Use of tryptamine derivatives for the preparation of a medicament for cerebral apoplexy

Abstract

The application discloses application of a tryptamine derivative or a pharmaceutically acceptable salt thereof in preparation of a medicine for preventing or treating a stroke, wherein the structure of the tryptamine derivative is shown in formula I: R1 is selected from any one of F and Cl; R2 is selected from any one of H, CH3 and C2H5; and R3 is selected from any one of CH3, C2H5 and COCH3. The most prominent feature of the tryptamine derivative is that the tryptamine derivative has a protective effect on cerebral ischemia-reperfusion injury, and can specifically act on MPO. The tryptamine derivative or the pharmaceutically acceptable salt thereof can significantly improve the clinical effective rate of stroke treatment.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine and relates to the application of a tryptophan derivative in the preparation of a drug for treating stroke. Background Technology

[0002] The high incidence and recurrence rate of stroke lead to severe long-term disability and death, seriously impacting human health. Stroke is a cerebrovascular disease characterized by acute focal damage to the central nervous system due to vascular causes. Based on its pathogenesis, stroke can be divided into ischemic stroke and hemorrhagic stroke, with ischemic stroke accounting for approximately 80% of stroke cases. Despite extensive research on stroke in recent years, clinical treatment outcomes for stroke patients remain unsatisfactory to date. Cerebral ischemia triggers a series of complex biochemical and molecular changes, including inflammatory responses and the production of reactive oxygen species. Studies show that stroke patients with systemic inflammation have a poorer prognosis; the inflammation in stroke is pathologically identified as neutrophil infiltration, which is positively correlated with ischemic injury.

[0003] Myeloperoxidase (MPO) is a heme-containing peroxidase primarily found in the azure-blue granules of neutrophils. It is a crucial component of the body's nonspecific immune defense system and a key marker of inflammatory responses and oxidative stress. When neutrophils are activated, MPO is released extracellularly. In the presence of halides, MPO converts hydrogen peroxide (H₂O₂) into bactericidal hypohalous acids, such as HOCl and HOBr. Hypohalous acids efficiently destroy the cell walls and proteins of pathogens such as bacteria and fungi, playing a key role in the first line of defense against invading pathogens. The maintenance of inflammatory responses and the role of MPO in preserving tissue damage during excessive secretion are related to the pathogenesis of many chronic inflammatory diseases. Studies have found that excessive MPO secretion damages the structural integrity and function of blood vessels, promoting the formation and separation of atherosclerotic plaques, thereby promoting vascular stenosis and thrombosis, ultimately leading to stroke. Serum MPO concentration is positively correlated with stroke severity and is associated with stroke prognosis. Following a stroke, excessive secretion of MPO by a large number of neutrophils leads to the production of various oxidants, which in turn promotes the generation of reactive oxygen species and reactive nitrogen species, and induces the production of a series of inflammatory mediators and pro-inflammatory factors (including interleukins and tumor necrosis factor), ultimately exacerbating brain damage. Therefore, MPO is considered a potential target for stroke treatment. Summary of the Invention

[0004] The purpose of this invention is to provide a class of tryptamine derivatives, the most prominent feature of which is their protective effect against cerebral ischemia-reperfusion injury. Furthermore, because these tryptamine derivatives can specifically act on MPO (metastatic neuropathy), they can also be used for neuroinflammatory diseases.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] In a first aspect, the present invention provides the use of a class of tryptamine derivatives or pharmaceutically acceptable salts thereof with structures as shown in Formula I in the preparation of medicaments for the prevention or treatment of stroke:

[0007] ;

[0008] Among them, R1 is selected from either F or Cl;

[0009] R2 is selected from any one of H, CH3, and C2H5;

[0010] R3 is selected from any one of CH3, C2H5, and COCH3.

[0011] Specifically, the use of tryptophan derivatives or pharmaceutically acceptable salts thereof with the following structures in the preparation of medicaments for the prevention or treatment of stroke:

[0012] , , , , , , , , , .

[0013] In a second aspect, the present invention provides the use of a class of tryptamine derivatives or pharmaceutically acceptable salts thereof with structures as shown in formula (I) in the preparation of medicaments for the prevention or treatment of cerebral ischemia-reperfusion injury or for the preparation of medicaments for the prevention or treatment of neuroinflammatory-related diseases.

