CN101817767A - 取代磺酰胺类化合物及其制备方法、药物组合物和应用 - Google Patents
取代磺酰胺类化合物及其制备方法、药物组合物和应用 Download PDFInfo
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- CN101817767A CN101817767A CN200910046727A CN200910046727A CN101817767A CN 101817767 A CN101817767 A CN 101817767A CN 200910046727 A CN200910046727 A CN 200910046727A CN 200910046727 A CN200910046727 A CN 200910046727A CN 101817767 A CN101817767 A CN 101817767A
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- Prior art keywords
- phenyl
- benzyl
- heterocyclic group
- group
- pharmaceutically acceptable
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Abstract
本发明涉及取代磺酰胺类化合物及其制备方法、药物组合物和应用,具体提供通式(I)所示取代磺酰胺类化合物或其药学上可接受的盐,式中Ar、X、Y、Z和R的定义如说明书中所述。该类化合物对通过GPR40介导的许多疾病例如糖尿病、乳腺癌和某些神经类疾病等有较好的防治作用。该类化合物为GTP结合蛋白偶联受体40拮抗剂。因此,有望开发成为新型的治疗糖尿病等相关疾病的药物。本发明还提供了该类化合物的制备方法及其药物组合物。
Description
技术领域
本发明涉及药物化学和药物治疗学领域,具体涉及取代磺酰胺类化合物及其制备方法、应用及包含此类化合物的药物组合物。
背景技术
糖尿病已经成为继肿瘤、心血管疾病之后第三大严重威胁人类健康的慢性非传染性疾病,是一个日益严重的公共卫生问题。世界卫生组织(WHO)最新公布的权威数据显示,近年来全球糖尿病发病率增长迅速。病患者人数已超过1.77亿,预计到2025年将达到3.7亿。而糖尿病在中国的严峻形势更是发人深省。截至2003年,中国已经成为糖尿病第二大国,拥有2380万糖尿病患者,仅次于印度。预计到2030年,糖尿病患者人数将突破4320万。鉴于目前严峻的形势,开发新型治疗糖尿病的药物是非常有必要的。糖尿病的发病机制相当复杂,而且和肥胖等其他疾病相互关联。所以一方面,我们要在现有作用靶点的基础上寻找更加有效和低毒的新一代药物;另一方面,我们要积极研究糖尿病的发病机制,寻找与糖尿病有关的新型靶点,并针对这些新靶点设计具有全新作用机制的、自主知识产权的新药。
胰岛素是胰岛β细胞分泌的一种激素,它具有重要的生理功能,其中最主要的就是调节糖的代谢。它能促进糖在人体组织中的利用,使葡萄糖转变成糖原和脂肪,抑制糖异生。它还调节脂肪和蛋白质的代谢,是人体内一种非常重要的生物活性物质。胰岛素分泌的缺乏首先使体内对葡萄糖的利用大大下降,血糖升高而导致糖尿病,并进而引发糖尿病并发症,对人体产生极大的危害。目前临床上治疗糖尿病的药物有很多种,对应的作用靶点也各不相同。如磺酰脲类药物抗糖尿病的作用机制是关闭ATP依赖性钾通道,打开电压依赖型钙通道,引起细胞外的钙离子内流,从而刺激胰岛素分泌;α-葡萄糖苷酶抑制剂,淀粉不溶素等药物可影响人体对碳水化合物的吸收,控制血糖水平;胰岛素增敏剂,比如PPARγ激动剂罗格列酮,主要的功能是提高患者体内组织对胰岛素的敏感性。另外还有许多其他的药物,如DPPIV(二肽基肽酶VI)抑制剂,胰岛素类似物等。总的来说,目前治疗糖尿病的药物还存在许多不足。因此,开发当前药物的替代品,或者寻找新的靶点,发现具有全新作用机制的新型药物,对于糖尿病的治疗具有非常重要的意义。
G-蛋白偶联受体(GPCR)是药物开发史上最有价值的受体药物靶标,涉及到目前市场上约60%的处方药物,覆盖了大多数医疗领域,在全球市场上的年销售额达到几十亿美元。基于GPCR的药物开发具有很大潜力,国际上各大制药公司都在开展GPCR相关的药物开发项目。GTP结合蛋白偶联受体40(G-Protein Coupling Receptor 40,GPR40)又叫自由脂肪酸受体1(Free Fatty Acid Receptor 1,FFAR1),是一个七次跨膜受体。配体为C12-C16的长链饱和脂肪酸(Long Chain Fatty Acid,LCFA)以及C18或C20的不饱和脂肪酸,下游主要与Gq偶联,部分与Gi偶联,对人、小鼠及大鼠的相关进化分析表明,GPR40氨基酸序列高度保守。主要在人的胰岛β细胞高表达和大脑普遍表达,其次在脂肪组织、白细胞等组织也有表达,可能与肥胖、糖尿病、肿瘤、老年性疾病等发病有关。在葡萄糖存在的情况下,自由脂肪酸(Free Fatty Acid,FFA)能通过刺激胰岛β细胞膜上的GPR40放大葡萄糖刺激的胰岛素分泌(Glucose Stimulated Insulin Secretion,GSIS),也就是说,FFA在人体内除了能充当营养物质以外,还可以起到一个信号分子的作用。
但如果长期暴露在高浓度的FFA中,胰岛细胞由于长时间大量分泌胰岛素,最终将会削弱胰岛素的分泌功能并且诱导β细胞的凋亡。GPR40在胰岛β细胞中表达最高,这说明GPR40在胰腺组织中是一种非常重要的受体。敲除GPR40的小鼠(GPR40-/-)和正常小鼠(GPR40+/+),分别用高脂饮食喂养8周后,两种小鼠肥胖程度相当,但GPR40+/+小鼠出现显著的高胰岛素血症、胰岛素抵抗、脂肪肝和糖耐量减低,而GPR40-/-小鼠未出现显著的糖耐量异常,并且随机血糖水平、胰岛素抵抗程度均低于GPR40+/+小鼠。GPR40转基因小鼠,小鼠胰岛β细胞功能受损,表现出血胰岛素水平下降和高血糖,这表明GPR40可能是连接肥胖(高脂肪酸水平)和2型糖尿病的重要关联因素,GPR40在高脂饮食下促进高胰岛素血症、胰岛素抵抗的形成和糖耐量受损。反之,高脂饮食下,GPR40缺陷对胰岛素抵抗和糖耐量受损具有保护作用。2007年Erik Flodgren等发现GPR40受体介导LCFA引发胰岛α细胞胰高血糖素的分泌。临床上肥胖症以及2型糖尿病患者,往往伴随体内FFA水平过高,可能会引起糖尿病等相关疾病。如果能用GPR40的拮抗剂来降低GPR40的生理活性,则有希望保护患者免受这一类疾病的困扰。同样,如果开发GPR40的激动剂,则有望增加病人的胰岛素分泌功能,对于某些胰岛素分泌能力不足的患者具有非常重要的意义。因此,以GPR40作为潜在的治疗糖尿病的新靶标,发现和改造作用于GPR40的小分子化合物,对于调节人体胰岛素分泌功能,治疗糖尿病,具有非常重要的研究价值和应用前景。
近年来,“计算机辅助药物设计”(Computer-Aided Drug Design,CADD)已成为现代药物研究与开发的一个重要方法和工具,将计算机辅助药物设计特别是计算机辅助组合化学库设计加入新药研究的循环,能缩短新药研究的周期,节省研究与开发费用,提高新药筛选的命中率。计算机辅助药物设计与其他现代药物研究方法结合,将推动药学和生命科学相关学科的迅速发展。CADD方法已广泛地应用于先导化合物的发现与优化,国际上一些大的制药公司充分重视这一技术在新药研究中的应用。经过多年努力,已有相当数量的通过计算机辅助药物设计的药物陆续上市,如Merck Sharp & Dohme(Harlow,UK)公司的碳酸酐酶抑制剂多佐胺(Dorzolamide),Roche(Welwyn,UK)公司的HIV蛋白酶抑制剂沙奎那韦(Saquinavir),Biota(Melbourne,Australia)公司的神经氨酸酐酶抑制剂Relenza和Roche(Basel,Switzerland)公司的凝血酶抑制剂Ro466240等;Searle公司开发的高选择性的COX-2抑制剂塞来考昔(Celecoxib)也是根据三维定量构效关系(3D-QSAR)研究结果设计的。“组合化学”(Combinatorial Chemistry)是近年来药物化学和合成化学中出现的一项新技术,能够迅速产生大量分子结构以进行高通量筛选(High Throughput Screening)。组合化学方法一经出现,就引起了人们的广泛关注。先导化合物的发现和优化一直是药物化学研究的难点和重点。特别是近一、二十年来生物学和其他相关高新技术取得了长足进步,产生了基于细胞和分子水平的高通量筛选技术,更使得合成大量新结构类型的化合物成了药物研究的瓶颈。组合化学的出现对于解决这一问题提供了巨大的可能性。因此,“组合化学和高通量筛选”已成为继CADD又一药物研究的核心技术。“结构生物学”也从原来的基础研究进入应用研究阶段,其中的一个主要应用领域是在分子和原子结构水平上研究药物与靶蛋白的相互作用,测定药物-蛋白质复合物的晶体结构,为新化合物的设计和先导化合物的结构改造提供有益的结构信息。近年来,这方面的研究进展非常迅速,结构生物学技术和方法在抗艾滋病药物、抗感冒病毒药物和抗癌药物等研究中均得到了成功的应用。目前人类基因组测序已经完成,与生物信息学相结合,结构生物学将会在药物作用新靶标的发现中起重要作用。
基于结构的药物设计已经被广泛的应用在药物研究领域,是我们进行药物分子设计的一种常用手段,其中,药物靶点的三维结构信息对于我们了解药物分子与靶标生物大分子之间的相互作用模式及进行药物分子设计是极为重要的。但GPCR家族是一类跨膜受体,结晶学的技术限制使得这一类膜蛋白的三维结构测定非常困难。虽然有一些机构可能已经测得某些GPCR蛋白的三维结构,但到目前为止,已报道的被成功解析三维结构的GPCR成员非常少。同源模建(Homology Modeling)技术目前被广泛应用于GPCR三维结构的模建中。该方法认为蛋白质的三维结构比其一级序列更为保守,因此可以用一条已知三维结构的同源蛋白为模板,根据目标蛋白和模板蛋白的序列同源性模建出目标蛋白的三维结构。同源模建方法在一定程度上弥补了实验上的不足。但GPCR蛋白的模板选择也非常有限,早期只有细菌视紫红质(Bacteriorhodopsin)的三维结构被成功测定;自从2000年GPCR家族中第一个X射线衍射晶体结构被成功解析以来,已有多个高分辨率的牛视紫红质(Bovine rhodopsin,BRHO)三维结构出现,使得GPCR家族三维结构的模建可靠性大大提高。
本发明以BRHO的晶体结构为模板,采用同源模建的方法,得到GPR40的三维结构;综合运用计算机辅助药物分子设计、组合化学、分子生物学和结构生物学方法,寻找具有GPR40受体拮抗作用的先导化合物,并针对其药理作用进行结构优化,本发明发现了取代的磺酰胺类化合物对GPR40受体有很好的拮抗活性,从而完成了本发明。
发明内容
本发明的一个目的是提供一种结构通式如式(I)所示的取代磺酰胺类化合物或其药学上可接受的盐。
其中:
芳香基Ar为非必需地被取代的C6-C20稠合杂环基、苄基、苯基、萘基或5~7元杂环基;所述取代被1~4个各自独立地选自卤素、C1-C8直链或支链饱和或不饱和烃基、C3-C7环烃基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、羧基、苄基、苯基、萘基和5~7元杂环基的基团取代;
X不存在或为-O-、-S-、-NH-、-NHC(O)-、-C(O)NH-、-C(O)-或-SO2-;
Y不存在或为C1-C8直链或支链饱和或不饱和烃基、C3-C7环烃基、三氟甲基、苯基、苄基、萘基或5~7元杂环基;其中,所述苯基、苄基、萘基和5~7元杂环基非必需地被1~4个各自独立地选自卤素、C1-C8直链或支链饱和或不饱和烃基、C3-C7环烃基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、羧基、巯基、苄基、苯基、萘基和5~7元杂环基的基团取代;
