CN108101780A - 一类氟比洛芬查尔酮类化合物、其制备方法和用途 - Google Patents

一类氟比洛芬查尔酮类化合物、其制备方法和用途 Download PDF

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CN108101780A
CN108101780A CN201810011604.4A CN201810011604A CN108101780A CN 108101780 A CN108101780 A CN 108101780A CN 201810011604 A CN201810011604 A CN 201810011604A CN 108101780 A CN108101780 A CN 108101780A
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flurbiprofen
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邓勇
谭正怀
杨杰
宋青
田超全
杨子仪
李维
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Sichuan University
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Abstract

本发明公开了一类新型的氟比洛芬查尔酮类化合物（I）及其药学上可接受的盐、其制备方法、药物组合物和在制备治疗和/或预防神经退行性相关疾病药物中的用途，包括但不限于血管性痴呆、阿尔茨海默氏症、帕金森症、亨廷顿症、HIV相关痴呆症、多发性硬化症、进行性脊髓侧索硬化症、神经性疼痛、青光眼等神经退行性疾病。

Description

一类氟比洛芬查尔酮类化合物、其制备方法和用途
技术领域
本发明属药物化学领域，涉及一类新型的氟比洛芬查尔酮类化合物（I）及其药学上可接受的盐、其制备方法、药物组合物和在制备治疗和/或预防神经退行性相关疾病药物中的用途，包括但不限于血管性痴呆、阿尔茨海默氏症、帕金森症、亨廷顿症、HIV相关痴呆症、多发性硬化症、进行性脊髓侧索硬化症、神经性疼痛、青光眼等神经退行性疾病。
背景技术
阿尔茨海默症（Alzheimer’s disease，AD，老年痴呆症）是一种以进行性认知障碍和记忆力损害为主的中枢神经系统退行性疾病，其发病率呈逐年上升趋势，成为仅次于心血管病和癌症的高发性疾病，在欧美等发达国家已上升为死亡原因的第四位。据世界卫生组织报告，全球65岁以上老人有10%智力障碍，其中二分之一发生痴呆，八十五岁以上发病率近50%。在我国AD患者人数约600-700万，发病率超过5%。随着全球人口老龄化进程的加快，其发病率呈明显上升趋势，据Alzheimer's Disease International在2013年12月公布的《阿尔茨海默症的全球影响：2013-2050》报告中指出，AD将成为未来几十年全球面临的最大健康挑战，到2030年，患者人数将由2013年的4400万上升到7600万，到2050年，这一数值将达到惊人的1.35亿。由于AD临床表现为记忆能力、定向能力、思维和判断能力减退，以及日常生活能力降低，甚至出现异常精神行为症状等，使患者护理难度较大，给社会和家庭带来沉重负担。目前已批准用于治疗轻/中度AD的药物有乙酰胆碱酯酶（AChE）抑制剂，以及用于重度AD治疗的N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，但临床使用表明，这些药物可通过提高患者体内乙酰胆碱水平或者抑制兴奋性氨基酸的兴奋毒性来缓解AD症状，但不能有效阻止或逆转病程，而且还会引起幻觉、意识混沌、头晕、头痛、恶心、肝脏毒性、食欲不振以及大便频繁等严重毒副作用，因而长期疗效不甚理想。因此，临床上迫切需要研发具有新型作用机制的AD治疗药物。
AD属多种因素引起的疾病，发病机理复杂，其发病机制至今还未完全阐明，但研究表明，患者脑内乙酰胆碱水平的下降、β-淀粉样蛋白的过度生成与沉积、脑血管内的血小板聚集、金属离子代谢紊乱、Ca2+平衡失调、tau-蛋白过度磷酸化导致的神经纤维缠结、谷氨酸受体活性过高、氧化应激产生大量活性氧（ROS）和自由基以及神经炎症反应等多种因素在AD的发病过程中扮演重要角色。针对上述发病因素，研究人员采用传统“一药一靶”药物设计策略，发现了大量对某一靶点具有高活性和高选择性的药物，如：胆碱酯酶抑制剂和N-甲基-D-天冬氨酸受体拮抗剂等。但这些药物存在作用靶点单一、临床使用毒副作用较多、对AD患者的长期疗效欠佳等问题。
