CN115501233B - 化合物在制备治疗和/或预防脱髓鞘疾病药物的用途 - Google Patents

化合物在制备治疗和/或预防脱髓鞘疾病药物的用途 Download PDF

Info

Publication number
CN115501233B
CN115501233B CN202211173609.XA CN202211173609A CN115501233B CN 115501233 B CN115501233 B CN 115501233B CN 202211173609 A CN202211173609 A CN 202211173609A CN 115501233 B CN115501233 B CN 115501233B
Authority
CN
China
Prior art keywords
demyelinating diseases
treating
formula
compound
medicament
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.)
Active
Application number
CN202211173609.XA
Other languages
English (en)
Other versions
CN115501233A (zh
Inventor
邓文斌
张豪杰
郭莹
刘焕彬
高宏
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.)
Sun Yat Sen University
Sun Yat Sen University Shenzhen Campus
Original Assignee
Sun Yat Sen University
Sun Yat Sen University Shenzhen Campus
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 Sun Yat Sen University, Sun Yat Sen University Shenzhen Campus filed Critical Sun Yat Sen University
Priority to CN202211173609.XA priority Critical patent/CN115501233B/zh
Publication of CN115501233A publication Critical patent/CN115501233A/zh
Application granted granted Critical
Publication of CN115501233B publication Critical patent/CN115501233B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245Oxadiazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52Purines, e.g. adenine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52Purines, e.g. adenine
    • A61K31/522Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs 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
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

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

Abstract

本发明提供化合物在制备治疗和/或预防脱髓鞘疾病药物的用途。本发明的式I~式V化合物可通过抑制TM7SF2提高胆固醇代谢途径中FF‑MAS的积累,促进少突胶质前体细胞向少突胶质细胞分化和成髓鞘;促进脱髓鞘疾病患者脑内原有少突胶质前体细胞向少突胶质细胞分化,形成髓鞘重新包裹轴突,恢复因髓鞘脱落损失引起的神经功能衰退,对脱髓鞘疾病具有治疗和/或减轻和/或预防作用。

