CN111320618A - 一类新型抗葡萄球菌的小分子化合物及其制法和用途 - Google Patents

一类新型抗葡萄球菌的小分子化合物及其制法和用途 Download PDF

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CN111320618A
CN111320618A CN201811540551.1A CN201811540551A CN111320618A CN 111320618 A CN111320618 A CN 111320618A CN 201811540551 A CN201811540551 A CN 201811540551A CN 111320618 A CN111320618 A CN 111320618A
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acetamide
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罗有福
耿福能
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Good Doctor Pharmaceutical Group Co ltd
Sichuan University
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Sichuan University
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Abstract

本发明公开了一类新型抗葡萄球菌的小分子化合物及其制法和用途，通过MRSA抗菌活性测定，结果表明该类小分子化合物对葡萄球菌MRSA具有较好的抗菌活性，在制备抗MRSA等葡萄球菌药物方面具有应用前景。该类新型抗葡萄球菌小分子化合物结构通式(Ⅰ)所示，

Description

一类新型抗葡萄球菌的小分子化合物及其制法和用途
技术领域：
本发明涉及医药技术领域，特别涉及一类新型小分子化合物及制备方法，以及在抗MRSA等葡萄球菌药物方面的应用。
背景技术：
一直以来，致病微生物引起的感染性疾病都是危害人类健康的重要因素。抗生素的发现和应用是人类在20世纪医药领域最伟大的成就之一，自此，医药领域进入了细菌所致疾病大大减少的黄金时代。但随着抗生素的过度使用，出现了多种抗生素耐药菌，如耐甲氧西林葡萄球菌(methicillin-resistant Staphylococcus aureus，MRSA)等。
MRSA被称为“超级细菌”，自1961年在英国被首次发现以来，即以惊人的速度在世界范围内蔓延，目前MRSA感染已经超过艾滋、结核和病毒性肝炎成为患者首位致死原因，严重威胁公共卫生安全。虽然利奈唑胺、达托霉素、磷酸泰地唑胺等新药陆续获得FDA批准用于MRSA的治疗，但已在临床使用多年的万古霉素仍然是治疗MRSA感染的一线药物。因此，急需寻找到结构新颖、高效低毒的抗MRSA等葡萄球菌药物。
因此发现新型的抗葡萄球菌的药物在葡萄球菌以及耐药葡萄球菌的治疗中显得尤为重要。
发明内容：
本发明的第一个目的在于提供一类新型抗葡萄球菌的小分子化合物及其制法；第二个目的在于提供该类新型小分子化合物在制备抗MRSA等葡萄球菌药物方面的应用。
本发明的第一方面，一类新型抗葡萄球菌的小分子化合物，含其药用盐，结构通式(Ⅰ)所示：
Figure BDA0001907764870000021
Q为
Figure BDA0001907764870000022
R1为吡啶基、噻吩基、嘧啶基、硝基苯基、2-甲基***-1-醇基、N-甲基乙酰胺基、(E)-2-丁烯-1-醇基、2-甲基异吲哚啉-1，3-二酮基、环戊醇基、乙醇基或三氟甲基-苯乙基。
根据权利1中一类新型小分子化合物，当Q为
Figure BDA0001907764870000023
时，R1为吡啶基、噻吩基、嘧啶基、硝基苯基、2-甲基***-1-醇基、N-甲基乙酰胺基、(E)-2-丁烯-1-醇基、2-甲基异吲哚啉-1，3-二酮基、环戊醇基、乙醇基或三氟甲基-苯乙基。
根据权利1中一类新型小分子化合物，当Q为
Figure BDA0001907764870000024
时，R1为吡啶基。
式(Ⅰ)化合物选自以下化合物：
(S)-N-((3-(3-氟-4-(4-(2-吡啶基)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure BDA0001907764870000025
(S)-N-((3-(3-氟-4-(4-(4-吡啶基)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure BDA0001907764870000031
(S)-N-((3-(3-氟-4-(4-(3-吡啶基)-1,2,3-三氮唑)苯基)-2-氧代5-噁唑烷基)甲基)乙酰胺
Figure BDA0001907764870000032
