CN113880801A - 一类三环化合物、其制备方法及其医药用途 - Google Patents

一类三环化合物、其制备方法及其医药用途 Download PDF

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CN113880801A
CN113880801A CN202010629198.5A CN202010629198A CN113880801A CN 113880801 A CN113880801 A CN 113880801A CN 202010629198 A CN202010629198 A CN 202010629198A CN 113880801 A CN113880801 A CN 113880801A
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compound
acid
formula
pharmaceutically acceptable
acceptable salt
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何广卫
储昭兴
许勤龙
莫佳佳
林高峰
赵炎
叶文峰
卞林翠
邵莉
谷元凤
郭敬
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Hefei Amvite Pharmaceutical Co ltd
Hefei Industrial Pharmaceutical Institute Co ltd
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Hefei Amvite Pharmaceutical Co ltd
Hefei Industrial Pharmaceutical Institute Co ltd
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Priority to CN202010629198.5A priority Critical patent/CN113880801A/zh
Priority to US17/800,361 priority patent/US20230140276A1/en
Priority to CN202180028913.2A priority patent/CN115427405B/zh
Priority to EP21833899.4A priority patent/EP4177248A4/en
Priority to JP2022532071A priority patent/JP2023531338A/ja
Priority to PCT/CN2021/090073 priority patent/WO2022001331A1/zh
Publication of CN113880801A publication Critical patent/CN113880801A/zh
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Abstract

本发明提供一类三环化合物、其制备方法及其医药用途，所述三环化合物具有下列式(I)的结构，本发明要求保护，式(I)结构的化合物或其药学上可接受的盐、复合盐、前药、互变异构体、立体异构体或者立体异构体的混合物；本发明化合物具有显著的拮抗组胺H1受体的活性，且抗M‑胆碱副作用更低，Herg毒性更低。

Description

一类三环化合物、其制备方法及其医药用途
(一)技术领域
本发明涉及药物化学领域，具体涉及一类三环化合物、制备方法及其医药用途，本发明的化合物与现有技术相比，具有显著的抗组胺活性和极低的抑制胆碱的作用，本发明还提供了其在制备预防和治疗过敏性疾病药物中的用途。
(二)背景技术
过敏性疾病如急性荨麻疹、慢性特发性荨麻疹、过敏性鼻炎、过敏性眼炎、过敏性皮肤病(包括湿疹、玫瑰糠疹、药疹、夏季皮炎、接触性皮炎、特应性皮炎)、过敏性紫癜、花粉过敏、支气管哮喘等，极大的降低了人们的生活质量。目前，用于临床上治疗这类疾病主要是以抗组胺药和免疫抑制剂为主。
其中抗组胺药物以H1受体拮抗剂为主，H1受体拮抗剂可竞争性地与H1受体结合而阻断组胺与H1受体的作用，进而抑制组胺发挥生物学效应，起到抗过敏的作用[ZolalyMA.Histamine H1 antagonists and clinical characteristics of febrile seizures[J].Int J Gen Med.2012,5:277-281]。目前临床常用的组胺H1受体拮抗剂主要分为两代，第一代抗组胺药包括氯苯那敏、苯海拉明、羟嗪等，都具有显著的中枢系统副作用，容易导致嗜睡、精神恍惚。第二代抗组胺药如特非那定、氯雷他定、地氯雷他定、阿司咪唑等，虽然改善了第一代抗组胺药物的中枢系统副作用，但是部分化合物存在严重的心脏毒性如特非那定和阿司咪唑，会引起心律失常、心电图出现Q-T间期延长，甚至出现心跳骤停及猝死。其他药物如氯雷他定、地氯雷他定等，虽然未见明显的心脏毒性，但是存在明显的抑制胆碱的副作用，如口干，眼睛干涩，严重会引起运动功能障碍。
因此，开发新的具有更高安全性的H1受体阻断剂，改善现有治疗药物的不足，降低中枢、心脏毒性和胆碱抑制活性，具有重要的价值。
本发明人申请的中国专利CN107602534B中公开了一系列具有抗组胺和抗炎双重活性的地氯雷他定衍生物，其中化合物LHC-7活性最佳，
Figure BDA0002567787970000021
但是在随后的研究中发现其具有很强的Herg毒性。
本发明人申请的中国专利CN109096251A中公开了一类多靶点地氯雷他定衍生物，包括化合物LP-2。
Figure BDA0002567787970000022
世界专利WO9200293A1中也公开了一系列的抗组胺化合物，其中包括以下结构的化合物1：
Figure BDA0002567787970000023
但该世界专利中未公开化合物1的实施方法、活性数据等。