近年来，随着对AD致病机理的不断阐明，发现AD的发生和发展具有多机制、多因素作用的特点，不同机制之间又相互关联相互影响，构成了AD发生和发展过程中复杂的网络调控系统。显然，研发可同时作用于AD病理过程中多个环节的治疗药物是目前的必然选择。基于上述结果，研究人员提出了“多靶点导向配基”（Multitarget-directed Ligands,MTDLs）策略来研发抗神经退行性疾病药物。所谓“多靶点配基”是指单一化学实体同时作用于疾病网络中的多个靶点，对各靶点的作用可产生协同效应，使总效应大于各单效应之和，此类化合物也称为“Multifunctional”或“Multipotential”药物。多靶点药物与多药联合应用以及复方药物的主要区别在于：可减少服药量、提高治疗效果、避免药物之间的相互作用及由此带来的毒副作用、均一的药代动力学特性、便于使用等。因此，研究开发具有新型化学结构、新型作用机制，且具有多靶点作用、低毒副作用的抗神经退行性疾病治疗药物不仅符合社会老龄化进程的迫切需求，而且具有良好的市场前景。设计并发现同时具有抗氧化应激、金属离子络合、抑制β-淀粉样蛋白的过度生成与沉积、以及抗神经炎症反应的多靶点AD治疗药物仍是目前重要的研究方向。
发明内容
本发明目的在于公开一类氟比洛芬查尔酮类化合物（I）及其药学上可接受的盐；
本发明另一目的在于公开该类氟比洛芬查尔酮类化合物（I）及其药学上可接受的盐的制备方法；
本发明的又一目的在于公开包含该类氟比洛芬查尔酮类化合物（I）及其药学上可接受的盐的药物组合物；
本发明再一目的在于公开该类氟比洛芬查尔酮类化合物（I）及其药学上可接受的盐具有多靶点作用，可用于制备治疗和/或预防神经退行性相关疾病的药物中的用途，包括但不限于血管性痴呆、阿尔茨海默氏病、帕金森症、亨廷顿症、HIV相关痴呆症、多发性硬化症、进行性脊髓侧索硬化症、神经性疼痛、青光眼等神经退行性疾病。
本发明所提供的氟比洛芬查尔酮类化合物（I）的化学结构通式为：
式中：Ar表示；R1和R2在芳环上任意可能的位置；R1和R2各自独立地表示H、OH、C1~C12烷基、C1~C12烷氧基、卤素、NR4R5；R4和R5各自独立地表示H、C1~C12烷基、苯基、苄基、取代苯基或取代苄基；NR4R5也表示四氢吡咯基、吗啉基、哌啶基、4-位被C1~C12烷基所取代的哌啶基、4-位被苄基或取代苄基所取代的哌啶基、哌嗪基、4-位被C1~C12烷基所取代的哌嗪基、4-位被苄基或取代苄基所取代的哌嗪基；X表示O或NH，R3表示H、C1~C12烷基；所述化合物为R构型、S构型、或R构型和S构型的任意比例混合物；上述术语“取代苄基”和“取代苯基”是指苯环上被1-4个选自下组的基团所取代的苯基或苄基：F、Cl、Br、I、C1-4烷基、C1-4烷氧基、三氟甲基、三氟甲氧基、NR6R7、羟基、硝基、氰基，这些取代基可在苯环的任意可能位置；R6和R7各自独立地表示H、C1~C12烷基，NR6R7也表示四氢吡咯基、吗啉基或哌啶基。
本发明所公开的氟比洛芬查尔酮类化合物（I）及其药学上可接受的盐可通过以下方法制备得到，其反应式如下：
式中：Ar、R3和X的定义与化学结构通式（I）相同。
对于上述合成路线，其具体制备方法描述如下：
以相应的芳甲醛类化合物（1）和3′-乙酰基-4′-羟基氟比洛芬类化合物（2）为起始原料，在溶剂和碱性条件下直接缩合，得相应的氟比洛芬查尔酮类化合物（I）。其中，反应所用碱为：碱金属氢氧化物、碱土金属氢氧化物、碱金属碳酸盐、碱土金属碳酸盐、碱金属碳酸氢盐、碱土金属碳酸氢盐、C1-8醇的碱金属盐、有机叔胺类或季铵碱类（如：三乙胺、三丁胺、三辛胺、吡啶、N-甲基吗啉、N-甲基哌啶、三乙烯二胺、四丁基氢氧化铵），优选碱为：氢氧化钾、氢氧化钠、碳酸钾、三乙胺或吡啶；反应所用溶剂为：C1-8脂肪醇、乙醚、四氢呋喃、2-甲基四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、氯仿、1,4-二氧六环、苯、甲苯或乙腈，优选溶剂为：甲醇、乙醇、异丙醇、N,N-二甲基甲酰胺、乙腈、四氢呋喃、二氯甲烷或甲苯；化合物（2）：化合物（1）：碱的摩尔投料比为1.0：1.0~5.0：1.0~20.0，优选摩尔投料比为1.0：1.0~3.0：1.0~10.0；反应温度为0~150℃，优选反应温度为室温~100℃；反应时间为1~120小时，优选反应时间为2~72小时。
