CN113683535B - 含氰胍结构的化合物及其制备方法与用途 - Google Patents

含氰胍结构的化合物及其制备方法与用途 Download PDF

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CN113683535B
CN113683535B CN202010417152.7A CN202010417152A CN113683535B CN 113683535 B CN113683535 B CN 113683535B CN 202010417152 A CN202010417152 A CN 202010417152A CN 113683535 B CN113683535 B CN 113683535B
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徐云根
朱启华
朱良瀚
崔芷莹
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Abstract

本发明公开了含氰胍结构的化合物及其制备方法与用途。本发明还公开了含有所述氰胍结构的化合物(I)或其药学上可接受的盐及药学上可接受的载体的组合物、及其在制备镇痛药物中的应用。本发明的化合物可用于治疗各种疼痛。

Description

含氰胍结构的化合物及其制备方法与用途
技术领域
本发明属于药物化学领域，具体涉及含氰胍结构的化合物及其制备方法与用途。
背景技术
疼痛已被现代医学列为继体温、脉搏、呼吸、血压之后的第五大生命体征。疼痛如不及时有效处理，将严重影响日常的生活质量和社会安定。尽管镇痛药的研究有了长足的进步，但无论是用于轻、中度疼痛的非甾体解热镇痛抗炎药，还是用于中、重度疼痛的止痛剂，都有着各自的副作用和局限性，有的还面临潜在的滥用问题。
治疗和缓解疼痛的主流药物是μ-阿片受体激动剂，长期使用μ-阿片受体激动剂会诱导其表达的下调和反馈调节机制，从而产生耐受性。但是，过度服用μ-阿片受体激动剂会产生一系列阿片样副作用(Opioidinduced adverse effects,OIAEs)，如成瘾、呼吸抑制、便秘等，从而影响了μ-阿片受体激动剂的广泛使用。因此，寻找安全、有效、副作用小的镇痛和抗炎药物具有重大的现实意义和社会意义。
现阶段阿片受体激动剂的研究方向主要集中在消除或者减轻阿片样副作用方面。研究发现，在μ-阿片受到配体结合并激活过程中，GPCR磷酸激酶使得GPCR磷酸化，随后激活β-arrestin 2通路，而β-arrestin 2是G蛋白偶联受体信号通路中关键的负调节蛋白，它介导了受体脱敏和内吞，β-arrestin2通路是介导阿片样副作用的主要原因。因此，开发偏向性μ-阿片受体激动剂(选择性不激活β-arrestin2通路)是目前寻找无阿片样副作用镇痛药的重要研究方向。
发明内容
发明目的：本发明公开了一类含有氰胍结构的化合物，并提供了该类化合物的具体制备方法以及作为镇痛药物的制药应用。
技术方案：本发明公开了一类如通式(I)所示的氰胍类衍生物或其药学上可接受的盐：
Figure BDA0002495444360000021
其中：
R1、R2、R3、R4各自独立地代表H、卤素、CN、NO2、C1～C6烷基、OH、C1～C6烷氧基、OCF3、NH2、NHCOCH3或C1～C6烷氨基；
R5代表Ar-、
Figure BDA0002495444360000022
其中Ar代表任意取代的苯环、任意取代的萘环、任意取代的芳杂环、任意取代的苯环并芳杂环、任意取代的芳杂环并芳杂环，n代表0或1，X代表CH2或CHCH3，所述的取代基是H、卤素、CN、NO2、CH3、OH、OCH3、OCF3、NH2或NHCOCH3。
R1、R3、R4优选代表H，R2优选代表H或OH。
R5优选代表
Figure BDA0002495444360000023
Figure BDA0002495444360000024
其中R6代表H、卤素、CN、NO2、CH3、OH、OCH3、OCF3、NH2或NHCOCH3，R6可以是单取代或双取代；Y1、Y2、Y3、Y4各自独立地代表N或C-R7，R7代表H、卤素、CH3、CF3、OH、OCH3、OCF3或CN；Z代表O、S或N-R8，R8代表H、C1～C3烷基；R5进一步代表
Figure BDA0002495444360000025
Figure BDA0002495444360000026
其中Y5、Y6各自独立地代表N或CH、C-OCH3；Z2代表O、S或NH；R5更进一步优选代表
Figure BDA0002495444360000027
Figure BDA0002495444360000028
Figure BDA0002495444360000031
在本发明的一些实施例中，R1、R3、R4代表H，R2代表H或OH，R5代表Ar-、
Figure BDA0002495444360000032
其中Ar代表任意取代的苯环、萘环、呋喃、吡咯、噻吩、吡啶、吡唑、咪唑，所述的取代基是H、F、OCH3，n代表0或1，X代表CH2或CHCH3。
在本发明的一些实施例中，R1、R3、R4代表H，R2代表H或OH，R5代表
Figure BDA0002495444360000033
Figure BDA0002495444360000034
在本发明的一些实施例中，R1、R3、R4代表H，R2代表H或OH，R5代表
Figure BDA0002495444360000035
更优选地，本发明所述氰胍类衍生物选自以下化合物：
Figure BDA0002495444360000036
Figure BDA0002495444360000041
上述化合物的药学上可接受的盐为通式(I)化合物的酸加成盐，其中用于成盐的酸为：氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
本发明通式(I)的化合物可用下列方法制备：
Figure BDA0002495444360000051
其中R1、R2、R3、R4、R5的定义同前。
由化合物II与化合物III反应制备化合物I的过程，所用溶剂为甲醇、乙醇、异丙醇、叔丁醇、2-甲氧基乙醇、四氢呋喃、乙腈或任意两者的混合溶剂。
化合物(II)可用下列方法制备：
Figure BDA0002495444360000052
其中R1、R2、R3、R4的定义同前。
由化合物IV与甲醇经酯化制备化合物V的过程，所用催化剂为浓硫酸、甲烷磺酸、氯化亚砜或草酰氯，优选氯化亚砜；溶剂为甲醇或甲苯，优选甲醇。
由化合物V与NH3经胺解反应制备化合物VI的过程，所用氨试剂为氨气或浓氨水；所用溶剂为四氢呋喃、乙腈、二氯甲烷、1,4二氧六环或浓氨水。
由化合物VI与甲醛经还原胺化反应制备化合物VII的过程，所用甲醛试剂为多聚甲醛或37％甲醛水溶液，优选37％甲醛水溶液；所用还原剂为三乙酰氧基硼氢化钠、氰基硼氢化钠、硼氢化钠或硼氢化钾，优选三乙酰氧基硼氢化钠；所用溶剂为四氢呋喃、乙腈、乙醇或任意两者的混合溶剂，优选乙腈。
由化合物VII经还原反应制备化合物II的过程，所用还原剂为氢化铝锂、硼氢化钠/路易斯酸或硼氢化钾/路易斯酸，其中路易斯酸为三氯化铝或氯化锌；所用溶剂为四氢呋喃、乙腈、乙醇、甲醇、N,N-二甲基甲酰胺或任意两者的混合溶剂，优选四氢呋喃。
化合物(III)可用下列方法制备：
Figure BDA0002495444360000061
其中R5的定义同前。
由化合物VIII与化合物IX反应制备化合物III的过程，所用溶剂为乙醇、甲醇、乙腈、四氢呋喃或任意两者的混合溶剂。
本发明还公开了一种药物组合物，其含有上述通式(I)化合物或其药学上可接受的盐及药学上可接受的载体。所述的化合物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、糖浆、悬浮剂、注射剂，可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本发明所述的通式(I)化合物及其立体异构体、水合物、溶剂合物或结晶在制备镇痛药物中的应用也在本发明的保护范围内。
