CN118221633A - 一种trpv1/urat1双重抑制剂、其制备方法及应用 - Google Patents
一种trpv1/urat1双重抑制剂、其制备方法及应用 Download PDFInfo
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- CN118221633A CN118221633A CN202410290766.1A CN202410290766A CN118221633A CN 118221633 A CN118221633 A CN 118221633A CN 202410290766 A CN202410290766 A CN 202410290766A CN 118221633 A CN118221633 A CN 118221633A
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- Prior art keywords
- benzo
- carboxamide
- piperazine
- dihydroxy
- ylmethyl
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Abstract
本发明涉及一种TRPV1/URAT1双重抑制剂或其可药用的盐,其具有式(I)所示的结构:其中,所述的A环选自苯环,环己基,;R1与R2各自独立选自氢、烷基、环烷基、烷氧基、氨基、卤素、腈基、硝基,其中所述烷基、环烷基、烷氧基任选进一步被一个或多个选自卤素、腈基、烷基、烷氧基的基团所取代;L选自脲基、硫脲基、酰胺基、哌嗪脲基、甲基哌嗪脲基、磺酰胺基、磺酰脲基、酯基、或羰基;X1、X2各自独立选自CH2、NH、O或S;m选自1、2或3;n选自0、1、2或3。该双重抑制剂涉及的结构在化合物设计上具有独特性和新颖性,在镇痛的同时能够有效降低血尿酸。
Description
技术领域
本发明属于痛风相关的药物学技术领域,具体涉及一种新型的TRPV1/URAT1双重抑制剂、其制备方法及含有该类化合物的药物组合物在制备痛风和/或高尿酸血症以及镇痛药物中的应用。
背景技术
痛风是一种由尿酸盐晶体沉积在关节和非关节结构中引起的常见疾病。高血清尿酸浓度(≥0.42mmol/L)是痛风发生的最重要危险因素。痛风表现为严重疼痛性关节炎的间歇性发作,由机体对沉积的尿酸钠结晶的先天性免疫反应引起,可描述为刺痛、啃咬、烧灼感或搏动性,给患者带来极大的痛苦。近年来,随着人们生活水平的提高及饮食结构的改变,加之不良的生活习惯,痛风的发病率呈现持续上升及逐年低龄化的趋势。
快速有效地控制急性炎症反应是治疗痛风发作的基础。目前可用非甾体抗炎药、秋水仙碱和皮质类固醇等单独或联合使用,但是此类药物仅能部分缓解疼痛,持续降低血清尿酸水平对痛风的长期治疗至关重要。常用降尿酸药物包括黄嘌呤氧化酶抑制剂(非布司他和别嘌醇)\肾尿酸盐转运蛋白抑制剂(雷西纳德)以及重组尿酸酶(普瑞凯希)等。上述药物均存在潜在的肝肾毒性和多器官不良反应。因此,寻找结构新颖、高效低毒的抗痛风新药迫在眉睫。
痛风是与高尿酸血症相关的关节炎,少数痛风患者存在尿酸产生或多的情况,多数患者发病与尿酸***减少或重吸收增多有关。尿酸盐在肠道和肾脏的转运改变,在高尿酸血症和痛风的发病机制中起着核心作用。全基因组关联研究表明尿酸盐转运蛋白基因SLC2A9(编码GLUT9)、SLC22A12(编码URAT1)、SLC17A1(编码NPT1)和ABCG2与血清尿酸盐水平的变化密切相关。其中URAT1在近端肾小管的顶膜通过离子交换机制介导肾小管90%以上的尿酸重吸收,开发URAT1抑制剂是新型抗高尿酸血症药物的一个有吸引力的靶点。截至目前,共有五种URAT1抑制剂在全球上市,即丙磺舒、磺吡酮、苯溴马隆、雷西纳德、地西纳德。然而,目前临床上URAT1抑制剂由于其严重不良反应,特别是严重的肝肾毒性而受到限制。因此,仍需开发安全、有效和特异的URAT1作为新型抗痛风药物。
TRPV1是瞬时受体电位阳离子通道的一个亚家族,在机体对温度和疼痛的感知中发挥重要作用。TRPV1激活后,引起钙离子内流,导致神经末梢释放P物质和降钙素基因相关肽等,从而引发疼痛。下调TRPV1表达或使用TRPV1拮抗剂可以有效阻止TRPV1激活,抑制疼痛信号的传导,缓解多种炎症和损伤带来的疼痛。TRPV1拮抗剂的研究已经成为目前最有前景的镇痛药研究方向之一。目前尚无TRPV1抑制剂上市,多个药物处于II/III期临床阶段,用于牙痛、疱疹后疼痛以及骨关节炎痛的治疗。开发TRPV1/URTA1双重抑制剂可以同时发挥镇痛及降尿酸作用,有望达到标本兼治的效果。
基于此,研发了本申请。
发明内容
本发明目的在于克服现有技术存在的缺陷,提供一种新型的TRPV1/URAT1双重抑制剂。本发明TRPV1/URAT1双重抑制剂涉及的结构在化合物设计上具有独特性和新颖性,在镇痛的同时能够有效降低血尿酸。
本发明还提供上述新型TRPV1/URAT1双重抑制剂在制备痛风和/或高尿酸血症药物、以及镇痛药物中的应用。
为实现上述发明目的,本发明采用如下技术方案:
一种TRPV1/URAT1双重抑制剂或其可药用的盐,其具有式(I)所示的结构:
其中,所述的A环选自苯环,环己基,
R1与R2各自独立选自氢、烷基、环烷基、烷氧基、氨基、卤素、腈基、硝基,其中所述烷基、环烷基、烷氧基任选进一步被一个或多个选自卤素、腈基、烷基、烷氧基的基团所取代;
L选自脲基、硫脲基、酰胺基、哌嗪脲基、甲基哌嗪脲基、磺酰胺基、磺酰脲基、酯基、或羰基;
X1、X2各自独立选自CH2、NH、O或S;
m选自1、2或3;
n选自0、1、2或3。
具体的,本发明的优选方案,优选自上述所定义的具有通式(I)的化合物或其可药用的盐;其中,
所述的A环选自苯环、
R1与R2各自独立的选自氢、C1-C4烷基、C1-C4烷氧基、卤素、氨基、腈基,其中所述烷基、烷氧基任选进一步被一个或多个选自卤素、腈基、烷基、烷氧基的基团所取代;
L选自脲基、硫脲基、哌嗪脲基、甲基哌嗪脲基、磺酰胺基、或磺酰脲基;
X1、X2各自独立选自CH2、O或S;
m选自1或2;
n选自0、1、2或3。
进一步优选的,所述的A环选自
R1与R2各自独立的选自氢、甲基、甲氧基、乙基、氟和氯;
L选自脲基或哌嗪脲基;
X1、X2各自独立选自O;
m选自1;
n选自0、1、2或3。
作为最优选,本发明所述TRPV1/URAT1双重抑制剂或其可药用的盐可以为下述任意一种或多种化合物:
4-(苯并[d][1,3]二羟基-5-基甲基)-N-环己基哌嗪-1-甲酰胺(I-1);
4-(苯并[d][1,3]二羟基-5-基甲基)-N-(对甲苯基)哌嗪-1-甲酰胺(I-2);
4-(苯并[d][1,3]二羟基-5-基甲基)-N-(苯基磺酰基)哌嗪-1-甲酰胺(I-3);
4-(苯并[d][1,3]二羟基-5-基甲基)-N-(4-(叔丁基)苯基)哌嗪-1-甲酰胺(I-4);
4-(苯并[d][1,3]二羟基-5-基甲基)-N-(4-(叔丁基)苯基)-3-甲基哌嗪-1-甲酰胺(I-5);
4-(苯并[d][1,3]二羟基-5-基甲基)-N-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-6);
4-(苯并[d][1,3]二羟基-5-基甲基)-N-(2-氟苯基)哌嗪-1-甲酰胺(I-7);
4-(苯并[d][1,3]二羟基-5-基甲基)-N-(2,4-二氟苯基)哌嗪-1-甲酰胺(I-8);
N-(2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)-4-苯基哌嗪-1-甲酰胺(I-9);
N-(苯并[d][1,3]二羟基-5-基)-4-苯基哌嗪-1-甲酰胺(I-10);
N-(2-(苯并[d][1,3]二羟基-5-基)乙基)-4-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-11);N-(2-(苯并[d][1,3]二羟基-5-基)乙基)-4-(4-氯苯基)哌嗪-1-甲酰胺(I-12);
