CN105924362A - 芳香环丙基胺类化合物、其药学上可接受的盐、其制备方法及其用途 - Google Patents
芳香环丙基胺类化合物、其药学上可接受的盐、其制备方法及其用途 Download PDFInfo
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- CN105924362A CN105924362A CN201610082466.XA CN201610082466A CN105924362A CN 105924362 A CN105924362 A CN 105924362A CN 201610082466 A CN201610082466 A CN 201610082466A CN 105924362 A CN105924362 A CN 105924362A
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Abstract
本发明涉及一种结构如通式(I)所示的芳香环丙基胺类化合物及其药学上可接受的盐，及其该类化合物的制备方法和该类化合物在制备预防或治疗耳聋的药物中的用途。其中，本发明所涉及的通式(I)中的R1、R2、R3、R4和R5如说明书和权利要求中所定义。
Description
技术领域
本发明涉及医药技术领域，具体而言，本发明涉及一种具有耳聋防治作用的芳香环丙基胺类化合物、其药学上可接受的盐、其制备方法及其在制备预防和治疗耳聋的药物中的用途。
背景技术
耳聋是高发病率的人类感官或功能缺陷性疾病。耳毒性药物是临床上造成听力损失或障碍的重要原因，同时也是临床上儿童听力损失或障碍的重要原因。由于内耳毛细胞损伤后缺乏再生能力，并且毛细胞的损伤会导致与其相连的螺旋神经节神经元退化，因此，毛细胞及螺旋神经节神经元损伤保护及其机制的研究在耳聋防治中尤为重要。
目前耳毒性药物所致毛细胞及螺旋神经节神经元的损伤保护研究主要集中在以下几个方面：1)减轻氧化应激反应损伤，如抗氧化剂和自由基清除剂等；2)抑制凋亡信号转导通路，如JNK信号通路、X连锁凋亡抑制蛋白(X-linked inhibitor of apoptosis proteins,XIAP)等；3)表观遗传学调控，如非编码微小RNA(miRNA)调控、DNA甲基化及组蛋白调控等。国内在耳毒性药物损伤听觉保护研究方面已经取得了一定成果。龚树生等研究表明，TrkB受体激动剂可以保护螺旋神经节神经元抵抗庆大霉素损伤(Yu Q,Chang Q,Liu X,Wang Y,Li H,Gong S et al.Protection of spiral ganglion neurons fromdegeneration using small-molecule TrkB receptor agonists.The Journal ofneuroscience，2013；33:13042-13052.)。李华伟等研究表明，过表达XIAP能够使耳蜗毛细胞抵抗新霉素造成的耳毒性损伤(Sun S,Sun M,Zhang Y,Cheng C,Waqas M,Yu H,He Y,Xu B,Wang L,Wang J,Yin S,Chai R,Li H.Invivo overexpression of X-linked inhibitor of apoptosis protein protectsagainst neomycin-induced hair cell loss in the apical turn of the cochleaduring the ototoxic-sensitive period.Frontiers in cellular neuroscience 2014,8:248.)。