有益效果：本发明公开了一种通式(I)所示的氰胍类衍生物，药理实验结果显示，本发明的化合物(I)可以产生的镇痛作用，可用于制备治疗各种疼痛的药物；本发明还公开了所述氰胍类衍生物的制备方法。
具体实施方式
实施例1
(S,E)-2-氰基-1-(2-(二甲基氨基)-3-苯基丙基)-3-苯乙基胍(I-1)的制备
L-苯丙氨酸甲酯(V-1)
向250mL三颈瓶中依次加入L-苯丙氨酸(IV-1,10g,605mmol)和100mL无水甲醇，固体大部分未溶解，冰浴条件下缓慢滴加甲磺酸(10mL,158mmol)，固体逐渐溶解，滴毕，加热回流反应3小时，TLC(二氯甲烷：甲醇＝15:1)监测原料反应完毕。将反应液冷却到室温，减压蒸馏除溶剂，得到无色油状物。冰浴条件下缓慢加入50mL饱和碳酸氢钠水溶液，调节pH至7-8，水层用乙酸乙酯萃取(50mL×3)，合并有机层，饱和氯化钠溶液(100mL)洗涤。无水硫酸钠干燥，抽滤，减压蒸馏除溶剂，真空干燥得到无色油状物10.48g，收率96.6％。1H-NMR(300MHz,DMSO-d6+D2O)δ(ppm):7.21-7.23(m,5H,ArH),3.85-3.95(m,1H,NH2 CH),3.5(s,3H,OCH3 ),3.41(dd,J＝7.8Hz,2H,ArCH2 )。ESI-MS(m/z):202.1[M+Na]+。
(S)-2-氨基-3-苯基丙酰胺(VI-1)
向250mL三颈瓶中依次加入V-1(10.48g,58.5mmol),缓慢滴加饱和氨水(50mL)，油状物逐渐溶于氨水溶液中，伴有缓慢放热现象，室温搅拌6小时，TLC(二氯甲烷：甲醇＝15:1)监测原料反应完毕。反应液用二氯甲烷萃取(50mL×5)，合并有机层，饱和氯化钠溶液(100mL)洗涤。无水硫酸钠干燥，抽滤，减压蒸馏除溶剂，真空干燥得乳白色固体8.5g，收率88.5％，m.p.95-98℃。1H-NMR(300MHz,CDCl3)δ(ppm):7.27-7.38(m,5H,ArH),3.65(dd,J＝4.0,9.5Hz,1H,NCH),3.31(dd,J＝4.0,13.7Hz,1H,ArCH2),2.75(dd,J＝9.5,13.7Hz,1H,ArCH2)。ESI-MS(m/z):187.1[M+Na]+。
(S)-2-二甲基氨基-3-苯基丙酰胺(VII-1)
向250mL三颈瓶中依次加入VI-1(8.5g,51.8mmol)和100mL乙腈，室温搅拌0.5小时，加入37％的甲醛水溶液(10mL,120mmol)，搅拌10分钟后，分批缓慢加入三乙酰氧基硼氢化钠(32.9g,155.4mmol)，加料完毕后室温搅拌6小时，TLC(二氯甲烷：甲醇＝10:1)监测原料反应完毕。抽滤，滤饼用50mL乙腈洗涤，滤液和洗液合并，减压蒸馏除溶剂，粗品用柱层析(二氯甲烷：甲醇＝100:1～50:1梯度洗脱)纯化，得到白色固体5.6g，收率56.3％，m.p.128-132℃。1H-NMR(300MHz,DMSO-d6+D2O)δ(ppm):7.11-7.26(m,5H,ArH),3.14-3.19(m,1H,NH2 CH),2.87-2.94(m,1H,ArCH2 ),2.47-2.50(m,1H,ArCH2 ),2.23(s,6H,N(CH3)2 )。ESI-MS(m/z):215.1[M+Na]+。
(S)-2-二甲氨基-3-苯基丙胺(II-1)
向50mL三颈瓶中依次加入VII-1(0.192g,1mmol)和10mL无水四氢呋喃，冰浴条件下，缓慢分批加入四氢铝锂(0.114g,3mmol)。加料完毕后移除冰浴，室温搅拌3小时，TLC(二氯甲烷：甲醇＝10:1)监测原料反应完毕。加入计算量的水淬灭四氢铝锂，抽滤，滤饼用乙酸乙酯(10mL)洗涤，减压蒸馏除溶剂，得到白色油状物0.15g，收率84.2％，不经后处理直接投下一步反应。
(Z)-N'-氰基-N-苯乙基氨基硫代甲亚氨酸甲酯(III-1)
向100mL三颈瓶中依次加入氰基碳酰亚胺二硫酸酯(IX,2.16g,148mmol)和15mL无水乙醇后，缓慢加入苯乙胺(1.21g,10mmol)，逐渐有白色固体析出，室温反应0.5小时，TLC(二氯甲烷：甲醇＝15:1)监测原料反应完毕。抽滤，滤饼用乙醚洗涤三次(5mL×3)，烘干，得白色固体1.25g，收率57.0％，m.p.176-178℃。1H-NMR(300MHz,DMSO-d6)δ(ppm):8.42(s,1H,NH),7.20-7.34(m,5H,ArH),3.48-3.53(m,2H,NCH2 ),2.84(t,J＝7.5Hz,2H,ArCH2 ),2.53(s,3H,SCH3 )。ESI-MS(m/z):242.1[M+Na]+。
(S,E)-2-氰基-1-(2-(二甲基氨基)-3-苯基丙基)-3-苯乙基胍(I-1)
50mL三颈瓶中，加入II-1(178mg,1.0mmol)、III-1(330mg,1.5mmol)和无水乙醇10mL,氮气保护下加热回流48小时，TLC(二氯甲烷：甲醇＝15:1)监测原料反应完毕。减压蒸馏除去溶剂，柱层析(二氯甲烷：甲醇＝200:1～100:1)纯化，得白色固体105mg，收率30.1％，纯度98.65％，m.p.116-120℃。1H-NMR(300MHz,CDCl3)δ(ppm):7.39-7.08(m,10H,ArH),4.72-4.73(m,1H,NH),3.42(s,1H,NH),2.92-2.97(m,3H,1/2NHCH2 ,NHCH2 ),2.78-2.84(m,3H,1/2NHCH2 ,ArCH2 ),2.40-2.28(m,1H,(CH3)2NCH),2.24(s,6H,N(CH3)2 ),1.18-1.28(m,2H,ArCH2 )；13C-NMR(75MHz,CDCl3)δ(ppm):157.97,138.82,138.61,132.62,128.54,128.33,128.15,128.02,125.80,65.24,41.16,39.88,39.60,35.98,31.03；HR-MS(ESI)m/z[M+H]+Calcd for C21H28N5,350.2372；Found:350.2449。
实施例2
(S,Z)-2-氰基-1-(2-(二甲基氨基)-3-苯基丙基)-3-(2-甲氧基苯基)胍(I-2)的制备
(Z)-N'-氰基-N-(2-甲氧基苯基)氨基硫代甲亚氨酸甲酯(III-2)
以2-甲氧基苯胺(1.23g,10mmol)为原料，操作同III-1，得到白色固体0.85g，收率34.8％，m.p.148-152℃。1H-NMR(300MHz,DMSO-d6)δ(ppm):7.88(s,1H,NH),7.23-7.29(m,2H,ArH),7.02-7.09(m,2H,ArH),3.92(s,3H,OCH3 ),2.60(s,3H,SCH3 )。ESI-MS(m/z):244.1[M+Na]+。
(S,Z)-2-氰基-1-(2-(二甲基氨基)-3-苯基丙基)-3-(2-甲氧基苯基)胍(I-2)
以II-1(178mg,1.0mmol)和III-2(331mg,1.5mmol)为原料，操作同I-1，得到淡黄色固体120mg,收率29.9％，纯度99.56％，m.p.172-175℃。1H-NMR(300MHz,CDCl3)δ(ppm):8.11-7.94(m,1H,ArH),7.37-7.30(m,2H,ArH),7.25-7.14(m,3H,ArH),6.96-6.90(m,2H,ArH),6.90-6.78(m,1H,ArH),5.57(s,1H,NH),3.87(s,3H,OCH3 ),3.44-3.28(m,1H,NCH2 ),3.26–3.31(m,1H,NCH2 ),3.00-3.11(m,1H,NCH),2.89–2.94(m,1H,ArCH2 ),2.72–2.84(m,1H,ArCH2 ),2.31(s,6H,N(CH3)2 ).13C-NMR(75MHz,CDCl3)δ(ppm):137.88,128.79,128.42,128.33,126.41,126.35,126.11,124.59,123.72,120.29,117.35,110.89,65.05,55.17,41.58,39.49,30.88.HR-MS(ESI)m/z[M+H]+Calcd for C20H26N5O,352.2059；Found:352.2137。
