g product, productive rate 64.9%
Mp:98-100 ℃
1HNMR (CDCl
3): 7.44-6.84 (m, 13H, ArH), 5.04 (s, 2H ,-OCH
2Ph), 3.9 (br.2H ,-NCH
2), 3.83 (s, 3H, OCH
3), 2.93-2.89 (t, 2H, J=8.1Hz ,-CH
2CH
2Ph).
Step B:
The compound that makes in embodiment 292.42g (5mmol) steps A, 10g () nickel powder, 62ml Virahol, 5.7ml acetate refluxed 8.5 hours down in oil bath, cooling, filter, filter residue is washed with Virahol, and steaming desolventizes, resistates adds rare sodium bicarbonate till do not have gas and produce, and uses ethyl acetate extraction, and extracting solution is washed with saturated common salt, drying, steaming desolventizes, silica gel column chromatography, get product 1.21g, productive rate 64%
1HNMR (CDCl
3): 7.44-6.66 (m, 12H, ArH), 5.04 (s, 2H, OCH
2Ph), 3.87 (t, 2H, J=7.2Hz ,-NCH
2), 3.79 (s, 3H ,-OCH
3), 3.48 (s, 2H, COCH
2), 2.89 (t, 2H, J=7.2Hz ,-CH
2CH
2Ph) .Ms:m/z (%): 374 (M+1), 373,176,163,148,91 (100%).
Step C:
1.21g (3.2mmol) compound that makes among the step B, 1gPd-C (moisture 50%), normal pressure hydrogenation is 6 hours in 50ml ethanol, filters, and dehydrated alcohol is washed, and steaming desolventizes, and gets the 675mg product, productive rate 73.5%
Step D:
Embodiment 31
The compound that makes among 100mg (0.353mmol) the step C, the 83mg Vanillin adds 1 hexahydropyridine in 10ml benzene, reflux 2 hours, steaming desolventizes, and uses acetic acid ethyl dissolution, use 0.5%HCl successively, water, saturated common salt washing, drying, steaming desolventizes, silica gel column chromatography gets the 60mg product, productive rate 40.8%
Mp.125-127 ℃
1HNMR (CD
3COCD
3): 7.58 (1H, s, CH=C), 7.04-6.80 (5H, m, Ar-H), 6.80-6.52 (5H, m, ar-H), 6.46 (1H, s, NH), 6.16 (1H, br, s, OH), 3.68 (3H, s, CH
3O), 3.64 (3h, s, CH
3O, 3.42 (3H, s, CH
3O), 3.36 (2H, t, J=7.2Hz, N-CH
2), 2.64 (2H, t, J=7.2Hz, N-C-CH
2) .Ms:m/z (%): 449 (M
+, 75), 328 (100), 313 (56), 298 (32), 270 (26), 137 (49).
Embodiment 32
Is raw material and 3 with embodiment 31 similar methods with compound 40, and the reaction of 4-dimethoxy benzaldehyde obtains following compounds:
1HNMR (CDCl
3): 8.68 (1H, s, CH=C), 7.64-6.63 (10H, m ,-Ar-H), 4.02 (3H, s ,-OCH
3), 3.95 (3H, s ,-OCH
3), 3.95-3.92 (5H), 3.85 (3H, s ,-OCH
3), 2.90 (2H, t, J=7.3Hz) Ms m/z (100%): 431 (M
+), 324 (100), 296,91.