近年来，表观遗传学调控是分子生物学领域研究的热点，这种调控反映了环境-基因-表型的相互作用，对于维持细胞稳定性具有重要意义。研究发现，表观遗传调控在生物早期发育、胚胎干细胞分化、神经系统发育及肿瘤发生发展过程中起着重要作用。组蛋白去乙酰化转移酶抑制剂通过调节钙稳态相关基因、凋亡基因及突触相关基因的表达，减轻顺铂所致的小鼠听力损伤，保护内耳毛细胞。在我们已有研究中，特异性抑制组蛋白甲基化转移酶G9a/GLP能够维持线粒体稳定性，抑制Caspase-3等经典细胞凋亡通路，从而实现抑制毛细胞凋亡和毛细胞保护的作用。赖氨酸特异性去甲基化酶1(lysine-specific demethylase1，LSD1)是最早发现的组蛋白去甲基化酶，它通过与CoREST形成复合物，特异性的作用于组蛋白H3K4产生去甲基作用。LSD1通过调节H3K4二甲基化水平在器官发育及细胞存活等生命过程中发挥重要作用，抑制LSD1上调H3K4me2可以影响干细胞的定向分化和肿瘤细胞的生长与存活(Whyte WA,Bilodeau S,Orlando DA,Hoke HA,FramptonGM,Foster CT,Cowley SM,Young RA:Enhancer decommissioning by LSD1during embryonic stem cell differentiation.Nature 2012,482(7384):221-225.)。
因此，仍需要能够预防和治疗耳聋、降低耳毒性、减少听力损伤、保护内耳毛细胞等方面的药物化合物。
发明内容
本发明的一个目的在于提供一种如通式(I)所示的芳香环丙基胺类化合物及其药学上可接受的盐：
其中：
R1、R2、R3和R4各自相同或不同地为氢、C1-C6烷基或卤素；
优选地，R1、R2、R3和R4各自相同或不同地为氢或卤素；
更优选地，R1、R2、R3和R4各自相同或不同地为氢或氟；
R5为直链或支链的C1-10烃基、C3-10环烃基、C6-20芳基或苄基；
优选地，R5为直链或支链的C1-6烃基、C3-7环烃基、C6-10芳基或苄基；
更优选地，R5为直链或支链的C1-6烷基、C3-7环烷基、C6-10芳基或苄基。
术语“烃基”是指烷基、烯基或炔基，例如“C1-6烃基”意为具有1-6个碳原子的链烃基，例如甲基、乙基、-CH＝CH2、-C≡CH、正丙基、异丙基、-CH＝CH-CH3、-CH2-CH＝CH2、正丁基、异丁基、-CH＝CH-CH2-CH3、-CH＝CH-CH＝CH2、-CH2-CH＝CH-CH3、仲丁基、叔丁基、正戊基、正己基。
所述卤素指氟、氯、溴或碘，优选氟、氯或溴，更优选氟或氯。
优选地，所述芳香环丙基胺类化合物的药学上可接受的盐为所述芳香环丙基胺类化合物的盐酸盐：
其中，R1、R2、R3、R4和R5如上所定义和优选。
更优选地，所述芳香环丙基胺类化合物的药学上可接受盐为：
对于所述芳香环丙基胺类化合物的药学上可以接受的盐，包括可药用酸加成盐，其通过用无机酸或有机酸处理该化合物的游离碱，可以得到其药学上可接受的盐。所述的无机酸为盐酸、氢溴酸、磷酸或硫酸；所述的有机酸为抗坏血酸、烟酸、柠檬酸、酒石酸、乳酸、马来酸、丙二酸、富马酸、乙醇酸、琥珀酸，丙酸、乙酸、三氟醋酸或甲磺酸等。本发明的化合物可以以未溶剂化的和与药学上可接受的溶剂(例如水，乙醇等)溶剂化的形式存在。通常，对于本发明的目的，认为溶剂化的形式等同于未溶剂化的形式。
本发明的另一目的在于提供一种上述芳香环丙基胺类化合物或其药学上可接受的盐的制备方法，该方法按如下反应路线进行，包括以下具体步骤：
其中，R1、R2、R3、R4和R5的定义如前所述，
步骤a)：在20～25℃的温度下、在碱性条件下、在溶剂中将式I-1所示的取代的对羟基苯甲醛和R5Br反应16-18h得到式I-2化合物；
其中，步骤a)中的所述碱性条件可以选择碳酸钾、碳酸钠、叔丁醇钾、氢化钠等，步骤a)中的溶剂可以选择DMF、DMSO、乙腈、二氧六环、THF等；
其中，步骤a)中的所述温度优选为20℃，步骤a)中的所述溶剂优选为DMF，步骤a)中的反应时间优选为18小时；
步骤b)：在-15～-10℃的温度下、在碱性条件下、在溶剂中将式I-2所示的化合物和Witting试剂反应30-60分钟得到式I-3化合物；
其中，步骤b)中的所述碱性条件可以选择乙醇钠、叔丁醇钾、氢化钠、正丁基锂等，步骤b)中的溶剂可以选择乙醇、DMF、DMSO、乙腈、THF等；
步骤b)中的所述温度优选为-15℃，步骤b)中的所述溶剂优选为THF，步骤b)中的所述Witting试剂优选为磷酸酯Witting试剂步骤b)中的反应时间优选为30分钟；
