CN113150022A - 3-取代五元环状硼酸酯衍生物及其药物组合物和制药用途 - Google Patents
3-取代五元环状硼酸酯衍生物及其药物组合物和制药用途 Download PDFInfo
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- CN113150022A CN113150022A CN202110444421.3A CN202110444421A CN113150022A CN 113150022 A CN113150022 A CN 113150022A CN 202110444421 A CN202110444421 A CN 202110444421A CN 113150022 A CN113150022 A CN 113150022A
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 8
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- 238000002360 preparation method Methods 0.000 claims abstract description 47
- 102000006635 beta-lactamase Human genes 0.000 claims abstract description 33
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 26
- 229940079593 drug Drugs 0.000 claims abstract description 24
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- 239000003781 beta lactamase inhibitor Substances 0.000 claims abstract description 17
- 229940126813 beta-lactamase inhibitor Drugs 0.000 claims abstract description 17
- 241000894006 Bacteria Species 0.000 claims abstract description 16
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Abstract
本发明提供了一种3‑取代五元环状硼酸酯衍生物及其药物组合物和制药用途,属于药物化学领域。该3‑取代五元环状硼酸酯衍生物的结构如式I所示。实验结果表明,该化合物不仅对SBL类β‑内酰胺酶具有良好的抑制活性,还对MBL类β‑内酰胺酶具有良好的抑制活性,可以作为丝氨酸β‑内酰胺酶抑制剂、金属β‑内酰胺酶抑制剂、金属β‑内酰胺酶和丝氨酸β‑内酰胺酶双重抑制剂,在制备抗耐药菌的药物中具有广阔的应用前景。
Description
技术领域
本发明属于药物化学领域,具体涉及一种对金属β-内酰胺酶和/或丝氨酸β-内酰胺酶具有抑制作用的3-取代五元环状硼酸酯衍生物及其药物组合物和制药用途。
背景技术
β-内酰胺类抗生素是目前临床上使用最广泛的抗生素(如头孢菌素类、碳青霉烯类等),其对革兰氏阳性菌和革兰氏阴性菌均有较好的抑菌效果,具有临床疗效好、毒性低、适应症广等优点。β-内酰胺类抗生素主要通过抑制细菌胞壁粘肽合成酶(即青霉素结合蛋白,简称PBP)的催化活性,从而阻止细胞壁粘肽合成,进而导致细菌胞壁缺损、菌体膨胀裂解而亡。然而,如今具有高效抗性的β-内酰胺抗生素耐药“超级”细菌不断出现且在全球范围内并快速蔓延,已成为当前国内外难治性感染的主要源头之一,因而解决β-内酰胺类抗生素耐药问题刻不容缓。
病原菌产生的β-内酰胺酶种类繁多,目前已发现和鉴别了超过1300种不同亚型的β-内酰胺酶:根据氨基酸序列同源性,这些β-内酰胺酶被分为A、B、C和D四类;根据催化机制的差异,这些β-内酰胺酶被分为两大类:丝氨酸β-内酰胺酶(SBL)和金属β-内酰胺酶(MBL)。目前多个SBL抑制剂如克拉维酸、舒巴坦、他唑巴坦和阿维巴坦已被批准用于临床,它们对产SBL青霉素或头孢菌素耐药菌的临床疗效较好。近期,美国FDA批准了含六元环状硼酸酯新型结构的β-内酰胺酶抑制剂vaborbactam与碳青霉烯类抗生素美罗培南联用治疗复杂尿路感染(cUTI)的成人治疗,治疗疾病包括由特定细菌引起的肾脏感染、肾盂肾炎;但是,该治疗方法对产MBL碳青霉烯耐药菌无效。
目前,还没有以金属β-内酰胺酶为靶点的药物上市,亟需开发能够有效抑制MBL的药物。面对种类不断增多的多重耐药(multidrug-resistant,MDR)、广泛耐药(extensively-drug resistant,XDR)甚至全耐药(pan-drug resistant,PDR)的“超级细菌”,现有的β-内酰胺酶抑制剂根本无法满足临床的需求,因此,开发对MBL和SBL具有双重抑制作用的抑制剂是解决细菌耐药的关键方向。
