[go: up one dir, main page]

WO2025113038A1 - Composé précurseur à base de structure d'édaravone et son procédé de préparation et son utilisation - Google Patents

Composé précurseur à base de structure d'édaravone et son procédé de préparation et son utilisation Download PDF

Info

Publication number
WO2025113038A1
WO2025113038A1 PCT/CN2024/128013 CN2024128013W WO2025113038A1 WO 2025113038 A1 WO2025113038 A1 WO 2025113038A1 CN 2024128013 W CN2024128013 W CN 2024128013W WO 2025113038 A1 WO2025113038 A1 WO 2025113038A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
edaravone
precursor compound
compound based
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/128013
Other languages
English (en)
Chinese (zh)
Inventor
李建波
张金洁
塞田叶尔太
张硕
张捷柯
郭军
黄静雯
张梦壹
王辰旭
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhengzhou University
Original Assignee
Zhengzhou University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhengzhou University filed Critical Zhengzhou University
Publication of WO2025113038A1 publication Critical patent/WO2025113038A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present application belongs to the technical field of organic chemical synthesis, and relates to a precursor compound based on the structure of edaravone, and a preparation method and application thereof.
  • Free radicals also known as "free radicals" in chemistry, are groups of atoms containing an unpaired electron. Since electrons must appear in pairs in chemical bonds when atoms form molecules, free radicals need to seize an electron from other substances to form stable substances. In chemistry, this phenomenon is called “oxidation”. Oxygen free radicals are mainly involved in biological systems, such as superoxide anion free radicals, hydroxyl free radicals, and lipid oxygen free radicals. Reactive oxygen free radicals in the body have certain functions, such as immunity and signal transduction processes, and the body's built-in antioxidant system plays a decisive role in preventing damage caused by free radicals.
  • oxidative stress causes free radicals to attack nerve cells, especially the damage and degeneration of the central nervous system is catastrophic, such as stroke, amyotrophic lateral sclerosis (ALS), Alzheimer's (AD), Parkinson's disease (PD), etc.
  • ALS amyotrophic lateral sclerosis
  • AD Alzheimer's
  • PD Parkinson's disease
  • Cerebral stroke is also known as "stroke”. It is an acute cerebrovascular disease. It is a group of diseases caused by brain tissue damage due to sudden rupture of brain blood vessels or blood vessel blockage that prevents blood from flowing into the brain. This disease not only has a high mortality rate, but is also one of the leading causes of disability among adults in my country.
  • the pathological mechanism that leads to sequelae of cerebral stroke and disability after treatment is that a large amount of reactive oxygen and free radicals are produced around the brain lesions during blood reperfusion after cerebral ischemia. These free radicals will cause irreversible damage to nerve cells and brain cells through cell membrane damage, protein damage, nucleic acid/DNA damage, and induction of various inflammatory mediators, and ultimately lead to the death of nerve cells or brain cells. Therefore, if only intravenous or thrombolytic therapy is used in the clinical treatment of stroke, it is difficult to completely solve and prevent the sequelae and disability problems and hidden dangers caused by free radical nerve damage to patients.
  • ALS amyotrophic lateral sclerosis
  • Lou Gehrig's disease is also a disease characterized by the damage, atrophy and death of nerve cells. Its pathogenesis has not yet been determined, but biology has proven that the disease is associated with superoxide dismutase (SOD). Mutation of SOD superoxide dismutase is one of the causes of ALS, which prevents SOD from decomposing harmful substances such as free radicals in mitochondria through dismutation reactions, thereby causing extensive damage to nerves.
  • SOD superoxide dismutase
  • AD Alzheimer's disease
  • oxidative stress is one of the hallmarks of Alzheimer's disease.
  • the free radicals in the oxidative stress response can promote the production of A ⁇ and tau protein phosphorylation, the abnormal accumulation of A ⁇ and other proteins, and can cause mutations in neuronal DNA and RNA, promoting the overall progression of AD.
