CN116018337A - 铜绿假单胞菌毒力因子LasB抑制剂 - Google Patents
铜绿假单胞菌毒力因子LasB抑制剂 Download PDFInfo
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- CN116018337A CN116018337A CN202180052870.1A CN202180052870A CN116018337A CN 116018337 A CN116018337 A CN 116018337A CN 202180052870 A CN202180052870 A CN 202180052870A CN 116018337 A CN116018337 A CN 116018337A
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- 241000589517 Pseudomonas aeruginosa Species 0.000 title claims abstract description 17
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Classifications
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- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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- C07C235/80—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms having carbon atoms of carboxamide groups and keto groups bound to the same carbon atom, e.g. acetoacetamides
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Abstract
本发明涉及式(Ia)化合物及其作为铜绿假单胞菌毒力因子LasB抑制剂的用途。这些化合物可用于治疗细菌感染,特别是由铜绿假单胞菌引起的感染。
Description
本发明涉及铜绿假单胞菌(Pseudomonas aeruginosa)毒力因子LasB的新型抑制剂。这些化合物可用于治疗细菌感染,特别是由铜绿假单胞菌引起的感染。
铜绿假单胞菌是一种革兰氏阴性细菌,被世界卫生组织列为当今最重要的病原体之一(世界卫生组织。《指导新抗生素研究、发现和开发的抗生素抗性细菌全球优先清单》。WHO 2017)。这种机会性细菌导致大约10%的医院获得性感染,并且在免疫功能低下和囊性纤维化患者中发生率很高(Magill,S.S.;Edwards,J.R.;Bamberg,W.;Beldavs,Z.G.;Dumyati,G.;Kainer,M.A.;Lynfield,R.;Maloney,M.;McAllister-Hollod,L.;Nadle,J.等人.N.Engl.J.Med.2014,370,1198–1208;Richards,M.J.;Edwards,J.R.;Culver,D.H.;Gaynes,R.P.Pediatrics 1999,103,e39;Valenza,G.;Tappe,D.;Turnwald,D.;Frosch,M.;C.;Hebestreit,H.;Abele-Horn,M.J.Cyst.Fibros.2008,7,123–127;Sordé,R.;Pahissa,A.;Rello,J.Infect.Drug Resist.2011,4,31–41)。由于市场上缺乏有效的治疗方法,迫切需要开发有效的抗生素(Mesaros,N.;Nordmann,P.;Plésiat,P.;Roussel-Delvallez,M.;Eldere,J.Van;Glupczynski,Y.;Laethem,Y.Van;Jacobs,F.;Lebecque,P.;Malfroot,A.等人.Clin.Microbiol.Infect.2007,13,560–578;Taubes,G.Science 2008,321,356–361)。该任务因病原体的高内在抗性而变得复杂(Hancock,R.E.W.;Speert,D.P.Drug Resist.Updat.2000,3,247–255;Strateva,T.;Yordanov,D.J.Med.Microbiol.2009,58,1133–1148)。
铜绿假单胞菌的外膜渗透性特别低,阻止抗生素进入细胞(Nikaido,H.;Yoshimura,F.J.Bacteriol.1982,152,636–642)。此外,其外排泵有效地将不需要的抗菌剂从细胞中输送出去,并且其诱导型染色体β-内酰胺酶能够使相应的β-内酰胺抗生素失活(Pos,K.M.Biochim.Biophys.Acta-Proteins Proteomics 2009,1794,782–793;Moreira,M.A.S.;Souza,E.C.de;Moraes,C.A.de.Brazilian J.Microbiol.2004,35,19–28;Hancock,R.E.W.;Woodruff,W.A.Clin.Infect.Dis.1988,10,770–775;Li,X.Z.;Livermore,D.M.;Nikaido,H.Antimicrob.Agents Chemother.1994,38,1732–1741)。另一个困难是铜绿假单胞菌菌株的突变耐药率上升(Thomson,J.M.;Bonomo,R.A.Curr.Opin.Microbiol.2005,8,518–524)。例如,氟喹诺酮类和氨基糖苷类的耐药性已达到30%(Gasink,L.B.;Fishman,N.O.;Weiner,M.G.;Nachamkin,I.;Bilker,W.B.;Lautenbach,E.Am.J.Med.2006,119,19–25;Poole,K.Antimicrob.AgentsChemother.2005,49,479–487)。此外,还描述了对几乎所有用于治疗铜绿假单胞菌感染的药物(例如头孢菌素和碳青霉烯类)的耐药性(Obritsch,M.D.;Fish,D.N.;MacLaren,R.;Jung,R.Pharmacotherapy 2005,25,1353–1364;ASCP药敏试验组。美国地理细菌易感性模式。Am.J.Clin.Pathol.1996,106,275–281)。这些事实强调了迫切需要新的治疗方案。
除了针对细菌生存能力的传统策略外,最近,人们还特别注意针对细菌毒力作为对抗微生物感染的替代方法(Dickey,S.W.;Cheung,G.Y.C.;Otto,M.Nat.Rev.DrugDiscov.2017,16,457–471;Rasko,D.A.;Sperandio,V.Nat.Rev.Drug Discov.2010,9,117–128)。毒力因子在致病菌中很常见,并通过破坏宿主或逃避其免疫反应而起作用(Strateva,T.;Mitov,I.Ann.Microbiol.2011,61,717–732)。毒力因子抑制剂降低细菌毒力,并以这种方式通过宿主的免疫***或在抗生素的帮助下清除病原体(Heras,B.;Scanlon,M.J.;Martin,J.L.Br.J.Clin.Pharmacol.2015,79,208–215;Clatworthy,A.E.;Pierson,E.;Hung,D.T.Nat.Chem.Biol.2007,3,541–548)。尽管只有少数化合物已获得临床批准,但许多体外和体内研究都支持该策略的有效性(Wagner,S.;Sommer,R.;Hinsberger,S.;Lu,C.;Hartmann,R.W.;Empting,M.;Titz,A.J.Med.Chem.2016,59,5929–5969)。这种新方法的主要优点是减少了对细菌的选择压力,从而降低了抗药性发展的风险。此外,这些抗毒力剂不会伤害共生细菌。
铜绿假单胞菌的一个众所周知的抗毒靶标是弹性蛋白酶LasB。这种胞外含锌蛋白酶在组织的致病性侵袭中起作用,并且被认为在急性感染期间主要相关(Liu,P.V.J.Infect.Dis.1974,130,S94–S99)。它具有分解弹性蛋白的能力,弹性蛋白是肺组织和血管的重要组成部分(Morihara,K.;Tsuzuki,H.;Oka,T.;Inoue,H.;Ebata,M.J.Biol.Chem.1965,240,3295–3304)。此外,LasB可以降解肺中的纤维蛋白、胶原蛋白和表面活性蛋白,并且还通过失活人免疫球蛋白A和G,细胞因子γ-干扰素和肿瘤坏死因子α以及降解抗菌肽LL-37来降低宿主的免疫力(Heck,L.W.;Morihara,K.;McRae,W.B.;Miller,E.J.Infect.Immun.1986,51,115–118;Heck,L.W.;Alarcon,P.G.;Kulhavy,R.M.;Morihara,K.;Mestecky,M.W.;Russell,J.F.J.Immunol.1990,144,2253–2257;Holder,I.A.;Wheeler,R.Can.J.Microbiol.1984,30,1118–1124;Galloway,D.R.Mol.Microbiol.1991,5,2315–2321;Parmely,M.;Gale,A.;Clabaugh,M.;Horvat,R.;Zhou,W.Infect.Immun.1990,58,3009–3014;Mariencheck,W.I.;Alcorn,J.F.;Palmer,S.M.;Wright,J.R.Am.J.Respir.Cell Mol.Biol.2003,28,528–537;Schmidtchen,A.等人.Mol.Microbiol.2002,46,157–168)。
由于LasB是一种有吸引力的抗毒力靶标,目前为止,文献中已经描述了几种LasB抑制剂:天然产物,如来自黑链霉菌(Streptomyces nigrescens)的链霉菌金属蛋白酶抑制剂TK-23(SMPI)和磷酰胺(Oda,K.;Koyama,T.;Murao,S.Biochim.Biophys.Acta 1979,571,147–156;Nishino,N.;Powers,J.C.J.Biol.Chem.1979,255,3482–19),含有金属螯合基序如硫醇或异羟肟酸基团的小肽(Kessler,E.;Israel,M.;Landshman,N.;Chechick,A.;Blumberg,S.Infect.Immun.1982,38,716–723;Cathcart,G.R.A.;Quinn,D.;Greer,B.;Harriott,P.;Lynas,J.F.;Gilmore,B.F.;Walker,B.Antimicrob.AgentsChemother.2011,55,2670–2678;Burns,F.R.;Paterson,C.A.;Gray,R.D.;Wells,J.T.Antimicrob.Agents Chemother.1990,34,2065–2069)和具有异羟肟酸酯、硫醇或巯基乙酰胺基团的小合成分子(Zhu,J.;Cai,X.;Harris,T.L.;Gooyit,M.;Wood,M.;Lardy,M.;Janda,K.D.Chem.Biol.2015,22,483–491;Adekoya,O.A.;S.;Wuxiuer,Y.;Bilto,I.;Marques,S.M.;Santos,M.A.;Nuti,E.;Cercignani,G.;Rossello,A.;Winberg,J.O.;etal.Eur.J.Med.Chem.2015,89,340–348)以及基于环庚三烯酚酮的化合物(Fullagar,J.L.;Garner,A.L.;Struss,A.K.;Day,J.A.;Martin,D.P.;Yu,J.;Cai,X.;Janda,K.D.;Cohen,S.M.Chem.Commun.2013,49,3197–3199)。
最近,一组N-芳基巯基乙酰酰胺被描述为有效的LasB抑制剂(Kany,A.M.;Sikandar,A.;Haupenthal,J.;Yahiaoui,S.;Maurer,C.K.;Proschak,E.;J.;Hartmann,R.W.ACS Infect.Dis.2018,4,988–997)。其中所描述的最有希望的化合物(化合物36)的晶体结构,揭示了在结合袋中存在两个分子。为了单分子占据活性位点,合成了一系列N-苄基酰胺/N-烷基酰胺衍生物。然而,这种方法未能改善初始配体的抑制效力。
本发明的目的是提供铜绿假单胞菌毒力因子LasB的新型抑制剂。
本发明提供式(Ia)的化合物
其中,
X是式-PO(OH)2、-SH、-C(=O)-NH-OH、任选取代的***基、-SR3、-PO(OH)(OR4)或-PO(OR4)(OR5)的基团;
R1是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基或任选取代的芳烷基或任选取代的杂芳烷基;或式-CH(R6)-C(=O)-NH-R7、或式-C(Me)2-CH2-C(=O)-NH-R7、或式-CH(R6)-CH2-C(=O)-NH-R7、或式-CH(R6)-R8;
R2是烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都可以任选地被取代;
R3是式-COR3a或-CON(R3b)2的基团;其中R3a是烷基、任选取代的苯基或任选取代的苄基,并且R3b独立地选自氢或烷基,任选取代的苯基或任选取代的苄基;
R4为烷基、任选取代的苯基或任选取代的苄基;
R5为烷基、任选取代的苯基或任选取代的苄基;
R6是氢或烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都可以任选地被取代;
R7是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的芳烷基或任选取代的杂芳烷基;
R8是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的芳烷基或任选取代的杂芳烷基;和
R1a是氢,或者,如果R1是式-CH(R6)-C(=O)-NH-R7的基团,则R1a和R6一起是式-(CH2)3-或-(CH2)4-;
或其药学上可接受的盐。
本发明还提供了式(I)的化合物
其中,X是式-PO(OH)2、-SH、-C(=O)-NH-OH、任选取代的***基、-SR3、-PO(OH)(OR4)或-PO(OR4)(OR5)的基团;
R1是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基或任选取代的芳烷基或任选取代的杂芳烷基;或式-CH(R6)-C(=O)-NH-R7、或式-C(Me)2-CH2-C(=O)-NH-R7、或式-CH(R6)-CH2-C(=O)-NH-R7、或式-CH(R6)-R8;
R2是烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都可以任选地被取代;
R3是式-COR3a或-CON(R3b)2的基团;其中R3a是烷基、任选取代的苯基或任选取代的苄基,并且R3b独立地选自氢或烷基,任选取代的苯基或任选取代的苄基;
R4为烷基、任选取代的苯基或任选取代的苄基;
R5为烷基、任选取代的苯基或任选取代的苄基;
R6是氢或烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都可以任选地被取代;
R7是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的芳烷基或任选取代的杂芳烷基;和
R8是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的芳烷基或任选取代的杂芳烷基;
或其药学上可接受的盐。
优选地,X是式-PO(OH)2、-SH、-C(=O)-NH-OH或***基的基团。
此外,本发明提供了式(I)的化合物
其中
X是式-SH,-PO(OH)2,-SR3,-PO(OH)(OR4)或-PO(OR4)(OR5);
R1是任选取代的芳基或任选取代的杂芳基;
R2是烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都可以任选地被取代;
R3是式-COR3a或-CON(R3b)2的基团;其中R3a是烷基、任选取代的苯基或任选取代的苄基,并且R3b独立地选自氢或烷基,任选取代的苯基或任选取代的苄基;
R4为烷基、任选取代的苯基或任选取代的苄基;
R5为烷基、任选取代的苯基或任选取代的苄基;
或其药学上可接受的盐。
根据另一个优选的实施方式,本发明提供了式(II)化合物
其中R1和R2如以上或以下定义;或其药学上可接受的盐。
根据另外优选的实施方式,本发明提供了式(II)的化合物
其中
R1是任选取代的芳基或任选取代的杂芳基;和
R2是烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都可以任选地被取代;
或其药学上可接受的盐。