(S)-N-((3-(3-氟-4-(4-(2-噻吩)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure BDA0001907764870000033
(S)-N-((3-(3-氟-4-(4-(2-吡啶基)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure BDA0001907764870000034
(S)-N-((3-(3-氟-4-(4-(5-吡啶基)-1,2,3-三氮唑)苯基)-2-氧代-5噁唑烷基)甲基)乙酰胺
Figure BDA0001907764870000035
(S)-N-((3-(3-氟-4-(4-(3-噻吩基)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure BDA0001907764870000041
(S,E)-N-((3-(3-氟-4-(4-(4-羟基-2-丁烯-2-醇基)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure BDA0001907764870000042
(S)-N-((3-(4-(4-((1,3-邻苯二甲亚酰-2-甲基)-1,2,3-三氮唑)-3-氟苯基丙酮)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure BDA0001907764870000043
(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure BDA0001907764870000044
(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure BDA0001907764870000051
(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure BDA0001907764870000052
(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure BDA0001907764870000053
(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure BDA0001907764870000054
(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure BDA0001907764870000055
(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure BDA0001907764870000061
具体实施方式
实施例1对编号1-a～1-r系列化合物进行了化学合成，得到正确的小分子化合物，具体的化学结构如表1所示。
表1化合物结构
Figure BDA0001907764870000062
Figure BDA0001907764870000071
Figure BDA0001907764870000081
(S)-N-((3-(3-氟-4-(4-(2-吡啶基)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1-a)的制备
Figure BDA0001907764870000082
向反应封管中，在(S)-N-((3-(4-叠氮-3-氟苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1.0eq.),CuSO4(0.02eq.)和抗坏血酸钠(0.1eq.)的水与叔丁醇的1:1溶液中加入2-乙炔基吡啶，室温搅拌24h，水洗、萃取、旋干，柱层析分离得白色固体41.0mg，产率：72.5％。1HNMR(400MHz,DMSO)δ＝9.03(s,1H),8.65(s,1H),8.26(t,J＝5.6Hz,1H),8.13(d,J＝7.8Hz,1H),7.94(dd,J＝17.6,8.8Hz,2H),7.83(dd,J＝13.2,2.0Hz,1H),7.57(dd,J＝8.8,2.0Hz,1H),7.41(t,J＝5.6Hz,1H),4.85–4.72(m,1H),4.22(t,J＝9.2Hz,1H),3.83(m,1H),3.46(t,J＝5.6Hz,2H),1.85(s,3H).13C NMR(100MHz,DMSO)δ＝170.52,155.76,154.47,153.29,150.22,149.85,148.13,141.27,137.84,126.93,124.99,123.86,120.17,114.52,106.48,72.41,47.75,41.85,22.92。HRMS(Q-TOF):calculated for[M]+396.1346,found[M+H]+397.1461。
实施例2(S)-N-((3-(3-氟-4-(4-(4-吡啶基)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1-b)的制备
