本发明涉及通式(Ⅰ)的四氢吡啶(或4-氢哌啶)丁基吡咯衍生 物以及其生理上可接受盐类单独或与其它止痛剂合用(在这种情况下 产生协同作用)在制备治疗人类和/或兽类急性疼痛、神经疼痛或感受 伤害疼痛药物方面的用途。

在我们的专利申请WO 96/04287中公开了具式(Ⅰ)的化合物 其对σ和5HT1A受体具有亲和力，其被要求可用于治疗焦虑、精神病、 癫痫、惊厥、记忆缺失、脑血管疾病以及老年性痴呆的药物。

我们现在发现通式(Ⅰ)的化合物以及其生理上可接受盐类单独或 与其它止痛剂合用(在这种情况下产生协同作用)在制备用于预防、 缓解或治疗人类和/或兽类急性疼痛、神经疼痛或感受伤害疼痛药物方 面极其有用。

本发明涉及具下列通式的四氢吡啶(或4-氢哌啶)丁基吡咯衍生 物以及其生理上可接受盐类之一在制备治疗哺乳动物(包括人类)急 性疼痛、神经疼痛或感受伤害疼痛药物方面的用途，

其中

R1,R2和R3可以相同也可以不同，它们代表氢原子，C1-C4烷基，三 氟甲基，羟基或烷氧基，两个相邻的基团可以形成六元芳香环的一部 分；

A代表碳原子，虚线代表附加键，或A代表碳原子和羟基基团之间 的(C-OH)，虚线代表无附加键；

Z1代表氮原子或可由C-R4表示的取代碳原子；

Z2代表氮原子或可由C-R5表示的取代碳原子；

Z4代表氮原子或可由C-R7表示的取代碳原子；

条件是Z1,Z2和Z4一起至多可以表示两个氮原子；并且

R4,R5,R6和R7可以相同也可以不同，它们代表氢原子，卤原子， C1-C4烷基，芳基或取代芳基，或两个相邻的基团可以形成六元芳香环 的一部分。

术语“卤原子”代表氟原子，氯原子或溴原子。

术语“芳基或取代芳基“代表苯基或被卤素取代的苯基。

术语“烷氧基”代表甲氧基或乙氧基。

术语“C1-C4烷基”代表直链或支链含有1-4个碳原子的饱和烃链 基团，例如甲基，乙基，丙基，异丙基，异丁基，仲丁基和叔丁基。

通式(Ⅰ)化合物生理上可接受盐类是指与无机酸和有机酸形成的 盐类，特别地是指与盐酸，溴氢酸，硫酸，磷酸，乙酸，乳酸，丙二 酸，琥珀酸，戊二酸，富马酸，苹果酸，酒石酸，柠檬酸，抗坏血酸， 马来酸，苯甲酸，苯乙酸，肉桂酸，水杨酸和烷基、环烷基或芳基磺 酸的盐。

通式(Ⅰ)衍生物治疗疼痛的用途是指在临床上作为止痛剂的用途。 术语急性疼痛包括但不限于头疼，关节疼，肌肉紧张或痛经。术语神 经疼包括但不限于慢性背疼，与关节炎有关的疼痛，疱疹，与癌症有 关的疼痛，幻觉肢体疼痛，生产过程中的疼痛或抵抗鸦片类物质的神 经疼痛。术语感受伤害疼痛包括但不限于术后疼痛，牙疼，手术引起 的疼痛，严重的烧伤引起的疼痛，分娩后疼痛或与生殖泌尿道有关的 疼痛。

根据我们在专利申请WO 96/04287中所描述的方法可以制备得到具 通式(Ⅰ)的衍生物。

在用于人类治疗时，本发明化合物的给药剂量可根据所治疗病情的 严重程度进行变化。正常情况下，给药剂量为1-100mg/天。本发明化 合物可作为唯一的活性成分进行给药，也可与另一个止痛药一起进行 给药，两者的比例为每1份具通式(Ⅰ)化合物对1-10份另一种止痛 剂，其目标是获得协同作用。其它止痛剂包括但不限于非甾体类抗炎 化合物，例如阿司匹林和吲哚美新，其它止痛剂例如扑尔息痛、麻醉 止痛剂或有关的化合物，例如吗啡，哌替啶或镇痛新。具有合适的药 物配比的本发明化合物可经不同的给药途径进行给药，例如口服、皮 透、非肠道、皮下、鼻内、肌内或静脉内等途径。在我们的专利申请 WO 96/04287中公开了含有通式(Ⅰ)化合物的药物组合物。

