WO2023019823A1 - 地氯雷他定及其盐在制备用于治疗运动功能障碍相关的神经退行性疾病的药物中的应用 - Google Patents
地氯雷他定及其盐在制备用于治疗运动功能障碍相关的神经退行性疾病的药物中的应用 Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4465—Non condensed piperidines, e.g. piperocaine only substituted in position 4
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- 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
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- A—HUMAN NECESSITIES
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- 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 invention relates to the field of pharmacotherapeutics, in particular to the application of desloratadine and its pharmaceutical composition in the preparation of drugs for the treatment of neurodegenerative diseases associated with motor dysfunction, more specifically, the present invention relates to desloratadine
- the tadine and its pharmaceutically acceptable salt or pharmaceutical composition thereof can improve the motor dysfunction of SOD1-G93A model mice and be used for preparing medicines for treating neurodegenerative diseases such as amyotrophic lateral sclerosis.
- ALS Amyotrophic lateral sclerosis
- SOD1 gene mutation is the pathogenic gene of ALS. Based on this, the first ALS model mouse, SOD1-G93A model mouse, came out in 1994.
- ALS is a rare disease, its cure rate is extremely low and there is no specific treatment drug available, which brings great pain to ALS patients and their families.
- riluzole was approved for marketing as early as 1995, but it was not approved by the FDA for the treatment of ALS until recently, and another drug, edaravone, was approved by the FDA in 2017. Approved for the treatment of ALS. But these two drugs can only temporarily prolong the survival of patients, and do not cure ALS. Therefore, it is of great social value and practical significance to explore the pathogenic mechanism of ALS, find new targets for the treatment of the disease, and develop effective drugs for the treatment of ALS.
- Desloratadine the main metabolite of loratadine, is clinically used to treat seasonal allergic rhinitis and chronic idiopathic urticaria. At present, there is no report on its ability to improve the motor dysfunction of SOD1-G93A model mice and thus play an anti-amyotrophic lateral sclerosis role. The present invention further discovers that desloratadine has the effect of improving the motor dysfunction of SOD1-G93A model mice, so the present invention further discovers its potentiality for the treatment of new indications.
- An object of the present invention is to provide a new medical application of desloratadine and a pharmaceutically acceptable salt thereof, that is, its application in the preparation of a medicament for treating amyotrophic lateral sclerosis.
- desloratadine and pharmaceutically acceptable salts thereof can be used as a small molecule compound for improving motor dysfunction in SOD1-G93A model mice.
- Another object of the present invention is to provide the use of a pharmaceutical composition comprising desloratadine or a pharmaceutically acceptable salt thereof in the preparation of a drug for the treatment of amyotrophic lateral sclerosis, said pharmaceutical composition comprising desloratadine Ratadine or its pharmaceutically acceptable salt and various pharmaceutically acceptable auxiliary materials.
- the invention also discloses the use of the pharmaceutical composition in the preparation of medicines for neurodegenerative diseases related to motor dysfunction.
- the invention discovers the new action mechanism and drug effect of desloratadine, and has the effect of improving the motor dysfunction of SOD1-G93A model mice.
- the compound can be used for treating diseases related to amyotrophic lateral sclerosis and motor dysfunction.
- Figure 1 shows that desloratadine can significantly improve the motor dysfunction of SOD1-G93A model mice in the Rotard test. * represents p ⁇ 0.05, *** represents p ⁇ 0.001, ### represents p ⁇ 0.001. ANOVA.
- Figure 2 shows that desloratadine can significantly improve the abnormal gait of SOD1-G93A model mice in the gait monitoring experiment. ** stands for p ⁇ 0.01, *** stands for p ⁇ 0.001, # stands for p ⁇ 0.05, ### stands for p ⁇ 0.001. ANOVA.
- Figure 3 shows that desloratadine can significantly improve the decrease in the grip strength of the limbs of the SOD1-G93A model mice in the cage test. , ** represents p ⁇ 0.01, *** represents P ⁇ 0.001. ANOVA.
- Figure 4 shows that desloratadine can significantly delay the onset time of SOD1-G93A model mice. * represents p ⁇ 0.05. Two-way analysis of variance.
- Figure 5 shows that desloratadine can significantly prolong the survival period of SOD1-G93A model mice. * represents p ⁇ 0.05. Two-way analysis of variance.
- Test implementation Desloratadine improved the motor dysfunction state of SOD1-G93A model mice in the behavioral experiments of Rotard rotating rod test, gait monitoring test and hanging cage test, and effectively delayed the development of SOD1-G93A model mice.
- the onset time of rats is prolonged, and their survival period is prolonged.
