CN113185569A - Ephedrine derivative for protecting nerve and preparation method thereof - Google Patents
Ephedrine derivative for protecting nerve and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an ephedrine derivative for protecting nerves and a preparation method thereof, wherein the preparation method comprises the following steps: adding ursolic acid, hydrolyzing to obtain intermediate product, and dehydrating with ephedrine in organic solvent to obtain ephedrine derivative with ether bond; the ephedrine derivative avoids the side effects of ephedrine, and has better effects of protecting nerve injury and improving memory function than single use of ephedrine; the derivative has the characteristics of simple operation process, cheap and easily obtained raw materials, short preparation period, easy control, small environmental pollution and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and relates to an ephedrine derivative for protecting nerves and a preparation method thereof.
Background
Ephedrine, belonging to alkaloid compounds, is widely present in ephedra. Ephedrine is alkaloid extracted from herba Ephedrae, is sympathetic excitatory amine, can activate alpha and beta receptors, directly improve norepinephrine receptor activity, and can significantly reduce damage of ischemia and anoxia on hippocampal nerve cells. However, the ephedrine is a limited dose of medicine, and patients taking a large amount of ephedrine for a long time can cause symptoms such as mental excitation, insomnia, palpitation, headache, blood pressure increase, etc., serious patients cause heart rate disorder, inhibit heart, even cause reversal reaction and secondary vasodilatation, generate drug dependence, and form drug-induced rhinitis for a long time.
Disclosure of Invention
In order to solve the above technical problems, the present invention provides a neuro-ephedrine derivative, which has a molecular structure of formula (I):
one object of the present invention is to provide a method for preparing ephedrine derivatives for protecting nerves, which comprises the following steps:
(1) weighing a certain amount of ursolic acid, placing the ursolic acid in a reactor, slowly adding concentrated sulfuric acid under the condition of ice-water bath, stirring and reacting for 2.5-4.5 h in ice bath, heating to 85-100 ℃ after the reaction is finished, stirring and reacting for 3-5 h under the action of acid, filtering, extracting filtrate with diethyl ether or dichloromethane, concentrating a water phase, extracting with propylene glycol diethyl ether, combining organic phases, concentrating and drying to obtain the ursolic acid;
(2) dissolving the product obtained in the step (1) in dipropylene glycol dimethyl ether, sequentially adding ephedrine and ferrierite, raising the temperature to 100-120 ℃, carrying out reflux reaction for 4-6 h, adding ice water to quench the reaction, sequentially washing the reaction liquid with sodium bicarbonate solution and water, filtering, and drying the filtrate with anhydrous magnesium sulfate to obtain a crude product; and (2) performing elution chromatography on the crude product by adopting a reverse phase silica gel column, wherein the mass ratio of a silica gel filler in the reverse phase silica gel column to the crude product is 1.8:1, eluting by using methanol-water mixed liquor with the volume ratio of 100:15, 85:20, 70:25, 55:30 and 40:35, collecting eluent with the methanol-water volume ratio of 85:20, concentrating under reduced pressure, and freeze-drying to obtain the target product.
In the preparation method, in the step (1), the concentration of the concentrated sulfuric acid is 78-98% by mass;
the acid is hydrochloric acid, formic acid, trifluoroacetic acid, acetic acid or methanesulfonic acid;
in the preparation method, in the step (2), the organic solvent is cyclohexanediol monomethyl ether, dipropylene glycol dimethyl ether, propylene glycol methyl ether, diethyl ether or dichloromethane;
the catalyst is gamma-alumina, ferrierite or calcium phosphate;
the silica gel column adopts a reverse phase silica gel column, and the filler of the silica gel column is C18 alkylsilane bonded silica gel; and/or the mass ratio of the silica gel filler in the reversed phase silica gel column chromatography to the crude product is 1.8-3.0: 1; and/or the eluent is a methanol-water mixed solution, wherein the volume ratio of methanol to water is 100:15, 85:20, 70:25, 55:30 and 40: 35; the eluent was collected at a methanol-water volume ratio of 85: 20.