本发明在现有技术的基础上研究开发了一系列新的化合物，并发现这些化合物表现出优异的效果和作用。尤其是本发明化合物既保留了显著的抗组胺的活性，同时比地氯雷他定、LHC-7、化合物1的抗胆碱活性更低，Herg毒性更低，本发明化合物具有更高的安全性。
(三)发明内容
本发明针对现有技术的不足，通过结构改造，提供一种新型三环化合物，药效学实验表明本发明的化合物显著的拮抗组胺H1受体活性，极显著的降低或者基本消除了现有技术中公开的化合物的抗胆碱活性，降低了现有技术的化合物 Herg毒性，具体而言，本发明提供一种具有下列式(I)的三环化合物或其药学上可接受的盐
Figure BDA0002567787970000031
式(I)中
X为H、OH；
n＝1-6；
A环为苯环、吡啶环、噻吩环；
R1、R4为H、卤素；
R2、R3选自H、羟基、＝O；
R5选自H、C1～C6的烷基；
R6为H，任意单取代或多取代的C1～C6的烷基、卤素、羟基、三氟甲基、氰基、氧三氟甲基、甲氧基、氨基、硝基、羧基。
优选的，式(I)中
n＝1-4；
R1为H、Cl；
R5为H；
R6为H、甲基、F、Cl、Br、羟基、三氟甲基、氰基、氧三氟甲基、甲氧基、氨基、硝基。
本发明所述的化合物或其药学上可接受的盐，包括下式结构的化合物：
Figure BDA0002567787970000032
其中
n＝1-6
X为H、OH；
R3为H、羟基、＝O；
R5选自H、C1～C6的烷基；
R6为H，任意单取代或多取代的C1～C6的烷基、卤素、羟基、三氟甲基、氰基、氧三氟甲基、甲氧基、氨基、硝基、羧基。
本发明所述的化合物或其药学上可接受的盐，包括下式结构的化合物
Figure BDA0002567787970000041
其中
n＝1-6
X为H、OH；
R5选自H、C1～C6的烷基。
本发明所述的所述药学上可接受的盐为式(I)化合物和碱金属或者碱土金属，氨基酸或者含有氨基的碱性化合物形成的盐，或者为式(I)化合物与无机酸或者有机酸形成的盐，或者为式(I)化合物多元酸碱金属或者碱土金属盐复合盐。具体的，本发明所述的所述药学上可接受的盐包括式(I)化合物的钾盐，钠盐，铵盐；式(I)化合物与盐酸、硫酸、磷酸、氢溴酸、马来酸、富马酸、枸橼酸、甲磺酸、对甲苯磺酸、酒石酸或醋酸形成的盐；所述式(I)化合物多元酸碱金属或者碱土金属盐复合盐中，其中的多元酸，选自枸橼酸、丁二酸、酒石酸、琥珀酸、富马酸、马来酸、草酸、硫酸、磷酸、亚硫酸、苹果酸，其中的碱金属或碱土金属选自钠、钾、钙、镁、锌。
本发明所述的化合物或其药学上可接受的盐，特别优选的，选自以下化合物：
Figure BDA0002567787970000051
Figure BDA0002567787970000061
本发明进一步包括，含有本发明化合物或其药学上可接受的盐的药物组合物。所述的药物组合物，选自片剂，胶囊、颗粒剂、口服液、栓剂、透皮制剂、注射剂。
本发明还包括，本发明所述的化合物或其药学上可接受的盐在制备预防和治疗过敏性疾病的药物中的用途。其中所述过敏性相关疾病选自：过敏性鼻炎、荨麻疹、慢性荨麻疹、过敏性紫癜、哮喘、过敏性皮炎、湿疹、过敏性结膜炎、特应性皮炎、鼻窦炎、慢性鼻窦炎。
本发明进一步包括本发明化合物的结晶形态，溶剂化物，前药、互变异构体、立体异构体或者立体异构体的混合物。
(四)生物活性
1.本发明化合物对组胺诱导的小鼠血管通透性的抑制作用
取ICR小鼠，体重18-22g，适应性饲养7天，随机分组，每组10只，即模型组、本发明化合物组、阳性药地氯雷他定组、LHC-7对照组、LP-2对照组，化合物1对照组。于造模前1h灌胃给药，对照组给予相应溶媒，化合物组给予 5mg/kg相应化合物，地氯雷他定组分别给予5mg/kg相应药物。小鼠用10％硫化钠将小鼠背部脱毛(3cm×3cm)，给药1h后于脱毛处皮内注射磷酸组胺生理盐水溶液1ug/0.1mL，注射后立即由尾静脉注射0.25％伊文思蓝溶液4ml/kg，30min 后脱臼处死，取下蓝染部分的皮肤打孔(直径15mm)，剪碎后浸泡于丙酮-生理盐水(7:3)溶液1ml中，24h后离心(3000r/min，10min)，取上清液，用紫外分光光度计在波长610nm处，以丙酮-生理盐水溶液空白校零，测定所取样本的吸光度值。
结果见表1，与模型组比较，各化合物组及地氯雷他定组均具有显著的抑制 组胺诱导小鼠皮肤血管通透性(P＜0.01)；与对照组比较，本发明化合物抑制率与 地氯雷他定、LHC-7化合物抑制率相当，优于化合物1(P＜0.05)。说明，本发明 化合物具有较强的抗组胺活性。
表1本发明化合物对组胺诱导的小鼠血管通透性的抑制作用
Figure BDA0002567787970000071
Figure BDA0002567787970000081
2.本发明化合物对毛果芸香碱诱导的大鼠流涎的试验结果
Wistar雄性大鼠，180-220g，分为空白组、模型组、地氯雷他定组、本发明化合物组，LHC-7对照组、化合物1对照组、每组10只。各组大鼠灌胃给予相应药物，15min后腹腔注射毛果芸香碱(1mg/kg，生理盐水溶解)诱导唾液分泌。立即腹腔注射10％水合氯醛麻醉大鼠，大鼠麻醉后，口腔内残留的唾液用棉球取出，然后将称重过(M1)的棉球放入口腔内(舌下两个，两侧各一个)，10分钟后取出立即测量棉球重量(M2)。
唾液分泌量＝M2-M1
抑制率＝给药组唾液分泌量/模型组唾液分泌量×100％
实验结果如下表所示，模型组腹腔注射毛果芸香碱1mg/kg，唾液分泌量显著增加，模型成功。灌胃给药地氯雷他定(1mg/kg)，LHC-1(10mg/kg)和化合物1(10mg/kg)唾液分泌量减少(P<0.01)，说明地氯雷他定、LHC-1和化合物1有明显的抑制胆碱的作用。灌胃给药本发明化合物(10mg/kg)唾液分泌量与模型组比较无统计学差异(P>0.05)，与对照组比较具有显著性差异(P＜0.05)。说明与化合物LHC-7、LP-2、化合物1及地氯雷他定相比，本发明化合物抑制胆碱的活性极低。
表2本发明化合物对毛果芸香碱诱导的大鼠流涎的抑制作用
Figure BDA0002567787970000082
Figure BDA0002567787970000091
3.本发明化合物Herg毒性测试