步骤c)：在30～40℃的温度下、在碱性条件下、在溶剂中将式I-3所示的化合物和亚甲基转移试剂反应30-60分钟得到式I-4化合物；
其中，步骤c)中的所述碱性条件可以选择叔丁醇钾、氢化钠、正丁基锂等，步骤c)中的溶剂可以选择DMF、DMSO、THF等；
步骤c)中的所述温度优选为30℃，步骤c)中的所述溶剂优选为DMSO，步骤c)中的所述亚甲基转移试剂优选为三甲基硫化碘步骤c)中的反应时间优选为30分钟；
步骤d)：在40-45℃的温度下、在碱性条件下、在溶剂中将式I-4所示的化合物反应3-4小时得到式I-5化合物；
其中，步骤d)中的所述碱性条件可以选择氢氧化锂、氢氧化钠、氢氧化钾、乙醇钠等，步骤d)中的溶剂可以选择甲醇、乙醇、正丙醇、异丙醇等；
步骤d)中的所述温度优选为40℃，步骤d)中的所述溶剂优选为甲醇，步骤d)中的所述碱性条件优选为氢氧化钠，步骤d)中的反应时间优选为3小时；
步骤e)：在85-90℃的温度下、在碱性条件下、在溶剂中将式I-5所示的化合物和叠氮化试剂反应16-18h得到式I-6化合物；
其中，步骤e)中的所述碱性条件可以选择DIPEA、三乙胺、吡啶等有机碱，步骤e)中的溶剂可以选择甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇等；
步骤e)中的所述温度优选为85℃，步骤e)中的所述溶剂优选为叔丁醇，步骤e)中的所述叠氮化试剂优选为DPPA，步骤e)中的反应时间优选为16h；
步骤f)：在20-25℃的温度下、在HX下、在溶剂中将式I-6所示的化合物反应3-4h得到式I-7化合物；
其中，步骤f)中的所述HX可以选择盐酸、三氟醋酸等，步骤f)中的溶剂可以选择乙醚、乙酸乙酯、二氧六环等；
步骤f)中的所述温度优选为20℃，步骤f)中的所述溶剂优选为二氧六环，步骤f)中的所述反应试剂优选为盐酸，步骤f)中的反应时间优选为3h。
本发明的另一目的在于提供上述通式(I)所示化合物及其药学上可接受的盐在制备预防或治疗与内耳毛细胞损伤相关的疾病的药物中的用途；
本发明的另一目的在于提供上述通式(I)所示化合物及其药学上可接受的盐在预防或治疗与内耳毛细胞损伤相关的疾病中的用途；
本发明的另一目的在于提供一种预防或治疗与内耳毛细胞损伤相关的疾病的方法，其特征在于，向受试者施用治疗有效量的一种或多种上述通式(I)所示化合物及其药学上可接受的盐；
所述与内耳毛细胞损伤相关的疾病包括神经性耳聋、混合性耳聋等；
本发明的另一目的在于提供了一种药物组合物，其含有治疗有效量的选自上述通式(I)的化合物及其药学上可接受的盐中的一种或多种，以及含有一种或多种可药用的载体；该药用组合物还可以进一步包含气味剂、香味剂等。
本发明所述的药物组合物优选含有重量比为1～99％的活性成份，其优选的比例是，通式(I)化合物或其药学上可接受的盐作为活性成分占总重量比65％～99％。
本发明所述的化合物和药物组合物可以是多种形式，如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等，并可以存在于适宜的固体或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。
附图说明
图1是斑马鱼侧线系统模型的示意图；
图2是正常组、对照组、A1至A8化合物处理组的神经丘免疫荧光情况；
图3是正常组、对照组、A1至A8化合物处理组的肌球蛋白7a+细胞数的柱状图；
图4是反应庆大霉素损伤致小鼠耳蜗组蛋白H3K4二甲基化表达下调的图。
具体实施方式
通过下列实施例说明本发明的技术方案。然而，应了解本发明保护的范围不限于这些实施例中的特定细节，因为鉴于本发明的公开内容，其他变化对本领域普通技术人员是已知和显而易见的。
本发明的具有通式(I)的化合物可通过下列合成途径合成，该途径包括类似于化学领域中所熟知的方法，特别是根据本文说明部分的方法。起始物质一般可由商业来源，如Aldrich化学公司(美国威斯康辛州密尔瓦基)取得，或通过本领域技术人员所熟知的方法即可制备(如通过下列书籍中所概述的方法制备：Louis F.Fieser与Mary Fieser之“用于有机合成作用之试剂”第1-19册(美国纽约Wiley公司1967-1999版本)；或“Beilsteins Handbuch derorganischen Chemie”Auf 1.版第4册及包括附刊(德国柏林Springer-Verlag公司出版)及亦可经由Beilstein线上资料库取得)。