根据另一个优选的实施方式,本发明提供了式(III)化合物
其中R1和R2如以上或以下定义;或其药学上可接受的盐。
根据另外优选的实施方式,本发明提供了式(III)的化合物
其中
R1是任选取代的芳基或任选取代的杂芳基;
和
R2是烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都可以任选地被取代;
或其药学上可接受的盐。
根据另一个优选的实施方式,本发明提供了式(IV)的化合物
其中R1和R2如以上或以下定义;或其药学上可接受的盐。
根据另外优选的实施方式,本发明提供了式(V)化合物
其中R1和R2如以上或以下定义;或其药学上可接受的盐。
根据另一个优选的实施方式,本发明提供了式(VI)化合物
其中R1和R2如以上或以下定义;或其药学上可接受的盐。
下列优选实施方式独立地适用于式(I)、(Ia)、(II)、(III)、(IV)、(V)和(VI)的化合物:
优选地,R1是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基或任选取代的芳烷基或任选取代的杂芳烷基。
进一步优选地,R1是任选取代的芳基或任选取代的杂芳基。
此外,优选地,R1是任选取代的苯基、任选取代的萘基或任选取代的杂芳基,其含有一个或两个环和5至10个选自C、O、N和S的环原子。
特别优选地,R1是任选取代的苯基或任选取代的杂芳基,其含有一个或两个环以及5、6、9或10个选自C、O、N和S的环原子。
进一步优选地,R1是含有5或6个选自C、O、N和S的环原子的任选取代的杂芳基。
更优选地,R1是任选取代的苯基。
进一步优选地,R1是式-Cy1-L-Cy2的基团,其中Cy1是含有1或2个环和3至7个碳环原子的任选取代的亚环烷基,任选取代的杂亚环烷基基团,其含有1或2个环和3至7个选自C、N、O和S的环原子,任选取代的亚苯基,或任选取代的杂亚芳基,其含有5或6个选自C、N、O和S的环原子;cy2是环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都可以任选地被取代;L是键或-O-、-S-、-NH-、-CH2-、-CO-、-NHCO-、-CO-NH-、-CH2-CO-NH-、-NH-CO-CH2-、-CH2-O-CO-NH-、-NH-CO-O-CH2-、-O-CO-NH-、-NH-CO-O-、-NHSO2-、-SO2NH-、-CH2-SO2-NH-、-NH-SO2-CH2-、-S-CH2-、-CH2-S-、-NH-CH2-、-CH2-NH-、-O-CH2-或-CH2-O-。
优选地,Cy2是任选取代的苯基、任选取代的联苯基、任选取代的萘基、任选取代的杂芳基,其含有一个或两个环以及5、6、9或10个选自C、O、N和S的环原子,含有3至7个环原子的任选取代的环烷基,含有3至7个选自C、N、O和S的环原子的任选取代的杂环烷基,含有9或10个选自C、N、S和O的环原子的任选取代的杂环烷基芳基,或式-CH(CH2Ph)Ph。
进一步优选地,L是键或-NHCO-、-CO-NH-、-CH2-CO-NH-、-NH-CO-CH2-、-NHSO2-或-SO2NH-。
此外,优选地,Cy1是1,4-亚苯基。
更优选地,R1是式-CH(R6)-C(=O)-NH-R7的基团。
此外,优选地,R1是式-CH(R6)-R8的基团。
进一步优选地,R6是氢或C1-6烷基、C3-7环烷基、含有3-7个选自C、N、O和S的环原子的杂环烷基,苯基或含有5或6个选自C、N、S和O的环原子的杂芳基,或式-CH2-R6a的基团,其中R6a是C3-7环烷基,含有3至7个选自C、N、O和S的环原子的杂环烷基,苯基或含有5或6个选自C、N、S和O的环原子的杂芳基。
特别优选地,R6是式-CH(CH3)2的基团。
此外,优选地,R7是任选取代的苯基或任选取代的C3-7环烷基;尤其是任选取代的苯基。
进一步优选地,R8是任选取代的苯并咪唑基团或任选取代的***基团或任选取代的咪唑基团。
此外,优选地,R8是下式的基团:
A1和A2各自独立地表示CH、N、NH、O或S;
B为RB1或式-Y-RB2的基团,其中
RB1是氢原子、卤素原子、CN、CF3、CH2-OH;NRT1RT2;或烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些基团都可以被任选地取代;
RT1和RT2各自独立地表示氢原子或(C1-C3)烷基,其可以被一个或多个相同或不同的选自卤素原子、OH、=O、和NH2的基团取代;
Y是-O-或-S-;和
RB2是氢原子或烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些基团可以任选地被取代。
进一步优选地,R8为下式的基团:
C1和C3各自独立地表示C或N;
C2、C4和C5各自独立地表示CH、N、NH、O或S;
D是任选取代的芳基或任选取代的杂芳基(特别优选地,D是任选取代的苯基)。
进一步优选地,R2是C1-6烷基;含有1-6个碳原子和1、2、3或4个选自O、S和N的杂原子的杂烷基;C4-10烷基环烷基;或C7-12芳烷基;所有这些都可以任选地被取代。
特别优选地,R2是C1-6烷基;含有1-6个碳原子和1、2、3或4个选自O、S和N的杂原子的杂烷基;或式-CH2-R21的基团,其中R21是C3-7环烷基、COOH、COOMe或任选取代的苯基。
此外,特别优选地,R2是C1-4烷基;或式-CH2-R21的基团,其中R21是C3-6环烷基、OMe、COOH、COOMe或任选取代的苯基。优选地,R21是未取代的或被一个或两个独立地选自OH、NO2和Me的取代基取代的苯基;进一步优选地,R21是未取代的苯基。
更优选地,R2是任选取代的苄基(即,可以任选被取代的式-CH2-Ph的基团)。此外,优选地,R2是未取代的苄基。
更优选地,R2是异丁基(即,式-CH2CH(CH3)2的基团)。
术语“任选取代的”是指未取代或被一个或多个(尤其是一个、两个或三个;优选一个或两个)取代基取代的基团。
如果基团R1和/或基团R2包含多于一个取代基,则这些取代基被独立地选择,即,它们可以相同或不同。
如果基团R1和/或基团R2被环状基团取代,如环烷基或杂环烷基,则该环状基团可以经由单键或双键键合至基团R1和/或基团R2上,或者该环状基团可以环化或稠合至基团R1和/或基团R2上。靛红是取代苯基的一个例子。
取代基的实例为氟、氯、溴和碘以及OH、SH、NH2、-SO3H、-SO2NH2、-COOH、-COOMe、-COMe(Ac)、-NHSO2Me、-SO2NMe2、-CH2NH2、-NHAc、-SO2Me、-CONH2、-CN、-NHCONH2、-NHC(NH)NH2、-NOHCH3、-N3和-NO2基团。取代基的其他实例为C1-C10烷基、C2-C10烯基、C2-C10炔基、C1-C10杂烷基、C3-C18环烷基、C1-C17杂环烷基、C4-C20烷基环烷基、C1-C19杂烷基环烷基、C6-C18芳基、C1-C17杂芳基、C7-C20芳烷基和C1-C19杂芳烷基;特别是C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C3-C10环烷基、C1-C9杂环烷基、C4-C12烷基环烷基、C1-C11杂烷基环烷基、C6-C10芳基、C1-C9杂芳基、C7-C12芳烷基和C1-C11杂芳烷基,进一步优选C1-C6烷基和C1-C6杂烷基。
优选的取代基是卤素原子(如F、Cl、Br、I)和式-OH、-O-C1-6烷基(如-OMe、-OEt、-O-nPr、-O-iPr、-O-nBu、-O-iBu和-O-tBu)、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、-COOH、-COOMe、-COCF3、-NHSO2Me、-SO2NMe2、-SO3H、-SO2NH2、-CONH2、-CH2NH2、-CN、-C1-6烷基(如-Me、-Et、-nPr、-iPr、-nBu、-iBu、-tBu和-CF3)、-SH、-S-CO-C1-6烷基、-S-C1-6烷基、-NHAc、-NO2、-C≡CH、-NHCONH2、-SO2Me、-SO2CF3、苯基、-C3-6环烷基(如环丙基、环丁基)和含有3-6个选自C、N、S和O的环原子的杂环烷基。
进一步优选的取代基是卤素原子(如F、Cl、Br)和式-OH、-O-C1-6烷基(如-OMe、-OEt、-O-nPr、-O-iPr、-O-nBu、-O-iBu和-O-tBu)、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、-COOH、-COOMe、-COMe、-NHSO2Me、-SO2NMe2、-SO3H、-SO2NH2、-CONH2、-CH2NH2、-CN、-C1-6烷基(如-Me、-Et、-nPr、-iPr、-nBu、-iBu、-tBu和-CF3)、-SH、-S-CO-C1-6烷基、-S-C1-6烷基、-NHAc、-NO2、-C≡CH、-NHCONH2、-SO2Me和环丙基。
取代基特别优选独立地选自卤素(特别是F和Cl)、-Me、-CF3、-OMe、-OH、-COOH、-CONH2、-COOMe、-COMe和-NO2。
取代基进一步特别优选独立地选自卤素(特别是F和Cl)、-Me、-CF3、-OMe、-OH、-COOH、-COOMe和-NO2。
本发明最优选的化合物是实施例中公开的化合物或其盐。
进一步优选以任何期望的方式组合本发明的优选实施方式(如,R1的任何实施方式可以与R2的任何实施方式组合)。
例如“亚苯基(phenylene)”中的后缀“-ene”是指相应的二价基团。
术语烷基是指含有1至20个碳原子,优选1至15个碳原子,特别是1至10个(如1、2、3或4个)碳原子的饱和、直链或支链烃基,如甲基(Me、CH3)、乙基(Et)、正丙基(nPr)、异丙基(iPr)、正丁基(nBu)、异丁基(iBu)、仲丁基(sBu)、叔丁基(tBu)、正戊基、异戊基、正己基、2,2二甲基丁基或正辛基。
特别优选的烷基是C1-6烷基;此外优选的烷基是C1-4烷基。
C1-6烷基是指含有1-6个碳原子的饱和、直链或支链烃基。C1-4烷基是指含有1-4个碳原子的饱和、直链或支链烃基。实例为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
术语烯基和炔基是指至少部分不饱和的、直链或支链的烃基,其含有2-20个碳原子,优选2-15个碳原子,特别是2-10个(如2、3或4个)碳原子,如乙烯基(乙烯基)、丙烯基(烯丙基)、异丙烯基、丁烯基、乙炔基(炔基)、丙炔基(如炔丙基)、丁炔基、异戊二烯基或2-己烯基。优选地,烯基具有一个或两个(特别优选一个)双键,并且炔基具有一个或两个(特别优选一个)三键。
此外,术语烷基、烯基和炔基是指其中一个或多个氢原子已被卤素原子(优选F或Cl)取代的基团,如2,2,2-三氯乙基或三氟甲基。
术语杂烷基是指其中一个或多个(优选1至8个;特别优选1、2、3或4个)碳原子已被氧、氮、磷、硼、硒、硅或硫原子(优选被氧、硫或氮原子)或被SO或SO2基团取代的烷基、烯基或炔基。此外,杂烷基还指羧酸或衍生自羧酸的基团,例如酰基、酰基烷基、烷氧基羰基、酰氧基、酰氧基烷基、羧烷基酰胺或烷氧羰基氧基。此外,术语杂烷基是指其中一个或多个氢原子已被卤素原子(优选F或Cl)取代的基团。
优选地,杂烷基包含1至12个碳原子和1至8个选自氧、氮和硫(特别是氧和氮)的杂原子。特别优选地,杂烷基包含1至6个(如1、2、3或4个)碳原子和1、2、3或4个(尤其是1、2或3个)选自氧、氮和硫(尤其是氧和氮)的杂原子。术语C1-C10杂烷基是指含有1-10个碳原子和1、2、3、4、5或6个选自O、S和/或N(特别是O和/或N)的杂原子的杂烷基。术语C1-C6杂烷基是指含有1-6个碳原子和1、2、3或4个选自O、S和/或N(特别是O和/或N)的杂原子的杂烷基。术语C1-C4杂烷基是指含有1-4个碳原子和1、2或3个选自O、S和/或N(特别是O和/或N)的杂烷基。
进一步优选地,杂烷基是指如上定义的烷基(直链或支链),其中一个或多个(优选1至6个;特别优选1、2、3或4个)碳原子已被氧,硫或氮原子或CO基团或SO基团或SO2基团取代;该基团优选包含1至6个(如1、2、3或4个)碳原子和1、2、3或4个(特别是1、2或3)选自氧、氮和硫(特别是氧和氮)的杂原子;该基团可以优选被一个或多个(优选1至6;特别优选1、2、3或4)氟、氯、溴或碘原子或OH、=O、SH、=S、NH2、=NH、N3、CN或NO2基团取代。
杂烷基的实例是下式的基团:Ra-O-Ya-、Ra-S-Ya-、Ra-SO-Ya-、Ra-SO2-Ya-、Ra-N(Rb)-SO2-Ya-、Ra-SO2-N(Rb)-Ya-、Ra-N(Rb)-Ya-、Ra-CO-Ya-、Ra-O-CO-Ya-、Ra-CO-O-Ya-、Ra-CO-N(Rb)-Ya-、Ra-N(Rb)-CO-Ya-、Ra-O-CO-N(Rb)-Ya-、Ra-N(Rb)-CO-O-Ya-、Ra-N(Rb)-CO-N(Rc)-Ya-、Ra-O-CO-O-Ya-、Ra-N(Rb)-C(=NRd)-N(Rc)-Ya-、Ra-CS-Ya-、Ra-O-CS-Ya-、Ra-CS-O-Ya-、Ra-CS-N(Rb)-Ya-、Ra-N(Rb)-CS-Ya-、Ra-O-CS-N(Rb)-Ya-、Ra-N(Rb)-CS-O-Ya-、Ra-N(Rb)-CS-N(Rc)-Ya-、Ra-O-CS-O-Ya-、Ra-S-CO-Ya-、Ra-CO-S-Ya-、Ra-S-CO-N(Rb)-Ya-、Ra-N(Rb)-CO-S-Ya-、Ra-S-CO-Ya-、Ra-O-CO-S-Ya、Ra-S-CO-S-Ya-、Ra-S-CS-Ya-、Ra-CS-S-Ya-、Ra-S-CS-N(Rb)-Ya-、Ra-N(Rb)-CS-S-Ya-、Ra-S-CS-O-Ya-、Ra-O-CS-S-Ya-,其中Ra是氢原子,C1-C6烷基、C2-C6烯基或C2-C6炔基;Rb是氢原子、C1-C6烷基、C2-C6烯基或C2-C6炔基;Rc是氢原子、C1-C6烷基、C2-C6烯基或C2-C6炔基;Rd是氢原子、C1-C6烷基、C2-C6烯基或C2-C6炔基,Ya为键、C1-C6亚烷基、C2-C6烯基或C2-C6炔基、其中每个杂烷基含有至少一个碳原子,并且一个或多个氢原子可以被氟或氯原子取代。
杂烷基的具体实例是甲氧基、三氟甲氧基、乙氧基、正丙氧基、异丙基氧基、正丁氧基、叔丁氧基、甲氧基甲基、乙氧基甲基、-CH2CH2OH、-CH2OH、SO2Me、-NHAc、甲氧基乙基、1-甲氧基乙基、1-乙氧基乙基、2-甲氧基乙基或2-乙氧基乙基、甲基氨基、乙基氨基、丙基氨基、异丙基氨基、二甲基氨基、二乙基氨基、异丙基乙基氨基、甲基氨基甲基、乙基氨基甲基、二异丙基氨基乙基、甲硫基、乙硫基、异丙硫基、烯醇醚、二甲基氨基甲基、二甲基氨基乙基、乙酰基、丙酰基、丁酰氧基、乙酰氧基、甲氧基羰基、乙氧基羰基、丙酰氧基、乙酰氨基或丙酰氨基、羧甲基、羧乙基或羧基丙基、N-乙基-N-甲基氨基甲酰基或N-甲基氨基甲酰基。杂烷基的其它实例是腈基(-CN)、异腈基、氰酸酯基、硫氰酸酯基、异氰酸酯基、异硫氰酸酯基和烷基腈基。
术语环烷基是指饱和或部分不饱和(例如环烯基)的环状基团,其包含一个或多个环(优选1或2),并且包含3至14个环碳原子,优选3至10个(特别是3,4,5,6或7)环碳原子。此外,环烷基还指其中一个或多个氢原子被氟、氯、溴或碘原子或被OH、=O、SH、=S、NH2、=NH、N3或NO2基团取代的基团,因此,例如环酮,如环己酮,2-环己烯酮或环戊酮。环烷基的其它具体实例是环丙基、环丁基、环戊基、螺[4,5]癸基、降冰片基、环己基、环戊烯基、环己二烯基、十氢萘基、双环[4.3.0]壬基、四氢萘基、环戊基环己基、氟环己基或环己-2-烯基。优选地,术语环烷基是指包含一个或多个环(优选1或2),并且包含3至14个环碳原子,优选3至10个(特别是3、4、5、6或7个)环碳原子的饱和环状基团。
术语杂环烷基是指如上文所定义的环烷基,其中一个或多个(优选1、2或3个)环碳原子已被氧、氮、硅、硒、磷或硫原子(优选被氧、硫或氮原子)或SO基团或SO2基团取代。杂环烷基优选具有1或2个环和3至10个(特别是3、4、5、6或7个)环原子(优选选自C、O、N和S)。此外,杂环烷基还指被氟、氯、溴或碘原子或被OH、=O、SH、=S、NH2、=NH、N3或NO2基团取代的基团。实例是哌啶基、脯氨酰基、咪唑烷基、哌嗪基、吗啉基(如-N(CH2CH2)2O)、乌洛托品基、吡咯烷基、四氢噻吩基、四氢吡喃基、四氢呋喃基或2-吡唑啉基以及内酰胺、内酯、环状酰亚胺和环状酸酐。
术语烷基环烷基是指同时含有根据上述定义的环烷基和烷基、烯基或炔基的基团,如烷基环烷基、环烷基烷基、烷基环烯基、烯基环烷基和炔基环烷基。烷基环烷基优选包含环烷基,所述环烷基包含一个或两个环和3至10个(特别是3、4、5、6或7个)环碳原子,以及一个或两个具有1或2至6个碳原子的烷基、烯基或炔基(特别是烷基)。
术语杂烷基环烷基是指如上定义的烷基环烷基,其中一个或多个(优选1、2或3个)碳原子已被氧、氮、硅、硒、磷或硫原子(优选被氧、硫或氮原子)或SO基团或SO2基团取代。杂烷基环烷基优选包含1或2个具有3至10个(特别是3、4、5、6或7个)环原子的环,和1或2个具有1或2至6个碳原子的烷基、烯基、炔基或杂烷基(特别是烷基或杂烷基)。这些基团的实例是烷基杂环烷基、烷基杂环烯基、烯基杂环烷基、炔基杂环烷基、杂烷基环烷基、杂烷基杂环烷基和杂烷基杂环烯基,所述环状基团是饱和的或单、二或三不饱和的。