Figure BDA0001907764870000091
向反应封管中，在(S)-N-((3-(4-叠氮-3-氟苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1.0eq.),CuSO4(0.02eq.)和抗坏血酸钠(0.1eq.)的水与叔丁醇的1:1溶液中加入4-乙炔基吡啶，室温搅拌24h，水洗、萃取、旋干，柱层析分离得白色固体41.0mg，产率：65.0％。1HNMR(400MHz,DMSO)δ＝9.31(d,J＝1.6Hz,1H),8.70(brs,2H),8.26(t,J＝5.6Hz,1H),7.96-7.92(m,3H),7.86(dd,J＝13.2,2.4Hz,1H),7.59(dd,J＝8.8,1.6Hz,1H),4.86–4.73(m,1H),4.22(t,J＝8.8Hz,1H),3.84(m,1H),3.46(t,J＝5.6Hz,2H),1.85(s,3H).13C NMR(100MHz,DMSO)δ170.52,155.61,154.47,153.13,150.95(2C),145.12,141.42,137.63(2C),126.89,125.30,119.87,114.59,106.47,72.43,47.76,41.85,22.92。HRMS(Q-TOF):calculated for[M]+396.1346,found[M+H]+397.1460。
实施例3(S)-N-((3-(3-氟-4-(4-(3-吡啶基)-1,2,3-三氮唑)苯基)-2-氧代5-噁唑烷基)甲基)乙酰胺(1-c)的制备
Figure BDA0001907764870000101
向反应封管中，在(S)-N-((3-(4-叠氮-3-氟苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1.0eq.),CuSO4(0.02eq.)和抗坏血酸钠(0.1eq.)的水与叔丁醇的1:1溶液中加入3-乙炔基吡啶，室温搅拌24h，水洗、萃取、旋干，柱层析分离得白色固体41.0mg，产率：79.4％。1HNMR(400MHz,DMSO)δ＝9.20(d,J＝1.6Hz,1H),9.17(s,1H),8.60(d,J＝4.0Hz,1H),8.33(dt,J＝8.0,2.0Hz,1H),8.26(t,J＝6.0Hz,1H),7.94(t,J＝8.8Hz,1H),7.86(dd,J＝13.2,2.0Hz,1H),7.59(dd,J＝11.2,2.4Hz,1H),7.54(dd,J＝5.2,8.0Hz,1H),4.87–4.71(m,1H),4.22(t,J＝9.2Hz,1H),3.84(m,1H),3.46(t,J＝5.6Hz,2H),1.85(s,3H).13C NMR(100MHz,DMSO)δ170.52,155.58,154.48,153.10,149.77,147.10,144.62,141.27,133.17,126.83,124.59,123.99,119.98,114.60,106.49,72.43,47.76,41.85,22.93。HRMS(Q-TOF):calculated for[M]+396.1346,found[M+H]+397.1461。
实施例4(S)-N-((3-(3-氟-4-(4-(2-噻吩)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1-d)的制备
Figure BDA0001907764870000102
向反应封管中，在(S)-N-((3-(4-叠氮-3-氟苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1.0eq.),CuSO4(0.02eq.)和抗坏血酸钠(0.1eq.)的水与叔丁醇的1:1溶液中加入2-乙炔基噻吩，室温搅拌24h，水洗、萃取、旋干，柱层析分离得白色固体41.0mg，产率：81.0％。1HNMR(400MHz,DMSO)δ＝8.97(d,J＝1.6Hz,1H),8.26(t,J＝6.0Hz,1H),7.91(t,J＝8.8Hz,1H),7.84(dd,J＝13.2,2.4Hz,1H),7.60(d,J＝4.8Hz,1H),7.59–7.53(m,2H),7.22–7.16(m,1H),4.86–4.72(m,1H),4.21(t,J＝9.2Hz,1H),3.83(m,1H),3.46(t,J＝5.6Hz,2H),1.85(s,3H).13C NMR(100MHz,DMSO)δ＝170.52,155.57,154.47,153.10,142.78,141.15,132.58,128.51,126.64,125.32,122.44,119.89,114.54,106.58,72.41,47.75,41.85,22.92。HRMS(Q-TOF):calculated for[M]+401.0958,found[M+H]+402.1117。
实施例5(S)-N-((3-(3-氟-4-(4-(2-吡啶基)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1-e)的制备