Z不存在或为氢、卤素、C1-C8直链或支链饱和或不饱和烃基、C3-C7环烃基、氰基、硝基、羟甲基、三氟甲基、苄基、苯基、萘基、5~7元杂环基、-O-、-S-、-NH-、-C(O)-、-C(O)O-、-SO2-、-NHC(O)-、-C(O)NH-或-CH2NH-;
R不存在或为氢、C1-C8直链或支链饱和或不饱和烃基、C3-C7环烃基、羟基、苯基、苄基和5~7元杂环基;且当Z不存在,R为5~7元杂环基时非必需地与所连接的苯基并合;其中,所述苯基、苄基和5~7元杂环基非必需地被1~4个各自独立地选自卤素、C1-C8直链或支链饱和或不饱和烃基、C3-C7环烃基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、羧基、巯基、苄基、苯基、萘基和5~7元杂环基的基团取代;
所述C6-C20稠合杂环基含有1~5个选自氧、硫和氮的杂原子;
所述5~7元杂环基含有1~3个选自氧、硫和氮的杂原子;
式(I)苯环上的-Z-R取代基团可以为1~5个,且各自独立地相同或者不同。
本发明的术语意义如下:
所述C6-C20稠合杂环基如果没有其他说明,指稠合的环结构,在性质上可以是芳族或非芳族的并且其适合含有6~20个环原子,更适合含有6~11个环原子,其中至少1个并且适合最多可至5个是杂原子。这些稠合杂环的实例包括苯并呋喃、苯并噻吩、吲哚、苯并噁唑、苯并噻唑、苯并咪唑、苯并异噁唑、苯并异噻唑、吲唑、苯并噁二唑、苯并噻二唑、苯并三氮唑、喹啉、异喹啉、噌啉、喹唑啉、喹噁啉、苯并三嗪、苯并卓酮、苯并卓酚酮、苯并氮杂卓、苯并二氮杂卓、呋喃并呋喃、噻吩并呋喃、呋喃并吡咯、噻吩并噻吩、噻吩并吡咯、吡咯并吡咯、呋喃并吡啶、噻吩并吡啶、吡咯并吡啶、呋喃并噁唑、呋喃并噻唑、呋喃并咪唑、噻吩并噁唑、噻吩并噻唑、噻吩并咪唑、吡咯并噁唑、吡咯并噻唑、吡咯并咪唑、呋喃并异噁唑、呋喃并异噻唑、呋喃并吡唑、噻吩并异噁唑、噻吩并异噻唑、噻吩并吡唑、吡咯并异噁唑、吡咯并异噻唑、吡咯并吡唑、呋喃并噁二唑、呋喃并噻二唑、呋喃并三氮唑、噻吩并噁二唑、噻吩并噻二唑、噻吩并三氮唑、吡咯并噁二唑、吡咯并噻二唑、吡咯并三氮唑、呋喃并哒嗪、呋喃并嘧啶、呋喃并三嗪、噻吩并哒嗪、噻吩并嘧啶、噻吩并三嗪、吡咯并哒嗪、吡咯并嘧啶、吡咯并三嗪、呋喃并氮杂卓、呋喃并二氮杂卓、噻吩并氮杂卓、噻吩并二氮杂卓、吡咯并氮杂卓、吡咯并二氮杂卓、噁唑并噁唑、噁唑并噻唑、噁唑并咪唑、噁唑并异噁唑、噁唑并异噻唑、噁唑并吡唑、噁唑并吡啶、噁唑并噁二唑、噁唑并噻二唑、噁唑并三氮唑、噁唑并哒嗪、噁唑并嘧啶、噁唑并砒嗪、噁唑并三嗪、噻唑并噻唑、噻唑并咪唑、噻唑并异噁唑、噻唑并异噻唑、噻唑并吡唑、噻唑并吡啶、噻唑并噁二唑、噻唑并噻二唑、噻唑并三氮唑、噻唑并哒嗪、噻唑并嘧啶、噻唑并砒嗪、噻唑并三嗪、咪唑并咪唑、咪唑并异噁唑、咪唑并异噻唑、咪唑并吡唑、咪唑并吡啶、咪唑并噁二唑、咪唑并噻二唑、咪唑并三氮唑、咪唑并哒嗪、嘌呤(咪唑并嘧啶)、咪唑并砒嗪、咪唑并三嗪、噁唑并氮杂卓、噁唑并二氮杂卓、噻唑并氮杂卓、噻唑并二氮杂卓、咪唑并氮杂卓、咪唑并二氮杂卓、异噁唑并异噁唑、异噁唑并异噻唑、异噁唑并吡唑、异噁唑并噁二唑、异噁唑并噻二唑、异噁唑并三氮唑、异噁唑并吡啶、异噁唑并哒嗪、异噁唑并嘧啶、异噁唑并砒嗪、异噁唑并三嗪、异噻唑并异噻唑、异噻唑并吡唑、异噻唑并噁二唑、异噻唑并噻二唑、异噻唑并三氮唑、异噻唑并吡啶、异噻唑并哒嗪、异噻唑并嘧啶、异噻唑并砒嗪、异噻唑并三嗪、吡唑并吡唑、吡唑并噁二唑、吡唑并噻二唑、吡唑并三氮唑、异噁唑并吡啶、吡唑并哒嗪、吡唑并嘧啶、吡唑并砒嗪、吡唑并三嗪、异噁唑并氮杂卓、异噁唑并二氮杂卓、异噻唑并氮杂卓、异噻唑并二氮杂卓、吡唑并氮杂卓、吡唑并二氮杂卓、噁二唑并吡啶、噁二唑并哒嗪、噁二唑并嘧啶、噁二唑并砒嗪、噁二唑并三嗪、噻二唑并吡啶、噻二唑并哒嗪、噻二唑并嘧啶、噻二唑并砒嗪、噻二唑并三嗪、三氮唑并吡啶、三氮唑并哒嗪、三氮唑并嘧啶、三氮唑并砒嗪、三氮唑并三嗪、噁二唑并氮杂卓、噁二唑并二氮杂卓、噻二唑并氮杂卓、噻二唑并二氮杂卓、三氮唑并氮杂卓、三氮唑并二氮杂卓、萘啶、吡啶并哒嗪、吡啶并嘧啶、吡啶并砒嗪、吡啶并三嗪、吡啶并氮杂卓、吡啶并二氮杂卓、哒嗪并哒嗪、哒嗪并嘧啶、哒嗪并砒嗪、哒嗪并三嗪、哒嗪并氮杂卓、哒嗪并二氮杂卓、嘧啶并嘧啶、蝶啶、嘧啶并三嗪、嘧啶并氮杂卓和嘧啶并二氮杂卓。
所述5~7元杂环基包括芳杂环基和脂杂环基,其实例包括呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、异噁唑基、异噻唑基、吡唑基、噁二唑基、噻二唑基、三氮唑基、吡啶基、哒嗪基、嘧啶基、砒嗪基、三嗪基、卓酮基、卓酚酮基、氮杂卓基、二氮杂卓基、哌啶基、四氢吡咯基、四氢呋喃基、哌嗪基、噁唑烷基、咪唑烷基、吡唑烷基和吗啉基。
所述烃基和环烃基包括烷基、链烯基、炔基、环烷基、环烯基和环炔基。本发明的另一个目的是提供本发明取代磺酰胺类化合物或其药学上可接受的盐的制备方法。
本发明的再一个目的是提供包含有效量的取代磺酰胺类化合物或其药学上可接受的盐的预防和/或治疗通过GPR40介导的糖尿病等相关疾病用的药物组合物。
本发明的又一目的是提供取代磺酰胺类化合物或其药学上可接受的盐作为对GPR40具有拮抗作用的小分子拮抗剂,在通过GPR40介导的糖尿病等相关疾病的预防和/或治疗中的应用。
本发明所涉及的化合物或其药学上可接受的盐可作为GPR40拮抗剂,通过拮抗糖尿病人体内GPR40的生理活性,从而调节胰岛β细胞胰岛素分泌和保护β细胞或增加胰岛素敏感性,达到抗糖尿病的目的。
本说明书中所述的“药学上可接受的盐”具体地可列举与丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸等有机酸和天冬氨酸、谷氨酸等酸性氨基酸形成酯后再与无机碱形成的盐,如钠、钾、钙、铝盐和铵盐,或与有机碱形成的盐,如甲胺盐、乙胺盐、乙醇胺盐等,或与赖氨酸、精氨酸、鸟氨酸等碱性氨基酸形成酯后的盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸的盐,或与甲酸、乙酸,苦味酸、甲磺酸、乙磺酸等有机酸所成的盐。
本发明式(I)化合物的优选实施方案是如下取代的磺酰胺类化合物或其药学上可接受的盐:
其中,
芳香基Ar、X、Y和R的定义与上述相同;
Z不存在或为C1-C8直链或支链饱和或不饱和烃基、C3-C7环烃基、苄基、苯基、5~7元杂环基、-O-、-S-、-NH-、-C(O)-、-C(O)O-、-SO2-、-NHC(O)-、-C(O)NH-或-CH2NH-;
其中,C6-C20稠合杂环基中含有至少一个苯环;例如:苯并噻二唑基、喹啉基、苯并噻吩基、吲哚基、苯并呋喃基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并异噁唑基、苯并异噻唑基、吲唑基、苯并噁二唑基、苯并三氮唑基、异喹啉基、噌啉基、喹唑啉基或喹噁啉基等;
式(I)苯环上的-Z-R取代基团为1~3个,且各自独立地相同或者不同。
本发明式(I)化合物的更优选实施方案是如下取代的磺酰胺类化合物或其药学上可接受的盐:
其中,
芳香基Ar为非必需地被取代的苯基或萘基;所述取代被1~4个各自独立地选自卤素、C1-C8烷基、C3-C7环烷基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、羧基、苄基、苯基、萘基和5~7元杂环基的基团取代;
X不存在或为-O-、-S-、-NH-、-NHC(O)-、-C(O)NH-、-C(O)-或-SO2-;
Y不存在或为C1-C8烷基、C3-C7环烷基、三氟甲基、苯基、苄基或5~7元杂环基;其中,所述苯基、苄基和5~7元杂环基非必需地被1~4个各自独立地选自卤素、C1-C8烷基、C3-C7环烷基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、羧基、巯基、苄基、苯基和5~7元杂环基的基团取代;
Z为C1-C8烷基、C3-C7环烷基或-O-;
R不存在或为氢、C1-C8烷基、C3-C7环烷基、羟基、苯基、苄基和5~7元杂环基;其中,所述苯基、苄基和5~7元杂环基非必需地被1~4个各自独立地选自卤素、C1-C8烷基、C3-C7环烷基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、羧基、巯基、苄基、苯基、萘基和5~7元杂环基的基团取代;
所述5~7元杂环基为吡唑基、哌啶基、吡啶基、吡咯基、呋喃基、咪唑基、噻吩基、噻二唑基、嘧啶基或三嗪基;
式(I)苯环上的-Z-R取代基团为1或2个,且各自独立地相同或者不同。
本发明最优选的化合物包括:
本发明提供式(I)所示多取代磺酰胺类化合物及其药学上可接受的盐的制备方法:
式中Ar、X、Y、Z和R的定义如上所述。
所述方法主要包括以下步骤:从-Ar-X-Y取代的磺酰氯和-Z-R取代的苯胺出发在碱性条件下进行成磺酰胺反应制得目标产物。
目标化合物(I)的合成路线如下式所示:
式中芳香基Ar、X、Y、Z和R的定义如上所述;
有机惰性溶剂中,等摩尔的化合物(Ia)和化合物(Ib)在碱性条件下进行反应,然后提纯;根据具体化合物的反应情况,反应温度为0℃~80℃;反应时间为4~24小时;其中目标化合物(I)的合成中所用的有机惰性溶剂选自乙醚、四氢呋喃、二氯甲烷、氯仿、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环和N-甲基吡咯烷酮;其中目标化合物(I)的合成中所用碱选自包括吡啶、三乙胺、4-二甲胺基吡啶(DMAP)、二异丙基乙基胺、氢化钠和叔丁醇钾的有机碱以及包括碳酸钠、碳酸钾、氢氧化钠、氢氧化钾的无机碱;其中提纯的方法包括柱层析和重结晶。
上述步骤所得的目标产物可分别经适当的方法如柱层析、重结晶等提纯,得到纯产物。
本发明的另一个方面涉及预防和/或治疗的药物组合物,所述药物组合物含有一种或多种有效量的式(I)所示取代磺酰胺类化合物或其药学上可接受的盐和至少一种药学上可接受的载体,其可用于体内治疗并具有生物相容性。所述药物组合物可以根据不同给药途径而制备成各种形式。本发明的药物组合物可以用于预防和/或治疗糖尿病等相关疾病。
本发明涉及的可以用于预防和/或治疗糖尿病等相关疾病的药物组合物是指包括一种或多种有效剂量的本发明式(I)化合物或其药学上可接受的盐和一种或多种适宜的可药用载体。这里的药用载体包括但不限于:离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如人血白蛋白、缓冲物质如磷酸盐、甘油、山梨酸,山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质、如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶态氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜂蜡、羊毛脂。
本发明化合物的药物组合物可以下面的任意方式施用:口服、喷雾吸入、直肠用药、鼻腔用药、颊部用药,局部用药、非肠道用药,如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内和颅内注射或输入,或借助一种外植储器用药。其中治疗许多疾病例如糖尿病,乳腺癌和某些神经类疾病等时优选口服或肌肉注射、腹膜内或静脉内给药方式。
在本发明的一个优选方式中,所述药物组合物为片剂、胶囊、粉末、糖浆、溶液状、悬浮液或气雾剂。在本发明的另一优选方式中,所述药物组合物为单位剂型,每剂包含0.05mg~500mg,优选0.5mg~200mg,更优选0.1mg~100mg的式(I)所示取代磺酰胺类化合物或其药学上可接受的盐。在上述药物组合物中,一种或多种有效量的式(I)所示取代磺酰胺类化合物或其药学上可接受的盐占所述药物组合物总重量的0.001-99.9重量%。
