Search

CN-121987604-A - Application of magnolol nitrone derivative in preparation of medicament for preventing or treating amyotrophic lateral sclerosis

CN121987604ACN 121987604 ACN121987604 ACN 121987604ACN-121987604-A

Abstract

The invention belongs to the technical field of medicines, and discloses application of magnolol nitrone derivatives in preparation of medicines for preventing or treating amyotrophic lateral sclerosis. The survival rate of SOD1G93A cells and TDP43M337V cells is remarkably reduced compared with that of the empty vector control cell group, and the survival rate of SOD1G93A cells and TDP43M337V cells can be remarkably improved after 0.1 mu M HL-3 hours.

Inventors

  • PENG YING
  • ZHANG DONGMING
  • PANG BO
  • MA JIE
  • ZANG YINGDA
  • SUN JINGYING
  • LAN JIAQI
  • TANG JINGSHU

Assignees

  • 中国医学科学院药物研究所

Dates

Publication Date
20260508
Application Date
20241104

Claims (9)

  1. 1. The application of magnolol nitrone derivative shown in the general formula (I) and pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating amyotrophic lateral sclerosis: R 1 is selected from H、CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH 2 CH 2 CH 3 ;R 2 CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、t-Bu、Ph、Bn.
  2. 2. The application of magnolol nitrone derivative shown in the general formula (II) and pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating amyotrophic lateral sclerosis: R 3 、R 4 are independently selected from H or And R 3 、R 4 is not H at the same time, R 5 is selected from CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、t-Bu、Ph、Bn.
  3. 3. Use according to any one of claims 1 and 2, characterized in that said compound is selected from the group consisting of:
  4. 4. Use according to any one of claims 1-3, 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.
  5. 5. Use of a pharmaceutical composition for the preparation of a medicament for preventing or treating amyotrophic lateral sclerosis, wherein the pharmaceutical composition comprises a magnolol derivative according to any one of claims 1-3, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  6. 6. Use according to claim 5, 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.
  7. 7. The use according to claim 5, 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.
  8. 8. 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.
  9. 9. Use according to any one of claims 1-3, characterized in that the preparation method of the magnolol nitrone derivative is as follows: The compounds of the present invention represented by the general formula I can be prepared by the following method: The compounds of the present invention represented by the general formula II can be prepared by the following method: Wherein the reaction condition (a) is paraformaldehyde, magnesium chloride, triethylamine and anhydrous tetrahydrofuran as solvent, the temperature is 60 ℃, the reaction condition (b) is R 2 NHOH, triethylamine, sodium sulfate, ethanol as solvent, the temperature is 90 ℃, the reaction condition (c) is RI, potassium carbonate, tetrahydrofuran as solvent, the room temperature, the reaction condition (d) is i reactants urotropine, glacial acetic acid as solvent, the temperature is 130 ℃, and the temperature is 33% sulfuric acid and the temperature is 100 ℃. The reaction condition (e) was 35% sodium hydroxide, chloroform as a solvent, and heated at 60 ℃. In the above compounds, R 1 、R 2 is as defined for R 1 、R 2 of formula I; the compounds included in I (a) are HK-1, HK-2, HK-3, HK-4, HK-5; the compounds included in I (b) are HK-6, HK-7, HK-8, HK-9, HK-10; the compound included in II (a) is HL-1, HL-2, HL-3, HL-4, HL-5; the compound included in II (b) is HL-6, HL-7, HL-8, HL-9 and HL-10; The compound included in II (c) is HL-11, HL-12.

Description

Application of magnolol nitrone derivative in preparation of medicament for preventing or treating amyotrophic lateral sclerosis Technical Field The invention relates to the field of medicines, in particular to application of magnolol nitrone derivatives in preparation of medicines for preventing or treating amyotrophic lateral sclerosis. Background Amyotrophic lateral sclerosis (Amyotrophic lateral sclerosis, ALS) is a neurological degenerative disease of the brain cortex, brain stem and spinal motor neurons of unknown etiology, with clinical manifestations being dominated by progressive skeletal muscle atrophy, weakness, muscle beam tremor, bulbar paralysis and cone beam symptoms. The disease is hidden, patients have multiple dyspnea in the later stage of the disease, and the average survival time is 3-5 years. ALS is therefore a disease with short survival and poor prognosis. Currently, the U.S. Food and Drug Administration (FDA) approves 4 drugs in total for the treatment of ALS, riluzole, edaravone, relyvrio and toferson, respectively. Wherein, riluzole and edaravone are marketed in FDA in 1996 and 2017, respectively, and riluzole is a glutamate antagonist that can prolong the survival of ALS patients by about 3 months. Edaravone is a free radical/active oxygen scavenger that can slightly improve patient symptoms. Relyvrio and toferson are FDA approved drugs on the market for nearly two years, wherein relyvrio acts by improving endoplasmic reticulum health and delaying neuronal cell death, and relyvrio can delay the survival of ALS patients for 6.5 months according to the results of clinical trials during its II, while toferson is only applicable to ALS patients with SOD1 mutations, but the efficacy of both requires further demonstration of phase III clinical trials. Thus, there is an urgent need for drugs that are effective in treating ALS. ALS is divided into familial (FAMILY ALS, FALS) and sporadic two types, wherein fALS accounts for 5-10% of all ALS patients, and the rest patients are sporadic. However, studies have shown that the actual genetic mutation is associated with both familial and sporadic ALS, whereas superoxide dismutase 1 (SOD 1) is the first perceived mutant gene, and that approximately 20% and 2% of patients in fALS and sporadic ALS are associated with their mutations. In recent years, more studies have shown that gene mutations such as 43kDa TAR DNA Binding Protein 43 (TDP 43) are also closely related to the onset of ALS. 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 synthesized a batch of magnolol/honokiol nitrone derivatives, presumably to have a certain preventive or therapeutic effect on ALS. Therefore, the main purpose of the invention is to research whether the magnolol nitrone derivative can improve related pathological damage caused by SOD 1G 93A or TDP 43M 337V by taking SOD 1G 93A stably transfected cells and TDP 43M 337V stably transfected cells as models, and provide effective data support for the treatment and intervention of amyotrophic lateral sclerosis. Disclosure of Invention The invention solves the technical problem of application of magnolol nitrone derivatives in preparing medicaments for preventing or treating amyotrophic lateral sclerosis. 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 derivatives and pharmaceutically acceptable salts thereof in preparing medicaments for preventing or treating amyotrophic lateral sclerosis. The invention relates to magnolol nitrone derivative shown in a general formula I or pharmaceutically acceptable salt thereof: R 1 is selected from H、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3; R 2 is selected from CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3、CH2CH(CH3)2、t-Bu、Ph、Bn; The invention relates to honokiol nitrone derivative shown in a general formula II or pharmaceutically acceptable salt thereof: R 3、R4 are independently selected from H or And R 3、R4 is not H at the same time, R 5 is selected from CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2CH2CH2CH3、CH2CH(CH3)2、t-Bu、Ph、Bn; Some of the compounds of the present invention have the structure and number: The compounds of the present invention represented by the general formula I can be prepared by the following method: The compounds of the present invention represented by the general formula II can be prepared by the following method: Wherein the reaction condition (a) is paraformaldehyde, magnesium chloride, triethylamine and anhydrous tetrahydrofuran as solvent, the temperature is 60 ℃, the reaction condition (b) is R 2 NHOH, triethylamine, sodium sulfate, ethanol as sol