Embodiment 33
Is that raw material and 2 thiophene carboxaldehyde reaction obtain following compounds with embodiment 31 similar methods with compound 40:
Mp.241-243 ℃
1HNMR (DMSO-d
6): 9.19 (1H, s ,-OH), 8.19 (1H, s, CH=C), 7.96-6.65 (10H, m ,-ArH), 3.87 (2H, t, J=4.5Hz ,-NCH
2), 3.79 (3H, s ,-OCH
3) 2.77 (2H, t, J=4.5Hz) .Ms:m/z (5): 377 (M
+), 270 (100), 199,107,66
Embodiment 34
Is that raw material and furfural reaction obtain following compounds with embodiment 31 similar methods with compound 40:
Mp.217-219 ℃
1HNMR (DMSO-d
6): 9.18 (1H, s ,-OH), 8.23 (1H, s, CH=C), 8.05-6.64 (10H, m,-ArH), 3.86 (2H, t, J=4.5Hz ,-NCH2), 3.80 (3H, s ,-OCH3), 2.77 (2H, t, J=4.5Hz) .Ms:m/z (%): 361 (M+), 254 (100), 241,183,84
Is that raw material and piperonylaldehyde reaction obtain following compounds with embodiment 31 similar methods with compound 40:
Mp.209-212 ℃
1HNMR (DMSO-d
6): 9.18 (1H, s ,-OH), 7.56 (1H, s, CH=C), 7.29-6.62 (10H, m ,-ArH), 6.12 (2H, s ,-O-CH
2-O), 3.83 (2H, t, J=7.2Hz, NCH
2), 3.64 (3H, s ,-OCH
3), 2.74 (2H, t, J=7.2Hz).
Embodiment 36
Is that raw material and 4-isopropyl benzene formaldehyde reaction obtain following compounds with embodiment 31 similar methods with compound 40:
Mp.217-220 ℃
1HNMR (DMSO-d
6): 9.18 (1H, s ,-OH), 7.64 (1H, s, CH=C), 7.62-6.63 (11H, m ,-ArH), 1.84 (2H, t, J=7.5Hz, N-CH
2), 3.63 (3H, s ,-OCH
3), 2.98-2.93 (1H, m), 2.76 (2H, t, J=7.5Hz), 1.23 (6H, d, J=6.9Hz, 2*CH
3).
Embodiment 37
Is raw material and 3 with embodiment 31 similar methods with compound 40, and the reaction of 5-dimethoxy benzaldehyde obtains following compounds:
1HNMR (CDCl
3): 7.77 (1H, s, CH=C), 7.34-6.52 (10H, m ,-ArH), 3.93 (2H, t, J=7.2Hz ,-N-CH
2), 3.82 (6H, s, 2*OCH
3), 3.65 (3H, s ,-OCH
3), 2.91 (2H, t, J=7.2Hz).
Embodiment 38
Is that raw material and 4-p-methoxybenzaldehyde obtain following compounds with embodiment 31 similar methods with compound 40:
Mp.210-216 ℃
1HNMR (DMSO-d
6): 9.14 (1H, s ,-OH), 7.61 (1H, s, CH=C), 7.7-6.63 (11H, m ,-ArH), and 3.86-3.83 (5H, s), 3.64 (3H, s ,-OCH
3), 2.76 (J=7.5Hz) embodiment 39 for 2H, t
Is raw material and 3 with embodiment 31 similar methods with compound 40, and 5-di-t-butyl-4-hydroxy benzaldehyde reaction obtains following compounds:
1HNMR (CDCl
3): 7.82 (s, 1H, CH=), 7.54-6.69 (m, 9H, ArH), 5.57 (s, 1H ,-OH), 3.95 (t, 2H, J=7.5HZ ,-CH2), 3.85 (s, 3H ,-OCH3), 2.92 (t, 2H, J=7.5HZ), 1.48 (s, 18H, 6*CH3).
] 22 couples of abdominal injection MPTP of experimental example 1 compound cause the influence of mouse movement imbalance model
Medicine and reagent: compound 22 CMC-Na suspendible, levodopa are Guangxi China Donglan pharmaceutical factory product, prepare identically with compound 22, and MPTP Military Medical Science Institute six gives.
Animal: 7～8 the week age C
57/ BL male mice is weighed and random packet.