除非另有说明，在下述反应路线中，所述的化合物的各符号具有相同的含义。为了说明的目的，下列所示的反应路线提供用于合成本发明的化合物以及关键中间产物的可能途径。有关个别反应步骤的更详细的说明，请见后述的实施例部分。本领域技术人员将了解可使用其他合成途径合成本发明的化合物。虽然在反应路线中显示及于后述部分论及特定的起始物质与试剂，但其可轻易地以其他起始物质与试剂替代，从而提供多种衍生物和/或适用其他反应条件。此外，鉴于本公开内容，可使用本领域技术人员所熟知的常规化学反应，而进一步修饰通过本文的方法所制备的众多化合物。
提供以下实验例以进一步阐明本发明。
实验样品分析所用仪器及试剂
核磁共振谱由Varian公司的Mercury-400型核磁共振仪测定。LC-MS由Thermo Finnigan LCQDECA×P型质谱仪测定。柱层析分离所用硅胶为青岛海洋化工厂产品(200～300目)。TLC硅胶板为烟台化工生产的HSF-254薄层层析预制板，采用紫外灯，碘缸显色。紫外灯为上海顾村电光仪器厂ZF-1型三用紫外分析仪。合成中所用原料为市售产品；或者通过本领域已知的方法制备；或者根据本文所述方法制备。
实施例1：2-(4-苄氧基-3-氟苯基)环丙基胺盐酸盐(A1)的制备
步骤1：中间体A1-2的制备
取250ml三口瓶，控温0～5℃，依次加入DMF，A1-1和K2CO3，再缓慢滴加BnBr，滴加完毕，维持温度20～25℃搅拌反应16-18h，TLC检测原料A1-1基本反应完全(PE/EA＝10:1，Rf＝0.4)。将反应液倾倒入冰水中，搅拌5～10min。抽滤，滤饼用冰水淋洗，20～25℃真空干燥，得白色固体物16.3g，摩尔收率99％。所得粗品无需纯化，直接投入下一步反应。
步骤2：中间体A1-3的制备
取250ml三口瓶，控温-5～0℃，依次加入干燥THF，t-BuOK；降温至-15～-10℃滴加TEPA，滴加完毕，维持温度-15～-10℃搅拌反应30min；再滴加A1-2/THF溶液，滴加完毕，维持温度-15～-10℃搅拌反应30min，TLC检测原料A1-2基本反应完全(PE/EA＝10:1，Rf＝0.45)。将反应液倾倒入冰水中，用EA提取2次，合并有机相，饱和盐水洗涤，无水硫酸镁干燥，35℃减压浓缩溶剂，得油状物粗品。柱层析纯化(PE/EA＝10:1)，得6.1g白色固体物，摩尔收率93％。
HNMR
A1-3(400MHz,CDCl3):δ(ppm)1.312-1.347(t,J＝6.8Hz,3H),4.226-4.280(q,J＝6.8Hz,2H),5.175(s,2H),6.266-6.306(d,J＝16Hz,1H),6.961-7.450(m,8H),7.548-7.588(d,J＝16Hz,1H)。
步骤3：中间体A1-4的制备
取50ml三口瓶，控温20～25℃，依次加入DMSO，Me3S(O)I，搅拌溶清；控温20～25℃，分批加入NaH，搅拌反应至反应液溶清约30min；控温20～25℃，滴加A1-3/DMSO溶液，滴加完毕，维持温度30～40℃搅拌反应约30min，TLC检测原料A1-3基本反应完全(PE/EA＝10:1，Rf＝0.5)。将反应液倾倒入冰水中，用EA提取2次，合并有机相，饱和盐水洗涤，无水硫酸镁干燥，35℃减压浓缩溶剂，得油状物粗品。柱层析纯化(PE/EA＝10:1)，得0.86g白色固体物，摩尔收率40％。
HNMR
A1-4(400MHz,CDCl3):δ(ppm)1.202-1.239(m,1H),1.260-1.296(t,J＝7.2Hz,3H),1.547-1.582(m,1H),1.802-1.823(m,1H),2.434-2.457(m,1H),4.137-4.191(q,J＝7.2Hz,2H),5.112(s,2H),6.778-6.915(m,3H),7.317-7.433(5H)。
