Pharmaceutical composition of class of NRF2 agonists and use thereof in preparation of neuroprotective drug

Abstract

Disclosed is a pharmaceutical composition, comprising an NRF2 agonist and borneol. The NRF2 agonist and the borneol act synergistically within a specific molar ratio range to enhance the overall anti-inflammatory and anti-oxidation biological activities of the drug, improve the oral bioavailability and target tissue distribution of the drug, and inhibit the off-target side effects of the NRF2 agonist, resulting in significant improvement in the drug efficacy and safety.

Description

Pharmaceutical compositions of a class of NRF2 agonists and their application in the preparation of neuroprotective drugs Technical Field

[0001] This invention relates to a class of compositions containing a small molecule NRF2 agonist and borneol, and the use of such compositions in neuroprotective drugs. Background Technology

[0002] Studies have shown that neurological diseases affect more than one-third of the world's population and are a leading cause of disability and death. Among the major complex neurological diseases leading to health loss, including stroke, Alzheimer's disease, diabetic neuropathy, meningitis, epilepsy, Parkinson's disease, multiple sclerosis, ataxia, amyotrophic lateral sclerosis (ALS), and even depression, anxiety disorders, ADHD in children, and alcohol-dependent brain injury, all are closely related to acute / chronic oxidative stress and inflammatory damage to nerve cells.

[0003] NRF2-Keap1 is a crucial redox-sensitive transcription factor signaling pathway in the human body, widely distributed in organs and nerve tissues. Under normal circumstances, NRF2 is anchored in the cytoplasm by Keap1 and remains silent. When drugs act on Keap1, they promote the dissociation of NRF2 from Keap1 and its rapid translocation into the cell nucleus, promoting the expression of a series of antioxidant enzymes within the cell, maintaining cellular redox homeostasis, protecting cells from oxidative stress damage, and inhibiting inflammation. Formulas (I-III) are natural fumaric acid derivatives, belonging to neuroprotective drugs with unclear mechanisms, possibly involving multiple mechanisms such as NRF2 agonism, and are mainly used to treat multiple sclerosis. Formulas (IV, V) are natural triterpenoid derivatives, belonging to targeted NRF2 agonists with clear mechanisms. At low concentrations (100 nanomoles and below), they are mainly used for the protection of skin, organs, and nerve cells, while at high concentrations (1000 nanomoles and above), they inhibit broad-spectrum cell growth and promote apoptosis.

[0004] However, existing NRF2 agonists, such as compounds of formula (IV) and (V), have significant drawbacks such as poor water solubility and poor permeability (belonging to the BCSIV class), resulting in low oral bioavailability, high variability in the human body, and significant side effects.

[0005] Borneol is a traditional Chinese medicine with a history of over a thousand years. According to the *Compendium of Materia Medica*, borneol has the effects of "opening the orifices and dispersing stagnant heat," and is often used as a guide drug to enhance the therapeutic effects of other medications. Although the target / pathway of borneol's action is not clearly defined, it possesses a range of pharmacological activities, including anti-inflammatory, antibacterial, antitumor, cardiovascular, and nervous system protective effects. It can also improve the absorption and distribution of other drugs in combination, and is currently widely used in modern Chinese herbal formulas and chemical drugs. Summary of the Invention

[0006] A first aspect of the present invention provides a pharmaceutical composition comprising an NRF2 agonist and borneol.

[0007] The NRF2 agonist is one of the compounds shown in formula (I), formula (II), formula (III), formula (IV) or formula (V).

[0008] The borneol is selected from one of the synthetic or natural borneols listed in the Chinese Pharmacopoeia (2020 edition).

[0009] In some embodiments, the NRF2 agonist is a compound of formula (I), formula (II) or formula (III), and the molar ratio of the NRF2 agonist to borneol is 40:1 to 50:1.

[0010] Preferably, the NRF2 agonist is a compound of formula (I).

[0011] Preferably, the molar ratio of the NRF2 agonist to borneol is 40:1.

[0012] In some embodiments, the NRF2 agonist is a compound of formula (IV) or (V), and the molar ratio of the NRF2 agonist to borneol is 2:1 to 4:1, for example 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3.0:1, 3.1:1, 3.2:1, 3.3:1, 3.4:1, 3.5:1, 3.6:1, 3.7:1, 3.8:1, 3.9:1, or 4:1.

