CN112358449A - 一种用于治疗脑卒中的含氮杂环化合物 - Google Patents
一种用于治疗脑卒中的含氮杂环化合物 Download PDFInfo
- Publication number
- CN112358449A CN112358449A CN202011304746.3A CN202011304746A CN112358449A CN 112358449 A CN112358449 A CN 112358449A CN 202011304746 A CN202011304746 A CN 202011304746A CN 112358449 A CN112358449 A CN 112358449A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- cerebral apoplexy
- cerebral
- pharmaceutically acceptable
- 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
Links
- 208000006011 Stroke Diseases 0.000 title claims abstract description 25
- 206010008190 Cerebrovascular accident Diseases 0.000 title abstract description 18
- 230000002490 cerebral effect Effects 0.000 title abstract description 17
- -1 Nitrogen-containing heterocyclic compound Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- 238000011282 treatment Methods 0.000 claims description 13
- 208000032382 Ischaemic stroke Diseases 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 5
- 229940126214 compound 3 Drugs 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 206010008118 cerebral infarction Diseases 0.000 abstract description 14
- 230000010410 reperfusion Effects 0.000 abstract description 9
- 201000006474 Brain Ischemia Diseases 0.000 abstract description 8
- 206010008120 Cerebral ischaemia Diseases 0.000 abstract description 8
- 230000000302 ischemic effect Effects 0.000 abstract description 8
- 238000012360 testing method Methods 0.000 abstract description 8
- 208000026106 cerebrovascular disease Diseases 0.000 abstract description 5
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 210000005013 brain tissue Anatomy 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 208000028867 ischemia Diseases 0.000 description 5
- 206010061216 Infarction Diseases 0.000 description 4
- 210000001367 artery Anatomy 0.000 description 4
- 210000004004 carotid artery internal Anatomy 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000007574 infarction Effects 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 208000028389 Nerve injury Diseases 0.000 description 3
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 description 3
- 229950009041 edaravone Drugs 0.000 description 3
- 230000008764 nerve damage Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229930189533 tanshinol Natural products 0.000 description 3
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010063837 Reperfusion injury Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 210000001168 carotid artery common Anatomy 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000003255 drug test Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 210000002551 anterior cerebral artery Anatomy 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000000269 carotid artery external Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000004744 fore-foot Anatomy 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000003657 middle cerebral artery Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000003188 neurobehavioral effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000023516 stroke disease Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229940126673 western medicines Drugs 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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
- C07D231/26—1-Phenyl-3-methyl-5- pyrazolones, unsubstituted or substituted on the phenyl ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种预防和治疗脑卒中特别是缺血性脑卒中的化合物,其在小鼠脑缺血再灌注试验中,显示出良好的治疗活性,其能够显著降低脑梗塞比例,能够用于预防和治疗脑卒中特别是缺血性脑卒中。
Description
技术领域
本发明涉及药物化学领域,具体涉及一种预防和治疗脑卒中特别是缺血性脑卒中的化合物,本发明还涉及所述化合物的制备方法、药物组合物及用途。
背景技术
第三次国民死因调查结果证实脑卒中已成为我国第一位死因,且年增长率超过8.7%,已严重影响国人生命健康。脑卒中主要分为缺血性卒中 (Ischemic stroke,IS)和出血性卒中(Hemorrhagic stroke,HS)两类,其中IS型病患占总发病患者的四分之三,是脑卒中致病的主要类型。IS救治的关键是“早诊断早干预”,目前的各种治疗均试图通过早期梗死脑组织血流再通来挽救缺血的脑组织,但其短暂的“治疗时间窗”阻碍了该治疗方式的推广。对于诸多患者,特别是在医疗条件相对落后、卒中救治体系相对薄弱的贫困和基层地区,患者就医时往往已经超出“治疗时间窗”,现有溶栓治疗已远远无法达到有效救治的目的。因此,亟待寻求高效、便于推广的IS救治方法。
目前的药物治疗脑卒中旨在阻断缺血导致的神经元坏死、延长耐受性缺血时间和治疗时间窗,增强神经元生存能力,逆转半暗带,减少梗死体积,促进神经功能恢复。
依达拉奉是由日本三菱东京株式会社开发的一种新型神经保护剂,是一种强效的自由基清除剂,于2001年在日本上市,用于治疗脑梗塞引起的神经病变,鉴于依达拉奉的抗氧化作用,其对缺血性脑卒中有良好的治疗效果。
研究表明,丹参素可以改善心肌缺血-再灌注损伤,对冠心病、心肌梗死的防治具有显著疗效,其脑保护作用也逐渐得到认可,能够快速透过血脑屏障到达梗死区域发挥疗效,有望成为改善脑I/R损伤的理想药物(参见“中风与神经疾病杂志”,袁晓捧等,36(6),571-573,2019年6月)。因此,本发明人通过分子拼合原理,将依达拉奉和丹参素引入同一分子结构中,并通过小鼠脑缺血再灌注试验,筛选出一个具有潜在治疗脑卒中活性的化合物。
综上所述,虽然各种化学药和天然药物处于不同研究阶段,但目前上市的治疗脑卒中药物中尚未有将依达拉奉和丹参素片段拼接的药物。因此,开发和研究具有治疗脑卒中活性的新化合物具有重要的临床意义。
发明内容
本发明所要解决的技术问题是:
本发明的第一个方面,是提供一种式I所示化合物及其药学上可接受的盐,其具有如下结构:
优选地,所述药学上可接受的盐选自:盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、乙酸盐、草酸盐、酒石酸盐等等;
本发明的另一方面提供一种制备式I化合物的方法,其合成路线如下:
化合物2与化合物3在缩合试剂作用下反应生成式I化合物。
具体反应步骤如下:将化合物2、7-氮杂-1-羟基苯并三唑(HOAt)、7-氮杂苯并三唑-1-基氧基三(吡咯烷基)鏻六氟磷酸盐(PyAOP)、二异丙基乙胺(DIPEA) 以及DMSO加入到反应瓶中,搅拌20-30min,加入化合物3的DMSO溶液,室温下搅拌反应12-20h,经后处理得到目标产物I。
优选地,化合物2与化合物3的投料摩尔比为1-2:1,优选为1.5:1。
本发明的另一方面提供一种药物组合物,其包含式I所示的化合物或其药学上可接受的盐,以及药学上可接受的载体、赋形剂。
本发明另一方面涉及一种式I化合物及其药学上可接受的盐或包含其药物组合物在制备治疗脑卒中的药物中的应用;优选地,所述脑卒中为缺血性脑卒中。
与现有技术相比,本发明的有益效果是:
(1)本发明提供了一类新的具有含氮杂环的治疗脑卒中化合物,拓宽了现有脑卒中治疗化合物的范围,可作为先导化合物继续优化;
(2)本发明式I所示的化合物在小鼠脑缺血再灌注试验中,显示出良好的治疗活性,能够用于预防和治疗脑卒中特别是缺血性脑卒中。
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。本发明化合物可以用合成领域技术人员熟知的许多方法来制备。式I化合物可以使用下面列出的反应和技术连同合成有机化学领域已知的方法或本领域技术人员所理解的其变体来制备。优选的方法包括但不限于下面描述的那些方法。反应在适用于所用试剂和材料且适用于要实现的转化的溶剂中进行。此外,在下面描述的合成方法中,应理解所有建议的反应条件(包括溶剂、反应气氛、反应温度、实验持续时间和后处理程序的选择)都选择为该反应的标准条件,这应该被有机合成领域技术人员容易确认。并非所有落入给定类别的化合物可以与某些所述方法中需要的某些反应条件相容。对与反应条件相容的取代基的这些限制将对于本领域技术人员而言是显而易见的,并且可使用替代方法。
实施例1:化合物I的合成
将化合物2(283mg,1.5mmol)、HOAt(273mg,2mmol)、PyAOP(1044mg, 2mmol)、DIPEA(347μL,2mmol)以及10mL DMSO加入到150mL三颈烧瓶中,搅拌15min,加入化合物3(198mg,1mmol)的DMSO(10mL)溶液,加毕,室温下搅拌反应18h,TLC检测反应结束后,加入20mL水以及30mL二氯甲烷,萃取后静置分液,有机相经硅胶柱层析分离得到黄褐色固体状的目标产物 I,收率49%,HPLC纯度97.6%。
