CN115160296A - 一种n-取代喹啉-4-胺类化合物及其制备、药物组合物和应用 - Google Patents
一种n-取代喹啉-4-胺类化合物及其制备、药物组合物和应用 Download PDFInfo
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- CN115160296A CN115160296A CN202210942408.5A CN202210942408A CN115160296A CN 115160296 A CN115160296 A CN 115160296A CN 202210942408 A CN202210942408 A CN 202210942408A CN 115160296 A CN115160296 A CN 115160296A
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Abstract
本发明涉及药物化学和药物治疗学领域，具体涉及作为乙酰胆碱酯酶抑制剂的通式I的一类N‑取代喹啉‑4‑胺类化合物，可用于治疗阿尔兹海默症和预防有机磷毒剂中毒的解毒药物。本发明还涉及该类化合物的制备方法、这类化合物以及其在药物学上可接受的盐、异构体、溶剂化物、前药和药物组合物。
Description
技术领域
本发明属于生物医药技术领域，涉及一种N-取代喹啉-4-胺类化合物及其制备与应用，具体涉及作为乙酰胆碱酯酶抑制剂的N-取代喹啉-4-胺类化合物、其制备方法、其在药物学上可接受的盐、异构体、溶剂化物、前药和药物组合物及用途。
背景技术
阿尔兹海默症(Alzheimer’s disease,AD)严重影响老年群体生活质量，对社会和家庭有着沉重的压力。随着老龄化程度的加深，迫切需要有效的治疗手段实现对AD患者的症状改善。
阿尔兹海默症的主要病理特征是大脑中β淀粉样蛋白(Aβ)聚集形成的老年斑、过度磷酸化的tau蛋白聚集而成的神经元纤维缠结、长期炎症反应以及神经元死亡等。
目前，AD治疗策略分为药物治疗和非药物治疗(如认知干预、康复训练)。用于AD治疗的药物包含乙酰胆碱酯酶抑制剂(AChEI)，如他克林(tacrine)、石杉碱甲(HuperzineA)、加兰他敏(galantamine)和卡巴拉汀(rivastigmine)；和 NMDA受体拮抗剂，如多奈哌齐(donepezil)。乙酰胆碱酯酶(AChE)是存在于人体突触间隙内一类重要的水解酶，主要功能是水解神经突触部位的乙酰胆碱终止神经冲动的传导。AChEI通过抑制中枢胆碱酯酶从而增加突触间隙中乙酰胆碱含量，增强胆碱神经功能，改善认知功能。除此之外，有机磷毒剂能和AChE活性位点关键的丝氨酸羟基反应形成稳定的磷酯键，使AChE长时间丧失催化水解活性，阻断乙酰胆碱的水解失活，由于乙酰胆碱在突触后膜的持续累积，将会过度刺激胆碱受体，最终引起肌肉痉挛、呼吸抑制、癫痫发作以至死亡等中毒症状。可逆的AChE抑制剂可占据酶活性位点，使有机磷毒剂无法发挥作用，从而预防有机磷毒剂中毒。
因此研究新型AChEI对开发AD治疗药物或有机磷毒剂中毒预防药具有重要意义。
发明内容
本发明的目的是提供一种N-取代喹啉-4-胺类化合物及其应用，涉及其作为药物的应用，是一类全新结构的乙酰胆碱酯酶可逆抑制剂，具有N-取代喹啉-4- 胺的基本结构，具有抑制乙酰胆碱酯酶活性的能力，特别是作为治疗阿尔兹海默症和预防有机磷毒剂中毒的解毒药物的应用。
为了实现上述目的，本发明采用的技术方案是：
一种N-取代喹啉-4-胺类化合物，其特征在于，该化合物的结构式如(Ⅰ)所示：
其中，R1,R2为H、卤素、C1～C3烷基、胺基、羟基、C1～C3烷基取代羟基、氰基、酰胺基或N-C1～C3烷基取代酰胺基；
R3为C1～C3烷基、羟甲基、哌嗪、N-甲基哌嗪、哌啶、四氢吡咯、苯基、取代苯基、吡啶基或其它芳香杂环集团；
X为C原子或N原子；
其喹啉母核部分还可为吡啶或吡啶并氮杂环等芳香基团。
所述的结构如式(Ⅰ)的化合物具有下面结构。
