CN117886808A - 一种1,3,4-噻二唑类肽脱甲酰基酶酶抑制剂及其制备与应用 - Google Patents
一种1,3,4-噻二唑类肽脱甲酰基酶酶抑制剂及其制备与应用 Download PDFInfo
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- CN117886808A CN117886808A CN202311693815.8A CN202311693815A CN117886808A CN 117886808 A CN117886808 A CN 117886808A CN 202311693815 A CN202311693815 A CN 202311693815A CN 117886808 A CN117886808 A CN 117886808A
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- compound
- thiadiazole
- peptide deformylase
- deformylase inhibitor
- inhibitor
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Abstract
本发明涉及一种1,3,4‑噻二唑类肽脱甲酰基酶酶抑制剂及其制备与应用。结构式如式(1)所示:其中,R1为正丁基或环戊甲基;R2为氢、直链烷烃、环状烷烃、芳环、取代联苯或杂环。本发明提供的1,3,4‑噻二唑类肽脱甲酰基酶抑制剂能够有效抑制细菌合成蛋白质,从而达到灭菌的目的。该类化合物对革兰氏阳性耐药菌特别是临床上棘手的耐甲氧西林葡萄球菌(MRSA)展现出优异的抑制活性,特别是部分优选化合物,其抑制活性达到对照品万古霉素、利奈唑胺4‑8倍。本发明提供的1,3,4‑噻二唑类肽脱甲酰基酶抑制剂还展现出对革兰氏阴性耐药菌的抑制活性,特别是对被称为“超级细菌”的耐药鲍曼不动杆菌,其抑菌活性达到0.5μg/mL,远远优于万古霉素、利奈唑胺。
Description
技术领域
本发明属于药物化学技术领域,尤其是涉及一种1,3,4-噻二唑类肽脱甲酰基酶酶抑制剂及其制备与应用。
背景技术
微生物感染导致的疾病如鼠疫、结核、霍乱等在历史上曾造成巨大的人口衰减。直到抗生素的出现,人类在面对细菌时才真正掌握了主动权。青霉素是最早被发现并用于临床救治细菌感染患者的抗生素,随着时间的推移,越来越多的抗生素被发现,并用于治疗细菌感染性疾病患者。
然而,人类在使用抗生素对抗细菌的同时,细菌也通过进化产生了耐药性。研究表明,细菌主要利用两种遗传策略对抗生素进行防御:1.基因突变,通常与抗菌化合物的作用机制有关,随着细菌在进化过程中每次基因突变结果的不断累积,细菌获得了各种耐药基因,也称为“天然耐药”;2.通过水平基因转移获得编码耐药决定因子的外源DNA,称为“获得性耐药”。获得性耐药使耐药基因能够在菌株之间转移,从而产生多重耐药,例如印度出现的NDM-1超级耐药肠杆菌。因此,细菌耐药性(Antimicrobial Resistance,AMR)的感染及日益严重已经成为新世纪抗感染治疗的一个新挑战,是当今世界对人类健康和生命的主要威胁。
现有的抗生素大多针对细菌生长周期的三个重要方面来发挥抑制作用:细菌细胞壁的合成、核糖体蛋白合成以及DNA复制。通过攻击同一组靶标来设计出能够战胜耐药菌的新型抗生素变得越来越困难。因此,面对细菌耐药性问题,我们迫切需要寻找新的抗菌靶点,开发具有抗多重耐药作用机制的抗菌药物。
肽脱甲酰基酶(Peptide Deformylase,PDF)是一种含亚铁离子(Fe2+)的金属蛋白酶,广泛存在于细菌体内。在原核生物的蛋白质合成过程中,起始密码子编码形成甲酰甲硫氨酸,在甲酰化酶的催化下,甲硫氨酸-tRNAf(Met-RNAfMet)转化为甲酰甲硫氨酸-tRNAf(Formyl-Met-RNAfMet),从而参与原核生物肽链合成的起始阶段,而tRNAm则携带普通的甲硫氨酸参与肽链合成,经过肽链的延长、终止和释放得到新生多肽。新生多肽并不都具有生物活性,要经过一定的加工和修饰才能成为成熟蛋白质。新生多肽在肽脱甲酰基酶的催化下,脱除N端甲酰基,然后通过甲硫氨酸氨肽酶(Methionine Aminopeptidase,MAP)脱除甲硫氨酸残基最终合成活性蛋白质。因此,通过抑制肽脱甲酰基酶,使蛋白合成停滞在脱除N端甲酰基阶段,可以有效抑制细菌的生长。目前以肽脱甲酰基酶为抗菌靶点的研究相对较多,且已经有四种药物(肽脱甲酰基酶抑制剂)走向临床阶段,分别为化合物BB83698、LBM415、GSK1322322、IDP-73152,结构分别如下:
