CN102670597B - Application of 5-(4-hydroxyl-3-methoxybenzylidene)rhodanine to preparation of medicament for treating Parkinson's disease - Google Patents
Application of 5-(4-hydroxyl-3-methoxybenzylidene)rhodanine to preparation of medicament for treating Parkinson's disease Download PDFInfo
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Abstract
The invention relates to an application of 5-(4-hydroxyl-3-methoxybenzylidene)rhodanine to preparation of a medicament for treating a Parkinson's disease.
Description
Technical field
The present invention relates to the purposes of 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine in preparation treatment parkinson medicine.
Background technology
5-(4-hydroxy 3-methoxybenzene methylene) rhodanine (5-(4-Hydroxy-3-methoxybenzylidene) rhodanine) is a kind of known compound, molecular weight: 267.32.According to the disclosure of United States Patent (USP) 5523314 and european patent application 93306959.3, this compounds and derivant thereof were once used to treat diabetes or senile dementia (Alzheimer ' s disease).
5-(4-hydroxy 3-methoxybenzene methylene) rhodanine has following chemical constitution:
Parkinson (Parkinson ' s disease, PD) claims again " Parkinsonism ", Parkinsonism or Parkinson's disease.Be the chronic progressive external dyskinetic disorder that is common in old people, this disease of system description is the female parkinson of Zhan internist of Britain the earliest, does not also know at that time which kind of disease is this disease should be included into, and claims this disease for " Parkinsonism ".Clinical manifestation is static tremor, muscle rigidity, bradykinesia and postural reflex obstacle.It is reported, in the crowd of PD more than 60 years old, sickness rate is about 1.5%, and U.S.'s number of patients has 1,000,000 at present, and the number of patients of China has exceeded 2,000,000, is only second to the prevalence of diabetes, coronary heart disease, cerebrovascular.Parkinson not only sickness rate is high, and after 2～8 years, has more the existing phenomenon that disables in various degree in morbidity, has a strong impact on patient's quality of life, adds medical expense, has brought mental burden and financial burden to society and family.
Parkinsonism is divided into following four classes:
1, parkinson disease
2, Secondary cases parkinsonism: refer to the parkinsonism that the reasons such as wound, poisoning, medicine, cerebrovascular, tumor, encephalitis cause
3, Heredodegeneration type parkinsonism
4, parkinson's plus syndrome
Clinical observation result shows for many years, takes different treatment behaviors, and the variation difference of Parkinsonian's state of an illness is very remarkable:
1. the patient who in early days just starts to accept rational therapy in morbidity, the overwhelming majority can delay the development of the state of an illness, and the state of an illness is relatively stable, and life can take care of oneself substantially.
2. although treatment, the patient of often interrupting, can not control the state of an illness mostly well, and the state of an illness there will be repeatedly and in various degree and increases the weight of.
3. develop into the just patient of begin treatment in late period, the state of an illness is often very serious, and existing treatment means is also very limited to improving disease, and patient there will be obvious disability conventionally.
Supplement in brain dopamine (DA) and be the most frequently used and the most effectively treat parkinsonian method at present.Early stage at PD, dopamine (DA) single therapy deferrable motor complication and dyskinetic generation, be applicable to 60 years old following patient especially.Exogenous D A can not see through blood brain barrier (BBB), enters in brain with its precursor levodopa by BBB, is transformed into DA through DOPA decarboxylase decarboxylation, thereby plays the effect that supplements DA in brain.Because DOPA decarboxylase is extensively present in the each internal organs of periphery and blood vessel wall, therefore in drug absorption and transmitting procedure, most of levodopa has been transformed into DA, stimulate periphery DA receptor, cause many-sided untoward reaction, as cardiovascular symptoms such as symptom of digestive tract and Blood pressure drop, arrhythmia such as nauseating, vomiting, anorexia.Be used for the treatment of parkinsonian other medicines and also comprise dopa decarboxylase inhibitor, dopamine-receptor stimulant, monoamine oxidase B inhibitor, catechol-oxygen position-methyltransferase inhibitors etc., but these medicines cause nausea, vomit the multiple untoward reaction such as even hepatic injury in clinical use procedure meeting.Studies show that in recent years, protection DA serotonergic neuron, slows down or prevents that the exploitation of the nerve protection medicine of the carrying out property degeneration of Striatum DA serotonergic neuron from will become the study hotspot of Drug therapy PD for a long time in future.