[0014] Specifically, the use of tryptamine derivatives or pharmaceutically acceptable salts thereof with the following structures in the preparation of medicaments for the prevention or treatment of cerebral ischemia-reperfusion injury or for the prevention or treatment of neuroinflammatory-related diseases:

[0015] , , , , , , , , , .

[0016] Furthermore, the neuroinflammatory diseases mentioned are multiple sclerosis, neuromyelitis optica, amyotrophic lateral sclerosis, and autoimmune encephalopathy.

[0017] The tryptamine derivatives of this invention can be provided in any form suitable for intended administration, suitable forms including pharmaceutically (i.e., physiologically) acceptable salts of the tryptamine derivatives of this invention. Pharmaceutically acceptable salts of the tryptamine derivatives can be synthesized by conventional chemical methods. Generally, pharmaceutically acceptable salts of the tryptamine derivatives can be prepared by reacting a free base or acid with an equistoichiometric or excess amount of an acid (inorganic or organic) or base (inorganic or organic) in a suitable solvent or solvent composition.

[0018] The drug comprises a tryptamine derivative or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0019] Although the tryptamine derivatives can be administered in the form of untreated compounds, the excipients in the pharmaceutical compositions may be one or more adjuvants, such as excipients, carriers, buffers, diluents and / or other conventional pharmaceutical excipients, in order to better facilitate the action of the active ingredient in the tryptamine derivatives.

[0020] It should be understood that excipients must be compatible with the other ingredients of the product and harmless to the recipients of the product, and therefore must be "acceptable".

[0021] Furthermore, the drug is any one of oral medication, injectable medication, intracerebral medication, or topical medication.

[0022] Furthermore, the dosage form of the oral medication is any one of lozenges, tablets, capsules, granules, or liquids.

[0023] More preferably, the dosage form of the oral medication can be a sublingual tablet.

[0024] Furthermore, the dosage form of the injectable drug is an injection solution or a powder for injection.

[0025] Furthermore, the aforementioned topical medication is a drug administered via the nasal cavity, specifically an intranasal dosage form capable of absorption through the nasal mucosa. The dosage form of the topical medication is any one of suppositories, sprays, films, nasal drops, nasal gels, or patches. The nasal mucosa surface is rich in capillaries, lymphatic vessels, and microvilli, with relatively large intercellular spaces. Furthermore, there is no first-pass effect from the gastrointestinal tract or metabolic breakdown by the liver. Therefore, after absorption through the nasal mucosa, the drug can directly enter the bloodstream and exert its therapeutic effect rapidly.

[0026] Thirdly, the present invention provides the use of a class of tryptamine derivatives or pharmaceutically acceptable salts thereof with structures as shown in formula (I) in the preparation of MPO inhibitors.

[0027] Specifically, the use of tryptophan derivatives or pharmaceutically acceptable salts thereof with the following structures in the preparation of MPO inhibitors:

[0028] , , , , , , , , , .

[0029] It should be noted that those skilled in the art can prepare the tryptamine derivatives described in this invention using conventional chemical synthesis methods.

[0030] Fourthly, the present invention provides a pharmaceutical composition comprising a tryptamine derivative or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0031] The present invention has the following beneficial effects:

[0032] (1) The tryptophan derivatives or pharmaceutically acceptable salts of the present invention can significantly improve the clinical efficacy of stroke treatment;

[0033] (2) The tryptamine derivatives or pharmaceutically acceptable salts of the present invention can be formulated into various dosage forms, including oral (tablets, tablets, capsules, etc.), injection, intracerebral administration, and external (nasal sprays, patches, etc.), to meet the clinical needs of different patients:

[0034] Furthermore, for patients unable to tolerate oral medication, topical formulations such as nasal sprays can be used for administration; for individuals with subclinical stroke, functional foods can facilitate early intervention and reduce the risk of chronic disease progression. Compared to existing drug treatments, this significantly expands the scope of application and improves treatment accessibility. Attached Figure Description

[0035] Figure 1 This study investigated the dose-response relationship of tail vein injection of tryptamine derivative ZC-03 on the protective effect against acute focal ischemia-reperfusion injury in rats. A: Representative image of TTC-stained brain sections, with white areas representing cerebral infarction. B: Infarct area in each ZC-03 dose group. C: Neurological deficit symptom scores in each ZC-03 dose group. Mean ± standard error. Compared with the model group, *P < 0.05, **P < 0.01, ***P < 0.001.