Description

化合物在制备治疗和/或预防脱髓鞘疾病药物的用途
本申请为申请号202110880211.9、申请日2021年08月02日、发明名称“化合物在制备治疗和/或预防脱髓鞘疾病药物的应用”的分案申请。
技术领域
本发明属于化合物新应用技术领域,尤其涉及化合物在制备治疗和/或预防脱髓鞘疾病药物的用途。
背景技术
在脊椎动物中枢神经系统中(Central nervous system,CNS),轴突髓鞘化实现神经冲动跳跃式传导,加快神经冲动传导速度。少突胶质细胞(Oligodendrocyte,OL)和施万细胞(Schwann cell)分别产生中枢神经系统和外周神经系统(peripheral nervoussystem,PNS)的髓鞘。其中,OL由少突胶质前体细胞(oligodendrocyte precursor cell,OPC)分化产生。多发性硬化(Multiple sclerosis,MS)、格林-巴利综合征(Guillain-Barresyndrome)、视神经脊髓炎(Neuro myelitis optica,NMO)等多种脱髓鞘疾病会引发神经轴突髓鞘损伤和脱失,进而造成神经功能缺损。正常情况下,成年个体脑内储存OPC可以被招募迁移到病灶地区并分化成OL,从而产生髓鞘包围轴突。但是在病理条件下,这一过程受到阻碍。目前以靶向免疫系统的治疗方式能够减少脱髓鞘疾病中免疫介导的损伤,但是,无法促进髓鞘的再生和神经轴突的修复。
髓鞘主要成分是脂质,约占干重的70%,可保护轴突并实现神经冲动跳跃式传导,加快神经信号传导速度。成年个体脑内存有少突胶质前体细胞,但在脱髓鞘疾病病理条件下,脑内少突胶质前体细胞难以自主分化成为少突胶质细胞和产生髓鞘。因此,需要发现促进少突胶质前体细胞分化的新化合物。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此,本发明第一个方面提出化合物或其衍生物在制备治疗和/或预防脱髓鞘疾病药物的应用,能够有效治疗和/或预防脱髓鞘疾病。
本发明的第二个方面提出了一种治疗和/或预防脱髓鞘疾病的药物组合物。
根据本发明的第一个方面,提出了下列式I~式V化合物或其衍生物在制备治疗和/或预防脱髓鞘疾病药物的应用:
其中,式I化合物的CAS号为2096197-23-6,化学名称为:3-(3,5-二甲基-1H-吡唑-1-基)-N-({1-氧代-2-[(吡啶-3-基)甲基]-1H,2H,3H,4H-吡咯[1,2-a]吡嗪-3-基}甲基)丙酰胺(3-(3,5-dimethyl-1H-pyrazol-1-yl)-N-({1-oxo-2-[(pyridin-3-yl)methyl]-1H,2H,3H,4H-pyrrolo[1,2-a]pyrazin-3-yl}methyl)propenamide);式II化合物的CAS号为1775503-94-0,化学名称为1-[(2,3-二氢-1-苯并呋喃-5-基)甲基]-4-[3-(甲氧基甲基)-1,2,4-恶二唑-5-基]-N-甲基吡咯烷-3-甲酰胺
(1-[(2,3-dihydro-1-benzofuran-5-yl)methyl]-4-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]-N-methylpyrrolidine-3-carboxamide);式III化合物的CAS号为686301-37-1,化学名称为:5-(2-{6-氨基-9-[(2S,3S,4R,5S)-3,4-二羟基-5-(羟甲基)氧代兰-2-基]-9H-嘌呤-8-基}肼基-1-叶立德酮)-1,3-二嗪烷-2,4,6-三酮(5-(2-{6-amino-9-[(2S,3S,4R,5S)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-9H-purin-8-yl}hydrazin-1-ylidene)-1,3-diazinane-2,4,6-trione);式IV的CAS号为:714914-49-5,化学名称为:1,1′-(1,2-苯撑二(亚甲基))二(5-甲基嘧啶-2,4(1H,3H)-二酮)(1,1'-(1,2-phenylenebis(methylene))bis(5-methylpyrimidine-2,4(1H,3H)-dione));式V化合物的CAS号为931589-90-1,化学名称为:2-[[2,3,6,7-四氢-7-[2-(4-甲氧基苯基)乙基]-1,3-二甲基-2,6-二氧-1H-嘌呤-8-基]硫]-丁酸(2-[[2,3,6,7-tetrahydro-7-[2-(4-methoxyphenyl)ethyl]-1,3-dimethyl-2,6-dioxo-1H-purin-8-yl]thio]-butanoicacid)。
