CN102429909A - Medicine for treating neurodegenerative diseases - Google Patents
Medicine for treating neurodegenerative diseases Download PDFInfo
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- CN102429909A CN102429909A CN2011103811758A CN201110381175A CN102429909A CN 102429909 A CN102429909 A CN 102429909A CN 2011103811758 A CN2011103811758 A CN 2011103811758A CN 201110381175 A CN201110381175 A CN 201110381175A CN 102429909 A CN102429909 A CN 102429909A
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Abstract
The invention discloses a new application of ectoine and derivatives thereof, namely application of ectoine and derivatives thereof in preparing medicines for treating neurodegenerative diseases. Wherein the tetrahydropyrimidine derivative comprises 1,4,5, 6-tetrahydro-2-methyl-5-hydroxy-4-pyrimidinecarboxylic acid. The oral administration effect is good, and the dosage is 0.01-100 mg/kg, so that the oral administration has good safety and effectiveness.
Description
Technical field
The present invention relates to the application in preparation neurodegenerative diseases medicine of tetrahydropyrimidine and derivant thereof.
Background technology
Neurodegenerative diseases is that gradual dysfunction and death take place a kind of neurocyte, thereby causes that individual behavior is unusual and even dead to be one type of disease of principal character.Such disease mainly comprises Alzheimer, parkinson disease, ALS, Huntington Chorea, cerebellar atrophy disease, multiple sclerosis, motor neuron, hereditary ataxia, hereditary spastic paraplegia, charcot marie tooth, epilepsy etc.Though the cause of disease of this type disease and the position of pathological changes have nothing in common with each other, all visible brain on the pathology is or/and spinal cord generation neuron regression degeneration, lose.Its cause of disease and pathogenesis it be unclear that, and have multiple suppositions such as exitotoxicity hypothesis, apoptosis hypothesis, immune inflammation hypothesis, mitochondrial fuctionning obstacle hypothesis and oxidative stress hypothesis for a long time.
Recent study shows that neurodegenerative diseases is built up relevant with some insoluble amylaceous fibrillins in tissue.These protein are built up finally can destroy neurocyte.Wherein multiple neurodegenerative diseases has been proved to be relevant with amyloid-beta.Research recently thinks that the pathogenic protein matter structure of different neurodegenerative diseases is basic identical.
Along with the appearance of social development and aged tendency of population, this group disease has become after cardiovascular disease and cancer, has a strong impact on the 3rd factor of human health.But except that disturbances in patients with Parkinson disease can prolong its life-span and improve its quality of life through rational use of drug, the therapeutic effect of other diseases is all undesirable.
Tetrahydropyrimidine, chemistry by name 1,4,5; 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic or 2-Methyl-1,4,5,6-tetrahydropyrimidine-4-carboxylic acid or (S)-2-methyl-1; 4,5,6-tetra-hydro pyrimidine-4-carboxylic acid or 1,4; 5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid, CAS number is 96702-03-3, is the amino acid derivativges of finding in the marine organism in 1985; Carboxymethyl Chitin in recent years, has been used to cosmetics.
Summary of the invention
To above-mentioned prior art, the purpose of this invention is to provide a kind of new purposes of tetrahydropyrimidine and derivant thereof, tetrahydropyrimidine and derivant thereof the application in preparation neurodegenerative diseases medicine specifically.
For realizing above-mentioned purpose, the technical scheme that the present invention adopts is:
The application in preparation neurodegenerative diseases medicine of tetrahydropyrimidine and derivant thereof.
Said tetrahydropyrimidinederivatives derivatives is 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic.
Said neurodegenerative diseases is selected from Alzheimer's disease, parkinson disease, ALS and Huntington Chorea.
The dose therapeutically effective of said tetrahydropyrimidine and derivant thereof is for being (0.1～100) mg/kg.
The dose therapeutically effective of said tetrahydropyrimidine and derivant thereof is for being (0.2～5) mg/kg.
Tetrahydropyrimidine described in the technical scheme of the present invention, chemistry 2-Methyl-1 by name, 4; 5,6-tetrahydropyrimidine-4-carboxylic acid or (S)-2-methyl-1,4; 5,6-tetra-hydro pyrimidine-4-carboxylic acid or 1,4; 5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid.1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is commonly called as the hydroxy tetrahydro pyrimidine, and CAS number is 96702-03-3, and this is that those skilled in the art are known.