  • Parkinson's disease is a chronic neurodegenerative disease that occurs frequently in middle-aged and elderly people. Its characteristic pathological changes are degeneration and necrosis of dopaminergic neurons in the substantia nigra, which in turn leads to a decrease in the content of dopamine (DA) in the striatum. The etiology is still unclear. Mitochondrial dysfunction, oxidative stress, uncontrolled iron metabolism, aging, and excitotoxic neurotoxicity all ultimately lead to excessive formation of free radicals, which in turn lead to neuronal death. Scavenging free radicals has become a promising treatment for PD.
  • Free radical damage is an important influencing factor causing many diseases such as central nervous system damage and degeneration. Free radical scavenging and antioxidant therapy are important means of treating many of the above central nervous system diseases.
  • the purpose of the present application is to provide a precursor compound based on the structure of edaravone or a pharmaceutically acceptable salt thereof, a preparation method and application.
  • the compound or a pharmaceutically acceptable salt thereof provided in the present application has good water solubility, improves the drug's concentration in the brain, the brain retention time, and thus improves the drug's effect.
  • the first aspect of the present application provides a precursor compound based on the structure of edaravone or a pharmaceutically acceptable salt thereof, having a general structural formula I
  • R1, R2, R3, and R4 are each independently selected from hydrogen, halogen, hydroxyl, thiol, nitro, amino, acetylamino, cyano, acetoxy, acetate, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, and trifluoromethoxy;
  • X is selected from Nitrogen, CH2, oxygen or sulfur; m is a natural number selected from 0 to 4; A is R6 and R7 are each independently selected from a hydrogen atom, a C1-C6 alkyl group, a C3-C7 cycloalkyl group or a C1-C5 alkyloxy C1-C5 alkyl group; or A is a C3-C10 heterocycle or substituted heterocycle containing 1 N atom.
  • R1, R2, R3, and R4 are all hydrogen; X is arbitrarily selected from CH2 or oxygen, and m is 0 or 2; A Selected from Or A is selected from
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-phenyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the salt is prepared by reacting the precursor compound based on the edaravone structure with an acid;
  • the acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, nicotinic acid, camphoric acid, gluconic acid, glucose Uronic acid, methanesulfonic acid, ethanesulfonic acid, aminosulfonic acid or p-toluenesulfonic acid.
  • the second aspect of the present application provides a method for preparing a precursor compound based on the edaravone structure, comprising:
  • the precursor compound based on the structure of edaravone according to the first aspect of the present application is prepared by acylation reaction with edaravone; wherein R1, R2, R3, and R4 are each independently selected from hydrogen, halogen, hydroxyl alkyl, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, trifluoromethoxy; m is a natural number selected from 0 to 4; Y is a halogen selected from Cl, Br or I;
  • R6 and R7 are each independently selected from a hydrogen atom, a C1-C6 alkyl group, a C3-C7 cycloalkyl group, a C1-C5 alkyloxy group, and a C1-C5 alkyl group;
  • A is a 3-10 membered heterocyclic ring or a substituted heterocyclic ring containing 1 N atom.
  • m is selected from 0 or 2; Y is selected from Cl; R1, R2, R3 and R4 are hydrogen atoms; A is selected from Or A is selected from
  • the third aspect of the present application provides an application of a precursor compound based on the structure of edaravone or a pharmaceutically acceptable salt thereof, wherein the precursor compound based on the structure of edaravone is used to prepare a drug for preventing or treating central nervous system damage and central nervous system degeneration diseases.
  • the central nervous system injury and central nervous system degenerative diseases include stroke, amyotrophic lateral sclerosis, Alzheimer's disease or Parkinson's disease.
  • the dosage form of the drug includes tablets, suppositories, soft capsules, hard capsules, solutions, suspensions, aerosols, injections, lyophilized powder injections, sustained-release preparations or various microparticle delivery systems, and is administered orally, intranasally, rectally, percutaneously or by injection.
  • the drug is in the form of an injection.
  • the present application provides a precursor compound based on the structure of edaravone or a pharmaceutically acceptable salt thereof, a preparation method and application thereof.
