CN117529474A - N-取代苯基磺酰胺类化合物及其用途 - Google Patents
N-取代苯基磺酰胺类化合物及其用途 Download PDFInfo
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- CN117529474A CN117529474A CN202280040679.XA CN202280040679A CN117529474A CN 117529474 A CN117529474 A CN 117529474A CN 202280040679 A CN202280040679 A CN 202280040679A CN 117529474 A CN117529474 A CN 117529474A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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Abstract
本发明涉及N‑取代苯基磺酰胺类化合物及其用途。具体地,本发明提供一种如式I化合物,或其光学异构体,或其外消旋体、或其药学上可接受的盐。本发明所述的化合物对瞬时受体电位通道蛋白具有优异的抑制作用,并对瞬时受体电位通道蛋白相关的疾病如炎症性肠病、肠易激综合征、疼痛和炎症等具有优异的治疗作用。
Description
本发明涉及药物化学和药物治疗学领域,具体地涉及一种N-取代苯基磺酰胺类化合物及其用途。
瞬时受体电位通道蛋白A1(transient receptor potential ankyrin 1,TRPA1)又称ANKTM1,是瞬时受体电位通道蛋白(transient receptor potential,TRP)通道家族的成员。TRPA1主要分布在背根神经(DRG)、三叉神经(TG)和迷走神经(VG)的初级感觉神经元上,且在肽能(富含神经肽CGRP和SP以及神经营养因子受体TrkA)和非肽能神经元(共表达嘌呤受体P2X3、Neurturin、Artemin、Mrg家族的G蛋白耦联受体以及GDNF受体家族中的GFR
α1和GFR
α2)均有表达。从分布的人体系统来看,TRPA1高表达在胃肠系统、外周神经系统、呼吸系统和泌尿系统,当这些器官组织出现功能异常时,TRPA1通道的表达和功能通常也同步发生异常。
炎症性肠病(inflammatory bowel disease,IBD)是一种在肠粘膜中形成糜烂或溃疡的慢性炎症性疾病。主要类型分为两大类:溃疡性结肠炎(ulcerative colitis,UC)和克罗恩氏病(Crohn’s disease,CD),前者主要限于结肠,而后者会影响胃肠道的任一段,最常见症状是腹泻和腹痛。目前,IBD的发病机制并不完全明确,常用的治疗手段包括5-氨基水杨酸类、糖皮质激素、抗生素以及免疫抑制剂四大类。这些药物存在耐受性,适用范围有限以及治疗效果不佳等缺点。研究表明,TRPA1在胃肠道调节中起着重要的功能。在小鼠盲肠和结肠的抑制性运动神经元、下行中间神经元、胆碱能和内在感觉神经元中检测到TRPA1免疫反应。越来越多的证据证明,TRPA1在肠和粘膜下神经丛的内在感觉神经元以及结肠粘膜表面上皮细胞中表达。对活动期和非活动期CD和UC患者的活检材料的研究中,发现TRPA1 mRNA显著上调。另外有研究也报道了CD患者结肠狭窄区域TRPA1表达的增加,包括手术和内窥镜检查。在DNBS、TNBS或DSS诱导的结肠炎体内模型中,给予TRPA1的选择性抑制剂HC-030031,或敲除TRPA1基因,动物结肠炎的症状得到显著减轻。因此,TRPA1的抑制剂能够用于IBD的治疗。
在肠易激综合征(irritable bowel syndrome,IBS)、胰腺炎症以及胃黏膜损伤等疾病的动物模型研究中,发现TRPA1的表达也明显上调。在啮齿动物模型中,TRPA1和TRPV1一起促进应激诱导的内脏痛觉过敏,也就是肠易激综合征。在急性胰腺炎模型中,TRPA1和TRPV1具有协同作用,共同调控急性炎症和痛觉过敏表型向慢性炎症和痛觉过敏表型的转变。而在大鼠急性胃黏膜损伤模型中,TRPA1拮抗剂HC-030031也显示出积极的结果。
内脏痛作为一种主要的内脏感觉,常由内脏受到机械性牵拉、痉挛、缺血或炎症等刺激所引起。通过不同的内脏高敏感动物模型如结肠炎、直结肠扩张或应激,证实TRPA1参与内脏高敏感的调控。神经源性疼痛是由中枢或外周神经系统损伤或者疾病引起的疼痛综合征,主要表现为痛觉过敏、异常痛敏和自发性疼痛等。与炎性痛不同,神经源性疼痛与炎症的中心环节血管反应无关,而取决于神经系统的损伤和功能紊乱,常常是由于外周神经的损伤引起的。近年来越来越多的研究显示,TRPA1通道在不同的神经源性疼痛中起到重要作用,例如糖尿病性神经病变和化疗药引起的神经病变等。最近研究还表明,TRPA1在牙痛、偏头痛等疼痛中也有介导作用,通过给予TRPA1的拮抗剂能明显缓解疼痛症状的产生。
炎症是具有血管系统的活体组织对损伤因子所发生的防御反应,其中炎症介质诸 如前列腺素、5-羟色胺、缓激肽等的刺激是引起炎症局部疼痛的主要原因。炎性痛是某些慢性疾病的共同困扰,临床上尚缺乏很有效的治疗手段。动物实验研究显示,TRPA1参与炎性反应,并在炎性疼痛中发挥重要作用,通过使用TRA1特异性阻断剂,可以明显减轻验大鼠炎性疼痛反应。哮喘与咳嗽的发病机制,随着研究的不断深入,越来越清晰。从目前的研究来看,TRPA1在哮喘和咳嗽的发生中扮演一个重要的作用。诱导哮喘与咳嗽的化合物,无论是细胞内源因子,还是外源因子,都能激活TRPA1。TRPA1的拮抗剂能够减轻哮喘症状,能阻断气道高反应性。
由于TRPA1在人体系统中广泛分布和表达,其功能的重要性不言而喻。除以上TRPA1参与的生理功能外,目前已报道的TRPA1抑制剂适应症的开发还涉及到慢性阻塞性肺疾病、镇咳、止痒、过敏性鼻炎、耳疾病、抗糖尿病、尿失禁等。TRPA1是已经被证实了的炎症性肠病、肠易激综合征、疼痛和炎症等治疗的新靶点,目前还没针对该靶点的上市药物。
炎症性肠病、肠易激综合征、疼痛等属于难治性疾病,因此,本领域迫切需要开发一种针对TRPA1靶点的治疗药物,从而提高疾病的治疗效果。
发明内容,
本发明的目的在于提供一种结构新颖的以TRPA1为靶点的化合物及其用途。
本发明的第一方面,提供一种式I化合物,或其光学异构体,或其外消旋体、或其药学上可接受的盐、或其前药;
式中:
Ar为取代或未取代的C6-C12芳基、取代或未取代的3-12元杂芳基、3-12元杂环烷环并C6-C12芳基、取代或未取代的C6-C12芳基-取代或未取代的C1-C8烷基-、或取代或未取代的3-12元杂芳基-取代或未取代的C1-C8烷基-;
X
1、X
2、X
3和X
4各自独立的为C、O、S或N;
标号为a、b、c、d和e
为单键或双键;
R
1为氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C7环烷基、或卤素;
R
2为氢、取代或未取代的C1-C10烷基、或取代或未取代的C3-C10环烷基;
A为
取代或未取代的C2-C6酯基、取代或未取代的C2-C6羧基、取代或未取代的C2-C6酰胺基、取代或未取代的3-8元杂环烷基、或取代或未取代的
2HN-HN-C(O)-;
m为0、1、2或3;
Y
1为N;
Y
2为O或S;
Y
3为NH、O或S;
Y
4为O或S;
Y
5为N;
R
3和R
4各自独立的为氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C12芳基、取代或未取代的C6-C12芳基-取代或未取代的C1-C3烷基-、取代或未取代的C2-C6酰基,或R
3、R
4与相邻的Y
1共同连接形成取代或未取代的3-8元杂环烷基;
R
5为氢、取代或未取代的C1-C6烷基、羟基、巯基或取代或未取代的C1-C6烷氧基;
n为0、1、2、3、4或5;
其中,所述的任一“取代”是指环或基团上的一个或多个(优选为1、2、3、4、5或6个)氢原子被选自下组的取代基所取代:C1-C8烷基、C3-C8环烷基、C1-C8卤代烷基、C3-C8卤代环烷基、卤素、硝基、-CN、羟基、巯基、氨基、C1-C4羧基、C2-C4酯基、C2-C4酰胺基、C1-C8烷氧基、C1-C8烷硫基、C1-C8卤代烷氧基、C1-C8卤代烷硫基、C6-C12芳基、5-10元杂芳基、5-10元杂环烷基;
所述的杂芳基、杂环烷环、杂环烷基的杂环上各自独立地具有1-4个(优选为1、2、3个或4个)选自N、O和S的杂原子。
在另一优选例中,Ar为取代或未取代的C6-C10芳基、取代或未取代的3-10元杂芳基、3-10元杂环烷环并C6-C10芳基、取代或未取代的C6-C10芳基-取代或未取代的C1-C6烷基-、或取代或未取代的3-10元杂芳基-取代或未取代的C1-C6烷基-。
在另一优选例中,Ar为取代或未取代的C6-C10芳基、取代或未取代的3-8元杂芳基、3-8元杂环烷环并C6-C10芳基、取代或未取代的C6-C10芳基-取代或未取代的C1-C4烷基-、或取代或未取代的3-8元杂芳基-取代或未取代的C1-C4烷基-。
在另一优选例中,Ar为取代或未取代的C6-C8芳基、取代或未取代的5-8元杂芳基、5-8元杂环烷环并C6-C8芳基、取代或未取代的C6-C8芳基-取代或未取代的C1-C3烷基-、或取代或未取代的5-8元杂芳基-取代或未取代的C1-C3烷基-。
在另一优选例中,Ar为取代或未取代的C6-C10芳基、取代或未取代的3-8元(优选5-8元)杂芳基。
在另一优选例中,Ar为苯基、卤代苯基、甲氧基苯基、三氟甲氧基苯基、三氟甲基苯基、甲基苯基、萘基、二氢呋喃并苯基、苯并噻唑基、吡啶基、卤代吡啶基、咪唑基、甲基咪唑基、噻吩基、卤代噻吩基或苯甲基。
在另一优选例中,Ar为苯基或噻吩基。
在另一优选例中,卤代苯基为单卤代苯基或双卤代苯基。
在另一优选例中,二氢呋喃并苯基为
在另一优选例中,所述Ar中的取代基选自下组:卤素(优选氟)、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基。
在另一优选例中,R
1为氢、取代或未取代的C1-C4烷基、取代或未取代的C3-C7环烷基、或卤素。
在另一优选例中,R
1为氢、取代或未取代的C1-C2烷基、取代或未取代的C3-C7环烷基、或卤素。
在另一优选例中,R
1为氢、取代或未取代的C1-C4烷基,优选为氢。
在另一优选例中,R
1为氢、甲基。
在另一优选例中,R
2为氢、取代或未取代的C1-C6烷基、或取代或未取代的C3-C7环烷基。
在另一优选例中,R
2为氢、取代或未取代的C1-C4烷基,优选为氢。
在另一优选例中,R
2为氢、或甲基。
在另一优选例中,A为
取代或未取代的C2-C4酯基、取代或未取代的C1-C4羧基、取代或未取代的C1-C4酰胺基、或取代或未取代的
2HN-HN-C(O)-。
在另一优选例中,A为
甲酯基、乙酯基、甲酸基、乙酰胺基、甲酰胺基、或
2HN-HN-C(O)-。
在另一优选例中,A为
在另一优选例中,A为
在另一优选例中,Y
3为N。
在另一优选例中,m为0、1或2。
在另一优选例中,R
3和R
4各自独立的为氢、取代或未取代的C1-C4烷基、取代或未取代的C3-C6环烷基、取代或未取代的C2-C4酰基,或R
3、R
4与相邻的Y
1共同连接形成取代或未取代的3-6元杂环烷基。
在另一优选例中,R
3和R
4各自独立的为氢、取代或未取代的C1-C2烷基、取代或未取代的C3-C6环烷基、取代或未取代的C2-C4酰基,或R
3、R
4与相邻的Y
1共同连接形成取代或未取代的3-6元杂环烷基。
在另一优选例中,R
3和R
4各自独立的为氢、甲基、三氟甲基-甲基-、乙基、环丙基、环丁基、乙酰基,或R
3、R
4与相邻的Y
1共同连接形成取代或未取代的氮杂环丁烷基。
在另一优选例中,当A为
时,R
3为氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代的C2-C4酰基,R
4为氢,优选R
3、R
4均为氢。
在另一优选例中,当A为
时,R
3为氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代的C6-C12芳基、取代或未取代的C6-C12芳基-取代或未取代的C1-C3烷基-,R
5为氢、取代或未取代的C1-C6烷基。
在另一优选例中,当A为
时,R
3为氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基,R
5为氢、取代或未取代的C1-C6烷基。
在另一优选例中,R
5为氢、羟基、巯基或取代或未取代的C1-C4烷氧基。
在另一优选例中,R
5为氢、羟基、巯基或甲氧基。
在另一优选例中,R
3、R
4与相邻的Y
1共同连接形成卤代氮杂环丁烷基。
在另一优选例中,X
1、X
2、X
3和X
4各自独立的为C、O、S或N。
在另一优选例中,X
1为C、O、S或N。
在另一优选例中,X
2为C、O、S或N。
在另一优选例中,X
3为C、O、S或N。
在另一优选例中,X
4为C、O、S或N。
在另一优选例中,X
1、X
2、X
3和X
4中的1个或多个(2、3个)为O、S或N,其余为C。
在另一优选例中,标号为a、b、c、d和e
各自独立地为单键或双键。
在另一优选例中,标号为a的
为单键或双键。
在另一优选例中,标号为b的
为单键或双键。
在另一优选例中,标号为c的
为单键或双键。
在另一优选例中,标号为d的
为单键或双键。
在另一优选例中,标号为e的
为单键或双键。
在另一优选例中,X
1、X
2、X
3、X
4与标号为a、b、c、d和e的
形成芳环或杂芳环。
在另一优选例中,所述的杂芳环的杂环上各自独立地具有1-4个(优选为1、2、3个或4个)选自N、O和S的杂原子。
在另一优选例中,X
1、X
2、X
3、X
4与标号为a、b、c、d和e的
形成呋喃环、噻吩环、吡咯环、噻唑环、吡唑环、异恶唑环、恶唑环、咪唑环、三唑环。
在另一优选例中,n为0、1、2、3或4。
在另一优选例中,所述的任一“取代”是指环或基团上的一个或多个(优选为1、2、3、4、5或6个)氢原子被选自下组的取代基所取代:C1-C6烷基、C3-C8环烷基、C1-C6卤代烷基、C3-C8卤代环烷基、卤素、硝基、-CN、羟基、巯基、氨基、C1-C4羧基、C2-C4酯基、C2-C4酰胺基、C1-C6烷氧基、C1-C6烷硫基、C1-C6卤代烷氧基、C1-C6卤代烷硫基、C6-C12芳基、5-10元杂芳基、5-10元杂环烷基。
在另一优选例中,所述的任一“取代”是指环或基团上的一个或多个(优选为1、2、3、4、5或6个)氢原子被选自下组的取代基所取代:C1-C4烷基、C3-C8环烷基、C1-C4卤代烷基、C3-C8卤代环烷基、卤素、硝基、-CN、羟基、巯基、氨基、C1-C4羧基、C2-C4酯基、C2-C4酰胺基、C1-C4烷氧基、C1-C4烷硫基、C1-C4卤代烷氧基、C1-C4卤代烷硫基、C6-C12芳基、5-10元杂芳基、5-10元杂环烷基。
在另一优选例中,所述的杂芳基、杂环烷环、杂环烷基的杂环上各自独立地具有1-4个(优选为1、2、3个或4个)选自N、O和S的杂原子。
在另一优选例中,所述化合物具有式I-1结构:
在另一优选例中,所述化合物具有式I-2结构:
在另一优选例中,所述化合物具有式I-3结构:
在另一优选例中,所述化合物具有式I-4结构:
在另一优选例中,所述化合物具有式I-5结构:
在另一优选例中,所述化合物具有式I-6结构:
在另一优选例中,所述化合物具有式I-7结构:
在另一优选例中,所述化合物具有式I-8结构:
在另一优选例中,所述化合物具有式Z结构:
其中,R
1、R
2、X
1、X
2、X
3、X
4、Ar、a、b、c、d、e、n如上所述;
R
A、R
B、R
C各自独立地为氢、取代或未取代的C1-C6烷基。
在另一优选例中,R
1、R
2、X
1、X
2、X
3、X
4、Ar、A、a、b、c、d、e、n各自独立地为实施例中所制备的化合物中的对应基团。
在另一优选例中,所述的化合物选自下组:
本发明第二方面,提供一种药物组合物,所述的药物组合物包括如本发明第一方面所述的式I化合物,或其光学异构体,或其外消旋体、或其药学上可接受的盐、或其前药;和药学上可接受的载体。
在另一优选例中,所述药物组合物的剂型为口服制剂、注射制剂或外用制剂。
在另一优选例中,所述所述药物组合物的剂型为固体制剂、液体制剂或半固体制剂。
在另一优选例中,所述药物组合物的剂型为片剂、注射剂、输液剂、膏剂、凝胶剂、溶液剂、微球、膜剂。
本发明第三方面,提供一种制备如本发明第一方面所述的式I化合物,或其光学异构体,或其外消旋体、或其药学上可接受的盐、或其前药的方法,其特征在于,所述的方法包括:
其中,X
1、X
2、X
3、X
4、R
1、R
2、n、Ar和R
3的定义如上所定义。
在另一优选例中,所述的方法包括:
其中,X
1、X
2、X
3、X
4、R
1、R
2、n、Ar和R
3的定义如上所定义。在另一优选例中,所述的方法包括:
其中,X
1、X
2、X
3、X
4、R
1、R
2、n、Ar和R
3的定义如上所定义。在另一优选例中,所述的方法包括:
其中,X
1、X
2、X
3、X
4、R
1、R
2、n、Ar和R
3的定义如上所定义。
在另一优选例中,所述的方法包括:
其中,X
1、X
2、X
3、X
4、R
1、n、Ar、R
3和R
4的定义如上所定义。
在另一优选例中,所述的方法包括:
其中,X
1、X
2、X
3、X
4、R
1、n、Ar、R
3和R
4的定义如上所定义。
在另一优选例中,所述的方法包括:
其中,X
1、X
2、X
3、X
4、R
1、n和Ar的定义如上所定义。
本发明第四方面,提供一种如本发明第一方面所述的式I化合物,或其光学异构体,或其外消旋体、或其药学上可接受的盐、或其前药或如本发明第二方面所述的药物组合物的用途,用于(a)制备瞬时受体电位通道蛋白TRPA1的抑制剂;和/或(b)制备预防和/或治疗与瞬时受体电位通道蛋白TRPA1相关的疾病的药物。
在另一优选例中,所述的与瞬时受体电位通道蛋白TRPA1相关的疾病选自下组:炎症性肠病、肠易激综合征、疼痛、炎症,或其组合。
在另一优选例中,所述的炎症性肠病包括克罗恩病和/或溃疡性结肠炎。
在另一优选例中,所述的疼痛包括内脏痛、急性炎性疼痛、慢性炎性疼痛、神经源性疼痛、肌纤维痛、头痛、神经痛或癌症引起疼痛。
在另一优选例中,所述的预防和/或治疗炎症性肠病包括选自下组的一种或多种方式进行:
(i)改善溃疡;
(ii)改善肠梗塞;
(iii)改善肠粘连;
(iv)增加肠壁增厚;和/或
(v)降低肠道炎症因子水平。
在另一优选例中,所述的预防和/或治疗克罗恩病和/或溃疡性结肠炎包括选自下 组的一种或多种方式进行:
(i)改善溃疡;
(ii)改善肠梗塞;
(iii)改善肠粘连;
(iv)增加肠壁增厚;和/或
(v)降低肠道炎症因子水平。
在另一优选例中,所述的炎症因子选自下组:TNF-α、IL-10,或其组合。
本发明第五方面,提供一种体外非治疗性和非诊断性的抑制瞬时受体电位通道蛋白活性的方法,包括步骤:将瞬时受体电位通道蛋白或表达所述蛋白的细胞与如本发明第一方面所述的式I化合物,或其光学异构体,或其外消旋体、或其药学上可接受的盐、或其前药进行接触,从而抑制瞬时受体电位通道蛋白的活性。
本发明第六方面,提供一种抑制瞬时受体电位通道蛋白或预防和/或治疗与瞬时受体电位通道蛋白TRPA1相关的疾病的方法,包括步骤:给需要的对象施用如本发明第一方面所述的式I化合物,或其光学异构体,或其外消旋体、或其药学上可接受的盐、或其前药或如本发明第二方面所述的药物组合物。
本发明的第七方面,提供了一种化合物,所述化合物如下式II-1~式II-6其中之一所示:
式中:
Ar为取代或未取代的C6-C12芳基、取代或未取代的3-12元杂芳基、3-12元杂环烷环并C6-C12芳基、取代或未取代的C6-C12芳基-取代或未取代的C1-C8烷基-、或取代或未取代的3-12元杂芳基-取代或未取代的C1-C8烷基-;
X
1、X
2、X
3和X
4各自独立的为C、O、S或N;
标号为a、b、c、d和e
为单键或双键;
R
1为氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C7环烷基、或卤素;
R
2为氢、取代或未取代的C1-C10烷基、或取代或未取代的C3-C10环烷基;
n为0、1、2、3、4或5;
