CN115448920A - 一种β-内酰胺酶抑制剂及其应用 - Google Patents
一种β-内酰胺酶抑制剂及其应用 Download PDFInfo
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- CN115448920A CN115448920A CN202211256901.8A CN202211256901A CN115448920A CN 115448920 A CN115448920 A CN 115448920A CN 202211256901 A CN202211256901 A CN 202211256901A CN 115448920 A CN115448920 A CN 115448920A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
本发明公开了一种阿维巴坦衍生物及包含其的药物组合物,其作为β‑内酰胺酶抑制剂的经口给药的前药,用于治疗细菌感染,特别是与β‑内酰胺类抗生素组合用于治疗细菌感染。本发明的化合物能够改善脂水分配系数,并且能够较好的释放出原药,具有较好的口服生物利用度。
Description
技术领域
本发明属于药物化学领域,具体涉及一种β-内酰胺酶抑制剂及其药物组合物和治疗细菌感染的用途。
背景技术
抗生素可以有效治疗细菌引起的感染性疾病,给临床带来了极大的便利。然而,抗生素的不合理使用乃至滥用,加快了细菌耐药发展的进程,给人类健康带来了极大挑战。β-内酰胺类抗生素作为历史最悠久、使用范围最广、临床最常使用的抗生素之一,其耐药问题也随之而来并且日趋严重。
β-内酰胺类抗生素耐药的最主要机制是细菌产生β-内酰胺酶,该酶能与β-内酰胺类抗生素的β-内酰胺环上的羰基共价结合,使其水解、灭活。1976年,第一个β-内酰胺酶抑制剂(克拉维酸)被发现,后来与β-内酰胺抗生素(阿莫西林)联合作为口服/静脉药物商业化。β-内酰胺酶抑制剂,虽然本身缺乏显著的抗生素活性,但可以保护β-内酰胺类抗生素免受微生物产生的酶(β-内酰胺酶)的破坏失活。自20世纪80年代以来,β-内酰胺酶抑制剂/抗生素组合已经成为治疗的标准部分。
在20世纪90年代中期,一种新的重要的非β-内酰胺类β-内酰胺酶抑制剂阿维巴坦被发现。它属于二氮杂二环类化合物(DBOs),是一类可逆的β-内酰胺酶抑制剂。然而目前,由于阿维巴坦结构中含有磺酸基和甲酰胺结构,水溶性较大,而脂溶性过低,导致其组织透膜性较差,无法进行口服,只能用于静脉注射。前药(prodrug)是指本身没有生物活性,但经过体内化学或者酶转化能够释放出有药效活性的代谢物或原药的化合物。前药设计是一种提高化合物脂溶性、增加口服吸收、提高生物利用度的常用有效策略。
中国发明专利CN110662746A公开了一种3-(((((2S,5R)-2-氨基甲酰基-7-氧代-1,6-二氮杂双环[3.2.1]辛-6-基)氧基)磺酰基)氧基)-2,2-二甲基丙酸酯衍生物和相关的化合物,其作为β-内酰胺酶抑制剂的经口给药的前药,用于治疗细菌感染。该发明的前药设计改善了阿维巴坦的口服生物利用度。大鼠的口服生物利用度实验中,阿维巴坦显示出1.2%的口服生物利用率(%F),而化合物(3)、(4)、(10)、(11)、(12)、(13)、(14)、(15)、(16)、(17)、(18)和(19)的口服生物利用率(%F)大于10%。同样,化合物(36)、(37)、(42)、(53)、(57)、(58)和(59)的口服生物利用率(%F)大于10%。在这些试验中,雷巴坦的口服生物利用率(%F)为1.8%,而化合物(20)、(22)、(23)和(25)的口服生物利用率(%F)大于5%。
有鉴于此,提供更多阿维巴坦的前药设计,以进一步提高阿维巴坦的口服生物利用率具有重要的临床价值。
发明内容
本发明针对现有技术存在的问题,提供了一种阿维巴坦衍生物,用以解决目前阿维巴坦口服生物利用度差的问题。
为实现上述目的,本发明采用的技术方案如下:
一方面,本发明提供了一种阿维巴坦衍生物,即通式I所示的化合物、或其药学上可接受的盐、代谢产物、溶剂合物或水合物:
其中,R1为C1-6烷基,或每个R1与其所键合的偕碳原子形成未取代或取代的C3-6环烷基、未取代或取代的杂环烷基;
R2为单键、未取代或取代的C1-6烷二基、未取代或取代的C5-6环烷二基、未取代或取代的“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”C5-6杂环烷二基、未取代或取代的C6芳烃二基或未取代或取代的“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”C5-6杂芳烃二基;
R3为C1-6烷基、-O(C=O)R6、-S(C=O)R6、-NH(C=O)R6、-O(C=O)OR6、-S(C=O)O-R6、-NH(C=O)OR6、-(C=O)OR6、-(C=O)OCH2O(C=O)R6、-(C=O)OCH2O(C=O)OR6、-(C=O)SR6、-(C=O)NHR6、-O(C=O)SR6、-O(C=O)NHR6、-S-S-R6、-SR6、-NHR6、C3-10环烷基、“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”杂环烷基、“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”杂芳基、未取代或取代的C6-10芳基、-CH=C(R6)2、或
R4为-(C=O)R7或-(C=O)OR7;
R5为氢、C3-6环烷基或C1-6烷基。
另一方面,本发明提供了一种包含上述阿维巴坦衍生物的药物组合物。
又一方面,本发明提供了上述阿维巴坦衍生物作为β-内酰胺酶抑制剂的应用。
再一方面,本发明提供了上述阿维巴坦衍生物、药物组合物在制备用于治疗细菌感染有关的疾病的药物中的应用。
本发明中,采用前药原理暂时“掩盖”阿维巴坦结构中的磺酸基和甲酰胺部分,改善原药本身的脂溶性,调节其脂水分配系数;磺酸基部分的前药经过体内酯酶作用释放出亲核基团,然后通过温和的分子内环合反应释放出原药;甲酰胺部分的前药是在酯酶作用下形成N-羟甲基的中间体,然后通过化学断裂下释放出原药和一分子甲醛。
本发明阿维巴坦前药脂水分配系数得到较好的改善,并且能够较好的释放出原药,具有较好的口服生物利用度,支持口服,对于拓宽阿维巴坦的给药途径提供了新的思路。
具体实施方式
以下,对本发明进行详细的说明。
一方面,本发明提供了一种阿维巴坦衍生物,即通式I所示的化合物、或其药学上可接受的盐、代谢产物、溶剂合物或水合物:
其中,R1为C1-6烷基,或每个R1与其所键合的偕碳原子形成未取代或R1-1取代的C3-6环烷基、未取代或R1-2取代的杂环烷基;
R1-1和R1-2独立地选自氢、卤素、氰基、羟基、C1-4烷基、C1-4烷氧基、卤代(C1-4烷基)、卤代(C1-4烷氧基)、-NR1-1-1R1-1-2、或、-(C=O)R1-1-3;
R1-1-1~R1-1-3独立地选自氢或C1-4烷基;
R2为单键、未取代或R2-1取代的C1-6烷二基、未取代或R2-2取代的C5-6环烷二基、未取代或R2-3取代的“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”C5-6杂环烷二基、未取代或R2-4取代的C6芳烃二基、未取代或R2-5取代的“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”C5-6杂芳烃二基;
R2-1~R2-5独立地选自卤素、氰基、氨基、羟基、未取代或R2-1-1取代的C1-4烷基、未取代或R2-1-2取代的C1-4烷氧基、-NR2-1-3R2-1-4、-(C=O)R2-1-5、-(C=O)NR2-1-6R2-1-7、-(C=O)OR2 -1-8、或-S(=O)2NR2-1-9R2-1-10;
R2-1-1和R2-1-2独立地选自卤素、羟基、氰基、氨基、或C1-4烷基;
R2-1-3~R2-1-10独立地选自氢或C1-4烷基;
R3为C1-6烷基、-O(C=O)R6、-S(C=O)R6、-NH(C=O)R6、-O(C=O)OR6、-S(C=O)O-R6、-NH(C=O)OR6、-(C=O)OR6、-(C=O)OCH2O(C=O)R6、-(C=O)OCH2O(C=O)OR6、-(C=O)SR6、-(C=O)NHR6、-O(C=O)SR6、-O(C=O)NHR6、-S-S-R6、-SR6、-NHR6、C3-10环烷基、“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”杂环烷基、“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”杂芳基、未取代或R3-1取代的C6-10芳基、-CH=C(R6)2、或
R3-1为氘、卤素、氰基、羟基、未取代或R3-1-1取代的C1-6烷基、未取代或R3-1-2取代的C1-6烷氧基、C3-10环烷基、C3-10环烷基-(C1-4烷基)、C3-10环烷基-氧基、杂环烷基、杂环烷基-(C1-4烷基)、杂环烷基-氧基、C6-10芳基、C6-10芳基-(C1-4烷基)、(C6-10芳基)-氧基、杂芳基、杂芳基-(C1-4烷基)、杂芳基-氧基、-NR3-1-3R3-1-4、-(C=O)R3-1-5、-(C=O)NR3-1- 6R3-1-7、-(C=O)OR3-1-8、-S(=O)2NR3-1-9R3-1-10、或、-O(C=O)R3-1-11;所述的杂环烷基为“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”4~10元杂环烷基;所述的杂芳基为“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”5~10元杂芳基;
R3-1-1和R3-1-2独立地选自卤素、氰基、羟基、氨基或C1-4烷基;
R3-1-3~R3-1-11独立地选自氢或C1-4烷基;
R6为未取代或R6-1取代的C3-10环烷基、未取代或R6-2取代的C3-10环烷基-(C1-6烷基)、未取代或R6-3取代的杂环烷基、未取代或R6-4取代的杂环烷基-(C1-6烷基)、未取代或R6 -5取代的杂芳基、未取代或R6-6取代的杂芳基-(C1-6烷基)、未取代或R6-7取代的C6-10芳基、未取代或R6-8取代的C6-10芳基-(C1-6烷基)、未取代或R6-9取代的C1-10烷基、未取代或R6-10取代的C1-10烷氧基-(C1-10烷基)或C1-10烷氨基-(C1-10烷基);
R6-1~R6-6独立地选自卤素、羟基、氰基、氨基、C1-6的烷基、卤代(C1-6烷基)、羟基(C1-6烷基)、C1-6烷氧基、-NR6-1-1R6-1-2、-(C=O)R6-1-3;
R6-1-1~R6-1-3独立地选自氢或C1-4烷基;
R6-7和R6-8独立地选自卤素、羟基、氰基、硝基、未取代或R6-7-1取代的C1-6烷基、C2-6烯基、C2-6炔基、未取代或R6-7-2取代的C1-6烷氧基、C6-10芳基-氧基、杂芳基-氧基、(C3-10环烷基)-氧基、C1-6烷胺基-C1-6烷氧基-、未取代或R6-7-3取代的C3-10环烷基、未取代或R6 -7-4取代的C3-10环烷基-(C1-6烷基)-、未取代或R6-7-5取代的杂环烷基、未取代或R6-7-6取代的杂环烷基-(C1-6烷基)-、未取代或R6-7-7取代的杂芳基、未取代或R6-7-8取代的杂芳基-(C1-6烷基)-、未取代或R6-7-9取代的C6-10芳基、未取代或R6-7-10取代的C6-10芳基-(C1-6烷基)-、-NR6-7-11R6-7-12、-(C=O)R6-7-13、-(C=O)NR6-7-14R6-7-15、-NR6-7-16(C=O)R6-7-17、-(C=O)OR6-7-18、-O(C=O)R6-7-19、-(S=O)2NR6-7-20R6-7-21、-NR6-7-22(S=O)2R6-7-23、或、-(S=O)2R6-7-24;所述的杂环烷基为“杂原子选自N、O或S中的一种或多种,杂原子数为1-3个的”4-10元杂环烷基;所述的杂芳基为“杂原子选自N、O或S中的一种或多种,杂原子数为1-3个的”5-10元杂芳基;
R6-7-1和R6-7-2独立地选自C1-4烷基、卤素、氰基、羟基或氨基;
R6-7-3~R6-7-10独立地选自氢、卤素、氰基、羟基、C1-4烷基、C1-4烷氧基、卤代(C1-4烷基)、卤代(C1-4烷氧基)、-NR6-7-3-1R6-7-3-2、或、-(C=O)R6-7-3-3;
R6-7-11~R6-7-24独立地选自氢或C1-4烷基;
R6-7-3-1~R6-7-3-3独立地选自氢或C1-4烷基;
R6-9和R6-10独立地选自C1-4烷基、卤素、氰基、羟基、-NR6-9-1R6-9-2;
R6-9-1和R6-9-2独立地选自氢或C1-4烷基;
R5为氢、C3-6环烷基或C1-6烷基;
R4为-(C=O)R7或-(C=O)OR7;
R7为未取代或R7-1取代的C1-10烷基、未取代或R7-2取代的C3-10环烷基、未取代或R7-3取代的C3-10环烷基-(C1-6烷基)-、未取代或R7-4取代的杂环烷基、未取代或R7-5取代的杂环烷基-(C1-6烷基)-、未取代或R7-6取代的杂芳基、未取代或R7-7取代的杂芳基-(C1-6烷基)-、未取代或R7-8取代的C6-10芳基、未取代或R7-9取代的C6-10芳基-(C1-6烷基)-、C1-10烷氧基-(C1-10烷基)、或、C1-10烷氨基-(C1-10烷基);所述的杂环烷基为“杂原子选自N、O或S中的一种或多种,杂原子数为1-3个的”4-10元杂环烷基;所述的杂芳基为“杂原子选自N、O或S中的一种或多种,杂原子数为1-3个的”5-10元杂芳基;
R7-1选自C1-4烷基、卤素、氰基、羟基、或、-NR7-1-1R7-1-2;
R7-1-1和R7-1-2独立地选自氢或C1-4烷基;
R7-2~R7-5独立地选自氢、卤素、氰基、羟基、C1-4烷基、C1-4烷氧基、卤代(C1-4烷基)、卤代(C1-4烷氧基)、-NR7-2-1R7-2-2、或、-(C=O)R7-2-3;
R7-6~R7-9独立地选自卤素、羟基、氰基、硝基、未取代或R7-6-1取代的C1-6的烷基、C2-6烯基、C2-6炔基、未取代或R7-6-2取代的C1-6烷氧基、C6-10芳基-氧基、杂芳基-氧基、(C3-10环烷基)-氧基、C1-6烷胺基-C1-6烷氧基-、未取代或R7-6-3取代的C3-10环烷基、未取代或R7-6-4取代的C3-10环烷基-(C1-6烷基)-、未取代或R7-6-5取代的杂环烷基、未取代或R7 -6-6取代的杂环烷基-(C1-6烷基)-、未取代或R7-6-7取代的杂芳基、未取代或R7-6-8取代的杂芳基-(C1-6烷基)-、未取代或R7-6-9取代的C6-10芳基、未取代或R7-6-10取代的C6-10芳基-(C1-6烷基)-、-NR7-6-11R7-6-12、-(C=O)R7-6-13、-(C=O)NR7-6-14R7-6-15、-NR7-6-16(C=O)R7-6-17、-(C=O)OR7-6-18、-O(C=O)R7-6-19、-(S=O)2NR7-6-20R7-6-21、-NR7-6-22(S=O)2R7-6-23、或、-(S=O)2R7 -6-24;所述的杂环烷基为“杂原子选自N、O或S中的一种或多种,杂原子数为1-3个的”4-10元杂环烷基;所述的杂芳基为“杂原子选自N、O或S中的一种或多种,杂原子数为1-3个的”5-10元杂芳基;
R7-6-1和R7-6-2独立地选自卤素、羟基、氰基、C1-4烷基、或-NR7-6-1-1R7-6-1-2;
R7-6-1-1和R7-6-1-2独立地选自氢或C1-4烷基;
R7-6-3~R7-6-10独立地选自氢、卤素、氰基、羟基、C1-4烷基、C1-4烷氧基、卤代(C1-4烷基)、卤代(C1-4烷氧基)、-NR7-6-3-1R7-6-3-2、或、-(C=O)R7-6-3-3;
R7-6-3-1~R7-6-3-3独立地选自氢或C1-4烷基;
R7-6-11~R7-6-24独立地选自氢或C1-4烷基。
进一步地,在式I各部分的上述定义中,各部分的优选基团如下:
R1分别独立地选自以下基团或者每个R1与其所键合的偕碳原子耦合形成以下基团:
R2分别独立地选自以下基团:
R3分别独立地选自以下基团:
其中U1选自氢、羟基、卤素、甲基、乙基、异丙基、叔丁基、三氟甲基、甲氧基、三氟甲氧基或羟甲基;
其中R7选自以下基团:
