CN114848640B - 化合物在制备抗炎药物中的应用 - Google Patents

化合物在制备抗炎药物中的应用 Download PDF

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CN114848640B
CN114848640B CN202210662428.7A CN202210662428A CN114848640B CN 114848640 B CN114848640 B CN 114848640B CN 202210662428 A CN202210662428 A CN 202210662428A CN 114848640 B CN114848640 B CN 114848640B
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CN114848640A (zh
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刘波
姚庆强
解维林
陈海蛟
杨新美
李妍
李莹
智英
汪海洋
赵晓东
张飞鹏
曲志强
曹本龙
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Shandong First Medical University and Shandong Academy of Medical Sciences
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Abstract

本发明涉及生物医药技术领域，具体涉及一类取代二芳基类化合物在制备抗炎药物中的应用。具有式Ⅰ所示结构。实验数据显示，本发明的化合物所测得的IL‑6的含量低于LPS诱导的RAW264.7细胞中的IL‑6的含量，说明一定程度上具有抗炎的活性。其中，CHJ04022R在0.5μM，1.0μM，2.0μM时，都能降低炎症因子IL‑23、IL‑1α、IFN‑γ、TNF‑α、MCP‑1、IL‑1β、IL‑6、IL‑17A、IFN‑β、GM‑CSF的含量，因此具有较优抗炎活性，并优于地塞米松。
Figure DDA0003691403970000011

Description

化合物在制备抗炎药物中的应用
技术领域
本发明涉及生物医药技术领域，具体涉及一类取代二芳基类化合物在制备抗炎药物中的应用。
背景技术
炎症反应从发病时间上可以分为两类：急性炎症性疾病和慢性炎症性疾病。炎症反应的快速激活可以保护受损组织，防止细菌感染，因此这种急性炎症是机体抵抗外来病原体入侵的一种抗病方式，是对机体有利的。但是当机体的促炎因子和抑炎因子一旦失衡，炎症就会持续存在，就会表现为慢性炎症反应。长期的慢性炎症会导致一些心脑血管疾病、糖尿病，甚至诱发癌症。研究报道表明，长期的慢性炎症不仅可以损害神经元细胞，毒害神经系统，还会促进神经元细胞加速释放大量炎症因子，导致恶性循环，从而加快神经系统的病变。当慢性炎症产生的炎症因子持续过量存在时，可导致机体功能下降。比如体液中TNF-α、IL-6等炎症因子过量存在时，可导致机体出现慢性炎症衰老的状况，它们可以加速人的衰老，诱发中老年疾病，如若帕金森、老年痴呆、骨质疏松等。
目前已知的炎症因子种类繁多、功能多样，但是它们也具有一定的特异性，即具体的炎症因子对身体疾病具有相关性。如肿瘤坏死因子、白介素家族等炎症因子在肺炎疾病中含量较高，是肺炎病理过程中重要的介导因子。在类风湿关节炎患者的滑膜组织上清液中检测出较高水平的IL-1，表明关节腔滑液中的IL-1与巨噬细胞、滑膜细胞的生成有关。TNF-α、IL-6等炎症因子也参与了类风湿关节炎疾病的发生、发展的过程，它们可以提高滑膜细胞的增殖和分化速度，导致滑膜内血管增多、滑膜增厚，同时也可以提高关节部位的代谢，从而使局部温度增高，加重炎症反应。因此，通过调节体内炎症因子的水平来改善身体功能、预防治疗相关疾病具有重大研究意义。
专利CN113387873A公开了一类取代二芳基类化合物式(I)、其制备方法、并包含其药物制剂及其医药用途。药理试验结果表明，本发明的取代二芳基类化合物对人肺癌(A549)、人卵巢癌(SKOV3)、人黑色素瘤(A375)和人结肠癌(LOVO)细胞均具有良好的抑制作用。式(I)：
Figure BDA0003691403950000021
该申请中，仅公开了该类化合物的抗癌用途，并未公开其抗炎功效。
专利CN2022102834159公开了一种化合物1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇(CHJ04022)旋光异构体及其制备方法和应用，该申请中，也仅仅公开了化合物1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇(CHJ04022)旋光异构体的抗癌用途，并未公开其抗炎功效。
关于通式(I)所示化合物或其药学上可接受的盐、其光学异构体的抗炎作用，目前未见有文献公开报道。
发明内容
本发明的第一个目的在于，提供通式(I)所示化合物或其药学上可接受的盐、其光学异构体在制备抗炎药物中的应用,
Figure BDA0003691403950000022
其中，R1为-OC2H5,-H,-CH(CH3)2,-Br,-CF3,-OCH3,-F,-Cl,-CH3
R2为-F,-CF3,-Br,-NHCOCH3,-Cl,-H,-OCH3,-CH(CH3)2
R3为-H,-CH3,-Cl,-Br,-NHCOCH3,-C3H7,-F,-C14H29,-OCH3
R4为-H,-Br,-CF3,-Cl
R5为-H,-Cl,-I,-Br,
R6为
Figure BDA0003691403950000031
优选的，所述化合物为
(R)-1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇(CHJ04022R)；
(S)-1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇(CHJ04022S)；
(R)-1-(2-乙氧基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
(S)-1-(2-乙氧基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；1-(2,6-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ02029)；
1-(4-溴-3-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ02049)；
1-(2,5-双(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ02050)；
1-(3-溴苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03001)；
1-(2-溴苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03003)；