Its pharmaceutical dosage form can have multiple.Because the ideal physicochemical property of tetrahydropyrimidine, its preparation scope is extremely wide, can be made into oral formulations such as tablet, capsule etc.; External preparation such as emulsifiable paste, ointment etc.; Ejection preparation such as injection, lyophilized powder etc.This is conspicuous those skilled in the art, and the technology of preparing of various preparations also is that those skilled in the art are known.
The inventor's surprised discovery in experimentation; Tetrahydropyrimidine and derivant thereof; Like the hydroxy tetrahydro pyrimidine, neurodegenerative diseases especially Alzheimer's disease, parkinson disease, ALS and Huntington Chorea there is unexpected therapeutical effect.
The specific embodiment
Below in conjunction with embodiment the present invention is done further explanation.Should be understood that following examples only are used to explain the present invention, rather than restriction protection scope of the present invention.
Embodiment 1 tetrahydropyrimidine and 1,4,5, the acute toxicity testing of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic
SPF level KM mice, male and female half and half, body weight 18g-22g, fasting is 8 hours before the administration, weigh, single-dose (irritating stomach or intravenous injection), dosage is 120mg/kg, observes 14 days continuously after the administration.Observation item comprises toxic reaction, body weight and histopathology.
The result shows, behind mice single gastric infusion or the intravenous administration 120mg/kg, does not see the overt toxicity reaction, body weight no significant difference when administration front and back and experiment finish, and pathological study is found significantly unusually.Tetrahydropyrimidine and 1,4,5 are described, the heavy dose of administration of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic single (120mg/kg) does not have significant toxic reaction.
Embodiment 2 tetrahydropyrimidines and 1,4,5, the long term toxicity test of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic
Machin, male and female half and half, random packet gives normal saline (matched group) respectively; 1,4,5 of the tetrahydropyrimidine of high, normal, basic three dosage and high, normal, basic three dosage, 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic, wherein high dose group is 80mg/kg, and middle dose groups is 40mg/kg, and low dose group is 10mg/kg.Two groups of gastric infusion group and intravenous administration groups are all established in administration every day 1 time, successive administration 30 days, matched group and each dose groups medicine.Carry out gross examination of skeletal muscle before the administration and after the administration, the body weight of monkey before the general symptom of record monkey, the record administration and after the administration, and regularly carry out hematology, urine and blood biochemical analysis reaches the electrocardiogram of monkey after the administration before the record administration.
The result shows that each dose groups the weight of animals and matched group do not have significant difference, and gross examination of skeletal muscle is no abnormal.The hematology of experimental group animal, urine and blood physicochemical data and matched group do not have significant difference.Tetrahydropyrimidine and 1,4,5 are described, the safety of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic long term administration is good, and toleration meets the requirements.
Embodiment 3 tetrahydropyrimidines and 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is to the pharmacodynamic study of Alzheimer's disease
SPF level SD rat, male and female half and half, body weight 158～176g.Stay one group of rat as normal control, all the other rats are adopted the modeling of nongenetic method.Behind the rat anesthesia, be fixed in stereotaxic instrument, wipe out art district hair; Partly sterilised, the sagittal otch of 1.5cm is done in center, the crown, and passivity is separated periosteum; With reference to the rat brain stereotaxic atlas; After bilateral nbM carried out solid location, respectively bore the hole of a diameter 1mm, be dissolved in the amino-(3-hydroxy-5-isoxazolyl)acetic acid. solution 1 μ l (containing amino-(3-hydroxy-5-isoxazolyl)acetic acid. 5 μ g) of 0.1M pH 7.4 phosphate buffers with the vertical injection of microsyringe in each corresponding point of bilateral skull.5 minutes inject time of every pin, let the acupuncture needle remain at a certain point 5 minutes, back suture operation otch, and partly sterilised, clear-headed back is conventional raises.
After the modeling success, with the rat random packet.First group is model control group, irritates stomach and gives normal saline; Second group of positive matched group irritated stomach and given galanthamine hydrobromide, and dosage is 10mg/kg; The 3rd group is the administration group, irritates stomach and gives tetrahydropyrimidine, and dosage is 95mg/kg; The 4th group is the administration group, irritates stomach and gives tetrahydropyrimidine 82mg/kg; The 5th group is the administration group, irritates stomach and gives tetrahydropyrimidine, and dosage is 69mg/kg; The 6th group is the administration group, irritates stomach and gives tetrahydropyrimidine, and dosage is 54mg/kg; The 7th group is the administration group, irritates stomach and gives 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 40mg/kg; The 8th group is the administration group, irritates stomach and gives 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 1mg/kg.The 9th group is the administration group, irritates stomach and gives 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 4mg/kg.