发明内容
本发明的目的在于提供一种对MBL具有抑制作用,对SBL具有抑制作用,甚至对MBL和SBL具有双重抑制作用的3-取代五元环状硼酸酯衍生物及其药物组合物和制药用途。
本发明提供了一种式I所示化合物、或其药学上可接受的盐、或其同位素化合物、或其立体异构体:
其中,n选自0~4的整数;
当n为1~4的整数时,R2为氢,R1各自独立的选自卤代或未卤代的C1~6烷基、卤代或未卤代的C1~6烷氧基、卤素、硝基、氨基、羟基、羧基、氰基、XLR3,或者两个R1连接形成3~6元环;
其中,X为NH、O或S;L为无或C1~4亚烷基;R3为取代或未取代的3~6元饱和或不饱和环烷基、取代或未取代的3~6元饱和或不饱和杂环基,所述取代基选自卤素、卤代或未卤代的C1~6烷基、卤代或未卤代的C1~6烷氧基;
当n为0时,R2为氢或C2~6烷基。
进一步地,所述化合物的结构如式II所示:
其中,n为1~3的整数;
R1各自独立的选自卤代或未卤代的C1~5烷基、卤代或未卤代的C1~5烷氧基、卤素、硝基、氨基、羟基、羧基、氰基,或者两个R1连接形成3~6元环。
进一步地,n为1或2;
R1各自独立的选自卤代或未卤代的C1~4烷基、卤代或未卤代的C1~4烷氧基、卤素、硝基、氰基,或者两个R1连接形成5~6元环。
进一步地,所述化合物的结构如式III所示:
其中,X选自O、S、CH2,Y选自O、S、CH2。
进一步地,所述化合物的结构如式IV所示:
其中,R2为氢、C2~4烷基,所述C2~4烷基优选为乙基或叔丁基。
进一步地,所述化合物为以下化合物之一:
本发明还提供了式II所述的化合物、或其药学上可接受的盐、或其同位素化合物、或其立体异构体的制备方法,所述方法包括以下步骤:
(1)式II-c所示化合物与式II-d所示化合物反应,制得式II-e所示化合物;
(2)式II-e所示化合物水解得到式II所示化合物;
其中n、R1如上所述;
优选的,步骤(1)中,式II-a所示化合物与式II-b所示化合物的摩尔比为1:(1~8),优选为1:5;所述反应温度为室温;
和/或,步骤(2)中,所述水解的方法为在式II-c所示化合物中加入碱,所述碱优选为无机碱,更优选为氢氧化钠。
本发明还提供了一种抑制β-内酰胺酶的药物组合物,它是以上述化合物、或其药学上可接受的盐、或其同位素化合物、或其立体异构体为活性成分,加上药学上可接受的辅料制得的制剂。
本发明还提供了上述化合物、或其药学上可接受的盐、或其同位素化合物、或其立体异构体在制备β-内酰胺酶抑制剂中的用途。
进一步地,所述β-内酰胺酶抑制剂为金属β-内酰胺酶抑制剂、丝氨酸β-内酰胺酶抑制剂、金属β-内酰胺酶和丝氨酸β-内酰胺酶双重抑制剂。
进一步地,所述β-内酰胺酶抑制剂为抗菌药物;所述抗菌药物优选为抗耐药细菌的药物,更优选为抗多重耐药细菌的药物、抗广泛耐药细菌的药物或抗全耐药细菌的药物。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
本发明化合物的基团中,Me为甲基,Et为乙基,iPr为异丙基,tBu为叔丁基。
本发明式I所示化合物中,n个R1可以在苯环上的任意位点取代。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀Ca~b烷基表示任何含“a”至“b”个碳原子的烷基。例如,C1~6烷基是指包含1~6个碳原子的直链或支链的烷基。
“环烷基”指饱和或不饱和的环状烃取代基;环状烃可以是单环也可以是多环。例如,“3~6元饱和或不饱和环烷基”指环碳原子数为3~6的饱和或不饱和环烷基。
“杂环基”指饱和或不饱和的环状烃取代基;环状烃可以是单环也可以是多环,且携带至少一个环杂原子(包括但不限于O、S或N)。例如,“3~6元饱和或不饱和杂环基”指环原子数为3~6的饱和或不饱和杂环基。
“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和或不饱和环),但不能含有杂原子如氮,氧,或硫,同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。
“杂芳基”指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
卤素为氟、氯、溴或碘。
“同位素化合物”指化合物中的一个或两个以上的原子被其对应的同位素替换后得到的化合物。比如化合物中的一个或两个以上的氢(H)被氘(D)或氚(T)替换后得到的化合物;比如化合物中的一个或两个以上的碳12被碳11或碳13替换后得到的化合物。
“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