1-(2-异丙基苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03004)；
1-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2-甲氧基-4-丙基苯氧基)丙-2-醇(CHJ03011)；
1-(4-溴苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03014)；
1-(3-异丙基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03015)；
1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(3-甲氧基苯氧基)丙-2-醇(CHJ03017)；
1-(5-溴-2-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03018)；
1-(3-溴-4-甲基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04010)；
1-(2-溴-5-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04011)；
1-(3,5-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04012)；
1-(3-溴-4-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04020)；
1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇(CHJ04022)；
1-(3-溴-5-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04023)；
1-(3-氯苯氧基)-3-((3-甲氧基-4-(2-(4(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04024)；
1-(2-碘苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04027)；
1-(3-溴-5-氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04034)；
N-(3-(2-羟基-3-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙氧基)苯基)乙酰胺(CHJ04058)；
1-(2,4-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04059)；
1-(5-溴-2-甲基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04060)；
N-(4-(2-羟基-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙氧基)苯基)乙酰胺(CHJ04061)；
1-(4-氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04083)；
1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(4-甲氧基苯氧基)丙-2-醇(CHJ04084)；
1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2-甲氧基苯氧基)丙-2-醇(CHJ04086)；
1-(2-溴-5)-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04065)；
1-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)-3-(2，4，6-三溴苯氧基)丙-2-醇(CHJ04068)；
1-(3，4-二氯苯氧基)-3-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04072)；
1-((4-(2-(二乙氨基)乙氧基)-3-甲氧基苄基)(甲基)氨基)-3-(2-异丙基苯氧基)丙-2-醇(CHJ04089)1-(2-溴-5-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-(甲氧基苄基)(甲基)氨基)丙-2-醇(CHJ04090)；
1-(3,4-二氯苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-(甲氧基苄基)(甲基)氨基)丙-2-醇(CHJ04091)；
1-(3-溴-4-氟苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-甲氧基苄基(甲基)氨基)丙-2-醇(CHJ04092)1-(4-溴-3)-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3(甲氧基苄基)(甲基)氨基)丙-2-醇(CHJ04093)；
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(4-溴-3-三氟甲基)苯氧基)丙-2-醇(CHJ04097)；
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(2-溴-5-三氟甲基)苯氧基)丙-2-醇(CHJ04099)；
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(4-溴苯氧基)丙-2-醇(CHJ05001)；
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(3-溴-4-氯苯氧基)丙-2-醇(CHJ05002)；
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(3-溴-4-甲基苯氧基)丙-2-醇(CHJ05003)。
优选的，所述化合物为
(R)-1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇；
(S)-1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇；
1-(4-溴-3)-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3(甲氧基苄基)(甲基)氨基)丙-2-醇(CHJ04093)；
1-(4-溴苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03014)；
1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(3-甲氧基苯氧基)丙-2-醇(CHJ03017)；