本发明化合物与对比专利化合物LHC-7、LP-2、化合物1及地氯雷他定相比，Herg毒性明显降低，特别是化合物1～4、7、8、11、21、26、29、32抑制 Herg的IC50>30μm，具有更高的安全性。
实施例编号 Herg IC<sub>50</sub>(μm)
1 >30
2 >30
3 >30
4 >30
7 >30
8 >30
11 >30
21 >30
26 >30
29 >30
32 >30
LHC-7 0.248
化合物1 2.033
LP-2 4.032
地氯雷他定 1.214
(五)具体实施方式
以下通过实施例进一步说明本发明，但不作为对本发明的限制。
实施例1
步骤1
Figure BDA0002567787970000101
向100mL三口瓶中依次加入三氯化铝(6.93g,52.0mmol)和DCM(35mL)，氮气保护，降温至-20℃，依次滴加2-甲基-2-苯基丙酸乙酯(5.00g,26.0mmol) 和溴乙酰氯(8.18g,52.0mmol)。加毕升温至0℃，反应6h。TLC(PE:EA＝10:1) 显示反应已完成。加入饱和碳酸氢钠溶液，调节pH至7。过滤，滤液分液，水层用DCM萃取(50mL)，合并有机相，用饱和食盐水洗涤(30mL×4)，无水硫酸钠干燥，过滤，浓缩并经柱层析(PE:EA＝40:1)纯化得到目标化合物中间体1(4.01 g,49.2％yeild)，淡黄色油状。
步骤2
Figure BDA0002567787970000102
向拇指瓶中依次加入中间体1(1.00g,3.2mmol)和三氟乙酸(2.0mL,26.8 mmol)，氮气保护，降温至0℃，滴加三乙基硅烷(1.0ml,3.2mmol)，搅拌30min 后升温至60℃，反应过夜。TLC(PE:EA＝20:1)显示反应已完成。冰水浴冷却，滴加饱和碳酸氢钠溶液，调节pH至7。EA萃取(30mL×3)，合并有机相，用饱和食盐水洗涤(40mL×3)，无水硫酸钠干燥。过滤浓缩并经柱层析(PE:EA＝100:1) 纯化得到目标化合物中间体2(520mg,54.4％yeild)，无色油状物。
步骤3
Figure BDA0002567787970000111
向25mL单口瓶中依次加入化合物2(375mg,1.25mmol)和DMF(6mL)、地氯雷他定(324mg,1.04mmol)和DIEA(269mg,2.08mmol)。置换氮气，70℃反应过夜。TLC(DCM:MeOH＝20:1)显示反应已完成。冰水浴冷却，加入水(15mL)淬灭反应，EA萃取(20mL×3)，合并有机相，用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥，过滤，浓缩并经制备板分离(DCM:MeOH＝20:1)纯化得到目标化合物中间体3(307mg,55.7％yeild)，黄色固体。
步骤4
Figure BDA0002567787970000112
向25mL单口瓶中依次加入化合物3(307mg,0.58mmol)、EtOH/H2O(4 mL/2mL)和氢氧化钠(70mg,1.74mmol)，70℃反应过夜。TLC(DCM:MeOH＝20:1) 显示反应已完成。滴加3N稀盐酸，调节pH至3，减压浓缩干，加入DCM(10mL) 溶解，过滤，滤除无机盐。滤液浓缩并经厚制备板分离(DCM:MeOH＝10:1)纯化得到目标化合物(105mg,36.1％yeild)，淡黄色固体。1HNMR(400MHz,CDCl3): δppm 8.44(dd,J1＝1.6Hz,J2＝4.8Hz,1H),7.49(dd,J1＝1.2Hz,J2＝4.4Hz,1H), 7.38(d,J＝8.4Hz,2H),7.12-7.17(m,3H),7.06-7.08(m,1H),6.92(d,J＝8.4Hz,2 H),3.29-3.39(m,2H),2.57-2.69(m,14H),1.57(s,6H)。
实施例2
参考实施例1的合成方法，以1-溴-3-氯丙烷替代溴乙酰氯，制得目标化合物(115mg,23.6％yield)，白色固体。1H NMR(400MHz,CD3OD):δppm 8.22-8.24 (dd,J1＝1.2Hz,J2＝4.8Hz,1H),7.54-7.56(m,1H),7.13-7.22(m,4H),6.96-7.09(m, 4H),3.24-3.34(m,2H),3.02-3.09(m,2H),2.35-2.82(m,6H),2.47-2.56(m,4H), 2.25-2.41(m,2H),1.76-1.86(m,2H),1.38(s,6H).13C NMR(100MHz,CD3OD): δ182.24,155.80,145.30,144.88,139.44,137.91,137.63,136.23,134.00,133.81, 133.74,132.60,129.58,128.50,127.21,125.33,125.19,122.46,55.88,52.26,31.64, 30.61,30.14,27.51,27.37,26.22,26.18,25.65.
实施例3
参考实施例1的合成方法，以1氯-3-溴丁烷替代溴乙酰氯，制得目标化合物(101mg,13.2％yield)，白色固体。1H NMR(400MHz,CD3OD):δppm 8.23(dd, J1＝4.9,J2＝1.6Hz,1H),7.55(dd,J1＝7.8,J2＝1.6Hz,1H),7.20-7.23(m,2H), 7.14-7.18(m,2H),7.07-7.09(m,1H),6.98-7.03(m,3H),3.24-3.34(m,2H), 2.96-3.04(m,2H),2.61-2.82(m,6H),2.45-2.54(m,4H),2.23-2.39(m,2H), 1.48-1.50(m,4H),1.38(s,6H).13C NMR(100MHz,CD3OD):δ181.61,155.33, 144.77,143.99,138.90,138.13,137.37,135.75,133.46,133.38,133.18,132.06, 129.08,127.99,126.69,124.81,124.62,121.93,55.58,51.77,33.47,30.11,29.63, 27.40,27.10,26.95,25.62,23.09.
