CN110240549A - 一种胺烷氧基查尔酮化合物及其制备方法和用途 - Google Patents
一种胺烷氧基查尔酮化合物及其制备方法和用途 Download PDFInfo
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- CN110240549A CN110240549A CN201910619780.0A CN201910619780A CN110240549A CN 110240549 A CN110240549 A CN 110240549A CN 201910619780 A CN201910619780 A CN 201910619780A CN 110240549 A CN110240549 A CN 110240549A
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- Prior art keywords
- amine
- acid
- alkali
- alkyloxybenzaldehydes
- chalcone compound
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
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- 201000010099 disease Diseases 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 18
- 150000001412 amines Chemical class 0.000 claims abstract description 17
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 10
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 8
- ZWVHTXAYIKBMEE-UHFFFAOYSA-N 2-hydroxyacetophenone Chemical compound OCC(=O)C1=CC=CC=C1 ZWVHTXAYIKBMEE-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000003335 secondary amines Chemical class 0.000 claims abstract description 6
- 239000007858 starting material Substances 0.000 claims abstract description 3
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- 239000003814 drug Substances 0.000 claims description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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- C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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Abstract
本发明公开了一种胺烷氧基查尔酮化合物及其制备方法和用途,包括以下步骤:(1)以3‑羟基苯甲醛为起始原料,在第一溶剂和第一碱性条件下,与二溴化合物反应,得到溴烷氧基苯甲醛;(2)溴烷氧基苯甲醛在第二溶剂和第二碱性条件下与仲胺反应,得到胺烷氧基苯甲醛;(3)胺烷氧基苯甲醛与2‑羟基苯乙酮在第三溶剂和第三碱性条件下,得到目标化合物胺烷氧基查尔酮化合物。本发明化合物体外具有选择性丁酰胆碱酯酶抑制活性、选择性单胺氧化酶B抑制活性、选择性金属离子螯合活性、抑制Aβ聚集活性,可用于治疗和/或预防神经退行性相关疾病。
Description
技术领域
本发明涉及属于药物化学领域,具体涉及一种胺烷氧基查尔酮化合物及其制备方法和用途。
背景技术