术语芳基是指含有一个或多个环和6至14个环碳原子,优选6至10个(特别是6个)环碳原子的芳族基团。芳基还指被氟、氯、溴或碘原子或被OH、SH、NH2、N3或NO2基团取代的基团。如苯基(Ph)、萘基、联苯、2-氟苯基、苯胺基、3-硝基苯基或4-羟基苯基。
术语杂芳基是指包含一个或多个环和5至14个环原子,优选5至10个(特别是5或6或9或10个)环原子的芳族基团,其包含一个或多个(优选1、2、3或4个)氧、氮,磷或硫环原子(优选是O、S或N)。所述表达杂芳基还指被氟、氯、溴或碘原子或被OH、SH、N3、NH2或NO2基团取代的基团。实例为吡啶基(如4-吡啶基)、咪唑基(如2-咪唑基)、苯基吡咯基(如3-苯基吡咯基)、噻唑基、异噻唑基、1,2,3-***基、1,2,4-***基、恶二唑基、噻二唑基、吲哚基、吲唑基、四唑基、吡嗪基、嘧啶基、吡嗪基、4-羟基吡啶基(4-吡啶酮基)、3,4-羟基吡啶基(3,4-吡啶酮基)、恶唑基、异恶唑基、***基、四唑基、异恶唑基、吲唑基、吲哚基、苯并咪唑基、苯并恶唑基、苯并异恶唑基、苯并噻唑基、哒嗪基、喹啉基、异喹啉基、吡咯基、嘌呤基、咔唑基、吖啶基、嘧啶基、2,3′-双呋喃基、吡唑基(如3-吡唑基)和异喹啉基。
术语芳烷基是指同时含有根据上述定义的芳基以及烷基、烯基、炔基和/或环烷基的基团,例如芳基烷基、芳基烯基、芳基炔基、芳基环烷基、芳基环烯基、烷基芳基环烷基和烷基芳基环烯基。芳烷基的具体实例是苯基环戊基、环己基苯基以及衍生自甲苯、二甲苯、均三甲苯、苯乙烯、苄基氯、邻氟甲苯、1H-茚酮、四氢萘、二氢萘、茚满酮、枯烯、芴和茚满的基团。芳烷基优选包含一个或两个芳环体系(尤其是1或2个环),每个包含6至10个碳原子和一个或两个包含1或2至6个碳原子的烷基、烯基和/或炔基,和/或包含3,4、5、6或7个环碳原子的环烷基。
术语杂芳烷基是指同时含有根据上述定义的芳基和/或杂芳基以及烷基、烯基、炔基和/或杂烷基和/或环烷基和/或杂环烷基的基团。杂芳烷基优选包含一个或两个芳环体系(尤其是1或2个环),每个芳环包含5或6至9或10个环原子(优选选自C,N,O和S),和一个或两个含有1或2至6个碳原子的烷基、烯基和/或炔基,和/或一个或两个含有1至6个碳原子和1、2或3个选自O、S和N的杂原子的杂烷基,和/或一个或两个各含有3、4、5、6或7个环碳原子的环烷基,和/或一个或两个各包含1、2、3或4个氧、硫或氮原子的3、4、5、6或7个环原子的杂环烷基。
实例为芳基杂烷基、芳基杂环烷基、芳基杂环烯基、芳基烷基杂环烷基、芳基烯基杂环烷基、芳基炔基杂环烷基、芳烷基杂环烯基、杂芳烷基、杂芳烯基、杂芳炔基、杂芳基杂烷基、杂芳基环烷基、杂芳基环烯基、杂芳基杂环烷基、杂芳基杂环烯基、杂芳烷基环烷基、杂芳基烷基杂环烯基、杂芳基杂烷基环烷基、杂芳基杂烷基环烯基和杂芳基杂烷基杂环烷基,环基团是饱和的或单、二和或三不饱和。具体实例为四氢异喹啉基、苯甲酰基、邻苯二甲酸基、2或3-乙基吲哚基、4-甲基吡啶基、2-、3-或4-甲氧基苯基、4-乙氧基苯基、2-、3-或4-羧基苯基烷基。
如上所述,术语环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基和杂芳烷基也指被氟、氯、溴或碘原子或被OH、=O、SH、=S、NH2、=NH、N3或NO2基团取代的基团。
术语卤素指的是F、Cl、Br或I。
当芳基、杂芳基、环烷基、烷基环烷基、杂烷基环烷基、杂环烷基、芳烷基或杂芳烷基含有多于一个环时,这些环可以通过单键或双键彼此键合,或者这些环可以是环状的、稠合的、或桥接的。
由于它们的取代,本发明的化合物可以含有一个或多个手性中心。因此,本发明包括所有纯的对映异构体和所有纯的非对映异构体,以及它们以任何混合比例的混合物。此外,本发明还包括本发明化合物的所有顺式/反式异构体及其混合物。此外,本发明包括本发明化合物的所有互变异构形式。
本发明进一步提供药物组合物,其包含一种或多种本文所述的化合物或其药学上可接受的盐、溶剂化物或水合物,任选地与一种或多种载体物质和/或一种或多种佐剂组合。本发明的药物组合物可以含有另外的抗菌化合物。
本发明的化合物或药物组合物可以与另外的抗菌化合物组合给药。
本发明还提供如本文所述的化合物或药物组合物,其用于治疗细菌感染,特别是由铜绿假单胞菌引起的感染。
本发明进一步提供了用于制备药物的如本文所述的化合物或如本文定义的药物组合物,所述药物用于治疗细菌感染,特别是由铜绿假单胞菌引起的细菌感染。
足够碱性化合物的药理学上可接受的盐的实例是生理上可接受的无机酸的盐,如盐酸、氢溴酸、硫酸和磷酸;或有机酸的盐,如甲磺酸、对甲苯磺酸、乳酸、乙酸、三氟乙酸、柠檬酸、琥珀酸、富马酸、马来酸和水杨酸。此外,足够酸性的化合物可以形成碱金属或碱土金属盐,如钠、钾、锂、钙或镁盐;铵盐;或有机碱盐,如甲胺、二甲胺、三甲胺、三乙胺、乙二胺、乙醇胺、氢氧化胆碱、葡甲胺、哌啶、吗啉、三-(2-羟乙基)胺、赖氨酸或精氨酸盐;所有这些也是本文所述化合物的盐的进一步实例。
本文所述的化合物可以是溶剂化的,尤其是水合的。溶剂化/水合作用可能发生在生产过程中,或者由于最初不含水的化合物的吸湿性。溶剂化物和/或水合物可以例如以固体或液体形式存在。
本文所述的化合物、它们的药理学上可接受的盐、溶剂化物和水合物以及制剂和药物组合物的治疗用途也在本发明的范围内。
通常,本文所述的化合物和药物组合物将通过使用本领域已知的既定和可接受的模式给药。
对于口服给药,这种有治疗作用的药剂可以通过以下途径之一给药:口服,如片剂,糖衣丸,包衣片剂,丸剂,半固体,软或硬胶囊,如软和硬明胶胶囊,水性或油性溶液,乳液,悬浮液或糖浆,肠胃外注射,包括静脉内、肌肉内和皮下注射,如作为可注射溶液或悬浮液,直肠栓剂,通过吸入或吹入,如作为粉末制剂,作为微晶体或喷雾剂(例如液体气雾剂),透皮,例如通过透皮给药***(TDDS),例如含有活性成分的膏药,或鼻内给药。为了生产这样的片剂、丸剂、半固体、包衣片剂、药片和硬胶囊,如明胶胶囊,治疗上有用的产品可与药学惰性的无机或有机赋形剂混合,如乳糖、蔗糖、葡萄糖、明胶、麦芽、硅胶、淀粉或其衍生物、滑石、硬脂酸或其盐、干脱脂奶等。对于软胶囊的生产,可以使用赋形剂,如植物油、石油、动物油或合成油、蜡、脂肪和多元醇。对于液体溶液、乳液或悬浮液或糖浆的生产,可以使用作为赋形剂,例如水、醇、盐水、葡萄糖水溶液、多元醇、甘油、脂质、磷脂、环糊精、植物油、石油、动物油或合成油。特别优选脂质,更优选磷脂(优选天然来源;特别优选粒径在300至350nm之间),优选在磷酸盐缓冲盐水(pH=7至8,优选7.4)中。对于栓剂,可以使用赋形剂,如植物油、石油、动物油或合成油、蜡、脂肪和多元醇。对于气溶胶制剂,可以使用适合于该目的的压缩气体,如氧气、氮气和二氧化碳。药学上有用的试剂还可以含有用于保存、稳定的添加剂,如UV稳定剂、乳化剂、甜味剂、芳香剂、改变渗透压的盐、缓冲剂、涂层添加剂和抗氧化剂。
通常,在对体重约80kg的成年人口服或肠胃外给药的情况下,每日剂量约为1mg至约10000mg,优选约5mg至约1000mg,是合适的,尽管在指示时可能会超过上限。每日剂量可以单剂量或分剂量给药,或者对于肠胃外给药,可以连续输注或皮下注射给药。
根据另外优选的实施方式,本发明提供了一种在受试者中抑制铜绿假单胞菌毒力因子LasB的方法,该方法包括向受试者施用有效量的式(I)化合物或其药学上可接受的盐。
根据另外优选的实施方式,本发明提供了一种用于治疗细菌感染的方法,其包括向需要这种治疗的受试者施用治疗有效量的式(I)化合物或其药学上可接受的盐。
根据另一个优选的实施方式,本发明提供了一种用于治疗细菌感染的方法,其包括向需要这种治疗的受试者施用包含式(I)化合物或其药学上可接受的盐的药物组合物。
革兰氏阳性病原体溶组织梭菌(Clostridium histolyticum)(最近更名为溶组织哈撒韦氏菌(Hathevaya histolytica)),破伤风梭菌(C.tetani)和蜡样芽孢杆菌(Bacillus cereus)产生胶原酶ColH和ColG(溶组织梭菌),ColT(破伤风杆菌)和ColQ1(蜡样芽孢杆菌菌株Q1)作为毒力因子,是治疗这些细菌感染的有吸引力的靶标E.;Kany,A.M.;Haupenthal,J.;Hüsecken,K.;Hoppe,I.J.;Voos,K.;Yahiaoui,S.;B.;Ducho,C.;Brandstetter,H.;Hartmann,R.W.J.Am.Chem.Soc.2017,139,12696–12703)。本发明的化合物也是这些胶原酶的有效抑制剂。
实施例
I.通用程序:
方案1:α-取代-N-芳基巯基乙酰胺和α-取代-N-杂芳基巯基乙酰胺的合成
(a)亚硝酸钠,6M HCl,-5℃至室温,(b)EDC.HCl,DCM,室温或ClCO2Et,Et3N,THF,室温;(c)硫代乙酸钾,丙酮,室温;(d)NaOH,MeOH,室温
通用程序A:2-氯链烷酸(1)的合成
在氮气气氛下将氨基酸(1.0当量)溶解在6 M盐酸(2mL/mmol或直至大部分溶解)中并冷却至-5℃。将亚硝酸钠(3.5当量)溶于水(0.3mL/mmol氨基酸)中并缓慢滴加。将混合物搅拌过夜,同时加热至室温。反应混合物用EtOAc/THF(3:1,3倍)萃取。合并的有机萃取物用饱和NaCl水溶液洗涤,经无水Na2SO4干燥并过滤。在减压下除去溶剂以得到粗产物,该粗产物无需进一步纯化用于下一步。
通用程序B-1:N-乙酰基-2-卤代-2-烷基乙酰胺衍生物(3)的合成
2-卤代烷酸(1.2当量)(2-氯链烷酸(1)为粗品或市售的2-溴链烷酸(2))和EDC.HCl(1.2当量)加入到相应的苯胺(1.0当量)在DCM中的溶液中。将所得混合物在室温下搅拌,直到起始苯胺被消耗(通过TLC或LC-MS监测)。将获得的溶液用1M HCl和饱和NaCl水溶液洗涤。将有机层用无水Na2SO4干燥,过滤并在减压下浓缩以提供粗产物。将获得的粗产物无需进一步纯化用于下一步,或使用柱色谱法纯化。
通用程序B-2:N-乙酰基-2-卤代-2-烷基乙酰胺衍生物(3)的合成
将2-卤代烷酸(1.0当量)(2-氯链烷酸(1)作为粗品或市售的2-溴链烷酸(2))溶解在THF中。在室温下将Et3N(1.0当量)加入该溶液中,然后滴加氯甲酸乙酯(1.1当量)。将相应的杂环胺(0.8当量)的溶液溶解在THF中并滴加到该混合物中。将反应在室温搅拌过夜。蒸发THF,将粗固体溶解在DCM中,并用KHCO3(10重量%)水溶液和水洗涤溶液。将有机层用无水Na2SO4干燥,过滤并在减压下浓缩以提供粗产物。通过快速色谱法纯化所得粗产物。
通用程序C:N-芳基-2-硫代乙酰基-2-烷基乙酰胺衍生物和N-杂芳基-2-硫代乙酰 基-2-烷基乙酰胺衍生物(4)的合成
将N-芳基-2-卤代-2-烷基乙酰胺衍生物或N-杂芳基-2-氯代-2-烷基甲酰胺衍生物(1.0当量)((3)纯化或作为粗品)溶解于丙酮中,并向溶液中加入硫代乙酸钾(2.0当量)。将所得混合物在室温下搅拌直至完全转化(通过TLC或LC-MS监测)。在真空下浓缩后,将所得残余物用H2O稀释并用EtOAc萃取。有机层用饱和NaCl水溶液洗涤,经无水Na2SO4干燥,过滤并减压蒸发。使用柱色谱法纯化粗残留物。
通用程序D:合成N-芳基-2-巯基-2-烷基乙酰胺衍生物和N-杂芳基-2-巯基-2-烷 基乙酰胺衍生物(II)
在氩气气氛下,将NaOH(3.0当量)加入到化合物4(1.0当量)的MeOH溶液中。在室温下搅拌反应。将反应混合物用2M HCl酸化,并用EtOAc萃取。将获得的有机层用0.5M HCl溶液和饱和NaCl水溶液洗涤,经无水Na2SO4干燥,过滤并在减压下蒸发。在杂环衍生物的情况下,代替HCl,用Amberlite IR-120将pH调节至酸性值。获得纯的产物或使用柱色谱或制备型HPLC纯化产物。
方案二:膦酸衍生物的合成
(a)EDC·HCl,DCM,室温;(b)P(OEt)3,纯净,150℃;(c)i)TMSBr,DCM,室温;ii)MeOH,室温
通用程序E:膦酸二乙酯衍生物的合成(5)
将N-芳基-2-溴-2-烷基乙酰胺衍生物(3)(1.0当量)悬浮在配有回流冷凝器的亚磷酸三乙酯(10当量)中,加热至150℃并搅拌总计18小时。大部分未反应的亚磷酸三乙酯在真空下蒸发,并通过柱色谱法纯化所得油。
通用程序F:膦酸衍生物的合成(III)
在15分钟的时间内,向膦酸二乙酯(5)(1.0当量)在干燥DCM中的溶液中滴加溴代三甲基硅烷(5.0当量)。将反应混合物在室温搅拌过夜。然后,加入MeOH并在室温下搅拌30分钟以裂解先前形成的TMS酯。溶剂在真空浓缩,所得油通过制备型HPLC纯化。
方案3:α-膦酸(2d)的合成
(a)HBr,NaNO2,H2O,0℃-室温,2h,定量,(b)EtOH,cat.H2SO4,回流,2h,81%,(c)P(OEt)3,纯净,150℃;48h,44%,(d)NaOH,EtOH,0℃-室温,48h,98%。
2-溴-4-甲基戊酸(2a)
将10.5g外消旋亮氨酸1(80.0mmol,1.0当量)溶于48%HBr(80mL)和72ml蒸馏水。将该混合物冷却至0℃,并在2小时内滴加NaNO2(8.82g,128.0mmol,1.6当量)溶于20ml蒸馏水中的溶液。在逐滴加水。将混合物加热至室温,并搅拌过夜。之后,将混合物转移到分液漏斗中并用丙酮(4×100mL)萃取。将合并的有机层用蒸馏水(400mL)和饱和NaCl水溶液(400mL)洗涤,经MgSO4干燥,过滤并减压浓缩。获得淡黄色液体化合物2a(15.06g,80.0mmol,定量),并在不进一步纯化的情况下用于下一步。
2-溴-4-甲基戊酸乙酯(2b)
向α-溴酸2a(15.06g,80.0mmol,1.0当量)中加入浓硫酸(30μl/mmol)的乙醇溶液(2mL/mmol),并将混合物回流2小时。之后,将溶液冷却至室温并在减压下浓缩。加入Et2O(150mL),有机层用饱和NaHCO3水溶液(150mL)洗涤,然后用饱和NaCl水溶液(150mL)洗涤。有机层经MgSO4干燥,过滤并在减压下浓缩。化合物2b(14.45g,64.7mmol,81%产率)为淡黄色液体,无需进一步纯化而用于下一步骤。
2-(二乙氧基磷酰基)-4-甲基戊酸酯(2c)
将α-溴酯2b(14.45g,64.7mmol,1.0当量)和P(OEt)3(22.41mL,129.4mmol,2.0当量)混合并加热至150℃ 48小时。之后,将混合物冷却至室温,并加入Et2O(350mL)。将混合物转移到分液漏斗中并用饱和NaCl水溶液(2×350mL)洗涤,用MgSO4干燥,过滤并在减压下浓缩。使用快速色谱(SiO2,己烷/EtOAc 1:1)纯化产物,并获得化合物2c(7.93g,28.3mmol,44%),为浅黄色油。1H NMR(CDCl3,500MHz)δppm:4.18-4.24(m,2H),4.11-4.17(m,4H),3.00-3.07(m,1H),1.95-2.07(m,1H),1.55-1.66(m,2H),1.33(dt,6H,J=2.3,7.0Hz),1.28(t,3H,J=7.2Hz),0.92(d,3H,J=6.1Hz),0.89(d,3H,J=6.3Hz)。13C NMR(CDCl3,126MHz)δppm:169.4(d,J=5.5Hz),62.7(d,J=6.4Hz),62.6(d,J=6.4Hz),61.3,44.5,43.4,35.5(d,J=5.5Hz),26.9(d,J=14.7Hz),22.9,21.2,16.4(d,J=3.7Hz),16.3(d,J=3.7Hz),14.1。31P NMR(CDCl3,202MHz)δppm:23.4。
HRMS(ESI+)C12H26O5P[M+1]+计算281.1518,实测281.1503。
2-(二乙氧基磷酰基)-4-甲基戊酸(2d)
将化合物2c(7.93g,28.3mmol,1.0当量)溶解在EtOH(270mL)中,并加入NaOH(2.15g,53.88mmol,2.0当量)溶于蒸馏水(100mL)中的溶液。将混合物在室温下搅拌过夜。使用LC-MS监控进度。完成后,将混合物转移到分液漏斗中。加入蒸馏水(300mL)和Et20(400mL),分离各层。使用HCl(6M)将水层酸化至pH=1,并用EtOAc(3×300mL)萃取。将合并的EtOAc-层用饱和水溶液(2×500mL)洗涤,用MgSO4干燥,过滤并在减压下浓缩。获得化合物2d(6.63g,26.29mmol,98%),为淡黄色油状物,其无需进一步纯化而使用。1H NMR(CDCl3,500MHz)δppm:8.33(br s,2H),4.13-4.25(m,4H),3.07(ddd,1H,J=3.1,11.3,23.0Hz),1.99(dddd,1H,J=4.8,8.5,11.4,13.5Hz),1.58-1.70(m,1H),1.49-1.57(m,1H),1.33(dt,6H,J=2.7,7.1Hz),0.92(d,3H,J=6.6Hz),0.89(d,3H,J=6.6Hz)。13C NMR(CDCl3,126MHz)δppm:171.9(d,J=3.7Hz),63.7(d,J=6.4Hz),62.9(d,J=6.4Hz),44.4,43.4,35.6(d,J=5.5Hz),26.8(d,J=13.8Hz),23.0,21.2,16.3(d,J=2.8Hz),16.2(d,J=2.8Hz)。31P NMR(CDCl3,202MHz)δppm:24.3。HRMS(ESI+)C10H22O5P[M+1]+计算253.1205,实测253.1191.