[0036] Figure 2The protective effects of ZC-01, ZC-02, ZC-04, ZC-05, ZC-06, ZC-07, ZC-08, and ZC-09 against acute focal ischemia-reperfusion injury in rats were evaluated. Where A represents the infarct area of ​​each drug, and B represents the neurological deficit symptom score of each drug. Mean ± standard error. Compared with the model group, *P < 0.05, **P < 0.01, ***P < 0.001.

[0037] Figure 3 The dose-response relationship of the protective effect of tail vein injection of tryptophan derivative CZ-03 on focal ischemic injury of the motor cortex in mice was investigated; where A: left forelimb foot drop rate in each dose group; B: asymmetry index of each dose group; mean ± standard error, *P < 0.05, **P < 0.01, ***P < 0.001, compared with the model group. Detailed Implementation

[0038] The 10 tryptophan derivatives used in Example 1 are known compounds with the following chemical structures:

[0039] ZC-01: ZC-02: ;

[0040] ZC-03: ZC-04: ;

[0041] ZC-05: ZC-06: ;

[0042] ZC-07: ZC-08: ;

[0043] ZC-09: ZC-10: .

[0044] Example 1

[0045] Effects of the compound on MPO activity in BV2 microglia stimulated by lipopolysaccharide (LPS)

[0046] BV2 microglia were cultured in DMEM / F12 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin solution. After cell counting, the density was maintained at 5 × 10⁶ cells / year. 4 pcs / cm 2Cells were seeded in 96-well plates, with 100 μL of cell suspension added to each well. The plates were incubated at 37°C with 95% air and 5% CO2 for 24 h. The old culture medium was discarded. 100 μL of the corresponding compound-containing culture medium (diluted to 1.0 μmol / L with the culture medium) was added to each well of the experimental group. A control group (100 μL of culture medium was added only) and a model group (100 μL of culture medium was added only) were also set up. The plates were incubated for 30 min. LPS (final concentration of 100 μg / L) was added to both the experimental and model groups and incubated for 6 h. The supernatant was discarded. Then, 100 μL of PBS was added and the plates were repeatedly frozen and thawed 3 times to ensure complete cell lysis. The plates were centrifuged at 4°C and 12000 g for 5 min and the supernatant was collected. MPO activity was determined according to the instructions of the myeloperoxidase activity kit. The collected supernatant was added to the detection well containing MPO enzyme, incubated at room temperature for 10 min, and after thorough mixing, the fluorescence intensity was measured at Ex / Em = 535 / 587 using a microplate reader. The results are shown in Table 1.

[0047] Table 1. Effects of compounds on MPO activity in LPS-stimulated BV2 microglia (1.0 μmol / L)

[0048] MPO activity (μU / mL) MPO activity (μU / mL) control group 1.07 ZC-05 2.84 Model group 3.93 ZC-06 2.35 ZC-01 2.74 ZC-07 2.26 ZC-02 2.37 ZC-08 2.15 ZC-03 2.01 ZC-09 2.37 ZC-04 2.57 ZC-10 2.56

[0049] As shown in Table 1, the compound has a significant inhibitory effect on the MPO activity of LPS-stimulated BV2 microglia, suggesting that the compound can be used to treat neuroinflammatory diseases such as multiple sclerosis, neuromyelitis optica, amyotrophic lateral sclerosis, and autoimmune encephalopathy, as well as stroke and cerebral ischemia-reperfusion injury.

[0050] Example 2

[0051] The protective effect of the compound against damage to primary cortical neurons cultured in vitro.

[0052] Culture of primary neurons: Pregnant mice at 15-16 days of gestation were used. After cervical dislocation, the uterus and placenta were separated. The fetal mice were disinfected sequentially with 0.1% benzalkonium chloride solution and 75% alcohol. The fetal mice were fixed with the left hand, and the skull was separated with ophthalmic forceps to expose the cerebral hemispheres. The cerebral cortex from both sides was carefully grasped with ophthalmic forceps and placed in a petri dish containing 10 mL of D-hanks. After all the tissues were collected, the meninges were removed and the tissues were placed in another petri dish containing 10 mL of D-hanks. Then, 5 mL of D-hanks was added for washing. The cortex was cut into small pieces with curved forceps and mixed with 0.125% trypsin at 37°C in a small beaker. The mixture was then incubated for 10 min. After removing the cells from the incubator, add 5 mL of DMEM + 10% FBS to terminate digestion. Mix well by pipetting, then transfer to a centrifuge tube and centrifuge at 1500 rpm for 5 min. Discard the supernatant, add another 4 mL of DMEM + 10% FBS, mix well by pipetting, and centrifuge again at 1500 rpm for 5 min. Discard the supernatant, add 2 mL of neuronal culture medium, disperse the cells by pipetting, and pass through a 400-mesh sieve. Dilute 10-fold, count the cells, and then seed them at 300 μL per well in a 24-well plate. Label the wells and incubate. Change the medium after one day, aspirating 120 μL and adding 450 μL. Change the medium again on the fourth day, aspirating 200 μL and adding 300 μL. On the seventh day, induce glutamate production.