Levodopa is the metabolic precursor thereof of dopamine, can pass through blood brain barrier, after entering Basal ganglia, form dopamine through decarboxylation, although playing a part to supplement reduction of Dopamine lacks. tremble and also often have and alleviate, but the slow and stiff improvement of moving is the most remarkable. the patient that symptom is lighter can recover to approach normal movable, and bedfast patient can take action followingly. share with decarboxylase inhibitor carbidopa around, can reduce the dosage that levodopa need be used, because the latter's katabolism is blocked, reducing untoward reaction (feels sick, cardiopalmus, flush), make more levodopa can effectively enter brain. breath rather has the dosage form of different carbidopa/levodopa fixed proportions: 10/100, 25/100, 25/250, also has a kind of slow releasing tablet 50/200mg dosage form.First peaceful with breath when treatment starts, according to patient's tolerance situation, progressively increased dosage every 4～7 days, until produce maximum effect.Slowly and carefully increase dosage, make patient take medicine at table or after meal, can make untoward reaction alleviate.Most patient needs the levodopa of total amount 400～1000mg every day, and gradation in every 2～5 hours is taken medicine, and at least needs every day the carbidopa of 100mg to alleviate untoward reaction around.Application is when levodopa treatment, and what often make that dosage is restricted is that untoward reaction is involuntary action (dyskinesia), shows as dance movement or the myodystonia of mouth-face or limbs.Along with the prolongation for the treatment of time, the also corresponding reduction of threshold value that these dyskinesias occur also there will be in the time applying compared with low dosage.Cease peaceful slow releasing tablet or Selegiline and can be used as useful auxiliary treatment.Other untoward reaction of levodopa comprises orthostatic hypotension, hallucination, nightmare and accidental toxic delirium.Hallucination and delirium are most commonly in old and have a dull-witted case.
Amantadine 100～300mg/ days oral, useful in the treatment of 50% early stage slight parkinson's syndrome case, can strengthen the effect of levodopa in the later stage of disease.Hidden booth and pergolide are peptide, can directly activate the dopamine receptor in Basal ganglia.Bromocriptine 5～60mg/d or pergolide 0.1～5.0mg/ days oral all useful to the case in each stage of disease.But, seldom can successfully apply bromocriptine or pergolide as independent medicine.Some new dopamine-receptor stimulants have higher specificity to D2 receptor, for example pramipexole and ropini-role.Selegiline is a kind of monoamine oxidase B inhibitors, can suppress one of to degrade in two relevant Major Enzymes with dopamine in brain, thereby the effect of each levodopa dosage is extended to some extent.Non-selective oxidase inhibitor is all blocked A type and Type B isozyme, if with the same use of cheese, often can produce hypertensive crisis (cheese effect); The oral hypertensive crisis that can not cause of Selegiline 5～10mg/d.Although Selegiline is almost there is no untoward reaction, it can strengthen the untoward reaction of levodopa as dyskinesia, and mental symptom, with nauseating, may must reduce levodopa dosage.Selegiline can postpone reinstating about approximately 1 year of levodopa as head with medicine.Selegiline may play potentiation to dopamine remaining in Early Parkinson's disease case brain, or reduces dopamine oxidative metabolism in brain, and neurodegenerative process is slowed down to some extent.
Anticholinergic agents can be used for the treatment of disease commitment, can be used as the ancillary drug of levodopa in the later stage.Conventional anticholinergic agents comprises benztropine, benzhexol.The antihistamine drug (25～200mg/d is oral as diphenhydramine, and orphenadrine 50～200mg/d is oral) with anticholinergic effect is trembled useful to treatment.There is tricyclic antidepressants (as oral in amitriptyline 10～150mg hora somni(hs)) the useful ancillary drug of levodopa often of anticholinergic effect, and contribute to Cure of depression.