According to a preferred embodiment of the above preparation method, the method comprises the following steps:
(1) weighing a certain amount of ursolic acid, placing the ursolic acid in a reactor, slowly adding 98% concentrated sulfuric acid by mass fraction under the ice-water bath condition, stirring and reacting for 3.5-4.5 h in an ice bath, heating to 95-100 ℃ after the reaction is finished, adding 10-15% hydrochloric acid solution by volume fraction, stirring and reacting for 3-5 h, filtering, extracting the filtrate with diethyl ether or dichloromethane, concentrating the water phase, extracting with propylene glycol diethyl ether, combining the organic phases, concentrating and drying to obtain the ursolic acid;
(2) dissolving the product obtained in the step (1) in dipropylene glycol dimethyl ether, sequentially adding ephedrine and ferrierite, raising the temperature to 100-120 ℃, carrying out reflux reaction for 4-6 h, adding ice water to quench the reaction, sequentially washing the reaction liquid with sodium bicarbonate solution and water, filtering, and drying the filtrate with anhydrous magnesium sulfate to obtain a crude product; and (2) performing elution chromatography on the crude product by adopting a reverse phase silica gel column, wherein the mass ratio of a silica gel filler in the reverse phase silica gel column to the crude product is 1.8:1, eluting by using methanol-water mixed liquor with the volume ratio of 100:15, 85:20, 70:25, 55:30 and 40:35, and performing decompression concentration and freeze drying on the eluent with the methanol-water volume ratio of 85:20 to obtain the target product.
The derivative is used for protecting nerve injury.
Compared with the prior art, the invention has the beneficial effects that:
the ephedrine derivative with a novel structure is prepared by combining the ephedrine and the ursolic acid, and the novel compound avoids the side effect of the ephedrine and has better effect of protecting nerve injury than the ephedrine which is used alone; novel compound p-Abeta25-35Has protective effect on SH-SY5Y cell injury, and can improve A beta1-42Memory function of mice with dysmnesia caused by scopolamine, cyclohexylidene amide and D-galactoseCan promote the synthesis of memory protein of the brain of the mouse and improve the learning memory and cognitive function of the mice with the consolidation disorder; the compound has the characteristics of simple operation process, cheap and easily obtained raw materials, short preparation period, easy control, small environmental pollution and suitability for industrial production.
Drawings
FIG. 1: example 1 is nuclear magnetic resonance hydrogen spectrum of ephedrine derivative for protecting nerve.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments for the purpose of making the objects, technical solutions and advantages of the present invention more apparent, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples.
Example 1
(1) Weighing 20.5g of ursolic acid, placing the ursolic acid in a reactor, slowly adding 98% concentrated sulfuric acid by mass fraction under the condition of ice-water bath, stirring and reacting for 3.5-4.5 h in ice bath, heating to 95-100 ℃ after the reaction is finished, adding 10-15% hydrochloric acid solution by volume fraction, stirring and reacting for 3-5 h, filtering, extracting filtrate with diethyl ether or dichloromethane, concentrating a water phase, extracting with propylene glycol diethyl ether, combining organic phases, concentrating and drying to obtain the ursolic acid;
(2) dissolving the product obtained in the step (1) in dipropylene glycol dimethyl ether, adding 13.5g of ephedrine, adding ferrierite, raising the temperature to 100-120 ℃, carrying out reflux reaction for 4-6 h, adding ice water to quench and react, washing the reaction liquid with sodium bicarbonate solution and water in sequence, filtering, and drying the filtrate with anhydrous magnesium sulfate to obtain a crude product; and (2) performing elution chromatography on the crude product by adopting a reverse phase silica gel column, wherein the mass ratio of a silica gel filler in the reverse phase silica gel column to the crude product is 1.8:1, eluting by using methanol-water mixed liquor with the volume ratio of 100:15, 85:20, 70:25, 55:30 and 40:35, collecting eluent with the methanol-water volume ratio of 85:20, concentrating under reduced pressure, and freeze-drying to obtain the target product. The yield was 76.82%.
And (3) nuclear magnetic resonance hydrogen spectrum detection:
the sample was placed in a sample tube, and 0.5ml of DCL3 (deuterated chloroform) was injected into the sample tube with a syringe to dissolve the sample sufficiently. The sample and the reagent are required to be fully mixed, the solution is clear and transparent, and has no suspended matters or other impurities, and a nuclear magnetic resonance hydrogen spectrogram is obtained through nuclear magnetic resonance identification, and the result is shown in figure 1.