Measure: normal control is established in experiment, model group (abdominal injection MPTP50mg/kg, 2 times, 16 hours at interval), compound 22 large, medium and small dosage groups, the L-dopa group, every treated animal 9-11 only, compound 22 dosage are respectively 150mg/kg, 75 and 37.5mg/kg.All respectively organize mouse before per injection MPTP and oral pharmaceutical every day on the the 1st to the 6th of injection back L-dopa 75mg/kg, all carry out the test of pole-climbing capacity before the oral pharmaceutical, every mouse allows the pole-climbing secondary, integration also calculates average mark, after mensuration on the 7th capacity of last injection back, weigh, disconnected vertebra method is put to death all animals, gets full brain, rapidly in the mensuration of relevant biochemical indicator is carried out at selective separating and striatum position on ice.Referring to Fig. 1, MPTP causes the influence of mouse movement imbalance model in 31 pairs of abdominal injections of compound 7 days.(50mg/kg is secondary altogether for mouse peritoneal injection MPTP, 16 hours at interval) the back a few days, mouse coordinated movement ability drop, and continuous once a day 6 administrations after preceding 40 minutes oral administrations of per injection MPTP and last injection of compound 150,75,37.5mg/kg, can promote the recovery of ataxic movement ability to some extent, its effect and L-dopa (75mg/kg) are suitable.22 pairs of methylarecaidins of experimental example 2 compounds cause the tremble influence of model of mouse
Medicine and reagent: methylarecaidin Bromide physiological saline solution, compound 22 and levodopa CMC-Na suspendible.
The male mice in kunming of animal: body weight 18-22 gram
Method: animal is divided five groups at random, and every treated animal 11-15, sequential method is asked ED
50Mouse oral normal saline or medicine to be measured (the administration volume is 0.1ml/10g) are after 60 minutes, tail vein injection is the methylarecaidin solution (volume is 0.1ml/10g) of amount accurately, the ratio of adjacent concentration is decided to be 0.75, muscular tremor, perpendicular tail, whole body shake, hydrostomia phenomenon appear according to having or not in 2 minutes, determine that this organizes the concentration of the quiet notes methylarecaidin of next mouse, and write down the intravenous injection methylarecaidin simultaneously and cause the latent period that mouse trembles and tremble the time length, quiet as calculated notes methylarecaidin causes the value of trembling and 95% fiducial limit thereof.Referring to Fig. 2, wherein represent the result of The compounds of this invention L-dopa and methylarecaidin contrast.The provide protection that this compound trembles to the mouse that methylarecaidin causes sees Table 1:
Table 1 compound is to the median effective dose (ED that trembles of the mouse due to the methylarecaidin
50) influence
Group ED
50(μ g/kg) 95%
(mg/kg) fiducial limit
Methylarecaidin 564.84 ± 63.57
Compound 37.5+ methylarecaidin 530.25 ± 104.59
L-dopa 75+ methylarecaidin 523.17 ± 62.07
*Compare P＜15 pairs of oxotremorines of 0.05 experimental example, 3 compounds with methylarecaidin contrast and cause the tremble influence of model of mouse]
Medicine and reagent: oxotremorine Sigma product, physiological saline solution, compound 22 and levodopa CMC-Na suspendible.
The male mice in kunming method of animal: body weight 18-22 gram: divide five groups at random, every treated animal 11-15, sequential method is asked ED
50Mouse oral normal saline or medicine to be measured, the administration volume is 0.1ml/10g, and after 60 minutes, intravenous injection is the oxotremorine solution of amount accurately, the equal 0.1ml/10g of volume, each is organized initial dose and is 50 μ g/kg, and the ratio of adjacent concentration is decided to be 0.68, writes down to have or not in 3 minutes muscular tremor, perpendicular tail, whole body shake, hydrostomia phenomenon to occur, with the latent period and the time length of trembling that mouse behind the quiet notes oxotremorine of record is trembled, calculate ED
50Value.The results are shown in Figure 3.Referring to table 2, its shows that compound is to the median effective dose (ED that trembles of the mouse due to the oxotremorine
50) influence.