本发明中,式I~式V化合物通过抑制TM7SF2提高胆固醇代谢途径中FF-MAS(FollicularFluid Meiosis-activating Sterol,卵丘细胞分泌促减数分裂甾醇,CAS号为:64284-64-6)的积累,而FF-MAS的积累可以促进少突胶质前体细胞向少突胶质细胞分化和成髓鞘。
在本发明的一些实施方式中,所述衍生物包括其药学上可接受的盐、酯、水合物、溶剂化物、结晶形式、对映异构体、立体异构体、醚、代谢物和前药。
在本发明的一些优选的实施方式中,所述药学上可接受的盐包括但不仅限于无机酸盐,有机酸盐,烷基磺酸盐和芳基磺酸盐中的至少一种;优选地,所述无机酸盐包括但不仅限于盐酸盐、氢溴酸盐、硝酸盐、硫酸盐和磷酸盐中的至少一种;优选地,所述有机酸盐包括但不仅限于甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐和柠檬酸盐中的至少一种;优选地,所述烷基磺酸盐包括但不仅限于甲基磺酸盐和乙基磺酸盐中的至少一种;所述芳基磺酸盐包括但不仅限于苯磺酸盐和对甲苯磺酸盐中的至少一种。
在本发明的一些更优选的实施方式中,所述治疗和/或预防脱髓鞘疾病药物为促进髓鞘再生的药物。
在本发明的一些更优选的实施方式中,所述促进髓鞘再生的药物为促进少突胶质前体细胞分化成熟或促进髓鞘相关蛋白的表达的药物。
在本发明的一些更优选的实施方式中,所述治疗和/或预防脱髓鞘疾病药物是以所述式I~式V化合物中的任意一种作为唯一活性成分或者包含所述式I~式V化合物中的至少一种的药物组合物。
在本发明的一些更优选的实施方式中,所述治疗和/或预防脱髓鞘疾病药物中所述式I~式V化合物的任意一种的含量为0.1~99wt%;优选为1~90wt%;进一步优选为10~85wt%。
在本发明的一些更优选的实施方式中,所述治疗和/或预防脱髓鞘疾病药物为汤剂、散剂、丸剂、酒剂、锭剂、胶剂、膏药、茶剂、曲剂、糕剂、露剂、棒剂、线剂、条剂、钉剂,灸熨剂,膏剂、丹剂、微型胶囊、静脉乳剂、脂质体制剂、气雾剂、前体药制剂、注射剂、合剂、口服安瓿剂、片剂、胶囊剂、滴丸剂、乳剂、软膏剂、橡胶硬膏、膜剂、海绵剂、离子透入剂、透皮吸收剂。
根据本发明的第二个方面,提出了一种治疗和/或预防脱髓鞘疾病的药物组合物,由式I~式V化合物或其衍生物至少一种以及药学上可接受的辅料组成。
本发明的有益效果为:本发明的式I~式V化合物可通过抑制TM7SF2提高胆固醇代谢途径中FF-MAS的积累,促进少突胶质前体细胞向少突胶质细胞分化和成髓鞘;促进脱髓鞘疾病患者脑内原有少突胶质前体细胞向少突胶质细胞分化,形成髓鞘重新包裹轴突,恢复因髓鞘脱落损失引起的神经功能衰退,对脱髓鞘疾病具有治疗和/或减轻和/或预防作用。
附图说明
下面结合附图和实施例对本发明做进一步的说明,其中:
图1为本发明式I~式V化合物对少突胶质前体细胞分化促进的量效关系。
图2为本发明式I~式V化合物与DMSO阴性对照对少突胶质前体细胞分化作用的免疫荧光结果,标尺为100μm。
图3为本发明式I~式V化合物对少突胶质前体细胞分化作用的蛋白印迹结果。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述,以充分地理解本发明的目的、特征和效果。显然,所描述的实施例只是本发明的一部分实施例,而不是全部实施例,基于本发明的实施例,本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例,均属于本发明保护的范围。
实施例
式I~式V化合物对少突胶质前体细胞(OPC)分化的促进作用
实验方法:
为了研究证实式I~式V化合物对OPC分化的作用,验证式I~式V化合物可以促进OPC分化和成熟作用。
实验用细胞:原代培养的少突胶质前体细胞(OPC)。
实验用药物和抗体:
本发明药物:式I~式V化合物
阴性对照药物:DMSO
阳性对照药物:甲状腺素3(T3)
细胞培养:脱颈处死E14.5的ICR孕鼠,酒精棉球擦拭腹部后剖开,分离子宫,先后由75%酒精和PBS浸洗,转移到含有适量HBSS的60mm皿中,转至生物安全柜操作;解剖显微镜下,用镊子和手术剪从子宫中分离胎鼠。镊子撕开大脑皮肤/头骨,去掉嗅球,小脑和基底核,将剩余大脑皮层转移到含有NPC培养基的新60mm皿中。镊子剪去头,四肢,尾巴和内脏,躯干转移至另外含有冷PBS的60mm皿中,用于MEF提取;用手术剪将所有大脑皮层剪成1mm3小块,移液枪轻柔吹打,过40μm滤网,1000rpm离心5min,弃上清,加适量NPC培养基重悬,转移至100mm皿中悬浮培养(平均每皿中培养3个胎鼠提取出的细胞),计为P0代,培养2-3天或神经球直径到达100μm进行传代。