本发明的起始原料——3＇-乙酰基-4＇-羟基氟比洛芬类化合物（2）可用本领域常见的技术制得，即：以氟比洛芬类化合物（消旋体或光学活性体）为原料，先采用现有技术转化为4＇-乙酰氧基氟比洛芬类化合物（参见：1、Robert James et al. WO 2003003012A1；2、Yao Chen. et al.Bioorganic & Medicinal Chemistry2013, 21, 2462-2470），然后在Lewis酸催化下经Fries重排反应即可制备得到3＇-乙酰基-4＇-羟基氟比洛芬类化合物（2）。
按照上述方法所得之氟比洛芬查尔酮类化合物（I）分子中，当R1和R2各自独立地表示NR4R5时，因分子中含有氨基，该氨基呈碱性，可与任何合适的酸通过药学上常规的成盐方法制得其药物学上可接受的盐，所述的酸为：盐酸、氢溴酸、硝酸、硫酸、磷酸、胺基磺酸、C1-6脂肪羧酸（如：甲酸、乙酸、丙酸等）、三氟乙酸、硬脂酸、扑酸、草酸、苯甲酸、苯乙酸、水杨酸、马来酸、富马酸、琥珀酸、酒石酸、柠檬酸、苹果酸、乳酸、羟基马来酸、丙酮酸、谷氨酸、抗坏血酸、硫辛酸、C1-6烷基磺酸（如：甲基磺酸、乙基磺酸等）、樟脑磺酸、萘磺酸、苯磺酸、对甲苯磺酸或1,4-丁二磺酸。
本发明所公开的药物组合物包括治疗有效量的一种或多种氟比洛芬查尔酮类化合物（I）或其药学上可接受的盐，该药物组合物可进一步含有一种或多种药学上可接受的载体或赋形剂。所述“治疗有效量”是指引起研究者或医生所针对的组织、系统或动物的生物或医药反应的药物或药剂的量；所述“组合物”是指通过将一种以上物质或组份混和而成的产品；所述“药学上可接受的载体”是指药学上可接受的物质、组合物或载体，如：液体或固体填充剂、稀释剂、赋形剂、溶剂或包囊物质，它们携带或转运某种化学物质。本发明所提供的药物组合物其理想的比例是，氟比洛芬查尔酮类化合物（I）或其药学上可接受的盐作为活性成分占总重量比5%～99.5%，其余部分为占总重量比95%以下。
本发明所公开的氟比洛芬查尔酮类化合物（I）及其药学上可接受的盐进行了如下的生物活性筛选。
（1）氟比洛芬查尔酮类化合物（I）与金属离子络合作用的测定
用甲醇溶解CuCl2·2H2O、ZnCl2、FeSO4·7H2O、AlCl3及待测化合物，配成75 μmol/L的溶液，向96孔板中加入100μL待测化合物溶液和100μL金属离子溶液，混匀，室温静置30 min，在Varioskan Flash Multimode Reader仪上记录混合物在200-600 nm范围内的紫外吸收曲线，并以100μL待测化合物溶液和100 μL甲醇混合液为对照，观察金属离子与待测化合物混合液的最大吸收峰的红移现象及最大吸收峰的强度。测定结果表明，氟比洛芬对上述金属离子均无络合作用，而本发明实施例中所公开的氟比洛芬查尔酮类化合物（I）均表现出对铜离子和铝离子有选择性络合作用。
（2）氟比洛芬查尔酮类化合物（I）的抗氧化活性（ORAC-FL方法）
参照文献（Qiang, X.M. et al.Eur. J Med. Chem.2014, 76, 314-331）所报道的方法进行测定，即：6-羟基-2,5,7,8-四甲基色烷-2-羧酸（Trolox）用pH7.4的PBS缓冲液配成10-80 μmol/L的溶液，荧光素（fluorescein）用pH7.4的PBS缓冲液配成250 nmol/L的溶液，2,2’-偶氮二异丁基脒二盐酸盐（AAPH）使用前用pH7.4的PBS缓冲液配成40 mmol/L的溶液。向96孔板中加入50-10 μmol/L的化合物溶液和荧光素溶液，混匀，37℃孵育15min，加入AAPH溶液，使每孔总体积为200 μL，混匀，立即置于Varioskan Flash Multimode Reader仪中，在485 nm激发波长和535 nm发射波长下连续测定90 min。计算出荧光衰减曲线下面积AUC，其中以1-8μmol/L的Trolox作为标准，以不加待测样品为空白，化合物的抗氧化活性结果表达为Trolox的当量，其计算公式为：[(AUC Sample-AUC blank)/(AUC Trolox-AUCblank)]×[(concentration of Trolox/concentration of sample)]，每个化合物每次测定3个复孔，每组实验独立重复三次。测定结果表明，对照药氟比洛芬的抗氧化活性小于Trolox的0.1倍，而本发明实施例中所公开的氟比洛芬查尔酮类化合物（I）的抗氧化活性为Trolox的0.3-5.0倍，说明该类化合物具有较强抗氧化活性；试验研究进一步发现氟比洛芬查尔酮类化合物（I）的手性中心对化合物的抗氧化活性基本无影响。
（3）氟比洛芬查尔酮类化合物（I）对Aβ 1-42自身聚集的抑制活性