N-(2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)-4-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-13);N-(苯并[d][1,3]二羟基-5-基)-4-(苯并[d][1,3]双羟基-5-基甲基)哌嗪-1-甲酰胺(I-14);
N-(苯并[d][1,3]二羟基-5-基甲基)-4-苯基哌嗪-1-甲酰胺(I-15);
4-(4-氯苯基)-N-(2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)哌嗪-1-甲酰胺(I-16);
N-(苯并[d][1,3]二羟基-5-基)-4-(4-氯苯基)哌嗪-1-甲酰胺(I-17);
N-(苯并[d][1,3]二羟基-5-基)-4-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-18);
N-(苯并[d][1,3]二羟基-5-基)-4-(4-硝基苯基)哌嗪-1-甲酰胺(I-19);
N-(苯并[d][1,3]二羟基-5-基甲基)-4-(4-氯苯基)哌嗪-1-甲酰胺(I-20);
N-(苯并[d][1,3]二羟基-5-基)-4-(2,4-二氟苯基)哌嗪-1-甲酰胺(I-21);
N-(2-(苯并[d][1,3]二羟基-5-基)乙基)-4-(2,4-二氟苯基)哌嗪-1-甲酰胺(I-22);
N-(苯并[d][1,3]二羟基-5-基)-4-(4-甲氧基苯基)哌嗪-1-甲酰胺(I-23);
N-(苯并[d][1,3]二羟基-5-基)-4-(2-甲氧基苯基)哌嗪-1-甲酰胺(I-24);
N-(苯并[d][1,3]二羟基-5-基甲基)-4-(2,3-二氯苯基)哌嗪-1-甲酰胺(I-25);
1,3-双(2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)脲(I-26);
1-(苯并[d][1,3]二氧杂环戊醇-5-基)-3-(2,3-二氢苯并[b][1,4]二氧环-6-基)脲(I-27)。
本发明提供了一种所述TRPV1/URAT1双重抑制剂、可接受的酯或其可药用的盐在制备治疗痛风和/或高尿酸血症药物中的应用。
本发明还提供了所述TRPV1/URAT1双重抑制剂或其可药用的盐在制备镇痛药物中的应用。
本发明还提供了一种药物组合物,其含有治疗有效量的所述TRPV1/URAT1双重抑制剂或其可药用的盐,以及适当的药学上可接受的载体、稀释剂或赋形剂等,该药物组合物可用于痛风和/或高尿酸血症的治疗。
本发明还提供了上述药物组合物在制备治疗痛风和/或高尿酸血症药物中的应用,以及在制备镇痛药物中的应用。
发明的详细说明:除非另有说明,否则下列用在说明书和权利要求书中的术语具有下述含义。
“烷基”指饱和的脂族烃基团,包括1至20个碳原子的直链和支链基团。优选含有1至10个碳原子的烷基,较优选含有1至6个碳原子的烷基,更优选含有1至3个碳原子的烷基,最优选为甲基。非限制性实施例包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、己基等,及其各种支链异构体等。烷基可以是取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,优选为一个或多个以下基团,独立地选自卤素、羟基、氰基、硝基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的基团所取代。
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,其包括3至20个碳原子,优选包括3至12个碳原子,更优选环烷基环包含3至10个碳原子。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。
“烷氧基”指-O-(烷基)和-O-(未取代的环烷基),其中烷基的定义如上所述。非限制性实施例包含甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。烷氧基可以是任选取代的或未取代的,当被取代时,取代基优选为一个或多个以下基团,独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基的基团所取代。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本发明所述化合物或其可药用的盐,或其前药与其他化学组分的混合物,其他化学组分例如可药用的载体和赋形剂。药物组合物的目的是促进生物体对活性成分的吸收,利于活性成分在生物体内发挥生物活性。
和现有技术相比,本发明的有益效果如下:
本发明发现了一类新型的TRPV1/URAT1双重抑制剂,并研究给出了其制备方法,其合成过程简单易操作,原料低廉易得,适合规模化生产。本发明还提供了以该类化合物为活性成分的药物组合物,以及它们在制备抗痛风或高尿酸血症药物、以及镇痛药物等中的应用。
附图说明
图1为化合物I-27对小鼠的降尿酸与抗炎症性疼痛作用。(A)化合物I-27处理后的小鼠血尿酸浓度;(B)化合物I-27对***诱导的I相炎症性疼痛抑制作用;(C)化合物I-27对***诱导的II相炎症性疼痛抑制作用。所有值均按SEM±平均值表示(每组n=6)。*p≤0.05和**p≤0.01使用单因素方差分析与模型小鼠相比,使用Tukey的多重事后比较测试进行分析。
具体实施方式
以下结合实施例对本发明的技术方案作进一步详细介绍,但本发明的保护范围并不局限于此。
下述实施例中,如无特殊说明,所用原料均为可以直接购买的普通市售产品或者可以采用本领域常规方法制备获得。室温指代25±5℃。
实施例1 4-(苯并[d][1,3]二羟基-5-基甲基)-N-环己基哌嗪-1-甲酰胺(I-1)
环己基异氰酸酯(II-2,0.2g,1.60mmol)溶于20ml无水二氯甲烷中,冰浴条件下缓慢滴加20ml含胡椒基哌嗪(II-1,0.37g,1.68mmol)的二氯甲烷溶液,0℃下继续反应30分钟后,减压蒸除溶剂,残余物经柱层析(石油醚/乙酸乙酯,4:1,v/v)纯化,得0.35g白色固体I-1,熔点121-123℃,产率63.2%。图谱数据如下。
1H NMR(300MHz,DMSO-d6)δ6.98–6.83(m,2H),6.75(dd,J=7.9,1.6Hz,1H),5.99(s,2H),3.40(s,3H),3.27(t,J=4.9Hz,4H),2.30(t,J=4.9Hz,4H),1.84–1.60(m,4H),1.60–1.41(m,1H),1.29–0.85(m,5H).13C NMR(75MHz,DMSO-d6)δ157.17,147.67,146.71,131.80,122.59,109.62,108.30,101.26,62.05,52.69,49.58,43.74,33.60,25.84,25.58.ESI-HRMS m/z:[M+H]+calcd for C19H27N3O3,345.2052;found,346.2137。
实施例2 4-(苯并[d][1,3]二羟基-5-基甲基)-N-(对甲苯基)哌嗪-1-甲酰胺(I-2)
合成方法同I-1,不同之处在于将起始原料II-2替换为对甲基苯异氰酸酯,得到白色固体0.21g,熔点103-105℃,产率45%,图谱数据如下。
1H NMR(300MHz,DMSO-d6)δ7.42–7.24(m,2H),7.03(d,J=8.2Hz,2H),6.96–6.82(m,2H),6.76(dd,J=7.9,1.6Hz,1H),6.00(s,2H),3.44(t,J=5.1Hz,4H),2.35(t,J=5.1Hz,4H),2.22(s,3H).13C NMR(75MHz,DMSO-d6)δ155.51,147.70,146.68,138.37,132.13,130.92,129.14,122.50,120.26,109.58,108.30,101.26,62.13,52.80,44.17,20.79.ESI-HRMS m/z:[M+H]+calcd for C20H23N3O3,353.1739;found,354.1817。
