CN105130970A - N-磺酰基高丝氨酸内酯类衍生物、其制备方法和用途 - Google Patents
N-磺酰基高丝氨酸内酯类衍生物、其制备方法和用途 Download PDFInfo
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- CN105130970A CN105130970A CN201410238384.0A CN201410238384A CN105130970A CN 105130970 A CN105130970 A CN 105130970A CN 201410238384 A CN201410238384 A CN 201410238384A CN 105130970 A CN105130970 A CN 105130970A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 236
- 229910052760 oxygen Inorganic materials 0.000 claims description 118
- 239000001301 oxygen Substances 0.000 claims description 118
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 116
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 116
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- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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Abstract
本发明涉及式I所示的高丝氨酸内酯类衍生物、其制备方法和用途。该化合物具有细菌群体感应调节作用,可用于预防和/或治疗细菌感染所致的相关疾病。
Description
技术领域
本发明属于医药化工领域,具体涉及N-磺酰基高丝氨酸内酯类衍生物、其制备方法、以及其用于制备预防和/或治疗革兰氏阴性菌引起的疾病的药物中的用途。
背景技术
在菌群生长过程中细菌能够不断产生化学信号分子(又称自诱导物)并分泌到周围环境中,当信号分子的浓度达到一定阈值时,就会调控或启动菌体相关基因的表达如生物发光、生物被膜的形成、毒性基因的表达等,以适应环境的变化,这一调控系统被称为细菌的群体感应(QuoromSensing,QS)信号系统。
QS系统首先是在海洋费氏弧菌(V.fischeri)中发现的,当菌体密度较高时,该细菌会产生生物发光现象,以此捕获食物、躲避天敌等。通过对其机制进行研究发现,在V.fischeri中,LuxI蛋白合成的N-乙酰基高丝氨酸内酯(acylhomoserinelactones,AHL)可以与LuxR编码的AHL受体蛋白氨基残端相结合并形成特定构象,使羧基端与靶DNA序列结合,从而激活发光基因的转录表达。类似的调节系统在许多革兰阴性或阳性菌中都被发现。其作用机制均表现为当细菌群体密度较低时,可产生少量的自身诱导信号,这些信号扩散到细胞外并立即被周围环境稀释。而当细菌群体密度不断上升,浓度达到一定阈值时,信号分子就会渗入到细胞内与相应的转录调节蛋白结合,形成转录调节蛋白信号分子聚合物,此聚合物能够结合到染色体信号分子的某个特定DNA序列上,使相关靶基因得到表达,同时产生更多的信号分子。细菌之间的这种信息交流传导虽然早已被提出来,但系统研究主要集中在近十年,如今这种效应已被证实存在于多种细菌之中。
20世纪70年代末,科学家们发现利用天然的或者人工合成的群体感应调节剂(包括激动剂或抑制剂)可以干扰信号系统的传导,调节细菌不良基因的表达。细菌群体感应调节剂不干扰体内细胞的正常生理功能,只是通过调节病原菌有害基因的表达,从而使其失去致病能力,因此被视为抗菌药发展的新方向,其中细菌群体感应抑制剂可以与抗生素联合用药,提高致病细菌对抗生素的敏感性,增强药物疗效,主要治疗多种革兰氏阴性菌引起的如心内膜炎、腹膜炎、胃肠炎、胆囊炎、膀胱炎、腹泻、脓胸、败血症等各种疾病。本发明的目的在于寻找新的细菌群体感应调节剂,以用于革兰氏阴性菌,特别是耐药革兰氏阴性菌所致疾病的预防和/或治疗。
发明内容
本发明的第一方面涉及式Ⅰ所示的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物,
其中,R选自噻吩基、呋喃基、吡咯基、吡啶基和苄基,上述基团任选地被选自以下的取代基单取代或多取代(例如二取代或三取代):卤素、三氟甲基、硝基、C1-6烷基。
根据本发明第一方面任一项所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物,其中,R选自噻吩基、氯代噻吩基、溴代噻吩基、硝基噻吩基、甲基噻吩基、呋喃基、硝基呋喃基、溴代呋喃基、甲基呋喃基、二溴代呋喃基、吡咯基、吡啶基、氯代吡啶基、氟代苄基、氯代苄基、溴代苄基、甲基苄基、三氟甲基苄基、二氯代苄基。
根据本发明第一方面任一项所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物,其选自:
(S)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物1);
(S)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-3-甲酰胺(化合物2);
(S)-5-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物3);
(S)-5-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物4);
(S)-5-硝基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物5);
(S)-4-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物6);
(S)-4-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物7);
(S)-3-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物8);
(S)-3-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物9);
(S)-3-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物10);
(S)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-2-甲酰胺(化合物11);
(S)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-3-甲酰胺(化合物12);
(S)-5-硝基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-2-甲酰胺(化合物13);
(S)-5-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-2-甲酰胺(化合物14);
(S)-2-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-3-甲酰胺(化合物15);
(S)-4,5-二溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-2-甲酰胺(化合物16);
(S)-1H-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)吡咯-2-甲酰胺(化合物17);
(S)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)吡啶-4-甲酰胺(化合物18);
(S)-6-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)吡啶-3-甲酰胺(化合物19);
(S)-4-氟-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物20);
(S)-4-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物21);
(S)-4-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物22);