方案4:双环膦酸酯的合成
L(接头):无接头,O,NH,S,CH2,CH2O,CH2S,SCH2,NHCH2,CO,NHCO,CONH,CH2CONH,NHSO2,SO2NH,CH2SO2NH
环1:芳香或饱和六元环
环2:芳香或饱和六元环或螺桨烷
(a)2d,EDC·HCl,DCM,室温或TBTU,NMM,DCM(或DMF),0℃至室温;
(b)TMSBr,DCM,室温;ii)MeOH,室温。
通用程序G:膦酸二乙酯衍生物(5a)的合成
苯胺(市售,或可根据在文献中找到的常规方案合成,实施例在如下通用程序G-1,G-2,G-3,G-4中给出)(1.0当量),将2-(二乙氧基磷酰基)-4-甲基戊酸(2d)(1.2当量)和N-甲基吗啉(2.5当量)溶解在DCM或DMF中。将反应混合物在冰浴中冷却并加入TBTU(1.5当量)。将温度保持30分钟,然后加热至室温。作为另一条替代路线,使用EDC·HCl(2.0当量)、HOBt(2.0当量)和DIPEA(2.5当量)代替TBTU/NMM。在这两种情况下,将反应混合物搅拌过夜,然后用水和饱和NaCl水溶液洗涤。将有机层用无水Na2SO4干燥,过滤并在减压下浓缩以提供粗产物。将获得的粗产物用于下一步,无需进一步纯化或使用柱色谱法纯化。
通用程序G-1:具有酰胺接头(CONH和CH
2
CONH)苯胺的合成
将相应的羧酸(1.2当量)溶解在DCM中并加入EDC·HCl(1.2当量),然后加入(4-氨基苯基)氨基甲酸叔丁酯(1.0当量)。将反应混合物在室温下搅拌。如果形成沉淀物,则将其过滤并用DCM洗涤。当没有形成沉淀物时,消耗原料后,将反应混合物用1M HCl(×2)和饱和NaCl水溶液(×1)洗涤,并在柱色谱上纯化。将获得的产物悬浮在0℃的DCM/TFA混合物(3:1)中。然后将混合物在室温下搅拌2小时。蒸发溶剂。加入EtOAc,用2.5M NaOH(×2)和饱和NaCl水溶液(×2)洗涤。将有机层用无水Na2SO4干燥,过滤并在减压下浓缩,得到所需的苯胺。
通用程序G-2:具有磺酰胺接头(SO2NH和CH2SO2NH)苯胺的合成
将(4-氨基苯基)氨基甲酸叔丁酯(1.0当量)溶解在DCM中并冷却至0℃。加入Et3N(1.2当量),然后加入相应的磺酰氯(1.1当量)。将反应混合物在室温下搅拌8小时。过滤沉淀物并在柱色谱上纯化滤液。将所得产物在0℃悬浮于DCM/TFA混合物(3:1)中。然后将混合物在室温下搅拌2小时。蒸发溶剂。加入EtOAc,用2.5M NaOH(×2)和饱和NaCl水溶液(×2)洗涤。将有机层用无水Na2SO4干燥,过滤并在减压下浓缩,得到所需的苯胺。
通用程序G-3:具有醚接头(CH2O)苯胺的合成
将(4-羟基苯基)氨基甲酸叔丁酯(1.0当量)溶解在DMF中。加入碳酸钾(2.0当量),并将反应混合物搅拌15分钟。然后在15分钟内逐滴加入相应的苄基溴,并在室温下搅拌过夜。加入水,用EtOAc(×3)萃取,并用饱和NaCl水溶液洗涤有机层。将有机层用无水Na2SO4干燥,过滤并在减压下浓缩。将获得的产物悬浮在0℃的DCM/TFA混合物(3:1)中。然后将混合物在室温下搅拌2小时。蒸发溶剂。加入EtOAc,用2.5M NaOH(×2)和饱和NaCl水溶液(×2)洗涤。将有机层用无水Na2SO4干燥,过滤并在减压下浓缩,得到所需的苯胺。
通用程序G-4:无接头苯胺的合成
将芳基胺(1.0当量)置于密封管中,随后是相应的硼酸(1.5当量)、NaOH 2M、四(三苯基膦)钯(0.02当量)和二恶烷/H2O(4:1,v:v)的混合物。将反应混合物用N2冲洗并进行微波辐射(150℃,150W)20分钟。冷却至室温后,加入EtOAc/H2O(1:1,v:v)的混合物以停止反应。水层用EtOAc(×3)萃取。有机层用饱和NaCl水溶液(1x)和水(1x)洗涤,用MgSO4干燥,过滤并减压浓缩。使用柱色谱法纯化残留物。
方案5:带有膦酸锌结合基序的二肽衍生物的合成
(a)IBCF,NMM,-20℃ THF,30分钟,(b)i)HCl(4M在二恶烷中),室温,12h,ii)2d,TBTU,NMM,DMF,0℃–室温,12h,c)TMSBr,室温,12小时,制备高效液相色谱。
通用程序H:苯胺取代衍生物(6)的合成
将相应的叔丁氧羰基保护的氨基酸(1.0当量)溶解在THF(0.1M)中并冷却至-20℃。然后滴加NMM(2.5当量)和氯甲酸异丁酯(1.0当量)。将反应混合物在该温度下搅拌30分钟,然后加入溶解在THF(1M)中的苯胺(1.0当量)。反应混合物达到室温后,用EtOAc稀释。有机相用KHSO4(1N)溶液、饱和NaHCO3溶液和饱和NaCl水溶液洗涤,经无水Na2SO4干燥,过滤并减压浓缩。柱色谱纯化提供相应的肽。
通用程序I:含磷二肽(5b)的合成
将叔丁氧羰基保护的肽(1.0当量)溶解在DCM(0.1M)中,并在0℃用HCl(10.0当量,4M在二恶烷中)处理。将混合物升温至室温,并在完全转化(TLC)后,在减压下除去溶剂,结果结晶盐酸盐残留,随后将其溶解在DMF(0.1M)中。向该溶液中加入2-(二乙氧基磷酰基)-4-甲基戊酸2d(1.1当量),并将反应混合物冷却至0℃。通过TBTU(1.1当量)和NMM(2.5当量)实现耦合。将反应混合物升温至室温,并在完全转化(TLC)后用EtOAc稀释,并依次用1NKHSO4溶液、饱和NaHCO3溶液和饱和NaCl水溶液洗涤。将有机层在无水Na2SO4上干燥,过滤,并且将残余物在没有进一步纯化的情况下用于下一步。
方案6:***衍生物的合成
(a)i)HCl(4M在二恶烷中),DCM,室温;18h,ii)TBTU,NMM,DMF 0℃-室温,22h;(b)CuSO4·5H2O,抗坏血酸钠,tBuOH/H2O/MeOH(2:2:1)室温,14小时;(c)TMSBr,DCM,室温,过夜,制备型HPLC。
通用程序J:炔基二乙基膦酸酯(8)的合成
炔烃组分7(1.0当量),其如先前报道(https://doi.org/10.1002/anie.201601564),溶解在DCM(10mL/mmol)中,并在室温下加入HCl(10.0当量,4M在二恶烷中)。将混合物搅拌18小时,然后在减压下浓缩。同时,将化合物2d(1.1当量)和TBTU(1.2当量)在DMF(5mL/mmol)中的混合物冷却至0℃并加入NMM(2.5当量)。将反应混合物搅拌30分钟,然后将叔丁氧羰基脱保护的烯基氨基酸溶解在DMF(5mL/mmol)中,并在0℃下滴加。将混合物搅拌22小时,并使其温热至室温。加入EtOAc后,有机层随后用饱和NaHCO3水溶液、1MHCl、水和饱和NaCl水溶液洗涤。有机层经Na2SO4干燥,过滤浓缩减压。粗产物通过自动组合闪光净化(Teledyne ISCO)纯化。
通用程序K:含1H-1,2,3-***的膦酸二乙酯(5c)的的合成
根据(https://doi.org/10.1016/j.ejmech.2019.06.007)合成相应的烯基膦酸二乙酯(1.0当量)和叠氮化物(1.1当量)的溶液,在tBuOH/H2O/MeOH(2:2:1,10mL/mmol)中用氩气吹扫。加入抗坏血酸钠(20mol%)和CuSO4·5H2O(10mol%),并将反应混合物在室温下搅拌14h。然后,加入饱和EDTA溶液,并用EtOAc(x3)萃取混合物,用饱和NH4Cl水溶液和饱和NaCl水溶液洗涤合并的有机层。在用无水Na2SO4干燥并过滤后,在减压下除去溶剂,得到标题化合物,该标题化合物在不进一步纯化的情况下用于下一步。
方案7:咪唑衍生物的合成
(a)i)HCl(4M在二恶烷中),DCM,室温;18h,ii)TBTU,NMM,DMF 0℃-室温,22h;(b)TMSBr,DCM,室温,过夜,制备型HPLC。
方案8:苯并环化杂五元环的合成
(a)TBTU,NMM,DMF,0C-室温,2d;(b)HOAc/甲苯(1:1),110℃,3h;(c)i)HCl(4M在1,4-二恶烷中),DCM,18h,室温;ii)TBTU,NMM,DMF,0-室温,21小时,d)TMSBr,DCM,室温,21小时,制备高效液相色谱。
通用程序L:苯并环化杂五元环(11)的合成
将相应的叔丁氧羰基保护的氨基酸(1.0当量)溶解在DMF(10mL/mmol)中。冷却至0℃后,随后加入NMM(1.1当量)和TBTU(1.1当量)。将反应混合物搅拌30分钟,并加入相应的亲核试剂(1.0)。3天后,加入饱和NH4Cl水溶液,用EtOAc(×3)萃取混合物,随后用饱和NaHCO3水溶液和饱和NaCl水溶液洗涤。有机层经Na2SO4干燥,过滤并减压浓缩,将粗产物再溶于甲苯(5mL),加入HOAc(5mL)。将混合物在回流下加热3小时,并通过缓慢加入饱和NaHCO3水溶液猝灭。搅拌20分钟后,用EtOAc(x3)萃取混合物,并用1M HCl洗涤。随后用饱和NaHCO3水溶液(x4)和饱和NaCl水溶液洗涤,在无水Na2SO4上干燥,过滤和减压浓缩后,得到标题化合物,其在下一步使用,无需进一步纯化。
方案9:异羟肟酸衍生物的合成
(a)i)NaOH,EtOH/H2O,室温,ii)EDC·HCl,DCM,室温;b)NH2OH,KCN,MeOH,室温
通用程序M:乙酯衍生物(12)的合成
将2-烷基丙二酸二乙酯(1.0当量)溶解在EtOH/H2O(4:1)中,并加入NaOH(1.2当量)。反应在室温下搅拌过夜。在减压下蒸发EtOH,加入饱和NaHCO3水溶液并用DCM萃取。有机层被丢弃。水层用6M HCl酸化,并用DCM萃取。有机层用饱和NaCl水溶液洗涤,经无水Na2SO4干燥,过滤并减压蒸发。获得的一元酸(1.2当量)和EDC将HCl(1.2当量)加入到相应的苯胺(1.0当量)在DCM中的溶液中。将所得混合物在室温下搅拌,直到起始苯胺被消耗(通过TLC或LC-MS监测)。将获得的溶液用1M HCl和饱和NaCl水溶液洗涤。将有机层用无水Na2SO4干燥,过滤并在减压下浓缩以提供粗产物。使用柱色谱法纯化获得的粗产物。
通用程序N:异羟肟酸衍生物(IV)的合成
将乙酯衍生物12(1.0当量)溶于MeOH中。加入H2O(与甲醇体积相同)中50重量%的NH2OH,然后加入KCN(0.2当量)。将混合物在室温下搅拌过夜。在减压下浓缩溶剂,并通过制备型HPLC纯化所得油。
方案10:***衍生物的合成
a)1H-1,2,3-***,K2CO3,丙酮,70℃
通用程序O:1H-1,2,3-***(V)和2H-1,2,3-***(VI)衍生物的合成。
将N-芳基-2-溴-2-烷基乙酰胺衍生物3(1.0当量)置于卷边小瓶中并溶解在丙酮中。加入1H-1,2,3-***(1.1当量)和K2CO3(1.1当量),并将混合物加热至70℃过夜。加入EtOAc,有机层用水和饱和NaCl水溶液洗涤,用无水Na2SO4干燥,过滤并在减压下浓缩。通过制备型HPLC纯化粗品。
II.合成实施例
实施例1
2-氯-3-苯基丙酸。
NMR(500MHz,CDCl3)δppm:7.37-7.24(m,5H),4.51(dd,J=7.8,6.9Hz,1H),3.42(dd,J=14.0,6.7Hz,1H),3.21(dd,J=14.1,7.9Hz,1H)。MS(ESI-)m/z183.25(M-H)-,147.23(M-H-HCl)-。
2-氯-N,3-二苯基丙酰胺。
(己烷/EtOAc=100:0至0:100)进行纯化。所得产物为白色固体(404mg,31%)。1HNMR(500MHz,DMSO-d6)δppm:7.95(s,1H),7.60-7.52(m,2H),7.38-7.28(m,6H),7.27-7.19(m,1H),7.11-7.04(m,1H),4.76(t,J=7.5Hz,1H),3.41(dd,J=13.8,7.2Hz,1H),3.13(dd,J=13.9,7.8Hz,1H)。MS(ESI+)m/z260.08(M+H)+。
S-(1-氧代-3-苯基-1-(苯基氨基)丙-2-基)乙硫酸酯。
的产物。1H NMR(500MHz,CDCl3)δppm:7.96(brs,1H),7.46(d,J=8.2Hz,2H),7.33-7.22(m,6H),7.12-7.07(m,1H),4.30(t,J=7.7Hz,1H),3.46(dd,J=14.1,8.5Hz,1H),3.01(dd,J=14.1,7.1Hz,1H),2.38(s,3H),1.59(s,3H)。13C NMR(126MHz,CDCl3)δppm:197.3,168.3,137.6,137.6,129.2,128.9,128.6,127.0,124.4,119.8,48.5,35.7,30.4.MS(ESI+)m/z300.17(M+H)+,258.10(M-Ac+2H)+。
2-巯基-N,3-二苯基丙酰胺(1)。
43%)。1H NMR(500MHz,CDCl3)δppm:8.02(brs,1H),7.46(d,J=8.1Hz,2H),7.36-7.29(m,4H),7.29-7.23(m,4H),7.14(t,J=7.6Hz,1H),3.72(dd,J=14.8,6.6Hz,1H),3.38(dd,J=13.8,6.5Hz,1H),3.24(dd,J=13.8,6.8Hz,1H),2.11(d,J=8.9Hz,1H)。13C NMR(126MHz,CDCl3)δppm:169.5,137.3,137.2,129.4,129.0,128.6,127.1,124.8,120.0,45.9,41.5。HRMS(ESI+)C15H5NOS[M+H]+计算258.0947,实测258.0943。
实施例2
S-(4-甲基-1-氧代-1-(对甲苯基氨基)戊烷-2-基)乙硫酸酯。
EDC·HCl(172mg,0.90mmol)和DCM(5mL)。将反应在室温下搅拌5小时。获得的粗产物在不进一步纯化的情况下用于下一步。根据通用程序C,使用从第一步获得的粗产物硫代乙酸钾(171mg,1.49mmol)和丙酮(7mL)实现第二步。将反应在室温下搅拌2.5小时。使用柱色谱(100%DCM)纯化粗产物。所得产物为米色固体(131mg,63%(经2步))。1H NMR(500MHz,DMSO-d6)δppm:10.23(s,1H),7.46(d,J=8.0Hz,2H),7.10(d,J=8.0Hz,2H),4.27(brt,J=7.5Hz,1H),2.35(s,3H),2.24(s,3H),1.88-1.75(m,1H),1.62-1.40(m,2H),0.95(d,J=6.5Hz,3H),0.88(d,J=6.5Hz,3H)。13C NMR(126MHz,DMSO-d6)δppm:194.5,168.6,136.2,132.6,129.1,119.4,46.4,41.7,30.3,25.9,22.5,22.1,20.5。HRMS(ESI+)C15H22NO2S[M+H]+计算280.1371,实测280.1358。