Figure BDA0001907764870000111
向反应封管中，在(S)-N-((3-(4-叠氮-3-氟苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1.0eq.),CuSO4(0.02eq.)和抗坏血酸钠(0.1eq.)的水与叔丁醇的1:1溶液中加入2-乙炔嘧啶，室温搅拌24h，水洗、萃取、旋干，柱层析分离得白色固体41.0mg，产率：85.0％。1H NMR(400MHz,DMSO)δ＝9.18(s,1H),8.93(d,J＝4.8Hz,1H),8.27(t,J＝5.6Hz,1H),7.95(t,J＝8.8Hz,1H),7.84(d,J＝13.6Hz,1H),7.58(d,J＝9.2Hz,1H),7.51(t,J＝4.8Hz,1H),4.80(m,1H),4.22(t,J＝8.8Hz,1H),3.90–3.76(m,1H),3.46(t,J＝5.2,2H),1.85(s,1H).13CNMR(100MHz,DMSO)δ170.54,158.68,158.36,155.78,154.47,153.31,147.27,141.29,128.03,126.97,120.92,119.93,114.48,106.45,72.41,47.75,41.85,22.92。HRMS(Q-TOF):calculated for[M]+397.1299,found[M+H]+398.1371。
实施例6(S)-N-((3-(3-氟-4-(4-(5-吡啶基)-1,2,3-三氮唑)苯基)-2-氧代-5噁唑烷基)甲基)乙酰胺(1-f)的制备
Figure BDA0001907764870000121
向反应封管中，在(S)-N-((3-(4-叠氮-3-氟苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1.0eq.),CuSO4(0.02eq.)和抗坏血酸钠(0.1eq.)的水与叔丁醇的1:1溶液中加入5-乙炔嘧啶，室温搅拌24h，水洗、萃取、旋干，柱层析分离得白色固体41.0mg，产率：72.3％。1H NMR(400MHz,DMSO)δ9.36(s,2H),9.30(d,J＝6.0Hz,1H),9.22(s,1H),8.27(t,J＝5.6Hz,1H),7.97(t,J＝8.8Hz,1H),7.89(dd,J＝13.2,5.2Hz,1H),7.61(dd,J＝9.6,2.0Hz,1H),4.80(m,1H),4.24(t,J＝9.2Hz,1H),3.85(m,1H),3.47(t,J＝2.8Hz,2H),1.85(s,3H).13C NMR(100MHz,DMSO)δ170.52,158.38,155.50,154.47,154.04,153.03,141.77,141.37,126.74,124.96,124.74,119.79,114.63,106.49,72.44,47.75,41.85,22.92。HRMS(Q-TOF):calculated for[M]+397.1299,found[M+H]+398.1364。
实施例7(S)-N-((3-(3-氟-4-(4-(3-噻吩基)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1-g)的制备
Figure BDA0001907764870000131
向反应封管中，加入叔丁醇试剂(1.0eq.)，然后依次加入铜(1.0eq.),硫酸铜(0.5eq.)和3-乙炔噻吩(1.5eq.)，65℃过夜搅拌，冷却至室温。水洗、DCM萃取3次，盐水洗有机层，硫酸钠干燥。除去溶剂后，残渣在PE/EA(4:1)中搅拌10分钟，过滤得得白色固体，产率：88.0％。1H NMR(400MHz,DMSO)δ＝8.92(d,J＝1.6Hz,1H),8.26(t,J＝5.6Hz,1H),7.98(dd,J＝2.8,1.2Hz,1H),7.92(t,J＝8.8Hz,1H),7.84(dd,J＝13.2,2.0Hz,1H),7.70(m,1H),7.62(dd,J＝5.2,1.2Hz,1H),7.57(dd,J＝8.8,1.6Hz,1H),4.80(m,1H),4.21(t,J＝9.0Hz,1H),3.84(m,1H),3.45(t,J＝5.6Hz,2H),1.85(s,3H).13C NMR(100MHz,DMSO)δ＝170.52,155.46,154.47,152.99,143.91,141.10,131.78,127.84,126.51,122.87,122.07,120.17,114.59,106.60,72.41,47.75,41.85,22.92。HRMS(Q-TOF):calculated for[M]+401.0958,found[M+Na]+424.0881。
实施例8(S,E)-N-((3-(3-氟-4-(4-(4-羟基-2-丁烯-2-醇基)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1-j)的制备
