CN109232341A - 一种化合物或其药学上可接受的盐及其用途 - Google Patents
一种化合物或其药学上可接受的盐及其用途 Download PDFInfo
- Publication number
- CN109232341A CN109232341A CN201811167208.7A CN201811167208A CN109232341A CN 109232341 A CN109232341 A CN 109232341A CN 201811167208 A CN201811167208 A CN 201811167208A CN 109232341 A CN109232341 A CN 109232341A
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- Prior art keywords
- formula
- pharmaceutically acceptable
- acceptable salt
- phenyl
- hydrogen
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Abstract
本发明提供了一种具有通式I的化合物或其药学上可接受的盐及其制备方法，本发明还提供了具有通式I的化合物或其药学上可接受的盐在制备治疗高原病、心肺损伤和/或血管损伤的药物组合物中的用途，优选为肺动脉高压、心力衰竭，所述的高原病选自在海拔2000m以上的高原环境下产生的急性高原病或慢性高原病。
Description
技术领域
本发明涉及生物医药领域，具体涉及一种符合通式I的化合物及其所述化合物或其药学上可接受的盐在制备治疗或预防高原病、心肺损伤和/或血管损伤的药物组合物中的用途，心肺损伤和/或血管损伤优选为肺动脉高压和/或心力衰竭。
背景技术
高原反应即高原病，是人到达一定海拔高度后，身体为适应因海拔高度而造成的气压差、含氧量少、空气干燥等的变化而产生的自然生理反应。高原反应的症状一般表现为头疼、心慌、疲倦、胸闷、气短、呕吐、食欲减退、抽搐、意识恍惚、认知能力骤降等。体征为心率加快、呼吸加深、血压轻度异常、颜面或四肢水肿、口唇紫绀等。目前预防和调治高原反应的多为红景天、高原宁、西洋参、丹参丸、百服宁等药品或相关保健品。例如专利CN103829245A、CN103948896A、CN104274808A、CN104288262A、CN104288735A、CN104288476A、CN104721202A、CN104706771A、CN105168308A、CN105193839A等，但是这些药品或食品存在见效慢、副作用多等缺陷。
肉桂酰胺类化合物对动物毒性小，具有抑制血管生长、抗肿瘤生长及转移的作用，被广泛的应用在制药领域。专利CN1217185A公开了肉桂酰胺抗肿瘤作用的新用途，该化合物对恶性肿瘤细胞具有增殖抑制作用，并且抑制血管生成。专利CN103371992A公开了(E)-氮-(4-肉桂酰胺丁基)苯甲酰胺在制备抗肿瘤药物中的应用，该化合物具有逆转肿瘤细胞多药耐药的作用，可以作为多药耐药逆转剂，也具有增加多药耐药细胞对抗肿瘤药物敏感性的作用，可以作为增敏剂。专利CN101195582A公开了肉桂酰胺衍生物及其水合物的制备方法，和在制备治疗心脑血管疾病的药物中的用途。专利CN102603666A公开了肉桂酰牛磺酰噻唑烷酸类化合物及其作为血管紧张素转化酶抑制剂的应用，旨在提供一类具有血管紧张素转化酶抑制活性的肉桂酰牛磺酰噻唑烷酸类化合物及其在制备治疗心血管疾病的药物中的应用。