[0053] Glutamate injury model: 300 μL of culture medium containing a compound (diluted to 1.0 μmol / L) was added to each well of the experimental group. A control group (300 μL of culture medium only) and a model group (300 μL of culture medium only) were also established. The mixture was incubated for 30 min. Except for the control group, each well of the other groups was further given glutamate and glycine (prepared using 5 mmol / L glutamate stock solution and 1 mmol / L glycine aqueous solution, respectively, in ultrapure water). The final concentrations of glutamate and glycine in the system were 50 μmol / L and 10 μmol / L, respectively. The medium was completely replaced after half an hour, and the mixture was incubated for 8 h. The culture medium (extracellular) was collected, i.e., the extracellular sample. After washing twice with PBS, 300 μL of double-distilled water was added, and the mixture was subjected to three freeze-thaw cycles at -80℃ before collection (intracellular) and storage at -20℃.

[0054] The procedure for determining the LDH (lactate dehydrogenase) leakage rate is as follows:

[0055] 1. Prepare the Master Reaction Mix according to Table 2:

[0056] Table 2. Preparation of mixed reaction systems

[0057] reagents Dosage LDH Assay Buffer 48 μL LDH Substrate Mix 2 μL

[0058] 2. Add 10 μL of extracellular sample and 5 μL of intracellular sample to a 96-well plate, then add Master Reaction Mix to bring the total volume to 50 μL. Measure the initial absorbance at 450 nm using a microplate reader. The results are shown in Table 3.

[0059] Table 3. Effects of compounds on LDH leakage rate in glutamate-damaged primary neurons (1.0 μmol / L)

[0060] LDH leakage rate (%) LDH leakage rate (%) control group 6.47 ZC-05 25.58 Model group 36.87 ZC-06 23.87 ZC-01 22.13 ZC-07 19.67 ZC-02 22.54 ZC-08 25.37 ZC-03 18.86 ZC-09 21.98 ZC-04 22.42 ZC-10 23.17

[0061] As shown in Table 3, the compound has a significant protective effect on the primary neuronal injury model stimulated by glutamate, suggesting that the compound can be used to treat neuroinflammatory diseases such as multiple sclerosis, neuromyelitis optica, amyotrophic lateral sclerosis, and autoimmune encephalopathy.

[0062] Example 3

[0063] Neuroprotective effect of tryptamine derivative ZC-03 on acute focal ischemia-reperfusion injury in rats.

[0064] Experimental animals: Sprague Dawley (SD) rats, 8-10 weeks old, weighing 260-280 g. All rats had free access to a stable supply of water and food, and all animal experiments were approved by the ethics committee. During the experiment, rats were randomly assigned to different experimental groups, and a double-blind method was used for experimental procedures and data analysis.

[0065] Test drug: tryptamine derivative ZC-03; the administration solvent was a mixture of 1% by volume Solutol HS-15 (polyethylene glycol-15-hydroxystearate) and 99% by volume 0.9% sodium chloride injection.

