WO2023060785A1 - 硝酮嗪衍生物在缺血性脑卒中治疗中的应用 - Google Patents

硝酮嗪衍生物在缺血性脑卒中治疗中的应用 Download PDF

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WO2023060785A1
WO2023060785A1 PCT/CN2022/000140 CN2022000140W WO2023060785A1 WO 2023060785 A1 WO2023060785 A1 WO 2023060785A1 CN 2022000140 W CN2022000140 W CN 2022000140W WO 2023060785 A1 WO2023060785 A1 WO 2023060785A1
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ischemic stroke
nitrozine
recanalization
treatment
group
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French (fr)
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刘伟
古建波
殷刚
王玉强
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广州喜鹊医药有限公司
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    • 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
    • A61K31/4965Non-condensed pyrazines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs 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

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  • the invention belongs to the technical field of biomedicine, and specifically relates to the application of nitrozine derivatives in the treatment of ischemic stroke and the preparation of medicines.
  • Stroke is a disease with cerebral ischemia or hemorrhagic injury as the main clinical manifestation. Stroke is divided into hemorrhagic stroke and ischemic stroke. The incidence of ischemic stroke is higher than that of hemorrhagic stroke, accounting for 60% to 70% of the total stroke. Ischemic stroke is mainly caused by cerebral embolism and local thrombus formation. Vascular stenosis and thromboembolism caused by atherosclerosis or emboli from the heart follow the blood flow to the brain, causing cerebral embolism, causing brain blood supply disorders, resulting in brain tissue ischemia and hypoxia leading to brain tissue necrosis, and eventually Cause a series of neurological deficits and obstacles to patients.
  • Stroke has become the number one cause of death in my country and the leading cause of disability among Chinese adults. Stroke has the characteristics of rapid onset and serious condition. Delay in medical treatment and treatment after the onset of stroke is the root cause of death and disability. There is a strict time window for the treatment of this urgent and critical disease. The length of time from onset to treatment directly determines the success rate of treatment.
  • Acute cerebral infarction lesions are composed of the ischemic center area and the surrounding ischemic penumbra. The brain tissue damage in the ischemic center area is characterized by irreversibility, while the ischemic penumbra has a large number of reversible state neurons.
  • Brain tissue ischemia and hypoxia at the site of embolism caused by intracranial vascular occlusion will cause electrochemical cascade cascade reactions in brain cells, coupled activation of signaling pathways in the damaged cells, and irreversible damage to the disease.
  • the blocked blood vessels can be opened in a short period of time and the blood circulation in the ischemic penumbra can be rebuilt, it will be beneficial to the survival and functional recovery of nerve cells in this area.
  • thrombolytic drugs commonly used clinically include streptokinase (streptokinase, SK), urokinase (urokinase, UK), anisyl plasminogen streptokinase activator complex (APSAC), recombinant staphylokinase (staphylokinase, SAK), tissue Type plasminogen activatorreteplase (tissuse plasminogen activator, t-PA), reteplase, lanoteplase, etc.
  • streptokinase streptokinase, SK
  • urokinase urokinase
  • APSAC anisyl plasminogen streptokinase activator complex
  • SAK recombinant staphylokinase
  • tissue Type plasminogen activator alteplase
  • t-PA tissue Type plasminogen activator reteplase
  • lanoteplase
  • fibrinolytic drugs can dissolve thrombus better, they usually have a short treatment time window.
  • the recombinant tissue plasminogen activator alteplase must be used within 6 hours after the onset of stroke.
  • most stroke survivors suffer from permanent neurological deficits (Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011; 473(7347) : 298-307).
  • the present invention provides the application of nitrozine derivatives and pharmaceutical compositions thereof in the treatment of ischemic stroke and the preparation of corresponding medicines.
  • nitrozine derivatives of the present invention have the structure of formula (I):
  • R 1 , R 2 and R 3 are independently C1-C6 alkyl;
  • R 4 is sec-butyl, isobutyl, tert-butyl, cyclopentyl or cyclohexyl.
  • the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl.
  • R 1 , R 2 and R 3 are all methyl, and R 4 is tert-butyl, so that the nitrozine derivative is nitrozine (abbreviated as TBN), molecular formula: C 12 H 19 N 3 O, chemical name: cis-2-methyl-N-[(3,5,6-trimethylpyrazine-2-)methine]2-propylamine oxide, the structure is as follows:
  • the present invention provides the application of the nitrozine derivative and its pharmaceutical composition in the treatment of ischemic stroke, comprising administering a therapeutically effective dose of the nitrozine derivative or its pharmaceutical composition, and recanalizing the occluded blood vessel Combined use.