[0013] Preferably, the NRF2 agonist is a compound of formula (V).

[0014] Preferably, the molar ratio of the NRF2 agonist to borneol is 2.5:1 to 3.5:1.

[0015] In some embodiments, the pharmaceutical composition further includes pharmaceutically acceptable excipients.

[0016] Preferably, the pharmaceutical composition can be formulated into pharmaceutically common dosage forms, such as tablets, capsules, injections, etc.

[0017] A second aspect of the present invention provides a method for preparing the pharmaceutical composition described in the first aspect, comprising the following steps:

[0018] The NRF2 agonist and borneol were added to an acetone solution at room temperature in proportion and stirred until completely dissolved. The solution was then rotary evaporated under vacuum until constant weight was obtained, yielding a white solid. The solid was dried overnight to obtain the final product.

[0019] The third aspect of the present invention provides the use of the pharmaceutical composition described in the first aspect or the pharmaceutical composition prepared according to the preparation method described in the second aspect in the preparation of a medicament for the prevention or treatment of acute or chronic neuronal damage-related central nervous system diseases.

[0020] In some implementations, the acute or chronic neuronal injury-related central nervous system disease is an acute or chronic oxidative stress and inflammatory neuronal injury disease.

[0021] Preferably, the neurological injury disease is selected from hemorrhagic or ischemic brain injury, stroke, Alzheimer's disease, diabetic neuropathy, meningitis, epilepsy, Parkinson's disease, multiple sclerosis, ataxia, amyotrophic lateral sclerosis, and even depression, anxiety, ADHD, alcohol-dependent brain injury, etc.

[0022] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0023] This invention develops a combination of NRF2 agonists and borneol that exhibits synergistic effects within a specific molar ratio range, enhancing the overall anti-inflammatory and antioxidant bioactivity of the drug, improving oral bioavailability and target tissue distribution, inhibiting off-target side effects of NRF2 agonists, and significantly improving both drug efficacy and safety. Detailed Implementation

[0024] The following embodiments are intended to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the invention to the scope of the embodiments described.

[0025] Example 1: Preparation of Compound Active Pharmaceutical Ingredients

[0026] Compound (V) (10g, 18.0mmol) and natural borneol (dextrin) (1.38g, 9.0mmol) were added to 200mL of acetone solution at room temperature and stirred until completely dissolved. The mixture was then rotary evaporated under vacuum to constant weight to obtain a white solid. The solid was dried under vacuum at 40°C overnight to obtain 11.29g of white solid, which is the compound raw material (1).

[0027] Compound (V), dextroborneol, and compound active pharmaceutical ingredient (1) were analyzed by HPLC and found to contain no additional impurities exceeding 0.10% after comparison. Compound active pharmaceutical ingredient (1) was tested by GC and found to contain 0.03% acetone solvent residue. Compound active pharmaceutical ingredient (1) was determined to be amorphous by PXRD.

[0028] Referring to the compound active pharmaceutical ingredient (1), compound active pharmaceutical ingredients (2) to (8) were prepared respectively. HPLC and GC detection showed no additional impurities or solvent residues exceeding 0.10%; PXRD test showed amorphous state (see Table 1).

[0029] Table 1 Information on Compound Raw Materials

[0030] Remark: a The molar ratio specifically refers to the ratio of NRF2 agonist to borneol.

[0031] Example 2: In vitro hydrogen peroxide-induced nerve cell damage experiment

[0032] PC12 neural cell line (rat adrenal medullary pheochromocytoma cell line) was seeded in 96-well culture plates at a seeding density of 2 × 10⁶ cells / well. 5 / mL, 200μL per well, 4 replicates per group. After cells stabilized for 24h, PBS (control group), blank solvent (model group), and drug treatment solutions (A to K) were added to each group and incubated with cells for 12h. Then, PBS was added to the control group, and 100μmol / L H2O2 was added to the model group and drug treatment group for 24h. The protective effect of the drug on oxidative stress-induced neuronal cell damage was observed using the CCK8 assay. After treatment of each experimental group, CCK8 reagent was added to each well at a ratio of CCK8:medium medium = 1:10, and the cells were incubated in a cell culture incubator for several hours. The absorbance was measured at a wavelength of 450nm.