实施例3 4-(苯并[d][1,3]二羟基-5-基甲基)-N-(苯基磺酰基)哌嗪-1-甲酰胺(I-3)
合成方法同I-1,不同之处在于将起始原料II-2替换为苯磺酰异氰酸酯,得到白色固体0.19g,熔点99-101℃,产率56%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ7.82(m,2H),7.68–7.55(m,1H),7.48(m,2H),6.99–6.86(m,2H),6.86–6.68(m,1H),6.00(d,J=4.4Hz,2H),3.58(s,2H),3.45(s,4H),2.51(p,J=1.8Hz,4H).13C NMR(101MHz,DMSO-d6)δ147.73,146.83,144.59,132.25,131.36,129.39,128.53,127.51,126.02,122.68,109.64,108.45,108.38,101.41,101.32,61.57,52.39,49.32,43.54.ESI-HRMS m/z:[M+H]+calcd for C19H21N3O5S,403.4530;found,404.1262。
实施例4 4-(苯并[d][1,3]二羟基-5-基甲基)-N-(4-(叔丁基)苯基)哌嗪-1-甲酰胺(I-4)
合成方法同I-1,不同之处在于将起始原料II-2替换为对叔丁基苯异氰酸酯,得到白色固体0.19g,熔点105-108℃,产率56%,图谱数据如下。
1H NMR(300MHz,DMSO-d6)δ8.42(s,1H),7.35(d,J=8.6Hz,2H),7.23(d,J=8.7Hz,2H),6.98–6.82(m,2H),6.76(dd,J=7.9,1.6Hz,1H),6.00(s,2H),3.42(m,6H),2.35(t,J=4.8Hz,4H),1.25(s,9H).13C NMR(75MHz,DMSO-d6)δ155.53,147.69,146.66,144.38,138.33,132.16,125.32,122.49,119.92,109.57,108.31,101.25,62.12,52.80,44.20,34.29,31.74.ESI-HRMS m/z:[M+H]+calcd for C23H29N3O3,395.2209;found,396.2266。
实施例5 4-(苯并[d][1,3]二羟基-5-基甲基)-N-(4-(叔丁基)苯基)-3-甲基哌嗪-1-甲酰胺(I-5)
Reagent and conditions.(i)CH3CN,Cs2CO3,60℃,4h;(ii)TFA,CH2Cl2,ice cold,2h;(iii)CH2Cl2,N2,triphosgene,DMAP,r.t.,6h。
第一步:胡椒基氯(0.2g,1.17mmol)溶于20ml乙腈中,加入4-N-叔丁氧羰基-2-甲基哌嗪(0.26g,1.29mmol)、碳酸铯(0.95g,2.925mmol),60℃加热反应4小时,反应结束后,过滤,收集滤液,减压蒸除溶剂。残余物经柱层析(石油醚/乙酸乙酯,4:1,v/v)纯化得到III-3。
第二步:上述得到的III-3粗品溶于20ml二氯甲烷中,加入4ml三氟乙酸,冰浴下反应2小时后,减压蒸除溶剂,得到0.2g III-4。
第三步:采用一锅煮法合成I-5,氮气保护下,将10ml含对叔丁基苯胺III-5(0.13g,0.85mmol)的无水二氯甲烷溶液缓慢滴加到10ml含三光气II-4(0.1g,0.28mmol)的二氯甲烷溶液中,加入4-二甲氨基吡啶DMAP(0.31g,2.55mmol),室温下搅拌30分钟,加入10ml含III-4(0.2g,0.85mmol)的无水二氯甲烷溶液,室温下继续反应6小时后,减压蒸除溶剂,残余物经柱层析(石油醚/乙酸乙酯,4:1,v/v)纯化,得0.23g白色固体I-5,熔点127-130℃,产率48.1%。图谱数据如下。
1H NMR(300MHz,DMSO-d6)δ8.40(s,1H),7.46–7.25(m,2H),7.31–7.17(m,2H),6.98–6.73(m,3H),5.99(s,2H),3.97–3.62(m,3H),3.21–2.57(m,4H),2.23(d,J=6.9Hz,2H),1.24(s,9H),1.10(d,J=6.1Hz,3H).13C NMR(75MHz,DMSO-d6)δ155.33,147.67,146.57,144.41,138.29,125.32,122.44,119.94,109.55,108.32,101.24,57.23,54.91,50.53,50.28,44.16,34.30,31.74,15.68.ESI-HRMS m/z:[M+H]+calcd for C24H31N3O3,409.2365;found,410.2437。
实施例6 4-(苯并[d][1,3]二羟基-5-基甲基)-N-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-6)
合成方法同I-1,不同之处在于将起始原料II-2替换为对三氟甲基苯异氰酸酯,得到白色固体0.15g,熔点103-105℃,产率56%,图谱数据如下。
1H NMR(300MHz,DMSO-d6)δ8.90(s,1H),7.67(d,J=3.9Hz,2H),7.57(d,J=8.7Hz,2H),6.96–6.71(m,3H),6.00(s,2H),3.46(t,J=5.0Hz,4H),2.37(t,J=4.9Hz,4H).13C NMR(75MHz,DMSO-d6)δ154.90,147.69,146.67,144.89,132.08,126.88,126.08,126.02,122.52,119.31,118.58,109.59,108.32,101.26,62.04,52.72,44.24.ESI-HRMS m/z:[M+H]+calcd forC20H20F3N3O3,407.1457;found,408.1531。
实施例7 4-(苯并[d][1,3]二羟基-5-基甲基)-N-(2-氟苯基)哌嗪-1-甲酰胺(I-7)
合成方法同I-1,不同之处在于将起始原料II-2替换为邻氟苯异氰酸酯,得到白色固体0.18g,熔点111-114℃,产率61%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ7.18–7.01(m,4H),6.86–6.79(m,2H),6.74(dd,J=8.0,1.6Hz,1H),5.97(s,2H),4.16(d,J=5.7Hz,2H),3.48(t,J=5.0Hz,4H),2.95(t,J=5.0Hz,4H).13C NMR(101MHz,DMSO-d6)δ157.77,156.67,154.25,147.55,146.24,140.26,140.18,135.39,125.32,125.29,123.14,123.06,120.63,119.98,119.95,116.51,116.31,108.32,108.26,101.15,50.64,50.61,43.99,43.76.ESI-HRMS m/z:[M+H]+calcd for C19H20FN3O3,357.1489;found,358.1575。
实施例8 4-(苯并[d][1,3]二羟基-5-基甲基)-N-(2,4-二氟苯基)哌嗪-1-甲酰胺(I-8)