1-(5-溴-2-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03018)；
1-(2-异丙基苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03004)；
1-(2,6-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ02029)；
1-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2-甲氧基-4-丙基苯氧基)丙-2-醇(CHJ03011)；
1-(2-溴-5-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04011)；
1-(3-氯苯氧基)-3-((3-甲氧基-4-(2-(4(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04024)；
1-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)-3-(2，4，6-三溴苯氧基)丙-2-醇(CHJ04068)；
1-(2-溴-5-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-(甲氧基苄基)(甲基)氨基)丙-2-醇(CHJ04090)；
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(2-溴-5-三氟甲基)苯氧基)丙-2-醇(CHJ04099)；
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(4-溴苯氧基)丙-2-醇(CHJ05001)；
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(3-溴-4-氯苯氧基)丙-2-醇(CHJ05002；
1-(3-溴-5-氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04034)。
上述的化合物的应用中，优选的，所述化合物为
(R)-1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇；
(S)-1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇；
1-(4-溴-3)-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3(甲氧基苄基)(甲基)氨基)丙-2-醇(CHJ04093)；
1-(4-溴苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03014)；
1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(3-甲氧基苯氧基)丙-2-醇(CHJ03017)；
1-(5-溴-2-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03018)。
更优选的，所述化合物为(R)-1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇。
或者，更优选的，所述化合物为(S)-1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇。
或者，更优选的，所述化合物为1-(4-溴-3)-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3(甲氧基苄基)(甲基)氨基)丙-2-醇(CHJ04093)。
或者，更优选的，所述化合物为1-(4-溴苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03014)。
或者，更优选的，所述化合物为1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(3-甲氧基苯氧基)丙-2-醇(CHJ03017)。
或者，更优选的，所述化合物为1-(5-溴-2-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03018)。
本发明中，各化合物的化学名，代号及结构式如下：
(R)-1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇(CHJ04022R)
Figure BDA0003691403950000081
(S)-1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇(CHJ04022S)
Figure BDA0003691403950000082
(R)-1-(2-乙氧基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(SAMS10R)
Figure BDA0003691403950000083
(S)-1-(2-乙氧基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(SAMS10S)
Figure BDA0003691403950000084
1-(2,6-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ02029)
Figure BDA0003691403950000091
1-(4-溴-3-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ02049)
Figure BDA0003691403950000092
1-(2,5-双(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ02050)
Figure BDA0003691403950000093
1-(3-溴苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03001)
Figure BDA0003691403950000094
1-(2-溴苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03003)
Figure BDA0003691403950000101
1-(2-异丙基苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03004)
Figure BDA0003691403950000102
1-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2-甲氧基-4-丙基苯氧基)丙-2-醇(CHJ03011)
Figure BDA0003691403950000103