- the present invention is used in SOD1-G93A model mice to detect the impact of desloratadine on the improvement of the state of mouse motor dysfunction.
- the state of motor dysfunction manifested in the behavioral experiments of the gait monitoring experiment and the hanging cage experiment.
- Rotard rotating rod test SOD1-G93A model mice will have motor dysfunction when they get sick, so the animal's forelimb and hindlimb motor coordination and balance function can be evaluated by detecting the length of time the mouse stays on the rotating rod.
- SOD1-G93A model mice have a shorter time from onset to death, which is similar to human ALS, and whether it can effectively delay the onset of the disease and prolong the survival cycle is an important indicator.
- mice The experimental mouse B6SJL-BTg(SOD1-G93A)1Gur/J(002726) was purchased from Jackson Laboratory, USA. A total of 48 SOD1-G93A mice were obtained through genetic identification, and their littermate wild-type mice were used as negative controls, and were randomly divided into 4 groups. They were: 1wild-type solvent group, 2wild-type DLT group (20mg/kg/day), 3model solvent group and 4model DLT group (20mg/kg/day). All mice were administered from the age of 56 days (8 weeks), and 12 mice in each group were killed from the beginning of administration to the age of 120 days, and blood from eyeballs, muscles and spinal cord were collected for pathology, biochemistry and immunity. academic analysis. The remaining mice were given the compound until death, which was used to detect the onset time and survival period of the mice.
- Rotard rotarod test From the age of 60 days, the motor function of SOD1-G93A model mice was tested using a Rotarod rotarod instrument. Mice were trained for one week to become familiar with the Rotarod apparatus. Beginning at 70 days of age, testing was performed twice a week. At the beginning of the experiment, mice were individually placed on the rotating cylinder of the rotarod apparatus, which was rotated at a constant speed of 12 revolutions per minute. Motor coordination and balance of each mouse was assessed by measuring the total movement time of the mouse on the rotarod. Three trials were performed for each animal, and the longest dwell time before falling was recorded, which was set at 180 s.