专利CN102241673B公开了一种具有通式I的丙烯酰胺类化合物或其异构体、可药用盐及溶剂化物及其在抗细胞凋亡、预防或治疗与细胞凋亡有关的疾病或症状的医药用途。专利CN102241646B公开了一种己烯酮类化合物及其在抗细胞凋亡、预防或治疗与细胞凋亡有关的疾病或症状的用途，特别是用于保护心肌细胞和预防、治疗与心肌细胞凋亡有关的疾病或症状中的用途。专利CN102241627B公开了一种脲类化合物及其在抗细胞凋亡、预防或治疗与细胞凋亡有关的疾病或症状的用途，特别是用于保护心肌细胞和预防、治疗与心肌细胞凋亡有关的疾病或症状中的用途。但均未公开本发明所述的化合物及其在制备治疗或预防高原病、心肺损伤和/或血管损伤的药物组合物中的用途，包括高急性高原病和/或慢性高原病。
发明内容
本发明提供了一种化合物或其药学上可接受的盐，所述的化合物结构为通式I；
其中，R1选自苯基、被取代的苯基、噻吩基或被取代的噻吩基，所述苯基的取代基选自卤原子、C1-C4烷基、卤代烷基、烷氧基、烷硫基、羟基、羧基、氰基、氨基或硝基，所述噻吩基的取代基选自卤原子、硝基、羟基、氰基、氨基、C1-C4烷基、C1-C4卤代烷基或C1-C4烷氧基；
所述被取代的苯基为苯基独立的被1个、2个、3个、4个或5个取代基取代，所述的被取代的噻吩基为噻吩基独立的被1个、2个或3个取代基取代；
R2、R3和R4独立的选自卤原子；
R5、R6和R7独立的选自氢或C1-C4烷基；
R8选自氢、甲基、乙基或苄基；
R9选自S或O；
n选自1-6的自然数。
本发明还包括所述通式I化合物的活性代谢物。
本发明所述的C1-C4烷基选自甲基、乙基、CH3CH2CH2-、(CH3)2CH-、CH3CH2CH2CH2-、(CH3)3C-、CH3CH2CH(CH3)-或(CH3)2CH-CH2-。
本发明所述的卤原子选自F、Cl、Br或I。
本发明所述的卤代烷基为所述C1-C4烷基的任意位置被卤原子取代。
本发明所述的烷氧基选自甲氧基、乙氧基、丙氧基、丁氧基、异丁氧基、仲丁氧基或叔丁氧基。
优选的，所述的通式I的化合物中：
R1选自苯基或被取代的苯基，所述苯基的取代基选自卤原子、C1-C4烷基；
R2、R3和R4独立的选自卤原子；
R5、R6和R7独立的选自氢；
R8选自氢或甲基；
R9为S；
n选自2-5的自然数。
在本发明的一个具体实施方式中，所述通式I的化合物中R1为苯基，R2、R3和R4均为Cl，R5、R6和R7均为氢，R8为氢，R9为S，n为2；其结构式为
本发明所述的符合通式I的化合物或其药学上可接受的盐的制备方法，包括如下步骤：
1)将邻硝基苯酚与式II所示化合物在碱性条件下反应，获得式III所示化合物；
2)氮气保护下，在步骤1)获得的式III所示化合物中加入钯/碳，氢气置换反应得到式IV所示化合物；
3)将步骤2)获得的式IV所示化合物与式V所示化合物反应得通式I所示化合物；
本发明还提供了一种符合通式I的化合物或其药学上可接受的盐在制备治疗或预防高原病的药物组合物中的用途；
其中，R1选自苯基、被取代的苯基、噻吩基或被取代的噻吩基，所述苯基的取代基选自卤原子、C1-C4烷基、卤代烷基、烷氧基、烷硫基、羟基、羧基、氰基、氨基或硝基，所述噻吩基的取代基选自卤原子、硝基、羟基、氰基、氨基、C1-C4烷基、C1-C4卤代烷基或C1-C4烷氧基；
R2、R3和R4独立的选自卤原子；
R5、R6和R7独立的选自氢或C1-C4烷基；
R8选自氢、甲基、乙基或苄基；
R9选自S或O；
n选自1-6的自然数。
本发明所述的C1-C4烷基选自甲基、乙基、CH3CH2CH2-、(CH3)2CH-、CH3CH2CH2CH2-、(CH3)3C-、CH3CH2CH(CH3)-或(CH3)2CH-CH2-。
本发明所述的卤原子选自F、Cl、Br或I。
本发明所述的卤代烷基为所述C1-C4烷基的任意位置被卤原子取代。
本发明所述的烷氧基选自甲氧基、乙氧基、丙氧基、丁氧基、异丁氧基、仲丁氧基或叔丁氧基。
优选的，所述通式I的化合物中：
R1选自苯基或被取代的苯基，所述苯基的取代基选自卤原子、C1-C4烷基；
R2、R3和R4独立的选自卤原子；