Experimental example 2 neuroprotective study of ephedrine derivatives in rats
1. Ephedrine derivative pair Abeta25-35Protective effect of SH-SY5Y cell injury
(1) Ephedrine derivative pair Abeta25-35Protective effect of SH-SY5Y cell injury
The ephedrine derivative of example 1 was used for the experiment. SH-SY5Y cells at 1X 10 per well4The cells were seeded in 96-well plates and cultured in DMEM/F12 medium containing 10% fetal bovine serum at 37 deg.C with 5% by volume CO2Culturing in an incubator. Cells were divided into 5 groups: normal control group (control group 1), model control group (control group 2), ephedrine derivative control group (experimental group, dosage 20. mu. mol/L), ephedrine group (control group 3, dosage 40. mu. mol/L), and ursolic acid group (control group 4, dosage 40. mu. mol/L). When the fusion rate of each group of cells reaches 80%, the culture solution is changed to contain the corresponding drugs and 20 mu mol/L condensed Abeta25-35The serum-free medium was continued for 24 hours. The MTT method measures the cell activity and calculates the relative survival rate of each cell, and the results are shown in Table 1.
TABLE 1 ephedrine derivative vs. Abeta25-35Protective effect of SH-SY5Y cell injury
The results in table 1 show that, compared with the model group, the relative survival rate of the ephedrine derivative to SH-SY5Y cells is significantly improved, and the effect is superior to that of the ursolic acid control group and the ephedrine control group, which indicates that the ephedrine derivative has stronger protective effect on nerve cell injury, and is more significant than that of ephedrine or ursolic acid when used alone.
(2) Ephedrine derivative pair Abeta1-42Influence of brain ventricle injection dementia rat model on learning and memory
Taking healthy SD rat, injecting Abeta into ventricle1-42And (3) molding, injecting the same amount of normal saline into a normal control group, and performing Morrist water maze and diving platform experiments to perform learning and memory behavioural detection 6 days after molding so as to evaluate whether molding is successful. After successful model evaluation, rats were randomly grouped as follows: normal control group (control group 1), model group (control group 2), positive drug group (control group 3), ephedrine group (control group 4), ursolic acid group (control group 5), experiment group, drug group is irritated and fed to administer corresponding drug, normal control group and model control group administer equivalent normal saline, administer for 6 days continuously. The learning and memory abilities of rats in each group are measured by the Morrist water maze and rat diving platform experiment, and the results are shown in tables 2 and 3.
TABLE 2 ephedrine derivatives vs. Abeta1-42Influence of brain ventricle injection dementia rat model on learning and memory
TABLE 3 ephedrine derivatives vs. Abeta1-42Rat diving platform experimental influence of dementia caused by ventricular injection
The escape period and the average search distance of the model group rat Morrist water maze experiment are obviously increased, the escape latency and the error times in the diving platform experiment are also obviously increased, and the result shows that the rat ventricles inject Abeta1-42Then, the traditional Chinese medicine shows obvious dementia symptoms, and the cognitive learning ability is obviously reduced. From table 2, the results of Morrist water maze experiment show that: on the 3 rd day of training, compared with the model group, the escape latency of rats in the positive drug group and the experimental group is obviously reduced, and the ephedrine group and the ursolic acid group have no obvious change; by the 4 th day of training, the escape latency of the rats in the experimental group is significantly less than that of the model group, and the ephedra herb is presentThe alkali group, the ursolic acid group and the model group have obvious changes; training to the 5 th day, compared with the model group, the average search distances of rats in the positive drug group and the experimental group are reduced to different degrees, and the average search distances of the ephedrine group and the ursolic acid group are not obviously different from those of the model group; on the 6 th day of training, compared with the model group, the escape latency and the average search distance of rats in each drug group are reduced to different degrees, wherein the effect of the experimental group is more obvious, is equivalent to that of the positive drug group and is superior to that of the ephedrine group and the ursolic acid group; in the jump table experiment: the residence latency of rats in each drug group is obviously increased compared with that in the model group, the escape latency is obviously reduced, the experimental group and the positive drug group are superior to the ephedrine group and the ursolic acid group, the number of platform skipping errors of each drug group is reduced to a different degree compared with that of the model group, and the number of errors of the experimental group and the positive drug group is reduced to a different degree compared with that of the ephedrine group and the ursolic acid group. The results of rat cognitive function and learning memory test show that the ephedrine derivative in the experimental group can obviously reduce Abeta1-42The dementia-causing rat water maze escape latency and average search distance, increase the stay latency of the rat diving platform experiment, reduce the escape latency and error times of the diving platform experiment, and the effect is superior to the independent action of ephedrine and ursolic acid.