阿尔茨海默症(Alzheimer’s disease,AD)是老年人中发病率和致死率最高的疾病之一。阿尔茨海默症国际协会(Alzheimer’s disease International,ADI)发布的《2015全球阿尔茨海默症报告》指出,2015年全球已有超过4600万人患上痴呆症,据预测,到2050年,全球将有1.315亿人口受到痴呆的困扰,其中中国痴呆症患者的发病率已达到6.61%。随着人均生存年龄的延长,本病已发展为社会和医疗保健***的主要负担,并且为社会、患者及家属带来了沉重的精神和经济压力。目前被FDA批准的药物主要为乙酰胆碱酯酶抑制剂和NMDA受体拮抗剂,这些药物仅能在短期内局部缓解AD患者的症状,并不能有效阻止或逆转该疾病的进程,而且还会导致经典的胆碱能毒性,如引起幻觉、意识混沌、头晕、恶心、肝脏毒性、食欲不振以及大便频繁等。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是一种慢性的、以进行性记忆和认知功能损害为特征的多病因、多环节参与的复杂神经退行性疾病,其主要病理学特征为β-淀粉样肽(β-amyloid peptide,Aβ)大量沉积形成的老年斑(Senile plaque,SP)、tau蛋白过度磷酸化形成的神经纤维缠结(Neurofibrillary tangle,NFT),并伴随神经元的凋亡和神经突触的退化等。近年来,许多研究者致力于从分子和细胞水平来揭示AD的发病机理,提出了多种假说,如:胆碱能神经元损伤、淀粉样蛋白的沉积、tau蛋白过度磷酸化、炎症、自由基氧化、金属离子失调等,因此,针对这些发病机制来发展的新型治疗途径和手段,将有希望缓解和改善AD患者的病情。
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,不同机制之间有相互关联相互影响,构成了AD发生和发展过程复杂的网络调控***。基于上述结果,研究人员提出了“多靶点导向药物(Multitarget-directedLigands,MTDLs)”策略来研发抗神经退行性疾病药物。所谓“多靶点药物”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,此类药也称为“Multifunctional”或“Multipotential”药物。因此,研究开发具有新型化学结构、新型作用机制,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。在前期报道中,发现了灯盏乙素苷元氨基甲酸酯类衍生物(CN10337956A、CN102603698A)、二苯乙烯或乙烷氨基甲酸酯类化合物(CN102816090A)、异黄酮氨基甲酸酯类化合物(CN102827131A),阿魏酸氨基甲酸酯类化合物(CN105837497A、CA105601540A、CN105646289A),这些化合物虽具有较好的乙酰胆碱酯酶抑制活性和抗氧化活性,且对Aβ聚集有一点的抑制作用,同时对丁酰胆碱酯酶的抑制活性非常差,导致这些化合物在动物模型中对AD的治疗疗效欠佳。中国专利CN105439876B、CN105481706B、CN105481796B中也均公开了一些查尔酮类化合物,这些化合物具有较好的乙酰胆碱酯酶抑制活性,对丁酰胆碱酶的抑制活性一般,对乙酰胆碱酯酶具有选择性抑制作用,这些药物仅能在短期内局部缓解AD患者的症状,并不能有效阻止或逆转该疾病的进程,不适合中重度阿尔茨海默病的治疗,且存在乙酰胆碱酯酶抑制带来的经典的胆碱能副作用。
发明内容
本本发明的第一目的在于公开一种胺烷氧基查尔酮化合物。
本发明的第二目的的还在于公开一种胺烷氧基查尔酮化合物的制备方法。
本发明的第三目的的还在于公开一种药物组合物,包括胺烷氧基查尔酮化合物或其药学上可接受的盐。
本发明的第四目的还在于公开一种胺烷氧基查尔酮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、神经性疼痛或者青光眼。
一种胺烷氧基查尔酮化合物,其化学结构通式如(I)所示:
其中,n为2-12;
R1、R2各自独立地表示C1~C12烷基、C3~C8环烷基、苯基、苄基、取代苯基或取代苄基,但R1和R2不同时为H;NR1R2也可表示四氢吡咯基、吗啉基、哌啶基、4-位被C1~C12烷基所取代的哌啶基、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。
优选地,所述的取代苄基或者取代苯基是指苯环上被1-4个选自下组的基团所取代:F、Cl、Br、I、C1-4烷基、C1-4烷氧基、三氟甲基、三氟甲氧基、硝基、氨基、二甲氨基、羧基、羟基和氰基,这些取代基可在苯环的任意可能位置。
一种胺烷氧基查尔酮化合物的制备方法,包括以下步骤:
(1)以3-羟基苯甲醛为起始原料,在第一溶剂和第一碱性条件下,与二溴化物反应,得到溴烷氧基苯甲醛;
(2)溴烷氧基苯甲醛在第二溶剂和第二碱性条件下与仲胺反应,得到胺烷氧基苯甲醛;
(3)胺烷氧基苯甲醛与2-羟基苯乙酮在第三溶剂和第三碱性条件下,得到目标化合物胺烷氧基查尔酮化合物。