包括在本发明范围内的说明性实施例包括以表1和2中所列出数据 为特征的化合物。

                                  表1 实施例  R1  R2  R3  R4  R5  Z1  Z2     R6  Z4     m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂)     1  H  H  H  H  H  N CH     Cl  CH  102-103℃ 3364(b.a.,OH), 2950,2810,1375, 1130,991,969, 760,696,605 KBr 1.56(quin,J=7.1Hz,2H)；1.65(b.a.,1H)；1.76 (d,J=12.4Hz,2H)；1.90(quin,J=7.6Hz,2H)；2.20(m, 2H)；2.40-2.55(a.c.,4H)；2.83(d,J=9.5Hz,2H)；4.11 (t,J=7Hz,2H)；7.21-7.42(a.c.,5H)；7.52(d,J=8.5Hz, 2H)(CDCl3)     2  H  H  H  H  H  C-CH3  N     Cl  CCl  86-89℃ 3196(b.a.,OH), 2951,2924,2824, 1406,1247,1146, 762,703KBr 1.59(m,J=5.3 J′=6.6,2H)；1.70-1.32(a.c.,4H)；2.16 (d,t,J=13.0Hz J′=4.4Hz,2H)；2.37(s,3H)；2.41-2.55 (a.c.,5H),2.79(d,J=11.3Hz,2H)；3.88(t,J=7.5Hz, 2H)；7.27(t,J=7.2Hz,1H)；7.36(t,J=7.6Hz,2H)；7.51 (d,J=7.3Hz,2H)(CDCl3)     3  H  H  H  H  H  CH  N  CH=CH-CH=CH-C  122-123℃ 3180(b.a.,OH), 2929,2818,1496, 1467,1459,1445, 1286,1219,1143, 1.51(quin,J=7.4Hz,2H)；1.73(d,J=12.7Hz,2H)；1.87 (quin,J=7.6Hz,2H)；2.10(dt,J=12.9Hz J′4.1Hz,2H)； 2.36-2.50(a.c.,4H)；2.70(d,J=11.2Hz,2H)；3.25(b.a., 1H)；4.12(t,J=7.1Hz,2H)；7.21-7.40(a.c.,6H)；7.51 实施例 R1  R2  R3  R4 R5  Z1  Z2     R6 Z4     m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂) 769,743,707 KBr (d,J=8.3Hz,2H)；7.70-7.75(a.c.,2H)(CDCl3)     4  H  H  H  H  H  CH  N     H  N     123℃ 3180(b.a.,OH), 2949,2919,2838, 1276,1145,1135, 1006,770,707, 676 KBr 1.45(quin,J=7.5Hz,2H)；1.69(d,J=12.9Hz,2H)；1.85 (quin,J=7.5Hz,2H)；2.07(dt,J=13.0Hz J′=4.1Hz,2H)； 2.33-2.45(a.c.,4H)；2.69(d,J=11.2Hz,2H)；2.93(b.a., 1H)；4.10(t,J=6.9Hz,2H)；7.18(t,J=7Hz,1H),7.27 (t,J=7.8Hz,2H)；7.46(d,J=8.3Hz,2H)；7.80(s,1H)； 7.91(s,1H)(CDCl3)     5  H  H  Cl  H  H  N CH     Cl  CH     106℃ 3145(b.a.,OH), 2947,291 8,2834, 1318,1147,1083, 1112,990,817, 612 KBr 1.47(quin,J=7.5Hz,2H)；1.69(d,J=11.9Hz,2H)；1.84 (quin,J=7.6Hz,2H)；2.05(dt,J=13Hz,J′=4.4Hz,2H)； 2.34-2.50(a.c.,5H)；2.72(d,J=11.2Hz,2H)；4.05 (t,J=7.0Hz,2H)；7.29(AB system,J=8.6Hz,2H)；7.36 (s,2H)；7.42(AB system,J=8.6Hz,2H)(CDCl3)     6  H  H  Cl  H  H C-CH3  N     Cl  CCl     油 3340(b.a.,OH), 2946,2820,1537, 1492,1471,1406, 1376,1247,1135, 1094,1013,828, 755 1.54(m,2H)；1.67-1.78(a.c.,4H)；2.06(dt,J=13Hz, J′=4.2Hz,2H)；2.32(s,3H)；2.38-2.45(a.c.,5H)；2.73 (d,J=11.2Hz,2H)；3.86(t,J=7.3Hz,2H)；7.28(AB system,J=8.6Hz,2H)；7.43(AB system,J=8.6Hz,2H) (CDCl3)     7  H CF3  H  H  H  N CH     Cl  CH     油 3360(b.a.,OH), 2948,2823,1438, 1378,1330,1212, 1.48(quin,J=7.6Hz,2H)；1.71(d,J=12.5Hz,2H)；1.85 (quin,J=7.6Hz,2H)；2.06-2.21(a.c.,3H)；2.36-2.43 (a.c.,4H)；2.76(d,J=11.5Hz,2H)；4.06(t,J=7.1Hz, 实施例 R1  R2  R3 R4 R5  Z1  Z2     R6 Z4     m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂) 1165,1124,1047, 972,804,704 膜 2H)；7.35(s,2H)；7.43-7.51(a.c.,2H)；7.66 (d,J=7.5Hz,1H)；7.79(s,1H)(CDCl3)     8  H CF3  H  H  H C-CH3  N     Cl  CCl     油 3340(b.a.,OH), 2948,2823,1408, 1330,1165,1126, 1075,789,763, 704 膜 1.57(quin,J=7.5Hz,2H)；1.70-1.80(a.c.,4H)；2.15 (dt,J=12.9Hz J′=3.6Hz,2H)；2.35(s,3H)；2.40-2.52 (a.c.,4H)；2.80(d,J=11.7Hz,2H)；3.88(t,J=7.0Hz, 2H)；7.42-7.57(a.c.,2H)；7.69(d,J=7.5Hz,1H)；7.82 (s,1H)(CDCl3)     9  H  H     F     H  H C-CH3  N     Cl  CCl     油 3330(b.a.,OH), 2946,2818,1509, 1406,1247,1222, 1160,835 膜 1.58(m,2H)；1.64-1.81(a.c.,4H)；2.14(dt,J=12.9Hz J′=3.6Hz2H)；2.32(s,3H)；2.43-2.60(a.c.,4H)；2.84 (d,J=11Hz,2H)；3.87(t,J=7.1Hz,2H)；4.18(b.a.,1H)； 7.01(t,J=8.8Hz,2H)；7.46(dd,J=8.8Hz J′=5.2Hz,2H) (CDCl3)     10  H  H  H  H  H  CH CH    CH=CH-CH=CH-C  109-111℃ 3190(b.a.,OH), 2956,2823,1461, 1446,1319,1303, 1218,1142,738, 703 KBr 1.57(m,2H)；1.73(d,J=14Hz,2H)；1.80(b.a.,1H)； 1.90(m,2H)；2.13(dt,J=13Hz J′=4Hz,2H),2.32-2.46 (a.c.,4H)；2.76(d,J=11.3Hz,2H)；4.16(t,J=7.1Hz, 2H)；6.50(d,J=3.1Hz,1H)；7.05-7.14(a.c.,2H)；7.18- 7.40(a.c.,5H)；7.50(d,J=7.8Hz,2H)；7.00 (d,J=7.3Hz,1H)(CDCl3)     11  H  H  CH3  H  H   C-CH3  N     Cl  CCl     油 3360(b.A.,OH), 2946,2818,1535, 1471,1406,1376, 1247,1134,817, 755 1.53(m,2H)；1.66-1.84(a.c.,4H)；2.09(dt,J=12.9Hz, J′=3.6Hz,2H)；2.33(s,3H)；2.36(s.3H)；2.39-2.50 (a.c.,4H)；2.77(d,J=11.2Hz,2H)；3.87(t,J=7.0Hz, 2H)；7.15(AB system,J=7.8Hz,2H)；7.33(AB system,J=7.8Hz,2H)(CDCl3)  实施例 R1  R2 R3  R4  R5  Z1  Z2     R6 Z4     m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂)     膜     12  H  H  H H  H  N CH     H  CH    89-91℃ 3137(b.A.,OH) 2947,2532,1396, 1378,1119,1046, 756,697 KBr 1.51(quin,J=7.6Hz,2H)；1.73(d,J=12.3Hz,2H)；1.89 (quin,J=7.6Hz,2H)；2.00-2.20(a.c.,3H)；2.35-2.45 (a.c.,4H)；2.76(d,J=10.2Hz,2H)；4.13(t,J=7.1Hz, 2H)；6.21(s,1H)；7.21(m,1H),7.30-7.37(a.c.,3H)； 7.44-7.52(a.c.,3H)(CDCl3)     13  H  H  H  H  H  N CH    CH=CH-CH=CH-C    107-109℃ 3311(b.a.,OH) 2953,2803,1465, 1375,1133,1117, 1043,1017,761, 744,704 KBr 1.53(m,2H)；1.71(d,J=12.2Hz,2H)；1.95(m,2H)； 2.10(m,2H)；2.29(b.a.,1H)；2.35-2.47(a.c.,4H)； 2.71(d,2H)；4.39(t,J=7.1Hz,2H)；7.13(t,1H)；7.22- 7.44(a.c.,5H)；7.50(d,J=8Hz,2H)；7.71(d,J=8.3Hz, 1H)；7.95(s,1H)(CDCl3)     14  H  H  H  H  H  N    C-CH=CH-     CH=CH  CH    120-122℃ 3295(b.a.,OH) 2946,2817,1377, 1126,786,735, 700 KBr 1.58(m,2H)；1.73(d,J=13.5Hz,2H)；1.90-2.20(a.c., 5H)；2.38-2.47(a.c.,4H)；2.75(d,J=10.5Hz,2H)；4.42 (t,J=6.6Hz,2H)；7.06(t,J=7.5Hz,1H)；7.22-7.37(a.c., 4H)；7.49(d,J=7.8Hz,2H)；7.61-7.71(a.c.,2H)；7.90 (s,1H)(CDCl3)     15  H  H  CH3  H  H  N CH     Cl CH    81-82℃ 3122(b.a.,OH) 2936,1475, 1434,1378,1319, 989,973,814 KBr 1.51(quin,J=7.6Hz,2H)；1.73(d,J=11.7Hz,2H)；1.87 (quin,J=7.6Hz,2H)；2.12(dt,J=12.8Hz J′=4.4Hz,2H)； 2.33(s,3H)；2.35-2.48(a.c.,5H)；2.74(d,J=11.2Hz, 2H)；4.07(t,J=7.1Hz,2H)；7.15(d,J=8Hz,2H)；7.25- 7.40(a.c.,4H)(CDCl3)     16  H  H CH3O  H  H  N CH     Cl  CH    122-123℃ 3190(b.a.,OH) 2954,2923,2827, 1509,1314,1243, 1.49(quin,J=7.6Hz,2H)；1.72(d,J=11.8Hz,2H)；1.84 (quin,J=7.4Hz,2H)；2.00-2.14(a.c.(dt+b.a.),3H)； 2.34-2.47(a.c.,4H)；2.72(d,J=11Hz,2H)；3.77(s,  实施例  R1  R2  R3  R4 R5  Z1  Z2     R6  Z4     m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂) 1178,971 KBr 3H)；4.05(t,J=7.1Hz,2H)；6.85(d,J=9Hz,2H)；7.24- 7.42(a.c.,4H)(CDCl3)     17  H  H  H  H  H  CPh  N     H  CH   108-110℃ 3220(b.a.,OH) 2944,2817,1473, 1446,1421,1136, 1046,787,773, 761,700 KBr 1.45(quin,J=7.6Hz,2H)；1.68-1.82(a.c.,4H)；2.08 (dt,J=13.0Hz J′=4.1Hz,2H)；2.29-2.42(a.c.,4H)；2.5 (b.a.,1H)；2.67(d,J=11.2Hz,2H)；4.01m(t,J=7.3Hz, 2H)；7.01(s.1H)；7.08(s,1H)；7.20-7.56(a.c.,10H) (CDCl3)     18  H  H  CH3  H  H  CH  N    CH=CH-CH=CH-C     油 3260(b.a.,OH) 2944,2817,1497, 1459,1381,1287, 1135,1046,817, 745 膜 1.58(quin,J=7.6Hz,2H)；1.74(d,J=12Hz,2H)；1.82 (b.a.,1H)；1.95(quin,J=7.6Hz,2H)；2.11(dt,2H)； 2.33(s,3H)；2.40-2.50(a.c.,4H)；2.74(d,J=11.5Hz, 2H)；4.20(t,J=7.1Hz,2H)；7.15(d,J=8.3Hz,2H)； 7.22-7.35(a.c.,3H)；7.37-7.43(a.c.,2H)；7.79(m, 1H)；7.87(s,1H)(CDCl3)     19  H  H  H  H  H  CH  N     Ph  CPh   138-139℃ 3194(b.a.,OH) 2939,2806,1 509, 1446,773,766, 758,696 KBr 1.38(m,2H)；1.56(m,2H)；1.72(d,J=12.4Hz,2H)； 2.09(dt,2H)；2.25(t,J=7.4Hz,2H)；2.39(m,2H)；2.66 (m.2H)；3.10(b.a.,1H)；3.78(t,J=7.2Hz,2H)；7.10- 7.52(a.c.,16H)；

