CN-121987603-A - Application of magnolol nitrone derivative HL-3 in preparation of medicines for preventing or treating cerebral infarction

Abstract

The invention belongs to the technical field of medicines, and discloses application of magnolol nitrone derivative HL-3 in preparation of medicines for preventing or treating cerebral infarction. HL-3 showed significant therapeutic effects in both in vitro and in vivo experiments. In an in vitro experiment, HL-3 can effectively relieve the damage caused by the oxygen glucose deprivation/reoxygenation (OGDR) of SK-N-SH cells at the concentration of 10 micromoles (mu M), and remarkably improve the survival rate of the cells, which shows that the SK-N-SH cells have a strong neuroprotective effect. In whole animal experiments, HL-3 showed significant therapeutic effects on both transient middle cerebral artery occlusion (tMCAO) and permanent middle cerebral artery occlusion (pMCAO) models of SD rats at doses of 1mg/kg and 10 mg/kg. Is characterized by reducing cerebral infarction volume and improving neurological score. These results indicate that HL-3 is effective in various models, has wide applicability and remarkable therapeutic potential, and provides a new and effective drug choice for cerebral infarction treatment.

Inventors

• PENG YING
• ZHANG DONGMING
• PANG BO
• MA JIE
• ZANG YINGDA
• SUN JINGYING
• KANG YUYING
• QU KAI

Assignees

• 中国医学科学院药物研究所

Dates

Publication Date

20260508

Application Date

20241104

Claims (7)

1. 1. The application of magnolol nitrone derivative HL-3 shown in the formula (I) and pharmaceutically acceptable salt thereof in preparing medicaments for preventing or treating cerebral infarction;
2. 2. use according to claim 1, characterized in that the pharmaceutically acceptable salt is selected from organic or inorganic acid salts, including hydrochloride, hydrobromide, sulfate, phosphate, acetate, citrate, malate, fumarate, tartrate, mesylate, carbonate, oxalate, lactate, succinate or gluconate.
3. 3. Use of a pharmaceutical composition comprising HL-3 according to claim 1, and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for the manufacture of a medicament for the prevention or treatment of cerebral infarction.
4. 4. Use according to claim 3, characterized in that the pharmaceutically acceptable carrier is selected from the group consisting of lipid-based carriers, polymeric-based carriers, protein and polypeptide-based carriers, inorganic nanocarriers, carbon-based nanomaterials, hydrogels and biodegradable materials.
5. 5. The use according to claim 3, wherein the pharmaceutical composition is selected from the group consisting of solutions, emulsions, suspensions, injections, eye drops, nose drops, lotions and liniments, the solid dosage forms are tablets, capsules, granules, powders, pellets, dripping pills, suppositories, films, patches, aerosols, powder sprays, and the semisolid dosage forms are ointments, gels, pastes.
6. 6. The use according to claim 7, wherein the solution comprises true solution and colloidal solution, the emulsion comprises o/w type, w/o type and multiple emulsion, the injection comprises water injection, powder injection and transfusion, the tablet comprises common tablet, enteric tablet, lozenge, dispersible tablet, chewing tablet, effervescent tablet and orally disintegrating tablet, and the capsule comprises hard capsule, soft capsule and enteric capsule.
7. 7. The use according to claim 1, characterized in that the preparation method of HL-3 is: Wherein, the reaction condition (a) is 35% sodium hydroxide, chloroform as solvent and heating at 60 ℃, and the reaction condition (b) is R 2 NHOH, triethylamine, sodium sulfate, ethanol as solvent and heating at 90 ℃.

Description

Application of magnolol nitrone derivative HL-3 in preparation of medicines for preventing or treating cerebral infarction Technical Field The invention relates to the field of medicines, in particular to application of magnolol nitrone derivative HL-3 in preparation of medicines for preventing or treating cerebral infarction. Background Cerebral infarction (Ischemic Stroke) is a serious disease that results in hypoxia, injury and even death of brain tissue due to interruption or significant reduction of cerebral blood flow. Its major causes include atherosclerosis, thrombosis, and embolism. Cerebral infarction is one of the main causes of death and disability worldwide, has a great influence on the quality of life of patients, and the currently effective treatment means are still limited. The existing drug treatment mainly focuses on the aspects of restoring cerebral blood flow, preventing reocclusion and protecting nerves. Thrombolytic drugs such as tissue plasminogen activator (tPA) have significant efficacy in the acute phase, but their use is limited by a strict time window and is associated with bleeding risk. Antiplatelet agents (e.g., aspirin) and anticoagulant agents (e.g., warfarin and direct oral anticoagulant) play an important role in preventing relapse. However, new medicines such as the you tinib (Urokinase), the Cerebrolysin (brain activin) and the Edaravone (Edaravone) which are put forward in recent years show therapeutic potential, but have the limitations of inconsistent curative effect, unknown bleeding risk and action mechanism, and the like, which indicates that a great deal of unmet demands still exist in the cerebral infarction treatment field, and a wide innovation space is provided for novel treatment strategies and drug development. The nitrone compounds are compounds with strong free radical scavenging capability, have strong scavenging effect on various active free radicals, and are researched and found to have certain therapeutic effect on diseases (such as cancers, cerebral apoplexy, parkinsonism and the like) caused by various free radicals. We creatively synthesize a honokiol nitrone derivative HL-3, and speculate that the honokiol nitrone derivative can also play a certain role in preventing or treating cerebral infarction. Therefore, the main purpose of the invention is to verify the therapeutic effect of HL-3 on cerebral infarction through in vitro and in vivo models. Specifically, the oxygen glucose deprivation/reoxygenation injury (OGDR) model of SK-N-SH cells was used to simulate the cerebral ischemic environment to evaluate the neuroprotective effect of drugs at the cellular level. Meanwhile, the permanent middle cerebral artery occlusion (pMCAO) and the transient middle cerebral artery occlusion (tMCAO) of SD rats are adopted to further verify the therapeutic effect of the medicine in vivo, including the capability of reducing brain tissue injury and relieving nerve function defects. Through the experiments, the potential application value of the medicine in cerebral infarction treatment can be comprehensively estimated. Disclosure of Invention The invention solves the technical problem of application of magnolol nitrone derivative HL-3 in preparing medicines for preventing or treating cerebral infarction. The invention solves the technical problems, and provides the following technical scheme: The first aspect of the technical scheme of the invention provides application of magnolol nitrone derivative HL-3 and pharmaceutically acceptable salt thereof in preparing medicines for preventing or treating cerebral infarction. The preparation method of HL-3 comprises the following steps: Wherein, the reaction condition (a) is 35 percent sodium hydroxide, chloroform as solvent and heating at 60 ℃, and the reaction condition (b) is R 2 NHOH, triethylamine, sodium sulfate, ethanol as solvent and heating at 90 ℃; In a further aspect the invention relates to pharmaceutical compositions comprising the compounds of the invention as active ingredient. The pharmaceutical composition is prepared according to methods well known in the art. Any dosage form suitable for human or animal use may be made by combining the compounds of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are typically present in the pharmaceutical compositions thereof in an amount of 0.1 to 95% by weight. The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by the enteral or parenteral route, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral, ocular, pulmonary and respiratory routes, skin, vaginal, rectal and the like. The dosage form may be a liquid, solid or semi-solid dosage form. The liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w type, w/o type and multiple e