其中U1选自氢、羟基、卤素、甲基、乙基、异丙基、叔丁基、三氟甲基、甲氧基、三氟甲氧基或羟甲基;
R5选自以下基团:
更进一步地,所述的式I化合物为以下任一化合物:
另一方面,本发明提供了一种包含上述阿维巴坦衍生物的药物组合物。
在一些实施方式中,本发明涉及的药物组合物,进一步包含药学上可接受的辅料。
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物,还可以提供方法,使受试者接受给药后活性成分以所期望速率溶出,或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂,或者提供某种功能,例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种:粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
在一些实施方式中,本发明涉及的药物组合物,进一步包含β-内酰胺类抗生素。
β-内酰胺类抗生素包括但不限青霉素G、青霉素钠、阿莫西林、苯唑西林、羧苄西林、美西林、甲氧西林、氯唑西林、双氯西林、氟氯西林、氨苄西林、依匹西林、哌拉西林、阿洛西林、美洛西林、阿帕西林、磺苄西林、替卡西林、海他西林、头孢拉定、头孢氨苄、头孢唑啉、头孢孟多、头孢呋辛、头孢呋辛、头孢曲松、头孢他定、头孢吡肟、头孢吡罗、头孢他林、头孢西丁、头孢霉素、拉氧头孢、比阿培南、多立培南、厄他培南、法罗培南、亚胺培南、美罗培南、帕尼培南、拉祖培南、替比培南和噻嗯霉素等。
在一些实施方式中,本发明涉及的药物组合物为口服剂型。
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如,常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
又一方面,本发明提供了上述阿维巴坦衍生物作为β-内酰胺酶抑制剂的应用。
再一方面,本发明提供了上述阿维巴坦衍生物、药物组合物在制备用于治疗细菌感染有关的疾病的药物中的应用。
所述细菌感染包括但不限于专性需氧细菌、专性厌氧细菌、兼性厌氧细菌和微需氧细菌;专性需氧细菌包括但不限于:革兰氏阴性球菌,例如,粘膜炎莫拉菌(Moraxellacatarrhalis)、淋病奈瑟菌(Neisseria gonorrhoeae)和脑膜炎奈瑟菌(N.meningitidi);革兰氏阳性杆菌,例如,空肠棒状杆菌(Corynebacterium jeikeium);抗酸杆菌,例如,鸟分枝杆菌(Mycobacterium avium)复合物、堪萨斯分枝杆菌(M.kansasii)、麻风衣原体(M.leprae)、结核分枝杆菌(M.tuberculosis)和诺卡氏菌(Nocardia sp);非发酵性、非肠杆菌科,例如,醋酸钙不动杆菌(Acinetobacter calcoaceticus)、伊丽莎白菌脑膜败血症(Elizabethkingia meningoseptica)(以前为黄杆菌脑膜败血症(Flavobacteriummeningosepticum))、绿脓杆菌(Pseudomonas aeruginosa)、产碱杆菌(P.alcaligenes)、其它假单胞菌(Pseudomonas sp)和嗜麦芽窄食单胞菌(Stenotrophomonas maltophilia);严格的革兰氏阴性球菌和杆菌,例如,布鲁氏菌(Brucella)、博德特氏菌(Bordetella)、弗朗西斯氏菌属(Francisella)和军团菌属(Legionella spp);螺旋体科(螺旋菌),例如,钩端螺旋体属(Leptospira sp)。专性厌氧细菌的例子包括:革兰氏阴性芽胞杆菌属(bacilli),例如,脆弱拟杆菌(Bacteroidesfragilis)、其它类杆菌(Bacteroides sp)、梭杆菌(Fusobacterium sp)、普雷沃菌(Prevotella sp);革兰阴性球菌,例如,细脉菌属(Veillonella sp.);革兰阳性球菌,例如,黑消化球菌(Peptococcus niger)和消化链球菌(Peptostreptococcus sp.);非芽孢型格兰氏阳性杆菌,例如,肉毒杆菌(Clostridium botulinum)、产气荚膜梭菌(C.perfringens)、破伤风杆菌(C.tetani)、其它梭菌属(Clostridium sp);和内生芽孢的革兰氏阳性杆菌,例如,肉毒杆菌(Clostridiumbotulinum)、产气荚膜梭菌(C.perfringens)、破伤风杆菌(C.tetani)及其它梭菌属(Clostridium sp)。兼性厌氧菌包括但不限于:催化酶阳性的格兰氏阳性球菌,例如,金黄葡萄球菌(Staphylococcusaureus)(凝固酶阳性)、表皮葡萄球菌(S.epidermidis)(凝固酶阴性)及其它凝固酶阴性葡萄球菌;格兰氏阳性球菌,催化酶阴性,例如,粪肠球菌(Enterococcusfaecalis)、肠球菌(E.faecium)、无乳链球菌(Streptococcus agalactiae)(B组链球菌)、牛链球菌(S.bovis)、肺炎链球菌(S.pneumoniae)、化脓性链球菌(S.pyogenes)(A组链球菌)、病毒性链球菌(viridans group streptococci)((变形链球菌(S.mutans)、链球菌(S.mitis)、唾液链球菌(S.salivarius)、血球链球菌(S.sanguis))、血管炎性链球菌(S.anginosus)((血管炎性链球菌(S.anginosus)、米氏链球菌(S.milleri)、S.constellatus))和麻疹孪生球菌(Gemella morbillorum);格兰氏阳性杆菌,例如,炭疽杆菌(Bacillus anthracis)、红斑丹毒丝菌(Erysipelothrix rhusiopathiae)和阴道加德菌(Gardnerella vaginalis)(革兰氏染色不定);革兰氏阴性杆菌,例如,肠杆菌科(Enterobacteriaceae)(柠檬细菌(Citrobacter sp)、产气肠杆菌(Enterobacter aerogenes)、大肠杆菌(Escherichiacoli)、克雷伯氏杆菌(Klebsiella sp)、摩根(氏)菌(Morganella morganii)、变形杆菌(Proteus sp)、志贺样邻单胞菌(Plesiomonasshigelloides)、雷氏普罗威登斯菌(Providencia rettgeri)、伤寒杆菌(Salmonellatyphi)、其它沙门氏菌(Salmonella sp)、粘质沙雷氏菌(Serratia marcescens)和志贺氏菌属(Shigella sp)、小肠结肠子尔赞氏菌(Yersinia enterocolitica)、鼠疫菌(Y.pestis));发酵性非肠杆菌科,例如,嗜水气单胞菌(Aeromonas hydrophila)、紫色菌(Chromobacterium violaceum)和多杀性巴氏杆菌(Pasteurella multocida);苛求革兰氏阴性球菌和杆菌,例如,放线共生放线杆菌(Actinobacillus actinomycetemcomitans)、杆菌状巴尔通氏体(Bartonellabacilliformis)、汉赛巴尔通体(B.henselae)、金塔纳巴尔通体(B.quintana)、保守艾肯内拉菌(Eikenella corrodens)、流感嗜血杆菌(Haemophilus influenzae)及其它嗜血杆菌属(Haemophilus sp);支原体,例如,肺炎支原体(Mycoplasma pneumoniae);密螺旋体科(螺旋菌),例如,博格多菲螺旋体(Borrelia burgdorferi)和苍白密螺旋体(Treponemapallidum)。微需氧菌的例子包括:弯曲杆菌,例如,空肠弯杆菌(Campylobacter jejuni)、幽门螺旋菌(Helicobacterpylori)、霍乱弧菌(Vi briocholerae)和创伤弧菌(V.vulnificus);专性胞内寄生菌;衣原体科,例如,沙眼衣原体(Chlamydiatrachomatis)、肺炎衣原体(Chlamydophila pneumoniae)和鹦鹉热衣原体(C.psittaci);考克菌科(coxiellaceae),例如,伯氏考克斯氏体(Coxiella burnetii);立克次体,例如,普氏立克次氏体(Rickettsia prowazekii)、立克次氏体(R.rickettsii)、伤寒立克次体(R.typhi)、恙虫病立克次体(R.tsutsugamushi)、查菲埃立克体(Ehrlichia chaffeensis)和嗜吞噬细胞无形体(Anaplasma phagocytophilum)。
在一些实施方案中,所述细菌的产生β-内酰胺酶。产生β-内酰胺酶的细菌包括但不限于结核分枝杆菌(Mycobacterium tuberculosis)、甲氧西林-耐受性金黄葡萄球菌(Staphylococcus aureus)、葡萄球菌(Staphyloccus)、肠杆菌(Enterobacteriaceae)、绿脓杆菌(Pseudomonas aeruginosa)、流感嗜血杆菌(Haemophilus influenzae)、克雷白氏杆菌(Klebsiella pneumoniae)、柠檬细菌(Citrobacter)和摩根菌(Morganella)。
定义和一般术语
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的游离体形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的游离体形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸(形成碳酸盐或碳酸氢盐)、磷酸(形成磷酸盐、磷酸一氢盐、磷酸二氢盐、硫酸(形成硫酸盐或硫酸氢盐)、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸;有机酸盐还包括氨基酸(如精氨酸等)的盐,以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。优选地,以常规方式使盐与碱或酸接触,再分离母体化合物,由此再生化合物的游离体形式。化合物的游离体形式与其各种盐的形式的不同之处在于某些物理性质,例如在极性溶剂中的溶解度不同。
本发明的“药学上可接受的盐”可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地,优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
术语“代谢产物”是指式I所示化合物或其盐通过体内代谢产生的药学活性产物。这种产物可以从例如所给药的化合物的氧化、还原、水解、酰胺化、脱酰胺、酯化、脱酯、葡糖醛酸化、酶促裂解等产生。因此,本发明包括本发明的化合物的代谢产物,包括使本发明的化合物与哺乳动物接触足够得到其代谢产物的一段时间的方法而产生的化合物。
代谢产物的鉴定典型地通过制备本发明化合物的放射性标记的同位素、将其以可检测的剂量(例如,大于约0.5mg/kg)非肠道给予动物,例如大鼠、小鼠、豚鼠、猴、或人,允许充分的时间以发生代谢(典型地约30秒到30小时)和从尿、血液或其它生物样本分离其转化产物。这些产物容易分离,因为它们是被标记的(其它通过利用能够结合存在于代谢物中的抗原表位的抗体分离)。以常规的方式确定代谢物结构,例如,通过MS,LC/MS或NMR分析。通常,代谢物的分析是以与本领域技术人员公知的常规药物代谢研究相同的方法进行的。只要代谢物产物不是以其它方式在体内不能被发现,否则它们可用于本发明化合物的治疗剂量给药的检定测定法。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氚(3H),碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
术语“溶剂合物”是指一个或者多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂合物的溶剂包括但不限于,水,异丙醇,甲醇,乙醇,二甲亚砜,乙酸乙酯,乙酸,乙醇胺或其混合物。
术语“水合物”是指溶剂分子是水所形成的缔合物。在一实施方案中,一个本发明化合物分子可以与一个水分子相结合,比如一水合物;在另一实施方案中,一个本发明化合物分子可以与多于一个的水分子相结合,比如二水合物;在又一实施方案中,一个本发明化合物分子可以与少于一个的水分子相结合,比如半水合物。应注意,本发明所述的水合物保留有非水合物形式的化合物的生物有效性。
术语“生物利用度”是指本文所公开的化合物被递送到所研究的动物或人的全身循环中的重量百分比。当静脉内施用时,药物的总暴露量(AUC(0-∞))通常被定义为100%生物利用度(F%)。“口服生物利用度”是指与静脉内注射相比,当口服药物组合物时,本文所公开的化合物被吸收到全身循环中的程度。
下面将结合具体实施例对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。另外,值得说明的是,本发明所涉及的原料如无特殊说明均为普通市售产品。
实施例1:化合物1的合成
3-(((((2S,5R)-2-(((乙酰氧甲基)氨基甲酰基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧)磺酰)氧)-2,2-二甲基丙酸乙酯
步骤一:化合物S4的合成
将化合物S1(100mg,0.4mmol)与二异丙基乙胺(77ul,0.44mmol)溶于氯苯(1ml)中,在35℃以下将9-芴基甲基氯甲酸酯(105mg,0.404mmol)的氯苯(1ml)溶液加入到反应混合物中,室温反应6h,得到化合物S2。然后将该溶液与羰基二咪唑(84.5mg,0.52mmol)混合,并室温下搅拌11小时,得到化合物S3。加入二乙胺(103ul)并在30℃下继续搅拌3.5小时。加入3M盐酸水溶液(0.6ml)调PH至酸性,并将混合物冷却至0℃。过滤分离固体,用水和1-氯丁烷(5ml×2)洗涤两次,干燥得到化合物S4(88mg,80%)。1HNMR(400MHz,DMSO)δ1.65(2H,m),1.86(1H,m),2.10(1H,m),2.91(2H,s),3.63(1H,s),3.72(1H,d,J=6.7Hz),4.92(2H,dd,J=18.1Hz,J=11.4Hz),7.38(7H,m)。
步骤二:化合物S6的合成
将化合物S4(88mg,0.32mmol)溶于乙腈中,向上述溶液中依次加入甲醛水溶液(37%,270ul),碳酸钾(5mg,0.04mmol),室温反应12h。反应完成后,乙酸乙酯萃取3次(10ml×3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,得到化合物S5。
将上述所得的化合物S5溶于吡啶(2ml)中,加入乙酸酐(50ul,0.5mmol),室温反应3h。反应完成后,乙酸乙酯萃取3次(10ml×3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析分离纯化,得到化合物S6(78mg,70%)。1HNMR(400MHz,Chloroform-d)δ7.35(dddd,J=13.5,5.3,2.2,1.4Hz,5H),6.48(t,J=4.5Hz,1H),5.03-4.93(m,2H),4.79(dt,J=11.7,0.9Hz,1H),4.72(dt,J=11.7,1.0Hz,1H),4.40(dd,J=6.7,4.4Hz,1H),3.83(dtd,J=6.4,4.0,2.5Hz,1H),3.78(dd,J=10.1,2.4Hz,1H),3.54(dd,J=10.1,3.8Hz,1H),2.19(dddd,J=12.4,8.2,6.8,5.9Hz,1H),2.15-2.05(m,1H),2.09(s,3H),1.95-1.84(m,1H),1.78(dddd,J=12.4,8.1,5.9,4.3Hz,1H)。
步骤三:化合物S7的合成