其化学反应通式为:
式中n、R1和R2的定义与胺烷氧基查尔酮化合物(I)的化学结构通式相同。
优选地,步骤(1)所述的第一溶剂为四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、C3-8脂肪酮、苯、甲苯、乙腈、二氯甲烷、氯仿、C1-8醇或者C5-8烷烃。
优选地,步骤(1)所述的第一碱性条件所用碱为碱金属氢氧化物、碱土金属氢氧化物、碱金属或碱土金属碳酸盐、碱金属或碱土金属碳酸氢盐、C1-6脂肪酸碱金属盐、哌啶、四氢吡咯、三乙胺、三丁胺、三辛胺、吡啶、N-甲基吗啉、N-甲基哌啶、三乙烯二胺和四丁基氢氧化铵中一种或几种。
优选地,步骤(1)所述的3-羟基苯甲醛、二溴化物、碱的摩尔投料比为1.0:1.0~50.0:1.0~100.0,反应温度为-20℃~130℃,反应时间为1~120h。
优选地,步骤(2)所述的第二溶剂为四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、C3-8脂肪酮、苯、甲苯、乙腈、二氯甲烷、氯仿、C1-8醇或者C5-8烷烃。
优选地,步骤(2)所述的第二碱性条件所用碱为碱金属氢氧化物、碱土金属氢氧化物、碱金属或碱土金属碳酸盐、碱金属或碱土金属碳酸氢盐、C1-6脂肪酸碱金属盐、哌啶、四氢吡咯、三乙胺、三丁胺、三辛胺、吡啶、N-甲基吗啉、N-甲基哌啶、三乙烯二胺和四丁基氢氧化铵中一种或几种。
优选地,步骤(2)所述的溴烷氧基苯甲醛、仲胺、碱的摩尔投料比为1.0:1.0~50.0:1.0~100.0,反应温度为-20℃~130℃,反应时间为1~120h。
优选地,步骤(3)所述的第三溶剂为四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、C3-8脂肪酮、苯、甲苯、乙腈、二氯甲烷、氯仿、C1-8醇、或C5-8烷烃。
优选地,步骤(3)所述的第三碱性条件所用碱为碱金属氢氧化物、碱土金属氢氧化物、碱金属或碱土金属碳酸盐、碱金属或碱土金属碳酸氢盐、C1-6脂肪酸碱金属盐、哌啶、四氢吡咯、三乙胺、三丁胺、三辛胺、吡啶、N-甲基吗啉、N-甲基哌啶、三乙烯二胺和四丁基氢氧化铵中一种或几种。
优选地,步骤(3)所述的胺烷氧基苯甲醛、2-羟基苯乙酮、碱的摩尔投料比为1.0:1.0~50.0:1.0~100.0,反应温度为-20℃~130℃,反应时间为1~120h。
本发明方法得到的胺烷氧基查尔酮化合物分子中含有氨基,该氨基显碱性,可与任何合适的酸通过药学上常规的成盐方法制得其药学上可接受的盐,所述的盐为:盐酸、氢溴酸、硝酸、硫酸、磷酸、C1-6脂肪羧酸、草酸、苯甲酸、水杨酸、马来酸、富马酸、琥珀酸、酒石酸、柠檬酸、C1-6烷基磺酸、樟脑磺酸、苯磺酸或者对甲苯磺酸的盐。
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胺烷氧基查尔酮化合物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、***或动物的生物或医药反应的药物或药剂的量;所述“组合物”是指通过一种以上物质或组分混合而成的产品;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;所述的胺烷氧基查尔酮化合物或其药学上可接受的盐作为活性成分占总重量比2%~99.5%。
阿尔茨海默病的主要临床表现为认知功能障碍、地点定向力和人物定向力障碍、精神行为异常以及并发感染或其他疾病而死亡。AD患者脑组织有三大显著的病理学特征:细胞内过度磷酸化的tau蛋白造成的神经元纤维缠结(Neurofibrillary tangles,NFT)、细胞外β-淀粉样肽(β-amyloid,Aβ)构成的老年斑(Senileplaques,SP)以及脑内基底核和前脑胆碱能神经元受损为主的神经元大量丢失。AD病因复杂,是环境和遗传因素相互作用的结果,其具体发病机制至今尚不十分明确。目前对于阿尔兹海默病的治疗并没有有效的根治方法,只能通过药物对病患的病情发展起到抑制延缓的作用。例如:美国食品和药品管理局(FDA)批准上市的他克林,多奈哌齐,卡巴拉汀和加兰他敏,长期临床研究表明,这些药物全部都是针对单一靶点的单靶点药物,只能调控该疾病网络的单一靶点或途径,仅能在短期内局部缓解AD患者的症状,并不能有效阻止或逆转该疾病的进程,而且还会导致经典的胆碱能毒性。