步骤4：中间体A1-5的制备
取50ml三口瓶，控温20～25℃，依次加入MeOH，A1-4，搅拌溶清；控温20～25℃，滴加NaOH水溶液，滴加完毕，维持温度40～45℃搅拌反应约3h，TLC检测原料A1-4基本反应完全(PE/EA＝5:1，Rf＝0.1)。35℃减压浓缩溶剂至干，得白色固体残余物；向残余物中加入水，用2N HCl调PH＝3～4，用EA提取2次，饱和盐水洗涤，无水硫酸镁干燥，35℃减压浓缩溶剂，得白色固体粗品，所得粗品无需纯化，直接投入下一步反应。
步骤5：中间体A1-6的制备
取50ml三口瓶，控温20～25℃，依次加入t-BuOH，A1-5，搅拌溶清；再加入DPPA，TEA。控温85～90℃，回流反应16～18h，TLC检测原料A1-5基本反应完全(PE/EA＝5:1，Rf＝0.45)。45℃减压浓缩溶剂至干，再加入EA溶解，有机相依次用5％柠檬酸水溶液洗涤，饱和盐水洗涤，饱和NaHCO3溶液洗涤，饱和盐水洗涤，无水硫酸镁干燥，35℃减压浓缩溶剂，得白色固体粗品。柱层析纯化(PE/EA＝15～10:1)，得0.25g白色固体物，摩尔收率40.3％。
HNMR
A1-6(400MHz,CDCl3):δ(ppm)1.057-1.091(m,1H),1.245-1.270(m,1H),1.435(s,9H),1.962-1.981(m,1H),2.620(br,1H),4.784(br,1H),5.086(s,2H),6.845-6.887(m,3H),7.245-7.397(m,5H)。
步骤6：化合物A1的制备
取50ml三口瓶，控温20～25℃，依次加入A1-6，盐酸二氧六环溶液，搅拌溶清；控温20～25℃，搅拌反应3h。TLC检测原料A1-5基本反应完全。45℃减压浓缩溶剂至干，得白色残余物，再加入丙酮，控温20～25℃，搅拌反应30min。抽滤，滤饼丙酮淋洗，20～25℃真空干燥得产品105mg，摩尔收率56％。
HNMR/LCMS
H003-A1(400MHz,CD3OD):δ(ppm)1.261-1.297(m,1H),1.392-1.402(m,1H),2.330-2.356(m,1H),2.770-2.789(m,1H),5.114(s,2H),6.890-7.079(m,3H),7.297-7.425(m,5H).LCMS[M+H]:98.8％,258。
实施例2：2-(4-甲氧基-3-氟苯基)环丙基胺盐酸盐(A2)的制备
除了使用溴甲烷代替BnBr以外，按照与实施例1中描述的相同的方法制备化合物A2。
A2(400MHz,DMSO):δ(ppm)1.127-1.177(m,1H),1.350-1.390(m,1H),2.306-2.331(m,1H),2.716-2.736(m,1H),3.790(s,3H),6.974-7.066(m,3H),8.603(br,3H).LCMS[M+H]:99.6％,182。
实施例3：2-(4-乙氧基-3-氟苯基)环丙基胺盐酸盐(A3)的制备
除了使用溴乙烷代替BnBr以外，按照与实施例1中描述的相同的方法制备化合物A3。
H003-A3(400MHz,CD3OD):δ(ppm)1.283-1.303(m,1H),1.383-1.418(m,4H),2.330-2.334(m,1H),2.785-2.803(m,1H),4.060-4.113(q,J＝6.8Hz,2H),6.921-7.041(m,3H).LCMS[M+H]:98.2％,196。
实施例4：2-(4-异丙氧基-3-氟苯基)环丙基胺盐酸盐(A4)的制备
除了使用2-溴丙烷代替BnBr以外，按照与实施例1中描述的相同的方法制备化合物A4。
H003-A4(400MHz,DMSO):δ(ppm)1.121-1.155(m,1H),1.208-1.223(d,J＝6Hz,6H),1.332-1.356(m,1H),2.280-2.285(m,1H),2.693-2.713(m,1H),4.503-4.534(m,2H),6.891-7.060(m,3H),8.558(br,3H).LCMS[M+H]:99.3％,210.