实施例3
(S,E)-2-氰基-1-(2-(二甲基氨基)-3-苯基丙基)-3-(4-甲氧基苄基)胍(I-3)的制备
(Z)-N'-氰基-N-(4-甲氧基苄基)氨基硫代甲亚氨酸甲酯(III-3)
以4-甲氧基苄胺(1.37g,10mmol)为原料，操作同III-1，得到白色固体0.98g，收率64.2％，m.p.159-161℃。1H-NMR(300MHz,CDCl3)δ(ppm):7.25(d,J＝8.1Hz,2H,ArH),6.92(d,J＝8.1Hz,2H,ArH),4.49(m,2H,ArCH2 ),3.84(s,3H,OCH3 ),2.53(s,3H,SCH3 )。ESI-MS(m/z):258.1[M+Na]+。
(S,E)-2-氰基-1-(2-(二甲基氨基)-3-苯基丙基)-3-(4-甲氧基苄基)胍(I-3)
以II-1(178mg,1.0mmol)和III-3(345mg,1.5mmol)为原料，操作同I-1，得到乳白色固体75mg,收率20.5％，纯度99.44％，m.p.90-94℃。1H-NMR(300MHz,CDCl3)δ(ppm):7.34-7.29(m,2H,ArH),7.05-7.24(m,5H,ArH),6.84-6.96(m,2H,ArH),4.23-4.25(m,2H,NHCH2 ),3.81(s,3H,OCH3 ),3.02-3.05(m,2H,NHCH2 ),2.87-2.93(m,1H,(CH3)2NCH),2.34-2.58(m,2H,ArCH2 ),2.15(s,6H,N(CH3)2 )。13C-NMR(75MHz,CDCl3)δ(ppm):160.23,158.74,137.84,128.75,128.34,128.20,126.10,125.89,118.38,113.61,64.78,54.85,44.92,39.17,30.63.HR-MS(ESI)m/z[M+H]+Calcd for C21H28N5O,366.2223；Found:366.2295。
实施例4
(S,Z)-2-氰基-1-(2-(二甲基氨基)-3-苯基丙基)-3-苯基胍(I-4)的制备
(Z)-N'-氰基-N-苯基氨基硫代甲亚氨酸甲酯(III-4)
以苯胺(0.93g,10mmol)为原料，操作同III-1，得到白色固体0.64g，收率33.5％，m.p.198-202℃。1H-NMR(300MHz,CDCl3)δ(ppm):7.89(brs,1H,NH),7.23-7.31(m,5H,ArH),2.49(s,3H,SCH3 )。ESI-MS(m/z):214.2[M+Na]+。
(S,Z)-2-氰基-1-(2-(二甲基氨基)-3-苯基丙基)-3-苯基胍(I-4)
以II-1(0.178g,1.0mmol)和III-4(0.286g,1.5mmol)为原料，操作同I-1，得到乳白色固体110mg,收率34.2％，纯度99.64％，m.p.134-138℃。HR-MS(ESI)m/z[M+H]+Calcdfor C19H24N5,322.1953；Found:322.2030。
实施例5
(S,E)-2-氰基-1-(2-(二甲基氨基)-3-苯基丙基)-3-(4-羟基苯乙基)胍(I-5)的制备
(Z)-N'-氰基-N-(4-羟基苯乙基)氨基硫代甲亚氨酸甲酯(III-5)
以对羟基苯乙胺(1.37g,10mmol)为原料，操作同III-1，得到白色固体0.89g，收率37.9％，m.p.180-182℃。1H-NMR(300MHz,CDCl3)δ(ppm):9.22(s,1H,OH),8.39(brs,1H,NH),7.00(d,J＝8.0Hz,2H,ArH),6.69(d,J＝8.0Hz,2H,ArH),3.43(q,J＝6.9Hz,2H,NHCH2 ),2.71(t,J＝7.6Hz,2H,ArCH2 ),2.53(s,3H,SCH3 )。ESI-MS(m/z):258.1[M+Na]+。
(S,E)-2-氰基-1-(2-(二甲基氨基)-3-苯基丙基)-3-(4-羟基苯乙基)胍(I-5)
以II-1(0.178g,1.0mmol)和III-5(0.352g,1.5mmol)为原料，操作同I-1，得到淡黄色固体75mg,收率20.5％，纯度98.98％，m.p.74-76℃。1H-NMR(300MHz,CDCl3)δ(ppm):7.23-7.37(m,3H,ArH),7.14(d,J＝7.4Hz,2H,ArH),7.04(d,J＝8.1Hz,2H,ArH),6.80(d,J＝8.1Hz,2H,ArH),5.76(brs,1H,NH),3.33-3.49(m,2H,NHCH2 CH2),2.99–3.01(m,3H,NHCH2 ,NHCH),2.80-2.98(m,3H,ArCH2 ,1/2ArCH2 ),2.31-2.37(m,1H,1/2ArCH2),2.32(s,6H,N(CH3)2 )。13C-NMR(75MHz,CDCl3)δ(ppm):154.78,137.56,129.22,129.22,128.44,128.20,127.91,126.24,118.22,115.28,42.63,41.78,39.48,33.98,32.38,30.73.HR-MS(ESI)m/z[M+H]+Calcd for C21H28N5O,366.2216；Found:366.2292.
实施例6
(S,E)-2-氰基-1-(2-(二甲基氨基)-3-苯基丙基)-3-(3-甲氧基苯乙基)胍(I-6)的制备
(Z)-N'-氰基-N-(3-甲氧基苯乙基)氨基硫代甲亚氨酸甲酯(III-6)
以间甲氧基苯乙胺(1.51g,10mmol)为原料，操作同III-1，得到白色固体1.26g，收率50.6％，m.p.138-142℃。1H-NMR(300MHz,CDCl3)δ(ppm):8.41(s,1H,NH),7.23(t,J＝7.8Hz,1H,ArH),6.80(m,3H,ArH),3.75(s,3H,OCH3 ),3.50(t,J＝8.7Hz,2H,ArCH2 ),2.81(t,J＝7.4Hz,2H,NHCH2 ),2.51(s,3H,SCH3 )。ESI-MS(m/z):250.1[M+H]+。
(S,E)-2-氰基-1-(2-(二甲基氨基)-3-苯基丙基)-3-(3-甲氧基苯乙基)胍(I-6)
以II-1(0.178g,1.0mmol)和III-6(0.373g,1.5mmol)为原料，操作同I-1，得到淡黄色固体130mg,收率35.5％，纯度99.65％，m.p.130-134℃。1H-NMR(300MHz,DMSO-d6)δ(ppm):7.27-7.32(m,2H,ArH),7.19-7.22(m,5H,ArH),6.57-6.78(d,J＝6.3Hz,2H,ArH),6.49(s,1H,ArH),3.73(s,3H,OCH3 ),3.27-3.54(d,J＝8.1Hz,2H,NHCH2 ),3.19-2.99(m,2H,NHCH2 ),2.81-3.08(d,J＝8.1Hz,2H,ArCH2 ),2.70-2.75(m,2H,ArCH2 ),2.44-2.32(m,1H,(CH3)2NCH),2.25(s,6H,N(CH3)2 ).13C-NMR(75MHz,DMSO-d6)δ(ppm):159.20,155.28,152.37,139.42,136.08,129.19,128.85,128.47,126.81,121.03,114.37,112.13,66.76,63.49,54.96,42.60,40.66,33.46,32.11.HR-MS(ESI)m/z[M+H]+Calcd for C22H30N5O,380.2372；Found:380.2553.