  • the compound or a pharmaceutically acceptable salt thereof of the present application has good water solubility and can release the free drug edaravone in the brain, making it significantly higher than the brain aggregation concentration of the original drug edaravone, prolonging the retention time of the drug in the brain, thereby improving the effect of the drug.
  • FIG1 is a graph comparing the concentrations of a precursor compound based on the structure of edaravone and edaravone in brain tissue in an embodiment of the present application;
  • FIG2 is a graph showing the concentration distribution of commercially available edaravone in different tissues at different times
  • FIG3 is a concentration distribution diagram of compound 1 of the present application in different tissues at different times;
  • FIG4 is a concentration distribution diagram of compound 2 of the present application in different tissues at different times;
  • FIG5 is a comparison of brain infarction foci after treatment with compounds 1 to 2 of the present application and the control group;
  • Figure 6 is a comparative diagram of the evaluation of intracellular oxidative stress levels and inflammatory levels in rats treated with compounds 1 to 2 of the present application and the control group; wherein Figure 6A is a comparative diagram of MDA obtained by different treatments, Figure 6B is a comparative diagram of SOD obtained by different treatments, Figure 6C is a comparative diagram of GSH-Px obtained by different treatments, Figure 6D is a comparative diagram of CAT obtained by different treatments, Figure 6E is a comparative diagram of TNF- ⁇ obtained by different treatments, and Figure 6F is a comparative diagram of TGF- ⁇ obtained by different treatments;
  • FIG7 is a comparison of the results of H&E staining and Nissl staining after treatment with compounds 1 to 2 of the present application and the control group;
  • FIG8 is a comparison chart of the ROS staining results after treatment with compounds 1 to 2 of the present application and the control group.
  • Free radical damage is an important factor causing many diseases such as central nervous system damage and degeneration. Free radical scavenging and antioxidant therapy are important means of treating many of the above central nervous system diseases.
  • 3-Methyl-1-phenyl-2-pyrazol-5-one also known as edaravone, is a new type of brain protective agent. It scavenges free radicals and inhibits lipid peroxidation, thereby inhibiting oxidative damage to brain cells, vascular endothelial cells, and nerve cells, and plays a brain protective role.
  • the main dosage form of edaravone used in clinical practice is injection.
  • the pKa of edaravone is 6.9 ⁇ 0.1. Therefore, under physiological pH conditions, about 50% of edaravone is ionized and exists in anionic form. This form is also a more reactive form. It is easy to react with ROS in the body and can provide 1 electron to free radicals to achieve the purpose of scavenging free radicals and produce antioxidant effects.
  • ROS reactive oxygen species
  • the existing technology mainly increases its content in the currently prepared preparations by adding antioxidants and cosolvents during the preparation process, such as adding sodium bisulfite, cysteine hydrochloride, etc., which will cause allergic reactions when used intravenously, which may bring unnecessary side effects or potential health hazards to patients; 2 Due to the existence of the blood-brain barrier, the anionic form of edaravone is difficult to pass through the blood-brain barrier, resulting in a small effective dose reaching the central nervous system, which is limited in the treatment of brain central nervous system diseases.
  • the present application provides a precursor compound based on the structure of edaravone and a preparation method and application thereof, which are described in detail below in conjunction with the accompanying drawings.
  • This experiment investigated the brain targeting of compounds 1 to 5 prepared in this application in vivo by a mouse in vivo distribution experiment.
  • the specific experimental process is as follows: 100 Kunming mice that meet the experimental criteria are randomly divided into 6 groups, including commercially available edaravone (PMP) group, compound 1 group, compound 2 group, compound 3 group, compound 4 group, and compound 5 group. Before the experiment, the tested Kunming mice were fasted for 12 hours and allowed to drink water freely. Among them, PMP was administered intravenously at 50 mg/kg, and compounds 1 to 5 were administered at equimolar doses with PMP.
  • PMP edaravone
  • FIG1 shows the contents of edaravone, compound 1, compound 2, compound 4 and compound 5 in brain tissue at 1 minute.