(S)-3-氟-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物23);
(S)-3-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物24);
(S)-3-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物25);
(S)-2-三氟甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物26);
(S)-2-氟-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物27);
(S)-2-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物28);
(S)-2-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物29);
(S)-2-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物30);
(S)-2-硝基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物31);
(S)-2,3-二氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物32);
(中间体1)。
本发明第二方面涉及本发明第一方面任一项所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物的制备方法,其包括以下步骤:将式3所示的中间体与RCOCl所示的酰氯反应,即得到本发明第一方面任一项所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物,
其中R的定义如本发明第一方面任一项所述。
根据本发明第二方面任一项所述的制备方法,其中式3所示的中间体是由高丝氨酸内酯氢溴酸盐与乙酰氨基苯磺酰氯反应制备得到。
在本发明的一个实施方案中,所述制备方法的反应流程如下所示:
其中R的定义如本发明第一方面任一项所述。
本发明的第三方面涉及药物组合物,其包含本发明第一方面任一项所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物,以及任选的一种或多种药学上可接受的载体或赋形剂。
根据本发明第三方面任一项的药物组合物,其还包含至少一种抗生素。
根据本发明第三方面任一项的药物组合物,其中所述抗生素包括但不限于β-内酰胺类(美罗培南、头孢氨苄、头孢他啶、头孢匹罗等)、氨基糖苷类(例如丁胺卡那、链霉素、妥布霉素、异帕米星等)、糖肽类(例如万古霉素、替考拉宁、多粘菌素等)、大环内酯类(例如罗红霉素、克拉霉素、阿奇霉素等)、四环素类(例如多西环素、米诺环素、替加环素等)、喹诺酮类(例如诺氟沙星、环丙沙星、加替沙星、帕珠沙星等)等。
本发明的第四方面涉及本发明第一方面任一项所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物用于制备作为细菌群体感应调节剂的药物的用途。
根据本发明第四方面任一项的用途,其中所述的细菌群体感应调节剂可以是细菌群体感应激动剂,也可以是细菌群体感应抑制剂。
在本发明的实施方案中,选自以下的化合物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物,可以用于制备作为细菌群体感应激动剂的药物,
(S)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-2-甲酰胺(化合物11);
(S)-2-氟-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物27);
(中间体1)。
在本发明的实施方案中,选自以下的化合物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物,可以用于制备作为细菌群体感应抑制剂的药物,
(S)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物1);
(S)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-3-甲酰胺(化合物2);
(S)-5-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物3);
(S)-5-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物4);
(S)-4-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物6);
(S)-4-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物7);
(S)-3-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物8);
(S)-3-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物9);
(S)-3-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物10);
(S)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-2-甲酰胺(化合物11);
(S)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-3-甲酰胺(化合物12);
(S)-5-硝基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-2-甲酰胺(化合物13);
(S)-2-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-3-甲酰胺(化合物15);
(S)-1H-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)吡咯-2-甲酰胺(化合物17);
(S)-4-氟-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物20);
(S)-4-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物21)。
本发明的第五方面涉及本发明第一方面任一项所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物用于制备预防和/或治疗由细菌感染所引起的疾病的药物中的用途。
根据本发明第五方面任一项的用途,其中所述的细菌为革兰氏阳性菌或革兰氏阴性菌,优选为革兰氏阴性菌。
根据本发明第五方面任一项的用途,其中所述的革兰氏阴性菌选自大肠杆菌,肺炎杆菌、变形杆菌、痢疾杆菌、布氏杆菌、流感(嗜血)杆菌、副流感(嗜血)杆菌、卡他(摩拉)菌、不动杆菌属、耶尔森菌属、巴斯德菌属、志贺菌属、百日咳杆菌、副百日咳杆菌、副溶血性杆菌、嗜肺军团菌、霍乱弧菌。
根据本发明第五方面任一项的用途,其中所述的由细菌感染所引起的疾病包括但不限于心内膜炎、腹膜炎、胃肠炎、胆囊炎、膀胱炎、腹泻、脓胸、败血症等各种疾病;优选地,所述疾病为对抗生素不敏感的上述耐药菌株所致的疾病。
本发明的第六方面涉及本发明第一方面任一项所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物用于制备预防和/或治疗由细菌群体感应所引起的疾病的药物的用途。
根据本发明第六方面任一项的用途,其中所述由细菌群体感应所引起的疾病,包括并不限于因大肠杆菌,肺炎杆菌、变形杆菌、痢疾杆菌、布氏杆菌、流感(嗜血)杆菌、副流感(嗜血)杆菌、卡他(摩拉)菌、不动杆菌属、耶尔森菌属、巴斯德菌属、志贺菌属、百日咳杆菌、副百日咳杆菌、副溶血性杆菌、嗜肺军团菌、霍乱弧菌等革兰氏阴性菌引起的包括并不限于心内膜炎、腹膜炎、胃肠炎、胆囊炎、膀胱炎、腹泻、脓胸、败血症等各种疾病;优选地,所述疾病为对抗生素不敏感的上述耐药菌株所致的疾病。
本发明的第七方面涉及本发明第一方面所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物在作为研究细菌群体感应调节的工具药中的用途。
本发明第八方面涉及预防和/或治疗由细菌感染所引起的疾病的方法,所述方法包括给有需要的受试者预防和/或治疗有效量的本发明第一方面所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物的步骤。