“盐”是将化合物或其立体异构体,与无机和/或有机酸和/或碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。
本发明中所述药学上可接受的盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
实验结果表明,本发明提供的化合物不仅对SBL类β-内酰胺酶具有良好的抑制活性,还对MBL类β-内酰胺酶具有良好的抑制活性,可以作为丝氨酸β-内酰胺酶抑制剂、金属β-内酰胺酶抑制剂、金属β-内酰胺酶和丝氨酸β-内酰胺酶双重抑制剂,在制备抗耐药菌的药物中具有广阔的应用前景。
本发明化合物的制备方法简单、条件温和、原料易得,适合工业化生产。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。
实施例1:本发明化合物1的合成
向化合物2-甲酰基苯硼酸(式III-c1,1.0当量)的丙烯酸乙酯(式II-d1,1ml)中加入DABCO(三乙烯二胺,1.0当量),室温反应,并通过薄层色谱(TLC)监测。反应完成后,将反应液用盐酸水溶液(1.0M,10mL)淬灭,并用乙酸乙酯(3×10mL)萃取,将有机相用硫酸钠干燥,过滤,取滤液在真空下浓缩干燥,得粗产物。然后将粗产物通过快速柱色谱纯化,以石油醚和乙酸乙酯作为洗脱剂(石油醚:乙酸乙酯体积比=7:1)得到产物乙基-2-基-2-(1-羟基-5-甲基-1,3-二氢苯并[c][1,2]氧杂硼-3--3-基)丙烯酸酯。即目标化合物1,收率89%。1HNMR(400MHz,DMSO-d6):δ=12.68(s,1H),9.21(s,1H),7.60(d,J=7.4Hz,1H),7.23–7.09(m,2H),6.99(d,J=7.3Hz,1H),6.12(s,1H),5.90(s,1H),5.71(s,1H),4.02(m,2H),1.89(m,3H);13C NMR(100MHz,DMSO-d6):δ=167.59,156.30,141.98,140.19,130.90,128.44,125.06,122.53,78.77,49.06,21.95。
实施例2:本发明化合物2的合成
向化合物2-甲酰基苯硼酸(式II-c2,1.0当量)的丙烯酸叔丁酯(式II-d2,1ml)中加入DABCO(三乙烯二胺,1.0当量),室温反应,并通过薄层色谱(TLC)监测。反应完成后,将反应液用盐酸水溶液(1.0M,10mL)淬灭,并用乙酸乙酯(3×10mL)萃取,将有机相用硫酸钠干燥,过滤,取滤液在真空下浓缩干燥,得粗产物。然后将粗产物通过快速柱色谱纯化,以石油醚和乙酸乙酯作为洗脱剂(石油醚:乙酸乙酯体积比=7:1)得到产物叔丁基-2-基-2-(1-羟基-5-甲基-1,3-二氢苯并[c][1,2]氧杂硼-3--3-基)丙烯酸酯。即目标化合物2,收率85%。1HNMR(400MHz,DMSO-d6):δ=12.68(s,1H),9.02(s,1H),7.50(d,J=7.4Hz,1H),7.24–7.09(m,2H),7.01(d,J=7.3Hz,1H),6.12(s,1H),5.90(s,1H),5.71(s,1H),1.21(s,9H);13C NMR(100MHz,DMSO-d6):δ=167.57,152.30,140.98,139.19,128.90,125.44,123.06,121.53,79.77,54.06,19.95。
实施例3:本发明化合物3的合成
向化合物2-甲酰基苯硼酸(式II-c3,1.0当量)的丙烯酸甲酯(式II-d3,1ml)中加入DABCO(三乙烯二胺,1.0当量),室温反应,并通过薄层色谱(TLC)监测。反应完成后,将反应液用盐酸水溶液(1.0M,10mL)淬灭,并用乙酸乙酯(3×10mL)萃取,将有机相用硫酸钠干燥,过滤,取滤液在真空下浓缩干燥,得粗产物。然后将粗产物通过快速柱色谱纯化,以石油醚和乙酸乙酯作为洗脱剂(石油醚:乙酸乙酯体积比=7:1)得到产物甲基-2-基-2-(1-羟基-5-甲基-1,3-二氢苯并[c][1,2]氧杂硼-3--3-基)丙烯酸酯(式II-e3)。
将式II-e3化合物用甲醇溶解,滴加氢氧化钠水溶液(1.0M),室温搅拌2.5小时,然后用盐酸水溶液(1.0M,10mL)酸化。将体系用乙酸乙酯(3×10mL)萃取,将有机相用硫酸钠干燥,过滤,取滤液在真空下浓缩干燥,得粗产物。然后将粗产物通过快速柱色谱纯化,得到淡黄色固体,即目标化合物3,收率80%。1H NMR(400MHz,Methanol-d4):δ=7.67(d,J=7.3Hz,1H),7.49–7.32(m,3H),6.28(s,1H),6.08(s,1H),5.80(s,1H);13C NMR(100MHz,Methanol-d4):δ=167.49,155.60,140.93,130.71,130.64,129.89,127.20,124.41,121.64,79.70.