1-(4-溴苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03014)
Figure BDA0003691403950000104
1-(3-异丙基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03015)
Figure BDA0003691403950000111
1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(3-甲氧基苯氧基)丙-2-醇(CHJ03017)
Figure BDA0003691403950000112
1-(5-溴-2-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ03018)
Figure BDA0003691403950000113
1-(3-溴-4-甲基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04010)
Figure BDA0003691403950000114
1-(2-溴-5-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04011)
Figure BDA0003691403950000121
1-(3,5-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04012)
Figure BDA0003691403950000122
1-(3-溴-4-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04020)
Figure BDA0003691403950000123
1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇(CHJ04022)
Figure BDA0003691403950000124
1-(3-溴-5-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04023)
Figure BDA0003691403950000131
1-(3-氯苯氧基)-3-((3-甲氧基-4-(2-(4(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04024)
Figure BDA0003691403950000132
1-(2-碘苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04027)
Figure BDA0003691403950000133
1-(3-溴-5-氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04034)
Figure BDA0003691403950000134
N-(3-(2-羟基-3-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙氧基)苯基)乙酰胺(CHJ04058)
Figure BDA0003691403950000141
1-(2,4-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04059)
Figure BDA0003691403950000142
1-(5-溴-2-甲基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04060)
Figure BDA0003691403950000143
N-(4-(2-羟基-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙氧基)苯基)乙酰胺(CHJ04061)
Figure BDA0003691403950000144
1-(4-氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04083)
Figure BDA0003691403950000151
1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(4-甲氧基苯氧基)丙-2-醇(CHJ04084)
Figure BDA0003691403950000152
1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2-甲氧基苯氧基)丙-2-醇(CHJ04086)
Figure BDA0003691403950000153
1-(2-溴-5)-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04065)
Figure BDA0003691403950000154
1-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)-3-(2，4，6-三溴苯氧基)丙-2-醇(CHJ04068)
Figure BDA0003691403950000161
1-(3，4-二氯苯氧基)-3-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇(CHJ04072)
Figure BDA0003691403950000162
1-((4-(2-(二乙氨基)乙氧基)-3-甲氧基苄基)(甲基)氨基)-3-(2-异丙基苯氧基)丙-2-醇(CHJ04089)
Figure BDA0003691403950000163
1-(2-溴-5-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-(甲氧基苄基)(甲基)氨基)丙-2-醇(CHJ04090)
Figure BDA0003691403950000164
1-(3,4-二氯苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-(甲氧基苄基)(甲基)氨基)丙-2-醇(CHJ04091)
Figure BDA0003691403950000171
1-(3-溴-4-氟苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-甲氧基苄基(甲基)氨基)丙-2-醇(CHJ04092)
Figure BDA0003691403950000172
1-(4-溴-3)-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3(甲氧基苄基)(甲基)氨基)丙-2-醇(CHJ04093)
Figure BDA0003691403950000173
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(4-溴-3-三氟甲基)苯氧基)丙-2-醇(CHJ04097)