合成方法同I-1,不同之处在于将起始原料II-2替换为2,4-二氟苯异氰酸酯,得到白色固体0.25g,熔点115-118℃,产率65%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ7.20(m,1H),7.10(m,1H),7.04–6.95(m,1H),6.86–6.81(m,2H),6.73(dd,J=8.0,1.6Hz,1H),5.97(s,2H),4.16(d,J=5.7Hz,2H),3.47(t,J=4.9Hz,4H),2.90(t,J=5.0Hz,4H).13C NMR(101MHz,DMSO-d6)δ157.75,156.50,147.55,146.24,137.17,137.14,137.08,137.05,135.38,120.92,120.88,120.83,120.79,120.71,120.63,111.62,111.58,111.41,111.37,108.32,108.26,105.35,105.10,104.84,101.15,50.97,44.00,43.76.ESI-HRMS m/z:[M+H]+calcd for C19H19F2N3O3,375.1394;found,376.1481。
实施例9N-(2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)-4-苯基哌嗪-1-甲酰胺(I-9)
采用一锅煮的方法合成I-9,氮气保护下,将10ml含6-氨基-1,4-苯并二氧杂环II-3(0.2g,1.32mmol)的无水二氯甲烷溶液缓慢滴加到10ml含三光气II-4(0.12g,0.40mmol)的二氯甲烷溶液中,加入4-二甲氨基吡啶DMAP(0.48g 3.96mmol),室温下搅拌30分钟,加入10ml含II-5苯基哌嗪(0.21g,1.32mmol)的无水二氯甲烷溶液,室温下继续反应6小时后,减压蒸除溶剂,残余物经柱层析(石油醚/乙酸乙酯,4:1,v/v)纯化,得0.23g白色固体I-9,熔点121-123℃,产率51.8%。图谱数据如下。
1H NMR(300MHz,DMSO-d6)δ8.44(s,1H),7.24(dd,J=8.6,7.2Hz,2H),7.08(d,J=2.5Hz,1H),7.01–6.95(m,2H),6.90(dd,J=8.8,2.5Hz,1H),6.81(d,J=1.0Hz,1H),6.72(d,J=8.7Hz,1H),4.27–4.11(m,4H),3.57(dd,J=6.6,3.7Hz,4H),3.14(dd,J=6.4,3.8Hz,4H).13CNMR(75MHz,DMSO-d6)δ155.56,151.41,143.19,138.86,134.49,129.43,119.71,116.81,116.28,113.54,109.41,64.63,64.33,48.83,44.06.ESI-HRMS m/z:[M+H]+calcd for C19H21N3O3,339.1583;found,340.1662。
实施例10N-(苯并[d][1,3]二羟基-5-基)-4-苯基哌嗪-1-甲酰胺(I-10)
合成方法同I-9,不同之处在于将起始原料II-3替换为苯并[d][1,3]二氧杂环戊烯-5-胺,得到白色固体0.21g,熔点108-111℃,产率44.6%,图谱数据如下。
1H NMR(300MHz,DMSO-d6)δ8.52(s,1H),7.33–7.12(m,3H),7.06–6.91(m,2H),6.91–6.71(m,3H),5.95(s,2H),3.65–3.48(m,4H),3.25–3.04(m,4H).13C NMR(75MHz,DMSO-d6)δ155.60,151.41,147.30,142.49,135.25,129.43,119.71,116.29,112.94,108.13,102.86,101.15,48.83,44.06.ESI-HRMS m/z:[M+H]+calcd for C18H19N3O3,325.1426;found,326.1506。
实施例11N-(2-(苯并[d][1,3]二羟基-5-基)乙基)-4-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-11)
合成方法同I-9,不同之处在于将起始原料II-3替换为2-(苯并[d][1,3]二氧杂环戊烯-5-基)乙-1-胺,将起始原料II-5替换为对三氟甲基苯基哌嗪,得到白色固体0.14g,熔点123-125℃,产率41.5%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ7.51(d,J=8.4Hz,1H),7.08(d,J=8.6Hz,2H),6.86–6.76(m,2H),6.76–6.58(m,2H),5.96(d,J=5.5Hz,2H),5.76(s,2H),3.59–3.40(m,3H),3.27–3.05(m,5H),2.77–2.56(m,2H).13C NMR(101MHz,DMSO-d6)δ158.32,157.72,153.63,147.59,145.94,145.86,145.84,134.06,134.02,126.77,126.61,126.57,126.53,124.08,121.95,121.92,118.65,118.33,115.30,114.78,109.50,109.48,108.51,101.08,101.04,55.35,51.62,47.27,44.66,43.42,42.51,41.51,40.58,36.29,36.08,35.57.ESI-HRMS m/z:[M+H]+calcd forC21H22F3N3O3,421.1613;found,422.1725。
实施例12N-(2-(苯并[d][1,3]二羟基-5-基)乙基)-4-(4-氯苯基)哌嗪-1-甲酰胺(I-12)
合成方法同I-9,不同之处在于将起始原料II-3替换为2-(苯并[d][1,3]二氧杂环戊烯-5-基)乙-1-胺,将起始原料II-5替换为对氯苯基哌嗪,得到黄色固体0.17g,熔点118-121℃,产率38.6%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ7.28–7.18(m,2H),7.05–6.90(m,2H),6.77(d,J=1.7Hz,1H),6.68(t,J=5.4Hz,1H),6.64(dd,J=7.9,1.7Hz,1H),5.95(s,2H),3.41(t,J=5.2Hz,4H),3.25–3.15(m,2H),3.06(t,J=5.2Hz,4H),2.65(t,J=6.4Hz,2H).13C NMR(101MHz,DMSO-d6)δ157.72,150.27,147.59,145.84,134.07,129.07,123.09,121.93,117.64,109.49,108.52,101.05,48.48,43.63,42.50,36.07.ESI-HRMS m/z:[M+H]+calcdfor C20H22ClN3O3,387.1350;found,388.1435。
实施例13N-(2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)-4-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-13)
合成方法同I-9,不同之处在于将起始原料II-5替换为对三氟甲基苯基哌嗪,得到白色固体0.25g,熔点114-117℃,产率44.6%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ8.46(d,J=2.6Hz,1H),8.20(d,J=6.9Hz,1H),7.53(d,J=8.7Hz,1H),7.10(d,J=8.7Hz,2H),6.95(d,J=7.1Hz,1H),6.89(dt,J=8.8,1.6Hz,1H),6.72(d,J=8.8Hz,1H),4.26–4.02(m,4H),3.57(dd,J=6.6,3.9Hz,4H),3.17(s,4H).13C NMR(101MHz,DMSO-d6)δ157.78,154.47,150.24,149.49,147.54,146.24,135.38,129.08,123.08,120.63,120.53,117.65,108.32,108.26,107.16,101.19,101.15,48.52,43.74,43.67,36.35.ESI-HRMS m/z:[M+H]+calcd for C20H20F3N3O3,407.1457;found,408.1545。