Mouse due to 15 pairs of oxotremorines of the table 2 compound median effective dose (ED that trembles
50) influence
Group ED50 (μ g/kg)
(μ g/kg) 95% fiducial limit 0+ oxotremorine 51.0 ± 6.6
Compound 37.5+ oxotremorine 51.0 ± 6.6
L-dopa 75+ oxotremorine 52.5 ± 7.1
* compare P＜0.05 with the oxotremorine contrast.
Referring to Fig. 4, the comparative result of visible The compounds of this invention 15 and L-dopa and oxotremorine.
Referring to Fig. 1-4, The compounds of this invention 150,75mg/kg shift to an earlier date administration in 60 minutes, make the ED that quivers that causes of mouse mainline methylarecaidin and oxotremorine
50Value obviously raises, shorten methylarecaidin and oxotremorine and bring out the time length of trembling, and can prolong the latent period that oxotremorine brings out the outbreak of trembling, and the The compounds of this invention effect is better than positive control drug L-dopa (75mg/kg). and mediator DOPAMINE CONTENT IN RABBIT, lipid peroxidation decrease in 20 pairs of Parkinson's disease model mices of experimental example 4 compounds brain
The influence of hindering
Dopamine HCL and metabolite content thereof are measured in 1 brain:
Method: high performance liquid phase-electrochemical detection method.
Animal-origin, modeling method and grouping medication are described with experimental example 1, used animal is the male black rat of C57/BL, compound 20 dosages are 150mg/kg, 75mg/kg, the levodopa dosage is 75mg/kg, each treated animal of sacrificed by decapitation on the 7th behind last injection MPTP, and operation is taken out full brain and is removed decerebellation under ice bath, separate cortex, striatum, add the 0.1moL.L of 10 times of volumes (w/v) of precooling
-1Perchloric acid (containing DHBA 1.5ng/20 μ l), homogenate (4 ℃) in ultrasonic 30 seconds, 1, the centrifugal 10min of 5000rpm ,-70 ℃ of preservations, HPLC measures preceding 4 ℃ of placements, get supernatant 20 μ l sample introductions during mensuration, and carbon 18 reverse-phase chromatographic columns (250 * 4.6mm), the content of mensuration DA, DOPAC, HVA.
The result calculates: marker method, internal standard substance are DHBA
2 MDA measure:
The TBA development process.After the ultrasonic homogenate of cerebral tissue striatum or cortex is centrifugal, when getting supernatant liquor 20 μ l mensuration mediator content, after adding 0.67%TBA boiling water bath heating 15min after remaining supernatant liquor is quantitative, flowing water is cooled to room temperature, reading the OD value at wavelength 532nm place on the semiautomatic biochemistry registering instrument, is standard substance with TEP, production standard curve under the same terms, according to the content of MDA in the typical curve calculating institute test sample product, heavily represent with the wet cerebral tissue of nmoL/100mg.The results are shown in Table 3.The improvement effect (high-efficient liquid phase technique) that Dopamine HCL and meta-bolites (pg/mg cerebral tissue) content thereof reduce in the mouse brain striatum that The compounds of this invention and L-Dopa cause mouse peritoneal injection MPTP sees Table 3
Table 3
3,4 dihydroxyphenyl acetic acid homovanillic acid group (mg/kg) number of animals Dopamine HCLs (DA)
(DOPAC) (HVA)
6536.7 2077.9 937.1 normal controls 10
±413.4 ±289.3 ±190.0
4031.5 1133.5 490.2MPTP(50) 9
±1052.0
*** ±148.8
*** ±40.9
***
4816.2 1356.4 736.3 compounds, 20 150+MPTP 8
±417.3
△ ±198.6
△ ±94.9
△
4666.4 1409.5 527.5 compounds, 20 75+MPTP 10
±792.5 ±165.2
△ +238.9
6751.1 1677.2 732.1L-dopa(150)+MPTP 9
± 1247.4
△ △ △± 454.6
△± 275.9
△ △ △P＜0.05,
△ △P＜0.01,
△ △ △P＜0.001 is compared with the MPTP control group
The compounds of this invention 150,75mg/kg shift to an earlier date administration has apparent in view raising effect to the reduction of Dopamine HCL and meta-bolites thereof in the MPTP induced mice brain striatum.Experimental example 5
40 of Kunming mouses, body weight 18-22g is divided into 4 groups at random, 10 every group, oral compound 23,37.5,75 of the present invention respectively, 150mg/kg or etc. capacity 0.5%CMC-Na.2h, 8h and 24h behind the medicine, respectively with 4 groups of parallel four casees putting into the autonomic activities case of mouse, the movable number of times in the record 10min.Compare with the 0.5%CMC-Na control group, each dosage group of compound of the present invention does not all make significant difference at each time point to the mouse autonomic activities in the 10min.The results are shown in Table 4, at different time points, difference that there are no significant between each group, P＞0.05 shows that compound of the present invention does not influence the autonomic activities of mouse.
