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CN1314814A - 四氢吡啶(或4－氢哌啶)丁基吡咯衍生物在制备治疗疼痛药物方面的用途 - Google Patents

四氢吡啶(或4－氢哌啶)丁基吡咯衍生物在制备治疗疼痛药物方面的用途 Download PDF

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CN1314814A
CN1314814A CN99810208A CN99810208A CN1314814A CN 1314814 A CN1314814 A CN 1314814A CN 99810208 A CN99810208 A CN 99810208A CN 99810208 A CN99810208 A CN 99810208A CN 1314814 A CN1314814 A CN 1314814A
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tetrahydropyridyl
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CN1134259C (zh
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R·米尔斯－威道
J·弗瑞格拉－坎斯坦萨
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Abstract

式Ⅰ四氢吡啶(或4－羟基哌啶)－丁基吡咯衍生物用于治疗包括人类的哺乳动物中急性疼痛,神经疼痛或感受伤害疼痛。其中R1,R2和R3可相同或不同且为氢原子,C1－C4烷基,羟基或烷氧基,或两个相邻基团形成部分环;A为C原子,虚线为附加的键,或A为与羟基结合的C原子,虚线为无附加键;Z1为N或CR4;Z2为N或CR5;Z4为N或CR7;R4,R5,R6和R7相同或不同,为氢,卤素,C1-C4烷基,芳基或取代芳基,或两个相邻基团形成部分另一环。

Description

四氢吡啶(或4-氢哌啶)丁基吡咯衍生物 在制备治疗疼痛药物方面的用途
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
Figure A9981020800111
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
Figure A9981020800141
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),2950,2810,1375,1130,991,969,760,696,605KBr 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)
769,743,707KBr (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),2949,2919,2838,1276,1145,1135,1006,770,707,676KBr 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 8,2834,1318,1147,1083,1112,990,817,612KBr 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(ABsystem,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=12.9HzJ′=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),2956,2823,1461,1446,1319,1303,1218,1142,738,703KBr 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(ABsystem,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)2947,2532,1396,1378,1119,1046,756,697KBr 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)2953,2803,1465,1375,1133,1117,1043,1017,761,744,704KBr 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)2946,2817,1377,1126,786,735,700KBr 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)2936,1475,1434,1378,1319,989,973,814KBr 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)
1178,971KBr 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)2944,2817,1473,1446,1421,1136,1046,787,773,761,700KBr 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)2939,2806,1 509,1446,773,766,758,696KBr 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)；
1379,1315,1140,1123,972,781,613KBr 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),2950,2820,1377,1311,971,829,761,613KBr 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℃ 3347,2944,2810,1562,1492,1376,1127,1094,1002,952,828,760,699KBr 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℃ 3230,2947,2915,1504,1219,1135,835,746KBr 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     HCl147-148℃ 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℃ 3303,2951,2805,1 506,1464,1376,1218,1162,1118,832,741KBr 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℃ 3325,2950,2923,2812,1509,1377,1218,1131,834,758KBr 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℃ 3400,2931,2812,1509,1229,1101,831,745KBr 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℃ 3430,2952,2925,1508,1223,1140,833,744KBr 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)
1379,1277,1145,1007,824,685KBr (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
Figure A9981020800221
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℃ 3113,2920,2745,1375,1325,1138,965,837,742,688KBr 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℃ 2939,1493,1436,1381,1306,1122,1097,973,843,824,730KBr 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(ABsystem,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℃ 2922,1531,1494,1469,1403,1380,1366,1245,1094,1010KBr 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(ABsystem,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℃ 2936,1512,1378,1326,1229,988,967KBr 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℃ 2934,1531,1512,1408,1247,1225,1167,818KBr 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 ·HCl203-204℃ 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 ·2HCl192-194℃ 3569,2941,2692,2556,1601,1446,769,753,698KBr 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℃ 2942,1465,1158,832,740,691KBr 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℃ 3049,2940,2778,1467,1371,1158,1143,1131,757,742,692KBr 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℃ 3115,2938,2740,1376,1328,1137,986,966,844,824,797KBr 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 CH3O H H N CH Cl CH 104-105℃ 2923,1533,1405,1379,1246,749KBr 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℃ 2939,2915,1500,1461,1377,1365,750KBr 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℃ 3130,2939,2770,1600,1506,1443,1259,954,780,774,750,696,649KBr 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)
2780,2760,1510,1492,1459,1224,1202,1161,771,751KBr 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 HCl177-178℃ 2940,2488,1500,1420,1390,742KBr 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℃ 2942,1512,1498,1460,1376,1221,756KBr 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 2930,1600,1510,1275KBr 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     HCl205-206℃ 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)
1119,1076KBr (a.c.,4H)；11.32(b.a.,1H)(DMSO-d6)
33a H H F H H N CH Cl CH HCl191-192℃ 2543,1512,1232,967,807KBr 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 HCl193-194℃ 2931,2566,742KBr 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 HCl160-161℃ 2930,2590,1512,1409,1241,827KBr 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 HCl198-199℃ 2472,1560,1450,1095,955；810,745KBr 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℃ 2935,1570,1493,1455,1379,1091,953,815,746KBr 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 HCl166-168℃ 3450,2429,2707,2593,1512,1437,1230,816,626KBr 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℃ 2941,1510,1374,1226,1162,806,759,741KBr 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 HCl208-209℃ 2574,2482,1510,1231,745KBr 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℃ 2913,1511,1470.1380,1327,1224,1172,1132,851,826,757KBr 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     HCl204-205℃ 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)
1454,1272,1242,1224,1166,819,745KBr (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℃ 2939,1510,1229,1209,1164,744KBr 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 HCl172-173℃ 3068,2948,1491,1445,1320,1308,1096,968,809,799KBr 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(SystAB,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 HCl180-181℃ 2955,2929,2530,1445,965,761,745KBr 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     HCl122-123℃ 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 HCl170-171℃ 2930,2554,1469,1459,1444,1278,1075,774,762,749,732,711,702,690KBr 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 HCl197-199℃ 2930,2482,1448,1280,1090,732KBr 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℃ 2928,1498,1280,1262,1137,1087,1060,747,723,691KBr 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 HCl164-165℃ 3460,2940,2550,1338,743KBr 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 HCl216-217℃ 3062,2561,1516,1248KBr 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 HCl166-167℃ 2336,1254KBr 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℃ 1720,1709,1513,1225,1193,1166,1133KBr 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)
1006,961,844,827,800,680KBr
59a H H Br H H CH N H N HCl162-164℃ 3066,2937,2479(b.a.)1514,1146,1012,802KBr 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℃ 2930,2775,2737,1509,1493,1381,1271,1141.1091,1010,961,847,828,680KBr 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=3Hz,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 HCl165-166℃ 2951,2505(b.a.)1502,1494,1275,1136,1098,1013,810,686KBr 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 HCl70℃(吸湿) 2935,2695,2591,1493,1094,777,702KBr 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 CCH3 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 CCH3 HCl178-180℃ 3434(b.a.),2935,2560,1443,1405,1298,748,692KBr 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 CCH3 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 CCH3 HCl182-184℃ 3432(b.a.),2936,2570,1495,1410,1298,1097,804,752KBr 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)
1280,1090,967,828,727KBr (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 HCl194-195℃ 2937,2479,1492,1282,1096,810,737KBr 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.)1726,1702,1594,1432,1221,1131.802KBr 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