Carrying out behavioristics with the Morris water maze after the administration detects.Water maze is the round pool of diameter 90cm, high 40cm, and depth of water 30cm indicates 4 place of entry on the pool wall, it is divided into 4 quadrants, places a circular platform at the 3rd quadrant center, and platform is lower than water surface 2cm, water temperature (27 ± 2) ℃.Each is organized rat and after administration, carried out water maze laboratory respectively on the 7th day.Test event is a sea trial, first three sky of water maze laboratory, and every day, trained rat was twice.After the training, rat is put into the pond from 4 place of entry respectively towards pool wall, surveys in its 90 seconds and successfully find the platform required time, promptly escape latency (Escape Latency, EL).If do not find platform in the 90s after the rat entry, then be placed on the platform and stopped 10 seconds.The result sees table 1.
Table 1 respectively organize escape latency test result after the rat administration (unit: second; Average)
| First group | Second group | The 3rd group | The 4th group | The 5th group | The 6th group | The 7th group | The 8th group | The 9th group | |
| EL | 21.19 | 10.63 | 2.94 | 2.09 | 2.85 | 3.07 | 4.62 | 2.33 | 2.91 |
Visible by table 1, tetrahydropyrimidine and 1,4; 5; 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic has significant therapeutic effect to Alzheimer's disease, can significantly improve behavioristics's index of Alzheimer's disease rat model, and therapeutic effect significantly is superior to existing medicine.
Embodiment 4 tetrahydropyrimidines and 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is to Parkinsonian pharmacodynamic study
SPF level Wistar rat, male and female half and half, body weight 150～180g.Stay one group of rat as normal control, all the other rats are adopted the modeling of nongenetic method.Behind the rat anesthesia, be fixed in stereotaxic instrument, wipe out art district hair; Partly sterilised; With reference to the rat brain stereotaxic atlas, right substantia nigra position coordinate is positioned, at twice the 6-hydroxy dopamine is injected right substantia nigra portion with microsyringe then and set up the rat Parkinson disease model.
After the modeling success, random packet, first group is the model group matched group, irritates stomach and gives normal saline; Second group of positive matched group irritated stomach and given body of Pramipexole dihydrochloride, and dosage is 1.5mg/kg; The 3rd group is the administration group, irritates stomach and gives tetrahydropyrimidine, and dosage is 10mg/kg; The 4th group is the administration group, irritates stomach and gives tetrahydropyrimidine 0.8mg/kg; The 5th group is the administration group, irritates stomach and gives tetrahydropyrimidine, and dosage is 20mg/kg; The 6th group is the administration group, irritates stomach and gives tetrahydropyrimidine, and dosage is 3mg/kg; The 7th group is the administration group, irritates stomach and gives 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 30mg/kg; The 8th group is the administration group, irritates stomach and gives 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 0.5mg/kg.The 9th group is the administration group, irritates stomach and gives 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 2mg/kg.
After administration was accomplished, the apomorphine that each organizes rats by intraperitoneal injection 0.01% brought out the rat circling behavior, and the number of revolutions in the rat 1 minute respectively organized in record.The result sees table 2.
Table 2 is respectively organized rat number of revolutions relatively (average)
| First group | Second group | The 3rd group | The 4th group | The 5th group | The 6th group | The 7th group | The 8th group | The 9th group | |
| Number of revolutions | 10.27 | 2.14 | 2.03 | 1.50 | 2.15 | 1.92 | 1.61 | 1.39 | 1.55 |
Visible by table 2, tetrahydropyrimidine and 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic has significant therapeutic effect to parkinson disease, can significantly improve behavioristics's index of Parkinson disease model rat, significantly reduces the number of revolutions of rat model.
Embodiment 5 tetrahydropyrimidines and 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is to the pharmacodynamic study of ALS
The ALS-SOD1G93A transgenic mice is according to document (Feng Xinhong; The detection [D] of experimentation normal person's peripheric venous blood SOD1 protein expression level of butylphthalide treatment and prevention amyotrophic lateral sclerosis SOD1-G93A transgenic mice; Beijing Union Medical College; 2011) preparation.
After the modeling success, with the rat random packet, first group is the model group matched group, irritates stomach and gives normal saline; Second group of positive matched group irritated stomach and given riluzole, and dosage is 10mg/kg; The 3rd group is the administration group, irritates stomach and gives tetrahydropyrimidine, and dosage is 0.3mg/kg; The 4th group is the administration group, irritates stomach and gives tetrahydropyrimidine 4mg/kg; The 5th group is the administration group, irritates stomach and gives tetrahydropyrimidine, and dosage is 6mg/kg; The 6th group is the administration group, irritates stomach and gives tetrahydropyrimidine, and dosage is 11mg/kg; The 7th group is the administration group, irritates stomach and gives 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 24mg/kg; The 8th group is the administration group, irritates stomach and gives 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 35mg/kg.The 9th group is the administration group, irritates stomach and gives 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 2.7mg/kg.