The influence of 23 pairs of mouse autonomic activitieses of table 4 compound of the present invention (n=10, x ± s)
Group 2h 8h 24h
Normal control 281.2 ± 39.8 197.6 ± 52.6 232.4 ± 43.2
Compound 150mg/kg 335.7 ± 74.2 216.3 ± 82.0 245.4 ± 45.6
75mg/kg 289.6±44.2 212.2±42.7 249.3±36.7
37.5mg/kg 306.1 ± 87.5 261.9 ± 92.6 257.7 ± 45.7 experimental examples 6
Adopt mouse diving tower method.60 of Kunming mouses, body weight 18-22g is divided into 6 groups at random.1h before the training, the administration group is oral compound 30,37.5,75 of the present invention respectively, 150mg/kg or positive control drug piracetam 600mg/kg; Model control group and normal control group all wait capacity 0.5%CMC-Na.30min administration group and all oral cycloheximide 120mg/kg of model control group before the training, the oral capacity DW that waits of normal control group.With mouse put in the diving tower instrument adapt to 3min after, pass to the 36V alternating-current, mouse is subjected to electric shock to jump onto safety island to hide electric shock.Every mouse is trained once, 5min.Repetition training is once compared with the cycloheximide model control group behind the 24h, and each dosage group of compound of the present invention all can significantly reduce the number of times that is shocked by electricity in the 5min, prolongs the latent period of jumping off safety island for the first time, and can shorten the time of being shocked by electricity.Compare with positive control drug piracetam 600mg/kg group, also shorten the time of being shocked by electricity in compound 150mg/kg energy significant prolongation latent period of the present invention.The results are shown in Table 5, show that mouse memory that compound compound of the present invention causes cycloheximide consolidates obstacle and improve significantly.
Table 5 diving tower method is observed 30 pairs of cycloheximide of The compounds of this invention and is caused mouse memory consolidation barrier
The influence that hinders (n=10, x ± s)
Group errors number latent period (s) is subjected to the electric shock time (s)
Normal control 1.5 ± 0.5
*276.3 ± 31.8
*4.2 ± 4.7
*
Model contrast 3.4 ± 2.1 71.6 ± 67.4 15.7 ± 8.2
Compound 150mg/kg 0.7 ± 0.5
*218 ± 75.2
* #2.4 ± 2.5
* ##
75mg/kg 1.1±0.9
** 204.5±75.0
** 3.8±5
**
37.5mg/kg 1.1 ± 0.6
*201.9 ± 97.6
*5.4 ± 5.5
*Piracetam 600mg/kg 1.1 ± 0.7
*106.4 ± 107.8
*8.1 ± 4.0
*Compare with model control group,
*P＜0.05,
*P＜0.01. and piracetam 600mg/kg group compare #P＜0.05, ##P＜0.01. experimental example 7
Adopt the water maze method.78 of Kunming mouses, body weight 18-22g is divided into 6 groups at random, 1h before the training, the administration group is oral compound 10,37.5,75 of the present invention respectively, 150mg/kg or piracetam 600mg/kg; Capacity 0.5%CMC-Na such as model control group and normal control group are all oral.30min administration group and the equal abdominal injection vetanarcol of model control group 20mg/kg before the training, capacity DW such as normal control group abdominal injection.Training every day of every animal once 2min/ time, was trained 3 days continuously.All administrations as stated above before training every day.Write down number of times that enters cecum (errors number) and the swimming time of every animal, the person of not swimming out of was by 120 seconds in the 2min.Tested the 2nd day, tangible space cognitive disorders has appearred in the model control group mouse, significantly reduces for each dosage group mouse wrong times of compound of the present invention, but does not see that swimming time significantly shortens, and piracetam 600mg/kg does not have the improvement effect; Tested the 3rd day, and significantly reduced for each dosage group mouse wrong times of compound of the present invention, compound 75mg/kg of the present invention and 150mg/kg can significantly shorten swimming time, swim out of percentage and obviously improve.Piracetam 600mg/kg is only effective aspect the minimizing errors number, and is not obvious to the effect of other indexs.The results are shown in Table 6, show that compound compound of the present invention can obviously improve the mouse spatial discrimination obstacle that vetanarcol cause.
