CN117603079A - 一种治疗疼痛的化合物和组合物 - Google Patents
一种治疗疼痛的化合物和组合物 Download PDFInfo
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- CN117603079A CN117603079A CN202311584860.XA CN202311584860A CN117603079A CN 117603079 A CN117603079 A CN 117603079A CN 202311584860 A CN202311584860 A CN 202311584860A CN 117603079 A CN117603079 A CN 117603079A
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- pain
- compound
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- pharmaceutically acceptable
- oxycodone
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明提供了一种可同时作用于NMDA受体NR2B亚基和α2δ双靶点的化合物，并且该化合物与羟考酮组合具有协同作用，预期可降低羟考酮的临床使用剂量，避免产生不良反应。
Description
技术领域
本发明属于医药领域，具体涉及一种治疗疼痛的化合物和组合物。
背景技术
疼痛已成为继心脑血管疾病、肿瘤之后第三大健康问题，严重影响人们的生命健康和生活质量。尽管目前所知的疼痛治疗药物和技术方法多种多样，但镇痛靶点的选择始终是疼痛治疗的基石。广为熟知的镇痛靶点为阿片受体，比较常见的阿片受体包括μ受体、κ受体、δ受体以及伤害感受性阿片类肽受体，这是临床上治疗中重度疼痛最常用的镇痛靶点。
羟考酮是一种由生物碱蒂巴因中提取的半合成阿片类药物，通过激动中枢神经系统的阿片μ及κ受体而产生镇痛、镇静作用，用于缓解持续的中度到重度疼痛。羟考酮的镇痛效能和时间与吗啡类似，但生物利用度是吗啡生物利用度的3～4倍。由于羟考酮生物利用度高，给药途径多，因而在临床上应用广泛，可用于缓解中至重度疼痛，如关节痛、背痛、癌性疼痛、手术后疼痛等，但临床发现高剂量连续使用羟考酮后，突然中断或减量，部分病人有戒断综合征的发生。因此，有必要解决高剂量连续使用羟考酮产生不良反应的问题。
由于阿片类药物存在一定的不良反应，非阿片类镇痛靶点的研究也受到重视和发展，为未来止痛之路开辟了更多方向，例如NMDA受体拮抗剂和VGCC拮抗剂。
NMDA受体(N-methyl-D-aspartic acid receptor)即为N-甲基-D-天冬氨酸受体，是离子型谷氨酸受体的一个亚型，在慢性疼痛和疼痛相关的神经毒性中发挥重要作用。哺乳动物神经系统的NMDA受体由NR1亚基和NR2亚基组成。NR2亚基包括NR2A、NR2B、NR2C、NR2D4亚型在成熟神经元中，突触内NMDA受体主要由NR1和NR2A亚基组成，突触外NMDA受体主要包含NR1和NR2B亚基。研究显示，靶向NR2B在镇痛的同时可以减少不良反应。因此，NR2B亚基选择性的NMDA受体拮抗剂可发挥镇痛作用，且减少不良反应的发生。但迄今为止测试的NMDA受体NR2B亚基选择性拮抗剂虽能消除部分不良反应，但均显示镇痛作用不足。
电压门钙通道(VGCC)是在可兴奋细胞的细胞膜中发现的一组电压门控离子通道，具有对钙离子的渗透性。在生理或静息膜电位下，VGCC是闭合的，在去极膜电位下被激活，当VGCC被激活后，钙离子内流，使钙敏感性钾通道激活、肌肉收缩、神经元激发、激素或者神经递质释放，从而导致疼痛发展。VGCC由α1亚单位和辅助蛋白α2δ、β、γ亚基共同构成。α2δ蛋白可以调节钙通道的密度及钙通道电压依赖性动力学，对α2δ表现出高亲合力结合的化合物可有效治疗疼痛，例如普瑞巴林和加巴喷丁。
尽管目前疼痛治疗药物和策略是多样的，但疼痛治疗领域仍存在一些亟待解决的问题，例如现有镇痛药物数量有限、镇痛效果不佳、阿片类药物的不良反应和社会危害等。如何优化阿片类药物的治疗效果以及开发新型镇痛药物，完善镇痛方案已成为临床上治疗疼痛的一个亟待解决的问题。
发明内容
本发明提供了一种可同时作用于NMDA受体NR2B亚基和α2δ双靶点的化合物，并且该化合物与羟考酮组合具有协同作用，预期可降低羟考酮的临床使用剂量，避免产生不良反应。
本发明的技术方案如下：
在本发明的一个方面中，提供了化合物1、其药学上可接受的盐或其立体异构体，