Figure BDA0003691403950000174
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(2-溴-5-三氟甲基)苯氧基)丙-2-醇(CHJ04099)
Figure BDA0003691403950000181
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(4-溴苯氧基)丙-2-醇(CHJ05001)
Figure BDA0003691403950000182
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(3-溴-4-氯苯氧基)丙-2-醇(CHJ05002)
Figure BDA0003691403950000183
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(3-溴-4-甲基苯氧基)丙-2-醇(CHJ05003)
Figure BDA0003691403950000184
本发明的第二个目的在于，提供一种药物组合物，含有上述任一项的化合物或其药学上可接受的盐、其光学异构体和药学上可接受的载体或赋形剂。
该组合物为临床上或药学上可接受的任一剂型，优选为口服制剂或注射剂。其中含有生理有效量的通式(I)所示的化合物0.01g～10g，可以为0.01g、0.015g、0.02g、0.025g、0.03g、0.04g、0.05g、0.1g、0.125g、0.2g、0.25g、0.3g、0.4g、0.5g、0.6g、0.75g、1g、1.25g、1.5g、1.75g、2g、2.5g、3g、4g、5g、6g、7g、8g、9g、10g等。
本发明任一化合物、其药学上可接受的盐，可以口服或肠胃外给药等方式施用于需要这种治疗的患者。
用于肠胃外给药时，可制成注射剂。注射剂可分为注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，可选用水性溶剂或非水性溶剂。最常用的水性溶剂为注射用水，也可用0.9％氯化钠溶液或其他适宜的水溶液；常用的非水性溶剂为植物油，主要为供注射用大豆油。配制注射剂时，可以不加入附加剂，也可根据药物的性质加入适宜的附加剂，如渗透压调节剂、pH值调节剂、增溶剂、填充剂、抗氧剂、抑菌剂、乳化剂、助悬剂等。
用于口服时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。
本发明所述的化合物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、针剂，可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本发明所述的化合物在临床上的给药方式可以采用口服、注射等方式。
本发明的化合物临床所用剂量为0.01-1000mg/天，也可根据病情的轻重或剂型的不同偏离此范围。
本发明的第三个目的在于，提供通式(I)所示化合物或其药学上可接受的盐、其光学异构体在制备治疗肺炎药物中的应用。
本发明的有益效果如下：
实验数据显示，本发明的化合物所测得的IL-6的含量低于LPS诱导的RAW264.7细胞中的IL-6的含量，说明一定程度上具有抗炎的活性。在此基础上选取抗炎活性最好的CHJ04022R进行了其对LPS诱导的RAW264.7细胞中的炎症因子的影响，LPS诱导的RAW264.7细胞中的炎症因子显著升高，CHJ04022R在0.5μM，1.0μM，2.0μM时，都能降低炎症因子IL-23、IL-1α、IFN-γ、TNF-α、MCP-1、IL-1β、IL-6、IL-17A、IFN-β、GM-CSF的含量，因此具有较优抗炎活性，并优于地塞米松。
附图说明
图1为化合物CHJ04022R对LPS诱导的RAW264.7细胞中IL-23含量的影响图；
图2为化合物CHJ04022R对LPS诱导的RAW264.7细胞中IL-1α含量的影响图；
图3为化合物CHJ04022R对LPS诱导的RAW264.7细胞中IFN-γ含量的影响图；
图4为化合物CHJ04022R对LPS诱导的RAW264.7细胞中TNF-α含量的影响图；
图5为化合物CHJ04022R对LPS诱导的RAW264.7细胞中MCP-1含量的影响图；
图6为化合物CHJ04022R对LPS诱导的RAW264.7细胞中IL-12P70含量的影响图；
图7为化合物CHJ04022R对LPS诱导的RAW264.7细胞中IL-1β含量的影响图；
图8为化合物CHJ04022R对LPS诱导的RAW264.7细胞中IL-10含量的影响图；
图9为化合物CHJ04022R对LPS诱导的RAW264.7细胞中IL-6含量的影响图；
图10为化合物CHJ04022R对LPS诱导的RAW264.7细胞中IL-27含量的影响图；
图11为化合物CHJ04022R对LPS诱导的RAW264.7细胞中IL-17A含量的影响图；
图12为化合物CHJ04022R对LPS诱导的RAW264.7细胞中IFN-β含量的影响图；
图13为化合物CHJ04022R对LPS诱导的RAW264.7细胞中GM-CSF含量的影响图。
图1-图13中，与Ctrl组相比，**P<0.01,***P<0.001和****P<0.0001；与Ctrl组相比，#P<0.05，##P<0.01,###P<0.001和####P<0.0001。单因素方差分析(One-way ANOVA)和Dunnett's multiple comparisons test检验。
具体实施方式
下面结合附图和具体实施方式来对本申请作进一步的说明，以便本领域的技术人员更了解本申请，但这些实施例仅用于说明本发明而不用于限制本发明的范围，即所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。
因此，以下对提供的本发明一部分实施例的详细描述并非旨在限制要求保护的本发明范围，而是仅仅是本发明的选定实施例。基于本发明的实施例，本领域技术人员在没有做出创造性劳动的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：本发明化合物对LPS诱导的RAW264.7细胞中的抗炎活性筛选实验
1、实验材料
DMSO(Sigma-Aldrich公司)，地塞米松(MCE公司)，LPS(美国sigma公司)DMEM，highglucose(Thermofisher公司)，Fetal Bovine Serum(Gibco公司)，PBS粉末(Sigma-Aldrich公司)，小鼠可溶性白介素6受体(sIL-6R)ELISA试剂盒(睿信生物)，细胞株：RAW264.7小鼠腹腔巨噬细胞系使用含10％胎牛血清的DMEM高糖完全培养基培养，每隔2-3d传代1次。细胞培养箱设置条件为：CO2浓度：5％，温度：37℃，取对数生长期的细胞用于实验。
2、实验方法
RAW264.7细胞(5x 104/well/1ml medium)接种在24孔培养板中，孵育24h后，加入10μM待测化合物和10μM DEX，孵育2h后加入LPS(终浓度：1μg/mL)继续诱导处理24h，然后收集上清，利用ELISA试剂盒检测IL-6的含量。
