CN114028403A - Application of medicine for treating chronic neurodegenerative disease - Google Patents
Application of medicine for treating chronic neurodegenerative disease Download PDFInfo
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Abstract
The invention relates to the use of 1- [3- (6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4, 3-d ] pyrimidin-5-yl) -4-ethoxybenzenesulfonyl ] -cis-3, 5-dimethylpiperazine citrate or Aildenafil citrate for the preparation of a medicament for the treatment of neurodegenerative diseases, including diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, different types of spinocerebellar ataxia drugs. The citric acid alidenafil has wide application prospect in preparing medicines for treating neurodegenerative diseases and treating neurodegenerative diseases.
Description
Technical Field
The invention relates to the use of 1- [3- (6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4, 3-d ] pyrimidin-5-yl) -4-ethoxybenzenesulfonyl ] -cis-3, 5-dimethylpiperazine citrate (Aildenafil citrate) for the manufacture of a medicament for the treatment of chronic neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), different types of spinocerebellar ataxia (SCA).
Background
Neurodegenerative diseases are caused by the loss of neurons and/or their myelin sheath, which worsen over time and present with dysfunction. The neurodegenerative disease has various pathogenic factors, such as oxidative stress, mitochondrial dysfunction, immunoinflammation and the like, and has good treatment effect on improving symptoms of patients with neurodegenerative diseases and conditioning brain functions by utilizing the advantages of multiple ways and multiple targets for treatment. The pathological changes accompanying the onset of neurodegenerative diseases are irreversible, when the cognitive disorder occurs in a patient, the course of the disease usually reaches the middle and late stages, and at the moment, the treatment can only slow down the development of the disease and cannot radically reverse the damage of a neural network. Therefore, the neurodegenerative disease should be diagnosed and treated as early as possible to prevent further development of the disease.
With the aging of the world population, senile dementia becomes one of the major diseases threatening the late life of the elderly. In 2019, nearly 5000 million people worldwide have AD, and by 2050, it is expected that the number of people will increase to 1.52 hundred million, and the vast majority of elderly people are over 65 years old. Currently the global total expenditure on AD has exceeded $ 1 trillion. In addition to the number of patients, the number of deaths due to stroke, aids and heart disease decreased between 2000 and 2018 due to the aggravation of aging development and the lack of therapeutic strategies, while the number of deaths due to AD increased 146.2%. According to the statistics of the civil bureau, 13.26 percent of the general population of China is the elderly over 60 years old, and the elderly have entered into the aging society. China is also the first country of the number of people suffering from AD at present, and more than 700 thousands of people suffer from AD at present and continue to increase rapidly. AD patients require long-term, patience care and are associated with severe mental symptoms. The annual cost per AD patient is approximately $ 2 million, and the national annual socioeconomic AD cost is $ 1677.4 million. Therefore, AD imposes a heavy economic burden on society and households. Senile dementia (AD) is a progressive neurodegenerative disease with memory loss, cognitive decline, and decline in daily living ability as its major clinical manifestations. The pathogenesis of the disease is complex and unclear, and various hypotheses exist, such as neurotransmitter deficiency, free radical damage, inflammatory reaction, amyloid protein, neurotoxic action, apoptosis, hormone deficiency and the like. Known pathological features of senile dementia include: senile plaque with beta-amyloid (A beta) aggregation appears outside brain nerve cells, neurofibrillary tangle formed by Tau protein abnormal aggregation in brain nerve cells, regional nerve cell death and the like.
Parkinson Disease (PD) is the second most common neurodegenerative disease with prevalence rates of up to 2-3% in people over 65 years of age. The neuropathological features of PD are loss of dopaminergic neuron death and aggregation of α -synuclein within dopaminergic neurons in the substantia nigra region of the midbrain. The molecular pathogenesis underlying PD involves a variety of pathways and mechanisms: alpha-synuclein aggregation, mitochondrial dysfunction, oxidative stress, calcium homeostasis imbalance, and the like.