[0033] Experimental results showed that hydrogen peroxide, being a peroxide, can form a large amount of active ROS at a concentration of 100 μM, causing significant damage to nerve cells (Table 2, Sequence 1 vs. Sequence 2). Triterpenoid NRF2 agonists, such as compound (V), significantly reduced the damage to nerve cells caused by hydrogen peroxide (Table 2, Sequence 2 vs. Sequence 10), while fumaric acid derivatives, such as compound (I), did not show significant cell-protective effects even at higher concentrations (Table 2, Sequence 2 vs. Sequence 11). Therefore, compound formulations containing triterpenoid NRF2 agonists are indeed significantly superior to those containing fumaric acid NRF2 agonists (Table 2, Sequences 3-7 vs. Sequences 8-9). Meanwhile, at a concentration level of 50 nM, neither natural nor synthetic borneol showed any cell-protective effect (Table 2, Sequence 2 vs. Sequences 12-13).

[0034] Surprisingly, borneol can enhance the cytoprotective effects of different NRF2 agonists.

[0035] Among them, the cell survival rate of the compound containing formula (I) and borneol at a molar ratio of 40:1 (Table 2, Sequence 8) was significantly different from that of the model group (Table 2, Sequence 2), while there was no significant difference in either the compound containing formula (I) or borneol alone (Table 2, Sequences 11-13).

[0036] In addition, in particular, the combination of compound (V) and borneol showed stronger cytoprotective effects compared to compound (V) alone (Table 2, sequences 3-7 vs. sequence 10). The molar ratio of NRF2 agonist to borneol in the range of 2.0 to 4.0 showed significant synergistic effects, with groups B and C almost completely recovering to normal.

[0037] Table 2 Results of in vitro hydrogen peroxide-induced nerve cell damage experiments

[0038] Note: *Model group vs. control group p<0.05; # Model group vs. treatment group, p<0.05; ^Treatment group A-E vs. treatment group H, p<0.05; ※ AEs in the control group vs. the treatment group, p>0.05

[0039] Example 3: In vitro nerve cell proliferation inhibition experiment

[0040] The CCK8 assay was used to test the inhibitory activity of the compound on the proliferation of PC12 neural cell line and mouse primary neurons. Following the cell culture method described in Example 2, after discarding the supernatant, 200 μL of the test compound, compound, and blank solvent (dissolved in DMSO and diluted with PBS) were added to each well, with four replicates per concentration. After culturing for 44 hours, CCK8 reagent was added to each well at a ratio of CCK8:medium medium = 1:10, and the cells were incubated in a cell culture incubator for several hours. The absorbance was measured at 450 nm.

[0041] Table 3 Results of in vitro nerve cell proliferation inhibition experiments

[0042] Remark: a Compound IC 50 The concentration is expressed as the molar concentration of the NRF2 agonist.

[0043] NRF2 agonists, especially triterpenoid NRF2 agonists, exhibit potent antioxidant and cytoprotective effects at 100 nM. However, when the drug concentration is increased tenfold to the μM level (1-10 μM), they exhibit significant cell proliferation inhibitory toxicity (Table 3, Sequence 2). Experimental results of compound drugs showed that borneol significantly reduced the cell proliferation inhibitory toxicity of triterpenoid NRF2 agonists (Table 3, Sequences 5-9), particularly in groups E, F, and H. The NRF2 agonist (V) and borneol compound, at a molar ratio of 4:1 to 2:1, reduced the in vitro cell proliferation inhibitory toxicity of formula (V) by one order of magnitude.

[0044] Example 4: Rat Ischemia-Reperfusion Brain Injury Model Experiment

[0045] 4.1 Experimental Materials

[0046] Healthy male SD rats were selected as experimental animals and divided into 8 groups of 10 rats each. The specific grouping, drug settings and administration routes are shown in Table 4.

[0047] Table 4. Experimental grouping information for the rat ischemia-reperfusion brain injury model

[0048] Note: All drugs in the treatment group were dissolved in corn oil using ultrasound.

[0049] 4.2 Experimental Methods

[0050] After rats passed the adaptation period examination, they were induced to be anesthetized. Under chloral hydrate anesthesia, a 4 / 0 surgical nylon monofilament with a rounded tip was introduced into the left internal carotid artery through the stump of the external carotid artery, advancing 20-21 mm to the carotid bifurcation until slight resistance was felt. At this point, the intraluminal fiber occluded the origin of the middle cerebral artery, blocking all blood flow sources of the internal carotid artery, anterior cerebral artery, and posterior cerebral artery. Throughout the process, the body temperature was maintained at 37±0.5℃. Regional cerebral blood flow was measured using a flexible probe and laser Doppler flowmeter (inclusion criteria: regional cerebral blood flow reduction of 85-95%). The fiber was removed 120 minutes after placement for reperfusion. In sham-operated animals, the occlusion wire was inserted only 7 mm above the carotid bifurcation. Drugs were administered immediately after reperfusion via gavage for 7 consecutive days.