在本发明的优选方式中,一种或多种有效量的式(I)所示取代磺酰胺类化合物或其药学上可接受的盐占所述药物组合物总重量的0.01-99重量%,更优选占总重量的0.1-90重量%。
一种制备药物组合物的方法,其特征在于,包括步骤:将一种或多种有效量的式(I)所示取代磺酰胺类化合物或其药学上可接受的盐,和药学上可接受的载体混合,从而制成药物组合物。
另外需要指出,本发明化合物的使用剂量和使用方法取决于诸多因素,包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的严重程度以及诊治医师的主观判断。建议剂量如为开始每日5mg~10mg/kg,维持量可减至每日3mg/kg。胶囊剂:0.25g/粒。注射液0.25g/5ml。口服溶液:5g/50ml。
附图说明
图1为化合物N41拮抗hGPR40激动剂亚油酸、油酸、棕榈油酸和月桂酸诱导的钙信号。
图2为化合物N41在hGPR120细胞株的选择性实验。
图3为不同剂量化合物N41拮抗10μM亚油酸GTP结合曲线。
图4为化合物N41抑制棕榈酸诱导的MIN6细胞胰岛素的分泌。
图5为化合物N41对棕榈酸诱导的MIN6细胞损伤的保护。
图6为化合物N41对胰岛素耐量的影响。
具体实施方式
优选实施例
第一部分:化合物合成实施例
下面进一步用实施例说明式(I)化合物的制备,但这些实施例绝不是对本发明的任何限制。实施例中的所有参数以及相关说明,除另有说明外,都是以质量为说明依据的。
下述制备例中,熔点采用上海精密科学仪器有限公司生产的X-4型熔点仪测定,温度未经校正;核磁共振由Bruker AMX-300/400型和1NVOA-600型核磁共振仪测定,TMS为内标,化学位移单位为ppm;质谱由MAT-711型和MAT-95型质谱仪测定;柱层析用硅胶200-300目,青岛海洋化工厂生产;TLC硅胶板为烟台化工厂生产的HSGF-254型薄层层析预制板;石油醚沸程为60~90℃;采用紫外灯、碘缸显色。以下陈述中“浓缩”(若未特别指出操作方法)指用旋转蒸发仪将制备化合物溶液中的溶剂蒸出;“干燥”(若未特别指出操作方法)指用DHG-9240A恒温干燥箱在30~80℃将制备化合物烘干。
实施例1 4-氟N-苯基苯磺酰胺(N1)的合成
对氟苯磺酰氯0.300g溶于5ml二氯甲烷溶液,加入0.118ml苯胺,5ml无水吡啶,室温下反应过夜。第二天,蒸除大部分吡啶后向体系加入25ml1M HCl,转移至分液漏斗,乙酸乙酯20ml萃取三次,合并有机相,饱和碳酸氢钠溶液20ml洗两遍,饱和食盐水20ml洗两遍,无水硫酸镁干燥。滤除干燥剂,后蒸干溶剂,硅胶柱层析(石油醚/乙酸乙酯=12/1)得产品白色粉末105mg,收率27.2%。mp 144-146℃;1H NMR(DMSO-d6):δ10.30(s,1H),7.79-7.83(m,2H),7.39(t,J=17.7Hz,2H),7.24(t,J=15.6Hz,2H),7.05-7.10(m,3H)。LRMS(EI)m/z 251(M+),92(100%);HRMS(EI)m/z计算值:C12H10FNO2S(M+)251.0416,实测值:251.0417。
实施例2 4-氟N-(4-异丙基苯基)苯磺酰胺(N2)的合成
除了用4-异丙基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率62.5%。mp 125-127℃;1H NMR(DMSO-d6):δ10.21(s,1H),7.79-7.84(m,2H),7.35-7.41(m,2H),7.10(d,J=7.5Hz,2H),7.01(t,J=8.4Hz,2H),2.72-2.81(m,1H),1.25(s,9H),1.11(d,J=1.8Hz,3H),1.10(s,3H)。LRMS(EI)m/z 293(M+),278(100%);HRMS(EI)m/z计算值:C15H16FNO2S(M+)293.0886,实测值:293.0881。
实施例3 N-(4-叔丁基苯基)-4-氟苯磺酰胺(N3)的合成
除了用4-叔丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率28.0%。mp 178-179℃;1HNMR(DMSO-d6):δ10.23(s,1H),7.80-7.85(m,2H),7.37-7.42(m,2H),7.26(d,J=8.4Hz,2H),7.01(d,J=8.7Hz,2H),1.20(s,9H)。LRMS(EI)m/z 307(M+),292(100%);HRMS(EI)m/z计算值:C16H18FNO2S(M+)307.1042,实测值:307.1044。
实施例4 4-氟-N-(4-戊氧基苯基)苯磺酰胺(N4)的合成
除了用4-戊氧基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率59.5%。mp 103-104℃;1HNMR(DMSO-d6):δ9.92(s,1H),7.71-7.75(m,2H),7.35-7.41(m,2H),6.93-6.97(m,2H),6.78-6.82(m,2H),3.85(t,J=13.2Hz,2H),1.63-1.68(m,2H),1.30-1.38(m,4H),0.87(t,J=13.5Hz,3H)。LRMS(EI)m/z 337(M+),108(100%);HRMS(EI)m/z计算值:C17H20FNO3S(M+)337.1148,实测值:337.1154。
实施例5 4-氟N-(4-辛氧基苯基)苯磺酰胺(N5)的合成
除了用4-辛氧基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率31.8%。mp 73-75℃;1H NMR(DMSO-d6):δ9.92(s,1H),7.70-7.75(m,2H),7.38(d,J=17.4Hz,2H),6.95(d,J=8.1Hz,2H),6.79(d,J=8.7Hz,2H),3.85(t,J=13.2Hz,2H),1.60-1.69(m,2H),1.25-1.38(m,10H),0.85(t,J=13.2Hz,3H)。LRMS(EI)m/z379(M+),108(100%);HRMS(EI)m/z计算值:C20H26FNO3S(M+)379.1617,实测值:379.1621。
实施例6 4-叔丁基-N-苯基苯磺酰胺(N6)的合成
除了用4-叔丁基苯磺酰氯代替对氟苯磺酰氯外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率41.1%。mp 155-157℃;1H NMR(DMSO-d6):δ10.32(s,1H),7.72(d,J=8.7Hz,2H),7.56(dd,J=1.8Hz & J=1.8Hz,2H),7.20-7.25(m,2H),7.13(t,J=7.8Hz,2H),7.01(d,J=7.2Hz,1H),1.25(s,9H)。LRMS(EI)m/z 289(M+),289(100%);HRMS(EI)m/z计算值:C16H19NO2S(M+)289.1136,实测值:289.1127。
实施例7 4-叔丁基-N-(4-异丙基苯基)苯磺酰胺(N7)的合成
除了用4-叔丁基苯磺酰氯代替对氟苯磺酰氯、4-异丙基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率37.9%。mp 144-145℃;1H NMR(DMSO-d6):δ10.20(s,1H),7.72(d,J=8.4Hz,2H),7.56(t,J=9.0Hz,2H),7.03-7.11(m,4H),2.73-2.78(m,1H),1.25(s,9H),1.10(d,J=6.9Hz,6H)。LRMS(EI)m/z 331(M+),316(100%);HRMS(EI)m/z计算值:C19H25NO2S(M+)331.1606,实测值:331.1613。
实施例8 4-叔丁基-N-(4-丁基苯基)苯磺酰胺(N8)的合成
除了用4-叔丁基苯磺酰氯代替对氟苯磺酰氯、用4-丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率34.1%。mp 113-114℃;1HNMR(DMSO-d6):δ10.15(s,1H),7.69(dd,J=1.5Hz & J=1.8Hz,2H),7.55(dd,J=1.8Hz & J=1.8Hz,2H),7.04(d,J=9.9Hz,4H),2.45(t,J=15.6Hz,2H),1.43-1.48(m,2H),1.25(s,9H),1.19-1.22(m,2H),0.83(t,J=13.8Hz,3H)。LRMS(EI)m/z 345(M+),345(100%);HRMS(EI)m/z计算值:C20H27NO2S(M+)345.1762,实测值:345.1764。
实施例9 4-叔丁基-N-(4-己基苯基)苯磺酰胺(N9)的合成
除了用4-叔丁基苯磺酰氯代替对氟苯磺酰氯、用4-己基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率30.6%。mp 79-80℃;1H NMR(DMSO-d6):δ10.16(s,1H),7.69(d,J=8.7Hz,2H),7.54(d,J=8.7Hz,2H),7.02(s,4H),2.43(t,J=15.0Hz,2H),1.43-1.48(m,2H),1.25(s,9H),1.21(s,6H),0.82(t,J=13.8Hz,3H)。LRMS(EI)m/z 373(M+),373(100%);HRMS(EI)m/z计算值:C22H31NO2S(M+)373.2075,实测值:373.2074。
实施例10 4-氯-N-(4-异丙基苯基)苯磺酰胺(N10)的合成
除了用4-氯苯磺酰氯代替对氟苯磺酰氯、用4-异丙基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率28.5%。mp 138-140℃;1H NMR(DMSO-d6):δ10.26(s,1H),7.75(d,J=8.4Hz,2H),7.63(dd,J=3.6Hz & J=3.3Hz,2H),7.11(d,J=8.4Hz,2H),7.01(t,J=8.4Hz,2H),2.50-2.52(m,1H),1.13(d,J=2.4Hz,3H),1.10(d,J=2.7Hz,3H)。LRMS(EI)m/z 309(M+),294(100%);HRMS(EI)m/z计算值:C15H16ClNO2S(M+)309.0590,实测值:309.0596。
实施例11 N-(4-丁基苯基)-4-氯苯磺酰胺(N11)的合成
除了用4-氯苯磺酰氯代替对氟苯磺酰氯、用4-丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率38.2%。mp 135-136℃;1H NMR(CDCl3):δ6.83(t,J=8.1Hz,2H),6.55(dd,J=1.8Hz & J=1.5Hz,2H),6.22(d,J=7.8Hz,2H),6.12(t,J=8.4Hz,2H),0.70(m,2H),0.45-0.78(m,2H),0.06(t,J=14.7Hz,3H)。LRMS(EI)m/z 323(M+),280(100%);HRMS(EI)m/z计算值:C16H18ClNO2S(M+)323.0747,实测值:323.0746。
实施例12 N-(4-丁氧基苯基)-4-氯苯磺酰胺(N12)的合成
