CN104744558B - 柠檬苦素‑7‑氨基衍生物、其制法以及医药用途 - Google Patents
柠檬苦素‑7‑氨基衍生物、其制法以及医药用途 Download PDFInfo
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Abstract
本发明涉及药物化学领域，具体涉及一类水溶性柠檬苦素‑7‑氨基衍生物(I)和(II)，其制备方法以及医药用途。药理实验证明，本发明化合物具有镇痛和抗炎作用，可用于临床缓解疼痛和炎症疾病。
Description
技术领域
本发明涉及药物化学领域，具体涉及一类水溶性柠檬苦素-7-氨基及脱氧柠檬苦素-7-氨基衍生物，它们的制备方法、以及镇痛、抗炎的作用。
背景技术
我国至少有一亿以上的疼痛患者。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，镇痛成为目前医药工作者面临的重要任务。目前，市售的主流镇痛药按作用机制和结构主要可分为阿片受体激动剂，非甾体抗炎药，以及抗惊厥剂等。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，另一方面由于镇痛药滥用造成的副作用也严重危害着人们的健康。因此，寻找安全、有效、副作用小的镇痛药物具有重大的现实意义和社会意义。
柠檬苦素类(limonoids)化合物是一类广泛存在于柑橘类等芸香科和楝科植物家族中的天然产物。迄今已分离得到大约300多种柠檬苦素类似物，研究发现柠檬苦素类化合物在镇痛、抗炎、抗癌、抗菌、抗病毒、抗氧化等方面具有作用。但是由于作用不够强，水溶性差，生物利用度低，影响了其临床使用。
发明内容
本发明公开了一类I、II通式的化合物，经药理实验显示，本发明的化合物具有较好的镇痛、抗炎活性。因此，本发明的式I、II化合物临床可用于缓解疼痛并且具有消炎的作用。
其中m＝1或2；
R代表：
R1,R2代表C1～C6的烷基；
本发明通式(I)化合物可用下列方法制备：
其中：
由化合物III经肟化制备化合物IV的过程，反应物为盐酸羟胺；催化剂为吡啶、三乙胺或碳酸钾；溶剂为甲醇、乙醇或异丙醇。
由化合物IV经还原制备化合物V的过程，还原剂为氰基硼氢化钠；催化剂为三氯化钛；溶剂为甲醇。
由化合物V经酰胺化制备化合物VI的过程，反应物为氯乙酰氯或3-氯丙酰氯；催化剂为4-二甲氨基吡啶(DMAP)或三乙胺；溶剂为二氯甲烷或四氢呋喃，优选二氯甲烷。
由化合物VI-1或VI-2经取代制备化合物I的过程，反应物为 其中R1,R2代表C1～C6的烷基；缚酸剂为反应物本身或碳酸钾；溶剂为丙酮或四氢呋喃，优选丙酮。
由化合物I经成盐制备化合物I·X的过程，反应物(X)为氯化氢、溴化氢、硫酸、碳酸、柠檬酸、酒石酸、乳酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸；溶剂甲醇、乙醇、二氯甲烷、丙酮、乙酸乙酯或四氢呋喃，或任意两者的混合溶剂。
本发明通式(II)化合物可用下列方法制备：
其中：
由化合物III经脱氧成双键制备化合物VII的过程，反应试剂为氢碘酸；反应溶剂为乙酸。
由化合物VII经肟化制备化合物VIII的过程，反应物为盐酸羟胺；催化剂为吡啶、三乙胺或碳酸钾；溶剂为甲醇、乙醇、乙腈或任意两者的混合溶剂。
由化合物VIII经还原制备化合物IX的过程，还原剂为氰基硼氢化钠；催化剂为三氯化钛；溶剂为甲醇。
由化合物IX经酰胺化制备化合物X的过程，反应物为氯乙酰氯或3-氯丙酰氯；催化剂为DMAP或三乙胺；溶剂为二氯甲烷或四氢呋喃，优选二氯甲烷。
由化合物X-1或X-2经取代制备化合物II的过程，反应物为 其中R1,R2代表C1～C6的烷基；缚酸剂为反应物本身或碳酸钾；溶剂为丙酮或四氢呋喃，优选丙酮。
由化合物II经成盐制备化合物II·X的过程，反应物(X)为氯化氢、溴化氢、硫酸、碳酸、柠檬酸、酒石酸、乳酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸；溶剂甲醇、乙醇、二氯甲烷、丙酮、乙酸乙酯或四氢呋喃，或任意两者的混合溶剂。
本发明的部分化合物的结构如下：
以下是本发明部分化合物的药理实验及结果。
本发明部分化合物的小鼠缩尾实验测试方法和结果如下：
ICR雄性小鼠，18～22g，随机分成对照组、阿司匹林组、柠檬苦素组、本发明化合物组，每组8只。将小鼠尾尖端3cm浸入48℃恒温水浴锅中，将小鼠尾尖端3cm浸入48℃的恒温水浴锅中，给药前测两次(间隔5分钟)，取其平均值。各给药组分别灌胃后，测定各组灌胃后30分钟，60分钟，90分钟，120分钟小鼠的缩尾潜伏期的变化，超过25秒无反应者，痛阈按25秒计。然后根据下列公式计算MPE(％)。结果见图1～3。
MPE(最大可能效应的百分比)＝100×∣(给药后痛阈-基础痛阈)/(强制停止时间-基础痛阈)∣。此处的cut-off time定义为25秒，来保护小鼠尾部皮肤不受损伤。
小鼠缩尾实验结果显示本发明部分化合物能够显著提升小鼠缩尾反应中的痛阈，具有较强的镇痛活性。
本发明部分化合物的小鼠醋酸扭体测试方法和结果如下：
ICR小鼠，雌雄各半，18～22g，随机分成模型组、阿司匹林组、柠檬苦素组、本发明化合物组，每组8只。各组灌胃给药1h后，给小鼠腹腔注射0.7％醋酸0.1ml/10g，立即观察并记录各组动物在15min内的扭体次数，然后根据下列公式计算小鼠扭体的抑制率，结果见表1。
抑制率＝(阴性对照组平均扭体次数－实验组平均扭体次数)÷阴性对照组平均扭体次数×100
表1柠檬苦素衍生物对小鼠醋酸扭体次数的影响(n＝8)
| 化合物 | 剂量(mg/kg) | 扭体次数 | 抑制率(％) |
| 模型 | — | 45.33±6.69 | — |
| 阿司匹林 | 200 | 18.90±3.26** | 58.30 |
| 柠檬苦素 | 70 | 22.83±3.61** | 49.63 |
| I-1·HCl | 70 | 21.67±2.80** | 52.21 |
| I-10·HCl | 70 | 19.33±4.70** | 57.35 |
| II-5·HCl | 70 | 21.75±6.35** | 52.02 |
| II-9·HCl | 70 | 16.63±4.36*** | 63.32 |
| II-10·HCl | 70 | 20.72±3.39** | 54.30 |
注：**P<0.01，***p<0.001与对照组相比。
小鼠醋酸扭体实验结果表明，腹腔注射0.7％醋酸0.1ml/10g后可引起小鼠的腹腔疼痛，出现扭体反应，本发明部分化合物对小鼠扭体反应具有明显的抑制作用。
本发明部分化合物的小鼠耳肿胀实验测试方法和结果如下：
ICR雄性小鼠，18～22g，随机分成模型组、萘普生组、柠檬苦素组、本发明化合物组，每组8只。各组灌胃给药90分钟后，随机分为模型组和各受试药组，每组8只。各组灌胃给药90分钟后在小鼠右耳涂二甲苯25ul致炎，30分钟后拉颈处死，用8mm打孔器对双耳打孔，取耳称重，计算肿胀率(％)和肿胀抑制率(％)。结果见表2。
表2柠檬苦素衍生物对小鼠耳肿胀的影响(n＝8)