一种N-取代喹啉-4-胺类化合物的制备方法，其特征在于，反应方程如下：
包括以下步骤：
4-氯-6,7二取代喹啉(II)与取代仲胺(III)在极性溶剂和酸性条件下，加热发生取代反应，然后通过冷却析晶或柱层析等方法，得到相应的N- 取代喹啉-4-胺类化合物(I)；
成分(II)与成分(III)的摩尔比为0.4～1.0，优选为0.8～0.9；反应中使用的酸为盐酸、硫酸、甲磺酸，三氟甲磺酸，对甲苯磺酸等，优选盐酸，使用酸的量为成分(II)摩尔量的5％-25％，优选为成分(II)摩尔量的10％-15％；反应溶剂为甲醇、乙醇、乙腈、四氢呋喃、DMF，DMSO等极性质子或非质子溶剂，优选乙醇或70％-95％的乙醇；反应多在常压下进行，无需进行无水无氧操作，反应温度一般为20℃-200℃，优选65℃-90℃；反应若使用乙醇或乙醇-水溶液做溶剂，反应过程中或反应结束后自然降温，析出产品，通过抽滤即得到较纯产品，进一步重结晶得到纯度更高产品；部分反应产品不能通过降温析出，通过柱层析方法进行获得高纯度产品。
所述的结构式为(Ⅰ)的一类化合物还可以是其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂化物、前药或药物组合物。
所述的结构式为(Ⅰ)的一类化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂化物、前药或药物组合物应用于一种药物。
所述的结构式为(Ⅰ)的一类化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂化物、前药或药物组合物应用于药物可以作为抑制乙酰胆碱酯酶抑制剂；应用于制备治疗阿尔兹海默病的药物；应用于制备预防有机磷类毒剂中毒的解毒剂。
本发明还涉及一种包含至少一种本发明化合物的药物，其优选的还一起包含一种或多种药理学可接受的赋形剂或载体，并且还涉及其用于上述目的的应用。这里的药用载体包括但不限于：离子交换剂，氧化铝，硬脂酸铝，卵磷脂，血清蛋白如人血白蛋白，缓冲物质如磷酸盐，甘油，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶态氧化硅，三硅酸镁，聚乙烯吡咯烷酮，纤维素物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜂蜡，羊毛脂。
该活性成分首选肌肉或静脉注射给药，其次包括口服或者胃肠外、肺、鼻、舌下、舌、颊、直肠、经皮、结膜、局部给药或以植入物的形式给药。
该活性成分还可以适于这些给药途径的给药形式进行给药。
适于口服给药的有可以迅速和/或以改变的方式传递活性成分的公知的给药形式，如片剂(未包衣片或包衣片)、缓控释剂型、胶囊、糖衣片、颗粒、小药丸、粉剂、乳剂、混悬液、气雾剂等口服剂型。
采用胃肠外给药可能可避免吸收步骤(静脉内、动脉内、心内、脊柱内或腰髓内给药)或者包含吸收(肌内、皮下、皮内、经皮或腹膜内给药)。适于胃肠外给药的给药形式特别是用于注射和输入的溶液、混悬液、乳剂、冷冻干燥物和无菌粉末形式等制剂。
适于其他给药途径的如吸入(特别是粉末吸入、喷雾)的药物、鼻滴剂/溶液、喷雾剂等剂型；用于舌、舌下或颊给药的片剂或胶囊、栓剂等剂型；用于耳朵和眼睛的制剂；用于皮肤的贴剂等；阴道胶囊、阴道栓剂、水性混悬液(洗剂、振摇混合物)、亲脂性混悬液、软膏、乳膏、乳液、糊剂、撒粉或植入物。
可以用本身已知的方法将该活性成分转化成所述的给药形式。其可以用惰性无毒的适宜药用赋形剂来实现。其特别是包括载体(例如微晶纤维素)、溶剂(例如液体聚乙二醇)、乳化剂(例如十二烷基硫酸钠)、分散剂(例如聚乙烯吡咯烷酮)、合成和天然生物聚合物(例如蛋白质)、稳定剂(例如抗氧剂和抗坏血酸)、着色剂(例如无机颜料如氧化铁)或矫味剂和/或掩味剂。在适宜的情况中，所说的活性成分可以以微囊包封的形式存在于一种或多种上述载体中。
除本发明式Ⅰ化合物外，上述药物制剂还可以包含其他药物活性成分的组合物。