参照文献（Qiang, X.M. et al.Eur. J Med. Chem.2014, 76, 314-331）所报道的方法进行测定，即：预处理后的Aβ 1-42用DMSO配成储备液，使用前用pH7.4的PBS缓冲液稀释至50μM；待测化合物用DMSO配成2.5 mM储备液，使用前用pH7.4的PBS缓冲液稀释至相应浓度，取20μL的Aβ 1-42溶液+20μL的待测化合物溶液、20μL的Aβ 1-42溶液+20μL的PBS缓冲液（含2%DMSO）于96孔板中，37℃孵育24h，然后加入160μL含有5μM硫黄素T的50mM的甘氨酸-NaOH缓冲液（pH=8.5），振摇5s后立即用多功能酶标仪在446 nm激发波长和490 nm发射波长下测定荧光值；Aβ 1-42+待测化合物的荧光值记为IFi，Aβ 1-42+PBS缓冲液的荧光值记为IFc，只含有PBS缓冲液的荧光值记为IF0，化合物抑制Aβ 1-42自身聚集的抑制率为：100-(IFi-IF0)/(IFc-IF0)*100；每个化合物每个浓度测定三个复孔，以姜黄素为阳性对照。测定结果表明，本发明实施例中所公开的氟比洛芬查尔酮类化合物（I）对Aβ 1-42自身聚集均具有显著抑制活性，在20.0 µM浓度下对Aβ 1-42自身聚集的抑制率在20.0%～65.0%之间；而临床上广泛使用的抗AD药物：多奈哌齐、卡巴拉汀、美金刚以及氟比洛芬在20.0 µM浓度下对Aβ 1-42自身聚集的抑制率均小于10%。
（4）氟比洛芬查尔酮类化合物（I）对Cu2+诱导的Aβ 1-42聚集的抑制活性
将CuCl2用HEPES缓冲液配成75 μM溶液，用HEPES缓冲液将化合物储备液（2.5 mM）和200 μM的Aβ 1-42储备液稀释至75 μM，分别取20μL Cu2+溶液+20μL Aβ 1-42溶液+20μL待测化合物溶液、20μL Cu2+溶液+20μL Aβ 1-42溶液+20μL HEPES缓冲液以及60μL HEPES缓冲液于96孔板中，混匀，37℃孵育24 h，然后加入190μL含有5μM硫黄素T的50mM的甘氨酸-NaOH缓冲液（pH=8.5），振摇5s后立即用多功能酶标仪在446nm激发波长和490nm发射波长下测定荧光值；Cu2++Aβ 1-42+待测化合物的荧光值记录为IFi，Cu2++Aβ 1-42+HEPES缓冲液的荧光值记录为IFc，只含有HEPES缓冲液的荧光值记录为IF0，化合物对Cu2+诱导的Aβ 1-42聚集的抑制率为：100-(IFi-IF0)/(IFc-IF0)*100。每个化合物每个浓度测定三个复孔，以姜黄素为阳性对照。测定结果表明，本发明实施例中所公开的氟比洛芬查尔酮类化合物（I）在25.0 µM浓度下对Cu2+诱导的Aβ 1-42聚集的抑制率在20.0%～98.0%之间；而姜黄素和氟比洛芬在相同浓度下的抑制率分别为54.0%和6.2%。
（5）氟比洛芬查尔酮类化合物（I）对神经炎症的抑制活性
（a）化合物和脂多糖（LPS）对BV-2细胞活性的影响
取对数生长期的BV-2细胞配成细胞悬液接种于96孔板，置37℃，5%CO2细胞培养箱内培养24 h待细胞贴壁后换为无血清的新鲜培养液90 μL，分别加入各浓度待测化合物10 μL预孵育30 min，每个浓度3个平行孔，同时设空白对照组；然后加或不加LPS，置37℃，5%CO2细胞培养箱内继续培养24 h，加入MTT溶液，37℃孵育4 h，弃去上清液，每孔加入200 μLDMSO溶液，轻微振荡10 min后，用酶标仪在490 nm处测定OD值，计算各受试样品不同浓度所测得OD值的均值，并按下列公司计算细胞存活率：细胞存活率（%）= 给药组OD均值/对照组OD均值×100%。测试结果表明，本发明实施例中所公开的所有氟比洛芬查尔酮类化合物（I）和LPS在不超过25 μM浓度下均未显示出细胞毒性（抑制率小于<5%）。
（b）氟比洛芬查尔酮类化合物（I）对LPS诱导的BV-2细胞释放NO的影响
取对数生长期的BV-2细胞配成细胞悬液接种于96孔板，置37℃，5%CO2细胞培养箱内培养24 h待细胞贴壁后换为无血清的新鲜培养液90 μL，分别加入各浓度待测化合物10 μL预孵育30 min，每个浓度3个平行孔，同时设空白对照组；然后加入LPS刺激，置37℃，5%CO2细胞培养箱内继续培养24 h，取不同处理组细胞培养上清液，加入等体积的Griess试剂I和等体积的Griess试剂II，室温避光反应10 min，在540 nm处测定吸光度以检测细胞上清液中NO水平（具体操作按照NO检测试剂盒说明书进行）。测试结果表明，本发明实施例中所公开的所有氟比洛芬查尔酮类化合物（I）在0.5 μM至25 μM浓度范围内均显示出较强的抑制LPS诱导的BV-2细胞NO生成作用（在2.5 μM浓度下的抑制率均超过20.0%），并具有明显的量效关系；且它们的抑制活性较相同浓度下的氟比洛芬显著增强（n=3，P<0.05），表明本发明实施例中所公开的氟比洛芬查尔酮类化合物（I）具有显著的抗神经炎症活性。试验还进一步发现，化合物（I）的手性中心对化合物的抗神经炎症活性无显著影响。