| 化合物 | 剂量(mg/kg) | 肿胀率(％) | 肿胀抑制率(％) |
| 模型 | — | 136.68±9.51 | — |
| 萘普生 | 150 | 94.01±8.75** | 31.22 |
| 柠檬苦素 | 100 | 91.03±14.17** | 33.40 |
| I-1·HCl | 100 | 72.56±8.12*** | 46.91 |
| I-5·HCl | 100 | 57.19±6.11***,# | 58.16 |
| I-7·HCl | 100 | 74.06±4.23*** | 45.82 |
| I-8·HCl | 100 | 76.57±4.62** | 43.98 |
| I-9·HCl | 100 | 68.37±12.06*** | 49.98 |
| I-10·HCl | 100 | 64.04±13.35*** | 53.15 |
注：**P<0.01，***P<0.001与对照组相比；#P<0.05与柠檬苦素组相比。
小鼠扭体实验结果显示本发明的化合物对小耳肿胀具有显著的抑制作用。其中化合物I-5·HCl表现出最强活性。
本发明的化合物将柠檬苦素的不溶于水的性质改变为可溶于水。
附图说明
图1是化合物I-1～I-5盐酸盐(100mg/kg)对小鼠缩尾的影响
图2是化合物I-7～I-10盐酸盐(100mg/kg)对小鼠缩尾的影响
图3是化合物II-2、II-4和II-5的盐酸盐(100mg/kg)对小鼠缩尾的影响
具体实施方式
实施例1
化合物IV的制备
在100ml茄形瓶中加入柠檬苦素(III)1.0g(0.002mol)，盐酸羟胺1.1g(0.016mol)，无水乙醇45ml，吡啶15ml，加热回流2.5h。薄层层析(TLC)检测，反应完全后将待反应液冷至室温，将其倒入事先配置好的5％稀盐酸125ml中，调其pH为酸性，冰水冷却。水层用50ml二氯甲烷萃取三次，合并萃取液，饱和食盐水洗三次，无水硫酸钠干燥。过滤，减压蒸除溶剂。粗品用二氯甲烷：甲醇(125:1)柱层析，得白色固体0.98g，收率95％。mp>250℃；1HNMR(CDCl3,500MHz),δ(ppm):7.70(1H,brs),7.39(2H,d,J＝1.7Hz),6.34(1H,s),5.46(1H,s),4.68(1H,d,J＝13.0Hz),4.36(1H,d,J＝13.0Hz),3.99(1H,brs),3.81(1H,s),3.57(1H,d,J＝11.8Hz),2.96(1H,dd,J1＝3.8Hz,J2＝16.7Hz),2.69(1H,dd,J1＝1.5Hz,J2＝16.7Hz),2.42(1H,d,J＝10.2Hz),1.92-2.02(2H,m),1.74–1.88(3H,m),1.49–1.51(1H,m),1.32(3H,s),1.23(3H,s),1.19(3H,s),0.97(3H,s).MS(ESI(-)70V)m/z 520.5([M+Cl]-.
实施例2
化合物V的制备
在250mL茄形瓶中，将1g(2.06mmol)化合物IV与70mL甲醇混合，冰浴下加入0.39g(6.19mmol)NaBH3CN和1.91g(24.74mmol)醋酸铵。在冰浴条件下滴加15mL TiCl3的盐酸溶液，滴毕后撤去冰浴，室温反应12h。TLC检测至反应完全，倒入300mL水中，水层用100mL二氯甲烷萃取三次，弃去二氯甲烷层。水层用NaOH调pH至8.5～9，用100mL二氯甲烷萃取三次，合并萃取液，饱和食盐水洗三次，无水硫酸钠干燥。过滤，减压蒸除溶剂。粗品用二氯甲烷：甲醇(75:1)柱层析，得化合物V白色固体0.61g，收率63％，234℃(分解)。
在25ml的茄形瓶中将0.2g V完全溶解在4ml二氯甲烷中，室温搅拌下缓慢滴入HCl饱和的乙醚溶液10ml，有白色固体析出，搅拌5min后，过滤，用乙醚溶液洗涤，得V·HCl白色固体0.21g，收率97％，244℃(碳化)。V·HCl:IR(KBr,υcm-1):3421,3315,3185,2967,2873,1740,1637,1596,1555,1419,1372,1263,1151,1039,1012,877,839,700,565.1H NMR(500MHz,DMSO),δ(ppm):7.92(brs,3H),7.71(s,1H),7.67(s,1H),6.49(s,1H),5.58(s,1H),4.42(dd,J1＝152.3Hz,J2＝13.2Hz,2H),4.10(s,1H),4.03(d,J＝2.7Hz,1H),3.74(brs,1H),2.60(dt,J1＝16.5Hz,J2＝10.0Hz,2H),2.39(dd,J1＝11.3Hz,J2＝6.9Hz,1H),2.14(d,J＝12.7Hz,1H),2.10–1.97(m,1H),1.95–1.86(m,1H),1.78(dd,J1＝24.6Hz,J2＝13.0Hz,1H),1.68(td,J1＝17.8Hz,J2＝8.5Hz,2H),1.20(s,3H),1.18(s,3H),1.02(s,3H),0.97(s,3H).13C NMR(75MHz,DMSO),δ(ppm):170.49,167.24,143.93,142.36,120.58,110.60,80.23,79.16,77.62,74.88,65.02,58.75,55.96,55.78,45.30,44.84,41.16,39.56,36.04,30.70,25.30,24.06,21.86,18.88,17.33,15.45.HR-ESIMS m/z 472.2329[M+H]+(calcd for C26H34NO7,472.233).
实施例3
化合物VI-1的制备
将1g(2.12mmol)化合物V溶于50mL二氯甲烷中，加入催化量的DMAP。在冰浴条件下，缓慢滴入176μL(2.34mmol)氯乙酰氯，滴毕后撤去冰浴，室温反应。TLC检测至反应完全，用150mL二氯甲烷稀释反应液，饱和食盐水洗三次，无水硫酸钠干燥。过滤，减压蒸除溶剂。粗品用二氯甲烷：甲醇(80:1)柱层析，得化合物VI-1白色固体0.98g，收率84％，m.p.>250℃。1H NMR(500MHz,CDCl3),δ(ppm):7.41(s,1H),7.41(s,1H),6.72(d,J＝8.3Hz,1H),6.31(s,1H),5.54(s,1H),4.48(dd,J1＝34.5Hz,J2＝13.1Hz,2H),4.11(dd,J1＝42.1Hz,J2＝15.4Hz,2H),4.15-4.20(m,1H),4.00(brs,1H),3.83(s,1H),2.93(dd,J1＝16.9Hz,J2＝3.7Hz,1H),2.60(dd,J1＝16.8Hz,J2＝1.7Hz,1H),2.37(dd,J1＝11.8Hz,J2＝5.8Hz,1H),2.14–2.06(m,1H),2.02–1.91(m,2H),1.83–1.67(m,2H),1.55–1.44(m,2H),1.29(s,6H),1.12(s,3H),1.10(s,3H).MS(ESI(-)70V)m/z 546.2[M-H]-.