实施例5：2-(4-丙氧基-3-氟苯基)环丙基胺盐酸盐(A5)的制备
除了使用溴丙烷代替BnBr以外，按照与实施例1中描述的相同的方法制备化合物A5。
HNMR/MS
A5(400MHz,DMSO):δ(ppm)0.94～0.97(t,J＝6.4Hz,3H),1.13～1.17(t,J＝6.4Hz,1H),1.34～1.37(m,1H),
1.68～1.74(m,2H),2.28～2.32(m,1H),2.72～2.76(m,1H),3.94～3.97(m,2H),6.93～7.08(m,3H),8.51(s,3H).MS[M+H]:210.
实施例6：2-(4-异丁氧基-3-氟苯基)环丙基胺盐酸盐(A6)的制备
除了使用异丁基溴代替BnBr以外，按照与实施例1中描述的相同的方法制备化合物A6。
A6(400MHz,DMSO):δ(ppm)0.95～0.97(d,J＝6.8Hz,6H),1.13～1.18(m,1H),1.35～1.36(m,1H),1.98～2.02(m,1H),2.28～2.32(m,1H),2.73～2.75(t,J＝4.4Hz,1H),3.77～3.78(d,6.4Hz,2H),6.93～7.08(m,3H),8.55(s,3H),MS[M+H]:224。
实施例7：2-(4-正丁氧基-3-氟苯基)环丙基胺盐酸盐(A7)的制备
除了使用正丁基溴代替BnBr以外，按照与实施例1中描述的相同的方法制备化合物A7。
A7(400MHz,DMSO):δ(ppm)0.90～0.94(m,3H),1.07～1.18(m,1H),1.35～1.45(m,3H),1.65～1.70(m,2H),2.28～2.29(m,1H),2.72～2.75(m,1H),3.99～4.02(m,2H),6.93～7.09(m,3H),8.46～8.50(m,3H)。MS[M+H]:224。
实施例8：2-(4-正己氧基-3-氟苯基)环丙基胺盐酸盐(A8)的制备
除了使用正己基溴代替BnBr以外，按照与实施例1中描述的相同的方法制备化合物A8。
A8(400MHz,CD3OD):(ppm)0.91～0.93(m,3H),1.26～1.35(m,6H),1.44～1.48(m,2H),1.73～1.78(m,2H),2.29～2.33(m,1H),2.78～2.79(m,1H),3.99～4.02(t,J＝6.4Hz,2H),6.92～7.03(m,3H)。MS[M+H]:252。
生物活性测试实施例
1)斑马鱼侧线系统模型的建立
如图1所示，建立了斑马鱼侧线系统模型其中显示了Brn3c:mGFP转基因斑马鱼的侧线神经系统毛细胞表达绿色荧光蛋白。
具体而言，图1显示了5dpf Brn3c:GFP转基因斑马鱼侧线器及神经丘的整体观，其中箭头代表初级侧线系统神经丘L1-L5和尾部神经丘T1-T3，星号代表次级侧线系统神经丘。
2)芳香环丙基胺类化合物对斑马鱼侧线系统毛细胞损伤的保护作用
通过上述斑马鱼侧线系统模型，发明人将毛细胞分为八组，正常组以斑马鱼饲养水培养，对照组以暴露于含400μM新霉素的斑马鱼饲养水中1小时，去除新霉素后，荧光显微镜观察斑马鱼侧线系统毛细胞损伤情况。A1-A8组以本发明相应的化合物A1-A8+含400μM新霉素的斑马鱼饲养水中培养，以检查经本申请化合物A1-A8处理后的毛细胞存活数。
其结果显示于图2和图3中。在图2中，第一列为Brn3c:mGFP转基因斑马鱼侧线器神经丘自带GFP绿色荧光，其表明斑马鱼毛细胞存活状态；第二列为毛细胞标志物肌球蛋白7a，其代表毛细胞存活率；第三列为DAPI标记的细胞核，其代表毛细胞细胞核；第四列为第一、三列合并的图示，其代表斑马鱼毛细胞自带荧光与毛细胞特异性标志物的共标结果，验证其存活率。