具体实施方式
通过下面的实施例可对本发明进行进一步的描述，然而，本发明的范围并不限于下述实施例。本领域的专业人员能够理解，在不背离本发明的精神和范围的前提下，可以对本发明进行各种变化和修饰。
实施例1 氟比洛芬查尔酮类化合物（I）的制备通法
在反应瓶中加入2.0 mmol相应的3′-乙酰基-4′-羟基氟比洛芬类化合物（2）、3.0 mmol相应的芳甲醛类化合物（1）、8.0 mmol无水碳酸钾和50 ml乙腈，搅拌均匀后，升温回流搅拌反应2.0～72.0小时（反应进程用TLC跟踪）；反应结束后，冷却至室温，用10%盐酸水溶液调节反应液pH至强酸性，再用饱和碳酸氢钠水溶液调节反应液pH至弱碱性，减压蒸除乙腈，残余液中加入50 mL去离子水，用150 mL二氯甲烷分三次萃取，有机层合并后用饱和氯化钠水溶液洗涤，经无水硫酸钠干燥后过滤，减压蒸除溶剂，残余物经硅胶柱层析纯化，得相应的氟比洛芬查尔酮类化合物（I），收率28.0%-93.0%，其化学结构均经1H-NMR、13C-NMR和ESI-MS确证；所得目标物的纯度经HPLC测定均大于97.0%。采用上述通法制备得到的目标物结构如下：
（1）当Ar表示苯环或取代苯环、X表示O时的化合物（I）：
；
部分化合物的1H-NMR数据如下：
1H NMR (CDCl3): 12.91 (brs, 1H), 7.99 (s,1H), 7.88 (d, J = 15.6 Hz, 1H),7.57-7.50 (m, 3H), 7.40 (d, J = 15.6 Hz,1H), 7.33-7.31 (m, 1H), 7.18-7.16 (m,4H), 7.05-7.03 (m, 1H), 3.76-3.72 (m, 1H), 2.21 (s, 3H), 1.41 (d, J = 6.4 Hz,3H)；
1H NMR (CDCl3): 12.98 (br,1H), 8.24 (d, J = 15.6 Hz, 1H), 8.08 (s, 1H),7.76 (d, J = 15.6 Hz, 1H), 7.65-7.51 (m, 2H), 7.43-7.35 (m, 2H), 7.20-7.16(m, 2H), 7.09 (d, J = 8.8 Hz, 1H), 6.99-6.92 (m, 2H), 3.92 (s, 3H), 3.82-3.79(m, 1H), 1.57 (d, J = 7.2 Hz, 3H)；
1H NMR (CDCl3): 13.00 (br, 1H), 8.03 (s,1H), 7.89 (d, J = 15.6 Hz, 1H),7.62-7.58 (m, 3H), 7.49 (d, J = 15.6 Hz,1H), 7.40-7.37 (m, 1H), 7.20-7.16 (m,2H), 7.07-7.06 (m, 1H), 6.91-6.90 (m, 2H), 3.82 (s, 3H), 3.80-3.77 (m, 1H),1.56 (d, J = 7.2Hz, 3H)；
1H NMR (DMSO-d 6 ): 12.65 (brs, 1H), 10.47 (br, 1H), 8.27 (s, 1H), 8.19 (d,J = 15.6 Hz, 1H), 8.03 (d, J = 15.6 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.71(d, J = 8.4 Hz, 1H), 7.56-7.52 (m,1H), 7.31-7.23 (m, 3H), 7.10 (d, J = 8.4Hz, 1H), 6.5 (d, J = 7.6 Hz, 1H), 6.88-6.85 (m, 1H), 3.84 (q, J = 7.2Hz, 1H),1.41 (d, J = 7.2 Hz, 3H)；