除了用4-氯苯磺酰氯代替对氟苯磺酰氯、用4-丁氧基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率46.7%。mp 125-126℃;1H NMR(DMSO-d6):δ9.98(s,1H),7.56(t,J=50.7Hz,2H,4H),6.67-7.06(m,4H),3.91(t,J=37.5Hz,2H),1.49-1.77(m,2H),1.28-1.38(m,2H),0.83(t,J=35.1Hz,3H)。LRMS(EI)m/z 339(M+),108(100%);HRMS(EI)m/z计算值:C16H18ClNO3S(M+)339.0696,实测值:339.0690。
实施例13 4-氯-N-(4-戊氧基苯基)苯磺酰胺(N13)的合成
除了用4-氯苯磺酰氯代替对氟苯磺酰氯、用4-戊氧基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物米色固体,收率30.5%。mp 113-115℃;1H NMR(DMSO-d6):δ9.98(s,1H),7.60-7.68(m,4H),7.95(t,J=12.0Hz,2H),6.79-6.83(m,2H),3.85(t,J=12.9Hz,2H),1.61-1.68(m,2H),1.28-1.38(m,2H),0.87(t,J=14.1Hz,3H)。LRMS(EI)m/z 353(M+),108(100%);HRMS(EI)m/z计算值:C17H20ClNO3S(M+)353.0852,实测值:353.0851。
实施例14 4-溴-N-(4-异丙基苯基)苯磺酰胺(N14)的合成
除了用4-溴苯磺酰氯代替对氟苯磺酰氯、用4-异丙基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率37.2%。mp 145-146℃;1H NMR(DMSO-d6):δ10.27(s,1H),7.76(dd,J=1.8Hz & J=2.1Hz,2H),7.67(dd,J=1.8Hz & J=2.1Hz,2H),7.11(d,J=8.1Hz,2H),7.01(d,J=8.1Hz,2H),2.77(t,J=13.5Hz,1H),1.11(d,J=6.9Hz,6H)。LRMS(EI)m/z 353(M+),134(100%);HRMS(ESI)m/z计算值:C15H16BrNO2SNa(M++Na)375.9983,实测值:375.9994。
实施例15 4-溴-N-(4-叔丁基苯基)苯磺酰胺(N15)的合成
除了用4-溴苯磺酰氯代替对氟苯磺酰氯、用4-叔丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率36.3%。mp 205-207℃;1H NMR(DMSO-d6):δ10.30(s,1H),7.78(d,J=8.4Hz,2H),7.68(d,J=9.0Hz,2H),7.26(d,J=8.1Hz,2H),7.01(d,J=8.4Hz,2H),1.02(s,9H)。LRMS(EI)m/z 367(M+),134(100%);HRMS(EI)m/z计算值:C16H18BrNO2S(M+)367.0242,实测值:367.0258。
实施例16 4-溴-N-(4-丁基苯基)苯磺酰胺(N16)的合成
除了用4-溴苯磺酰氯代替对氟苯磺酰氯、用4-丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率42.9%。mp 149-150℃;1H NMR(DMSO-d6):δ10.21(s,1H),7.77(dd,J=1.2Hz & J=1.5Hz,2H),7.63-7.71(m,2H),7.06(d,J=7.2Hz,2H),6.98(t,J=8.7Hz,2H),2.45(t,J=4.8Hz,2H),1.39-1.52(m,2H),1.18-1.30(m,2H),0.84(d,J=14.4Hz,3H)。LRMS(EI)m/z 367(M+),148(100%);HRMS(EI)m/z计算值:C16H18BrNO2S(M+)367.0242,实测值:367.0252。
实施例17 N-(4-异丙基苯基)-4-甲基苯磺酰胺(N17)的合成
除了用4-甲基苯磺酰氯代替对氟苯磺酰氯、用4-异丙基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率30.8%。mp 169-171;1H NMR(DMSO-d6):δ10.11(s,1H),7.64(d,J=7.8Hz,2H),7.34(d,J=8.1Hz,2H),7.09(d,J=8.1Hz,2H),7.00(t,J=7.8Hz,2H),2.72-2.81(m,2H),2.33(s,3H),1.11(d,J=6.9Hz,6H)。LRMS(EI)m/z 289(M+),274(100%);HRMS(EI)m/z计算值:C16H19NO2S(M+)289.1136,实测值:289.1127。
实施例18 N-(4-丁基苯基)-4-甲基苯磺酰胺(N18)的合成
除了用4-甲基苯磺酰氯代替对氟苯磺酰氯、用4-丁基基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率44.7%。mp 83-84℃;1H NMR(DMSO-d6):δ10.05(s,1H),7.61(d,J=8.1Hz,2H),7.31(d,J=8.1Hz,2H),6.96-7.03(m,4H),2.43(t,J=15.6Hz,2H),1.39-1.49(m,2H),1.16-1.28(m,2H),0.84(t,J=14.4Hz,3H)。LRMS(EI)m/z 303(M+),260(100%);HRMS(EI)m/z计算值:C17H21NO2S(M+)303.1293,实测值:303.1287。
实施例19 4-氰基-N-苯基苯酰胺(N19)的合成
除了用4-氰基苯磺酰氯代替对氟苯磺酰氯外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率46.9%。mp 156-158℃;1H NMR(DMSO-d6):δ10.55(s,1H),8.04(dd,J=1.8Hz & J=1.8Hz,2H),7.89-7.92(m,2H),7.24-7.29(m,2H),7.08(t,J=14.7Hz,3H)。LRMS(EI)m/z 258(M+),92(100%);HRMS(EI)m/z计算值:C13H10N2O2S(M+)258.0463,实测值:258.0467。
实施例20 N-(4-丁基苯基)-4-氰基苯酰胺(N20)的合成
除了用4-氰基苯磺酰氯代替对氟苯磺酰氯、4-丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率23.6%。mp 90-91℃;1H NMR(DMSO-d6):δ10.41(s,1H),8.03(d,J=8.7Hz,2H),7.88(d,J=8.4Hz,2H),7.06(d,J=8.1Hz,2H),6.99(d,J=8.7Hz,2H),2.45(t,J=15.6Hz,2H),1.40-1.50(m,2H),1.16-1.28(m,2H),0.84(t,J=14.4Hz,3H)。LRMS(EI)m/z 314(M+),271(100%);HRMS(EI)m/z计算值:C17H18N2O2S(M+)314.1089,实测值:314.1095。
实施例21 N-(4-丁氧基苯基)-4-氰基苯磺酰胺(N21)的合成
除了用4-氰基苯磺酰氯代替对氟苯磺酰氯、4-丁氧基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率39.4%。mp 117-118℃;1H NMR(DMSO-d6):δ10.18(s,1H),8.03(d,J=8.7Hz,2H),7.83(d,J=8.4Hz,2H),6.96(d,J=9.0Hz,2H),6.81(d,J=8.7Hz,2H),3.86(t,J=12.9Hz,2H),1.59-1.68(m,2H),1.32-1.44(m,2H),0.89(t,J=14.7Hz,3H)。LRMS(EI)m/z 330(M+),108(100%);HRMS(EI)m/z计算值:C17H18N2O3S(M+)330.1038,实测值:330.1040。
实施例22 4-氰基-N-4-(辛氧基苯基)苯磺酰胺(N22)的合成
除了用4-氰基苯磺酰氯代替对氟苯磺酰氯、4-辛氧基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率35.6%。mp 156-158℃;1H NMR(DMSO-d6):δ10.17(s,1H),8.03(d,J=8.7Hz,2H),7.83(d,J=8.4Hz,2H),6.96(d,J=8.7Hz,2H),6.80(d,J=9.0Hz,2H),3.85(t,J=12.9Hz,2H),1.60-1.67(m,2H),1.24-1.38(m,10H),0.85(t,J=13.2Hz,3H)。LRMS(EI)m/z 386(M+),108(100%);HRMS(EI)m/z计算值:C21H26N2O3S(M+)386.1664,实测值:386.1665。
实施例23 N-苯基萘-2-磺酰胺(N23)的合成
除了用萘-2-磺酰氯代替对氟苯磺酰氯外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率30.3%。mp 138-139℃;1H NMR(DMSO-d6):δ10.39(s,1H),8.43(s,1H),8.09(t,J=18.9Hz,2H),7.98(d,J=8.1Hz,1H),7.78(dd,J=1.8Hz & J=1.8Hz,1H),7.60-7.70(m,2H),7.11-7.22(m,4H),6.97(t,J=14.4Hz,1H)。LRMS(EI)m/z 283(M+),127(100%);HRMS(EI)m/z计算值:C16H13NO2S(M+)283.0667,实测值:283.0665。
实施例24 N-(4-异丙基苯基)萘-2-磺酰胺(N24)的合成
除了用萘-2-磺酰氯代替对氟苯磺酰氯、4-异丙基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率39.1%。mp 145-146℃;1H NMR(DMSO-d6):δ10.30(s,1H),8.42(s,1H),8.10(t,J=15.3Hz,2H),8.00(d,J=7.2Hz,1H),7.80(dd,J=1.8Hz & J=1.8Hz,1H),7.64-7.69(m,2H),7.02-7.09(m,4H),2.70-2.75(m,1H),1.07(d,J=6.9Hz,6H)。LRMS(EI)m/z 325(M+),310(100%);HRMS(EI)m/z计算值:C19H19NO2S(M+)325.1136,实测值:325.1129。
实施例25 N-(4-丁基苯基)萘-2-磺酰胺(N25)的合成
除了用萘-2-磺酰氯代替对氟苯磺酰氯、4-丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率46.8%。mp 109-110℃;1H NMR(DMSO-d6):δ10.38(s,1H),8.39(d,J=1.5Hz,1H),8.09(t,J=15.3Hz,2H),8.00(d,J=8.1Hz,1H),7.77(dd,J=1.8Hz & J=1.8Hz,1H),7.63-7.71(m,2H),7.01(s,4H),2.41(t,J=15.0Hz,2H),1.39-1.44(m,2H),1.15-1.23(m,2H),0.82(t,J=14.7Hz,3H)。LRMS(EI)m/z339(M+100%);HRMS(EI)m/z计算值:C20H21NO2S(M+)339.1293,实测值:339.1301。
实施例26 N-(4-戊氧基苯基)萘-2-磺酰胺(N26)的合成