然而,当前在研的PDF抑制剂存在一个共性问题:拟肽类PDF抑制剂在人体代谢过程中会产生较强的氧化性代谢产物,引起机体的高铁血红蛋白血症。PDF抑制剂的另一个缺点是抗菌谱较窄,虽然PDF在细菌中广泛存在,但由于细菌结构的差异,目前在研的PDF抑制剂绝大部分仅对革兰氏阳性菌有效,对革兰氏阴性菌则几乎无抑制作用。
发明内容
基于现有的拟肽类PDF抑制剂在人体代谢过程中会产生较强的氧化性代谢产物,引起机体的高铁血红蛋白血症,以及PDF抑制剂绝大部分仅对革兰氏阳性菌有效,对革兰氏阴性菌则几乎无抑制作用的问题,本发明提供一种1,3,4-噻二唑类肽脱甲酰基酶酶抑制剂及其制备与应用。
本发明针对在研PDF抑制剂存在的共性问题(拟肽类PDF抑制剂在人体代谢过程中会产生较强的氧化性代谢产物,引起机体的高铁血红蛋白血症)进行了研究分析,原因可能是含酰胺键的药物进入人体后,首先会水解成苯氨类衍生物,在肝脏处经由酶代谢之后会产生N-苯基羟胺,而少量的N-苯基羟胺便可将大量血红蛋白氧化为高铁血红蛋白,使血液里血红蛋白数目减少,引起血氧浓度降低,使机体出现缺氧症状。
为了避免出现高铁血红蛋白血症这一不良反应,应该对PDF抑制剂结构进行优化,减少化合物中的酰胺键,避免或大幅减少N-苯基羟胺的产生。
本发明提供的1,3,4-噻二唑类肽脱甲酰基酶酶抑制剂为一种含有1,3,4-噻二唑的新型肽脱甲酰基酶抑制剂抗菌药物,该类药物能有效杀除对已有抗生素有耐药性的细菌。与已有PDF抑制剂仅能杀灭革兰氏阳性菌不同,本发明提供的1,3,4-噻二唑PDF抑制剂优选化合物对耐药的革兰氏阳性菌及阴性菌均具有良好的杀灭能力。此外,使用1,3,4-噻二唑取代原拟肽类PDF抑制剂中的酰胺键,可以避免苯胺类砌块的使用,从而有效减少或避免代谢物中N-苯基羟胺的生成,降低高铁血红蛋白症的行成。
本发明的目的可以通过以下技术方案来实现:
本发明首先提供一种1,3,4-噻二唑类肽脱甲酰基酶抑制剂,结构式如式(1)所示:
其中,R1为正丁基或环戊甲基;R2为氢、直链烷烃、环状烷烃、芳环、取代联苯或杂环。
在本发明的一个实施方式中,R2基团的环状烷烃选自以下结构中的一种:
在本发明的一个实施方式中,R2基团的直链烷烃选自
在本发明的一个实施方式中,R2基团的芳环选自以下结构中的一种:
在本发明的一个实施方式中,R2基团的杂环选自以下结构中的一种:
在本发明的一个实施方式中,1,3,4-噻二唑类肽脱甲酰基酶抑制剂选自以下结构中的一种:
本发明进一步提供所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂的制备方法,包括以下步骤:
S1:化合物1中羧基在缩合剂CDI的作用下与水合肼反应制备得到化合物2(为一种酰肼化合物);
S2:在缩合剂EDCI、HOBT、NMM作用下,化合物2与化合物A(Boc保护的L-脯氨酸)中的羧基反应形成化合物3;
S3:化合物3在劳森试剂的作用下关环形成化合物4(为一种1,3,4-噻二唑化合物);
S4:化合物4在三氟醋酸和二氯甲烷中反应,得到化合物5;
S5:化合物5与化合物B在HATU、DIPEA作用下缩合得到化合物6;
S6:化合物6在三氟醋酸和二氯甲烷中反应,得到化合物7,即所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂;
其中,化合物1、化合物2、化合物A、化合物3、化合物4、化合物5、化合物B、化合物6、化合物7的结构以及所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂的制备工艺如下所示:
在本发明的一个实施方式中,步骤S1中,化合物1与CDI和水合肼的摩尔比为1.0﹕1.1~2.0﹕2.0~5.0,步骤S1的反应温度为0-40℃,反应时间5-24小时。
在本发明的一个实施方式中,步骤S2中,化合物2与化合物A、EDCI、HOBT、NMM的摩尔比为1.0﹕1.1~1.5﹕1.0~2.0﹕1.0~2.0﹕2.0~5.0,步骤S2的反应温度为0~40℃,反应时间5~24小时。
在本发明的一个实施方式中,步骤S3中,化合物3与劳森试剂的摩尔比为1.0﹕1.0~1.5,步骤S3的反应温度为80~120℃,反应时间为1~12小时。
在本发明的一个实施方式中,步骤S4中,化合物4与三氟醋酸的摩尔比为1.0﹕5.0~25,步骤S4的反应温度为0~40℃,反应时间1~10小时。
在本发明的一个实施方式中,步骤S5中,化合物5与化合物B、HATU、DIPEA的摩尔比为1.0﹕1.1~1.5﹕1.2~3.0﹕2.0~5.0,步骤S5的反应温度为0~40℃,反应时间5~24小时。
在本发明的一个实施方式中,步骤S6中,化合物6与三氟醋酸的摩尔比为1.0﹕5.0~25,步骤S6的反应温度为0~40℃,反应时间1~10小时。
本发明还进一步提供了所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂药学上可接受的盐。药学上可接受的盐是指在可靠的医药评价范围内,化合物的盐类适于与人或较低等动物的组织相接触而无不适当的毒性、刺激及过敏反应等,具有相当合理的收益与风险比例,通常是水或油可溶的或可分散的,并可有效地用于其预期的用途。其药学上可接受的盐可根据本领域技术人员的常规技术手段获得。
本发明还进一步提供了所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂的溶剂合物。其溶剂合物可根据本领域技术人员的常规技术手段获得。
本发明还进一步提供所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂、其药学上可接受的盐、或其溶剂合物在制备抑制细菌的药物中的应用。
在本发明的一个实施方式中,提供所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂、其药学上可接受的盐、或其溶剂合物在制备抑制耐药细菌的药物中的应用。
更进一步地,提供所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂、其药学上可接受的盐、或其溶剂合物在制备抑制革兰氏阳性耐药菌或革兰氏阴性耐药菌的药物中的应用。
再进一步地,提供所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂、其药学上可接受的盐、或其溶剂合物在制备抑制耐药鲍曼不动杆菌的药物中的应用。
与现有技术相比,本发明具有以下优点及有益效果:
1、本发明提供的1,3,4-噻二唑类肽脱甲酰基酶抑制剂能够有效抑制细菌合成蛋白质,从而达到灭菌的目的。该类化合物对革兰氏阳性耐药菌特别是临床上棘手的耐甲氧西林葡萄球菌(MRSA)展现出优异的抑制活性,特别是优化后的部分化合物,其抑制活性达到对照品万古霉素、利奈唑胺4-8倍。
2、本发明提供的1,3,4-噻二唑类肽脱甲酰基酶抑制剂还展现出对革兰氏阴性耐药菌的抑制活性,特别是对被称为“超级细菌”的耐药鲍曼不动杆菌,其抑菌活性达到0.5μg/mL,远远优于万古霉素、利奈唑胺等已上市药物。
具体实施方式
下面结合具体实施例对本发明进行详细说明。
以1,3,4-噻二唑类肽脱甲酰基酶抑制剂选自以下结构时,
R2=4-硝基苯甲酸为列来具体展示该类1,3,4-噻二唑类肽脱甲酰基酶抑制剂的通用合成方法。利用该通用合成方法,通过更换R1、R2基团,即可以合成得到其它所有化合物。
实施例1.4-硝基苯甲酰肼的合成
称取4-硝基苯甲酸(5.0g)溶于四氢呋喃(37.5mL)中,加入N,N'-羰基二咪唑(CDI)(6.3g)室温搅拌4h,待4-硝基苯甲酸反应完全后将反应液滴加到THF(25mL)的80%一水合肼(5.8g)中,室温搅拌12h。反应完全后,蒸出THF,残余物中加入乙酸乙酯(30mL),水(30mL),搅拌15min,分液,水相再用乙酸乙酯提取3次,合并有机相,有机层用无水硫酸钠干燥后旋干,得黄色固体产物。产物可直接用于下一步反应。