其中,所述的任一“取代”是指环或基团上的一个或多个(优选为1、2、3、4、5或6个)氢原子被选自下组的取代基所取代:C1-C8烷基、C3-C8环烷基、C1-C8卤代烷基、C3-C8卤代环烷基、卤素、硝基、-CN、羟基、巯基、氨基、C1-C4羧基、C2-C4酯基、C2-C4酰胺基、C1-C8烷氧基、C1-C8烷硫基、C1-C8卤代烷氧基、C1-C8卤代烷硫基、C6-C12芳基、5-10元杂芳基、5-10元杂环烷基;
所述的杂芳基、杂环烷环、杂环烷基的杂环上各自独立地具有1-4个(优选为1、2、3个或4个)选自N、O和S的杂原子。
在另一优选例中,所述中间体选自下组:
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
图1为本发明化合物I
A-51、I
A-30、I
D-5、I
A-55在DNBS诱导大鼠结肠炎模型中的结肠长度(A)、结肠重量(B)、溃疡面积(C)、宏观结肠损伤评分(D)结果。
图2为本发明化合物I
A-51、I
A-30、I
D-5、I
A-55在DNBS诱导大鼠结肠炎模型中的各组动物代表性结直肠照片(A为空白对照组、B为模型-溶媒组、C为奥沙拉嗪钠组、D为化合物I
A-51组、E为化合物I
A-30组、F为化合物I
D-5组、G为化合物I
A-55组)。
图3为本发明化合物I
A-51、I
A-30、I
D-5、I
A-55在DSS诱导的C57BL/6小鼠的炎症性肠炎模型中的DAI评分结果。
图4为本发明化合物I
A-51、I
A-30、I
D-5、I
A-55在DSS诱导的C57BL/6小鼠的炎症性肠炎模型中对结直肠重量和长度的影响结果。
图5为本发明化合物I
A-51、I
A-30、I
D-5、I
A-55在DSS诱导的C57BL/6小鼠的炎症性肠炎模型中,结直肠炎症因子TNF-α和IL-10的ELISA分析结果。
图6为本发明化合物I
A-51、I
A-30、I
D-5和I
A-55在醋酸在ICR小鼠上诱导的扭体痛模型的扭体次数结果。
本发明人通过广泛而深入的研究,首次意外地开发了一种式I化合物,或其光学异构体,或其外消旋体、或其药学上可接受的盐。实验表明,本发明式I化合物对TRPA1具有显著的抑制效果。本发明的式I化合物可有效治疗与TRPA1靶点相关的炎症性肠病、肠易激综合征、疼痛和炎症等。在此基础上,完成了本发明。
术语
如本文所用,术语“包含”、“包括”、“含有”可互换使用,不仅包括封闭式定义,还包括半封闭、和开放式的定义。换言之,所述术语包括了“由……构成”、“基本上由……构成”。
如本文所用,术语“瞬时受体电位通道蛋白TRPA1”、“TRPA1”和““瞬时受体电位通道蛋白A1”可互换使用,英文名为transient receptor potential ankyrin 1。
应当理解,本领域的普通技术人员可以选择本发明的化合物上的取代基和取代型式以产生化学上稳定的化合物,所述化合物可以通过本领域己知的技术以及下文所阐述的方法合成。如果被超过一个(多个)取代基团取代,应当理解,这多个基团可以是在同一个碳上或在不同碳上,只要产生稳定的结构即可。
如本文所用,术语“取代”或“取代的”是基团上的氢原子被非氢原子基团取代,但需要满足其化合价要求并且由取代生成化学稳定的化合物,即不会自发进行诸如环化、消除等转变的化合物。
如本文所用,“R
1”、“R1”和“R
1”的含义相同,可相互替换,其它类似定义的含义相同。
如本文所用,术语“烷基”指只含碳原子的直链(即,无支链)或支链饱和烃基,或直链和支链组合的基团。当烷基前具有碳原子数限定(如C1-C10烷基)指所述的烷基含有1-10个碳原子,例如,C1-C4烷基指含有1-4个碳原子的烷基,代表性实例包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
在本发明中,术语“卤素”指F、Cl、Br或I。
在本发明中,术语“卤代”是指被卤素取代。
如本文所用,术语“卤代烷基”是指烷基的一个或多个(优选为1、2、3或4个)氢被卤素取代,所述的烷基和卤素如上所定义,当烷基前具有碳原子数限定(如C1-C6卤代烷基)指所述的烷基含有1-6个碳原子,例如,C1-C6卤代烷基指含有1-6个碳原子的卤代烷基,代表性实例包括但不限于-CF3、-CHF
2、单氟代异丙基、双氟代丁基、或类似基团。
如本文所用,术语“环烷基”指具有饱和的或部分饱和的单元环,二环或多环(稠环、桥环或螺环)环系基团。当某个环烷基前具有碳原子数限定(如C3-C12)时,指所述的环烷基具有3-12个环碳原子。在一些优选实施例中,术语“C3-C8环烷基”指具有3-8个环碳原子的饱和或部分饱和的单环或二环烷基,包括环丙基、环丁基、环戊基、环庚基、或类似基团。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的二环或多环基团,这些可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳二环或多环基团,其中一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团,这些可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。如下是环烷基的代表性实例,包括但不限于:
如本文所用,术语“卤代环烷基”是指环烷基的一个或多个(优选为1、2、3或4个)氢被卤素取代,所述的环烷基和卤素如上所定义,当环烷基前具有碳原子数限定(如C3-C8卤代烷基)指所述的环烷基含有3-8个环碳原子,例如,C3-C8卤代烷基指含有3-6碳原子的卤代环烷基,代表性实例包括但不限于单氟代环丙基、单氯代环丁基、单氟代环戊基、双氟代环庚基,或类似基团。
术语“烷氧基”指R-O-基团,其中R为烷基,烷基为如上本文所定义,当烷氧基前具有碳原子数限定,如C1-C8烷氧基基指所述的烷氧基中的烷基具有1-8个碳原子。烷 氧基的代表性示例包括但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、叔丁氧基,或类似基团。
如本文所用,术语“烷硫基”指R-O-基团,其中R为烷基,烷基为如上本文所定义,当烷硫基前具有碳原子数限定,如C1-C8烷硫基指所述的烷硫基中的烷基具有1-8个碳原子。烷硫基的代表性示例包括但不限于:甲硫基、乙硫基、正丙硫基、异丙硫基、叔丁硫基,或类似基团。
如本文所用,术语“卤代烷氧基”是指卤代烷基-O-,所述的卤代烷基如上所定,例如,C1-C6卤代烷氧基指含有1-6个碳原子的卤代烷氧基,代表性实例包括但不限于、单氟代甲氧基、单氟代乙氧基、双氟代丁氧基、或类似基团。
如本文所用,术语“卤代烷硫基”是指卤代烷基-S-,所述的卤代烷基如上所定,例如,C1-C6卤代烷硫基指含有1-4个碳原子的卤代烷硫基,代表性实例包括但不限于、单氟代甲硫基、单氟代乙硫基、双氟代丁硫基、或类似基团。
术语“杂环烷环”是指完全饱和的或部分不饱和的的环(包含但不限于如3-7元单环,7-11元双环,或8-16元三环系统),其中至少有一个杂原子存在于至少有一个碳原子的环中。当杂环前有元数限定时,指的是杂环的环原子个数,例如3-16元杂环指的是具有3-16个环原子的杂环。每个含有杂原子的杂环上可以带有一个或多个(如1,2,3或4个)杂原子,这些杂原子各自独立地选自氮原子、氧原子或硫原子,其中氮原子或硫原子可以被氧化,氮原子也可以被季铵化。杂环可以连接到环或环系分子的任何杂原子或碳原子的残基上。典型的单环杂环烷环包括但不限于氮杂环丁烷环、氧杂环丁烷、咪唑啉环、咪唑烷环、四氢呋喃环、哌啶环、哌嗪环、2-氧代哌嗪环、2-氧代哌啶环、4-哌啶酮环、四氢吡喃环、吗啡啉环、硫代吗啡啉环、硫代吗啡啉亚砜环、硫代吗啡啉砜环、1,3-二噁烷环和四氢-1,1-二氧噻吩环等。多环杂环烷环包括螺环、稠环和桥环的杂环环;其中涉及到的螺环、稠环和桥环的杂环任选与其他环通过单键相连接,或者通过环上的任意两个或两个以上的原子与其它环烷环、杂环进一步并环连接。
术语“杂环烷基”是指完全饱和的或部分不饱和的的环状基团(包含但不限于如3-7元单环,7-11元双环,或8-16元三环系统),其中至少有一个杂原子存在于至少有一个碳原子的环中。当杂环烷基前有元数限定时,指的是杂环烷基的环原子个数,例如3-16元杂环烷基指的是具有3-16个环原子的杂环烷基。每个含有杂原子的杂环上可以带有一个或多个(如1,2,3或4个)杂原子,这些杂原子各自独立地选自氮原子、氧原子或硫原子,其中氮原子或硫原子可以被氧化,氮原子也可以被季铵化。杂环烷基可以连接到环或环系分子的任何杂原子或碳原子的残基上。典型的单环杂环烷基包括但不限于氮杂环丁烷基、氧杂环丁烷基、咪唑啉基、咪唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环烷基包括螺环、稠环和桥环的杂环基;其中涉及到的螺环、稠环和桥环的杂环烷基任选与其他基团通过单键相连接,或者通过环上的任意两个或两个以上的原子与其它环烷环、杂环进一步并环连接。
术语“芳环”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环),是一种芳香环状烃类化合物,当芳环前面具有碳原子数限定,如C6-C12芳环,则指所述的芳环具有6-12个环碳原子,例如苯环和萘环。所述芳环可以稠合于其它碳环(包括饱和或不饱和环),但不能含有杂原子如氮、氧、或硫,同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。代表性地芳环为苯环和萘环,或类似环。
术语“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,是一种芳香环状烃类化合物基团,当芳基前面具有碳原子数限定, 如C6-C12芳基,则指所述的芳基具有6-12个环碳原子,例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和或不饱和环),但不能含有杂原子如氮、氧、或硫,同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。如下是芳基代表性实例,包括但不限于:
术语“杂芳环”指具有一个到多个(优选为1、2、3或4个)杂原子的芳族杂环,其可以是单环(单环的)或者稠合在一起或共价地连接的多环(二环的、三环的或多环的),每个含有杂原子的杂环上可以具有一个或多个(如1、2、3、4个)各自独立选自下组的杂原子:氧、硫和氮。当杂芳环前有元数限定时,指的是杂芳环的环原子个数,例如5-12元杂芳环指的是具有5-12个环原子的杂芳环,代表性的例子包括但不限于:吡咯环、吡唑环、咪唑环、噁唑环、异噁唑环、噻唑环、噻二唑环、异噻唑环、呋喃环、吡啶环、吡嗪环、嘧啶环、哒嗪环、三氮嗪环、三氮唑环及四氮唑环等。
术语“杂芳基”指具有一个到多个(优选为1、2、3或4个)杂原子的芳族杂环系基团,其可以是单环(单环的)或者稠合在一起或共价地连接的多环(二环的、三环的或多环的),每个含有杂原子的杂环上可以带有一个多个(如1、2、3、4个)各自独立选自下组的杂原子:氧、硫和氮。当杂芳基前有元数限定时,指的是杂芳基的环原子个数,例如5-12元杂芳基指的是具有5-12个环原子的杂芳基,代表性的例子包括但不限于:吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。
如本文所用,术语“羧基”指具-COOH基团或-烷基-COOH基团,烷基为如上本文所定义,例如“C
2-C
4羧基”是指-C
1-C
3烷基-COOH结构的基团,羧基的代表性示例包括(但不限于):-COOH、-CH
2COOH、-C
2H
4COOH,或类似基团。
如本文所用,术语“酯基”指具R-CO-O-基团或-CO-O-R基团,其中R为烷基,烷基为如上本文所定义,例如“C
2-C
4酯基”是指C
1-C
3烷基-CO-O-结构的基团或者-CO-O-C
1-C
3烷基结构的基团,酯基的代表性示例包括但不限于:CH
3COO-、C
2H
5COO-、C
3H
8COO-、(CH
3)
2CHCOO-、-COOCH
3、-COOC
2H
5、-COOC
3H
8,或类似基团。
如本文所用,术语“酰胺基”指具R-CO-N-基团或-CO-N-R基团,其中R为烷基,烷基为如上本文所定义,例如“C
2-C
4酰胺基”是指C
1-C
3烷基-CO-N-结构的基团或者-CO-N-C
1-C
3烷基结构的基团,酰胺基的代表性示例包括但不限于:CH
3CO-N-、C
2H
5CO-N-、C
3H
8CO-N-、(CH
3)
2CHCO-N-、-CO-N-CH
3、-CO-N-C
2H
5、-CO-N-C
3H
8,或类似基团。
如本文所用,在单独或作为其他取代基一部分时,术语"氨基"表示-NH
2。
如本文所用,在单独或作为其他取代基一部分时,术语"硝基"表示-NO
2。
如本文所用,在单独或作为其他取代基一部分时,术语"羟基"表示-OH。
如本文所用,在单独或作为其他取代基一部分时,术语"巯基"表示-SH。
在本说明书中,应解释为所有取代基为未取代的,除非在本文中明确描述为“取代的”。术语“取代”是指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基,优选地,所述的取代是指环或基团上的一个或多个(优选为1、2、3、4、5或6个)氢原子被选自下组的取代基所取代:C1-C8烷基、C3-C8环烷基、C1-C8卤代烷基、C3-C8卤代环烷基、卤素、硝基、-CN、羟基、巯基、氨基、C1-C4羧基、C2-C4酯基、C2-C4酰胺基、C1-C8烷氧基、C1-C8烷硫基、C1-C8卤代烷氧基、C1-C8卤代烷硫基、C6-C12 芳基、5-10元杂芳基、5-10元杂环烷基;
在本发明中,术语“预防”表示预防疾病和/或它的附随症状的发作或者保护对象免于获得疾病的方法。本文中使用的"预防"还包括延迟疾病和/或它的附随症状的发作和降低对象的得病的风险。
本发明所述的“治疗”包括延缓和终止疾病的进展,或消除疾病,并不需要100%抑制、消灭和逆转。在一些实施方案中,与不存在本发明所述的组合物、药盒、食品盒或保健品盒、活性成分组合时观察到的水平相比,本发明所述组合物或药物组合物通过抑制与瞬时受体电位通道蛋白TRPA1相关的疾病减轻、抑制和/或逆转了例如至少约10%、至少约30%、至少约50%、或至少约80%。
活性成分
如本文所用,“本发明化合物”、“本发明的N-取代苯基磺酰胺类化合物”、或“式I化合物”可互换使用,指式I化合物,或其光学异构体,或其外消旋体、或其药学上可接受的盐、或其前药。应理解,该术语还包括上述组分的混合物。
本发明提供了一种式I化合物,或其光学异构体,或其外消旋体、或其药学上可接受的盐、或其前药;
式中:
Ar为取代或未取代的C6-C12芳基、取代或未取代的3-12元杂芳基、3-12元杂环烷环并C6-C12芳基、取代或未取代的C6-C12芳基-取代或未取代的C1-C8烷基-、或取代或未取代的3-12元杂芳基-取代或未取代的C1-C8烷基-;
X
1、X
2、X
3和X
4各自独立的为C、O、S或N;
标号为a、b、c、d和e
为单键或双键;
R
1为氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C7环烷基、或卤素;
R
2为氢、取代或未取代的C1-C10烷基、或取代或未取代的C3-C10环烷基;
A为
取代或未取代的C2-C6酯基、取代或未取代的C2-C6羧基、取代或未取代的C2-C6酰胺基、或取代或未取代的
2HN-HN-C(O)-;m为0、1、2或3;
Y
1为N;
Y
2为O或S;
Y
3为NH、O或S;
Y
4为O或S;
Y
5为N;
R
3和R
4各自独立的为氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C2-C6酰基,或R
3、R
4与相邻的Y
1共同连接形成取代或未取代的3-8元杂环烷基;
R
5为氢、羟基、巯基或取代或未取代的C1-C6烷氧基;
n为0、1、2、3、4或5;
其中,所述的任一“取代”是指环或基团上的一个或多个(优选为1、2、3、4、5或6个)氢原子被选自下组的取代基所取代:C1-C8烷基、C3-C8环烷基、C1-C8卤代烷基、C3-C8卤代环烷基、卤素、硝基、-CN、羟基、巯基、氨基、C1-C4羧基、C2-C4酯基、C2-C4酰胺基、C1-C8烷氧基、C1-C8烷硫基、C1-C8卤代烷氧基、C1-C8卤代烷硫基、C6-C12芳基、5-10元杂芳基、5-10元杂环烷基;
所述的杂芳基、杂环烷环、杂环烷基的杂环上各自独立地具有1-4个(优选为1、2、3个或4个)选自N、O和S的杂原子。
优选地,所述的式I化合物如上本发明第一方面所述。
术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐,适合形成盐的酸包括(但并不限于):盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。一类优选的盐是本发明化合物与碱形成的金属盐,适合形成盐的碱包括(但并不限于):氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、磷酸钠等无机碱、氨水、三乙胺、二乙胺等有机碱。
本发明所述的如式I所示化合物可通过常规方法转化为其药学上可接受的盐,例如,可将相应的酸的溶液加入到上述化合物的溶液中,成盐完全后除去溶剂即得本发明所述化合物的相应的盐。
本发明优选的化合物如本申请实施例所制备的具体化合物。
代表性地,本发明所述的化合物选自下表1:
表1
制备方法
本发明还提供了本发明式I所示的化合物I
A~I
W的制备方法。
本发明还提供了用于制备上述化合物的中间体IV~XXVII的制备方法。
具体合成策略分别如下:
I
A~I
F的合成:
其中,X
1、X
2、X
3、X
4、R
1、n、Ar、R
2和R
3的定义如上述本发明第一方面所述。
将取代碘苯II、取代或未取代的五元杂芳基硼酸III、四三苯基膦钯和碳酸钠溶解于甲苯、甲醇和水的混合溶液中,氮气保护条件下,加热回流过夜。反应结束后,蒸干溶剂,往体系中加入水,用乙酸乙酯萃取三次,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到中间体IV。
将中间体IV、取代或未取代的磺酰氯溶解于吡啶和四氢呋喃的混合溶液中,封管50-100℃反应过夜。反应结束后,蒸干溶剂,残余物经柱层析分离得到中间体V。
将中间体V溶解于四氢呋喃溶液中,加入适量醋酸和雷尼镍,50-100℃反应1-2小时。反应结束后,抽滤除去雷尼镍,滤液蒸干,残余物经柱层析分离得到中间体VI。
将中间体VI溶解于乙醇溶液中,加入取代胺,室温反应过夜。反应结束后,蒸干溶剂,残余物经柱层析分离得到化合物I
C。
将中间体VI溶解于乙醇溶液中,加入取代胺,室温反应过夜,于第二天往体系中分批次加入硼氢化钠,反应1小时。反应结束后,蒸干溶剂,残余物经柱层析分离得到化合物I
A。
将中间体V溶解于氨甲醇溶液中,加入雷尼镍,通入氢气,室温反应过夜。反应结束后,抽滤除去雷尼镍,滤液蒸干,残余物经柱层析分离得到化合物I
D。
将化合物I
D溶解于二氯甲烷溶液中,加入三乙胺和醋酸酐,室温反应过夜。反应结束后,蒸干溶剂,残余物经柱层析分离得到化合物I
E。
将中间体V溶解于乙腈溶液中,加入碳酸钾和取代烷基碘,60-80℃反应三小时。反应结束后,蒸干溶剂,残余物经柱层析分离得到中间体VII。
将中间体VII溶解于四氢呋喃溶液中,加入适量醋酸和雷尼镍,50-100℃反应1-2小时。反应结束后,抽滤除去雷尼镍,滤液蒸干,残余物经柱层析分离得到中间体VIII。
将中间体VIII溶解于乙醇溶液中,加入取代胺,室温反应过夜,于第二天往体系中分批次加入硼氢化钠,反应1小时。反应结束后,蒸干溶剂,残余物经柱层析分离 得到化合物I
B。
将中间体VII溶解于氨甲醇溶液中,加入雷尼镍,通入氢气,室温反应过夜。反应结束后,抽滤除去雷尼镍,滤液蒸干,残余物经柱层析分离得到化合物I
F。
I
G、I
H、I
J、I
K和I
P的合成:
其中,X
1、X
2、X
3、X
4、R
1、n、Ar、R
3和R
4的定义如上述本发明第一方面所述。。
将取代碘苯IX、取代或未取代的五元杂芳基硼酸III、四三苯基膦钯和碳酸钠溶解于甲苯、甲醇和水的混合溶液中,氮气保护条件下,加热回流过夜。反应结束后,蒸干溶剂,往体系中加入水,用乙酸乙酯萃取三次,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到中间体X。
将中间体X、取代或未取代的磺酰氯溶解于吡啶和四氢呋喃的混合溶液中,封管50-100℃反应过夜。反应结束后,蒸干溶剂,残余物经柱层析分离得到化合物I