随着对AD病理机制研究的不断深入,科学家发现AD的发生和发展是多种因素相互作用的多病因疾病,不是简单的单一因素引起,有十分复杂的生理和病理机制。因此,寻求能同时作用于AD的多个致病靶点的多靶点导向药物成为AD药物研究的新方向。2014年12月FDA批准固定剂量美金刚-多奈哌齐复方制剂Namzaric用于治疗中重度AD患者为病人提供了一个固定剂量组合的药剂,这种药剂在一个胶囊中实现了两种治疗效果,该复方制剂让多靶点药物的研发看到了希望,目前处于临床研究的多靶点已经获得了可喜的结果,例如:灯盏乙素苷元氨基甲酸酯类衍生物(CN10337956A、CN102603698A)、二苯乙烯或乙烷氨基甲酸酯类化合物(CN102816090A)、异黄酮氨基甲酸酯类化合物(CN102827131A),阿魏酸氨基甲酸酯类化合物(CN105837497A、CA105601540A、CN105646289A),查尔酮类化合物(CN105439876B、CN105481706B、CN105481796B)。但是,研究发现,随着AD的发展,AD患者脑部AChE水平逐渐降低,而BuChE活性度显著增加,在敲除AChE基因小鼠体内,选择性AChE抑制剂并没有影响ACh水平,而选择性BuChE抑制剂则使ACh水平增加了5倍,说明到了AD中重度阶段,丁酰胆碱酯酶则取代了乙酰胆碱酯酶来水解乙酰胆碱,而上述化合物对丁酰胆碱酯酶的抑制活性非常差,对乙酰胆碱酯酶具有选择性抑制作用,导致这些化合物在动物模型中对AD的治疗疗效欠佳。而且进一步研究发现,选择性BuChE抑制剂能够避免典型的胆碱能毒性,且正常情况下BuChE的缺失几乎没有健康方面的副作用,选择性丁酰胆碱酯酶抑制剂将对AD(尤其是中重度AD患者)治疗极具潜力。因此,本发明设计基于选择性抑制丁酰胆碱酯酶的多靶点抗AD抑制剂将为中重度阿尔茨海默病患者带来新的希望。另外,选择性单胺氧化酶B抑制剂,选择性金属离子螯合剂,抗氧剂,抑制Aβ聚集对于AD也有一定的帮助。为此,本发明创造性地提出了一种胺烷氧基查尔酮化合物,并取得了如下积极有益效果:
1.本发明化合物对丁酰胆碱酯酶具有显著抑制作用,其IC50为0.031μM~4.9μM;对乙酰胆碱酯酶具有中等或较弱的抑制活性,其IC50为15.3μM~29.7μM;本发明化合物对丁酰胆碱酯酶具有显著选择性抑制作用。
本发明化合物对Aβ1-42自身诱导的聚集均具有显著抑制作用,在25.0μM浓度下对Aβ1-42自身聚集的抑制率大于65.0%。
本发明所公开的胺烷氧基查尔酮化合物均为选择性金属离子螯合剂。
本发明所公开的化合物的抗氧化活性为Trolox的1.1-1.2倍,本发明化合物具有强抗氧化活性。
本发明所公开的化合物对单胺氧化酶A和单胺氧化酶B均具有显著抑制作用,其IC50分别为≥31.5μM,0.32μM~6.7μM,本发明化合物为选择性MAO-B抑制剂。
本发明所公开的化合物对东莨菪碱致小鼠获得记忆障碍具有显著的改善作用,与模型组比较均具有统计学差异(p<0.05)。
因此,本发明化合物可用于血管痴呆,帕金森,亨廷顿舞蹈症等中枢神经退行性疾病治疗或者预防,尤其适合中重度中枢神经退行性疾病治疗或者预防。
2.本发明原料来源广泛,成本低廉,反应条件温和,操作方便。
附图说明
图1为本发明化合物对东莨菪碱诱导小鼠记忆障碍影响效应图。
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
一种胺烷氧基查尔酮化合物,其化学结构通式如(I)所示:
其中,n、R1、R2的定义见下表1。
表1本发明胺烷氧基查尔酮化合物
一种胺烷氧基查尔酮化合物的制备方法,包括以下步骤:
(1)将2.0mmol相应的3-羟基苯甲醛(1)、3.0mmol碳酸钾、6.0mmol二溴化物(2)和15mL乙腈加入反应瓶中,加热至65℃反应10小时,反应结束后,经常规处理,用硅胶柱层析纯化(洗脱液:石油醚:丙酮=50:1v/v),得相应的烷氧基苯甲醛(3);
(2)相应的烷氧基苯甲醛(3)2.0mmol,仲胺NR1R2(4)2.5mmol和3.0mmol碳酸钾加入含有20mL乙腈的反应瓶中,加热至65℃反应10小时,经常规处理后,用硅胶柱层析纯化(洗脱液:石油醚:丙酮=30:1v/v),得相应的胺烷氧基苯甲醛化合物(5);
(3)2.0mmol相应的胺烷氧基苯甲醛化合物(5),3.0mmol相应的2-羟基苯乙酮(6)和20mL乙醇加入反应瓶中,搅拌均匀后,加入50%KOH水溶液10mL,室温搅拌24小时(反应进程用TLC跟踪),反应结束后,减压蒸干溶剂,残余物中加入30mL去离子水,用10%HCl调节pH至强酸性,再用饱和碳酸氢钠溶液调节pH至弱碱性,用120mL二氯甲烷分三次萃取,有机层合并用饱和氯化钠溶液洗涤,经无水硫酸钠干燥过滤,减压蒸除溶剂,残余物经硅胶柱层析纯化(洗脱液:石油醚:丙酮=100:1v/v),得相应的胺烷氧基查尔酮类化合物(I),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%。