本发明还提供了一种药物制剂，所述药物制剂包含化合物1、其药学上可接受的盐或其立体异构体和药学上可接受的载体。所述药学上可接受载体，包含本领域中常规的辅料成分，例如、填充剂、粘合剂、稀释剂、崩解剂、润滑剂、着色剂、调味剂、抗氧化剂和润湿剂等。
在一些实施方案中，所述药物制剂可以是药学上可接受的各种剂型，如片剂、胶囊剂、口服液剂、混悬液、颗粒剂、粉剂、微粒剂、微丸、微型片剂、速溶膜剂、鼻喷雾剂、透皮贴剂、注射剂或各种缓控释制剂等。所述药物组合物可以经口服、经粘膜、经直肠或肠胃外(包括血管内、静脉内、腹膜内、皮下、肌肉内和胸骨内)给药，优选以口服给药。给药剂量可根据患者的年龄、性别和疾病类型进行适当调整。
对于口服给药，所述药物组合物可呈例如片剂、胶囊、液体胶囊、悬浮液或溶液等形式。所述药物组合物优选以含有特定量活性成分的剂量单位形式制得。例如，所述药物组合物可以包含约0.1至1000mg，优选约0.25至250mg，且更优选约0.5至100mg范围内的量的活性成分的片剂或胶囊。用于人类或其它哺乳动物的适合日剂量可根据患者的病况及其它因素而广泛变化，但可使用常规方法确定。
本发明提供的化合物1、其药学上可接受的盐或其立体异构体同时具有NMDA受体NR2B亚基和VGCC的α2δ亚基双重拮抗作用，可以有效治疗疼痛。
本发明还提供了化合物1、其药学上可接受的盐或其立体异构体在制备用于治疗NMDA受体NR2B亚基和/或VGCC的α2δ亚基介导的疾病药物中的应用。
本发明还提供了化合物1、其药学上可接受的盐或其立体异构体在制备治疗疼痛药物中的应用。所述疼痛包括术后疼痛、癌性疼痛、神经性疼痛、创伤性疼痛、化学性疼痛、烧伤痛、缺血性疼痛、类风湿性关节炎疼痛和骨痛等。
在本发明的一个方面中，提供了一种药物组合物，包含第一活性成分：羟考酮或其盐；和第二活性成分：化合物1、其药学上可接受的盐或其立体异构体。所述两种活性成分既可以同时给药，也可以间隔一段时间给药。本发明还提供了所述药物组合物在制备治疗疼痛药物中的应用。所述疼痛包括术后疼痛、癌性疼痛、神经性疼痛、创伤性疼痛、化学性疼痛、烧伤痛、缺血性疼痛、类风湿性关节炎疼痛和骨痛等。
本发明还提供了羟考酮或其盐，和化合物1、其药学上可接受的盐或其立体异构体在制备治疗疼痛药物中的应用。所述疼痛包括术后疼痛、癌性疼痛、神经性疼痛、创伤性疼痛、化学性疼痛、烧伤痛、缺血性疼痛、类风湿性关节炎疼痛和骨痛等。
本发明相对于现有技术，具有如下的优点及有益效果：
1.化合物1可以同时作用于NMDA受体NR2B亚基和VGCC的α2δ亚基，具有显著的亲和力和拮抗作用。
2.化合物1与羟考酮组合使用可以显著提高镇痛效果，因而可降低羟考酮给药剂量，避免高剂量连续使用羟考酮产生不良反应的问题。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的酸加成盐的实例包括无机酸盐、有机酸盐，还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，盐的制备方法为：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明意欲包括存在于本发明化合物中的原子的所有同位素。同位素包括原子数相同但质量数不同的那些原子。作为一般实例且非限制性地，氢的同位素包括氘和氚。碳的同位素包括13C和14C。本发明的同位素标记化合物一般可通过本领域技术人员已知的常规技术或通过类似于本文所述的方法，使用适当同位素标记试剂代替另外使用的非标记试剂来制备。
化合物经手工或者软件命名，市售化合物采用供应商目录名称。
具体实施方式
实施例1化合物1的合成
步骤1：化合物1-2的合成
将化合物三苯基磷乙酸叔丁酯(12.2g,32.4mmol,1.20eq)溶于195mL无水四氢呋喃中，将化合物1-1(5.00g,27.0mmol,1.00eq)溶于100mL无水四氢呋喃后，缓慢滴加至三苯基磷乙酸叔丁酯的四氢呋喃溶液中，25℃下搅拌16小时。薄层色谱法(石油醚:乙酸乙酯＝5:1)显示反应结束。向反应液中加入100mL水，用乙酸乙酯萃取两次，每次200mL。合并有机相，用200mL饱和食盐水洗涤一次，随后用无水硫酸钠干燥，滤液浓缩干，得到粗品。粗品经柱层析纯化(石油醚：乙酸乙酯＝5:1)得到化合物1-2(7.10g，白色固体，收率：92.7％)。MS(ESI)m/z:283.2[M+H]+。1H NMR(400MHz,CHLOROFORM-d)δ7.57-7.47(m,3H),7.38(d,J＝8.4Hz,2H),6.36(d,J＝16.0Hz,1H),1.54(s,9H).
步骤2：化合物1-3的合成
将1,1'-联萘-2,2'-双二苯膦(54.9mg,88.2μmol,0.05eq)，双(二亚芐基丙酮)钯(30.4mg,52.9μmol,0.03eq)加入到100mL丙酮中，在20℃氮气保护条件下搅拌30分钟。将化合物1-2(500mg,1.77mmol,1.00eq)，化合物3,5-二甲基金刚烷-1-胺(316mg,1.77mmol,1.00eq)和叔丁醇钠(237mg,2.47mmol,1.40eq)加入至上述反应体系中氮气置换10分钟。反应液在110℃下搅拌24小时。薄层色谱法(石油醚:乙酸乙酯＝5:1)显示反应结束。向反应液中加入30mL水，乙酸乙酯萃取两次，每次30mL，合并有机相，用20mL饱和食盐水洗涤一次，无水硫酸钠干燥，滤液浓缩得到粗品。粗品经柱层析纯化(石油醚：乙酸乙酯＝4:1)得到化合物1-3(145mg,淡黄色油状，收率：20.0％,纯度：93.0％)。MS(ESI)m/z:382.3[M+H]+.1H NMR(400MHz,CHLOROFORM-d)δ7.50(br d,J＝15.8Hz,1H),7.31(br d,J＝7.9Hz,2H),6.79-6.59(m,2H),6.15(br d,J＝15.9Hz,1H),2.20(br d,J＝2.4Hz,1H),1.80(br s,2H),1.65-1.57(m,4H),1.53(s,9H),1.40-1.29(m,4H),1.18(s,2H),0.88(s,6H).
步骤3：化合物1-4的合成
将硝基甲烷(1.56g,25.5mmol,1.38mL,11.2eq)，四丁基氟化铵(1M,2.28mL,1.00eq)溶于9mL无水四氢呋喃中，将化合物1-3(870mg,2.28mmol,1.00eq)溶于9mL无水四氢呋喃后，缓慢滴加至上述反应液中，控制温度为10–20℃,滴加完后，在80℃条件下搅拌12小时。薄层色谱法(石油醚：乙酸乙酯＝5:1)显示反应结束。浓缩除去有机相，并向体系中加入5mL 1M盐酸，用乙酸乙酯萃取两次，每次10mL,用无水硫酸钠干燥，滤液浓缩得到粗品，粗品经柱层析纯化(石油醚：乙酸乙酯＝5:1)得到化合物1-4(615mg,淡黄色油状，收率：43.8％,纯度：72％)。MS(ESI)m/z:443.4[M+H]+。
步骤4：化合物1-5的合成
将化合物1-4(610mg,1.38mmol,1.00eq)和钯碳催化剂(610mg,573μmol,10％纯度,0.416eq)溶于12mL无水四氢呋喃，在50℃，H2(50Psi)条件下搅拌12小时。薄层色谱法(石油醚：乙酸乙酯＝5:1)显示反应结束。过滤，滤液浓缩得到化合物1-5(530mg，淡黄色，粗品)。MS(ESI)m/z:413.3[M+H]+。
步骤5：化合物1的合成
将化合物1-5(530mg,1.28mmol,1.00eq)加入到盐酸(12M,53.00mL,495eq)中，在25℃条件下搅拌2小时。液质色谱显示反应结束。反应液浓缩得到粗品。粗品经柱层析纯化(石油醚：乙酸乙酯＝5:1)得到化合物1(132mg,白色固体，收率：25.8％，纯度：98.6％)。MS(ESI)m/z:357.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.52-12.05(m,1H),11.33(br s,2H),8.12(br s,3H),7.53-7.35(m,4H),3.14(td,J＝5.8,12.0Hz,1H),3.08-2.96(m,1H),2.87(dd,J＝5.7,16.4Hz,1H),2.60(dd,J＝8.9,16.3Hz,1H),2.18(br s,1H),1.76(br s,2H),1.65-1.48(m,4H),1.32-1.21(m,4H),1.16-1.02(m,2H),0.84(s,6H).
试验例1化合物与钙离子通道蛋白Cav2.2α2δ的亲和力
CHO细胞中表达的人重组钙通道Cav2.2/β3/α2δ-1受体保存于改良的HEPES/KOH缓冲液(pH 7.4)中。化合物(检测浓度为10000、2500、625、156.3、39.1、9.77、2.44、0.61nM)与5nM[3H]加巴喷丁一起加入3μg膜悬液中，25℃下孵育120min。非特异性结合以10μM加巴喷丁封闭。过滤并清洗滤膜，然后计数滤膜，测定[3H]加巴喷丁的特异性结合。采用CBIS数据分析软件分析化合物活性。计算化合物对[3H]加巴喷丁与膜结合的抑制率，并拟合化合物的IC50值。抑制率％＝(阴性对照平均值-CPM)/(阴性对照平均值-阳性对照平均值)*100。试验结果见表1。
表1化合物与钙离子通道蛋白Cav2.2α2δ的亲和力
试验结果显示，化合物1对钙离子通道蛋白Cav2.2α2δ有较高的亲和力。
试验例2化合物对NMDA受体NR2B亚基的拮抗作用
细胞以总体积20μL接种聚-D-赖氨酸包被的384孔微孔板中，37℃孵育。加入1×染料和2.5mM丙磺舒组成的1×染料上样缓冲液，37℃孵育60min。在EC80动剂存在下向细胞中加入待测化合物(检测浓度：10000、3333、1111、370、123、41.1、13.7、4.57、1.52、5.08nM)，室温下避光孵育细胞30min，以平衡平板温度。在FLIPR Tetra(MDS)上测定化合物活性。采用CBIS数据分析软件分析化合物活性。计算抑制百分比，并拟合化合物的IC50值。％抑制率＝100％×(1-(供试品平均值-溶剂对照品平均值)/(EC80对照品平均值-溶剂对照品平均值))。试验结果见表2。
表2化合物对NMDA受体NR2B亚基的拮抗作用
试验结果显示，化合物1对NMDA受体NR2B亚基有显著的拮抗作用。
试验例3化合物1及其与羟考酮联用的体内药效研究
雄性昆明小鼠40只，按体重随机分为4组：假手术组、模型组、盐酸羟考酮组(10mg/kg)、化合物1组(10mg/kg)、盐酸羟考酮组+化合物1组(分别是5mg/kg和5mg/kg)，每组10只动物，所有动物均单次灌胃给药，给药体积为10mL/kg，假手术组和模型组给予等体积生理盐水，各试验组小鼠造模前60min给予相应药物。将小鼠单独置于透明塑料盒内适应10min。右后足皮下注射20μL 2.5％福尔马林溶液，造模后立即置于透明塑料盒内观察，每5min记录1次小鼠右后足出现抖足、舔足、缩足的累计时间。分别以s为单位统计各试验组0min～5min(第I时相)，15min～40min(第II时相)小鼠累计疼痛反应时间。试验结果见表3，盐酸羟考酮给药组的第I相时间和第II相时间均显著低于模型组；同样，化合物1给药组的第I相时间和第II相时间也均显著低于模型组。盐酸羟考酮与化合物1的联合用药组结果显示，给药第I相时间和第II相时间，均显著低于盐酸羟考酮给药组和化合物1组，具有协同作用。
表3化合物对福尔马林诱导的小鼠疼痛行为的影响
与假手术组比较，#P<0.01；与模型组比较，*P<0.01；与羟考酮组比较，&P<0.01；与化合物1组比较，％P<0.01。
Claims (7)
1.化合物1、其药学上可接受的盐或其立体异构体，
2.一种药物制剂，其特征在于包含权利要求1所述的化合物1、其药学上可接受的盐或其立体异构体，和药学上可接受的载体。
3.权利要求1所述化合物，或权利要求2所述药物制剂在制备用于治疗NMDA受体NR2B亚基和/或VGCC的α2δ亚基介导的疾病的药物中的应用。
4.一种药物组合物，包含羟考酮或其盐，和权利要求1所述的化合物1、其药学上可接受的盐或其立体异构体。
5.权利要求1所述化合物，权利要求2所述药物制剂或权利要求4所述药物组合物在制备用于治疗疼痛的药物中的应用。
6.羟考酮或其盐，和权利要求1所述的化合物1、其药学上可接受的盐或其立体异构体在制备用于治疗疼痛药物中的应用。
7.根据权利要求5～6任一所述的应用，其中，所述疼痛包括术后疼痛、癌性疼痛、神经性疼痛、创伤性疼痛、化学性疼痛、烧伤痛、缺血性疼痛、类风湿性关节炎疼痛和骨痛。
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