G。
将化合物I
G溶解于四氢呋喃溶液,氮气保护,于冰浴条件下分批次加入四氢铝锂,室温反应1-4小时。后处理,往体系中依次加入水,氢氧化钠水溶液和水,抽滤,滤液蒸干,残余物经柱层析分离得到化合物I
H。
将化合物I
H溶解于二氯甲烷溶液中,于冰浴条件下加入三苯基膦和四溴化碳,室温反应1-4小时。反应结束后,蒸干溶剂,残余物溶解于N,N-二甲基甲酰胺溶液中,加入取代胺和碳酸钾,60-90℃反应过夜。反应结束后,往体系中加入水,用乙酸乙酯萃取三次,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到化合物I
J。
将化合物I
G溶解于乙醇溶液中,加入取代胺,60-100℃反应过夜。反应结束后,蒸干溶剂,残余物经柱层析分离得到化合物I
P。
将化合物I
G溶解于四氢呋喃溶液中,加入氢氧化锂水溶液,40-60℃反应过夜。反应结束后,蒸干溶剂,往体系中加入适量稀盐酸调节PH至3-4,用乙酸乙酯萃取三次,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到化合物I
K。
I
Q的合成:
其中,X
1、X
2、X
3、X
4、R
1、n、Ar、R
3和R
4的定义如上述本发明第一方面所述。。
将取代氟苯XI、取代或未取代五元含氮杂芳环化合物XII溶解于二甲基亚砜溶液中,加入氢氧化钠,氮气保护条件下40-80℃反应过夜。反应结束后,往体系中加入水,用乙酸乙酯萃取三次,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到中间体XIII。
将中间体XIII溶解于乙醇和水的混合溶液中,加入铁粉和氯化铵,60-80℃反应1小时。反应结束后,抽滤,滤液浓缩,用二氯甲烷萃取三次,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到中间体XIV。
将中间体XIV、取代或未取代的磺酰氯溶解于吡啶和四氢呋喃的混合溶液中,封管50-100℃反应过夜。反应结束后,蒸干溶剂,残余物经柱层析分离得到中间体XV。
将中间体XV溶解于四氢呋喃溶液,氮气保护,于冰浴条件下加入四氢铝锂,室温反应1-4小时。后处理,往体系中依次加入水,氢氧化钠水溶液和水,抽滤,滤液蒸干,残余物经柱层析分离得到中间体XVI。
将中间体XVI溶解于二氯甲烷溶液中,加入氯铬酸吡啶盐,室温反应1小时。后处理,抽滤,滤液蒸干,残余物经柱层析分离得到中间体XVII。
将中间体XVII溶解于乙醇溶液中,加入取代胺,室温反应过夜,于第二天往体系中分批次加入硼氢化钠,反应1小时。反应结束后,蒸干溶剂,残余物经柱层析分离得到化合物I
Q。
I
R和I
S的合成:
其中,X
1、X
2、X
3、X
4、R
1、n和Ar的定义如上述本发明第一方面所述。。
将氨基取代的苯乙腈溶解于乙腈溶液中,加入N-溴代丁二酰亚胺,室温反应0.5-2小时。反应结束后,蒸干溶剂,残余物经柱层析分离得到中间体XVIII。
将中间体XVIII、取代或未取代的五元杂芳基硼酸III、四三苯基膦钯和碳酸钠溶解于甲苯、甲醇和水的混合溶液中,氮气保护条件下,加热回流过夜。反应结束后,蒸干溶剂,往体系中加入水,用乙酸乙酯萃取三次,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到中间体XIX。
将中间体XIX、取代或未取代的磺酰氯溶解于吡啶和四氢呋喃的混合溶液中,封管50-100℃反应过夜。反应结束后,蒸干溶剂,残余物经柱层析分离得到中间体XX。
将中间体XX溶解于氨甲醇溶液中,加入雷尼镍,通入氢气,室温反应过夜。反应结束后,抽滤除去雷尼镍,滤液蒸干,残余物经柱层析分离得到化合物I
R。
将化合物I
R溶解于二氯甲烷和甲醇的混合溶液中,加入二碳酸二叔丁酯,室温反应过夜。反应结束后,蒸干溶剂,残余物经柱层析分离得到中间体XXI。
将中间体XXI溶解于四氢呋喃溶液,氮气保护条件下,冰浴加入四氢铝锂,60-80℃反应过夜。后处理,往体系中依次加入水,氢氧化钠水溶液和水,抽滤,滤液蒸干,残余物经柱层析分离得到化合物I
S。
I
U的合成:
其中,X
1、X
2、X
3、X
4、R
1、n和Ar的定义如上述本发明第一方面所述。。
将中间体VIII,叔丁基亚磺酰胺和硫酸铜溶解于30毫升无水1,2-二氯乙烷溶液中,加热,反应过夜。反应结束后,待体系冷却至室温,抽滤,滤液浓缩,残余物经柱层析分离得到中间体XXII。
将中间体XXII溶解于无水四氢呋喃溶液中,于-78℃条件下缓慢滴加甲基溴化镁的四氢呋喃溶液,加料完毕缓慢升至-20℃反应。反应结束后,冰浴条件下往体系中加入氯化胺水溶液淬灭,加入水,用乙酸乙酯萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到中间体XXIII。
将中间体XXIII溶解于乙醇溶液中,加入盐酸的乙醇溶液,60℃反应。反应结束后,蒸干溶剂,往残余物中加入水,加入适量碳酸氢钠水溶液,调节pH8~9,用乙酸乙酯萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到化合物I
U。
I
V的合成:
其中,X
1、X
2、X
3、X
4、R
1、n和Ar的定义如上述本发明第一方面所述。。
采用合成中间体V类似的方法,得到中间体XXV。
将中间体XXV溶解于二氯甲烷溶液中,加入甲胺的乙醇溶液,四乙氧基钛,室温反应过夜。于冰水浴条件下缓慢加入硼氢化钠,室温反应。反应结束后,往体系中加入水,用二氯甲烷萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到化合物I
V。
I
W的合成:
其中,X
1、X
2、X
3、X
4、R
1、n和Ar的定义如上述本发明第一方面所述。。
采用合成中间体V类似的方法,得到中间体XXVII.
将中间体XXVII溶解于乙酸乙酯溶液中,加入盐酸的乙醇溶液,室温反应。反应结束后,蒸干溶剂,往残余物中加入水,加入适量碳酸氢钠水溶液,调节pH8~9,用乙酸乙酯萃取,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到化合物I
W。
瞬时受体电位通道蛋白(TRP)
瞬时受体电位通道蛋白是一类存在于细胞膜上的重要阳离子通道构成的蛋白超家族。瞬时受体电位通道蛋白包括多个亚族,如TRPA1、TRPC、TRPM、TRPV、TRPML和TRPP亚族。
研究发现,TRPA1通道蛋白与炎症性肠病、疼痛、肠易激综合征、炎症等疾病相关,TRPA1是治疗炎症性肠病、疼痛、肠易激综合征、炎症等疾病的靶标。
用途
本发明还提供了一种抑制瞬时受体电位通道蛋白TRPA1的方法,以及治疗与TRPA1相关的疾病的方法。
本发明化合物可用于抑制瞬时受体电位通道蛋白TRPA1,进而预防或治疗与瞬时受体电位通道蛋白TRPA1相关的疾病。
在本发明中,与瞬时受体电位通道蛋白TRPA1相关的疾病的例子包括(但并不限于):炎症性肠病、疼痛、肠易激综合征、炎症。代表性的,所述的炎症性肠病包括溃疡性结肠炎和克罗恩病;所述的疼痛包括(但不限于):内脏痛、急性炎性疼痛、慢性炎性疼痛、神经源性疼痛、肌纤维痛、头痛、神经痛或癌症引起疼痛。
在一个优选实施例中,本发明提供了一种体外非治疗性和非诊断性的抑制瞬时受体电位通道蛋白TRPA1活性的方法,包括例如在体外培养体系中,将瞬时受体电位通道蛋白TRPA1或表达所述瞬时受体电位通道蛋白的细胞与本发明所述的化合物进行接触,从而抑制瞬时受体电位通道蛋白TRPA1的活性。
本发明还提供了一种抑制瞬时受体电位通道蛋白TRPA1的方法,该方法可以是治疗性的或非治疗性的。通常,该方法包括步骤:给需要的对象施用本发明所述的化合物。
优选地,所述对象包括人和非人哺乳动物(啮齿动物、兔、猴、家畜、狗、猫等)。
克罗恩病
克罗恩病是一种炎症性肠病,会引起胃肠道炎症。任何年龄的人都有可能患克罗恩病,但通常发病年龄在13至30岁之间。最常见的病变部位,是小肠的下半部分(称为回肠)和结肠的上半部分,从口腔到肛门的胃肠道的任何部位,都可能出现克罗恩病的病变。
溃疡性结肠炎
溃疡性结肠炎是一种病因尚不明确的直肠以及结肠慢性非特异性炎症性疾病。病变主要限于大肠粘膜与粘膜下层。临床主要表现为腹泻、粘液脓血便、腹痛,多成反复发作,迁延不愈。
组合物和施用方法
本发明提供了一种用于抑制瞬时受体电位通道蛋白TRPA1活性的组合物。所述的组合物包括(但并不限于):药物组合物、食品组合物、膳食补充剂、饮料组合物等。
典型地,所述的组合物为药物组合物,所述的药物组合物包括如本发明所述的化合物;和药学上可接受的载体。
在本发明中,药物组合物的剂型包括(但不限于)口服制剂、注射剂、外用制剂。
代表性的包括(但不限于):片剂、注射剂、输液剂、膏剂、凝胶剂、溶液剂、微球、膜剂。
术语“药学上可接受的载体”指的是:一种或多种相容性固体、半固体、液体或凝胶填料,它们适合于人体或动物使用,而且必须有足够的纯度和足够低的毒性。“相容性”是指药物组合物中的各组分和药物的活性成分以及它们之间相互掺和,而不明显降低药效。
应理解,在本发明中,所述的载体没有特别的限制,可选用本领域常用材料,或用常规方法制得,或从市场购买得到。药学可接受的载体部分例子有纤维素及其衍生物(如甲基纤维素、乙基纤维素、羟丙甲基纤维素、羧甲基纤维素钠等)、明胶、滑石粉、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油、等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、缓冲剂、螯合剂、增稠剂、pH调节剂、透皮促进剂、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、抑菌剂、无热原水等。
代表性的,液体剂型除了活性药物成分外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例如,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂等。
药物制剂应与给药方式相匹配。本发明药剂还可与其他协同治疗剂一起使用(包括之前、之中或之后使用)。使用药物组合物或制剂时,是将安全有效量的药物施用于所需对象(如人或非人哺乳动物),所述安全有效量通常至少约10微克/千克体重,而且在大多数情况下不超过约8毫克/千克体重,较佳地该剂量是约10微克/千克体重-约1毫克/千克体重。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明的主要优点包括:
(a)本发明提供了一类结构新颖且具有优异TRPA1抑制活性的式I化合物。
(b)本发明化合物具有优异的炎症性肠病治疗药效。
(c)本发明化合物具有优异的镇痛药效。
(d)本发明化合物的毒性小、药效强,因此安全窗口大。
(e)本发明化合物的成药性好。
(f)本发明化合物具有优异的药代动力学性质。
(g)本发明化合物适合口服给药。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例1
化合物I
A的合成:
第一步:3-氨基-4-(呋喃-2-基)苯甲腈(IV-1)
将3-氨基-4-碘苯腈(244.0mg,1mmol),呋喃-2-硼酸(123.1mg,1.1mmol),四三苯基膦钯(57.8mg,0.05mmol)和碳酸钠(318.0mg,3mmol)溶解于26毫升的甲苯/甲醇/水(体积/体积/体积=9:3:1)混合溶液中,回流反应过夜。反应结束后,蒸干溶剂,向残余物中加入水,用乙酸乙酯萃取三次,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到中间体IV-1,类白色固体(172.0mg,93.4%)。
1H NMR(400MHz,CDCl
3)δ7.69(d,J=1.9Hz,1H),7.50(dd,J=1.8,0.7Hz,1H),7.30(dd,J=8.4,2.0Hz,1H),6.70(d,J=8.4Hz,1H),6.59(dd,J=3.4,0.7Hz,1H),6.51(dd,J=3.4,1.9Hz,1H)。
第二步:N-(5-氰基-2-(呋喃-2-基)苯基)-4-氟苯磺酰胺(V-1)
将中间体IV-1(92.1mg,0.5mmol)和4-氟苯磺酰氯(97.3mg,0.5mmol)溶解于10毫升的四氢呋喃/吡啶(体积/体积=1:1)混合溶液中,封管80℃反应过夜。反应完成后,蒸干溶剂,残余物经柱层析分离得到中间体V-1,黄色固体(94.8mg,55.4%)。
1H NMR(500MHz,DMSO)δ10.13(s,1H),8.04(d,J=1.9Hz,1H),7.81–7.77(m,2H),7.76(d,J=1.3Hz,1H),7.67(dd,J=8.4,2.0Hz,1H),7.38(dd,J=12.2,5.5Hz,2H),7.20(d,J=8.4Hz,1H),7.01(d,J=3.4Hz,1H),6.60(dd,J=3.4,1.8Hz,1H)。
第三步:4-氟-N-(5-甲酰基-2-(呋喃-2-基)苯基)苯磺酰胺(中间体VI-1)
将中间体V-1(68.5mg,0.2mmol)溶解于12毫升的四氢呋喃/醋酸(体积/体积=5:1)混合溶液中,往体系中加入适量雷尼镍水溶液,通入氢气,60℃反应一小时。反应结 束后,抽滤除去雷尼镍,滤液蒸干,残余物经柱层析分离得到中间体VI-1,黄色固体(32.9mg,47.6%)。
1H NMR(400MHz,DMSO)δ10.11(s,1H),9.94(s,1H),8.13(d,J=1.9Hz,1H),7.82–7.75(m,3H),7.71(dd,J=8.3,2.0Hz,1H),7.40–7.33(m,2H),7.20(d,J=8.3Hz,1H),6.98(dd,J=3.4,0.5Hz,1H),6.60(dd,J=3.4,1.8Hz,1H)。
第四-五步:4-氟-N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(化合物I
A-1)
将中间体VI-1(27.6mg,0.08mmol)溶解于乙醇溶液中,加入1毫升甲胺的乙醇溶液(30-33wt%),反应过夜,再加入硼氢化钠(3.0mg,0.08mmol)。反应结束后,蒸干溶剂,残余物经柱层析分离得到化合物I
A-1,白色固体(14.0mg,48.7%)。
HPLC:99.1%;LC-MS(m/z):361.10(M+H)
+;
1H NMR(400MHz,DMSO)δ7.82–7.66(m,2H),7.66–7.54(m,2H),7.38(d,J=3.1Hz,1H),7.25(d,J=1.5Hz,1H),7.22–7.10(m,2H),6.81(d,J=7.7Hz,1H),6.51(dd,J=3.3,1.8Hz,1H),3.83(s,2H),2.40(s,3H)。
采取合成I
A-1类似的方法,得到以下化合物:
2-氟-N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-2)
HPLC:99.0%;LC-MS(m/z):361.09(M+H)
+;
1H NMR(400MHz,DMSO)δ7.74(td,J=7.6,1.5Hz,1H),7.64–7.55(m,2H),7.51(s,1H),7.43–7.30(m,2H),7.13(dd,J=15.1,7.9Hz,2H),6.72(d,J=7.8Hz,1H),6.49(dd,J=3.2,1.8Hz,1H),3.85(s,2H),2.43(s,3H)。
3-氟-N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-3)
HPLC:98.9%;LC-MS(m/z):361.11(M+H)
+;
1H NMR(400MHz,DMSO)δ7.64–7.55(m,2H),7.53(d,J=7.8Hz,1H),7.48–7.35(m,3H),7.32(d,J=1.3Hz,1H),7.19(td,J=8.5,2.3Hz,1H),6.76(d,J=8.1Hz,1H),6.51(dd,J=3.2,1.8Hz,1H),3.87(s,2H),2.43(s,3H)。
N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-4)
HPLC:99.4%;LC-MS(m/z):343.10(M+H)
+;
1H NMR(400MHz,DMSO)δ7.75–7.66(m,2H),7.60(d,J=8.0Hz,2H),7.43–7.31(m,4H),7.21(s,1H),6.82(d,J=8.0Hz,1H),6.51(dd,J=3.3,1.8Hz,1H),3.76(s,2H),2.35(s,3H)。
2-甲氧基-N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-5)
HPLC:98.8%;LC-MS(m/z):373.11(M+H)
+;
1H NMR(400MHz,DMSO)δ7.75(d,J=1.2Hz,1H),7.67(dd,J=7.8,1.6Hz,1H),7.58(d,J=8.0Hz,1H),7.54–7.45(m,1H),7.15–7.08(m,3H),7.03(t,J=11.0Hz,1H),6.96(dd,J=17.7,10.3Hz,1H),6.63–6.53(m,1H),3.70(s,3H),3.59(s,2H),2.16(s,3H)。
4-甲氧基-N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-6)
HPLC:97.9%;LC-MS(m/z):373.16(M+H)
+;
1H NMR(400MHz,DMSO)δ7.67–7.56(m,4H),7.24(d,J=3.1Hz,1H),7.11(s,1H),6.94(d,J=8.8Hz,3H),6.53(dd,J=3.3,1.8Hz,1H),3.77(s,3H),3.70(s,2H),2.30(s,3H)。
4-氯-N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-7)
HPLC:99.4%;LC-MS(m/z):377.11(M+H)
+;
1H NMR(400MHz,DMSO)δ7.72–7.66(m,2H),7.61(d,J=8.1Hz,2H),7.42(d,J=8.5Hz,3H),7.28(s,1H),6.80(d,J=7.5Hz,1H),6.51(dd,J=3.3,1.8Hz,1H),3.87(s,2H),2.44(s,3H)。
2-三氟甲氧基-N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-8)
HPLC:96.9%;LC-MS(m/z):427.10(M+H)
+;
1H NMR(400MHz,DMSO)δ7.93–7.87(m,1H),7.64–7.56(m,2H),7.53(s,1H),7.46(t,J=7.1Hz,1H),7.35–7.24(m,3H),6.73(d,J=7.3Hz,1H),6.47(dd,J=3.2,1.8Hz,1H),3.85(s,2H),2.43(s,3H)。
4-三氟甲氧基-N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-9)
HPLC:98.8%;LC-MS(m/z):427.19(M+H)
+;
1H NMR(400MHz,DMSO)δ7.82–7.75(m,2H),7.61(dd,J=11.1,4.5Hz,2H),7.34(t,J=10.5Hz,3H),7.30(d,J=1.5Hz,1H),6.89(d,J=7.5Hz,1H),6.50(dd,J=3.3,1.8Hz,1H),3.90(s,2H),2.42(s,3H)。
4-甲基-N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-10)
HPLC:98.7%;LC-MS(m/z):357.13(M+H)
+;
1H NMR(400MHz,DMSO)δ7.62(d,J=1.0Hz,1H),7.59(dd,J=8.1,4.0Hz,3H),7.29(d,J=3.2Hz,1H),7.20(d,J=8.0Hz,2H),7.16(d,J=1.2Hz,1H),6.88(d,J=7.9Hz,1H),6.52(dd,J=3.3,1.8Hz,1H),3.74(s,2H),2.33(s,3H),2.30(s,3H)。