[0066] Preparation of a rat model of focal cerebral ischemia-reperfusion: A middle cerebral artery occlusion (MCAO) model was established using the middle cerebral artery suture occlusion method. First, rats were placed in the induction chamber of a TEC-3 small animal anesthesia machine and anesthetized with isoflurane gas. The rats were then fixed in a supine position on a rat board connected to a breathing mask. The skin was disinfected, and a midline incision was made in the neck. The right common carotid artery, external carotid artery, and internal carotid artery were separated. The vagus nerve was gently dissected, and the external carotid artery was ligated and cut. The proximal end of the common carotid artery was clamped. An incision was made distal to the ligation suture of the external carotid artery, and a 2438-A5 suture occluded (with a hemispherical tip and a 5-6 mm silicone coating at the front end) was inserted, passing through the bifurcation of the common carotid artery into the internal carotid artery. The suture was then slowly inserted until slight resistance was felt (approximately 20 mm from the bifurcation), thus blocking the blood supply to the middle cerebral artery. The neck skin was sutured, the rats were disinfected, and they were returned to their cages. After 80 minutes of ischemia, the rats were anesthetized again, fixed on a rat board, the skin on their necks was cut open, the suture plug was located and gently pulled out, blood supply was restored and reperfusion was performed, the skin on their necks was sutured, the rats were disinfected, and they were put back into their cages for rearing.

[0067] A rat model of cerebral ischemia-reperfusion injury was established using MCAO (cerebral ischemia-reperfusion injury). Eighty minutes after MCAO modeling and reperfusion, rats were immediately injected via tail vein with different doses of tryptamine derivative ZC-03. The dosages of ZC-03 were 0.5, 1.0, and 2.0 mg / kg, with an injection volume of 0.2 mL / 100 g body weight. Rats in the model group received an equal volume of the injected solvent via tail vein. Neurological deficits were evaluated 48 hours after ischemia-reperfusion. Animals were then sacrificed with carbon dioxide, and brain tissue was collected, stained with TTC (Total Traumatic Acid), and the infarct area was measured. Experimental data were processed using GraphPad, and statistical analysis was performed using one-way ANOVA. Data are expressed as Mean ± SEM, and P < 0.05 was considered statistically significant.

[0068] Determination of cerebral infarction area: After euthanizing the animal with carbon dioxide, brain tissue was collected. The olfactory bulb, cerebellum, and lower brainstem were removed. The brain surface was rinsed with 0.9% sodium chloride injection to remove bloodstains, and residual water was aspirated. The brain was then placed at -80℃ for 7 min. Immediately after removal, a coronal section was made perpendicularly downward at the plane of visual intersection, and slices were cut posteriorly every 2 mm. The brain slices were placed in freshly prepared TTC (20 g / L) staining solution with sodium chloride injection and incubated at 37℃ for 90 min. Normal brain tissue stained deep red, while ischemic brain tissue appeared pale white. After rinsing with sodium chloride injection, the brain slices were quickly arranged sequentially from front to back, and residual water was aspirated. The slices were photographed. Image analysis software (Image Tool) was used to statistically analyze the photographs, delineating the right ischemic area (white area) and the right side area, and calculating the percentage of cerebral infarction area.

[0069] Cerebral infarction area % = 100 × (total ischemic area / total area on the right side).

[0070] The modified Bederson 5-point scale was used to evaluate the neurological deficit symptoms in rats with focal cerebral ischemia-reperfusion injury.

[0071] 0: When the animal is suspended by its tail, both of its forelimbs extend toward the floor and there are no other behavioral defects;

[0072] 1: When the tail is lifted and suspended in the air, the animal's left forelimb will show wrist and elbow flexion, shoulder internal rotation, elbow abduction, and close contact with the chest wall.

[0073] 2: Place the animal on a smooth flat surface and push the surgical side shoulder to move to the opposite side, reducing resistance;

[0074] 3: When the animal walks freely, it will circle or turn towards the side opposite to the surgery.

[0075] 4: Flexibility of limbs, with no spontaneous movement of the limbs.

[0076] The results are as follows Figure 1 As shown, compared with the model group, ZC-03 significantly reduced the infarct area in a dose-dependent manner and significantly improved the neurological deficit symptoms, indicating that the tryptamine derivative with ZC-03 as the representative compound of this invention has a significant protective effect on rats with ischemic stroke.

[0077] Example 4

[0078] Neuroprotective effects of tryptamine derivatives ZC-01, ZC-02, ZC-04, ZC-05, ZC-06, ZC-07, ZC-08, ZC-09, and ZC-10 on acute focal ischemia-reperfusion injury in rats.

[0079] Experimental animals: Same as in Example 1.

[0080] Test drugs:

[0081] Tryptamine derivatives ZC-01, ZC-02, ZC-04, ZC-05, ZC-06, ZC-07, ZC-08, ZC-09, and ZC-10; the administration solvent is a mixture of 1% by volume Solutol HS-15 and 99% by volume 0.9% sodium chloride injection.