Figure BDA0001907764870000132
向反应封管中，加入叔丁醇试剂(1.0eq.)，然后依次加入铜(1.0eq.),硫酸铜(0.5eq.)和丙炔醇乙氧基化合物(PME)(1.5eq.)，65℃过夜搅拌，冷却至室温。水洗、DCM萃取3次，盐水洗有机层，硫酸钠干燥。除去溶剂后，残渣在PE/EA(4:1)中搅拌10分钟，过滤得得白色固体，产率：47.3％。1H NMR(400MHz,CDCl3)δ＝8.06(d,J＝2.8Hz,1H),7.93(t,J＝8.8Hz,1H),7.80(dd,J＝13.2,2.4Hz,1H),7.30(d,J＝13.2Hz,1H),6.26(t,J＝6.0Hz,1H),4.84(m,1H),4.79(s,2H),4.11(t,J＝8.8Hz,1H),3.83(m,8H),2.04(s,3H).13C NMR(100MHz,CDCl3)δ＝171.37,154.59,154.05,152.11,139.61,125.02,113.71,106.56,72.55,72.16,70.17,64.33,61.78,47.35,41.80,23.06。HRMS(Q-TOF):calculated for[M]+393.1448,found[M+Na]+416.1393。
实施例9(S)-N-((3-(4-(4-((1,3-邻苯二甲亚酰-2-甲基)-1,2,3-三氮唑)-3-氟苯基丙酮)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1-k)的制备
Figure BDA0001907764870000141
向反应封管中，加入叔丁醇试剂(1.0eq.)，然后依次加入铜(1.0eq.),硫酸铜(0.5eq.)和N-乙烯基乙酰胺(1.5eq.)，65℃过夜搅拌，冷却至室温。水洗、DCM萃取3次，盐水洗有机层，硫酸钠干燥。除去溶剂后，残渣在PE/EA(4:1)中搅拌10分钟，过滤得得白色固体，产率：91.0％。1H NMR(400MHz,DMSO)δ＝8.40(t,J＝6.0Hz,1H),8.36(d,J＝2.0Hz,1H),8.25(t,J＝6.4Hz,1H),7.81(m,2H),7.53(dd,J＝9.6,2.8Hz,1H),4.79(m,1H),4.38(d,J＝5.6Hz,2H),4.19(t,J＝8.8Hz,1H),3.81(m,1H),3.44(t,J＝5.6Hz,1H),1.85(s,3H),1.84(s,3H).13C NMR(100MHz,DMSO)δ170.52,169.68,155.47,154.46,153.00,146.06,140.92,126.64,124.72,120.21,114.53,106.45,72.38,47.72,41.84,34.48,22.95。HRMS(Q-TOF):calculated for[M]+390.1452,found[M+Na]+413.1418。
实施例10(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1-l)的制备
Figure BDA0001907764870000151
向(S)-N-((3-(4-叠氮-3-氟苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1.0eq.)的叔丁醇/水(1:3)溶液中依次加入氧化铜(0.05eq.)、抗坏血酸钠(0.1eq.)和3-甲基-2-戊烯-4-炔醇(1.2eq.)，65℃过夜搅拌，冷却至室温。水洗、DCM萃取3次，盐水洗有机层，硫酸钠干燥。除去溶剂后，残渣在PE/EA(4:1)中搅拌10分钟，过滤得得白色固体，产率：68.9％。1H NMR(400MHz,DMSO)δ＝8.52(d,J＝2.0Hz,1H),8.26(t,J＝6.0Hz,1H),7.86(t,J＝8.4Hz,1H),7.82(dd,J＝13.2,2.4Hz,1H),7.54(dd,J＝8.8,1.6Hz,1H),5.75(t,J＝7.2Hz,1H),4.78(m,2H),4.33(t,J＝5.6Hz,2H),4.20(t,J＝9.2Hz,1H),3.82(m,1H),3.45(t,J＝5.6Hz,2H),2.12(s,3H),1.84(s,3H).13C NMR(100MHz,DMSO)δ＝170.52,155.66,154.47,153.19,146.86,141.11,132.28,126.91,124.72,123.74,120.05,114.51,106.30,72.40,59.38,47.75,41.85,22.91。HRMS(Q-TOF):calculated for[M]+389.1499,found[M+Na]+412.1415。
实施例11(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1-m)的制备
Figure BDA0001907764870000161