3、统计分析
采用GraphPad Prism 9统计作图软件，数据采用平均数±标准差(Mean±SD)表示，不同组间的数据差异采用单因素方差分析，然后用Dunnett’s检验，以P＜0.05表示有显著性统计学差异。
4、实验结果
表1.各组别IL-6含量(pg/ml,Mean±SD)
Figure BDA0003691403950000211
与Control组相比，***P<0.001；与LPS组相比，#P<0.05,##P<0.01和###P<0.001。单因素方差分析(One-way ANOVA)和Dunnett’s检验。
实验数据显示，大多数化合物所测得的IL-6的含量低于LPS诱导的RAW264.7细胞中的IL-6的含量，说明一定程度上具有抗炎的活性。在此基础上选取抗炎活性最好的CHJ04022R进行了其对LPS诱导的RAW264.7细胞中的炎症因子的影响。
实施例2：化合物CHJ04022R在LPS诱导的RAW264.7细胞中的抗炎活性实验
1、实验材料
DMSO(Sigma-Aldrich公司)，地塞米松(MCE公司)，LPS(美国sigma公司)DMEM，highglucose(Thermofisher公司)，Fetal Bovine Serum(Gibco公司)，PBS粉末(Sigma-Aldrich公司)，LEGENDplexTMMouse Inflammation Panel(13-plex)(美国Biolegend公司)。细胞株：RAW264.7小鼠腹腔巨噬细胞系使用含10％胎牛血清的DMEM高糖完全培养基培养，每隔2-3d传代1次。细胞培养箱设置条件为：CO2浓度：5％，温度：37℃，取对数生长期的细胞用于实验。:
2、实验方法
RAW264.7细胞(1.5x105/well/1.5ml medium)接种在6孔培养板中，孵育24h后，加入待测化合物(终浓度：0.5μM，1μM和2μM)和地塞米松(终浓度为1μM)，继续孵育2h后，加入LPS(终浓度：1μg/mL)诱导处理24h，然后收集上清，参考BIOLEGEND试剂盒说明书检测IL-23、IL-1α、IFN-γ、TNF-α、MCP-1、IL-12P70、IL-1β、IL-10、IL-6、IL-27、IL-17A、IFN-β和GM-CSF的含量。
3统计分析
采用GraphPad Prism 9统计作图软件，数据采用平均数±标准差(Mean±SD)表示，不同组间的数据差异采用单因素方差分析，然后用Dunnett's multiple comparisonstest检验，以P＜0.05表示有显著性统计学差异。
3、实验结果
各组炎症因子含量见图1—图13和表2。
图1—图13和表2说明了CHJ04022R显著降低炎症因子含量。
LPS诱导的RAW264.7细胞中的炎症因子显著升高，CHJ04022R在0.5μM，1.0μM，2.0μM时，都能降低炎症因子IL-23、IL-1α、IFN-γ、TNF-α、MCP-1、IL-1β、IL-6、IL-17A、IFN-β、GM-CSF的含量(对IL-12P70，IL-10，IL-27的影响较弱)，因此具有较优抗炎活性，并优于Dex(地塞米松)。
Figure BDA0003691403950000231

Claims (9)

1.通式(I)所示化合物或其药学上可接受的盐、其光学异构体在制备抗炎药物中的应用,
Figure FDA0004119948730000011
其中，R1为-OC2H5,-H,-CH(CH3)2,-Br,-CF3,-OCH3,-F,-Cl,-CH3,
R2为-F,-CF3,-Br,-NHCOCH3,-Cl,-H,-OCH3,-CH(CH3)2,
R3为-H,-CH3,-Cl,-Br,-NHCOCH3,-C3H7,-F,-C14H29,-OCH3,
R4为-H,-Br,-CF3,-Cl,
R5为-H,-Cl,-I,-Br,
R6为
Figure FDA0004119948730000012
2.如权利要求1所述的化合物的应用，其特征在于，所述化合物为
(R)-1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇；
(S)-1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇；
(R)-1-(2-乙氧基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
(S)-1-(2-乙氧基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(2,6-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(4-溴-3-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(2,5-双(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(3-溴苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(2-溴苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(2-异丙基苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2-甲氧基-4-丙基苯氧基)丙-2-醇；
1-(4-溴苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(3-异丙基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(3-甲氧基苯氧基)丙-2-醇；
1-(5-溴-2-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(3-溴-4-甲基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(2-溴-5-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(3,5-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(3-溴-4-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇；
1-(3-溴-5-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(3-氯苯氧基)-3-((3-甲氧基-4-(2-(4(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(2-碘苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(3-溴-5-氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