  • the present invention also provides the application of the nitrozine derivatives in the preparation of corresponding medicines.
  • the recanalization of the occluded vessel is mechanical thrombectomy or drug thrombolysis.
  • the thrombolytic drug for thrombolysis of the drug is selected from the group consisting of streptokinase (streptokinase, SK), urokinase (urokinase, UK), anisyl plasminogen streptokinase activator complex (APSAC), histostaphylokinase (Recombinant Stapylokinase -Sak), tissue-type plasminogen activator alteplase (tissuse plasminogen activator, t-PA), prourokinase (prourokinase), nattokinase (nattokinase, NK), lumbrokinase (Lumbrukinase), Retidy reteplase, tenecteplase (TNK-tPA), monteplase, lanoteplase (NPA), desmoteplase, pamiteplase , solinase), t
  • the thrombolytic drug of the present invention is alteplase (t-PA).
  • the mechanical thrombectomy described in the present invention is used in combination with a nitroxazine derivative.
  • the dosage of the thrombolytic drug of the present invention is determined by the clinician according to the severity of the disease, the response of the disease, any treatment-related toxicity, the patient's age, the patient's weight and health status during thrombolysis.
  • the number of doses can be in accordance with conventional methods in the art.
  • the therapeutically effective dose of the nitrozine derivatives in the present invention is 100-3000 mg/person/time.
  • the specific amount administered will depend on the severity of the disease, the response of the disease, any toxicity associated with the treatment, the age and state of health of the patient.
  • the specific administration method and administration times can be in accordance with the conventional administration methods of nitroxazine derivatives, for example, it can be administered one or more times per day.
  • the recanalization of the occluded vessel and the nitroxazine derivative can be performed simultaneously or sequentially. In certain embodiments, both are administered to the patient at the same time. In certain embodiments, the recanalization of the occluded vessel is administered to the patient prior to administration of the Nitronazine Derivative. In certain embodiments, recanalization of the occluded vessel is administered to the patient subsequent to administration of the Nitronazine Derivative.
  • the time difference between the recanalization of the occluded vessel and the nitrozine derivative is no more than 24 hours, and in certain more specific embodiments, the time difference between the recanalization of the occluded vessel and the nitrozine derivative is no more than 12 hours. .
  • the ischemic stroke in the present invention is acute ischemic stroke.
  • the nitroxazine derivative as an active pharmaceutical component is formulated into a pharmaceutical composition using a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is in any form suitable for oral, sublingual, topical inhalation (nasal spray), rectal, intramuscular, intradermal, subcutaneous or intravenous administration.
  • the amount of a composition of the invention required for treatment will vary depending on the route of administration, the nature of the condition being treated, the age and health of the patient, and is ultimately at the discretion of the participating clinician.
  • the desired dose may be presented in a single dose or in divided doses at appropriate intervals, eg, two, three or more times daily, as required to achieve or achieve therapy.
  • pharmaceutically acceptable carrier refers to a substance that does not interfere with the physiological effects of the nitroxazine derivatives and is non-toxic to mammals including humans.
  • the pharmaceutical composition of the nitrozine derivatives of the present invention is formulated by methods known to those skilled in the art using the nitrozine derivatives and pharmaceutically acceptable carriers. These compositions include, but are not limited to, solids, capsules, pills, suppositories, liquids (such as injections), oils, emulsions, sprays, gels, aerosols, inhalants, and patches.
  • thrombolytic drugs such as alteplase (t-PA) are used for thrombolytic therapy of ischemic stroke. After thrombolytic therapy, most stroke survivors still suffer from permanent neurological deficits (Carmeliet P , Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011; 473(7347): 298-307).
  • nitroxazine + t-PA significantly improved the NIHSS score of neurological function of patients on the 14th day and the 90th day.
  • the combined use of nitrozine + t-PA significantly improved the neurological mRS score of patients, and the complete cure rate (mRS 0 points) was greatly improved compared with that of the t-PA group alone; the prognosis of combined use of nitrozine + t-PA (mRS 0-2 points) significantly improved compared with the t-PA group alone.