除了用萘-2-磺酰氯代替对氟苯磺酰氯、4-戊氧基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率44.3%。mp 98-100℃;1H NMR(DMSO-d6):δ10.03(s,1H),8.34(d,J=1.2Hz,1H),8.07-8.11(m,2H),8.00(d,J=7.5Hz,1H),7.51(dd,J=1.8Hz & J=1.8Hz,1H),7.60-7.70(m,2H),6.97-7.01(m,2H),6.75(dd,J=3.0Hz & J=3.6Hz,2H),3.80(t,J=12.6Hz,2H),1.56-1.63(m,2H),1.23-1.33(m,2H),0.83(t,J=13.8Hz,3H)。LRMS(EI)m/z 369(M+),108(100%);HRMS(EI)m/z计算值:C21H23NO3S(M+)369.1399,实测值:369.1398。
实施例27 N-(4-丁基苯基)-4-(三氟甲基)苯磺酰胺(N27)的合成
除了用4-三氟甲基苯磺酰氯代替对氟苯磺酰氯、4-丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率49.7%。mp 106-107℃;1H NMR(DMSO-d6):δ10.38(s,1H),7.94(s,4H),7.05-7.08(m,2H),7.00(dd,J=2.4Hz & J=1.5Hz,1H),2.46(t,J=15.6Hz,2H),1.41-1.48(m,2H),1.19-1.26(m,2H),0.84(t,J=14.1Hz,3H)。LRMS(EI)m/z 357(M+),314(100%);HRMS(EI)m/z计算值:C17H18F3NO2S(M+)357.1010,实测值:357.1017。
实施例28 N-(4-丁基苯基)-4-(甲磺酰基)苯磺酰胺(N28)的合成
除了用4-甲磺酰基苯磺酰氯代替对氟苯磺酰氯、4-丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率38.2%。mp 179-180℃;1H NMR(DMSO-d6):δ8.11(d,J=8.7Hz,2H),7.98(d,J=8.4Hz,2H),7.07(d,J=8.7Hz,2H),7.00(d,J=8.7Hz,2H),3.28(s,3H),2.47(t,J=15.6Hz,2H),1.42-1.49(m,2H),1.21-1.28(m,2H),0.86(t,J=14.7Hz,3H)。LRMS(EI)m/z 367(M+),324(100%);HRMS(EI)m/z计算值:C17H21NO4S2(M+)367.0912,实测值:367.0912。
实施例29 N-(4-丁氧基苯基)-4-(甲磺酰基)苯磺酰胺(N29)的合成
除了用4-甲磺酰基苯磺酰氯代替对氟苯磺酰氯、4-丁氧基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率40.6%。mp 194-196℃;1H NMR(DMSO-d6):δ10.20(s,1H),8.09-8.12(m,2H),7.91-7.95(m,2H),6.98(dd,J=2.4Hz & J=2.4Hz,1H),6.82(dd,J=2.4Hz & J=2.1Hz,1H),3.87(t,J=12.6Hz,2H),3.29(s,3H),1.60-1.67(m,2H),1.36-1.43(m,2H),0.91(t,J=15.0Hz,3H)。LRMS(EI)m/z 383(M+),108(100%);HRMS(EI)m/z计算值:C17H21NO5S2(M+)383.0861,实测值:383.0872。
实施例30 N-(4-丁基苯基)-1-苄基磺酰胺(N30)的合成
除了用苄基磺酰氯代替对氟苯磺酰氯、4-丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率49.0%。mp 104-105℃;1H NMR(DMSO-d6):δ9.71(s,1H),7.32-7.40(m,3H),7.24-7.30(m,2H),7.11-7.17(m,4H),4.41(s,1H),2.54(t,J=15.0Hz,2H),1.49-1.60(m,2H),1.25-1.37(m,2H),0.91(t,J=14.7Hz,3H)。LRMS(EI)m/z 303(M+),91(100%);HRMS(EI)m/z计算值:C17H21NO2S(M+)303.1293,实测值:303.1296。
实施例31 N-(4-己基苯基)-1-苄基磺酰胺(N31)的合成
除了用苄基磺酰氯代替对氟苯磺酰氯、4-己基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率44.1%。mp 77-78℃;1H NMR(DMSO-d6):δ9.72(s,1H),7.33-7.38(m,3H),7.25-7.28(m,2H),7.10-7.17(m,4H),4.41(s,2H),1.53-1.57(m,2H),1.30(d,J=8.7Hz,6H),0.87(t,J=13.2Hz,3H)。LRMS(EI)m/z 331(M+),91(100%);HRMS(EI)m/z计算值:C19H25NO2S(M+)331.1606,实测值:331.1598。
实施例32 N-(4-丁氧基苯基)-1-苄基磺酰胺(N32)的合成
除了用苄基磺酰氯代替对氟苯磺酰氯、4-丁氧苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率43.4%。mp 105-106℃;1H NMR(DMSO-d6):δ9.53(s,1H),7.34-7.36(m,3H),7.27(t,J=7.5Hz,2H),7.14(d,J=9.0Hz,2H),6.90(d,J=8.7Hz,2H),4.34(s,2H),3.93(t,J=12.9Hz,2H),1.66-1.71(m,2H),1.40-1.47(m,2H),0.93(t,J=15.0Hz,3H)。LRMS(EI)m/z 319(M+),108(100%);HRMS(EI)m/z计算值:C17H21NO3S(M+)319.1242,实测值:319.1250。
实施例33 N-(4-异丙基苯基)联苯基-4-磺酰胺(N33)的合成
除了用联苯基-4-磺酰氯代替对氟苯磺酰氯、4-异丙基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率35.7%。mp 195-197℃;1H NMR(DMSO-d6):δ10.26(s,1H),7.85(s,4H),7.70(d,J=7.5Hz,2H),7.40-7.52(m,3H),7.05-7.13(m,4H),2.75-2.79(m,1H),1.11(d,J=6.3Hz,6H)。LRMS(EI)m/z 351(M+),134(100%);HRMS(EI)m/z计算值:C21H21NO2S(M+)351.1293,实测值:351.1295。
实施例34 N-(4-丁基苯基)联苯基-4-磺酰胺(N34)的合成
除了用联苯基-4-磺酰氯代替对氟苯磺酰氯、4-丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率36.5%。mp 163-164℃;1H NMR(DMSO-d6):δ10.22(s,1H),7.80-7.86(m,4H),7.70(d,J=7.5Hz,2H),7.42-7.52(m,3H),7.05(t,J=18.6Hz,4H),2.45(t,J=15.3Hz,2H),1.40-1.48(m,2H),1.19-1.27(m,2H),0.84(t,J=14.7Hz,3H)。LRMS(EI)m/z 365(M+,100%);HRMS(EI)m/z计算值:C22H23NO2S(M+)365.1449,实测值:365.1457。
实施例35 N-苯基-4-(1H-吡唑-1-基)苯磺酰胺(N35)的合成
除了用4-(1H-吡唑-1-基)苯磺酰氯代替对氟苯磺酰氯外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率48.3%。mp 161-163℃;1H NMR(CDCl3):δ7.11(d,J=2.4Hz,1H),7.01(d,J=8.1Hz,2H),6.92(d,J=9.0Hz,3H),6.38-6.43(m,2H),6.24-6.31(m,3H),6.13(s,1H),5.66(d,J=1.8Hz,1H)。LRMS(EI)m/z 299(M+,100%);HRMS(EI)m/z计算值:C15H13N3O2S(M+)299.0728,found299.0730。
实施例36 N-(4-丁基苯基)-4-(1H-比唑-1-基)苯磺酰胺(N36)的合成
除了用4-(1H-吡唑-1-基)苯磺酰氯代替对氟苯磺酰氯、4-丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率38.4%。mp 167-168℃;1HNMR(DMSO-d6):δ10.15(s,1H),8.59(d,J=2.4Hz,1H),8.01(d,J=8.4Hz,2H),7.83(d,J=7.8Hz,3H),6.99-7.07(m,4H),6.61(d,J=2.4Hz,1H),2.45(t,J=15.0Hz,2H),1.41-1.51(m,2H),1.17-1.29(m,2H),0.84(t,J=14.4Hz,3H)。LRMS(EI)m/z 355(M+),148(100%);HRMS(EI)m/z计算值:C19H21N3O2S(M+)355.1354,实测值:355.1345。
实施例37 N-(4-丁基苯基)苯并[1,2,5]噻二唑-5-磺酰胺(N37)的合成
除了用苯并[1,2,5]噻二唑-5-磺酰氯代替对氟苯磺酰氯、4-丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率34.7%。mp 120-122℃;1H NMR(DMSO-d6):δ10.48(s,1H),8.43(d,J=0.6Hz,1H),8.29(dd,J=0.9Hz & J=0.6Hz,1H),7.96(dd,J=1.8Hz & J=1.8Hz,1H),7.00-7.06(m,4H),2.41(t,J=15.3Hz,2H),1.35-1.45(m,2H),1.11-1.24(m,2H),0.80(t,J=14.4Hz,3H)。LRMS(EI)m/z 347(M+),304(100%);HRMS(EI)m/z计算值:C16H17N3O2S2(M+)347.0762,实测值:347.0763。
实施例38 N-(4-丁基苯基)-4-(2-氯苯氧基)苯磺酰胺(N38)的合成
除了用4-(2-氯苯氧基)苯磺酰氯代替对氟苯磺酰氯、4-丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率46.7%。mp 106-107℃;1H NMR(DMSO-d6):δ10.10(s,1H),7.73(d,J=8.7Hz,2H),7.64(dd,J=1.8Hz & J=1.5Hz,1H),7.41-7.46(m,1H),7.26-7.36(m,2H),6.98-7.06(m,6H),2.46(t,J=15.6Hz,2H),1.41-1.51(m,2H),1.20-1.27(m,2H),0.85(t,J=14.4Hz,3H)。LRMS(EI)m/z 415(M+,100%);HRMS(EI)m/z计算值:C22H22ClNO3S(M+)415.1009,实测值:415.1007。
实施例39 N-4-(丁基苯基)-4-(2-甲氧苯氧基)苯磺酰胺(N39)的合成