根据本发明第八方面任一项的方法,其中所述的细菌为革兰氏阳性菌或革兰氏阴性菌,优选为革兰氏阴性菌。
根据本发明第八方面任一项的方法,其中所述的由细菌感染所引起的疾病包括但不限于因大肠杆菌,肺炎杆菌、变形杆菌、痢疾杆菌、布氏杆菌、流感(嗜血)杆菌、副流感(嗜血)杆菌、卡他(摩拉)菌、不动杆菌属、耶尔森菌属、巴斯德菌属、志贺菌属、百日咳杆菌、副百日咳杆菌、副溶血性杆菌、嗜肺军团菌、霍乱弧菌等革兰氏阴性菌引起的包括并不限于心内膜炎、腹膜炎、胃肠炎、胆囊炎、膀胱炎、腹泻、脓胸、败血症等各种疾病;优选地,所述疾病为对抗生素不敏感的上述耐药菌株所致的疾病。
本发明第九方面涉及预防和/或治疗由细菌群体感应所引起的疾病的方法,所述方法包括给有需要的受试者预防和/或治疗有效量的本发明第一方面所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物的步骤。
根据本发明第九方面任一项的方法,其中所述由细菌群体感应所引起的疾病,包括并不限于因大肠杆菌,肺炎杆菌、变形杆菌、痢疾杆菌、布氏杆菌、流感(嗜血)杆菌、副流感(嗜血)杆菌、卡他(摩拉)菌、不动杆菌属、耶尔森菌属、巴斯德菌属、志贺菌属、百日咳杆菌、副百日咳杆菌、副溶血性杆菌、嗜肺军团菌、霍乱弧菌等革兰氏阴性菌引起的包括并不限于心内膜炎、腹膜炎、胃肠炎、胆囊炎、膀胱炎、腹泻、脓胸、败血症等各种疾病;优选地,所述疾病为对抗生素不敏感的上述耐药菌株所致的疾病。
发明详述
本发明中使用的各种短语和术语具有本领域技术人员公知的一般含义,但是在本文中有特别定义的,以本文中所定义的含义为准。
如用于本文的,术语“卤素”具有本领域公知的一般含义,并且通常包括F、Cl、Br、I,还可包括它们的同位素形式,在本发明中优选为F、Cl、Br。
如用于本文的,术语“C1-6烷基”是指含1-6个碳原子的直链、支链或环状烷基,包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、戊基、新戊基、己基、环丙基、环丁基、环戊基、环己基等。
如用于本文的,以下术语所代表的基团具有本领域公知的一般含义:噻吩基、呋喃基、吡咯基、吡啶基、苄基、三氟甲基、硝基、甲基。
如用于本文的,术语“消旋体”和“旋光异构体”具有其本领域公知的一般含义。
根据本发明,本发明涉及如通式Ⅰ所示化合物或其立体异构体的合适的可药用盐或水合物,其中可药用的盐包括但是并不局限于通式Ⅰ化合物与无机酸如盐酸、硫酸、磷酸、亚磷酸、氢溴酸和硝酸所成的盐以及与各种有机酸,如马来酸、苹果酸、延胡索酸、琥珀酸、酒石酸、柠檬酸、乙酸、乳酸、甲磺酸、对甲苯磺酸、棕榈酸等所成的盐.本发明中的一些化合物可能与水或各种有机溶剂结晶或重结晶,在这种情况下,可能形成各种溶剂化物。本发明包括那些化学计量的溶剂化物,包括水合物,也包括在用低压升华干燥法制备时形成的包含可变量水的化合物。
根据本发明,本发明式Ⅰ化合物的立体异构体指本发明中部分化合物可能以光学异构体或互交异构体的形式存在,本发明包括其所有存在形式,特别是纯异构体的形式.不同的异构体形式可以以各种常规的手段与其它形式的异构体分离或拆分开,或者某种异构体可以以各种常规的合成方法或立体专一或不对称合成的方法得到.既然式I化合物是以药用为目的的,可以理解它们最好以纯的形式提供,例如至少60%的纯度,更合适的75%,更好的85%,最好至少98%的纯度(%是指重量百分比)。不纯化合物的制备方法可用来用于药用组合物中更纯的形式.这些不够纯的产物中至少含有1%,更适合的5%,更好的至少10%的如通式Ⅰ所示的化合物或其可药用的衍生物。
根据本发明,上述通式I化合物可用以下典型的示例性的方法制备,所述方法包括以下步骤:
1)将甲硫氨酸加入到由水,2-异丙醇和冰醋酸组成的混合溶液中,均匀搅拌加入溴乙酸,加热回流2小时,冷却至室温后浓缩成黄色油状液体。再向其中加入2-异丙醇和甲苯(1:1V/V)的混合溶液,减压浓缩得到橙色油状液体。向油状物加入二氧六环和浓盐酸,50℃加热20分钟后移除加热,室温搅拌过夜,随后将反应置于冰浴,有黄色固体析出,抽滤,用2-异丙醇洗涤滤饼至白色,得到中间体1。
2)将中间体1和三乙胺溶于乙醇溶液中,0℃下分批加入对乙酰氨基苯磺酰氯,室温搅拌过夜后将反应物倒入冰水中强力搅拌1小时,过滤收集析出的白色固体,冰水洗涤,真空干燥,乙醇重结晶,得到白色固体(中间体2)。
3)搅拌下将6N盐酸加入中间体2的乙醇溶液中,加热回流4小时,减压浓缩反应混合物,将剩余物溶于水,用氨水将溶液pH值调至7-8,搅拌1小时,过滤收集析出的白色固体,冰水洗涤,真空干燥,乙醇重结晶得到白色固体(中间体3)。
4)将中间体3置于三口瓶中,加入三乙胺,0℃冰浴下滴加酰氯(RCOCl),10分钟内滴完,移除冰浴,室温搅拌过夜,次日将反应体系减压抽滤,滤液用水洗涤,有机层有淡黄色固体析出,过滤收集析出固体,真空干燥后得到淡黄色固体(式I化合物)。
其中R的定义同本发明第一方面任一项所述。
本发明还涉及药物组合物,其包括至少一种式Ⅰ化合物和至少一种药用载体或赋形剂。通式Ⅰ的化合物或其可药用的盐可以单独使用,或与可药用的载体或赋形剂一起以药物组合物的形式使用,当以药物组合物的形式使用时,通常将有效剂量的本发明通式Ⅰ化合物或其可药用盐或水合物以及一种或多种可药用载体或稀释剂结合制成适当的施用形式或剂量形式,这一程序包括通过合适的方式将组分混合、粒化、压缩或溶解。
本发明药用组合物可以以下方面的任意方式施与:口服、喷雾吸入、直肠给药、鼻腔给药、阴道给药、局部给药、非肠道给药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内或颅内注射或输入,或借助一种外植的储器用药,其中优选口服、肌注、腹膜内或静脉内用药方式。
本发明的药物组合物中含有的药用载体包括但不局限于:离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血清蛋白,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,羧甲基纤维素钩,聚丙烯酸酯,蜂蜡,羊毛醋等。载体在药物组合物中的含量可以是1重量%~98重量%,通常大约占到80重量%,为方便起见,局部麻醉剂,防腐剂,缓冲剂等可直接溶于载体中。
口服制剂如口服片剂和胶囊可以含有赋形剂如粘合剂,如糖浆,阿拉伯胶,山梨醇,黄芪胶,或聚乙烯吡咯烷酮,填充剂,如乳糖,蔗糖,玉米淀粉,磷酸钙,山梨醇,氨基乙酸,润滑剂,如硬脂酸镁,滑石,聚乙二醇,硅土,崩解剂,如马铃薯淀粉,或可接受的增润剂,如月桂醇钠硫酸盐.片剂可以用制药学上公知的方法包衣。
口服液形式的本发明药物组合物可以制成水和油的悬浮液,溶液,乳浊液,糖浆或酏剂,也可以制成干品,用前补充水或其它合适的媒质。这种液体制剂可以包含常规的添加剂,如悬浮剂,山梨醇,纤维素甲醚,葡萄糖糖浆,凝胶,羟乙基纤维素,羧甲基纤维素,硬脂酸铝凝胶,氢化的食用油脂,乳化剂,如卵磷脂,山梨聚醣单油酸盐,阿拉伯树胶;或非水载体(可能包含可食用油),如杏仁油,油脂如甘油,乙二醇,或乙醇;防腐剂,如对羟基苯甲酸甲酯或丙酯,山梨酸。如需要可添加调味剂或着色剂。栓剂可包含常规,的栓剂基质,如可可黄油或其它甘油酯。非肠道给药,液态剂型通常由化合物和至少一种消毒或无茵的载体制成。载体首选水.依照所选载体和药物浓度的不同,化合物既可溶于载体中也可制成悬浮溶液,在制成注射用溶液时先将化合物溶于水中,过滤消毒后装入封口瓶或安瓿中。当皮肤局部施用时,本发明化合物可以制成适当的软膏,洗剂,或霜剂的形式,其中活性成分悬浮或溶解于一种或多种的载体中。其中软膏制剂可以使用的载体包括但不局限于:矿物油,液体凡士林,白凡士林,丙二醇,聚氧化乙烯,聚氧化丙烯,乳化蜡和水;洗剂和霜剂可使用的载体包括但不限于:矿物油,脱水山梨糖醇单硬脂酸酯,吐温60,十六烷酯蜡,十六碳烯芳醇,2-辛基十二烷醇,苄醇和水。依据给药方式的不同,组合物中可以含有重量比0.1%,或更合适的重量比10-60%的活性组分.但组合物为单位剂型时,每个单位最好包含50~500毫克活性成分.依据给药途径和给药频率的不同,用于成人的适宜治疗剂量,例如可为每天100-3000毫克,如每天1500毫克。
必须认识到,通式Ⅰ化合物的最佳给药剂量和间隔是由疾病或症状的严重程度、化合物性质和诸如给药的形式、路径和部位以及所治疗的特定哺乳动物等条件决定的,而这一最佳给药剂量可由临床医生来确定。
发明的有益效果
本发明提供了一系列新型的群体感应调节剂,群体感应调节剂不干扰细胞的正常生理活动,只是通过调节病原菌有害基因的表达,从而使其失去致病能力,因此被视为抗菌药发展的新方向,其中细菌群体感应抑制剂可以与抗生素联合用药,可用于预防和/或治疗多种革兰氏阴性菌引起的如心内膜炎、腹膜炎、胃肠炎、胆囊炎、膀胱炎、腹泻、脓胸、败血症等各种疾病,特别适用于对现有抗生素不敏感的耐药革兰氏阴性菌所致疾病的预防和/或治疗。
具体实施方式