将上述所得化合物S6(78mg,0.23mmol),钯/碳(10%重量,8mg),溶于甲醇(1ml)溶液中,在1atm(气球)下氢化,直到薄层色谱分析表明反应完成(约30分钟)。混合物通过硅藻土垫过滤,然后用20mL的甲醇彻底冲洗垫。滤液在真空(水浴温度不超过25℃)下浓缩,使产品为透明无色的油。将油在真空下干燥1小时,得到化合物S7(52mg,90%),残渣立即用于下一步,无需进一步纯化。1HNMR(400MHz,Chloroform-d)δ6.46(t,J=4.4Hz,1H),5.91(s,1H),4.96(dd,J=4.5,1.0Hz,2H),4.38-4.31(m,1H),3.81-3.70(m,2H),3.69(dd,J=9.8,3.9Hz,1H),2.16-2.04(m,2H),2.08(s,3H),1.99(ddt,J=12.5,8.0,6.2Hz,1H),1.80(dddd,J=11.4,9.0,6.0,4.4Hz,1H)。
步骤四:化合物1a的合成
在氩气氛围下,将硫酰氯(0.11mL,1.5mmol)的乙醚(1ml)溶液中冷却到-78℃。然后将3-羟基-2,2-二甲基丙酸乙酯,吡啶的乙醚溶液逐滴加入上述反应液中,滴加1小时以上。将反应液缓慢升温至室温,然后在室温下搅拌,直到TLC分析表明反应完全。将混合物过滤,收集滤液,浓缩,得到化合物1a,可直接用于下一步,无需进一步纯化。1HNMR(400MHz,CDCl3):δ4.50(s,2H),4.19(q,J=6.9Hz,2H),1.31(s,6H),1.28(t,J=6.9Hz,3H)。
步骤五:化合物1的合成
将上述所得化合物S7(52mg,0.2mmol)和1,3-二甲基四氢嘧啶-2(1H)-1(3.01mL)溶于THF(3.0mL)中,在氩气氛围下冷却至-78℃。滴加双(三甲基硅基)氨基钠的四氢呋喃溶液(2M;滴加0.12mL,0.24mmol),在-78℃下搅拌10分钟。然后通过注射器快速将3-(氯磺酰基)氧乙基-2,2-二甲基丙酸乙酯(59mg,0.24mmol)的THF(0.5mL)溶液加入反应混合物中。-78℃下反应10min后,加热室温,室温下搅拌,直至TLC分析判断反应完成(约2h)。反应完成后,乙酸乙酯萃取3次(10ml×3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析分离纯化,得到化合物1(18mg,20%)。1HNMR(400MHz,Chloroform-d)δ6.19(t,J=4.5Hz,1H),5.02-4.91(m,2H),4.42-4.34(m,1H),4.26(d,J=9.9Hz,1H),4.24-4.14(m,1H),4.18-4.08(m,2H),3.83(dtd,J=6.4,3.8,2.5Hz,1H),3.77(dd,J=10.1,2.6Hz,1H),3.71(dd,J=10.1,3.8Hz,1H),2.19-2.07(m,2H),2.07(s,2H),2.01(ddt,J=12.3,8.1,6.2Hz,1H),1.91-1.81(m,2H),1.30-1.21(m,9H).MS(EI,m/z):466(M++1)。
实施例2:化合物2的合成
2,2-二甲基-3-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰)丙酸乙酯
合成方法如实施例1。1HNMR(400MHz,Chloroform-d)δ6.35(t,J=4.4Hz,1H),5.01-4.88(m,2H),4.40-4.31(m,2H),4.24-4.08(m,2H),3.98(d,J=9.9Hz,2H),3.87-3.80(m,2H),3.76-3.70(m,2H),2.36(dq,J=10.1,7.8Hz,2H),2.12-1.95(m,2H),1.84(dddd,J=12.3,7.9,6.0,4.4Hz,1H),1.71(dddd,J=12.6,8.1,6.8,5.9Hz,1H),1.29-1.20(m,7H),1.13(t,J=7.9Hz,3H).MS(EI,m/z):480(M++1)。
实施例3:化合物3的合成
((2S,5R)-6-(((3-乙氧基-2,2-二甲基-3-氧代丙氧基)磺酰)氧基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺基)甲基丁酸酯
合成方法如实施例1。1HNMR(400MHz,Chloroform-d)δ6.33(t,J=4.5Hz,1H),5.01-4.73(m,2H),4.40(dd,J=6.8,4.4Hz,2H),4.25(d,J=9.9Hz,1H),4.25-4.16(m,1H),4.14(dq,J=10.1,7.0Hz,2H),3.87-3.76(m,2H),3.57(dd,J=10.1,3.8Hz,1H),2.41-2.26(m,2H),2.20(dddd,J=12.5,8.2,6.8,5.9Hz,1H),2.09(dddd,J=12.4,8.2,5.9,4.1Hz,1H),1.97-1.87(m,1H),1.77(dddd,J=12.5,8.2,5.9,4.4Hz,1H),1.73-1.55(m,2H),1.30-1.21(m,8H),0.97(t,J=7.5Hz,3H).MS(EI,m/z):494(M++1)。
实施例4:化合物4的合成
((2S,5R)-6-(((3-乙氧基-2,2-二甲基-3-氧代丙氧基)磺酰)氧基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺)戊酸甲酯
合成方法如实施例1。1HNMR(400MHz,Chloroform-d)δ6.24(t,J=4.4Hz,1H),5.01-4.89(m,2H),4.38(dd,J=6.8,4.4Hz,2H),4.17(d,J=9.9Hz,1H),4.23(dq,J=10.1,7.0Hz,1H),4.19-4.08(m,2H),3.87-3.76(m,2H),3.63(dd,J=10.0,3.9Hz,1H),2.33(td,J=7.0,3.8Hz,2H),2.20(dddd,J=12.4,8.1,6.7,5.9Hz,1H),2.07(dddd,J=12.4,8.2,5.9,4.1Hz,1H),1.93(ddt,J=12.4,8.2,6.1Hz,1H),1.78(dddd,J=12.4,8.1,5.9,4.4Hz,1H),1.64(pd,J=6.9,2.5Hz,2H),1.48-1.30(m,2H),1.34-1.21(m,8H),0.94(t,J=7.6Hz,3H).MS(EI,m/z):508(M++1)。
实施例5:化合物5的合成
2,2-二甲基-3-(((((2S,5R)-7-氧代-2-(((特戊酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰)丙酸乙酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.33(t,J=4.5Hz,1H),5.01-4.91(m,2H),4.39(dd,J=6.7,4.3Hz,2H),4.25(d,J=9.9Hz,1H),4.25-4.16(m,1H),4.19-4.08(m,2H),3.87-3.78(m,2H),3.59(dd,J=10.0,3.9Hz,1H),2.17(dddd,J=12.4,8.1,6.7,5.9Hz,1H),2.08(dddd,J=12.3,8.1,5.9,4.0Hz,1H),1.91(ddt,J=12.5,8.2,6.1Hz,1H),1.77(dddd,J=12.4,8.0,5.9,4.4Hz,1H),1.30-1.21(m,8H),1.17(s,9H).MS(EI,m/z):508(M++1).
实施例6:化合物6的合成
3-(((((2S,5R)-2-((((异丁烯氧基)甲基)氨基甲酰基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧)磺酰)氧)-2,2-二甲基丙酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.37(t,J=4.4Hz,1H),5.02-4.91(m,2H),4.39(dd,J=6.8,4.4Hz,2H),4.25(d,J=9.9Hz,1H),4.23-4.16(m,1H),4.17(dd,J=9.9,7.1Hz,2H),3.87-3.79(m,2H),3.60(dd,J=10.1,3.8Hz,1H),2.55(hept,J=7.1Hz,1H),2.19(dddd,J=12.4,8.1,6.7,5.9Hz,1H),2.09(dddd,J=12.4,8.2,5.9,4.1Hz,1H),1.92(ddt,J=12.5,8.2,6.2Hz,1H),1.77(dddd,J=12.4,8.2,5.9,4.4Hz,1H),1.30-1.22(m,8H),1.16(dd,J=25.1,7.2Hz,6H).MS(EI,m/z):494(M++1).
实施例7:化合物7的合成
((2S,5R)-6-(((3-乙氧基-2,2-二甲基-3-氧代丙氧基)磺酰)氧基)-7-氧代-1,6-二氮双环[3.2.1]辛烷-2-甲酰胺)2-甲基丁酸甲酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.29(t,J=4.4Hz,1H),5.03–4.93(m,2H),4.39(dd,J=6.8,4.4Hz,2H),4.28(d,J=9.9Hz,1H),4.25–4.12(m,2H),4.03(d,J=9.9Hz,1H),3.86(dtd,J=6.5,3.9,2.5Hz,1H),3.77(dd,J=10.1,2.6Hz,1H),3.59(dd,J=10.1,3.8Hz,1H),2.33(dtd,J=13.6,7.3,6.3Hz,1H),2.19(dddd,J=12.5,8.1,6.8,5.9Hz,1H),2.09(dddd,J=12.4,8.2,5.9,4.2Hz,1H),1.96–1.85(m,1H),1.77(dddd,J=12.4,8.1,5.9,4.3Hz,1H),1.67(dddd,J=23.2,14.0,13.3,6.9Hz,2H),1.29–1.20(m,8H),1.13(d,J=7.2Hz,3H),0.92(t,J=7.0Hz,3H).MS(EI,m/z):508(M++1).
实施例8:化合物8的合成
((2S,5R)-6-(((3-乙氧基-2,2-二甲基-3-氧代丙氧基)磺酰)氧基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺)甲基环丙烷甲酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.40(t,J=4.5Hz,1H),5.04–4.94(m,2H),4.43(d,J=9.9Hz,1H),4.30(dd,J=6.6,4.4Hz,1H),4.25–4.10(m,2H),4.07(d,J=9.7Hz,1H),3.92–3.82(m,2H),3.67(dd,J=10.0,3.9Hz,1H),2.22–2.00(m,3H),1.88(dddd,J=12.3,8.2,6.0,4.4Hz,1H),1.61(p,J=6.4Hz,1H),1.29–1.20(m,9H),1.06(tdd,J=10.1,6.4,0.8Hz,2H),0.88(tdd,J=10.1,6.5,1.0Hz,2H).MS(EI,m/z):492(M++1).
实施例9:化合物9的合成
((2S,5R)-6-(((3-乙氧基-2,2-二甲基-3-氧代丙氧基)磺酰)氧基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺)甲基环戊烷甲酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.22(t,J=4.5Hz,1H),4.99(d,J=4.4Hz,2H),4.43–4.35(m,2H),4.29(d,J=9.9Hz,1H),4.25–4.08(m,2H),4.07(d,J=9.7Hz,1H),3.84(dtd,J=6.4,4.0,2.4Hz,1H),3.78(dd,J=10.1,2.6Hz,1H),3.62(dd,J=10.1,3.8Hz,1H),2.62–2.53(m,1H),2.20–2.10(m,1H),2.10–2.00(m,1H),1.97–1.84(m,3H),1.78–1.66(m,4H),1.66–1.54(m,3H),1.29–1.20(m,8H).MS(EI,m/z):520(M++1).
实施例10:化合物10的合成
((2S,5R)-6-(((3-乙氧基-2,2-二甲基-3-氧代丙氧基)磺酰基)氧基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺)甲基环己烷甲酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.27(t,J=4.5Hz,1H),4.97(d,J=4.4Hz,2H),4.36(dd,J=6.6,4.4Hz,1H),4.27(d,J=9.9Hz,1H),4.24–4.16(m,1H),4.18–4.08(m,2H),3.84(dtd,J=6.4,4.0,2.5Hz,1H),3.74(dd,J=10.1,2.4Hz,1H),3.66(dd,J=10.1,3.8Hz,1H),2.28(dq,J=9.5,6.3Hz,1H),2.16–1.95(m,3H),1.97–1.90(m,1H),1.94–1.85(m,1H),1.88–1.79(m,1H),1.71–1.59(m,4H),1.58–1.46(m,1H),1.43–1.31(m,3H),1.28–1.19(m,9H).MS(EI,m/z):534(M++1).
实施例11:化合物11的合成
(2S,5R)-6-(((3-乙氧基-2,2-二甲基-3-氧代丙氧基)磺酰基)氧基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺)甲基苯甲酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ7.86–7.78(m,2H),7.59–7.50(m,1H),7.48–7.40(m,2H),6.34(t,J=4.4Hz,1H),5.16–5.02(m,2H),4.36(dd,J=6.7,4.3Hz,2H),4.28(d,J=9.7Hz,1H),4.24–4.09(m,3H),3.87–3.75(m,2H),3.70(dd,J=10.1,3.7Hz,1H),2.14(dddd,J=12.5,8.0,6.7,6.0Hz,1H),2.06(dddd,J=12.4,8.0,5.9,4.1Hz,1H),1.97(ddt,J=12.6,8.0,6.2Hz,1H),1.84(dddd,J=12.4,8.1,5.9,4.3Hz,1H),1.30–1.20(m,8H).MS(EI,m/z):528(M++1).
实施例12:化合物12的合成
((2S,5R)-6-(((3-乙氧基-2,2-二甲基-3-氧代丙氧基)磺酰基)氧基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺)甲基四氢呋喃-3-甲酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.19(t,J=4.5Hz,1H),4.99(d,J=4.4Hz,2H),4.43–4.33(m,2H),4.25–4.08(m,3H),4.03(dd,J=10.5,6.5Hz,1H),3.91–3.85(m,1H),3.88–3.83(m,1H),3.87–3.76(m,2H),3.74(dd,J=10.1,2.5Hz,1H),3.60(dd,J=10.1,3.8Hz,1H),2.84(p,J=6.5Hz,1H),2.36(dddd,J=13.4,6.6,5.7,4.8Hz,1H),2.22(dddd,J=13.2,6.4,5.5,4.6Hz,1H),2.10(dddd,J=12.4,8.2,6.7,5.8Hz,1H),2.00(ddt,J=12.4,8.2,6.2Hz,1H),1.86(dddd,J=12.4,8.2,6.0,4.4Hz,1H),1.75(dddd,J=12.4,8.2,5.8,4.1Hz,2H),1.29–1.20(m,8H).MS(EI,m/z):522(M++1).