除了用4-(2-甲氧苯氧基)苯磺酰氯代替对氟苯磺酰氯、4-丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率42.5%。mp 111-112℃;1HNMR(DMSO-d6):δ10.05(s,1H),7.67(d,J=9.0Hz,2H),7.26-7.28(m,1H),7.20(d,J=7.8Hz,1H),7.14(d,J=6.9Hz,1H),6.97-7.06(m,5H),6.90(d,J=8.7Hz,2H),3.69(s,3H),2.46(t,J=15.0Hz,2H),1.42-1.50(m,2H),1.21-1.28(m,2H),0.86(t,J=14.4Hz,3H)。LRMS(E1)m/z 411(M+,100%);HRMS(EI)m/z计算值:C23H25NO4S(M+)411.1504,实测值:411.1504。
实施例40 N-(4-丁基苯基)喹啉-8-磺酰胺(N40)的合成
除了用喹啉-8-磺酰氯代替对氟苯磺酰氯、4-丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率40.1%。mp 183-183℃;1H NMR(DMSO-d6):δ9.88(s,1H),9.15(dd,J=1.8Hz & J=2.1Hz,1H),8.51(dd,J=1.5Hz & J=1.5Hz,1H),8.30(dd,J=7.5Hz & J=11.4Hz,1H),8.24-8.27(m,1H),7.66-7.75(m,2H),6.87-6.95(m,4H),2.35(t,J=15.6Hz,2H),1.32-1.42(m,2H),1.11-1.23(m,2H),0.80(t,J=14.4Hz,3H)。LRMS(EI)m/z 340(M+),69(100%);HRMS(EI)m/z计算值:C19H20N2O2S(M+)340.1245,实测值:340.1244。
实施例41 N-(4-丁基苯基)-4-氟苯磺酰胺(N41)的合成
除了用4-丁基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物白色固体,收率45.6%。1H NMR(DMSO-d6):δ7.74-7.79(m,2H),7.03-7.12(m,4H),6.97(dd,J=1.5Hz & J=1.5Hz,2H),2.53(t,J=11.7Hz,2H),1.49-1.56(m,2H),1.25-1.34(m,2H),0.89(t,J=10.8Hz,3H)。LRMS(EI)m/z 307(M+),264(100%);HRMS(EI)m/z计算值:C16H18NFO2S(M+)307.1042,实测值:307.1044。
实施例42 N-[4-(3-乙酰基-苄基磺酰基)苯基]-3,4-二甲氧基-苯磺酰胺(N42)的合成
除了用3,4-二甲氧基-苯磺酰氯代替对氟苯磺酰氯、1-[3-(4-胺基-苯磺酰基甲基)苯乙酮(Journal of the Chemical Society.1945,566-71.)代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物,收率46.0%。1H NMR(CDCl3):δ7.75-7.65(m,2H),7.30-7.58(m,3H),7.16-7.20(m,2H),6.91(dd,J=1.5Hz & J=1.5Hz,2H),6.69(dd,J=1.5Hz & J=1.5Hz,2H),5.17(s,2H),3.83(s,6H),2.50(s,3H)。
实施例43 N-[4-(4-丁基-苯磺酰胺基)苯基异丁酰胺(N43)的合成
除了用4-丁基-苯磺酰氯代替对氟苯磺酰氯、N-(4-胺基-苯基)异丁酰胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物,收率52.0%。1H NMR(CDCl3):δ7.81(m,2H),7.45(m,2H),7.39(dd,J=1.5Hz & J=1.5Hz,2H),6.61(dd,J=1.5Hz & J=1.5Hz,2H),2.68(m,1H),2.62(t,2H),1.59(m,2H),1.31(m,2H),1.14(d,2H),0.9(t,3H)。
实施例44 N-(4-苄基苯基)-3-(哌啶-1-羰基)-苯磺酰胺(N44)的合成
除了用3-(哌啶-1-羰基)-苯磺酰氯(Aurora Screening Library)代替对氟苯磺酰氯、4-苄基苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物,收率43.0%。1H NMR(CDCl3):δ8.48(m,1H),8.11(m,1H),7.91(m,1H),7.37(m,2H),7.33(m,2H),7.26(m,1H),7.23(dd,J=1.5Hz & J=1.5Hz,2H),7.03(m,1H),6.98(dd,J=1.5Hz & J=1.5Hz,2H),3.96(s,2H),3.77(m,4H),1.59(m,1H),1.53(m,4H)。
实施例45 N-(4-(4-苯硫基)苯基)-3-(哌啶-1-羰基)苯磺酰胺(N45)的合成
除了用3-(哌啶-1-羰基)-苯磺酰氯(Aurora Screening Library)代替对氟苯磺酰氯、4-苯硫基-苯胺(Chemistry--AEuropean Journal.2007,13,5100-5105.)代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物,收率40.0%。1H NMR(CDCl3):δ8.48(m,1H),8.11(m,1H),7.91(m,1H),7.41(m,2H),7.25(m,2H),7.19(m,1H),7.16(dd,J=1.5Hz & J=1.5Hz,2H),7.03(m,1H),6.43(dd,J=1.5Hz & J=1.5Hz,2H),3.77(m,4H),1.59(m,1H),1.53(m,4H)。
实施例46 N-(4-苯氧基-苯基)-3-苄基磺酰基-苯磺酰胺(N46)的合成
除了用3-苄基磺酰基-苯磺酰氯代替对氟苯磺酰氯、4-苯氧基-苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物,收率37.0%。1H NMR(CDCl3):δ8.49(m,1H),8.01(m,1H),7.86(m,2H),7.41(dd,J=1.5Hz & J=1.5Hz,2H),7.26(m,1H),7.14-7.17(m,3H),7.02(m,2H),6.76(dd,J=1.5Hz & J=1.5Hz,2H),5.17(s,2H)。
实施例47 N-(4-((4-苯基氨甲基)苯基)-3-(吡啶-2-氧代)苯磺酰胺(N47)的合成
除了用3-(吡啶-2-氧代)-苯磺酰氯代替对氟苯磺酰氯、4-苯基氨甲基-苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物,收率45.0%。1H NMR(CDCl3):δ8.49(m,1H),8.01(m,1H),7.86(m,2H),7.41(dd,J=1.5Hz & J=1.5Hz,2H),7.26(m,1H),7.14-7.17(m,3H),7.02(m,2H),6.76(dd,J=1.5Hz & J=1.5Hz,2H),5.17(s,2H)。
实施例48 4-(3-溴-4-[[(2-甲基环丙基)羰基]氨基]-苯磺酰胺基)苯甲酰胺(N48)的合成
除了用3-溴-4-[[(2-甲基环丙基)羰基]氨基]-苯磺酰氯(Ambinter Stock Screening Collection)代替对氟苯磺酰氯、4-胺基-苯甲酰胺(Nature Protocols.2006,1,2590-2595.)代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物,收率33.0%。1H NMR(CDCl3):δ8.08(m,1H),7.98(m,1H),7.78(m,1H),7.53(dd,J=1.5Hz & J=1.5Hz,2H),7.16(dd,J=1.5Hz & J=1.5Hz,2H),1.15(m,1H),0.91(s,3H),0.65(m,1H),0.61(m,1H),0.40(m,1H)。
实施例49 N-(4-苯甲酰基苯基)-3-(吡啶-2-氧代)苯磺酰胺(N49)的合成
除了用3-(吡啶-2-氧代)-苯磺酰氯代替对氟苯磺酰氯、(4-胺基-苯基)-苯乙酮(Synthetic Communications.2007,37,4381-4388.)代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物,收率42.0%。1H NMR(CDCl3):δ7.78(dd,J=1.5Hz & J=1.5Hz,2H),7.64-7.66(m,2H),7.52-7.56(m,6H),7.42(s,1H),7.21(s,1H),7.08(dd,J=1.5Hz & J=1.5Hz,2H),6.95(s,1H),6.54(m,1H),6.40(s,1H)。
实施例50 3-(吡啶-2-氧代)-N-[4-(1H-吡咯-2-基)-苯基]-苯磺酰胺(N50)的合成
除了用3-(吡啶-2-氧代)-苯磺酰氯代替对氟苯磺酰氯、4-(1H-吡咯-2-)-苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物,收率50.0%。1H NMR(CDCl3):δ7.66(m,1H),7.52-7.56(m,4H),7.42(s,1H),7.21(m,1H),6.95(m,2H),6.69(dd,J=1.5Hz & J=1.5Hz,2H),6.54(s,1H),6.40(dd,J=1.5Hz & J=1.5Hz,2H),6.15(m,1H)。
实施例51 N-(4-(呋喃-2-基)苯基)-2-甲氧基-5-3-(吡啶-2-氧代)-苯磺酰胺(N51)的合成
除了用3-(吡啶-2-氧代)-苯磺酰氯代替对氟苯磺酰氯、4-(呋喃-2-基)苯胺(Maybridge Building Blocks)代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物,收率41.0%。1H NMR(CDCl3):δ7.66(m,1H),7.86(m,1H),7.66(m,1H),7.54(dd,J=1.5Hz& J=1.5Hz,2H),7.41(m,1H),7.21(m,1H),7.07-7.13(m,3H),6.68-6.69(m,3H),6.54(m,1H),6.40(m,1H),3.83(s,3H)。
实施例52 2-乙氧基-4-(4-苯硫基-苯磺酰基)-苯甲酸甲酯(N52)的合成
除了用4-苯硫基-苯磺酰氯代替对氟苯磺酰氯、4-胺基-2-乙氧基-苯甲酸甲酯代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物,收率47.0%。1H NMR(CDCl3):δ7.66-7.69(m,5H),7.41(dd,J=1.5Hz & J=1.5Hz,2H),7.19-7.25(m,3H),6.65(m,1H),6.29(s,1H),4.09(t,2H),3.89(s,3H),1.32(q,3H)。
实施例53 5-(苯并噻吩-2-磺酰胺)-2-三氟甲基-苯甲酸(N53)的合成
除了用苯并噻吩-2-磺酰氯代替对氟苯磺酰氯、5-胺基-2-三氟甲基-苯甲酸代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物,收率44.0%。1H NMR(CDCl3):δ11.0(s,1H),7.98(s,1H),7.70-7.79(m,3H),7.50-7.58(m,3H),7.20(s,1H).