向(S)-N-((3-(4-叠氮-3-氟苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1.0eq.)的叔丁醇/水(1:3)溶液中依次加入氧化铜(0.05eq.)、抗坏血酸钠(0.1eq.)和N-丙炔基邻苯二甲酸胺(1.2eq.)，65℃过夜搅拌，冷却至室温。水洗、DCM萃取3次，盐水洗有机层，硫酸钠干燥。除去溶剂后，残渣在PE/EA(4:1)中搅拌10分钟，过滤得得白色固体，产率：70.5％。1H NMR(400MHz,DMSO)δ＝8.55(s,1H),8.24(t,J＝4.0Hz,1H),7.86(m,5H),7.51(dd,J＝7.6,1.2Hz,1H),6.51(s,1H),4.95(s,2H),4.77(m,1H),4.18(t,J＝9.2Hz,1H),3.80(m,1H),3.43(t,J＝5.6Hz,2H),1.83(s,3H).13C NMR(100MHz,DMSO)δ＝170.50,167.86,155.49,154.45,153.02,143.44,141.07,135.03(2C),132.14,126.72,125.10,123.72(2C),120.00,114.44,106.25,72.37,47.71,41.83,33.31,31.77,22.90。HRMS(Q-TOF):calculated for[M]+478.1401,found[M+Na]+501.1303。
实施例12(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1-n)的制备
Figure BDA0001907764870000162
向(S)-N-((3-(4-叠氮-3-氟苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1.0eq.)的叔丁醇/水(1:3)溶液中依次加入氧化铜(0.05eq.)、抗坏血酸钠(0.1eq.)和1-乙炔基环戊醇(1.2eq.)，65℃过夜搅拌，冷却至室温。水洗、DCM萃取3次，盐水洗有机层，硫酸钠干燥。除去溶剂后，残渣在PE/EA(4:1)中搅拌10分钟，过滤得得白色固体，产率：87.5％。1H NMR(400MHz,DMSO)δ＝8.28(d,J＝2.4Hz,1H),8.26(t,J＝6.0Hz,1H),7.84(t,J＝8.8Hz,1H),7.80(m,1H),7.53(dd,J＝9.2,2.0Hz,1H),5.14(s,1H),4.82(m,1H),4.20(t,J＝9.2Hz,1H),3.82(m,1H),3.45(d,J＝5.6Hz,2H),2.05(m,3H),1.84(s,3H),1.73(m,3H).13C NMR(100MHz,DMSO)δ＝170.51,155.58,154.47,152.99,140.81,126.61,123.01,120.46,114.50,106.59,77.87,72.37,47.72,41.84,41.20(2C),23.80(2C),22.91。HRMS(Q-TOF):calculated for[M]+403.1656,found[M+Na]+426.1541。
实施例13(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1-o)的制备
Figure BDA0001907764870000171
向(S)-N-((3-(4-叠氮-3-氟苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1.0eq.)的叔丁醇/水(1:3)溶液中依次加入氧化铜(0.05eq.)、抗坏血酸钠(0.1eq.)和(S)-(-)-3-丁炔-2-醇(1.2eq.)，65℃过夜搅拌，冷却至室温。水洗、DCM萃取3次，盐水洗有机层，硫酸钠干燥。除去溶剂后，残渣在PE/EA(4:1)中搅拌10分钟，过滤得得白色固体，产率：90.5％。1H NMR(400MHz,DMSO)δ＝8.34(d,J＝1.6Hz,1H),8.26(t,J＝5.8Hz,1H),7.84(m,2H),7.53(dd,J＝8.8,1.6Hz,1H),5.39(d,J＝5.2Hz,1H),4.92(m,1H),4.82(m,1H),4.27-4.14(t,J＝5.2Hz,1H),3.82(m,1H),3.45(t,J＝5.6Hz,2H),1.84(s,3H),1.48(d,J＝6.8Hz,3H).13CNMR(100MHz,DMSO)δ＝170.52,155.51,154.05,153.04,140.77,126.67,123.28,120.43,114.50,106.34,72.37,61.94,47.72,41.84,24.10,22.91。HRMS(Q-TOF):calculated for[M]+403.1656,found[M+Na]+426.1541。
实施例14(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1-p)的制备
Figure BDA0001907764870000181