实施例4
化合物VI-2的制备
以化合物V和3-氯丙酰氯为原料，操作同化合物VI-1的方法，粗品用二氯甲烷：甲醇(80:1)柱层析，得化合物VI-2白色固体0.94g，收率79％，192℃(分解)。1H NMR(500MHz,CDCl3),δ(ppm):7.40(s,2H),6.31(s,1H),5.72(d,J＝8.4Hz,1H),5.52(s,1H),4.46(dd,J1＝31.7Hz,J2＝13.1Hz,2H),4.26–4.12(m,1H),3.99(s,1H),3.97(s,1H),3.86(t,J＝5.7Hz,2H),2.92(dd,J1＝16.8Hz,J2＝3.6Hz,1H),2.74–2.62(m,1H),2.63(dd,J1＝35.3Hz,J2＝16.7Hz,2H),2.36(dd,J1＝11.7Hz,J2＝5.8Hz,1H),2.10(d,J＝13.3Hz,1H),1.96(d,J＝13.3Hz,2H),1.82–1.64(m,2H),1.53–1.47(m,2H),1.29(s,6H),1.11(s,3H),1.07(s,3H).MS(ESI(+)70V)m/z 584.2[M+Na]+.
实施例5
化合物I-1的制备
在50mL茄形瓶中，在15mL丙酮中加入2.74mL(2.74mmol)1M二甲胺的THF溶液和0.63g(4.57mmol)碳酸钾，室温搅拌30min后加入0.5g(0.91mmol)化合物VI-1，升温至60℃反应5h。TLC检测至反应完全，停止冷却后，将反应液减压蒸除大部分溶剂。用150mL二氯甲烷稀释反应液，饱和食盐水洗三次，无水硫酸钠干燥。过滤，减压蒸除溶剂。粗品用二氯甲烷：甲醇(50:1)柱层析，得化合物I-1白色固体0.31g，收率61％，198℃(分解)。1H NMR(500MHz,CDCl3),δ(ppm):7.64(brs,1H),7.39(s,2H),6.30(s,1H),5.52(s,1H),4.48(dd,J1＝38.2Hz,J2＝13.2Hz,2H),4.19(td,J1＝10.2Hz,J2＝4.7Hz,1H),4.00(s,1H),3.94(s,1H),3.13(brs,2H),2.91(dd,J1＝16.8Hz,J2＝3.6Hz,1H),2.59(d,J＝15.7Hz,1H),2.42(s,6H),2.37(dd,J1＝11.9Hz,J2＝5.9Hz,1H),1.97(d,J＝11.7Hz,3H),1.82–1.65(m,2H),1.56–1.43(m,2H),1.30(s,3H),1.27(s,3H),1.11(s,3H),1.09(s,3H).13C NMR(75MHz,CDCl3),δ(ppm):169.06,166.45,142.73,140.74,119.64,109.25,80.27,78.86,77.19,71.74,65.21,61.85,58.52,55.51,55.13,46.59,45.24,45.03,41.76,39.01,35.05,30.20,26.44,25.92,21.17,18.88,18.34,14.50.HR-ESIMS m/z 557.2854[M+H]+(calcdfor C30H41N2O8,557.2857).
以化合物I-1为起始原料，操作同V·HCl的方法，得I-1·HCl白色固体0.20g，收率94％，m.p.>250℃。I-1·HCl:IR(KBr,υcm-1):3415,3197,2973,2873,2666,1737,1672,1549,1472,1363,1283,1260,1142,1045,1033,877,812,700,606,562.1H NMR(500MHz,CDCl3),δ(ppm):11.51(brs,1H),8.84(d,J＝7.6Hz,1H),7.40(s,2H),6.33(s,1H),5.48(s,1H),4.62(d,J＝12.8Hz,1H),4.43(s,1H),4.37(d,J＝12.9Hz,1H),4.24(d,J＝8.6Hz,2H),3.97(d,J＝30.6Hz,2H),3.15(s,3H),3.07(s,3H),2.92(d,J＝16.5Hz,1H),2.63(d,J＝16.6Hz,1H),2.33(d,J＝11.3Hz,1H),1.95–1.63(m,6H),1.59–1.43(m,1H),1.35(s,3H),1.27(s,3H),1.12(s,3H),1.06(s,3H).
实施例6
化合物I-2的制备
以化合物VI-1和二乙胺为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得I-2白色固体0.37g，收率69％，246℃(碳化)。1H NMR(500MHz,CDCl3),δ(ppm):7.78(d,J＝8.7Hz,1H),7.40(s,2H),6.30(s,1H),5.54(s,1H),4.48(dd,J1＝27.15Hz,J2＝13.1,2H),4.10(brs,1H),3.99(s,1H),3.91(s,1H),3.05(dd,J1＝44.7Hz,J2＝17.6Hz,2H),2.92(dd,J1＝16.8Hz,J2＝3.6Hz,1H),2.69–2.46(m,5H),2.43–2.32(m,1H),2.11–2.02(m,1H),2.01–1.90(m,2H),1.82–1.63(m,2H),1.55–1.46(m,1H),1.42–1.30(m,1H),1.28(s,3H),1.26(s,1H),1.11(s,2H),1.09(s,1H),1.06(t,J＝6.9Hz,6H).13C NMR(75MHz,CDCl3),δ(ppm):171.48,169.48,166.75,143.23,141.26,120.16,109.76,80.81,79.36,77.55,77.23,72.59,65.70,58.82,57.58,56.48,55.95,48.85,46.79,45.50,41.86,39.53,35.52,30.75,26.29,26.06,21.69,19.18,18.75,15.00,12.66.HR-ESIMS m/z 585.3177[M+H]+(calcd for C32H45N2O8,585.3179).
以化合物I-2为起始原料，操作同V·HCl的方法，得I-2·HCl白色固体0.18g，收率84％，220℃(分解)。I-2·HCl:IR(KBr,υcm-1):3421,3191,2979,2867,2613,2471,1737,1681,1555,1466,1398,1366,1286,1142,1048,1030,877,803,700,606,556.1H NMR(500MHz,CDCl3),δ(ppm):11.01(brs,1H),9.10(d,J＝8.3Hz,1H),7.42(s,2H),6.35(s,1H),5.50(s,1H),4.60(d,J＝13.0Hz,1H),4.41(s,1H),4.36(d,J＝13.0Hz,1H),4.26(dd,J1＝37.6Hz,J2＝15.8Hz,2H),4.00(s,1H),3.88(s,1H),3.61(d,J＝6.4Hz,1H),3.56–3.44(m,2H),3.39(s,1H),2.93(d,J＝16.5Hz,1H),2.65(d,J＝16.6Hz,1H),2.32(d,J＝11.3Hz,1H),2.00–1.86(m,5H),1.84–1.71(m,3H),1.56(t,J＝6.8Hz,3H),1.50(t,J＝6.6Hz,3H),1.37(s,3H),1.28(s,3H),1.14(s,3H),1.05(s,3H).