部分目标化合物的结构表征
I-28:1H NMR(400MHz,CDCl3)δ12.81(s,1H,OH),8.08(d,J=7.2Hz,1H,Ar-H),7.94(d,J=7.6Hz,1H,Ar-H),7.87(d,J=15.6Hz,CH=CH),7.64(d,J=15.6Hz,1H,CH=CH),7.50(t,J=8.0Hz,1H,Ar-H),7.41(t,J=7.6Hz,1H,Ar-H),7.33(t,J=8.0Hz,2H,2×Ar-H),7.24(d,J=7.2Hz,1H,Ar-H),7.18(d,J=8.0Hz,2H,2×Ar-H),7.03(d,J=8.0Hz,1H,Ar-H),6.96(q,J=7.6Hz,2H,2×Ar-H),4.07(t,J=5.2Hz,2H,OCH2),3.67(s,2H,phCH2),3.59(t,J=5.6Hz,2H,phCH2),3.00(t,J=6.0Hz,2H,NCH2),1.89-1.86(m,4H,2×CH2).13CNMR(100MHz,CDCl3)193.8,163.6,159.4,145.4,137.9,136.4,136.0,131.6,130.0,129.8,129.5,128.3,127.1,126.8,121.5,120.4,120.0,118.9,118.6,117.1,114.2,67.6,46.9,46.1,28.2,26.6,24.4.MS(ESI)m/z:414.2[M+H]+。
I-31:1H NMR(400MHz,CDCl3)δ12.81(s,1H,OH),8.00-7.91(m,1H,Ar-H),7.87(d,J=15.2Hz,1H,CH=CH),7.66(d,J=15.2Hz,1H,CH=CH),7.54-7.49(m,2H,2×Ar-H),7.35-7.28(m,3H,3×Ar-H),7.24-7.19(m,2H,2×Ar-H),7.16-7.11(m,2H,2×Ar-H),7.07-7.00(m,2H,2×Ar-H),6.96(t,J=8.4Hz,1H,Ar-H),4.04(t,J=6.0Hz,2H,OCH2),3.51(d,J=5.6Hz,2H,phCH2),2.98-2.95(m,2H,NCH2),2.60(d,J=6.8Hz,2H,NCH2),2.56-2.51(m,2H,NCH2),2.05-2.01(m,4H,2×CH2),1.86-1.80(m,5H,2×CH2+CH).MS(ESI)m/z:470.3[M+H]+。
I-32:1H NMR(400MHz,CDCl3)δ12.80(s,1H,OH),7.87(d,J=7.6Hz,1H,Ar-H),7.75(d,J=15.2Hz,1H,CH=CH),7.56(d,J=15.2Hz,1H,CH=CH),7.39(t,J=8.0Hz,1H,Ar-H),7.23(t,J=8.0Hz,1H,Ar-H),7.20-7.13(m,1H,Ar-H),7.09-7.06(m,3H,3×Ar-H),7.04(t,J=7.2Hz,1H,Ar-H),6.98-6.90(m,3H,3×Ar-H),6.88-6.84(m,1H,Ar-H),4.02(s,2H,phCH2),3.94(t,J=5.2Hz,2H,OCH2),3.15-3.13(m,2H,phCH2),3.01-2.99(m,2H,NCH2),2.94-2.91(m,2H,NCH2),1.97-1.95(m,2H,CH2),1.82-1.78(m,2H,CH2).MS(ESI)m/z:428.2[M+H]+。
I-35:1H NMR(400MHz,CDCl3)δ12.81(s,1H,OH),7.96(d,J=7.6Hz,1H,Ar-H),7.88(d,J=15.6Hz,1H,CH=CH),7.67(d,J=15.2Hz,1H,CH=CH),7.54-7.48(m,1H,Ar-H),7.36-7.31(m,2H,2×Ar-H),7.29-7.23(m,2H,2×Ar-H),7.20-7.16(m,2H,2×Ar-H),7.10(d,J=7.2Hz,1H,Ar-H),7.03(d,J=8.4Hz,2H,2×Ar-H),6.96(t,J=5.6Hz,1H,Ar-H),4.04(s,2H,phCH2),3.92(t,J=5.2Hz,2H,OCH2),3.15-3.13(m,2H,phCH2),2.34(t,J=7.6Hz,2H,NCH2),2.13-2.08(m,2H,NCH2),1.91-1.83(m,4H,2×CH2),1.64-1.59(m,2H,CH2).MS(ESI)m/z:442.2[M+H]+。