2-巯基-4-甲基-N-(对甲苯基)戊酰胺(2)。
应在室温下搅拌2小时。使用制备型HPLC(H2O(HCOOH 0.05%)-CH3CN(HCOOH0.05%):9.0-1.0至0.0-10.0)纯化粗产物。所得产物为米色固体(38mg,50%,MP=90℃)。1H NMR(500MHz,DMSO-d6)δppm:9.99(s,1H),7.47(d,J=8.0Hz,2H),7.11(d,J=8.0Hz,2H),3.51(brt,J=7.8Hz,1H),2.93(s,1H),2.25(s,3H),1.84-1.73(m,1H),1.67-1.56(m,1H),1.54-1.43(m,1H),0.91(d,J=7.0Hz,3H),0.86(d,J=6.5Hz,3H)。13C NMR(126MHz,DMSO-d6)δppm:170.9,136.5,132.4,129.2,119.2,44.4,39.9,25.8,22.2,22.1,20.5。HRMS(ESI+)C13H20NOS[M+H]+计算238.1266,实测238.1254。
表1:根据上述程序制备了以下其它的化合物:
实施例63
(4-甲基-1-氧代-1-(对甲苯基氨基)戊烷-2-基)膦酸二乙酯。
1.02mmol),EDC·HCl(196mg,1.02mmol)和DCM(15mL)。将反应在室温下搅拌5小时。获得的粗产物在不进一步纯化的情况下用于下一步。根据通用程序E,使用从第一步骤获得的粗产物和亚磷酸三乙酯(1.5mL,17.1mmol)实现第二步骤。使用柱色谱法(己烷/EtOAc=1:1)纯化粗产物。所得产物为白色固体(114mg,39%(经2步))。1H NMR(500MHz,CDCl3)δppm:8.41(s,1H),7.39(d,J=8.4Hz,2H),7.08(d,J=8.4Hz,2H),4.21-4.08(m,4H),2.97(ddd,J=22.6,11.3,3.5Hz,1H),2.28(s,3H),2.09-1.99(m,1H),1.77-1.68(m,1H),1.61-1.52(m,1H),1.32(q,J=7.1Hz,6H),0.97-0.91(m,6H)。13C NMR(126MHz,CDCl3)δppm:165.6(J=1.8Hz),135.3,133.8,129.4,119.8,63.0(J=7.4Hz),62.8(J=6.4Hz),45.2(J=128.6Hz),35.8(J=4.6Hz),26.6(J=13.8Hz),23.2,21.2,20.8,16.4(J=1.8Hz),16.4(J=2.8Hz)。MS(ESI+)m/z342.2[M+H]+。
(4-甲基-1-氧代-1-(对甲苯基氨基)戊烷-2-基)膦酸(63)。
-1-(对甲苯基氨基)戊烷-2-基)膦酸。反应在室温下搅拌过夜。然后,加入MeOH(10mL),将反应混合物再搅拌30分钟,并在减压下蒸发溶剂。使用制备型HPLC(CH3CN(HCOOH0.05%)-H2O(HCOOH 0.05%):1.0:9.0至10.0:0.0)纯化粗产物。所得产物为白色固体(56mg,71%)。1H NMR(500MHz,DMSO-d6)δppm:9.84(s,1H),7.47(d,J=8.4Hz,2H),7.07(d,J=8.2Hz,2H),2.95(ddd,J=22.4,11.4,2.9Hz,1H),2.22(s,3H),1.99-1.89(m,1H),1.51-1.34(m,2H),0.87-0.82(m,6H)。13C NMR(126MHz,DMSO-d6)δppm:167.6(J=4.6Hz),137.0,131.8,129.0,119.0,46.0(J=126.8Hz),35.8(J=3.7Hz),26.5(J=14.7Hz),23.3,21.4,20.5。31P NMR(202MHz,DMSO-d6)δppm:20.1。HRMS(ESI–)C13H19NO4P[M-H]-计算284.1057,实测284.1058。
实施例95
方案11:无接头联苯衍生物的合成。
a)Pd(PPh3)4,二恶烷/H2O(4:1,v:v,3mL),NaOH(2M),微波(150℃,150W,20min);b)EDC·HCl,DCM,室温,2小时;c)i)TMSBr,DCM,室温,过夜;ii)MeOH,室温
(1-((2-(4-异丙氧基苯基)嘧啶-5-基)氨基)-4-甲基-1-氧戊烷-2-基)膦酸二乙
酯。
基)氨基)-4-甲基-1-氧戊烷-2-基)膦酸二乙酯。使用柱色谱法(0%至3%的DCM/MeOH)纯化粗产物。所得产物为白色固体(84mg,69%)。1H NMR(500MHz,CDCl3)δppm:10.27(s,1H),8.79(s,2H),7.90(d,J=8.8Hz,2H),6.69(d,J=8.8Hz,2H),4.50(hept,J=6.0Hz,1H),4.32-4.17(m,2H),4.10(p,J=7.2Hz,2H),3.34(ddd,J=22.8,11.3,2.8Hz,1H),2.17-2.06(m,1H),1.60-1.52(m,1H),1.43(dtd,J=13.1,10.2,2.9Hz,1H),1.31(ddd,J=19.2,12.6,6.2Hz,12H),0.86(dd,J=13.1,6.5Hz,6H)。MS(ESI+)m/z 464[M+H]+。
(1-((2-(4-异丙氧基苯基)嘧啶-5-基)氨基)-4-甲基-1-氧戊烷-2-基)膦酸(95)。
苯基)嘧啶-5-基)氨基)-4-甲基-1-氧戊烷-2-基)膦酸(95)。反应在室温下搅拌过夜。然后,加入MeOH(4mL),将反应混合物再搅拌30分钟,并在减压下蒸发溶剂。使用制备型HPLC(CH3CN(HCOOH 0.05%)-H2O(HCOOH 0.05%)纯化粗产物。所得产物为白色固体(41mg,72%)。1H NMR(500MHz,DMSO-d6)δppm:10.46(s,1H),9.05(s,2H),8.24(d,J=8.9Hz,2H),7.01(d,J=8.9Hz,2H),4.70(dt,J=12.1,6.0Hz,1H),3.04(ddd,J=22.4,11.1,2.3Hz,1H),2.00(ddd,J=15.4,10.0,3.7Hz,1H),1.61-1.35(m,2H),1.30(d,J=6.0Hz,6H),0.88(d,J=6.3Hz,6H)。13C NMR(126MHz,DMSO-d6)δppm:169.24,169.20,159.76,158.52,147.75,132.71,129.72,129.36,115.87,69.75,47.05,46.05,36.10,36.06,26.98,26.87,23.59,22.28,21.82。31P NMR(202MHz,DMSO-d6)δppm:18.93.MS(ESI+)m/z 408[M+H]+。
实施例108
方案12:具有磺酰胺接头联苯衍生物的合成。
a)i)Et3N,DCM,0℃-室温,8h,ii)TFA,DCM,室温,2h,b)EDC·HCl,DCM,室温,过夜,c)TMSBr,DCM,室温,过夜。
N-(4-氨基苯基)-3,4-二氯苯磺酰胺。
温下搅拌8小时。过滤沉淀物并在柱色谱法(己烷/EtOAc=7/3)上纯化滤液,得到(4-((3,4-二氯苯基)磺酰胺基)苯基)氨基甲酸叔丁酯(316mg,52%)。将获得的(4-((3,4-二氯苯基)磺酰胺基)苯基)氨基甲酸叔丁酯悬浮在3.5mL的DCM/TFA(3:1)中,并在室温下搅拌2小时。处理后,得到N-(4-氨基苯基)-3,4-二氯苯磺酰胺(193mg,81%),为米色固体。1HNMR(500MHz,DMSO-d6)δppm:9.65(brs,1H),7.81(d,J=8.4Hz,1H),7.77(d,J=2.0Hz,1H),7.54(dd,J=8.5,2.1Hz,1H),6.66(d,J=8.7Hz,2H),6.40(d,J=8.7Hz,2H),5.01(brs,2H)。MS(ESI-)m/z 314.99[M-H]-。
(1-((4-((3,4-二氯苯基)磺酰胺基)苯基)氨基)-4-甲基-1-氧戊烷-2-基)膦酸二
乙酯。
0.52mmol)和DIPEA(110μl,0.62mmol)在DCM(5mL)。使用柱色谱法(己烷/EtOAc=3/7)纯化粗产物。所得产物为白色泡沫(84mg,58%)。1H NMR(500MHz,DMSO-d6)δppm:10.27(brs,1H),10.11(s,1H),7.88(d,J=2.1Hz,1H),7.83(d,J=8.4Hz,1H),7.61(dd,J=8.4,2.1Hz,1H),7.49-7.44(m,2H),7.05-7.00(m,2H),4.06-3.95(m,4H),3.15(ddd,J=22.6,11.3,3.1Hz,1H),1.98-1.88(m,1H),1.49-1.29(m,2H),1.18(dt,J=9.1,7.1Hz,6H),0.85(d,J=6.6Hz,6H)。MS(ESI+)m/z 551.12[M+H]+。
(1-((4-((3,4-二氯苯基)磺酰胺基)苯基)氨基)-4-甲基-1-氧戊烷-2-基)膦酸
(108)。
搅拌过夜。然后,加入MeOH(4mL),将反应混合物再搅拌30分钟,并在减压下蒸发溶剂。使用制备型HPLC(CH3CN(HCOOH 0.05%)-H2O(HCOOH 0.05%:1.0:9.0至10.0:0.0))纯化粗产物。所得产物为白色固体(48mg,70%)。1H NMR(500MHz,DMSO-d6)δppm:10.22(s,1H),9.92(s,1H),7.89(d,J=2.1Hz,1H),7.82(d,J=8.4Hz,1H),7.60(dd,J=8.4,2.1Hz,1H),7.51-7.46(m,2H),7.01-6.97(m,2H),2.93(ddd,J=22.5,11.3,2.8Hz,1H),1.97-1.88(m,1H),1.49-1.34(m,2H),0.83(d,J=6.4Hz,6H)。13C NMR(126MHz,DMSO-d6)δppm:167.8(d,J=5.5Hz),139.66,136.86,135.99,132.15,131.73,131.51,128.40,126.85,122.33,119.82,46.0(d,J=126.8Hz),35.7(d,J=3.7Hz),26.4(d,J=14.7Hz),23.2,21.3。31P NMR(202MHz,DMSO-d6)δppm:19.8。HRMS(ESI-)C18H20Cl2N2O6PS[M-H]-计算493.0162,实测493.0156。
实施例147
方案13:具有亚甲基接头联苯衍生物的合成。
a)Et3N(3当量),DCM,室温,16h,b)TFA(5当量),DCM,室温,19h,c)EDC·HCl(1.2当量),HOBt(1.2当量),DIPEA(2.4当量),DMF,室温,18h,d)TMSBr(7当量),DCM,室温,23h。
(S)-(1-(4-氯苄基)哌啶-3-基)氨基甲酸叔丁酯。
(205.5mg,1mmol,1当量)并溶解在干燥DCM(2.5mL,0.4M)中,然后在氮气气氛下加入Et3N(303.6mg,418.1μl,3mmol,3当量)。将反应混合物在室温下搅拌。并在反应完成后(LCMS,16h)加入水(5mL),并用DCM(3×10mL)萃取反应混合物。将合并的有机相在无水Na2SO4上干燥,过滤,并在减压下除去挥发物,以获得为白色固体的标题化合物(322mg),其用于下一步而不进一步纯化。
(S)-1-(4-氯苄基)哌啶-3-胺。
DCM(3mL,0.4M)。向所得溶液中加入TFA(383μl,5当量),并保持反应混合物在室温下搅拌。反应完成后(LCMS,19h),减压除去溶剂,得到油状残余物,用2M NaOH溶液处理,用EtOAc(3×20mL)萃取。将合并的有机相在无水Na2SO4上干燥,过滤,并在减压下除去挥发物,以获得油形式的标题化合物(207mg),其在不进一步纯化的情况下用于下一步。
(1-(S)-1-(4-氯苄基)哌啶-3-基)氨基)-4-甲基-1-氧戊烷-2-基)膦酸二乙酯。
HOBt·H2O(68.2mg,0.44mmol,2当量)并溶于DMF(1.5mL)。向所得溶液中加入EDC·HCl(85.3mg,0.44mmol,2当量)和DIPEA(93μl,0.53mmol,2.4当量),并保持反应在室温下搅拌。完全转化(LCMS,18h)后,将水(5mL)和EtOAc(5mL)添加到反应中。除去有机相,并用EtOAc(3x10mL)萃取水相。将合并的有机相通过无水Na2SO4的垫,过滤并在减压下浓缩以得到标题化合物(55mg),该标题化合物在不进一步纯化的情况下用于下一步。
(1-((S)-1-(4-氯苄基)哌啶-3-基)氨基)-4-甲基-1-氧戊烷-2-基)膦酸(147)。
燥DCM(1mL)。向所得溶液中滴加溴三甲基硅烷(107μl,0.81mmol,7当量),反应在室温下保持搅拌。反应完成后(LCMS,23小时),加入MeOH(2mL),并在室温下搅拌。30分钟。减压除去挥发物,在制备型HPLC上纯化粗品,得到白色无定形固体的标题化合物(21mg,0.052mmol,45%)。
非对映异构体的混合物:
主要非对映体:1H NMR(500MHz,DMSO-d6)δppm:10.05(s,1H),7.72-7.24(m,4H),4.43-4.18(m,2H),4.08-3.92(m,1H),3.44-3.04(m,2H),3.00-2.30(m,3H),1.98-1.80(m,2H),1.80-1.62(m,2H),1.54-1.27(m,3H),0.81(dd,J=6.4,5.8Hz,6H)。13C NMR(126MHz,DMSO-d6)δ169.4,158.6(dd,J=31.2,30.6Hz),134.8,133.8,133.7,129.3,58.7,54.3,51.0,45.9(d,J=124.0Hz),43.9,36.0,26.9(t,J=14.5Hz)、23.6、21.8。31P NMR(202MHz,DMSO-d6)δppm:19.7。