下面通过具体的中间体和实施例进一步说明本发明,但是,应当理解为,这些中间体和实施例仅用于更详细具体地说明,而不应理解为用于以任何形式限制本发明。
本发明对试验中所使用的材料以及试验方法进行一般性和/或具体的描述。虽然为达到本发明目的所使用的许多材料和操作方法是本领域公知的,但是本发明仍然在此作尽可能详细描述。本领域技术人员清楚,在下文中,如果未特别说明,本发明所用材料和操作方法是本领域公知的。
下面的实施例中,化合物熔点由YRT-4型熔点仪测定,温度未经校正。比旋光度由OA公司Polaar3005型精密自动旋光仪测定。1H-NMR光谱由BrukerARX400型核磁仪测定。FAB质谱由Zabspect高分辨磁质谱仪测定。
【中间体的制备】
【中间体1的制备】(L)-高丝氨酸内酯氢溴酸盐
将20.0g(134mmol)L-甲硫氨酸加入到80ml水,80ml2-异丙醇和32ml冰乙酸组成的混合溶液中均匀搅拌,然后加入18.8g(134mmol)溴乙酸,加热回流2小时,冷却至室温后浓缩成黄色油状液体。向其中加入70ml2-异丙醇和甲苯(1:1V/V),混合后浓缩得到橙色油状液体。向油状物加入56ml二氧六环和28ml浓盐酸,50℃加热15分钟后移除加热,室温搅拌过夜。随后将反应体系置于冰浴4小时,有淡黄色固体析出,抽滤,2-异丙醇洗涤滤饼至白色,得到产物(中间体1)10.9g,收率45%。
1H-NMR(400MHz,D2O)δppm:8.76(s,3H),4.46(t,1H,J=8.0Hz,J=7.6Hz),4.35–4.31(m,2H),2.56–2.51(m,1H),2.30–2.27(m,1H);EI-MS(m/z):102.1[M+H]+;m.p.220-224℃;(c=0.1,H2O)。
【中间体2的制备】(s)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)乙酰胺
将对乙酰氨基苯磺酰氯16.8g(72mmol)分批加入0℃的(L)-高丝氨酸内酯氢溴酸盐(中间体1)10.9g(60mmol)和三乙胺25.5mL(120mmol)的120mL乙醇溶液中,室温搅拌过夜。次日将反应物倒入冰水(200mL)中搅拌1小时,过滤收集析出的白色固体,冰水洗涤,真空干燥,乙醇重结晶,得到白色固体(中间体2)12g,收率67%。
1H-NMR(400MHz,DMSO)δppm:10.33(s,1H),8.16(d,1H,J=8.0Hz),7.75(s,4H),4.34-4.30(m,1H),4.21(m,1H),4.08(m,1H),2.08-2.06(m,4H),1.80(m,1H);EI-MS(m/z):299.34[M+H]+;m.p.174-176℃。
【中间体3的制备】(s)-4-氨基-N-(2-氧四氢呋喃-3-基)苯磺酰氨
搅拌下将20mL6N盐酸加入(s)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)乙酰胺10g(33mmol)的40mL乙醇溶液中,加热回流反应4小时,减压浓缩反应混合物,将剩余物溶于水,用1N氨水将溶液pH值调至7-8,搅拌1小时后过滤,收集析出白色固体,冰水洗涤,真空干燥,乙醇重结晶得到白色固体(中间体3)5.2g,收率57%。
1H-NMR(400MHz,DMSO)δppm:7.72(d,1H,J=9.2Hz),7.45(d,2H,J=8.4Hz),6.61(d,2H,J=8.8Hz),5.95(m,2H),4.21(m,2H),4.09(m,1H),2.06(m,1H),1.78(m,1H);EI-MS:m/z=256.4[M+H]+;m.p.162-165℃。
【实施例】
【实施例1】(s)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物1)
将0.52g(2.03mmol)(s)-4-氨基-N-(2-氧四氢呋喃-3-基)苯磺酰氨(中间体3)置于15ml无水二氯甲烷三口瓶中,加入三乙胺0.41g(4.06mmol),0℃冰浴下缓慢滴加0.36g(2.44mmol)噻吩-2-甲酰氯,10分钟内滴完,移除冰浴,室温搅拌过夜。次日将反应体系减压抽滤,滤液用水洗涤,有机层析出淡黄色固体,减压抽滤,真空干燥后得到淡黄色固体产物(化合物1)0.44g,产率60%。
1H-NMR(400MHz,DMSO)δppm:10.57(s,1H),8.25(1H,d,J=8.0Hz),8.22(d,1H,J=8.0Hz),8.07(d,1H,J=8.0Hz),7.93(m,3H),7.82(d,2H,J=8.0Hz),7.26(d,1H,J=8.0Hz),4.37(m,1H),4.23(m,1H),4.11(m,1H),2.14(m,1H),1.84(m,1H);EI-MS:m/z=366.9[M+H]+;m.p.114-119℃。
【实施例2】(s)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-3-甲酰胺(化合物2)
以中间体3和噻吩-3-甲酰氯为原料,操作同实施例1。得土黄色固体产物(化合物2)。
1H-NMR(400MHz,DMSO)δppm:10.38(s,1H),8.42(1H,s),8.20(d,1H,J=8.0Hz),7.96(d,2H,J=8.0Hz),7.82(m,2H),7.68(d,2H,J=8.0Hz),4.37(m,1H),4.23(m,1H),4.11(m,1H),2.14(m,1H),1.83(m,1H);EI-MS:m/z=367.0[M+H]+;m.p.212-216℃。
【实施例3】(s)-5-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物3)
以中间体3和5-氯-噻吩-2-甲酰氯为原料,操作同实施例1。得桔黄色固体产物(化合物3)。
1H-NMR(400MHz,DMSO)δppm:10.64(s,1H),8.21(d,1H,J=8.0Hz),7.94(m,3H),7.82(d,2H,J=8.0Hz),7.32(s,1H),4.37(m,1H),4.22(m,1H),4.10(m,1H),2.14(m,1H),1.83(m,1H);EI-MS:m/z=401.1[M+H]+;m.p.243-249℃。
【实施例4】(s)-5-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物4)
以中间体3和5-溴-噻吩-2-甲酰氯为原料,操作同实施例1。得桔黄色固体产物(化合物4)。
1H-NMR(400MHz,DMSO)δppm:10.63(s,1H),8.21(d,1H,J=8.0Hz),7.91(m,3H),7.83(d,2H,J=8.0Hz),7.40(s,1H),4.36(m,1H),4.22(m,1H),4.10(m,1H),2.13(m,1H),1.83(m,1H);EI-MS:m/z=445.0[M+H]+;m.p.197-199℃。
【实施例5】(s)-5-硝基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物5)
以中间体3和5-硝基-噻吩-2-甲酰氯为原料,操作同实施例1。得白色固体产物(化合物5)。
1H-NMR(400MHz,DMSO)δppm:10.96(s,1H),8.23(d,2H,J=8.0Hz),8.10(d,1H,J=8.0Hz),7.93(m,4H),4.36(m,1H),4.21(m,1H),4.09(m,1H),2.13(m,1H),1.83(m,1H);EI-MS:m/z=434.2[M+Na]+;m.p.208-220℃。
【实施例6】(s)-4-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物6)
以中间体3和4-溴-噻吩-2-甲酰氯为原料,操作同实施例1。得桔黄色固体产物(化合物6)。
1H-NMR(400MHz,DMSO)δppm:10.66(s,1H),8.24(d,1H,J=8.0Hz),8.12(d,2H,J=8.0Hz),7.94(m,2H),7.86(m,2H),4.38(m,1H),4.23(m,1H),4.11(m,1H),2.14(m,1H),1.84(m,1H);EI-MS:m/z=445.0[M+H]+;m.p.197-203℃。
【实施例7】(s)-4-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物7)
以中间体3和4-甲基-噻吩-2-甲酰氯为原料,操作同实施例1。得淡黄色固体产物(化合物7)。
1H-NMR(400MHz,DMSO)δppm:10.50(s,1H),8.23(d,1H,J=8.0Hz),7.94(m,3H),7.81(d,2H,J=8.0Hz),7.51(d,1H,J=8.0Hz),4.37(m,1H),4.23(m,1H),4.11(m,1H),2.14(m,1H),1.83(m,1H);EI-MS(m/z):381.1[M+H]+;m.p.187-188℃。