  • Figure 1 is a graph showing the proportion of patients with NHISS scores of 0-1 points in the t-PA group and the combined administration group;
  • Fig. 3 is a graph showing the proportion of patients with mRS ⁇ 2 points in the t-PA group and the combined administration group.
  • the present invention adopts multi-center, random, double-blind, parallel trial clinical research design.
  • Patients with acute ischemic stroke included in the clinical trial center were used as subjects (all signed informed consent), and were divided into non-thrombolysis group and thrombolysis group.
  • the non-thrombolysis group was normal saline (saline) group and nitroxazine group.
  • Thrombolysis group was t-PA group and nitrozine+t-PA combined administration group.
  • Administration method 1400 mg of the drug nitroxazine is dissolved in a sodium chloride injection bag (specification: 100 mL), and administered intravenously, and the administration time is 30 minutes.
  • t-PA dose: 0.9mg/Kg/time
  • usage add to normal saline
  • 10% of the dose is immediately injected intravenously within 1-2 minutes
  • the remaining 90% is intravenously injected within 60 minutes.
  • t-PA was administered only once on the first day of acute ischemic stroke.
  • Medication schedule of nitrosazine D1-D7 administered twice a day, with an interval of 12 hours, for 7 consecutive days.
  • the nitroxazine group significantly improved the neurological function of the patients on the 30th and 90th days, and the percentage of patients with mRS 0-1 points increased by 6.6 and 3.3 percentage points respectively compared with the Saline control group.
  • the Lsmeans mRS (1.12) of the nitrosine + t-PA combined administration group improved by 0.49 points compared with the Lsmeans mRS (1.61) of the t-PA group, that is, every 2 people improved 1 point. It can be understood that after treatment, compared with every 10 patients in the t-PA group who could not take care of themselves, only 5 patients could not take care of themselves after the combined administration, and 5 patients could take care of themselves, which greatly improved the quality of these 5 patients. quality of life.