次要非对映体:1H NMR(500MHz,DMSO-d6)δppm:10.05(s,1H),8.39-7.77(m,4H),4.47-4.18(m,3H),3.44-3.04(m,2H),3.00-2.30(m,3H),1.98-1.80(m,2H),1.80-1.62(m,2H),1.54-1.27(m,3H),0.81(dd,J=6.4,5.8Hz,6H)。13C NMR(126MHz,DMSO-d6)δ169.7,158.6(dd,J=31.2,30.6Hz),134.9,133.8,133.7,129.2,58.7,54.3,51.5,45.6(d,J=125.0Hz),43.9,27.8(dd,J=33.1,15.6Hz),23.6,21.8。31P NMR(202MHz,DMSO-d6)δppm:19.6。
HRMS(ESI+)C18H29ClN2O4P[M+1]+计算403.1553,实测403.1537。
实施例151
(3-((3,4-二氯苯基)氨基甲酰基)双环[1.1.1]戊烷-1-基)氨基甲酸叔丁酯。
基)氨基)双环[1.1.1]戊烷-1-羧酸(46.6mg,0.205mmol,1.0当量)并溶解在DMF(2mL)中,冷却至0℃,加入TBTU(73.0mg,0.23mmol,1.1当量),随后加入NMM(24μl,0.23mmol,1.1当量)。将反应混合物在指定温度下搅拌1小时,然后加入3,4-二氯苯胺(33mg,0.205mmol)。搅拌16小时并升温至室温后,加入EtOAc,随后用饱和NaHCO3溶液、1MHCl、水和饱和NaCl水溶液洗涤。将有机层在Na2SO4上干燥,过滤并在减压下浓缩,以获得为无色固体的标题化合物(42mg,0.113mmol,55%),其在不进一步纯化的情况下用于下一步。1HNMR(CDCl3,500MHz)δppm:7.77-7.76(m,1H),7.38-7.37(m,2H),7.12(bs,1H),5.00(bs,1H),2.37(s,6H),1.47(s,9H)。13C NMR(CDCl3,126MHz)δppm:167.4,136.8,132.9,130.6,121.4,118.8,53.8,45.1,28.4。MS(ESI+):m/z[M+H]+=372。
(1-((3-((3,4-二氯苯基)氨基甲酰基)双环[1.1.1]戊烷-1-基)氨基)-4-甲基-1-
氧戊烷-2-基)膦酸二乙酯。
1.08mmol,4M在二恶烷中)用于脱保护。在肽偶联中使用2-(二乙氧基磷酰基)-4-甲基戊酸2d(30mg,0.119mmol),NMM(31μl,0.298mmol)和TBTU(43mg,0.131mmol),获得黄色油状标题化合物(36.7mg,0.073mmol,67%),用于下一步,无需进一步纯化。MS(ESI+):m/z[M+H]+=506。
(1-((3-((3,4-二氯苯基)氨基甲酰基)双环[1.1.1]戊烷-1-基)氨基)-4-甲基-1-
氧戊烷-2-基)膦酸(151)。
(36mg,0.071mmol)和溴三甲基硅烷(47μl,0.356mmol)经制备型HPLC纯化后得到无色固体状标题化合物(8.6mg,0.019mmol,27%)。
非对映异构体的混合物1H NMR(500MHz,丙酮-d6)δppm:8.05(d,J=2.3Hz,1H),7.62(dd,J=8.9Hz,J=2.3Hz,1H),7.44(d,J=8.9Hz,1H),3.02-2.94(m,1H)、2.40(s,6H)、2.01-1.98(m,1H)、1.65-1.61(m,1H)、1.59-1.53(m,1H)、0.92(d,J=6.3Hz,6H)。13C NMR(126MHz,丙酮-d6)δppm:169.9,167.8,138.9,131.6,130.4,125.6,121.0,119.3,53.8,45.8,45.0,44.8,38.2,35.7,26.7,22.6,21.0.31P NMR(202MHz,丙酮-d6)δppm:24.7,24.6。HRMS(ESI+)C18H24Cl2N2O5P[M+H]+计算449.0794,实测449.0798。
实施例152
(S)-(1-((3,4-二氯苯基)氨基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸叔丁酯。
当量)。将反应混合物在该温度下搅拌30分钟,然后加入溶解在THF(1M)中的苯胺(324mg,2mmol,1.0当量)。反应混合物达到室温后,用EtOAc稀释。用KHSO4(1N)溶液、饱和NaHCO3水溶液和饱和NaCl水溶液洗涤有机相,经Na2SO4干燥,过滤并减压除去溶剂。通过柱色谱法(SiO2,己烷/EtOAc9:1)纯化,得到相应的(S)-(1-(3,4-二氯苯基)氨基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸叔丁酯(523.8mg,1.44mmol,72%产率)。1H NMR(500MHz,CDCl3)δppm:8.85(brs,1H),7.70(brs,1H),7.2-7.3(m,2H),5.27(brd,1H,J=8.2Hz),4.06(brt,1H,J=7.6Hz),2.15(brd,1H,J=6.1Hz),1.47(s,9H),1.03(dd,6H,J=2.7,6.7Hz)。13C NMR(126MHz,CDCl3,)δppm:170.7,137.2,132.5,130.2,121.2,118.6,61.1,30.5,28.3,19.3,18.4。HRMS(ESI+)C16H23Cl2N2O3[MH]+计算361.1080,实测361.1080。
(1-(((S)-1-((3,4-二氯苯基)氨基)-3-甲基-1-氧代丁烷-2-基)氨基)-4-甲基- 1-氧代戊烷-2-基)膦酸(152)。
当量,44M在二恶烷中)。将混合物加热至室温,并在完全转化(TLC)后,在减压下除去溶剂,结果结晶盐酸盐残留,随后将其溶解在DMF(2.8mL,0.1M)中。向该溶液中加入2-(二乙氧基磷酰基)-4-甲基戊酸2d(77.7mg,0.308mmol,1.1当量),并将反应混合物冷却至0℃。通过TBTU(98.9mg,0.308mmol,1.1当量)和NMM(0.08mL,2.5当量)实现偶联。将反应混合物加热至室温,并在完全反应(TLC)后用EtOAc稀释,并依次用1N KHSO4溶液、饱和NaHCO3溶液和饱和NaCl水溶液洗涤。在Na2SO4下干燥并减压除去溶剂后,残余物(1-(S)-1-(3,4-二氯苯基)氨基)-3-甲基-1-氧代丁烷-2-基)氨基)-4-甲基-1-氧代戊烷-2-基)膦酸二乙酯(136.7mg,0.28mmol,定量)在没有进一步纯化的情况下用于下一步。向二乙基膦酸二肽(136.7mg,0.28mmol)在DCM(0.1M)中的溶液中,经15分钟滴加溴三甲基硅烷(0.26mL,1.93mmol)。将反应混合物在室温下搅拌过夜。然后加入MeOH并在室温下搅拌30分钟以裂解先前形成的TMS酯。在减压下除去溶剂,并通过Waters自噬器***(APS)用PhenomenexGemini C18柱(250×4.6mm,粒径5μm)使用质量触发检测纯化粗产物,获得二肽152(51.7mg,0.12mmol,43%),为白色无定形固体。
非对映异构体的混合物:
主要非对映体:1H NMR(500MHz,MeOH-d4,)δppm:8.04(d,1H,J=2.4Hz),7.62(dd,1H,J=2.4,8.9Hz),7.42(d,1H,J=8.9Hz),4.45(d,1H,J=5.0Hz),3.24(ddd,1H,J=2.7,11.6,23.3Hz),2.42(qd,1H,J=6.9,12.1Hz),1.47-1.61(m,3H),0.9-1.1(m,19H),0.99(d,3H,J=7.02Hz),0.98(d,3H,J=6.87Hz),0.95(d,6H,J=6.56Hz)。13C NMR(126MHz,MeOH-d4)δppm:172.7,172.5(d,J=4.6Hz),139.6,133.2,131.5,128.2,123.5,121.6,60.7,47.1,46.0,36.3(d,J=4.6Hz),31.2,28.4(d,J=15.6Hz),23.7,21.8,19.9,17.831P NMR(202MHz,MeOH-d4)δppm:22.7.
次要非对映体:1H NMR(500MHz,MeOH-d4)δppm:7.92(dd,1H,J=0.61,1.83Hz),7.44-7.46(m,1H),4.27(d,1H,J=7.48Hz),3.24(ddd,1H,J=2.7,11.9,22.4Hz),1.95-2.20(m,2H),1.28-1.35(m,2H),1.05(d,3H,J=6.71Hz),1.00(d,3H,J=6.71Hz),0.92(d,3H,J=6.10Hz),0.90(d,3H,J=6.26Hz)。13C NMR(126MHz,MeOH-d4)δppm:172.6,172.0(d,J=4.6Hz),139.7,133.5,131.7,128.1,122.8,120.8,61.5,46.8,45.8,37.3(d,J=4.6Hz),32.3,28.1(d,J=15.6Hz),23.8,21.9,19.1。31P NMR(202MHz,MeOH-d4)δppm:22.4。HRMS(ESI+)C17H26Cl2N2O5P[M+H]+计算439.0956,439.0935。
实施例170
方案14:***衍生物的合成,以化合物170为例。
(a)i)HCl(4M在二恶烷中),DCM,室温,18h;ii)TBTU,NMM,DMF 0℃-室温,22h,76%(2步);(b)CuSO4·5H2O,抗坏血酸钠,tBuOH/H2O/MeOH(2:2:1)室温,14h,84%;(c)TMSBr,DCM,室温,23h,制备高效液相色谱,26%。
(4-甲基-1-(((S)-4-甲基戊-1-炔-3-基)氨基)-1-氧戊烷-2-基)膦酸二乙酯。
2.85mL,11.4mmol,4M在二恶烷中)以获得相应的叔丁氧羰基脱保护的醇胺盐酸盐。将混合物搅拌18小时,然后在减压下浓缩。同时,将化合物2d(396mg,1.57mmol)和TBTU(562mg,1.75mmol)在DMF(7.5mL)中的混合物冷却至0℃,并加入NMM(0.91mL,3.58mmol)。将反应混合物搅拌30分钟,然后将预先制备的叔丁氧羰基脱保护的醇胺盐酸盐溶解在DMF(7.5mL)中,并在0℃下滴加。将混合物搅拌22小时,并使其温热至室温。加入EtOAc后,有机层随后用饱和NaHCO3水溶液、1M HCl、水和饱和NaCl水溶液洗涤。将有机层在Na2SO4上干燥,并在减压下除去溶剂。通过自动组合闪光纯化(TeledyneISCO)纯化粗产物,得到359mg(4-甲基-1-(S)-4-甲基戊-1-炔-3-基)氨基)-1-氧戊烷-2-基)膦酸二乙酯(1.08mmol,2步76%)。1H NMR(500MHz,CDCl3)δppm:6.68-6.58(m,1H),4.67-4.64(m,1H),4.18-4.09(m,4H),2.87-2.80(m,1H),2.24-2.23(m,1H),1.99-1.93(m,2H),1.70-1.61(m,1H),1.56-1.52(m,1H),1.34-1.30(m,6H),1.02-1.00(m,6H),0.95-0.90(m,6H)。MS(ESI+):m/z[M+H]+=332。
(1-(((S)-1-(3,4-二氯苯基)-1H-1,2,3-***-4-基)-2-甲基丙基)氨基)-4-甲
基-1-氧戊烷-2-基)膦酸酯。
膦酸酯(293mg,0.89mmol)和4-叠氮基-1,2-二氯苯(170mg,0.904mmol)溶液,用氩气吹扫。加入抗坏血酸钠(20mol%)和CuSO4·5H2O(10mol%),并将反应混合物在室温下搅拌14h。然后,加入饱和EDTA溶液并用EtOAc(x3)萃取混合物,用饱和NH4Cl水溶液和饱和NaCl水溶液洗涤合并的有机层。在Na2SO4干燥并过滤后,蒸发溶剂以产生标题化合物(394mg,0.759mmol,84%,非对映异构体的混合物),其在不进一步纯化的情况下用于下一步。MS(ESI+):m/z[M+H]+520。
(1-(((S)-1-(3,4-二氯苯基)-1H-1,2,3-***-4-基)-2-甲基丙基)氨基)-4-甲
基-1-氧戊烷-2-基)膦酸(170)。
备型HPLC纯化后得到标题化合物(12mg,0.026mmol,26%,非对映异构体的混合物:
主要非对映体:1H NMR(500MHz,MeOH-d4)δppm:8.44(s,1H),8.10-8.09(m,1H),7.83-7.80(m,1H),7.75-7.73(m,1H),4.99-4.97(m,1H),3.03-2.96(m,1H),2.35-2.30(m,1H),2.13-2.06(m,1H),1.49-1.43(m,2H),1.06-0.98(m,6H),0.87-0.84(m,6H)。31P NMR(202MHz,MeOH-d4)δppm:22.3.次要非对映体:1H NMR(500MHz,MeOH-d4)δppm:8.58(s,1H),8.10-8.09(m,1H),7.83-7.80(m,1H),7.73-7.70(m,1H),5.08-5.07(m,1H),3.17-3.12(m,1H),2.42-2.35(m,1H),2.02-1.98(m,1H),1.61-1.51(m,2H),0.98-0.95(m,6H)。31P NMR(202MHz,MeOH-d4,)δppm:22.3。HRMS(ESI+)C18H26Cl2N4O4P[M+H]+计算463.1063,实测463.1065。
实施例171
方案15:咪唑衍生物的合成,以化合物171为例。
(a)i)盐酸(4M在二恶烷中),DCM,室温,18小时;ii)TBTU,NMM,DMF0℃-室温,22小时;(b)TMSBr,DCM,室温,过夜,制备型HPLC。26%.