实施例7
(Z)-2-氰基-1-((S)-2-(二甲基氨基)-3-苯基丙基)-3-(1-噻吩-3-基)丙-2-基)胍(I-7)的制备
(E)-3-(2-硝基丙烯基)噻吩(XI-1)
于100mL三颈瓶中，冰浴条件下将甲酸(7.5mL,190mmol)缓慢滴加到乙醇胺(8.5mL,142mmol)中，后缓慢滴加3-噻吩甲醛(X-1 3.9mL,45mmol)，搅拌10分钟后缓慢滴加硝基乙烷(13mL,138mmol),滴加完毕后加热回流反应5小时，溶液由淡黄色变为橙黄色，TLC(石油醚：乙酸乙酯＝4:1)监测原料反应完毕。冷却到室温，冰浴条件下加入50mL冰水混合物，有大量黄色固体析出，搅拌0.5小时后抽滤，滤饼用大量冰水洗涤，滤饼置于红外灯下烘干得到淡黄色固体4.2g。滤液用乙酸乙酯(50mL×3)萃取，合并有机层，饱和氯化钠溶液(100mL×2)洗涤。无水硫酸钠干燥，抽滤，减压蒸除溶剂，得到深黄色固体。固体用石油醚：乙酸乙酯＝100：1打浆两次(5mL×2)，过滤，滤饼用少量相同极性的溶剂洗涤，烘干得到淡黄色固体0.85g，TLC确证两批固体为同一物质，合计5.05g，收率66.4％，m.p.75-78℃。1H-NMR(300MHz,DMSO-d6)δ(ppm):8.13(s,2H,ArH,ArCH＝C),7.72-7.53(m,1H,ArH),7.48(d,J＝4.9Hz,1H,ArH),2.45(s,3H,CCH3 ).ESI-MS(m/z):192.0[M+Na]+。
1-(噻吩-3-基)丙基-2-胺(XII-1)
于250mL三颈瓶中，冰浴条件下加入无水四氢呋喃100mL，分批缓慢加入四氢铝锂(6.831g,180mmol),后缓慢滴入XI-1(5.05g,26.3mmol)的无水四氢呋喃溶液(50mL)，滴加完毕后加热回流0.5小时，溶液由黄色变为浅黄色，TLC(二氯甲烷：甲醇＝15:1)监测原料反应完毕。反应体系冷却至室温，置于冰浴条件下，缓慢滴加计算量(10mL)的蒸馏水(保证体系不剧烈爆沸)以淬灭四氢铝锂。加入20mL乙酸乙酯稀释反应体系，抽滤，滤饼用乙酸乙酯洗涤(50mL×3)。收集滤液，减压蒸除溶剂。后加入50mL乙酸乙酯，10％的稀盐酸50mL(调节pH至1～2)，蒸馏水萃取(50mL×3)，合并水层。冰浴条件下加入10％的NaOH溶液调节pH至9～10，乙酸乙酯萃取(50mL×3)，合并有机层，饱和氯化钠溶液洗涤(100mL×2)。无水硫酸钠干燥，减压蒸除溶剂，得到淡黄色油状物3.2g，收率86.3％，不经进一步处理继续投下一步反应。
(Z)-N'-氰基-N-(1-(噻吩-3-基)丙-2-基)氨基硫代甲亚氨酸甲酯(III-7)
100mL三颈瓶中，加入XII-1(3.2g,22.7mmol)，无水乙醇30mL和氰基碳酰亚胺二硫酸酯(4.91g,34.1mmol),室温搅拌10分钟固体溶解，加热回流6h，TLC(二氯甲烷：甲醇＝15:1)监测原料反应完毕。反应体系冷却至室温，减压蒸馏除溶剂，得到深黄色油状物。加入20mL乙醚和1mL二氯甲烷室温搅拌12h，有大量淡黄色固体生成，抽滤，滤饼用少量乙醚冲洗，红外灯下干燥，得到淡黄色固体2.06g，收率37.9％，m.p.94-97℃。1H-NMR(300MHz,CDCl3)δ(ppm):8.19(d,J＝8.0Hz,1H,NH),7.37(d,J＝4.8Hz,1H,ArH),6.88–6.98(m,2H,ArH),4.14–4.21(m,1H,1/2ArCH2 ),2.98–3.13(m,2H,1/2ArCH2,CHCH3),2.55(s,3H,SCH3 ),1.18(d,J＝6.6Hz,3H,CH3 )。ESI-MS(m/z):262.0[M+Na]+。
(Z)-2-氰基-1-((S)-2-(二甲基氨基)-3-苯基丙基)-3-(1-噻吩-3-基)丙-2-基)胍(I-7)
以II-1(178mg,1.0mmol)和III-7(358mg,1.5mmol)为原料，操作同I-1，得到淡黄色固体130mg,收率35.2％，纯度99.65％，m.p.72-75℃。HR-MS(ESI)m/z[M+H]+Calcd forC20H28N5S,370.1987；Found:370.2066。
实施例8
(S,E)-2-氰基-1-(2-(二甲基氨基)-3-(4-羟基苯基)丙基)-3-苯乙基胍(I-8)的制备L-酪氨酸甲酯(V-2)
以L-酪氨酸(IV-2,10.91g,60.3mmol)为原料，操作同V-1，得到乳白色固体9.41g，收率92.3％，m.p.137-141℃。1H-NMR(300MHz,DMSO-d6+D2O)δ(ppm):6.65-7.00(m,4H,ArH),3.20-3.32(m,1H,NH2 CH),2.62-2.78(dd,J＝7.8Hz,2H,ArCH2 )。ESI-MS(m/z):218.1[M+Na]+。
(S)-2-氨基-3-(4-羟基苯基)丙酰胺(VI-2)
以V-2(9.41g,55.7mmol)为原料，操作同VI-1，得到淡黄色固体7.36g，收率73.4％，m.p.86-89℃。1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):6.99(d,J＝8.1Hz,2H,ArH),6.66(d,J＝7.9Hz,2H,ArH),3.32(t,J＝6.7Hz,1H,NH2 CH),2.77(dd,J＝5.7,7.9Hz,1H,1/2ArCH2 ).2.58(d,J＝7.9Hz,1H,1/2ArCH2 ).ESI-MS(m/z):203.1[M+Na]+。
(S)-2-二甲氨基-3-(4-羟基苯基)丙酰胺(VII-2)
以VI-2(7.63g,40.9mmol)为原料，操作同VII-1，得到淡黄色固体3.81g，收率42.6％，m.p.102-104℃。1H-NMR(300MHz,DMSO-d6+D2O)δ(ppm):9.12(s,1H,OH),7.16(s,1H,1/2CONH2),6.98(d,J＝8.0Hz,2H,ArH),6.85(s,1H,1/2CONH2),6.63(d,J＝8.5Hz,2H,ArH),3.43-3.45(m,1H,NH2 CH),3.11(dd,J＝5.4,9.1Hz,1H,1/2ArCH2 ),2.81(dd,J＝9.1,13.5Hz,1H,NCH),2.62(dd,J＝5.3,13.5Hz,1H,1/2ArCH2 )，2.25(s,6H,N(CH3)2 )。ESI-MS(m/z):231.1[M+Na]+。
(S)-2-二甲基氨基-3-(4-羟基苯基)丙胺(II-2)
以VII-2(0.208g,1mmol)为原料，操作同II-1，得到淡黄色油状物0.18g，收率92.8％。不经后处理直接投下一步反应。
(S,E)-2-氰基-1-(2-(二甲基氨基)-3-(4-羟基苯基)丙基)-3-苯乙基胍(I-8)
以II-2(0.194g,1.0mmol)和III-1(0.33g,1.5mmol)为原料，操作同I-1，得到淡黄色透明固体50mg,收率13.7％，纯度99.26％，m.p.158-160℃。HR-MS(ESI)m/z[M+H]+Calcdfor C21H28N5O,366.2216；Found:366.2303.
实施例9
(S,Z)-2-氰基-1-(2-(二甲基氨基)-3-(4-羟基苯基)丙基)-3-(2-甲氧基苯基)胍(I-9)的制备
以II-2(194mg,1.0mmol)和III-2(332mg,1.5mmol)为原料，操作同I-1，得到淡黄色固体30mg,收率8.17％，纯度99.26％，m.p.172-175℃。1H-NMR(300MHz,CDCl3)δ(ppm):7.28-7.34(m,1H,ArH),7.18-7.20(m,1H,ArH),6.99-7.01(m,2H,ArH),6.95(d,J＝8.0Hz,2H,ArH),6.80(d,J＝8.0Hz,2H,ArH),3.87(s,3H,OCH3 ),3.26-3.30(m,1H,(CH3)2NCH),3.03-3.11(m,1H,1/2NHCH2 ),2.89-2.93(m,1H,1/2NHCH2 ),2.73-2.81(m,1H,ArCH2 ),2.23-2.28(m,1H,ArH),2.36(s,6H,N(CH3)2 )。13C-NMR(75MHz,DMSO-d6)δ(ppm):155.46,152.70,129.83,129.34,126.74,126.44,125.70,125.60,120.29,117.18,115.10,111.69,60.68,55.55,41.70,30.01,29.15.HR-MS(ESI)m/z[M+H]+Calcd for C20H26N5O2,368.2008；Found:368.2087.