Claims (7)

1．通式(Ⅰ)的四氢吡啶(或4-氢哌啶)丁基吡咯衍生物或其生理上可接受盐类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，羟基或烷氧基基团，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代表碳原子和羟基之间的(C-OH)，虚线代表缺乏附加键；
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。
2．权利要求1中所述的通式(Ⅰ)化合物或其生理上可接受的盐类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选自氢原子，氟原子，氯原子，溴原子，三氟甲基，羟基，甲氧基，甲基，乙基，丙基，异丙基，仲丁基和叔丁基。
3．权利要求1中所述的通式(Ⅰ)化合物或其生理上可接受的盐类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的选择应使两个相邻的基团可以形成六元芳香环的一部分。
4．权利要求1中所述的通式(Ⅰ)化合物或其生理上可接受的盐类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R4,R5,R6和R7选自氢原子，氟原子，氯原子，溴原子，三氟甲基，羟基，甲氧基，甲基，乙基，丙基，异丙基，仲丁基，叔丁基，苯基，被卤原子取代的苯基。
5．权利要求1中所述的通式(Ⅰ)化合物或其生理上可接受的盐类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R4,R5,R6和R7的选择应使两个相邻的基团可以形成六元芳香环的一部分。
6．权利要求1中所述的通式(Ⅰ)化合物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，式Ⅰ化合物选自下列化合物：
[1]4-氯-1-[4-(4-羟基-4-苯基-1-哌啶基)丁基]-1H-吡唑[2]4,5-二氯-1-[4-(4-羟基-4-苯基-1-哌啶基)丁基]-2-甲基-1H-咪唑
[3]1-[4-(4-羟基-4-苯基-1-哌啶基)丁基]-1H-苯并咪唑
[4]1-[4-(4-羟基-4-苯基--哌啶基)丁基]-1H-1,2,4-三唑
[5]4-氯-1-{4-[4-(4-氯代苯基)-4-羟基-1-哌啶基]丁基}-1H-吡唑
[6]4,5-二氯-1-{4-[4-羟基-4-(4-氯代苯基)-1-哌啶基]丁基}-2-甲基-1H-咪唑
[7]4-氯-1-{4-[4-羟基-4-(3-三氟甲基苯基)-1-哌啶基]丁基}-1H-吡唑
[8]4,5-二氯-1-{4-[4-羟基-4-(3-三氟甲基苯基)-1-哌啶基]丁基}-2-甲基-1H-咪唑
[9]4,5-二氯-1-{4-[4-(4-氟苯基)-4-羟基-1-哌啶基]丁基}-2-甲基-1H-咪唑
[10]1-[4-(4-羟基-4-苯基-1-哌啶基)丁基]-1H-吲哚
[11]4,5-二氯-1-{4-[4-羟基-4-(4-甲基苯基)-1-哌啶基]丁基}-2-甲基-1H-咪唑
[12]1-[4-(4-羟基-4-苯基-1-哌啶基)丁基]-1H-吡唑
[13]1-[4-(4-羟基-4-苯基-1-哌啶基)丁基]-1H-吲唑
[14]2-[4-(4-羟基-4-苯基-1-哌啶基)丁基]-2H-吲唑
[15]4-氯-1-{4-[4-羟基-4-(4-甲基苯基)-1-哌啶基]丁基}-1H-吡唑
[16]4-氯-1-{4-[4-羟基-4-(4-甲氧基苯基)-1-哌啶基]丁基}-1H-吡唑
[17]1-[4-(4-羟基-4-苯基-1-哌啶基)丁基]-2-苯基-1H-咪唑
[18]1-{4-[4-羟基-4-(4-甲基苯基)-1-哌啶基]丁基}-1H-苯并咪唑
[19]4,5-二苯基-1-[4-(4-羟基-4-苯基-1-哌啶基)丁基]-1H-咪唑
[20]4-氯-1-{4-[4-羟基-4-(1-萘基)-1-哌啶基]丁基}-1H-吡唑
[21]4-氯-1-{4-[4-羟基-4-(2-萘基)-1-哌啶基]丁基}-1H-吡唑
[22]4-氯-1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡唑
[23]1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-苯并咪唑
[24]1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-1,2,4-三唑
[25]4-氯-1-{4-[4-(4-氯苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡唑
[26]4,5-二氯-1-{4-[4-(4-氯苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-2-甲基-1H-咪唑
[27]4-氯-1-{4-[4-(3-三氟甲基苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡唑
[28]4,5-二氯-2-甲基-1-{4-[4-(3-三氟甲基苯基)-1-(1,2,3,6-四氢吡啶基)]-丁基}-1H-咪唑
[29]4-氯-1-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡唑
[30]4,5-二氯-1-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-2-甲基-1H-咪唑
[31]4,5-二氯-1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-2-甲基-1H-咪唑
[32]4,5-二氯-1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-2-甲基-1H-咪唑盐酸盐
[33]4,5-二氯-1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-2-甲基-1H-咪唑二盐酸盐
[34]1-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吲哚
[35]1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吲哚
[36]4,5-二氯-2-甲基-1-{4-[4-(4-甲基苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-咪唑
[37]1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡唑
[38]1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吲唑
[39]2-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-2H-吲唑
[40]4-氯-1-{4-[4-(4-甲基苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡唑
[41]4-氯-1-{4-[4-(4-甲氧基苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡唑
[42]4-氯-1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丙基}-1H-吡唑
[43]4,5-二氯-1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丙基}-2-甲基-1H-咪唑
[44]2-苯基-1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-咪唑
[45]1-{4-[4-(4-甲基苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-苯并咪唑
[46]4,5-二苯基-1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-咪唑
[47]4-氯-1-{4-[4-(1-萘基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡唑
[48]4-氯-1-{4-[4-(2-萘基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡唑
[49]1-{2-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]乙基}-1H-苯并吡唑
[50]1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-苯并咪唑盐酸盐
[51]1-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-苯并咪唑
[52]1-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-苯并咪唑盐酸盐
[53]4,5-二氯-2-甲基-1-{4-[4-(3-氟甲基苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-咪唑盐酸盐
[54]4-氯-1-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡唑盐酸盐
[55]1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吲唑盐酸盐
[56]4,5-二氯-1-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-2-甲基-1H-咪唑盐酸盐
[57]4-(4-氯苯基)-1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡唑盐酸盐
[58]4-(4-氯苯基)-1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡唑
[59]1-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-三唑盐酸盐
[60]1-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-三唑
[61]1-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-2-甲基-1H-苯并咪唑
[62]1-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吲唑
[63]2-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-2H-吲唑
[64]2-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-2H-苯并三唑盐酸盐
[65]2-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-2H-苯并三唑
[66]1-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-苯并三唑盐酸盐
[67]2-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-苯并三唑
[68]4-氯-1-{4-[4-(4-氯苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡唑盐酸盐
[69]1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡唑盐酸盐
[70]1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-三唑盐酸盐
[71]2-苯基-1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-咪唑盐酸盐
[72]1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡咯盐酸盐
[73]1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡咯
[74]4-(4-氯苯基)-1-[4-(4-羟基-4-苯基-1-哌啶基)]丁基}-1H-吡唑
[75]1-{4-[4-(4-氟苯基)-4-羟基-1-哌啶基]丁基}-1H-苯并咪唑
[76]4-氯-1-{4-[4-羟基-4-(3-三氟甲基苯基)-1-哌啶基]丁基}-1H-吡唑
[77]1-{4-[4-(4-氟苯基)-4-羟基-1-哌啶基]丁基}-1H-吲唑
[78]2-{4-[4-(4-氟苯基)-4-羟基-1-哌啶基]丁基}-2H-吲唑
[79]2-{4-[4-(4-氟苯基)-4-羟基-1-哌啶基]丁基}-2H-苯并三唑
[80]1-{4-[4-(4-氟苯基)-4-羟基-1-哌啶基]丁基}-1H-苯并三唑
[81]3-氯-1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吲唑
[82]3-氯-1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吲唑盐酸盐
[83]1-{4-[4-羟基-4-(4-氟苯基)-1-哌啶基]丁基}-1H-三唑
[84]1-{4-[4-羟基-4-(4-氯苯基)-1-哌啶基]丁基}-1H-三唑
[85]4,5-二氯-1-{4-[4-(4-羟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-2-甲基-1H-咪唑盐酸盐
[86]4,5-二氯-1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-咪唑盐酸盐
[87]1-{4-[4-(4-氟苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-三唑柠檬酸盐
[88]1-{4-[4-(4-溴苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-三唑
[89]1-{4-[4-(4-溴苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-三唑盐酸盐
[90]1-{4-[4-(4-氯苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-三唑
[91]1-{4-[4-(4-氯苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-三唑盐酸盐
[92]2-苯基-1-{4-[4-(4-氯苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-咪唑
[93]2-苯基-1-{4-[4-(4-氯苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-咪唑盐酸盐
[94]2,5-二甲基-1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡咯
[95]2,5-二甲基-1-{4-[4-苯基-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡咯盐酸盐
[96]2,5-二甲基-1-{4-[4-(4-氯苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡咯
[97]2,5-二甲基-1-{4-[4-(4-氯苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡咯盐酸盐
[98]1-{4-[4-(4-氯苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡咯
[99]1-{4-[4-(4-氯苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-吡咯盐酸盐
[100]1-{4-[4-(4-氯苯基)-1-(1,2,3,6-四氢吡啶基)]丁基}-1H-三唑盐酸盐
7．权利要求1中所述的通式(Ⅰ)化合物或其生理上可接受的盐类与疼痛治疗中常用的另一个止痛剂一起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。
CNB998102083A 1998-07-10 1999-07-09 四氢吡啶(或4-氢哌啶)丁基吡咯衍生物在制备治疗疼痛药物方面的用途 Expired - Fee Related CN1134259C (zh)