实施例13:化合物13的合成
((2S,5R)-6-(((3-乙氧基-2,2-二甲基-3-氧代丙氧基)磺酰基)氧基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺)甲基四氢噻吩-3-甲酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.24(t,J=4.5Hz,1H),4.96(d,J=4.6Hz,2H),4.43-4.33(m,2H),4.24-4.08(m,3H),3.87-3.77(m,2H),3.64(dd,J=10.1,3.8Hz,1H),3.26(dd,J=13.3,5.2Hz,1H),3.17(tt,J=6.4,5.2Hz,1H),3.12-3.00(m,3H),2.70(dddd,J=12.6,6.4,4.2,3.5Hz,1H),2.21(dddd,J=12.6,8.2,6.8,5.9Hz,1H),2.07(dddd,J=12.3,8.1,5.9,4.0Hz,1H),2.00(ddt,J=12.7,6.4,3.8Hz,1H),1.91(ddt,J=12.5,8.1,6.1Hz,1H),1.78(dddd,J=12.5,8.2,5.9,4.4Hz,1H),1.28-1.19(m,9H).MS(EI,m/z):538(M++1).
实施例14:化合物14的合成
3-(((((2S,5R)-2-(((2-环戊基乙酰氧基)甲基)氨基甲酰基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧)磺酰)氧)-2,2-二甲基丙酸乙酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.5Hz,1H),4.97(d,J=4.4Hz,2H),4.40(dd,J=6.8,4.2Hz,1H),4.29(d,J=9.9Hz,2H),4.24-4.09(m,2H),4.10(d,J=9.9Hz,1H),3.88(dtd,J=6.3,3.9,2.5Hz,1H),3.78(dd,J=10.1,2.6Hz,1H),3.61(dd,J=10.1,3.8Hz,1H),2.51(dd,J=15.9,7.5Hz,1H),2.29(dd,J=15.8,7.6Hz,1H),2.26-2.14(m,2H),2.09(dddd,J=12.4,8.2,5.9,4.1Hz,1H),1.98-1.85(m,3H),1.72-1.50(m,5H),1.41-1.30(m,2H),1.29-1.20(m,8H).MS(EI,m/z):534(M++1).
实施例15:化合物15的合成
3-(((((2S,5R)-2-((((3-环丙基丙酰基)氧)甲基)氨基甲酰基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧)磺酰)氧)-2,2-二甲基丙酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.4Hz,1H),4.97(d,J=4.4Hz,2H),4.39-4.30(m,2H),4.20(dq,J=10.1,7.0Hz,1H),4.19-4.08(m,2H),3.87-3.76(m,2H),3.72(dd,J=10.1,3.8Hz,1H),2.36(dt,J=15.6,7.9Hz,1H),2.28(dt,J=15.3,8.0Hz,1H),2.18-2.02(m,2H),1.97(ddt,J=12.5,7.9,6.2Hz,1H),1.90-1.75(m,2H),1.52(dtd,J=12.5,7.9,6.2Hz,1H),1.34-1.18(m,14H),1.01(hept,J=6.1Hz,1H).MS(EI,m/z):520(M++1).
实施例16:化合物16的合成
((2S,5R)-6-((((3-甲基-2-氧代四氢-2H-吡喃-3-基)甲氧基)磺酰)氧基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺)甲基丙酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.27(t,J=4.4Hz,1H),5.01-4.91(m,2H),4.40(dd,J=6.8,4.4Hz,1H),4.32(d,J=9.7Hz,2H),4.08(d,J=9.7Hz,1H),4.08-3.97(m,2H),3.88(dtd,J=6.5,4.0,2.6Hz,1H),3.77(dd,J=10.1,2.6Hz,1H),3.57(dd,J=10.1,3.8Hz,1H),2.45-2.27(m,2H),2.19(dddd,J=12.5,8.4,6.8,5.9Hz,1H),2.00-1.72(m,6H),1.75-1.65(m,1H),1.20(s,2H),1.13(t,J=7.9Hz,3H).MS(EI,m/z):478(M++1).
实施例17:化合物17的合成
3-((((((2S,5R)-2-((((甲氧基羰基)氧基)甲基)氨基甲酰基)-7-氧代-1,6-二氮杂双环[3.2.1]辛基-6-基)氧基)磺酰基)氧基)-2,2-二甲基丙酸乙酯
化合物S5的合成方法如实施例1。
步骤三:化合物S8的合成
将化合物S5(89mg,0.29mmol)加入二氯甲烷溶剂(1ml)中,室温下依次加入吡啶(36ul,0.44mmol),氯甲酸甲酯(42ul,0.44mmol),室温反应,直至TLC显示反应完全(约4h)。反应完成后,乙酸乙酯萃取3次(10ml×3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析分离纯化,得到化合物S8(84mg,80%)。1H NMR(400MHz,Chloroform-d)δ7.38-7.28(m,5H),6.60(t,J=4.5Hz,1H),5.03(d,J=4.4Hz,2H),4.79(dt,J=11.8,1.0Hz,1H),4.72(dt,J=11.9,0.9Hz,1H),4.42(dd,J=6.8,4.3Hz,1H),3.81(s,3H),3.86-3.75(m,2H),3.55(dd,J=10.1,3.8Hz,1H),2.21(dddd,J=12.5,8.2,6.7,5.9Hz,1H),1.92-1.81(m,1H),1.83-1.67(m,2H).
步骤四:化合物S9的合成
将上述所得化合物S8(84mg,0.23mmol),钯/碳(10%重量,9mg),溶于甲醇(1ml)溶液中,在1atm(气球)下氢化,直到薄层色谱分析表明反应完成(约30分钟)。混合物通过硅藻土垫过滤,然后用20mL的甲醇彻底冲洗垫。滤液在真空(水浴温度不超过25℃)下浓缩,使产品为透明无色的油。将油在真空下干燥1小时,得到化合物S9(57mg,90%),残渣立即用于下一步,无需进一步纯化。1H NMR(400MHz,Chloroform-d)δ6.64(t,J=4.4Hz,1H),5.90(s,1H),5.00(d,J=4.4Hz,2H),4.43(dd,J=6.7,4.3Hz,1H),3.81(s,3H),3.83-3.70(m,2H),3.56(dd,J=10.0,3.9Hz,1H),2.24-2.07(m,2H),1.97-1.86(m,1H),1.80(dddd,J=12.4,8.2,5.9,4.4Hz,1H).
步骤五:化合物17的合成
将上述所得化合物S9(57mg,0.2mmol)和1,3-二甲基四氢嘧啶(1mL)溶于THF(3.0mL)中,在氩气氛围下冷却至-78℃。滴加双(三甲基硅基)氨基钠的四氢呋喃溶液(2M;滴加0.12mL,0.24mmol),在-78℃下搅拌10分钟。然后通过注射器快速将3-(氯磺酰基)氧乙基-2,2-二甲基丙酸乙酯(59mg,0.24mmol)的THF(0.5mL)溶液加入反应混合物中。-78℃下反应10min后,加热室温,室温下搅拌,直至TLC分析判断反应完成(约2h)。反应完成后,乙酸乙酯萃取3次(10ml×3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析分离纯化,得到化合物17(19mg,20%)。1H NMR(400MHz,Chloroform-d)δ6.33(t,J=4.5Hz,1H),5.02(d,J=4.4Hz,2H),4.44(dd,J=6.8,4.4Hz,1H),4.24-4.14(m,2H),4.14-4.08(m,1H),3.99(d,J=9.9Hz,1H),3.87-3.78(m,5H),3.60(dd,J=10.0,3.9Hz,1H),2.23(dddd,J=12.4,8.1,6.6,5.9Hz,1H),2.08(dddd,J=12.4,8.2,5.9,4.1Hz,1H),1.97-1.86(m,1H),1.77(dddd,J=12.4,8.1,5.9,4.4Hz,1H),1.29-1.20(m,9H).MS(EI,m/z):482(M++1).
实施例18:化合物18的合成
3-((((((2S,5R)-2-((((乙氧基羰基)氧基)甲基)氨基甲酰基)-7-氧代-1,6-二氮杂双环[3.2.1]辛基-6-基)氧基)磺酰基)氧基)-2,2-二甲基丙酸苄酯
合成方法如实施例17。1H NMR(400MHz,Chloroform-d)δ7.33(s,3H),7.37–7.27(m,2H),6.28(t,J=4.4Hz,1H),5.18(d,J=11.8Hz,1H),5.07–5.02(m,3H),4.44–4.38(m,2H),4.30–4.19(m,2H),4.14(dq,J=10.1,7.0Hz,1H),4.02(d,J=9.7Hz,1H),3.87–3.80(m,1H),3.78(dd,J=10.1,2.6Hz,1H),3.69(dd,J=10.1,3.8Hz,1H),2.12–2.01(m,1H),1.89–1.72(m,3H),1.35(t,J=7.0Hz,3H),1.26(s,2H),1.21(s,3H).MS(EI,m/z):558(M++1).
实施例19:化合物19的合成
3-(((((2S,5R)-2-(((((环戊氧基)羰基)氧基)甲基)氨基甲酰基)-7-氧代-1,6-二氮杂双环[3.2.1]辛基-6-基)氧基)磺酰基)氧基)-2,2-二甲基丙酸乙酯
合成方法如实施例17。1H NMR(400MHz,Chloroform-d)δ6.23(t,J=4.5Hz,1H),5.03(d,J=4.4Hz,2H),4.91(p,J=5.5Hz,1H),4.43(dd,J=6.7,4.3Hz,2H),4.25(d,J=9.9Hz,1H),4.22–4.06(m,3H),3.84(dtd,J=6.4,3.9,2.5Hz,1H),3.79(dd,J=10.1,2.4Hz,1H),3.62(dd,J=10.1,3.8Hz,1H),2.22(dddd,J=12.5,8.1,6.8,5.9Hz,1H),2.07(dddd,J=12.4,8.2,5.9,4.2Hz,1H),1.97–1.86(m,3H),1.87–1.65(m,5H),1.67–1.55(m,2H),1.29–1.20(m,8H).MS(EI,m/z):536(M++1).
实施例20:化合物20的合成
3-(((((2S,5R)-2-(((2-乙氧基乙酰氧基)甲基)氨基甲酰)-7-羰基-1,6-二氮杂二环[3.2.1]辛烷-6-基)氧代)磺酰)氧代)-2,2-二甲基丙酸乙酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.31(t,J=4.5Hz,1H),5.05–4.94(m,2H),4.41(d,J=9.9Hz,1H),4.36–4.29(m,2H),4.25–4.09(m,4H),4.04(d,J=15.4Hz,1H),3.84(dtd,J=6.4,3.9,2.5Hz,1H),3.77(dd,J=10.1,2.6Hz,1H),3.68(dd,J=10.1,3.8Hz,1H),3.41(s,2H),2.14–2.01(m,2H),1.99–1.81(m,2H),1.29–1.20(m,9H).MS(EI,m/z):496(M++1).
实施例21:化合物21的合成
3-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)磺酰)氧基)-2,2-二甲基-丙酸苄酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ7.37–7.25(m,5H),6.26(t,J=4.5Hz,1H),5.12(s,2H),4.95(d,J=4.4Hz,2H),4.47(d,J=9.9Hz,2H),4.44–4.37(m,1H),4.11(d,J=9.7Hz,1H),3.87–3.77(m,2H),3.58(dd,J=10.0,3.9Hz,1H),2.37(ddt,J=25.4,15.6,7.7Hz,2H),2.28–2.17(m,1H),1.99–1.88(m,2H),1.80–1.70(m,1H),1.27(s,2H),1.22(s,3H),1.17–1.10(m,3H).MS(EI,m/z):542(M++1).
实施例22:化合物22的合成
3-(((((2S,5R)-2-(((乙酰氧甲基)氨基甲酰基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧)氧基)磺酰)-2,2-二甲基丙酸乙酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.27(t,J=4.4Hz,1H),5.01–4.91(m,2H),4.38(dd,J=6.7,4.3Hz,1H),4.23(d,J=9.9Hz,2H),4.12(d,J=9.7Hz,1H),3.96–3.77(m,4H),3.58(dd,J=10.1,3.8Hz,1H),2.37(qd,J=7.8,6.7Hz,2H),2.20(dddd,J=12.5,8.1,6.8,5.9Hz,1H),2.08(dddd,J=12.4,8.2,5.9,4.2Hz,1H),1.97–1.83(m,2H),1.78(dddd,J=12.3,8.0,5.9,4.4Hz,1H),1.28(s,2H),1.23(s,3H),1.17–1.10(m,3H),0.91(dd,J=25.1,6.9Hz,6H).MS(EI,m/z):508(M++1).
实施例23:化合物23的合成
3-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰)-2,2-二甲基-丙酸丁酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.27(t,J=4.4Hz,1H),5.01–4.91(m,2H),4.42(dd,J=6.7,4.2Hz,1H),4.28(d,J=9.9Hz,2H),4.14–4.01(m,3H),3.83(dtd,J=6.3,3.9,2.4Hz,1H),3.78(dd,J=10.1,2.6Hz,1H),3.57(dd,J=10.1,3.8Hz,1H),2.41(dd,J=15.4,7.7Hz,1H),2.35(dd,J=15.6,7.8Hz,1H),2.23–2.10(m,1H),1.97–1.84(m,2H),1.75(dddd,J=12.0,8.7,5.8,4.1Hz,1H),1.72–1.60(m,1H),1.62–1.50(m,1H),1.47–1.34(m,1H),1.37–1.21(m,6H),1.14(t,J=7.9Hz,3H),0.90(t,J=7.6Hz,3H).MS(EI,m/z):508(M++1).
实施例24:化合物24的合成
3-草坦基-2,2-二甲基-3-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰)丙酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.29(t,J=4.5Hz,1H),5.17(p,J=5.5Hz,1H),5.06–4.91(m,2H),4.44–4.36(m,2H),3.96(d,J=9.9Hz,1H),3.90–3.80(m,5H),3.74(dd,J=10.1,2.6Hz,1H),3.57(dd,J=10.1,3.8Hz,1H),2.46–2.35(m,1H),2.39–2.27(m,2H),1.98(ddt,J=12.4,8.1,6.2Hz,1H),1.87(dddd,J=12.5,8.2,5.9,4.4Hz,1H),1.75(dddd,J=12.3,8.2,5.8,4.1Hz,1H),1.25(s,4H),1.14(t,J=7.9Hz,3H).MS(EI,m/z):508(M++1).
实施例25:化合物25的合成
(5-甲基-2-氧代-1,3-二氧戊环-4-基)甲基2,2-二甲基-3-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮双环[3.2.1]辛烷-6-基)氧)磺酰)氧)丙酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.27(t,J=4.4Hz,1H),4.98(d,J=4.4Hz,2H),4.84(dq,J=14.7,1.0Hz,1H),4.75(dq,J=14.5,1.0Hz,2H),4.35(dd,J=6.7,4.4Hz,1H),4.23(d,J=9.9Hz,1H),4.12(d,J=9.9Hz,1H),3.87–3.76(m,2H),3.75(dd,J=10.1,3.7Hz,1H),2.44–2.28(m,2H),2.15(dddd,J=12.5,7.9,6.7,6.0Hz,1H),2.11–2.00(m,4H),1.96(ddt,J=12.4,7.9,6.2Hz,1H),1.84(dddd,J=12.3,8.2,6.0,4.4Hz,1H),1.28(s,2H),1.23(s,3H),1.17–1.10(m,3H).MS(EI,m/z):564(M++1).