  • the compounds of the present application have a higher concentration in brain tissue at the same time point than commercially available edaravone.
  • compounds 1 to 5 are represented by Compound 1 to 5. *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001 indicate that the experimental group is significantly different from the PMP group.
  • the Kunming mice were fasted for 12 hours and allowed to drink water freely.
  • Edaravone was intravenously administered at 50 mg/kg, and compound 1 and compound 2 were administered at equimolar doses with PMP. After the injection, the mice were killed by dislocation of the neck at 1, 3, 5, 10, and 15 minutes, and tissue samples such as brain, heart, liver, spleen, lung, and kidney were taken out respectively. Then, each drug was treated according to the in vivo sample treatment method, and 5 Kunming mice were used at each time point. The contents of Edaravone, compound 1, and compound 2 in brain tissue at different time points are shown in Figures 2 to 4.
  • the present application calculates the brain targeting evaluation index after intravenous injection of drugs in mice.
  • the various pharmacokinetic parameters are calculated using DAS (Data Analysis System) software, where the targeting evaluation indexes are the relative uptake rate Re and the peak concentration ratio Ce . These two indexes are used to evaluate the brain targeting of drugs. A value greater than 1 indicates that the drug has brain targeting, and a value greater than 1 indicates that the drug has brain targeting. The larger the value, the better the brain targeting effect of the drug.
  • the calculation formula is shown below, and the results of the brain targeting evaluation index after intravenous injection of the drug in mice are statistically shown in Table 1.
  • the relative uptake rate of the precursor compound based on edaravone provided by the present application is as high as 5.11-11.76, and the peak concentration ratio is as high as 6.49-12.19. This shows that compared with edaravone sold on the market, the precursor compound based on edaravone in the present application can effectively increase the accumulation of edaravone in the brain and has significant in vivo brain targeting.
  • the specific experimental process is as follows: SPF-level male SD rats, weighing 250 ⁇ 5g, were fasted for 12h before the experiment and had free access to water. The rats were randomly divided into 8 groups, namely, edaravone (PMP) group, compound 1 group, compound 2 group, sham operation group, neck surgery and vascular treatment model group (MCAO group), etc., a total of 5 groups.
  • PMP edaravone
  • MCAO group vascular treatment model group
  • the rat focal cerebral ischemia-reperfusion model was established with reference to the modified Zea-Longa suture method.
  • the rats were anesthetized by intraperitoneal injection of sodium pentobarbital 1%, 45 mg/kg, and the dosage was increased or decreased according to the animal's anesthesia condition.
  • the rats were fixed in the center of the operating table in a supine position.
  • the rats were disinfected 0.5 cm below the mandible in the anterior neck area, and a longitudinal incision was made in the middle right of the neck.
  • the muscles and fascia were separated with microscissors to expose the common carotid artery (CCA) to the visual field, and the vagus nerve under the CCA was separated.
  • CCA common carotid artery
  • the external carotid artery (ECA) and the internal carotid artery (ICA) were found along the CCA.
  • the CCA and ECA were ligated with auxiliary lines, and the ICA was clamped with micro-artery clamps.
  • a wound was cut about 10 mm below the ligature of the CCA, and the suture was inserted.
  • the auxiliary line was slightly tightened, the micro-artery clamp was removed, and the suture was slowly sent into the ICA until there was slight resistance, the auxiliary line was tightened, the suture was marked, and the suture was sutured. After 1 hour, reperfusion was performed and the suture was withdrawn into the CCA to restore blood supply to the middle cerebral artery. No suture was inserted in the sham operation group (Sham).
  • the corresponding drugs were administered by intravenous injection. Neck surgery and vascular treatment were the same as the model group (MCAO group), PMP (3 mg/kg) was given, compound 1 group was given compound 1 (7.08 mg/kg, equimolar to PMP), compound 2 group was given compound 2 (7.08 mg/kg, equimolar to PMP), and the sham operation group was given normal saline (same volume as PMP). After 24 hours of drug treatment, the animals were killed and the brains were removed. The residual blood was rinsed with normal saline, and subsequent experiments were performed. The whole process was carried out at room temperature (24-25°C).