实施例10
(S,E)-2-氰基-1-(2-(二甲基氨基)-3-(4-羟基苯基)丙基)-3-(4-甲氧基苄基)胍(I-10)的制备
以II-2(194mg,1.0mmol)和III-3(356mg,1.5mmol)为原料，操作同I-1，得到淡黄色固体45mg,收率11.8％，纯度98.18％，m.p.126～128℃。1H-NMR(300MHz,CDCl3)δ(ppm):7.37(d,J＝7.8Hz,2H,ArH),7.30(d,J＝7.8Hz,2H,ArH),7.01(d,J＝7.9Hz,2H,ArH),6.81(d,J＝7.9Hz,2H,ArH),4.79(s,2H,ArH),6.81-7.02(d,J＝6.3Hz,2H,ArH),6.62-6.83(d,J＝6.3Hz,2H,ArH),4.79(s,3H,OCH3 ),3.21(s,2H,NHCH2 ),2.90-2.94(m,1H,(CH3)2NCH),2.70-2.82(m,1H,ArCH2 ),2.39(s,6H,N(CH3)2 ),2.27-2.30(m,2H,ArCH2 ),2.04-2.06(m,1H,ArCH2 )。HR-MS(ESI)m/z[M+H]+Calcd for C21H28N5O2,382.2165；Found:382.2087.
实施例11
(Z)-2-氰基-1-((S)-2-(二甲基氨基)-3-苯基丙基)-3-(1-(噻吩-2-基)丙-2-基)胍(I-11)的制备
(E)-2-(2-硝基丙-1-烯-1-基)噻吩(XI-2)
以2-噻吩甲醛(X-2,5.04g,45mmol)为原料,操作同XI-1，得到黄色固体5.9g，收率77.5％，m.p.71-73℃。1H-NMR(300MHz,DMSO-d6)δ(ppm):8.42(s,1H,ArCH＝),8.06(d,J＝5.1Hz,1H,ArH),7.79(d,J＝3.6Hz,1H,ArH),7.32(t,J＝4.4Hz,1H,ArH),2.49(s,3H,CH3 )。ESI-MS(m/z):192.0[M+Na]+。
1-(噻吩-2-基)丙-2-胺(XII-2)
以XI-2(5.9g,34.9mmol)为原料，操作同XII-1，得到淡黄色油状物3.2g，收率65.0％，不经后处理直接投下一步反应。
(Z)-N'-氰基-N-(1-(噻吩-2-基)丙烷-2-基)氨基硫代甲亚氨酸甲酯(III-8)
以XII-2(3.2g,22.7mmol)为原料，操作同III-7，得到淡黄色固体2.36g，收率43.5％，m.p.126-129℃。1H-NMR(300MHz,DMSO-d6)δ(ppm):8.19(d,J＝8.0Hz,1H,NH),7.32-7.41(m,1H,ArH),6.95–6.98(m,1H,ArH),6.88-6.90(m,1H,ArH),4.14-4.21(m,1H,NHCH),2.98–3.13(m,2H,ArCH2 ),2.55(s,3H,SCH3 ),1.18(d,J＝6.6Hz,3H,CHCH3 )。ESI-MS(m/z):262.1[M+Na]+。
(Z)-2-氰基-1-((S)-2-(二甲基氨基)-3-苯基丙基)-3-(1-(噻吩-2-基)丙-2-基)胍(I-11)
以II-1(178mg,1.0mmol)和III-8(336mg,1.5mmol)为原料，操作同I-1，得到淡黄色固体65mg,收率17.6％，纯度97.23％，m.p.80～82℃。HR-MS(ESI)m/z[M+H]+Calcd forC20H28N5S,370.19；Found:370.2066。
实施例12
(Z)-2-氰基-1-((S)-2-(二甲基氨基)-3-苯基丙基)-3-(1-(6-甲氧基萘-2-基)丙-2-基)胍(I-12)的制备
(E)-2-甲氧基-6-(2-硝基丙-1-烯-1-基)萘(XI-3)
冰浴条件下，在100mL三颈瓶中加入6-甲氧基-3-萘甲醛(X-3,1.86g,10mmol)和硝基乙烷(7.13mL,100mmol)，大部分未溶解，后缓慢滴加环己胺(5.72mL,50mmol)，白色固体逐渐溶解，溶液变为淡黄色。滴加完毕后冰浴搅拌20分钟，后缓慢滴加醋酸(20mL,过量)，加热至70℃反应2小时，TLC(石油醚：乙酸乙酯＝4:1)监测原料反应完毕。反应体系冷却到室温，有大量橘黄色固体析出，抽滤，滤饼用少量乙腈洗涤，红外灯下烘干，得到橘黄色固体2.02g，收率83.1％，m.p.92-95℃。1H-NMR(300MHz,DMSO-d6)δ(ppm):8.24(s,1H,ArH),8.16(s,1H,ArH),7.94(dd,J＝8.7,4.5Hz,2H,ArH),7.69(d,J＝8.3Hz,1H,ArCH),7.41(d,J＝2.7Hz,1H,ArH),6.97-7.27(dd,J＝2.4,8.9Hz,1H,ArH),3.91(s,3H,OCH3 )。ESI-MS(m/z):266.1[M+Na]+。
1-(6-甲氧基萘-2-基)丙-2-胺(XII-3)
以XI-3(2.02g,8.31mmol)为原料，操作同XII-1，得到淡黄色油状物1.6g，收率89.6％，不经后处理直接投下一步反应。
(Z)-N'-氰基-N-(1-(6-甲氧基萘-2-基)丙-2-基)氨基硫代甲亚氨酸甲酯(III-9)
以XII-3(1.6g,7.45mmol)为原料，操作同III-7，得到淡黄色固体1.82g，收率78.0％，m.p.126-129℃。1H-NMR(300MHz,DMSO-d6)δ(ppm):8.20(d,J＝8.0Hz,1H,ArH),7.76(d,J＝8.4Hz,2H,ArH),7.63(s,1H,NH),7.33(d,J＝8.4Hz,1H,ArH),7.28(s,1H,ArH),7.14(d,J＝8.4Hz,1H,ArH),4.30(m,1H,NHCH),3.86(s,3H,OCH3 ),2.83-3.04(m,2H,ArCH2 ),1.19(d,J＝6.6Hz,3H,SCH3 )。ESI-MS(m/z):236.1[M+Na]+。
(Z)-2-氰基-1-((S)-2-(二甲基氨基)-3-苯基丙基)-3-(1-(6-甲氧基萘-2-基)丙-2-基)胍(I-12)
以II-1(178mg,1.0mmol)和III-9(614mg,1.5mmol)为原料，操作同I-1，得到淡黄色固体65mg,收率16.7％，纯度98.46％，m.p.74～78℃。HR-MS(ESI)m/z[M+H]+Calcd forC27H34N5O,444.2685；Found:444.2763.
实施例13
(Z)-2-氰基-1-((S)-2-(二甲基氨基)-3-苯基丙基)-3-(1-(呋喃-2-基)丙-2-基)胍(I-13)的制备
(E)-2-(2-硝基丙烯基)呋喃(XI-4)
以糠醛(X-4,1.92g,20mmol)为原料，操作同XI-3，得到乳白色固体2.35g，收率76.8％，m.p.54-56℃。1H-NMR(300MHz,DMSO-d6)δ(ppm):8.07(s,1H,ArH),7.95(s,1H,ArCH),7.24(d,J＝3.6Hz,1H,ArH),6.78(dd,J＝1.8,3.6Hz,1H,ArH),2.52(s,3H,CH3 )。ESI-MS(m/z):176.1[M+Na]+。
1-(呋喃-2-基)丙-2-胺(XII-4)
以XI-4(2.35g,15.4mmol)为原料，操作同XII-1，得到淡黄色油状物1.23g，收率63.9％，不经后处理直接投下一步反应。
(Z)-N'-氰基-N-(1-(呋喃-2-基)丙-2-基)氨基硫代甲亚氨酸甲酯(III-10)
以XII-4(1.23g,9.84mmol)为原料，操作同III-7，得到黄色固体0.85g，收率38.7％，m.p.94-96℃。1H-NMR(300MHz,DMSO-d6)δ(ppm):8.14(d,J＝7.2Hz,1H,ArH),7.55(s,1H,NH),6.37(d,J＝2.6Hz,1H,ArH),6.15(d,J＝3.0Hz,1H,NH),4.23-4.27(m,1H,NHCH),2.55-2.95(m,2H,ArCH2 ),2.55(s,3H,SCH3 ),1.16(d,J＝6.6Hz,3H,CHCH3 )。ESI-MS(m/z):246.1[M+Na]+。
(Z)-2-氰基-1-((S)-2-(二甲基氨基)-3-苯基丙基)-3-(1-(呋喃-2-基)丙-2-基)胍(I-13)
以II-1(178mg,1.0mmol)和III-10(291mg,1.5mmol)为原料，操作同I-1，得到白色固体50mg,收率14.2％，纯度98.12％，m.p.98～102℃。HR-MS(ESI)m/z[M+H]+Calcd forC20H28N5O,354.2216；Found:354.2396.