实施例26:化合物26的合成
1-((((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)甲基)环己烷-1-羧酸乙酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.4Hz,1H),4.95(d,J=4.4Hz,2H),4.38–4.29(m,2H),4.24–4.05(m,2H),4.07(d,J=9.7Hz,1H),3.88(dtd,J=6.5,4.0,2.6Hz,1H),3.75(dd,J=10.1,2.6Hz,1H),3.66(dd,J=10.1,3.8Hz,1H),2.37(qd,J=7.8,4.3Hz,2H),2.13(dddd,J=12.4,7.9,6.7,5.9Hz,1H),2.05(dddd,J=12.4,8.1,6.0,4.2Hz,1H),2.00–1.89(m,3H),1.83(dddd,J=12.3,8.1,5.9,4.3Hz,1H),1.71(ddd,J=12.7,6.8,4.8Hz,2H),1.62–1.39(m,6H),1.23(t,J=6.9Hz,3H),1.14(t,J=7.9Hz,3H).MS(EI,m/z):520(M++1).
实施例27:化合物27的合成
1-((((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)甲基)环戊烷-1-羧酸乙酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.4Hz,1H),5.05–4.91(m,2H),4.40(dd,J=6.6,4.4Hz,1H),4.31(d,J=9.7Hz,2H),4.20(dq,J=10.1,6.9Hz,1H),4.19–4.07(m,2H),3.87–3.75(m,2H),3.59(dd,J=10.0,3.9Hz,1H),2.45–2.29(m,2H),2.20(dddd,J=12.5,8.2,6.8,5.9Hz,1H),2.06(dddd,J=12.4,8.2,5.9,4.1Hz,1H),1.97(ddt,J=6.5,2.9,2.0Hz,1H),1.97–1.86(m,2H),1.83–1.74(m,1H),1.78–1.67(m,3H),1.71–1.63(m,2H),1.23(t,J=7.0Hz,3H),1.17–1.10(m,3H).MS(EI,m/z):506(M++1).
实施例28:化合物28的合成
步骤一:化合物28a的合成
在0℃下,氩气氛围中,向2,2-二甲基丁烷-1,4-二醇(105mg,0.9mmol)的DCM(1mL)搅拌溶液中加入2,6-二甲基苯甲酰基氯(0.13g,0.74mmol)、吡啶(0.12mL,3.0mmol)和N,N-4-二甲基氨基吡啶(催化量)。将该反应混合物逐渐升温至室温,并将该混合物搅拌过夜。加入1N HCl(3mL),淬灭,分离有机层和水层,并将水层用DCM萃取(10ml×3)。将合并的有机层用饱和NaHCO3洗涤,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析分离纯化,得到化合物28a(94mg,50%)。1H NMR(400MHz,Chloroform-d)δ8.08–8.02(m,2H),7.54(ddt,J=8.0,6.9,1.5Hz,1H),7.48–7.40(m,2H),4.05(s,2H),3.29(d,J=6.8Hz,2H),3.06(t,J=6.9Hz,1H),1.01(s,6H).
步骤二:化合物28b的合成
在氩气氛围中,将新蒸馏的磺酰氯(122μL,1.7mmol)的Et2O(1.0mL)溶液冷却至-78℃。用15分钟的时间,将4-羟基-3,3-二甲基丁基2,6-二甲基苯甲酸酯(28a)(94mg,0.45mmol)和吡啶(136μL,1.7mmol)的Et2O(1.5mL)溶液逐滴加入到该磺酰氯溶液中。用Et2O(2×20mL)冲洗烧瓶,并将冲洗液加入到该反应混合物中。将该混合物在-78℃下搅拌10分钟,而后升温至室温,并搅拌1小时。过滤,浓缩,得到化合物28b,无需进一步纯化,直接用于下一步。1H NMR(500MHz,Chloroform-d)δ8.08–8.02(m,2H),7.58–7.51(m,1H),7.48–7.40(m,2H),4.02(s,2H),3.76(s,2H),1.05(s,6H)。
步骤三:化合物28的合成
将上述所得化合物S7(52mg,0.2mmol)和1,3-二甲基四氢嘧啶-2(1H)-1(3.01mL)溶于THF(3.0mL)中,在氩气氛围下冷却至-78℃。滴加双(三甲基硅基)氨基钠的四氢呋喃溶液(2M;滴加0.12mL,0.24mmol),在-78℃下搅拌10分钟。然后通过注射器快速将化合物28b的THF(0.5mL)溶液加入反应混合物中。-78℃下反应10min后,加热室温,室温下搅拌,直至TLC分析判断反应完成(约2h)。反应完成后,乙酸乙酯萃取3次(10ml×3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析分离纯化,得到化合物28(21mg,20%)。1HNMR(400MHz,Chloroform-d)δ8.08–8.02(m,2H),7.55(ddt,J=8.0,6.9,1.5Hz,1H),7.48–7.41(m,2H),6.12(t,J=4.5Hz,1H),4.97(d,J=4.6Hz,2H),4.39(dd,J=6.8,4.2Hz,1H),4.14(dd,J=25.6,10.4Hz,2H),3.99(d,J=11.0Hz,1H),3.87–3.77(m,2H),3.70(d,J=10.1Hz,1H),3.58(dd,J=10.1,3.8Hz,1H),2.26–2.16(m,1H),2.07(s,2H),1.98–1.87(m,1H),1.77(ddddd,J=20.2,12.1,8.2,6.1,4.1Hz,2H),1.10(s,2H),1.05(s,2H).MS(EI,m/z):528(M++1).
实施例29:化合物29的合成
2,2-二甲基-3-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)2-甲基苯甲酸丙酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ7.89–7.83(m,1H),7.40(ddd,J=7.9,4.9,3.7Hz,1H),7.34–7.26(m,2H),6.27(t,J=4.4Hz,1H),4.96(d,J=4.4Hz,2H),4.45–4.35(m,2H),4.12(d,J=11.0Hz,1H),3.97(d,J=11.2Hz,1H),3.89–3.78(m,3H),3.69–3.58(m,2H),2.52(s,3H),2.36(ddq,J=31.4,15.7,7.8Hz,2H),2.21–2.10(m,1H),2.11–2.01(m,1H),1.96–1.84(m,2H),1.17–1.06(m,5H),1.03(s,3H).MS(EI,m/z):556(M++1).
实施例30:化合物30的合成
2,2-二甲基-3-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)2,6-二甲基苯甲酸丙酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ7.32(dd,J=8.2,7.5Hz,1H),7.14(d,J=7.7Hz,2H),6.25(t,J=4.4Hz,1H),4.96(d,J=4.4Hz,2H),4.37(dd,J=6.7,4.4Hz,2H),4.13(d,J=11.0Hz,1H),4.03(d,J=10.0Hz,1H),3.98(d,J=11.0Hz,1H),3.87–3.5(m,2H),3.71(dd,J=10.2,3.8Hz,2H),3.65(d,J=9.9Hz,1H),2.42(dd,J=15.6,7.8Hz,1H),2.39(s,5H),2.33(dq,J=15.7,7.9Hz,1H),2.18–2.07(m,1H),2.06(tdd,J=8.1,6.0,4.0Hz,1H),1.98(ddt,J=12.5,7.9,6.2Hz,1H),1.84(dddd,J=12.4,8.2,6.0,4.4Hz,1H),1.14(t,J=7.9Hz,3H),1.02(s,2H),0.97(s,3H).MS(EI,m/z):570(M++1).
实施例31:化合物31的合成
2,2-二甲基-3-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)2-氟-6-甲氧基苯甲酸丙酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ7.41(td,J=7.9,4.9Hz,1H),6.92(td,J=7.9,1.2Hz,1H),6.73(dd,J=7.8,1.3Hz,1H),6.28(t,J=4.4Hz,1H),4.96(d,J=4.4Hz,2H),4.40(dd,J=6.6,4.4Hz,2H),4.23(d,J=11.0Hz,2H),4.15(d,J=9.9Hz,1H),4.00(d,J=11.0Hz,1H),3.88–3.77(m,4H),3.72(d,J=9.9Hz,1H),3.57(dd,J=10.1,3.8Hz,1H),2.36(ddt,J=21.1,15.6,7.7Hz,2H),2.19(dddd,J=12.5,8.1,6.7,5.9Hz,1H),2.09(dddd,J=12.4,8.2,5.9,4.2Hz,1H),1.92(ddt,J=12.5,8.2,6.1Hz,1H),1.79(dddd,J=12.5,8.2,5.9,4.4Hz,1H),1.17–1.08(m,5H),1.05(s,3H).MS(EI,m/z):590(M++1).
实施例32:化合物32的合成
2,2-二甲基-3-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)2,6-二甲氧基苯甲酸丙酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ7.41(td,J=7.9,4.9Hz,1H),6.92(td,J=7.9,1.2Hz,1H),6.75(dd,J=7.8,1.3Hz,1H),6.28(t,J=4.4Hz,1H),4.96(d,J=4.4Hz,2H),4.40(dd,J=6.6,4.4Hz,1H),4.23(d,J=11.0Hz,2H),4.15(d,J=9.9Hz,2H),4.00(d,J=11.0Hz,1H),3.86(s,3H)3.88–3.77(m,4H),3.72(d,J=9.9Hz,1H),3.57(dd,J=10.1,3.8Hz,1H),2.36(ddt,J=21.1,15.6,7.7Hz,2H),2.19(dddd,J=12.5,8.1,6.7,5.9Hz,1H),2.09(dddd,J=12.4,8.2,5.9,4.2Hz,1H),1.92(ddt,J=12.5,8.2,6.1Hz,1H),1.79(dddd,J=12.5,8.2,5.9,4.4Hz,1H),1.17–1.08(m,5H),1.05(s,3H).MS(EI,m/z):602(M++1).
实施例33:化合物33的合成
2,2-二甲基-3-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)3-氟-2,6-二甲氧基苯甲酸酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ7.18–7.11(m,1H),6.82(dd,J=8.4,5.1Hz,1H),6.26(t,J=4.5Hz,1H),4.96(d,J=4.5Hz,2H),4.39(dd,J=6.7,4.4Hz,1H),4.25–4.15(m,2H),4.04(d,J=11.0Hz,2H),3.89(s,3H),3.87–3.77(m,5H),3.75(d,J=9.9Hz,1H),3.57(dd,J=10.0,3.9Hz,1H),2.46–2.29(m,2H),2.18(dddd,J=12.5,8.1,6.7,5.9Hz,1H),2.08(dddd,J=12.4,8.2,5.9,4.1Hz,1H),1.97–1.87(m,1H),1.79(dddd,J=12.3,8.1,5.9,4.3Hz,1H),1.17–1.08(m,5H),1.05(s,3H).MS(EI,m/z):620(M++1).
实施例34:化合物34的合成
2-乙基-2-((((((2S,5R)-7-氧代-2-(((丙氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧)磺酰)氧)丁基丙酸酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.5Hz,1H),4.96(d,J=4.4Hz,2H),4.43(dd,J=6.6,4.4Hz,1H),4.11(d,J=10.8Hz,1H),3.96–3.89(m,2H),3.87–3.74(m,3H),3.57(dd,J=10.1,3.8Hz,1H),2.38(dq,J=8.9,7.9Hz,4H),2.33(dddd,J=12.5,8.1,6.8,5.9Hz,1H),2.07(dddd,J=12.4,8.1,5.9,4.1Hz,1H),1.92(ddt,J=12.5,8.1,6.1Hz,1H),1.80(dddd,J=12.5,8.2,5.9,4.4Hz,1H),1.57(dq,J=13.2,7.2Hz,2H),1.47(dq,J=13.2,7.2Hz,2H),1.15(q,J=7.8Hz,6H),0.84(t,J=7.1Hz,6H).MS(EI,m/z):522(M++1).
实施例35:化合物35的合成
3,3-二甲基-4-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰)丁基丙酸酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.4Hz,1H),5.01–4.91(m,2H),4.41(dd,J=6.7,4.1Hz,1H),4.25(dt,J=11.7,6.5Hz,2H),4.00(dt,J=11.7,6.4Hz,1H),3.87–3.75(m,3H),3.68(d,J=9.9Hz,1H),3.59(dd,J=10.1,3.9Hz,1H),2.47–2.25(m,4H),2.17(dddd,J=11.7,8.6,6.6,5.9Hz,1H),2.08(dddd,J=12.4,8.3,6.0,4.1Hz,1H),1.97–1.84(m,2H),1.73(dt,J=13.9,6.4Hz,1H),1.45(dt,J=13.7,6.5Hz,1H),1.14(td,J=7.8,3.0Hz,6H),1.03(s,2H),0.98(s,3H).MS(EI,m/z):508(M++1).
实施例36:化合物36的合成
((2S,5R)-7-氧代-6-(((2,2,3,3-四甲基-4-(丙氧基)丁氧基)磺酰)氧基)-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺)甲基丙酸酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.5Hz,1H),4.96(d,J=4.4Hz,2H),4.38(dd,J=6.7,4.4Hz,1H),4.13–4.04(m,2H),3.96–3.85(m,3H),3.78(dd,J=10.1,2.6Hz,1H),3.71(dd,J=10.1,3.8Hz,1H),2.43(dq,J=15.6,7.8Hz,1H),2.41–2.35(m,1H),2.38–2.27(m,2H),2.18–2.01(m,2H),1.96(ddt,J=12.4,7.8,6.2Hz,1H),1.84(dddd,J=12.5,8.2,6.0,4.4Hz,1H),1.17(q,J=7.9Hz,6H),1.01(d,J=1.2Hz,6H),0.96(d,J=1.3Hz,6H).MS(EI,m/z):536(M++1).
实施例37:化合物37的合成
3,3-二甲基-4-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰)辛酸丁酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ6.27(t,J=4.5Hz,1H),4.96(d,J=4.4Hz,2H),4.41(dd,J=6.7,4.3Hz,1H),4.23(dt,J=11.7,6.6Hz,2H),4.02(dt,J=11.7,6.4Hz,1H),3.90–3.80(m,2H),3.78(dd,J=10.1,2.5Hz,2H),3.68(d,J=9.9Hz,1H),3.58(dd,J=10.1,3.8Hz,1H),2.44–2.35(m,1H),2.38–2.29(m,2H),2.31–2.12(m,2H),2.08(dddd,J=12.4,8.1,5.9,4.1Hz,1H),1.96–1.79(m,2H),1.57(dt,J=12.9,6.9Hz,1H),1.55–1.42(m,2H),1.39(dt,J=13.7,6.4Hz,1H),1.35–1.16(m,6H),1.17–1.10(m,3H),1.03(s,3H),0.98(s,3H),0.94–0.84(m,3H).MS(EI,m/z):578(M++1).