OPC分化实验:P5代神经球经Accutase酶消化成单细胞,按照4×104细胞/孔密度种到96孔板(预先多聚鸟氨酸和Laminin包被),OPC培养基培养2天将NPC诱导分化成OPC;弃掉OPC培养基,DPBS洗1次,更换为OL培养基,并分别加入0.05μM、0.1μM、1μM、20μM的式I~式V化合物,每块96孔板设阴性对照(DMSO,0.2%,v/v)和阳性对照(T3,100nM),分化3天将OPC分化成OL;将分化后的细胞用4%PFA固定,MBP(髓磷脂碱性蛋白,myelin basic protein,MBP)免疫荧光染色;染色结果用高内涵成像系统Scan-R成像,以MBP+细胞百分数为指标,选取DMSO阴性对照组为标准,MBP+细胞比例高于这个标准的为可促进OPC分化。
蛋白质提取与免疫印迹分析:
P5代神经球经Accutase酶消化成单细胞,按照1.2×106细胞/孔密度种到6孔板(预先由多聚鸟氨酸和Laminin包被)。按照上述分化方法,经两天的OPC分化和三天的OL分化后提取蛋白质;弃去培养基,DPBS洗1次。加入150μL/孔RAPI裂解液,4℃静置30min;刮棒收集,14000rpm,4℃离心15min,收集上清,使用BCA试剂盒测定蛋白浓度。加入速溶型蛋白上样缓冲液(变性,还原型,5×),100℃加热10min使蛋白变性,-20℃保存或立刻使用。
配制12%分离胶,加入TEMED后摇匀。灌入玻璃板中,加入去离子水液封,室温放置30min凝固;弃去去离子水,加入浓缩胶(已加TEMED),之后插入梳子,确保无气泡产生,室温放置20min凝固。冲洗胶板,放入电泳槽,加入足量电泳液,拔掉梳子,左右分别加入10μL和5μLMarker。中间加入蛋白样品。每组样品1加入15μL,同组其他样品根据BCA试剂盒测定吸光度值计算比值加入。120V恒压20min,使条带电泳至分离胶与浓缩胶分界线。之后100V电泳40min-60min至Marker充分展开。剪取合适大小的PVDF膜,浸入甲醇活化5min。加入适量转膜液至托盘,将滤纸和海绵垫浸入转膜液;撬开胶板,去除浓缩胶和周围多余分离胶。放置在滤纸上。打开转膜用夹子,按照黑面-海绵垫-滤纸-胶-PVDF膜-滤纸-海绵垫-白面放置,夹紧夹子;将夹子放入转膜槽,夹子黑面对应转膜槽黑面,白面对应转膜槽红面。倒入适量转膜液,并放两个小冰盒至转膜槽。之后置于冰中。300mA转膜1.5h。
从转膜槽中取出PVDF膜,加适量5%脱脂奶粉,室温振摇封闭2h;弃去5%脱脂奶粉,TBST洗3次,每次10min;加入适量一抗,4℃孵育过夜;吸走一抗,TBST洗3次,每次10min;加入适量二抗(2.5%脱脂奶粉稀释),室温摇晃孵育2h;吸走二抗,TBST洗3次,每次10min;发光显影成像:ECL增强化学发光液A液和B液等体积混合,均匀滴在膜上,仪器曝光成像。
结果如图1~图3所示,图1中,“**”表示为P<0.01,“***”表示为P<0.001,“****”表示为P<0.0001,当P<0.01时,与阴性对照组0.2%DMSO组比较,组间具有显著性差异。表示为可看出,式Ⅰ~式Ⅴ的MBP(少突胶质细胞成熟表达的蛋白)阳性细胞率(MBP+%)与化合物浓度之间具有相关性,其中0.05μM式Ⅰ、0.1μM式Ⅱ、0.1μM式Ⅲ、0.1μM式Ⅳ和1μM式Ⅴ与阴性对照组相比较具有最好的MBP阳性细胞率,即最好的促进少突胶质前体细胞分化活性。
图2中,蓝色表示为细胞核(由DAPI染色),红色表示为MBP,标尺为100μm,可看出,相较于阴性对照组0.2%DMSO组,式Ⅰ~式Ⅴ的MBP表达量明显升高,直接证明式Ⅰ~式Ⅴ在相应浓度下能够促进少突胶质前体细胞分化成熟。
从图3可以看出,根据MBP蛋白表达量情况,式Ⅰ~式Ⅴ的MBP表达高于阴性对照组0.2%DMSO组,即式Ⅰ~式Ⅴ促进MBP表达,表明式Ⅰ~式Ⅴ能够促进少突胶质前体细胞分化成熟。
上面对本发明实施例作了详细说明,但是本发明不限于上述实施例,在所属技术领域普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下作出各种变化。此外,在不冲突的情况下,本发明的实施例及实施例中的特征可以相互组合。