Table 6 water maze method is observed compound 10 vetanarcol of the present invention and is caused mouse spatial discrimination barrier
The influence that hinders (n=13, x ± s)
Group errors number swimming time (s) is swum out of percentage (%)
Normal control 6.6 ± 2.8
*73.7 ± 41.8 70.0
Model contrast 10.8 ± 4.6 89.7 ± 28.6 69.2d2 compound 37.5mg/kg 7.6 ± 2.4
*77.1 ± 31.4 76.9
Compound 75mg/kg 7.0 ± 4.8
*76.1 ± 43.8 69.2
Compound 150mg/kg 6.5 ± 5.7
*62.2 ± 37.0 84.6
Piracetam 600mg/kg 7.8 ± 4.5 73.2 ± 40.3 76.9
Normal control 5.6 ± 3.6
*69.5 ± 45.9
*61.5
Model contrast 11.5 ± 4.0 107.5 ± 22.6 30.8d3 compound 37.5mg/kg 8.3 ± 3.4
*98.5 ± 36.0 46.2
Compound 75mg/kg 7.2 ± 4.7
*66.2 ± 46.8
*69.2
Compound 150mg/kg 5.5 ± 3.4
*64.9 ± 46.4
*69.2
Piracetam 600mg/kg 7.4 ± 4.4
*80.2 ± 46.5 46.2
Compare with model control group,
*P＜0.05,
*P＜0.01.Experimental example 8
Adopt darkness avoidance test.72 of Kunming mouses, body weight 18-22g is divided into 6 groups at random, 12 every group.Tested the 1st day, 1h before the training, the administration group is oral compound 22,37.5,75 of the present invention respectively, 150mg/kg or piracetam 600mg/kg; Capacity 0.5%CMC-Na such as model control group and normal control group are all oral.30min administration group and model control group all oral 40% pure 0.1ml/10g body weight before the training, the oral capacity DW that waits of normal control group.Mouse is put in bright chamber darkroom inlet dorsad, and starts record immediately, when animal enters the darkroom and shocked by electricity back taking-up animal.Behind the 24h, press the said process administration, repetition training is compared with the normal control group, behind the ethanol of mouse oral 40%, tangible memory represents obstacle occurs, and errors number increases, and shorten latent period.Oral compound 150mg/kg of the present invention of mouse and 75mg/kg can significantly reduce the number of times that is shocked by electricity in the 3min behind the 24h, in the latent period that compound 150mg/kg of the present invention and energy significant prolongation are shocked by electricity for the first time, compound 37.5mg/kg of the present invention does with not obvious.Piracetam 600mg/kg also has obvious effect.The results are shown in Table 7, show that compound compound of the present invention can obviously improve the mouse memory reproduction obstacle that ethanol causes.