实施例14
(S,E)-2-氰基-1-(2-(二甲基氨基)-3-苯基丙基)-3-(3-氟苯乙基)胍(I-14)的制备(Z)-N'-氰基-N-(3-氟苯乙基)氨基硫代甲亚氨酸甲酯(III-11)
以间氟苯乙胺(1.39g,10mmol)为原料，操作同III-1，得到白色固体1.56g，收率65.8％，m.p.169-172℃。1H-NMR(300MHz,DMSO-d6)δ(ppm):8.42(s,1H,NH),7.34-7.39(m,1H,ArH),7.06-7.19(m,3H,ArH),3.24-3.35(m,2H,NHCH2 ),2.86(t,J＝6.3Hz,2H,ArCH2 ),2.52(s,3H,SCH3 )。ESI-MS(m/z):260.1[M+Na]+。
(S,E)-2-氰基-1-(2-(二甲基氨基)-3-苯基丙基)-3-(3-氟苯乙基)胍(I-14)
以II-1(178mg,1.0mmol)和III-11(355mg,1.5mmol)为原料，操作同I-1，得到白色固体120mg,收率32.6％，纯度97.59％，m.p.137～142℃。1H-NMR(300MHz,CDCl3)δ(ppm):7.30-7.38(m,2H,ArH),7.29-7.22(m,2H,ArH),7.08-7.17(m,2H,ArH),6.85–7.08(m,3H,ArH),5.68(s,1H,NH),3.39-3.42(m,2H,NHCH2 CH2),3.09-2.92(m,3H,NHCH2 ,(CH3)2NCH),2.89-2.71(m,3H,3/2ArCH2 ),2.28-2.35(m,1H,1/2ArCH2 ),2.25(s,6H,N(CH3)2 ).HR-MS(ESI)m/z[M+H]+Calcd for C21H27FN5,368.2172；Found:368.2349。
实施例15
(Z)-2-氰基-1-((S)-2-(二甲基氨基)-3-苯基丙基)-3-(1-(吡啶-3-基)丙-2-基)胍(I-15)的制备
(E)-3-(2-硝基丙烯基)吡啶(XI-5)
100mL三颈瓶中，冰浴条件下，将3-吡啶甲醛(X-5,2.14g,20mmol)溶于10mL无水乙醇溶液中，加入硝基乙烷(2.16mL,30mmol)，后缓慢滴加2MNaOH溶液10mL，固体逐渐溶解，溶液变为淡黄色，室温搅拌6小时，TLC(石油醚：乙酸乙酯＝4:1)监测原料反应完毕。减压蒸馏除溶剂，得到淡黄色油状物3.25g，收率89.2％。不经后处理直接投下一步反应。向50mL三颈瓶中，加入上次黄色油状物3.25g，后依次加入10mL二氯甲烷，三乙胺(3.42mL,25mmol)和乙酸酐(2.4mL,25mmol)加热回流2h，TLC(石油醚：乙酸乙酯＝4:1)监测原料反应完毕。粗品柱层析(石油醚：乙酸乙酯＝50:1)纯化，得到透明油状物0.65g，收率19.8％。1H-NMR(300MHz,DMSO-d6)δ(ppm)8.79(s,1H,ArH),8.65(d,J＝4.8Hz,1H,ArH),8.13(s,1H,ArH),8.02-8.15(m,1H,ArH),7.54(dd,J＝4.8,8.2Hz,1H,ArCH),2.42(s,3H,CH3 )。ESI-MS(m/z):187.1[M+Na]+。
1-(吡啶-3-基)丙基-2-胺(XII-5)
以XI-5(0.65g,3.96mmol)为原料，操作同XII-1，得到淡黄色油状物0.51g，收率94.7％，不经后处理直接投下一步反应。
(Z)-N'-氰基-N-(1-(吡啶-3-基)丙-2-基)氨基硫代甲亚氨酸甲酯(III-12)
以XII-5(0.51g,3.75mmol)为原料，操作同III-7，得到淡黄油状物0.76g，收率58.1％。1H-NMR(300MHz,CDCl3)δ(ppm):8.51-8.56(m,2H,ArH),7.47-7.60(m,1H,ArH),7.28-7.34(m,1H,ArH),3.99–4.29(m,1H,CHCH3),2.98(dd,J＝4.8,7.0Hz,1H,1/2ArCH2 ),2.85(dd,J＝4.8,6.2Hz,1H,1/2ArCH2 ),2.49(s,3H,SCH3 ),1.09-1.31(d,J＝6.6Hz,3H,CHCH3 )。ESI-MS(m/z):257.1[M+Na]+。
(Z)-2-氰基-1-((S)-2-(二甲基氨基)-3-苯基丙基)-3-(1-(吡啶-3-基)丙-2-基)胍(I-15)
以II-1(178mg,1.0mmol)和III-12(315mg,1.5mmol)为原料，操作同I-1，得到白色固体60mg,收率16.5％，纯度98.65％，m.p.120～124℃。1H-NMR(300MHz,CDCl3)δ(ppm):8.40-8.61(m,2H,ArH),7.58(s,1H,ArH),7.31-7.38(m,3H,ArH),7.15-7.17(m,4H,ArH),3.00-3.13(m,2H,NHCH2 ),2.88-2.96(m,2H,NHCH2 ),2.83-2.86(m,3H,(CH3)2NCH,ArCH2 ),2.39(s,6H,N(CH3)2 ),1.28-1.31(m,2H,ArCH2 ),0.96-1.18(d,J＝6.6Hz,3H,CHCH3 ).13C-NMR(75MHz,CDCl3-d6)δ(ppm):158.97,150.18,147.42,139.64,136.54,134.06,128.99,128.27,125.85,123.24,117.86,64.94,64.52,48.01,41.52,31.34,28.99,20.17.HR-MS(ESI)m/z[M+H]+Calcd for C21H29N6,365.2375；Found:365.2453。
实施例16
(Z)-2-氰基-1-((S)-2-(二甲基氨基)-3-苯基丙基)-3-(1-(吡啶-4-基)丙-2-基)胍(I-16)的制备
(E)-4-(2-硝基丙烯基)吡啶(XI-6)
以4-吡啶甲醛(X-6,2.14g,20mmol)为原料，操作同XI-5，得到淡黄透明油状物1.23g，收率37.5％。1H-NMR(300MHz,DMSO-d6)δ(ppm):8.69(d,J＝6.2Hz,2H,ArH),8.03(s,1H,ArCH),7.53(d,J＝6.2Hz,2H,ArH),2.37(s,3H,CH3 )。ESI-MS(m/z):187.1[M+Na]+。
1-(4-吡啶基)丙-2-胺(XII-6)
以XI-6(1.23g,7.5mmol)为原料，操作同XII-1，得到淡黄色油状物0.66g，收率64.7％。不经后处理直接投下一步反应。
(Z)-N'-氰基-N-(1-(吡啶-4-基)丙-2-基)氨基硫代甲亚氨酸甲酯(III-13)
以XII-6(0.66g,4.85mmol)为原料，操作同III-7，得到淡黄色油状物0.55g，收率58.2％。1H-NMR(300MHz,CDCl3)δ(ppm):8.53-8.58(m,4H,ArH),7.10-7.15(m,2H,ArH),2.92–3.07(m,1H,NHCH),2.79(dd,J＝7.2,13.6Hz,1H,1/2ArCH2 ),2.79(dd,J＝6.0,13.6Hz,1H,1/2ArCH2 ),2.46(s,3H,SCH3 ),0.88(d,J＝6.6Hz,3H,CHCH3 )。ESI-MS(m/z):257.1[M+Na]+。
(Z)-2-氰基-1-((S)-2-(二甲基氨基)-3-苯基丙基)-3-(1-(吡啶-4-基)丙-2-基)胍(I-16)
以II-1(178mg,1.0mmol)和III-13(351mg,1.5mmol)为原料，操作同I-1，得到白色固体70mg,收率19.2％，纯度99.12％，m.p.89～92℃。HR-MS(ESI)m/z[M+H]+Calcd forC21H29N6,365.2375；Found:365.2453.