实施例4
参考实施例1的合成方法，制得目标化合物(170mg,29.1％yield)，白色固体。1HNMR(400MHz,CD3OD):δppm 8.31-8.33(m,1H),7.63-7.65(m,1H), 7.16-7.27(m,6H),7.11(d,J＝8.4Hz,1H),6.99-7.01(m,1H),3.35-3.42(m,2H), 3.11-3.15(m,1H),2.53-2.89(m,10H),2.44-2.49(m,1H),2.33-2.39(m,1H), 1.89-1.97(m,2H),1.49(s,6H).13C NMR(100MHz,CD3OD):δ182.36,156.30, 147.60,145.79,140.23,139.94,138.41,136.74,134.50,134.28,134.25,133.09, 130.09,129.01,127.94,125.89,125.83,125.63,123.46,122.97,56.30,52.87,32.75, 31.12,30.65,28.15,28.01,26.68,26.67,26.16.
实施例5
参考实施例1的合成方法，以2-溴乙烷替代溴乙酰氯，制得目标化合物(120 mg,41.9％yield)，类白色固体。得到粗品110mg。1H NMR(400MHz,CD3OD):δ ppm 8.21-8.22(m,1H),7.55(d,J＝7.81Hz,1H),7.29-7.35(m,2H),7.22-7.27(m,2 H),7.12-7.18(m,2H),7.05-7.10(m,1H),6.98-7.03(m,1H),3.80(br,2H), 3.25-3.37(m,2H),2.96-3.03(m,2H),2.72-2.81(m,2H),2.58-2.65(m,2H), 2.44-2.50(m,2H),2.30-2.40(m,1H),2.18-2.28(m,1H),1.42(s,6H).13C NMR (100MHz,CD3OD)δ181.08,156.39,147.76,145.75,139.88,138.38,136.77, 134.48,134.16,133.06,130.19,130.07,128.98,126.11,125.80,122.92,60.29,53.40, 52.72,31.12,30.63,28.17,28.05,26.28
实施例6
参考实施例1的合成方法，以1-溴-3-氯丙烷替代溴乙酰氯，制得目标化合物(150mg,23.7％yield)，白色固体。1H NMR(400MHz,CD3OD):δppm 8.33-8.35 (m,1H),7.64-7.67(m,1H),7.38-7.41(m,1H),7.18-7.29(m,4H),7.13-7.15(m,3 H),3.35-3.45(m,2H),3.25-3.29(m,2H),3.02-3.14(m,4H),2.68-2.91(m,6H), 2.45-2.63(m,2H),2.07-2.14(m,1H),1.49(s,6H).13C NMR(100MHz,CD3OD): δ186.31,156.99,146.94,146.76,140.90,139.35,139.21,137.52,135.83,135.41, 134.10,133.99,130.88,130.04,129.92,126.78,126.76,126.69,126.14,123.92, 57.17,53.91,48.46,31.95,31.53,29.51,28.47,28.33,28.28,25.76.
实施例7
参考实施例1的合成方法，制得目标化合物(175mg,80.0％yield,98％purity)，白色固体。1H NMR(400MHz,CDCl3):δppm 8.42(d,J＝4.4Hz,1H),7.68(d, J＝1.6Hz,1H),7.60-7.57(m,1H),7.47-7.46(m,1H),7.16-7.12(m,4H),7.04(d, J＝8.0Hz,1H),3.40-3.27(m,2H),2.99(br,2H),2.99-2.49(m,10H),2.33(s,2H), 1.96-1.93(m,2H),1.58-1.56(m,6H).
实施例8
参考实施例1的合成方法，制得目标化合物(104mg,30.8％)，淡黄色固体。1H NMR(400MHz,CD3OD):δppm 8.35(dd,J1＝4.9Hz,J2＝1.5Hz,1H),7.67(dd, J1＝7.8Hz,J2＝1.4Hz,1H),7.31–7.25(m,2H),7.20(dd,J1＝8.1Hz,J2＝2.1Hz,1H), 7.1(d,J＝8.2Hz,1H),7.07(d,J＝7.8Hz,1H),6.95(d,J＝1.6Hz,1H),6.91(dd, J1＝7.8Hz,J2＝1.8Hz,1H),3.81(s,3H),3.48–3.35(m,4H),3.15–3.00(m,4H), 2.94–2.81(m,2H),2.72–2.61(m,4H),2.59–2.42(m,2H),2.05–1.94(m,2H),1.52 (s,6H).13C NMR(400MHz,CD3OD)δppm 180.16,157.20,155.81,145.83,140.05, 138.62,136.49,135.37,134.59,133.32,132.23,129.85,129.33,129.03,126.26, 125.89,123.12,117.60,108.17,56.30,54.37,52.60,46.49,30.98,30.62,27.48,27.31, 26.55,26.00,24.30.
实施例9
参考实施例1的合成方法，制得目标化合物(240mg,收率85％)。1H NMR 400MHz(CD3OD):δ8.31(dd,J1＝1.6Hz,J2＝5.2Hz,1H),7.63(dd,J1＝2.0Hz, J2＝8.0Hz,1H),7.22-7.27(m,2H),7.16-7.18(m,1H),7.10(d,J＝3.6Hz,1H), 6.71-6.88(m,3H),3.31-3.44(m,2H),2.96-3.00(m,2H),2.83-2.87(m,2H),2.61 (m,2H),2.40-2.54(m,7H),2.28-2.37(m,1H),1.80-1.86(m,2H),1.45(s,6H). 13C NMR 100MHz(CD3OD)δ156.70,146.37,145.73,144.21,139.83,138.29, 136.84,135.83,134.51,133.46,132.94,130.24,128.96,128.88,125.72,123.47, 122.85,116.25,114.00,99.97,56.40,53.22,31.19,30.61,28.84,28.74,27.83,26.73, 26.71,24.92.