实施例  R1    R2 R3  R4  R5 Z1  Z2  R6 Z4  m.p.     IRcm-1     1H-RMN(300MHz).δ(溶剂)     20  CH=CH-CH=CH  H  H  H  N  CH  Cl  CH   油 3357(b.a.,OH), 2946,2833,1434, 1.44(quin,J=7.3Hz,2H)；1.77(quin,J=7.5Hz,2H)； 2.15-2.30(a.c.,5H)；2.34(t,J=7.5Hz,2H)；2.57(m,2H)； 1379,1315,1140, 1123,972,781, 613 KBr 2.73(d,J=11.3Hz,2H)；3.99(t,J=7.1Hz,2H)；7.26-7.46 (a.c.,6H)；7.73(d,J=8.1Hz,1H)；7.82(m.1H)；8.91 (m,1H)(CDCl3)     21  H   CH=CH-CH=CH  H  H  N     CH     Cl CH     142-143℃ 3131(b.a.,OH), 2950,2820,1377, 1311,971,829, 761,613 KBr 1.55(quin,J=7.5Hz,2H)；1.70-1.97(a.c.,5H)；2.29 (dt,J=12.7Hz,J′=4.1Hz,2H)；2.41-2.55(a.c.,4H)；2.83 (d,J=11.7Hz,2H)；4.11(t,J=7.0Hz,2H)；7.39-7.50 (a.c.,4H)；7.64(dd,J=9.1Hz,J′=1.5Hz,1H)；7.81-7.85 (a.c.,3H)；7.95(s,1H)(CDCl3)

 实施例  R1  R2 R3  R4  R5  Z1  Z2     R6 Z4     盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂)     22  H  H  H  H  H  N  CH     C6HCl  CH    137-140℃ 3347,2944,2810, 1562,1492,1376, 1127,1094,1002, 952,828,760,699  KBr 1.56(m,2H)；1.74(m,2H)；1.80(b.a.,1H)；1.94(m, 2H)；2.40(dt,J=13.1Hz,J′=4.0Hz,2H)；2.40-2.50(a.c., 4H)；2.77(m,2H)；4.15(t,J=7.0Hz,2H),7.25-7.40 (a.c.,7H)；7.50(d,J=8.3Hz,2H)；7.61(s,1H)；7.72 (s,1H)(CDCl3)     23  H  H  F  H  H  CH  N    CH=CH-CH=CH-C    120-122℃ 3230,2947,2915, 1504,1219,1135, 835,746 KBr 1.58(m,2H)；1.70(m,2H)；1.93(m,2H)；2.12(m,2H)； 2.40-2.55(a.c.,4H)；2.76(m,2H)；4.19(t,J=7.0Hz, 2H)；7.02(m,2H)；7.26(m,2H)；7.30-7.50(a.c.,3H)； 7.74(m,1H)；7.83(s,1H)(CDCl3)     24  H  CF3  H  H  H  N  CH     Cl  CH     HCl    147-148℃ 3259,2465,2420, 2365,1328,1108, 1073 1.62-1.84(a.c.,6H)；2.53(m,2H)；3.09-3.40(a.c.,6H)； 4.12(t,J=6.8Hz,2H)；5.76(s,1H)；7.51(s,1H)；7.52- 7.82(a.c.,4H)；8.02(s,1H)；10.96(b.a.,1H) 实施例 R1  R2  R3  R4  R5  Z1  Z2     R6 Z4    盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂) KBr (DMSO-d6)     25  H  H  F  H  H  N  CH    CH=CH-CH=CH-C    136-137℃ 3303,2951,2805, 1 506,1464,1376, 1218,1162,1118, 832,741 KBr 1.54(m,2H)；1.60-1.80(a.c.,3H)；1.97(m,2H)；2.06 (dt,J=13.0Hz,J′=4.3Hz,2H)；2.30-2.43(a.c.,4H；2.72 (m,2H)；4.40(t,J=7.0Hz,2H)；6.99(t,J=8.8Hz,2H)； 7.12(m,1H)；7.32-7.47(a.c.,4H)；7.71(d,J=8.1Hz, 1H)；7.96(s,1H)(CDCl3-CD3OD[1∶1])     26  H  H  F  H  H  N    C-CH=CH-CH=CH  CH    148-150℃ 3325,2950,2923, 2812,1509,1377, 1218,1131,834, 758 KBr 1.57(m,2H)；1.70-1.77(a.c.,3H)；1.98-2.19(a.c.,4H)； 2.35-2.49(a.c.,4H)；2.77(d,J=11.2Hz,2H)；4.45 (t,J=7.0Hz,2H)；6.98-7.15(a.c,3H)；7.25-7.49(a.c., 3H)；7.63(d,J=8.3Hz,1H)；7.69(d,J=7.8Hz,1H)；7.91 (s,1H)(CDCl3-CD3OD[1∶1])     27  H  H  F  H  H  N    C-CH=CH-CH=CH  N    109-110℃ 3400,2931,2812, 1509,1229,1101, 831,745 KBr 1.47-1.80(a.c.,4H)；1.90-2.25(a.c.,5H)；2.30-2.55 (a.c.,4H)；2.70(m,2H)；4.78(t,J=6.9Hz,2H)；7.01 (t,J=8.7Hz,2H)；7.26-7.54(a.c.,4H)；7.85(dd,J=6.7Hz, J′=3.0Hz,2H)(CDCl3-CD3OD[1∶1])     28  H  H  F  H  H  N  N    CH=CH-CH=CH-C    102-103℃ 3430,2952,2925, 1508,1223,1140, 833,744 KBr 1.45-1.80(a.c.,4H)；1.85-2.25(a.c.,5H)；2.25-2.55 (a.c.,4H)；2.77(m,2H)；4.69(t,J=6.9Hz,2H)；7.01 (t,J=8.7Hz,2H)；7.26-7.53(a.c.,5H)；8.06(d,J=7.3Hz, 1H)(CDCl3-CD3OD[1∶1])     29  H  H  F  H  H  CH  N     H  N     油 3350(b.a.,OH), 2947,2818,1509, 1222,1138,836, 681 膜 1.55(m,2H),1.74(d,J=12.6Hz,2H)；1.94(m,2H)； 2.13(m,2H)；2.40-2.55(a.c.；4H)；2.79(m,2H)；4.20 (t,J=6.9Hz,2H)；7.02(t,J=8.4Hz,2H)；7.46(m,2H)； 7.91(s,1H),8.04(s,1H)(CDCl3)     30  H  H  Cl  H  H  CH  N     H  N    89-91℃ 3119(b.a.,OH), 2956,2829 1509, 1.46(m,2H)；1.71(m,2H)；1.90(quin,J=7.4Hz,2H)； 2.05(m,2H)；2.33-2.50(a.c.,4H)；2.54(b.a.,1H)；2.72 实施例 R1  R2  R3  R4  R5  Z1  Z2     R6  Z4 盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂) 1379,1277,1145, 1007,824,685  KBr (m,2H)；4.16(t,J=7.1Hz,2H)；7.28(m,2H)；7.42(m, 2H)；7.86(s,1H)；7.99(s,1H)(CDCl3)