The diagnosis and treatment of neurodegenerative diseases have made great progress, but far from meeting clinical requirements, such as senile dementia, several compounds which take acetylcholinesterase (AChE) as a target point are developed to improve the level of acetylcholine in brain, such as tacrine, donepezil, rivastigmine, galantamine and the like, but the medicaments can only relieve the disease symptoms, and the glutamate protectant memantine developed later can only simply relieve the disease symptoms. Researchers have made progress in recent years in elucidating the key aspects of the mechanism of neurodegenerative diseases, and despite the difficulties faced in the study of therapeutic regimens, new therapeutic strategies are still actively being developed and tested, and new drugs are constantly being sought.
Aildenafil citrate (Aildenafil citrate), chemical name: 1- [3- (6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4, 3-d)]Pyrimidin-5-yl) -4-ethoxybenzenesulfonyl radicals]-cis-3, 5-dimethylpiperazine citrate of the formula: c23H32N6O4S·C6H8O7Molecular weight: 680.73, chemical structural formula:
is effective in treating male Erectile Dysfunction (ED).
Chinese patent (application No. 02100198.7) discloses aildenafil and its preparation method, but does not relate to citric acid aildenafil crystal form and its preparation method.
In the process of researching and preparing the citric acid alidenafil, the inventor discovers that the citric acid alidenafil has polymorphism, such as CN101671337A, CN101671339A, CN101691372A, CN101671338A, CN101698668A, CN101830903A and the like, respectively researches the crystal form A, B, C, D, O, V of the citric acid alidenafil, and the inventor has obtained invention patents.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide the application of the citric acid alidenafil in the preparation of medicines for treating neurodegenerative diseases. Neurodegenerative diseases refer to chronic neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, different types of spinocerebellar ataxia, and so on.
In order to achieve the purpose, the invention adopts the following technical scheme: an application of a medicine for treating chronic neurodegenerative diseases, which is prepared by using a compound with a structure shown in a formula I, namely a citric acid alidenafil compound as a medicinal raw material.
Further, the treatment of chronic neurodegenerative diseases includes the treatment of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, various types of spinocerebellar ataxia drugs.
Further, the treatment of chronic neurodegenerative diseases includes treatment of Alzheimer disease and Parkinson disease.
Further, the medicinal raw material citric acid alidenafil compound with the structure of the formula 1 comprises citric acid alidenafil crystal form A, B, C, D, V, O compound.
The invention has the beneficial effects that: the invention provides an application of citric acid alidenafil in the preparation of drugs for treating neurodegenerative diseases; neurodegenerative diseases refer to chronic neurodegenerative diseases including alzheimer's disease, parkinson's disease, huntington's disease, amyotrophic lateral sclerosis, different types of spinocerebellar ataxia, and the like; the citric acid alidenafil has wide application prospect in preparing medicines for treating neurodegenerative diseases and treating neurodegenerative diseases.
Detailed Description
The present invention will be further described with reference to the following examples for facilitating understanding of those skilled in the art, and the description of the embodiments is not intended to limit the present invention.
Pharmacodynamic test 1:
(I) test materials
1. Laboratory animals and groups
(1) Laboratory animal
Kunming mouse, male, initial body weight 20 + -2 g, provided by university of Dalian medical laboratory animal center, certification number: SCXK (Liao) 2008 + 0002.
(2) Feeding conditions
Feeding in SPF environment at 22 + -3 deg.C and 50% humidity for 12 h.
(3) Grouping of laboratory animals
After 3 days of adaptive feeding, mice were grouped by random number table method: blank control group, model group, alidenafil group, and citric acid alidenafil (crystal form A-D, crystal form V, crystal form O), each group contains 10.
2. Main reagent and experimental medicine
Scopolamine hydrobromide, shanghai standing grain pharmaceuticals, inc; the preparation is prepared from Aidinafei and Aidinafei citrate (A-D crystal form, V crystal form and O crystal form), and the dosage is 10 mg/kg.