实施例10
参考实施例1的合成方法，制得目标化合物(240mg,收率85％)。1H NMR 400MHz(CD3OD):δ8.31(dd,J1＝1.6Hz,J2＝5.2Hz,1H),7.63(dd,J1＝2.0Hz, J2＝8.0Hz,1H),7.22-7.27(m,2H),7.16-7.18(m,1H),7.10(d,J＝3.6Hz,1H), 6.71-6.88(m,3H),3.31-3.44(m,2H),2.96-3.00(m,2H),2.83-2.87(m,2H),2.61 (m,2H),2.40-2.54(m,7H),2.28-2.37(m,1H),1.80-1.86(m,2H),1.45(s,6H). 13C NMR 100MHz(CD3OD)δ156.70,146.37,145.73,144.21,139.83,138.29, 136.84,135.83,134.51,133.46,132.94,130.24,128.96,128.88,125.72,123.47, 122.85,116.25,114.00,99.97,56.40,53.22,31.19,30.61,28.84,28.74,27.83,26.73, 26.71,24.92.
实施例11
参考实施例1的合成方法，制得目标化合物(60mg,收率19.4％)。1H NMR 400MHz(CD3OD):δ8.32(dd,J1＝1.6Hz,J2＝4.8Hz,1H),7.65(d,J＝8.0Hz,1H), 7.06-7.28(m,7H),3.35-3.45(m,2H),3.17(s,2H),2.75-2.92(m,6H),2.56-2.67(m, 4H),2.35-2.52(m,2H),1.89-1.97(m,2H),1.48(s,6H).13C NMR 100MHz (CD3OD)δ163.37,160.96,157.67,149.76,149.69,147.20,141.35,139.83,138.11, 135.92,135.85,135.42,134.54,131.20,127.24,124.38,114.04,113.81,71.58,57.69, 54.20,32.50,32.05,29.40,29.26,27.86,27.82,26.81,26.79,26.38.
实施例12
参考实施例1的合成方法，制得目标化合物(231mg,75.3％yield)，类白色固体。1HNMR(400MHz,CD3OD):δppm 8.33(d,J＝4.28Hz,1H),7.77(br,1H), 7.35(br,1H),7.18-7.27(m,2H),7.11-7.15(m,1H),7.07(br,1H),6.95(d,J＝7.05 Hz,1H),6.88(d,J＝12.09Hz,1H),3.27-3.59(m,4H),3.03(br,2H),2.16-2.95(m, 10H),2.00(br,2H),1.42(s,6H).13C NMR(100MHz,CD3OD):δppm 178.56, 161.58,159.14,140.79,140.71,139.57,135.49,133.21,130.33,129.38,128.63, 126.12,125.64,123.35,123.32,114.68,114.45,55.46,51.93,42.95,30.89,30.14, 31.10,26.90,24.75,24.40.
实施例13
参考实施例1的合成方法，制得目标化合物(150mg,32.8％yield)，白色固体。1HNMR(400MHz,CD3OD):δppm 8.23(dd,J1＝1.2Hz,J2＝4.4Hz,1H),7.56(d, J＝7.2Hz,1H),7.14-7.18(m,2H),7.01-7.10(m,4H),6.88(s,1H),3.25-3.34(m,2 H),2.99(s,1H),2.49-2.82(m,10H),2.35-2.39(m,1H),2.25-2.28(m,1H), 2.14-2.17(m,3H),1.71-1.79(m,2H),1.37(s,6H).13C NMR(100MHz,CD3OD): δ156.49,145.74,145.17,139.89,138.33,136.79,136.41,134.98,134.50,133.93, 133.03,130.12,128.96,128.06,127.39,125.76,123.27,122.88,56.75,53.06,46.86, 31.31,30.62,29.57,28.44,28.31,26.58,26.57,25.45,18.23.
实施例14
参考实施例1的合成方法，制得目标化合物(177mg,46.9％yield)，棕色固体。1HNMR(400MHz,CD3OD):δppm 8.34(d,J＝4.28Hz,1H),7.67(d,J＝7.55Hz,1 H),7.24-7.33(m,3H),7.17-7.22(m,1H),7.10-7.15(m,1H),6.94-7.01(m,2H), 3.36-3.47(m,2H),3.13-3.15(m,2H),2.68-2.96(m,6H),2.55-2.65(m,4H), 2.46-2.50(m,1H),2.36-2.40(m,1H),2.31(s,3H),1.87-2.02(m,2H),1.51(s,6H). 13C NMR(100MHz,CD3OD):δppm 184.87,157.69,147.21,144.56,141.36,139.86, 139.45,138.13,137.77,135.93,135.75,135.60,134.53,132.65,131.49,130.44, 127.26,126.74,126.62,124.40,57.78,54.22,33.41,32.53,32.06,29.55,29.41,28.17, 27.65,21.12.
实施例15
参考实施例1的合成方法，制得目标化合物(95mg,24.9％yield)，白色固体。1HNMR(400MHz,CD3OD):δppm 8.32(dd,J1＝1.2Hz,J2＝5.2Hz,1H),7.63-7.67 (m,2H),7.54-7.56(m,1H),7.22-7.27(m,3H),7.16-7.18(m,1H),7.11(d,J＝4.0 Hz,1H),3.34-3.44(m,2H),3.05-3.13(m,2H),2.67-2.91(m,8H),2.55-2.61(m,2 H),2.33-2.49(m,2H),1.85-1.93(m,2H),1.50(s,6H).13C NMR(100MHz, CD3OD):δ182.30,156.42,146.60,145.76,139.91,138.37,136.83,136.77,134.72, 134.51,134.08,133.05,130.50,130.12,129.82,129.00,127.51,127.22,125.80, 123.05,122.93,56.46,52.94,52.92,31.13,30.63,28.97,28.29,28.16,26.55.