Table 7 darkness avoidance test is observed compound of the present invention ethanol is caused that mouse memory reproduces barrier
The influence that hinders (n=2, x ± s)
Group errors number latent period (s)
Normal control 1.0 ± 0.9
*115.1 ± 63.5
*
Model contrast 7.7 ± 7.1 48.1 ± 47.3
Compound 37.5mg/kg 3.6 ± 2.3 61.1 ± 63.2
75mg/kg 2.0±2.2
* 77.8±77.3
150mg/kg 1.2±0.9
** 104.9±52.1
*
Piracetam 600mg/kg 1.7 ± 1.7
*102.2 ± 75.8
*
Compare with model control group,
*P＜0.05,
*P＜0.01.Experimental example 9
Adopt Morris water maze method.Kunming mouse 60, body weight 18-22g is divided into normal control group, model group, compound of the present invention 27 at random, 150mg/kg group, 75mg/kg group, 37.5mg/kg group and piracetam 600mg/kg group.1h before the training, oral each the dosage compound of compound of the present invention and piracetam group, capacity 0.5%CMC-Na solution such as normal control group and model group are oral.30min before the training, model group, compound group of the present invention and piracetam group abdominal injection Scopolamine 2.5mg/kg, capacity DW such as normal control group abdominal injection.During training safety island is put in the first quartile, animal is from other three quadrants entry, and every day, each was trained once, continuous 5 days.The record animal is found the latent period and the movement locus of platform from following water in 90 seconds, and allows animal stop 5 seconds at platform.Can not find platform in 90 seconds, main examination is put in platform with it and stopped 5 seconds.Tested the 6th day, and removed safety island, mouse is write down the movement locus in 90 seconds from the third quadrant entry.Water maze diameter 120cm, the high 40cm of water is the suspension of milk powder, water temperature 23-25 ℃, safety island places 1cm place under the liquid level.Compare with the model control group mouse, from testing the 3rd day, each dosage group of compound of the present invention can significantly shorten mouse search latent period and total detection range gradually; Mouse is taked orthoscopic and trend formula decision search safety island gradually morely, and the model control group mouse is adopted circulating type and random mode then morely.Tested the 6th day, after removing safety island, each organizes the total detection range there was no significant difference of mouse, but accumulation search time and the accumulation detection range significant prolongation of compound 150mg/kg group of the present invention in the purpose quadrant, in the purpose quadrant in percentage ratio in total search time accumulation search time (effectively search time percentage ratio) and the purpose quadrant percentage ratio (effectively detection range percentage ratio) of accumulation detection range in total detection range all obviously increase, each dosage group mouse of compound of the present invention obviously increases by the number of times of former safety island position.The results are shown in Figure 6～9, show that compound of the present invention can obviously improve the mouse space learning dysfunction that Scopolamine causes.
Claims (18)
1. general formula (I) compound or its isomer
It is characterized in that: its A, B ring can be phenyl ring, or contains a heteroatomic fragrant heterocycle; R1 when A, B are phenyl ring, R2, R3, R4 can be positioned at 2,3,4,5 one of A, B ring at the same time or separately, and R1 when A, B are heterocycle, R2, R3, R4 can be positioned at any position of A, B ring at the same time or separately; R1, R2, R3, R7 can be hydrogen C1-C7 straight or branched alkyl, alkoxyl group, nitro, hydroxyl, acyloxy, trihalogenmethyl, halogen at the same time or separately; The same R1 of the definite division of R4, R2, R3, outside the R7, when B ring during for phenyl ring, R4 can directly link to each other by covalent linkage with R5 when being positioned at 2 of B ring; R5 can be hydrogen, C1-7 straight or branched alkyl or directly links to each other with R4 by covalent linkage; R6 can be hydrogen, C1-7 straight or branched alkyl, carboxyl, ester group (R6=-CO2R8, R8 can be C1-7 straight or branched alkyl), the integer of n=1-4.
2, according to compound or its isomer of claim 1, it is characterized in that comprising following formula: compound (Ia)
Wherein A, B ring is phenyl ring simultaneously; R1, R2, R3, R4, R7 such as claim 1 definition; R5, R6 is all hydrogen, n=2.