- Gait monitoring experiment In order to obtain footprints, the front and rear feet of SOD1-G93A model mice were painted with red and green non-toxic pigments, respectively. Mice walked along a track with a length of 50 cm and a width of 10 cm, and the gait of the mice was recorded. All mice were tested weekly with three runs per run. Mouse footprints were analyzed and the average of three resulting statistics was used in the analysis of recorded mouse stride lengths.
- the onset time of transgenic mice was defined as the date when the transgenic mouse fell from the Rotarod for the first time and could not persist for 180 seconds.
- the death date of the transgenic mice was defined as the death of the mice that could not complete the righting reflex within 30 seconds when lying on their side, and the day was recorded as the death date of the mice.
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Abstract
本发明公开了地氯雷他定(Desloratadine，DLT)及其药学上可接受的盐在制备治疗运动功能障碍相关的神经退行性疾病药物中的新用途。本发明通过大量实验表明，地氯雷他定及其药学上可接受的盐可以改善SOD1-G93A模型小鼠在Rotard转棒实验、步态监测实验和吊笼实验的行为学实验中表现出的运动功能障碍状态，并有效延缓SOD1-G93A模型小鼠的发病时间，延长其生存周期。可用于治疗包括肌萎缩侧索硬化症在内的运动功能障碍相关的神经退行性疾病。
Description
本发明涉及药物治疗学领域，具体涉及地氯雷他定及其药物组合物在制备用于治疗运动功能障碍相关的神经退行性疾病的药物中的应用，更具体地，本发明涉及地氯雷他定及其药学上可接受的盐或其药物组合物具有改善SOD1-G93A模型小鼠运动功能障碍，用于制备治疗肌萎缩侧索硬化症等神经退行性疾病的药物中的用途。
肌萎缩侧索硬化症(Amyotrophic latera sclerosis，ALS)是一种致命的神经系统退行性疾病，又称“渐冻症”，主要累及脊髓、大脑皮质和脑干运动神经元。ALS通常发生在中老年或更晚，患者发病后会表现为进行性肌肉萎缩和无力，最终常因呼吸衰竭死亡，大部分患者发病后的生存时间只有2至4年。全球约45万ALS患者，患病率约为1/20 000，且于2018年我国将ALS纳入《第一批罕见病目录》。1993年研究发现SOD1基因突变是ALS的致病基因，基于此，1994年第一个ALS模型小鼠SOD1-G93A模型小鼠问世，该动物模型已被广泛用于ALS研究。尽管ALS为一种罕见病，但由于其治愈率极低，且无特效治疗药物可以使用，给ALS患者以及家属带来了巨大的痛苦。目前临床仅有两种用于治疗ALS的药物，其中利鲁唑早在1995年被批准上市，但直到最近才被FDA批准可用于ALS的治疗，另一药物依达拉奉于2017年被FDA批准用于ALS的治疗。但这两种药物仅可以短暂延长患者生存期，并不可治愈ALS。因此，探索ALS的致病机制，寻找治疗该疾病的新靶点，研发有效治疗ALS的药物，具有重要的社会价值和实用意义。
抗ALS药物研发困难，与其发病机制尚未明确有关。目前研究认为运动神经元损伤是由多种致病原因相互作用引起的，包括遗传因素、蛋白质聚集、神经炎症、氧化应激、线粒体功能的损伤、谷氨酸兴奋性毒性和内质网应激等(Kiernan M C,Vucic S,Cheah B C,et al.Amyotrophic lateral sclerosis[J].Lancet,2011,377(9769):942-955)，因此，本发明从ALS可能的多个发病机制出发，寻找治疗ALS的药物。
地氯雷他定，是氯雷他定的主要代谢物，临床上用于治疗季节性变应性鼻炎和慢性特发性荨麻疹。目前对于其改善SOD1-G93A模型小鼠运动功能障碍，从而起到抗肌萎缩侧索硬化症的作用未见报道。本发明进一步发现地氯雷他定具有改善SOD1-G93A模型小鼠运动功能障碍作用，因此本发明进一步发现了它对新的适应症治疗的潜在性。
发明内容
本发明的一个目的是提供地氯雷他定及其药学上可接受的盐的新的医药用途，即其在制备用于治疗肌萎缩侧索硬化症的药物中的用途。
在所述用途中，地氯雷他定及其药学上可接受的盐可以作为改善SOD1-G93A模型小鼠运动功能障碍的小分子化合物。
本发明的另一目的是提供包含地氯雷他定或其药学上可接受的盐的药物组合物在制备用于治疗肌萎缩侧索硬化症药物中的用途，所述药物组合物包含地氯雷他定或其药学上可接受的盐及药学上可接受的各种辅料。
本发明还公开了该药物组合物在制备与运动功能障碍相关的神经退行性疾病的药物中的用途。
本发明发现了地氯雷他定的新的作用机制和药效，具有改善SOD1-G93A模型小鼠运动功能障碍作用。该化合物可用于治疗肌萎缩侧索硬化症及运动功能障碍相关的疾病治疗。
图1为地氯雷他定能够明显改善SOD1-G93A模型小鼠在Rotard转棒实验中表现的运动功能障碍。*代表p＜0.05，***代表p＜0.001，###代表p＜0.001。单因素方差分析。