实施例16
参考实施例1的合成方法，制得目标化合物(72mg,18.9％yield)，白色固体。1HNMR(400MHz,CD3OD):δppm 8.36(dd,J1＝1.2Hz,J2＝4.8Hz,1H),7.68(dd, J1＝1.6Hz,J2＝11.6Hz,1H),7.44-7.61(m,3H),7.27-7.31(m,2H),7.13-7.22(m,2 H),3.38-3.45(m,2H),3.21-3.25(m,2H),2.83-2.95(m,6H),2.60-2.77(m,4H), 2.41-2.55(m,2H),1.98-2.07(m,2H),1.61(s,6H).13C NMR(100MHz,CD3OD): δ181.33,156.14,145.81,141.94,139.96,139.36,138.47,136.64,134.69,134.52, 133.52,133.17,131.48,129.98,129.02,128.18,128.09,128.04,127.88,127.85, 126.64,125.85,123.92,123.01,56.04,52.75,52.72,47.11,31.53,31.06,30.61,27.83, 27.67,25.69.
实施例17
参考实施例1的合成方法，制得目标化合物(85mg,40％yield)。淡黄色固体。1HNMR 400MHz(CD3OD):δppm 8.23(dd,J1＝1.2Hz,J2＝4.8Hz,1H),7.54(dd, J1＝1.6Hz,J2＝7.6Hz,1H),7.47(d,J＝2.0Hz,1H),7.14-7.22(m,3H),7.07(dd, J1＝2.0Hz,J2＝8.0Hz,1H),7.01-7.03(m,2H),3.24-3.35(m,2H),3.06-3.13(m,2H), 2.70-2.82(m,6H),2.60(t,J＝7.6Hz,2H),2.49-2.55(m,2H),2.39-2.43(m,1H), 2.28-2.33(m,1H),1.77-1.84(m,2H),1.38(s,6H).13C NMR 100MHz (CD3OD)181.75,156.19,147.93,145.80,139.96,138.46,137.24,136.66,134.52, 133.84,133.09,130.04,129.97,129.67,129.01,125.85,125.40,125.35,123.56, 123.00,56.08,52.72,32.33,31.09,30.63,27.89,27.74,26.39,26.37,24.67.
实施例18
参考实施例1的合成方法，制得目标化合物(100mg,33％yield)。淡黄色固体。1HNMR 400MHz(CD3OD):δppm 8.33(dd,J1＝1.6Hz,J2＝4.8Hz,1H),7.65(dd, J1＝1.6Hz,J2＝7.6Hz,1H),7.40(d,J＝2.0Hz,1H),7.24-7.29(m,3H),7.07(dd, J1＝2.4Hz,J2＝8.4Hz,1H),7.12(d,J＝8.0Hz,1H),3.35-3.45(m,2H),3.17-3.20(m,2 H),2.80-2.93(m,6H),2.70(t,J＝8.0Hz,2H),2.59-2.67(m,2H),2.48-2.53(m,1H), 2.37-2.43(m,1H),1.88-1.96(m,2H),1.49(s,6H).13C NMR 100MHz (CD3OD)181.75,156.19,147.93,145.80,139.96,138.46,137.24,136.66,134.52, 133.84,133.09,130.04,129.97,129.67,129.01,125.85,125.40,125.35,123.56, 123.00,56.08,52.72,32.33,31.09,30.63,27.89,27.74,26.39,26.37,24.67.
实施例19
参考实施例1的合成方法，制得目标化合物(115mg,13％yield)。淡黄色固体。1HNMR 400MHz(CD3OD):δppm 8.33(dd,J1＝1.6Hz,J2＝4.8Hz,1H),7.96(d, J＝2.0Hz,1H),7.85(dd,J1＝1.2Hz,J2＝7.6Hz,1H),7.60(dd,J1＝2.0Hz,J2＝8.4Hz,1 H),7.24-7.29(m,3H),7.18(dd,J1＝2.0Hz,J2＝8.0Hz,1H),7.12(d,J＝8.0Hz,1H), 3.36-3.45(m,2H),3.23-3.27(m,2H),2.79-2.99(m,8H),2.62-2.69(m,2H), 2.49-2.55(m,1H),2.39-2.46(m,1H),1.92-1.98(m,2H),1.52(s,6H).13C NMR 100MHz(CD3OD)181.31,156.21,148.89,147.91,145.80,139.95,138.43,136.67, 134.52,133.84.133.14,132.82,131.20,131.03,130.02,128.99,125.84,122.97, 121.82,56.17,52.73,31.08,30.63,29.25,27.87,27.72,26.23,26.21,25.48.
实施例20
参考实施例1的合成方法，制得目标化合物(260mg,72.0％yield)，白色固体。1HNMR(400MHz,CD3OD):δppm 8.34(d,J＝4.8Hz,1H),7.75(s,1H), 7.67(d,J＝3.6Hz,1H),7.62(d,J＝8.0Hz,1H),7.51(dd,J1＝1.6Hz,J2＝8.4Hz,1 H),7.25-7.29(m,2H),7.20(d,J＝8.4Hz,1H),7.14(d,J＝8.0Hz,1H),3.27-3.45 (m,4H),2.48-3.01(m,12H),2.03-2.06(m,2H),1.61(s,6H).13C NMR(100MHz, CD3OD):δ179.00,155.05,148.47,144.79,139.23,138.98,137.77,137.48,135.58, 133.85,133.53,132.16,132.08,131.54,128.95,128.00,127.36,124.84,123.53, 122.01,54.74,51.47,45.75,30.23,30.02,29.59,26.47,26.28,24.23.