2,4-二氟-N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-11)
HPLC:99.6%;LC-MS(m/z):379.10(M+H)
+;
1H NMR(400MHz,DMSO)δ7.72(dd,J=15.3,8.4Hz,1H),7.63(dd,J=13.7,4.5Hz,2H),7.36–7.22(m,3H),7.06(t,J=8.4Hz,2H),6.50(dd,J=3.3,1.8Hz,1H),3.95(s,2H),2.47(s,3H)。
2,6-二氟-N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-12)
HPLC:99.1%;LC-MS(m/z):379.11(M+H)
+;
1H NMR(400MHz,DMSO)δ7.51(dd,J=10.2,5.4Hz,3H),7.32–7.24(m,2H),6.91(t,J=8.3Hz,2H),6.72(d,J=8.1Hz,1H),6.48–6.39(m,1H),3.73(s,2H),2.33(s,3H)。
4-三氟甲基-N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-13)
HPLC:98.5%;LC-MS(m/z):411.10(M+H)
+;
1H NMR(400MHz,DMSO)δ7.88(d,J=8.1Hz,2H),7.74(d,J=8.3Hz,2H),7.61(dd,J=14.2,4.5Hz,2H),7.33(t,J=4.8Hz,2H),6.90(s,1H),6.49(dd,J=3.3,1.8Hz,1H),3.92(s,2H),2.44(s,3H)。
N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)萘-2-磺酰胺(I
A-14)
HPLC:97.9%;LC-MS(m/z):393.13(M+H)
+;
1H NMR(500MHz,DMSO)δ8.33(s,1H),8.00(d,J=7.2Hz,1H),7.92(dd,J=7.6,4.7Hz,2H),7.77(dd,J=8.6,1.5Hz,1H),7.64–7.53(m,4H),7.38(s,1H),7.27(s,1H),6.84(d,J=7.6Hz,1H),6.50(dd,J=3.1,1.8Hz,1H),3.78(s,2H),2.28(s,3H)。
N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)-2,3-二氢苯并呋喃-5-磺酰胺(I
A-15)
HPLC:97.7%;LC-MS(m/z):385.14(M+H)
+;
1H NMR(400MHz,DMSO)δ7.67(d,J=1.2Hz,1H),7.60(d,J=8.0Hz,1H),7.51(s,1H),7.42(dd,J=8.4,1.9Hz,1H),7.19–7.11(m,2H),7.05(t,J=7.8Hz,1H),6.75(d,J=8.4Hz,1H),6.54(dd,J=3.3,1.8Hz,1H),4.58(t,J=8.8Hz,2H),3.74(s,2H),3.15(t,J=8.7Hz,2H),2.32(s,3H)。
N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)苯并噻唑-6-磺酰胺(I
A-16)
HPLC:99.3%;LC-MS(m/z):400.07(M+H)
+;
1H NMR(400MHz,DMSO)δ9.46(d,J=8.4Hz,1H),8.54(d,J=1.4Hz,1H),8.04(d,J=8.5Hz,1H),7.84(dd,J=8.5,1.6Hz,1H),7.60(d,J=8.1Hz,2H),7.40(d,J=18.2Hz,1H),7.29(s,1H),6.81(s,1H),6.50(dd,J=3.2,1.8Hz,1H),3.84(s,2H),2.35(s,3H)。
N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)吡啶-3-磺酰胺(I
A-17)
HPLC:99.6%;LC-MS(m/z):344.11(M+H)
+;
1H NMR(400MHz,DMSO)δ8.83(s,1H),8.53(d,J=3.9Hz,1H),8.10–7.93(m,1H),7.66–7.54(m,2H),7.39(dd,J=15.7,10.9Hz,3H),6.79(s,1H),6.51(dd,J=3.2,1.8Hz,1H),3.91(s,2H),2.46(s,3H)。
6-氯-N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)吡啶-3-磺酰胺(I
A-18)
HPLC:98.1%;LC-MS(m/z):378.06(M+H)
+;
1H NMR(500MHz,DMSO)δ8.55(d,J=2.5Hz,1H),8.01(dd,J=8.4,2.6Hz,1H),7.71(d,J=8.1Hz,1H),7.67(d,J= 1.3Hz,1H),7.64(d,J=8.4Hz,1H),7.50(d,J=7.6Hz,1H),7.32(d,J=1.6Hz,1H),6.98(d,J=3.1Hz,1H),6.53(dd,J=3.4,1.8Hz,1H),4.09(s,2H),2.50(s,3H)。
N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)-1-甲基-1H-咪唑-4-磺酰胺(I
A-19)
HPLC:98.5%;LC-MS(m/z):347.12(M+H)
+;
1H NMR(400MHz,DMSO)δ7.79–7.71(m,4H),7.48(dd,J=8.2,1.7Hz,1H),7.34(d,J=1.5Hz,1H),7.13(t,J=5.4Hz,1H),6.62(dd,J=3.4,1.8Hz,1H),4.04(s,2H),3.70–3.64(m,3H),2.50(s,3H)。
N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)噻吩-2-磺酰胺(I
A-20)
HPLC:98.9%;LC-MS(m/z):349.06(M+H)
+;
1H NMR(400MHz,DMSO)δ7.66–7.58(m,2H),7.52(d,J=4.7Hz,1H),7.45(s,1H),7.40(d,J=1.4Hz,1H),7.31–7.24(m,1H),6.95–6.87(m,1H),6.82(d,J=6.9Hz,1H),6.52(dd,J=3.3,1.8Hz,1H),3.91(s,2H),2.46(s,3H)。
N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)噻吩-3-磺酰胺(I
A-21)
HPLC:99.0%;LC-MS(m/z):349.08(M+H)
+;
1H NMR(400MHz,DMSO)δ7.96(d,J=1.9Hz,1H),7.68(d,J=7.9Hz,2H),7.58(dd,J=5.1,3.0Hz,1H),7.26(s,1H),7.18(dd,J=5.1,1.2Hz,3H),6.55(dd,J=3.4,1.8Hz,1H),3.94(s,2H),2.45(s,3H)。
5-氯-N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)噻吩-2-磺酰胺(I
A-22)
HPLC:96.9%;LC-MS(m/z):383.03(M+H)
+;
1H NMR(400MHz,DMSO)δ7.74–7.65(m,2H),7.40(s,1H),7.32(d,J=1.6Hz,1H),7.23(d,J=4.0Hz,1H),7.08(d,J=4.0Hz,1H),6.98(s,1H),6.53(dd,J=3.4,1.8Hz,1H),4.06(s,2H),2.50(s,3H)。
5-溴-N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)噻吩-2-磺酰胺(I
A-23)
HPLC:97.4%;LC-MS(m/z):426.99(M+H)
+;
1H NMR(400MHz,DMSO)δ7.73 –7.58(m,2H),7.30(d,J=22.8Hz,2H),7.14(d,J=5.6Hz,3H),6.52(d,J=1.7Hz,1H),4.02(s,2H),2.50(s,3H)。
N-(2-(呋喃-2-基)-5-((甲胺基)甲基)苯基)-1-苯基甲烷磺酰胺(I
A-24)
HPLC:97.8%;LC-MS(m/z):357.16(M+H)
+;
1H NMR(400MHz,DMSO)δ7.68–7.61(m,2H),7.33–7.24(m,6H),7.13(d,J=3.4Hz,1H),7.03(d,J=7.9Hz,1H),6.51(dd,J=3.2,1.8Hz,1H),4.31(s,2H),3.81(s,2H),2.42(s,3H)。
N-(2-(呋喃-2-基)-5-((2,2,2-三氟乙基)氨基)甲基)苯基)苯磺酰胺(I
A-25)
HPLC:99.3%;LC-MS(m/z):411.10(M+H)
+;
1H NMR(400MHz,DMSO)δ7.72(dd,J=4.4,2.6Hz,3H),7.69–7.61(m,2H),7.55(t,J=7.6Hz,2H),7.29(d,J=8.0Hz,1H),6.97(d,J=3.3Hz,1H),6.90(s,1H),6.58(dd,J=3.3,1.8Hz,1H),3.68(d,J=3.5Hz,2H),3.10(dt,J=15.5,7.8Hz,2H)。
N-(2-(呋喃-2-基)-4-((甲胺基)甲基)苯基)苯磺酰胺(I
A-26)
HPLC:98.8%;LC-MS(m/z):343.16(M+H)
+;
1H NMR(400MHz,DMSO)δ7.77–7.62(m,4H),7.44(d,J=7.3Hz,3H),7.33(s,1H),7.06(d,J=7.8Hz,2H),6.56(dd,J=3.3,1.8Hz,1H),3.96(s,2H),2.50(s,3H)。
4-氟-N-(2-(呋喃-2-基)-4-((甲胺基)甲基)苯基)苯磺酰胺(I
A-27)
HPLC:99.2%;LC-MS(m/z):361.14(M+H)
+;
1H NMR(500MHz,MeOD)δ7.67(ddd,J=8.1,4.9,2.5Hz,3H),7.56(d,J=1.7Hz,1H),7.39(d,J=8.3Hz,1H),7.27(dd,J=8.3,2.1Hz,1H),7.14–7.09(m,2H),6.83(d,J=3.4Hz,1H),6.49(dd,J=3.4,1.8Hz,1H),3.98(s,2H),2.59(s,3H)。
2-氟-N-(2-(呋喃-2-基)-4-((甲胺基)甲基)苯基)苯磺酰胺(I
A-28)
HPLC:97.0%;LC-MS(m/z):361.09(M+H)
+;
1H NMR(400MHz,DMSO)δ7.70–7.64(m,2H),7.56(s,1H),7.53(s,1H),7.39–7.31(m,1H),7.16(d,J=8.6Hz,1H),7.10(t,J=8.0Hz,2H),6.87(d,J=8.4Hz,1H),6.49–6.46(m,1H),3.89(s,2H),2.45 (s,3H)。
N-(2-(呋喃-2-基)-4-((甲胺基)甲基)苯基)噻吩-2-磺酰胺(I
A-29)
HPLC:98.1%;LC-MS(m/z):349.07(M+H)
+;
1H NMR(400MHz,DMSO)δ7.74(d,J=1.9Hz,1H),7.65–7.57(m,2H),7.34–7.25(m,2H),7.16(d,J=8.3Hz,1H),7.08(d,J=7.8Hz,1H),6.99–6.93(m,1H),6.52(dd,J=3.2,1.8Hz,1H),3.97(s,2H),2.5(s,3H)。
N-(2-(呋喃-2-基)-4-((甲胺基)甲基)苯基)噻吩-3-磺酰胺(I
A-30)
HPLC:98.4%;LC-MS(m/z):349.09(M+H)
+;
1H NMR(500MHz,CDCl
3)δ7.70–7.65(m,1H),7.62(d,J=8.3Hz,1H),7.48(dt,J=5.1,2.6Hz,1H),7.37(d,J=1.9Hz,1H),7.25(dd,J=8.3,2.0Hz,1H),7.18–7.12(m,1H),6.98–6.92(m,1H),6.43(ddd,J=4.1,3.4,1.3Hz,2H),3.72(s,2H),2.45(s,3H)。
N-(2-(呋喃-2-基)-4-((甲胺基)甲基)苯基)吡啶-3-磺酰胺(I
A-31)
HPLC:98.6%;LC-MS(m/z):344.11(M+H)
+;
1H NMR(400MHz,DMSO)δ8.80(s,1H),8.51(d,J=4.3Hz,1H),7.99(d,J=7.9Hz,1H),7.70(s,1H),7.61(s,1H),7.53(d,J=2.8Hz,1H),7.38(dd,J=7.8,4.9Hz,1H),7.22(d,J=8.4Hz,1H),6.93(d,J=8.5Hz,1H),6.53(s,1H),3.93(s,2H),2.49–2.48(m,3H)。
N-(4-((乙氨基)甲基)-2-(呋喃-2-基)苯基)噻吩-3-磺酰胺(I
A-32)
HPLC:99.3%;LC-MS(m/z):363.09(M+H)
+;
1H NMR(500MHz,DMSO)δ7.77(s,1H),7.70(d,J=2.1Hz,1H),7.63(s,1H),7.45(d,J=16.5Hz,2H),7.19(d,J=8.2Hz,1H),7.14(d,J=5.0Hz,1H),6.98(d,J=7.4Hz,1H),6.54(dd,J=3.1,1.8Hz,1H),3.92(s,2H),2.87(q,J=7.1Hz,2H),1.15(t,J=7.2Hz,3H)。
N-(4-((环丙胺基)甲基)-2-(呋喃-2-基)苯基)噻吩-3-磺酰胺(I
A-33)
HPLC:99.4%;LC-MS(m/z):375.09(M+H)
+;
1H NMR(500MHz,DMSO)δ7.98(d,J=1.8Hz,1H),7.72(d,J=1.4Hz,1H),7.67(dd,J=4.9,2.8Hz,2H),7.21(dd,J=5.1,1.2Hz,1H),7.11(dd,J=8.2,1.9Hz,1H),7.06(d,J=2.8Hz,1H),6.88(d,J=8.1Hz,1H),6.57(dd,J=3.4,1.8Hz,1H),3.75(s,2H),2.10(s,1H),0.35(dd,J=32.6,11.5Hz,4H)。
N-(4-((环丁胺基)甲基)-2-(呋喃-2-基)苯基)噻吩-3-磺酰胺(I
A-34)
HPLC:96.9%;LC-MS(m/z):389.09(M+H)
+;
1H NMR(500MHz,CDCl
3)δ7.69–7.64(m,1H),7.61(d,J=8.3Hz,1H),7.47(d,J=5.5Hz,1H),7.38(s,1H),7.24(d,J=1.9Hz,1H),7.16(dd,J=5.1,3.1Hz,1H),6.97–6.94(m,1H),6.46–6.39(m,2H),3.68(s,2H),3.32–3.24(m,1H),2.25–2.14(m,2H),1.69(dd,J=16.8,12.4Hz,4H)。
N-(5-((甲胺基)甲基)-2-(5-甲基呋喃-2-基)苯基)苯磺酰胺(I
A-35)
HPLC:96.8%;LC-MS(m/z):357.12(M+H)
+;
1H NMR(400MHz,DMSO)δ7.70–7.64(m,2H),7.57(d,J=8.0Hz,1H),7.48–7.38(m,3H),7.18(s,1H),7.11(s,1H),6.96(d,J=8.0Hz,1H),6.11(d,J=2.2Hz,1H),3.80(s,2H),2.37(s,3H),2.27(d,J=15.0Hz,3H)。
N-(3-(呋喃-2-基)-4-((甲胺基)甲基)苯基)苯磺酰胺(I
A-36)
HPLC:97.5%;LC-MS(m/z):343.13(M+H)
+;
1H NMR(400MHz,CD
3OD)δ7.83–7.78(m,2H),7.69(dd,J=1.8,0.7Hz,1H),7.57–7.52(m,1H),7.49–7.44(m,2H),7.41(d,J=2.3Hz,1H),7.33(d,J=8.3Hz,1H),7.13(dd,J=8.3,2.3Hz,1H),6.71(dd,J=3.4,0.7Hz,1H),6.59(dd,J=3.5,1.9Hz,1H),4.19(s,2H),2.66(s,3H)。
N-(4-(呋喃-2-基)-3-((甲胺基)甲基)苯基)苯磺酰胺(I
A-37)
HPLC:99.2%;LC-MS(m/z):343.03(M+H)
+;
1H NMR(400MHz,DMSO)δ7.78–7.71(m,2H),7.69(dd,J=1.8,0.7Hz,1H),7.59–7.47(m,3H),7.44(d,J=8.5Hz,1H),7.26(d,J=2.3Hz,1H),7.02(dd,J=8.5,2.4Hz,1H),6.62(dd,J=3.4,0.6Hz,1H),6.53(dd,J=3.4,1.8Hz,1H),3.68(s,2H),2.21(s,3H)。
N-(4-(呋喃-2-基)-2-((甲胺基)甲基)苯基)苯磺酰胺(I
A-38)
HPLC:97.6%;LC-MS(m/z):343.06(M+H)
+;
1H NMR(400MHz,DMSO)δ7.82–7.73(m,2H),7.61(d,J=1.1Hz,1H),7.42(dd,J=10.6,5.2Hz,4H),7.34(dd,J=8.5,2.1Hz,1H),7.11(d,J=8.6Hz,1H),6.60(d,J=3.2Hz,1H),6.50(dd,J=3.3,1.8Hz,1H),3.96(s,2H),2.47(s,3H)。
N-(3-(呋喃-2-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-39)
HPLC:98.4%;LC-MS(m/z):343.17(M+H)
+;
1H NMR(500MHz,DMSO)δ7.83–7.78(m,2H),7.76(d,J=1.7Hz,1H),7.60(dt,J=5.0,4.4Hz,1H),7.55(t,J=7.4Hz,2H),7.46(s,1H),7.36(t,J=1.6Hz,1H),7.12(s,1H),6.80(d,J=3.4Hz,1H),6.59(dd,J=3.4,1.8Hz,1H),3.91(s,2H),2.40(s,3H)。
N-(5-(呋喃-2-基)-2-((甲胺基)甲基)苯基)苯磺酰胺(I
A-40)
HPLC:99.0%;LC-MS(m/z):343.14(M+H)
+;
1H NMR(400MHz,DMSO)δ7.80(dd,J=6.6,3.0Hz,2H),7.68(d,J=1.2Hz,1H),7.48–7.39(m,4H),7.09(d,J=7.8Hz,1H),6.98(d,J=7.5Hz,1H),6.65(d,J=3.1Hz,1H),6.53(dd,J=3.3,1.8Hz,1H),3.90(s,2H),2.44(s,3H)。
4-氟-N-(2-(呋喃-3-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-41)
HPLC:96.7%;LC-MS(m/z):361.20(M+H)
+;
1H NMR(400MHz,DMSO)δ7.95(s,1H),7.66(dd,J=7.0,3.5Hz,3H),7.57(d,J=7.3Hz,1H),7.51(d,J=8.0Hz,1H),7.31(t,J=8.8Hz,2H),7.17(s,1H),6.73(s,1H),4.02(s,2H),2.44(s,3H)。
N-(2-(呋喃-3-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-42)
HPLC:97.7%;LC-MS(m/z):343.10(M+H)