按照以下合成路线一,合成本发明的化合物4~38。合成路线一:
(1)2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲醛类化合物(式II-b所示化合物)的制备
向圆底烧瓶(25mL)中添加双(频哪醇合)二硼(4.8mmol,1.2当量)、2-溴苯甲醛衍生物(4mmol,1.0当量,式II-a)、PdCl2(dppf)(88mg,0.12mmol)和KOAc(12mmol,3.0当量),将混合物用隔膜密封,用氩气吹扫几次,然后将干燥的1,4-二恶烷(15mL)加入该混合物中,并在80℃下搅拌8h。将所得粗反应混合物用饱和NaHCO3稀释,乙酸乙酯萃取。收集合并的有机层,经无水硫酸钠干燥并真空浓缩。将浓缩后的残余物通过快速柱色谱纯化,得到2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲醛类化合物(式II-b所示化合物)。
(2)2-甲酰基苯硼酸类化合物(式II-c所示化合物)的制备
本发明采用的式II-c所示化合物均能够通过购买市售产品得到,也可以通过以下方法制得。
向2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲醛类化合物(式II-b所示化合物)(1.0当量)的THF/H2O混合溶液(THF:H2O体积比=10:1)中添加NaIO4(1.5当量),将混合物在室温下搅拌20分钟,直到混合均匀。然后加入HCl水溶液(1.0M),搅拌2小时。然后将所得体系用二氯甲烷(3×50mL)萃取,经无水硫酸钠干燥,并将有机层真空浓缩。将浓缩后的残余物通过快速柱色谱纯化,得到2-甲酰基苯硼酸类化合物(式II-c所示化合物)。
(3)苯并氧杂硼环丙烯酸酯类化合物(式II-e所示化合物)的制备
向2-甲酰基苯硼酸类化合物(式II-c,1.0当量)的四氢呋喃(1ml)中加入DABCO(三乙烯二胺,1.0当量),滴加1,1,1,3,3,3-六氟丙烷-2-基丙烯酸酯(式II-d,5.0当量),室温反应,并通过薄层色谱(TLC)监测。反应完成后,将反应液用盐酸水溶液(1.0M,10mL)淬灭,并用乙酸乙酯(3×10mL)萃取,将有机相用硫酸钠干燥,过滤,取滤液在真空下浓缩干燥,得粗产物。然后将粗产物通过快速柱色谱纯化,得到苯并氧杂硼环丙烯酸酯类化合物(即式II-e所示化合物)。
(4)终产物(式II所示化合物)的制备
将上述步骤(3)合成的苯并氧杂硼环丙烯酸酯类化合物(即式II-e所示化合物)用甲醇溶解,滴加氢氧化钠水溶液(1.0M),室温搅拌2.5小时,然后用盐酸水溶液(1.0M,10mL)酸化。将体系用乙酸乙酯(3×10mL)萃取,将有机相用硫酸钠干燥,过滤,取滤液在真空下浓缩干燥,得粗产物。然后将粗产物通过快速柱色谱纯化,得到终产物(即式II所示化合物)。
以下为具体化合物4~38的制备方法与结构表征:
实施例4:化合物4的合成
(1)向圆底烧瓶(25mL)中添加双(频哪醇合)二硼(4.8mmol,1.2当量)、2-溴-5-甲基苯甲醛(4mmol,1.0当量)、PdCl2(dppf)(88mg,0.12mmol)和KOAc(12mmol,3.0当量),将混合物用隔膜密封,用氩气吹扫几次,然后将干燥的1,4-二恶烷(15mL)加入该混合物中,并在80℃下搅拌8h。将所得粗反应混合物用饱和NaHCO3稀释,乙酸乙酯萃取。收集合并的有机层,经无水硫酸钠干燥并真空浓缩。将浓缩后的残余物通过快速柱色谱纯化,以石油醚和乙酸乙酯(石油醚:乙酸乙酯体积比=20:1)作为洗脱剂,得到化合物5-甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲醛。
(2)向5-甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲醛(1.0当量)的THF/H2O混合溶液(32mL,THF:H2O体积比=10:1)中添加NaIO4(1.5当量),将混合物在室温下搅拌20分钟,直到混合均匀。然后加入HCl水溶液(1.0M,10mL),搅拌2小时。然后将所得体系用二氯甲烷(3×50mL)萃取,经无水硫酸钠干燥,并将有机层真空浓缩。将浓缩后的残余物通过快速柱色谱纯化,以石油醚和乙酸乙酯作为洗脱剂(石油醚:乙酸乙酯体积比=2:1),得到化合物(5-甲基-2-甲酰基苯基)硼酸。
本实施例采用的(5-甲基-2-甲酰基苯基)硼酸可以通过上述方法制备,也可以购买市售产品。
(3)向化合物(5-甲基-2-甲酰基苯基)硼酸(1.0当量)的四氢呋喃(1ml)中加入DABCO(1.0当量),滴加1,1,1,3,3,3-六氟丙烷-2-基丙烯酸酯(5.0当量),室温反应,并通过TLC监测。反应完成后,将反应液用盐酸水溶液(1.0M,10mL)淬灭,并用乙酸乙酯(3×10mL)萃取,将有机相用硫酸钠干燥,过滤,取滤液在真空下浓缩干燥,得粗产物。然后将粗产物通过快速柱色谱纯化,以石油醚和乙酸乙酯作为洗脱剂(石油醚:乙酸乙酯体积比=7:1)得到产物1,1,1,3,3,3-六氟丙烷-2-基-2-(1-羟基-5-甲基-1,3-二氢苯并[c][1,2]氧杂硼-3--3-基)丙烯酸酯。
(4)将上述合成的1,1,1,3,3,3-六氟丙烷-2-基-2-(1-羟基-5-甲基-1,3-二氢苯并[c][1,2]氧杂硼-3--3-基)丙烯酸酯用甲醇溶解,滴加氢氧化钠水溶液(1.0M),室温搅拌2.5小时,然后用盐酸水溶液(1.0M,10mL)酸化。将体系用乙酸乙酯(3×10mL)萃取,将有机相用硫酸钠干燥,过滤,取滤液在真空下浓缩干燥,得粗产物。然后将粗产物通过快速柱色谱纯化,得到淡黄色固体,即目标化合物4,收率80%。1H NMR(400MHz,DMSO-d6):δ=12.78(s,1H),9.23(s,1H),7.60(d,J=7.4Hz,1H),7.23–7.09(m,2H),6.12(s,1H),5.90(s,1H),5.71(s,1H),2.33(s,3H);13C NMR(100MHz,DMSO-d6):δ=167.39,156.40,141.68,140.99,130.90,128.84,125.06,122.53,78.77,49.06,21.95。