实施例7
化合物I-3的制备
以化合物VI-1和吡咯烷为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得I-3白色固体0.33g，收率62％，230℃(碳化)。1H NMR(500MHz,CDCl3),δ(ppm):7.40(s,2H),6.31(s,1H),5.53(s,1H),4.48(dd,J1＝49.7Hz,J2＝13.0Hz,2H),4.22(brs,1H),3.99(s,1H),3.93(s,1H),3.73–2.45(brs,6H),2.92(dd,J1＝16.7Hz,J2＝3.3Hz,1H),2.60(d,J＝16.7Hz,1H),2.43–2.30(m,1H),2.19–1.82(m,6H),1.82–1.62(m,3H),1.60–1.43(m,2H),1.29(s,3H),1.27(s,3H),1.11(s,3H),1.08(s,3H).13C NMR(75MHz,CDCl3),δ(ppm):169.02,166.49,142.73,140.73,119.63,114.12,109.25,80.26,78.89,77.26,76.73,65.24,58.73,55.40,53.83,46.82,45.07,38.96,35.08,30.21,25.88,23.67,21.20,19.00,18.43,14.52.HR-ESIMS m/z 583.3012[M+H]+(calcd for C32H43N2O8,583.3014).
以化合物I-3为起始原料，操作同V·HCl的方法，得I-3·HCl白色固体0.19g，收率89％，248℃(碳化)。IR(KBr,υcm-1):3404,3209,2967,2879,2584,1740,1678,1546,1451,1366,1283,1142,1045,1018,880,803,603,562.
实施例8
化合物I-4的制备
以化合物VI-1和哌啶为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得I-4白色固体0.39g，收率72％，196℃(碳化)。
以化合物I-4为起始原料，操作同V·HCl的方法，得I-4·HCl白色固体0.19g，收率89％，234℃(碳化)。I-4·HCl:IR(KBr,υcm-1):3439,3191,2955,2879,2648,2513,1734,1675,1555,1454,1393,1366,1292,1233,1142,1027,871,809,703,597.1H NMR(300MHz,CDCl3),δ(ppm):10.91(brs,1H),9.15(d,J＝2.8Hz,1H),7.40(s,2H),6.33(s,1H),5.48(s,1H),4.60(d,J＝12.5Hz,1H),4.40(t,J＝25.4Hz,2H),4.12(s,2H),3.99(s,1H),3.93(s,1H),3.68–3.19(m,4H),2.93(d,J＝14.0Hz,1H),2.64(d,J＝16.8Hz,1H),2.31(d,J＝9.8Hz,1H),2.22–2.04(m,2H),2.01–1.71(m,11H),1.36(s,3H),1.27(s,3H),1.12(s,3H),1.05(s,3H).13C NMR(75MHz,CDCl3),δ(ppm):169.19,167.15,163.32,142.71,140.64,119.48,109.24,80.12,78.95,77.80,76.71,69.13,65.42,59.74,57.43,55.80,53.10,52.71,48.23,45.28,43.32,38.61,35.30,30.11,29.84,29.19,26.30,22.74,21.16,21.02,19.80,18.91,14.45.HR-ESIMS m/z 597.3171[M+H]+(calcd for C33H45N2O8,597.3170).
实施例9
化合物I-5的制备
以化合物VI-1和吗啉为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得I-5白色固体0.35g，收率64％，210℃(碳化)。1H NMR(500MHz,CDCl3),δ(ppm):7.55(brs,1H),7.41(s,2H),6.30(s,1H),5.54(s,1H),4.50(dd,J1＝19.0Hz,J2＝13.1Hz,2H),4.08(brs,1H),4.00(s,1H),3.93(s,1H),3.75(s,4H),3.03(s,2H),2.92(dd,J1＝16.9Hz,J2＝3.6Hz,1H),2.69–2.44(m,5H),2.39(dd,J1＝11.8Hz,J2＝6.8Hz,1H),2.15–1.90(m,3H),1.84–1.64(m,2H),1.55–1.47(m,1H),1.44–1.32(m,1H),1.28(s,3H),1.25(s,3H),1.14(s,3H),1.12(s,3H).13C NMR(75MHz,CDCl3),δ(ppm):169.39,169.22,166.66,143.29,141.30,120.04,109.70,80.83,79.32,77.23,67.21,65.60,61.79,58.66,57.14,55.94,53.91,46.52,45.44,41.64,39.67,35.45,30.76,26.04,25.64,21.73,19.08,18.65,15.21.HR-ESIMS m/z 599.2977[M+H]+(calcd for C32H43N2O9,599.2963).
以化合物I-5为起始原料，操作同V·HCl的方法，得I-5·HCl白色固体0.17g，收率78％，248℃(碳化)。IR(KBr,υcm-1):3433,3227,2961,2861,1737,1678,1546,1454,1393,1360,1286,1124,1024,874,806,603.
实施例10
化合物I-6的制备
在50mL茄形瓶中，将0.5g(0.91mmol)化合物VI-2溶于15mL丙酮中，加入181μL(2.74mmol)1M二甲胺的THF溶液，室温搅拌30min后升温至60℃反应24h。TLC检测至反应完全，停止冷却后，将反应液减压蒸除大部分溶剂。用150mL二氯甲烷稀释反应液，饱和食盐水洗三次，无水硫酸钠干燥。过滤，减压蒸除溶剂。粗品用二氯甲烷：甲醇(50:1)柱层析，得化合物I-6白色固体0.22g，收率43％。
以化合物I-6为起始原料，操作同V·HCl的方法，得I-6·HCl白色固体0.15g，收率74％，218℃(分解)。I-6·HCl:IR(KBr,υcm-1):3439,2949,2684,1746,1667,1540,1460,1387,1363,1286,1233,1219,1142,1042,1024,871,806,765,697,597.1H NMR(300MHz,CDCl3),δ(ppm):11.04(s,1H),8.27(s,1H),7.39(s,2H),6.33(s,1H),5.48(s,1H),4.62(d,J＝13.4Hz,1H),4.39(dd,J1＝31.4Hz,J2＝21.0Hz,2H),3.94(d,J＝28.5Hz,2H),3.67–3.35(m,2H),3.13(d,J＝28.9Hz,2H),2.95(s,7H),2.67(d,J＝16.9Hz,1H),2.29(d,J＝10.1Hz,1H),1.99–1.65(m,6H),1.56–1.43(m,1H),1.38(s,3H),1.26(s,3H),1.12(s,3H),0.97(s,3H).13C NMR(75MHz,CDCl3),δ(ppm):169.38,169.01,167.59,142.69,140.60,119.50,109.23,80.11,78.94,77.97,68.49,65.55,59.92,55.37,53.74,52.02,48.55,45.36,43.50,43.16,43.00,38.45,35.39,30.69,30.51,30.05,26.28,21.12,19.97,19.02,13.76.HR-ESIMS m/z 571.3025[M+H]+(calcd for C31H43N2O8,571.3014).