实施例21-25
参照实施例1的合成方法，制备得实施例21-32化合物，具体如下
Figure BDA0002567787970000171
Figure BDA0002567787970000181
实施例33
Figure BDA0002567787970000182
向25mL的单口瓶内加入实施例1化合物(190mg,0.36mmol)和甲醇(2mL)，磁力搅拌，N2保护。向体系内加入NaOH(15mg,0.37mmol)的水(0.5mL)溶液。加毕，反应在室温下搅拌过夜。TLC(DCM:MeOH＝10:1)监测原料与产物在同一位置。将反应液减压浓缩，得到185mg粗品。将粗品用正庚烷(6mL)打浆1h，抽滤，滤饼用正庚烷(3mL×2)洗涤，烘干(-0.1MPa,45℃,18h)，得到实施例33 化合物(173mg,86.6％yield)，类白色固体。HPLC:98.637％。1HNMR(400MHz, CD3OD):δppm 8.29(dd,J1＝4.8Hz,J2＝1.6Hz,1H),7.63(dd,J1＝7.6Hz,J2＝1.6Hz, 1H),7.41-7.36(m,1H),7.24-7.19(m,2H),7.16-7.13(m,1H),7.11-7.04(m,4H),3.43-3.34(m,2H),2.89-2.76(m,4H),2.62-2.58(t,J＝7.5Hz,2H),2.48-2.34(m, 3H),2.25-2.15(m,3H),1.83-1.78(m,2H),1.44(s,6H).
实施例34
Figure BDA0002567787970000183
参考实施例33的制备方法，将NaOH替换为KOH，制得实施例34化合物(173 mg,86.6％yield)，类白色固体。HPLC:98.433％。1H NMR(400MHz,CD3OD):δ ppm 8.29(dd,J1＝4.8Hz,J2＝1.6Hz,1H),7.63(dd,J1＝7.6Hz,J2＝1.6Hz,1H), 7.41-7.36(m,1H),7.24-7.19(m,2H),7.16-7.13(m,1H),7.11-7.04(m,4H), 3.43-3.34(m,2H),2.89-2.76(m,4H),2.62-2.58(t,J＝7.5Hz,2H),2.48-2.34(m, 3H),2.25-2.15(m,3H),1.83-1.78(m,2H),1.44(s,6H),HRMS(ESI):m/z Calculated 538.1789.
实施例35～42
参考实施例33的制备方法，制得下列化合物
Figure BDA0002567787970000191
Figure BDA0002567787970000201
Figure BDA0002567787970000211
本发明专利的组合物实施例，以实施例33化合物为例，包含但不限于下列实施例中使用的辅料及处方配比。
实施例44
实施例33化合物包衣片(1000片)
片芯处方
Figure BDA0002567787970000212
包衣液处方
Figure BDA0002567787970000213
Figure BDA0002567787970000221
制备方法：实施例33化合物、硬脂酸镁过120目筛，微晶纤维素、磷酸氢钙、预胶化淀粉过100目筛，备用；称取处方配比量的实施例33化合物、微晶纤维素、磷酸氢钙、预胶化淀粉，按等量递增法过80目筛混匀，用30％的乙醇溶液作为润湿剂制软材，20目筛制粒，50～60℃干燥3～4小时，20目筛整粒，加入处方量的硬脂酸镁，混匀，压片制得。
实施例45
实施例33化合物的普通片(1000片)
Figure BDA0002567787970000222
制备方法：实施例33化合物、硬脂酸镁过120目筛，微晶纤维素、羧甲基淀粉钠、乳糖过80目筛，备用；称取处方配比量的实施例33化合物、微晶纤维素、羧甲基淀粉钠和乳糖，按等量递增法过80目筛混匀，用30％的乙醇溶液作为润湿剂制软材，30目筛制粒，50～60℃干燥3～4小时，30目筛整粒，加入处方量的硬脂酸镁，混匀，压片制得。
实施例46
实施例33化合物的胶囊(1000粒)
Figure BDA0002567787970000223
制备方法：实施例33化合物、硬脂酸镁过120目筛，低取代羟丙基纤维素、羧甲基淀粉钠、乳糖过80目筛，备用；称取处方配比量的实施例33化合物、低取代羟丙基纤维素、羧甲基淀粉钠和乳糖，按等量递增法过80目筛混匀，用30％的乙醇溶液作为润湿剂制软材，30目筛制粒，50～60℃干燥3～4小时，30目筛整粒，加入处方量的硬脂酸镁，混匀，灌装胶囊即可。
实施例47
实施例33化合物的颗粒剂(1000包)
Figure BDA0002567787970000231
制备方法：实施例33化合物、微晶纤维素、蔗糖粉、羧甲基淀粉钠、乳糖、阿斯巴甜过100目筛，橘子香精、十二烷基硫酸钠过80目筛，备用；称取处方配比量的实施例33化合物、微晶纤维素、蔗糖粉、羧甲基淀粉钠、乳糖、阿斯巴甜按等量递增法混匀，用3％聚维酮的30％乙醇溶液制软材，20目筛制粒，50～60℃干燥3～4小时，18目筛整粒，加入处方量的橘子香精、十二烷基硫酸钠，混匀，装袋封口制得。
实施例48
实施例33化合物口服液(1000瓶)
Figure BDA0002567787970000232
Figure BDA0002567787970000241