I-38:1H NMR(400MHz,CDCl3)δ12.79(s,1H,OH),7.91(d,J=8.4Hz,1H,Ar-H),7.87(d,J=16.0Hz,1H,CH=CH),7.62(d,J=15.6Hz,1H,CH=CH),7.49(t,J=7.6Hz,1H,Ar-H),7.32(t,J=8.0Hz,1H,Ar-H),7.23(d,J=7.6Hz,1H,Ar-H),7.17(s,1H,Ar-H),7.11-7.08(m,3H,3×Ar-H),7.03-7.01(m,2H,2×Ar-H),6.97(d,J=9.2Hz,1H,Ar-H),6.92(d,J=7.6Hz,1H,Ar-H),4.01(t,J=6.0Hz,2H,OCH2),3.66(s,2H,phCH2),2.91(t,J=5.2Hz,2H,phCH2),2.77(t,J=5.6Hz,2H,NCH2),2.55(t,J=7.6Hz,2H,NCH2),1.85-1.80(m,2H,CH2),1.70-1.62(m,2H,CH2),1.56-1.51(m,2H,CH2),1.46-1.39(m,2H,CH2).13C NMR(100MHz,CDCl3)193.7,163.6,159.6,145.5,136.4,136.0,134.4,134.2,130.0,129.7,128.7,126.6,126.2,125.7,121.3,120.4,120.1,118.9,117.1,114.4,68.1,58.1,55.9,50.8,29.2,28.8,27.3,26.9,26.0.MS(ESI)m/z:456.2[M+H]+。
生物活性试验
(1)胺烷氧基查尔酮化合物(I)对乙酰胆碱酯酶和丁酰胆碱酯酶的抑制活性
向96孔板中依次加入1.0mmol/L碘化硫代乙酰胆碱或硫代丁酰胆碱(均购自Sigma公司)30μL,pH8.0的PBS缓冲液40μL,待测化合物溶液20μL(DMSO含量小于1%)和10μL电鳗乙酰胆碱酯酶(EeAChE)或马血清丁酰胆碱酯酶(eqBuChE),加毕混匀后,37℃孵育15min,向各孔中加入质量分数为0.2%的5,5'-二硫代-双(2-硝基)苯甲酸(DTNB,购自Sigma公司)溶液30μL显色,用酶标仪测定412nm处各孔的光密度(OD值),与不加待测样品的空白孔比较,计算化合物对酶的抑制率[酶抑制率=(1-样品组OD值/空白组OD值)×100%];选择化合物的五至六个浓度,测定其酶抑制率,并以该化合物摩尔浓度的负对数与酶的抑制率线性回归,求得50%抑制率时的摩尔浓度即为该化合物的IC50,见表2。
表2本发明化合物的AChE/BChE和MAO-A/MAO-B抑制活性检测结果
选择性指数SI1=IC50(BuChE)/IC50(AChE);选择性指数SI2=IC50(MAO-A)/IC50(MAO-B);
测定结果表明,本发明化合物对丁酰胆碱酯酶具有显著抑制作用,其IC50为0.031μM~4.9μM;对乙酰胆碱酯酶具有中等或较弱的抑制活性,其IC50为15.3μM~29.7μM;而阳性对照药物——donepezil对乙酰胆碱酯酶和丁酰胆碱酯酶抑制的IC50为0.019μM和4.76μM。本发明化合物对丁酰胆碱酯酶具有显著选择性抑制作用。
(2)胺烷氧基查尔酮(I)抑制Aβ聚集活性测定
取20μL的Aβ1-42溶液+20μL的待测化合物溶液、20μL的Aβ1-42溶液+20μL PBS缓冲液(含2%DMSO)、20μL PBS缓冲液(含2%DMSO)+20μL PBS缓冲液(含25%DMSO)于黑色96孔板中,化合物和Aβ1-42的最终浓度均为25μM。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Varioskan Flash MultimodeReader(Thermo Scientific)多功能酶标仪在446nm激发波长和490nm发射波长下测定荧光值;Aβ1-42+待测化合物的荧光值记录为IFi,Aβ1-42+PBS缓冲液的荧光值记录为IFc,只含有PBS缓冲液的荧光值记录为IF0,由化合物抑制Aβ1-42自身聚集的抑制率计算公式为:100-(IFi-IF0)/(IFc-IF0)*100。每个化合物每个浓度测定两个复孔,检测结果见表3。
表3本发明化合物抑制Aβ聚集活性和抗氧化活性检测结果
测定结果表明,在25.0μM浓度下本发明化合物对Aβ1-42自身聚集的抑制率大于65.0%,姜黄素在相同浓度下的抑制率为47.3%,本发明化合物对Aβ1-42自身诱导的聚集均具有显著抑制作用。