1H NMR (DMSO-d 6 ): 12.88 (brs, 1H), 12.63 (brs, 1H), 10.33 (brs, 1H), 8.34(s, 1H), 7.91 (d, J = 15.6 Hz, 1H), 7.83 (d, J = 15.6 Hz, 1H), 7.80 (d, J =8.4 Hz, 2H), 7.65 (m, 1H), 7.56-7.53 (m, 1H), 7.25-7.23 (m, 2H), 7.08 (d, J =8.4 Hz ,1H), 6.85-6.83 (m, 2H), 3.77(q, J = 7.2 Hz, 1H), 1.41 (d, J = 7.2 Hz,3H)；
1H NMR (CDCl3): 13.14 (brs,1H), 8.18 (d, J = 15.2 Hz ,1H), 8.08 (s, 1H),7.68 (d, J = 15.2 Hz, 1H), 7.64-7.56 (m, 2H), 7.43-7.39 (m, 1H), 7.20-7.16(m, 2H), 7.07 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 8.8Hz, 1H), 6.46-6.46 (m,1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.87-3.79 (m, 1H), 1.57 (d, J = 7.2 Hz, 3H)；
1H NMR (DMSO-d 6): 12.62 (brs, 2H), 9.56 (brs,1H), 8.27 (s, 1H), 8.23 (d,J = 15.6 Hz, 1H), 7.99 (d, J = 15.6 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.55-7.54 (m, 2H), 7.26-7.23 (m, 2H), 7.11-7.05 (m, 2H), 6.82-6.86 (m, 1H), 3.84(s, 3H), 3.79-3.74 (m, 1H), 1.41 (d, J = 6.4 Hz, 3H)；
1H NMR (DMSO-d 6): 12.50 (brs, 2H), 10.00 (brs, 1H), 8.27 (s, 1H), 8.17(d, J = 15.6 Hz, 1H), 8.02 (d, J = 15.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H),7.56-7.52 (m, 1H), 7.46-7.45 (m, 1H), 7.26-7.23 (m, 2H), 7.10 (d, J = 8.4 Hz,1H), 6.95-6.88 (m, 2H), 3.74 (s, 3H), 3.73-3.69 (m, 1H), 1.41 (d, J = 7.2 Hz,3H)；
1H NMR (DMSO-d 6): 12.74 (brs, 2H), 9.21 (brs, 1H), 8.32 (s, 1H), 7.87 (d,J = 15.2 Hz, 1H), 7.76 (d, J = 15.2 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.57-7.53 (m, 1H), 7.43 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.09(d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 3.84 (s, 3H), 3.78-3.76 (m,1H), 1.41 (d, J = 6.8Hz, 3H)；
1H NMR (CDCl3): 13.32 (brs, 1H), 8.04 (s, 1H), 7.89 (d, J = 15.6 Hz, 1H),7.62-7.52 (m, 3H), 7.40 (m, 1H), 7.40-7.36 (m, J = 15.6 Hz, 1H), 7.20-7.18(m, 2H), 7.07 (d, J = 8.8 Hz, 1H), 6.64 (d, J = 8.8 Hz, 2H), 3.83-3.79 (m,1H), 3.00 (s, 6H), 1.58 (d, J = 6.8 Hz, 3H)；
1H NMR (CDCl3): 13.04(brs, 1H), 8.32 (d, J = 15.6 Hz, 1H), 8.09 (s, 1H),7.65 (d, J = 15.6 Hz, 1H), 7.69-7.63 (m, 2H), 7.43-7.34 (m, 2H), 7.21-7.16(m, 2H), 7.11-7.06 (m, 2H), 7.04-7.00 (m, 1H), 3.81-3.79 (m, 1H), 2.80 (s,6H), 1.57 (d, J = 7.2 Hz, 3H)；