R5、R6和R7独立的选自氢；
R8选自氢或甲基；
R9为S；
n选自2-5的自然数。
在本发明的一个具体实施方式中，所述通式I的化合物中R1为苯基，R2、R3和R4均为Cl，R5、R6和R7均为氢，R8为氢，R9为S，n为2；其化学结构式为
本发明所述的高原病选自在高原环境下产生的急性高原病和慢性高原病。
优选的，所述的急性高原病选自高原昏迷、高原脑水肿、高原肺水肿或脑、肺异常症状同时存在的混合型疾病；所述的慢性高原病选自高原心脏病、高原红细胞增多症、高原高血压、高原低血压或心脏病、红细胞增多症同时存在的混合型疾病。
优选的，所述高原病的临床表现选自头疼、头昏、心慌、心率加快、疲倦、胸闷、气短、呼吸加深、恶心、呕吐、失眠、乏力、眼花、嗜睡、食欲减退、抽搐、意识恍惚、手足麻木、唇指发绀、颜面水肿、四肢水肿或认知能力骤降中的一种或两种以上的组合。
本发明所述的高原环境为海拔2000m以上，具有低压、缺氧的条件。优选的，所述的高原环境为海拔2700m以上，具有低压、缺氧的条件下。
在本发明的具体实施方式中，所述的高原环境为海拔5500m以上，具有低压、缺氧的条件下。
本发明还提供了一种符合通式I的化合物或其药学上可接受的盐在制备治疗或预防心肺损伤和/或血管损伤的药物组合物中的用途；优选的，所述的心肺损伤和/或血管损伤为肺动脉高压和/或心力衰竭。进一步优选的，所述的心力衰竭为右室肥厚。
本发明所述的药物组合物中包含作为活性成分的具有通式I的化合物或其药学上可接受的盐，和药物辅料。
优选的，所述的药物辅料选自溶剂、乳化剂、增塑剂、崩解剂、填充剂、粘合剂、甜味剂或润滑剂中的一种或两种以上的组合。
本发明所述的溶剂选自水、醇类、酚类、醚类、卤代烃、酮类、醛类、腈类、酰胺、砜、羟丙基-β-环糊精(HP-β-CD)、亚砜或羧酸中的一种或两种以上的组合。
优选的，所述的溶剂选自甲醇、乙醇、异丙醇、羟丙基-β-环糊精、聚乙二醇-15-羟基硬脂酸酯、二氯甲烷丙酮或乙酸乙酯中的一种或两种以上的组合。
本发明所述的乳化剂选自聚乙二醇油酸酯、聚乙烯醇、甘油硬脂酸酯或吐温-80中的一种或两种以上的组合。优选的，所述的乳化剂选自聚乙二醇油酸酯或甘油硬脂酸酯中的一种或其组合。
本发明所述的增塑剂选自聚乙二醇、蓖麻油、甘油或山梨醇中的一种或两种以上的组合。优选的，所述的增塑剂选自聚乙二醇或蓖麻油中的一种或其组合。
本发明所述的崩解剂选自交联聚维酮、羟甲纤维素钠、甲基纤维素钠淀粉或低取代羟丙纤维素中的一种或两种以上的组合。优选的，所述的崩解剂选自羟甲纤维素钠或甲基纤维素钠淀粉中的一种或其组合。
本发明所述的填充剂选自微晶纤维素、赤藓醇、山梨醇、甘露醇、预胶化淀粉、碳酸钙、蔗糖或乳糖中的一种或两种以上的组合。优选的，所述填充剂选自山梨醇、甘露醇、预胶化淀粉或乳糖中的一种或两种以上的组合。
本发明所述的粘合剂选自聚乙烯吡咯烷酮、卡波姆、羟丙基纤维素、明胶、瓜尔胶、羟甲基纤维素钠、羟丙甲纤维素、硅酸镁铝、乙基纤维素、羟乙基纤维素、预胶凝淀粉、阿拉伯胶、聚乙烯醇、聚维酮、麦芽糊精或海藻酸钠中的一种或两种以上的组合。优选的，所述粘合剂选自硅酸镁铝、羟甲基纤维素钠或聚乙烯吡咯烷酮中的一种或两种以上的组合。
本发明所述的甜味剂选自阿司帕坦、木糖醇、薄荷脑、薄荷香精、安塞蜜、甜菊糖苷、或三氯蔗糖中的一种或两种以上的组合。优选的，所述的甜味剂选自薄荷香精、三氯蔗糖或安塞蜜中的一种或两种以上的组合。
本发明所述的润滑剂选自滑石粉、氢化硬脂酸钙、十二烷基硫酸镁、硬脂酰醇富马酸钠、水合硅胶钠、氢化蓖麻油、硬脂酸锌、硬脂酸镁或中的一种或两种以上的组合。优选的，所述润滑剂选自氢化蓖麻油、硬脂酸锌或氢化硬脂酸钙中的一种或两种以上的组合
本发明所述化合物的药物组合物通过口服、喷雾吸入、直肠用药、鼻腔用药、颊部用药、局部用药、非肠道用药。例如，皮下、静脉、肌内、鞘内、心室内、胸骨内、颅内或腹膜内注射或输入的途径向体内施加药物组合物，或借助外植储器用药。