实施例5:化合物5的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物5,收率85%。1HNMR(400MHz,Methanol-d4):δ=7.45(d,J=8.1Hz,1H),6.85–6.78(m,2H),6.16(s,1H),5.90(s,1H),5.67(s,1H),3.69(s,3H);13C NMR(100MHz,Methanol-d4):δ=167.71,162.59,158.11,141.05,131.19,124.24,114.35,106.40,79.20,54.33;
实施例6:化合物6的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物6,收率82%。1HNMR(400MHz,Methanol-d4)δ=7.54(d,J=8.1Hz,1H),6.97–6.80(m,2H),6.25(s,1H),5.99(s,1H),5.77(s,1H),4.02(q,J=7.0Hz,2H),1.37(t,J=7.0Hz,3H);13C NMR(100MHz,Methanol-d4):δ=167.69,161.86,158.07,141.07,131.20,124.21,114.82,107.01,79.17,63.18,13.64。
实施例7:化合物7的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物7,收率71%。1HNMR(400MHz,Methanol-d4)δ=7.54(d,J=8.1Hz,1H),6.91(d,J=2.2Hz,1H),6.87(dd,J=8.1,2.2Hz,1H),6.25(s,1H),5.99(s,1H),5.77(s,1H),4.02(m,1H)1.30(s,6H);13C NMR(100MHz,Methanol-d4):δ=167.73,160.79,158.09,141.12,131.26,124.04,115.89,108.24,79.13,69.60,29.33,20.88,20.78。
实施例8:化合物8的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物8,收率86%。1HNMR(400MHz,Methanol-d4):δ=7.55(dd,J=8.1,5.6Hz,1H),7.06–6.93(m,2H),6.19(s,1H),5.93(s,1H),5.73(s,1H);13C NMR(100MHz,Methanol-d4):δ=167.32,166.28,163.81,158.46,158.37,140.35,132.02,131.93,124.73,114.92,114.70,108.91,108.68,79.29,79.26。
实施例9:化合物9的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物9,收率70%。1HNMR(400MHz,Methanol-d4):δ=7.50(d,J=7.8Hz,1H),7.32(d,J=1.8Hz,1H),7.24(dd,J=7.8,1.7Hz,1H),6.20(s,1H),5.93(s,1H),5.74(s,1H);13C NMR(100MHz,Methanol-d4):δ=167.25,157.54,140.22,136.93,131.24,127.63,124.94,121.97,79.37。
实施例10:化合物10的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物10,收率75%。1HNMR(400MHz,Methanol-d4):δ=7.78(d,J=7.8Hz,1H),7.50(d,J=1.8Hz,1H),7.34(dd,J=7.8,1.7Hz,1H),6.20(s,1H),5.93(s,1H),5.74(s,1H);13C NMR(100MHz,Methanol-d4):δ=176.25,157.54,140.22,136.93,131.24,127.63,124.94,120.97,77.35。
实施例11:化合物11的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物11,收率83%。1HNMR(400MHz,Methanol-d4):δ=7.80(d,J=7.6Hz,1H),7.69(s,1H),7.63(d,J=7.6Hz,1H),6.32(s,1H),6.11(s,1H),5.88(s,1H);13C NMR(100MHz,Methanol-d4):δ=167.14,156.14,140.01,132.51,132.19,130.60,129.44,125.60,125.31,124.06,124.02,122.90,118.42,118.38,79.93。
实施例12:化合物12的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物12,收率84%。1HNMR(400MHz,DMSO-d6):δ=12.81(s,1H),9.29(s,1H),7.52(s,1H),7.25(q,J=8.1Hz,2H),6.11(s,1H),5.91(s,1H),5.70(s,1H),2.34(s,3H);13C NMR(100MHz,DMSO-d6):δ=167.41,153.17,152.25,141.80,136.80,132.15,131.25,124.75,121.96,78.78,21.34。