英文缩写与其中文全称对照
具体实施方式
关于制备通式(Ⅰ)化合物更详尽的资料见实施例，但下面的实施例仅是本发明优选的说明性方案，对本发明不构成任何限制。
1、7-氯-4-(4-(吡啶-4-基)哌嗪-1-基)喹啉
25mL圆底瓶中加入4,7-二氯喹啉0.80g(L1,4.0mmol),1-(吡啶-4-基)哌嗪0.69g(L63,4.2mmol)，乙醇15mL，再加入浓盐酸(0.4mL)，油浴升温，回流8h，析出沉淀，自然冷却至室温，抽滤，5mL乙醇洗，真空干燥，得白色固体1，称重0.61g，收率47％。1H NMR(400MHz,DMSO)δ8.75(d,J＝4.8Hz,1H), 8.22(d,J＝4.9Hz,2H),8.13(d,J＝9.0Hz,1H),8.02(s,1H),7.60(d,J＝8.9Hz, 1H),7.08(d,J＝4.8Hz,1H),6.92(d,J＝5.0Hz,2H),3.62(s,4H),3.31(s,4H).13C NMR(101MHz,DMSO)δ156.17,154.60,152.16,149.59,149.31,133.85,127.70, 126.14,125.98,121.22,109.47,108.46,51.09,45.26.MS(ESI+)m/z(％):325.1[M+H]+.
2、4-(4-(7-氯喹啉-4-基)哌嗪-1-基)苯酚
25mL圆底瓶中加入4,7-二氯喹啉0.40g(L1,2.0mmol),4-(哌嗪-1-基)苯酚 0.45g(L81,2.5mmol)，乙醇10mL，再加入浓盐酸(0.3mL)，油浴升温，回流 12h，自然冷却至室温，未析出沉淀，反应液直接拌样，柱层析(DCM：MeOH＝30:1， v/v)，得棕灰色固体2，称重0.16g，收率24％。1H NMR(400MHz,DMSO)δ8.94 (s,1H),8.74(d,J＝4.9Hz,1H),8.08(d,J＝9.0Hz,1H),8.01(s,1H),7.57(dd,J＝ 8.9,1.0Hz,1H),7.04(d,J＝5.0Hz,1H),6.88(d,J＝8.6Hz,2H),6.72(d,J＝8.6 Hz,2H),3.36-3.26(m,4H),3.25-3.19(m,4H).13C NMR(101MHz,DMSO)δ156.21, 152.13,151.23,149.57,143.89,133.60,128.04,126.01,125.78,121.34,118.02, 115.53,109.44,51.85.MS(ESI+)m/z(％):340.1[M+H]+.
3、7-氯-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)喹啉
25mL圆底瓶中加入4,7-二氯喹啉0.40g(L1,2.0mmol),1-甲基-4-(哌啶-4-基)哌嗪0.39g(L97,2.1mmol)，乙醇9mL，再加入浓盐酸(0.3mL)，油浴升温，回流8h，析出少量沉淀，自然冷却至室温，抽滤，滤液直接拌样，柱层析(DCM：MeOH＝25:1，v/v)，得白色固体3，称重0.19g，收率27％。1H NMR(400MHz, DMSO)δ8.66(d,J＝4.1Hz,1H),8.03(d,J＝8.8Hz,1H),7.98(s,1H),7.59(d,J＝ 8.4Hz,1H),7.03(d,J＝4.1Hz,1H),3.72-3.53(d,J＝10.9Hz,2H),3.12-2.96(m, 4H),2.95-2.76(m,6H),2.74-2.65(m,1H),2.63(s,3H),2.11-1.97(m,2H),1.87-1.65 (m,2H).13C NMR(101MHz,DMSO)δ156.76,151.85,148.92,133.92,127.21, 126.16,125.75,121.24,109.27,60.38,52.90,51.05,46.34,43.00,27.31.MS(ESI+) m/z(％):345.2[M+H]+.