实施例2.(S)-2-(2-(4-硝基苯甲酰基)肼-1-羰基)吡咯烷-1-甲酸叔丁酯
反应瓶中加入(S)-1-(叔丁氧羰基)吡咯烷-2-羧酸(5.8g)、1-羟基苯并***(4.4g)、二氯甲烷(90mL),冷至0℃。再向反应瓶中加入N-甲基吗啉(13.5mL)、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(8.6g)以及上述步骤所得产物,升至室温,搅拌12h。反应完全后,反应液用水洗2次,1mol/L盐酸溶液洗两次、饱和碳酸氢钠溶液洗2次,有机层加无水硫酸钠干燥后旋干,硅胶柱层析纯化得浅黄色固体产物6.9g,产率61%。
1H NMR(400MHz,CDCl3)δ9.75(s,1H),9.41(s,1H),8.26(d,J=8.7Hz,2H),8.00(d,J=8.7Hz,2H),4.42(s,1H),3.57–3.25(m,2H),2.30(d,J=43.0Hz,1H),2.14–1.87(m,3H),1.49(s,9H).
实施例3.(S)-2-(5-(4-硝基苯基)-1,3,4-噻二唑-2-基)吡咯烷-1-甲酸叔丁酯
步骤3:将上述反应产物(3.8g)溶于1,4-二氧六环(65mL)中,加入劳森试剂(4.4g)加热至115℃,回流反应3h,降至室温,加水淬灭反应,再加乙酸乙酯提取3次,有机相用饱和氯化钠溶液洗2次,用饱和碳酸氢钠溶液洗两次。洗涤后的有机相用无水硫酸钠钠干燥后浓缩,最后经EA:PE 1:3(v/v)柱层析纯化得产物1.5g,产率40%。
1H NMR(400MHz,CDCl3)δ8.27(d,J=7.1Hz,2H),8.06(d,J=8.8Hz,2H),5.26(s,1H),3.67–3.28(m,2H),2.67–2.15(m,2H),1.97(s,2H),1.37(d,J=46.9Hz,9H).
实施例4.(S)-2-(4-硝基苯基)-5-(吡咯烷-2-基)-1,3,4-噻二唑
将步骤3得到的反应产物(0.88g)中加入二氯甲烷(6mL)溶解,再加入三氟乙酸(6mL),室温搅拌4h,待反应完全后蒸干,加入6mL二氯甲烷溶解,再用饱和碳酸氢钠溶液洗3次,二氯甲烷层干燥后旋干,得黄色固体产物0.6200g,产率95%。产物无需纯化,直接进行下步反应。
实施例5.N-((4-甲氧基苄基)氧)-N-((R)-2-((S)-2-(5-(4-硝基苯基)1,3,4-噻二唑-2-基)吡咯烷-1-甲酰基)己基)甲酰胺
称取(R)-2-((N-((4-甲氧基苄基)氧基)甲酰胺基)甲基)己酸(0.09g,0.3mmol,参考European Journal of Medicinal Chemistry,86(2014)133e152中报道的制备方法合成),加入二氯甲烷(2mL)溶解,再加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)(0.13g)、DIPEA(0.11g),室温搅拌20min。再加入上述反应液,室温搅拌10h。反应完全后,反应液用1mol/L盐酸溶液洗两次、饱和碳酸氢钠溶液洗2次,洗涤后的有机相用无水硫酸钠钠干燥后浓缩得粗产物,再经柱层析纯化得产物0.0943g,产率为55%。
1H NMR(400MHz,CDCl3)δ8.32(d,J=8.8Hz,2H),8.10(d,J=8.7Hz,2H),7.85(dd,J=21.6,12.7Hz,1H),7.46–7.28(m,2H),6.96–6.79(m,2H),5.36(d,J=6.4Hz,1H),5.01–4.57(m,2H),3.81(d,J=5.0Hz,3H),3.80–3.70(m,2H),3.61(t,J=13.3Hz,2H),2.64(d,J=14.1Hz,1H),2.20(d,J=7.9Hz,2H),1.99(d,J=37.4Hz,2H),1.25(s,6H),0.82(t,J=7.0Hz,3H).