实施例13:化合物13的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物13,收率72%。1HNMR(400MHz,DMSO-d6):δ=12.82(s,1H),9.30(s,1H),7.29–7.12(m,2H),7.03(dd,J=8.4,2.6Hz,1H),6.09(s,1H),5.89(s,1H),5.69(s,1H),3.77(s,3H);13C NMR(100MHz,DMSO-d6):δ=167.75,159.64,148.31,142.22,124.95,123.56,118.78,114.64,78.92,55.95。
实施例14:化合物14的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物14,收率80%。1HNMR(400MHz,Methanol-d4):δ=7.28(s,1H),6.98(d,1H),6.89(m,1H),6.52(s,1H),5.90(s,1H),5.56(s,1H),4.06(q,2H),1.34(m,3H);13C NMR(100MHz,Methanol-d4):δ=171.05,156.30,149.31,137.32,131.95,130.56,127.08,114.60,78.40,64.95,14.81。
实施例15:化合物15的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物15,收率70%。1HNMR(400MHz,Methanol-d4):δ=7.40(s,1H),6.99(d,1H),6.91(m,1H),6.34(s,1H),5.90(s,1H),5.56(s,1H),1.42(s,9H);13C NMR(100MHz,Methanol-d4):δ=171.30,151.25,148.40,137.54,133.49,130.56,127.08,114.60,86.57,78.50,27.81。
实施例16:化合物16的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物16,收率91%。1HNMR(400MHz,Methanol-d4):δ=7.30(dd,J=8.4,4.5Hz,1H),7.18(dd,J=8.1,2.5Hz,1H),7.06(ddd,J=9.3,8.4,2.5Hz,1H),6.17(s,1H),5.93(s,1H),5.71(s,1H);13C NMR(100MHz,Methanol-d4):δ=167.66,163.82,162.20,151.37,141.00,125.00,123.91,123.85,118.25,118.09,115.67,115.53,79.88。
实施例17:化合物17的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物17,收率81%。1HNMR(400MHz,Methanol-d4):δ=7.48(d,J=2.0Hz,1H),7.38–7.24(m,2H),6.19(s,1H),5.93(s,1H),5.73(s,1H);13C NMR(100MHz,Methanol-d4):δ=167.19,153.86,140.34,133.45,130.63,129.35,125.02,123.32,79.67。
实施例18:化合物18的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物18,收率81%。1HNMR(400MHz,Methanol-d4):δ=7.76(d,J=2.0Hz,1H),7.61–7.46(m,2H),6.53(s,1H),5.90(s,1H),5.61(s,1H);13C NMR(100MHz,Methanol-d4):δ=168.19,153.43,143.35,132.15,130.03,129.35,125.02,123.32,113.56,79.67。
实施例19:化合物19的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物19,收率86%。1HNMR(400MHz,Methanol-d4):δ=7.88(s,1H),7.72(d,J=8.1Hz,1H),7.57(d,J=8.1Hz,1H),6.32(s,1H),6.11(s,1H),5.87(s,1H).13C NMR(100MHz,Methanol-d4):δ=168.42,160.65,141.31,131.18,130.87,128.84,128.80,127.90,127.86,127.21,127.04,124.52,123.80,81.47。
实施例20:化合物20的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物20,收率87%。1HNMR(400MHz,DMSO-d6):δ=12.81(s,1H),9.29(s,1H),7.52(d,1H),7.25(m,2H),6.11(s,1H),5.91(s,1H),5.70(s,1H),2.34(s,3H);13C NMR(100MHz,DMSO-d6):δ=168.41,152.17,151.25,140.80,135.80,131.15,130.25,125.75,120.96,79.78,23.34。
实施例21:化合物21的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物21,收率75%。1HNMR(400MHz,DMSO-d6):δ=12.52(s,1H),9.01(s,1H),7.01–6.89(m,2H),6.85(dd,J=8.4,2.6Hz,1H),5.73(s,1H),5.53(s,1H),5.29(s,1H),3.34(s,3H);13C NMR(100MHz,DMSO-d6):δ=169.95,161.84,150.51,144.42,126.15,125.76,120.98,116.84,80.12,57.15。