实施例11
化合物I-7的制备
以化合物VI-2和二乙基胺为原料，操作同I-6的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得I-7白色固体0.26g，收率49％，172℃(膨胀)。
以化合物I-7为起始原料，操作同V·HCl的方法，得I-7·HCl白色固体0.17g，收率80％，196℃(分解)。I-7·HCl:IR(KBr,υcm-1):3410,3244,2973,2879,2654,2477,1743,1661,1537,1463,1398,1357,1286,1145,1045,1024,871,812,700,600.1H NMR(300MHz,DMSO),δ(ppm):10.44(s,1H),8.01(d,J＝9.1Hz,1H),7.70(s,1H),7.67(s,1H),6.48(s,1H),5.46(s,1H),4.43(s,2H),4.21(s,1H),4.04(s,1H),3.82(s,1H),3.59(s,5H),3.10(s,4H),2.85–2.66(m,3H),2.59(d,J＝15.9Hz,1H),2.36(d,J＝9.2Hz,1H),2.15(d,J＝10.2Hz,1H),1.98–1.66(m,3H),1.31–1.21(m,9H),1.18(s,3H),0.97(s,3H),0.83(s,3H).13C NMR(75MHz,DMSO),δ(ppm):170.20,168.82,167.30,143.34,141.62,120.32,110.19,79.62,78.71,77.55,70.39,65.28,57.56,54.93,53.23,46.77,46.66,46.46,46.11,45.12,42.72,38.37,35.71,30.12,29.25,28.73,26.25,21.39,19.30,18.00,14.06,8.51,8.36.HR-ESIMS m/z 599.3329[M+H]+(calcd for C33H47N2O8,599.3327).
实施例12
化合物I-8的制备
以化合物VI-2和吡咯烷为原料，操作同I-6的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得I-9白色固体0.24g，收率45％，176℃(分解)。
以化合物I-8为起始原料，操作同V·HCl的方法，得I-8·HCl白色固体0.15g，收率74％，176℃(膨胀)。I-8·HCl:IR(KBr,υcm-1):3421,3256,2955,2873,2690,2589,2477,1737,1664,1549,1457,1398,1289,1236,1145,1042,1027,874,812,700,597.1H NMR(500MHz,CDCl3),δ(ppm):11.16(s,1H),8.18(d,J＝8.3Hz,1H),7.39(s,2H),6.33(s,1H),5.48(s,1H),4.61(d,J＝13.1Hz,1H),4.39(s,1H),4.34(d,J＝13.0Hz,1H),3.96(d,J＝20.8Hz,1H),3.87(s,1H),3.82(s,2H),3.66–3.51(m,2H),3.48(q,J＝7.0Hz,1H),3.30–2.96(m,4H),2.92(dd,J1＝16.7Hz,J2＝3.5Hz,1H),2.66(d,J＝16.4Hz,1H),2.36(s,3H),2.29(d,J＝10.1Hz,1H),2.17(s,4H),1.91–1.76(m,4H),1.38(s,3H),1.26(s,3H),1.12(s,3H),0.97(s,3H).13C NMR(75MHz,CDCl3),δ(ppm):169.80,169.53,167.85,143.14,141.06,120.02,109.71,80.58,79.44,78.41,77.19,69.03,66.02,60.40,55.83,54.33,53.97,52.60,51.28,48.97,45.83,43.91,38.93,35.85,31.94,31.03,30.54,26.74,23.38,21.60,20.42,19.49,14.31.HR-ESIMS m/z 597.3169[M+H]+(calcd for C33H45N2O8,597.317).
实施例13
化合物I-9的制备
以化合物VI-2和哌啶为原料，操作同I-6的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得I-9白色固体0.27g，收率50％，m.p.>192℃。
以化合物I-9为起始原料，操作同V·HCl的方法，得I-9·HCl白色固体0.18g，收率83％，212℃(分解)。I-9·HCl:IR(KBr,υcm-1):3421,3256,2955,2654,2548,1737,1664,1540,1454,1395,1366,1289,1260,1142,1048,1021,880,809,771,697,603,550.1H NMR(500MHz,CDCl3),δ(ppm):10.60(s,1H),8.25(d,J＝8.9Hz,1H),7.40(s,1H),7.39(s,1H),6.34(s,1H),5.48(s,1H),4.64(d,J＝13.0Hz,1H),4.38(s,1H),4.34(d,J＝13.3Hz,1H),3.98(s,1H),3.92(s,1H),3.77–3.59(m,2H),3.48(dd,J1＝14.1Hz,J2＝7.0Hz,2H),3.30–3.02(m,2H),2.99–2.73(m,7H),2.66(d,J＝16.5Hz,1H),2.29(d,J＝11.0Hz,1H),2.19–2.04(m,2H),2.00–1.85(m,5H),1.38(s,3H),1.26(s,3H),1.11(s,3H),0.98(s,3H).13C NMR(75MHz,CDCl3),δ(ppm):169.89,167.94,143.12,141.15,120.00,109.76,80.59,79.43,78.35,69.08,65.99,60.37,55.82,54.02,53.63,53.30,52.56,49.02,45.83,43.95,38.94,35.89,31.04,30.51,30.41,26.72,22.79,21.91,21.53,20.45,19.47,14.29.HR-ESIMS m/z 611.3327[M+H]+(calcd for C34H47N2O8,611.3327).
实施例14
化合物I-10的制备
以化合物VI-2和吗啉为原料，操作同I-6的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得I-10白色固体0.32g，收率59％，m.p.>250℃。
以化合物I-10为起始原料，操作同V·HCl的方法，得I-10·HCl白色固体0.18g，收率83％，218℃(分解)。I-10·HCl:IR(KBr,υcm-1):3415,3256,2967,2873,2566,2460,1746,1664,1543,1460,1390,1289,1124,1045,1024,877,800,762,694,597,553.1H NMR(500MHz,CDCl3),δ(ppm):11.56(s,1H),8.07(s,1H),7.39(s,2H),6.33(s,1H),5.47(s,1H),4.63(d,J＝11.7Hz,1H),4.36(s,2H),4.20–4.00(m,4H),3.95(d,J＝26.7Hz,2H),3.47(s,1H),3.21(s,1H),2.91(d,J＝16.2Hz,1H),2.67(d,J＝16.5Hz,1H),2.48(s,4H),2.30(d,J＝10.4Hz,1H),1.90–1.76(m,3H),1.37(s,3H),1.26(s,3H),1.11(s,3H),0.96(s,3H).13C NMR(75MHz,CDCl3),δ(ppm):169.93,169.43,167.93,143.16,141.14,119.94,109.72,80.57,79.41,78.38,69.15,66.00,63.72,60.30,55.85,53.54,52.55,48.97,45.83,43.89,38.92,35.89,30.94,30.52,30.08,26.79,21.57,20.42,19.43,14.27.HR-ESIMS m/z 613.3119[M+H]+(calcd for C33H45N2O9,613.312).