+;
1H NMR(400MHz,DMSO)δ8.32(s,1H),7.72–7.64(m,2H),7.62(t,J=1.7Hz,1H),7.50–7.35(m,4H),7.11(s,1H),6.91(d,J=7.4Hz,1H),6.84(s,1H),3.73(s,2H),2.32(s,3H)。
N-(2-(呋喃-3-基)-5-((甲胺基)甲基)苯基)噻吩-3-磺酰胺(I
A-43)
HPLC:97.9%;LC-MS(m/z):349.08(M+H)
+;
1H NMR(400MHz,DMSO)δ7.97(d,J=1.7Hz,1H),7.93(s,1H),7.65(d,J=1.6Hz,1H),7.62(dd,J=5.2,2.9Hz,1H),7.50(d,J=8.1Hz,1H),7.34(s,1H),7.18(s,1H),7.12(dd,J=5.1,1.4Hz,1H),6.72(s,1H),4.00(s,1H),2.50(s,3H)。
N-(2-(呋喃-3-基)-5-((甲胺基)甲基)苯基)噻吩-2-磺酰胺(I
A-44)
HPLC:96.6%;LC-MS(m/z):349.07(M+H)
+;
1H NMR(400MHz,CD
3OD)δ7.70(s,1H),7.63(dd,J=5.0,1.3Hz,1H),7.46(t,J=1.7Hz,1H),7.41(dt,J=7.8,4.1Hz,2H),7.35(dd,J=3.7,1.3Hz,1H),7.22(dd,J=8.0,1.8Hz,1H),7.00(dd,J=5.0,3.7Hz,1H),6.50(dd,J=1.9,0.8Hz,1H),3.99(s,2H),2.58(s,3H)。
4-氟-N-(5-((甲胺基)甲基)-2-(噻吩-2-基)苯基)苯磺酰胺(I
A-45)
HPLC:98.5%;LC-MS(m/z):377.11(M+H)
+;
1H NMR(400MHz,DMSO)δ7.66(dd,J=8.6,5.3Hz,2H),7.60(t,J=6.9Hz,2H),7.49(d,J=8.2Hz,1H),7.38(d,J=3.3Hz,1H),7.32(t,J=8.8Hz,2H),7.15(s,1H),7.10–7.03(m,1H),4.04(s,2H),2.48(s,3H)。
N-(2-(噻吩-2-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-46)
HPLC:99.2%;LC-MS(m/z):359.08(M+H)
+;
1H NMR(400MHz,DMSO)δ7.72(dd,J=7.8,1.5Hz,2H),7.61(d,J=8.0Hz,1H),7.50(d,J=3.2Hz,1H),7.45–7.34(m,4H),7.26(s,1H),7.02(dd,J=5.1,3.8Hz,1H),6.86(s,1H),3.85(s,2H),2.40(s,3H)。
N-(2-(噻吩-2-基)-5-((甲胺基)甲基)苯基)噻吩-2-磺酰胺(I
A-47)
HPLC:98.9%;LC-MS(m/z):365.05(M+H)
+;
1H NMR(400MHz,CD3OD)δ7.67(dd,J=5.0,1.3Hz,1H),7.60(d,J=1.7Hz,1H),7.50(d,J=8.0Hz,1H),7.42(dd,J=5.1,1.2Hz,1H),7.36(dd,J=3.8,1.4Hz,1H),7.33–7.29(m,1H),7.02(ddd,J=5.3,3.7,1.8Hz,2H),6.99–6.93(m,1H),4.14(s,2H),2.68(s,3H)。
N-(2-(噻吩-2-基)-5-((甲胺基)甲基)苯基)噻吩-3-磺酰胺(I
A-48)
HPLC:97.4%;LC-MS(m/z):365.07(M+H)
+;
1H NMR(400MHz,CD3OD)δ7.87(dd,J=3.1,1.3Hz,1H),7.56(d,J=1.7Hz,1H),7.51–7.40(m,3H),7.31(dd,J=8.0,1.9Hz,1H),7.08(dd,J=5.2,1.3Hz,1H),7.02(ddd,J=4.9,4.3,2.4Hz,2H),4.12(s,2H),2.66(s,3H)。
N-(2-(噻吩-3-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-49)
HPLC:96.7%;LC-MS(m/z):359.08(M+H)
+;
1H NMR(400MHz,DMSO)δ7.68(d,J=1.9Hz,1H),7.64–7.59(m,2H),7.54–7.47(m,2H),7.43(t,J=7.5Hz,2H),7.34(d,J=7.8Hz,1H),7.29(d,J=5.0Hz,1H),7.10(s,1H),7.05(d,J=7.9Hz,1H),3.70(s,2H),2.29(s,3H)。
N-(5-((甲胺基)甲基)-2-(1H-吡咯-2-基)苯基)苯磺酰胺(I
A-50)
HPLC:98.8%;LC-MS(m/z):342.12(M+H)
+;
1H NMR(400MHz,DMSO)δ7.79–7.69(m,2H),7.50(d,J=8.0Hz,1H),7.44–7.31(m,3H),7.24(s,1H),6.81(s,2H),6.46(d,J=2.6Hz,1H),6.06(s,1H),3.84(s,2H),2.39(s,3H)。
N-(5-((甲胺基)甲基)-2-(噻唑-2-基)苯基)苯磺酰胺(I
A-51)
HPLC:98.1%;LC-MS(m/z):360.10(M+H)
+;
1H NMR(400MHz,DMSO)δ8.20(d,J=8.1Hz,1H),7.85(t,J=4.4Hz,1H),7.79(dt,J=7.5,3.9Hz,2H),7.56(dd,J=7.8,3.7Hz,2H),7.41–7.32(m,3H),6.72(t,J=23.0Hz,1H),3.94(s,2H),2.47(s,3H)。
N-(5-((甲胺基)甲基)-2-(1H-吡唑基-4-基)苯基)苯磺酰胺(I
A-52)
HPLC:99.4%;LC-MS(m/z):343.12(M+H)
+;
1H NMR(400MHz,DMSO)δ7.97(s,2H),7.68(d,J=7.4Hz,2H),7.56(t,J=7.3Hz,1H),7.48(t,J=7.1Hz,3H),7.12(d,J=7.7Hz,1H),7.01(s,1H),3.73(s,2H),2.31(s,3H)。
N-(2-(3,5-二甲基异恶唑-4-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-53)
HPLC:97.3%;LC-MS(m/z):372.34(M+H)
+;
1H NMR(400MHz,DMSO)δ7.73(d,J=6.8Hz,2H),7.58–7.45(m,3H),7.09(d,J=7.7Hz,2H),6.98(d,J=7.7Hz,1H),3.70(s,2H),2.30(s,3H),2.20(s,3H),2.06(s,3H)。
N-(5-((甲胺基)甲基)-2-(1H-吡唑基-5-基)苯基)苯磺酰胺(I
A-54)
HPLC:96.0%;LC-MS(m/z):343.16(M+H)
+;
1H NMR(400MHz,DMSO)δ7.81(d,J=2.2Hz,1H),7.73(d,J=7.4Hz,2H),7.67(d,J=8.0Hz,1H),7.56–7.49(m,2H),7.44(t,J=7.5Hz,2H),6.97(d,J=7.9Hz,1H),6.78(d,J=2.2Hz,1H),3.72(s,2H),2.29(s,3H)。
N-(5-((甲胺基)甲基)-2-(1H-吡唑基-3-基)苯基)苯磺酰胺(I
A-55)
HPLC:97.4%;LC-MS(m/z):343.19(M+H)
+;
1H NMR(400MHz,DMSO)δ7.81(d,J=2.0Hz,1H),7.72(d,J=7.4Hz,2H),7.67(d,J=8.0Hz,1H),7.55–7.48(m,2H),7.44(t,J=7.5Hz,2H),6.98(d,J=7.6Hz,1H),6.77(d,J=2.1Hz,1H),3.73(s,2H),2.29(s,3H)。
N-(2-(1-甲基-1H-吡唑-4-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-56)
HPLC:97.8%;LC-MS(m/z):357.13(M+H)
+;
1H NMR(400MHz,DMSO)δ8.05(s,1H),7.77(s,1H),7.69(d,J=7.2Hz,2H),7.56(t,J=7.2Hz,1H),7.49(t,J=7.4Hz,2H),7.43(d,J=8.3Hz,1H),7.06(d,J=5.2Hz,2H),3.86(s,3H),3.72(s,2H),2.32(s,3H)。
N-(5-((甲胺基)甲基)-2-(1,3,5-三甲基-1H-吡唑-4-基)苯基)苯磺酰胺(I
A-57)
HPLC:98.1%;LC-MS(m/z):385.16(M+H)
+;
1H NMR(400MHz,DMSO)δ7.77(d,J=7.3Hz,2H),7.64(t,J=7.4Hz,1H),7.55(t,J=7.5Hz,2H),7.20(d,J=5.7Hz, 2H),7.07(d,J=8.2Hz,1H),3.84(s,2H),3.67(s,3H),2.38(s,3H),1.94(s,3H),1.90(s,3H)。
N-(2-(3,5-二甲基-1H-吡唑-4-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-58)
HPLC:98.5%;LC-MS(m/z):371.15(M+H)
+;
1H NMR(400MHz,DMSO)δ7.82(t,J=8.6Hz,2H),7.66(t,J=7.4Hz,1H),7.56(dd,J=18.5,11.1Hz,2H),7.28(t,J=9.2Hz,1H),7.21(s,1H),7.15(t,J=9.5Hz,1H),3.99(s,2H),2.48(s,3H),1.95(s,6H)。
N-(5-((甲胺基)甲基)-2-(5-甲基噻唑-2-基)苯基)苯磺酰胺(I
A-59)
HPLC:99.3%;LC-MS(m/z):374.19(M+H)
+;
1H NMR(400MHz,DMSO)δ8.09(t,J=7.6Hz,1H),7.77(dd,J=6.5,3.0Hz,2H),7.58–7.45(m,2H),7.43–7.32(m,3H),6.75(d,J=7.7Hz,1H),3.90(s,2H),2.47(s,3H),2.44(s,3H)。
N-(2-(1-甲基-1H-咪唑-5-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-60)
HPLC:99.4%;LC-MS(m/z):357.13(M+H)
+;
1H NMR(400MHz,DMSO)δ7.64(dd,J=9.5,8.2Hz,3H),7.50(t,J=7.2Hz,1H),7.44(t,J=7.3Hz,2H),7.28(d,J=1.1Hz,1H),7.11(d,J=7.7Hz,1H),6.94(d,J=7.4Hz,1H),6.67(d,J=0.7Hz,1H),3.78(s,2H),3.40–3.34(s,3H),2.36(s,3H)。
N-(2-(1H-咪唑-5-基)-5-((甲胺基)甲基)苯基)苯磺酰胺(I
A-61)
HPLC:98.3%;LC-MS(m/z):343.13(M+H)
+;
1H NMR(400MHz,DMSO)δ8.00(s,1H),7.69(d,J=9.0Hz,3H),7.62(d,J=8.0Hz,1H),7.56–7.51(m,2H),7.43(t,J=7.7Hz,2H),6.99(t,J=10.5Hz,1H),3.71(s,2H),2.28(s,3H)。
N-(2-(呋喃-2-基)-5-((2,2,2-三氟乙基)氨基)甲基)苯基)苯磺酰胺(I
A-62)
HPLC:99.3%;LC-MS(m/z):411.35(M+H)
+;
1H NMR(400MHz,DMSO)δ9.66(s,1H),7.72(dd,J=4.4,2.6Hz,3H),7.69–7.61(m,2H),7.55(t,J=7.6Hz,2H),7.29(d,J=8.0Hz,1H),6.97(d,J=3.3Hz,1H),6.90(s,1H),6.58(dd,J=3.3,1.8Hz,1H),3.68(d,J=3.5Hz,2H),3.10(dt,J=15.5,7.8Hz,2H),2.85(s,1H).
实施例2
化合物I
C的合成:
N-(2-(呋喃-2-基)-5-((羟亚氨基)甲基)苯基)苯磺酰胺(I
C-1)
将中间体VI-4(65.5mg,0.2mmol)溶解于10毫升的乙醇溶液中,加入1毫升羟胺水溶液(50wt%),室温反应过夜。反应结束后,蒸干溶剂,残余物经柱层析分离得到化合物I
C-1,黄色固体(32.9mg,47.6%)。
HPLC:99.2%;LC-MS(m/z):343.13(M+H)
+;
1H NMR(500MHz,DMSO)δ11.33(s,1H),9.74(s,1H),8.01(s,1H),7.74–7.66(m,4H),7.62(t,J=7.4Hz,1H),7.53(t,J=7.6Hz,2H),7.48(dd,J=8.2,1.5Hz,1H),7.20(d,J=1.5Hz,1H),7.01(d,J=3.4Hz,1H),6.58(dd,J=3.4,1.8Hz,1H)。
采取合成I
C-1类似的方法,得到以下化合物:
N-(2-(呋喃-2-基)-5-((甲氧基亚氨基)甲基)苯基)苯磺酰胺(I
C-2)
HPLC:97.5%;LC-MS(m/z):357.01(M+H)
+;
1H NMR(400MHz,DMSO)δ9.76(s,1H),8.02(d,J=5.7Hz,2H),7.73(dd,J=19.4,9.4Hz,5H),7.61(t,J=7.2Hz,1H),7.52(t,J=7.6Hz,2H),7.06(d,J=3.3Hz,1H),6.59(s,1H),3.74(s,3H)。
实施例3
化合物I
D的合成:
N-(5-(氨基甲基)-2-(呋喃-2-基)苯基)苯磺酰胺(I
D-1)
将中间体V-4(64.9mg,0.2mmol)溶解于5毫升的氨甲醇溶液中,加入适量雷尼镍水溶液,通入氢气,室温过夜。后处理:抽滤除去雷尼镍,滤液蒸干,残余物经柱层析分离得到化合物I
D-1,白色固体(44.3mg,63.8%)。
HPLC:99%;LC-MS(m/z):329.10(M+H)
+;
1H NMR(400MHz,DMSO)δ7.71(dd,J=7.7,1.4Hz,2H),7.61(d,J=8.1Hz,2H),7.39(q,J=6.2Hz,3H),7.29(s,2H),6.90(d,J=7.2Hz,1H),6.50(dd,J=3.1,1.8Hz,1H),3.81(s,2H)。
采取合成I
D-1类似的方法,得到以下化合物:
N-(5-(氨基甲基)-2-(呋喃-2-基)苯基)-4-氟苯磺酰胺(I
D-2)
HPLC:98.7%;LC-MS(m/z):347.09(M+H)
+;
1H NMR(400MHz,DMSO)δ7.74(dd,J=8.7,5.6Hz,2H),7.60(d,J=8.7Hz,2H),7.36(s,1H),7.30(s,1H),7.18(t,J=8.9Hz,2H),6.83(d,J=7.6Hz,1H),6.50(dd,J=3.2,1.8Hz,1H),3.81(s,2H)。
N-(5-(氨基甲基)-2-(呋喃-2-基)苯基)噻吩-3-磺酰胺(I
D-3)
HPLC:99.3%;LC-MS(m/z)335.04(M+H)
+;
1H NMR(400MHz,DMSO)δ7.81–7.75(m,1H),7.59(d,J=8.0Hz,2H),7.47–7.41(m,2H),7.36(s,1H),7.15(dd,J=5.0,1.1Hz,1H),6.74(d,J=8.1Hz,1H),6.50(dd,J=3.2,1.8Hz,1H),3.79(s,2H)。
N-(4-(氨基甲基)-2-(呋喃-2-基)苯基)苯磺酰胺(I
D-4)
HPLC:98.2%;LC-MS(m/z):329.15(M+H)
+;
1H NMR(400MHz,DMSO)δ7.70–7.64(m,3H),7.60(d,J=0.9Hz,1H),7.54(d,J=3.1Hz,1H),7.37–7.31(m,3H),7.14(d,J=8.4Hz,1H),6.87(dd,J=8.5,2.2Hz,1H),6.52(dd,J=3.2,1.8Hz,1H),3.82(s,2H)。
N-(4-(氨基甲基)-2-(呋喃-2-基)苯基)噻吩-3-磺酰胺(I
D-5)
HPLC:97.5%;LC-MS(m/z):335.06(M+H)
+;
1H NMR(400MHz,DMSO)δ8.09(d,J=1.8Hz,1H),7.87(d,J=1.5Hz,1H),7.80(s,1H),7.75(dd,J=5.0,3.0Hz,1H),7.33(dd,J=8.2,1.5Hz,1H),7.29(d,J=4.3Hz,1H),7.05(d,J=3.3Hz,1H),6.95(d,J=8.2Hz,1H),6.64(dd,J=3.2,1.7Hz,1H),4.02(d,J=3.7Hz,2H)。
N-(4-(氨基甲基)-2-(呋喃-2-基)苯基)-4-氟苯磺酰胺(I
D-6)
HPLC:98.9%;LC-MS(m/z):347.11(M+H)
+;
1H NMR(400MHz,DMSO)δ7.67(dt,J=11.6,5.8Hz,2H),7.63(d,J=2.0Hz,1H),7.57(s,1H),7.51(d,J=3.0Hz,1H),7.16–7.08(m,3H),6.85(dd,J=8.5,2.0Hz,1H),6.49(dd,J=3.1,1.8Hz,1H),3.80(s,2H)。
N-(4-(氨基甲基)-2-(1H-吡唑-3-基)苯基)噻吩-3-磺酰胺(I
D-7)
HPLC:97.9%;LC-MS(m/z):335.11(M+H)
+;
1H NMR(400MHz,DMSO)δ7.96(s,1H),7.71(s,1H),7.65(s,1H),7.55–7.46(m,1H),7.40(d,J=8.4Hz,1H),7.14(d,J=4.9Hz,1H),7.07(d,J=8.0Hz,1H),6.70(s,1H),3.84(s,2H)。
N-(5-(氨基甲基)-2-(1H-吡唑-3-基)苯基)噻吩-3-磺酰胺(I
D-8)
HPLC:97.6%;LC-MS(m/z)335.16(M+H)
+;
1H NMR(400MHz,DMSO)δ8.10(d,J=1.9Hz,1H),7.70(dd,J=9.0,4.8Hz,2H),7.59–7.49(m,2H),7.17(d,J=5.1Hz,1H),6.96(d,J=7.8Hz,1H),6.77(d,J=1.6Hz,1H),3.84(s,2H)。
实施例4
化合物I
E的合成:
N-(3-(呋喃-2-基)-4-(噻吩-3-磺胺基)苄基)乙酰胺(I
E)
将化合物I
D-5(66.8mg,0.2mmol)溶解于10毫升的二氯甲烷溶液中,加入醋酸酐(26.5mg,0.26mmol)和三乙胺(60.7mg,0.6mmol),室温反应过夜。反应结束后,蒸干溶剂,残余物经柱层析分离得到化合物I
E,白色固体(35.1mg,46.6%)。
HPLC:98.8%;LC-MS(m/z):377.08(M+H)
+;
1H NMR(400MHz,CDCl
3)δ7.70(dd,J=3.0,1.2Hz,1H),7.62(d,J=8.3Hz,1H),7.49(d,J=1.2Hz,1H),7.31(d,J=1.7Hz,1H),7.22–7.16(m,2H),6.99(dd,J=5.2,1.2Hz,1H),6.49–6.38(m,2H),4.40(d,J=5.8Hz,2H),2.04(d,J=3.1Hz,3H)。
实施例5
化合物I
B的合成:
第一步:N-(4-氰基-2-(呋喃-2-基)苯基)-N-甲基噻吩-3-磺酰胺(VII-1)
将中间体V-30(1.3g,3.93mmol)和碳酸钾(2.2g,15.9mmol)溶解于20毫升乙腈溶液中,加入碘甲烷(1.7g,12.0mmol),于75℃条件下反应三小时。反应结束后,蒸干溶剂,残余物经柱层析分离得到中间体VII-1,类白色固体(0.7g,2.0mmol)。