实施例6.N-羟基-N-((R)-2-((S)-2-(5-(4-硝基苯基)-1,3,4-噻二唑-2-基)吡咯烷-1-酰基)己基)甲酰胺
上述产物(0.0943g,0.17mmol)加入二氯甲烷(2mL)溶解,再加入三氟乙酸(1mL),0℃下搅拌3h,待反应完全后蒸出二氯甲烷,残余物加入二氯甲烷(4mL)溶解、再用饱和碳酸氢钠溶液(4mL)洗涤有机相至碱性,有机相用无水硫酸钠钠干燥后旋干,得粗产物,最后经柱层析纯化得产物50mg,产率为66%。
1H NMR(400MHz,CDCl3)δ8.34(d,J=8.8Hz,2H),8.09(d,J=8.9Hz,2H),5.54(dd,J=7.3,2.5Hz,1H),3.94–3.79(m,2H),3.76–3.60(m,2H),3.18(dd,J=6.8,3.5Hz,1H),2.63–2.40(m,1H),2.28(dd,J=12.3,7.5Hz,2H),2.15(s,1H),1.70–1.52(m,2H),1.31(dd,J=5.7,3.4Hz,4H),0.86(d,J=3.2Hz,3H).HRMS(ESI):calculated for C20H25N5O5S[M+Na]+=470.1474,found 470.1496.
部分其他代表性化合物:
化合物20:
1H NMR(400MHz,CDCl3)δ8.61(dd,J=8.6,7.1Hz,1H),8.19(dd,J=8.7,1.8Hz,1H),8.15–8.08(m,1H),7.86(s,1H),5.65(dd,J=21.7,7.4Hz,1H),3.95(d,J=18.6Hz,1H),3.77(dd,J=22.5,10.8Hz,3H),3.23(s,1H),2.64(s,1H),2.44–2.25(m,2H),2.17(s,1H),1.63(d,J=7.6Hz,2H),1.36–1.27(m,4H),0.86(t,J=5.8Hz,3H).HRMS(ESI):calculated for C20H24FN5O5S[M+Na]+=488.1374,found 488.1360
化合物29:
1H NMR(400MHz,CDCl3)δ7.79(s,1H),7.54–7.38(m,2H),7.18–7.02(m,1H),5.65–5.37(m,1H),3.84(dt,J=16.5,10.6Hz,2H),3.73–3.59(m,2H),3.46(s,1H),2.64(d,J=48.9Hz,1H),2.26(dd,J=22.6,16.3Hz,2H),2.11(s,1H),1.64(d,J=27.3Hz,2H),1.29(s,4H),0.87(t,J=6.2Hz,3H).
HRMS(ESI):calculated for C18H24N4O3S2[M+Na]+=431.1182,found 431.1183
化合物33:
1H NMR(400MHz,CDCl3)δ7.89(d,J=4.2Hz,1H),7.78(s,1H),7.38(d,J=4.2Hz,1H),5.55(d,J=5.5Hz,1H),3.98–3.79(m,2H),3.69(dd,J=16.8,10.2Hz,1H),3.54–3.38(m,1H),3.19(d,J=6.4Hz,1H),2.70(d,J=3.2Hz,1H),2.43–2.24(m,2H),2.16(s,1H),1.59(d,J=6.2Hz,1H),1.46(s,1H),1.29(s,4H),0.85(t,J=6.4Hz,3H).
