CN111574432A - 一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及用途 - Google Patents
一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及用途 Download PDFInfo
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- CN111574432A CN111574432A CN202010556427.5A CN202010556427A CN111574432A CN 111574432 A CN111574432 A CN 111574432A CN 202010556427 A CN202010556427 A CN 202010556427A CN 111574432 A CN111574432 A CN 111574432A
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- aminobutyric acid
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Abstract
本发明公开了一种式(Ⅰ)可溶性环氧水解酶和γ‑氨基丁酸双重抑制剂及其药学上可接受的盐,其中R1选自‑H或‑F或‑Cl或‑Br或‑CN或‑NO2;R2选自‑CF3或‑OCF3或‑CN或‑NO2。本发明所述的化合物及其药学上可接受的盐可用于缓解疼痛和治疗或预防神经性疼痛。
Description
一、技术领域
本发明涉及药物化学领域,具体涉及一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其用途。
二、背景技术
在过去的几十年里,疼痛一直是医学上有待解决的一个难题,它给整个社会带来负担的同时还严重降低了人们的生活质量。疼痛是一种复杂的信号传导过程,源于有害物质的损伤以及炎性介质的释放,例如细胞因子、离子、缓激肽、***素和白三烯等,它们直接作用于疼痛感受器,并驱动动作电位发出疼痛的感觉。通常,疼痛是避免进一步损伤的信号。目前虽然很多方法可以缓解疼痛,但是大多数这些方法具有剂量依赖或限制性使用的副作用。因此,我们需要新的疗法来治疗疼痛。
2011年IASP官方学术期刊PAIN发表了神经病理性疼痛(Neuropathic Pain,NPP)的新定义:躯体感觉神经***的损伤或疾病直接造成的疼痛,可继发于多种疾病或损伤,如中风,糖尿病等。NPP是目前最难治疗的疾病之一,给社会以及个人的生活带来了巨大的负担。因此,急需研究新的方法来治疗神经病理性疼痛。
在神经病变中对有效的可溶性环氧水解酶(sEH)抑制剂作用的初步研究旨在比较疼痛模型中COX水平与炎性疼痛的关系。Inceoglu等[Proceedings of the NationalAcademy of Sciences of the United States ofAmerica,2008,105(48):18901~18906]发现在慢性疼痛模型中sEH抑制可以阻断糖尿病神经病变,因此它被提议作为阴性对照实验模型。这是令人兴奋的一件事,因为大多阻断COX的NSAID对神经病理性疼痛几乎没有效果[European Journal of Pharmacology,2013,700(1-3):93~101]。Inceoglu[Proc NatlAcad Sci U S A,2012,109(28):11390~11395]等在临床前模型中探索sEH抑制剂对糖尿病性神经病变的作用,揭示了sEH抑制剂对机械疼痛阈值的剂量依赖性改善,且sEH抑制剂优于加巴喷丁的标准治疗。这种抗痛觉过敏与葡萄糖耐量、胰岛素耐受和葡萄糖刺激的胰岛素分泌的变化无关。Wagner等[Behavioural Brain Research,2017,326:69~76]在先天秋田小鼠I型糖尿病模型中进一步研究证明了sEH抑制剂的作用。在以秋田小鼠中为模型的研究中发现sEH抑制剂对小鼠糖尿病性神经病变有效,且sEH活性与该疾病严重性相关。Guedes A等[Equine Veterinary Journal,2017,49(3):345~351]在治疗严重的马蹄叶炎的研究中发现,sEH抑制剂比以往的标准治疗方法更有效,且sEH抑制剂作为治疗这种疾病的方法持续成功。由此可以推断sEH抑制剂可能是治疗神经病理性疼痛的有效策略之一。
现有环氧化物水解酶抑制剂的研究技术文献:
脲类抑制剂(J.Med.Chem.McElroy jm020269o supporting Info page1~39)、CN106163521、CN101304737:脲类抑制剂是近年来研究得比较多的,作用机制是脲素中的羰基氧与EH中的Tyr381、Tyr465以氢键结合,与Gln382相互作用来稳定环氧化物的负电荷,其羰基端的Asp333还可以接受酶抑制剂的氢键然后共同作用。然而当脲素药效团左右连接的基团不同时,它们的抑制效果也就不同。因此可以根据左右基团的不同将脲类抑制剂进行以下分类:
1)环烷烃-脲类抑制剂(Annu Rev Pharmacol Toxicol,2005,45:311~333.、BiolChem,2000,15:265~275);
2)金刚烷-脲类抑制剂(Bioorganic&Medicinal Chemistry Letters 19(2009)1784~1789、Protein Sci,2006,15:58~64.、J M ed Chem,2007,50:5217~5226)、CN102464631;
3)芳基-脲类抑制剂(Bioorganic&Medicinal Chemistry Letters,2006,16:5773~5777.、J Med Chem,2010,40:222~238.)
4)肽基-脲类抑制剂(Adv Drug Deliv Rev,2001,46:3~26)
5)哌啶-脲类抑制剂(Bioorganic&Medicinal Chemistry Letters,2010,20:571~575.、Bioorganic&Medicinal Chemistry Letters,2009,19:5314-5320.)
6)螺环-脲类抑制剂(Bioorganic Chemistry 80(2018)655~667)
酰胺类抑制剂:酰胺类抑制剂与脲类抑制剂在主体结构上既有相似之处也有不同的地方,但是分别对它们的主体结构进行左右对称和不对称的修饰时,生物活性变化很明显。
1)金刚烷-酰胺类抑制剂(CN102664631)、(J M ed Chem,2007,50:3825~3840)
2)哌啶-酰胺类抑制剂(Bioorganic&Medicinal Chemistry Letters,2009,19:2354~2359)
由于环氧化物水解酶抑制剂具有以下几种药理作用:抗炎、保护肾脏、保护神经、保护心肌、保护心肺功能、治疗镇痛、促使血管舒张、防止动脉硬化等作用。据不完全统计目前已经商业化的药物有DCU、AUDA、TPPU等;但是由于存在一些毒副作用或者口服性较差的缺点,激发了人们对它的进一步研究。从水溶性、稳定性、口服性等这几个方面去研究,希望能找到一种快速、高效、选择性强的抑制剂,从而达到更好的治疗相关疾病的效果。
痛性糖尿病周围神经病为糖尿病周围神经病的一种类型。多见于血糖控制不理想的糖尿病患者,或者突然发生血糖波动者,如酮症酸中毒等。临床表现为体重快速和明显的下降,周围神经损害以远端为主,主要症状是疼痛、烧灼感和针刺感。
据估计,神经性疼痛会影响总人口的7~10%,极大地影响人们的日常功能和生活质量。
多种备选方案可用于处理疼痛。实例包括非甾类消炎药品((NSAID)或麻醉镇痛药(例如阿片类)。但是,非甾类消炎药品的使用引起不良副作用,例如胃肠伤害或肾病,且麻醉镇痛药的使用引起不良副作用,例如便秘、磕睡、恶心或呕吐。
相反,神经性疼痛通过使用抗惊厥剂治疗,例如加巴喷丁或普瑞巴林,且出现中枢神经***副作用如眩晕、恶心或呕吐的频率高。因此,有待出现用于神经性疼痛的新型镇痛药及治疗剂。
随着药理学的发展,人可溶性环氧化物水解酶的作用和机理正在不断地被发现和阐明,也进一步证明了其抑制剂作为治疗镇痛药尤其神经性疼痛药的合理性和有效性.。随着研究的推进,将会有越来越多的、也更加优异的人可溶性环氧化物水解酶抑制剂被设计和合成出来,这些现有技术文献中并无一个描述了本发明的普瑞巴林与脲类环氧化物水解酶巧妙对接的衍生物,且没有此类文献暗示本发明化合物作为药物的功效。因此,我们研发此类产品,将可能会为治疗镇痛药尤其神经性疼痛药以及炎症疼痛相关疾病的治疗提供另一条可行的途径.。
同时,研发中枢神经***药物就像黑箱一样,很难判断最终会得到什么样的惊喜。
三、发明内容
本发明待实现的目的:
本发明提供了可用于治疗或预防各类疼痛或神经性疼痛的杰出化合物及其药物应用。
实现所述目的手段:
本发明发明人已经进行了集中研究以实现上述目的。结果,我们发现了显示出改善各类疼痛或神经性疼痛的可溶性环氧水解酶和γ-氨基丁酸双重抑制剂,由此完成了本发明。
具体地,本发明概括如下:
(1)式(Ⅰ)所示的一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其药学上可接受的盐:
其中:R1选自-H或-F或-Cl或-Br或-CN或-NO2;R2选自-CF3或-OCF3或-CN或-NO2。
(2)根据(1)的一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其药学上可接受的盐,其中R1为-H或-F或-Cl,R2为-CF3或-OCF3。
(3)根据(1)或(2)的一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其药学上可接受的盐,其中化合物优选以下结构:
(4)根据(1)或(2)或(3)一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其药学上可接受的盐,其中药学上可接受的盐为盐酸盐、氢溴酸盐、氢碘酸盐、氢氟酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、乙二酸盐、丙二酸盐、丁酸盐、乳酸盐、甲磺酸盐、乙磺酸盐、对甲苯磺酸盐、马来酸盐,苯甲酸盐、琥珀酸盐、苦味酸盐、酒石酸、柠檬酸盐、富马酸盐。
(5)包含根据(1)~(4)任何一个的一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂或其药学上可接受的盐,及药学上可以接受的载体或赋形剂的药物组合物。
(6)包括根据(1)~(5)任一项的一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其药学上可接受的盐的镇痛药。
(7)包括根据(1)~(5)任一项的一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其药学上可接受的盐用于神经性疼痛的治疗或预防剂。
(8)包括根据(1)~(5)任一项的一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其药学上可接受的盐用于炎症性疼痛的治疗或预防剂。
(9)根据(1)~(5)任一项的一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其药学上可接受的盐用于制造镇痛药的用途。
(10)根据(1)~(5)任一项的一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其药学上可接受的盐用来制造神经性疼痛的治疗或预防剂的用途
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
本发明的要点在于:
1)将人可溶性环氧化物水解酶脲类抑制剂与普瑞巴林形成多靶点孪药,能够明显增加镇痛效果,可用于制备治疗神经性疼痛中的药物;
2)化学性质稳定,适中的水溶性,增加了脲类抑制剂的水溶性,具有良好的成药性。
四、具体实施方式
下面的实施例可以对本发明进行进一步的描述,然而,这些实施例不应作为对本发明范围的限制。
实施例1(S)-1-(1-(3-(氨基甲基)-5-甲基己酰基)哌啶-4-基)-3-(3-氟-4-(三氟甲氧基)苯基)脲(化合物I1)的合成
制备工艺反应流程:
1、步骤1
在500ml三口瓶中,依次加入S(+)氨己烯酸(24g,0.15mol)、二恶烷170ml及去离子水170ml,室温搅拌下加入氢氧化钠(18g,0.45mol),完毕后搅拌5min,加入BOC酸酐(43.6g,0.2mol)的50ml二恶烷溶液,将得到的混合液在室温搅拌1.5h,TLC鉴别反应完毕后,减压浓缩除去大部分二恶烷,剩余物用***(3×100ml)萃取,除去有机相,水层用10%枸橼酸水溶液调节pH酯至1~2,静置20min,析出大量白色固体,过滤,固体用适量水洗,55℃~60℃真空干燥4h,得白色固体粉末33.6g,收率86%,HPLC含量97.2%,直接用于下一步反应。
2、步骤2
将3-氟-4-(三氟甲氧基)苯胺(68g,0.35mol)、甲苯(400ml)及吡啶31ml加入到1000ml反应釜中,搅拌溶解,冷却至-5~0℃,滴入固体光气(60g,0.2mol)的120ml甲苯溶液,滴入完毕保持温度在-5~0℃搅拌1.5h,TLC(乙酸乙酯-石油醚=1:10)鉴别反应完毕后,冷却至-10℃,分批加入4-氨基哌啶-1-羧酸叔丁酯(80g,0.4mol),加入过程中检测反应体系pH,维持在8-9,若pH偏低,加入适量的吡啶,加入完毕,维持温度反应0.5h,再升温至室温搅拌反应3h,TLC(乙酸乙酯-石油醚=1:10)鉴别反应完毕后,加入冷水200ml,搅拌20min,静置分层,水层用甲苯(3×200ml)萃取,合并有机层,无水硫酸镁干燥,减压浓缩至干,直接用于下一步。
3、步骤3
步骤2产品,加入二恶烷450ml及6N盐酸溶液45ml,室温搅拌反应混合物1.5h,TLC鉴别反应[展开剂:乙酸乙酯:甲醇=10:1],反应完毕,加入***300ml,搅拌1h,过滤,固体用***适量洗涤,35℃~40℃真空干燥6h,得白色固体粉末76.5g,两步总收率68%,HPLC含量96.9%,直接用于下一步反应。
4、步骤4
将步骤3产物(32g,0.1mol)、步骤1产物(31g,0.12mol)溶于二氯甲烷300ml中,搅拌下,加入DCC(27g,0.13mol)及DMAP(5g),室温搅拌15h,过滤出去不溶物DCHU,减压浓缩至干,将产物溶于甲苯(300ml),加水,用饱和碳酸氢钠溶液(3×50ml)洗涤,饱和氯化钠溶液50ml洗涤,无水硫酸钠干燥,减压浓缩至干,得类白色固体粉末41g,收率73%,HPLC含量94.3%,直接用于下一步反应。
5、步骤5
步骤4产品,加入二恶烷410ml及6N盐酸溶液12ml,室温搅拌反应混合物2h,TLC鉴别反应[展开剂:乙酸乙酯:甲醇=10:1],反应完毕,加入异丙醚350ml,搅拌1h,过滤,固体用异丙醚适量洗涤,55℃~60℃真空干燥4h,所得固体用乙腈重结晶,得白色结晶性固体粉末27.5g,收率81.1%,HPLC含量98.7%。
1H-NMR(500MHz,CDCl3/TMS,ppm):
δ8.53(s,1H);7.84(s,1H);7.33(d,J=7.8Hz,1H);7.01(d,J=7.8Hz,1H);6.45(s,1H);3.68(m,1H);3.52~3.59(t,J=6.3Hz,4H);1.76~2.04(t,J=6.3Hz,4H);1.99~2.31(d,J=7.8Hz,2H);1.66(m,1H);2.46~2.72(t,J=6.3Hz,2H);1.37(t,J=6.3Hz,2H);1.74(m,1H);0.93(s,6H)。
MS:m/z(M+H+)463.5。
实施例2(S)-1-(1-(3-(氨基甲基)-5-甲基己酰基)哌啶-4-基)-3-(3-氟-4-(三氟甲基)苯基)脲(化合物I2)的合成
参照实施例1,其中步骤2中将3-氟-4-(三氟甲氧基)苯胺替换为将3-氟-4-(三氟甲基)苯胺,方便地制得了化合物I2,7.6g,总收率(从步骤2开始计)33.6%,HPLC含量98.2%。
1H-NMR(500MHz,CDCl3/TMS,ppm):
δ8.54(s,1H);7.85(s,1H);7.33(d,J=7.8Hz,1H);7.02(d,J=7.8Hz,1H);6.44(s,1H);3.68(m,1H);3.50~3.58(t,J=6.3Hz,4H);1.77~2.06(t,J=6.3Hz,4H);1.99~2.33(d,J=7.8Hz,2H);1.65(m,1H);2.43~2.70(t,J=6.3Hz,2H);1.35(t,J=6.3Hz,2H);1.71(m,1H);0.95(s,6H)。
MS:m/z(M+H+)447.5。
实施例3(S)-1-(1-(3-(氨基甲基)-5-甲基己酰基)哌啶-4-基)-3-(4-(三氟甲氧基)苯基)脲(化合物I3)的合成
参照实施例1,其中步骤2中将3-氟-4-(三氟甲氧基)苯胺替换为将4-三氟甲基苯胺,方便地制得了化合物I3,6.1g,总收率(从步骤2开始计)38.2%,HPLC含量97.8%。
1H-NMR(500MHz,CDCl3/TMS,ppm):
δ8.56(s,1H);7.28(d,J=7.8Hz,2H);6.87(d,J=7.8Hz,2H);6.53(s,1H);3.70(m,1H);3.53~3.62(t,J=6.3Hz,4H);1.79~2.08(t,J=6.3Hz,4H);1.94~2.30(d,J=7.8Hz,2H);1.65(m,1H);2.41~2.74(t,J=6.3Hz,2H);1.37(t,J=6.3Hz,2H);1.72(m,1H);0.94(s,6H)。
MS:m/z(M+H+)445.3。
实施例4(S)-1-(1-(3-(氨基甲基)-5-甲基己酰基)哌啶-4-基)-3-(3-氯-4-(三氟甲氧基)苯基)脲(化合物I4)的合成
参照实施例1,其中步骤2中将3-氟-4-(三氟甲氧基)苯胺替换为将3-氯-4-(三氟甲基)苯胺,方便地制得了化合物I4,3.7g,总收率(从步骤2开始计)29.3%,HPLC含量99.1%。
1H-NMR(500MHz,CDCl3/TMS,ppm):
δ8.54(s,1H);7.56(s,1H);7.33(d,J=7.8Hz,1H);7.01(d,J=7.8Hz,1H);6.43(s,1H);3.68(m,1H);3.50~3.59(t,J=6.3Hz,4H);1.73~2.06(t,J=6.3Hz,4H);1.99~2.35(d,J=7.8Hz,2H);1.64(m,1H);2.44~2.70(t,J=6.3Hz,2H);1.36(t,J=6.3Hz,2H);1.70(m,1H);0.93(s,6H)。
MS:m/z(M+H+)479.3。
对比实施例 化合物I5的合成
参照实施例1,其中步骤4用环己基甲酸替换步骤1产物,方便地制得了化合物I5,2.4g,HPLC含量98.3%,LC-MS:416.7。
实施例5溶解度试验
溶解度是依据中国药典2015版方法在室温23℃条件下测定所得。
由此可见,本发明的水溶性增加8倍以上,且具有pH依赖性。
实施例6化学稳定性试验
将样品置于80℃热水中恒温6h取样,HPLC分析:
项目 | 母体化合物(%) | 步骤3产物(%) | 普瑞巴林(%) |
化合物I<sub>1</sub> | 98.6 | 0.7 | 0.7 |
化合物I<sub>2</sub> | 99.1 | 0.4 | 0.4 |
化合物I<sub>3</sub> | 99.3 | 0.3 | 0.3 |
化合物I<sub>4</sub> | 98.6 | 0.2 | 0.2 |
化合物I<sub>5</sub> | 97.2 | 1.4 | —— |
实验结果显示,本发明化合物水溶液稳定显著。
实施例7镇痛效果评估
使ddY小鼠在禁食状况下生长至少16h同时允许自由摄入水,并向其口服给药测试化合物的溶液或溶剂(0.1ml/5g)。作为用于测试化合物溶液的溶剂,使用二甲亚砜:吐温80:27%羟丙基β环糊精(1:1:8)。给药45min以后腹膜内给药0.6%乙酸的溶液(0.1ml/5g)以引起扭体反应(即,伸展或拱起身体的运动)。计数从给药乙酸溶液10min以后至此后10min的期间出现的扭体反应的数目,且该次数被指定为疼痛的指标。给药溶剂的组中反应的次数指定为100%,且抑制50%此类反应的测试化合物的浓度指定为ED50值,结果见下表:
化合物 | ED50(mg/kg)[90%置信区间] |
化合物I<sub>1</sub> | 0.12[0.09-0.20] |
化合物I<sub>2</sub> | 0.19[0.11-0.25] |
化合物I<sub>3</sub> | 0.16[0.13-0.27] |
化合物I<sub>4</sub> | 0.27[0.16-0.42] |
化合物I<sub>5</sub> | 8.67[6.57-10.23] |
普瑞巴林 | 2.42[1.62-3.95] |
测试结果表明本发明的化合物可以通过口服给药提供杰出的镇痛效果。
Claims (10)
2.根据权利要求1所述的一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其药学上可接受的盐,其特征在于:R1为-H或-F或-Cl,R2为-CF3或-OCF3。
4.权利要求1~3所述的一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其药学上可接受的盐,其特征在于:所述的药学上可接受的盐为盐酸盐、氢溴酸盐、氢碘酸盐、氢氟酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、乙二酸盐、丙二酸盐、丁酸盐、乳酸盐、甲磺酸盐、乙磺酸盐、对甲苯磺酸盐、马来酸盐,苯甲酸盐、琥珀酸盐、苦味酸盐、酒石酸、柠檬酸盐、富马酸盐。
5.一种药物组合物,其含有治疗有效剂量的根据权利要求1~4中任何一项所述的化合物或其药学上可接受的盐,及药学上可以接受的载体或赋形剂。
6.包括根据权利要求1~5中任一项的一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其药学上可接受的盐的镇痛药。
7.包括根据权利要求1~5中任一项的一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其药学上可接受的盐用于神经性疼痛的治疗或预防剂。
8.包括根据权利要求1~5中任一项的一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其药学上可接受的盐用于炎症性疼痛的治疗或预防剂。
9.根据权利要求1~5中任一项的一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其药学上可接受的盐用于制造镇痛药的用途。
10.根据权利要求1~5中任一项的一种可溶性环氧水解酶和γ-氨基丁酸双重抑制剂及其药学上可接受的盐用来制造神经性疼痛的治疗或预防剂的用途。
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