  • the sign of the success of the model is the appearance of Horner's sign and hemiplegia mainly in the contralateral forelimb after the model animal wakes up from anesthesia.
  • the various pathological indicators of the rats were measured 24 hours after reperfusion.
  • the TTC method was used to detect the area of cerebral infarction, and the results are shown in Figure 5.
  • SOD Superoxide dismutase
  • GSH-Px glutathione peroxidase
  • MDA malondialdehyde
  • CAT catalase
  • SOD is an important endogenous antioxidant enzyme that catalyzes the conversion of superoxide free radicals produced by cell mitochondria into hydrogen peroxide and oxygen to exert antioxidant effects and reduce the damage of reactive oxygen species to cells.
  • MDA as one of the secondary products of lipid oxidation, can aggravate tissue oxidative damage, so it is a lipid peroxidase.
  • An important indicator of oxidation used to evaluate the level of tissue oxidative stress.
  • GSH-Px is an antioxidant enzyme present in mitochondria that inhibits lipid peroxidation, thereby protecting cells from oxidative stress and thus protecting cells from oxidative stress damage.
  • CAT exists in the peroxisome of cells and generally has a protective and detoxifying effect on the human body. It can remove reactive oxygen species (ROS) produced in the body, so it is used to evaluate the level of intracellular oxidative stress.
  • ROS reactive oxygen species
  • Tumor necrosis factor-alpha TNF- ⁇
  • TGF- ⁇ transforming growth factor- ⁇
  • TNF- ⁇ TNF- ⁇
  • TGF- ⁇ TGF- ⁇
  • TNF- ⁇ TNF- ⁇
  • TGF- ⁇ TGF- ⁇
  • TGF- ⁇ TGF- ⁇
  • TGF- ⁇ TGF- ⁇
  • TGF- ⁇ TGF- ⁇
  • TGF- ⁇ TGF- ⁇
  • TGF- ⁇ TGF- ⁇
  • TGF- ⁇ is a member of the transforming growth factor family. It is a polypeptide cytokine with multiple biological functions. It is produced by lymphocytes, NK cells and macrophages, and has anti-infection and antiviral effects. It is often used to evaluate the level of inflammation.
  • rats were given physiological saline (equal volume with PMP), PMP, compound 1 and compound 2 with equal molar amount with PMP) according to the grouping 1 hour after reperfusion.
  • the rats were killed and the brains were removed 24 hours after drug treatment.
  • the residual blood was washed with physiological saline, and the weight was weighed after absorbing the water, and the antioxidant factors and inflammatory factors were detected according to the corresponding instructions.
  • the results are shown in Figure 3.
  • NNSSL Nissl staining
  • ROS brain tissue reactive oxygen species immunofluorescence staining
  • the brain neurons of the control group (Sham group) are clearly visible, the cytoplasm is dark, the nuclei are purple-blue and round, the morphology is normal and closely arranged, and there are no pathological changes.
  • the number of cells in the model group (MCAO group) is significantly reduced, the nucleus staining becomes lighter, the interstitial space becomes larger, a large number of neurons die, and the integrity is low.
  • the number of nuclear condensation in the model rats is significantly reduced, the number of normal cells increases, and the interstitial space is basically the same as the control group, indicating that compound 1 and compound 2 can significantly reduce brain tissue damage and have a good therapeutic effect on stroke.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Sont divulgués dans la présente demande un composé précurseur à base de structure d'édaravone, ou un sel pharmaceutiquement acceptable de celui-ci, son procédé de préparation et son utilisation. Le composé ou le sel pharmaceutiquement acceptable de celui-ci selon la présente demande présente une solubilité dans l'eau relativement bonne, et peut libérer l'édaravone médicamenteuse libre dans le cerveau pour que la concentration en édaravone médicamenteuse libre accumulée dans le cerveau soit significativement supérieure à celle de l'édaravone médicamenteuse brute, ce qui permet de prolonger le temps de séjour du médicament dans le cerveau, et d'améliorer ainsi l'effet d'action du médicament.
PCT/CN2024/128013 2023-11-28 2024-10-29 Composé précurseur à base de structure d'édaravone et son procédé de préparation et son utilisation Pending WO2025113038A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202311600626.1A CN117843573A (zh) 2023-11-28 2023-11-28 一种基于依达拉奉结构的前体化合物及其制备方法和应用
CN202311600626.1 2023-11-28