图2为地氯雷他定能够明显改善SOD1-G93A模型小鼠在步态监测实验中表现的步态异常现象。**代表p＜0.01，***代表p＜0.001，#代表p＜0.05，###代表p＜0.001。单因素方差分析。
图3为地氯雷他定能够明显改善SOD1-G93A模型小鼠在吊笼实验中表现的四肢握力下降现象。，**代表p<0.01，***代表P<0.001。单因素方差分析。
图4为地氯雷他定能够明显推迟SOD1-G93A模型小鼠的发病时间。*代表p<0.05。双因素方差分析。
图5为地氯雷他定能够明显延长SOD1-G93A模型小鼠的生存周期。*代表p<0.05。双因素方差分析。
下面结合具体实施例对本发明作进一步阐述，但这些实施例不应解释为限制本发明。
试验实施：地氯雷他定改善SOD1-G93A模型小鼠在Rotard转棒实验、步态监测实验和吊笼实验的行为学实验中表现出的运动功能障碍状态，并有效延缓SOD1-G93A模型小鼠的发病时间，延长其生存周期。
本发明在SOD1-G93A模型小鼠中以检测地氯雷他定对小鼠运动功能障碍状态改善的影响，实验表明地氯雷他定具有明显改善SOD1-G93A模型小鼠在Rotard转棒实验、步态监测实验和吊笼实验的行为学实验中表现出的运动功能障碍状态。
1、实验原理
1)Rotard转棒实验：SOD1-G93A模型小鼠发病时会发生运动功能障碍，因此可以通过检测小鼠停留在旋转棒上的时间长度来评估动物前肢和后肢运动协调和平衡功能。
2)步态监测实验：SOD1-G93A模型小鼠在发病开始时表现为步态不稳，静止性震颤，逐渐发展成为后肢萎缩，疾病晚期发展成为双后肢完全瘫痪，步长显著缩短，通过步态分析评估小鼠前后肢运动协调调功能。
3)吊笼实验：SOD1-G93A模型小鼠发病后出现后肢萎缩，四肢握力下降情况，通过吊笼实验检测小鼠四肢的抓握力量。
4)发病时间和生存周期检测：SOD1-G93A模型小鼠发病到死亡时间较短，与人ALS类似，是否有效推迟疾病发生及延长生存周期是一个重要的指标。
2、实验材料与方法
1)动物分组：实验小鼠B6SJL-BTg(SOD1-G93A)1Gur/J(002726)购自美国Jackson Laboratory公司。通过基因鉴定得到SOD1-G93A小鼠共48只，其同窝野生型小鼠作为阴性对照，随机分为4组。分别为：①野生型溶剂组②野生型DLT组(20mg/kg/day)、③模型溶剂组和④模型DLT组(20mg/kg/day)。所有小鼠均从56日龄(8周龄)开始给药，其中每组小鼠各12只从给药开始至120日龄处死，眼球取血、肌肉和脊髓等组织进行病理、生化和免疫学分析。剩余小鼠一直给予化合物直至死亡，用于检测小鼠发病时间及生存周期。
2)Rotard转棒实验：从60日龄起，使用Rotarod转棒仪对SOD1-G93A模型小鼠运动功能进行检测。小鼠接受一周训练，以熟悉Rotarod仪器。从70日龄开始，每周检测两次。实验开始时，小鼠被单独放置在转棒仪的旋转圆柱体上，以每分钟12转的转速恒速旋转。通过测量小鼠在旋转棒上的总运动时间来评估每只小鼠的运动协调性和平衡性。每只动物进行三次试验，记录跌落前最长的停留时间，最长停留时间设定为180秒。
3)步态监测实验：为了获得脚印，SOD1-G93A模型小鼠的前脚和后脚分别涂上红色和绿色无毒颜料。小鼠沿着一条长50厘米，宽10厘米的跑道行走，记录小鼠步态。所有小鼠每周测试一次，每次跑三遍。对小鼠足迹进行了分析，记录小鼠的步长的分析中使用了三次结果统计的平均值。
4)吊笼实验：从第8周开始每周检测一次。实验时在地上铺上软垫保护小鼠，接着将小鼠放在笼盖上，确定小鼠抓握住笼盖后迅速将笼盖翻转并同时开始计时。记录小鼠抓握笼盖的最长时间，最长时间规定为90秒，不足90秒时记录具体时间。每次实验重复三次并取最好成绩作为记录。
5)发病时间和生存周期检测：转基因小鼠发病时间定义为首次从Rotarod转棒仪上掉落无法坚持到180秒时的日期。将转基因小鼠死亡日期规定为小鼠侧卧时30秒内无法完翻正反射判定其死亡，该天记录为小鼠死亡日期。
3、实验结果
结果如图1所示，与模型溶剂组相比，模型DLT组小鼠整体转棒实验成绩更好，模 型DLT组小鼠在发病时期(101天至115天)在转棒仪上停留时间远长与模型溶剂组小鼠，表明地氯雷他定具有改善小鼠运动协调和平衡功能的作用；如图2所示，模型DLT组小鼠在第15周后的步长分析结果明显优于模型溶剂组小鼠，表明地氯雷他定具有改善模型小鼠步态异常作用；如图3所示，模型DLT组小鼠在14到15周龄时在吊笼实验中坚持时间优于模型溶剂组小鼠，表明地氯雷他定具有增强小鼠肌肉力量功能；如图4所示，给予地氯雷他定治疗能够推迟SOD1-G93A模型小鼠第一次从转棒上跌落下的时间，推迟发病时间(模型溶剂组＝97.6±1.473d,模型DLT组＝103.4±1.705d，p＜0.05)。如图5所示，模型DLT组小鼠不能完成翻正反射时间延迟，表明地氯雷他定具有延长SOD1-G93A模型小鼠生存周期的作用(模型溶剂组＝126±1.721d，模型DLT组＝131.6±1.51d，p＜0.05)。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (5)
- 地氯雷他定及其药学上可接受的盐在制备用于治疗运动功能障碍相关的神经退行性疾病的药物中的应用。
- 地氯雷他定及其药学上可接受的盐在制备用于治疗肌萎缩侧索硬化症药物中的应用。
- 根据权利要求1所述的用途，其中，地氯雷他定及其药学上可接受的盐能够改善SOD1-G93A模型小鼠运动功能障碍。
- 含有地氯雷他定或其药学上可接受的盐的药物组合物在制备用于治疗运动功能障碍相关的神经退行性疾病的药物中的应用。
- 一种药物组合物在制备用于治疗肌萎缩侧索硬化症药物中的应用，所述药物组合物包含地氯雷他定或其药学上可接受的盐及药学上可接受的辅料。
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