【实施例8】(s)-3-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物8)
以中间体3和3-甲基-噻吩-2-甲酰氯为原料,操作同实施例1。得白色固体产物(化合物8)。
1H-NMR(400MHz,DMSO)δppm:10.36(s,1H),8.23(d,1H,J=8.0Hz),7.88(d,2H,J=8.0Hz),7.79(d,2H,J=8.0Hz),7.72(m,1H),7.06(d,1H,J=8.0Hz),4.36(m,1H),4.23(m,1H),4.11(m,1H),2.14(m,1H),1.83(m,1H);EI-MS:m/z=381.0[M+H]+;m.p.176-178℃。
【实施例9】(s)-3-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物9)
以中间体3和3-氯-噻吩-2-甲酰氯为原料,操作同实施例1。得淡黄色固体产物(化合物9)。
1H-NMR(400MHz,DMSO)δppm:10.63(s,1H),8.23(d,1H,J=8.0Hz),7.96(m,1H),7.87(d,2H,J=8.0Hz),7.82(d,2H,J=8.0Hz),7.24(d,1H,J=8.0Hz),4.37(m,1H),4.23(m,1H),4.11(m,1H),2.13(m,1H),1.83(m,1H);EI-MS:m/z=401.3[M+H]+;m.p.219-221℃。
【实施例10】(s)-3-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物10)
以中间体3和3-氯-噻吩-2-甲酰氯为原料,操作同实施例1。得淡黄色固体产物(化合物10)。
1H-NMR(400MHz,DMSO)δppm:10.71(s,1H),8.24(d,1H,J=8.0Hz),7.92(m,1H),7.87(d,2H,J=8.0Hz),7.83(d,2H,J=8.0Hz),7.27(d,1H,J=8.0Hz),4.37(m,1H),4.23(m,1H),4.11(m,1H),2.13(m,1H),1.83(m,1H);EI-MS:m/z=444.9[M+H]+;m.p.151-154℃。
【实施例11】(s)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-2-甲酰胺(化合物11)
以中间体3和呋喃-2-甲酰氯为原料,操作同实施例1。得桔黄色固体产物(化合物11)。
1H-NMR(400MHz,DMSO)δppm:10.49(s,1H),8.18(d,1H,J=8.0Hz),7.96(m,3H),7.82(d,2H,J=8.0Hz),7.40(d,1H,J=8.0Hz),6.72(d,1H,J=8.0Hz),4.36(m,1H),4.23(m,1H),4.11(m,1H),2.17(m,1H),1.86(m,1H);EI-MS:m/z=351.1[M+H]+;m.p.195-196℃。
【实施例12】(s)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-3-甲酰胺(化合物12)
以中间体3和呋喃-3-甲酰氯为原料,操作同实施例1。得淡黄色固体产物(化合物12)。
1H-NMR(400MHz,DMSO)δppm:10.28(s,1H),8.44(s,1H),8.21(d,1H,J=8.0Hz),7.92(m,5H),7.02(d,1H,J=8.0Hz),4.36(m,1H),4.23(m,1H),4.10(m,1H),2.13(m,1H),1.82(m,1H);EI-MS:m/z=351.1[M+H]+;m.p.202-209℃。
【实施例13】(s)-5-硝基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-2-甲酰胺(化合物13)
以中间体3和5-硝基-呋喃-2-甲酰氯为原料,操作同实施例1。得淡黄色固体产物(化合物13)。
1H-NMR(400MHz,DMSO)δppm:10.97(s,1H),8.26(d,1H,J=8.0Hz),7.95(d,2H,J=8.0Hz),7.85(m,3H),7.71(d,1H,J=8.0Hz),4.37(m,1H),4.23(m,1H),4.10(m,1H),2.13(m,1H),1.86(m,1H);EI-MS:m/z=396.0[M+H]+;m.p.113-120℃。
【实施例14】(s)-5-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-2-甲酰胺(化合物14)
以中间体3和5-溴-呋喃-2-甲酰氯为原料,操作同实施例1。得淡黄色固体产物(化合物14)。
1H-NMR(400MHz,DMSO)δppm:10.56(s,1H),8.24(d,1H,J=8.0Hz),7.94(d,2H,J=8.0Hz),7.81(d,2H,J=8.0Hz),7.45(d,1H,J=8.0Hz),6.87(d,1H,J=8.0Hz),4.36(m,1H),4.23(m,1H),4.10(m,1H),2.13(m,1H),1.83(m,1H);EI-MS:m/z=453.1[M+Na]+;m.p.190-196℃。
【实施例15】(s)-2-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-3-甲酰胺(化合物15)
以中间体3和2-甲基-呋喃-3-甲酰氯为原料,操作同实施例1。得淡黄色固体产物(化合物15)。
1H-NMR(400MHz,DMSO)δppm:10.05(s,1H),8.21(d,1H,J=8.0Hz),7.94(d,2H,J=8.0Hz),7.79(d,2H,J=8.0Hz),7.63(d,1H,J=8.0Hz),7.09(d,1H,J=8.0Hz),4.36(m,1H),4.23(m,1H),4.11(m,1H),2.53(s,3H),2.13(m,1H),1.83(m,1H);EI-MS:m/z=365.0[M+H]+;m.p.185-187℃。
【实施例16】(s)-4,5-二溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-2-甲酰胺(化合物16)
以中间体3和4,5-二溴-呋喃-2-甲酰氯为原料,操作同实施例1。得淡黄色固体产物(化合物16)。
1H-NMR(400MHz,DMSO)δppm:10.66(s,1H),8.23(d,1H,J=8.0Hz),7.94(d,2H,J=8.0Hz),7.82(d,2H,J=8.0Hz),7.69(d,1H,J=8.0Hz),4.36(m,1H),4.23(m,1H),4.11(m,1H),2.14(m,1H),1.85(m,1H);EI-MS:m/z=529.0[M+Na]+;m.p.217-219℃。
【实施例17】(s)-1H-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)吡咯-2-甲酰胺(化合物17)
以中间体3和吡咯-2-甲酰氯为原料,操作同实施例1。得淡黄色固体产物(化合物17)。
1H-NMR(400MHz,DMSO)δppm:11.79(d,1H,J=8.0Hz),10.10(s,1H),8.17(d,1H,J=8.0Hz),7.95(d,2H,J=8.0Hz),7.80(d,2H,J=8.0Hz),7.12(d,1H,J=8.0Hz),7.02(d,1H,J=8.0Hz),6.20(d,1H,J=8.0Hz),4.36(m,1H),4.23(m,1H),4.11(m,1H),2.13(m,1H),1.83(m,1H);EI-MS:m/z=365.0[M+H]+;m.p.170-174℃。
【实施例18】(s)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)吡啶-4-甲酰胺(7-19)(化合物18)
以中间体3和吡啶-4-甲酰氯为原料,操作同实施例1。得白色固体产物(化合物18)。
1H-NMR(400MHz,DMSO)δppm:10.86(s,1H),8.81(m,2H),8.23(d,1H,J=8.0Hz),7.97(d,2H,J=8.0Hz),7.86(m,4H),4.36(m,1H),4.23(m,1H),4.11(m,1H),2.14(m,1H),1.83(m,1H);EI-MS:m/z=362.1[M+H]+;m.p.174-185℃。