实施例54 N-[3-(5-氯-呋喃-2-基)-苯基]-4-羟基-3-三氟甲基-苯磺酰胺(N54)的合成
除了用4-羟基-3-三氟甲基-苯磺酰氯代替对氟苯磺酰氯、3-(5-氯-呋喃-2-基)-苯胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物,收率38.0%。1H NMR(CDCl3):δ7.99(s,1H),7.58(s,1H),7.44-7.46(m,2H),7.16(s,1H),7.07(s,1H),6.89(s,1H),6.54-59(m,2H)。
实施例55 7-乙酰基-喹啉-2-磺酸(3,4-二甲硫基-苯基)-酰胺(N55)的合成
除了用7-乙酰基-喹啉-2-磺酰氯代替对氟苯磺酰氯、3,4-二甲硫基-苯胺(Journal ofChemical Research,Synopses,1986,11,432)代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物,收率43.0%。1H NMR(CDCl3):δ8.74(m,1H),8.56(s,1H),8.04-8.14(m,3H),7.15(s,1H),7.04(m,1H),6.29(s,1H),2.53(s,6H)。
实施例56 6-(氰基甲基)-N-(4-(丙胺基)苯基)吡啶-2-磺酰胺(N56)的合成
除了用6-(氰基甲基)吡啶-2-磺酰氯代替对氟苯磺酰氯、N-丙基-苯基-1,4-二胺(Russian Chemical Bulletin(Translation of Izvestiya Akademii Nauk,Seriya Khimicheskaya),2003,52,273-275)代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物,收率36.0%。1H NMR(CDCl3):δ7.89-7.93(m,2H),7.18(s,1H),6.35-6.41(m,1H),4.00(s,2H),3.35(t,2H),1.57(m,2H),0.90(t,3H)。
实施例57 5-[2-(6-溴-7-三氟甲氧基-萘-2-基)-乙烯基]-1H-咪唑-2-磺酸(3-丙基-1H-吲哚-5-基)-酰胺(N57)的合成
除了用5-[2-(6-溴-7-三氟甲氧基-萘-2-基)-乙烯基]-1H-咪唑-2-磺酰氯代替对氟苯磺酰氯、3-丙基-1H-吲哚-5-胺代替苯胺外,按实施例1相同的方法操作及后处理,得到标题化合物,收率45.0%。1H NMR(CDCl3):δ8.14(s,1H),7.68-7.73(m,2H),7.44(m,1H),7.26-7.30(m,2H),7.18(s,1H),6.95-7.07(m,3H),6.38(dd,J=1.5Hz & J=1.5Hz,2H),2.50(t,2H),1.59(m,2H),0.90(t,3H)。
第二部分:生物活性测试试验实施例
试验实施例1:待测化合物钙信号检测
筛选模型通过在CHO-K1细胞株稳定转染hGPR40受体或hGPR120表达载体,建立基于检测钙信号的化合物筛选模型。筛选可拮抗EC80浓度的游离脂肪酸引发的钙信号的化合物。
1、实验材料与仪器
1.1受试样品:所有的受试化合物均为中国科学院上海药物研究所DDDC提供。所有化合物均溶于DMSO。用DMSO溶解后储备浓度均为0.1M,临用前稀释成所需受试浓度。
1.2细胞株:中国仓鼠卵巢癌细胞株CHO-K1购自美国细胞库(ATCC)。
1.3质粒:pcDNA-hGPR40和pcDNA-hGPR120购自上海华大天源生物科技有限公司。
1.4细胞培养以及分子生物学试剂:F12(Ham’s F12营养培养基),游离钙荧光探针Fluo-4AM染料,潮霉素B购自Amersco公司;转染试剂FUGEN6转染试剂购自ROCHE公司;胎牛血清(Fatal bovine serum,FBS)购自Hyclone公司;游离脂肪酸购自Sigma公司。
1.5主要仪器:FlexStation 384II购自Molecular Devices公司。
2、实验方法
2.1将hGPR40-CHO细胞按30000个/孔的量接种于96孔板,用含10%胎牛血清,F12培养过夜,约20小时。
2.2吸去培养基每孔加含3μM Fluo-4AM,2.5mM丙磺舒(probenecid)的Krebs缓冲液(NaCl 129.4mM、KCl 5.2mM、CaCl2 2.8mM、KH2PO4 1.3mM、MgSO4·7H2O 1.3mM、NaHCO3 24.8mM、10mM HEPES及2.8mM葡萄糖,调节到pH 7.4)100μl,孵育90分钟。
2.3吸去培养基,用不含Fluo-4AM,2.5mM丙磺舒Krebs缓冲液洗三次。
2.4每孔加入100μl不含Fluo-4AM,2.5mM丙磺舒的Krebs缓冲液。
2.5每孔加待测化合物预孵育10分钟,DMSO含量均低于1%。
2.6在FlexStation 384III检测加入根据实验需要的相应浓度的亚油酸刺激的荧光强度的变化。
3、实验结果
待测化合物实验结果见表1。根据表1所示,化合物N41的活性最好。
亚油酸、油酸、棕榈油酸和月桂酸为GPR40受体的激动剂,在所建的hGPR40-CHO细胞模型上EC50分别为4.52μM、4.87μM、3.49μM、3.81μM。图1为化合物N41拮抗hGPR40激动剂亚油酸、油酸、棕榈油酸和月桂酸诱导的钙信号。由图1可以看出化合物N41都可剂量依赖地拮抗上述激动剂(EC50浓度),IC50分别为6.28±2.56μM、6.00±0.25μM、7.07±1.76μM、4.58±0.05μM。图2为化合物N41在hGPR120细胞株的选择性实验。图2显示出化合物N41浓度达到10μM时也不影响亚油酸在hGPR120细胞株的EC50值,表明化合物N41为选择性的GPR40受体拮抗剂。
表1化合物剂量依赖的拮抗EC80浓度亚油酸的IC50的结果(±SD)
试验实施例2:化合物N41的GTP-EU结合实验
当配体与受体GPR40结合,G蛋白α亚基构象改变,并与GTP结合以代替GDP,从而α亚基与βγ亚基解离,但是由于GTP酶的存在,可使结合的GTP水解为GDP,α亚基恢复最初构象,进而α亚基重新与βγ亚基复合体结合,在这个过程中,由于加入了不易被水解的GTP-EU,缓冲液洗去未结合的GTP-EU,然后检测GTP-Eu的量从而判断受体与配体的结合的程度(J.Biomol.Screen.2000,5,455-461)。
1、实验材料与仪器
1.1细胞株:稳定表达hGPR40受体的CHO-K1细胞株。
1.2试剂:DELFIAR GTP结合试剂盒购自Perkin Elmer公司,牛血清白蛋白购自上海捷贝斯生物公司,其他常规化学试剂购自上海国药集团。
1.3仪器:Flexstation III酶标仪(Molecular Devices公司),低温离心机。
2、实验方法
收集稳定表达hGPR40受体的CHO-K1细胞膜蛋白30μg,与含GPR40受体激动剂(10μM亚油酸),或者不含GPR40受体激动剂的基础缓冲液(1mM MgCl2、0.2μM GDP、20mM NaCl、500μg/ml皂角苷、1mM脱氧胆酸钠、50mM Hepes)120μl每孔,孵育30分钟,然后每孔加10μl 300nM GTP-EU,继续孵育6小时。3000rpm离心5分钟,每孔加wash缓冲液200μl,3000rpm离心5分钟,每孔再加冲洗缓冲液200μl,3000rpm离心5分钟,检测荧光值,激发波长340nm,发射波长为615nm。
3、实验结果
图3所示为不同剂量化合物N41拮抗10μM亚油酸GTP结合曲线。可以看出,化合物N41可剂量依赖的拮抗10μM亚油酸诱导的GTP置换,IC50为1.15±0.5μM。结合钙信号检测数据进一步验证了N41为GPR40受体的拮抗剂。
试验实施例3:化合物N41拮抗棕榈酸诱导的胰岛素分泌实验
1、实验材料与仪器
1.1细胞株:小鼠胰岛β细胞株MIN6。
1.2材料:胰岛素检测试剂盒购自美国Linco Research公司。
2、实验方法
将40000个/孔的量的细胞接种于96孔板,用含10%胎牛血清的高糖DMEM培养48小时。吸去培养基,用不含葡萄糖的Krebs缓冲液(0.05%(w v-1)BSA)洗3次。随后每孔加入含2.5mM的葡萄糖的Krebs(0.05%(w v-1)BSA)缓冲液100μl,继续孵育30分钟。用不含葡萄糖的Krebs缓冲液洗2次,每孔加入化合物和25mM葡萄糖的Krebs(0.05%(w v-1)BSA)缓冲液200μl,继续孵育2小时。取上清检测胰岛素含量。检测步骤依据试剂盒说明书操作。
3、实验结果
图4为化合物N41抑制棕榈酸诱导的MIN6细胞胰岛素的分泌。表明化合物N41在1μM、3μM时可抑制棕榈酸诱导的胰岛素的分泌(*p<0.05,**p<0.01,与0μM N41+45μM棕榈酸比较)。