[0051] 4.3 Evaluation Indicators

[0052] Weight and general condition were measured every two days before and after the operation. At the end of the experiment, the neurological function deficit score (NSS score, including motor, sensory, balance and reflex scores) was performed, and then the cerebral infarction volume was measured.

[0053] 4.4 Experimental Results

[0054] Table 5. Experimental results of the rat model of ischemia-reperfusion brain injury.

[0055] Note: * Solvent group vs. sham surgery group p<0.05; # The p-value of the drug-treated group versus the solvent group was <0.05; the p-value of the drug-treated group A versus the drug-treated group D-Ep was <0.05.

[0056] Based on the above experimental conditions and results, it can be seen that NRF2 agonist formulation (V) can improve neurobehavioral deficits caused by ischemia-reperfusion brain injury in rats and reduce cerebral infarction volume, while borneol alone has no significant effect (Table 5, sequence 2 vs. sequence 3 / 4). The combined use of formulation (V) and borneol not only reduced the cerebral infarction volume caused by ischemia-reperfusion in rats but also significantly reduced NSS neurobehavioral deficit scores, especially in groups D and E. Compared with group A, which received NRF2 agonist alone, the combined treatment showed significant improvement in both major efficacy assessment indicators.

[0057] Example 5: Mouse model of alcoholic brain injury and ataxia

[0058] 5.1 Experimental Materials

[0059] Healthy male C57BL / 6J mice were selected as experimental animals and divided into 8 groups of 10 mice each. The specific grouping, drug administration settings and routes of administration are shown in Table 6.

[0060] Table 6. Experimental grouping information for the mouse alcoholic brain injury ataxia model.

[0061] Note: All drugs in the treatment group were dissolved in 10% DMSO + 10% Solutol + 80% physiological saline.

[0062] 5.2 Experimental Methods

[0063] Mice trained with rotarods were randomly divided into groups based on their motor coordination and body weight during the rotarod test. The model group mice received 28% (v / v) alcohol via gavage, in addition to 5% (v / v) alcohol in their basal drinking water. The gavage dose was gradually increased (from 0 to 6 g / kg body weight) over the first two weeks, and then maintained at 6 g / kg body weight for the next four weeks. The control group received an equal volume of saline via gavage without added alcohol. The first administration was given before mouse modeling began, once daily for five weeks.

[0064] 5.3 Evaluation Indicators

[0065] During the experiment, body weight and clinical status were measured twice a week. Two weeks after modeling, rotarod tests were performed weekly, and the results of the rotarod tests were the average of the three tests conducted on the same day.

[0066] 5.4 Experimental Results

[0067] Table 7. Experimental results of the mouse model of alcoholic brain injury and ataxia.

[0068] Note: *Model group vs. normal control group p<0.05; # The p-value of the A-F group versus the model group was <0.05; the p-value of the A-F group versus the normal control group was <0.05.

[0069] Experimental results showed that, compared with the model group mice, the NRF2 agonist formulation (V) significantly increased the movement time on the rotarod, while borneol alone had a weaker effect. Although it increased the movement time, it was still significantly different from the normal control group mice (Table 7, Sequence 2 vs. Sequence 3 / Sequence 4). The combined use of formulation (V) and borneol significantly improved the motor coordination ability of mice on the rotarod (Table 7, Sequences 5-8), especially in the treatment groups D and E, where the movement time was significantly increased compared with the model group mice. After drug withdrawal, the effect of the compound drug in improving ataxia in mice was somewhat persistent. Regarding the experimental endpoint of mouse body weight, alcohol-induced modeling led to a significant decrease in mouse body weight, but continuous administration did not cause further weight loss.

[0070] Example 6: Single-dose p-value and brain tissue distribution experiment in rats

[0071] 6.1 Experimental Materials

[0072] Healthy SD rats were selected as experimental animals and divided into 3 groups of 24 rats each, with half males and half females. The specific grouping, drug administration settings and routes of administration are shown in Table 8.