[0082] Preparation of a rat model of focal cerebral ischemia-reperfusion: Same as in Example 1.

[0083] A rat model of cerebral ischemia-reperfusion injury was established using MCAO (cerebral ischemia-reperfusion injury). Eighty minutes after MCAO modeling and reperfusion, rats were immediately injected via the tail vein with tryptamine derivatives ZC-01, ZC-02, ZC-04, ZC-05, ZC-06, ZC-07, ZC-08, ZC-09, and ZC-10. The dosage of each drug was 1.0 mg / kg, and the injection volume was 0.2 mL / 100 g body weight. Rats in the model group received an equal volume of the drug solution via the tail vein. Neurological deficits were evaluated 48 hours after ischemia. Animals were then sacrificed with carbon dioxide, and brain tissue was collected, stained with TTC (Total Traumatic Acid), and the infarct area was measured. Experimental data were processed using GraphPad, and statistical analysis was performed using one-way ANOVA. Data are expressed as Mean ± SEM, and P < 0.05 was considered statistically significant.

[0084] The modified Bederson 5-point scale was used to evaluate the neurological deficit symptoms in rats with focal cerebral ischemia-reperfusion injury (same as in Example 1).

[0085] Measurement of cerebral infarction area: Same as in Example 1.

[0086] The results are as follows Figure 2 As shown, compared with the model group, ZC-01, ZC-02, ZC-04, ZC-05, ZC-06, ZC-07, ZC-08, ZC-09, and ZC-10 all significantly reduced the cerebral infarction area and significantly improved neurological deficit symptoms, indicating that ZC-01, ZC-02, ZC-04, ZC-05, ZC-06, ZC-07, ZC-08, ZC-09, and ZC-10 have significant protective effects against ischemic stroke in rats.

[0087] Example 5

[0088] Protective effect of tryptophan derivative ZC-03 on focal ischemic injury of the motor cortex in mice.

[0089] Experimental animals: C57BL / 6J mice, SPF grade, 6-8 weeks old, weighing 22 ± 2g, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. All mice had free access to a stable supply of water and food, and all animal experiments were approved by the ethics committee. During the experiment, mice were randomly assigned to different experimental groups, and a double-blind method was used for experimental procedures and data analysis.

[0090] Test drug: tryptamine derivative ZC-03; the administration solvent was a mixture of 1% by volume Solutol HS-15 (polyethylene glycol-15-hydroxystearate) and 99% by volume 0.9% sodium chloride injection.

[0091] Preparation of a mouse model of focal ischemic injury in the motor cortex: Mice were first placed in the induction chamber of a TEC-3 small animal anesthesia machine and anesthetized with isoflurane. They were then fixed to a stereotaxic apparatus connected to a breathing mask. The skin was disinfected, and the skull was exposed by cutting along the midline of the brain. The skull was dried with a bulb syringe. The anterior fontanelle and λ point were located and marked. The D values ​​of the anterior fontanelle and λ point were read and adjusted to ensure they did not exceed 0.2 mm. A cold light source with an inner diameter of 2.5 mm and an outer diameter of 4.5 mm was positioned 1.8 mm to the right of the anterior fontanelle. Rose red (100 mg / kg) was injected intraperitoneally. Five minutes later, the mice were irradiated with a cold light source of 16000 Lux for 15 minutes. The optical fiber of the cold light source was removed, the area was disinfected, the head skin was sutured, and the mice were returned to their cages.

[0092] Grid Experiment:

[0093] A square frame with dimensions of 32 cm (length), 20 cm (width), and 50 cm (height) and a 12×12 mm mesh was used. Each mouse was placed individually on the mesh and allowed to move spontaneously. The number of missteps on the left and right forelimbs and the total number of steps were recorded, and the misstep percentage (the ratio of missteps to total steps) was calculated. The misstep percentage is used to evaluate the degree of damage to the motor cortex of the experimental animal; a higher misstep percentage indicates more severe damage to the mouse's motor cortex.

[0094] The criteria for judging a mouse's misstep are: 1. The mouse's foot does not step on the grid and passes through the mesh; 2. The mouse's wrist joint remains on the grid for an extended period of time. Both of these situations are considered missteps.

[0095] Percentage of missteps = (Number of missteps / Total steps) × 100%.