分子式:C19H19N3O5;ESI-MS:370.72[M+H]+
1H NMR(400MHz,CDCl3)δ1.90(s,3H),2.19(s,3H),2.83(s,1H),3.12 (m,2H),4.59(m,1H),5.43(d,2H),6.63-6.81(m,3H),7.60(m,2H), 7.85(m,2H)。
实施例2:式I所示化合物治疗缺血性脑卒中的作用
小鼠线栓法制作局灶性脑缺血模型的药理实验是验证药物具有防治缺血性脑卒中作用是常用的动物实验。用栓线法制备ICR小鼠脑缺血再灌注模型(制备方法详见《西药新药临床前研究指导原则汇编》的药学药理学毒理学部分,中华人民共和国卫生部药政管理局,1993:73;《药理实验方法学》第二版,人民卫生出版社,1982:830、1113),除假手术组外,其余各组均用该模型鼠试验。
1、动物
ICR小鼠,雄性,体重20~22g。每组20只,共分3组,化合物I组:1mg/kg;假手术组:给予与药物实验组等量的生理盐水进行假手术;模型组:给予与药物实验组等量的生理盐水进行脑缺血再灌注手术。
2、实验方法
将小鼠用10%水合氯醛腹腔注射麻醉,颈正中切口,分离、结扎右侧颈总动脉近心端、颈外动脉及其分支动脉。分离右侧颈内动脉,沿颈内动脉向下分离翼颚动脉,根部结扎该分枝。在颈内动脉近端备线、远端放置动脉夹,颈总动脉分叉处切口,插入尼龙线,栓线进入颈内动脉,入颅至大脑前动脉,阻断大脑中动脉所有血流来源。撤掉动脉夹,扎紧备线,外留1cm长线头,缝合皮肤。缺血1 小时后静脉注射给药。继续缺血1小时后再灌注。再灌注8小时再次注射给药。假手术组除不插线外,其余步骤同上。
观察再灌注24小时后存活鼠以下指标:
(1)对脑梗塞体积的影响:每组取10只小鼠,处死取大脑,切下厚约2mm冠状脑片,立刻置于2%TTC溶液中,37℃孵育30分钟。梗塞区呈现白色,非梗塞区呈现红色。数码相机拍摄记录,用计算机图像处理测出各区面积,并计算梗塞区占整个脑组织的百分比(%)。
(2)观察存活鼠24小时后行为变化,进行行为学评分:参考Zea Longa的5 分制评分标准:0分为正常,无神经损伤症状;1分为不能完全伸展对侧前爪;2 分为向外侧转圈;3分为向对侧倾倒;4分为不能自发行走,意识丧失。
3、实验结果
表1:实验各组小鼠脑缺血再灌注后的脑梗塞面积
注:与模型组相比,#P<0.01
试验结果表明:假手术组小鼠脑组织无梗塞。模型组小鼠缺血侧脑组织有明显梗塞现象,脑梗塞/全脑(%)为50.6±3.6%。而化合物I在较低剂量时即可显著降低脑梗塞百分比,该结果证明上述试验化合物可以对小鼠脑缺血再灌注损伤引起的脑梗塞起到很好的保护作用。
表2:实验各组小鼠脑缺血再灌注后的神经行为学评分
分组 | 剂量(mg/Kg) | 行为学评分(分) |
假手术组 | - | 0 |
模型组 | - | 3.8±0.4<sup>#</sup> |
化合物I组 | 1 | 1.1±0.3<sup>#</sup> |
注:与模型组相比,#P<0.05
试验结果表明:假手术组小鼠未表现出任何异常症状。而模型组小鼠出现或向外侧转圈、或向对侧倾倒、或不能完全伸展对侧前爪的神经损伤症状。化合物I在较低剂量时即可显著降低缺血再灌注小鼠的行为评分,该结果证明上述试验化合物可以明显改善因缺血再灌注引起的神经损伤症状。
以上描述了本发明优选实施方式,然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。
Claims (6)
2.根据权利要求1所述的式I化合物或其药学上可接受的盐,所述药学上可接受的盐选自:盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、乙酸盐、草酸盐、酒石酸盐等。
4.一种药物组合物,其包含权利要求1-2任一项所述式I化合物或其药学上可接受的盐,以及药学上可接受的载体。
5.权利要求1-2任一项所述的式I所示的化合物或其药学上可接受的盐在制备治疗脑卒中的药物中的应用。
6.根据权利要求5所述的应用,其特征在于,所述脑卒中为缺血性脑卒中。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011304746.3A CN112358449A (zh) | 2020-11-19 | 2020-11-19 | 一种用于治疗脑卒中的含氮杂环化合物 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011304746.3A CN112358449A (zh) | 2020-11-19 | 2020-11-19 | 一种用于治疗脑卒中的含氮杂环化合物 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112358449A true CN112358449A (zh) | 2021-02-12 |
Family
ID=74534001
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202011304746.3A Pending CN112358449A (zh) | 2020-11-19 | 2020-11-19 | 一种用于治疗脑卒中的含氮杂环化合物 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN112358449A (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112979663A (zh) * | 2021-05-17 | 2021-06-18 | 深圳市第二人民医院(深圳市转化医学研究院) | 一种具有神经康复作用的含氮化合物及其应用 |
CN113336704A (zh) * | 2021-06-11 | 2021-09-03 | 上海大学 | 丹参素衍生物及其制备方法和医药用途 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060223837A1 (en) * | 2005-03-24 | 2006-10-05 | Ellen Codd | Biaryl derived amide modulators of vanilloid VR1 receptor |