Catechol is to transmethylase (COMT) inhibitor as tolcapone (tolcapone) and entacapone, and the degraded that can block dopamine, also can be used as the useful ancillary drug of levodopa.Propranolol 10mg every day 2 times to 40mg every day 4 times is oral, useful to the kinetic tremor occurring in some case or intentional tremor once in a while.
In prior art, have no report 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine effective in cure to parkinson.The inventor finds that this compound has very strong antioxidant activity, has very strong protective effect to nerve.
Summary of the invention
The invention provides the parkinsonian Therapeutic Method of a kind of new treatment, the method comprises 5-(the 4-hydroxy 3-methoxybenzene methylene) rhodanine that uses medicine effective quantity to parkinson patient.Particularly, the invention provides the new medicinal usage of a kind of 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine, or the purposes of 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine in preparation treatment parkinson medicine.Described medicine is tablet, pill, membrane, drop pill, mixture, capsule, granule or the injection of 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine.Be preferably oral.
Use the disclosed method of United States Patent (USP) 5523314 can obtain compound 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine, this compound is specifically documented in the middle of description embodiment 20.
" pharmaceutically acceptable salt " of the present invention refers to that compound 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine is to the nontoxic in fact salt compound of biology of living.Its typical salt compound includes but not limited to pharmaceutically acceptable organic acid, and mineral acid or pharmaceutically acceptable alkali metal or organic base react the salt forming with compound 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine.Pharmaceutically acceptable mineral acid comprises hydrochloric acid, phosphoric acid, sulphuric acid, hydrobromic acid, phosphorous acid etc.Be preferably hydrochloric acid.Specifically, salt of the present invention also comprises hydrochlorate, hydrobromate, nitrate, sulfate, metaphosphate, the disulfate of 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine, sulphite, phosphate, hydrophosphate, dihydric phosphate, pyrophosphate, hydriodate, hydrofluoride, propionate, fumarate, oxalates, citrate, lactate, maleate etc.5-(4-hydroxy 3-methoxybenzene methylene) rhodanine pharmaceutically acceptable salt is preferably 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine hydrochlorate.
Compound 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine and the pharmaceutically acceptable salt thereof that the present invention relates to are made injection, oral agents, preferred oral dosage form, this peroral dosage form comprises the known dosage form of tablet, capsule and slow release formulation etc.In preparation when all kinds of dosage form, the compounds of this invention or pharmaceutically acceptable salt and pharmaceutically acceptable carrier can be made to pharmaceutical composition according to the technology of well known to a person skilled in the art.The oral dose of this compound is preferably 5mg/kg body weight-25mg/kg body weight.
5-(4-hydroxy 3-methoxybenzene methylene) rhodanine is-individually there is the very compound of strong anti-oxidation activity, there is very strong neuroprotective.
Detailed description of the invention
Embodiment 1
5-(4-hydroxy 3-methoxybenzene methylene) rhodanine causes the ethological impact of parkinson disease (PD) rat model to 6-OHDA
Experiment purpose: this experiment is prepared Rat Model with Parkinson Disease by inject 6-hydroxy dopamine (6-OHDA) in SD Rats With Unilateral striatum.Using dosage is respectively 5-(the 4-hydroxy 3-methoxybenzene methylene) rhodanine of 35mg/kg body weight, 70mg/kg body weight and treats, with positive drug group (levodopa 10mg/kg+ benserazide 2.5mg/kg) and sham operated rats comparison, the behavioristics of observing pharmaceutical intervention changes, to evaluate the large action effect of antagonism PD.
One, material and method
1. material
1.1 are subject to test product: 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine is yellow powder.Make suspension with 1%CMC (sodium carboxymethyl cellulose) water hydrotropy.