HRMS(ESI):calculated for C18H23N5O5 S2[M+Na]+=476.1038,found 476.1031
本发明提供的1,3,4-噻二唑类肽脱甲酰基酶抑制剂选自以下式(2)结构时,
其R2不同选择时,其对MRSA1、MSSA1、S.epider midis、E.coli、A.baumannii的最低抑菌浓度(MIC,μg/mL)如表1所示。
抑菌活性采用微量稀释法测定,即先配置浓度分别为160、80、40、20、10、5、2.5、1.25、0.625、0.3、0.16、0.08μg/mL的系列样品溶液,然后分别取上述样品溶液1mL加入9cm无菌平板,加入血琼脂培养基9mL,立即混匀,置水平台待凝后得到浓度依次为16、8、4、2、1、0.5、0.25、0.125、0.06、0.03、0.016、0.008μg/mL的含药平板。最后将试验菌悬液按编号顺序加入96孔板相应孔内,放置于多点接种仪。取制备的各含药平板按浓度由低至高顺序接种。倒置于35℃培养16小时,取出观察结果,记录生长状况。
表1式(2)所示化合物R2不同选择时的最低抑菌浓度(MIC,μg/mL)
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上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改,并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此,本发明不限于上述实施例,本领域技术人员根据本发明的揭示,不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (10)
1.一种1,3,4-噻二唑类肽脱甲酰基酶抑制剂,其特征在于,结构式如式(1)所示:
其中,R1为正丁基或环戊甲基;R2为氢、直链烷烃、环状烷烃、芳环、取代联苯或杂环。
2.根据权利要求1所述的一种1,3,4-噻二唑类肽脱甲酰基酶抑制剂,其特征在于,R2基团的环状烷烃选自以下结构中的一种:
R2基团的直链烷烃选自
R2基团的芳环选自以下结构中的一种:
R2基团的杂环选自以下结构中的一种:
3.根据权利要求1所述的一种1,3,4-噻二唑类肽脱甲酰基酶抑制剂,其特征在于,1,3,4-噻二唑类肽脱甲酰基酶抑制剂选自以下结构中的一种:
4.权利要求1-3中任一项所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂的制备方法,其特征在于,包括以下步骤:
S1:化合物1中羧基在缩合剂CDI的作用下与水合肼反应制备得到化合物2;
S2:在缩合剂EDCI、HOBT、NMM作用下,化合物2与化合物A中的羧基反应形成化合物3;
S3:化合物3在劳森试剂的作用下关环形成化合物4;
S4:化合物4在三氟醋酸和二氯甲烷中反应,得到化合物5;
S5:化合物5与化合物B在HATU、DIPEA作用下缩合得到化合物6;
S6:化合物6在三氟醋酸和二氯甲烷中反应,得到化合物7,即所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂;
其中,1,3,4-噻二唑类肽脱甲酰基酶抑制剂的制备路线图如下所示:
5.根据权利要求4所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂的制备方法,其特征在于,
步骤S1中,化合物1与CDI和水合肼的摩尔比为1.0﹕1.1~2.0﹕2.0~5.0,步骤S1的反应温度为0-40℃,反应时间5-24小时;
步骤S2中,化合物2与化合物A、EDCI、HOBT、NMM的摩尔比为1.0﹕1.1~1.5﹕1.0~2.0﹕1.0~2.0﹕2.0~5.0,步骤S2的反应温度为0~40℃,反应时间5~24小时;
步骤S3中,化合物3与劳森试剂的摩尔比为1.0﹕1.0~1.5,步骤S3的反应温度为80~120℃,反应时间为1~12小时;
步骤S4中,化合物4与三氟醋酸的摩尔比为1.0﹕5.0~25,步骤S4的反应温度为0~40℃,反应时间1~10小时;
步骤S5中,化合物5与化合物B、HATU、DIPEA的摩尔比为1.0﹕1.1~1.5﹕1.2~3.0﹕2.0~5.0,步骤S5的反应温度为0~40℃,反应时间5~24小时;
步骤S6中,化合物6与三氟醋酸的摩尔比为1.0﹕5.0~25,步骤S6的反应温度为0~40℃,反应时间1~10小时。
6.权利要求1-3中任一项所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂药学上可接受的盐或溶剂合物。
7.权利要求1-3中任一项所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂、其药学上可接受的盐、或其溶剂合物在制备抑制细菌的药物中的应用。
8.根据权利要求7所述的应用,其特征在于,所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂、其药学上可接受的盐、或其溶剂合物在制备抑制耐药细菌的药物中的应用。
9.根据权利要求8所述的应用,其特征在于,所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂、其药学上可接受的盐、或其溶剂合物在制备抑制革兰氏阳性耐药菌或革兰氏阴性耐药菌的药物中的应用。
10.根据权利要求8所述的应用,其特征在于,所述1,3,4-噻二唑类肽脱甲酰基酶抑制剂、其药学上可接受的盐、或其溶剂合物在制备抑制耐药鲍曼不动杆菌的药物中的应用。
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