1H NMR(400MHz,DMSO)δ8.33–8.29(m,1H),8.27(d,J=1.8Hz,1H),7.90(dd,J=5.1,2.9Hz,2H),7.77(dd,J=8.3,1.8Hz,1H),7.34(dd,J=5.1,0.9Hz,1H),7.23(d,J=3.4Hz,1H),6.99(d,J=8.3Hz,1H),6.74(dd,J=3.3,1.7Hz,1H),3.18(s,3H)。
第二-四步:N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)-N-甲基噻吩-3-磺酰胺(I
B)
采用合成I
A-1类似的方法,得到化合物I
B,类白色固体(90mg,36.5%)。
HPLC:99.1%;LC-MS(m/z)363.15(M+H)
+;
1H NMR(400MHz,DMSO)δ8.27(dt,J=8.2,4.1Hz,1H),7.95(d,J=1.7Hz,1H),7.90(dd,J=5.1,3.0Hz,1H),7.85(d,J=1.4Hz,1H),7.37–7.28(m,2H),7.14(d,J=3.4Hz,1H),6.75(d,J=8.1Hz,1H),6.71(dd,J=3.4,1.8Hz,1H),3.92(s,2H),3.17(s,3H),2.44(s,3H)。
实施例6
化合物I
F的合成:
N-(4-(氨基甲基)-2-(呋喃-2-基)苯基)-N-甲基噻吩-3-磺酰胺(I
F)
采用合成I
D类似的方法,得到化合物I
F,类白色固体(35.6mg,31.3%)。
HPLC:99.4%;LC-MS(m/z)349.11(M+H)
+;
1H NMR(400MHz,DMSO)δ8.26(dd,J=2.9,1.2Hz,1H),7.91–7.86(m,2H),7.82(s,1H),7.35(dd,J=5.1,1.2Hz,1H),7.23(dd,J=8.1,1.7Hz,1H),7.11(d,J=3.3Hz,1H),6.68(t,J=5.6Hz,2H),3.79(s,2H),3.16(s,3H),2.33(s,2H)。
实施例7
化合物I
G的合成:
4-(呋喃-2-基)-3-(苯磺酰胺)苯甲酸甲酯(I
G)
采用合成V-1类似的方法,得到化合物I
G,黄色固体(810mg,32.1%)。
HPLC:98.9%;LC-MS(m/z)358.08(M+H)
+;
1H NMR(400MHz,DMSO)δ7.84(dd,J=21.9,11.2Hz,3H),7.70(d,J=7.7Hz,2H),7.64(t,J=7.2Hz,1H),7.55(t,J=7.5Hz,2H),7.42(s,1H),7.17(d,J=3.3Hz,1H),6.63(s,1H),3.84(s,3H)。
实施例8
化合物I
H的合成:
N-(2-(呋喃-2-基)-5-(羟甲基)苯基)苯磺酰胺(I
H)
将化合物I
G(500mg,1.4mmol)溶解于10毫升的无水四氢呋喃溶液中,氮气保护条件下,0℃下加入四氢铝锂(213mg,5.6mmol),室温反应1小时。反应接受,往体系中依次加入213微升的水,213微升的氢氧化钠水溶液(15%wt),639微升的水,过滤,滤液蒸干,残余物经柱层析分离得到化合物I
H,黄色油状物(270mg,58.6%)。
HPLC:97.0%;LC-MS(m/z):330.11(M+H)
+;
1H NMR(400MHz,DMSO)δ9.66(s,1H),7.71(dd,J=5.2,3.3Hz,3H),7.64(ddd,J=6.4,4.2,2.5Hz,2H),7.55(dd,J=10.4,4.7Hz,2H),7.26(dd,J=8.1,1.6Hz,1H),6.94(d,J=2.9Hz,2H),6.57(dd,J= 3.4,1.8Hz,1H),5.22(t,J=5.7Hz,1H),4.40(d,J=5.5Hz,2H)。
实施例9
化合物I
J的合成:
N-(4-((二甲氨基)甲基)-2-(呋喃-2-基)苯基)噻吩-3-磺酰胺(I
J-1)
将N-(2-(呋喃-2-基)-4-(羟甲基)苯基)噻吩-3-磺酰胺(1.68g,5mmol)溶解于50毫升的二氯甲烷溶液中,于冰浴条件下加入三苯基膦(1.97g,7.5mmol)和四溴化碳(2.49g,7.5mmol),室温反应2小时,蒸干溶剂,残余物溶解于20毫升的N,N-二甲基甲酰胺溶液中,加入二甲胺盐酸盐(0.82g,10mmol)和碳酸钾(0.83g,6mmol),80℃反应过夜。后处理,往体系中加入水,用乙酸乙酯萃取三次,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到化合物I
J-1,黄色固体(105mg,5.8%)。
HPLC:96.6%;LC-MS(m/z):363.08(M+H)
+;
1H NMR(500MHz,DMSO)δ8.00(dd,J=2.9,1.2Hz,1H),7.71(t,J=3.5Hz,1H),7.70–7.63(m,2H),7.24–7.20(m,1H),7.11–7.07(m,2H),6.90(t,J=8.1Hz,1H),6.60–6.56(m,1H),3.50(s,2H),2.23(s,6H)。
N-(4-((3-氟氮杂环丁烷-1-基)甲基)-2-(呋喃-2-基)苯基)噻吩-3-磺酰胺(I
J-2)
采取合成I
J-1类似的方法,得到化合物I
J-2,黄色固体(84mg,4.1%)。
HPLC:98.3%;LC-MS(m/z):393.09(M+H)
+;
1H NMR(500MHz,DMSO)δ8.04(dd,J=2.9,1.1Hz,1H),7.77–7.67(m,2H),7.61(d,J=1.6Hz,1H),7.23(dd,J=5.1,1.2Hz,1H),7.09(dd,J=8.1,1.7Hz,1H),7.01(d,J=3.3Hz,1H),6.84(d,J=8.1Hz,1H),6.59(dd,J=3.3,1.8Hz,1H),3.63(s,2H),3.60–3.48(m,2H),3.14(d,J=22.3Hz,2H),2.05–1.92(m,1H)。
实施例10
化合物I
P的合成:
4-(呋喃-2-基)-N-甲基-3-(苯磺胺基)苯甲酰胺(I
P-1)
将化合物I
G(0.71g,2mmol)溶解于10毫升乙醇溶液中,加入甲胺的乙醇溶液(2mL,30-33wt%),60℃反应4小时。后处理,残余物经柱层析(石油醚:乙酸乙酯=1:3)得化合物I
P-1,黄色固体(64mg,9.0%)。
HPLC:97.7%;LC-MS(m/z):357.09(M+H)
+;
1H NMR(400MHz,DMSO)δ9.83(s,1H),8.46(d,J=4.5Hz,1H),7.81–7.71(m,3H),7.66(d,J=7.7Hz,2H),7.61(t,J=7.2Hz,1H),7.51(dd,J=13.8,5.9Hz,3H),7.05(d,J=3.3Hz,1H),6.58(s,1H),2.74(d,J=4.4Hz,3H)。
采取合成I
P-1类似的方法,得到以下化合物:
4-(呋喃-2-基)-3-(苯磺酰胺)苯甲酰胺(I
P-2)
HPLC:98.2%;LC-MS(m/z):343.11(M+H)
+;
1H NMR(400MHz,DMSO)δ9.79(s,1H),7.94(s,1H),7.76(d,J=8.2Hz,1H),7.70(d,J=8.5Hz,2H),7.62(d,J=8.2Hz,2H),7.57(t,J=6.9Hz,1H),7.52–7.42(m,3H),7.33(s,1H),7.03(d,J=3.5Hz,1H),6.55(dt,J=2.9,1.4Hz,1H)。
N-(2-(呋喃-2-基)-5-(肼羰基)苯基)苯磺酰胺(I
P-3)
HPLC:97.5%;LC-MS(m/z):358.04(M+H)
+;
1H NMR(400MHz,DMSO)δ9.77(s,2H),7.73–7.71(m,1H),7.69(s,2H),7.66–7.62(m,2H),7.58(t,J=7.4Hz,1H),7.48(t,J=7.8Hz,2H),7.43(s,1H),7.04(d,J=3.4Hz,1H),6.58–6.52(m,1H),4.47(s,2H)。
实施例11
化合物I
K的合成:
4-(呋喃-2-基)-3-(苯磺酰胺)苯甲酸(I
K)
将化合物I
G(0.36g,1mmol)溶解于10毫升四氢呋喃溶液中,加入10毫升氢氧化锂水溶液(50%wt),50℃反应过夜。反应结束后,蒸干溶剂,往体系中加入适量稀盐酸调节PH为3-4,用乙酸乙酯萃取三次,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离化合物I
K,白色固体(0.12g,34.9%)。
HPLC:99.1%;LC-MS(m/z):344.06(M+H)
+;
1H NMR(400MHz,DMSO)δ12.99(s,1H),9.89(s,1H),7.84(dd,J=21.9,11.2Hz,3H),7.70(d,J=7.7Hz,2H),7.64(t,J=7.2Hz,1H),7.55(t,J=7.5Hz,2H),7.42(s,1H),7.17(d,J=3.3Hz,1H),6.63(s,1H)。
实施例12
化合物I
Q的合成:
第一步:3-硝基-4-(1H-吡咯-1-基)苯甲酸甲酯(XIII-1)
将4-氟-3-硝基苯甲酸甲酯(2.0g,10.0mmol),吡咯(2g,29.8mmol)和氢氧化钠(0.56g,14.0mmol)溶解于5毫升的无水二甲基亚砜溶液中,氮气保护条件下50℃反应过夜。后处理,往体系中加入水,乙酸乙酯萃取,硫酸钠干燥,蒸干溶剂,残 余物经柱层析分离得到中间体XIII-1,黄色固体(700mg,28.3%)。
1H NMR(400MHz,DMSO)δ8.51(d,J=3.2Hz,1H),8.38–8.25(m,1H),7.84(dd,J=8.1,5.3Hz,1H),7.06(d,J=2.3Hz,2H),6.36(d,J=2.2Hz,2H),3.96(s,3H)。
第二步:3-氨基-4-(1H-吡咯-1-基)苯甲酸甲酯(XIV-1)
将中间体XIII-1(0.7g,2.84mmol)溶解于20毫升乙醇和水(v/v=1:1)的混合溶液中,往体系中加入铁粉(0.8g,14.2mmol)和氯化铵(0.76g,14.2mmol),于75℃反应一小时。后处理:过滤,浓缩滤液,二氯甲烷萃取,硫酸钠干燥,蒸干溶剂柱层析(石油醚:乙酸乙酯=5:1)得到XIV-1,黄色固体(540mg,87.8%)。
1H NMR(400MHz,DMSO)δ7.56(d,J=1.3Hz,1H),7.27(dd,J=8.1,1.5Hz,1H),7.20(d,J=8.1Hz,1H),7.03(s,2H),6.33(s,2H),5.23(s,2H),3.88(s,3H)。
第三-四步:N-(5-(羟甲基)-2-(1H-吡咯-1-基)苯基)苯磺酰胺(XVI-1)
采取合成I
H类似的方法,得到中间体XVI-1,黄色固体(270mg,58.6%)。
1H NMR(400MHz,DMSO)δ7.90(dd,J=8.3,1.4Hz,1H),7.71–7.61(m,4H),7.57(t,J=7.7Hz,2H),7.49(d,J=8.3Hz,1H),7.03(s,2H),6.27(s,2H),3.84(s,3H)。
第五步:N-(5-甲酰基-2-(1H-吡咯-1-基)苯基)苯磺酰胺(XVII-1)
将中间体XVI-1(270mg,0.82mmol)溶解于10毫升无水二氯甲烷溶液中,加入204毫克的氯铬酸吡啶盐(204mg,0.95mmol),于室温条件下反应1小时。反应接受后,抽滤,蒸干滤液,残余物经柱层析分离得到中间体XVII-1,黄色油状物(160mg,59.8%)。
1H NMR(500MHz,DMSO)δ10.06(s,1H),9.90(s,1H),7.87(dd,J=8.2,1.8Hz,1H),7.70–7.60(m,3H),7.53(ddd,J=8.3,6.5,2.8Hz,4H),7.01(t,J=2.2Hz,2H),6.32–6.19(m,2H)。
第六步:N-(5-((甲胺基)甲基)-2-(1H-吡咯-1-基)苯基)苯磺酰胺(I
Q-1)
采取合成I
A-1类似的方法,得到化合物I
Q-1,白色固体(130mg,77.7%)。
HPLC:99.2%;LC-MS(m/z):342.15(M+H)
+;
1H NMR(500MHz,DMSO)δ7.63(dd,J=8.6,7.0Hz,2H),7.44–7.35(m,3H),7.27(d,J=1.8Hz,1H),7.07(d,J=8.0Hz,1H),6.95(t,J=2.1Hz,2H),6.83(dd,J=8.0,1.7Hz,1H),6.09(t,J=2.1Hz,2H),3.74(s,2H),2.33(s,3H)。
采取合成I
Q-1类似的方法,得到以下化合物:
N-(5-((甲胺基)甲基)-2-(1H-吡唑基-1-基)苯基)苯磺酰胺(I
Q-2)
HPLC:99.5%;LC-MS(m/z):343.10(M+H)
+;
1H NMR(400MHz,DMSO)δ8.53(s,1H),7.70(s,1H),7.63(d,J=7.2Hz,2H),7.54(d,J=8.2Hz,1H),7.49(s,1H),7.40(dt,J=23.4,7.0Hz,3H),6.91(d,J=8.0Hz,1H),6.43(s,1H),3.87(s,2H),2.41(s,3H)。
N-(5-((甲胺基)甲基)-2-(2H-1,2,3-三唑-2-基)苯基)苯磺酰胺(I
Q-3)
HPLC:98.9%;LC-MS(m/z):344.09(M+H)
+;
1H NMR(400MHz,DMSO)δ8.03(s,2H),7.62(d,J=7.5Hz,2H),7.50(s,1H),7.44(t,J=7.1Hz,1H),7.37(t,J=7.5Hz,2H),7.32(d,J=8.1Hz,1H),6.94(d,J=8.1Hz,1H),3.84(s,2H),2.38(s,3H)。
N-(5-((甲胺基)甲基)-2-(1H-1,2,3-三唑-1-基)苯基)苯磺酰胺(I
Q-4)
HPLC:97.5%;LC-MS(m/z):344.05(M+H)
+;
1H NMR(400MHz,DMSO)δ8.65(s,1H),7.85(s,1H),7.76–7.68(m,2H),7.56–7.46(m,2H),7.39(d,J=4.7Hz,3H),6.81(d,J=7.8Hz,1H),3.97(s,2H),2.48(s,3H)。
实施例13
化合物I
R的合成:
第一步:2-(4-氨基-3-溴苯基)乙腈(XVIII-1)
将对氨基苯乙腈(5.0g,37.83mmol)溶解于50毫升的乙腈溶液中,往体系中加入N-溴代丁二酰亚胺(6.7g,37.83mmol),室温反应30分钟,TLC监测原料反应完。后处理:蒸干溶剂,柱层析(石油醚:乙酸乙酯=4:1)得到标题化合物,浅黄色固体中间体XVIII-1(7.3g,91.4%)。
1H NMR(400MHz,CDCl
3)δ7.40(d,J=1.7Hz,1H),7.09(dd,J=8.2,1.9Hz,1H),6.79(d,J=8.2Hz,1H),3.65(s,2H)。
第二-四步:N-(4-(2-氨基乙基)-2-(呋喃-2-基)苯基)噻吩-3-磺酰胺(I
R)
采取合成I
A-1类似的方法,得到化合物I
R,浅棕色固体(2.1g,90.22%)。
HPLC:98.0%;LC-MS(m/z):349.07(M+H)
+;
1H NMR(400MHz,DMSO)δ8.08(dd,J=3.0,1.3Hz,1H),7.77(d,J=1.2Hz,1H),7.75(dd,J=5.1,3.0Hz,1H),7.62(d,J=2.0Hz,1H),7.29(dd,J=5.1,1.3Hz,1H),7.14(dd,J=8.2,2.0Hz,1H),7.05(d,J= 3.4Hz,1H),6.88(d,J=8.2Hz,1H),6.62(dd,J=3.4,1.8Hz,1H),3.06(s,2H),2.97–2.89(m,2H)。
实施例14
化合物I
S的合成:
第一步:3-(呋喃-2-基)-4-(噻吩-3-磺胺基)苯乙基氨基甲酸叔丁酯(XX-1)
将化合物I
R(600mg,1.72mmol)溶解于35毫升二氯甲烷/甲醇(体积/体积=6:1)的混合溶液中,加入二碳酸二叔丁酯(530mg,2.43mmol),室温反应过夜。反应结束后,蒸干溶剂,残余物经柱层析分离得到中间体XX-1,无色油状物(520mg,67.40%)。
1H NMR(400MHz,DMSO)δ8.06(dd,J=3.0,1.3Hz,1H),7.77–7.72(m,2H),7.56(d,J=1.9Hz,1H),7.27(dd,J=5.1,1.2Hz,1H),7.09–7.01(m,2H),6.92(t,J=5.4Hz,1H),6.83(d,J=8.1Hz,1H),6.62(dd,J=3.4,1.8Hz,1H),3.17(dd,J=13.5,6.6Hz,2H),2.72(t,J=7.2Hz,2H),1.38(s,9H)。
第二步:N-(2-(呋喃-2-基)-4-(2-(甲胺基)乙基)苯基)噻吩-3-磺酰胺(I
S)
将中间体XX-1(520mg,1.16mmol)溶解于30毫升四氢呋喃溶液中,0℃下加入四氢铝锂(221mg,5.82mmol),80℃反应过夜。反应结束后,往体系中依次加入221微升水,221微升氢氧化钠水溶液(10%wt),221微升水,抽滤,滤液蒸干,残余物经柱层析分离得到化合物I
S,浅棕色固体(70mg,16.65%)。
HPLC:97.3%;LC-MS(m/z):363.10(M+H)
+;
1H NMR(400MHz,DMSO)δ7.79(d,J=1.9Hz,1H),7.64(s,1H),7.53–7.47(m,2H),7.41(d,J=3.2Hz,1H),7.19–7.15(m,1H),7.12(d,J=8.3Hz,1H),6.84(dd,J=8.3,2.1Hz,1H),6.55(dd,J=3.2,1.8Hz,1H),3.01–2.93(m,2H),2.78–2.71(m,2H),2.50(s,3H)。
实施例15
化合物I
U的合成:
第一步:N-(4-((叔丁基亚砜)亚氨基)甲基)-2-(呋喃-2-基)苯基)-N-甲基苯磺酰胺(XXII-1)
将中间体N-(4-甲酰基-2-(呋喃-2-基)苯基)-N-甲苯磺酰胺(VIII-2)(682.8mg,2.0mmol),叔丁基亚磺酰胺(266.6mg,2.2mmol)和硫酸铜(478.8mg,3.0mmol)溶解于30毫升无水1,2-二氯乙烷溶液中,加热至85℃,反应过夜。反应结束后,待体系冷却至室温,抽滤,滤液浓缩,残余物经柱层析分离得到中间体XXII-1,类白色固体(683.4mg,76.9%)。
1H NMR(400MHz,DMSO)δ8.64(s,1H),8.43(d,J=1.8Hz,1H),7.88(d,J=1.3Hz,1H),7.81(ddd,J=14.7,7.9,4.7Hz,4H),7.72(t,J=7.6Hz,2H),7.22(d,J=3.4Hz,1H),6.89(d,J=8.2Hz,1H),6.74(dd,J=3.4,1.8Hz,1H),3.19(s,3H),1.24(s,9H).
第二步:N-(4-(1-(叔丁基亚砜)氨基)乙基)-2-(呋喃-2-基)苯基)-N-甲苯磺酰胺(XXIII-1)
将中间体XXII-1(666.8mg,1.5mmol)溶解于30毫升无水四氢呋喃溶液中,于-78℃条件下缓慢滴加1.5毫升甲基溴化镁的四氢呋喃溶液(1M/L,1.5mmol),加料完毕缓慢升至-20℃反应6小时。反应结束后,冰浴条件下往体系中加入氯化胺水溶液淬灭,加入水,用乙酸乙酯萃取三次,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到中间体XXIII-1,黄色的固体(425.4mg,61.6%)。
1H NMR(400MHz,DMSO)δ7.95(d,J=1.7Hz,1H),7.85–7.76(m,4H),7.72(t,J=7.6Hz,2H),7.28(dt,J=12.4,6.2Hz,1H),7.14(d,J=3.4Hz,1H),6.73–6.65(m,2H),5.84(d,J=7.3Hz,1H),4.52–4.42(m,1H),3.16(s,3H),1.46(d,J=6.8Hz,3H),1.18(s,9H).