实施例14N-(苯并[d][1,3]二羟基-5-基)-4-(苯并[d][1,3]双羟基-5-基甲基)哌嗪-1-甲酰胺(I-14)
合成方法同I-9,不同之处在于将起始原料II-3替换为苯并[d][1,3]二氧杂环戊烯-5-胺,将起始原料II-5替换为胡椒基哌嗪。得到白色固体0.17g,熔点117-120℃,产率41.8%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),7.26(d,J=1.6Hz,1H),7.13(d,J=2.0Hz,1H),7.04(dd,J=8.0,1.7Hz,1H),6.99(d,J=7.9Hz,1H),6.92–6.72(m,2H),6.07(s,2H),5.95(s,2H),4.21(d,J=16.1Hz,4H),3.33–3.22(m,4H),2.96(s,2H).13C NMR(101MHz,DMSO-d6)δ155.20,148.64,147.90,147.31,142.71,134.84,126.01,113.05,111.73,108.85,108.17,102.85,101.93,101.22,58.96,50.62,41.33.ESI-HRMS m/z:[M+H]+calcdfor C20H21N3O5,383.1481;found,384.1572。
实施例15N-(苯并[d][1,3]二羟基-5-基甲基)-4-苯基哌嗪-1-甲酰胺(I-15)
合成方法同I-9,不同之处在于将起始原料II-3替换为3,4-亚甲二氧基苄胺,得到白色固体0.12g,熔点108-111℃,产率36.5%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ7.22(dd,J=8.7,7.2Hz,2H),7.13(s,1H),7.01–6.93(m,2H),6.85–6.83(m,1H),6.82(s,1H),6.74(dd,J=8.0,1.6Hz,1H),5.97(s,2H),4.16(d,J=5.8Hz,2H),3.46(d,J=5.3Hz,4H),3.09(dd,J=6.3,3.9Hz,4H).13C NMR(101MHz,DMSO-d6)δ157.82,151.45,147.64,147.54,146.24,135.40,129.40,120.63,120.54,119.65,116.25,108.40,108.32,108.25,108.15,101.19,101.15,48.79,43.83,43.74,43.22.ESI-HRMS m/z:[M+H]+calcdfor C19H21N3O3,339.1583;found,340.1665。
实施例16 4-(4-氯苯基)-N-(2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)哌嗪-1-甲酰胺(I-16)
合成方法同I-9,不同之处在于将起始原料II-5替换为对氯苯基哌嗪,得到棕色固体0.15g,熔点117-120℃,产率32.5%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),7.32–7.20(m,2H),7.07(d,J=2.4Hz,1H),7.02–6.98(m,2H),6.89(dd,J=8.8,2.5Hz,1H),6.78–6.75(m,1H),6.72(d,J=8.8Hz,1H),4.24–4.19(m,4H),3.56(t,J=5.1Hz,4H),3.21–3.07(m,4H).13C NMR(101MHz,DMSO-d6)δ155.51,150.20,143.52,143.19,138.87,138.76,134.47,133.90,129.10,123.14,117.67,117.25,116.79,113.53,111.99,109.41,107.87,64.68,64.63,64.33,48.56,43.91.ESI-HRMS m/z:[M+H]+calcd for C19H20ClN3O3,373.1193;found,374.1287。
实施例17N-(苯并[d][1,3]二羟基-5-基)-4-(4-氯苯基)哌嗪-1-甲酰胺(I-17)
合成方法同I-9,不同之处在于将起始原料II-3替换为苯并[d][1,3]二氧杂环戊烯-5-胺,将起始原料II-5替换为对氯苯基哌嗪,得到棕色固体0.14g,熔点115-115℃,产率31.5%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ8.50(s,1H),7.28–7.22(m,2H),7.15(d,J=2.0Hz,1H),7.03–6.96(m,2H),6.85(dd,J=8.4,2.1Hz,1H),6.79(d,J=8.4Hz,1H),5.95(s,2H),3.56(t,J=5.2Hz,4H),3.24–3.07(m,4H).13C NMR(101MHz,DMSO-d6)δ155.56,150.19,147.64,147.29,142.51,135.21,129.11,123.15,117.68,112.96,111.39,108.55,108.12,102.86,101.25,101.15,48.55,43.91.ESI-HRMS m/z:[M+H]+calcd for C18H18ClN3O3,359.1037;found,360.1113。
实施例18N-(苯并[d][1,3]二羟基-5-基)-4-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺(I-18)
合成方法同I-9,不同之处在于将起始原料II-3替换为苯并[d][1,3]二氧杂环戊烯-5-胺,将起始原料II-5替换为对三氟甲基苯基哌嗪,得到白色固体0.17g,熔点123-125℃,产率33.5%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.24–8.18(m,1H),7.53(d,J=8.7Hz,1H),7.17(d,J=2.1Hz,1H),7.11(d,J=8.7Hz,1H),7.00–6.97(m,1H),6.88(dd,J=8.4,2.1Hz,1H),6.79(d,J=8.4Hz,1H),5.95(s,2H),3.59(t,J=5.2Hz,4H),3.33(t,J=5.5Hz,4H).13CNMR(101MHz,DMSO-d6)δ157.35,155.58,153.58,147.26,142.48,139.58,135.24,126.79,126.66,126.62,118.32,114.82,112.97,108.11,107.40,102.86,101.14,47.33,43.73.ESI-HRMSm/z:[M+H]+calcd for C19H18F3N3O3,393.1300;found,394.1370。
实施例19N-(苯并[d][1,3]二羟基-5-基)-4-(4-硝基苯基)哌嗪-1-甲酰胺(I-19)