2. Memory improvement effect of ephedrine derivative on scopolamine induced memory acquisition disorder mice
Taking healthy mice, carrying out intraperitoneal injection on scopolamine for molding according to the dose of 1mg/kg, and injecting the same amount of normal saline into a normal control group. After 6 days, Morrist water maze and diving platform experiments are carried out to carry out learning and memory behavioural detection so as to evaluate whether the molding is successful. After successful model evaluation, rats were randomly grouped as follows: the drug group is fed with corresponding drugs, and the normal control group and the model control group are given with the same amount of normal saline for continuous administration for 6 days. The learning and memory abilities of rats in each group are measured by the Morrist water maze and rat diving platform experiment, and the results are shown in tables 4 and 5.
TABLE 4 Effect of ephedrine derivatives on scopolamine-induced memory acquisition in the Morrist Water maze experiment in mice
TABLE 5 Effect of ephedrine derivatives on scopolamine-induced memory gain in mouse diving platform experiment
Compared with a normal group, the escape latency and the average search distance of the Morrist water maze experiment of the mouse in the model group are obviously increased, the stay latency in the jump bench experiment is obviously reduced, the escape latency and the error times are also obviously increased, and the results show that after the mouse is injected with scopolamine in the abdominal cavity, the cholinergic nerve pathway M receptor is blocked, the cholinergic nerve function of the mouse is inhibited, and the learning, working and memory damage of the mouse occurs. After the drugs are given, the mouse Morrist water maze experiment has different degrees of reduction in escape latency and average search distance, wherein the experiment group and the positive drug group have more obvious reduction. In the diving platform experiment, compared with the model group, the residence latency of mice in the experimental group, the positive drug group, the ephedrine group and the ursolic acid group is increased, the escape latency is reduced, and the error frequency is reduced. The results show that the ephedrine derivative can improve the function of the cholinergic nerve of the brain center of the mouse, improve the learning and working memory capacity of the mouse with the memory acquisition disorder caused by the cholinergic nerve damage, and has better effect than the single use of the ephedrine or the ursolic acid.
3. Memory improvement effect of ephedrine derivative on cyclohexylidene amide induced memory acquisition disorder mice
Healthy mice were selected and injected with cyclohexylidene amide intraperitoneally, and normal groups were injected with the same amount of physiological saline. After 6 days, Morrist water maze and diving platform experiments are carried out to carry out learning and memory behavioural detection so as to evaluate whether the molding is successful. After successful model evaluation, rats were randomly grouped as follows: the drug group is fed with corresponding drugs, and the normal control group and the model control group are given with the same amount of normal saline for continuous administration for 6 days. The learning and memory abilities of rats in each group are measured by the Morrist water maze and rat diving platform experiment, and the results are shown in tables 6 and 7.