1H NMR (CDCl3): 13.33 (brs, 1H), 8.05 (s, 1H), 7.92 (d, J = 15.6 Hz, 1H),7.61(d, J = 8.8 Hz, 1H), 7.54(d, J = 8.8 Hz, 2H), 7.43-7.39 (m, 1H), 7.41 (d,J = 15.6 Hz, 1H), 7.21-7.17 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 6.65-6.63 (m,2H), 3.82 (q, J = 7.2 Hz, 1H), 3.39 (q, J = 6.8 Hz, 4H), 1.58 (d, J = 7.2 Hz,3H), 1.19 (q, J = 6.8Hz, 6H)；
1H NMR (CDCl3): 13.21 (brs, 1H), 8.05 (s, 1H), 7.89 (d, J = 16.0 Hz, 1H),7.61 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.45-7.40 (m, 1H), 7.41(d, J = 16.0 Hz, 1H), 7.21-7.17 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 6.86 (d, J= 8.4 Hz, 2H), 3.82-3.81 (m, 1H), 3.31 (s, 4H), 1.68-1.64 (m, 6H), 1.57 (d, J= 6.6 Hz, 3H)；
1H NMR (CDCl3): 13.12 (brs,1H), 8.06 (s,1H), 7.91 (d, J = 15.2 Hz, 1H,),7.64 (d, J = 8.4 Hz,2H), 7.59 (d, J = 8.8 Hz,2H), 7.48 (d, J = 15.2 Hz,1H),7.44-7.40 (m,1H), 7.23-7.18 (m,2H), 7.10 (d, J = 8.8 Hz,1H), 6.88 (d, J = 8.8Hz,2H), 3.87-3.80 (m,5H), 3.28-3.26 (m, 4H), 1.59 (d, J = 7.2Hz ,3H)；
1H NMR (CDCl3): 12.98 (brs,1H), 8.06 (s,1H), 7.91 (d, J = 15.2 Hz, 1H),7.64 (d, J = 8.4 Hz, 1H), 7.48(d, J = 15.2 Hz,1H), 7.43-7.39 (m,1H), 7.28-7.26 (m, 1H), 7.21-7.15 (m,3H), 7.10 (d, J = 8.4Hz, 1H), 6.90 (d, J = 8.4 Hz,1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.81 (q, J = 6.8 Hz, 1H), 1.58 (d, J = 6.8Hz, 3H)。
（2）当Ar表示苯环或取代苯环、X表示NH时的化合物（I）：
。
（3）当Ar表示芳杂环时的化合物（I）：
；
部分化合物的1H-NMR数据如下：
1H NMR (CDCl3): 12.91 (brs, 1H), 8.07 (d, J = 16.0 Hz, 1H), 8.01 (s,1H),7.65 (d, J = 8.8 Hz, 1H), 7.45-7.40 (m,3H), 7.42 (d, J = 16.0 Hz,1H), 7.22-7.18 (m, 2H), 7.11-7.09 (m,2H), 3.82-3.81 (m, 1H), 1.58 (d, J = 7.2 Hz, 3H)；
1H NMR (DMSO-d 6): 12.48 (brs,2H), 9.04 (s,1H), 8.62 (s,1H), 8.38-8.32 (m,2H), 8.21 (d, J = 14.4 Hz, 1H), 7.87 (d, J = 14.4 Hz,1H), 7.17 (brs, 1H),7.53-7.49 (m,2H), 7.24 (brs,2H), 7.12 (brs,2H), 3.86-3.75 (m,1H), 1.40 (m,3H)；