  • Nitronazine derivatives have good safety and tolerability.
  • the inventors have learned from research that after thrombolysis, it is more favorable for the nitroxazine derivatives to reach the lesion site, and it is more conducive to the survival of nerve cells and the recovery of nerve function at the lesion site. Based on this finding, in the treatment of ischemic stroke, more nitroxazine derivatives will reach the lesion site after mechanical thrombectomy or other thrombolytic drugs, which is also conducive to the survival and functional recovery of nerve cells in the lesion site.

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Abstract

本发明提供硝酮嗪衍生物在缺血性脑卒中治疗中的应用,其包括施用治疗有效量的硝酮嗪衍生物或其药物组合物。临床实验中,出乎意料的发现,硝酮嗪+t-PA明显改善患者第30天和第90天的神经功能NIHSS评分。此外,硝酮嗪+t-PA明显改善患者的神经功能mRS评分,完全治愈率(mRS 0分)比单用t-PA组大大提高。

Description

硝酮嗪衍生物在缺血性脑卒中治疗中的应用 技术领域
本发明属于生物医药技术领域,具体涉及硝酮嗪衍生物在缺血性脑卒中的治疗和药物制备中的应用。
背景技术
脑卒中是以脑部缺血或出血性损伤为主要临床表现的疾病。脑卒中分为出血性脑卒中和缺血性脑卒中两类。缺血性脑卒中的发病率高于出血性脑卒中,占脑卒中总数的60%~70%。缺血性脑卒中主要是由于脑栓塞及局部血栓的形成所致。动脉粥样硬化引起的血管狭窄、血栓栓塞或者是来源于心脏的栓子随血流至脑部引起脑栓塞,引起脑部血液供应障碍,使得脑组织缺血、缺氧导致脑组织坏死,最终给患者造成一系列的神经功能缺损和障碍。
脑卒中已成为我国第一位死亡原因,也是中国成年人残疾的首要原因。脑卒中具有发病急骤、病情严重的特点,患者发病后延迟就诊与治疗是致死、致残的根本原因。这一急危重症,在救治上有严格的时间窗规定,从发病到接受救治时间的长短,直接决定着救治成功率的高低。急性脑梗死病灶是由缺血中心区和四周缺血半暗带组合而成,缺血中心区的脑组织损伤存在着不可逆性的特点,缺血半暗带当中则有着大量的、正在处于可逆状态下的神经元。颅内血管堵塞引发栓塞部位的脑组织缺血、缺氧,会造成脑细胞发生电化学级联瀑布样反应,有关受损细胞内信号通路产生偶连活化,使疾病发生不可逆性损伤。但如果能够在较短时间内实现阻塞血管的开通,使得缺血半暗带血循环重建,则有利于该区域神经细胞的存活及其功能恢复。
对于缺血性脑卒中的治疗,临床主要采用机械取栓和药物溶栓实现闭塞血管再通。临床上常用的溶栓药物有链激酶(streptokinase,SK)、尿激酶(urokinase,UK)、茴酰化纤溶酶原链激酶激活剂复合物(APSAC)、重组葡激酶(staphylokinase,SAK)、组织型纤溶酶原激活剂阿替普酶(tissuse plasminogen activator,t-PA)、瑞替普酶、拉诺替普酶等。纤维蛋白溶解药虽然能较好的溶解血栓,但是它们通常具有较短的治疗时间窗,比如重组组织纤溶酶原激活剂阿替普酶就必须在脑卒中发作后6h内使用。此外,即使成功的进行了闭塞血管再通,大多数脑卒中幸存者仍然患有永久性的神经 功能缺陷(Carmeliet P,Jain RK.Molecular mechanisms and clinical applications of angiogenesis.Nature.2011;473(7347):298-307)。
发明内容
为了解决现有技术中的问题,本发明提供硝酮嗪衍生物及其药物组合物在缺血性脑卒中的治疗和制备相应药物中的应用。
本发明所述硝酮嗪衍生物具有式(I)的结构:
Figure PCTCN2022000140-appb-000001
其中,R 1、R 2和R 3各自独立的为C1-C6烷基;R 4为仲丁基、异丁基、叔丁基、环戊基或环己基。
优选地,所述C1-C6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基或正戊基。
进一步优选地,R 1、R 2和R 3均为甲基,R 4为叔丁基,从而所述硝酮嗪衍生物即为硝酮嗪(简称TBN),分子式:C 12H 19N 3O,化学名:顺-2-甲基-N-[(3,5,6-三甲基吡嗪-2-)次甲基]2-丙胺氧化物,结构如下:
Figure PCTCN2022000140-appb-000002
本发明提供了所述硝酮嗪衍生物及其药物组合物在缺血性脑卒中治疗中的应用,包括施用治疗有效量的硝酮嗪衍生物或其药物组合物,并与闭塞血管再通联合使用。
本发明还提供了所述硝酮嗪衍生物在制备相应药物中的应用。
根据本发明的一个实施方案,所述闭塞血管再通为机械取栓或药物溶栓。
所述药物溶栓的溶栓药物选自链激酶(streptokinase,SK)、尿激酶(urokinase,UK)、茴酰化纤溶酶原链激酶激活剂复合物(APSAC)、组葡激酶(Recombinant Stapylokinase r-Sak)、组织型纤溶酶原激活剂阿替普酶(tissuse plasminogen activator,t-PA)、尿激酶原(prourokinase)、纳豆激酶(nattokinase,NK)、蚓激酶(Lumbrukinase)、 瑞替普酶(reteplase)、替奈普酶(tenecteplase,TNK-tPA)、孟替普酶(monteplase)、兰替普酶(lanoteplase,NPA)、去氨普酶(desmoteplase)、帕米普酶(pamiteplase,solinase)、替尼普酶(tenecteplase,TNKase)、安克洛酶(ancrod)、蛇毒溶栓酶中的一种或几种混合。
根据本发明的一个实施方案,本发明所述溶栓药物为阿替普酶(t-PA)。
根据本发明的一个实施方案,本发明所述机械取栓和硝酮嗪衍生物联合使用。
本发明所述溶栓药物用量由临床医生在溶栓时根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄、患者的体重和健康状态来确定,具体给药方式和给药次数可以按照本领域常规方式。
本发明所述硝酮嗪衍生物的治疗有效剂量为100-3000mg/人/次。具体的给予量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。具体给药方式和给药次数可以按照硝酮嗪衍生物的常规给药方式,例如可以每日施用一次或多次。
在一些实施方案中,闭塞血管再通和硝酮嗪衍生物可以同时或先后进行。在某些实施方案中,二者同时施予患者。在某些实施方案中,闭塞血管再通在给予硝酮嗪衍生物前已施予患者。在某些实施方案中,闭塞血管再通在给予硝酮嗪衍生物后再给予患者。在某些实施方案中,闭塞血管再通和硝酮嗪衍生物先后时间差不超过24小时,在某些更具体的实施方案中,闭塞血管再通和硝酮嗪衍生物先后时间差不超过12小时。
根据本发明的一个实施方案,本发明所述缺血性脑卒中为急性缺血性脑卒中。
根据本发明的一个实施方案,作为活性药物组分的硝酮嗪衍生物使用药物上可接受的载体来配制成药物组合物。所述的药物组合物为任意适合口服、舌下、局部吸入(鼻腔喷雾)、直肠、肌内、真皮内、皮下或者静脉内给药的组合物形式。用于治疗所需要的本发明组合物的量将根据给药途径、所治疗情况的性质、患者年龄和健康情况的不同而改变,最终由参与的临床医师决定。所需剂量可以以单剂量或者分次剂量(采用合适间隔)来提供,例如由于实现或达到治疗需要,每天两次、三次或者三次以上。
本发明所使用的术语“药物上可接受的载体”是指不会干扰硝酮嗪衍生物的生理作用、且对哺乳动物包括人无毒性的物质。使用硝酮嗪衍生物和药物上可接受的载体通过本领域技术人员公知的方法来配置本发明的硝酮嗪衍生物的药物组合物。这些组 合物包括但不限制于固体、胶囊、丸剂、栓剂、液体(如注射剂)、油、乳剂、喷雾、凝胶、气溶胶、吸入剂和贴剂。
临床上常用的溶栓药物如阿替普酶(t-PA)进行缺血性脑卒中的溶栓治疗,溶栓治疗后大多数脑卒中幸存者仍然患有永久性的神经功能缺陷(Carmeliet P,Jain RK.Molecular mechanisms and clinical applications of angiogenesis.Nature.2011;473(7347):298-307)。
在临床实验中,出乎意料的发现,硝酮嗪+t-PA联合使用明显改善患者第14天和第90天的神经功能NIHSS评分。此外,硝酮嗪+t-PA联合使用明显改善患者的神经功能mRS评分,完全治愈率(mRS 0分)比单用t-PA组大大提高;硝酮嗪+t-PA联合使用预后(mRS 0-2分)比单用t-PA组明显提高。从临床实验结果来看,硝酮嗪+t-PA联合使用治疗后90天的疗效远好于30天,而单用t-PA治疗后30天与90天的疗效无明显差异。同时,临床实验中硝酮嗪具有良好的安全性与耐受性。
附图说明
图1是t-PA组和联合给药组中NHISS评分为0-1分患者所占比例结果图;
图2是t-PA组和联合给药组中mRS=0分的患者所占比例结果图;
图3是t-PA组和联合给药组中mRS≤2分的患者所占比例结果图。
具体实施方式
下面通过具体实施例对本发明进行具体描述,在此指出以下实施例只用于对本发明进行进一步说明,不能理解为对本发明保护范围的限制。除特殊说明外,本发明所述份数均为重量份,所述百分比均为质量百分比。