TABLE 6 Effect of ephedrine derivatives on memory acquisition by cycloheximide in Morrist Water maze experiment in mice
TABLE 7 Effect of ephedrine derivatives on the acquisition of memory by cycloheximide in a mouse diving bench test
Proteins are the motive force for brain cell division activities because a large part of brain cells are collagen cells, which are composed of collagen, and these collagen not only constitute brain cells, but also form the blood brain barrier, thus effectively protecting the brain, and the memory decline is related to the shortage of proteins in the human body. Cyclohexylidene amide is a protein synthesis inhibitor, which can block the formation of memory protein, and further influence brain learning and cognitive dysfunction. The escape latency and the average search distance of the model group mouse Morrist water maze experiment are obviously increased compared with the normal group, the stay latency in the jumping platform experiment is obviously reduced compared with the normal group, the escape latency and the error times are obviously increased, and the results show that the learning and memory ability of the mouse is reduced after the mouse is injected with the cyclohexylidene in the abdominal cavity, and the mouse modeling is successful. After the drug is given, compared with a model group, the Morrist water maze experiment of each group of mice with the drug has different degrees of escape latency and reduction of average search distance, wherein the effect of the experiment group is equivalent to that of a positive drug group and is superior to that of an ephedrine group and an ursolic acid group; after the drug is administered, compared with the model group, the residence latency of each mouse in the drug group in the jump bench experiment is obviously improved, the escape latency and the error frequency are reduced, wherein the effect of the drug group is basically equivalent to that of the positive drug group. The experimental results show that the ephedrine derivative can promote the synthesis of brain memory protein and improve the learning memory and cognitive functions of mice with memory consolidation disorder.
4. Memory improvement effect of ephedrine derivative on D-galactose-induced brain aging mice
Healthy mice were selected and injected subcutaneously with D-galactose, and normal control groups were injected with the same amount of physiological saline. After 6 days, Morrist water maze and diving platform experiments are carried out to carry out learning and memory behavioural detection so as to evaluate whether the molding is successful. After successful model evaluation, rats were randomly grouped as follows: the drug group is fed with corresponding drugs, and the normal control group and the model control group are given with the same amount of normal saline for continuous administration for 6 days. The learning and memory abilities of rats in each group are measured by the Morrist water maze and rat diving platform experiment, and the results are shown in tables 8 and 9.
TABLE 8 Effect of ephedrine derivatives on D-galactose induced memory acquisition in the Morrist Water maze experiment in mice
TABLE 9 Effect of ephedrine derivatives on D-galactose induced memory acquisition in mouse diving platform experiment
D-galactose can induce the model animal to generate oxidative stress reaction, thereby causing mitochondrial damage and neurodegenerative deformation, and further reducing the cognitive ability of the animal. As can be seen from the table, the escape latency and the average search distance of the Morrist water maze experiment of the mouse in the model group are greatly increased compared with those of the normal group, the stay latency in the jump bench experiment is obviously reduced compared with that of the normal group, and the escape latency and the error times are obviously increased, which shows that the learning and memory ability of the mouse is obviously reduced after the mouse is injected with D-galactose subcutaneously. After administration, the avoidance latency and the average search distance of the Morrist water maze test of the mice in the drug group are reduced by different degrees compared with those in the model group, wherein the reduction degree of the test group is more obvious, and the action effect is basically equivalent to that of the positive drug group. In the diving platform experiment, the retention latency of the drug group is obviously improved compared with that of the model group, the escape latency is obviously reduced, and the experimental group has a trend superior to that of positive drugs. The experimental results show that the ephedrine derivative can reduce neurotoxicity caused by oxidative stress injury, thereby slowing down the aging process, reducing the loss of cholinergic neurons, further improving neurodegenerative deformation and improving the cognitive ability of animals.
Claims (4)
1. A neuro-protective ephedrine derivative, characterized in that it has a molecular structure of formula (I):
2. a preparation method of ephedrine derivatives for protecting nerves is characterized by comprising the following steps:
(1) weighing a certain amount of ursolic acid, placing the ursolic acid in a reactor, slowly adding concentrated sulfuric acid under the condition of ice-water bath, stirring and reacting for 2.5-4.5 h in ice bath, heating to 85-100 ℃ after the reaction is finished, stirring and reacting for 3-5 h under the action of acid, filtering, extracting filtrate with diethyl ether or dichloromethane, concentrating a water phase, extracting with propylene glycol diethyl ether, combining organic phases, concentrating and drying to obtain the ursolic acid;
(2) dissolving the product obtained in the step (1) in an organic solvent, sequentially adding ephedrine and a catalyst, raising the temperature to 80-120 ℃, carrying out reflux reaction for 4-6 h, adding ice water to quench the reaction, sequentially washing the reaction liquid with a sodium bicarbonate solution and water, filtering, and drying the filtrate with anhydrous magnesium sulfate to obtain a crude product; purifying the crude product by silica gel column elution chromatography, collecting eluent, concentrating and drying to obtain a target product;
in the step (1), the concentration of the concentrated sulfuric acid is 78-98% by mass;
the acid is hydrochloric acid, formic acid, trifluoroacetic acid, acetic acid or methanesulfonic acid;
in the step (2), the organic solvent is cyclohexanediol monomethyl ether, dipropylene glycol dimethyl ether, propylene glycol methyl ether, diethyl ether or dichloromethane;
the catalyst is gamma-alumina, ferrierite or calcium phosphate;
the silica gel column adopts a reverse phase silica gel column, and the filler of the silica gel column is C18 alkylsilane bonded silica gel; and/or the mass ratio of the silica gel filler in the silica gel column chromatography to the crude product is 1.8-3.0: 1; and/or the eluent is a methanol-water mixed solution, wherein the volume ratio of methanol to water is 100:15, 85:20, 70:25, 55:30 and 40: 35; the eluent was collected at a methanol-water volume ratio of 85: 20.