3. Main instrument
The mouse dark-avoiding reflection box, the institute of medicine of Chinese medical science institute; the institute of the Chinese medical science institute of science and technology of mouse diving tower reflection case; the Morris Water maze institute of Med of Chinese academy of sciences; BOM-EXBP-0001 animal behavior trace analysis System, Noldus, Netherlands.
(II) Experimental methods and results
1. Establishment of mouse model for senile dementia
Experiments adopt a method of injecting scopolamine hydrobromide into the abdominal cavity, and the senile dementia animal model is established by inhibiting M receptors to cause the change of central cholinergic system functions. On the 7 th day of drug intervention, after 30 minutes of gavage, scopolamine hydrobromide (2mg/kg) was injected intraperitoneally into each group of mice except the blank control group, which was injected with an equal volume of normal saline.
2. Pharmaceutical intervention
After adaptive feeding for three days, the Aidinafei group and the Aidinafei citrate (A-D crystal form, V crystal form and O crystal form) are respectively and correspondingly administered to each treatment group, the dosage is 10mg/kg, and the blank control group and the model group are administered with physiological saline with the same volume for 1 time every day for 15 days continuously.
3. Behavioural test
(1) Dark avoidance experiment
On the 7 th day of drug intervention, after 30min of gavage administration, scopolamine hydrobromide (2mg/kg) was injected intraperitoneally into mice of each group except the blank control group, and an equal volume of normal saline was injected intraperitoneally into the blank control group. After 10min, putting the mouse into a reaction box to adapt for 3min, then electrifying a copper grid at the bottom of a dark room, putting the mouse back to the opening into a bright room, carrying out the experiment for 5min, putting the mouse which does not enter the dark room within 5min into the dark room, and receiving electric shock for 3s, wherein the training process is carried out; after training is finished for 24 hours, the mouse is placed in a bright room with the back opposite to the opening, the time (latency) when the mouse enters the dark room for the 1 st time and the number of times (error number) when the mouse enters the dark room within 5min are recorded, the latency of the mouse which does not enter the dark room within 5min is counted according to 300s, and the test process is shown.
As a result: compared with a blank control group, the average incubation period of the mice in the model group is obviously shortened, the error frequency is obviously increased (P is less than 0.01), and the scopolamine hydrobromide can cause the learning and memory disorder of the mice. The idenafil group and the idenafil citrate (A-D crystal form, V crystal form and O crystal form) have an improvement effect on mouse dysmnesia caused by scopolamine hydrobromide, which is shown in that the latency of the idenafil group and the idenafil citrate in 6 different crystal form groups is obviously prolonged and the error frequency is obviously reduced compared with a model group mouse; moreover, the 8 groups were compared pairwise with no significant difference (P > 0.05).
Each incubation period and number of errors (n ═ 10; x ± s)
| Group of | Incubation period(s) | Number of mistakes (times) |
| Blank control group | 296.34±14.84 | 0.11±0.32 |
| Model set | 44.77±29.86 | 4.26±1.34 |
| Edinafil group | 197.61±99.13 | 0.66±0.51 |
| Aidinafei citrate (A crystal form) | 256.93±64.88 | 0.33±0.56 |
| Aidinafei citrate (B crystal form) | 254.32±65.61 | 0.36±0.13 |
| Aidinafei citrate (C crystal form) | 250.01±77.89 | 0.40±0.58 |
| Aidinafei citrate (D crystal form) | 248.35±80.44 | 0.44±0.23 |
| Aidinafei citrate (V crystal form) | 251.11±87.34 | 0.39±0.56 |
| Aidinafei citrate (O crystal) | 240.56±71.15 | 0.42±0.47 |
(2) Diving platform experiment
After 30min of intragastric administration, the blank control group was injected with an equal volume of normal saline and the other groups were injected with scopolamine hydrobromide 2 mg/kg. After 10min, the mouse is placed in a box to freely move for 5min, the environment is familiar, then a metal rod at the bottom of the box is electrified with alternating current, the mouse receives electric shock stimulation, the experiment lasts for 5min, the mouse is not placed on the platform within 5min, the mouse is guided to the platform, the mouse is tested after 24h, the mouse is placed on the platform and is electrified simultaneously, the time (latency period) for jumping off the platform for the first time and the times (error times) for jumping off the platform within 5min are recorded, and therefore the memory capacity of the mouse is reflected.