【实施例19】(s)-6-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)吡啶-3-甲酰胺(化合物19)
以中间体3和6-氯-吡啶-3-甲酰氯为原料,操作同实施例1。得淡黄色固体产物(化合物19)。
1H-NMR(400MHz,DMSO)δppm:10.85(s,1H),8.96(d,1H,J=8.0Hz),8.36(d,1H,J=8.0Hz),8.25(d,1H,J=8.0Hz),7.96(d,2H,J=8.0Hz),7.85(d,2H,J=8.0Hz),7.76(d,1H,J=8.0Hz),4.38(m,1H),4.23(m,1H),4.09(m,1H),2.14(m,1H),1.83(m,1H);EI-MS:m/z=396.1[M+H]+;m.p.190-191℃。
【实施例20】(S)-4-氟-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物20)
以中间体3和4-氟-苯乙酰氯为原料,操作同实施例1。得淡黄色固体产物(化合物20)。
1H-NMR(400MHz,DMSO)δppm:10.58(s,1H),8.18(d,1H,J=8.0Hz),7.77(m,4H),7.36(d,2H,J=8.0Hz),7.17(dd,2H,J=8.0Hz),4.34(m,1H),4.20(m,1H),4.09(m,1H),3.69(s,2H),2.09(m,1H),1.80(m,1H);EI-MS:m/z=393.1[M+H]+;m.p.187-194℃。
【实施例21】(S)-4-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物21)
以中间体3和4-氯-苯乙酰氯为原料,操作同实施例1。得白色固体产物(化合物21)。
1H-NMR(400MHz,DMSO)δppm:10.57(s,1H),8.16(d,1H,J=8.0Hz),7.76(m,4H),7.37(m,4H),4.33(m,1H),4.21(m,1H),4.09(m,1H),3.70(s,2H),2.10(m,1H),1.80(m,1H);EI-MS:m/z=409.2[M+H]+;m.p.169-180℃。
【实施例22】(S)-4-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物22)
以中间体3和4-溴-苯乙酰氯为原料,操作同实施例1。得淡黄色固体产物(化合物22)。
1H-NMR(400MHz,DMSO)δppm:10.57(s,1H),8.16(d,1H,J=8.0Hz),7.77(m,4H),7.52(d,2H,J=8.0Hz),7.29(d,2H,J=8.0Hz),4.33(m,1H),4.20(m,1H),4.09(m,1H),3.68(s,2H),2.10(m,1H),1.80(m,1H);EI-MS:m/z=453.3[M+H]+;m.p.184-186℃。
【实施例23】(S)-3-氟-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物23)
以中间体3和3-氟-苯乙酰氯为原料,操作同实施例1。得淡黄色固体产物(化合物23)。
1H-NMR(400MHz,DMSO)δppm:10.58(s,1H),8.16(d,1H,J=8.0Hz),7.76(m,4H),7.37(m,1H),7.18(m,3H),4.32(m,1H),4.21(m,1H),4.09(m,1H),3.73(s,2H),2.10(m,1H),1.80(m,1H);EI-MS:m/z=393.2[M+H]+;m.p.175-177℃。
【实施例24】(S)-3-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物24)
以中间体3和3-氯-苯乙酰氯为原料,操作同实施例1。得白色固体产物(化合物24)。
1H-NMR(400MHz,DMSO)δppm:10.59(s,1H),8.18(d,1H,J=8.0Hz),7.76(m,4H),7.37(m,4H),4.33(m,1H),4.21(m,1H),4.09(m,1H),3.73(s,2H),2.10(m,1H),1.80(m,1H);EI-MS:m/z=409.1[M+H]+;m.p.188-190℃。
【实施例25】(S)-3-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物25)
以中间体3和3-甲基-苯乙酰氯为原料,操作同实施例1。得白色固体产物(化合物25)。
1H-NMR(400MHz,DMSO)δppm:10.58(s,1H),8.18(d,1H,J=8.0Hz),7.78(m,4H),7.16(m,4H),4.33(m,1H),4.20(m,1H),4.08(m,1H),3.73(s,2H),2.11(m,1H),1.80(m,1H);EI-MS:m/z=389.1[M+H]+;m.p.191-193℃。
【实施例26】(S)-2-三氟甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物26)
以中间体3和2-三氟甲基-苯乙酰氯为原料,操作同实施例1。得白色固体产物(化合物26)。
1H-NMR(400MHz,DMSO)δppm:10.63(s,1H),8.18(d,1H,J=8.0Hz),7.74(m,6H),7.53(m,2H),4.33(m,1H),4.22(m,1H),4.08(m,1H),3.98(s,2H),2.10(m,1H),1.81(m,1H);EI-MS:m/z=443.3[M+H]+;m.p.197-198℃。
【实施例27】(S)-2-氟-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物27)
以中间体3和2-氟-苯乙酰氯为原料,操作同实施例1。得白色固体产物(化合物27)。
1H-NMR(400MHz,DMSO)δppm:10.62(s,1H),8.17(d,1H,J=8.0Hz),7.76(m,4H),7.19(m,4H),4.32(m,1H),4.21(m,1H),4.06(m,1H),3.78(s,2H),2.11(m,1H),1.80(m,1H);EI-MS:m/z=393.3[M+H]+;m.p.185-186℃。
【实施例28】(S)-2-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物28)
以中间体3和2-氯-苯乙酰氯为原料,操作同实施例1。得白色固体产物(化合物28)。
1H-NMR(400MHz,DMSO)δppm:10.64(s,1H),8.18(d,1H,J=8.0Hz),7.78(m,4H),7.44(m,4H),4.33(m,1H),4.21(m,1H),4.08(m,1H),3.89(s,2H),2.11(m,1H),1.81(m,1H);EI-MS:m/z=409.2[M+H]+;m.p.223-228℃。
【实施例29】(S)-2-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物29)
以中间体3和2-溴-苯乙酰氯为原料,操作同实施例1。得白色固体产物(化合物29)
1H-NMR(400MHz,DMSO)δppm:10.65(s,1H),8.18(d,1H,J=8.0Hz),7.79(m,4H),7.62(d,1H,J=8.0Hz),7.42(m,2H),7.22(m,1H),4.34(m,1H),4.22(m,1H),4.08(m,1H),3.91(s,2H),2.13(m,1H),1.83(m,1H);EI-MS:m/z=475.2[M+Na]+;m.p.227-229℃。
【实施例30】(S)-2-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物30)
以中间体3和2-甲基-苯乙酰氯为原料,操作同实施例1。得白色固体产物(化合物30)
1H-NMR(400MHz,DMSO)δppm:10.56(s,1H),8.17(d,1H,J=8.0Hz),7.78(m,4H),7.16(m,4H),4.35(m,1H),4.21(m,1H),4.08(m,1H),3.73(s,2H),2.10(m,1H),1.81(m,1H);EI-MS:m/z=389.2[M+H]+;m.p.208-210℃。
【实施例31】(S)-2-硝基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物31)
以中间体3和2-硝基-苯乙酰氯为原料,操作同实施例1。得桔黄色固体产物(化合物31)