实施例22:化合物22的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物22,收率85%。1HNMR(400MHz,Methanol-d4):δ=7.38(d,1H),7.08(d,1H),6.99(m,1H),6.62(s,1H),6.01(s,1H),5.66(s,1H),4.16(q,2H),1.44(m,3H);13C NMR(100MHz,Methanol-d4):δ=170.05,155.30,148.31,136.32,130.95,129.56,126.08,113.60,77.40,63.95,13.81。
实施例23:化合物23的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物23,收率71%。1HNMR(400MHz,Methanol-d4)δ=7.84(d,J=8.1Hz,1H),7.23(d,J=2.2Hz,1H),7.04(dd,J=8.1,2.2Hz,1H),6.56(s,1H),6.31(s,1H),6.02(s,1H),3.95(m,1H),1.30(d,6H);13C NMR(100MHz,Methanol-d4):δ=167.73,160.79,158.09,141.12,131.26,124.04,115.89,108.24,79.13,69.60,29.33,20.88,20.78。
实施例24:化合物24的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物24,收率78%。1HNMR(400MHz,Methanol-d4)δ=7.44(d,J=7.1Hz,1H),7.38(td,J=7.6,4.5Hz,1H),7.16–7.08(m,1H),6.33(s,1H),6.12(s,1H),5.71(s,1H);13C NMR(100MHz,Methanol-d4):δ=166.89,158.50,156.02,140.02,139.89,139.36,130.11,130.05,127.15,125.67,125.63,117.20,117.00,77.76。
实施例25:化合物25的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物25,收率78%。1HNMR(400MHz,Methanol-d4):δ=7.58(d,J=2.0Hz,1H),7.48–7.34(m,2H),6.29(s,1H),5.90(s,1H),5.83(s,1H);13C NMR(100MHz,Methanol-d4):δ=167.59,153.06,140.74,133.65,130.93,129.65,125.32,123.72,79.77。
实施例26:化合物26的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物26,收率83%。1HNMR(400MHz,Methanol-d4):δ=7.53(d,J=2.0Hz,1H),7.44–7.23(m,2H),6.25(s,1H),5.87(s,1H),5.78(s,1H);13C NMR(100MHz,Methanol-d4):δ=166.99,153.96,139.24,132.29,129.93,129.65,124.31,122.53,79.65。
实施例27:化合物27的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物27,收率83%。1HNMR(400MHz,Methanol-d4):δ=7.80(d,J=7.6Hz,1H),7.69(m,1H),7.63(d,J=7.6Hz,1H),6.32(s,1H),6.11(s,1H),5.88(s,1H);13C NMR(100MHz,Methanol-d4):δ=167.14,156.14,140.01,132.51,132.19,130.60,129.44,125.60,125.31,124.06,124.02,122.90,118.42,118.38,79.93。
实施例28:化合物28的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物28,收率89%。1HNMR(400MHz,DMSO-d6):δ=12.09(s,1H),9.19(s,1H),7.43(d,1H),7.22(m,2H),6.17(s,1H),5.99(s,1H),5.75(s,1H),2.35(s,3H);13C NMR(100MHz,DMSO-d6):δ=167.41,151.17,150.25,143.80,137.80,131.15,129.25,123.75,120.76,79.58,24.34。
实施例29:化合物29的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物29,收率76%。1HNMR(400MHz,DMSO-d6):δ=12.42(s,1H),9.31(s,1H),7.23–7.01(m,2H),6.85(dd,J=8.4,2.6Hz,1H),5.73(s,1H),5.53(s,1H),5.29(s,1H),3.34(s,3H);13C NMR(100MHz,DMSO-d6):δ=169.95,161.84,150.51,144.42,126.15,125.76,120.98,116.84,80.12,57.15。