[0096] Cylinder Experiment:

[0097] Mice were placed inside a transparent resin-glass cylinder with a diameter of 10 cm and a height of 15 cm. Their spontaneous standing and exploration were observed to assess the mice's preference for their left and right forelimbs during exploration. The time spent with the left and right forelimbs, and with both forelimbs simultaneously, was recorded. The ratio of the time spent with the left and right forelimbs against the cylinder wall during spontaneous exploration was calculated. The asymmetry index was defined as the difference between the percentage of time spent with the ipsilateral forelimb against the wall and the percentage of time spent with the contralateral forelimb against the wall. A higher asymmetry index indicates poorer motor coordination and more severe damage to the motor cortex.

[0098] A photo-induced ischemia-induced cortical injury model was established in mice. Two hours after the ischemia-induced model, mice were immediately injected via the tail vein with different doses of the tryptamine derivative ZC-03. The doses of ZC-03 were 0.5, 1.0, and 2.0 mg / kg, with an injection volume of 0.2 ml / 10 g body weight. Mice in the model group received an equal volume of the drug solution via the tail vein. Mortality was recorded daily after the onset of cortical ischemia. On day 7 post-injury, a grid test was used to determine the error rate of the forelimbs. On day 7 post-injury, a cylinder test was used to determine the motor asymmetry index of the affected and contralateral forelimbs to assess the impact on motor function. Experimental data were processed using GraphPad and statistically analyzed using one-way ANOVA. Data are expressed as Mean ± SEM, and P < 0.05 was considered statistically significant.

[0099] The results are as follows Figure 3 As shown, compared with the model group, ZC-03 significantly improved the motor dysfunction of the left forelimb in a dose-dependent manner and significantly reduced the asymmetry index of the mouse forelimb, indicating that ZC-03 has a significant protective effect on mice with light-induced ischemia.

[0100] Finally, it should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. The use of tryptamine derivatives or pharmaceutically acceptable salts thereof with the structure shown in Formula I in the preparation of drugs for the prevention or treatment of stroke: ； in, R1 is selected from either F or Cl; R2 is selected from any one of H, CH3, and C2H5; R3 is selected from any one of CH3, C2H5, and COCH3.

2. The use of tryptamine derivatives or pharmaceutically acceptable salts thereof with the structures shown below in the preparation of medicaments for the prevention or treatment of stroke: ， ， ， ， ， ， ， ， ， 。 3. The use of tryptamine derivatives or pharmaceutically acceptable salts thereof with the structure shown in Formula I in the preparation of drugs for the prevention or treatment of cerebral ischemia-reperfusion injury or for the prevention or treatment of neuroinflammatory diseases: ； in, R1 is selected from either F or Cl; R2 is selected from any one of H, CH3, and C2H5; R3 is selected from any one of CH3, C2H5, and COCH3.

4. The use of tryptamine derivatives or pharmaceutically acceptable salts thereof with the structures shown below in the preparation of medicaments for the prevention or treatment of cerebral ischemia-reperfusion injury or for the prevention or treatment of neuroinflammatory diseases: ， ， ， ， ， ， ， ， ， 。 5. The application according to claim 3 or 4, characterized in that: The neuroinflammatory diseases mentioned are multiple sclerosis, neuromyelitis optica, amyotrophic lateral sclerosis, and autoimmune encephalopathy.

6. The application according to any one of claims 1-4, characterized in that: The drug comprises a tryptamine derivative or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

7. The application according to any one of claims 1-4, characterized in that: The drug is any one of oral medication, injectable medication, intracerebral medication, or topical medication.

8. The application according to claim 7, characterized in that: The dosage form of the oral medication is any one of lozenges, tablets, capsules, granules, or liquids; the dosage form of the injectable medication is an injectable solution or powder for injection; the dosage form of the topical medication is a medication administered via the nose, and the dosage form of the topical medication is any one of suppositories, sprays, films, or patches.

9. The use of tryptamine derivatives with structures as shown in Formula I or pharmaceutically acceptable salts thereof in the preparation of MPO inhibitors: ； in, R1 is selected from either F or Cl; R2 is selected from any one of H, CH3, and C2H5; R3 is selected from any one of CH3, C2H5, and COCH3.

10. The use of tryptamine derivatives or pharmaceutically acceptable salts thereof with the structures shown below in the preparation of MPO inhibitors: ， ， ， ， ， ， ， ， ， 。

Images