向反应封管中，加入叔丁醇试剂(1.0eq.)，然后依次加入铜(1.0eq.),硫酸铜(0.5eq.)和1-乙炔基-2-(三氟甲基)苯(1.5eq.)，65℃过夜搅拌，冷却至室温。水洗、DCM萃取3次，盐水洗有机层，硫酸钠干燥。除去溶剂后，残渣在PE/EA(4:1)中搅拌10分钟，过滤得得白色固体，产率：86.8％。1H NMR(400MHz,DMSO)δ＝8.77(s,1H),8.26(t,J＝6.0Hz,1H),7.93(m,2H),7.84(m,2H),7.70(m,1H),7.58(d,J＝10.4Hz,1H),4.81(m,1H),4.56(m,1H),4.22(t,J＝9.2Hz,1H),3.83(m,1H),3.45(m,2H),1.85(s,3H).13C NMR(100MHz,DMSO)δ170.52,155.65,154.48,153.18,144.45,141.24,133.21,132.59,129.75,129.27,127.31,126.90(2C),125.78,119.93,114.56,106.47,72.42,47.76,41.85,22.92。HRMS(Q-TOF):calculated for[M]+390.1452,found[M+Na]+413.1418。
实施例15(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1-q)的制备
Figure BDA0001907764870000191
向(S)-N-((3-(4-叠氮-3-氟苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1.0eq.)的叔丁醇/水(1:3)溶液中依次加入氧化铜(0.05eq.)、抗坏血酸钠(0.1eq.)和(R)-(+)-3-丁炔-2-醇(1.2eq.)，65℃过夜搅拌，冷却至室温。水洗、DCM萃取3次，盐水洗有机层，硫酸钠干燥。除去溶剂后，残渣在PE/EA(4:1)中搅拌10分钟，过滤得得白色固体，产率：82.5％。1H NMR(400MHz,DMSO)δ＝8.34(d,J＝1.6Hz,1H),8.25(t,J＝5.6Hz,1H),7.81(m,2H),7.53(dd,J＝8.8,2.0Hz,1H),5.38(d,J＝4.8Hz,1H),4.92(m,1H),4.78(m,1H),4.20(t,J＝8.8Hz,1H),3.81(m,1H),3.45(t,J＝5.6Hz,2H),1.84(s,3H),1.48(d,J＝6.4Hz,3H)。HRMS(Q-TOF):calculated for[M]+363.1343,found[M+Na]+386.1215。
实施例16(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺(1-r)的制备
Figure BDA0001907764870000192
-5℃氮气保护下，将中间体8(500mg,1eq.)和(S)-N-[2-乙酰氧基-3-氯丙基]乙酰胺(2eq.)溶解在THF(25mL)中。随后在反应体系中加入甲醇(2eq.)。搅拌10分钟后，将t-BuOLi(3eq.)加入反应体系后继续在-5℃搅拌30分钟。加热至室温，搅拌过夜。加入25mL水后，加入DCM(25mL)萃取，重复3次，盐水洗有机层3次。真空干燥除去溶剂，柱层析分离得黄色固体，产率：82.47％。1H NMR(400MHz,DMSO)δ8.50(m,1H),8.26(t,J＝6.4Hz,1H),7.79(m,1H),7.72(m,4H),7.45(m,1H),7.21(m,1H),7.15(m,1H),6.88(dd,J＝3.2,2.0Hz,1H),4.78(m,1H),4.18(t,J＝9.2Hz,1H),3.80(m,1H),3.45(t,J＝5.6Hz,2H),1.85(s,3H).13C NMR(101MHz,DMSO)δ170.51,154.51,153.89,153.85,149.64,138.40,137.03,126.68,125.91,123.58,123.37,121.20,120.91,119.42,114.71,108.98,106.90,72.27,47.73,41.87,22.93。HRMS(Q-TOF):calculated for[M]+:394.1441,found[M+H]+:395.1523。
为评价本发明化合物的抗菌活性，对本发明化合物进行了细胞和分子水平的药理活性测定。
实施例17测定对MRSA菌株ATCC33591的最低抑菌浓度即MIC。受试菌株：MRSAATCC33591
实验方法：从MHA平板挑取单克隆菌于3mL MHB中，过夜培养。取过夜菌液测OD600，稀释至3mL MHB中(OD＝0.05)，37℃220rpm摇菌至对数生长期(0.4～0.8OD)，测OD600，调整菌液至1×105CFU/mL备用。利用多点接种仪，涂板于系列倍比稀释的琼脂平板，37℃静置培养18h。细菌生长的最小浓度即MIC。
实验结果：
表2MRSA ATCC33591MIC(μg/mL)
Figure BDA0001907764870000211
以上的化合物MIC结果说明，发明的该系列具有新颖化学结构的小分子化合物具有作为抗MRSA药物进行开发的极大潜力，或为今后的抗耐药菌感染药物的开发提供新的可能。