(3)胺烷氧基查尔酮化合物(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75μmol/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分钟,在多功能酶标仪上记录200-600nm范围内的紫外吸收曲线,并以100μL待测化合物溶液和100μL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,加入Cu2+和Al3+后,化合物I-32的最大吸收波长从361nm分别迁移到418nm和426nm,表明化合物I-32能够与Cu2+和Al3+形成络合物;而加入Zn2+和Fe2+后则最大吸收波长没有发生迁移,说明本发明所公开的胺烷氧基查尔酮化合物均为选择性金属离子螯合剂。
(4)胺烷氧基查尔酮(I)的抗氧化活性(ORAC-FL方法)
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10-80μmol/L的溶液,荧光素(flrorescein)用pH7.4的PBS缓冲液配成250nmol/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40mmol/L的溶液。向96孔板中加入50-10μmol/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200μL,混匀,立即置于Varioskan Flash Multimode Reader仪中,在485nm激发波长和535nm发射波长下连续测定90min。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-AUC blank)]/[(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,检测结果见表3。
测定结果表明,本发明所公开的化合物的抗氧化活性为Trolox的1.1-1.2倍,具有强抗氧化活性。
(5)胺烷氧基查尔酮(I)对单胺氧化酶A和单胺氧化酶B的抑制活性取犬尿胺溶液(225μM或150μM)100μL,加入不同浓度(0-500μM)的待测化合物溶液100μL,12.5μg/mL的MAO-A溶液(或MAO-B)300μL,使反应体系总体积为500μL(犬尿胺、待测化合物和MAO-A(或MAO-B)的最终浓度分别为45μM、0-100μM和7.5μg/mL,含4%的DMSO),混匀,37℃孵育20min。加入2mol/L的NaOH溶液400μL和水1000μL终止反应,16000g离心10min,取上清液,在激发波长310nm,发射波长400nm处测定荧光强度;将4-羟基喹啉溶于500μL磷酸钾缓冲液(最终浓度0.047-1.56μM,含4%DMSO),加入2mol/L的NaOH溶液400μL和水1000μL,在同样条件下建立标准曲线.通过GraphPad Prism以犬尿胺被氧化的初速度对抑制剂浓度的对数作图,绘制剂量相关的S曲线,计算出化合物抑制单胺氧化酶的IC50。绘制S曲线至少选择三个不同数量级的六个抑制剂浓度,每组实验独立重复三次,检测结果见表2。
测定结果表明,本发明所公开的化合物对单胺氧化酶A和单胺氧化酶B均具有显著抑制作用,其IC50分别≥31.5μM,0.32μM~6.7μM,而阳性对照药物——Rasagiline对MAO-A和MAO-B的IC50为0.587μM和0.0281μM,说明本发明化合物为选择性MAO-B抑制剂,对于AD具有潜在的治疗效应。
(6)胺烷氧基查尔酮(I)对东莨菪碱所致小鼠记忆获得障碍的影响
60只小鼠,18~22g,雌雄各半,随机分为:正常组,模型组,多奈哌齐组(5mg/kg),受试药高、中、低剂量组(16.8、5.6、1.9mg/kg),每组10只动物。每组小鼠按给药剂量分上下午给药,连续给药3次,除正常组以外其他各组腹腔注射东莨菪碱3mg·kg-1。末次给药后50min进行造模,造模后20min进行跳台法训练,将动物放入反应箱内适应3min,然后立即通以36V交流电,训练5min,并记录每次小鼠受到电击的次数(错误次数),并由此作为学***台的潜伏期以及5min内的错误次数,结果见图1。
测定结果表明,正常组的潜伏期为159.7sec,单独给予东莨菪碱后,潜伏期降低到了70.4sec,当给予多奈哌齐(5mg/kg),潜伏期增加到了151.7sec,说明该模型运行良好。另外当给予本发明化合物I-32高、中、低剂量后,高、中剂量组潜伏期分别延长至126.4sec和118.9sec(p<0.05),说明本发明所公开的化合物对东莨菪碱致小鼠获得记忆障碍具有显著的改善作用,与模型组比较均具有统计学差异(p<0.05)。