1H-NMR(400MHz,DMSO)δppm:10.66(s,1H),8.18(d,1H,J=8.0Hz),8.08(d,1H,J=8.0Hz),7.75(m,5H),7.59(m,2H),4.34(m,1H),4.21(m,1H),4.18(s,2H),4.08(m,1H),2.11(m,1H),1.81(m,1H);EI-MS:m/z=420.4[M+H]+;m.p.216-219℃。
【实施例32】(S)-2,3-二氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物32)
以中间体3和2,3-二氯-苯乙酰氯为原料,操作同实施例1。得淡黄色固体产物(化合物32)
1H-NMR(400MHz,DMSO)δppm:10.67(s,1H),8.17(d,1H,J=8.0Hz),7.77(m,4H),7.56(d,1H,J=8.0Hz),7.36(m,2H),4.34(m,1H),4.20(m,1H),4.08(m,1H),3.97(s,2H),2.11(m,1H),1.81(m,1H);EI-MS:m/z=443.3[M+H]+;m.p.230-237℃。
【实验例】本发明细菌群体感应调节剂的活性评价
本发明涉及细菌群体感应调节剂的活性可以用以下方法检测
1.初筛方法
1.1准备工作:称量不同的待测化合物(实施例1-32制备的化合物1-32及中间体1-3)后将其分别溶于200μlDMSO(甲基亚砜)中,配置成浓度为0.065M的溶液,称取5.0mg诱导剂N-己酰高丝氨酸内酯(C6-HSL,西格玛公司)溶解于200μlDMSO中(浓度为0.125M),化合物和诱导剂均保存于4℃备用,紫色色杆菌CV026(由美国德克萨斯州立大学McLeanJC教授惠赠,该菌是野生型ChromobacteriumviolaceumATCC31532的Tn-5的突变体,参考文献见Latifi,A.,etal.,Mol.Microbiol,17,333-343(1995)以及Winson,M.K.,etal.,Proc.Natl.Acad.Sci.USA,92,9427-9431(1995))于摇床中30℃,200rpm振荡培养。
1.2具有激动活性化合物的初筛方法:将400μl紫色色杆菌CV026加入5ml融化的半固体LB培养基(胰蛋白胨1%,氯化钠1%,酵母提取物0.5%)中混合均匀,然后将混合后的培养基一并倾倒在固体LB平板上,待平板凝固后,将溶解的待测化合物(实施例1-32制备的化合物1-32)取1μl点样,晾干后置于30℃烘箱中倒置培养16-18h。通过LB平板上的紫色色杆菌能否被诱导出紫色以及紫色强弱来判断待测化合物的激动活性。
1.3具有抑制活性化合物的初筛方法:将诱导剂C6-HSL二倍梯度进行梯度稀释1000倍,然后取15μl和400μl对数期的紫色色杆菌CV026混合均匀,加入到5ml融化的半固体LB培养基中,将混合后的诱导剂、紫色色杆菌、半固体LB一并倒在固体LB平板上,待平板凝固后将溶解的待测化合物(实施例1-32制备的化合物1-32以及中间体1-3)取1μl点样,晾干后置于30℃烘箱中倒置培养16-18h。根据LB平板上紫色色杆菌被抑制后出现的白色圆圈大小,初步判断化合物的抑制活性。
经初步筛选,本发明的17个化合物具有细菌群体感应调节活性,具体筛选结果参见表1。
2.对紫色色杆菌群体感应产生抑制作用的化合物IC50测定
2.1取12孔板每孔自左向右,自上而下分别标记为原浓度、2、4、8、16、32、64、128、256、DMSO组、空白组。
2.2挑取生长于LB固体平板上的紫色色杆菌CV026单克隆于5ml新鲜LB液体培养基中培养至对数期,然后取50μl分别接种于5ml的LB培养基中,培养至光密度OD值约为1.0左右,与LB培养基按照1:9的比例混合均匀(此时的OD大约为0.15),然后按照2ml/每孔加入12孔板中。
2.3将具有群体感应抑制活性的初筛化合物用DMSO溶解后(浓度0.065M),分别取10μl于10μl的DMSO溶液中,以达到2倍稀释的目的,以此类推,将每种化合物梯度稀释(梯度稀释2、4、8、16、32、64、128、256倍)至最高倍数256倍。
2.4每孔加入15μl稀释1000倍的诱导剂C6-HSL(原浓度0.125M)和8μl的各稀释梯度化合物,DMSO对照组加入8μl的DMSO,空白对照组加入8μl的LB培养基,最后保证12孔板中的2ml体系培养物能够充分混合均匀。
2.5将12孔培养板置于30℃摇床中,130rpm培养10-12h。
2.6待培养完成后,每孔均取1ml培养物于1.5mlEP管中,12000rpm离心10分钟,吸去培养物上清后每EP管加入500μlDMSO溶解紫色色素,待色素完全溶解后12000rpm再次离心10分钟,然后取200μl上层色素于96孔培养板中,利用酶标仪测定其在585nm处的吸光度值,然后和对应浓度绘制关系曲线,得出IC50值,具体结果列于表2。
表1细菌群体感应调节活性活性初筛结果
化合物号 | 调节活性 | 化合物号 | 调节活性 |
中间体1 | + | 中间体2 | - |
1 | - | 2 | - |
3 | - | 4 | - |
6 | - | 7 | - |
8 | - | 9 | - |
10 | - | 11 | ± |
12 | - | 13 | - |
15 | - | 17 | - |
20 | - | 21 | - |
27 | + |
表1中“+”代表化合物具有群体感应激动活性,“-”代表化合物具有群体感应抑制活性,“±”代表化合物既具有群体感应激动活性又具有群体感应抑制活性。
表2具有群体感应抑制活性化合物的IC50值(uM)
化合物号 | IC50 |
8 | 69.22±1.42 |
9 | 9.19±0.34 |
10 | 13.51±0.54 |
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解。根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (15)
1.式Ⅰ所示的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物,
其中,R选自噻吩基、呋喃基、吡咯基、吡啶基和苄基,上述基团任选被选自以下的取代基单取代或多取代(例如二取代或三取代):卤素、三氟甲基、硝基、C1-6烷基。
2.权利要求1的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物,其中,R选自噻吩基、氯代噻吩基、溴代噻吩基、硝基噻吩基、甲基噻吩基、呋喃基、硝基呋喃基、溴代呋喃基、甲基呋喃基、二溴代呋喃基、吡咯基、吡啶基、氯代吡啶基、氟代苄基、氯代苄基、溴代苄基、甲基苄基、三氟甲基苄基、二氯代苄基。
3.权利要求1或2所述的式Ⅰ所示的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物,其选自:
(S)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物1);
(S)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-3-甲酰胺(化合物2);
(S)-5-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物3);
(S)-5-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物4);
(S)-5-硝基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物5);
(S)-4-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物6);
(S)-4-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物7);
(S)-3-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物8);
(S)-3-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物9);
(S)-3-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)噻吩-2-甲酰胺(化合物10);
(S)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-2-甲酰胺(化合物11);
(S)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-3-甲酰胺(化合物12);
(S)-5-硝基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-2-甲酰胺(化合物13);