As a result: compared with a blank control group, the average latency of the mice in the model group is shortened, and the error frequency is increased (P < 0.01). In the test of the next day, compared with the model group, the incubation period of mice in the Aidinafei group and Aidinafei citrate (A-D crystal form, V crystal form and O crystal form) 7 different crystal form groups is obviously prolonged, and the error frequency is obviously reduced; moreover, the 8 groups were compared pairwise with no significant difference (P > 0.05).
Latency and number of errors (n 10; x ± s)
| Group of | Incubation period(s) | Number of mistakes (times) |
| Blank control group | 300.00±0.00 | 0.00±0.00 |
| Model set | 22.49±15.69 | 3.92±1.44 |
| Edinafil group | 186.92±91.61 | 0.89±0.62 |
| Aidinafei citrate (A crystal form) | 218.98±52.34 | 0.66±0.46 |
| Aidinafei citrate (B crystal form) | 201.65±50.78 | 0.71±0.52 |
| Aidinafei citrate (C crystal form) | 209.46±53.18 | 0.68±0.52 |
| Aidinafei citrate (D crystal form) | 213.28±51.46 | 0.65±0.56 |
| Aidinafei citrate (V crystal form) | 215.01±53.87 | 0.78±0.66 |
| Aidinafei citrate (O crystal) | 211.63±51.24 | 0.75±0.67 |
(3) Water maze experiment
The water temperature was maintained at 26 + -1 deg.C for 5 days, and the platform was located in the middle of one quadrant, 1cm below the water surface. During the experiment, the room is kept quiet, the temperature is kept at about 25 ℃, the light is soft, and the surrounding reference objects are kept unchanged. 30min after the administration by gavage, 10min before the experiment, except for the blank control group, the other groups were injected with scopolamine hydrobromide 2mg/kg in the abdominal cavity, and the blank control group was injected with normal saline with the same volume in the abdominal cavity.
1) Experiment of location navigation
The 1 st day of the water maze experiment is adaptive training, the platform in the pool is removed, a mouse can freely swim in the pool for 120s, the following 4 days are trained for 4 times every day, the training interval is 60s every time, a water inlet point is randomly selected to be filled with water (four times are filled with water from four quadrants respectively) during training, the mouse is placed in the water facing to the pool wall, the mouse is forced to learn to search the platform arranged below the water surface, the time (latency) required for searching the platform in 120s and the swimming distance are recorded, if the mouse cannot find the platform in 120s, the mouse is guided to the platform and stays at the platform for 60s, and the latency is recorded as 120 s.
2) Experiment of space exploration
And on the 5 th day of the water maze experiment, after the positioning navigation experiment is completed, removing the platform from the pool, putting the experimental animal into the water from the opposite side of the quadrant where the original platform is positioned, and recording the time of reaching the original platform for the first time and the times of crossing the position of the original platform in 120 s.
As a result: the mean latency and swimming distance of the mice were significantly longer in the model group compared to the blank control group (P < 0.01). Compared with the model group, the average latency and the swimming distance of the mice in the Aidinafil group and the Aidinafil citrate A crystal form group are obviously shortened, and the average latency and the swimming distance of the mice among 2 groups have no obvious difference (P is more than 0.05).