CN106831686A (zh) * | 2017-03-13 | 2017-06-13 | 牡丹江医学院 | 一种用于预防和治疗缺血性脑卒中的药物及其用途 |
-
2020
- 2020-11-19 CN CN202011304746.3A patent/CN112358449A/zh active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060223837A1 (en) * | 2005-03-24 | 2006-10-05 | Ellen Codd | Biaryl derived amide modulators of vanilloid VR1 receptor |
CN106831686A (zh) * | 2017-03-13 | 2017-06-13 | 牡丹江医学院 | 一种用于预防和治疗缺血性脑卒中的药物及其用途 |
Non-Patent Citations (1)
Title |
---|
平丽红 等: "《实用治疗药物学》", 31 March 2018 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112979663A (zh) * | 2021-05-17 | 2021-06-18 | 深圳市第二人民医院(深圳市转化医学研究院) | 一种具有神经康复作用的含氮化合物及其应用 |
CN113336704A (zh) * | 2021-06-11 | 2021-09-03 | 上海大学 | 丹参素衍生物及其制备方法和医药用途 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JPH02233610A (ja) | 血管新生阻害剤 | |
EP3305291B1 (en) | Uses of benzimidazole derivative for nocturnal acid breakthrough | |
CN112358449A (zh) | 一种用于治疗脑卒中的含氮杂环化合物 | |
AU2017366514A1 (en) | Piperidine-2,6-dione derivative and treatment for ulcerative colitis | |
WO2011006653A1 (en) | An agent for restoring lost memory on the basis of n,n'-substituted 3,7-diazabicyclo[3.3.1] nonanes | |
CN110613726B (zh) | 核苷化合物的应用 | |
WO2008124823A1 (en) | Method of treating melanoma | |
CN112266382A (zh) | 一种用于治疗脑卒中的含硫杂环化合物 | |
CN112209920A (zh) | 一种用于治疗脑卒中的含氧杂环化合物 | |
NL7908101A (nl) | Nieuwe farmaceutische preparaten met analgetische, anti-pyretische en/of anti-inflammatore activiteit. | |
US4918193A (en) | Methods for preparing 3-[N-phenyl-acetylaminopiperidine]-2,6-dion | |
JP2010155861A (ja) | 末梢神経系の疾患の治療のためのピリミジンヌクレオチドの使用 | |
RU2721282C2 (ru) | Способ лечения рассеянного склероза (варианты) | |
HUT69710A (en) | The use of quinoline-3-carboxamide compounds for preparing pharmaceutical compositions suitable for treatment of diabetes | |
US7956079B2 (en) | Antihepatitis C virus agent and anti-HIV agent | |
JPH07507280A (ja) | (−)−メトリフォネート含有薬剤 | |
AU2015363757B2 (en) | Diarylmethylidene piperidine derivatives and their use as delta opioid receptor agonists | |
CN113827603B (zh) | 瑞德西韦在制备治疗胶质瘤药物中的应用 | |
US3961064A (en) | Pharmaceutical composition for remedy of hyperammoniemia | |
CN110551121B (zh) | 谷氨酰胺酰氨基正己酰咔啉羧酸苄酯,其制备,活性和应用 | |
US3864487A (en) | Antiarhythmic pharmaceutical preparation containing ethyl 10-{60 -morpholylpropionyl) phenthiazine-2-carbamate hydrochloride | |
US4894393A (en) | Dithiocarbamate-choline adduts and use thereof in treatment of brain diseases | |
JP3681770B2 (ja) | 老年性痴呆症又はアルツハイマー病治療剤 | |
US20220362202A1 (en) | Drug For Treating And Preventing Dementia | |
JPS59231057A (ja) | カルボン酸アミド化合物およびその誘導体 |
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 | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210212 |
|
RJ01 | Rejection of invention patent application after publication |