实施例15
化合物VII的制备
在250mL的茄形瓶中依次加入4g(9mmol)柠檬苦素，70mL氢碘酸和70mL醋酸，在60℃反应。TLC跟踪至反应完全，待反应液冷却后缓慢倒入400mL饱和亚硫酸钠溶液中，用150mL二氯甲烷萃取三次，合并萃取液，分别用饱和碳酸氢钠溶液，饱和食盐水各洗二次，无水硫酸钠干燥。过滤，减压蒸除溶剂。粗品用乙腈和水重结晶，得白色或淡黄色晶体2.7g，收率70％，m.p.>250℃。IR(KBr,υcm-1):3486,3162,2943,2884,1743,1702,1605,1502,1401,1451,1401,1372,1286,1157,1021,874,806,700,606,576.1H NMR(CDCl3,500MHz),δ(ppm):7.50(s,1H),7.45(s,1H),6.85(s,1H),6.42(d,J＝0.95Hz,1H),5.01(s,1H),4.63(dd,J1＝56.0Hz,J2＝13.1Hz,2H),4.11(brs,1H),2.98(dd,J1＝16.9Hz,J2＝3.6Hz,1H),2.82(t,J＝16.0Hz,1H),2.65(dd,J1＝16.9Hz,J2＝1.95Hz,1H),2.61(dd,J1＝16.1Hz,J2＝3.8Hz,1H),2.54(q,J＝7.4Hz,1H),2.31(dd,J1＝15.8Hz,J2＝3.7Hz,1H),2.13–2.03(m,1H),1.91-1.81(m,1H),1.65–1.54(m,1H),1.61–1.58(m,1H),1.42(s,3H),1.31(s,3H),1.26(s,3H),1.20(s,3H).MS(ESI(-)70V)m/z 455.2[M+H]+.
实施例16
化合物VIII的制备
在100mL茄形瓶中加入1.0g(2mmol)化合物VII，0.15g(2.2mmol)盐酸羟胺，0.35g(2.5mmol)碳酸钾，无水乙醇20mL，乙腈20mL，加热回流5h。TLC跟踪至反应完全，待反应液冷至室温，过滤除去碳酸钾固体，将滤液浓缩至3mL后，用150mL二氯甲烷稀释，用饱和食盐水洗三次，无水硫酸钠干燥。过滤，减压蒸除溶剂。粗品用二氯甲烷：甲醇(125:1)柱层析，得白色固体0.70g，收率70％，248℃(碳化)。IR(KBr,υcm-1):3681,3522,3339,3120,2926,1737,1678,1507,1422,1304,1157,1051,974,880,691,556.1H NMR(CDCl3,500MHz),δ(ppm):7.75(brs 1H,),7.50(s,1H),7.43(s,1H),6.72(s,1H),6.41(d,J＝1.05Hz,1H),5.10(s,1H),4.47(dd,J1＝46.3Hz,J2＝13.0Hz,2H),4.06(brs,1H),3.33(dd,J1＝22.0Hz,J2＝4.8Hz,1H),2.93(dd,J1＝10.05Hz,J2＝3.6Hz,1H),2.63(dd,J1＝16.8Hz,J2＝2.3Hz,1H),2.41(q,J＝5.7Hz,1H),2.31(dd,J1＝17.1Hz,J2＝14.9Hz,1H),2.13–1.96(m,2H),1.86-1.78(m,1H),1.78–1.51(m,2H),1.47(s,3H),1.33(s,3H),1.28(s,3H),1.20(s,3H).13C NMR(75MHz,DMSO),δ(ppm):170.34,164.90,159.62,143.23,141.75,120.24,116.68,110.32,81.01,80.04,77.85,64.23,56.33,54.85,45.51,45.32,44.81,37.92,35.70,30.27,28.30,25.85,21.59,20.00,19.79,16.58.MS(ESI(+)70V)m/z 470.2[M+H]+.
实施例17
化合物IX的制备
以化合物VIII为原料，操作同V的方法，粗品用二氯甲烷：甲醇(75:1)柱层析，得白色固体IX 0.44g，收率45％。
以化合物IX为起始原料，操作同V·HCl的方法，得V·HCl白色固体0.20g，收率93％，m.p.>250℃。IX·HCl:IR(KBr,υcm-1):3436,3130,2951,2885,1722,1616,1510,1460,1360,1281,1281,1154,1101,1024,945,871,808,771,697,597.1H NMR(500MHz,DMSO),δ(ppm):8.10(brs,3H),7.71(s,1H),7.69(s,1H),6.51(s,1H),6.13(s,1H),5.11(s,1H),4.53(dd,J1＝58.6Hz,J2＝13.3Hz,2H),3.96(brs,2H),2.68–2.54(m,3H),2.25–2.11(m,1H),2.07–1.91(m,2H),1.76–1.48(m,3H),1.22(s,3H),1.16(s,3H),1.15(s,3H),1.01(s,3H).13C NMR(75MHz,DMSO),δ(ppm):171.64,170.46,164.62,143.79,142.17,120.65,116.24,110.77,81.46,80.30,79.05,65.53,54.66,50.03,45.78,43.86,37.76,37.59,35.89,30.39,27.41,25.68,21.87,21.65,17.39,16.14,4.24.HR-ESIMS m/z 456.2375[M+H]+(calcd for C26H34NO6,456.2381).
实施例18
化合物X-1的制备
以化合物IX和氯乙酰氯为原料，操作同化合物VI-1的方法，粗品用二氯甲烷：甲醇(80:1)柱层析，得X-1白色固体1.03g，收率88％，216℃(分解)。1H NMR(500MHz,CDCl3),δ(ppm):7.48(s,1H),7.44(s,1H),6.70(d,J＝7.9Hz,1H),6.40(s,1H),5.79(s,1H),4.99(s,1H),4.51(dd,J1＝32.8Hz,J2＝13.3Hz,2H),4.42(d,J＝7.7Hz,1H),4.08(s,1H),4.06(s,2H),2.98–2.85(m,1H),2.56(d,J＝16.7Hz,1H),2.20(t,J＝9.8Hz,1H),2.07–1.91(m,4H),1.91–1.81(m,1H),1.64–1.52(m,2H),1.28(s,3H),1.24(s,3H),1.22(s,3H),1.14(s,3H).MS(ESI(+)70V)m/z554.2[M+Na]+.
实施例19
化合物X-2的制备
以化合物IX和3-氯丙酰氯为原料，操作同化合物VI-1的方法，粗品用二氯甲烷：甲醇(80:1)柱层析，得X-2白色固体1.02g，收率85％，210℃(碳化)。1H NMR(500MHz,CDCl3),δ(ppm):7.46(s,1H),7.44(s,1H),6.71(s,1H),6.38(s,1H),5.84(s,1H),4.97(s,1H),4.68–4.39(m,3H),4.06(s,1H),3.90–3.75(m,1H),3.75–3.58(m,1H),2.93(d,J＝45.9Hz,1H),2.82(d,J＝13.6Hz,1H),2.70–2.55(m,2H),2.51(d,J＝16.5Hz,1H),2.36(t,J＝9.5Hz,1H),2.12(d,J＝13.7Hz,1H),2.05–1.73(m,5H),1.23(s,3H),1.20(s,3H),1.18(s,3H),1.10(s,3H).MS(ESI(+)70V)m/z 568.2[M+Na]+.