(1-(((S)-1-(5-(3,4-二氯苯基)-1H-咪唑-2-基)-2-甲基丙基)氨基)-4-甲基-1-
氧戊烷-2-基)膦酸二乙酯。
二氯苯基)-1H-咪唑-2-基)-2-甲基丙基)氨基甲酸叔丁酯。将(S)-(1-(5-(3,4-二氯苯基)-1H-咪唑-2-基)-2-甲基丙基)氨基甲酸叔丁酯(77mg,0.200mmol)溶于DCM(2mL)和HCl(0.25mL,1.00mmol,4M在二恶烷中)。在完全消耗原料(LCMS)后,蒸发溶剂,得到(S)-1-(5-(3,4-二氯苯基)-1H-咪唑-2-基)-2-甲基丙-1-胺盐酸盐,其用于偶联步骤而不进一步纯化。使用通用程序I,使用上述(S)-1-(5-(3,4-二氯苯基)-1H-咪唑-2-基)-2-甲基丙-1-胺盐酸盐,化合物2d(51mg,0.200mmol),TBTU(70.6mg,0.220mmol),NMM(53μl,0.500mmol)在DMF(2mL)中合成标题化合物。使用自动组合闪光纯化(Teledyne ISCO)得到标题化合物(22mg,0.042mmol,21%)作为非对映异构体的混合物。MS(ESI+):m/z[M+H]+519。
非对映异构体的混合物:
主要非对映体:1H NMR(500MHz,CDCl3)δppm:7.88(bs,1H),7.54(dd,J=8.2Hz,J=1.8Hz,1H),7.39(d,J=8.4Hz,1H),7.25(bs,1H),5.26-5.23(m,1H),4.20-4.09(m,4H),3.00-2.93(m,1H),2.76-2.68(m,1H),2.18-2.11(1H),1.70-1.61(m,1H),1.52-1.44(m,1H),1.34(dd,J=6.10Hz,3H),1.30(dd,J=7.1Hz,3H),1.02(d,J=6.8Hz,3H),0.94(dd,J=7.1Hz,6H),0.90(d,J=6.7Hz,3H)。31P NMR(202MHz,CDCl3)δppm:26.3。
次要非对映体(选定信号):1H NMR(500MHz,CDCl3)δppm:7.93(d.J=1.8Hz,1H),7.64(dd,J=8.4Hz,J=1.8Hz,1H),7.41(d,J=8.4Hz,1H),4.08-4.04(m,4H),3.09-3.03(m,1H),2.58-2.51(m,1H)。31P NMR(202MHz,CDCl3)δppm:26.5。
(1-(((S)-1-(5-(3,4-二氯苯基)-1H-咪唑-2-基)-2-甲基丙基)氨基)-4-甲基-1-
氧戊烷-2-基)膦酸(171)
(28μl,0.212mmol)。通过制备型HPLC纯化得到标题化合物,为无色固体(5.2mg,0.011mmol,26%,非对映异构体的混合物)。
非对映异构体的混合物:
主要非对映体:1H NMR(500MHz,MeOH-d4)δppm:8.09(d,J=1.8Hz,1H),7.88(s,1H),7.79(dd,J=8.4Hz,J=1.7Hz,1H),7.62(d,J=8.64Hz,1H),5.21(d,J=5.0Hz,),3.33-3.25(m,1H),2.52-2.46(m,1H),2.10-2.04(m,1H),1.62-1.53(m,2H),1.09(d,J=6.9Hz,3H),1.01(d,J=6.9Hz,3H),0.95(dd,J=5.7Hz,6H)。13C NMR(126MHz,MeOH-d4)δppm:174.3,151.1,134.5,132.9,132.5,131.1,128.9,126.8,117.6,61.7,54.1,47.636.0,32.3,28.8,23.5,22.1,19.4,17.5,14.6。31P NMR(202MHz,MeOH-d4)δppm:19.7。
次要非对映体(选定信号):1H NMR(500MHz,MeOH-d4)δppm:8.04(d,J=2.1Hz,1H),7.97(d,J=1.8Hz,1H),7.89(bs,1H),7.63(d,J=7.6Hz,1H),3.18-3.16(m,1H),2.42-2.38(m,1H),1.54-1.53(m,2H),1.13(d,J=6.7Hz,3H),0.92(d,J=6.4Hz,3H),0.90(d,J=6.4hz,3H)。13C NMR(126MHz,MeOH-d4)δppm:134.6,132.7,128.8,126.9,54.9,32.7,23.6,22.0,19.7。
实施例172
方案16:苯并咪唑衍生物的合成,以化合物172为例。
(a)TBTU,NMM,DMF,0℃-室温,2d,定量;(b)HOAc/甲苯(1:1),110℃,3小时;(c)i)HCl(4M在1,4-二恶烷中),DCM,室温,18h;ii)TBTU,NMM,DMF,0℃-室温,21h,97%(3步);d)TMSBr,DCM,室温,21h,制备型HPLC,1.2%。
(S)-(1-((2-氨基-5-苯氧基苯基)氨基)-3-甲基-1-氧代丁烷-2-基)氨基甲酸叔
丁酯。
2.75mmol)。将反应混合物在该温度下搅拌30分钟,并加入4-苯氧基苯-1,2-二胺(500mg,2.5mmol)。再加热到室温过夜,用饱和NaHCO3水溶液淬灭反应,并用EtOAc(x3)萃取。合并的有机层随后用1M HCl、水和饱和NaCl水溶液洗涤,经Na2SO4干燥,过滤并在真空中浓缩。获得粗产物为棕色泡沫(1.00g,2.50mmol,定量),并在不进一步纯化的情况下用于下一步。1H NMR(500MHz,CDCl3)δppm:7.62(bs,1H),7.34-7.31(m,2H),7.11-7.08(m,2H),7.02-7.00(m,2H),6.42-6.39(m,2H),5.11(bs,1H),3.99-3.97(m,1H),2.31-2.23(m,1H),1.46(s,9H),1.07(dd,J=6.71Hz,3H),1.04(dd,J=6.71Hz,3H)。MS(ESI+):m/z[M+H]+400。
(S)-(2-甲基-1-(5-苯氧基-1H-苯并[d]咪唑-2-基)丙基)氨基甲酸叔丁酯。
/HOAc(1:1)中,并在回流下加热(预热油浴)3小时。冷却至室温后,小心地加入NaHCO3水溶液直至pH=9。然后将该溶液搅拌20分钟,用EtOAc(x3)萃取,用饱和NaHCO3水溶液(x4)、水(x2)和饱和NaCl水溶液洗涤。将有机层在Na2SO4上干燥,过滤并在减压下浓缩,以得到标题化合物,为橙色固体(191mg,0.500mmol,定量),其在不进一步纯化的情况下用于下一步。MS(ESI+):m/z[M+H]+382。
(4-甲基-1-(((S)-2-甲基-1-(5-苯氧基-1H-苯并[d]咪唑-2-基)丙基)氨基)-1-
氧戊烷-2-基)膦酸二乙酯。
18小时。然后在减压下浓缩。同时,将2-(二乙氧基磷酰基)-4-甲基戊酸2d(116mg,0.459mmol)和TBTU(181mg,0.505mmol)在DMF(2.5mL)中的混合物冷却至0℃,并加入NMM(121μl,1.15mmol)。将反应混合物搅拌30分钟,然后在0℃下滴加溶解在DMF(2.5mL)中的叔丁氧羰基脱保护的苯并咪唑氨基酸衍生物。搅拌21小时后,加入EtOAc和1M HCl,水层用EtOAc(x2)萃取。合并的有机层用水和饱和NaCl水溶液洗涤。在Na2SO4干燥并过滤后,减压除去溶剂,获得标题化合物为褐色树脂(208mg,0.405mmol,97%)。标题化合物在没有任何进一步纯化的情况下用于下一步。MS(ESI+):m/z[M+H]+516。
(4-甲基-1-(((S)-2-甲基-1-(5-苯氧基-1H-苯并[d]咪唑-2-基)丙基)氨基)-1-
氧戊烷-2-基)膦酸(172)。
(1.74mg,0.004mmol,1.2%)。
非对映异构体的混合物
主要非对映体:1H NMR(500MHz,DMSO-d6,)δppm:8.14-8.12(m,1H),7.53-7.51(m,1H),7.37-7.33(m,2H),7.13-7.05(m,2H),6.97-6.95(m,2H),4.94-4.91(m,1H),3.28-3.22(m,1H),2.32-2.26(m,1H),1.87-1.81(m,1H)1.50-1.37(m,2H),0.98-0.96(m,3H),0.93-0.92(m,3H),0.87-0.86(m,6H)。13C NMR(126MHz,DMSO-d6)δppm:169.8,158.6,156.2,151.9,130.5,123.1,118.1,60.2,53.7,36.5,32.4,27.3(d,J=14.7Hz),23.5,22.0,19.8,18.8。31P NMR(202MHz,DMSO-d6)δppm:20.7。次要非对映体(选定信号):1H NMR(500MHz,DMSO-d6)δppm:8.45-8.43(m,1H),7.49-7.48(m,1H),6.92-6.89(m,2H),5.13-5.11(m,1H),1.96-1.92(m,1H),0.78-0.76(m,6H)。13C NMR(126MHz,DMSO-d6)δppm:170.71,158.5,157.4,152.1,123.4,118.2,115.1,53.2,34.9,30.6,26.8(d,J=14.7Hz),23.4,21.9,19.7,17.4。31P NMR(202MHz,DMSO-d6)δppm:20.9。
HRMS(ESI+)[M+H]+:计算460.1996,实测460.1982。
实施例173
4-甲基-2-(对甲苯基氨基甲酰基)戊酸乙酯。
和EDC·HCl(515mg,2.68mmol)加入到对甲苯胺(240mg,2.23mmol)在DCM(20mL)中的溶液中。将所得混合物在室温下搅拌过夜。处理后,使用柱色谱法(Hex/EtOAc=8/2)纯化获得的粗产物。得到的产物为橙色晶体(441mg,71%)。1H NMR(500MHz,CDCl3)δppm:8.45(brs,1H),7.42(d,J=8.1Hz,2H),7.13(d,J=8.1Hz,2H),4.31-4.17(m,2H),3.43(t,J=7.7Hz,1H),2.32(s,3H),1.94-1.80(m,2H),1.69-1.61(m,1H),1.35-1.28(m,3H),0.96(d,J=6.6Hz,6H)。13C NMR(126MHz,CDCl3)δppm:173.2,166.4,135.0,134.0,129.4,119.8,61.7,52.4,40.8,26.4,22.5,22.0,20.9,14.1。MS(ESI+):m/z[M+H]+=278。
N1-羟基-2-异丁基-N3-(对甲苯基)丙二酰胺(173)。
搅拌过夜。溶剂在真空中浓缩,所得油通过制备型HPLC(CH3CN(HCOOH0.05%)-H2O(HCOOH 0.05%):1.0:9.0至10.0:0.0)纯化。所得产物为白色固体(49mg,52%)。1H NMR(500MHz,DMSO-d6)δppm:10.54(s,1H),9.66(s,1H),9.00(s,1H),7.45(d,J=8.4Hz,2H),7.10(d,J=8.4Hz,2H),3.18(t,J=7.6Hz,1H),2.24(s,3H),1.67(t,J=7.2Hz,2H),1.47(dquin,J=13.4,6.7Hz,1H),0.87(brd,J=6.6Hz,3H),0.87(brd,J=6.6Hz,3H)。13C NMR(126MHz,DMSO-d6)δppm:167.6,166.5,136.3,132.4,129.2,119.4,49.9,38.1,25.8,22.5,22.3,20.5。HRMS(ESI+)C14H21N2O3[M+H]+计算265.1547,实测265.1545。
实施例174和实施例177
4-甲基-N-(对甲苯基)-2-(1H-1,2,3-***-1-基)戊酰胺(174)和4-甲基-N-(对甲
苯基)-2-(2H-1,2,3-***-2-基)戊酰胺(177)。
根据通用程序O,使用2-溴-4-甲基-N-(对甲苯基)戊酰胺(70mg,0.25mmol)(根据通用程序B-1合成),丙酮(7mL),1H-1,2,3-***(18.7mg,0.27mmol)和K2CO3(37.4mg,0.27mmol)合成4-甲基-N-(对甲苯基)-2-(1H-1,2,3-***-1-基)戊酰胺(174)和4-甲基-N-(对甲苯基)-2-(2H-1,2,3-***-2-基)戊酰胺(177)。通过制备型HPLC(CH3CN(HCOOH0.05%)-H2O(HCOOH 0.05%):1.0:9.0至10.0:0.0)纯化粗产物,得到产品174(20.3mg,30%)和177(30mg,45%),为白色固体。
4-甲基-N-(对甲苯基)-2-(1H-1,2,3-***-1-基)戊酰胺(174)。
3H),2.16-2.06(m,1H),2.01-1.93(m,1H),1.31-1.20(m,1H),0.93(d,J=6.8Hz,3H),0.90(d,J=6.6Hz,3H)。13C NMR(126MHz,DMSO-d6)δppm:166.6,135.7,133.3,133.1,129.3,123.9,119.5,61.6,40.4,24.5,22.4,21.5,20.5。HRMS(ESI+)C15H21N4O[M+H]+计算273.1710,实测273.1708。
4-甲基-N-(对甲苯基)-2-(2H-1,2,3-***-2-基)戊酰胺(177)。
J=13.8,7.8,6.2Hz,1H),1.47-1.36(m,1H),0.91(t,J=6.2Hz,6H)。13C NMR(126MHz,DMSO-d6)δppm:166.2,135.9,134.5,132.9,129.2,119.4,65.8,24.5,22.5,21.7,20.5。HRMS(ESI+)C15H21N4O[M+H]+计算273.1710,实测273.1708。
III.生物评价
抗LasB活性:
本发明化合物的活性根据Kany,A.M.;Sikandar,A.;Haupenthal,J.;Yahiaoui,S.;Maurer,C.K.;Proschak,E.;J.;Hartmann,R.W.ACS Infect.Dis.2018,4,988–997中所述的方法测定。
α-苄基化衍生物:
表2:α-苄基巯基乙酰酰胺对LasB的活性。
对映异构体的活性:
为了阐明立体中心的构型是否对活性有影响,使用具有制备型HPLC的手性柱分离实施例1和4的化合物的对映体(E1和E2,根据它们从手性柱的洗脱顺序标记)并独立检测。尽管两种对映体均具有活性,但观察到两种构型之间的活性差异(表3)。对于这两种化合物,E2对映体的活性更高。
表3.实施例1和4的外消旋混合物和纯对映体的活性。
为了确保在测定过程中不发生外消旋化,检测了在甲醇和水性缓冲液(50mMTris,pH7.2,2.5mM CaCl2)中的构型稳定性。CD光谱在一小时内保持不变,表明在此期间不会发生外消旋化。
选择性:
含锌人酶的抑制经常被描述为LasB抑制剂,并在选择性化合物的开发中造成了严重困难。特别是,应避免抑制基质金属蛋白酶(MMPs)。为了进一步研究这个问题,已经测试了三种衍生物(实施例1、5和8的化合物)对几种人类脱靶的选择性,包括六种MMP、ADAM17(TACE)、HDAC-3和HDAC-8(表4)。化合物对MMP和HDAC的选择性特别高,而ADAM17的抑制作用要强得多。
表4.实施例1、5和8对脱靶的选择性。(n.i.=<10%抑制)。
细胞毒性:
实施例1和5的化合物对细胞系HepG2、HEK293和A549无毒(表5)。另外,评价对铜绿假单胞菌PA14的抑制作用以排除本发明化合物的抗菌作用。这很重要,因为它的目标是针对细菌的毒力而不是细菌的生存能力。结果表明,两种化合物对PA14的MIC值以及细胞系中的细胞毒性(IC50值)均大于100μM,因此没有问题。
表5.实施例1和5的细胞毒性数据和PA14抑制。
α-烷基化衍生物:
在Cα-位置带有烷基取代基的化合物对活性非常有利,其IC50值(表6和7)可达亚微摩尔。其中,实施例2中在芳族核具有4-Me取代基和异丁基链的化合物,被证明是最有前途的化合物之一,因此进一步研究了选择性和细胞毒性(表8)。
表6.α-烷基化衍生物及其对LasB的相应活性。
1在Kany等人中公开的化合物。
表7.在α-位带有异丁基的化合物及其对LasB的相应活性。
表8.实施例2的化合物的选择性和细胞毒性数据。n.i.=抑制<10%。
由于实施例2的化合物已经在体外LasB抑制试验中显示出令人印象深刻的活性、对广谱人酶的高选择性,并且在体外没有细胞毒性迹象,因此对其进行更高级的安全性筛选(表9)。关于hERG钾通道的抑制的IC50值被确定为>10μM。此外,确定实施例2的化合物对五种人CYP450亚型的影响特别重要,表明抑制作用弱或无抑制。此外,使用微型Ames(mini-Ames)反向突变测定法对实施例2的化合物进行分析,在125μg/mL的浓度下未观察到遗传毒性。
表9.实施例2的化合物的高级安全性概况:hERG/CYP抑制和mini-Ames试验。
hERG | CYP1A | CYP2C9 | CYP3A4 | CYP2C19 | CYP2D6 | 微型Ames | |
<![CDATA[IC<sub>50</sub>[μM]]]> | >10 | >25 | >25 | 15 | 1.0 | 22.3 | 无遗传毒性 |
此外,实施例2的化合物在小鼠中进行药代动力学(PK)研究(表10)。静脉内注射(静脉注射),剂量为10mg/kg,可在血液中检测2小时。初步结果表明高清除率和低总暴露量,但分布的体积可以解释良好的组织渗透。
表10.实施例2的PK参数。
<![CDATA[C<sub>max</sub>[ng/mL]]]> | 200 |
<![CDATA[T<sub>max</sub>[min]]]> | 15* |
<![CDATA[T<sub>1/2</sub>[min]]]> | 50 |
CL/F[mL/min/kg] | 505±119 |
<![CDATA[AUC<sub>0-t</sub>[ng/mL*h]]]> | 241±22 |