Claims (8)

1.式IV化合物或其药学上可接受的盐在制备治疗和/或预防脱髓鞘疾病药物的应用:
2.根据权利要求1所述的应用,其特征在于:所述治疗和/或预防脱髓鞘疾病药物为促进髓鞘再生的药物。
3.根据权利要求2所述的应用,其特征在于:所述促进髓鞘再生的药物为促进少突胶质前体细胞分化成熟或促进髓鞘相关蛋白的表达的药物。
4.根据权利要求1所述的应用,其特征在于:所述治疗和/或预防脱髓鞘疾病药物是以所述式IV化合物作为唯一活性成分或者包含所述式IV化合物的药物组合物。
5.根据权利要求1所述的应用,其特征在于:所述治疗和/或预防脱髓鞘疾病药物中所述式IV化合物的含量为0.1~99wt%。
6.根据权利要求1所述的应用,其特征在于:所述治疗和/或预防脱髓鞘疾病药物中所述式IV化合物的含量为1~90 wt %。
7.根据权利要求1所述的应用,其特征在于:所述治疗和/或预防脱髓鞘疾病药物为汤剂、散剂、丸剂、酒剂、锭剂、胶剂、茶剂、曲剂、糕剂、露剂、棒剂、线剂、条剂、钉剂、灸熨剂、膏剂、丹剂、脂质体制剂、气雾剂、注射剂、合剂、片剂、胶囊剂、滴丸剂、乳剂、膜剂、海绵剂、离子透入剂、透皮吸收剂。
8.一种治疗和/或预防脱髓鞘疾病的药物组合物,其特征在于:由如权利要求1所述的式IV化合物或其药学上可接受的盐至少一种以及药学上可接受的辅料组成。
CN202211173609.XA 2021-08-02 2021-08-02 化合物在制备治疗和/或预防脱髓鞘疾病药物的用途 Active CN115501233B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202211173609.XA CN115501233B (zh) 2021-08-02 2021-08-02 化合物在制备治疗和/或预防脱髓鞘疾病药物的用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211173609.XA CN115501233B (zh) 2021-08-02 2021-08-02 化合物在制备治疗和/或预防脱髓鞘疾病药物的用途
CN202110880211.9A CN113616657B (zh) 2021-08-02 2021-08-02 化合物在制备治疗和/或预防脱髓鞘疾病药物的应用

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN202110880211.9A Division CN113616657B (zh) 2021-08-02 2021-08-02 化合物在制备治疗和/或预防脱髓鞘疾病药物的应用

Publications (2)

Publication Number Publication Date
CN115501233A CN115501233A (zh) 2022-12-23
CN115501233B true CN115501233B (zh) 2023-11-07

Family

ID=78382175

Family Applications (5)

Application Number Title Priority Date Filing Date
CN202211173846.6A Active CN115501234B (zh) 2021-08-02 2021-08-02 化合物在制备防治脱髓鞘疾病药物的用途
CN202110880211.9A Active CN113616657B (zh) 2021-08-02 2021-08-02 化合物在制备治疗和/或预防脱髓鞘疾病药物的应用
CN202211173609.XA Active CN115501233B (zh) 2021-08-02 2021-08-02 化合物在制备治疗和/或预防脱髓鞘疾病药物的用途
CN202211174824.1A Active CN115501235B (zh) 2021-08-02 2021-08-02 一种化合物在制备防治脱髓鞘疾病药物的应用
CN202211173737.4A Active CN115501227B (zh) 2021-08-02 2021-08-02 化合物在制备防治脱髓鞘疾病药物的应用

Family Applications Before (2)

Application Number Title Priority Date Filing Date
CN202211173846.6A Active CN115501234B (zh) 2021-08-02 2021-08-02 化合物在制备防治脱髓鞘疾病药物的用途
CN202110880211.9A Active CN113616657B (zh) 2021-08-02 2021-08-02 化合物在制备治疗和/或预防脱髓鞘疾病药物的应用

Family Applications After (2)

Application Number Title Priority Date Filing Date
CN202211174824.1A Active CN115501235B (zh) 2021-08-02 2021-08-02 一种化合物在制备防治脱髓鞘疾病药物的应用
CN202211173737.4A Active CN115501227B (zh) 2021-08-02 2021-08-02 化合物在制备防治脱髓鞘疾病药物的应用

Country Status (1)

Country Link
CN (5) CN115501234B (zh)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108379246A (zh) * 2018-05-16 2018-08-10 中国人民解放军第二军医大学 莽草酸在制备预防或治疗脱髓鞘疾病药物中的应用
WO2020072456A1 (en) * 2018-10-02 2020-04-09 Case Western Reserve University Compounds for treating myelin related disorders