Latency(s) in Water maze experiments for groups of mice (n ═ 10; x. + -. s)
The swimming distance (cm) of each group of mice in the water maze experiment (n ═ 10; x ± s)
| Group of | The next day | The fifth day |
| Blank control group | 1110.01±400.72 | 350.74±190.94 |
| Model set | 1990.55±474.66 | 1601.44±530.67 |
| Edinafil group | 1355.65±466.23 | 943.21±380.17 |
| Aidinafei citrate (A crystal form) | 1310.73±440.27 | 930.69±395.34 |
Compared with the blank control group mouse, the time for the model group mouse to reach the original platform for the first time is obviously prolonged (P <0.01), and the shuttle frequency of the mouse at the original platform position is obviously reduced (P <0.01), which indicates that the scopolamine hydrobromide damages the space memory capability of the mouse. The first time that the Aidinafil group and Aidinafil citrate A crystal form mice reach the original platform is obviously shortened, and the shuttling times of the mice at the original platform are obviously increased compared with those of the model group mice (P < 0.01). The first arrival time of the Aidinafei group mice and the Aidinafei A citrate crystal form group mice and the shuttle frequency of the original platform position have no significant difference (P is more than 0.05).
The movement locus diagram shows that the movement locus of mice in the blank control group, the alidenafil group and the citric acid alidenafil A crystal form group is clear, and the movement locus of the mice in the model group is disordered.
First time to reach original platform time and shuttle times (n is 10; x + -s)
| Group of | Time(s) | Number of shutdowns (times) |
| Blank control group | 19.44±11.13 | 5.28±2.17 |
| Model set | 70.98±38.16 | 1.21±0.79 |
| Edinafil group | 32.86±16.77 | 3.42±1.54 |
| Aidinafei citrate (A crystal form) | 29.11±13.44 | 3.57±1.49 |
Pharmacodynamic test 2:
selecting 50 healthy SD male rats with SPF grade, Daihai Bai Yitong Biotechnology limited company, animal license number SCXK (Guangdong) 2020-. All rats are fed with conventional feed, water is freely drunk, black/white illumination is alternated for 12 hours, the temperature is 20-25 ℃, and the humidity is 40-50%.
Parkinson disease model establishment
10 rats of 50 rats are randomly selected and divided into normal groups, the rest 40 rats are selected according to a rat brain stereotaxic map, the right side substantia nigra compacta part and the midbrain ventral dorsal cap part of the rat are injected with 20 mu g of 6-hydroxyDA solution, and the rat is repeatedly injected with Apomorphine (APO) of 0.5mg/kg in the abdominal cavity at the 2 nd to 7 th week. And (3) the success standard of the model is that the circle-turning experiment is completed by intraperitoneal APO induction, when the rat starts to rotate, the time is 30min, and the circle-turning per minute is more than 7 circles, which represents that the model is successfully established.
Grouping and intervention
30 model rats were randomly divided into a model group, an aildenafil group and an aildenafil form a group, 10 each. The administration of 10mg/kg for the edenafil group and the edenafil crystal form A group is performed with intragastric intervention, the administration of equal volume of physiological saline for the normal group and the model group is performed with intragastric intervention, the times/d are 1, and the continuous intervention is 8 w.
Experiment of water maze
Evaluating the learning and memory ability of the rat through a water maze experiment, and positioning navigation, wherein the experiment time is 5d, the experiment time is divided into two time periods every day, the training is carried out for 4 times, the interval time is more than 2h each time, the center of one quadrant is selected as a water entry point of the rat, and the time (the escape latency) of the rat for recording the platform time of the rat from entering water and climbing water is counted; rats failed to find the platform within 120s, required manual guidance, and stayed on the platform for 15s, with an escape latency time of 120 s. On the 5 th day of the experiment, the concealed platform was removed, the rat was placed in water for 120s, and the number of times the rat crossed the platform was counted.
As a result:
compared with the normal group, the model group, the idenafil group and the idenafil crystal form A group have prolonged escape latency, reduced platform crossing times and statistical difference (P is less than 0.05). Compared with the model group, the idenafil group and the idenafil crystal form A group have the advantages of short escape latency, reduced number of turns, increased platform crossing times and statistical difference (P is less than 0.05).