实施例38:化合物38的合成
3,3-二甲基-4-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)3-甲氧基丙酸丁酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.4Hz,1H),4.97(d,J=4.4Hz,2H),4.36(dd,J=6.7,4.4Hz,1H),4.17(dt,J=11.7,6.4Hz,2H),4.08(dt,J=11.7,6.4Hz,2H),4.02–3.88(m,2H),3.84(dtd,J=6.4,4.0,2.5Hz,1H),3.82–3.74(m,2H),3.74–3.67(m,2H),3.33(s,3H),2.64–2.48(m,2H),2.44–2.27(m,2H),2.18–2.01(m,2H),1.97(ddt,J=12.5,7.9,6.2Hz,1H),1.84(dddd,J=12.3,8.2,6.0,4.4Hz,1H),1.47(dt,J=13.9,6.5Hz,1H),1.39(dt,J=13.7,6.5Hz,1H),1.17–1.10(m,3H),1.03(s,2H),0.98(s,2H).MS(EI,m/z):538(M++1).
实施例39:化合物39的合成
3,3-二甲基-4-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)丁基5-乙酰氧基戊酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.4Hz,1H),4.98(d,J=4.4Hz,2H),4.38(dd,J=6.8,4.4Hz,1H),4.21–4.03(m,3H),4.02(dt,J=11.7,6.5Hz,2H),3.83(dtd,J=6.5,4.0,2.6Hz,1H),3.79–3.72(m,2H),3.63(d,J=10.1Hz,1H),3.57(dd,J=10.1,3.8Hz,1H),2.49(dq,J=15.8,7.9Hz,1H),2.42(dd,J=8.1,4.0Hz,1H),2.42–2.32(m,2H),2.20(dddd,J=12.5,8.1,6.6,5.9Hz,1H),2.07(dddd,J=12.4,8.2,5.9,4.2Hz,1H),2.02(s,3H),1.96–1.85(m,1H),1.86–1.61(m,6H),1.55(dt,J=13.9,6.4Hz,1H),1.14(t,J=7.9Hz,3H),1.04(s,2H),0.99(s,3H).MS(EI,m/z):594(M++1).
实施例40:化合物40的合成
4,4-二甲基-5-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰)丙酸戊酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ6.28(t,J=4.4Hz,1H),4.95(d,J=4.4Hz,2H),4.42(dd,J=6.8,4.1Hz,1H),4.13(dt,J=11.3,6.0Hz,2H),4.05(dt,J=11.5,6.0Hz,1H),3.87–3.80(m,1H),3.81–3.72(m,2H),3.68(d,J=9.9Hz,1H),3.57(dd,J=10.1,3.8Hz,1H),2.43–2.31(m,4H),2.21–2.11(m,1H),2.08(dddd,J=12.3,8.4,5.9,4.1Hz,1H),1.98–1.86(m,2H),1.72–1.53(m,2H),1.39(dt,J=12.8,6.3Hz,1H),1.36–1.27(m,1H),1.14(td,J=7.9,4.0Hz,6H),1.01(s,2H),0.96(s,3H).MS(EI,m/z):522(M++1).
实施例41:化合物41的合成
((2S,5R)-6-(((2,2-二甲基-4-(2-苯基乙酰氧基)丁氧基)磺酰基)氧基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺)甲基丙酸酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ7.33–7.22(m,3H),7.16–7.10(m,2H),6.27(t,J=4.4Hz,1H),4.97(d,J=4.4Hz,2H),4.40(dd,J=6.8,4.4Hz,2H),4.21(dt,J=11.7,6.4Hz,1H),4.06(dt,J=11.7,6.5Hz,1H),3.87–3.74(m,3H),3.73–3.56(m,3H),3.50(dt,J=13.7,1.1Hz,1H),2.44–2.27(m,2H),2.18(dddd,J=12.5,8.1,6.8,5.9Hz,1H),2.09(dddd,J=12.4,8.1,5.9,4.1Hz,1H),1.92(ddt,J=12.4,8.1,6.1Hz,1H),1.80(dddd,J=12.4,8.1,5.9,4.3Hz,1H),1.47(dt,J=13.9,6.5Hz,1H),1.39(dt,J=13.9,6.4Hz,1H),1.17–1.10(m,3H),1.03(s,2H),0.98(s,3H).MS(EI,m/z):570(M++1).
实施例42:化合物42的合成
2,2-二甲基-5-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰)丙酸戊酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ6.24(t,J=4.5Hz,1H),4.96(d,J=4.4Hz,2H),4.45(dd,J=6.6,4.4Hz,1H),4.11–4.00(m,3H),3.96(d,J=1.3Hz,2H),3.53–3.41(m,2H),2.37(qd,J=7.9,2.2Hz,4H),1.95(dddd,J=12.3,7.9,6.1,4.4Hz,1H),1.86–1.76(m,2H),1.76–1.70(m,2H),1.69–1.58(m,1H),1.42(hept,J=6.6Hz,2H),1.15(td,J=7.9,3.5Hz,6H),1.06(s,3H),1.01(s,3H).MS(EI,m/z):522(M++1).
实施例43:化合物43的合成
2,2,4,4-四甲基-5-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)苯甲酸戊酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ8.05–7.99(m,2H),7.59–7.52(m,1H),7.50–7.40(m,2H),6.24(t,J=4.5Hz,1H),4.96(d,J=4.4Hz,2H),4.47(dd,J=6.7,4.4Hz,1H),4.07–3.99(m,3H),3.90(d,J=0.7Hz,2H),3.53–3.41(m,2H),2.36(q,J=7.8Hz,2H),1.95(dddd,J=12.3,7.9,6.1,4.3Hz,1H),1.86–1.70(m,2H),1.70–1.56(m,1H),1.49–1.39(m,2H),1.15(t,J=7.9Hz,3H),1.00(dd,J=25.0,11.8Hz,12H).MS(EI,m/z):598(M++1).
实施例44:化合物44的合成
2,2,4,4-四甲基-5-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)戊基2,6-二甲氧基苯甲酸酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ7.42(t,J=8.3Hz,1H),6.85(d,J=8.3Hz,2H),6.30(t,J=4.4Hz,1H),4.96(d,J=4.5Hz,2H),4.45(dd,J=6.7,4.4Hz,1H),4.10–4.00(m,3H),3.93–3.85(m,8H),3.50(dd,J=10.1,3.8Hz,1H),3.45(dd,J=10.1,2.6Hz,1H),2.37(q,J=7.9Hz,2H),1.93(dddd,J=12.3,7.9,6.2,4.4Hz,1H),1.86–1.71(m,2H),1.69–1.58(m,1H),1.44(s,2H),1.15(t,J=7.9Hz,3H),1.06–0.94(m,12H).MS(EI,m/z):658(M++1).
实施例45:化合物45的合成
2,2,4,4-四甲基-5-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧)磺酰)氧)戊基2-甲氧基苯甲酸酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ7.81(dd,J=8.1,1.6Hz,1H),7.43(td,J=8.1,1.6Hz,1H),7.22(td,J=8.1,1.3Hz,1H),7.00(dd,J=8.3,1.3Hz,1H),6.30(t,J=4.4Hz,1H),4.96(d,J=4.5Hz,2H),4.45(dd,J=6.7,4.4Hz,1H),4.09–4.00(m,3H),3.90(d,J=5.1Hz,5H),3.50(dd,J=10.1,3.8Hz,1H),3.45(dd,J=10.1,2.6Hz,1H),2.37(q,J=7.9Hz,2H),1.95(dddd,J=12.3,7.9,6.1,4.3Hz,1H),1.86–1.71(m,2H),1.70–1.59(m,1H),1.44(s,2H),1.15(t,J=7.9Hz,3H),1.07–0.95(m,12H).MS(EI,m/z):628(M++1).
实施例46:化合物46的合成
2,2,4,4-四甲基-5-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)戊基2,3-二甲基苯甲酸酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ7.80(dd,J=7.8,1.2Hz,1H),7.20(t,J=7.9Hz,1H),7.13(ddq,J=7.8,1.5,0.8Hz,1H),6.30(t,J=4.4Hz,1H),4.97(d,J=4.5Hz,2H),4.45(dd,J=6.7,4.4Hz,1H),4.07–4.00(m,3H),3.90(d,J=0.7Hz,2H),3.50(dd,J=10.1,3.8Hz,1H),3.45(dd,J=10.1,2.6Hz,1H),2.41–2.32(m,5H),2.23(d,J=0.7Hz,3H),1.95(dddd,J=12.3,7.9,6.1,4.3Hz,1H),1.86–1.71(m,2H),1.70–1.59(m,1H),1.50–1.39(m,2H),1.15(t,J=7.9Hz,3H),1.00(dd,J=24.9,11.9Hz,12H).MS(EI,m/z):626(M++1).
实施例47:化合物47的合成
2,2,4,4-四甲基-5-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)戊基2,6-二甲基苯甲酸酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ7.24–7.16(m,3H),6.30(t,J=4.4Hz,1H),4.96(d,J=4.5Hz,2H),4.45(dd,J=6.7,4.4Hz,1H),4.12(d,J=11.0Hz,1H),4.09–4.00(m,2H),3.90(d,J=0.7Hz,2H),3.50(dd,J=10.1,3.8Hz,1H),3.45(dd,J=10.1,2.6Hz,1H),2.44–2.32(m,8H),1.95(dddd,J=12.3,7.9,6.1,4.3Hz,1H),1.86–1.71(m,2H),1.70–1.59(m,1H),1.50–1.39(m,2H),1.15(t,J=7.9Hz,3H),1.04(s,3H),0.99(d,J=3.3Hz,6H),0.95(s,3H).MS(EI,m/z):626(M++1).
实施例48:化合物48的合成
2,2,4,4-四甲基-5-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧)磺酰)氧)戊基2-乙酰氧基苯甲酸酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ7.89(dd,J=8.0,1.6Hz,1H),7.55(td,J=8.1,1.6Hz,1H),7.27(td,J=8.0,1.2Hz,1H),7.13(dd,J=8.2,1.3Hz,1H),6.30(t,J=4.4Hz,1H),4.96(d,J=4.5Hz,2H),4.45(dd,J=6.7,4.4Hz,1H),4.14(d,J=11.0Hz,1H),4.08–4.00(m,2H),3.90(d,J=0.7Hz,2H),3.50(dd,J=10.1,3.8Hz,1H),3.45(dd,J=10.1,2.6Hz,1H),2.37(q,J=7.9Hz,2H),2.24(s,3H),1.93(dddd,J=12.3,7.9,6.2,4.4Hz,1H),1.86–1.70(m,2H),1.69–1.58(m,1H),1.45(d,J=2.4Hz,2H),1.15(t,J=7.9Hz,3H),1.04(s,3H),1.00(d,J=2.4Hz,6H),0.95(s,3H).MS(EI,m/z):656(M++1).
实施例49:化合物49的合成
((2S,5R)-6-((((2,2-二甲基-6-(2-苯基乙酰氧基)己基)氧)磺酰)氧)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺)甲基丙酸酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ7.35–7.24(m,3H),7.16(ddtd,J=6.6,4.4,2.1,1.0Hz,2H),6.24(t,J=4.5Hz,1H),4.96(d,J=4.4Hz,2H),4.45(dd,J=6.7,4.4Hz,1H),4.12(t,J=6.1Hz,2H),4.03(dtd,J=6.4,4.0,2.5Hz,1H),3.92(s,2H),3.57(t,J=1.0Hz,2H),3.53–3.41(m,2H),2.36(q,J=7.8Hz,2H),1.95(dddd,J=12.3,7.9,6.1,4.3Hz,1H),1.86–1.59(m,5H),1.52–1.32(m,4H),1.15(t,J=7.9Hz,3H),1.00(s,3H),0.95(s,3H).MS(EI,m/z):598(M++1).
实施例50:化合物50的合成
4,4-二甲基-5-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)戊烷-1,2-二醇二丙酸酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ6.24(t,J=4.5Hz,1H),5.06(tt,J=6.4,5.5Hz,1H),4.97(d,J=4.4Hz,2H),4.45(dd,J=6.7,4.4Hz,1H),4.27(d,J=5.7Hz,2H),4.03(dtd,J=6.3,4.0,2.5Hz,1H),3.98(s,2H),3.53–3.41(m,2H),2.36(qdd,J=7.9,6.8,1.1Hz,6H),2.00–1.89(m,3H),1.86–1.71(m,2H),1.70–1.59(m,1H),1.19–1.12(m,9H),1.10(s,3H),1.05(s,3H).MS(EI,m/z):594(M++1).
实施例51:化合物51的合成
4-甲基-5-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)戊烷-1,2-二醇二丙酸酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ6.24(t,J=4.5Hz,1H),4.99–4.90(m,3H),4.45(dd,J=6.8,4.4Hz,1H),4.33(d,J=5.6Hz,2H),4.07–3.97(m,3H),3.53–3.41(m,2H),2.41–2.30(m,6H),2.07–1.97(m,1H),2.00–1.90(m,3H),1.86–1.70(m,2H),1.70–1.59(m,1H),1.19–1.11(m,9H),1.06(d,J=6.9Hz,3H).MS(EI,m/z):580(M++1).
实施例52:化合物52的合成
5-(((((2S,5R)-2-(((乙酰氧甲基)氨基甲酰基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)-4-甲基戊烷-1,2-二基双(2-苯乙酸)
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ7.32–7.22(m,6H),7.22(tdp,J=4.0,2.9,1.0Hz,4H),6.14(t,J=4.4Hz,1H),5.06–4.95(m,3H),4.43(dd,J=6.7,4.3Hz,1H),4.37–4.25(m,2H),4.07–3.97(m,3H),3.58(q,J=0.8Hz,4H),3.50(dd,J=10.1,3.8Hz,1H),3.45(dd,J=10.1,2.6Hz,1H),2.08(s,3H),2.07–1.94(m,1H),1.98–1.90(m,3H),1.86–1.70(m,2H),1.69–1.58(m,1H),1.06(d,J=6.9Hz,3H).MS(EI,m/z):690(M++1).
实施例53:化合物53的合成
((2S,5R)-6-((((2,2-二甲基-6-(丙酰硫代)己基)氧代)磺酰)氧代)-7-羰基-1,6-二氮杂二环[3.2.1]辛烷-2-碳杂草酰氨基<乙二酰氨基>)甲基丙酸盐
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ6.24(t,J=4.5Hz,1H),4.96(d,J=4.4Hz,2H),4.45(dd,J=6.8,4.4Hz,1H),4.03(dtd,J=6.4,4.0,2.5Hz,1H),3.92(s,3H),3.53–3.40(m,2H),2.87(t,J=6.4Hz,2H),2.65(q,J=7.9Hz,2H),2.36(q,J=7.8Hz,2H),1.95(dddd,J=12.3,7.9,6.1,4.3Hz,1H),1.86–1.70(m,2H),1.70–1.60(m,1H),1.64–1.55(m,2H),1.54–1.45(m,2H),1.42(td,J=6.4,1.1Hz,2H),1.17(dt,J=15.7,7.9Hz,6H),1.01(s,2H),0.96(s,3H).MS(EI,m/z):552(M++1).
实施例54:化合物54的合成
2-甲氧基乙基2,2-二甲基-3-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰)丙酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.24(t,J=4.5Hz,1H),5.01–4.91(m,2H),4.45(dd,J=6.6,4.4Hz,1H),4.26(d,J=9.9Hz,1H),4.24–4.14(m,3H),4.02(dtd,J=6.5,4.0,2.6Hz,1H),3.68–3.54(m,2H),3.53–3.41(m,2H),3.39(s,3H),2.36(q,J=7.9Hz,2H),1.92(dddd,J=12.3,7.9,6.1,4.3Hz,1H),1.86–1.70(m,2H),1.66–1.58(m,1H),1.28(s,3H),1.23(s,3H),1.19–1.12(m,3H).MS(EI,m/z):510(M++1).