第三步:N-(4-(1-氨基乙基)-2-(呋喃-2-基)苯基)-N-甲苯磺酰胺(I
U-1)
将中间体XXIII-1(368.5mg,0.8mmol)溶解于20毫升乙醇溶液中,加入2毫升盐酸的乙醇溶液(2M/L,4.0mmol),60℃反应2小时。反应结束后,蒸干溶剂,往残余物中加入水,加入适量碳酸氢钠水溶液,调节pH8~9,用乙酸乙酯萃取三次,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到化合物I
U-1,类白色的固体(180.1mg,63.2%)。
HPLC:99.1%;LC-MS(m/z):357.62(M+H)
+;
1H NMR(400MHz,DMSO)δ7.90(d,J=1.6Hz,1H),7.83–7.74(m,4H),7.70(t,J=7.6Hz,2H),7.24(dd,J=8.2,1.7Hz,1H),7.12(d,J=3.3Hz,1H),6.69(dd,J=3.3,1.7Hz,1H),6.61(d,J=8.2Hz,1H),4.13–3.95(m,1H),3.14(s,3H),1.28(d,J=6.6Hz,3H).
采用合成I
U-1类似的方法,得到以下化合物:
N-(4-(1-氨基乙基)-2-(呋喃-2-基)苯基)苯磺酰胺(I
U-2)
HPLC:99.3%;LC-MS(m/z):343.52(M+H)
+;
1H NMR(400MHz,CDCl
3)δ7.57(t,J=7.2Hz,3H),7.43(dd,J=14.5,7.0Hz,2H),7.35(d,J=1.7Hz,1H),7.32–7.24(m,3H),6.40(dd,J=3.2,1.8Hz,1H),6.34(d,J=3.3Hz,1H),4.09(q,J=6.5Hz,1H),1.36(d,J=6.6Hz,3H).
N-(4-(1-氨基丙基)-2-(呋喃-2-基)苯基)苯磺酰胺(I
U-3)
HPLC:99.1%;LC-MS(m/z):357.55(M+H)
+;
1H NMR(400MHz,CDCl
3)δ7.78–7.69(m,4H),7.56–7.45(m,3H),7.29(d,J=3.0Hz,1H),7.17–7.11(m,1H),7.06(d,J=8.4Hz,1H),6.59(dd,J=3.3,1.8Hz,1H),4.10–4.00(m,1H),1.98–1.73(m,2H),0.78(t,J=7.4Hz,3H).
N-(4-(1-氨基丁基)-2-(呋喃-2-基)苯基)苯磺酰胺(I
U-4)
HPLC:99.3%;LC-MS(m/z):371.45(M+H)
+;
1H NMR(400MHz,DMSO)δ7.79–7.69(m,4H),7.51(dq,J=14.4,7.1Hz,3H),7.28(d,J=2.9Hz,1H),7.15(d,J=6.9Hz,1H),7.05(d,J=8.4Hz,1H),6.60(dd,J=3.2,1.8Hz,1H),4.14(dd,J=9.1,5.9Hz,1H),1.92–1.69(m,2H),1.18(ddd,J=32.6,16.7,8.4Hz,2H),0.86(t,J=7.3Hz,3H).
N-(4-(1-氨基-2-甲基丙基)-2-(呋喃-2-基)苯基)苯磺酰胺(I
U-5)
HPLC:99.1%;LC-MS(m/z):371.62(M+H)
+;
1H NMR(400MHz,DMSO)δ7.78–7.67(m,4H),7.57–7.44(m,3H),7.29(d,J=2.7Hz,1H),7.11–7.01(m,2H),6.59(dd,J=3.3,1.8Hz,1H),3.86(d,J=8.4Hz,1H),2.06(td,J=14.5,7.5Hz,1H),1.02(d,J=6.6Hz,3H),0.73(d,J=6.7Hz,3H).
N-(4-(氨基(环丙基)甲基)-2-(呋喃-2-基)苯基)苯磺酰胺(I
U-6)
HPLC:99.0%;LC-MS(m/z):369.62(M+H)
+;
1H NMR(400MHz,DMSO)δ7.75(dd,J=6.5,2.6Hz,3H),7.67(s,1H),7.51(d,J=2.9Hz,1H),7.46–7.38(m,3H),7.16(d,J=8.4Hz,1H),7.06–6.97(m,1H),6.58(d,J=1.8Hz,1H),3.43(d,J=9.6Hz,1H),1.28(s,1H),0.65(t,J=6.9Hz,1H),0.58–0.45(m,2H),0.31(dd,J=14.4,8.5Hz,1H).
N-(4-(氨基(苯基)甲基)-2-(呋喃-2-基)苯基)苯磺酰胺(I
U-7)
HPLC:99.2%;LC-MS(m/z):405.52(M+H)
+;
1H NMR(400MHz,DMSO)δ8.23(s,3H),7.78(s,1H),7.77–7.71(m,3H),7.58–7.46(m,5H),7.42(t,J=7.6Hz,2H),7.34(t,J=7.2Hz,1H),7.23(d,J=2.8Hz,1H),7.15(d,J=8.5Hz,1H),7.00(d,J=8.4Hz,1H),6.60(d,J=1.8Hz,1H),5.46(s,1H).
N-(4-(1-氨基-2-苯乙基)-2-(呋喃-2-基)苯基)苯磺酰胺(I
U-8)
HPLC:99.5%;LC-MS(m/z):419.71(M+H)
+;
1H NMR(400MHz,DMSO)δ8.48(s,3H),7.74–7.66(m,4H),7.54(t,J=7.1Hz,1H),7.48(t,J=7.4Hz,2H),7.24(t,J=7.2Hz,2H),7.19(d,J=7.0Hz,2H),7.10(d,J=7.2Hz,3H),6.95(d,J=8.4Hz,1H),6.59–6.54(m,1H),4.42(dd,J=9.2,5.9Hz,1H),3.28–3.20(m,1H),3.08(dd,J=13.5,9.6Hz,1H).
N-(5-(1-氨基乙基)-2-(呋喃-2-基)苯基)苯磺酰胺(I
U-9)
HPLC:99.2%;LC-MS(m/z):343.51(M+H)
+;
1H NMR(400MHz,DMSO)δ7.77(d,J=3.4Hz,2H),7.61(d,J=6.5Hz,2H),7.46(d,J=2.3Hz,1H),7.40(s,3H),7.28(s,1H),6.79(d,J=8.1Hz,1H),6.53(s,1H),4.07(d,J=6.4Hz,1H),1.33(d,J=6.4Hz,3H).
实施例16
化合物I
V的合成:
第一-二步:N-(4-乙酰基-2-(呋喃-2-基)苯基)苯磺酰胺(XXV-1)
采用合成V-1类似的方法,得到中间体XXV-1。
1H NMR(400MHz,CDCl
3)δ8.33(s,1H),8.04(s,1H),7.86(d,J=8.2Hz,1H),7.75(d,J=8.1Hz,3H),7.60(s,1H),7.54(t,J=7.1Hz,1H),7.42(t,J=7.3Hz,2H),6.57(d,J=11.6Hz,2H),2.60(s,3H).
第三步:N-(2-(呋喃-2-基)-4-(1-(甲胺基)乙基)苯基)苯磺酰胺(I
V-1)
将中间体XXV-1(682.8mg,2mmol)溶解于20毫升的二氯甲烷溶液中,加入1毫升甲胺的乙醇溶液(30-33%wt),四乙氧基钛(456.2mg,2mmol),室温反应过夜。第二天,于冰水浴条件下缓慢加入硼氢化钠(151.3mg,4mmol),室温反应四小时。反应结束后,往体系中加入水,用二氯甲烷萃取三次,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到化合物I
V-1,白色固体(165.1mg,23.2%)。
HPLC:99.0%;LC-MS(m/z):357.40(M+H)
+;
1H NMR(400MHz,CDCl
3)δ7.62(dd,J=12.1,7.9Hz,3H),7.52–7.43(m,2H),7.35(dd,J=16.8,4.8Hz,3H),7.27(dd,J=8.4,1.9Hz,1H),6.45(dd,J=3.3,1.8Hz,1H),6.40(d,J=3.3Hz,1H),3.68(q,J=6.5Hz,1H),2.32(s,3H),1.39(d,J=6.6Hz,3H).
采用合成I
V-1类似的方法,得到以下化合物:
N-(2-(呋喃-2-基)-5-(1-(甲胺基)乙基)苯基)苯磺酰胺(I
V-2)
HPLC:99.0%;LC-MS(m/z):357.45(M+H)
+;
1H NMR(400MHz,DMSO)δ7.74(d,J=6.6Hz,2H),7.65(dd,J=9.3,4.5Hz,2H),7.52–7.41(m,3H),7.30(d,J=3.1Hz,1H),7.07(s,1H),6.95(d,J=8.1Hz,1H),6.56(dd,J=3.2,1.8Hz,1H),3.72(q,J=6.4Hz,1H),2.18(s,3H),1.26(d,J=6.7Hz,3H).
实施例17
化合物I
W的合成:
第一步:2-(4-(呋喃-2-基)-3-(苯磺胺基)苯基)吡咯烷-1-羧酸叔丁酯(XXVII-1)
采用合成V-1类似的方法,得到中间体XXVII-1.
1H NMR(400MHz,DMSO)δ9.71(s,1H),7.69(dd,J=22.9,16.6Hz,5H),7.56(d,J=29.8Hz,2H),7.13(t,J=13.5Hz,1H),7.01(t,J=10.5Hz,1H),6.59(d,J=17.1Hz,2H),4.80–4.47(m,1H),3.37(d,J=11.6Hz,1H),3.21(s,1H),2.16(d,J=48.0Hz,1H),1.81–1.69(m,1H),1.51(d,J=11.7Hz,1H),1.40(s,3H),1.27(s,1H),1.14(s,6H).
第二步:N-(2-(呋喃-2-基)-5-(吡咯烷-2-基)苯基)苯磺酰胺(I
W)
将中间体XXVI-1(234.3mg,0.5mmol)溶解于30毫升的乙酸乙酯溶液中,加入1毫升盐酸的乙醇溶液(2M/L,2.0mmol),室温反应3小时。反应结束后,蒸干溶剂,往残余物中加入水,加入适量碳酸氢钠水溶液,调节pH8~9,用乙酸乙酯萃取三次,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,残余物经柱层析分离得到化合物I
W,类白色的固体(70.0mg,38.0%)。
HPLC:99.1%;LC-MS(m/z):368.34(M+H)
+;
1H NMR(400MHz,DMSO)δ7.75(dd,J=7.3,1.9Hz,2H),7.61(d,J=9.9Hz,2H),7.41(dd,J=12.4,5.0Hz,4H),7.19(s,1H),6.85(d,J=8.0Hz,1H),6.54(dd,J=3.0,1.7Hz,1H),4.20–4.14(m,1H),3.10(t,J=7.2Hz,2H),2.13(td,J=12.0,7.2Hz,1H),1.92–1.84(m,2H),1.66(dq,J=17.5,8.8Hz,1H).
实施例18
TRPA1的抑制活性
在本实施例中,测试本发明部分实施例制备的化合物对瞬时受体电位通道蛋白A1(TRPA1)的抑制活性。其中,阳性对照化合物采用式A化合物(WO2010075353):
方法如下:
通过IonWorks Barracuda(IWB)自动化膜片钳检测的测试方法:稳定表达mTRPA1的HEK293细胞,用含有15g/mL Blasticidin S HCl、200g/mL Hygromycin B和10%FBS血清的DMEM培养基,置于T175的培养瓶中,放入37℃,5%CO
2的培养箱中培养,待细胞密度生长到~80%时,移走培养液,用无钙镁的磷酸缓冲液(PBS)冲洗一遍,加入3mL的Trypsin消化2分钟,加入7mL培养液终止消化。将细胞收集到15mL的离心管中以800转/每分钟离心3分钟,去除上清液后将细胞加入适当体积的细胞外液重悬,使细胞密度控制在2-3×10
6/mL并用于IWB实验。细胞外液配方(in mM):140NaCl,5KCl,1MgCl
2,10HEPES,0.5EGTA,10Glucose(pH 7.4);细胞内液配方(in mM):140CsCl,10HEPES,5EGTA,0.1CaCl
2,1MgCl
2(pH 7.2)。两性霉素B与实验当天用DMSO新鲜配制成28mg/mL,再用细胞内液配制成0.1mg/mL的终浓度。
IWB实验使用population patch clamp(PPC)板,全部检测过程由仪器自动完成,即在PPC板的384孔中加入细胞外液,并在PPC板下即plenum内加入细胞内液后,加入6L的细胞液进行封接测试,最后将plenum中的细胞内液换成含两性霉素B的细胞内液,使封接的细胞穿孔后形成全细胞记录模式。记录TPRA1电流的采样频率为10kHz,细胞钳制在0mV,电压刺激命令(channel protocol)为一个300ms从-100mV到+100mV的斜坡(ramp)电压,每10s给予此电压刺激,mTRPA1电流由300M AITC诱发。
数据记录和电流幅度测量导出由IWB软件完成(version 2.5.3,Molecular Devices Corporation,Union City,CA)。封接阻抗低于20MΩ的孔将不记录数据统计。原始电流数据由软件进行漏减矫正,TRPA1电流幅度在+100mV时测得。实验的每块PPC板都将有一个HC030031的剂量效应数据作为阳性对照,如HC030031的IC
50值超过以往每块板上得到的IC
50平均值的3倍时,将进行复测。化合物剂量效应曲线和IC
50由GraphPad Prism 5.02(GraphPad Software,San Diego,CA)进行拟合计算。
实验结果
对本发明的部分化合物通过IonWorks Barracuda(IWB)自动化膜片钳检测的测试方法,进行IC
50抑制活性测试,活性数据如表2所示。
表2.本发明的部分化合物对TRPA1的抑制活性数据(IC
50,μM)
编号 | IC 50(μM) | 编号 | IC 50(μM) | 编号 | IC 50(μM) | 编号 | IC 50(μM) |
I A-1 | +++++ | I A-2 | +++++ | I A-3 | +++++ | I A-4 | +++++ |
I A-5 | +++++ | I A-6 | ++++ | I A-7 | ++++ | I A-8 | +++ |
I A-9 | ++ | I A-10 | +++++ | I A-11 | +++++ | I A-12 | ++++ |
I A-13 | +++ | I A-14 | + | I A-15 | +++++ | I A-16 | ++++ |
I A-17 | ++++ | I A-18 | +++ | I A-20 | +++++ | I A-21 | +++++ |
I A-22 | ++ | I A-23 | +++ | I A-24 | ++ | I A-25 | ++ |
I A-26 | +++++ | I A-27 | +++++ | I A-28 | +++++ | I A-29 | ++++++ |
I A-30 | ++++++ | I A-31 | ++++ | I A-32 | ++++++ | I A-33 | +++++ |
I A-34 | +++++ | I A-35 | +++++ | I A-36 | ++ | I A-39 | ++ |
I A-40 | + | I A-41 | ++++ | I A-42 | +++++ | I A-43 | +++++ |
I A-44 | +++++ | I A-45 | +++++ | I A-46 | +++++ | I A-47 | +++++ |
I A-48 | +++++ | I A-49 | +++++ | I A-50 | ++ | I A-51 | ++++++ |
I A-52 | ++ | I A-53 | ++++ | I A-54 | +++++ | I A-55 | ++++++ |
I A-56 | +++ | I A-57 | ++ | I A-58 | + | I A-59 | ++++ |
I A-61 | +++ | I B | ++++++ | I C-1 | ++ | I D-1 | ++++++ |
I D-2 | +++++ | I D-3 | ++++++ | I D-4 | +++++ | I D-5 | ++++++ |
I D-6 | +++++ | I D-7 | +++++ | I D-8 | +++++ | I E | ++ |
I F | ++++++ | I H | ++ | I J-1 | +++++ | I J-2 | +++++ |
I Q-1 | +++++ | I Q-2 | +++++ | I Q-3 | +++++ | I Q-4 | ++++ |
I R | +++++ | I S | +++++ | 式A化合物 | + | I A-62 | + |
I U-1 | +++++ | I U-2 | +++++ | I U-3 | ++++++ | I U-4 | ++++++ |
I U-5 | ++++++ | I U-6 | ++++++ | I U-7 | +++++ | I U-8 | +++ |
I U-9 | ++++++ | I V-1 | +++++ | I V-2 | +++++ | I W | +++++ |
其中活性:(μM):
50≤IC
50<100:+
20≤IC
50<50:++
10≤IC
50<20:+++
5≤IC
50<10:++++
1≤IC
50<5:+++++
IC
50<1:++++++
结果表明,本发明的化合物对TRPA1表现出强效抑制活性。
实施例19
考察本发明部分实施例制备的化合物对2,4-二硝基苯磺酸(2,4-Dinitrobenzenesulfonic acid,DNBS)诱导的Wistar大鼠溃疡性肠炎的治疗效果(对应克罗恩病)
实验过程
1、实验动物
动物种属及品系:Wistar大鼠
给药记录:无给药史
性别、体重:雄性,150g左右
养殖方/供应商:上海斯莱克实验动物饲养有限公司
适应期:5天
房间:普通区房间
室内温度:20–26℃
室内相对湿度:40-70%
灯光:日光灯照明,12小时照明(08:00-20:00)及12小时无照明
动物饲养:每笼2-4只大鼠(同一给药组)
食物:无限量获取饲料(经辐照消毒,江苏省协同医药生物工程有限公司,中国)
水:无限量获取饮用水(经过反渗透处理和高压灭菌处理)
从上海斯莱克实验动物饲养有限公司购入共计80只Wistar大鼠,其中10只作为备用动物,用于挑选合适体重范围的动物入组,以期控制因体重波动导致的疾病程度波动。
2、分组
根据动物体重,使用BioBook软件筛选70只动物进行随机分组,以确保每组动物 的体重值相似,以减少偏差。
表3.动物分组及给药方式
3、实验设计
3.1、将DNBS粉末用30%乙醇溶解,终浓度为60mg/mL。
3.2、结直肠炎的诱导:实验前大鼠禁食40小时,并且在禁食期间给大鼠皮下注射5%葡萄糖盐水。实验第0天,腹腔注射舒泰和5mg/kg甲苯噻嗪麻醉禁食大鼠。G2组-G7组,将软管从肛门伸入到结直肠左曲,用DNBS灌肠诱导大鼠结直肠炎。正常对照组(G1)以同样的方法用30%乙醇灌肠。
3.3、给药方案:G1组动物和G2组动物DNBS诱导后用溶媒给药,G3组DNBS诱导后给予300mg/kg的奥沙拉嗪钠,G4组~G7组DNBS诱导后分别给予10mg/kg的本发明化合物。给药时间、具体的给药剂量、给药途径参照表3。从造模第0天就开始给药,连续给药7天,第6天处死动物。
3.4、检测指标:实验结束后,所有动物吸入过量CO
2法并脱颈椎处以安乐死。打开腹腔,取出结直肠,立即测量结直肠长度,纵向剖开结直肠,冲洗干净后,记录结直肠重量和溃疡面积,并整体拍照,同时依据表4宏观评估大鼠结直肠损伤。
表4.宏观评估大鼠结肠损伤评分
3.5、实验观察
每天观察动物的健康状态及对手术和药物的综合反应。
4、统计分析
实验数据以均值±标准误统计。使用Graphpad Prism、SPSS或Sigmaplot软件进行统计分析。具体的数据以图表的形式呈现。P<0.05被认为具有统计学差异。
实验结果
在实验观察中,所有动物均未出现任何外观或行为异常表现。
按照实验方案,Wistar大鼠用DNBS结肠内灌注诱导其产生炎症性结肠炎。结肠炎表现为结肠长度显著缩短,结肠重量显著增加,结肠溃疡面积显著增大,宏观结肠损伤评分显著升高。各组动物的结肠长度、重量和溃疡面积数据,如表5和图1所示。各组动物的宏观结肠损伤评分数据,如表6和图1所示。各组动物的代表性结直肠照片如图2所示。