[0073] Table 8. Grouping information for single-dose p-value and brain tissue distribution in rats.

[0074] Note: All drugs in the treatment group were dissolved in 10% DMSO + 10% Solutol + 80% physiological saline.

[0075] 6.2 Experimental Methods

[0076] Plasma and brain tissue were collected from rats at 0.5h, 2h, 4h, 8h and 24h after a single oral administration. Six rats (half male and half female) were used at each time point. The compound (V) to be tested was extracted with organic solvent. The concentration of the compound was detected by an established and validated LC-MS bioanalytical method. The drug-time curves of plasma and brain tissue were plotted using Winnonlin software.

[0077] 6.3 Evaluation Indicators

[0078] Time to peak concentration (T) of compound (V) in plasma maxPeak concentration C max Half-life T 1 / 2 The area under the curve (AUC) during drug administration, and the ratio of cerebral blood concentration at 4 h and 8 h after drug administration.

[0079] 6.4 Experimental Results

[0080] Table 9 Results of single-dose pharmacokinetic (PK) experiment in rats

[0081] Note: *The ratio of B-C in the treatment group to Ap in the treatment group was <0.05.

[0082] Table 10 Results of the experiment on the ratio of blood brain concentration in rats after a single dose.

[0083] Note: Plasma concentration is in ng / mL; brain concentration is in ng / g; *At the same time, the B-C group vs the Ap group were treated with the same drug at the same time point.

[0084] Based on the above experimental conditions and results, it can be seen that when formula (V) and borneol are used in combination, borneol increases the absorption rate of formula (V), that is, the peak concentration is significantly increased within the same peak time, and the in vivo exposure increases, but borneol hardly affects the metabolic rate of formula (V) (Table 9); at the same time, borneol significantly increases the distribution of formula (V) in brain tissue; as time goes on, the ratio of cerebral blood concentration in each group increases, but when formula (V) is used in combination with borneol, the ratio of cerebral blood concentration is still significantly increased compared with the single-use group (Table 10).

[0085] Example 7: Repeated-dose experiment in rats over 14 days

[0086] 7.1 Experimental Materials

[0087] Healthy SD rats were selected as experimental animals and divided into 4 groups of 12 rats each, with half males and half females. The specific grouping, drug administration settings and routes of administration are shown in Table 11.

[0088] Table 11 Grouping information for the 14-day repeated drug administration experiment in rats

[0089] Note: The drugs in the treatment group were dissolved in corn oil using ultrasound.

[0090] 7.2 Experimental Methods

[0091] Rats were administered the drug under the above conditions, and clinical observations were conducted daily before and after administration. Body weight was measured three times a week. After administration, blood was collected from half of the rats (half male and half female) for hematological and blood biochemical examinations. Organs (brain, heart, liver, kidney, spleen, lung, thymus, adrenal gland, testes, ovaries, and uterus) were grossly dissected, weighed, and organ coefficients were calculated. Histopathological examinations of the organs were performed. The remaining rats were allowed to recover for 7 days after administration, and the same examinations were then performed.

[0092] 7.3 Experimental Results

[0093] Rats were subjected to a 14-day repeated-dose safety test at 2 times (drug groups A and B) and 4 times (drug group C) of the pharmacodynamic experimental dose of compound raw material (1). The compound had the highest dose of natural borneol. The experimental results showed that when formula (V) was used alone, rats in drug group A experienced a decrease in body weight, which did not fully recover after the recovery period. Blood biochemistry results showed an increase in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which returned to normal range at the end of the experiment. At the same time, autopsy revealed an increase in the weight of liver and kidney tissues, and pathological results showed abnormalities in liver and kidney tissues, which did not fully recover within 7 days. The above results indicate that formula (V) had no visible harmful effects (N) in the 14-day repeated-dose experiment in rats. OAEL)<31.2mg / kg; When formula (V) was used in combination with borneol, compared with the solvent control group rats, no abnormal state or toxic reaction was observed in the administration group B rats, no obvious abnormality of various indicators, pathological results showed normal, and after the recovery period, all indicators were within the normal reference range; however, the administration group C rats showed symptoms of shallow breathing, tearing and diarrhea, blood biochemistry results showed increased AST and ALT, increased liver and kidney tissue weight, pathological results showed abnormal liver and kidney tissue, and bile duct hyperplasia. Based on the above results, it is indicated that the NOAEL of compound raw material (1) in the 14-day repeated administration experiment in rats was >31.2mg / kg, but not more than 62.4mg / kg.