1H NMR (DMSO-d 6): 12.48 (brs, 2H), 9.04 (s,1H), 8.62 (s,1H), 8.38-8.32(m,2H), 8.21 (d, J = 14.4 Hz, 1H), 7.87 (d, J = 14.4 Hz,1H), 7.17 (brs, 1H),7.53-7.49 (m,2H), 7.24 (brs,2H), 7.12 (brs,2H), 3.86-3.75 (m,1H), 1.40 (m,3H)。
实施例2 氟比洛芬查尔酮类化合物（I）与酸成盐制备通法
在反应瓶中加入按照上述实施例所得之氟比洛芬查尔酮类化合物（I）（即：R1和R2各自独立地表示NR4R5时的化合物）1.0 mmol和丙酮20 ml，搅拌均匀后加入3.0 mmol相应的酸，升温回流搅拌反应20分钟，反应结束后冷却至室温，减压蒸除溶剂，残余物用常规方法重结晶，过滤析出的固体，即得相应的氟比洛芬查尔酮类化合物（I）的盐，其化学结构经1H NMR和ESI-MS确证。

Claims (9)

1.一类氟比洛芬查尔酮类化合物或其药学上可接受的盐，其特征在于该类化合物的化学结构通式如（I）所示：
式中：Ar表示；R1和R2在芳环上任意可能的位置；R1和R2各自独立地表示H、OH、C1~C12烷基、C1~C12烷氧基、卤素、NR4R5；R4和R5各自独立地表示H、C1~C12烷基、苯基、苄基、取代苯基或取代苄基；NR4R5也表示四氢吡咯基、吗啉基、哌啶基、4-位被C1~C12烷基所取代的哌啶基、4-位被苄基或取代苄基所取代的哌啶基、哌嗪基、4-位被C1~C12烷基所取代的哌嗪基、4-位被苄基或取代苄基所取代的哌嗪基；X表示O或NH；R3表示H、C1~C12烷基；所述化合物为R构型、S构型、或R构型和S构型的任意比例混合物；上述术语“取代苄基”和“取代苯基”是指苯环上被1-4个选自下组的基团所取代的苯基或苄基：F、Cl、Br、I、C1-4烷基、C1-4烷氧基、三氟甲基、三氟甲氧基、NR6R7、羟基、硝基、氰基，这些取代基可在苯环的任意可能位置；R6和R7各自独立地表示H、C1~C12烷基，NR6R7也表示四氢吡咯基、吗啉基或哌啶基。
2.如权利要求1所述的氟比洛芬查尔酮类化合物或其药学上可接受的盐，其特征在于所述的药学上可接受的盐为此类氟比洛芬查尔酮类化合物与盐酸、氢溴酸、硝酸、硫酸、磷酸、胺基磺酸、C1-6脂肪羧酸、三氟乙酸、硬脂酸、扑酸、草酸、苯甲酸、苯乙酸、水杨酸、马来酸、富马酸、琥珀酸、酒石酸、柠檬酸、苹果酸、乳酸、羟基马来酸、丙酮酸、谷氨酸、抗坏血酸、硫辛酸、C1-6烷基磺酸、樟脑磺酸、萘磺酸、苯磺酸、对甲苯磺酸或1,4-丁二磺酸的盐。
3.如权利要求1-2任一项所述氟比洛芬查尔酮类化合物或其药学上可接受的盐的制备方法，其特征在于所述化合物可通过以下方法制备得到：
式中：Ar、R3和X的定义与化学结构通式（I）相同；
以相应的芳甲醛类化合物（1）和3′-乙酰基-4′-羟基氟比洛芬类化合物（2）为起始原料，在溶剂和碱性条件下直接缩合，得相应的氟比洛芬查尔酮类化合物（I）。
4.如权利要求3所述氟比洛芬查尔酮类化合物或其药学上可接受的盐的制备方法，其特征在于缩合反应所用碱为：碱金属氢氧化物、碱土金属氢氧化物、碱金属碳酸盐、碱土金属碳酸盐、碱金属碳酸氢盐、碱土金属碳酸氢盐、C1-8醇的碱金属盐、三乙胺、三丁胺、三辛胺、吡啶、N-甲基吗啉、N-甲基哌啶、三乙烯二胺、四丁基氢氧化铵；反应所用溶剂为：C1-8脂肪醇、乙醚、四氢呋喃、2-甲基四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、二氯甲烷、氯仿、1,4-二氧六环、苯、甲苯或乙腈。
5.如权利要求3所述氟比洛芬查尔酮类化合物或其药学上可接受的盐的制备方法，其特征在于缩合反应中化合物（2）：化合物（1）：碱的摩尔投料比为1.0：1.0~5.0：1.0~20.0；反应温度为0~150℃；反应时间为1~120小时。
6.一类药物组合物，其特征在于包含如权利要求1-2任一项所述的氟比洛芬查尔酮类化合物或其药学上可接受的盐以及一种或多种药学上可接受的载体或赋形剂。
7.如权利要求1-2任一项所述的氟比洛芬查尔酮类化合物或其药学上可接受的盐在制备治疗和/或预防神经退行性相关疾病药物中的用途，这类神经退行性相关疾病为：血管性痴呆、阿尔茨海默氏症、帕金森症、亨廷顿症、HIV相关痴呆症、多发性硬化症、进行性脊髓侧索硬化症、神经性疼痛、或青光眼。
8.一类化合物，其特征在于它是具有化学结构通式（2）所示的化合物：
式中：X表示O或NH，R3表示H、C1~C12烷基。
9.如权利要求8所述任意化合物在制备如权利要求1-2任一项所述的氟比洛芬查尔酮类化合物或其药学上可接受的盐的应用。
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