在图2中，从第一列图像可以看出，所有经本申请化合物A1-A8处理的斑马鱼均表现有荧光，表明所有化合物均具有抗毛细胞损伤的保护作用；此外，A1-A8组荧光强于对照组，表明所有化合物抗毛细胞损伤的保护作用高于参考物；同样，在第二列图像中，经本申请化合物处理组的毛细胞标志物肌球蛋白7a显著高于对照组，与正常组相当，由此可以看出本申请的化合物能够有效抑制毛细胞死亡；在第四列图像中，经本申请化合物A1-A8处理毛细胞存活率表明能够有效抑制毛细胞死亡，且好于对照组。
图3是图2中的毛细胞计数的柱状图，由图3可以看出，经本申请化合物处理组的毛细胞计数显著高于对照组，特别是其中A1、A3、A6和A8的技术均达到对照组两倍以上。
通过上述的斑马鱼平台筛选，发明人发现，芳香环丙基胺类化合物A3，A6，A8能够有效的抑制毛细胞死亡，达到斑马鱼侧线神经丘毛细胞保护的目的，这种差异具有统计学意义。计数结果显示新型化合物处理后毛细胞残留数均高于对照组。
3)组蛋白H3K4me2在毛细胞损伤过程中表达下调
以1mmol庆大霉素处理小鼠耳蜗基底膜，然后用Leica sp5激光共聚焦显微镜观测其荧光强度。结果参见图4。图4中，第1列表示肌球蛋白7a标记的毛细胞，第2列表示二甲基化的H3K4组蛋白，第3列表示DAPI标记的细胞核，第4列是前3列图像组合的结果。其中A-C(即第1-3行)分别表示损伤0分钟、2小时和4小时之后的二甲基化的组蛋白H3K4的免疫荧光强度变化。从第2列的对比可以看出，由庆大霉素处理毛细胞过程中，二甲基化的H3K4组蛋白的荧光强度明显降低。从3行可以看出，庆大霉素处理的毛细胞形态受到损伤。结果可以得出，毛细胞损伤可能与H3K4的二甲基化下调相关；本申请化合物A1-A8作用机制可能在于特异性的作用于LSD1，通过调节组蛋白H3K4发挥作用。
D：对照组和实验组H3K4me2表达的Western blotting结果。
E：对照组和实验组H3K4me2表达的Western blotting灰度分析结果。
用Bio-Rad蛋白质印记装置进行Western blot检测。结果显示正常组(即图中nor组)耳蜗组蛋白H3K4me2(17kDa)有一定强度表达；1mmol庆大霉素损伤4h后(即图中crl 4h组)耳蜗毛细胞H3K4me2表达强度明显下调。E：用image J软件进行灰度分析，绘制柱状图结果发现，庆大霉素损伤组组蛋白H3K4me2(17kDa)表达强度明显减弱，与正常组相比差异具有明显统计学意义(P<0.05)。
上述例子仅作为说明的目的，本发明的范围并不受此限制。对本领域的技术人员来说进行修改是显而易见的，本发明以所附权利要求保护的范围为准。
Claims (10)
1.一种如通式(I)所示的芳香环丙基胺类化合物及其药学上可接受的盐：
其中：
R1、R2、R3和R4各自相同或不同地为氢、C1-C6烷基或卤素；
R5为直链或支链的C1-10烃基、C3-10环烃基、C6-20芳基或苄基。
2.根据权利要求1所述的芳香环丙基胺类化合物及其药学上可接受的盐，
其中，所述R1、R2、R3和R4各自相同或不同地为氢或卤素；
所述R5为直链或支链的C1-6烃基、C3-7环烃基、C6-10芳基或苄基。
3.根据权利要求1所述的芳香环丙基胺类化合物及其药学上可接受的盐，
其中，所述R1、R2、R3和R4各自相同或不同地为氢或氟；
所述R5为直链或支链的C1-6烷基、C3-7环烷基、C6-10芳基或苄基。
4.根据权利要求1所述的芳香环丙基胺类化合物及其药学上可接受的盐，其中，所述芳香环丙基胺类化合物的药学上可接受的盐为：
5.根据权利要求1所述的芳香环丙基胺类化合物及其药学上可接受的盐，