Comparison of the number of revolutions and the water maze test (x + -s, n is 10)
Senile dementia and Parkinson's disease are chronic degenerative diseases, and the preferred administration route of the pharmaceutical composition is oral administration. The dosage forms comprise tablets, granules, capsules, sustained-release tablets, sustained-release pellets and the like. Preferably tablet, granule, and capsule.
Capsule containing citric acid alidenafil crystal form A
Prescription: 60 g of citric acid alidenafil crystal form A, 50 g of starch, 40 g of lactose, 10 g of sucrose, 35 g of microcrystalline cellulose, a proper amount of 10% polyvinylpyrrolidone ethanol solution and 1 g of magnesium stearate, and 1000 granules are prepared.
The process comprises the following steps: sieving the citric acid alidenafil crystal form A and the auxiliary materials with a 80-mesh sieve, weighing according to the prescription amount, preparing into proper granules by using a polyvinyl pyrrolidone ethanol solution with 10 percent as an adhesive through a 16-mesh sieve, drying at 65 ℃, grading with a 14-mesh sieve, adding magnesium stearate, uniformly mixing, measuring the content of the granules, calculating the loading amount, and filling into capsules.
Tablets containing crystalline form A of Aidenafil citrate
Prescription: 70 g of citric acid alidenafil crystal form A, 5 g of microcrystalline cellulose, 140 g of lactose, 10 g of PEG-4000, 1 g of magnesium stearate, 14 g of povidone K30, 10 g of croscarmellose sodium and a proper amount of distilled water, and the tablets are prepared into 1000 tablets.
The process comprises the following steps: pulverizing PEG-4000 and crystalline form A of citric acid aildenafil together, sieving with 80 mesh sieve, mixing with other materials, making soft material with distilled water, granulating with 16 mesh sieve, drying at 40-45 deg.C in drying oven, grading with 16 mesh sieve, adding magnesium stearate into the dried granules, mixing, and tabletting.
The pharmaceutical composition contains citric acid alidenafil in an amount of 50-70 mg per unit dosage form.
The invention provides an application of citric acid alidenafil compound as medicine raw material for preparing medicine for treating chronic neurodegenerative diseases, and citric acid alidenafil has wide application prospect in preparing medicine for treating neurodegenerative diseases and treating neurodegenerative diseases.
The above description is only a part of the description of the present invention, and for those skilled in the art, there may be variations in the embodiments and applications of the concept of the present invention, and the description should not be construed as limiting the present invention.
Claims (3)
1. The application of a medicament for treating chronic neurodegenerative diseases is characterized in that: the application of the medicine for treating chronic neurodegenerative diseases, which is prepared by using the compound with the structure of the formula I, namely the citric acid alidenafil compound, as a medicinal raw material.
2. The use of a medicament according to claim 1 for the treatment of chronic neurodegenerative diseases, wherein: the chronic neurodegenerative disease treatment comprises the treatment of Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and different types of spinocerebellar ataxia drugs.
3. The use of a medicament according to claim 1 for the treatment of chronic neurodegenerative diseases, wherein: the treatment of chronic neurodegenerative diseases comprises the treatment of Alzheimer disease and Parkinson disease.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115054585A (en) * | 2022-07-11 | 2022-09-16 | 北京悦康科创医药科技股份有限公司 | Tablets containing Aidenafil citrate and preparation method and application thereof |
| CN115813862A (en) * | 2022-12-14 | 2023-03-21 | 北京悦康科创医药科技股份有限公司 | Granules containing Aidenafil citrate as well as preparation method and application thereof |
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2021
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115054585A (en) * | 2022-07-11 | 2022-09-16 | 北京悦康科创医药科技股份有限公司 | Tablets containing Aidenafil citrate and preparation method and application thereof |
| CN115054585B (en) * | 2022-07-11 | 2022-11-18 | 北京悦康科创医药科技股份有限公司 | Tablets containing Aidenafil citrate and preparation method and application thereof |
| CN115813862A (en) * | 2022-12-14 | 2023-03-21 | 北京悦康科创医药科技股份有限公司 | Granules containing Aidenafil citrate as well as preparation method and application thereof |
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