N-(3-(2-羟基-3-(3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙氧基)苯基)乙酰胺
1-(2,4-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(5-溴-2-甲基苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
N-(4-(2-羟基-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙氧基)苯基)乙酰胺
1-(4-氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(4-甲氧基苯氧基)丙-2-醇；
1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2-甲氧基苯氧基)丙-2-醇；
1-(2-溴-5)-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)-3-(2，4，6-三溴苯氧基)丙-2-醇；
1-(3，4-二氯苯氧基)-3-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-((4-(2-(二乙氨基)乙氧基)-3-甲氧基苄基)(甲基)氨基)-3-(2-异丙基苯氧基)丙-2-醇；
1-(2-溴-5-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-(甲氧基苄基)(甲基)氨基)丙-2-醇；
1-(3,4-二氯苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-(甲氧基苄基)(甲基)氨基)丙-2-醇；
1-(3-溴-4-氟苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-甲氧基苄基(甲基)氨基)丙-2-醇；
1-(4-溴-3)-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3(甲氧基苄基)(甲基)氨基)丙-2-醇；
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(4-溴-3-三氟甲基)苯氧基)丙-2-醇；
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(2-溴-5-三氟甲基)苯氧基)丙-2-醇；
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(4-溴苯氧基)丙-2-醇；
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(3-溴-4-氯苯氧基)丙-2-醇；
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(3-溴-4-甲基苯氧基)丙-2-醇。
3.如权利要求2所述的化合物的应用，其特征在于，所述化合物为
(R)-1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇；
(S)-1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇；
1-(4-溴-3)-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3(甲氧基苄基)(甲基)氨基)丙-2-醇)；
1-(4-溴苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(3-甲氧基苯氧基)丙-2-醇；
1-(5-溴-2-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(2-异丙基苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(2,6-二氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2-甲氧基-4-丙基苯氧基)丙-2-醇；
1-(2-溴-5-(三氟甲基)苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-(3-氯苯氧基)-3-((3-甲氧基-4-(2-(4(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇；
1-((3-甲氧基-4-(2-(吡咯烷基-1-基)乙氧基)苄基)(甲基)氨基)-3-(2，4，6-三溴苯氧基)丙-2-醇；
1-(2-溴-5-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3-(甲氧基苄基)(甲基)氨基)丙-2-醇；
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(2-溴-5-三氟甲基)苯氧基)丙-2-醇；
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(4-溴苯氧基)丙-2-醇；
1-((4-(2-(1H-咪唑-1-基)乙氧基)-(3-甲氧基苄基)(甲基)氨基)-3-(3-溴-4-氯苯氧基)丙-2-醇；
1-(3-溴-5-氯苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇。
4.如权利要求3所述的化合物的应用，其特征在于，所述化合物为(R)-1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇。
5.如权利要求3所述的化合物的应用，其特征在于，所述化合物为(S)-1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(2,4,6-三溴苯氧基)丙-2-醇。
6.如权利要求3所述的化合物的应用，其特征在于，所述化合物为1-(4-溴-3)-(三氟甲基)苯氧基)-3-((4-(2-(二乙氨基)乙氧基)-3(甲氧基苄基)(甲基)氨基)丙-2-醇。
7.如权利要求3所述的化合物的应用，其特征在于，所述化合物为1-(4-溴苯氧基)-3-((3-甲氧基-4-(2-(4-(甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇。
8.如权利要求3所述的化合物的应用，其特征在于，所述化合物为1-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)-3-(3-甲氧基苯氧基)丙-2-醇。
9.如权利要求3所述的化合物的应用，其特征在于，所述化合物为1-(5-溴-2-氟苯氧基)-3-((3-甲氧基-4-(2-(4-甲基哌啶-1-基)乙氧基)苄基)(甲基)氨基)丙-2-醇。
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