实施例55:化合物55的合成
2,2-二氟乙基2,2-二甲基-3-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰)丙酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.51(t,J=2.2Hz,1H),6.24(t,J=4.5Hz,1H),5.01–4.91(m,2H),4.45(dd,J=6.6,4.4Hz,1H),4.26(d,J=9.9Hz,1H),4.22–4.18(m,3H),4.02(dtd,J=6.5,4.0,2.6Hz,1H),3.53–3.41(m,2H),2.36(q,J=7.9Hz,2H),1.95(dddd,J=12.3,7.9,6.1,4.3Hz,1H),1.86–1.70(m,2H),1.71–1.61(m,1H),1.27(s,2H),1.22(s,2H),1.15(t,J=7.9Hz,3H).MS(EI,m/z):516(M++1).
实施例56:化合物56的合成
3,5-二甲基-2-(2-甲基-1-(((((2S,5R)-7-氧代-2-(((丙酰氧基)甲基)氨基甲酰基)-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰基)丙-2-基)苯甲酸甲酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ7.53(d,J=2.0Hz,1H),7.02–6.97(m,1H),6.24(t,J=4.5Hz,1H),4.96(d,J=4.4Hz,2H),4.45(d,J=4.2Hz,3H),4.03(dtd,J=6.4,4.0,2.5Hz,1H),3.89(s,3H),3.55–3.41(m,2H),2.41–2.28(m,5H),2.20(s,3H),1.96(dddd,J=12.3,7.9,6.1,4.3Hz,1H),1.86–1.70(m,2H),1.70–1.59(m,1H),1.42(s,3H),1.37(s,3H),1.15(t,J=7.9Hz,3H).MS(EI,m/z):570(M++1).
实施例57:化合物57的合成
((2S,5R)-7-氧代-6-((((3,5,5-三甲基-2-氧代四氢呋喃-3-基)甲氧基)磺酰)氧基)-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺)甲基丙酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.35(t,J=4.5Hz,1H),5.01–4.93(m,2H),4.45(dd,J=6.8,4.4Hz,1H),4.30–4.22(m,2H),4.02(dtd,J=6.4,4.0,2.6Hz,2H),3.45(qd,J=10.1,3.2Hz,2H),2.33(q,J=7.9Hz,2H),2.14(d,J=0.7Hz,2H),1.92(dddd,J=12.2,7.7,6.1,4.4Hz,1H),1.87–1.72(m,2H),1.69–1.58(m,1H),1.34(s,2H),1.29(s,2H),1.23–1.12(m,6H).MS(EI,m/z):492(M++1).
实施例58:化合物58的合成
((2S,5R)-6-(((4-(乙酰硫)-2,2-二甲基丁氧基)磺酰基)氧基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺)甲基丙酸酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ6.34(t,J=4.5Hz,1H),5.03–4.91(m,2H),4.43(dd,J=6.6,4.4Hz,1H),4.03(dtd,J=6.4,4.0,2.6Hz,1H),3.97(d,J=10.1Hz,1H),3.91(d,J=9.9Hz,1H),3.53–3.41(m,2H),2.93(t,J=5.1Hz,2H),2.41–2.32(m,5H),1.92(dddd,J=12.2,7.7,6.1,4.4Hz,1H),1.87–1.72(m,2H),1.69–1.58(m,3H),1.20–1.12(m,3H),1.05(s,3H),1.00(s,3H).MS(EI,m/z):510(M++1).
实施例59:化合物59的合成
((2S,5R)-6-(((3-(乙酰硫)-2,2-二甲基丙氧基)磺酰基)氧基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺)甲基丙酸酯
合成方法如实施例28。1H NMR(400MHz,Chloroform-d)δ6.33(t,J=4.5Hz,1H),5.01–4.92(m,2H),4.45(dd,J=6.8,4.4Hz,1H),4.10–3.99(m,3H),3.53–3.42(m,2H),2.87(s,3H),2.41–2.32(m,5H),1.92(dddd,J=12.2,7.8,6.1,4.3Hz,1H),1.88–1.71(m,2H),1.69–1.55(m,1H),1.19–1.10(m,5H),1.08(s,3H).MS(EI,m/z):496(M++1).
实施例60:化合物60的合成
环丙基3-(((((2S,5R)-2-(((乙酰氧甲基)氨基甲酰基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧基)磺酰)氧基)-2,2-二甲基丙酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.08(t,J=4.5Hz,1H),5.02–4.91(m,2H),4.45(dd,J=6.8,4.4Hz,1H),4.33(p,J=5.5Hz,2H),4.23(s,1H),4.02(dtd,J=6.4,4.0,2.6Hz,1H),3.53–3.41(m,2H),2.07(s,3H),1.95(dddd,J=12.3,7.9,6.1,4.4Hz,1H),1.88–1.71(m,2H),1.68–1.55(m,5H),1.26(s,6H).MS(EI,m/z):478(M++1).
实施例61:化合物61的合成
环丁基甲基3-(((((2S,5R)-2-((乙酰氧甲基)氨基甲酰基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧磺酰基)氧)-2,2-二甲基丙酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.09(t,J=4.5Hz,1H),5.05–4.93(m,2H),4.45(dd,J=6.6,4.4Hz,1H),4.26(d,J=9.9Hz,1H),4.21(d,J=9.9Hz,1H),4.06–3.98(m,3H),3.53–3.41(m,2H),2.07(s,3H),2.01–1.86(m,2H),1.86–1.76(m,1H),1.80–1.72(m,2H),1.75–1.48(m,8H),1.25(s,4H).MS(EI,m/z):506(M++1).
实施例62:化合物62的合成
吡啶-3-基甲基3-(((((2S,5R)-2-((乙酰氧甲基)氨基甲酰基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧磺酰基)氧)-2,2-二甲基丙酸酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ8.60(t,J=1.8Hz,1H),8.46(dt,J=3.7,1.8Hz,1H),7.77(dt,J=7.9,2.0Hz,1H),7.30(dd,J=7.9,3.5Hz,1H),6.09(t,J=4.5Hz,1H),5.32(d,J=4.2Hz,2H),4.97(d,J=4.6Hz,2H),4.45(dd,J=6.8,4.4Hz,1H),4.28(d,J=9.9Hz,1H),4.21(d,J=9.9Hz,1H),4.03(dtd,J=6.5,4.0,2.6Hz,1H),3.53–3.41(m,2H),2.07(s,2H),1.94(dddd,J=12.3,7.9,6.0,4.3Hz,1H),1.86–1.70(m,2H),1.69–1.59(m,2H),1.27(s,3H),1.22(s,3H).MS(EI,m/z):529(M++1).
实施例63:化合物63的合成
((2S,5R)-6-(((3-((乙氧羰基)氧)-2,2-二甲基丙氧基)磺酰)氧)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺)乙酸甲酯
合成方法如实施例17。1H NMR(400MHz,Chloroform-d)δ6.16(t,J=4.5Hz,1H),5.05–4.97(m,2H),4.47(dd,J=6.7,4.4Hz,1H),4.26(q,J=7.0Hz,2H),4.11–3.99(m,5H),3.6–3.41(m,2H),2.09(s,2H),1.97(dddd,J=12.2,7.7,6.1,4.4Hz,1H),1.85(ddd,J=12.6,6.3,1.7Hz,1H),1.81–1.73(m,1H),1.72–1.58(m,2H),1.36(t,J=7.0Hz,3H),1.13(s,3H),1.06(s,3H).MS(EI,m/z):496(M++1).
实施例64:化合物64的合成
((2S,5R)-6-(((新戊氧基)磺酰)氧基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-2-甲酰胺)乙酸甲酯
合成方法如实施例1。1H NMR(400MHz,Chloroform-d)δ6.13(t,J=4.5Hz,1H),5.04–4.94(m,2H),4.45(dd,J=6.8,4.4Hz,1H),4.03(dtd,J=6.4,4.1,2.6Hz,1H),3.89(d,J=0.9Hz,2H),3.52–3.41(m,2H),2.08(s,2H),1.92(dddd,J=12.2,7.7,6.2,4.3Hz,1H),1.84–1.70(m,2H),1.64–1.53(m,2H),1.03(s,3H).MS(EI,m/z):408(M++1).
实施例65:化合物65的合成
3-(((((2S,5R)-2-(((乙酰氧甲基)(甲基)氨基甲酰基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧磺酰基)氧)-2,2-二甲基丙酸酯
化合物S6的合成如实施例1。
步骤四:化合物S10的合成
将化合物S6(80mg,0.23mmol)的四氢呋喃溶液(1ml),0度冰浴下加入到氢化钠(11mg,0.46mmol)的四氢呋喃溶液中,搅拌1小时。0度冰浴下加入碘甲烷(98mg,0.69mmol),回流过夜。反应完成后,加水淬灭,乙酸乙酯萃取3次(10ml×3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析分离纯化,得到化合物S10(50mg,60%)。1H NMR(400MHz,Chloroform-d)δ7.38–7.28(m,5H),5.54(d,J=9.3Hz,1H),5.34(d,J=9.3Hz,1H),4.79(dt,J=11.8,1.0Hz,1H),4.75–4.66(m,2H),3.82(dtd,J=6.5,4.0,2.5Hz,1H),3.70(dd,J=10.1,2.6Hz,1H),3.52(dd,J=10.1,3.8Hz,1H),2.96(s,3H),2.14–1.93(m,6H),1.77(dddd,J=12.4,8.1,6.1,4.4Hz,1H).
步骤五:化合物S11的合成
参考化合物S8的合成。1H NMR(400MHz,Chloroform-d)δ5.93(s,1H),5.70(d,J=9.3Hz,1H),5.59(d,J=9.3Hz,1H),4.71(dd,J=6.6,4.5Hz,1H),3.79–3.71(m,2H),3.57–3.50(m,1H),2.97(s,3H),2.13–1.94(m,5H),1.91–1.74(m,2H).
步骤六:化合物65的合成
参考化合物1的合成。1H NMR(400MHz,Chloroform-d)δ5.70(d,J=9.3Hz,1H),5.59(d,J=9.3Hz,1H),4.73–4.66(m,1H),4.23–4.16(m,1H),4.20–4.10(m,2H),4.08(d,J=9.9Hz,1H),3.83(dtd,J=6.2,4.0,2.6Hz,1H),3.77(dd,J=10.1,2.6Hz,1H),3.55(dd,J=10.1,3.8Hz,1H),2.97(s,3H),2.09(s,3H),2.15–1.99(m,2H),1.78(dddd,J=12.2,8.0,6.5,4.4Hz,2H),1.29–1.20(m,8H).MS(EI,m/z):480(M++1).
实施例66:化合物66的合成
3-(((((2S,5R)-2-(环丙基((丙酰氧基)甲基)氨基甲酰基)-7-氧代-1,6-二氮杂双环[3.2.1]辛烷-6-基)氧)磺酰)氧)-2,2-二甲基丙酸乙酯
合成方法如实施例65。1H NMR(400MHz,Chloroform-d)δ5.33(s,1H),4.73(dd,J=6.8,4.4Hz,1H),4.28(d,J=9.9Hz,1H),4.24–4.14(m,3H),4.03(dtd,J=6.5,4.0,2.6Hz,1H),3.54–3.43(m,2H),3.13(p,J=5.8Hz,1H),2.37(q,J=7.9Hz,2H),1.93(dddd,J=12.3,7.9,6.0,4.4Hz,2H),1.89–1.71(m,2H),1.68–1.57(m,2H),1.30–1.12(m,15H).MS(EI,m/z):520(M++1).