在本发明的具体实施方式中，通过口服的途径向体内施加药物组合物。
优选的，所述的药物组合物的剂型为口服液、丸剂、颗粒剂、片剂或胶囊中的一种或两种以上的组合。
本发明还进一步提供了一种含有通式I的化合物或其药学上可接受的盐的药物组合物的制备方法，包括1)将含有通式I的化合物或其药学上可接受的盐均匀分散到药物辅料中；2)混合压制成片剂、颗粒剂、将颗粒装入胶囊壳中制成胶囊、热熔后滴加至冷凝液中制成滴丸。
本发明进一步提供了符合通式I的化合物或其药学上可接受的盐在制备5500m高原环境下保护大鼠心肺功能的药物组合物中的用途。
本发明所述的“和/或”包括择一列出的项目以及任何数量的项目组合。
本发明所述的“包括”是开放式的描述，含有所描述的指定成分或步骤，以及不会实质上影响的其他指定成分或步骤。
本发明所述的“治疗”表示在疾病已开始发展后减缓、中断、阻止、控制、停止、减轻、或逆转一种体征、症状、失调、病症、或疾病的进展或严重性，但不一定涉及所有疾病相关体征、症状、病症、或失调的完全消除。
本发明所述的“或其药学上可接受的盐”指由药学上可接受的无毒性的酸或碱制备而来的盐，其中的酸或碱包括无机酸或碱或有机酸或碱。所述的无机酸选自盐酸、氢溴酸、磷酸、氢碘酸或硫酸。所述的无机碱选自钙、镁、锂、钠、锌、铝或钾。所述的有机酸选自甲酸、羟基乙酸、丙酸、醋酸、琥珀酸、甲磺酸、乙磺酸、顺丁烯二酸、谷氨酸、苯甲酸、硬脂酸、海藻酸、苯磺酸、葡萄糖醛酸、双羟萘酸或半乳糖醛酸。所述的有机碱选自二乙醇胺、胆碱、普鲁卡因、赖氨酸或1,2-乙二胺。
附图说明
以下，结合附图来详细说明本发明的实施例，其中：
图1：应用血流动力学评价模型组、对照组及试验组大鼠的mPAP的变化结果；其中，模型组为模拟5500米高原环境，在低压氧舱中饲养14天，给予不含药品的溶剂；对照组为同一房间正常环境下饲养，给予不含药品的溶剂；和试验组为模拟5500米高原环境，在低压氧舱中饲养14天，给予溶解配置好的N-(2,2,2-三氯-1-(3-(2-(2-羟乙基)苯基)硫脲基)乙基)肉桂酰胺药物；
图2：应用超声心动图检测模型组、对照组及试验组大鼠的EF的变化结果；其中，模型组为模拟5500米高原环境，在低压氧舱中饲养14天，给予不含药品的溶剂；对照组为同一房间正常环境下饲养，给予不含药品的溶剂；和试验组为模拟5500米高原环境，在低压氧舱中饲养14天，给予溶解配置好的N-(2,2,2-三氯-1-(3-(2-(2-羟乙基)苯基)硫脲基)乙基)肉桂酰胺药物；
图3：应用超声心动图检测模型组、对照组及试验组大鼠的FS的变化结果；其中，模型组为模拟5500米高原环境，在低压氧舱中饲养14天，给予不含药品的溶剂；对照组为同一房间正常环境下饲养，给予不含药品的溶剂；和试验组为模拟5500米高原环境，在低压氧舱中饲养14天，给予溶解配置好的N-(2,2,2-三氯-1-(3-(2-(2-羟乙基)苯基)硫脲基)乙基)肉桂酰胺药物；
图4：应用超声心动图检测模型组、对照组及试验组大鼠的肺动脉直径的变化结果；其中，模型组为模拟5500米高原环境，在低压氧舱中饲养14天，给予不含药品的溶剂；对照组为同一房间正常环境下饲养，给予不含药品的溶剂；和试验组为模拟5500米高原环境，在低压氧舱中饲养14天，给予溶解配置好的N-(2,2,2-三氯-1-(3-(2-(2-羟乙基)苯基)硫脲基)乙基)肉桂酰胺药物；
图5：应用超声心动图检测模型组、对照组及试验组大鼠的三尖瓣位移的变化结果；其中，模型组为模拟5500米高原环境，在低压氧舱中饲养14天，给予不含药品的溶剂；对照组为同一房间正常环境下饲养，给予不含药品的溶剂；和试验组为模拟5500米高原环境，在低压氧舱中饲养14天，给予溶解配置好的N-(2,2,2-三氯-1-(3-(2-(2-羟乙基)苯基)硫脲基)乙基)肉桂酰胺药物。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明的部分实施例，而不是全部。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1符合通式I的化合物的制备