3, according to compound or its isomer of claim 1, it is characterized in that comprising following formula: compound (Ib)
Wherein A ring is for containing a heteroatomic fragrant heterocycle, and the B ring is a phenyl ring, R1, R2, R3, R4, R7 such as claim 1 definition; R5, R6 is all hydrogen, n=2.
4, according to compound or its isomer of claim 1, it is characterized in that comprising following formula: compound (Ic)
Wherein A ring is phenyl ring, and the B ring is for containing a heteroatomic heterocycle, R1, R2, R3, R4, R7 such as claim 1 definition; R5, R6 is all hydrogen, n=2.
5, according to compound or its isomer of claim 1, it is characterized in that comprising following formula: compound (Id)
Wherein, A, B are heterocycle simultaneously, R1, R2, R3, R4, R7 such as claim 1 definition; R5, R6 is all hydrogen, n=2.
6, according to compound or its isomer of claim 1, it is characterized in that comprising following formula: compound (Ie)
A wherein, the B ring is phenyl ring simultaneously, R1, R2, R3, R7 such as claim 1 definition, R5, R6 is all hydrogen, n=1; R8 is a C1-8 straight or branched alkyl.
7, according to compound or its isomer of claim 1, it is characterized in that comprising following formula: compound (If)
Wherein A ring is benzene or heterocycle, and B can be the benzene R1 of benzene or replacement, R2, R3, R7 such as claim 1 definition, R4=R5 is directly continuous by covalent linkage, n=2.
8,, it is characterized in that described compound comprises according to the described compound of the arbitrary claim of claim 1-7 or its isomer:
9, prepare the method for the described compound of claim 1 or its isomer, it may further comprise the steps:
With substituted benzaldehyde or contain a heteroatomic heterocycle formaldehyde with substituted phenylacetic acid or contain a heteroatomic substituted heterocycle acetate; condensation obtains 2 in the presence of acid anhydrides; 3-disubstituted benzenes or heterocycle vinylformic acid; again with the substituted aniline condensation; when containing the substituting group of protection on phenyl ring or the heterocycle; during as acetoxyl group, can obtain the object of deprotection through alkaline hydrolysis.
10, the method for preparing compound that claim 7 requires or its isomer may further comprise the steps:
The substituted benzene substituted aniline after three halogen acetylizes, obtains-substituted benzene ethyl replacement Oxoindole through metallic nickel cyclization under acidic conditions again.Then, be substituted phenyl aldehyde again, or contain a heteroatomic heterocycle formaldehyde condensation, obtain object.
11, a kind ofly prevent and/or treat parkinsonian pharmaceutical composition, it is characterized in that containing the described compound of arbitrary claim 1-7 or its isomer as active ingredient, and pharmaceutically acceptable carrier.
12, a kind ofly prevent and/or treat parkinsonian pharmaceutical composition, it is characterized in that containing compound as claimed in claim 8 or its isomer as active ingredient, and pharmaceutically acceptable carrier.
13, according to the pharmaceutical composition of claim 11 or 12, it is characterized in that described pharmaceutical composition can tablet, capsule, pill or injection form use.
14, prevent and/or treat application in the Parkinson medicine as the arbitrary compound of claim 1-7 or its isomer in preparation.
15, compound as claimed in claim 8 or its isomer prevent and/or treat application in the Parkinson medicine in preparation.
16, as the arbitrary compound of claim 1-7 or its isomer in preparation at the medicine that improves learning memory disorder or be used for that memory capability goes down and Alzheimers disease (Alzheimer ' s disease, the application in medicine for treatment AD).
17, as claim 8 compound or its isomer in preparation at the medicine that improves learning memory disorder or be used for that memory capability goes down and Alzheimers disease (Alzheimer ' s disease, the application in medicine for treatment AD).
18. application as claimed in claim 16 is characterized in that people's dosage range is 75-300mg, is equivalent to 4.5～18mg/kg/ day.
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