实施例20
化合物II-1的制备
以化合物X-1和1M二甲胺的THF溶液为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得II-1白色固体0.13g，收率26％，198℃(收缩)。
以化合物II-1为起始原料，操作同V·HCl的方法，得II-1·HCl白色固体0.13g，收率61％，m.p.>250℃。II-1·HCl:IR(KBr,υcm-1):3445,3221,3073,2967,2884,1708,1555,1466,1416,1360,1286,1260,1201,1154,1092,1024,877,812,700,603.1H NMR(500MHz,CDCl3),δ(ppm):12.23(s,1H),9.29(s,1H),7.49(s,1H),7.43(s,1H),6.41(s,1H),5.82(s,1H),4.96(s,1H),4.59(s,1H),4.50(d,J＝8.1Hz,2H),4.32(s,1H),3.80(d,J＝40.1Hz,2H),3.48(d,J＝6.8Hz,1H),2.94(s,4H),2.89(s,4H),2.70(d,J＝13.9Hz,1H),2.53(d,J＝17.5Hz,1H),2.17(s,1H),2.00(s,1H),1.90(s,2H),1.35(s,3H),1.32(s,3H),1.26(s,3H),1.14(s,3H).13C NMR(75MHz,DMSO),δ(ppm):174.22,170.14,164.65,163.13,143.30,141.67,120.15,112.57,110.24,80.96,79.92,78.52,65.38,57.57,51.74,50.93,45.39,44.62,42.94,42.44,37.96,37.37,35.51,29.63,26.85,25.20,24.16,21.47,17.38,15.94.HR-ESIMS m/z 541.2909[M+H]+(calcd for C30H41N2O7,541.2908).
实施例21
化合物II-2的制备
以化合物X-1和二乙胺为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得II-2白色固体0.41g，收率77％，172℃(分解)。
以化合物II-2为起始原料，操作同V·HCl的方法，得II-2·HCl白色固体0.16g，收率75％。II-2·HCl:IR(KBr,υcm-1):3439,3197,2979,2890,2578,2477,1749,1678,1563,1463,1363,1286,1257,1154,1098,1021,930,874,812,697,600.1H NMR(500MHz,CDCl3),δ(ppm):11.20(brs,1H),9.32(d,J＝9.8Hz,1H),7.48(s,1H),7.44(s,1H),6.41(s,1H),5.84(s,1H),4.96(s,1H),4.59(d,J＝9.4Hz,1H),4.49(q,J＝13.7Hz,2H),4.34(s,1H),4.08(d,J＝15.1Hz,1H),3.84(d,J＝15.4Hz,1H),3.61–3.44(m,1H),3.42–3.14(m,3H),2.99–2.83(m,2H),2.76(d,J＝13.9Hz,1H),2.53(d,J＝16.7Hz,1H),1.99(t,J＝14.1Hz,1H),1.90(d,J＝7.3Hz,2H),1.62–1.49(m,3H),1.43(t,J＝7.1Hz,3H),1.38(t,J＝7.1Hz,3H),1.33(s,3H),1.30(s,3H),1.24(s,3H),1.13(s,3H).13C NMR(75MHz,CDCl3),δ(ppm):173.59,169.85,165.18,162.87,143.19,141.33,119.70,113.63,109.92,82.27,80.44,78.68,66.13,52.25,51.63,49.02,48.77,45.62,45.03,38.39,38.24,35.38,29.69,27.97,25.97,24.83,21.58,17.85,17.40,10.01.HR-ESIMS m/z569.3217[M+H]+(calcd forC32H45N2O7,569.3221).
实施例22
化合物II-3的制备
以化合物X-1和吡咯烷为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得II-3白色固体0.38g，收率71％，228℃(分解)。
以化合物II-3为起始原料，操作同V·HCl的方法，得II-3·HCl白色固体0.18g，收率85％，244℃(碳化)。II-3·HCl:IR(KBr,υcm-1):3446,3215,2061,2967,2884,2584,1743,1716,1556,1460,1384,1290,1260,1148,1042,1022,927,871,812,768,703,603.1H NMR(300MHz,DMSO),δ(ppm):10.35(brs,1H),9.25(d,J＝9.9Hz,1H),7.71(s,1H),7.70(d,J＝1.6Hz,1H),6.51(s,1H),5.64(s,1H),5.08(s,1H),4.54(q,J＝13.7Hz,2H),4.41(d,J＝9.8Hz,1H),4.25–4.02(m,2H),3.91(dd,J1＝15.4Hz,J2＝7.3Hz,1H),3.65–3.52(m,2H),3.12–2.78(m,2H),2.75–2.52(m,4H),2.14(t,J＝13.5Hz,1H),2.06–1.80(m,5H),1.80–1.46(m,2H),1.38(d,J＝13.0Hz,1H),1.18(s,6H),1.15(s,3H),1.00(s,3H).13C NMR(75MHz,DMSO),δ(ppm):174.07,170.13,164.62,163.53,143.31,141.68,120.15,112.63,110.25,80.95,79.93,78.62,65.32,54.97,53.54,53.48,51.66,51.11,45.40,44.62,38.15,37.38,35.54,29.69,26.86,25.18,24.17,22.60,22.46,21.46,17.39,15.93.HR-ESIMS m/z 567.3062[M+H]+(calcd for C32H43N2O7,567.3065).
实施例23
化合物II-4的制备
以化合物X-1和哌啶为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得II-4白色固体0.32g，收率66％，186℃(分解)。
以化合物II-4为起始原料，操作同V·HCl的方法，得II-4·HCl白色固体0.16g，收率71％，248℃(碳化)。II-4·HCl:IR(KBr,υcm-1):3448,3209,3050,2950,2884,2643,2530,1740,1716,1556,1454,1387,1360,1290,1260,1225,1198,1148,1098,1022,939,924,875,812,774,694,600.1H NMR(500MHz,CDCl3),δ(ppm):11.63(brs,1H),9.47(d,J＝9.5Hz,1H),7.46(s,1H),7.43(s,1H),6.39(s,1H),5.79(s,1H),4.96(s,1H),4.58(d,J＝8.9Hz,1H),4.50(q,J＝13.4Hz,2H),4.34(s,1H),3.83(d,J＝11.1Hz,1H),3.63(d,J＝9.9Hz,1H),3.43(d,J＝10.2Hz,2H),3.06(d,J＝9.9Hz,1H),2.90(dd,J1＝12.4Hz,J2＝7.0Hz,3H),2.73(d,J＝13.6Hz,1H),2.54(d,J＝16.8Hz,1H),2.16–1.85(m,8H),1.64–1.43(m,4H),1.36(s,3H),1.31(s,3H),1.25(s,3H),1.13(s,3H).13C NMR(75MHz,CDCl3),δ(ppm):173.66,169.85,165.12,161.89,143.17,141.32,119.67,113.75,109.88,82.26,80.32,78.73,66.16,59.34,53.71,53.37,52.97,51.93,45.61,44.90,38.47,38.36,35.27,29.81,27.94,25.88,24.72,22.93,21.62,21.43,18.09,17.42.HR-ESIMS m/z581.3223[M+H]+(calcdfor C30H45N2O7,581.3221).