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ES2151828B1 (es) 2001-08-16
EP1097698A2 (en) 2001-05-09
EP1097698B1 (en) 2003-05-07
UA57149C2 (uk) 2003-06-16
JP2002520261A (ja) 2002-07-09
WO2000002519A2 (es) 2000-01-20
DK1097698T3 (da) 2003-09-01
IL140854A0 (en) 2003-09-17
AU747073B2 (en) 2002-05-09
CA2336784A1 (en) 2000-01-20
RU2202347C2 (ru) 2003-04-20
ATE239476T1 (de) 2003-05-15
BG64725B1 (bg) 2006-01-31
CZ200175A3 (cs) 2001-07-11
SK372001A3 (en) 2001-10-08
KR100758740B1 (ko) 2007-09-14
ID28817A (id) 2001-07-05
NO20010147L (no) 2001-01-09
HUP0102868A2 (hu) 2001-12-28
AU747073C (en) 2003-06-19
MXPA01000369A (es) 2003-06-19
AR019894A1 (es) 2002-03-20
USRE39113E1 (en) 2006-05-30
NO20010147D0 (no) 2001-01-09
PT1097698E (pt) 2003-09-30
HUP0102868A3 (en) 2003-01-28
DE69907685T2 (de) 2004-03-11
KR20010071824A (ko) 2001-07-31
IL140854A (en) 2006-12-31
NZ509556A (en) 2002-08-28
US6384055B1 (en) 2002-05-07
ES2198136T3 (es) 2004-01-16
TW589317B (en) 2004-06-01
CZ292015B6 (cs) 2003-07-16

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