N-(2,2,2-三氯-1-(3-(2-(2-羟乙基)苯基)硫脲基)乙基)肉桂酰胺的合成过程如下：
具体步骤为：
步骤一：
将邻硝基苯酚(2克，14.38毫摩尔)，2-溴乙醇(1.8克，14.38毫摩尔)和碳酸钾(2.98克，21.57毫摩尔)溶于N，N-二甲基甲酰胺(10毫升)中，然后加热到80℃，反应16小时。将反应混合液冷却到室温后，用水(30毫升)稀释。再用乙酸乙酯萃取(20毫升×3)，将萃取液合并后用饱和食盐水(20毫升)洗涤，有机相分离后用无水硫酸铵干燥，过滤。滤液减压浓缩，残余物经快速分离机分离(型号：40g Silica Flash Column，洗脱剂：0～55％乙酸乙酯/石油醚，流速：100毫升/分钟)，得到黄色油状液体2-(2-硝基苯氧基)乙醇(1.2g，含量40％，收率18％)。1H NMR(CDCl3,400MHz),δppm：7.87(dd,J＝8.1Hz,1.7Hz,1H)，7.48-7.61(m,1H)，7.11(dd,J＝8.4Hz,0.9Hz,1H)，7.04-7.09(m,1H)，4.22-4.27(m,1H)，3.99(br d,J＝2.9Hz,2H)，2.57-2.74(m,1H)。
步骤二：
将2-(2-硝基苯氧基)乙醇(1.2克,2.62毫摩尔)溶于甲醇(15毫升)，在氮气保护下加入钯/碳(0.2克，10％)。将反应混合物用氢气置换数次后，在氢气下(15psi)，25℃反应12小时。将反应混合物过滤，滤液减压浓缩得到黄色油状液体2-(2-氨基苯氧基)乙醇(0.4克,收率99.6％)。MS(ESI):154.1(M+1)。
步骤三：
将2-(2-氨基苯氧基)乙醇(0.07克，0.45毫摩尔)和N-(2,2,2-三氯-1-异硫氢基乙基)肉桂酰胺(0.15克，0.45毫摩尔)溶于四氢呋喃(3毫升)中，加热到60℃反应1小时。将反应液减压浓缩，残余物经制备HPLC分离(柱型号：Luna C18 150×255um。洗脱剂：A，水(含0.225％的甲酸)，B，乙腈。洗脱剂梯度：B％，45％-72％。洗脱时间：10分钟)得到白色固体N-(2,2,2-三氯-1-(3-(2-(2-羟乙基)苯基)硫脲基)乙基)肉桂酰胺(84.25毫克，收率38％)。1H NMR(DMSO-d6,400MHz)，δppm:9.71(s,1H)，9.02(d,J＝8.8Hz,1H)，8.44(brs,1H)，7.83(br d,J＝7.8Hz,1H)，7.52-7.65(m,3H)，7.38-7.52(m,4H)，7.13-7.19(m,1H)，7.07-7.12(m,1H)，6.90-6.98(m,1H)，6.80(d,J＝15.8Hz,1H)，4.86(t,J＝5.6Hz,1H)，4.08(t,J＝5.1Hz,2H)，75(q,J＝5.3Hz,2H)。MS(ESI):488.0(M+1)。
实施例2N-(2,2,2-三氯-1-(3-(2-(2-羟乙基)苯基)硫脲基)乙基)肉桂酰胺对高原病的治疗作用
1、材料与方法
1.1动物
SD大鼠40只，雄性，清洁级，购自北京维通利华实验动物有限公司，许可证号：SCXK(京)2016-0006。低压氧舱饲养，定时给予全价营养饲料喂食，室温22-25℃，湿度50％-70％。
1.2试剂与样品
N-(2,2,2-三氯-1-(3-(2-(2-羟乙基)苯基)硫脲基)乙基)肉桂酰胺(试验组)粉剂由实施例1制备获得；
二甲基亚砜(DMSO)购买自selleck；
聚乙二醇200购买自国药集团材料试剂有限公司。