实施例24
化合物II-5的制备
以化合物X-1和吗啉为原料，操作同I-1的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得II-5白色固体0.39g，收率71％，198℃(分解)。
以化合物II-5为起始原料，操作同V·HCl的方法，得II-5·HCl白色固体0.19g，收率87％，240℃(碳化)。II-5·HCl:IR(KBr,υcm-1):3428,3204,3069,2922,2853,1751,1718,1681,1555,1461,1359,1293,1257,1228,1126,1097,1024,873,812,702,608.1H NMR(500MHz,CDCl3),δ(ppm):12.54(brs,1H),9.34(d,J＝9.7Hz,1H),7.48(s,1H),7.44(s,1H),6.40(s,1H),5.76(s,1H),4.96(s,1H),4.57(d,J＝9.4Hz,1H),4.55–4.43(m,2H),4.30(s,1H),4.12–3.94(m,4H),3.86(d,J＝13.9Hz,1H),3.72(d,J＝13.8Hz,1H),3.38(s,1H),3.31(d,J＝11.7Hz,3H),2.91(dd,J1＝16.9,J2＝3.1Hz,1H),2.84(t,J＝9.8Hz,1H),2.66(d,J＝14.4Hz,1H),2.54(d,J＝16.9Hz,1H),2.00(t,J＝14.1Hz,1H),1.96–1.86(m,2H),1.68(s,2H),1.62(d,J＝14.2Hz,1H),1.58–1.47(m,2H),1.34(s,3H),1.29(s,3H),1.26(s,3H),1.13(s,3H).13C NMR(75MHz,DMSO),δ(ppm):174.21,170.12,164.69,162.65,143.30,141.68,120.14,112.58,110.26,80.95,79.94,78.59,65.33,62.78,56.39,51.78,51.07,45.40,44.62,38.11,37.40,35.52,29.65,26.82,25.17,24.15,21.46,17.39,15.92.HR-ESIMS m/z 583.3010[M+H]+(calcd for C32H43N2O8,583.3014).
实施例25
化合物II-6的制备
以化合物X-2和1M二甲胺的THF溶液为原料，操作同I-6的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得II-6白色固体0.11g，收率22％。
以化合物II-6为起始原料，操作同V·HCl的方法，得II-6·HCl白色固体0.18g，收率85％。II-6·HCl:IR(KBr,υcm-1):3412,2057,2930,2853,2677,1746,1718,1640,1563,1444,1404,1224,1151,1020,877,808,604,506.1H NMR(300MHz,CDCl3),δ(ppm):10.93(s,1H),8.89(d,J＝10.0Hz,1H),7.49(s,1H),7.45(s,1H),6.42(s,1H),5.84(s,1H),4.97(s,1H),4.70–4.46(m,3H),4.38(s,1H),3.40(s,2H),3.19–3.03(m,1H),2.98–2.81(m,9H),2.75(d,J＝13.6Hz,1H),2.57(d,J＝16.4Hz,1H),2.08–1.96(m,3H),1.68–1.48(m,3H),1.36(s,3H),1.34(s,3H),1.25(s,3H),1.15(s,3H).13C NMR(75MHz,CDCl3),δ(ppm):173.53,169.57,168.29,165.26,142.68,140.86,119.18,113.22,109.42,81.90,80.05,78.23,65.65,54.16,51.62,51.33,45.10,44.82,42.99,42.67,38.06,37.85,34.94,30.66,29.44,29.20,27.17,25.29,24.11,21.08,17.29,16.90.HR-ESIMS m/z 555.3077[M+H]+(calcd for C31H43N2O7,555.3065).
实施例26
化合物II-9的制备
以化合物X-2和哌啶为原料，操作同I-6的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得II-9白色固体0.39g，收率72％，228℃(分解)。
以化合物II-9为起始原料，操作同V·HCl的方法，得II-9·HCl白色固体0.13g，收率61％。II-9·HCl:IR(KBr,υcm-1):3433,3244,3055,2943,2878,2654,2548,1743,1717,1667,1546,1454,1384,1289,1254,1222,1195,1148,1098,1039,1015,874,812,697,600,579.1H NMR(300MHz,CDCl3),δ(ppm):10.40(brs,1H),8.97(brs,1H),7.46(s,1H),7.43(s,1H),6.39(s,1H),5.82(s,1H),4.95(s,1H),4.64–4.45(m,3H),4.35(s,1H),3.58–3.03(m,5H),2.81(dd,J1＝32.7Hz,J2＝15.0Hz,6H),2.65–2.40(m,5H),1.93(dd,J1＝33.1Hz,J2＝12.9Hz,9H),1.34(s,3H),1.32(s,3H),1.22(s,3H),1.12(s,3H).13C NMR(75MHz,CDCl3),δ(ppm):173.51,169.59,168.87,165.18,142.65,140.83,119.22,113.19,109.44,81.88,80.03,78.19,65.70,53.47,53.21,52.86,51.59,51.29,45.09,44.84,38.03,37.79,34.92,29.99,29.44,29.19,27.19,25.32,24.09,22.50,21.36,21.09,17.36,16.91.HR-ESIMS m/z 595.3384[M+H]+(calcd for C34H47N2O7,595.3378).
实施例27
化合物II-10的制备
以化合物X-2和吗啉为原料，操作同I-6的方法，粗品用二氯甲烷：甲醇(50:1)柱层析，得II-10白色固体0.42g，收率75％，198℃(分解)。
以化合物II-10为起始原料，操作同V·HCl的方法，得II-10·HCl白色固体0.17g，收率80％，230℃(分解)。II-10·HCl:IR(KBr,υcm-1):3445,3250,2967,2932,2879,2572,2460,1743,1708,1664,1540,1457,1286,1257,1148,1127,1018,930,871,809,774,697,606.1H NMR(500MHz,CDCl3),δ(ppm):11.40(s,1H),8.78(d,J＝9.3Hz,1H),7.47(s,1H),7.43(s,1H),6.40(s,1H),5.79(s,1H),4.95(s,1H),4.67–4.40(m,3H),4.30(s,1H),4.02(tt,J1＝23.8Hz,J2＝12.1Hz,4H),3.52–3.36(m,3H),3.29(s,1H),3.04(d,J＝9.2Hz,3H),2.95–2.75(m,3H),2.68(d,J＝14.0Hz,1H),2.53(d,J＝16.8Hz,1H),2.05–1.84(m,3H),1.60(d,J＝14.0Hz,1H),1.56–1.44(m,2H),1.33(s,3H),1.29(s,3H),1.22(s,3H),1.12(s,3H).13C NMR(75MHz,CDCl3),δ(ppm):173.93,169.98,168.90,143.18,141.36,119.63,113.74,109.90,82.39,80.55,78.80,66.06,63.91,63.76,53.78,52.40,52.22,51.95,51.90,45.59,45.24,38.54,38.47,35.41,30.11,29.94,27.67,25.74,24.56,21.55,17.78,17.38.HR-ESIMS m/z 597.3164[M+H]+(calcd for C33H45N2O8,597.3170).
实施例28
片剂
取实施例5中所得化合物0.5g，淀粉2g，糊精1g混合，用适量30％乙醇作湿润剂，制粒，压片。
Claims (6)
1.通式(I)或(II)的化合物或其药学上可接受的盐：
其中m＝1或2；
R代表：
R1、R2代表C1～C6的烷基。
2.权利要求1通式(I)化合物的制备方法，包括：
其中R和m的定义同权利要求1。
3.权利要求1通式(II)化合物的制备方法，包括：
其中R和m的定义同权利要求1。
4.权利要求1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)或(II)化合物与下列酸形成的酸加成盐：氯化氢、溴化氢、硫酸、碳酸、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。
5.一种药物组合物，其中含有权利要求1的化合物或其药学上可接受的盐及药学上可接受的载体。
6.权利要求1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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