Claims (6)

1.一类新型小分子化合物，其结构通式(Ⅰ)如下所示：
Figure FDA0001907764860000011
Q为
Figure FDA0001907764860000012
R1为吡啶基、噻吩基、嘧啶基、硝基苯基、2-甲基***-1-醇基、N-甲基乙酰胺基、(E)-2-丁烯-1-醇基、2-甲基异吲哚啉-1，3-二酮基、环戊醇基、乙醇基或(三氟甲基)-苯乙基。
2.根据权利要求1中一类新型小分子化合物，当Q为
Figure FDA0001907764860000015
时，R1为吡啶基、噻吩基、嘧啶基、硝基苯基、2-甲基***-1-醇基、N-甲基乙酰胺基、(E)-2-丁烯-1-醇基、2-甲基异吲哚啉-1，3-二酮基、环戊醇基、乙醇基或(三氟甲基)-苯乙基。
3.根据权利要求1中一类新型小分子化合物，当Q为
Figure FDA0001907764860000013
时，R1为吡啶基。
4.根据权利要求1中一类新型小分子化合物，及其药用盐，其特征在于，式(Ⅰ)化合物选自以下化合物：
(S)-N-((3-(3-氟-4-(4-(2-吡啶基)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure FDA0001907764860000014
(S)-N-((3-(3-氟-4-(4-(4-吡啶基)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure FDA0001907764860000021
(S)-N-((3-(3-氟-4-(4-(3-吡啶基)-1,2,3-三氮唑)苯基)-2-氧代5-噁唑烷基)甲基)乙酰胺
Figure FDA0001907764860000022
(S)-N-((3-(3-氟-4-(4-(2-噻吩)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure FDA0001907764860000023
(S)-N-((3-(3-氟-4-(4-(2-吡啶基)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure FDA0001907764860000024
(S)-N-((3-(3-氟-4-(4-(5-吡啶基)-1,2,3-三氮唑)苯基)-2-氧代-5噁唑烷基)甲基)乙酰胺
Figure FDA0001907764860000031
(S)-N-((3-(3-氟-4-(4-(3-噻吩基)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure FDA0001907764860000032
(S,E)-N-((3-(3-氟-4-(4-(4-羟基-2-丁烯-2-醇基)-1,2,3-三氮唑)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure FDA0001907764860000033
(S)-N-((3-(4-(4-((1,3-邻苯二甲亚酰-2-甲基)-1,2,3-三氮唑)-3-氟苯基丙酮)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure FDA0001907764860000034
(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure FDA0001907764860000035
(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure FDA0001907764860000041
(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure FDA0001907764860000042
(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure FDA0001907764860000043
(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure FDA0001907764860000044
(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure FDA0001907764860000051
(S)-N-((3-(3-氟-4-(3-(2-吡啶基)-1-吡咯基)苯基)-2-氧代-5-噁唑烷基)甲基)乙酰胺
Figure FDA0001907764860000052
5.根据权利要求1-4所述的新型小分子化合物，其特征在于化合物可以与酸根形成药学上可以接受的盐。
6.根据权利要求1-5所述的新型小分子化合物及其盐在制备抗耐甲氧西林金黄色葡萄球菌(MRSA)等葡萄球菌药物方面的用途。
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