3. The method of claim 2, comprising the steps of:
(1) weighing a certain amount of ursolic acid, placing the ursolic acid in a reactor, slowly adding 98% concentrated sulfuric acid by mass fraction under the ice-water bath condition, stirring and reacting for 3.5-4.5 h in an ice bath, heating to 95-100 ℃ after the reaction is finished, adding 10-15% hydrochloric acid solution by volume fraction, stirring and reacting for 3-5 h, filtering, extracting the filtrate with diethyl ether or dichloromethane, concentrating the water phase, extracting with propylene glycol diethyl ether, combining the organic phases, concentrating and drying to obtain the ursolic acid;
(2) dissolving the product obtained in the step (1) in dipropylene glycol dimethyl ether, sequentially adding ephedrine and ferrierite, raising the temperature to 100-120 ℃, carrying out reflux reaction for 4-6 h, adding ice water to quench the reaction, sequentially washing the reaction liquid with sodium bicarbonate solution and water, filtering, and drying the filtrate with anhydrous magnesium sulfate to obtain a crude product; and (2) performing elution chromatography on the crude product by adopting a normal-phase silica gel column, wherein the mass ratio of a silica gel filler in the normal-phase silica gel column to the crude product is 1.8:1, eluting by using methanol-water mixed liquor with the volume ratio of 100:15, 85:20, 70:25, 55:30 and 40:35, collecting eluent with the methanol-water volume ratio of 85:20, concentrating under reduced pressure, and freeze-drying to obtain the target product.
4. The derivative of claim 1 for use in protecting nerve damage.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1977951A (en) * | 2005-12-02 | 2007-06-13 | 北京科莱博医药开发有限责任公司 | Gastrodia elata plant extract for preventing senile dementia and its preparing method |
| CN101991564A (en) * | 2009-08-18 | 2011-03-30 | 杭州萨韦坦生物科技有限公司 | Production process for separating, extracting and purifying bioactive substance calcium nervonate and application thereof to treatment of Alzheimer's disease |
| CN104095849A (en) * | 2013-04-02 | 2014-10-15 | 中国医学科学院药物研究所 | Multiple-target effects of isoflavone derivative and its application in improvement of learning and memory |
| CN107998314A (en) * | 2018-01-31 | 2018-05-08 | 吉林修正药业新药开发有限公司 | A kind of Chinese medicine composition of kidney-tonifying and brain tonic and preparation method thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1977951A (en) * | 2005-12-02 | 2007-06-13 | 北京科莱博医药开发有限责任公司 | Gastrodia elata plant extract for preventing senile dementia and its preparing method |
| CN101991564A (en) * | 2009-08-18 | 2011-03-30 | 杭州萨韦坦生物科技有限公司 | Production process for separating, extracting and purifying bioactive substance calcium nervonate and application thereof to treatment of Alzheimer's disease |
| CN104095849A (en) * | 2013-04-02 | 2014-10-15 | 中国医学科学院药物研究所 | Multiple-target effects of isoflavone derivative and its application in improvement of learning and memory |
| CN107998314A (en) * | 2018-01-31 | 2018-05-08 | 吉林修正药业新药开发有限公司 | A kind of Chinese medicine composition of kidney-tonifying and brain tonic and preparation method thereof |
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Application publication date: 20210730 |