After the administration 24 hours, mice is carried out behavioristics's experiment, experimental project is the transfer rod experiment.Experimental mouse is positioned on the transfer rod appearance of diameter 3.5cm, rotating speed 12rpm, the long latency that the record mice falls, with 180 seconds be cut off value, surpass 180 seconds by 180 seconds records, less than 180 seconds is by record actual time.Experimental result is seen table 3.
Table 3 is respectively organized mice transfer rod experiment (unit: second incubation period; Average)
| First group | Second group | The 3rd group | The 4th group | The 5th group | The 6th group | The 7th group | The 8th group | The 9th group | |
| Incubation period | 32.6 | 87.4 | 172.6 | 195.1 | 165.3 | 181.9 | 196.0 | 188.3 | 189.5 |
Visible by table 3, tetrahydropyrimidine and 1,4; 5; 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic administration group mice transfer rod experiment significantly is longer than model group and riluzole administration group, points out tetrahydropyrimidine and 1,4 incubation period; 5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic can significantly improve ALS mouse movement ability and balanced capacity.
Embodiment 6 tetrahydropyrimidines and 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is to the pharmacodynamic study of Huntington Chorea
SPF level Wistar rat, male, body weight 230～260g.Stay one group of rat as normal control, all the other rats are adopted the modeling of nongenetic method.Behind the rat anesthesia, be fixed in stereotaxic instrument,, divide with microsyringe and four times quinolinic acid to be injected right side surcingle shell nuclear and set up rat Huntington chorea disease model with reference to the rat brain stereotaxic atlas.
After the modeling success, random packet, first group is the model group matched group, irritates stomach and gives normal saline; Second group of positive matched group irritated stomach and given tetrabenazine, and dosage is 8mg/kg; The 3rd group is the administration group, irritates stomach and gives tetrahydropyrimidine, and dosage is 10mg/kg; The 4th group is the administration group, irritates stomach and gives tetrahydropyrimidine 0.8mg/kg; The 5th group is the administration group, irritates stomach and gives tetrahydropyrimidine, and dosage is 20mg/kg; The 6th group is the administration group, irritates stomach and gives tetrahydropyrimidine, and dosage is 3mg/kg; The 7th group is the administration group, irritates stomach and gives 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 30mg/kg; The 8th group is the administration group, irritates stomach and gives 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 0.5mg/kg.The 9th group is the administration group, irritates stomach and gives 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 2mg/kg.
After the administration 12 hours, each group rat is carried out behavioristics's experiment, experimental project is spacious experiment.Experimental period is to carry out between 9:00～10:00 in the morning, and spacious experimental box is 100cm * 100cm * 50cm black inwall opaque plastics case, and the bottom surface is divided into 25 big grids such as 20cm * 20cm.Before the experiment plastic box is cleaned the residual abnormal smells from the patient of elimination, experiment is carried out under quiet environment.Placing behind the plastic box record rat to climb lattice at 5 minutes rat counts summation, erects number of times.The number of times of standing that two fore paw built on stilts 1cm are above is for erectting number of times.The result sees table 4.
Table 4 is respectively organized rat and is respectively organized rat and climb lattice and count summation (A), erect number of times (B)
| First group | Second group | The 3rd group | The 4th group | The 5th group | The 6th group | The 7th group | The 8th group | The 9th group | |
| A | 11.4 | 32.7 | 94.2 | 102.5 | 69.7 | 91.0 | 82.6 | 86.5 | 83.7 |
| B | 0 | 1.4 | 2.7 | 2.4 | 1.6 | 2.2 | 1.9 | 3.5 | 5.7 |
Table 4 numerical value is the average of respectively organizing measured value.
By the visible tetrahydropyrimidine and 1,4,5 of table 4,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic administration group rat climbs the lattice summation in 5 minutes and is significantly higher than model group and tetrabenazine group, erects number of times and also is higher than model group and tetrabenazine group.Prompting tetrahydropyrimidine and 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic can significantly improve behavioristics's index of Huntington Chorea rat, Huntington Chorea is had the good curing effect.