                                       表2 实施例 R1  R2  R3  R4 R5  Z1  Z2     R6  Z4     盐/m.p.     IRcm-1     1H-RMZ(300MHz),δ(溶剂)     1a  H  H  H  H  H  N CH     Cl  CH     62-64℃ 3113,2920,2745, 1375,1325,1138, 965,837,742, 688 KBr 1.56(quin,J=7.6Hz.2H)；1.91(quin,J=7.6Hz, 2H)；2.47(t,J=7.4Hz,2H)；2.58(m,2H)；2.65 (t,J=5.6Hz,2H)；3.14(m.2H)；4.11(t,J=7.1Hz, 2H)；6.06(m.1H)；7.23-7.42(a.c.,7H)(CDCl3)     2a  H  H  H  H  H  CH  N   CH=CH-CH=CH-C     66-69℃ 2933,1495,745, 694,665 膜 1.55(quin,J=7.6Hz,2H)；1.92(quin,J=7.6Hz, 2H)；2.43(t,J=7.3Hz,2H)；2.52(m,2H)；2.61 (t,J=5.6Hz,2H)；3.07(m,2H)；4.14(t,J=7.1Hz, 2h)；6.02(m,1H)；7.20-7.40(a.c.,8H)；7.80(m, 1H)；7.86(s,1H)(CDCl3) 实施例 R1  R2  R3 R4 R5     Z1  Z2     R6  Z4     盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂)     3a  H  H  H  H  H  CH  N     H  N     63-64℃ 2942,1438,1381, 1271,1142,1006, 753,697,681, KBr 1.56(m,2H)；1.95(m,2H)；2.47(t,J=7.1Hz, 2H)；2.56(m,2H)；2.66(t,J=5.3Hz,2H)；3.11 (m,2H)；4.19(t,J=7.0Hz,2H)；6.05(s,1H)；7.21 (m,1H)；7.30(t,J=7.6Hz,2H)；7.36(d,J=7.8Hz, 2H)；7.94(s,1H)；8.06(s.1H)(CDCl3)     4a  H  H  Cl  H  H  N CH     Cl  CH     103-104℃ 2939,1493,1436, 1381,1306,1122, 1097,973,843, 824,730 KBr 1.54(m,2H)；1.90(m,2H)；2.45(t,J=7.4Hz, 2H)；2.51(m,2H)；2.65(t,J=5.6Hz,2H)；3.10 (m,2H)；4.10(t,J=7.0Hz,2H)；6.03(m,1H)； 7.26(AB system,J=8.6Hz,2H)；7.29(AB system,J=8.6Hz,2H)；7.37(s,1H)；7.41(s,1H) (CDCl3)     5a  H  H  Cl  H  H  C-CH3  N     Cl  CCl     119-120℃ 2922,1531,1494, 1469,1403,1380, 1366,1245,1094, 1010 KBr 1.59(m,2H)1.76(m,2H)；2.36(s,3H), 2.42- 2.53(a.c.,4H)；2.67(t,J=5.3Hz,2H)；3.12(m, 2H)；3.88(t,J=7.4Hz,2H)；6.04(m,1H)；7.27 (AB system,J=9.1Hz,2H)；7.30(AB system,J=9.1Hz,2H)(CDCl3)     6a  H CF3  H  H  H  N  CH     Cl  CH     油 2944,1434,1375, 1331,1247,1165, 1126,1076,972, 800,698 膜 1.53,(quin,J=7.5Hz,2H)；1.89(quin,J=7.7Hz, 2H)；2.45(t,J=7.3Hz,2H)；2.54(m,2H)；2.66 (t,J=5.5Hz,2H)；3.10(m,2H)；4.08(t,J=7.1Hz, 2H)；6.10(m,1H)；7.35-7.56(a.c.,5H),7.59(s, 1H)(CDCl3) 实施例 R1  R2  R3 R4 R5    Z1  Z2     R6  Z4 盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂)     7a  H CF3  H  H  H  C-CH3  N     Cl  CCl     油 2931,2815,1533, 1405,1331,1246, 1165,1125,1076, 797,699 膜 1.62(quin,J=6.6Hz,2H)；1.77(quin,J=7.6Hz, 2H)；2.37(s,3H)；2.51(t,J=7.2Hz,2H)；2.60(m, 2H)；2.71(t,J=5.6Hz,2H)；3.17(m,2H)；3.89 (t,J=7.3Hz,2H)；6.14(m,1H)；7.40-7.50(a.c., 2H)；7.55(d,J=7.5Hz,1H)；7.62(s,1H)(CDCl3)     8a  H  H  F  H  H  N CH     Cl  CH     86-87℃ 2936,1512,1378, 1326,1229,988, 967 KBr 1.60(quin,J=7.5Hz,2H)；1.91(quin,J=7.5Hz, 2H)；2.50-2.82(a.c.,4H)；2.76(t,J=5.6Hz,2H)； 3.19(m,2H)；4.11(t,J=6.9Hz,2H)；5.97(s,1H)； 6.99(t,J=8.8Hz,2H)；7.32(dd,J=8.8Hz J′=5.4Hz, 2H)；7.38(s,1H)；7.40(s,1H)(CDCl3)     9a  H  H  F  H  H  C-CH3  N     Cl  CCl     79-82℃ 2934,1531,1512, 1408,1247,1225, 1167,818 KBr 1.74(m,4H)；2.35(s,3H)；2.60-2.72(a.c.,4H)； 2.90(m,2H)；3.33(m,2H)；3.88(m,2H)；5.95(s, 1H)；6.99(t,J=8.6Hz,2H)；7.31(a.c.,2H) (CDCl3)     10a  H  H  H  H  H  C-CH3  N     Cl  CCl     油 2929,1533,1405, 1246,748 膜 1.59(m,2H)；76(m,2H)；2.37(s,3H)；2.49 (t,J=7.3Hz,2H)；2.58(m,2H)；2.69(t,J=5.4Hz, 2H)；3.14(m,2H),3.89(t,J=74Hz,2H)；6.06 (m,1H)；7.22-7.40(a.c.,5H)(CDCl3)     11a  H  H  H  H  H  C-CH3  N     Cl  CCl     ·HCl     203-204℃ 2930,2576,1407, 1376,1245,750, KBr 1.69(m,2H)；1.81(m,2H)；2.35(s,3H)；2.71 (d,J=7.2Hz,1H)；2.91(m,1H)；3.17(a.c.,3H)； 3.56(m,1H)；3.75(m,1H)；3.90-3.97(a.c.,3H)； 6.17(s,1H)；7.25-7.40(a.c.,3H)；7.47 (d,J=7.6Hz,2H)；11.30(b.a.,1H)(DMSO-d6) 实施例 R1  R2 R3 R4 R5  Z1  Z2     R6  Z4    盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂)     12a  H  H  H  H  H  C-CH3  N     Cl  CCl     ·2HCl     192-194℃ 3569,2941,2692, 2556,1601,1446, 769,753,698 KBr 1.67(m,2H)；1.79(m,2H)；2.36(s,3H)；2.69 (d,J=18.0Hz,1H)；2.88(m,1H)；3.15(a.c.,3H)； 3.54(m,1H)；3.72(m,1H)；3.85-3.98(a.c.,3H)； 6.15(s,1H)；7.22-7.38(a.c.,3H)；7.45 (d,J=7.3Hz,2H)；9.93(b.a.,1H)；11.36(b.a.,1H) (DMSO-d6)     13a  H  H  F  H  H  CH CH   CH=CH-CH=CH-C      油 2937,1510,1464, 1230,1161,816, 742 膜 1.61(quin,J=7.7Hz,2H)；1.93(quin,J=7.6Hz, 2H)；2.42-2.58(a.c.,4H)；2.66(t,J=5.6Hz,2H)； 3.11(m,2H)；4.17(t,J=7.0Hz,2H)；5.98(m, 1H)；6.51(d,J=3.9Hz,1H)；6.95-7.39(a.c.,8H)； 7.65(d,J=7.8Hz,1H)(CDCl3)     14a  H  H  H  H  H  CH  CH   CH=CH-CH=CH-C      油 2938,1510,1485, 1463,1446,1376, 1336,1315,763, 740,695 膜 1.63(quin,J=7.4Hz,2H)；1.94(quin,J=7.4Hz, 2H)；2.49(t,J=7.6Hz,2H)；2.60(m,2H)；2.69 (t,J=5.3Hz,2H)；3.14(m,2H)；4.19(t,J=7.1Hz, 2H)；6.08(m,1H)；6.53(m,1H)；7.08-7.44(a.c., 9H)；7.67(d,J=8.1Hz,1H)(CDCl3)     15a  H  H  CH3  H  H  C-CH3  N     Cl  CCl     87-88℃ 2939,2916,1529, 1404,1378,1243, 1166,1131,1016 膜 1.59(m,2H)；1.75(m,2H)；2.32(s,3H)；2.36(s, 3H)；2.47(t,J=7.2Hz,2H)；2.54(m,2H)；2.67 (t,J=5.2Hz,2H)；3.11(m,2H)；3.87(t,J=7.3Hz, 2H)；6.01(s,1H)；7.11(AB system,J=8.1Hz, 2H)；7.27(AB system,J=8.1Hz,2H)(CDCl3)   实施例 R1  R2 R3  R4 R5  Z1  Z2     R6  Z4     盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂)     16a  H  H  H  H  H  N CH     H  CH     36-38℃ 2941,1396,748, 695 膜 1.54(quin,J=7.6Hz,2H)；1.91(quin,J=7.6Hz, 2H)；2.45(t,J=7.6Hz,2H)；2.55(m,2H)；2.65 (t,J=5.6Hz,2H)；3.11(m.2H)；4.14(t,J=7.1Hz, 2H)；6.03(m,1H)；6.21(m,1H)；7.20-7.39(a.c., 6H)；7.49(m,1H)(CDCl3)     17a  H  H  H  H  H  N  CH    CH=CH-CH=CH-C     50-52℃ 2942,1465,1158, 832,740,691 KBr 1.61(quin,2H)；2.00(quin,J=7.5Hz,2H)；2.43- 2.58(a.c.,4H)；2.68(m,2H)；3.14(s,2H)；4.43 (t,J=6.6Hz,2H)；6.02(s,1H)；7.13(t,J=7.3Hz, 1H)；7.20-7.51(a.c.,7H)；7.73(d,J=7.9Hz,1H)； 7.99(s,1H)(CDCl3)     18a  H  H  H  H  H  N    C-CH=CH-     CH=CH  CH     73-75℃ 3049,2940,2778, 1467,1371,1158, 1143,1131,757, 742,692 KBr 1.60(quin,J=7.6Hz,2H)；2.09(quin,J=7.4Hz, 2H)；2.48(t,J=7.4Hz,2H)；2.55(m,2H)；2.66 (t,J=5.6Hz,2H)；3.11(d,J=2.9Hz,2H)；4.45 (t,J=7.1Hz,2H)；6.03(s,1H)；7.07(t,J=7.5Hz' 1H)；7.20-7.39(a.c.,6H)；7.63(d,J=4.3Hz,1h)； 7.70(d,J=8Hz,1H)；7.91(s,1H)(CDCl3)     19a  H  H  CH3  H  H  N CH     Cl  CH     72-73℃ 3115,2938,2740, 1376,1328,1137, 986,966,844, 824,797 KBr 1.55(quin,2H)；1.90(quin,J=7.5Hz,2H)；2.33 (s,3H)；2.46(t,J=7.5Hz,2H)；2.55(m,2H)；2.66 (t,J=64Hz,2H)；3.11(m,2H)；4.10(t,J=7.0Hz, 2H)；6.01(s,1H)；7.12(AB system,J=8Hz,2H)； 7.27(AB system,J=8Hz,2H)；7.37(s,1H)；7.41 (s,1H)(CDCl3)   实施例 R1  R2  R3  R4 R5     Z1  Z2     R6 Z4     盐/m.p.        IRcm-1     1H-RMN(300MHz),δ(溶剂)     20a  H  H CH3  O  H  H  N  CH     Cl  CH     104-105℃ 2923,1533,1405, 1379,1246,749 KBr 1.54(quin,2H)；1.89(quin,J=7.6Hz,2H)；2.44 (t,J=7.4Hz,2H)；2.52(m,2H)；2.65(t,J=5.3Hz, 2h)；3.10(m,2H)；3,78(s,3H)；4.09(t,J=7.0Hz, 2H)；5.95(s,1H)；6.84(AB system,J=8.5Hz, 2H)；7.31(AB system,J=8.5Hz,2H)；7.36(s, 1H)；7.40(s,1H)(CDCl3)     21a  H  H  H  H  H  N  CH     Cl  CH     油 2948,2923,2811, 2774,1446,1382, 1316,971,748, 695 膜 2.08(quin,J=7.0Hz,2H)；2.42(t,J=7.0Hz,2H)； 2.58(m,2H)；2.67(t,J=5.6Hz,2H)；3.13(m, 2H)；4.17(t,J=6.9Hz,2H)；6.07(m,1H)；7.23- 7.45(a.c.,7H)(CDCl3)     22a  H  H  H  H  H  CCH3  N     Cl  CCl     油 2923,1533,1405, 1379,1246,749 膜 1.95(quin,J=7.2Hz,2H)；2.39(s,3H)；2.46 (t,J=7.0Hz,2H)；2.58(m,2H)；2.69(t,J=4.9Hz, 2H)；3.13(m,2H)；3.96(t,J=7.3Hz,2H)；6.07 (m,1H)；7.20-7.41(a.c.,5H)(CDCl3)     23a  H  H  H  H  H  CPh  N     H  CH     油 2940,1496,1474, 1445,1379,1275, 774,698 膜 1.51(m,2H)；1.81(m,2H)；2.40(t,J=7.4Hz, 2H)；2.56(m,2H)；2.63(t,J=4.9Hz,2H)；3.09 (m,2H)；4.04(t,J=7.2Hz,2H)；6.03(m.1H)； 7.03(m,1H)；7.13(m,1H)；7.22-7.48(a.c.,8H)； 7.58(m,2H)(CDCl3)  实施例 R1 R2  R3  R4  R5  Z1  Z2     R6    Z4     盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂)     24a  H  H  CH3  H  H  CH  N    CH=CH-CH=CH-C     90-91℃ 2939,2915,1500, 1461,1377,1365, 750 KBr 1.59(m,2H)；1.95(m,2H)；2.32(s,3H)；2.46 (t,J=7.3Hz,2H)；2.53(m,2H)；2.63(t,J=5.5Hz, 2H)；3.08(m,2H)；4.20(t,J=6.95Hz,2H)；6.00 (s,1H)；7.11(d,J=7.8Hz,2H)；7.27(a.c.,4H)； 7.40(m,1H)；7.80(m,1H)；7.89(s,1H)(CDCl3)     25a  H  H  H  H  H  CH  N     Ph  Cph     100-101℃ 3130,2939,2770, 1600,1506,1443, 1259,954,780, 774,750,696, 649 KBr 1.46(quin,J=7.5Hz,2H)；1.65(quin,J=7.6Hz, 2H)；2.33(t,J=7.3Hz,2H)；2.53(m,2H)；2.60 (m,2H)；3.05(m,2H)；3.84(t,J=7.2Hz,2H)； 6.02(m,1H)；7.05-7.50(a.c.,15H)；7.61(s,1H) (CDCl3)     26a   CH=CH-CH=CH  H  H  H  N  CH  Cl CH     油 3057,3043,2942, 2806,2768,1378, 1365,971,801, 778 膜 1.61(quin,J=7.5Hz,2H)；1.95(quin,J=7.6Hz,2H)； 2.51-2.57(a.c.,4H)；2.76(t,J=56Hz,2H)；3.20(m,2H)； 4.14(t,J=7.1Hz,2H)；5.74(m,1H)；7.26-7.50(a.c.,6H)； 7.75(d,J=8Hz,1H)；7.84(m,1H)；8.02(m,1H)； (CDCl3)     27a  H    CH=CH-CH=CH  H  H  N  CH  Cl CH     95-96℃ 3111,2920,2806, 1374,1326,966, 826,749,612, KBr 1.57(m.2H)；1.92(m,2H)；2.48(m,2H)；2.71 (a.c.,4H)；3.18(m,2H)；4.11(m,2H)；6.22(m,1H)； 7.38-7.50(a.c.,4H)；761(m,1H)；7.75-7.84(a.c.,4H) (CDCl3)