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2001267882A1 (en) * 2000-06-30 2002-01-14 Chugai Seiyaku Kabushiki Kaisha Preventives and remedies for diseases in association with demyelination
WO2004037159A2 (en) * 2002-10-23 2004-05-06 Obetherapy Biotechnology Compounds, compositions and methods for modulating fat metabolism
US9551036B2 (en) * 2013-02-25 2017-01-24 Whitehead Institute For Biomedical Research Metabolic gene mesenchymal signatures and uses thereof
JP6308699B2 (ja) * 2014-09-08 2018-04-11 国立大学法人大阪大学 脱髄疾患の予防又は治療剤
CA3031818A1 (en) * 2016-07-27 2018-02-01 Case Western Reserve University Compounds and methods of promoting myelination
MX2019001757A (es) * 2016-08-12 2019-08-16 Univ California Terapias de remielinizacion.
WO2019126759A1 (en) * 2017-12-22 2019-06-27 Convelo Therapeutics, Inc. Compounds and methods of promoting myelination
US20210023218A1 (en) * 2018-03-08 2021-01-28 The Scripps Research Institute Methods for promoting myelination and for treating demyelinating diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108379246A (zh) * 2018-05-16 2018-08-10 中国人民解放军第二军医大学 莽草酸在制备预防或治疗脱髓鞘疾病药物中的应用
WO2020072456A1 (en) * 2018-10-02 2020-04-09 Case Western Reserve University Compounds for treating myelin related disorders

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Diverse chemical scaffolds enhance oligodendrocyte formation by inhibiting CYP51, TM7SF2, or EBP";Dharmaraja Allimuthu等;Cell Chem Biol;第26卷(第4期);593–599 *
714-914-49-5.STN on the web.2004,结构式. *
SOLID STATE PHOTODIMERIZATION OF THYMINE DERIVATIVES XYLENE DERIVATIVES;NORIMUTSU THONAI 等;Journal of Photopolymer Science and Technology;第9卷(第1期);63-64 *

Also Published As

Publication number Publication date
CN113616657A (zh) 2021-11-09
CN115501234A (zh) 2022-12-23
CN115501235A (zh) 2022-12-23
CN115501233A (zh) 2022-12-23
CN115501235B (zh) 2023-11-07
CN115501227B (zh) 2023-09-19
CN115501234B (zh) 2023-08-08
CN113616657B (zh) 2022-12-20
CN115501227A (zh) 2022-12-23

Similar Documents

Publication Publication Date Title
WO2018004143A1 (ko) 성체줄기세포 유래의 엑소좀-모사 나노베지클을 포함하는 혈관 신생 촉진용 조성물
JP7486328B2 (ja) 神経突起伸長促進剤、神経細胞の樹状突起発現促進剤、及び神経栄養因子様作用物質
JP2021522822A (ja) 幹細胞由来の細胞培養物、幹細胞由来の三次元組織製品、及びそれらの製造及び使用方法
Alemdar et al. Liposomal formulations of tacrolimus and rapamycin increase graft survival and fiber outgrowth of dopaminergic grafts
CN115501233B (zh) 化合物在制备治疗和/或预防脱髓鞘疾病药物的用途
Yan et al. Effects of vestibular damage on the sleep and expression level of orexin in the hypothalamus of rats and its correlation with autophagy and Akt tumor signal pathway
CN102625707A (zh) Hip/pap或其衍生物的新应用
JP6994613B2 (ja) 神経発生性疾患および障害を処置する方法
CN108159045B (zh) 红波罗花碱a及其衍生物在制备预防或治疗中枢神经系统疾病药物中的应用
JP4232866B2 (ja) 細胞障害抑制剤
JP4625419B2 (ja) 神経細胞生長発育及び神経幹細胞生成促進化合物
CN116747230A (zh) 促进髓鞘再生的化合物及其在治疗阿尔茨海默病中应用
CN108938631B (zh) Sag在制备治疗发育期缺氧缺血脑损伤疾病的药物中的应用
WO2011140682A1 (zh) (2e)-3-苯基-n-[2,2,2-三氯-1-[[(8-喹啉基氨基)硫代甲基]氨基]乙基]-2-丙烯酰胺及其医药用途
CN111973606B (zh) 一种化合物治疗血管增生以及糖尿病视网膜病变的新用途
CN116036239B (zh) Nep1-40在制备特异性抑制幻觉作用的药物中的应用
TWI804455B (zh) 羅索沙星在抑制三陰性乳癌的轉移上的用途
CN106631871A (zh) 一种神经酰胺类化合物和应用
CN116459261A (zh) Lit-001在治疗焦虑疾病中的应用
CN112121049A (zh) 顺式阿曲库铵在制备治疗男性性腺功能减退症的药物中的应用
CN117582430A (zh) 富马酸二甲酯在制备降低顺铂所致耳毒性药物中的应用
CN113181216A (zh) 一种间充质干细胞外泌体-am1241复合体及其在治疗阿尔茨海默病中的应用
CN117919238A (zh) 麦角硫因在制备治疗和改善帕金森的药物中应用

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant