CN117586223A - 一种酚噻嗪类化合物及其用途 - Google Patents
一种酚噻嗪类化合物及其用途 Download PDFInfo
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- CN117586223A CN117586223A CN202311033423.9A CN202311033423A CN117586223A CN 117586223 A CN117586223 A CN 117586223A CN 202311033423 A CN202311033423 A CN 202311033423A CN 117586223 A CN117586223 A CN 117586223A
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Abstract
本发明提供了式I所示化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物;本发明化合物用于局部麻醉时起效快,单次给药后麻醉作用时间延长,在浸润麻醉与阻滞麻醉中,甚至在炎性状态下均具有较长的局部麻醉作用时间,解决了目前局麻药物使用过程中与肾上腺素联用的副作用问题,具有更好的安全性。本发明化合物可用于制备安全的、具有长时间局部麻醉的药物,具有局部麻醉作用时间长、神经损伤更小、安全性高且兼具抗炎作用的优点。
Description
技术领域
本发明属于生物医药领域,具体涉及一种酚噻嗪类化合物及其用途。
背景技术
局部麻醉药(Local anesthetics,局麻药)是一类能在用药局部可逆性的阻断感觉神经冲动发生与传递的药品,简称“局麻药”。在动物或人意识清醒的条件下,在局部可逆的阻断感觉神经冲动产生与信号传导,使有关神经支配的部位出现暂时性感觉丧失,从而可逆的引起局部组织痛觉消失的一类药物。一般的,局麻药的作用局限于给药部位并随药物从给药部位扩散而迅速消失。局部麻醉药通过直接抑制神经细胞和纤维膜上的相关离子通道,阻滞动作电位的产生和神经冲动的传导,从而产生局部麻醉作用。目前公认的局麻药作用机制,是阻断神经细胞膜上的电压门控性Na+通道,使神经冲动传导阻滞,从而产生局部麻醉作用。
临床目前所使用的局麻药均为不具备电荷的疏水性化合物,因此容易通过扩散和渗透方式通过细胞膜进入神经细胞达到钠通道的阻断位点。这些麻醉药阻断钠通道从而阻断神经元的兴奋性。实际上,这些局部麻醉药分子虽然容易通过扩散进入神经细胞内发挥作用,但同时也容易通过扩散作用从给药部位迅速扩散,游离出神经细胞,导致局部麻醉作用无法长时间持续。即使加大使用剂量也只能在一定程度内延长局部麻醉时间,这些局部麻醉药物,无法获得理想的长时间局部麻醉作用。目前临床常用的局部麻醉药物作用时间大多不超过4小时。由于传统局部麻醉药的作用维持时间较短,不得不使用镇痛泵来维持神经阻滞,采取椎管内、神经根、皮下等部位的置管,大大增加了医疗成本和感染的发生率。
由于口腔门诊手术的操作特点,局麻药的应用十分广泛。口腔局麻药一般用于门诊的小手术如牙拔除术、牙种植术、根管治疗术及龈下洁治根面平整术等,麻醉方式以浸润麻醉和阻滞麻醉最为多见。这些特点要求局麻药起效快,持续时间适中且毒性小,因此,中效局麻药如利多卡因、甲哌卡因、丙胺卡因和阿替卡因等成为了合理的选择。其中,阿替卡因是目前口腔治疗中最为广泛使用的局麻药,也是效能最强的酰胺类麻醉药,结构如下:
然而阿替卡因也存在在一些亟待解决的问题:
一方面,阿替卡因与一氧化氮类似,都具有血管舒张作用,促进了其全身吸收,但麻醉时间有限。因此,为了延长麻醉时间、减少麻醉药用量和减少出血,提高术野的可视化程度,临床要在局麻药中加入肾上腺素。但肾上腺素的加入限制了阿替卡因在特殊患者如儿童、妇女、心脑血管疾病、糖尿病、甲亢等患者中的应用。同时,肾上腺素引起的局部血管收缩可能导致神经和软组织缺血而使功能受损。尽管大多数文献都承认肾上腺素有一个安全范围,其浓度阈值仍不清楚。因此,鉴于老龄化社会中潜在心血管风险的患者数量不断增加,传统局部麻醉药物并不能满足所有口腔诊疗操作的需求。
另一方面,局部麻醉药在炎症环境下不易起效或不起效,口腔颌面部是人体解剖结构最复杂的区域,丰富的血管加之口腔内及牙齿上长期存在着各种菌群使得口腔颌面部易发生牙源性的炎症反应,最常见的即智齿冠周炎。这些炎症反应会对患者造成极大痛苦,然而临床上大多需要先对炎症反应进行控制,通过冠周冲洗及抗生素的使用使炎症尽快消除,在炎症消除之后对病源牙进行拔除或其他治疗,这是因为在炎症状态下,局麻药无法发挥正常功能。而一些急性炎症状态患者需要紧急手术干预时,术中和术后都会受到极大痛苦,此时如果局部麻醉剂能够发挥稳定的作用,对治疗操作造成的疼痛会是极大缓解。
因此,进一步研究安全、稳定起效、麻醉起效时间短且麻醉时间长、能产生一定抗炎作用的局部麻醉药,具有重要意义。
发明内容
本发明的目的在于提供一种新型的用于局部麻醉的化合物。
式I所示化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物:
其中,R4为C1~8烃基、C1~8烷氧基、3~8元环烃基、苯基或苄基;
其中,R1为C1~8烃基,且R2和R3连接形成环A:
环A中:Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh分别独立选自H、卤素、取代或未取代的:C1~8烃基、C1~8烷氧基或3~8元环烃基;
M为NR5,L为C3~4烷烃链且R5为H,或L为C1~4烷烃链且R5为取代或未取代的C1~8烃基、C1~8烷氧基、3~8元环烃基、苯基或苄基;所述取代的取代基个数为1~3个,所述取代基分别独立选自羟基、卤素、氨基、C1~8烷氧基、3~8元环烃基或C1~8酯基;且环A为时,L不为亚甲基链;或,M为O、CH2、S、SO或SO2,L为C2~4支链烷烃链;
或,R1为C1~8直链烷基,且R2为被1~3个羟基、/>氨基、C1~4烷氧基或C1~4烷基氨基取代的C1~8烷基,R3为氢、未取代或被1~3个羟基或C1~4烷氧基取代的C1~8烷基;L为C1~4烷烃链;
或,R1为异丁基;R2、R3分别独立选自氢、取代或未取代的C1~8烃基,或取代或未取代的C1~8烷氧基,所述取代的取代基个数为1~5个,所述取代基分别独立选自羟基或C1~4烷氧基;L为C1~4烷烃链。
优选的,R4为甲基。
优选的,R1为C1~8烷基且R2和R3连接形成环A;优选地,R1为甲基,且R2和R3连接形成环A。
优选的,环A中:Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh分别独立选自H或C1~8烷基,优选为H或甲基。
优选的,M为NR5,L为C3~4烷烃链且R5为H,或,L为C1~4烷烃链且R5为取代或未取代的C1~8烷基、3~8元环烷基或苯基;所述取代的取代基个数为1或2个,所述取代基分别独立选自羟基、C1~4烷氧基或C1~8酯基;且环A为时,L不为亚甲基链。
优选的,M为NR5,L为C1~4烷烃链且R5为取代或未取代的C1~4烷基、环丙烷基或苯基;所述取代的取代基个数为1个,所述取代基为羟基、甲氧基或甲酯基;且环A为时,L不为亚甲基链。
优选的,所述化合物具有式I-A所示结构:
优选的,所述化合物具有式I-A-1或1-A-2所示结构:
优选的,所述化合物具有式I-A-3所示结构:
其中,R5选自C1~4烷基。
优选的,所述化合物具有式I-B所示结构:
优选的,所述化合物具有式I-B-1、式I-B-2、式I-B-3或式I-B-4所示结构:
优选的,所述化合物具有式I-C所示结构:
优选的,所述化合物具有式I-C-1所示结构:
优选的,所述化合物具有式I-D所示结构:
优选的,所述化合物具有式I-D-1所示结构:
优选的,所述化合物具有式I-E所示结构:
优选的,所述化合物具有式I-D-1所示结构:
优选的,所述化合物具有式I-F所示结构:
优选的,所述化合物具有式I-F-1所示结构:
优选的,R1为C1~8直链烷基,且R2被1个羟基、/>氨基、C1~4烷氧基或C1~4烷基氨基取代的C1~3烷基,R3为氢、未取代或被1个羟基或C1~4烷氧基取代的C1~3烷基;L为C1~4烷烃链。
优选的,L为
优选的,R1为异丁基;R2、R3分别独立选自氢或C1~8烷基;L为C1~4烷烃链。
优选的,L为
本发明还提供式II所示化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物:
其中,L`为C1~4烷烃链;
其中,R5为C1~8烷基;
其中,X`为O、S、CH2、NR7,R7为Ri取代或未取代的C1~8烷基、苯基或苄基;Ri为羟基、3~8元环烃基、C1~8烷氧基或C1~8酯基;R6为C1~8烷基;m和n为整数,且m+n=2或4或5;
或,X为C时,R6为C1~8烷基;m和n为整数,且m+n=4或5;
k选自0、1、2或3。
优选的,L`为
优选的,R5为C1~4烷基,R6为C1~4烷基,X`为O、S、CH2、NR7,R7为Ri取代或未取代的C1~4烷基或苯基,Ri为羟基、3~6元环烃基、C1~4烷氧基或C1~4酯基。
优选的,R6为甲基,X为O、S、NR7,R7为Ri取代或未取代的C1~4烃基或苯基,Ri为羟基、环丙基、甲氧基或甲酯基。
优选的,所述化合物具有式II-A至式II-F任一项所示结构:
优选的,所述化合物具有式II-G至式II-M任一项所示结构:
优选的,所述化合物具有式II-G至式II-M任一项所示结构:
优选的,所述化合物为如下任一结构:
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优选的,所述药学上可接受的盐是指由式I所示化合物与药学上可接受的无机酸或有机酸形成;
优选地,所述无机酸或有机酸为盐酸、氢溴酸、乙酸、硫酸、甲磺酸、对甲苯磺酸、琥珀酸、碳酸、酒石酸、月桂酸、马来酸、枸橼酸或苯甲酸。
本发明还提供上述化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物在制备麻醉药物中的用途,优选地,所述麻醉药物为局部麻醉药物。
本发明还提供上述化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物在制备抗炎药物中的用途。
本发明还提供一种药物,它是以上述化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物为活性成分,加上药学上可接受的辅料制备而成的制剂。
本发明的有益效果:本发明化合物用于局部麻醉时起效快,单次给药后麻醉作用时间延长,与局麻药物阿替卡因2小时的局麻作用时间相比,本发明化合物的局麻作用时间能显著延长达到4小时;同时,本发明化合物在炎性状态下仍能发挥长效局部麻醉作用,与炎性状态下局麻药物阿替卡因0.5小时的局麻作用时间相比,本发明化合物在炎性状态下的局麻作用时间能显著延长至1小时。
本发明化合物在浸润麻醉与阻滞麻醉中均具有较长的局部麻醉作用,解决了目前局麻药物使用过程中与肾上腺素联用的副作用问题,具有更好的安全性。本发明化合物可用于制备安全的、具有长时间局部麻醉的药物,具有局部麻醉作用时间长、神经损伤更小、安全性高的优点。
本发明所述“烷烃链”是指直链或支链的烷烃去掉2个氢原子形成的烷基链。
“烷基”是指直链或支链烷基,即直链或支链的烷烃去掉1个氢原子形成的基团。
“C1~8酯基”是指RCOO-,其中R为C1~8烷基,甲酯基即CH3COO-。
“C1~4烷基氨基”是指RNH-,其中R为C1~4烷基。
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。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。
实施例1
步骤1:将3-氨基-4-甲基噻吩-2-羧酸甲酯(20.0g,116.8mmol)溶于100mL DCM中,加入碳酸钾(32.3g,233.6mmol),随后于-20℃下加入预先溶于20mL DCM的2-溴丙酰溴(32.8g,151.9mmol),室温搅拌24h。反应完成后用水(100mL×3)洗涤,收集有机相用无水硫酸钠干燥。过滤后浓缩至20mL,加入PE(200mL)搅拌过夜,过滤得到产物3-(2-溴丙酰胺基)-4-甲基噻吩-2-羧酸甲酯(35.0g,97.8%)为灰白色固体。
1H NMR(400MHz,CDCl3)δ9.30(s,1H),7.16(s,1H),4.57(q,J=7.0Hz,1H),3.87(s,3H),2.18(s,3H),1.97(d,J=7.0Hz,3H).
步骤2:将3-(2-溴丙酰胺基)-4-甲基噻吩-2-羧酸甲酯(10.0g,32.7mmol)溶于30mL DMF中,加入碳酸钾(3.86g,65.3mmol)逐滴滴加丙胺(3.86g,65.3mmol)。随后室温下搅拌5h。反应完成后用200mL DCM稀释,用水(200mL×4)洗涤,收集有机相用无水硫酸钠干燥。过滤干燥浓缩。残留物用柱层析纯化(DCM/MeOH=50:1)得到产物4-甲基-3-(2-(丙氨基)丙酰胺基)噻吩-2-羧酸甲酯(8.66g,93.2%)为淡黄色油,将其溶于80mL甲醇中,滴加盐酸(16mL,2M),室温搅拌1h,旋干,溶于水中,过滤,滤液冻干得到产物的盐酸盐。
1H NMR(400MHz,D2O)δ7.36(s,1H),4.19(q,J=7.0Hz,1H),3.73(s,3H),2.97(ddt,J=40.5,12.2,7.6Hz,2H),2.05–1.91(m,3H),1.63(dd,J=12.0,7.2Hz,5H),0.89(t,J=7.4Hz,3H).
步骤3:将化合物4-甲基-3-(2-(丙氨基)丙酰胺基)噻吩-2-羧酸甲酯(5.0g,17.6mmol)溶于20mL MeOH中,滴加预先溶于14mL水中的氢氧化钠(1.4g,35.2mmol),随后将反应液于50℃下搅拌2h。反应完成后,减压浓缩,残留物溶于100mL水中,用100mL DCM洗涤,水相随后用盐酸(2M)调整pH至7,随后用乙酸乙酯萃取水相,收集有机相用无水硫酸钠干燥。过滤干燥浓缩。得到粗产品4-甲基-3-(2-丙氨基丙酰胺基)噻吩-2-羧酸(4.59g,96.6%)。
1H NMR(400MHz,MeOD)δ7.02(s,1H),3.48(q,J=6.7Hz,1H),2.73–2.56(m,2H),2.12(s,3H),1.62–1.52(m,2H),1.46–1.39(m,3H),0.94(t,J=7.4Hz,3H).
HRMS(EI)m/z:calcd for C12H19N2O3S,271.1111;found 271.1114[M+H]+.
HPLC purity:95.393%,tR=18.609min.
步骤4:将4-甲基-3-(2-丙氨基丙酰胺基)噻吩-2-羧酸(500mg,1.85mmol)溶于20mL DMF中,加入碳酸氢钠(311mg,3.70mmol)后室温下逐滴滴加异丁基氯(340mg,3.7mmol),随后50℃下反应5h,反应完成后用200mL DCM稀释,100mL水洗四次,收集有机相用无水硫酸钠干燥。过滤干燥浓缩。残留物用柱层析纯化(DCM/MeOH=40:1)得到产物4-甲基-3-(2-(丙氨基)丙酰胺基)噻吩-2-羧酸异丁酯(180mg,29.8%)为无色油状物。
1H NMR(400MHz,D2O)δ7.48–7.34(m,1H),4.27(q,J=6.9Hz,1H),4.02(dd,J=6.3,2.2Hz,2H),3.05(ddt,J=27.5,12.1,7.8Hz,2H),2.71(s,1H),2.06(s,3H),1.97(dt,J=12.1,6.5Hz,1H),1.81–1.64(m,5H),0.98(t,J=7.4Hz,3H),0.91(d,J=6.6Hz,6H).
13C NMR(101MHz,D2O)δ169.00,162.69,136.99,136.64,128.10,124.37,71.63,56.21,48.22,27.37,19.29,18.26,15.98,12.83,10.20.
HRMS(EI)m/z:calcd for C16H17N2O3S,327.1737;found 327.1739[M+H]+.
HPLC purity:96.722%,tR=17.558min.
实施例2
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将3-(2-溴丙酰胺基)-4-甲基噻吩-2-羧酸甲酯(1.5g,4.90mmol)溶于20mL DMF中,加入碳酸钾(1.35g,9.80mmol),滴加乙基哌嗪(671mg,5.88mmol)。随后50℃下反应3h,反应完成后用200mL DCM稀释,200mL水洗四次,收集有机相用无水硫酸钠干燥。过滤干燥浓缩。残留物用柱层析纯化(DCM/MeOH=40:1)得到产物3-(2-(4-乙基哌嗪-1-基)丙酰胺基)-4-甲基噻吩-2-羧酸甲酯(1.47g,88.4%)为淡黄色油。将其溶于20mL甲醇中,滴加盐酸(5mL,2M),室温搅拌1h,旋干,溶于水中,过滤,滤液冻干得到产物的盐酸盐。
1H NMR(400MHz,CDCl3)δ9.92(s,1H),7.13(d,J=0.9Hz,1H),3.84(s,3H),3.22(q,J=7.0Hz,1H),2.69(d,J=40.6Hz,8H),2.47(q,J=7.2Hz,2H),2.16(d,J=0.9Hz,3H),1.35(d,J=7.0Hz,3H),1.12(t,J=7.2Hz,3H).
13C NMR(151MHz,D2O)δ174.13,163.21,137.88,136.70,128.09,123.71,63.16,52.31,51.94,50.87,13.61,12.94,8.52.
HRMS(EI)m/z:calcd for C16H26N3O3S,340.1689;found 340.1685[M+H]+.
HPLC purity:99.316%,tR=15.207min.
实施例3
反应步骤同实施例2,产物为无色油状物,产率77.1%。
1H NMR(400MHz,D2O)δ7.38(s,1H),4.18(d,J=6.0Hz,1H),4.05–3.88(m,2H),3.74(s,3H),3.59(d,J=12.2Hz,1H),3.42(d,J=12.1Hz,1H),2.93(t,J=11.6Hz,1H),2.82(t,J=11.7Hz,1H),1.99(s,3H),1.67(d,J=6.9Hz,3H),1.18(dd,J=14.0,6.3Hz,6H).
13C NMR(151MHz,D2O)δ168.18,163.02,136.54,136.52,128.32,124.49,69.52,64.51,55.06,52.85,52.41,17.40,17.28,13.68,12.68.
HRMS(EI)m/z:calcd for C16H25N2O4S,341.1530;found 341.1523[M+H]+.
HPLC purity:98.351%,tR=16.100min.
实施例4
反应步骤同实施例2,产物为无色油状物,产率80.8%。
1H NMR(400MHz,D2O)δ7.37(s,1H),4.11(q,J=6.9Hz,1H),3.74(s,3H),3.52(d,J=11.5Hz,1H),3.33(d,J=11.4Hz,1H),2.66(t,J=12.0Hz,1H),2.52(t,J=12.0Hz,1H),1.99(s,3H),1.85(ddt,J=29.5,15.0,10.8Hz,3H),1.65(d,J=7.0Hz,3H),0.86(dt,J=15.5,7.8Hz,7H).
13C NMR(151MHz,D2O)δ168.75,163.06,136.69,136.59,128.34,124.47,64.17,57.70,55.18,52.44,38.27,29.04,28.70,17.65,17.58,13.80,12.74.
HRMS(EI)m/z:calcd for C17H27N2O3S,339.1737;found 339.1732[M+H]+.
HPLC purity:96.029%,tR=19.084min.
实施例5
反应步骤同实施例2,产物为白色油状物,产率21.0%。
1H NMR(400MHz,CDCl3)δ10.20(s,1H),7.12(s,1H),3.93–3.75(m,7H),3.43(dd,J=10.8,9.1Hz,1H),2.81(ddt,J=12.2,9.1,4.5Hz,1H),2.63(tdd,J=11.4,7.9,4.1Hz,2H),2.17(s,3H),1.27(d,J=7.0Hz,3H),1.08(d,J=6.3Hz,3H).
13C NMR(101MHz,CDCl3)δ172.50,162.81,142.20,136.06,127.13,117.76,73.36,67.36,58.11,52.22,51.77,46.64,15.75,14.23,8.67.
HRMS(EI)m/z:calcd for C15H23N2O4S,327.1373;found 327.1364[M+H]+.
HPLC purity:95.906%,tR=15.160min and 16.403min.
实施例6
反应步骤同实施例2,产物为无色油状物,产率88.9%。
1H NMR(400MHz,CDCl3)δ10.07(s,1H),7.20–7.03(m,1H),3.84(s,3H),3.32(q,J=7.0Hz,1H),2.96(dt,J=12.7,7.2Hz,2H),2.85(d,J=6.4Hz,6H),2.17(d,J=0.9Hz,3H),1.32(d,J=7.0Hz,3H).
13C NMR(151MHz,D2O)δ168.22,163.00,136.61,136.56,128.32,124.45,64.02,52.42,24.19,13.44,12.71.
HRMS(EI)m/z:calcd for C14H21N2O3S2,329.0988;found 329.0980[M+H]+.
HPLC purity:96.255%,tR=16.582min.
实施例7
反应步骤同实施例2,产物为淡黄色油状物,产率94.8%。
1H NMR(400MHz,CDCl3)δ10.06(s,1H),7.14(s,1H),3.84(s,3H),3.70(t,J=4.5Hz,4H),3.32(q,J=6.9Hz,1H),2.92–2.72(m,2H),2.69–2.37(m,6H),2.18(s,3H),1.44(d,J=6.9Hz,3H).
13C NMR(101MHz,CDCl3)δ173.85,162.91,141.94,136.14,127.25,118.39,67.02,59.18,58.09,53.71,53.47,51.83,44.94,20.09,15.53.
HRMS(EI)m/z:calcd for C16H26N3O4S,356.1639;found 356.1630[M+H]+.
HPLC purity:99.524%,tR=13.584min.
实施例8
反应步骤同实施例2,产物为无色油状物,产率61.7%。
1H NMR(400MHz,CDCl3)δ10.05(s,1H),7.13(s,1H),4.19(dddd,J=10.3,8.6,6.2,2.4Hz,1H),3.83(d,J=1.8Hz,3H),3.27(q,J=7.0Hz,1H),2.71(dt,J=10.9,2.0Hz,1H),2.57(dd,J=10.9,1.6Hz,1H),2.35(d,J=10.9Hz,1H),2.18(dd,J=3.0,0.8Hz,3H),1.93(q,J=11.1Hz,1H),1.46(s,2H),1.44(s,1H),1.36(s,1H),1.34(s,1H),1.30(s,1H),1.29(d,J=2.6Hz,1H),1.23(d,J=3.6Hz,3H),1.12(dd,J=7.3,6.4Hz,3H).
13C NMR(101MHz,D2O)δ168.36,167.97,163.07,136.79,136.64,136.52,136.45,128.38,128.34,124.39,71.72,71.62,65.08,64.36,63.70,59.03,55.57,54.70,52.97,52.48,52.40,27.36,27.09,20.65,17.71,13.75,12.73,12.01.
HRMS(EI)m/z:calcd for C17H27N2O4S,355.1686;found 355.1680[M+H]+.
HPLC purity:96.215%,tR=19.348min and 19.955min.
实施例9
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反应步骤同实施例2,产物为无色固体,产率17.6%。
1H NMR(400MHz,CDCl3)δ9.99(s,1H),7.18–7.03(m,1H),3.82(s,3H),3.68(q,J=7.0Hz,1H),3.60–3.49(m,4H),3.31(s,6H),2.91–2.71(m,4H),2.18–2.11(m,3H),1.32(d,J=7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ172.82,162.49,141.58,136.23,126.73,126.64,119.42,71.76,61.58,61.49,58.84,51.80,51.68,50.80,15.35,15.29,10.17,10.11.
HRMS(EI)m/z:calcd for C16H27N2O5S,359.1635;found 359.1630[M+H]+.
HPLC purity:95.108%,tR=14.932min.
实施例10
反应步骤同实施例2,产物为无色油,产率35.3%。
1H NMR(400MHz,CDCl3)δ10.42(s,1H),7.07(d,J=1.1Hz,1H),3.78(s,3H),3.73–3.56(m,2H),3.51(q,J=7.0Hz,1H),3.47–3.29(m,1H),2.77(ddd,J=12.9,8.6,3.9Hz,1H),2.66–2.45(m,3H),2.16(d,J=1.0Hz,3H),1.25(d,J=7.0Hz,3H),1.07(t,J=7.1Hz,3H).
13C NMR(101MHz,CDCl3)δ172.70,163.79,143.16,135.91,127.95,116.76,60.60,60.16,53.07,52.13,44.81,16.00,13.39,9.28.
HPLC purity:95.438%,tR=17.154min.
实施例11
反应步骤同实施例2,产物为灰色油,产率19.7%。
1H NMR(400MHz,CDCl3)δ10.24(s,1H),7.08(d,J=1.4Hz,1H),3.76(d,J=1.6Hz,3H),3.75–3.53(m,6H),3.49(qd,J=7.1,1.4Hz,1H),2.76(ddt,J=12.4,10.0,3.1Hz,2H),2.60(dq,J=13.5,2.4Hz,2H),2.12(t,J=1.1Hz,3H),1.29(dd,J=7.1,1.8Hz,3H).
13C NMR(101MHz,CDCl3)δ172.21,163.91,142.75,136.47,128.00,118.01,60.95,60.17,52.54,52.24,15.57,9.40.
HPLC purity:99.487%,tR=16.202min.
实施例12
反应步骤同实施例2,产物为淡黄油,产率52.3%。
1H NMR(400MHz,CDCl3)δ9.82(d,J=18.2Hz,1H),7.05(d,J=1.0Hz,1H),3.76(s,3H),3.12(dq,J=17.8,7.0Hz,1H),2.86–2.68(m,3H),2.60–2.35(m,2H),2.26(s,3H),2.21–1.97(m,5H),1.27(dd,J=7.0,2.5Hz,3H),1.01(dd,J=8.7,6.2Hz,3H).
13C NMR(101MHz,CDCl3)δ172.61,172.45,162.74,141.86,141.80,136.25,127.00,118.52,118.43,64.75,64.68,59.98,58.02,57.93,55.85,54.83,52.68,51.74,47.88,42.45,42.41,15.54,15.48,12.72,12.10.
HPLC purity:99.293%,tR=18.441min.
实施例13
反应步骤同实施例2,产物为淡黄油,产率31.9%。
1H NMR(400MHz,CDCl3)δ10.05(s,1H),7.08(d,J=1.2Hz,1H),3.76(s,3H),3.46(q,J=7.0Hz,1H),3.37–2.91(m,8H),2.16–2.07(m,3H),1.57–1.26(m,3H).
13C NMR(101MHz,CDCl3)δ170.48,163.40,142.22,135.87,127.76,117.27,64.49,52.02,51.67,48.49,15.82,10.85.
HPLC purity:98.852%,tR=20.326min.
实施例14
步骤1:将3-(2-溴丙酰胺基)-4-甲基噻吩-2-羧酸甲酯(2.0g,6.53mmol)溶于15mLDMF和15mL ACN的混合溶剂中,加入碳酸钾(1.81g,13.06mmol)、哌嗪-1-羧酸叔丁酯(1.46g,7.84mmol),随后室温下搅拌9h,反应完成后,真空浓缩,残留物用100mL DCM溶解,用100mL水洗4次。收集有机相用无水硫酸钠干燥。过滤干燥浓缩。残留物用柱层析纯化(DCM/MeOH=50:1)得到产物4-(1-((2-(甲氧羰基)-4-甲基噻吩-3-基)氨基)-1-氧代丙-2-基)哌嗪-1-羧酸叔丁酯(2.68g,99.7%)为无色油。
1H NMR(400MHz,CDCl3)δ9.96(s,1H),7.05(d,J=1.1Hz,1H),3.76(s,3H),3.52(tt,J=13.1,7.0Hz,4H),3.17(q,J=7.0Hz,1H),2.65–2.39(m,4H),2.10(d,J=1.0Hz,3H),1.41(s,9H),1.27(d,J=7.0Hz,3H).
步骤2:将4-(1-((2-(甲氧羰基)-4-甲基噻吩-3-基)氨基)-1-氧代丙-2-基)哌嗪-1-羧酸叔丁酯(2.68g,6.51mmol)溶于10mL二氧六环中,滴加氯化氢二氧六环溶液(4M;4mL,16mmol),室温下反应5h,过滤。滤饼用二氧六环清洗后得到产物4-甲基-3-(2-(哌嗪-1-基)丙酰胺基)噻吩-2-羧酸甲酯(2.0g,79.8%)为白色固体。
1H NMR(400MHz,D2O)δ7.39(dd,J=10.7,4.3Hz,1H),4.35(dq,J=8.9,6.5Hz,1H),3.83–3.69(m,5H),3.68–3.56(m,6H),2.08–1.93(m,3H),1.71(d,J=7.0Hz,3H).
13C NMR(101MHz,D2O)δ168.20,163.08,163.04,136.64,136.61,128.43,124.49,124.44,64.24,52.52,46.97,40.89,40.86,13.95,13.91,12.84,12.80.
HPLC purity:99.543%,tR=17.497min.
实施例15
将3-(2-溴丙酰胺基)-4-甲基噻吩-2-羧酸甲酯(4.78g,15.6mmol)溶于30mL DMF中,加入碳酸钾(4.32g,31.2mmol)、1-异丙基哌嗪(2.4g,18.7mmol),随后将反应液50℃搅拌3h,反应完成后真空浓缩,残留物用100mL DCM溶解,用100mL水洗4次。收集有机相浓缩,溶于水后滴加2M盐酸调整pH至2-3,水相用DCM洗涤,随后再用2M的氢氧化钠溶液将水相pH调整至10-11,水相用DCM萃取。收集有机相用无水硫酸钠干燥。过滤干燥浓缩。得到产物3-(2-(4-异丙基哌嗪-1-基)丙酰胺基)-4-甲基噻吩-2-羧酸甲酯(5.4g,97.8%)为无色油。将产物溶于50mL甲醇中,滴加15mL 2M盐酸,室温搅拌1h,旋干,溶于水中,过滤,滤液冻干得到产物的盐酸盐。
1H NMR(400MHz,CDCl3)δ9.94(s,1H),7.20–7.02(m,1H),3.84(s,3H),3.21(q,J=7.0Hz,1H),2.70(dq,J=12.9,6.4Hz,9H),2.17(d,J=0.9Hz,3H),1.35(d,J=7.0Hz,3H),1.09(d,J=6.5Hz,6H).
13C NMR(151MHz,D2O)δ173.85,163.22,137.85,136.69,128.11,123.71,63.16,58.43,52.32,47.62,16.05,13.64,12.94.
HRMS(EI)m/z:calcd for C17H28N3O3S,354.1846;found 354.1840[M+H]+.
HPLC purity:98.948%,tR=15.932min.
实施例16
反应步骤同实施例15,产物为无色固体,产率61.7%。
1H NMR(400MHz,CDCl3)δ9.91(s,1H),7.21–7.04(m,1H),3.84(s,3H),3.22(q,J=7.0Hz,1H),2.66(d,J=51.4Hz,7H),2.40(d,J=8.6Hz,1H),2.33(s,3H),2.20–2.11(m,3H),1.35(d,J=7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ172.54,162.72,141.78,136.20,127.10,127.02,118.45,64.84,55.28,51.86,51.76,46.10,46.02,15.60,15.55,12.59,12.53.
HRMS(EI)m/z:calcd for C15H24N3O3S,326.1533;found 326.1526[M+H]+.
HPLC purity:98.402%,tR=14.715min.
实施例17
反应步骤同实施例15,产物为白色油,产率70.8%。
1H NMR(400MHz,CDCl3)δ9.91(s,1H),7.10(s,1H),3.81(s,3H),3.17(q,J=7.0Hz,1H),2.66(d,J=26.6Hz,8H),2.14(d,J=0.9Hz,3H),1.32(d,J=7.0Hz,3H),1.08(s,9H).
13C NMR(101MHz,CDCl3)δ172.76,162.70,141.80,136.19,127.11,127.04,118.49,64.83,53.74,51.83,51.72,45.84,25.92,25.86,15.63,15.58,15.54,12.74,12.67.
HRMS(EI)m/z:calcd for C18H30N3O3S,368.2002;found 368.1995[M+H]+.
HPLC purity:98.050%,tR=15.109min.
实施例18
反应步骤同实施例15,产物为无色油,产率51.0%。
1H NMR(400MHz,CDCl3)δ10.02(s,1H),7.20–7.04(m,1H),3.93–3.79(m,7H),3.18(q,J=7.0Hz,1H),2.74–2.55(m,4H),2.17(d,J=0.9Hz,3H),1.36(d,J=7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ172.31,162.87,141.96,136.11,127.25,127.21,118.00,67.14,65.39,51.86,51.79,50.71,15.68,15.64,12.74,12.71.
HRMS(EI)m/z:calcd for C14H21N2O4S,313.1217;found 313.1210[M+H]+.
HPLC purity:99.358%,tR=16.611min.
实施例19
反应步骤同实施例15,产物为淡黄色固体,产率74.0%。
1H NMR(400MHz,CDCl3)δ9.95(s,1H),7.04(d,J=1.2Hz,1H),3.77(s,3H),3.14(q,J=7.0Hz,1H),2.70–2.34(m,4H),2.09(d,J=1.0Hz,3H),1.63(pd,J=7.8,7.1,3.2Hz,4H),1.41(p,J=6.0Hz,2H),1.24(d,J=7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ172.95,162.71,141.79,136.20,126.94,118.55,65.39,51.78,51.42,26.24,24.25,15.57,11.71.
HPLC purity:95.461%,tR=17.941min.
实施例20
反应步骤同实施例15,产物为灰色固体,产率60.2%。
1H NMR(400MHz,CDCl3)δ10.01(s,1H),7.33–7.27(m,2H),7.13(d,J=1.1Hz,1H),7.02–6.94(m,2H),6.88(tt,J=7.3,1.1Hz,1H),3.82(s,3H),3.44–3.24(m,5H),2.82(dddd,J=36.3,10.8,6.8,3.8Hz,4H),2.19(d,J=1.0Hz,3H),1.40(d,J=7.0Hz,3H).
13C NMR(101MHz,Chloroform-d)δ172.39,162.78,151.33,141.89,136.16,129.16,127.14,119.76,118.26,116.16,65.02,51.85,50.25,49.36,15.63,12.67.
HPLC purity:98.645%,tR=20.010min.
实施例21
将3-(2-溴丙酰胺基)-4-甲基噻吩-2-羧酸甲酯(1.22g,3.98mmol)溶于20mL DMF中,加入碳酸钾(3.30g,23.91mmol)、1-丙基哌嗪(511mg,3.98mmol),随后将反应液室温搅拌过夜,反应完成后过滤,将滤液真空浓缩,残留物溶于100mL DCM中,用100mL水洗4次。收集有机相用无水硫酸钠干燥。过滤干燥浓缩。残留物用柱层析纯化(DCM/MeOH=40:1)得到产物4-甲基-3-(2-(4-丙基哌嗪-1-基)丙酰胺基)噻吩-2-羧酸甲酯(912mg,74.8%)为无色油。将产物溶于10mL甲醇中,滴加5mL 2M盐酸,室温搅拌1h,旋干,溶于水中,过滤,滤液冻干得到产物的盐酸盐。
1H NMR(400MHz,CDCl3)δ9.89(s,1H),7.10(d,J=1.4Hz,1H),3.82(d,J=1.1Hz,3H),3.27–3.12(m,1H),2.87–2.38(m,8H),2.38–2.28(m,2H),2.14(d,J=1.1Hz,3H),1.59–1.44(m,2H),1.38–1.28(m,3H),0.96–0.81(m,3H).
13C NMR(101MHz,CDCl3)δ172.58,162.71,141.79,136.21,127.02,118.49,64.87,60.67,53.41,51.78,20.07,15.55,12.53,11.99.
HPLC purity:98.935%,tR=18.446min.
实施例22
反应步骤同实施例21,产物为无色油,产率52.7%。
1H NMR(400MHz,CDCl3)δ9.84(s,1H),7.05(d,J=1.2Hz,1H),3.77(s,3H),3.14(q,J=7.0Hz,1H),2.90–2.36(m,8H),2.36–2.28(m,2H),2.09(d,J=1.0Hz,3H),1.50–1.38(m,2H),1.33–1.21(m,5H),0.86(t,J=7.3Hz,3H).
13C NMR(101MHz,CDCl3)δ172.56,162.73,141.80,136.22,127.03,118.49,64.87,58.47,53.43,51.79,29.05,20.81,15.55,14.07,12.53.
HPLC purity:99.409%,tR=19.173min.
实施例23
反应步骤同实施例21,产物为无色油,产率58.1%。
1H NMR(400MHz,CDCl3)δ9.84(s,1H),7.05(s,1H),3.76(s,3H),3.46(t,J=5.6Hz,2H),3.29(s,3H),3.14(q,J=7.0Hz,1H),2.78–2.41(m,10H),2.09(s,3H),1.27(d,J=7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ172.56,162.71,141.79,136.20,127.02,118.47,70.17,64.85,58.91,57.88,53.78,51.77,15.54,12.50.
HPLC purity:99.002%,tR=18.203min.
实施例24
反应步骤同实施例21,产物为无色油,产率82.0%。
1H NMR(400MHz,Chloroform-d)δ9.91(s,1H),7.10(d,J=1.0Hz,1H),3.82(s,3H),3.21(q,J=7.0Hz,1H),2.70(dd,J=26.5,4.6Hz,8H),2.29(d,J=6.6Hz,2H),2.15(d,J=1.0Hz,3H),1.34(d,J=7.0Hz,3H),0.88(ddtd,J=11.4,7.9,6.5,4.8Hz,1H),0.59–0.44(m,2H),0.17–0.07(m,2H).
13C NMR(101MHz,CDCl3)δ172.35,162.50,141.61,135.98,126.82,118.20,64.65,63.51,53.23,51.53,15.35,12.27,8.15,3.70.
HPLC purity:99.556%,tR=18.690min.
实施例25
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反应步骤同实施例21,产物为无色油,产率40.9%。
1H NMR(400MHz,Chloroform-d)δ9.84(s,1H),7.05(d,J=1.0Hz,1H),3.76(s,3H),3.58(t,J=5.4Hz,2H),3.15(q,J=7.0Hz,1H),2.74–2.49(m,10H),2.09(d,J=1.0Hz,3H),1.28(d,J=7.0Hz,3H).
13C NMR(101MHz,CDCl3)δ172.54,162.86,141.93,136.27,127.19,118.41,64.96,59.37,57.88,53.13,51.87,15.65,12.72.
HPLC purity:99.721%,tR=17.124min.
实施例26
步骤1:反应步骤同实施例1步骤1,白色固体,产率88.8%。
1H NMR(400MHz,CDCl3)δ9.36(s,1H),7.10(s,1H),3.97(s,2H),3.82(s,3H),2.13(d,J=1.0Hz,3H).
步骤2:同实施例2,产物为无色油,产率46.3%。
1H NMR(400MHz,CDCl3)δ9.85(s,1H),7.06(s,1H),3.77(s,3H),3.12(s,2H),2.64(dt,J=13.6,4.6Hz,9H),2.12(s,3H),1.02(d,J=6.5Hz,6H).
13C NMR(101MHz,CDCl3)δ167.83,161.70,140.49,135.23,126.11,117.67,61.03,53.47,52.97,50.77,47.70,17.65,14.59.
HPLC purity:97.830%,tR=17.898min.
实施例27
步骤1:反应步骤同实施例1步骤1,白色固体,产率87.0%。
1H NMR(400MHz,CDCl3)δ9.26(s,1H),7.09(d,J=1.1Hz,1H),4.33(dd,J=7.8,5.7Hz,1H),3.81(s,3H),2.26–2.01(m,5H),1.06(t,J=7.3Hz,3H).
步骤2:同实施例2,产物为无色油,产率28.7%。
1H NMR(400MHz,CDCl3)δ9.75(s,1H),7.05(d,J=1.5Hz,1H),3.77(s,3H),2.89–2.84(m,1H),2.63(ddt,J=25.6,19.5,8.7Hz,9H),2.13(d,J=1.4Hz,3H),1.85–1.67(m,2H),1.06–0.92(m,9H).
13C NMR(101MHz,CDCl3)δ170.73,161.90,141.18,135.03,126.24,116.70,70.52,53.50,50.74,47.86,20.80,17.63,17.59,15.02,10.19.
HPLC purity:99.081%,tR=19.175min.
实施例28
反应步骤同实施例1,产物为无色油,产率36.3%。
1H NMR(400MHz,D2O)δ7.43(s,1H),4.27(q,J=7.0Hz,1H),4.21(t,J=6.5Hz,2H),3.15–2.97(m,2H),2.83(s,1H),2.07(s,3H),1.80–1.65(m,7H),0.96(dt,J=22.1,7.4Hz,6H).
13C NMR(101MHz,D2O)δ169.06,162.85,136.86,136.64,128.20,128.16,124.55,67.53,56.21,48.20,21.52,19.29,15.93,12.81,10.18,9.63.
HRMS(EI)m/z:calcd for C15H15N2O3S,313.1580;found 313.1580[M+H]+.
HPLC purity:97.343%,tR=19.234min.
实施例29
反应步骤同实施例1,产物为无色油,产率43.1%。
1H NMR(400MHz,D2O)δ7.31(d,J=7.5Hz,1H),4.17(dt,J=13.6,6.7Hz,3H),3.06–2.84(m,2H),2.74(s,1H),1.97(d,J=1.5Hz,3H),1.70–1.52(m,7H),1.28(qt,J=9.4,4.9Hz,2H),0.88(td,J=7.4,1.3Hz,3H),0.83–0.75(m,3H).
13C NMR(101MHz,D2O)δ168.99,162.78,137.05,136.65,128.07,124.46,65.80,56.21,48.21,30.05,19.30,18.62,15.96,12.99,12.83,10.20.
HRMS(EI)m/z:calcd for C16H17N2O3S,327.1737;found 327.1737[M+H]+.
HPLC purity:98.835%,tR=19.758min.
实施例30
反应步骤同实施例1,产物为无色油,产率50.7%。
1H NMR(400MHz,D2O)δ7.44(d,J=0.9Hz,1H),4.29(dq,J=10.5,7.1Hz,3H),3.15–2.97(m,2H),2.83(s,1H),2.07(s,3H),1.84–1.63(m,5H),1.31(t,J=7.1Hz,3H),0.98(t,J=7.5Hz,3H).
13C NMR(101MHz,D2O)δ169.10,162.81,136.84,136.64,128.19,124.62,62.23,56.19,48.18,19.28,15.87,13.52,12.80,10.17.
HRMS(EI)m/z:calcd for C14H23N2O3S,299.1424;found 299.1427[M+H]+.
实施例31
反应步骤同实施例1,产物为无色油,产率31.5%。
1H NMR(400MHz,Chloroform-d)δ6.97(s,1H),4.24(t,J=6.1Hz,1H),3.84–3.75(m,1H),2.79(qd,J=5.0,3.1Hz,1H),1.83–1.73(m,1H),1.57–1.46(m,1H),1.44–1.36(m,1H),1.40–1.30(m,1H),1.33–1.24(m,5H),0.90(dt,J=8.6,6.9Hz,3H).
HRMS(EI)m/z:calcd for C20H34N2O3S,299.1424;found 383.2369[M+H]+.
实施例32
反应步骤同实施例2,产物为无色油状物,产率71.5%。
1H NMR(400MHz,Chloroform-d)δ9.47(s,1H),6.98(s,1H),3.91(s,3H),3.57(q,J=6.4Hz,1H),2.86–2.69(m,3H),2.25(d,J=0.7Hz,3H),1.74–1.47(m,4H),1.39–1.26(m,4H),1.11(d,J=5.9Hz,3H),0.92(d,J=6.4Hz,3H).
HRMS(EI)m/z:calcd for C17H26N2O3S,339.1737;found 339.1670[M+H]+.
实施例33
反应步骤同实施例2,将3-(2-(4-乙基哌嗪-1-基)丙酰胺基)-4-甲基噻吩-2-羧酸甲酯溶于甲醇中,室温下滴加盐酸溶液,室温搅拌1h后旋干,残留物溶于水中后过滤除去杂质,滤液冻干后得到产物的盐酸盐。
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以上化合物制备过程中的反应条件与实施例1相同,区别在于根据取代基的差异替换对应的原料。
实施例106
将1a(20.0g,116.80mmol)溶于100mL二氯甲烷(DCM)中,加入23.6g三乙胺,0℃滴加溶于20mL DCM的2-溴丙酰溴(27.7g,128.5mmol),室温搅拌反应12h,利用TLC监测反应情况。待反应基本完全,用DCM萃取,有机相用无水硫酸钠干燥,过滤后减压旋干溶剂。得到33.2g类白色固体粉末1c,产率93%。
1H NMR(500MHz,Chloroform-d)δ9.30(s,1H),7.16(s,1H),4.57(q,J=7.0Hz,1H),3.87(s,3H),2.18(s,3H),1.97(d,J=7.0Hz,3H).
将化合物1c(3.0g,9.80mmol)和碳酸钾(2.7g,19.60mmol)加入到30mL DMF,搅拌下加入1d(1.08g,10.78mmol),50℃搅拌反应2h,将反应液减压旋干,粗产品用硅胶柱柱层析纯化,洗脱剂:DCM:MeOH=50:1,纯化后得到2.8g无色油状物1。产率88%。
1H NMR(500MHz,Chloroform-d)δ9.43(s,1H),6.98(s,1H),3.91(s,2H),3.78(d,J=0.9Hz,1H),3.65(d,J=0.9Hz,1H),3.45(q,J=6.8Hz,1H),2.97(ddd,J=12.3,4.4,1.9Hz,1H),2.66–2.55(m,4H),2.50(ddd,J=11.4,4.4,1.9Hz,1H),1.32(d,J=6.6Hz,3H),1.07(t,J=7.2Hz,3H).
实施例107
将化合物1c(2.0g,6.53mmol)和碳酸钾(1.8g,13.06mmol)加入到20mL DMF,搅拌下加入2b(1.08g,10.78mmol),50℃搅拌反应2h,将反应液减压旋干,粗产品用硅胶柱柱层析纯化,洗脱剂:DCM:MeOH=50:1,纯化后得到1.8g无色油状物2c。产率81%。
1H NMR(500MHz,Chloroform-d)δ9.43(s,1H),6.98(s,1H),3.91(s,2H),3.73(t,J=0.7Hz,1H),3.66(d,J=0.8Hz,1H),3.46(q,J=6.7Hz,1H),3.02(ddd,J=12.3,4.6,2.7Hz,1H),2.99–2.87(m,2H),2.79(dddd,J=25.4,12.2,4.4,2.6Hz,2H),1.32(d,J=6.8Hz,3H),1.15(d,J=6.8Hz,3H),1.10(d,J=6.6Hz,3H).
将2c(1.0g,2.95mmol)溶于20mL MeOH中,加入氢氧化钠溶液,50℃搅拌2h,TLC监测反应完全。过滤后,减压蒸干溶剂。将固体溶于50mL水中,正丁醇萃取(50mL×5),有机相用无水硫酸钠干燥,减压浓缩,得800mg白色固体,将固体溶于20mL DMF中,加入溴乙烷(495mg,5.89mmol),室温反应5h,TLC监测反应完全。加入100mL DCM,200mL水洗3次,有机相用无水硫酸钠干燥后,减压蒸干溶剂。柱层析纯化得到750mg无色油状物2,产率72%。
1H NMR(500MHz,Chloroform-d)δ9.42(s,1H),6.98(s,1H),4.32(q,J=6.4Hz,2H),3.73(t,J=0.7Hz,1H),3.66(d,J=0.7Hz,1H),3.46(q,J=6.7Hz,1H),3.02(ddd,J=12.3,4.6,2.7Hz,1H),2.99–2.87(m,2H),2.79(dddd,J=25.4,12.2,4.3,2.6Hz,2H),1.36(t,J=6.4Hz,3H),1.32(d,J=6.8Hz,3H),1.15(d,J=6.8Hz,3H),1.10(d,J=6.6Hz,3H).
实施例108
将实施例70产物600mg溶解于甲醇10mL,冰浴下滴加2倍物质的量的0.1mol/L的盐酸-甲醇溶液,减压浓缩。残留物溶于水后过滤,滤液真空冻干,得到白色固体3。
实施例109
将原料4a(3.0g,14.98mmol)溶于30mL ACN中,加入碳酸钾(4.14g,29.96mmol)和1-溴丁烷(2.26g,16.48mmol),常温下搅拌过夜,TLC监测反应完全。过滤,减压浓缩ACN,得粗产品。用硅胶柱柱层析纯化(EA:PE=20%),得2.0g无色油状物,产率85%。
1H NMR(500MHz,Chloroform-d)δ2.84–2.70(m,4H),2.62(dt,J=6.0,5.2Hz,2H),2.50(dt,J=11.2,6.3Hz,2H),2.44(t,J=6.5Hz,2H),2.15–2.08(m,1H),1.76–1.66(m,2H),1.51–1.42(m,2H),1.37–1.27(m,2H),0.93(t,J=7.4Hz,3H).
将其溶于10mL DCM中,加入10mL TFA,常温搅拌反应1h,点板反应完全,旋干溶剂得4c。将化合物1c(3.56g,11.63mmol)和碳酸钾(6.43g,46.54mmol)加入到30mL DMF,搅拌下加入4c(12.80mmol),室温搅拌反应5h,将反应液减压旋干,粗产品用硅胶柱柱层析纯化,洗脱剂:DCM:MeOH=50:1,纯化后得到3.6g无色油状物4。产率81%。
实施例110
将实施例109产物1.0g溶解于甲醇15mL,冰浴下滴加等物质的量的0.1mol/L的硫酸-甲醇溶液,减压浓缩至干。残留物溶于水后过滤,滤液真空冻干,得到白色固体(5)。
按照上述实施例的方法,得到以下实施例化合物:
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以上化合物制备过程中的反应条件与实施例107相同,区别在于根据取代基的差异替换对应的原料。
以下通过实验例证明本发明的有益效果。以下实验中,各实施例制备得到的化合物以实施例的序号命名,例如,实施例1制备得化合物命名为化合物1。
实验例1、本发明化合物的局部麻醉作用
1、坐骨神经阻滞模型
选取实施例1~168制备的化合物(化合物1-168),阿替卡因阳性对照组给予8组完全适应实验环境的受试大鼠,每组6只。
给药剂量为:阿替卡因组浓度为2%水溶液,待测药物浓度均为62mmol/L的生理盐水溶液。
每只大鼠给药或对照的注射体积为0.5ml,通过神经定位器导向定位,注射于大鼠坐骨神经附近。通过von Frey刺激仪,刺激大鼠注射药物体侧足底,观测局部麻醉效果。同时,由后肢蹬踏试验(Postural Extensor Thrust,PET)评价大鼠运动功能情况:垂直提起大鼠并使注射侧后肢蹬在电子天平台面上,此时大鼠后肢肌力由肢体蹬踏天平而显示出的数值表示。肢体完全麻痹时,读数为肢体自身重量,约20g。测量值超过基线与肢体重量差值的一半视为运动功能恢复,小于或等于该值视为运动功能消失。
表1本发明化合物的坐骨神经局部麻醉效果
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实验结果表明,该类药物能够产生较阿替卡因更强的麻醉作用,相同给药剂量下该类药物在坐骨神经阻滞模型中能够产生大于2小时的局部麻醉感觉阻滞时间。
2、大鼠皮下浸润模型
250~300克体重的大鼠背部剃毛消毒后,在裸露的背部一侧画出直径约1.5厘米圆形,并将圆形进行6等分。在中心的皮肤处皮下注射含有药物的溶液0.5mL(以生理盐水为溶剂,2%阿替卡因(62mmol/L),本发明专利所述化合物浓度范围62mmol/L)。将Von Frey纤维丝中100克力度的纤维丝与针头绑定进行皮肤局部刺激。药物注射1min后,使用上述方法在6个划分范围内进行刺激,若在同一等分范围内的连续3次刺激均未出现背部皮肤收缩行为,视为药效效应阳性,若出现背部皮肤收缩则视为局部麻醉效应消失。6个等分范围中有4个或4个以上区域显示局部麻醉阳性,则视为药物的局部麻醉有效,6个等分范围中少于4个区域显示阳性,视为局部麻醉失效。每种化合物使用6只大鼠进行实验。
表2本发明化合物的皮下浸润局部麻醉效果
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实验结果表明,相同给药剂量下,该类药物较阿替卡因相比,在大鼠皮下浸润模型中能够产生大于3小时的局部麻醉作用时间。
实验例2、本发明化合物的安全性
1、小鼠LD50值
随机选取18.0g-21.0g小鼠进行小鼠尾静脉LD50测量,实验采用序贯法。用75%酒精棉球轻轻擦拭鼠尾,软化小鼠尾巴角质层,扩张尾静脉,用注射器经尾静脉注射不同浓度药物。给药速度10-15秒,注射液体总体积不超过1.0mL。根据预实验结果,在最高剂量(即一定致死剂量的最小值)和最低剂量(即不致死剂量的最大值)之间按照等比数列设置另外三个剂量,共五个剂量组,组间剂量比值以1︰0.6至1︰0.85为佳。从中间剂量开始给药,观察小鼠死亡情况。若小鼠未死亡,则下一只小鼠给予高一个剂量;若小鼠死亡,则下一只大鼠给予低一个剂量;以此类推进行实验,直到同向出现6个交叉则实验结束。
采用序贯法计算公式LD50=lg-1[X0+i(A/N)±0.5]计算药物的LD50。
其中取中心组d(组距)为0,随剂量增大依次为1、2,剂量减小依次为-1、-2;X0表示d=0时的对数剂量;i(对数剂量组距)表示公比倒数的对数值;a为相应剂量下阳性的个数;分别用N和A代表a和ad的总和。
表3本发明化合物的小鼠尾静脉LD50值测量结果
实验结果表明,该类药物的小鼠LD50值较阳性药物阿替卡因高,说明该类化合物较阿替卡因具有更高的安全性高。
2、神经病理损伤评估
选取实施例1~168的药物,阿替卡因阳性对照组分别给予完全适应实验环境的受试大鼠,每组8只。
给药剂量为:阿替卡因2%水溶液,待测药物浓度均为62mmol/L的水溶液。每只大鼠给药或对照的注射体积为0.5mL,注射于大鼠坐骨神经附近。在坐骨神经注射后第7天和第14天,将实验大鼠异氟醚麻醉下心脏注射布比卡因安乐死。取注射部位坐骨神经约1.5cm,存于10%甲醛溶液中48h,HE染色并切成5μm厚度的切片。
神经病理损伤评估显示:实施例1~168的药物与阿替卡因阳性对照组相比,在神经损伤、血管增生、脱髓鞘程度、肌肉炎症、结缔组织炎症程度方面都没有显著差异,具有良好的安全性。
实验例3、本发明化合物在炎症环境下仍能发挥作用且具有抗炎作用
1、CFA诱导的足底炎症模型
选取实施例1~168的药物,阿替卡因阳性对照组分别给予完全适应实验环境的受试大鼠,每组8只。每只大鼠右侧足底注射CFA(完全弗式佐剂)48h后可观察到足底明显肿胀且VonFrey刺激仪测量大鼠右后爪缩爪阈值明显降低,此时可进行足底皮下给药。
给药剂量为:阿替卡因2%水溶液,待测药物浓度均为62mmol/L的水溶液。每只大鼠给药或对照的注射体积为0.2mL,注射于大鼠足底肿胀部位皮下。通过von Frey刺激仪,刺激大鼠注射药物体侧足底,观测局部麻醉效果。起效后每10min测试一次,测量值超过肢体重量与基线差值的一半视为麻醉起效,小于或等于该值视为麻醉失效。
表4本发明化合物在CFA诱导的足底炎症模型发挥作用
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实验结果表明,相同给药剂量下,该类药物较阿替卡因相比,在CFA诱导的足底炎症模型中能够产生至少大于1小时的局部麻醉作用时间。
2、细胞分子水平LPS炎症模型
将1*10^5细胞(DRG原代细胞)种于6孔板中,24h待贴壁后将两种细胞分为3组,第一组使用完全培养基处理48h,第二组先使用1ug/ml LPS处理24h,后更换完全培养基处理24h,第三组先使用1ug/ml LPS处理24h,后更换含1mM本发明化合物的完全培养基处理24h。提取各组细胞RNA,逆转录为cDNA后,使用RT-QPCR方法检测各组中炎症因子(IL1β,IL6,TNFα)表达改变
实施例15制备的化合物(化合物15):
实施例16制备的化合物(化合物16):
实施例22制备的化合物(化合物22):
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实验结果表明,该类药物能够明显降低LPS诱导下的细胞炎症因子(IL1β,IL6,TNFα)水平,差异有统计学意义(P<0.05)
综上所述,本发明化合物用于局部麻醉时起效快,单次给药后麻醉作用时间延长,在浸润麻醉与阻滞麻醉中均具有较长的局部麻醉作用,解决了目前局麻药物使用过程中与肾上腺素联用的副作用问题,具有更好的安全性。本发明化合物可用于制备安全的、具有长时间局部麻醉的药物,具有局部麻醉作用时间长、神经损伤更小、安全性高、能产生抗炎作用的优点。