4、7-甲氧基-4-(4-甲基哌嗪-1-基)哌啶-1-基)喹啉-6-甲酰胺
25mL圆底瓶中加入4-氯-7-甲氧基喹啉-6-甲酰胺0.24g(L3,1.0mmol),1-甲基-4-(哌啶-4-基)哌嗪0.19g(L97,1.0mmol)，乙醇5mL，再加入浓盐酸0.2mL，油浴升温，回流12h，自然冷却至室温，反应液直接拌样，柱层析(DCM：MeOH＝20:1，v/v)，得白色固体5，称重0.23g，收率60％。1H NMR(400MHz,DMSO)δ8.61(d,J＝5.0Hz,1H),8.41(s,1H),7.81(s,1H),7.68(s,1H),7.40(s,1H),6.85 (d,J＝5.1Hz,1H),3.99(s,3H),3.57(d,J＝11.9Hz,2H),2.83(t,J＝11.6Hz,2H), 2.71-2.52(m,4H),2.48-2.21(m,5H),2.15(s,3H),1.94(d,J＝11.1Hz,2H), 1.79-1.56(m,2H).13C NMR(101MHz,DMSO)δ166.24,157.32,156.96,152.44,151.34,127.50,122.68,116.54,107.95,107.65,60.69,55.98,54.59,51.48,48.25,45.36,27.84.MS(ESI+)m/z(％):384.2[M+H]+.
5、5-氯-1-(1-(7-氯喹啉-4-基)哌啶-4-基)-1H-苯并咪唑-2(3H)-酮
10mL圆底瓶中加入4,7-二氯喹啉0.20g(L1,1.0mmol),5-氯-1-(哌啶-4-基) -1H-苯并[d]咪唑-2(3H)-酮0.27g(L97,1.1mmol)，DMSO 3mL，油浴升温， 105℃搅拌6h，油浴中自然降至室温，依次加入浓盐酸0.3mL和EA 9mL，析出沉淀，抽滤，5mL EA洗，真空干燥，得浅黄色固体6，称重0.15g，收率36％。1H NMR(400MHz,DMSO)δ11.18(s,1H),8.71(d,J＝6.9Hz,1H),8.24(d,J＝9.1 Hz,1H),8.08(d,J＝1.6Hz,1H),7.80–7.66(m,1H),7.36(d,J＝8.4Hz,1H),7.29 (d,J＝7.1Hz,1H),7.14–7.01(m,2H),4.65(t,J＝11.8Hz,1H),4.23(d,J＝12.6Hz,2H),3.57(t,J＝12.6Hz,2H),2.75–2.55(m,2H),1.93(d,J＝11.0Hz,2H).13C NMR(101MHz,DMSO)δ160.39,153.63,142.05,139.97,137.95,129.24,128.83, 128.01,126.45,125.12,120.20,119.13,117.51,109.88,108.86,105.91,51.24,49.34, 28.42.MS(ESI+)m/z(％):413.1[M+H]+.
6、7-氯-4-(4-甲基哌嗪-1-基)喹啉
25mL圆底瓶中加入4,7-二氯喹啉0.40g(L1,2.0mmol),N-甲基哌嗪0.20g (R1-4,2.0mmol)，乙醇8mL，再加入浓盐酸0.3mL，油浴升温，回流12h，析出沉淀，自然冷却至室温，抽滤，5mL乙醇洗，真空干燥，得白色固体8，称重0.46g，收率88％。1H NMR(400MHz,DMSO)δ12.03(s,1H),8.86(d,J＝6.6 Hz,1H),8.37(s,1H),8.23(d,J＝9.1Hz,1H),7.75(d,J＝8.9Hz,1H),7.38(d,J＝ 6.6Hz,1H),4.43-4.16(m,2H),4.08-3.81(m,2H),3.68-3.49(m,2H),3.46-3.20(m, 2H),2.84(s,3H).13C NMR(101MHz,DMSO)δ160.42,143.27,139.85,138.19, 128.23,127.33,119.61,118.06,107.32,51.64,48.19,42.15.MS(ESI+)m/z(％):262.1[M+H]+.
7、7-甲氧基-4-(4-甲基哌嗪-1-基)喹啉-6-甲酰胺
25mL圆底瓶中加入4-氯-7-甲氧基喹啉-6-甲酰胺0.24g(L3,1.0mmol),N-甲基哌嗪0.11g(R1-4,1.1mmol)，乙醇5mL，再加入浓盐酸0.2mL，油浴升温，回流12h，析出沉淀，自然冷却至室温，抽滤，3mL乙醇洗，真空干燥，得白色固体10，称重0.27g，收率90％。1H NMR(400MHz,DMSO)δ15.92–14.70(m, 1H),11.95(s,1H),8.75(d,J＝6.7Hz,1H),8.40(s,1H),7.98(s,1H),7.88(s,1H), 7.73(s,1H),7.27(d,J＝6.7Hz,1H),4.50-4.15(m,2H),4.02(s,3H),3.98-3.76(m, 2H),3.72-3.51(m,2H),3.41–3.29(m,2H),2.85(s,3H).13C NMR(101MHz, DMSO)δ164.84,160.40,159.95,142.64,142.44,128.57,125.19,113.03,106.05, 100.28,56.60,51.42,48.14,41.79.MS(ESI+)m/z(％):301.2[M+H]+.