1.2 reagent: 6 hydroxy dopamine (6-OHDA), Sigma company product, article No. H116, lot number 115K4613; Apomorphine (Apomorphine, APO), Sigma company product, article No. A4393, lot number 085K1223.
1.3 animals: SD rat, male, body weight is greater than 180g, and by Beijing, Wei Tongliization animal company provides.
2. method
The foundation of 2.1 Parkinson disease in rats (PD) model
Bull healthy SD rat is bought rear Normal group, sham operated rats and the model module of being divided at random.After sieve module lumbar injection 1% pentobarbital sodium (50mg/kg body weight) anesthesia, be fixed on rat brain stereotactic apparatus in strict accordance with cranium prosposition (bregma and posterior level height differ below 0.1mm, and the other 4mm place level height of opening in skull sagittal suture both sides differs below 0.1mm).Cut off scalp, peel off after periosteum, in prescribed limit, determine concrete coordinate labelling according to rat body weight and head size, with the saturating skull of the careful brill of dental burr.According to Paxinos Watson collection of illustrative plates, determine right side striatum (CPU) coordinate, row injection (AP:0.5mm, ML:-2.5mm, VD:-5mm at 2; AP:-0.5mm, ML:-4.2mm, VD:-5mm) by determining that slow microsyringe inserting needle is arrived prescribed depth by coordinate.To 2 each injection 6-OHDA 15 μ g of CPU, 2 μ l (being dissolved in the normal saline that mass fraction is 0.1% ascorbic acid), injection speed is 1 μ l/ minute, let the acupuncture needle remain at a certain point 10 minutes, the slowly withdraw of the needle 3 minutes (1mm/ minute).Sham operated rats is injected respectively the normal saline containing 0.1% ascorbic acid of same volume by above-mentioned same procedure to 2.Postoperative, the each group of rat muscle injection penicillin of performing the operation, to prevent and treat infection.
The screening of 2.2 Parkinson disease in rats (PD) model
Within postoperative the 4th week, start rat 6-OHDA PD model to be rotated experiment screening, APO cervical region subcutaneous injection (1mg/kg body weight), observing its behavior in 30 minutes changes, turn to strong side if rat is constant, and rotating cycle > 100r/30 minute, maximum number of revolutions per minute is more than or equal to 7r/ minute, represents to damage to stablize, and is considered as successfully parkinson disease (PD) rat model.
2.3 test groupings
Screen successful model and be divided at random model group (n=10 only), 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine dosage group 1 (n=11 only), 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine dosage group 2 (n=11 only), positive drug group (n=10 only), sham operated rats (n=13 is only), Normal group (n=12 is only).
2.4 pharmaceutical intervention
Within after grouping the 1st day, start drug treatment.5-(4-hydroxy 3-methoxybenzene methylene) rhodanine dosage group 1 (70mg/kg), 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine dosage group 2 (35mg/kg), positive drug group (levodopa 10mg/kg+ benserazide 2.5mg/kg body weight) difference every day gavage 1 time, Normal group, model group and sham operated rats give the 1%CMC water of respective volume, continuous 2 weeks.
2.5 Behavioral assessment
Successive administration starts behavioristics and detects after 2 weeks.
2.5.1 apomorphine induction rotation test
With apomorphine (Apomorphine, APO) row rat (comprising model group, administration group, sham operated rats) cervical region subcutaneous injection (1mg/kg body weight), observes and records it and in 30 minutes, turn to the number of turns and the average revolution per minute of being good for side.
2.5.2 gimbal lever's test
The balancing length of a member 105cm × wide 4cm × high 3cm, rod is liftoff 80cm, two ends are supported by yoke.One end of rod is sintering, long 20cm, and another section is outrun, connects a large mouse cage behind outrun, under rod, has 1m2, thick 12cm mat prevents rat traumatic injury.When experiment, rat is placed on to sintering in the face of mouse cage direction, starts timing simultaneously, record pass by time (incubation period) of sintering and rat of rat and pass by time of the whole gimbal lever, the maximum permission time of incubation period is 1 minute, and the maximum permission time of the cross bar of passing by is 2 minutes.Rat is first trained 3 times, then starts formal experiment.