合成方法同I-9,不同之处在于将起始原料II-3替换为苯并[d][1,3]二氧杂环戊烯-5-胺,将起始原料II-5替换为对硝基苯基哌嗪,得到黄色固体0.21g,熔点117-120℃,产率34.8%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.16–8.01(m,2H),7.15(d,J=2.0Hz,1H),7.10–6.97(m,2H),6.85(dd,J=8.4,2.0Hz,1H),6.80(d,J=8.4Hz,1H),5.95(d,J=3.9Hz,2H),3.60(t,J=6.9Hz,4H),3.53(t,J=6.9Hz,4H).13C NMR(101MHz,DMSO-d6)δ155.53,154.97,147.63,147.30,142.58,137.37,135.10,134.57,126.18,113.07,113.00,111.43,108.55,108.14,102.93,101.38,101.25,101.18,46.40,43.42.ESI-HRMS m/z:[M+H]+calcd forC18H18N4O5,370.1277;found,371.1366。
实施例20N-(苯并[d][1,3]二羟基-5-基甲基)-4-(4-氯苯基)哌嗪-1-甲酰胺(I-20)
合成方法同I-9,不同之处在于将起始原料II-3替换为3,4-亚甲二氧基苄胺,将起始原料II-5替换为对氯苯基哌嗪,得到黄色固体0.13g,熔点117-121℃,产率33.3%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ7.24–7.20(m,1H),7.13(t,J=5.8Hz,1H),7.01–6.92(m,1H),6.86–6.76(m,2H),6.73(dd,J=8.0,1.7Hz,1H),6.63–6.57(m,2H),5.96(s,2H),4.15(d,J=5.7Hz,2H),3.45(t,J=5.2Hz,4H),3.09(t,J=6.2Hz,4H).13C NMR(101MHz,Chloroform-d)δ157.60,154.29,149.67,149.37,147.76,146.69,133.56,129.09,129.02,125.01,120.91,120.82,117.60,108.39,108.34,108.18,106.58,101.02,100.96,49.13,44.77,44.71,43.67,39.05,36.24.ESI-HRMS m/z:[M+H]+calcd for C19H20ClN3O3,373.1193;found,374.1268。
实施例21N-(苯并[d][1,3]二羟基-5-基)-4-(2,4-二氟苯基)哌嗪-1-甲酰胺(I-21)
合成方法同I-9,不同之处在于将起始原料II-3替换为苯并[d][1,3]二氧杂环戊烯-5-胺,将起始原料II-5替换为2,4-二氟苯基哌嗪,得到米白色固体0.23g,熔点112-114℃,产率37.8%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ8.49(s,1H),7.22(m,1H),7.15(d,J=2.1Hz,1H),7.14–7.07(m,1H),7.05–6.97(m,1H),6.85(dd,J=8.4,2.1Hz,1H),6.79(d,J=8.4Hz,1H),5.95(s,2H),3.58(t,J=5.0Hz,4H),2.96(t,J=5.0Hz,4H).13C NMR(101MHz,DMSO-d6)δ158.94,158.82,156.65,156.54,156.42,155.53,154.18,154.06,147.29,142.50,137.10,137.07,137.01,136.98,135.22,120.98,120.94,120.89,120.85,112.95,111.64,111.61,111.43,111.39,108.12,105.38,105.13,104.86,102.86,101.15,50.98,50.95,44.26.ESI-HRMSm/z:[M+H]+calcd forC18H17F2N3O3,361.1238;found,362.1309。
实施例22N-(2-(苯并[d][1,3]二羟基-5-基)乙基)-4-(2,4-二氟苯基)哌嗪-1-甲酰胺(I-22)
合成方法同I-9,不同之处在于将起始原料II-3替换为2-(苯并[d][1,3]二氧杂环戊烯-5-基)乙-1-胺,将起始原料II-5替换为2,4-二氟苯基哌嗪,得到白色固体0.15g,熔点113-115℃,产率40.5%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ7.20(ddd,J=12.2,9.0,2.9Hz,1H),7.14–6.94(m,2H),6.77(d,J=1.7Hz,1H),6.71–6.63(m,2H),5.96(s,2H),5.76(s,1H),3.43(t,J=4.9Hz,4H),3.27–3.17(m,2H),2.88(t,J=5.0Hz,4H),2.66(dd,J=8.4,6.6Hz,2H).13C NMR(101MHz,Chloroform-d)δ157.54,147.82,146.19,136.42,133.06,121.87,119.74,109.33,109.19 108.53,100.99,50.74,43.91,42.27,36.03,35.54.ESI-HRMS m/z:[M+H]+calcd for C20H21F2N3O3,389.1551;found,390.1625。
实施例23N-(苯并[d][1,3]二羟基-5-基)-4-(4-甲氧基苯基)哌嗪-1-甲酰胺(I-23)
合成方法同I-9,不同之处在于将起始原料II-3替换为苯并[d][1,3]二氧杂环戊烯-5-胺,将起始原料II-5替换为对甲氧基苯基哌嗪,得到棕色固体0.16g,熔点106-109℃,产率38.5%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ8.49(d,J=2.0Hz,1H),7.17(dd,J=12.3,2.1Hz,1H),7.01–6.90(m,2H),6.90–6.69(m,5H),5.95(s,2H),3.69(s,3H),3.56(t,J=5.1Hz,4H),3.01(t,J=5.1Hz,4H).13C NMR(101MHz,Chloroform-d)δ155.33,154.37,147.84,145.30,143.84,133.04,118.88,114.54,113.61,107.95,103.75,101.18,55.59,50.80,44.24.ESI-HRMS m/z:[M+H]+calcd for C19H21N3O4,355.1532;found,356.1618。
实施例24N-(苯并[d][1,3]二羟基-5-基)-4-(2-甲氧基苯基)哌嗪-1-甲酰胺(I-24)
合成方法同I-9,不同之处在于将起始原料II-3替换为苯并[d][1,3]二氧杂环戊烯-5-胺,将起始原料II-5替换为邻甲氧基苯基哌嗪,得到棕色固体0.16g,熔点111-114℃,产率36.5%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),7.22–7.12(m,1H),7.03–6.71(m,6H),5.95(s,2H),3.80(s,3H),3.56(t,J=4.9Hz,4H),2.95(t,J=4.9Hz,4H).13C NMR(101MHz,Chloroform-d)δ155.45,152.25,147.80,143.76,140.74,133.18,123.54,121.06,118.42,113.65,111.31,107.91,103.78,101.15,55.46,50.54,44.32.ESI-HRMS m/z:[M+H]+calcdfor C19H21N3O4,355.1532;found,356.1626。
实施例25N-(苯并[d][1,3]二羟基-5-基甲基)-4-(2,3-二氯苯基)哌嗪-1-甲酰胺(I-25)