实施例17
(Z)-1-(1-(1H-吲哚-3-基)丙-2-基)-2-氰基-3-((S)-2-(二甲基氨基)-3-苯丙基)胍(I-17)的制备
(E)-3-(2-硝基丙-1-烯-1-基)-1H-吲哚(XI-7)
以3-吲哚甲醛(X-7,2.90g,20mmol)为原料，操作同XI-3，得到黄色固体3.40g，收率84.2％，不经后处理直接投下一步反应。
1-(1H-吲哚-3-基)-2-丙胺(XII-7)
以XI-7(3.40g,16.8mmol)为原料，操作同XII-1，得到黄色油状物2.5g，收率85.5％，不经后处理直接投下一步反应。
(Z)-N-(1-(1H-吲哚-3-基)丙-2-基)-N'-氰基氨基硫代甲亚氨酸甲酯(III-14)
以XII-7(2.50g,14.3mmol)为原料，操作同III-7，得到淡黄色固体1.84g，收率47.3％，m.p.157-160℃。1H-NMR(300MHz,CDCl3)δ(ppm):8.18(s,1H,ArH),7.55-7.66(m,1H,ArH),7.38-7.42(m,1H,ArH),7.14-7.28(m,2H,ArH),7.10(s,1H,ArH),2.98-3.05(m,2H,ArCH2 ),2.37(s,3H,SCH3 ),1.60(s,1H,NHCH),1.09-1.28(d,J＝5.7Hz,3H,CHCH3 ).ESI-MS(m/z):295.1[M+Na]+。
(Z)-1-(1-(1H-吲哚-3-基)丙-2-基)-2-氰基-3-((S)-2-(二甲基氨基)-3-苯丙基)胍(I-17)
以II-1(178mg,1.0mmol)和III-14(340mg,1.5mmol)为原料，操作同I-1，得到白色固体75mg,收率18.7％，纯度98.98％，m.p.82～86℃。HR-MS(ESI)m/z[M+H]+Calcd forC24H31N6,403.2532；Found:403.2607.
实施例18
(Z)-1-(1-(1H-吡咯-2-基)丙-2-基)-2-氰基-3-((S)-2-(二甲基氨基)-3-苯丙基)胍(I-18)的制备
(E)-2-(2-硝基丙-1-烯-1-基)-1H-吡咯(XI-8)
以2-吡咯甲醛(X-8.1.90g,20mmol)为原料，操作同XI-3，得到白色固体2.35g，收率77.3％，m.p.112-115℃。1H-NMR(300MHz,DMSO-d6)δ(ppm):8.12(s,1H,ArH),7.95(s,1H,ArCH),7.12-7.24(m,1H,ArH),6.65-6.78(m,1H,ArH),2.52(s,3H,CH3 )。ESI-MS(m/z):175.0[M+Na]+。
1-(2-1H-吡咯基)-2-丙胺(XIII-8)
以XI-8(2.35g,15.5mmol)为原料，操作同XII-1，得到淡黄色油状物1.23g，收率64.0％，不经后处理直接投下一步反应。
(Z)-N-(1-(1H-吡咯-2-基)丙-2-基-N'-氰基)氨基硫代甲亚氨酸甲酯(III-15)
以XII-8(1.23g,9.9mmol)为原料，操作同III-7，得到深棕色油状物0.59g，收率26.8％。1H-NMR(300MHz,DMSO-d6)δ(ppm):8.19(d,J＝8.2Hz,1H,ArH),7.32-7.41(m,1H,NH),6.85–7.02(m,2H,ArH),4.11-4.25(m,1H,NHCH),2.94-3.03(m,2H,ArCH2 ),2.55(s,3H,SCH3 ),1.18(d,J＝1.2Hz,3H,CHCH3 )。ESI-MS(m/z):245.1[M+Na]+。
(Z)-1-(1-(1H-吡咯-2-基)丙-2-基)-2-氰基-3-((S)-2-(二甲基氨基)-3-苯丙基)胍(I-18)
以II-1(178mg,1.0mmol)和III-15(331mg,1.5mmol)为原料，操作同I-1，得到黄色固体30mg,收率8.52％，纯度：98.26％，m.p.82～85℃。1H-NMR(300MHz,CDCl3)δ(ppm):8.12(s,1H,ArH),7.33-7.38(m,2H,ArH),7.14-7.16(m,2H,ArH),6.31-6.71(m,1H,ArH),6.11(s,1H,ArH),5.92(s,1H,ArH),4.22-4.35(q,J＝5.9Hz,1H,CHCH3),3.84-3.99(m,1H,NHCH2 ),2.98-3.07(m,3H,NHCH2 ,NHCH,ArCH2),2.85-2.68(m,3H,ArCH2 ),2.36(s,6H,N(CH3)2 ),1.02-1.19(d,J＝5.1Hz,3H,CHCH3 ).HR-MS(ESI)m/z[M+H]+Calcd for C20H29N6,353.2375；Found:353.2452.