实施例67:体外酶活性测定和IC50测定
使用临床相关纯化β-内酰胺酶在96孔酶板中进行酶抑制试验:96孔微量滴定板中10mM HEPES缓冲液(pH7.5)中KPC-2(10ng/孔)。硝基酚(Sigma-Aldrich,St Louis,密西西比州),显色头孢菌素(λ,482nm;εM(15000M-1cm-1)为报告基板,KPC-2为100M。
酶在不同浓度的抑制剂的存在preincubated(0.006到3000海里,化合物溶解在DMSO和随后稀释反应缓冲区,最大残余DMSO浓度不超过1%)10分钟(允许酶抑制剂的形成共价复杂)。然后加入硝基酚,使用Envision UV荧光板阅读器(Perkin Elmer,Waltham,Mass.)在30℃下通过未受抑制的酶组分水解10分钟。水解速率数据用于确定抑制活性,以IC50值表示(对应于抑制50%酶促反应所需的化合物浓度(M))。
在这次试验中,阿维巴坦显示IC50值为8nM。
实施例68:最低抑制浓度
临床分离的sbl阳性菌株为阴沟肠杆菌KPC-2/TEM-1、肺炎克雷伯菌SHV-11/TEM-1/KPC-3、肺炎克雷伯菌SHV-11/OXA-181、鲍曼不动杆菌OXA-23和肺炎克雷伯菌TEMOSBL/CTX-M-14/OXA-48。前4个分离株由P.Nordmann提供,最后一个分离株购自国际卫生管理协会(IHMA)。
MEM和MEM/ANT3310最小抑制浓度(MICs)采用微量肉汤稀释法,根据临床和实验室标准协会(CLSI)指南,采用阳离子调节的Mueller-Hinton(CAMBH;正欲)。将菌落直接从培养皿中取出,用生理盐水配制成相当于0.5麦克法兰标准液S10的悬浮液。微型板块是接种后15分钟内调整剂悬浊度,和孵化37℃16到20h。质量控制(QC)测试执行每天的测试按照CLSI使用以下隔离:写明ATCC25922大肠杆菌和铜绿假单胞菌写明ATCC 27853。
在这次试验中,阿维巴坦显示MIC值为16μg/mL。
实施例69:大鼠中的口服生物利用度
对3只雄性Sprague-Dawley(SD)大鼠分别静脉注射(IV)和口服(OP)阿维巴坦(5mg/kg)和试验化合物(10mg/kg)后,进行药物动力学(PK)研究,并测定血浆中的阿维巴坦。将阿维巴坦(溶于磷酸盐缓冲盐水(PBS)(pH7.5)中,达到0.4mg/ml,用于静脉注射。
将口服化合物在10%乙醇/40%聚乙二醇(PEG)400/50%注射用水(WFI)(pH6.5)中以1mg/ml进行配制。
给大鼠插入导管,在各个时间点,从颈静脉收集血液样品(300μL至400μL),采集血样至K2EDTA抗凝管中,于冰上暂存至离心,采血后60min内需离心出血浆(2-8℃条件下,以8000rpm离心5min),离心后将血浆转移至96孔板或离心管中。对于对照组动物,通过心脏穿刺采集血液,收获血浆,并在-70℃下冷冻,直到进一步分析为止。
使用乙腈沉淀来处理血浆样品,并用LC-MS/MS分析。在规定的浓度水平下,与试验物质一起加入无药血浆的等分样品,生成血浆标准曲线。使用相同方法,将加标(spiked)血浆样品与未知血浆样品一起处理。将处理后的血浆样品在-70℃下储存,直到接受LC-MS/MS分析为止,此时记录峰面积,并使用相应的标准曲线来测定未知血浆样品中的受试物浓度。
采用Watson LIMS(Thermo Fisher Scientific,版本7.6,ThermoFisher,USA)管理生物样品,并根据质谱工作站采集的样品峰面积计算与汇总标曲、QC与样品浓度数据。使用WinNonlin.Certara L.P.Pharsight,St.Louis,MO,对血浆数据进行非分区分析(NCA),得到IV和PO给药后的化合物的药物动力学参数(AUClast、AUCINF、T1/2、Tmax和Cmax)。
在这次试验中,阿维巴坦显示出1.4%的口服生物利用度(%F)。
表1为本发明化合物对β-内酰胺酶的抑制活性,最小抑制浓度和口服生物利用度:其中,A:IC50<8nM,B:IC50=8nM-16nM;MIC:m:MIC>16μg/mL,n:MIC=10μg/mL-16μg/mL;α:F>50%,β:50%>F>40%,γ:40%>F>20%。
如表1所示,1)实施例化合物对β-内酰胺酶具有显著的抑制活性,抑制活性优于或与阿维巴坦相当。2)实施例化合物对待测菌株具有显著的抑制活性(MIC),抑制活性优于或与阿维巴坦相当。3)实施例化合物在大鼠中表现出优良的口服生物利用度,明显优于阿维巴坦,支持口服给药。
表1化合物1-66对β-内酰胺酶的抑制活性(IC50),最小抑制浓度(MIC)及口服生物利用度(%F)
最后应当说明的是,以上内容仅用以说明本发明的技术方案,而非对本发明保护范围的限制,本领域的普通技术人员对本发明的技术方案进行的简单修改或者等同替换,均不脱离本发明技术方案的实质和范围。
Claims (10)
1.一种如式I所示的化合物或其药学上可接受的盐、代谢产物、溶剂合物或水合物:
其中,R1为C1-6烷基,或每个R1与其所键合的偕碳原子形成未取代或R1-1取代的C3-6环烷基、未取代或R1-2取代的杂环烷基;
R1-1和R1-2独立地选自氢、卤素、氰基、羟基、C1-4烷基、C1-4烷氧基、卤代(C1-4烷基)、卤代(C1-4烷氧基)、-NR1-1-1R1-1-2、或、-(C=O)R1-1-3;
R1-1-1~R1-1-3独立地选自氢或C1-4烷基;
R2为单键、未取代或R2-1取代的C1-6烷二基、未取代或R2-2取代的C5-6环烷二基、未取代或R2-3取代的“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”C5-6杂环烷二基、未取代或R2-4取代的C6芳烃二基、未取代或R2-5取代的“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”C5-6杂芳烃二基;
R2-1~R2-5独立地选自卤素、氰基、氨基、羟基、未取代或R2-1-1取代的C1-4烷基、未取代或R2-1-2取代的C1-4烷氧基、-NR2-1-3R2-1-4、-(C=O)R2-1-5、-(C=O)NR2-1-6R2-1-7、-(C=O)OR2-1-8、或-S(=O)2NR2-1-9R2-1-10;
R2-1-1和R2-1-2独立地选自卤素、羟基、氰基、氨基、或C1-4烷基;
R2-1-3~R2-1-10独立地选自氢或C1-4烷基;
R3为C1-6烷基、-O(C=O)R6、-S(C=O)R6、-NH(C=O)R6、-O(C=O)OR6、-S(C=O)O-R6、-NH(C=O)OR6、-(C=O)OR6、-(C=O)OCH2O(C=O)R6、-(C=O)OCH2O(C=O)OR6、-(C=O)SR6、-(C=O)NHR6、-O(C=O)SR6、-O(C=O)NHR6、-S-S-R6、-SR6、-NHR6、C3-10环烷基、“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”杂环烷基、“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”杂芳基、未取代或R3-1取代的C6-10芳基、-CH=C(R6)2、或
R3-1为氘、卤素、氰基、羟基、未取代或R3-1-1取代的C1-6烷基、未取代或R3-1-2取代的C1-6烷氧基、C3-10环烷基、C3-10环烷基-(C1-4烷基)、C3-10环烷基-氧基、杂环烷基、杂环烷基-(C1-4烷基)、杂环烷基-氧基、C6-10芳基、C6-10芳基-(C1-4烷基)、(C6-10芳基)-氧基、杂芳基、杂芳基-(C1-4烷基)、杂芳基-氧基、-NR3-1-3R3-1-4、-(C=O)R3-1-5、-(C=O)NR3-1-6R3-1-7、-(C=O)OR3-1-8、-S(=O)2NR3-1-9R3-1-10、或、-O(C=O)R3-1-11;所述的杂环烷基为“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”4~10元杂环烷基;所述的杂芳基为“杂原子选自N、O和S中的一种或多种,杂原子数为1-3个的”5~10元杂芳基;
R3-1-1和R3-1-2独立地选自卤素、氰基、羟基、氨基或C1-4烷基;
R3-1-3~R3-1-11独立地选自氢或C1-4烷基;
R6为未取代或R6-1取代的C3-10环烷基、未取代或R6-2取代的C3-10环烷基-(C1-6烷基)、未取代或R6-3取代的杂环烷基、未取代或R6-4取代的杂环烷基-(C1-6烷基)、未取代或R6-5取代的杂芳基、未取代或R6-6取代的杂芳基-(C1-6烷基)、未取代或R6-7取代的C6-10芳基、未取代或R6-8取代的C6-10芳基-(C1-6烷基)、未取代或R6-9取代的C1-10烷基、未取代或R6-10取代的C1-10烷氧基-(C1-10烷基)或C1-10烷氨基-(C1-10烷基);
R6-1~R6-6独立地选自卤素、羟基、氰基、氨基、C1-6的烷基、卤代(C1-6烷基)、羟基(C1-6烷基)、C1-6烷氧基、-NR6-1-1R6-1-2、-(C=O)R6-1-3;
R6-1-1~R6-1-3独立地选自氢或C1-4烷基;
R6-7和R6-8独立地选自卤素、羟基、氰基、硝基、未取代或R6-7-1取代的C1-6烷基、C2-6烯基、C2-6炔基、未取代或R6-7-2取代的C1-6烷氧基、C6-10芳基-氧基、杂芳基-氧基、(C3-10环烷基)-氧基、C1-6烷胺基-C1-6烷氧基-、未取代或R6-7-3取代的C3-10环烷基、未取代或R6-7-4取代的C3-10环烷基-(C1-6烷基)-、未取代或R6-7-5取代的杂环烷基、未取代或R6-7-6取代的杂环烷基-(C1-6烷基)-、未取代或R6-7-7取代的杂芳基、未取代或R6-7-8取代的杂芳基-(C1-6烷基)-、未取代或R6-7-9取代的C6-10芳基、未取代或R6-7-10取代的C6-10芳基-(C1-6烷基)-、-NR6-7-11R6-7-12、-(C=O)R6-7-13、-(C=O)NR6-7-14R6-7-15、-NR6-7-16(C=O)R6-7-17、-(C=O)OR6 -7-18、-O(C=O)R6-7-19、-(S=O)2NR6-7-20R6-7-21、-NR6-7-22(S=O)2R6-7-23、或、-(S=O)2R6-7-24;所述的杂环烷基为“杂原子选自N、O或S中的一种或多种,杂原子数为1-3个的”4-10元杂环烷基;所述的杂芳基为“杂原子选自N、O或S中的一种或多种,杂原子数为1-3个的”5-10元杂芳基;
R6-7-1和R6-7-2独立地选自C1-4烷基、卤素、氰基、羟基或氨基;
R6-7-3~R6-7-10独立地选自氢、卤素、氰基、羟基、C1-4烷基、C1-4烷氧基、卤代(C1-4烷基)、卤代(C1-4烷氧基)、-NR6-7-3-1R6-7-3-2、或、-(C=O)R6-7-3-3;
R6-7-11~R6-7-24独立地选自氢或C1-4烷基;
R6-7-3-1~R6-7-3-3独立地选自氢或C1-4烷基;
R6-9和R6-10独立地选自C1-4烷基、卤素、氰基、羟基、-NR6-9-1R6-9-2;
R6-9-1和R6-9-2独立地选自氢或C1-4烷基;
R5为氢、C3-6环烷基或C1-6烷基;
R4为-(C=O)R7或-(C=O)OR7;
R7为未取代或R7-1取代的C1-10烷基、未取代或R7-2取代的C3-10环烷基、未取代或R7-3取代的C3-10环烷基-(C1-6烷基)-、未取代或R7-4取代的杂环烷基、未取代或R7-5取代的杂环烷基-(C1-6烷基)-、未取代或R7-6取代的杂芳基、未取代或R7-7取代的杂芳基-(C1-6烷基)-、未取代或R7-8取代的C6-10芳基、未取代或R7-9取代的C6-10芳基-(C1-6烷基)-、C1-10烷氧基-(C1-10烷基)、或、C1-10烷氨基-(C1-10烷基);所述的杂环烷基为“杂原子选自N、O或S中的一种或多种,杂原子数为1-3个的”4-10元杂环烷基;所述的杂芳基为“杂原子选自N、O或S中的一种或多种,杂原子数为1-3个的”5-10元杂芳基;
R7-1选自C1-4烷基、卤素、氰基、羟基、或、-NR7-1-1R7-1-2;
R7-1-1和R7-1-2独立地选自氢或C1-4烷基;
R7-2~R7-5独立地选自氢、卤素、氰基、羟基、C1-4烷基、C1-4烷氧基、卤代(C1-4烷基)、卤代(C1-4烷氧基)、-NR7-2-1R7-2-2、或、-(C=O)R7-2-3;
R7-6~R7-9独立地选自卤素、羟基、氰基、硝基、未取代或R7-6-1取代的C1-6的烷基、C2-6烯基、C2-6炔基、未取代或R7-6-2取代的C1-6烷氧基、C6-10芳基-氧基、杂芳基-氧基、(C3-10环烷基)-氧基、C1-6烷胺基-C1-6烷氧基-、未取代或R7-6-3取代的C3-10环烷基、未取代或R7-6-4取代的C3-10环烷基-(C1-6烷基)-、未取代或R7-6-5取代的杂环烷基、未取代或R7-6-6取代的杂环烷基-(C1-6烷基)-、未取代或R7-6-7取代的杂芳基、未取代或R7-6-8取代的杂芳基-(C1-6烷基)-、未取代或R7-6-9取代的C6-10芳基、未取代或R7-6-10取代的C6-10芳基-(C1-6烷基)-、-NR7-6-11R7-6-12、-(C=O)R7-6-13、-(C=O)NR7-6-14R7-6-15、-NR7-6-16(C=O)R7-6-17、-(C=O)OR7 -6-18、-O(C=O)R7-6-19、-(S=O)2NR7-6-20R7-6-21、-NR7-6-22(S=O)2R7-6-23、或、-(S=O)2R7-6-24;所述的杂环烷基为“杂原子选自N、O或S中的一种或多种,杂原子数为1-3个的”4-10元杂环烷基;所述的杂芳基为“杂原子选自N、O或S中的一种或多种,杂原子数为1-3个的”5-10元杂芳基;
R7-6-1和R7-6-2独立地选自卤素、羟基、氰基、C1-4烷基、或-NR7-6-1-1R7-6-1-2;
R7-6-1-1和R7-6-1-2独立地选自氢或C1-4烷基;
R7-6-3~R7-6-10独立地选自氢、卤素、氰基、羟基、C1-4烷基、C1-4烷氧基、卤代(C1-4烷基)、卤代(C1-4烷氧基)、-NR7-6-3-1R7-6-3-2、或、-(C=O)R7-6-3-3;
R7-6-3-1~R7-6-3-3独立地选自氢或C1-4烷基;
R7-6-11~R7-6-24独立地选自氢或C1-4烷基。
5.一种药物组合物,其特征在于,含有治疗有效量的一种或多种如权利要求1-4任一项所述的化合物或其药学上可接受的盐、代谢产物、溶剂合物或水合物作为活性成分。
6.根据权利要求5所述的药物组合物,其特征在于,进一步包含药学上可接受的载体。
7.根据权利要求5所述的药物组合物,其特征在于,进一步包含抗生素。
8.根据权利要求7所述的药物组合物,其特征在于,所述抗生素包括β-内酰胺类抗生素。
9.根据权利要求5-8任一项所述的药物组合物,其特征在于,所述药物组合物包括口服剂型。
10.权利要求1-4任一项所述的化合物或其药学上可接受的盐、代谢产物、溶剂合物或水合物或权利要求5-9任一项所述的药物组合物在制备用于治疗细菌感染的药物中的用途。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017045510A1 (zh) * | 2015-09-16 | 2017-03-23 | 山东轩竹医药科技有限公司 | β-内酰胺酶抑制剂及其用途 |
CN110662746A (zh) * | 2017-05-10 | 2020-01-07 | 阿里萨制药有限公司 | 3-(((((2S,5R)-2-氨基甲酰基-7-氧代-1,6-二氮杂双环[3.2.1]辛-6-基)氧基)磺酰基)氧基)-2,2-二甲基丙酸酯衍生物和相关的化合物作为β-内酰胺酶抑制剂的经口给药的前药用于治疗细菌感染 |
CN111448182A (zh) * | 2017-10-02 | 2020-07-24 | 阿里萨制药有限公司 | 氨曲南衍生物及其用途 |
CN111954671A (zh) * | 2018-08-09 | 2020-11-17 | 安塔比奥公司 | 作为丝氨酸β-内酰胺酶抑制剂的二氮杂双环辛酮 |
CN114302725A (zh) * | 2019-08-29 | 2022-04-08 | 阿里萨制药公司 | 用于治疗细菌感染的β内酰胺抗生素和阿维巴坦衍生物的口服施用组合 |
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- 2022-10-14 CN CN202211256901.8A patent/CN115448920A/zh active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017045510A1 (zh) * | 2015-09-16 | 2017-03-23 | 山东轩竹医药科技有限公司 | β-内酰胺酶抑制剂及其用途 |
CN110662746A (zh) * | 2017-05-10 | 2020-01-07 | 阿里萨制药有限公司 | 3-(((((2S,5R)-2-氨基甲酰基-7-氧代-1,6-二氮杂双环[3.2.1]辛-6-基)氧基)磺酰基)氧基)-2,2-二甲基丙酸酯衍生物和相关的化合物作为β-内酰胺酶抑制剂的经口给药的前药用于治疗细菌感染 |
CN111448182A (zh) * | 2017-10-02 | 2020-07-24 | 阿里萨制药有限公司 | 氨曲南衍生物及其用途 |
CN111954671A (zh) * | 2018-08-09 | 2020-11-17 | 安塔比奥公司 | 作为丝氨酸β-内酰胺酶抑制剂的二氮杂双环辛酮 |
CN114302725A (zh) * | 2019-08-29 | 2022-04-08 | 阿里萨制药公司 | 用于治疗细菌感染的β内酰胺抗生素和阿维巴坦衍生物的口服施用组合 |
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