试验组(N-(2,2,2-三氯-1-(3-(2-(2-羟乙基)苯基)硫脲基)乙基)肉桂酰胺)的配置方法：10％的DMSO溶解N-(2,2,2-三氯-1-(3-(2-(2-羟乙基)苯基)硫脲基)乙基)肉桂酰胺+50％的聚乙二醇200+40％的双蒸水。
模型组和对照组：10％的DMSO+50％的聚乙二醇200+40％的双蒸水。
1.3仪器
低压氧舱(贵州风雷航空军械有限公司)；小动物呼吸机(kent scientific，美国)；多功能生理仪(Millar,美国)；全自动动物血液细胞分析仪(迈瑞公司)；小动物超声(Visual Sonics Inc，加拿大)。
1.4实验设计与过程
将30只大鼠随机分为3组，每组10只，将其中两组20只大鼠放入低压氧舱中，模拟5500米高原环境，饲养14天后随机分为模型组，试验组(10mg/kg)分别给予相同的药物，另一组10只大鼠放在同一房间正常环境中饲养，作为对照组。14天后测量各实验组大鼠的肺动脉压(mPAP)；右室射血分数(EF)；右室缩短分数(FS)；肺动脉直径(PV diam(mm))；三尖瓣位移(tapes)。
1.5指标检测方法
3％的戊巴比妥钠，0.2mL/100g腹腔注射麻醉大鼠，应用超声心动图检测肺动脉直径、三尖瓣位移；射血分数EF；缩短分数FS。将麻醉好的大鼠仰卧位固定于手术台上，气管切管，连接呼吸机，开胸，暴露心脏。导管插入右心室，记录右心室收缩压。再缓慢向前推进，可经右心室流出道到达肺动脉，应用血流动力学评价肺动脉压力mPAP。
1.6统计学方法
所有数据用x±s表示，组间比较为单因素方差分析，P＜0.05为差异有统计学意义，采用SPSS19.0软件包进行统计学处理。
2、实验结果
2.1对大鼠肺动脉压的影响
大鼠在低压低氧环境饲养14天后，如图1所示，与对照组相比，模型组大鼠的mPAP明显升高，差异具有显著性(P＜0.05)。在低压低氧环境下，与模型组相比，试验组大鼠的mPAP明显降低。
2.2对大鼠EF的影响
大鼠在低压低氧环境饲养14天后，如图2所示，与对照组相比，模型组大鼠的EF明显降低，差异具有显著性(P＜0.05)。在低压低氧环境下，与模型组相比，试验组大鼠的EF明显升高，差异有统计学意义(P＜0.05)。
2.3对大鼠右室FS的影响
大鼠在低压低氧环境饲养14天后，如图3所示，与对照组相比，模型组大鼠的FS明显降低，差异具有显著性(P＜0.05)。在低压低氧环境下，与模型组相比，试验组大鼠的FS明显升高，差异有统计学意义(P＜0.05)。
2.4对大鼠肺动脉直径的影响
大鼠在低压低氧环境饲养14天后，如图4所示，与对照组相比，模型组大鼠的肺动脉腔径明显降低，差异具有显著性(P＜0.05)。在低压低氧环境下，与模型组相比，试验组大鼠的肺动脉直径增加，差异有统计学意义(P＜0.05)。
2.5对大鼠心室三尖瓣位移的影响
大鼠在低压低氧环境饲养14天后，如图5所示，与对照组相比，模型组大鼠的三尖瓣位移明显降低，差异具有显著性(P＜0.05)。在低压低氧环境下，与模型组相比，试验组大鼠的三尖瓣位移增加，差异有统计学意义(P＜0.05)。
上述结果表明，试验组对模拟5500米高原环境大鼠的肺动脉高压、血管增生等具有保护作用，表明本发明所述的化合物或其药学上可接受的盐对高原环境下的急性高原病或慢性高原病、肺动脉高压、右心肥厚等具有治疗作用，可以开发成对抗高原环境下产生反应的药物，尤其对于心肺功能的保护作用最显著。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。
Claims (10)
1.一种化合物或其药学上可接受的盐，其特征在于，所述的化合物结构为通式I；
其中，R1选自苯基、被取代的苯基、噻吩基或被取代的噻吩基，所述苯基的取代基选自卤原子、C1-C4烷基、卤代烷基、烷氧基、烷硫基、羟基、羧基、氰基、氨基或硝基，所述噻吩基的取代基选自卤原子、硝基、羟基、氰基、氨基、C1-C4烷基、C1-C4卤代烷基或C1-C4烷氧基；