其中，所述芳香环丙基胺类化合物的药学上可以接受的盐，包括可药用酸加成盐，其通过用无机酸或有机酸处理该化合物的游离碱而得到的药学上可接受的盐，
所述的无机酸为盐酸、氢溴酸、磷酸或硫酸；所述的有机酸为抗坏血酸、烟酸、柠檬酸、酒石酸、乳酸、马来酸、丙二酸、富马酸、乙醇酸、琥珀酸、丙酸、乙酸、三氟醋酸或甲磺酸。
6.一种芳香环丙基胺类化合物及其药学上可接受的盐的制备方法，该方法包括以下步骤：
其中，R1、R2、R3、R4和R5的定义如权利要求1中所述，
步骤a)：在20～25℃的温度下、在碱性条件下、在溶剂中将式I-1所示的取代的对羟基苯甲醛和R5Br反应16-18h得到式I-2化合物；
其中，步骤a)中的所述碱性条件为碳酸钾、碳酸钠、叔丁醇钾或氢化钠，步骤a)中的溶剂为DMF、DMSO、乙腈、二氧六环或THF；
步骤b)：在-15～-10℃的温度下、在碱性条件下、在溶剂中将式I-2所示的化合物和Witting试剂反应30-60分钟得到式I-3化合物；
其中，步骤b)中的所述碱性条件为乙醇钠、叔丁醇钾、氢化钠或正丁基锂，步骤b)中的溶剂为乙醇、DMF、DMSO、乙腈或THF；
步骤c)：在30～40℃的温度下、在碱性条件下、在溶剂中将式I-3所示的化合物和亚甲基转移试剂反应30-60分钟得到式I-4化合物；
其中，步骤c)中的所述碱性条件为叔丁醇钾、氢化钠或正丁基锂，步骤c)中的溶剂为DMF、DMSO或THF；
步骤d)：在40-45℃的温度下、在碱性条件下、在溶剂中将式I-4所示的化合物反应3-4小时得到式I-5化合物；
其中，步骤d)中的所述碱性条件为氢氧化锂、氢氧化钠、氢氧化钾或乙醇钠，步骤d)中的溶剂为甲醇、乙醇、正丙醇或异丙醇；
步骤e)：在85-90℃的温度下、在碱性条件下、在溶剂中将式I-5所示的化合物和叠氮化试剂反应16-18h得到式I-6化合物；
其中，步骤e)中的所述碱性条件为DIPEA、三乙胺或吡啶，步骤e)中的溶剂为甲醇、乙醇、正丙醇、异丙醇、正丁醇或叔丁醇；
步骤f)：在20-25℃的温度下、在HX的存在下、在溶剂中将式I-6所示的化合物反应3-4h得到式I-7化合物；
其中，步骤f)中的所述HX为盐酸或三氟醋酸，步骤f)中的溶剂为乙醚、乙酸乙酯或二氧六环。
7.根据权利要求6所述的制备方法，
其中，步骤a)中的所述温度为20℃，步骤a)中的所述溶剂为DMF，步骤a)中的反应时间为18小时；
步骤b)中的所述温度为-15℃，步骤b)中的所述溶剂为THF，步骤b)中的所述Witting试剂为磷酸酯Witting试剂步骤b)中的反应时间为30分钟；
步骤c)中的所述温度为30℃，步骤c)中的所述溶剂为DMSO，步骤c)中的所述亚甲基转移试剂为三甲基硫化碘步骤c)中的反应时间为30分钟；
步骤d)中的所述温度为40℃，步骤d)中的所述溶剂为甲醇，步骤d)中的所述碱性条件为氢氧化钠，步骤d)中的反应时间为3小时；
步骤e)中的所述温度为85℃，步骤e)中的所述溶剂为叔丁醇，步骤e)中的所述叠氮化试剂为DPPA，步骤e)中的反应时间为16h；
步骤f)中的所述温度为20℃，步骤f)中的所述溶剂为二氧六环，步骤f)中的所述HX为盐酸，步骤f)中的反应时间为3h。
8.根据权利要求1所述的芳香环丙基胺类化合物及其药学上可接受的盐在制备预防或治疗与内耳毛细胞损伤相关的疾病的药物中的用途。
9.根据权利要求8所述的用途，其中，所述与内耳毛细胞损伤相关的疾病为神经性耳聋或混合性耳聋。
10.一种药物组合物，其含有治疗有效量的选自根据权利要求1所述的芳香环丙基胺类化合物及其药学上可接受的盐中的一种或多种，以及含有一种或多种可药用的载体。
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