实施例 R1  R2 R3 R4 R5  Z1  Z2    R6     Z4 盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂)     28a  H  H F  H  H  CH  N  CH=CH-CH=CH-C 135-136℃ 3050,2920, 2.54(m,2H)；2.74(t,J=5.6Hz,2h)；2.92(t,J=6.7Hz, 实施例 R1  R2  R3  R4 R5  Z1  Z2     R6 Z4    盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂) 2780, 2760,1510, 1492, 1459,1224, 1202, 1161,771,751 KBr 2H)；3.24(m,2H)；4.35(t,J=6.7Hz,2H)；5.98(m,1H)； 7.00(t,J=8.7Hz,2H)；7.26-7.40(a.c.,4H)；7.42(m,1H)； 7.81(m,1H)；8.01(s,1H)(CDCl3)     29a  H  H  H  H  H  CH  N    CH=CH-CH=CH-C     HCl    177-178℃ 2940,2488, 1500, 1420,1390,742 KBr 1.70-1.90(a.c.,4H)；2.78(m,2H)；3.17(m,2H)； 3.20-3.50(b.a.,2H)；3.79(m,2H)；4.30(t,J=6.6Hz,2H)； 6.15(s,1H)；7.17-7.40(a.c.,5H)；7.45(d,J=7.3Hz,2H)； 7.65(m,2H)；8.35(s,1H)(DMSO-d6)     30a  H  H  F  H  H  CH  N    CH=CH-CH=CH-C    106-108℃ 2942,1512, 1498, 1460,1376, 1221, 756 KBr 1.59(quin,J=7.5Hz,2H)；1.96(quin,J=7.5Hz,2H)；2.40- 2.50(a.c.,4H)；2.63(t,J=5.5Hz,2H)；3.09(m,2H)；4.21 (t,J=7.1Hz,2H)；5.97(m,1H)；6.98(t,J=8.1Hz,2H)； 7.20-735(a.c.,4H)；7.40(m,1H)；7.80(m,1H)；7.89(s, 1H)(CDCl3)     31a  H  H  F  H  H  CH  N    CH=CH-CH=CH-C     HCl 2930,1600, 1510, 1275 KBr 1.70-2.00(a.c.,4H)；2.78(m,2H)；3.20(m,2H)；3.20- 3.60(b.a.,2H)；3.81(m,2H)；4.38(t,J=6.6Hz,2H)；6.13 (s,1H)；7.19(t,J=8.7Hz,2H)；7.33(m,2H)；7.49(m, 2H)；7.71(d,J=7.8Hz,1H)；7.77(d,J=7.6Hz,1H)；8.79 (s,1H)；11.20(b.a.,1H)(DMSO-d6)     32a  H  CF3  H  H  H CCH3  N     Cl  CCl     HCl    205-206℃ 2930,2490, 1330, 1243,1164, 1.67(m,2H)；1.79(m,2H)；2.33(s,3H)；2.79(m,1H)； 2.91(m,1H)；3.10-3.20(a.c.,3H)；3.55(m,1H)；3.77 (m,1H)；3.91-4.00(a.c.,3H)；6.33(s,1H)；7.58-7.80 实施例  R1  R2 R3  R4  R5  Z1  Z2     R6  Z4    盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂) 1119, 1076 KBr (a.c.,4H)；11.32(b.a.,1H)(DMSO-d6)     33a  H  H  F  H  H  N  CH     Cl  CH     HCl   191-192℃ 2543,1512, 1232, 967,807 KBr 1.71-1.85(a.c.,4H)；2.68(m,1H)；2.86(m,1H)；3.10- 3.20(a.c.,3H)；3.55(m,1H)；3.72(m,1H)；3.90(m, 1H)；4.12(t,J=6.5Hz,2H)；6.14(s,1H)；7.20(t,J=8.7Hz, 2H)；7.40-7.55(a.c.,3H)；8.06(s,1H)；11.20(b.a.,1H) (DMSO-d6)     34a  H  H  H  H  H  N  CH    CH=CH-CH=CH-C     HCl   193-194℃ 2931,2566,742 KBr 1.80(m,2H)；1.91(m,2H)；2.67(m,1H)；2.88(m,1H)； 3.10-3.20(a.c.,3H)；3.52(m,1H)；3.71(m,1H)；3.90 (m,1H)；4.46(t,J=6.7Hz,2H)；6.15(s,1H)；7.14 (t,J=7.5Hz,1H)；7.25-7.41(a.c.,4H)；7.46(d,J=8.6Hz, 2H)；7.71(d,J=8.6Hz,1H)；7.75(d,J=8.3Hz,1H)；8.08 (s,1H)；11.18(b.a.,1H)(DMSO-d6)     35a  H  H  F  H  H CCH3  N     Cl  CCl     HCl   160-161℃ 2930,2590, 1512, 1409,1241,827 KBr 1.67(m,2H)；1.79(m,2H)；2.33(s,3H)；2.67(m,1H)； 2.90(m,1H)；3.10-3.25(a.c.,3H)；3.54(m,1H)；3.72 (m,1H)；3.85-3.98(a.c.,3H)；6.13(s,1H)；7.19(m, 2H)；7.50(m,2H)；11.28(b.a.,1H)(DMSO-d6)     36a  H  H  H  H  H  N  CH     4-ClPh  CH     HCl   198-199℃ 2472,1560, 1450, 1095,955；810, 745 KBr 1.77(m,2H)；1.87(m,2H)；2.70(m,1H)；2.86(m,1H)； 3.16(a.c.,3H)；3.55(m,1H)；3.73(m,1H)；3.90(m, 1H)；4.17(t,J=6.6Hz,2H)；6.15(m,1H)；7.25-7.47(a.c., 7H)；7.59(m,2H)；7.90(s,1H)；8.27(s,1H)；10.91 (b.a.,1H)(DMSO-d6) 实施例 R1  R2  R3  R4  R5  Z1  Z2     R6  Z4   盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂)     37a  H  H  H  H  H  N  CH   4-ClPh  CH   126-127℃ 2935,1570, 1493, 1455,1379, 1091, 953,815,746 KBr 1.60(m,2H)；1.97(m,2H)；2.48(t,J=7.3Hz,2H)；2.56 (m,2H)；2.67(t,J=5.1Hz,2H)；3.13(m,2H)；4.18 (t,J=7.1Hz,2H)；6.05(m,1H)；7.23-7.40(a.c.,9H)；7.61 (s,1H)；7.74(s,1H)(CDCl3)     38a  H  H  F  H  H  CH  N     H  N     HCl   166-168℃ 3450,2429, 2707, 2593,1512, 1437, 1230,816,626 KBr 1.74(m,2H)；1.86(m,2H)；2.68(m,1H)；2.84(m,1H)； 3.16(a.c.,3H)；3.53(m,1H)；3.70(m,1H)；3.91(m, 1H)；4.27(t,J=6.7Hz,2H)；6.12(s,1H)；7.19(t,J=8.9Hz, 2H)；7.50(dd,J=8.9Hz,J′=5.5Hz,2H)；8.23(s,1H)；8.93 (s,1H)；11.02(b.a.,1H)(DMSO-d6)     39a  H  H  F  H  H  CH  N     H  N     油 2944,2808, 2773, 1602,1510, 1273, 1227,1161, 1140, 846,824,681 膜 1.60(m,2H)；1.97(m,2H)；2.40-2.70(a.c.,6H)；3.12 (m,2H)；4.22(t,J=6.9Hz,2H)；5.99(m,1H)；6.98(m, 2H)；7.35(m,2H)；7.95(s,1H)；8.07(s.1H)(CDCl3)     40a  H  H  F  H  H CCH3  N    CH=CH-CH=CH-C     油 2932,1512, 1456, 1404,1231,744 膜 1.63(m,2H)；1.88(m,2H)；2.42-2.55(a.c.,4H)；2.61 (s.3H)；2.65(t,J=5.5Hz,2H)；3.09(m,2H)；4.14 (t,J=7.3Hz,2H)；5.97(m,1H)；6.99(m,2H)；7.19-7.35 (a.c.,5H)；7.68(m,1H)(CDCl3)     41a  H  H  F  H  H  N  CH    CH=CH-CH=CH-C     油 2932,2805, 1.57(m,2H)；1.99(m,2H)；2.42-2.50(a.c.,4H)；2.62 实施例 R1  R2  R3  R4  R5  Z1  Z2     R6  Z4    盐/m.p.      IRcm-1     1H-RMN(300MHz),δ(溶剂) 1511, 1465,1230, 1160, 825,752,741 膜 (t,J=5.6Hz,2H)；3.06(m,2H)；4.42(t,J=6.9Hz,2H)； 5.95(m,1H)；6.97(t,J=8.8Hz,2H)；7.12(m,1H)；7.25- 7.41(a.c.,4H)；7.71(d,J=8Hz,1H)；7.99(s,1H) (CDCl3)     42a  H  H  F  H  H  N    C-CH=CH-CH=CH  CH   102-103℃ 2941,1510, 1374, 1226,1162,806, 759,741 KBr 1.59(quin.,J=7.0Hz,2H)；2.09(quin.,J=7.5Hz,2H)； 2.40-2.50(a.c.,4H)；2.64(t,J=6.2Hz,2H)；3.10(m,2H)； 4.45(t,J=7.1Hz,2H)；5.96(m,1H)；6.98(t,J=8.8Hz, 2H)；7.07(t,J=7.6Hz,1H)；7.20-7.35(a.c.,3H)；7.63 (d,J=8.5Hz,1H)；7.71(d,J=8.6Hz,1H)；7.90(s.1H) (CDCl3)     43a  H  H  F  H  H  N    C-CH=CH-CH=CH  N     HCl    208-209℃ 2574,2482, 1510, 1231,745 KBr 1.80(m,2H)；2.11(quin,J=7.2Hz,2H)；2.69(m,1H)； 2.83(m,1H)；3.10-3.20(a.c.,3H)；3.52(m,1H)；3.71 (m,1H)；3.88(m,1H)；4.80(t,J=6.3Hz,2H)；6.11(s, 1H)；7.19(m,2H)；7.41(m,2H)；7.50(m,2H)；7.91(m, 2H)；11.07(b.a.,1H)(DMSO-d6)     44a  H  H  F  H  H  N    C-CH=CH-CH=CH  N    76-77℃ 2913,1511, 1470. 1380,1327, 1224, 1172,1132,851, 826,757 KBr 1.60(quin.,J=7.5Hz,2H)；2.19(quin.,J=8.2Hz,2H)； 2.41-2.59(a.c.,4H)；2.64(t,J=5.7Hz,2H)；3.08(m,2h)； 4.77(t,J=7.0Hz,2H)；5.95(m,1H)；6.97(t,J=8.8Hz, 2H)；7.25-7.40(a.c.,4H)；7.85(m,2H)(CDCl3)     45a  H  H  F  H  H  N  N    CH=CH-CH=CH-C     HCl    204-205℃ 2928,2680, 2573, 2559,1515, 1.81(m,2H)；1.99(m,2H)；2.67(m,1H)；2.84(m,1H)； 3.10-3.20(a.c.,3H)；3.53(m,1H)；3.72(m,1H)；3.90 (m,1H)；4.76(t,J=6.9Hz,2H)；6.12(s.1H)；7.19 实施例 R1  R2  R3  R4  R5  Z1  Z2     R6  Z4   盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂) 1454, 1272,1242, 1224, 1166,819,745 KBr (t,J=8.8Hz,2H)；7.39(t,J=7.6Hz,1H)；7.45-7.60(a.c., 3H)；7.94(d,J=8.3Hz,2H)；8.03(d,J=8.3Hz,2H)；11.04 (b.a.,1H)(DMSO-d6) 46a  H  H  F  H  H  N  N    CH=CH-CH=CH-C    88-90℃ 2939,1510, 1229, 1209,1164,744 KBr 1.58(quin.,J=7.5Hz,2H)；2.07(quin,J=7.5Hz,2H)； 2.40-2.50(a.c.,4H)；2.61(m,2H)；3.05(m,2H)；4.66 (t,J=7.0Hz,2H)；5.95(m,1H)；6.96(t,J=8.8Hz,2H)； 7.23-7.38(a.c.,3H)；7.44(m,1H)；7.52(m,1H)；8.04 (d,J=8.3Hz,1H)(CDCl3) 47a  H  H  Cl  H  H  N  CH     Cl  CH     HCl    172-173℃ 3068,2948, 1491, 1445,1320, 1308, 1096,968,809, 799 KBr 1.71(m,2H)；1.80(m,2H)；2.70(m,1H)；2.83(m,1H)； 3.15-330(a.c.,3H)；3.44(m,1H)；3.72(m,1H)；3.89 (m,1H)；4.11(t,J=6.5Hz,2H)；6.20(s,1H)；7.41(Syst AB,JAB=8.8Hz,2H)；7.48(Syst.AB,JAB=8.8Hz,2H)； 7.52(s,1H)；8.04(s,1H)；10.98(b.a.,1H)(DMSO-d6) 48a  H  H  H  H  H  N  CH     H  CH     HCl    180-181℃ 2955,2929, 2530, 1445,965,761, 745 KBr 1.70-190(a.c.,4H)；2.69(m,1H)；2.89(m,1H)；3.10- 3.20(a.c.,3H)；3.53(m,1H)；3.70(m,1H)；3.91(m, 1H)；4.15(t,J=6.5Hz,2H)；6.16(m,1H)；6.23(m,1H)； 7.28-7.50(a.c.,6H)；7.78(m,1H)；11.26(b.a.,1H) (DMSO-d6) 49a  H  H  H  