Publications (1)

Publication Number Publication Date
WO2025113038A1 true WO2025113038A1 (fr) 2025-06-05

Family

ID=90535577

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/128013 Pending WO2025113038A1 (fr) 2023-11-28 2024-10-29 Composé précurseur à base de structure d'édaravone et son procédé de préparation et son utilisation

Country Status (2)

Country Link
CN (1) CN117843573A (fr)
WO (1) WO2025113038A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117843573A (zh) * 2023-11-28 2024-04-09 郑州大学 一种基于依达拉奉结构的前体化合物及其制备方法和应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112714760A (zh) * 2018-09-17 2021-04-27 J2H生物科技有限公司 依达拉奉前体药物化合物及其在治疗或改善神经退行性或运动神经元疾病中的医药用途
WO2021107686A1 (fr) * 2019-11-28 2021-06-03 제이투에이치바이오텍 주식회사 Composé de promédicament d'edaravone et son utilisation pharmaceutique pour le traitement ou le soulagement de maladies neurodégénératives ou motoneuronales
CN113024422A (zh) * 2021-03-12 2021-06-25 中国医学科学院放射医学研究所 丁苯酞开环化合物、药物化合物以及它们的制备方法、组合物和应用
CN116751132A (zh) * 2023-05-25 2023-09-15 郑州大学 一种脑靶向的丙泊酚前体药物及其制备方法和应用
CN116836118A (zh) * 2023-08-02 2023-10-03 郑州大学 一种基于依达拉奉的前体化合物、制备方法和应用
CN117843573A (zh) * 2023-11-28 2024-04-09 郑州大学 一种基于依达拉奉结构的前体化合物及其制备方法和应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112714760A (zh) * 2018-09-17 2021-04-27 J2H生物科技有限公司 依达拉奉前体药物化合物及其在治疗或改善神经退行性或运动神经元疾病中的医药用途
WO2021107686A1 (fr) * 2019-11-28 2021-06-03 제이투에이치바이오텍 주식회사 Composé de promédicament d'edaravone et son utilisation pharmaceutique pour le traitement ou le soulagement de maladies neurodégénératives ou motoneuronales
CN113024422A (zh) * 2021-03-12 2021-06-25 中国医学科学院放射医学研究所 丁苯酞开环化合物、药物化合物以及它们的制备方法、组合物和应用
CN116751132A (zh) * 2023-05-25 2023-09-15 郑州大学 一种脑靶向的丙泊酚前体药物及其制备方法和应用
CN116836118A (zh) * 2023-08-02 2023-10-03 郑州大学 一种基于依达拉奉的前体化合物、制备方法和应用
CN117843573A (zh) * 2023-11-28 2024-04-09 郑州大学 一种基于依达拉奉结构的前体化合物及其制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LI XUEJIAO, WANG XINXIN, MIAO LONGFEI, GUO YUYING, YUAN RENBIN, TIAN HONGQI: "Design, synthesis, and neuroprotective effects of novel hybrid compounds containing edaravone analogue and 3-n-butylphthalide ring-opened derivatives", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ELSEVIER, AMSTERDAM NL, vol. 556, 1 June 2021 (2021-06-01), Amsterdam NL , pages 99 - 105, XP093320787, ISSN: 0006-291X, DOI: 10.1016/j.bbrc.2021.03.171 *