本发明采用多中心、随机、双盲、平行试验临床研究设计。临床试验中心纳入的急性缺血性脑卒中患者作为受试者(均签署知情同意书),分为非溶栓组和溶栓组。非溶栓组为生理盐水(saline)组和硝酮嗪组。溶栓组为t-PA组和硝酮嗪+t-PA联合给药组。
研究对象:以《中国急性缺血性脑卒中诊治指南(2018)》为诊断标准,经临床试验中心筛选出确诊为急性缺血性脑卒中的患者。
给药方法:药物硝酮嗪1400mg溶于氯化钠注射液袋(规格:100mL),静脉注射给药,给药时间为30min。t-PA:剂量:0.9mg/Kg/次,用法:加入生理盐水中,10%剂量在1-2分钟内立即静脉推注,其余90%在60分钟内静脉点滴注射。t-PA在发生急性缺血性脑卒中首日给药,只给药一次。硝酮嗪用药时程:D1-D7一日两次给药,间隔12h,连续7天。
结果:
(一)非溶栓组中,相对于生理盐水组,硝酮嗪组明显改善患者第30和90天的神经功能,mRS的0-1分患者百分比较Saline对照组分别提高6.6和3.3百分点。
(二)溶栓组中,相对于单用t-PA组,硝酮嗪+t-PA联合给药组明显改善患者第14天和第90天的神经功能NIHSS评分,具体结果见图1,其中NIHSS 0-1分比t-PA组分别提高12.57%和34.54%(P=0.023)。硝酮嗪+t-PA联合给药组明显改善第30和90天的患者的神经功能mRS评分,完全治愈率(mRS 0分)结果见图2,比t-PA组分别提高33.80%和65.73%(P=0.044);良好功能预后(mRS 0-2分)结果见图3,90天后联合给药组比t-PA组提高10.50%。
(三)试验完成后(第90天),硝酮嗪+t-PA联合给药组的Lsmeans mRS(1.12)较t-PA组的Lsmeans mRS(1.61)改善了0.49分,即每2个人改善了1分。可以理解为经过治疗后,相比于t-PA组每10个患者生活不能自理,联合给药后只有5个生活不能自理,而有5个患者生活可以自理,极大地改善了这5个患者的生存质量。
(四)安全性方面:硝酮嗪衍生物具有良好的安全性与耐受性。
试验中发现,单用硝酮嗪治疗缺血性脑卒中能改善患者的神经功能,而硝酮嗪+t-PA联合给药对患者的神经功能改善效果更好。硝酮嗪+t-PA联合给药后第30天、第90天的神经功能NIHSS评分相较于t-PA组有明显提升,同时研究发现硝酮嗪治疗后90天的疗效远好于30天,而t-PA治疗后30天与90天的疗效无明显差异。
发明人研究获知溶栓后更有利于硝酮嗪衍生物到达病灶部位,更有利于病灶部位神经细胞的存活和神经功能恢复。基于这一发现,在缺血性脑卒中的治疗中,机械取栓或者其他溶栓药物后也有更多的硝酮嗪衍生物到达病灶部位,同样利于病灶部位神经细胞的存活及其功能恢复。

Claims (12)

  1. 硝酮嗪衍生物在缺血性脑卒中治疗中的应用,其包括施用治疗有效量的硝酮嗪衍生物或其药物组合物,并与闭塞血管再通联合使用;其中,所述硝酮嗪衍生物具有式(I)的结构:
    Figure PCTCN2022000140-appb-100001
    其中,R 1、R 2和R 3各自独立的为C1-C6烷基;R 4为仲丁基、异丁基、叔丁基、环戊基或环己基。
  2. 如权利要求1所述的应用,其中所述C1-C6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基或正戊基。
  3. 如权利要求1所述的应用,其中所述硝酮嗪衍生物具有下述结构:
    Figure PCTCN2022000140-appb-100002
  4. 如权利要求1所述的应用,其中,所述闭塞血管再通为机械取栓或药物溶栓。
  5. 如权利要求4所述的应用,其中,所述闭塞血管再通为药物溶栓,所述药物溶栓的溶栓药物选自链激酶、尿激酶、茴酰化纤溶酶原链激酶激活剂复合物、组葡激酶、组织型纤溶酶原激活剂阿替普酶、尿激酶原、纳豆激酶、蚓激酶、瑞替普酶、替奈普酶、孟替普酶、兰替普酶、去氨普酶、帕米普酶、替尼普酶、安克洛酶、蛇毒溶栓酶中的一种或几种混合。
  6. 如权利要求5所述的应用,其中,所述溶栓药物为阿替普酶。
  7. 如权利要求4所述的应用,其中,所述闭塞血管再通为机械取栓。
  8. 如权利要求1所述的应用,其中,所述缺血性脑卒中为急性缺血性脑卒中。
  9. 如权利要求1所述的应用,其中,所述治疗有效量为100-3000mg/人/次。
  10. 如权利要求1所述的应用,其中,所述药物组合物包括治疗有效量的硝酮嗪或其药学上可接受的盐,以及药学上可接受的载体。
  11. 如权利要求8所述的应用,其中,所述药物组合物的给药途径为口服、舌下、局部吸入、直肠、肌内、真皮内、皮下、静脉内给药,或其组合。
  12. 如权利要求8所述的应用,其中,所述药物组合物可与药学上可接受的载体制成各种剂型,所述剂型为固体、胶囊、丸剂、栓剂、液体、油剂、乳剂、喷雾剂、凝胶、气溶胶、吸入剂或贴剂。
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