R2、R3和R4独立的选自卤原子；
R5、R6和R7独立的选自氢或C1-C4烷基；
R8选自氢、甲基、乙基或苄基；
R9选自S或O；
n选自1-6的自然数。
2.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，所述通式I的化合物中：
R1选自苯基或被取代的苯基，所述苯基的取代基选自卤原子、C1-C4烷基；
R2、R3和R4独立的选自卤原子；
R5、R6和R7独立的选自氢；
R8选自氢或甲基；
R9为S；
n选自2-5的自然数。
3.根据权利要求2所述的化合物或其药学上可接受的盐，其特征在于，所述通式I的化合物中R1为苯基，R2、R3和R4均为Cl，R5、R6和R7均为氢，R8为氢，R9为S，n为2。
4.一种权利要求1所述的化合物或其药学上可接受的盐的制备方法，其特征在于，
1)将邻硝基苯酚与式II所示化合物在碱性条件下反应，获得式III所示化合物；
2)氮气保护下，在步骤1)获得的式III所示化合物中加入钯/碳，氢气置换反应得到式IV所示化合物；
3)将步骤2)获得的式IV所示化合物与式V所示化合物反应得通式I所示化合物；
5.具有通式I的化合物或其药学上可接受的盐在制备治疗或预防高原病的药物组合物中的用途。
6.根据权利要求5所述的用途，其特征在于，所述的高原病选自在高原环境下产生的急性高原病和慢性高原病。
7.根据权利要求6所述的用途，其特征在于，所述的高原环境为海拔2000m以上，具有低压、缺氧的条件。
8.具有通式I的化合物或其药学上可接受的盐在制备治疗或预防心肺损伤和/或血管损伤的药物组合物中的用途；优选的，所述的心肺损伤和/或血管损伤为肺动脉高压和/或心力衰竭。
9.根据权利要求5-8任一所述的用途，其特征在于，所述的药物组合物中包含作为活性成分的具有通式I的化合物或其药学上可接受的盐，和药物辅料。
10.根据权利要求9所述的用途，其特征在于，所述的药物辅料选自溶剂、乳化剂、增塑剂、崩解剂、填充剂、粘合剂、甜味剂或润滑剂中的一种或两种以上的组合。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102241673A (zh) * | 2010-05-14 | 2011-11-16 | 中国人民解放军总医院 | 丙烯酰胺类化合物及其医药用途 |
| CN102241646A (zh) * | 2010-05-14 | 2011-11-16 | 中国人民解放军军事医学科学院毒物药物研究所 | 己烯酮类化合物及其医药用途 |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102241627A (zh) * | 2010-05-14 | 2011-11-16 | 中国人民解放军总医院 | 脲类化合物及其医药用途 |
| CN102241673A (zh) * | 2010-05-14 | 2011-11-16 | 中国人民解放军总医院 | 丙烯酰胺类化合物及其医药用途 |
| CN102241646A (zh) * | 2010-05-14 | 2011-11-16 | 中国人民解放军军事医学科学院毒物药物研究所 | 己烯酮类化合物及其医药用途 |
Non-Patent Citations (1)
| Title |
|---|
| JUAN LIU，等: "SAR, Cardiac Myocytes Protection Activity and 3D-QSAR Studies of Salubrinal and its Potent Derivatives", 《CURRENT MEDICINAL CHEMISTRY》 * |
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