H  H  CH  N     H  N     HCl    122-123℃ 2937,2370, 1503, 1276,1142,774, 755 1.74(m,2H)；1.84(m,2H)；2.72(m,1H)；2.87(m,1H)； 3.10-3.20(a.c.,3H)；3.54(m,1H)；3.73(m,1H)；3.88 (m,1H)；4.22(t,J=6.6Hz,2H)；6.15(s,1H)；7.27-7.70 (a.c.,3H)；7.47(m,2H)；7.97(s,1H)；8.59(s,1H)；  实施例 R1 R2  R3  R4  R5  Z1  Z2     R6  Z4   盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂) KBr 11.20(b.a.,1H)(DMSO-d6)     50a  H  H  H  H  H  CPh  N     H  CH     HCl   170-171℃ 2930,2554, 1469, 1459,1444, 1278, 1075,774,762, 749,732,711, 702, 690 KBr 1.62-1.78(a.c.,4H)；2.75(m,2H)；3.00(m,2H)；3.25 (m,2H)；3.69(m,2H)；4.08(t,J=6.7Hz,2H)；6.13(s, 1H)；7.07(s,1H)；7.24-7.40(a.c.,3H)；7.42-7.52(a.c., 6H)；7.62(Syst.AB,JAB=7.6Hz,2H)(DMSO-d6)     51a  H  H  H  H  H  CH  CH     H  CH     HCl   197-199℃ 2930,2482, 1448,1280, 1090,732 KBr 1.60-1.80(a.c.,4H)；2.70(m,1H)；2.84(m,1H)；3.08- 3.22(a.c.,3H)；3.50(m,1H)；3.71(m,1H)；3.86-3.96 (a.c.,3H)；5.97(t,J=2.1Hz,2H)；6.16(m,1H)；6 76 (t,J=2.1Hz,2H)；7.25-7.50(a.c.,5H)；10.74(b.a.,1H) (DMSO-d6)     52a  H  H  H  H  H  CH  CH     H  CH   58-60℃ 2928,1498, 1280, 1262,1137, 1087, 1060,747,723, 691 KBr 1.58(m,2H)；1.84(m,2H)；2.47(t,J=7.5Hz,2H)；2.58 (m,2H)；2.68(m,2H)；3.13(m,2H)；3.92(t,J=7.1Hz, 2H)；6.06(m,1H)；6.15(t,J=2.2Hz,2H)；6.67 (t,J=2.2Hz,2H)；7.24-7.42(a.c.,5H)(CDCl3)     53a  H  H  H  H  H  N  CCl   CH=CH-CH=CH-C     油 2939,1495, 1467, 1338,745 膜 1.58(quin,J=7.6Hz,2H)；1.99(quin,J=7.6Hz,2H)； 2.47(m,2H)；2.55(m,2H)；2.65(m,2H)；3.10(m,2H)； 4.36(t,J=7.1Hz,2H)；6.04(m,1H)；7.18-7.42(a.c.,8H)； 7.67(d,J=7.6Hz,1H)(CDCl3)   实施例  R1  R2  R3 R4  R5  Z1  Z2     R6  Z4    盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂)     54a  H  H  H  H  H  N  CCl  CH=CH-CH=CH-C     HCl   164-165℃ 3460,2940, 2550, 1338,743 KBr 1.80(m,2H)；1.90(m,2H)；2.70(m,1H)；2.87(m,1H)； 3.07-3.22(a.c.,3H)；3.52(m,1H)；3.71(m,1H)；3.87 (m,1H)；4.43(t,J=6.6Hz,2H)；6.14(s,1H)；7.20-7.52 (a.c.,7H)；7.65(m,1H)；7.79(m,1H)；11.16(b.a.,1H) (DMSO-d6)     55a  H  H  OH  H  H CCH3  N     Cl  CCl     HCl   216-217℃ 3062,2561, 1516,1248 KBr 1.69(m,2H)；1.75(m,2H)；2.33(s,3H)；2.68(m,1H)； 2.79(m,1H)；3.14(a.c.,3H)；3.55(m,1H)；3.68(m, 1H)；3.87-4.00(a.c.,3H),5.97(s,1H)；6.77(Syst. AB,J=8.8Hz,2H)；7.28(Syst.AB,J=8.8Hz,2H)；9.62 (s,1H)；10.82(b.a.,1H)(DMSO-d6)     56a  H  H  H  H  H  CH  N     Cl  CCl     HCl   166-167℃ 2336,1254 KBr 1.75(a.c.,4H)；2.70(m,1H)；2.87(m,1H)；3.17(a.c., 3H)；3.56(m,1H)；3.74(m,1H)；3.87-4.15(a.c.,3H), 6.17(s,1H)；7.27-7.40(a.c.,3H)；7.47(m,2H),7.91(s, 1H)；11.02(b.a.,1H)(DMSO-d6)     57a  H  H  F  H  H  CH  N     H  N   柠檬酸盐   132-133℃ 1720,1709, 1513,1225, 1193,1166,1133 KBr 1.90(m,2H)；2.08(quint.,J=7.5Hz,2H)；2.86(AB, J=15.5Hz,4H)；2.93(b.a.,2H)；3.29(m,2H)；3.54(t, J=5.9Hz,2H)3.93(b.a.,2H)；4.43(t,J=6.6Hz,2H)； 6.17(b.a.,1H)；7.19(m,2H)；7.59(m,2H)；8.10(s,1H)； 8.60(s,1H)(MeOH-d4)     58a  H  H  Br  H  H  CH  N     H  N   113-115℃ 2939,2773, 2736,1509, 1490,1380, 1271,1140.1071, 1.55(m,2H)；1.95(m,2H)；2.40-255(a.c.,4H)；2.64 (m,2H)；3.08(m,2H), 4.20(t,J=7.1Hz,2H)；6.03(m, 1h)；7.22(AB,J=8.5Hz,2H)；7.40(AB,J=8.5Hz,2H)； 7.93(s,1H)；8.05(s,1H)(CDCl3) 实施例  R1  R2  R3  R4  R5  Z1  Z2     R6  Z4 盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂) 1006,961,844, 827,800,680 KBr     59a  H  H  Br  H  H  CH  N     H  N     HCl 162-164℃ 3066,2937, 2479(b.a.)1514, 1146,1012,802 KBr 1.76(m,2H)；1.84(m,2H)；2.71(m,1H)；2.85(m,1H)； 3.17(a.c.,3H)；3.55(m,1H)；3.74(m,1H)；3.80(m, 1H),4.23(t,J=6.6Hz,2H)；6.22(s,1H)；7.42(Syst. AB,J=8.1Hz,2H)；7.56(Syst.AB,J=8.1Hz,2H)；7.98 (s,1H)；8.60(s,1H)(DMSO-d6)     60a  H  H  Cl  H  H  CH  N     H  N 101-103℃ 2930,2775, 2737,1509, 1493,1381, 1271,1141.1091, 1010,961,847, 828,680 KBr 1.56(quint,J=7.5Hz,2H)；1.97(quint,J=7.5Hz,2H)； 2.40-2.70(a.c.,4H)；2.66(t,J=5.7Hz,2H)；3.10(d,J=3 Hz,2H),4.21(t,J=7.0Hz,2H)；6.04(s,1H)；7.20-7.35 (m,4H)；7.94(s,1H)；8.06(s,1H)(CDCl3)     61a  H  H  Cl  H  H  CH  N     H  N     HCl 165-166℃ 2951,2505(b.a.) 1502,1494, 1275,1136, 1098,1013,810, 686 KBr 1.73(m,2H)；1.83(m,2H)；2.70(m,1H)；2.85(m,1H)； 3.10-3.20(a.c.,3H)；3.54(m,1H)；3.73(m,1H)；3.88 (m,1H),4.22(t,J=6.6Hz,2H)；6.20(s,1H)；7.42(Syst. AB,J=8.6Hz,2H)；749(Syst.AB,J=8.6Hz,2H)；7.97 (s,1H)；8.59(s,1H)；11.17(b.a.,1H)(DMSO-d6)     62a  H  H  Cl  H  H  CPh  N     H  CH      油 1445,1379, 1271, 774,681 膜 1.48(m,2H)；1.80(m,2H)；2.36(t,J=7.4Hz,2H)；2.47 (m,2H)；2.59(m,2H)；3.04(d,J=3Hz,2H),4.03(t, J=7.4Hz,2H)；6.01(s,1H)；7.01(d,J=1.2Hz,1H)； 7.11(d,J=1.2Hz,1H)；7.27(m.,4H)；7.35-7.60(a.c., 5H)(CDCl3)   实施例 R1 R2  R3  R4 R5  Z1  Z2     R6  Z4    盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂)     63a  H  H  Cl  H  H  CPh  N     H  CH     HCl     70℃    (吸湿) 2935,2695, 2591,1493, 1094,777,702 KBr 1.65(m,2H)；1.80(m,2H)；2.67(m,1H)；2.82(m,1H)； 3.05-3.21(a.c.,3H)；3.55(m,1H)；3.69(m,1H)；3.88 (m,1H),4.20(t,J=6.6Hz,2H)；6.18(s,1H)；7.40(Syst. AB,J=8.7Hz,2H)；7.47(Syst.AB,J=8.7Hz,2H)；7.60- 7.80(a.c.,5H)；7.83(s,1H)；7.96(s,1H)(DMSO-d6+ TFA)     64a  H  H  H  H  H CCH3  CH     H CCH  3     油 2929.1408,1299, 746,693 膜 1.65(a.c.,4H)；2.23(s,6H)；2.48(m,2H)；2.58(m.2H)； 2.69(m,2H)；3.15(m,2H)；3.76(t,J=7.2Hz,2H)；5.76 (s,2H)；6.06(s,1H)；7.20-7.40(a.c.,5H)(CDCl3)     65a  H  H  H  H  H CCH3  CH     H CCH  3     HCl 178-180℃ 3434(b.a.),2935, 2560,1443, 1405,1298,748, 692 KBr 1.56(m,2H)；1.77(m,2H)；2.15(s,6H)；2.70(m,1h)； 2.84(m,1H)；3.08-3.22(a.c.,3H)；3.59(m,1H)；3.70- 3.80(a.c,3H)；3.93(m,1H)；)；5.59(s,2H)；6.17(s, 1H)；7.25-7.50(a.c.,5H)；10.72(b.a.,1H)(DMSO-d6)     66a  H  H  Cl  H  H CCH3  CH     H CCH  3  86-88℃ 2933,1493, 1413,1376, 1300,750 膜 1.65(a.c.,4H)；2.24(s,6H)；2.48(m,2H)；2.54(m.2H)； 2.69(m,2H)；3.15(m,2H)；3.77(t,J=7.1Hz,2H)；5.77 (s,2H)；6.06(s,1H)；7.30(m,4H)(CDCl3)     67a  H  H     Cl  H  H CCH3  CH     H CCH  3     HCl 182-184℃ 3432(b.a.),2936, 2570,1495, 1410,1298, 1097,804,752 KBr 1.56(m,2H)；1.76(m,2H)；2.14(s,6H)；2.70(m,1H)； 2.84(m,1H)；3.00-3.28(a.c,3H)；3.58(m,1H)；3.69- 3.77(a.c.,3H)；3.92(m,1H)；)；5.58(s,2H)；6.22(s, 1H)；7.42(AB,J=8.6,2H)；7.50(AB,J=8.6,2H)；10.65 (b.a.,1H)(DMSO-D6)     68a  H  H  Cl  H  H  CH  CH     H  CH 102-104℃ 2931,1492, 1.56(t,J=7.5Hz,2H)；1.84(t,J=7.4Hz,2H)；2.46  实施例 R1 R2  R3  R4  R5  Z1  Z2     R6  Z4 盐/m.p.     IRcm-1     1H-RMN(300MHz),δ(溶剂) 1280,1090,967, 828,727 KBr (t,J=7.5Hz,2H)；2.53(m,2H)；2.66(t,J=5.6Hz,2H)； 3.12(m,2H)；3.92(t,J=7.1Hz,2H)；6.05(m,1H)；6.15 (d,J=1.8Hz,2H)；6.66(d,J=1.8Hz,2H)；7.26(AB,J=8.4, 2H)；7.30(AB,J=8.4,2H)(CDCl3)   69a H  H  Cl  H  H  CH  CH     H  CH   HCl 194-195℃ 2937,2479, 1492,1282, 1096,810,737 KBr 1.72(m,4H)；2.65(m,1H)；2.87(m,1H)；3.08-3.22 (a.c.,3H)；3.52(m,1H)；3.70(m,1H)；3.80-4.00(a.c., 3H)；5.96(t,J=2.1Hz,2H)；6.19(s,1H)；6.76(t,J=2.1Hz, 2H)；7.42(AB,J=8.6Hz,2H)；7.48(AN,J=8.6Hz,2H)； 11.12(b.a.,1H)(DMSO-d6)   70a H  H  Cl  H  H  CH  N     H  N 柠檬酸盐  133℃ 3384(b.a.),3200- 2200(b.a.)1726, 1702,1594, 1432,1221, 1131.802 KBr 1.54(m,2H)；1.83(m,2H)；2.54(Syst.AB,J=15Hz, 2H)；2.63(Syst.AB,J=15Hz,2H)；2.82(m,2H)；3.03 (m,2H)；3.20-3.50(a.c.,4H)；4.21(t,J=6.8Hz,2H)； 6.20(s,1H)；740(Syst.AB,J=8.8Hz,2H)；7.48(Syst. AB,J=8.8Hz,2H)；7.97(s,1H)；8.52(s,1H)(DMSO- d6) 生物学分析