(S)-5-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-2-甲酰胺(化合物14);
(S)-2-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-3-甲酰胺(化合物15);
(S)-4,5-二溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)呋喃-2-甲酰胺(化合物16);
(S)-1H-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)吡咯-2-甲酰胺(化合物17);
(S)-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)吡啶-4-甲酰胺(化合物18);
(S)-6-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)吡啶-3-甲酰胺(化合物19);
(S)-4-氟-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物20);
(S)-4-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物21);
(S)-4-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物22);
(S)-3-氟-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物23);
(S)-3-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物24);
(S)-3-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物25);
(S)-2-三氟甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物26);
(S)-2-氟-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物27);
(S)-2-氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物28);
(S)-2-溴-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物29);
(S)-2-甲基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物30);
(S)-2-硝基-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物31);
(S)-2,3-二氯-N-(4-(N-(2-氧四氢呋喃-3-基)氨磺酰基)苯基)苯乙酰胺(化合物32);
(中间体1)。
4.权利要求1-3任一项所述的式Ⅰ所示的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物的制备方法,其包括以下步骤:将式3所示的中间体与RCOCl所示的酰氯反应,即得到权利要求1-3任一项所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物,
其中R的定义如权利要求1-3任一项所述。
5.权利要求4的制备方法,其中式3所示的中间体由高丝氨酸内酯氢溴酸盐与乙酰氨基苯磺酰氯反应制备得到。
6.药物组合物,其包含权利要求1-3任一项所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物,以及任选的一种或多种药学上可接受的载体或赋形剂。
7.权利要求6的药物组合物,其还包含至少一种抗生素。
8.权利要求1-3任一项所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物用于制备作为细菌群体感应调节剂(例如细菌群体感应抑制剂或激动剂)的药物的用途。
9.权利要求1-3任一项所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物用于制备预防和/或治疗由细菌感染所引起的疾病的药物的用途。
10.权利要求9的用途,其中所述的细菌为革兰氏阳性菌或革兰氏阴性菌,优选为革兰氏阴性菌。
11.权利要求10的用途,其中所述的革兰氏阴性菌选自大肠杆菌,肺炎杆菌、变形杆菌、痢疾杆菌、布氏杆菌、流感(嗜血)杆菌、副流感(嗜血)杆菌、卡他(摩拉)菌、不动杆菌属、耶尔森菌属、巴斯德菌属、志贺菌属、百日咳杆菌、副百日咳杆菌、副溶血性杆菌、嗜肺军团菌、霍乱弧菌。
12.权利要求9的用途,其中所述的由细菌感染所引起的疾病包括但不限于心内膜炎、腹膜炎、胃肠炎、胆囊炎、膀胱炎、腹泻、脓胸、败血症等。
13.权利要求1-3任一项所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物用于制备预防和/或治疗由细菌群体感应所引起的疾病的药物的用途。
14.权利要求13的用途,其中所述的由细菌群体感应所引起的疾病包括但不限于因大肠杆菌,肺炎杆菌、变形杆菌、痢疾杆菌、布氏杆菌、流感(嗜血)杆菌、副流感(嗜血)杆菌、卡他(摩拉)菌、不动杆菌属、耶尔森菌属、巴斯德菌属、志贺菌属、百日咳杆菌、副百日咳杆菌、副溶血性杆菌、嗜肺军团菌、霍乱弧菌等革兰氏阴性菌引起的包括并不限于心内膜炎、腹膜炎、胃肠炎、胆囊炎、膀胱炎、腹泻、脓胸、败血症等各种疾病;优选地,所述疾病为对抗生素不敏感的上述耐药菌所致的疾病。
15.权利要求1-3任一项所述的高丝氨酸内酯类衍生物、其消旋体或旋光异构体、其药学可接受的盐、溶剂合物或水合物在作为研究细菌群体感应调节的工具药的用途。
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KR1020167037013A KR102443954B1 (ko) | 2014-05-30 | 2015-05-25 | N-설포닐 호모세린 락톤 유도체, 그의 제조 방법 및 용도 |
PCT/CN2015/079673 WO2015180597A1 (zh) | 2014-05-30 | 2015-05-25 | N-磺酰基高丝氨酸内酯类衍生物、其制备方法和用途 |
JP2016569948A JP6595509B2 (ja) | 2014-05-30 | 2015-05-25 | N−スルホニルホモセリンラクトン誘導体、その調製方法及び使用 |
US15/314,888 US10071994B2 (en) | 2014-05-30 | 2015-05-25 | N-sulfonyl homoserine lactone derivatives, preparation method and use thereof |
EP15798935.1A EP3150594A4 (en) | 2014-05-30 | 2015-05-25 | N-sulfonyl homoserine lactone derivatives, preparation method therefor and use |
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CN111108103B (zh) * | 2017-07-21 | 2023-10-20 | 港大科桥有限公司 | 影响色素生产及用于治疗细菌性疾病的化合物 |
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WO2015180597A1 (zh) | 2015-12-03 |
RU2700924C2 (ru) | 2019-09-24 |
CN105130970B (zh) | 2019-06-25 |
EP3150594A1 (en) | 2017-04-05 |
RU2016147189A3 (zh) | 2018-12-27 |
JP6595509B2 (ja) | 2019-10-23 |
RU2016147189A (ru) | 2018-07-04 |
US10071994B2 (en) | 2018-09-11 |
US20180179193A1 (en) | 2018-06-28 |
KR102443954B1 (ko) | 2022-09-16 |
JP2017516809A (ja) | 2017-06-22 |
EP3150594A4 (en) | 2018-01-17 |
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