Embodiment 71, and 4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is to the pharmacodynamic study of epilepsy
SPF level SD rat,, male and female half and half, body weight 150～180g.Stay one group of rat as normal control, all the other rat modelings.Modeling method is following:
Rats by intraperitoneal injection lithium chloride 125mg/kg, 18 hours pneumoretroperitoneum injection PILO 10mg/kg.As do not have III～V grade standard person that epilepsy outbreak or epilepsy outbreak do not reach the Racine standard, every at a distance from 30 minutes repetition lumbar injection PILOs 1 time, till maximal dose 60mg/kg.Attack degree is carried out classification by the Racine standard, and outbreak reaches III～V level, and the animal that the status epilepticus outbreak is not alleviated gets into status epilepticus, thinks that epilepsy model prepares successfully.
After the modeling success, random packet, first group is the model group matched group, irritates stomach and gives normal saline; Second group of positive matched group irritated stomach and given topiramate, and dosage is 20mg/kg; The 3rd group is the administration group, irritates stomach and gives 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 0.3mg/kg.
After the administration, observe rat epilepsy situation, the incubation period of writing down each treated animal epilepsy, and carry out classification according to the Racine standard.The result sees table 5.
Table 5 is respectively organized (the unit: second incubation period of rat epilepsy; Average) and grade (average)
| The model group matched group | Positive controls | The administration group | |
| Incubation period | 72.9 | 97.1 | 154.5 |
| The grade of outbreak | 5.2 | 3.6 | 1.9 |
Visible 1,4,5 by table 5, significantly be longer than model group matched group and positive controls the incubation period of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic administration group rat epilepsy, and the grade of epilepsy also significantly reduces.Prompting 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic has the good curing effect to epilepsy.
Execute the prescription and the preparation thereof of routine 8 tetrahydropyrimidine oral tablets
Tetrahydropyrimidine 200g
Lemon yellow 0.03g
Microcrystalline Cellulose 500g
Micropowder silica gel 4g
Magnesium stearate 15g
Polyvinylpyrrolidone 20 g
With tetrahydropyrimidine, microcrystalline Cellulose, lemon yellow, polyvinylpyrrolidone mix homogeneously, cross 80 mesh sieves
Net adds micropowder silica gel, magnesium stearate, mixes 3 min, and tabletting promptly gets.
Embodiment 91, and 4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-capsular prescription of 4-pyrimidine carboxylic and preparation thereof
1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic 200g
Microcrystalline Cellulose 50g
Carboxymethyl starch sodium 60g
Sodium lauryl sulphate 18g
Silica 1 2g
1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is crossed 100 mesh sieves, and all the other adjuvants are crossed 80 mesh sieves, mixes all
Even, adopt roll-in method to carry out dry granulation, be packed into capsule and get final product.
[0043] embodiment 10 1, and 4,5, prescription and preparation thereof that 6-tetrahydrochysene-2-methyl-5-hydroxyl-injection of 4-pyrimidine carboxylic is dissolved
Take by weighing 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic, it is an amount of to add water, adds Polyethylene Glycol 400 by recipe quantity, stirs to make it dissolving, adds sodium benzoate and 900ml water, and mixing adds water to 1000ml, filters, sterilization, packing promptly gets.
Claims (5)
1. tetrahydropyrimidine and derivant thereof the application in preparation neurodegenerative diseases medicine.
2. application according to claim 1 is characterized in that: said tetrahydropyrimidinederivatives derivatives is 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic.
3. application according to claim 1 is characterized in that: said neurodegenerative diseases is selected from Alzheimer's disease and ALS.
4. according to the described application of claim 1-3, it is characterized in that: the dose therapeutically effective of said tetrahydropyrimidine and derivant thereof is for being (0.1～100) mg/kg.
5. according to the described application of claim 1-3, it is characterized in that: the dose therapeutically effective of said tetrahydropyrimidine and derivant thereof is for being (0.2～5) mg/kg.
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Non-Patent Citations (3)
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| 《 FEBS Letters》 20050808 Mathumai Kanapathipillai, et al. ectoine and hydroxyectoine inhibit aggregation and neurotoxicity of Alzheimer's beta-amyloid 摘要，第4775页左栏第1段至右栏第2段，图3-5 1-5 第579卷, * |
| JOON SEOK LEE, ET AL.: "high-throughput analysis of Alzheimer"s beta-amyloid aggregation using a microfluidic self-assembly of monomersf", 《ANAL. CHEM.》 * |
| MATHUMAI KANAPATHIPILLAI, ET AL.: "ectoine and hydroxyectoine inhibit aggregation and neurotoxicity of Alzheimer’s beta-amyloid", 《 FEBS LETTERS》 * |
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