实施例19
(Z)-1-(1-(1H-吡唑-3-基)丙-2-基)-2-氰基-3-((S)-2-(二甲基氨基)-3-苯丙基)胍(I-19)的制备
(E)-3-(2-硝基丙烯基)-1H-吡唑(XI-9)
以1-H-吡唑-3-甲醛(X-9,1.92g,20mmol)为原料，操作同XI-3，得到黄色固体2.5g，收率81.7％。1H-NMR(300MHz,CDCl3)δ(ppm):9.90(s,1H,NH),8.04(s,1H,ArCH),7.71(d,J＝2.6Hz,1H,ArH),6.63(d,J＝2.4Hz,1H,ArH),2.64(s,3H,CH3 )。ESI-MS(m/z):176.0[M+Na]+。
1-(3-1H-吡唑基)丙-2-胺(XII-9)
以XI-9(2.5g,16.3mmol)为原料，操作同XII-1，得到淡黄色油状物1.23g，收率60.3％，不经后处理直接投下一步反应。
(Z)-N-(1-(1H-吡唑-3-基)丙-2-基)-N'-氰基氨基硫代甲亚氨酸甲酯(III-16)
以XII-9(1.23g,9.83mmol)为原料，操作同III-7，得到淡黄色透明油状物0.54g，收率24.2％。1H-NMR(300MHz,DMSO-d6)δ(ppm):7.58(d,J＝2.3Hz,1H,ArH),6.20(d,J＝2.3Hz,1H,ArH),4.11-4.25(m,1H,NHCH),3.06(dd,J＝5.1,14.9Hz,1H,ArCH2),2.90(dd,J＝5.2,14.9Hz,1H,ArCH2),2.55(s,3H,SCH3 ),1.24(d,J＝6.6Hz,3H,CHCH3 )。ESI-MS(m/z):246.1[M+Na]+。
(Z)-1-(1-(1H-吡唑-3-基)丙-2-基)-2-氰基-3-((S)-2-(二甲基氨基)-3-苯丙基)胍(I-19)
以II-1(178mg,1mmol)和III-16(335mg,1.5mmol)为原料，操作同I-1，得到白色固体35mg,收率9.90％，纯度98.45％，m.p.101～103℃。HR-MS(ESI)m/z[M+H]+Calcd forC19H28N7,354.2328；Found:354.4852。
实施例20
(Z)-1-(1-(1H-咪唑-4-基)丙-2-基)-2-氰基-3-((S)-2-(二甲基氨基)-3-苯)基)胍(I-20)的制备
(E)-4-(2-硝基丙-1-烯-1-基)-1H-咪唑(XI-10)
以1-H-咪唑-4-甲醛(X-10,1.92g,20mmol)为原料，操作同XI-3，得到无色透明油状物2.05g，收率66.9％。1H-NMR(300MHz,CDCl3)δ(ppm):7.99(s,1H,ArCH),7.81(s,1H,ArH),7.43(s,1H,ArH),2.75(s,3H,CH3 )。ESI-MS(m/z):276.0[M+Na]+。
1-(1H-咪唑-4-丙基)-2-胺(XII-10)
以XI-10(2.05g,13.4mmol)为原料，操作同XII-1，得到淡黄色油状物0.95g，收率58.5％，不经后处理直接投下一步反应。
(Z)-N-(1-(1H-咪唑-4-丙基)-2-基)-N'-氰基氨基硫代甲亚氨酸甲酯(III-17)
以XII-10(0.95g,7.84mmol)位原料，操作同III-7，得到白色透明油状物0.53g，收率30.3％。1H-NMR(300MHz,DMSO-d6)δ(ppm):7.58(s,1H,ArH),6.23(s,2,ArH),4.11-4.25(m,1H,NHCH),3.06(dd,J＝5.1,14.9Hz,1H,ArCH2),2.90(dd,J＝5.2,14.9Hz,1H,ArCH2),2.55(s,3H,SCH3 ),1.17-1.21(d,J＝6.6Hz,3H,CHCH3 )。ESI-MS(m/z):246.1[M+Na]+。
(Z)-1-(1-(1H-咪唑-4-基)丙-2-基)-2-氰基-3-((S)-2-(二甲基氨基)-3-苯)基)胍(I-20)
以II-1(178mg,1.0mmol)和III-17(335mg,1.5mmol)为原料，操作同I-1，得到白色固体45mg,收率12.7％，纯度98.52％，m.p.98～101℃。HR-MS(ESI)m/z[M+H]+Calcd forC19H28N7,354.2328；Found:354.4852。
实施例21
上述制备所得部分化合物的药理学实验及结果如下：
1.小鼠热板镇痛活性实验
实验方法：昆明种雌雄小鼠(n+2)*10只，将恒温水浴箱加热到55(±0.5)℃，将小鼠置于热板上，以其足部接触热板到开始舔后足的时间为HPPT，剔除HPPT大于30s或小于5s的动物，选择符合标准的小鼠按体重随机分为(n+2)组，分别为模型对照组、阳性药盐酸吗啡(10mg/kg)组、n个化合物(10mg/kg)的灌胃剂量组。给药一次。以给药前3次热板法HPPT的平均值为基础痛阈，对超过60s无反应者则终止刺激，以60s痛反应计时，给药后30min开始记录痛阈时间。其中，HPPT(pain threshold in hot-plate test)是小鼠出现舔足的时间。
统计学处理：所有数据均以x±s表示，HPPT组内比较采用自身配对t检验，组间比较采用团体t检验，p<0.05为差异有显著性。
实验结果：对本发明部分化合物进行小鼠体内热板法镇痛活性实验，结果见表1和表2。
表1化合物I-1～I-10对小鼠热板法模型的镇痛作用(x±s n＝8)
Figure BDA0002495444360000231
与模型对照组比较，aP＜0.05，aaP＜0.01，与盐酸吗啡组比较，bP＜0.05，bbP＜0.01.
表2化合物I-11～I-20对小鼠热板法模型的镇痛作用(x±s n＝8)
Figure BDA0002495444360000232
Figure BDA0002495444360000241
表1和表2实验结果表明，本发明部分化合物对所测化合物均有不同程度的镇痛作用，其中化合物I-1、I-4、I-7、I-11、I-15、1-18和I-19的镇痛作用较强，而化合物I-7和I-11的镇痛活性与吗啡相当。
2.GPRC-arrestin和GPCR-cAMP激酶激动活性测试
2.1实验方法：384孔反应板分为化合物孔(GPCR-cAMP选择0.5nM,5nM和50nM三个浓度梯度，GPRC-arrestin选择0.5μM,5μM和50μM三个浓度梯度)、阳性对照孔和阴性对照孔。化合物孔加入激酶溶液，37℃下孵育30分钟。再将5μL不同浓度的激动剂加入到细胞中，并在37℃温育60分钟。后与20μL裂解液温育1小时，然后与20μL XS+EA试剂在室温温育3小时，生成测定信号。用PerkinElmer EnvisionTM仪器读取化学发光信号。
数据分析：活性百分比＝100％*(测试样品的平均吸光度-空白对照的平均吸光度)/(阳性对照的平均吸光度-空白对照的平均吸光度)
2.2实验结果：对本发明部分化合物进行GPRC-arrestin和GPCR-cAMP激酶激动活性实验，结果见表3。
表3化合物I-1～I-20Arrestin和cAMP活性数据
Figure BDA0002495444360000242
较高剂量(50μM)下均没有显示出arrestin通路的激动活性，这意味着由arrestin通路介导的吗啡样副作用(呼吸抑制性，耐受性等)很小甚至没有。在较低剂量(50nM)下化合物I-1、I-2、I-4、I-9、I-11和I-18有一定的MOR激活活性。

Claims (9)

1.通式(I)的化合物或其药学上可接受的盐：
Figure RE-FDA0003751622770000011
其中：
R1、R2、R3、R4各自独立地代表H、卤素、CN、NO2、C1～C6烷基、OH、C1～C6烷氧基、OCF3、NH2、NHCOCH3或C1～C6烷氨基；
R5代表
Figure RE-FDA0003751622770000012
Figure RE-FDA0003751622770000013
其中R6代表H、卤素、CN、NO2、CH3、OH、OCH3、OCF3、NH2或NHCOCH3；Y1、Y2、Y3、Y4各自独立地代表N或C-R7，R7代表H、卤素、CH3、CF3、OH、OCH3、OCF3或CN；Z1代表O、S或N-R8，R8代表H、C1～C3烷基。
2.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，R1、R3、R4代表H，R2代表H或OH。
3.根据权利要求2所述的化合物或其药学上可接受的盐，其特征在于，R2代表H。
4.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，R5代表
Figure RE-FDA0003751622770000014
Figure RE-FDA0003751622770000015
其中Y5、Y6各自独立地代表N或CH、C-OCH3；Z2代表O、S或NH。
5.根据权利要求4所述的化合物或其药学上可接受的盐，其特征在于，R5代表
Figure RE-FDA0003751622770000016
Figure RE-FDA0003751622770000021
6.根据权利要求2所述的化合物或其药学上可接受的盐，其特征在于R1、R3、R4代表H，R2代表H或OH，R5代表
Figure RE-FDA0003751622770000022
Figure RE-FDA0003751622770000023
7.根据权利要求1～6中任一项所述的化合物或其药学上可接受的盐，其中药学上可接受的盐为权利要求1的通式(I)化合物与下列酸形成的酸加成盐：氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
8.一种药物组合物，其特征在于，包含权利要求1～6中任一项所述的化合物或其药学上可接受的盐及药学上可接受的载体。
9.权利要求1～6中任一项的化合物或其药学上可接受的盐在制备镇痛药物中的用途。
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Publication number Priority date Publication date Assignee Title
CN1090575A (zh) * 1992-08-13 1994-08-10 厄普约翰公司 K-通道阻滞剂氰基胍类
WO2001009096A2 (en) * 1999-08-03 2001-02-08 Abbott Laboratories Potassium channel openers
CN104903310A (zh) * 2012-11-13 2015-09-09 阵列生物制药公司 可用于治疗疼痛的双环脲、硫脲、胍及氰基胍化合物

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US6645968B2 (en) * 1999-08-03 2003-11-11 Abbott Laboratories Potassium channel openers

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1090575A (zh) * 1992-08-13 1994-08-10 厄普约翰公司 K-通道阻滞剂氰基胍类
WO2001009096A2 (en) * 1999-08-03 2001-02-08 Abbott Laboratories Potassium channel openers
CN104903310A (zh) * 2012-11-13 2015-09-09 阵列生物制药公司 可用于治疗疼痛的双环脲、硫脲、胍及氰基胍化合物

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