8、N’-(7-氯喹啉-4-基)异烟碱酰肼
25mL圆底瓶中加入4,7-二氯喹啉0.40g(L1,2.0mmol),异烟肼0.28g(L89,2.0mmol)，乙醇10mL，再加入浓盐酸0.3mL，油浴升温，回流7h，析出沉淀，自然冷却至室温，抽滤，5mL乙醇洗，真空干燥，得白色固体11，称重0.57 g，收率95％。1H NMR(400MHz,DMSO)δ9.04(d,J＝6.3Hz,2H),8.76-8.56(m, 2H),8.31(d,J＝6.3Hz,2H),8.17(d,J＝1.8Hz,1H),7.91(dd,J＝9.1,1.9Hz,1H), 7.17(d,J＝7.0Hz,1H).13C NMR(101MHz,DMSO)δ163.44,156.29,146.48, 143.78,142.85,138.95,138.23,128.04,125.22,123.71,119.32,113.52,99.34.MS (ESI+)m/z(％):299.1[M+H]+.
9、7-甲氧基-4-(4-甲基哌嗪-1-基)氨基)喹啉-6-甲酰胺
10mL圆底瓶中加入4-氯-7-甲氧基喹啉-6-甲酰胺0.24g(L3,1.0mmol),4-甲基哌嗪-1-胺0.12g(L90,1.1mmol)，乙醇5mL，再加入浓盐酸0.2mL，油浴升温，回流12h，析出沉淀，自然冷却至室温，抽滤，3mL乙醇洗，真空干燥，得白色固体14，称重0.20g，收率64％。1HNMR(400MHz,DMSO)δ15.29–14.08(m, 1H),12.25–11.27(m,1H),10.82(s,1H),8.81(s,1H),8.57(d,J＝6.7Hz,1H),7.86 (d,J＝11.5Hz,2H),7.62(s,1H),7.18(d,J＝6.6Hz,1H),4.00(s,3H),3.78-3.47(m, 2H),3.43-3.25(m,4H),3.24-3.01(m,2H),2.79(s,3H).13C NMR(101MHz,DMSO)δ165.32,159.93,154.76,142.70,140.78,126.00,125.69,108.20,99.72,98.26, 56.42,52.35,50.46,42.04.MS(ESI+)m/z(％):316.2[M+H]+.
依据实施例1--实施例9的相似方法，目前化合物如下：
实施例10：化合物对AChE抑酶能力的测试。
1、实验目的
评价本发明化合物对乙酰胆碱酯酶(AChE)的抑制能力。
2、实验材料
碘化硫代乙酰胆碱(acetylthiocholine iodine,ATCh)，5,5’-二硫双(2-硝基苯甲酸)(5,5’-Dithiobis(2-nitrobenzonic acid),DTNB)和hAChE(来源于人红细胞)。离心机(SIGMA 3-18K)，酶标仪(Bio Rad Microplate Reader Model 550)，天平(METTLERTOLEDO)，恒温箱(Blue-part,上海恒科)，排枪(BIOHIT)，96孔板。
3、实验试剂准备方法
3.1不同pH值缓冲液配制方法：
A液：0.2M NaH2PO4,NaH2PO4·2H2O(M.W.156.01)31.202g加1000mL蒸馏水；
B液：0.2M Na2HPO4,Na2HPO4·12H2O(M.W.358.14)71.628g加1000mL 蒸馏水；
pH＝7.0PBS缓冲液：A液39mL加B液61mL加蒸馏水100mL。
pH＝7.4PBS缓冲液：A液19mL加B液81mL加蒸馏水100mL。
3.2DTNB配制方法
29.7mg/100mL pH＝7.0PBS缓冲液溶解，浓度0.75mM，0-4℃保存，当天即用。
3.3ATCh配制方法
8.7mg/10mL pH＝7.4PBS缓冲液溶解，浓度3mM，0-4℃保存，当天即用。。
3.4酶的前处理
hAChE(sigma)，用PBS(pH＝7.4,0.1％BSA)稀释至相应浓度，0-4℃保存，当天即用。
3.5药物的溶解和稀释