V/F[L/kg] | 45.5±2.8 |
*第一测量点
α-羧甲基衍生物:
实施例54(表1)的化合物对LasB的活性如下:IC50=3.9±0.4μM。
杂环衍生物:
表11.杂环衍生物及其相应的抗LasB活性。
膦酸衍生物:
表12.膦酸衍生物及其相应的抗LasB活性。根据上述程序制备实施例63至89。
表13.其他膦酸衍生物及其相应的抗LasB活性。根据上述程序制备实施例90至151。
表14:α-膦酸二肽及其相应的抗LasB活性。根据上述程序制备实施例152至169。
所有膦酸酯均显示出优异的选择性和细胞毒性特征,以及对PA14细菌生长无抑制作用(表15、17和18)。
表15.实施例63、92、108和152化合物的选择性、细胞毒性和PA14抑制。
n.i.=抑制<10%;n.d.=未确定
表16:以***,咪唑和苯并咪唑作为杂五环和苯并环杂五环的实例。
根据上述程序制备化合物170和172。
表17.实施例170和172对脱靶的选择性。
(n.i.=<10%抑制;n.d.=未确定)。
表18.实施例170和172的细胞毒性数据和PA14抑制作用
由于实施例63和170的化合物在体外LasB测定中显示出令人印象深刻的活性、对广谱人酶具有高选择性,并且在体外无细胞毒性迹象,因此对它们进行更高级的安全性筛选(SafetyScreen44板,由EurofinsCEREP进行)。该筛选包括44个不同的靶标,包括GPCR,转运蛋白,离子通道,核受体,激酶和其他非激酶酶。实施例63和170的化合物对所有测试靶标的对照特异性结合没有抑制(在化合物浓度为1.0E-0.5M时<22%抑制)。
异羟肟酸衍生物:
表19.异羟肟酸衍生物及其相应的抗LasB活性。
根据上述程序制备实施例173。
表20.实施例173的化合物的选择性、细胞毒性和PA14抑制。
***衍生物:
表21.***衍生物及其相应的抗LasB活性。
根据上述程序制备实施例174至178。
*n=1
表22.实施例174和177的化合物的选择性、细胞毒性和PA14抑制。
n.i.=抑制<10%;n.d.=未确定
Claims (42)
1.式(Ia)的化合物:
其中,
X是式-PO(OH)2、-SH、-C(=O)-NH-OH、任选取代的***基、-SR3、-PO(OH)(OR4)或-PO(OR4)(OR5)的基团;
R1是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基或任选取代的芳烷基或任选取代的杂芳烷基;或式-CH(R6)-C(=O)-NH-R7的基团、或式-C(Me)2-CH2-C(=O)-NH-R7的基团、或式-CH(R6)-CH2-C(=O)-NH-R7的基团或式-CH(R6)-R8的基团;
R2是烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都任选地被取代;
R3是式-COR3a或-CON(R3b)2的基团;其中R3a是烷基、任选取代的苯基或任选取代的苄基,并且R3b独立地选自氢或烷基,任选取代的苯基或任选取代的苄基;
R4为烷基、任选取代的苯基或任选取代的苄基;
R5为烷基、任选取代的苯基或任选取代的苄基;
R6是氢或烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都任选地被取代;
R7是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的芳烷基或任选取代的杂芳烷基;
R8是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的芳烷基或任选取代的杂芳烷基;和
R1a是氢,或者,如果R1是式-CH(R6)-C(=O)-NH-R7的基团,则R1a和R6一起是式-(CH2)3-或-(CH2)4-;
或其药学上可接受的盐,
用于治疗细菌感染。
2.式(Ia)化合物的用途:
其中,
X是式-PO(OH)2、-SH、-C(=O)-NH-OH、任选取代的***基、-SR3、-PO(OH)(OR4)或-PO(OR4)(OR5)的基团;
R1是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基或任选取代的芳烷基或任选取代的杂芳烷基;或式-CH(R6)-C(=O)-NH-R7的基团、或式-C(Me)2-CH2-C(=O)-NH-R7的基团、或式-CH(R6)-CH2-C(=O)-NH-R7的基团、或式-CH(R6)-R8的基团;
R2是烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都任选地被取代;
R3是式-COR3a或-CON(R3b)2的基团;其中R3a是烷基、任选取代的苯基或任选取代的苄基,并且R3b独立地选自氢或烷基,任选取代的苯基或任选取代的苄基;
R4为烷基、任选取代的苯基或任选取代的苄基;
R5为烷基、任选取代的苯基或任选取代的苄基;
R6是氢或烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都任选地被取代;
R7是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的芳烷基或任选取代的杂芳烷基;
R8是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的芳烷基或任选取代的杂芳烷基;和
R1a是氢,或者,如果R1是式-CH(R6)-C(=O)-NH-R7的基团,则R1a和R6一起是式-(CH2)3-或-(CH2)4-;
或其药学上可接受的盐,
用于制备治疗细菌感染的药物。
3.一种用于治疗患有或易受细菌感染的受试者的方法,所述方法包括向所述受试者施用有效量的式(Ia)化合物:
其中,
X是式-PO(OH)2、-SH、-C(=O)-NH-OH、任选取代的***基、-SR3、-PO(OH)(OR4)或-PO(OR4)(OR 5)的基团;
R1是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基或任选取代的芳烷基或任选取代的杂芳烷基;或式-CH(R6)-C(=O)-NH-R7的基团、或式-C(Me)2-CH2-C(=O)-NH-R7的基团、或式-CH(R6)-CH2-C(=O)-NH-R7的基团、或式-CH(R6)-R8的基团;
R2是烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都任选地被取代;
R3是式-COR3a或-CON(R3b)2的基团;其中R3a是烷基、任选取代的苯基或任选取代的苄基,并且R3b独立地选自氢或烷基,任选取代的苯基或任选取代的苄基;
R4为烷基、任选取代的苯基或任选取代的苄基;
R5为烷基、任选取代的苯基或任选取代的苄基;
R6是氢或烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都任选地被取代;
R7是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的芳烷基或任选取代的杂芳烷基;
R8是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的芳烷基或任选取代的杂芳烷基;和
R1a是氢,或者,如果R1是式-CH(R6)-C(=O)-NH-R7的基团,R1a和R6一起是式-(CH2)3-或-(CH2)4-;
或其药学上可接受的盐。
6.如权利要求1、4或5中任一项所述的化合物或如权利要求2、4或5中任一项所述的用途或如权利要求3、4或5中任一项所述的方法,其特征在于,R2是C1-6烷基;含有1-6个碳原子和1、2、3或4个选自O、S和N的杂原子的杂烷基;C4-10烷基环烷基;或C7-12芳烷基;所有这些都任选地被取代。
7.如权利要求1、4或5中任一项所述的化合物或如权利要求2、4或5中任一项所述的用途或如权利要求3、4或5中任一项所述的方法,其特征在于,R2是任选取代的苄基。
8.如权利要求1、4或5中任一项所述的化合物或如权利要求2、4或5中任一项所述的用途或如权利要求3、4或5中任一项所述的方法,其特征在于,R2是式-CH2CH(CH3)2的基团。
9.如权利要求1或4至8中任一项所述的化合物或如权利要求2或4至8中任一项所述的用途或如权利要求3至8中任一项所述的方法,其特征在于,R1是任选取代的芳基或任选取代的杂芳基。
10.如权利要求1或4至8中任一项所述的化合物或如权利要求2或4至8中任一项所述的用途或如权利要求3至8中任一项所述的方法,其特征在于,R1是任选取代的苯基,任选取代的萘基或任选取代的杂芳基,其包含一个或两个环和5至10个选自C、O、N和S的环原子。
11.如权利要求1或4至8中任一项所述的化合物或如权利要求2或4至8中任一项所述的用途或如权利要求3至8中任一项所述的方法,其特征在于,R1是任选取代的苯基。
12.如权利要求1或4至8中任一项所述的化合物或如权利要求2或4至8中任一项所述的用途或如权利要求3至8中任一项所述的方法,其特征在于,R1是式-Cy1-L-Cy2的基团,其中Cy1是含有1或2个环和3至7个碳环原子的任选取代的环亚烷基,含有1或2个环和3至7个选自C、N、O和S的环原子的任选取代的杂环亚烷基,任选取代的亚苯基,或含有5或6个选自C、N、O和S的环原子的任选取代的杂亚芳基;Cy2是环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都任选地被取代;L是键或-O-、-S-、-NH-、-CH2-、-CO-、-NHCO-、-CO-NH-、-CH2-CO-NH-、-NH-CO-CH2-、-CH2-O-CO-NH-、-NH-CO-O-CH2-、-O-CO-NH-、-NH-CO-O-、-NHSO2-、-SO2NH-、-CH2-SO2-NH-、-NH-SO2-CH2-、-S-CH2-、-CH2-S-、-NH-CH2-、-CH2-NH-、-O-CH2-或-CH2-O-。
13.如权利要求12所述的化合物或用途或方法,其特征在于,Cy2是任选取代的苯基、任选取代的联苯基、任选取代的萘基、含有一个或两个环和5、6、9或10个选自C、O、N和S的环原子的任选取代的杂芳基、含有3至7个环原子的任选取代的环烷基、含有3至7个选自C、N、O和S的环原子的任选取代的杂环烷基、含有9或10个选自C、N、S和O的环原子的任选取代的杂环烷基芳基、或式-CH(CH2Ph)Ph。
14.如权利要求12或13所述的化合物或用途或方法,其特征在于,L是键或-NHCO-、-CO-NH-、-CH2-CO-NH-、-NH-CO-CH2-、-NHSO2-或-SO2NH-。
15.如权利要求12至14中任一项所述的化合物或用途或方法,其特征在于,Cy1为1,4-亚苯基。
16.如权利要求1或4至8中任一项所述的化合物或如权利要求2或4至8中任一项所述的用途或如权利要求3至8中任一项所述的方法,其特征在于,R1是式-CH(R6)-C(=O)-NH-R7或式-CH(R6)-R8的基团。
17.如权利要求16所述的化合物或用途或方法,其特征在于,R6是氢或C1-6烷基、C3-7环烷基、含有3-7个选自C、N、O和S的环原子的杂环烷基、苯基或含有5或6个选自C、N、S和O的环原子的杂芳基、或式-CH2-R6a的基团,其中R6a是C3-7环烷基,含有3至7个选自C、N、O和S的环原子的杂环烷基,苯基或含有5或6个选自C、N、S和O的环原子的杂芳基。
18.如权利要求16或17所述的化合物或用途或方法,其特征在于,R6是式-CH(CH3)2的基团。
19.如权利要求16至18中任一项所述的化合物或用途或方法,其特征在于,R7是任选取代的苯基或任选取代的C3-7环烷基。
20.如权利要求16至19中任一项所述的化合物或用途或方法,其特征在于,R8是任选取代的苯并咪唑基团或任选取代的***基团或任选取代的咪唑基团。
21.如权利要求1或4至20中任一项所述的化合物或如权利要求2或4至20中任一项所述的用途或如权利要求3至20中任一项所述的方法,其特征在于,所述细菌感染是由铜绿假单胞菌引起的。
22.式(Ia)的化合物:
其中,
X是式-PO(OH)2、-SH、-C(=O)-NH-OH、任选取代的***基、-SR3、-PO(OH)(OR4)或-PO(OR4)(OR5)的基团;
R1是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基或任选取代的杂芳基或任选取代的芳烷基或任选取代的杂芳烷基;或式-CH(R6)-C(=O)-NH-R7的基团、或式-C(Me)2-CH2-C(=O)-NH-R7的基团、或式-CH(R6)-CH2-C(=O)-NH-R7的基团、或式-CH(R6)-R8的基团;
R2是烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都任选地被取代;
R3是式-COR3a或-CON(R3b)2的基团;其中R3a是烷基、任选取代的苯基或任选取代的苄基,并且R3b独立地选自氢或烷基,任选取代的苯基或任选取代的苄基;
R4为烷基、任选取代的苯基或任选取代的苄基;
R5为烷基、任选取代的苯基或任选取代的苄基;
R6是氢或烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基,所有这些都任选地被取代;
R7是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的芳烷基或任选取代的杂芳烷基;
R8是任选取代的环烷基、任选取代的杂环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的芳烷基或任选取代的杂芳烷基;和
R1a是氢,或者,如果R1是式-CH(R6)-C(=O)-NH-R7的基团,则R1a和R6一起是式-(CH2)3-或-(CH2)4-;
或其药学上可接受的盐。
25.如权利要求22至24中任一项所述的化合物,其特征在于,R2是C1-6烷基;杂烷基,其含有1至6个碳原子和1、2、3或4个选自O、S和N的杂原子;C4-10烷基环烷基;或C7-12芳烷基;所有这些都任选地被取代。
26.如权利要求22至24中任一项所述的化合物,其特征在于,R2是任选取代的苄基。
27.如权利要求22至24中任一项所述的化合物,其特征在于,R2是式-CH2CH(CH3)2的基团。
28.如权利要求22至27中任一项所述的化合物,其特征在于,R1是任选取代的芳基或任选取代的杂芳基。
29.如权利要求22至27中任一项所述的化合物,其特征在于,R1是任选取代的苯基、任选取代的萘基或任选取代的杂芳基,其含有一个或两个环和5至10个选自C、O、N和S的环原子。
30.如权利要求22至27中任一项所述的化合物,其特征在于,R1是任选取代的苯基。
31.如权利要求22至27中任一项所述的化合物,其特征在于,R1是式-Cy1-L-Cy2的基团,其中Cy1是含有1个或2个环和3至7个碳环原子的任选取代的亚环烷基、含有1或2个环和3至7个选自C、N、O和S的环原子的任选取代的杂环亚烷基、任选取代的亚苯基、或含有5或6个选自C、N、O和S的环原子的任选取代的杂亚芳基;Cy2是环烷基、杂环烷基、烷基环烷基、杂烷基环烷基、芳基、杂芳基、芳烷基或杂芳烷基、所有这些都任选地被取代;L是键或-O-、-S-、-NH-、-CH2-、-CO-、-NHCO-、-CO-NH-、-CH2-CO-NH-、-NH-CO-CH2-、-CH2-O-CO-NH-、-NH-CO-O-CH2-、-O-CO-NH-、-NH-CO-O-、-NHSO2-、-SO2NH-、-CH2-SO2-NH-、-NH-SO2-CH2-、-S-CH2-、-CH2-S-、-NH-CH2-、-CH2-NH-、-O-CH2-或-CH2-O-。
32.如权利要求31所述的化合物,其特征在于,Cy2是任选取代的苯基、任选取代的联苯基、任选取代的萘基、含有一个或两个环和5、6、9或10个选自C、O、N和S的环原子的任选取代的杂芳基、含有3至7个环原子的任选取代的环烷基、含有3至7个选自C、N、O和S的环原子的任选取代的杂环烷基、含有9或10个选自C、N、S和O的环原子的任选取代的杂环烷基芳基,或式-CH(CH2Ph)Ph。
33.如权利要求31或32所述的化合物,其特征在于,L是键或-NHCO-、-CO-NH-、-CH2-CO-NH-、-NH-CO-CH2-、-NHSO2-或-SO2NH-。
34.如权利要求31至33中任一项所述的化合物,其特征在于,Cy1是1,4-亚苯基。
35.如权利要求22至27中任一项所述的化合物,其特征在于,R1是式-CH(R6)-C(=O)-NH-R7的基团或式-CH(R6)-R8的基团。
36.如权利要求35所述的化合物,其特征在于,R6是氢或C1-6烷基、C3-7环烷基、含有3-7个选自C、N、O和S的环原子的杂环烷基、苯基或含有5或6个选自C、N、S和O的环原子的杂芳基,或式-CH2-R6a的基团,其中R6a是C3-7环烷基,含有3至7个选自C、N、O和S的环原子的杂环烷基,苯基或含有5或6个选自C、N、S和O的环原子的杂芳基。
37.如权利要求35或36所述的化合物,其特征在于,R6是式-CH(CH3)2的基团。
38.如权利要求35至37中任一项所述的化合物,其特征在于,R7是任选取代的苯基或任选取代的C3-7环烷基。
39.如权利要求35至37中任一项所述的化合物,其特征在于,R8是任选取代的苯并咪唑基团或任选取代的***基团或任选取代的咪唑基团。
40.药物组合物,其包含如权利要求22至39中任一项所述的化合物和任选的一种或多种载体物质和/或一种或多种佐剂和/或一种或多种其他抗菌化合物。
41.如权利要求22至39中任一项所述的化合物或如权利要求40所述的药物组合物用于治疗细菌感染。
42.如权利要求22至39中任一项所述的化合物或如权利要求40所述的药物组合物用于治疗由铜绿假单胞菌引起的细菌感染。
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