合成方法同I-9,不同之处在于将起始原料II-3替换为3,4-亚甲二氧基苄胺,将起始原料II-5替换为2,3-二氯苯基哌嗪,得到白色固体0.12g,熔点118-121℃,产率27.5%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ7.38–7.27(m,2H),7.20–7.07(m,2H),6.85(d,J=1.3Hz,1H),6.74(dd,J=7.9,1.6Hz,1H),5.97(s,2H),4.17(d,J=5.7Hz,2H),3.49(t,J=4.9Hz,4H),2.94(t,J=4.8Hz,4H).13C NMR(101MHz,Chloroform-d)δ157.64,150.80,146.77,134.10,133.40,127.63,125.04,120.88,118.72,108.34,101.00,51.15,44.78.ESI-HRMS m/z:[M+H]+calcd for C19H19Cl2N3O3,407.0803;found,408.0897。
实施例26 1,3-双(2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)脲(I-26)
合成方法同I-9,不同之处在于将起始原料II-5替换为6-氨基-1,4-苯并二氧杂环,得到棕色固体0.25g,熔点98-101℃,产率50.5%,图谱数据如下。
1H NMR(400MHz,DMSO-d6)δ8.35(s,2H),7.07(d,J=2.2Hz,2H),6.86–6.65(m,4H),4.20(tt,J=8.6,6.7,3.1Hz,8H).13C NMR(101MHz,DMSO-d6)δ153.09,143.52,138.77,133.89,117.25,112.02,107.90,64.68,64.32.ESI-HRMS m/z:[M+H]+calcd forC17H16N2O5,328.1059;found,329.1136。
实施例27 1-(苯并[d][1,3]二氧杂环戊醇-5-基)-3-(2,3-二氢苯并[b][1,4]二氧环-6-基)脲(I-27)
合成方法同I-9,不同之处在于将起始原料II-5替换为苯并[d][1,3]二氧杂环戊烯-5-胺,得到棕色固体0.27g,熔点103-106℃,产率56.5%,图谱数据如下。
1H NMR(300MHz,DMSO-d6)δ8.66–8.28(m,2H),7.27–6.98(m,2H),6.85–6.64(m,4H),5.96(s,2H),4.31–4.12(m,4H).13C NMR(75MHz,DMSO-d6)δ153.16,147.63,143.51,142.42,142.38,138.80,138.76,134.64,134.58,133.88,133.83,117.26,112.06,112.02,111.42,111.36,108.55,107.93,107.88,101.38,101.34,101.25,64.67,64.32.ESI-HRMSm/z:[M+H]+calcd for C16H14N2O5,314.0903;found,315.0992。
本发明中化合物的TRPV1及URAT1抑制活性及体内镇痛与降尿酸活性可以通过使用如下所述的测定***测定。以下生物学测试实施例描述解释本发明。
本发明测试例中具体条件的实验方法通常按常规条件或按照商品制造厂商所建议的条件。未注明具体来源的试剂,为市场购买的常用试剂。
测试例1本发明化合物对hTRPV1-HEK293稳转细胞的抑制活性
本发明使用以下方法测定本发明化合物的hTRPV1抑制活性。
将稳定表达hTRPV1的HEK293细胞以2.5×104/孔的密度接种至96孔黑板上,置于37℃、5%CO2的细胞培养箱中过夜培养,培养基为补充10%胎牛血清(FBS)的DMEM培养基;在室温下装载Fluo-3AM钙离子荧光探针,首先配制2mM钙离子荧光探针Fluro-3AM的DMSO母液,向Fluo-3AM/的DMSO母液中加16.5mg Pluronic F127,防止Fluo-3AM在HBSS(Hank’s平衡盐溶液)中聚合并能帮助其进入细胞。用HBSS稀释Fluo-3AM溶液,制备5μM的Fluo-3AM工作液,将上述工作液加入细胞板中,每孔10μL,37℃培养30分钟。每孔加入50μL含有1%胎牛血清的HBSS,继续培养40分钟。用台式液洗涤细胞4次,每孔加入40μL不同浓度的样品,每个样品浓度设置3个复孔,阳性对照组加入等量的N-(4-(叔丁基)苯基)-4-(3-氯吡啶-2-基)哌嗪-1-甲酰胺(BCTC),阴性对照组加入台氏液(英文全称Tyrode'ssolution)。37℃孵育30分钟后给予辣椒碱刺激(50nM),随后检测辣椒碱刺激前后λex=488nm和λex=540nm吸光度值来表征胞浆钙离子浓度,结果见表1。
抑制率=(空白组差值-实验组差值)/空白组差值(差值=给辣椒碱前后荧光值的差)
表1:hTRPV1受体抑制活性
由表1可以看出:本发明所述化合物对TRPV1具有不同程度的抑制活性,其中化合物I-8、I-13、I-14、I-22、I-25、I-26和I-27优于阳性对照BCTC。
测试例2本发明化合物对hURAT1稳转细胞的抑制活性
本发明使用以下方法测定本发明化合物的hURAT1抑制活性。
将稳定表达hURAT1的HEK-293T细胞以7000/孔的密度接种到96孔细胞培养板中,培养基为补充10%胎牛血清(FBS)的DMEM培养基,待细胞贴壁后,用200μL/孔37℃的PBS缓冲液冲洗细胞1次。吸干各孔,之后立即加入50μL/孔含有对应化合物和2.5μCi/ml14C-尿酸溶液,使用苯溴马隆作为阳性对照。将培养板在37℃的培养箱中孵育8分钟,立即在每个孔中加入150μL 0℃的PBS缓冲液以终止吸收。用PBS缓冲液轻轻冲洗细胞3次,尽量避免细胞脱落。每孔中加入50μL RIPA裂解液,置于振荡器上以900rpm的速度震荡5分钟。最后,微孔板送至MicroBeta2(PerkinElmer公司生产)仪器上测定放射活性。分析数据,使用GraphPadPrism 5软件计算各化合物IC50,结果见表2。
表2:部分化合物对hURAT1受体抑制活性
由表2可以看出:本发明中所测试的化合物对URAT1具有不同程度的抑制作用,其中化合物I-27对URAT1抑制活性最强。
测试例3本发明化合物对CYP酶不同亚型的抑制活性
孵育体系为100μL PBS溶液(100mmol/L,PH=7.4),内含人肝微粒体HLM(蛋白含量0.2mg/mL),还原型烟酰胺腺嘌呤二核苷酸磷酸NADPH(1mmol/L)、单个CYPs亚型探针底物(非那西汀50μmol/L;双氯芬酸10μmol/L;美芬妥英20μmol/L;右美沙芬20μmol/L;睾酮80μmol/L)、系列浓度的抑制剂(化合物I-27)。孵育前,先将HLM、CYPs探针底物、系列浓度抑制剂(0,0.1,0.5,1,5,10,20,50,100μmol/L)、PBS溶液混合均匀,在37℃水浴锅中预孵育5min,再加入NADPH启动反应,继续在37℃水浴锅中孵育至各个CYP亚型特定底物孵育时间(双氯芬酸孵育时间为10min;睾酮孵育时间为15min;非那西汀、右美沙芬孵育时间为20min;美芬妥英孵育时间为60min)后,加入100μL含200ng/ml内标***的0℃甲醇溶液终止反应,涡旋2min,4℃条件下14000转/min离心10min,移取上清进样分析,使用AB Sciex4500QTRAP质谱测定加入不同浓度抑制剂情况下其代谢产物的生成量,每个浓度平行制备3份同时测定。以空白对照组中代谢产物的含量为100%,以其余各组代谢产物的含量与空白对照组的百分比计算剩余酶活性(%)。以药物浓度的对数值为横坐标,剩余酶活性为纵坐标,采用GraphPad Prism计算得到化合物对不同CYP酶的抑制活性,结果见表3。