采用Swiss Albino小鼠作为实验动物，用几个分析实验对本发明 化合物的止痛活性进行了研究。对由苯基苯醌诱导的扭曲分析、热板 分析以及热点分析进行了描述。这些说明性的实施例描述了一些药理 学分析，但不应以任何方式限制本发明的范围。

按照E.Siegmund等人(Proc.Soc.Exp.Biol.Med.95:729-731, 1957)所述方法进行由苯基苯醌诱导的扭曲分析。在这项实验中，小 鼠经口服或皮下(s.c.)接受本发明化合物，60分钟后(口服给药) 或30分钟后(皮下给药)，经腹膜(i.p.)注射接受0.02％苯基苯醌 水溶液，剂量为10ml/kg。止痛程度用每个分析剂量下相对于对照组 扭曲程度的百分比来表示。利用所得到的结果，可以计算出半数有效 剂量(ED-50)，也就是说该剂量可以抑制50％由苯基苯醌诱导的扭曲。 按照M.Ocana等人(Europ.J.Pharmacol.168:377-378,1990) 所述的方法进行下列的热板分析。经s.c.或i.p.给予研究产品，30 分钟后开始记录止痛效果。为了进行这项实验，将实验动物置于金属 板上，温度保持在50-55℃，记录动物舔其后爪和跳起来的时间，将 此作为潜伏期。与对照组动物的潜伏期比较，在每个剂量下计算止痛 活性。利用所得到的结果计算ED-50。