称取相应质量的药物(例如药物分子量为500，则称取药物5mg)，用1mL 70％甲醇溶液溶解得浓度为1*10-2M浓度的药物。药物的稀释：吸取上述药物溶液50μL至96孔板中，每个药物两孔，115μL PBS缓冲液稀释，得浓度为3*10-3 M的药物溶液，再吸取上述药物溶液15μL，加135μL PBS缓冲液稀释，得浓度为3*10-4M的药物溶液。溶剂对照组依照相同的方法将溶解液稀释。经测试，溶剂对照对实验结果没有影响。
4、化合物抑酶率的测试
4.1、活性测试原理
活性测试采用的是微量DTNB法。ATCh是ACh的类似物，可以被AChE催化水解生成乙酸和碘化硫代胆碱(TCh)(见反应A)，TCh可以同 DTNB快速定量反应生成黄色阴离子5-硫基-2-硝基苯甲酸(RS-)(反应B)，后者在405,412,415nm等波长处有最大吸收，可通过测量生成RS-吸光度(OD值)对生成的TCh定量，从而计算出AChE的活性。
对于一般的的酶促反应如下式：
E表示酶，S表示底物，ES是酶-底物络合物，P是产物，k表示相关的正负反应速率常数。
因进行实验所用酶的浓度远小于底物浓度，即[ES]<<[S]，可以近似认为[ES] 是恒定的，于是有公式3-1：
用[E]0表示酶的起始浓度，则[E]0＝[E]+[ES]，即[E]＝[E]0-[ES]，将其带入公
式3-1可得公式3-2，如下所示：
因为中间体ES浓度很小，可近似认为底物的消耗浓度等于产物的生成浓度，即-d[S]/dt＝d[P]/dt。因此产物的生成速率可表示为公式3-3：
将3-2带入3-3，对于如下反应式得到的反应A，
[H2O]可认为恒定不变，其k-2＝0，于是得到公式3-4：
令KM＝(k-1+k2)/k1，KM为Michaelis常量，于是得到公式3-5：
通过公式3-5可以看出，反应速率只和底物浓度有关，若底物浓度很大，可认为反应在开始的一段时间内底物浓度不变，因此反应速率也就是恒定的，如果测得固定反应时间点产物浓度，即能以此按正比例推算反应速率，也就是酶的催化活性。而反应B中，经AChE催化所得产物TCh和DTNB的显色反应是瞬间定量完成的，最终所测的OD值正比于RS-浓度，即正比于催化水解产物TCh浓度，因此可通过测量显色物质RS-的OD值来反映酶活性。本实验选用的底物浓度(ATCh,3.0mM)经预实验证明完全满足以上条件，在酶促反应开始后50min内，经测试OD值同反应时间成正比例关系，因此酶促反应开始后固定时间点(如30min)显色测得的OD值即可用于衡量AChE活性。
4.2、抑酶率的测试
本实验首先将不同药物与AChE孵温，再加入ATCh反应，最后加入DTNB 显色，通过与正常AChE测试结果进行比对，计算酶活性率，进而计算出抑酶率。通过测定多个浓度(1000,500,100,20，2,0.2μM)的抑酶率，计算出IC50值。
a)酶的稀释：将AChE原液(20U/mL)用PBS(0.1M，PH＝7.4，0.1％BSA)稀释2000倍，0-4℃保存。
b)抑酶：取上述酶的稀释液20μL加入相应浓度药物20μL中(96孔板中操作，药物终浓度1000,500,200,100，50,10μM)，25℃抑酶15min。阳性对照为20μLPBS缓冲液代替相应浓度药物。
c)反应：常温下30μL ATCh(3.0mM,pH＝8.0PBS,0.1％BSA)加入上述酶中，反应30min。
d)显色：加入10μL HCl(0.1M)和150μL DTNB(0.75mM,0.1MPBS,pH 7.0)，离心1min除去气泡，5min内用酶标仪测412nM处的OD值。
抑酶率计算方法：％Activity＝(S-B)*100/(P-B).S＝抑酶组OD值.P＝正常组OD值，B＝PBS空白组OD值(溶剂本底值)。抑酶率：％Inhibition＝1-％ Activity。
IC50计算方法(采用以下公式对不同浓度的抑酶率进行非线性拟合，计算IC50值)：％Activity＝100*IC50/(IC50+[Ox])
表1：依据实施例已合成化合物对hAChE的IC50(μM)
微量DTNB法的反应原理