最后说明的是,以上实施例仅用以说明本发明的技术方案而非限制,本领域普通技术人员对本发明的技术方案所做的其他修改或者等同替换,只要不脱离本发明技术方案的精神和范围,均应涵盖在本发明的权利要求范围当中。
Claims (10)
1.一种胺烷氧基查尔酮化合物,其特征在于,其化学结构通式如(I)所示:
其中,n为2-12;
R1、R2各自独立地表示C1~C12烷基、C3~C8环烷基、苯基、苄基、取代苯基或取代苄基,但R1和R2不同时为H;或者NR1R2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、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。
2.根据权利要求1所述的胺烷氧基查尔酮化合物,其特征在于,所述的取代苄基或者取代苯基是指苯环上被1-4个选自下组的基团所取代:F、Cl、Br、I、C1-4烷基、C1-4烷氧基、三氟甲基、三氟甲氧基、硝基、氨基、二甲氨基、羧基、羟基和氰基,这些取代基可在苯环的任意可能位置。
3.一种胺烷氧基查尔酮化合物的制备方法,其特征在于,包括以下步骤:
(1)以3-羟基苯甲醛为起始原料,在第一溶剂和第一碱性条件下,与二溴化物反应,得到溴烷氧基苯甲醛;
(2)溴烷氧基苯甲醛在第二溶剂和第二碱性条件下与仲胺反应,得到胺烷氧基苯甲醛;
(3)胺烷氧基苯甲醛与2-羟基苯乙酮在第三溶剂和第三碱性条件下,得到目标化合物胺烷氧基查尔酮化合物。
4.根据权利要求3所述的胺烷氧基查尔酮化合物的制备方法,其特征在于,步骤(1)所述的第一溶剂为四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、C3-8脂肪酮、苯、甲苯、乙腈、二氯甲烷、氯仿、C1-8醇或者C5-8烷烃;
步骤(1)所述的第一碱性条件所用碱为碱金属氢氧化物、碱土金属氢氧化物、碱金属或碱土金属碳酸盐、碱金属或碱土金属碳酸氢盐、C1-6脂肪酸碱金属盐、哌啶、四氢吡咯、三乙胺、三丁胺、三辛胺、吡啶、N-甲基吗啉、N-甲基哌啶、三乙烯二胺和四丁基氢氧化铵中一种或几种;
步骤(1)所述的3-羟基苯甲醛、二溴化物、碱的摩尔投料比为1.0:1.0~50.0:1.0~100.0,反应温度为-20℃~130℃,反应时间为1~120h。
5.根据权利要求3所述的胺烷氧基查尔酮化合物的制备方法,其特征在于,步骤(2)所述的第二溶剂为四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、C3-8脂肪酮、苯、甲苯、乙腈、二氯甲烷、氯仿、C1-8醇或者C5-8烷烃;
步骤(2)所述的第二碱性条件所用碱为碱金属氢氧化物、碱土金属氢氧化物、碱金属或碱土金属碳酸盐、碱金属或碱土金属碳酸氢盐、C1-6脂肪酸碱金属盐、哌啶、四氢吡咯、三乙胺、三丁胺、三辛胺、吡啶、N-甲基吗啉、N-甲基哌啶、三乙烯二胺和四丁基氢氧化铵中一种或几种;
步骤(2)所述的溴烷氧基苯甲醛、仲胺、碱的摩尔投料比为1.0:1.0~50.0:1.0~100.0,反应温度为-20℃~130℃,反应时间为1~120h。
6.根据权利要求3所述的胺烷氧基查尔酮化合物的制备方法,其特征在于,步骤(3)所述的第三溶剂为四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、C3-8脂肪酮、苯、甲苯、乙腈、二氯甲烷、氯仿、C1-8醇或者C5-8烷烃;
步骤(3)所述的第三碱性条件所用碱为碱金属氢氧化物、碱土金属氢氧化物、碱金属或碱土金属碳酸盐、碱金属或碱土金属碳酸氢盐、C1-6脂肪酸碱金属盐、哌啶、四氢吡咯、三乙胺、三丁胺、三辛胺、吡啶、N-甲基吗啉、N-甲基哌啶、三乙烯二胺和四丁基氢氧化铵中一种或几种;
步骤(3)所述的胺烷氧基苯甲醛、2-羟基苯乙酮、碱的摩尔投料比为1.0:1.0~50.0:1.0~100.0,反应温度为-20℃~130℃,反应时间为1~120h。
7.一种胺烷氧基查尔酮化合物药学上可接受的盐,所述的盐由酸通过药学上常规的成盐方法制得其药学上可接受的盐,所述的盐为:盐酸、氢溴酸、硝酸、硫酸、磷酸、C1-6脂肪羧酸、草酸、苯甲酸、水杨酸、马来酸、富马酸、琥珀酸、酒石酸、柠檬酸、C1-6烷基磺酸、樟脑磺酸、苯磺酸或者对甲苯磺酸的盐。
8.一种药物组合物,包括胺烷氧基查尔酮化合物或其药学上可接受的盐。
9.根据权利要求8所述的药物组合物,其特征在于,所述的胺烷氧基查尔酮化合物或其药学上可接受的盐的重量含量为2%~99.5%。
10.一种胺烷氧基查尔酮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。
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