按照M.Ocana等人(Br.J.Pharmacol.110:1049-1054,1993) 所描述的方法进行尾部从热点后撤的分析。将小鼠引入一个固定器中， 将其置于尾部轻敲仪器上(L17100,Letica,SA)。将一束光聚焦于 动物的尾部，光的顶部距之4cm远，记录尾部自动后撤的潜伏期。在 给予本发明研究产品10分钟前，记录基本的潜伏期。经s.c.给予产 品后，在10,20,30,40,45,60,90和120分钟时记录尾部后撤的 潜伏期。在R.J.Tallarida和R.B.Murray(带有计算机程序的药理 学计算指南，Springer-Verlag,Berlin,p.297,1987)所描述 方法的时间段内，计算每一只动物在潜伏期曲线下的面积。与对照组 潜伏期曲线下的面积记性比较，计算每个剂量的止痛程度。利用这些 数据可以计算DE-50。

本发明产品在由苯基苯醌诱导的扭曲分析中具有显著的止痛活性。 其中的几种产品具有与吗啡相当的活性，并且比那些可以抑制前列腺 素生物合成的产品(例如阿司匹林和安乃近)具有明显的优势(参见 表3)。

在热板分析中也证实了这些产品的止痛活性，这可以认为是对中枢 神经系统水平上止痛活性的证明(参见表4)。

应用于小鼠身上的热束分析也证实了这些产品的止痛活性，并发 现在所获得的热板分析结果与生热束分析结果之间存在良好的相关性 (参见这些产品的止痛活性表5)。

进一步地，还证明了本发明化合物与其它止痛剂(例如镇痛新)一 起可以显示出协同的止痛活性。这一点可由实施例47a化合物显现出 来(参见表6)。明显地，当将小鼠置于55℃的热板上时，其舔食其 爪子的潜伏时间在合用实施例47a化合物与镇痛新时要比分别使用这 两种药物得到的潜伏时间之和大得多。

总之，本发明产品在不同的止痛分析中显示出明显的止痛活性，例 如苯基苯醌、热板和应用于小鼠尾部的生热束分析。这些产品的活性 明显地优于那些前列腺素生物合成抑制剂，例如阿司匹林和安乃近， 它们具有与吗啡相当的活性。我们还证实了它们与其它止痛剂协同作 用的能力，正如在小鼠热板分析中与镇痛新一起给予实施例47a化合 物所显示的情况一样。

           表3-在小鼠身上由苯基苯醌诱导的扭曲分析中的止痛活性 产    品         ED-50(mg/Kg)  口服途径  S.C.途径 实施例5     20     28 实施例6     80     34 实施例33a     30     2 实施例35a     37     1 实施例38a     5     1 实施例41a     58     6 实施例47a     19     26 实施例48a     38     1 实施例49a     2     1 实施例50a     10     2 实施例51a     9     3 实施例59a     13     2 实施例61a     22     2 实施例63a     44     33 吗啡     4     1 安乃近     223     24 阿司匹林     100     80

        表4-在小鼠热板(55℃)分析中的止痛活性 产    品   ED-50(mg/kg,sc) 实施例38a     7 实施例47a     89 实施例48a     5 实施例49a     4 实施例50a     58 实施例51a     2 实施例59a     43 实施例61a     48 吗啡     2

         表5-小鼠尾部生热束分析中的止痛活性     产    品  ED-50(mg/Kg,sc)     实施例51a     5     实施例59a     60     实施例63a     70     吗啡     4

              表6-在小鼠热板分析中的止痛活性     产品  剂量(mg/kg,ip) 潜伏期(秒) 实施例63a     40     5 实施例63a     10     6 实施例63a     +   镇痛新     40     +     10     20