制备方法：阿斯巴甜、橘子香精、枸橼酸钠溶于现制注射用水中，过滤，常温下加入处方量的实施例33化合物，溶解，过滤，灌装。
实施例49
实施例33化合物糖浆剂
Figure BDA0002567787970000242
制备方法：将蔗糖加入900ml注射用水中，加热煮沸，溶解、趁热过滤，冷却至室温备用；将处方量的实施例33化合物、阿斯巴甜、橘子香精、枸橼酸钠溶于60mL注射用水中，过滤，加入至上述糖浆液中，加注射用水至1000mL，混匀，灌装制得。
实施例50
实施例33化合物的滴眼液
Figure BDA0002567787970000243
制备方法：将聚山梨醇酯80、柠檬酸、氯化钠、实施例33化合物和氯化苯甲烃铵完全溶解在无菌注射用水70ml中，并用硼砂调pH至7.8，然后用无菌注射用水加至体积为100mL，过滤，滤液灭菌，并装于适于滴眼液的容器内制得。
实施例51
实施例33化合物的注射液(1000支)
Figure BDA0002567787970000251
制备方法：将柠檬酸、磷酸氢二钠、乙二胺四乙酸二钠溶解于1600mL注射用水中，加入处方量的实施例33化合物和氯化钠搅拌至完全溶解，0.1mol/L稀盐酸调pH至7.0-7.8，加入处方量活性炭，搅拌吸附后脱碳过滤，加入注射用水至2000mL，然后用0.22μm滤器过滤，灌装于2mL安剖瓶中。安剖瓶封口并115℃灭菌30分钟后制得。
实施例52
实施例33化合物的鼻喷雾剂
Figure BDA0002567787970000252
制备方法：制备过程如下：取处方量约60％的缓冲液于配制容器中，加入生物黏附剂，使其充分溶胀，直至完全溶解；加入抑菌剂、等渗调节剂、金属离子螯合剂搅拌溶解；分次加入环糊精，搅拌溶解后，再加入实施例33化合物，搅拌1～2h，待完全溶解后添加缓冲液至全量，混合均匀。测定pH和含量合格后，药液于0.45μm微孔滤膜过滤至澄明，再于0.22μm微孔滤膜过滤除菌，分装至已灭菌的鼻喷雾瓶中，加带有定量喷雾泵的瓶盖，密闭低温贮存。
实施例53
实施例33化合物的滴鼻剂
Figure BDA0002567787970000261
制备方法：甘露醇/聚氧乙烯40氢化蓖麻油、维生素E、实施例33化合物加入至注射用水中至10mL，缓慢60℃加热，加入甘油酸酯后高速剪切分散乳化机分散，柠檬酸调pH至6.0后过滤，高压灭菌后置于容器中制得。

Claims (10)

1.一种具有下列式(I)的三环化合物或其药学上可接受的盐
Figure FDA0002567787960000011
式(I)中
X为H、OH；
n＝1-6；
A环为苯环、吡啶环、噻吩环；
R1、R4为H、卤素；
R2、R3选自H、羟基、＝O；
R5选自H、C1～C6的烷基；
R6为H，任意单取代或多取代的C1～C6的烷基、卤素、羟基、三氟甲基、氰基、氧三氟甲基、甲氧基、氨基、硝基、羧基。
2.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，式(I)中n＝1-4；
R1为H、Cl；
R5为H；
R6为H、甲基、F、Cl、Br、羟基、三氟甲基、氰基、氧三氟甲基、甲氧基、氨基、硝基。
3.权利要求1所述的化合物或其药学上可接受的盐，具有下式结构
Figure FDA0002567787960000021
其中
n＝1-6
X为H、OH；
R3为H、羟基、＝O；
R5选自H、C1～C6的烷基；
R6为H，任意单取代或多取代的C1～C6的烷基、卤素、羟基、三氟甲基、氰基、氧三氟甲基、甲氧基、氨基、硝基、羧基。
4.权利要求1所述的化合物或其药学上可接受的盐，具有下式结构
Figure FDA0002567787960000022
其中
n＝1-6
X为H、OH；
R5选自H、C1～C6的烷基。
5.权利要求1-4所述的任意一项权利要求中的化合物或其药学上可接受的盐，其特征在于，所述选药学上可接受的盐为式(I)化合物和碱金属或者碱土金属，氨基酸或者含有氨基的碱性化合物形成的盐，或者为式(I)化合物与无机酸或者有机酸形成的盐，或者为式(I)化合物多元酸碱金属或者碱土金属盐复合盐。
6.权利要求5所述的化合物或其药学上可接受的盐，其特征在于，包括式(I)化合物的钾盐，钠盐，铵盐以及式(I)化合物与盐酸、硫酸、磷酸、氢溴酸、马来酸、富马酸、枸橼酸、甲磺酸、对甲苯磺酸、酒石酸或醋酸形成的盐；所述式(I)化合物多元酸碱金属或者碱土金属盐复合盐中，其中的多元酸，选自枸橼酸、丁二酸、酒石酸、琥珀酸、富马酸、马来酸、草酸、硫酸、磷酸、亚硫酸、苹果酸，其中的碱金属或碱土金属选自钠、钾、钙、镁、锌。
7.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，选自以下化合物：
Figure FDA0002567787960000031
Figure FDA0002567787960000041
8.含有权利要求1化合物或其药学上可接受的盐的药物组合物，其剂型选自片剂，胶囊剂、颗粒剂、口服液、口喷剂、栓剂、透皮制剂、注射剂、滴鼻剂、滴眼液、鼻喷剂。
9.权利要求1的化合物或其药学上可接受的盐在制备预防和治疗过敏性疾病的药物中的用途。
10.权利要求9所述的用途，其中所述过敏性相关疾病选自：过敏性鼻炎、荨麻疹、慢性荨麻疹、过敏性紫癜、哮喘、过敏性皮炎、湿疹、过敏性结膜炎、特应性皮炎、鼻窦炎、慢性鼻窦炎。
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