Also Published As

Publication number Publication date
CN117843573A (zh) 2024-04-09

Similar Documents

Publication Publication Date Title
KR850000072B1 (ko) 5-(2-포르밀-3-히드록시페녹시)펜타노익산류
EP0719551A2 (fr) Séparation d'aminoarginin, utilisée pour bloquer la formation d'oxyde nitrique dans le corps
US5158883A (en) Method of using aminoarginine to block nitric oxide formation in vitro
KR102563378B1 (ko) 2-(1-아실옥시-n-펜틸)벤조산 및 염기성 아미노산 또는 아미노구아니딘이 형성하는 염, 이의 제조 방법 및 용도
JPS636058B2 (fr)
WO2025113038A1 (fr) Composé précurseur à base de structure d'édaravone et son procédé de préparation et son utilisation
CN113336704A (zh) 丹参素衍生物及其制备方法和医药用途
SU1635899A3 (ru) Способ получени 3-[(1Н-имидазол-4-ил)метил]-2-оксибензолметанолов
WO2019218864A1 (fr) MÉDICAMENT DÉRIVÉ D'AMINE D'ESTER ORGANIQUE DE L'ACIDE 2-(α-HYDROXYPENTYL)BENZOÏQUE
CN107753469B (zh) Ndga类似物在制备抗氧化药物中的应用
US4897423A (en) Dinitrobenzenesulfonamides
WO2004110449A1 (fr) Aporphine et oxoaporphine et leur utilisation a des fins medicales
WO2018068696A1 (fr) Sinoménine pégylée et dérivé associé, et procédé de préparation et utilisation de ceux-ci
WO2023134732A9 (fr) Prévention ou traitement de maladies cardiovasculaires à l'aide de promédicaments d'aspirine et d'autres ains à forte pénétration
CN101658522A (zh) 他克林短链二聚体在制备治疗神经退行性疾病药物中的应用
CN116836118A (zh) 一种基于依达拉奉的前体化合物、制备方法和应用
CN113387909B (zh) 2,3-环氧丁二酰衍生物的医药用途
CA1133913A (fr) N-(1-methyl-2-pyrrolidinyl-methyl)-2,3-dimethoxy-5- methylsulfamoyl benzamide et ses derives; leurs methodes de preparation, et leur utilisation dans le traitement de troubles de l'appareil urinaire inferieur
AU2019218153B2 (en) Therapeutic drug for neurodegenerative disease and application thereof
CN106946866A (zh) 一种预防和治疗脑卒中的药物及其制备方法
JP2711939B2 (ja) ６−クロロ−５−フルオロ−３−（２−テノイル）−２−オキシンドール−１−カルボキサミドのリジン塩
CN114315689B (zh) 二硫烷基邻苯二甲酰亚胺类化合物、其制备方法和用途
JPH09157236A (ja) フェニレンジアミン誘導体及びラジカルスカベンジャー、脳梗塞抑制剤、脳浮腫抑制剤
JPWO2003087091A1 (ja) キノキサリンジオン誘導体無水物の新規結晶
US20240025868A1 (en) Phenothiazine compounds for the treatment of alzheimer's disease and other age-related and neurological diseases

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24896129

Country of ref document: EP

Kind code of ref document: A1