Claims (35)
1.式I所示化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物:
其中,R4为C1~8烃基、C1~8烷氧基、3~8元环烃基、苯基或苄基;
其中,R1为C1~8烃基,且R2和R3连接形成环A:
环A中:Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh分别独立选自H、卤素、取代或未取代的:C1~8烃基、C1~8烷氧基或3~8元环烃基;
M为NR5,L为C3~4烷烃链且R5为H,或L为C1~4烷烃链且R5为取代或未取代的C1~8烃基、C1~8烷氧基、3~8元环烃基、苯基或苄基;所述取代的取代基个数为1~3个,所述取代基分别独立选自羟基、卤素、氨基、C1~8烷氧基、3~8元环烃基或C1~8酯基;且环A为时,L不为亚甲基链;或,M为O、CH2、S、SO或SO2,L为C2~4支链烷烃链;
或,R1为C1~8直链烷基,且R2为被1~3个羟基、/>氨基、C1~4烷氧基或C1~4烷基氨基取代的C1~8烷基,R3为氢、未取代或被1~3个羟基或C1~4烷氧基取代的C1~8烷基;L为C1~4烷烃链;
或,R1为异丁基;R2、R3分别独立选自氢、取代或未取代的C1~8烃基,或取代或未取代的C1~8烷氧基,所述取代的取代基个数为1~5个,所述取代基分别独立选自羟基或C1~4烷氧基;L为C1~4烷烃链。
2.如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,R4为甲基。
3.如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,R1为C1~8烷基且R2和R3连接形成环A;优选地,R1为甲基,且R2和R3连接形成环A。
4.如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,环A中:Ra、Rb、Rc、Rd、Re、Rf、Rg、Rh分别独立选自H或C1~8烷基,优选为H或甲基。
5.如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,M为NR5,L为C3~4烷烃链且R5为H,或,L为C1~4烷烃链且R5为取代或未取代的C1~8烷基、3~8元环烷基或苯基;所述取代的取代基个数为1或2个,所述取代基分别独立选自羟基、C1~4烷氧基或C1~8酯基;且环A为时,L不为亚甲基链。
6.如权利要求5所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,M为NR5,L为C1~4烷烃链且R5为取代或未取代的C1~4烷基、环丙烷基或苯基;所述取代的取代基个数为1个,所述取代基为羟基、甲氧基或甲酯基;且环A为时,L不为亚甲基链。
7.如权利要求1~6任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物具有式I-A所示结构:
8.如权利要求7所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物具有式I-A-1或1-A-2所示结构:
9.如权利要求8所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物具有式I-A-3所示结构:
其中,R5选自C1~4烷基。
10.如权利要求1~4任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物具有式I-B所示结构:
11.如权利要求10所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物具有式I-B-1、式I-B-2、式I-B-3或式I-B-4所示结构:
12.如权利要求1~4任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物具有式I-C所示结构:
13.如权利要求12所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物具有式I-C-1所示结构:
14.如权利要求1~4任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物具有式I-D所示结构:
15.如权利要求14所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物具有式I-D-1所示结构:
16.如权利要求1~4任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物具有式I-E所示结构:
17.如权利要求16所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物具有式I-D-1所示结构:
18.如权利要求1~4任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物具有式I-F所示结构:
19.如权利要求18所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物具有式I-F-1所示结构:
20.如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,R1为C1~8直链烷基,且R2被1个羟基、/>氨基、C1~4烷氧基或C1~4烷基氨基取代的C1~3烷基,R3为氢、未取代或被1个羟基或C1~4烷氧基取代的C1~3烷基;L为C1~4烷烃链。
21.如权利要求20所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,L为
22.如权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,R1为异丁基;R2、R3分别独立选自氢或C1~8烷基;L为C1~4烷烃链。
23.权利要求1所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,L为
24.式II所示化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物:
其中,L`为C1~4烷烃链;
其中,R5为C1~8烷基;
其中,X`为O、S、CH2、NR7,R7为Ri取代或未取代的C1~8烷基、苯基或苄基;Ri为羟基、3~8元环烃基、C1~8烷氧基或C1~8酯基;R6为C1~8烷基;m和n为整数,且m+n=2或4或5;
或,X为C时,R6为C1~8烷基;m和n为整数,且m+n=4或5;
k选自0、1、2或3。
25.如权利要求24所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,L`为
26.如权利要求25所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,R5为C1~4烷基,R6为C1~4烷基,X`为O、S、CH2、NR7,R7为Ri取代或未取代的C1~4烷基或苯基,Ri为羟基、3~6元环烃基、C1~4烷氧基或C1~4酯基。
27.如权利要求26所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,R6为甲基,X为O、S、NR7,R7为Ri取代或未取代的C1~4烃基或苯基,Ri为羟基、环丙基、甲氧基或甲酯基。
28.如权利要求24所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物具有式II-A至式II-F任一项所示结构:
29.如权利要求24所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物具有式II-G至式II-M任一项所示结构:
30.如权利要求24所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物具有式II-G至式II-M任一项所示结构:
31.如权利要求1~30任一项所述的化合物,或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述化合物为如下任一结构:
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32.根据权利要求1~30任一项所述的化合物,或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物,其特征在于,所述药学上可接受的盐是指由式I所示化合物与药学上可接受的无机酸或有机酸形成;
优选地,所述无机酸或有机酸为盐酸、氢溴酸、乙酸、硫酸、甲磺酸、对甲苯磺酸、琥珀酸、碳酸、酒石酸、月桂酸、马来酸、枸橼酸或苯甲酸。
33.权利要求1~32任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物在制备麻醉药物中的用途,优选地,所述麻醉药物为局部麻醉药物。
34.权利要求1~32任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物在制备抗炎药物中的用途。
35.一种药物,其特征在于,它是以权利要求1~32任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代化合物为活性成分,加上药学上可接受的辅料制备而成的制剂。
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