[0094] Example 8 Acute Toxicity Test in Rats

[0095] 8.1 Experimental Materials

[0096] Healthy SD rats were selected as experimental animals and divided into 5 groups of 12 rats each, with half males and half females. The specific grouping, drug administration settings and routes of administration are shown in Table 12.

[0097] Table 12 Grouping information for rat acute toxicity test

[0098] Note: All drugs in the treatment group were dissolved in 10% DMSO + 10% Solutol + 80% physiological saline.

[0099] 8.2 Experimental Methods

[0100] After the rats passed the adaptation period test, they were fasted overnight and administered a single dose by gavage under the experimental conditions described above. They were observed for 14 consecutive days after administration, with daily clinical observation and three weekly body weight measurements. Toxicity reactions and animal mortality were recorded, and blood was collected weekly for hematological and blood biochemical tests. After the experiment, the major organs were grossly dissected, organ coefficients were calculated, and histopathological examinations were performed.

[0101] 8.3 Experimental Results

[0102] After a single administration of each dose of the drug to rats, rats in group A showed a series of toxic reactions, including swelling and redness of the mouth and nose, tearing, and weight loss. The animals died on the 4th day of the observation period, suggesting that the maximum tolerated dose (MTD) of formula (V) in the acute toxicity test of a single oral administration was <100 mg / kg. In addition to shallow breathing, tearing, and diarrhea, rats in group B also showed signs of salivation and weight loss, accompanied by elevated AST and ALT, increased liver and kidney tissue weight, and abnormal pathological results. However, no animals died during the observation period. Rats in group C showed the same symptoms as rats in group B, but the first rat died on the 3rd day of the observation period. Rats in group D died on the day of administration. The above results indicate that when formula (V) is used in combination with borneol, the MTD of the compound raw material (1) in the acute toxicity test of a single oral administration is <200 mg / kg.

[0103] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition, characterized in that... This includes NRF2 agonists and borneol, wherein the NRF2 agonist is a compound represented by formula (I), (II), (III), (IV), or (V).

2. The pharmaceutical composition according to claim 1, characterized in that, Borneol can be either synthetic or natural.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The NRF2 agonist is a compound represented by formula (I), formula (II) or formula (III), and the molar ratio of the NRF2 agonist to borneol is 40:1 to 50:

1. Preferably, the NRF2 agonist is a compound represented by formula (I), and more preferably, the molar ratio of the NRF2 agonist to borneol is 40:

1.

4. The pharmaceutical composition according to claim 1 or 2, characterized in that, The NRF2 agonist is a compound of formula (IV) or (V), and the molar ratio of the NRF2 agonist to borneol is 2:1 to 4:

1.

5. The pharmaceutical composition according to claim 4, characterized in that, The NRF2 agonist is a compound represented by formula (V).

6. The pharmaceutical composition according to claim 5, characterized in that, The molar ratio of the NRF2 agonist to borneol is 2.5:1 to 3.5:

1.

7. A method for preparing the pharmaceutical composition according to any one of claims 1-6, characterized in that, The preparation method includes the following steps: The NRF2 agonist and borneol were added to an acetone solution at room temperature and stirred until completely dissolved. The solution was then rotary evaporated under vacuum until constant weight was obtained, yielding a white solid. The solid was dried overnight to obtain the final product.

8. The use of the pharmaceutical composition according to any one of claims 1-6 or the pharmaceutical composition prepared by the method of claim 7 in the preparation of a medicament for the prevention or treatment of acute or chronic neuronal damage-related central nervous system diseases.

9. The application according to claim 8, characterized in that, The aforementioned acute or chronic neuronal damage-related central nervous system diseases are acute or chronic oxidative stress and inflammatory neuronal damage diseases.

10. The application according to claim 8 or 9, characterized in that, The central nervous system diseases related to acute or chronic neuronal damage are selected from ischemic brain injury, stroke, Alzheimer's disease, diabetic neuropathy, meningitis, epilepsy, Parkinson's disease, multiple sclerosis, ataxia, amyotrophic lateral sclerosis, and even depression, anxiety, ADHD in children, and alcohol-dependent brain injury.

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