一般酶促反应机理
Claims (10)
1.一种N-取代喹啉-4-胺类化合物，其特征在于，该化合物的结构式如(Ⅰ)所示：
其中，R1,R2为H、卤素、C1～C3烷基、胺基、羟基、C1～C3烷基取代羟基、氰基、酰胺基或N-C1～C3烷基取代酰胺基；
R3为C1～C3烷基、羟甲基、哌嗪、N-甲基哌嗪、哌啶、四氢吡咯、苯基、取代苯基、吡啶基或其它芳香杂环集团；
X为C原子或N原子；
其喹啉母核部分还可为吡啶或吡啶并氮杂环等芳香基团。
2.根据权利要求1所述的一种N-取代喹啉-4-胺类化合物、或其在药物学上可接受的盐、异构体、溶剂化物、前药和药物组合物，其中所述化合物选自以下：
3.一种如权利要求1所述的N-取代喹啉-4-胺类化合物的制备方法，反应方程如下：
包括步骤：
4-氯-6,7二取代喹啉(II)与取代仲胺(III)在极性溶剂和酸性条件下，加热发生取代反应，然后通过冷却析晶或柱层析等方法，得到相应的N-取代喹啉-4-胺类化合物(I)；
成分(II)与成分(III)的摩尔比为0.4～1.0，优选为0.8～0.9；反应中使用的酸为盐酸、硫酸、甲磺酸，三氟甲磺酸，对甲苯磺酸等，优选盐酸，使用酸的量为成分(II)摩尔量的5％-25％，优选为成分(II)摩尔量的10％-15％；反应溶剂为甲醇、乙醇、乙腈、四氢呋喃、DMF，DMSO等极性质子或非质子溶剂，优选乙醇或70％-95％的乙醇；反应多在常压下进行，无需进行无水无氧操作，反应温度一般为20℃-200℃，优选65℃-90℃；
反应若使用乙醇或乙醇-水溶液做溶剂，反应过程中或反应结束后自然降温，析出产品，通过抽滤即得到较纯产品，进一步重结晶得到纯度更高产品；部分反应产品不能通过降温析出，通过柱层析方法进行获得高纯度产品。
4.根据权利要求1所述的一种N-取代喹啉-4-胺类化合物，其特征在于，所述的结构式为(Ⅰ)的一类化合物包括：治疗有效量的一种或多种权利要求1所述通式(Ⅰ)所示化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂化物、前药或药物组合物。
5.根据权利要求4所述的一种N-取代喹啉-4-胺类化合物，其特征在于，所述的结构式为(Ⅰ)的一类化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂化物、前药或药物组合物应用于一种药物。
6.根据权利要求4所述的一种N-取代喹啉-4-胺类化合物，其特征在于，所述的结构式为(Ⅰ)的一类化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂化物、前药或药物组合物作为乙酰胆碱酯酶抑制剂；
7.根据权利要求4所述的一种N-取代喹啉-4-胺类化合物，其特征在于，所述的结构式为(Ⅰ)的一类化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂化物、前药或药物组合物应用于制备治疗阿尔兹海默病的药物；
8.根据权利要求4所述的一种N-取代喹啉-4-胺类化合物，其特征在于，所述的结构式为(Ⅰ)的一类化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂化物、前药或药物组合物应用于制备预防有机磷类毒剂中毒的解毒剂。
9.根据权利要求4所述的一种N-取代喹啉-4-胺类化合物，其特征在于，所述的一种药物包括赋形剂或载体。
10.根据权利要求4所述的一种N-取代喹啉-4-胺类化合物，其特征在于，所述的载体包括离子交换剂，氧化铝，硬脂酸铝，卵磷脂，血清蛋白如人血白蛋白，缓冲物质如磷酸盐，甘油，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶态氧化硅，三硅酸镁，聚乙烯吡咯烷酮，纤维素物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜂蜡，羊毛脂。
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