试验实施例4:化合物N41保护棕榈酸诱导的MIN6细胞损伤
1、实验材料与仪器
1.1细胞株:小鼠胰岛β细胞株MIN6。
1.2材料:MTT购自上海捷贝斯生物公司。
2、实验方法
将40000个/孔的量的细胞接种于96孔板,用含10%胎牛血清,高糖DMEM培养过夜。第二天,每孔细胞加入不同剂量的化合物(终浓度为0.3μM、1μM、3μM、10μM),含或者不含400μM棕榈酸,继续培养48小时。每孔加MTT溶液(PBS配置5mg/ml,pH=7.4)20μl,继续孵育4小时,终止培养,每孔加入三联液(三联溶解液:SDS 10g,异丁醇5ml,10M HCl 0.1ml用双蒸水溶解配成100ml)100μl,37℃孵育8小时,震荡10分钟,570nm比色。
3、实验结果
图5为化合物N41对棕榈酸诱导的MIN6细胞损伤的保护。表明化合物N41在0.1μM,0.3μM,1μM时皆可抑制棕榈酸诱导的细胞数量的减少。提示该化合物可能具有保护棕榈酸诱导的MIN6细胞损伤的作用(*p<0.05,**p<0.01,与0μM N41+400μM棕榈酸比较)。
试验实施例5:化合物N41提高Zucker肥胖大鼠胰岛素敏感性
1、实验动物与材料
Zucker肥胖大鼠从日本引进,由本实验室繁殖;Zucker肥胖大鼠是一种自发遗传性肥胖、胰岛素抵抗、高胰岛素血症大鼠。8周龄,雌性,每组4-6只。血糖仪及试纸为强生公司产品。
2、实验方法
N41用丙二醇溶解,腹腔注射给药,共6周。实验期间定期检测摄食量和体重。胰岛素耐量实验作为胰岛素敏感性指标,方法为:禁食6小时,然后腹腔注射胰岛素(0.75U/kg),注射后0、15、30、60、90分钟检测血糖。给药6周后,取血,检测血清胰岛素水平。
3、实验结果
从表2可以看出,化合物N41对摄食量和体重没有影响,但是显著降低了血清胰岛素含量,这可能是化合物N41长期拮抗GPR40的结果。图6为化合物N41对胰岛素耐量的影响。图6表明,化合物N41给药组大鼠在15和30分钟的血糖明显低于模型组,因此化合物N41提高了Zucker肥胖大鼠胰岛素敏感性。
表2化合物N41对体重、摄食量、胰岛素的影响(±SD)
工业实用性
本发明的取代磺酰胺类化合物在计算机虚拟筛选以及GTP结合蛋白偶联受体40(G-Protein Coupling Receptor 40,GPR40;或Free Fatty Acid Receptor 1,FFAR1)实验、拮抗亚油酸诱导GPR40/CHO细胞内钙流实验、游离脂肪酸诱导Min6细胞胰岛素分泌实验模型上有较强的拮抗活性,并可增强肥胖胰岛素抵抗大鼠Zucker Fatty的胰岛素敏感性。因而可作为糖尿病等相关疾病预防和/或治疗的药物。
因此,本发明的取代磺酰胺类化合物可用于制备预防和/或治疗糖尿病等相关疾病的药物。
Claims (12)
1.式(I)所示的取代磺酰胺类化合物或其药学上可接受的盐,
其中:
芳香基Ar为非必需地被取代的C6-C20稠合杂环基、苄基、苯基、萘基或5~7元杂环基;所述取代被1~4个各自独立地选自卤素、C1-C8直链或支链饱和或不饱和烃基、C3-C7环烃基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、羧基、苄基、苯基、萘基和5~7元杂环基的基团取代;
X不存在或为-O-、-S-、-NH-、-NHC(O)-、-C(O)NH-、-C(O)-或-SO2-;
Y不存在或为C1-C8直链或支链饱和或不饱和烃基、C3-C7环烃基、三氟甲基、苯基、苄基、萘基或5~7元杂环基;其中,所述苯基、苄基、萘基和5~7元杂环基非必需地被1~4个各自独立地选自卤素、C1-C8直链或支链饱和或不饱和烃基、C3-C7环烃基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、羧基、巯基、苄基、苯基、萘基和5~7元杂环基的基团取代;
Z不存在或为氢、卤素、C1-C8直链或支链饱和或不饱和烃基、C3-C7环烃基、氰基、硝基、羟甲基、三氟甲基、苄基、苯基、萘基、5~7元杂环基、-O-、-S-、-NH-、-C(O)-、-C(O)O-、-SO2-、-NHC(O)-、-C(O)NH-或-CH2NH-;
R不存在或为氢、C1-C8直链或支链饱和或不饱和烃基、C3-C7环烃基、羟基、苯基、苄基和5~7元杂环基;且当Z不存在,R为5~7元杂环基时非必需地与所连接的苯基并合;其中,所述苯基、苄基和5~7元杂环基非必需地被1~4个各自独立地选自卤素、C1-C8直链或支链饱和或不饱和烃基、C3-C7环烃基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、羧基、巯基、苄基、苯基、萘基和5~7元杂环基的基团取代;
所述C6-C20稠合杂环基含有1~5个选自氧、硫和氮的杂原子;
所述5~7元杂环基含有1~3个选自氧、硫和氮的杂原子;
式(I)苯环上的-Z-R取代基团为1~5个,且各自独立地相同或者不同。
2.根据权利要求1所述的式(I)所示的取代磺酰胺类化合物或其药学上可接受的盐,其特征在于,其中,
芳香基Ar、X、Y和R的定义与权利要求1相同;
Z不存在或为C1-C8直链或支链饱和或不饱和烃基、C3-C7环烃基、苄基、苯基、5~7元杂环基、-O-、-S-、-NH-、-C(O)-、-C(O)O-、-SO2-、-NHC(O)-、-C(O)NH-或-CH2NH-;
其中,C6-C20稠合杂环基中含有至少一个苯环;
式(I)苯环上的-Z-R取代基团为1~3个,且各自独立地相同或者不同。
3.根据权利要求2所述的式(I)所示的取代磺酰胺类化合物或其药学上可接受的盐,其特征在于,其中,
芳香基Ar为非必需地被取代的苯基或萘基;所述取代被1~4个各自独立地选自卤素、C1-C8烷基、C3-C7环烷基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、羧基、苄基、苯基、萘基和5~7元杂环基的基团取代;
X不存在或为-O-、-S-、-NH-、-NHC(O)-、-C(O)NH-、-C(O)-或-SO2-;
Y不存在或为C1-C8烷基、C3-C7环烷基、三氟甲基、苯基、苄基或5~7元杂环基;其中,所述苯基、苄基和5~7元杂环基非必需地被1~4个各自独立地选自卤素、C1-C8烷基、C3-C7环烷基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、羧基、巯基、苄基、苯基和5~7元杂环基的基团取代;
Z为C1-C8烷基、C3-C7环烷基或-O-;
R不存在或为氢、C1-C8烷基、C3-C7环烷基、羟基、苯基、苄基和5~7元杂环基;其中,所述苯基、苄基和5~7元杂环基非必需地被1~4个各自独立地选自卤素、C1-C8烷基、C3-C7环烷基、氰基、硝基、氨基、羟基、羟甲基、三氟甲基、羧基、巯基、苄基、苯基、萘基和5~7元杂环基的基团取代;
所述5~7元杂环基为吡唑基、哌啶基、吡啶基、吡咯基、呋喃基、咪唑基、噻吩基、噻二唑基、嘧啶基或三嗪基;
式(I)苯环上的-Z-R取代基团为1或2个,且各自独立地相同或者不同。
6.根据权利要求5所述的式(I)所示的取代磺酰胺类化合物或其药学上可接受的盐的制备方法,其特征在于,反应所用的有机惰性溶剂选自乙醚、四氢呋喃、二氯甲烷、氯仿、二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环和N-甲基吡咯烷酮;反应所用碱选自吡啶、三乙胺、4-二甲胺基吡啶、二异丙基乙基胺、氢化钠和叔丁醇钾的有机碱以及包括碳酸钠、碳酸钾、氢氧化钠、氢氧化钾的无机碱;其中提纯的方法包括柱层析和重结晶。
7.一种药物组合物,其特征在于,所述药物组合物含有一种或多种有效量的式(I)所示取代磺酰胺类化合物或其药学上可接受的盐和至少一种药学上可接受的载体。
8.根据权利要求7所述的药物组合物,其特征在于,所述药物组合物为单位剂型,每剂包含0.05mg~500mg的一种或多种式(I)所示取代磺酰胺类化合物或其药学上可接受的盐;一种或多种式(I)所示取代磺酰胺类化合物或其药学上可接受的盐占所述药物组合物总重量的0.001-99.9重量%。
9.权利要求7或8所述的药物组合物的制备方法,其特征在于,将一种或多种有效量的式(I)所示取代磺酰胺类化合物或其药学上可接受的盐和药学上可接受的载体混合,从而制成。
10.权利要求1所述的式(I)所示的取代磺酰胺类化合物或其药学上可接受的盐在制备GPR40拮抗剂的药物中的用途。
11.权利要求1所述的式(I)所示的取代磺酰胺类化合物或其药学上可接受的盐在制备治疗GPR40介导的疾病的药物中的用途。
12.根据权利要求11所述的用途,其特征在于,所述GPR40介导的疾病包括糖尿病。
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