使用的人肝微粒中含有各种待测试CYP亚型,实验过程中分别使用各个亚型特异性底物来考察化合物对该类型酶的抑制作用。表3的结果表明,I-27对肝药酶亚型CYP1A2、CYP2C9和CYP2D6基本没有抑制,对CYP2C19和CYP3A4M具有弱的抑制作用,说明化合物I-27具有较高的安全性。
表3.I-27对CYP1A2、CYP2C9、CYPC19、CYP2D6和CYP3A4M抑制活性评估
测试例4本发明化合物的体内降尿酸活性可以通过如下所述的小鼠高尿酸模型***测定:
使用8周龄清洁级昆明小鼠进行适应性喂养后,按照体重随机分组,每组6只。阳性对照组给予苯溴马隆,化合物组给予本发明的化合物I-27,给药剂量为20mg/kg,空白对照组(vehicle)给予等体积的0.5%的羧甲基纤维素钠溶液。急性高尿酸血症模型由450mg/kg次黄嘌呤灌胃给药和300mg/kg氧嗪酸钾腹腔注射诱导。诱导高尿酸血症后4小时,使用尿酸试纸检测血尿酸(SUA)水平,结果见图1中A。图1中可以看出:本发明化合物I-27可显著降低血尿酸水平(323.1±75.2μM),且降尿酸效果优于阳性对照苯溴马隆(512.6±52.4μM)。
测试例5本发明化合物的体内镇痛活性可以通过使用如下所述的小鼠疼痛模型测定***测定:
使用8周龄清洁级昆明小鼠进行适应性喂养后,按照体重随机分组,每组6只。实验开始前,小鼠灌胃给本发明化合物I-27,给药剂量为30mg/kg,空白对照组(vehicle)给予等体积的0.5%的羧甲基纤维素钠溶液,阳性对照组给予等量的N-(4-(叔丁基)苯基)-4-(3-氯吡啶-2-基)哌嗪-1-甲酰胺(BCTC)。1h后,在右后侧脚趾皮下注射100μL 5%***溶液,分别记录I相(0-5min)和II相(15-45min)反应舔足时间,结果见图1中B与C。其中,I-27组小鼠的I相反应舔足时间为0.7±0.2min,而II相反应舔足时间为4.2±0.5min,说明其可有效抑制***诱导的炎症性疼痛,且镇痛效果较好。相比之下,BCTC组小鼠的舔足时间与空白对照组无明显差异。
综上说明,本发明所述双重抑制剂及以该类化合物为活性成分的药物组合物具有镇痛功效且同时能够有效降低血尿酸,可以用于制备抗痛风或高尿酸血症药物、以及镇痛药物等。
上述实施例为本发明较佳的试试方式,但本发明的试试方式并不受上述实施例的限制,其它的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (9)
1.一种TRPV1/URAT1双重抑制剂或其可药用的盐,其特征在于,具有式(I)所示的结构:
其中,所述的A环选自苯环,环己基, ;
R1与R2各自独立选自氢、烷基、环烷基、烷氧基、氨基、卤素、腈基、硝基,其中所述烷基、环烷基、烷氧基任选进一步被一个或多个选自卤素、腈基、烷基、烷氧基的基团所取代;
L选自脲基、硫脲基、酰胺基、哌嗪脲基、甲基哌嗪脲基、磺酰胺基、磺酰脲基、酯基、或羰基;
X1、X2各自独立选自CH2、NH、O或S;
m选自1、2或3;
n选自0、1、2或3。
2.如权利要求1所述的TRPV1/URAT1双重抑制剂或其可药用的盐,其特征在于,
所述的A环选自苯环、;
R1与R2各自独立的选自氢、C1-C4烷基、C1-C4烷氧基、卤素、氨基、腈基,其中所述烷基、烷氧基任选进一步被一个或多个选自卤素、腈基、烷基、烷氧基的基团所取代;
L选自脲基、硫脲基、哌嗪脲基、甲基哌嗪脲基、磺酰胺基、或磺酰脲基;
X1、X2各自独立选自CH2、O或S;
m选自1或2;
n选自0、1、2或3。
3.如权利要求1所述的TRPV1/URAT1双重抑制剂或其可药用的盐,其特征在于,
所述的A环选自;
R1与R2各自独立的选自氢、甲基、甲氧基、乙基、氟和氯;
L选自脲基或哌嗪脲基;
X1、X2各自独立选自O;
m选自1;
n选自0、1、2或3。
4.如权利要求1所述的TRPV1/URAT1双重抑制剂或其可药用的盐,其特征在于,所述TRPV1/URAT1双重抑制剂或其可药用的盐为下述任意一种或多种化合物:
4-(苯并[d][1,3]二羟基-5-基甲基)-N-环己基哌嗪-1-甲酰胺;
4-(苯并[d][1,3]二羟基-5-基甲基)-N-(对甲苯基)哌嗪-1-甲酰胺;
4-(苯并[d][1,3]二羟基-5-基甲基)-N-(苯基磺酰基)哌嗪-1-甲酰胺;
4-(苯并[d][1,3]二羟基-5-基甲基)-N-(4-(叔丁基)苯基)哌嗪-1-甲酰胺;
4-(苯并[d][1,3]二羟基-5-基甲基)-N-(4-(叔丁基)苯基)-3-甲基哌嗪-1-甲酰胺;
4-(苯并[d][1,3]二羟基-5-基甲基)-N-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺;
4-(苯并[d][1,3]二羟基-5-基甲基)-N-(2-氟苯基)哌嗪-1-甲酰胺;
4-(苯并[d][1,3]二羟基-5-基甲基)-N-(2,4-二氟苯基)哌嗪-1-甲酰胺;
N-(2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)-4-苯基哌嗪-1-甲酰胺;
N-(苯并[d][1,3]二羟基-5-基)-4-苯基哌嗪-1-甲酰胺;
N-(2-(苯并[d][1,3]二羟基-5-基)乙基)-4-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺;
N-(2-(苯并[d][1,3]二羟基-5-基)乙基)-4-(4-氯苯基)哌嗪-1-甲酰胺;
N-(2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)-4-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺;
N-(苯并[d][1,3]二羟基-5-基)-4-(苯并[d][1,3]双羟基-5-基甲基)哌嗪-1-甲酰胺;
N-(苯并[d][1,3]二羟基-5-基甲基)-4-苯基哌嗪-1-甲酰胺;
4-(4-氯苯基)-N-(2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)哌嗪-1-甲酰胺;
N-(苯并[d][1,3]二羟基-5-基)-4-(4-氯苯基)哌嗪-1-甲酰胺;
N-(苯并[d][1,3]二羟基-5-基)-4-(4-(三氟甲基)苯基)哌嗪-1-甲酰胺;
N-(苯并[d][1,3]二羟基-5-基)-4-(4-硝基苯基)哌嗪-1-甲酰胺;
N-(苯并[d][1,3]二羟基-5-基甲基)-4-(4-氯苯基)哌嗪-1-甲酰胺;
N-(苯并[d][1,3]二羟基-5-基)-4-(2,4-二氟苯基)哌嗪-1-甲酰胺;
N-(2-(苯并[d][1,3]二羟基-5-基)乙基)-4-(2,4-二氟苯基)哌嗪-1-甲酰胺;
N-(苯并[d][1,3]二羟基-5-基)-4-(4-甲氧基苯基)哌嗪-1-甲酰胺;
N-(苯并[d][1,3]二羟基-5-基)-4-(2-甲氧基苯基)哌嗪-1-甲酰胺;
N-(苯并[d][1,3]二羟基-5-基甲基)-4-(2,3-二氯苯基)哌嗪-1-甲酰胺;
1,3-双(2,3-二氢苯并[b][1,4]二氧杂环己烷-6-基)脲;
1-(苯并[d][1,3]二氧杂环戊醇-5-基)-3-(2,3-二氢苯并[b][1,4]二氧环-6-基)脲。
5.权利要求1所述TRPV1/URAT1双重抑制剂或其可药用的盐在制备治疗痛风和/或高尿酸血症药物中的应用。
6.权利要求1所述TRPV1/URAT1双重抑制剂或其可药用的盐在制备镇痛药物中的应用。
7.一种药物组合物,其特征在于,含有治疗有效量的权利要求1至4任一所述TRPV1/URAT1双重抑制剂或其可药用的盐,以及药学上可接受的载体或赋形剂。
8.权利要求7所述药物组合物在制备治疗痛风和/或高尿酸血症药物中的应用。
9.权利要求7所述药物组合物在制备镇痛药物中的应用。
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