2.6 statistical method
This experimental result represents with X ± SD, carries out statistical analysis with the one factor analysis of variance of SPSS software.
Two, result
1, apomorphine induction rotation test: compared with model group, the number of times that turns that 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine dosage group 1 can significantly reduce apomorphine induction has minimizing trend, but 35mg/kg dosage group 2 slightly increases.(in table 1).
2, gimbal lever experiment: 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine successive administration 14 days under 70mg/kg dosage group 1,35mg/kg dosage group 2 dosage, shorten the incubation period that 6-OHDA causes PD rat model and cross bar, spend the bar time and significantly reduce (P < 0.05, P < 0.01), (in table 2,3).
Table 1 apomorphine induction rat rotation test result
###p < 0.001, with sham operated rats comparison; With model group comparison, * P < 0.05
Table 2 Ge Zu rat gimbal lever experimental result incubation period
With model group comparison, * P < 0.05, * * P < 0.01.
Bar interpretation is crossed by the table 3 Ge Zu rat gimbal lever
With model group comparison, * P < 0.05, * * P < 0.01.
The present embodiment adopts injection 6-OHDA in one-sided striatum to cause PD model.And carry out 2 kinds of Animal Behavior Science and detected.Result shows:
1. apomorphine experiment: obviously increase (P < 0.001) to strong sideway swivel campaign because Ipsilateral nigrostriatum pathway injury causes animal model.Through the treatment of 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine gavage, after 14 days, its number of revolutions has minimizing trend.
2. gimbal lever's experiment: the motion initiating of model mouse and moving equilibrium ability are all obviously than sham-operation poor (P < 0.05, P < 0.01).Through two dosage gavages of 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine after 14 days, above-mentioned performance is all improved (P < 0.05), wherein dosage group 1 action effect the best (P < 0.01) to moving equilibrium ability.Positive drug is also significantly improved (P < 0.01).
5-(4-hydroxy 3-methoxybenzene methylene) rhodanine, can significantly improve 6-OHDA and cause PD rat model operation harmony after 14 days through continuous gastric infusion, has good anti-Parkinson effect.
Claims (5)
1.5-(4-hydroxy 3-methoxybenzene methylene) rhodanine or its pharmaceutically acceptable salt purposes in preparation treatment parkinson medicine.
2. purposes according to claim 1, wherein said medicine is tablet, pill, membrane, drop pill, mixture, capsule, granule or the injection of 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine or its pharmaceutically acceptable salt.
3. purposes according to claim 1, wherein the pharmaceutical dosage of 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine or its pharmaceutically acceptable salt is 5mg/kg Ti Chong – 25mg/kg body weight.
4. purposes according to claim 1, wherein 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine pharmaceutically acceptable salt is hydrochlorate, hydrobromate, nitrate, sulfate, metaphosphate, disulfate, sulphite, phosphate, hydrophosphate, dihydric phosphate, pyrophosphate, hydriodate, hydrofluoride, propionate, fumarate, oxalates, citrate, lactate or maleate.
5. purposes according to claim 1, wherein 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine pharmaceutically acceptable salt is 5-(4-hydroxy 3-methoxybenzene methylene) rhodanine hydrochlorate.
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| KR102195895B1 (en) * | 2019-04-19 | 2020-12-28 | 한국생명공학연구원 | pharmaceutical composition for treating or preventing Parkinson's disease comprising STT as an active ingredient |
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| Liu J等.Evaluation of dihydropyrimidin-(2H)-one analogues and rhodanine derivatives as tyrosinase inhibitors.《Bioorganic & medicinal chemistry letters》.2011,第21卷(第8期), * |
| Tyrosine mRNA is expressed in human substantia nigra;Xu Y等;《Molecular brain research,》;19971231;第45卷(第1期);第159-162页 * |
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