由实验结果可知,在本实验中,阳性药奥沙拉嗪钠能够显著降低模型小鼠结肠重量及溃疡面积。本发明的化合物I
A-51、I
A-30、I
D-5、I
A-55均能够明显抑制模型小鼠结肠缩短,显著降低肠重、溃疡面积和宏观结肠损伤评分。且10mg/kg给药剂量的本发明各化合物组药效,要强于或不弱于300mg/kg的阳性对照组,说明本发明的化合物针对DNBS诱导大鼠结肠炎治疗药效强、起效剂量低。
表5.结肠长度、重量和溃疡面积
表6.宏观评估大鼠结肠损伤评分
综上所述,本发明的化合物I
A-51、I
A-30、I
D-5、I
A-55对DNBS诱导大鼠结肠炎具有很好的防治作用,能够开发成为治疗克罗恩病的药物。
实施例20
考察本发明部分实施例制备的化合物对DSS(dextran sulfate sodium)诱导的C57BL/6小鼠的炎症性肠炎的药效研究(对应溃疡性结肠炎)
实验过程
1、实验动物
动物种属及品系:C57BL/6小鼠
给药记录:无给药史
性别、体重:雌性,18-20g左右
养殖方/供应商:上海斯莱克实验动物有限公司
适应期:7天
房间:SPF房间
室内温度:20–26℃
室内相对湿度:40-70%
灯光:日光灯照明,12小时照明(08:00-20:00)及12小时无照明
动物饲养:每笼2-5只小鼠(同一给药组)
食物:无限量获取饲料(经辐照消毒,上海斯莱克实验动物责任有限公司,中国)
水:无限量获取饮用水(经超纯水过滤系统净化的自来水)
从上海斯莱克实验动物技术有限公司购入共计80只C57BL/6小鼠,其中10只作为备用动物,用于挑选合适体重范围的动物入组。所有备用动物不接受任何的给药或者造模操作,并在试验结束时统一进行安乐死。
2、分组
根据动物体重,在Day-3筛选70只动物使用BioBook软件进行随机分组,以确保每组动物的体重值相似,以减少偏差,具体分组信息见下表7。
表7.分组及给药方案
3、实验设计
3.1、将适量的DSS粉末溶解于高压灭菌过的饮用水溶媒中,配置成3%DSS溶液。
3.2、结肠炎的诱导:在Day-3,70只小鼠按照表7被随机分为7组。从第0天开始到第4天,第2组到第7组小鼠饮用含3%DSS水溶液5天,之后小鼠自由饮用正常用水(从第5天到剖检前)。初次给予DSS饮用水的当天计为第0天。DSS水溶液用不透光的深色袋子包裹,保证避光。每2天更换一次DSS水溶液。
3.3、给药方案:见表7。
3.4、肠炎评价:
(1)小鼠体重、粪便、出血情况
每天记录所有组小鼠体重、粪便、出血变化。根据下表8进行三项评分,并加和在一起作为每日疾病活动指数(Disease activity index,DAI)评分。
表8.疾病活动指数(DAI)评分
(2)肠的重量、长度
采血后,动物接受过量CO
2后脱颈处死。剪开腹腔,取小鼠结直肠,去除结肠周围的组织,测量从回盲瓣到肛门的纵向长度。剖开结直肠,对内容粪便进行评分,清洗肠内物,对结肠整体拍照,称重。
(3)ELISA分析
利用市售的ELISA分析试剂盒,对各组结直肠炎症因子TNF-α和IL-10进行分析。
3.5、实验观察
每天观察动物的健康状态及对DSS和药物的综合反应。任何除与疾病发展有关的外观或行为异常表现被详细记录于澎立生物实验观察表中。
4、统计分析
数据以均值±标准误统计。使用Graphpad Prism,SPSS软件进行统计分析。具体的数据以图表的形式呈现。当P<0.05时,则认为在统计学上有差异。
实验结果
在实验观察中,所有动物均未出现任何外观或行为异常表现。
本实验根据实验方案对C57BL/6小鼠用口服DSS饮用水的方法诱导其产生急性结肠炎。接受DSS饮用水的动物表现出了急性结肠炎的临床症状,包括体重下降、腹泻和血便,以及剖检所见的肠长度的缩短、肠重量的增加。各组动物的DAI评分数据,如图3所示;各组动物的结直肠重量和长度的结果,如图4所示;各组动物的结直肠炎症因子TNF-α和IL-10的ELISA分析结果图5所示。
由实验结果可知,在本实验中阳性药Cyclosporine A在多个指标中均表现出明显的药效,表明本模型成功构建。本发明的化合物I
A-51、I
A-30、I
D-5、I
A-55能够显著降低模型小鼠DAI评分、降低结直肠的重量和和增加结直肠的长度,同时可以显著降低各组动物的结直肠炎症因子TNF-α和IL-10水平。且10mg/kg给药剂量的本发明各化合物组药效,要强于或不弱于60mg/kg的阳性对照组,说明本发明的化合物针对DSS诱导的C57BL/6小鼠的炎症性肠炎具有较好的治疗药效。
综上所述,本发明的化合物I
A-51、I
A-30、I
D-5、I
A-55对DSS诱导的C57BL/6小鼠的炎症性肠炎具有很好的防治作用,能够开发成为治疗溃疡性结肠炎的药物。
实施例21
考察本发明部分实施例制备的化合物对用醋酸在ICR小鼠上诱导的扭体痛模型的药效测试。
小鼠醋酸扭体痛模型是经典的评价药物治疗内脏疼痛和炎症疼痛的药效模型。
实验过程
1、实验动物
动物种类和品系:ICR小鼠
药物处理史:无
性别、年龄、体重:雄性,8周龄,20-25g
繁育者/供应商:上海斯莱克实验动物有限公司
适应期:不少于7天
房间:普通级房间
室温:19–26℃
相对湿度:40-70%
光照循环:日光灯照明,12小时照明(08:00-20:00)及12小时无照明
动物饲养:按组别分5只/笼
食物:自由摄取(辐照饲料,上海斯莱克实验动物有限公司,中国)
水:自由摄取(Mol Ultrapure Water System过滤的市自来水)
共70只小鼠从上海斯莱克实验动物有限公司引进,动物为SPF级,动物购进时约7周龄。
2、分组
根据动物体重,通过BioBook随机分配功能将动物随机分配到各个处理组中,以达到近似的各组均重,减少组间偏差。
表9.动物分组及给药方式
3、实验设计
3.1、使用前12h内,用0.9%的生理盐水配制质量体积分数为0.6%的冰醋酸溶液。
3.2、给药处理:G1组动物口服给0.9%的生理盐水;G2-G6参照表9的给药方案具体给本发明的化合物。
3.3、造模处理:G1组动物,灌胃给予0.9%的生理盐水,1h后,腹腔注射0.6%的冰醋酸诱导疼痛反应(10ml/kg)。G2-G8组动物,在给药后不同组别按照表9设计的方案,腹腔注射0.6%的冰醋酸诱导疼痛反应(10ml/kg)。
3.4、测量:造模处理前记录所有小鼠的体重。醋酸处理后随即进行扭体测试记录。行为观察期持续20min。单人对扭体进行计数(1次标准扭体为腹肌收缩,肌体延伸和后肢伸展)。动物于测试完毕后,用CO
2处死。
3.5、实验观察:每天进行动物健康观察和对药物处理的一般反应。记录所有异常的健康和行为表现。
4、统计分析
实验数据以均值±标准误统计。使用Graphpad Prism,SPSS或Sigmaplot软件进行统计分析。具体的数据以图表的形式呈现。P<0.05被认为具有统计学差异。
实验结果
实验各组的扭体次数统计如图6所示。从图6可以看出,与G1模型组相比,本发明的化合物I
A-51、I
A-30、I
D-5、I
A-55能够显著降低模型小鼠的扭体次数,且药效基本与200mpk的阿司匹林汀相当,表现出强效的镇痛活性。
综上所述,本发明的化合物I
A-51、I
A-30、I
D-5、I
A-55具有良好的镇痛药效,能够开发成为疼痛治疗的药物。
实施例22
考察本发明部分实施例制备的化合物对趋化因子受体CCR9的拮抗活性
实验过程
1.受试药物及阳性对照药物
1.1受试药物
名称:具体见表10
贮存方法:避光,冷藏保存
配药浓度:10mM、1mM、100μM、10μM、1μM、100nM、10nM、DMSO。
工作浓度:100μM、10μM、1μM、100nM、10nM、1nM、100pM、DMSO。
1.2阳性对照:Vercirnon(CCR9拮抗剂)
名称:Vercirnon
贮存方法:避光,-80℃密闭保存
配药浓度:10mM、1mM、100μM、10μM、1μM、100nM、10nM、DMSO。
工作浓度:100μM、10μM、1μM、100nM、10nM、1nM、100pM、DMSO。
1.3 CCL25(CCR9激动剂)
名称:CCL25
贮存方法:避光,-80℃密闭保存
配药浓度:15μM。
工作浓度:150nM。
2.试剂与仪器:
2.1主要试剂:DMEM培养基(GIBCO);二甲亚砜(Sigma);FLUO-4,AM(Invitrogen)
2.2主要仪器:Flexstation-3(Molecular Devices)
3.分组、剂量设置:
3.1剂量设置依据:
根据测试IC
50的要求,设置化合物的测试浓度梯度和设置复孔。
3.2剂量设置与组别:
所有受试物均设8个浓度,每个浓度设3个复孔。
4.实验原理和方法:
实验原理:
通过建立了共转目标受体和G16的细胞系,使得受体被激活后能引起Gα16蛋白的活化,进而激活磷脂酶C(PLC)产生IP3和DAG,IP3可与细胞内内质网和线粒体上的IP3受体结合,从而引起胞内钙的释放。因此,测定胞内钙的变化可以作为检测目标受体活化状态的方法。Fluo-4/AM是一种钙荧光探针指示剂用来测量钙离子,作为非极性脂溶性的化合物,进入细胞后在细胞脂解酶的作用下,AM基团解离,释出Fluo-4;由于Fluo-4是极性分子,不易通过脂质双分子膜,它可使Fluo-4长时间保留在细胞内。最终可以通过测量被激发的荧光强度来反映G蛋白被激活的水平。如果筛选的化合物能够激动目标受体,则可以使钙流反应大大升高。反之,如果筛选的化合物能够拮抗目标受体,则可以使钙流反应大大降低。
实验步骤:
1.将稳定表达目标受体/Gα16的细胞种于96孔板,培养过夜。
2.吸去种有细胞的孔内的培液,加入新鲜配制的染料40μl/孔,37℃培养箱内恒温孵育40分钟。
3.用钙缓冲液将待测的药物稀释并混匀。
拮抗模式:
4.将染料吸尽弃去,用新鲜配制的钙缓冲液洗一遍后,换上50μl溶解有待测药物的钙缓冲液。
5.用FlexStation II仪检测,第15秒开始由仪器自动加入25μl溶解有已知激动剂的钙缓冲液,最终读取525nm处荧光值。
5.数据处理和统计分析:
拮抗模式
通过以下公式计算得到各样品各浓度条件下的细胞反应率(%Response)。
L
Sample表示待测样品的检测信号值,L
Blank表示阳性拮抗剂完全抑制的检测信号值,L
Agonist表示阳性激动剂刺激DMSO空白组后的检测信号值。
IC
50值是通过GraphPad Prism计算得到。
6.实验结果:
测试结果如表10所示。由结果可知,本发明的化合物对趋化因子受体CCR9拮抗活性IC
50均大于10μM,表明本发明的化合物不具有趋化因子受体CCR9拮抗活性。
类似的,还测试了本发明的化合物对其他趋化因子受体的拮抗活性,比如CCR1~CCR10,测试结果表明,本发明的化合物均不具有趋化因子受体的拮抗活性。 因此,本发明的化合物用于炎症性肠病的治疗,不是通过对趋化因子受体的拮抗,而是通过全新的药物作用机制,即对离子通道TRPA1的抑制。
表10.本发明的化合物对趋化因子受体CCR9的拮抗活性结果
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (17)
- 一种式I化合物,或其光学异构体,或其外消旋体、或其药学上可接受的盐、或其前药;式中:Ar为取代或未取代的C6-C12芳基、取代或未取代的3-12元杂芳基、3-12元杂环烷环并C6-C12芳基、取代或未取代的C6-C12芳基-取代或未取代的C1-C8烷基-、或取代或未取代的3-12元杂芳基-取代或未取代的C1-C8烷基-;X 1、X 2、X 3和X 4各自独立的为C、O、S或N;标号为a、b、c、d和e 为单键或双键;R 1为氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C7环烷基、或卤素;R 2为氢、取代或未取代的C1-C10烷基、或取代或未取代的C3-C10环烷基;A为 取代或未取代的C2-C6酯基、取代或未取代的C2-C6羧基、取代或未取代的C2-C6酰胺基、取代或未取代的3-8元杂环烷基、或取代或未取代的 2HN-HN-C(O)-;m为0、1、2或3;Y 1为N;Y 2为O或S;Y 3为NH、O或S;Y 4为O或S;Y 5为N;R 3和R 4各自独立的为氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C12芳基、取代或未取代的C6-C12芳基-取代或未取代的C1-C3烷基-、取代或未取代的C2-C6酰基,或R 3、R 4与相邻的Y 1共同连接形成取代或未取代的3-8元杂环烷基;R 5为氢、取代或未取代的C1-C6烷基、羟基、巯基或取代或未取代的C1-C6烷氧基;n为0、1、2、3、4或5;其中,所述的任一“取代”是指环或基团上的一个或多个(优选为1、2、3、4、5或6个)氢原子被选自下组的取代基所取代:C1-C8烷基、C3-C8环烷基、C1-C8卤代烷 基、C3-C8卤代环烷基、卤素、硝基、-CN、羟基、巯基、氨基、C1-C4羧基、C2-C4酯基、C2-C4酰胺基、C1-C8烷氧基、C1-C8烷硫基、C1-C8卤代烷氧基、C1-C8卤代烷硫基、C6-C12芳基、5-10元杂芳基、5-10元杂环烷基;所述的杂芳基、杂环烷环、杂环烷基的杂环上各自独立地具有1-4个(优选为1、2、3个或4个)选自N、O和S的杂原子。
- 如权利要求1所述的化合物,其特征在于,Ar为取代或未取代的C6-C10芳基、取代或未取代的3-10元杂芳基、3-10元杂环烷环并C6-C10芳基、取代或未取代的C6-C10芳基-取代或未取代的C1-C6烷基-、或取代或未取代的3-10元杂芳基-取代或未取代的C1-C6烷基-。
- 如权利要求1所述的化合物,其特征在于,Ar为取代或未取代的C6-C10芳基、取代或未取代的3-10元杂芳基。
- 如权利要求1所述的化合物,其特征在于,X 1、X 2、X 3、X 4与标号为a、b、c、d和e的 形成杂芳环,所述的杂芳环的杂环上各自独立地具有1-4个(优选为1、2、3个或4个)选自N、O和S的杂原子。
- 如权利要求1所述的化合物,其特征在于,R 1为氢、取代或未取代的C1-C4烷基;R 2为氢、取代或未取代的C1-C4烷基。
- 如权利要求1所述的化合物,其特征在于,A为
- 如权利要求1所述的化合物,其特征在于,所述化合物具有式Z结构:其中,R 1、R 2、X 1、X 2、X 3、X 4、Ar、a、b、c、d、e、n如权利要求1所述;R A、R B、R C各自独立地为氢、取代或未取代的C1-C6烷基。
- 如权利要求1所述的化合物,其特征在于,所述的化合物选自下组:
- 一种药物组合物,其特征在于,所述的药物组合物包括如权利要求1所述的式I化合物,或其光学异构体,或其外消旋体、或其药学上可接受的盐、或其前药;和药学上可接受的载体。
- 一种制备如权利要求1所述的式I化合物,或其光学异构体,或其外消旋体、或其药学上可接受的盐、或其前药的方法,其特征在于,所述的方法包括方法一至四的其中之一:方法一:或方法二:或方法三:或方法四:其中,X 1、X 2、X 3、X 4、R 1、R 2、n、Ar和R 3的定义如权利要求1所述。
- 一种如权利要求1所述的式I化合物,或其光学异构体,或其外消旋体、或其药学上可接受的盐、或其前药或如权利要求9所述的药物组合物的用途,其特征在于,用于(a)制备瞬时受体电位通道蛋白TRPA1的抑制剂;和/或(b)制备预防和/或治疗与瞬时受体电位通道蛋白TRPA1相关的疾病的药物。
- 如权利要求11所述的用途,其特征在于,所述的与瞬时受体电位通道蛋白TRPA1相关的疾病选自下组:炎症性肠病、肠易激综合征、疼痛、炎症,或其组合。
- 如权利要求12所述的用途,其特征在于,所述的炎症性肠病包括克罗恩病和/或溃疡性结肠炎。
- 如权利要求12所述的用途,其特征在于,所述的疼痛包括内脏痛、急性炎性疼痛、慢性炎性疼痛、神经源性疼痛、肌纤维痛、头痛、神经痛或癌症引起疼痛。
- 一种体外非治疗性和非诊断性的抑制瞬时受体电位通道蛋白活性的方法,其特征在于,包括步骤:将瞬时受体电位通道蛋白或表达所述蛋白的细胞与如权利要求1所述的式I化合物,或其光学异构体,或其外消旋体、或其药学上可接受的盐、或其前药进行接触,从而抑制瞬时受体电位通道蛋白的活性。
- 一种抑制瞬时受体电位通道蛋白或预防和/或治疗与瞬时受体电位通道蛋白TRPA1相关的疾病的方法,其特征在于,包括步骤:给需要的对象施用如权利要求1所述的式I化合物,或其光学异构体,或其外消旋体、或其药学上可接受的盐、或其前药或如权利要求9所述的药物组合物。
- 一种化合物,其特征在于,所述化合物如下式II-1~式II-6的其中之一所示:其中:Ar为取代或未取代的C6-C12芳基、取代或未取代的3-12元杂芳基、3-12元杂环烷环并C6-C12芳基、取代或未取代的C6-C12芳基-取代或未取代的C1-C8烷基-、或取代 或未取代的3-12元杂芳基-取代或未取代的C1-C8烷基-;X 1、X 2、X 3和X 4各自独立的为C、O、S或N;标号为a、b、c、d和e 为单键或双键;R 1为氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C7环烷基、或卤素;R 2为氢、取代或未取代的C1-C10烷基、或取代或未取代的C3-C10环烷基;n为0、1、2、3、4或5;其中,所述的任一“取代”是指环或基团上的一个或多个(优选为1、2、3、4、5或6个)氢原子被选自下组的取代基所取代:C1-C8烷基、C3-C8环烷基、C1-C8卤代烷基、C3-C8卤代环烷基、卤素、硝基、-CN、羟基、巯基、氨基、C1-C4羧基、C2-C4酯基、C2-C4酰胺基、C1-C8烷氧基、C1-C8烷硫基、C1-C8卤代烷氧基、C1-C8卤代烷硫基、C6-C12芳基、5-10元杂芳基、5-10元杂环烷基;所述的杂芳基、杂环烷环、杂环烷基的杂环上各自独立地具有1-4个(优选为1、2、3个或4个)选自N、O和S的杂原子。
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WO2008008375A2 (en) * | 2006-07-14 | 2008-01-17 | Chemocentryx, Inc. | Triazolyl pyridyl benzenesulfonamides as ccr2 or ccr9 modulators for the treatment of inflammation |
KR100932093B1 (ko) * | 2006-09-27 | 2009-12-16 | 주식회사종근당 | 미세소관 형성 저해제로서 유용한 벤조페논 유도체 |
TW201026700A (en) | 2008-12-22 | 2010-07-16 | Hydra Biosciences Inc | Compositions useful for treating disorders related to TRPA1 |
WO2010126002A1 (ja) * | 2009-04-28 | 2010-11-04 | 塩野義製薬株式会社 | ヘテロ環スルホンアミド化合物を含有する医薬 |
JP6272833B2 (ja) * | 2013-04-04 | 2018-01-31 | 武田薬品工業株式会社 | 複素環化合物 |
KR20150144121A (ko) * | 2014-06-16 | 2015-12-24 | 에스에프씨 주식회사 | 유기발광 화합물 및 이를 포함하는 유기전계발광소자 |
WO2020097408A1 (en) * | 2018-11-09 | 2020-05-14 | Nimbus Artemis, Inc. | Acly inhibitors and uses thereof |
WO2021092163A1 (en) * | 2019-11-06 | 2021-05-14 | Nocion Therapeutics, Inc. | Phosphonium ion channel blockers and methods for use |
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2021
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- 2022-06-10 CN CN202280040679.XA patent/CN117529474A/zh active Pending
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