实施例30:化合物30的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物30,收率78%。1HNMR(400MHz,Methanol-d4):δ=7.45(d,1H),7.23(d,1H),6.97(m,1H),6.53(s,1H),6.01(s,1H),573(s,1H),4.01(q,2H),1.23(m,3H);13C NMR(100MHz,Methanol-d4):δ=167.05,155.23,148.13,136.23,130.59,129.65,126.80,113.06,77.04,63.59,13.18。
实施例31:化合物31的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物31,收率70%。1HNMR(400MHz,Methanol-d4):δ=7.45(s,1H),6.99(d,1H),6.89(m,1H),6.43(s,1H),5.78(s,1H),5.65(s,1H),1.23(s,9H);13C NMR(100MHz,Methanol-d4):δ=170.30,159.25,147.40,139.54,132.49,131.56,129.08,114.90,86.77,78.50,27.91。
实施例32:化合物32的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物32,收率79%。1HNMR(400MHz,Methanol-d4)δ=7.41(d,J=7.1Hz,1H),7.32(td,J=7.6,4.5Hz,1H),7.12–7.03(m,1H),6.31(s,1H),6.11(s,1H),5.72(s,1H);13C NMR(100MHz,Methanol-d4):δ=167.89,159.50,155.02,139.92,139.21,139.01,130.31,130.15,127.25,125.77,125.33,117.30,117.10,77.56。
实施例33:化合物33的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物33,收率83%。1HNMR(400MHz,Methanol-d4):δ=7.59(d,J=2.0Hz,1H),7.49–7.35(m,2H),6.30(s,1H),5.91(s,1H),5.84(s,1H);13C NMR(100MHz,Methanol-d4):δ=167.39,153.16,140.84,133.75,130.73,129.75,125.42,123.82,79.97。
实施例34:化合物34的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物34,收率79%。1HNMR(400MHz,Methanol-d4):δ=7.56(d,J=2.0Hz,1H),7.41–7.26(m,2H),6.33(s,1H),5.70(s,1H),5.41(s,1H);13C NMR(100MHz,Methanol-d4):δ=166.19,151.43,141.35,130.15,128.03,127.35,123.02,121.32,111.56,77.67。
实施例35:化合物35的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物35,收率83%。1HNMR(400MHz,Methanol-d4):δ=7.57(d,J=2.0Hz,1H),7.47–7.33(m,2H),6.28(s,1H),5.89(s,1H),5.82(s,1H);13C NMR(100MHz,Methanol-d4):δ=167.37,153.14,140.82,133.73,130.71,129.73,125.40,123.80,79.95。
实施例36:化合物36的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物36,收率81%。1HNMR(400MHz,DMSO-d6):δ=12.77(s,1H),9.02(s,1H),7.01(s,1H),6.89(s,1H),6.12(s,1H),5.87(s,1H),5.68(s,1H),1.77(s,3H),1.74(s,3H);13C NMR(100MHz,DMSO-d6):δ=167.71,152.42,149.83,149.50,142.21,125.29,112.75,105.63,78.83,56.21,56.13。
实施例37:化合物37的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物37,收率84%。1HNMR(400MHz,DMSO-d6):δ=12.79(s,1H),9.10(s,1H),7.21(s,1H),6.90(s,1H),6.11(s,1H),5.85(s,1H),5.68(s,1H),3.77(s,3H),3.74(s,3H);13C NMR(100MHz,DMSO-d6):δ=167.91,152.44,149.82,149.50,142.20,125.27,112.78,105.65,78.81,56.23,56.10。
实施例38:化合物38的合成
根据上述合成路线一,参照化合物4的制备方法,得到目标化合物38,收率73%。1HNMR(400MHz,Methanol-d4):δ=6.86(s,1H),6.74(s,1H),6.14(s,1H),5.89–5.85(m,2H),5.83(s,1H),5.66(s,1H);13C NMR(100MHz,Methanol-d4):δ=167.74,151.13,151.01,148.01,141.13,124.09,107.91,102.47,101.53,101.40,79.09,69.46。
以下通过实验例证明本发明的有益效果。
实验例1:本发明化合物对MBL和SBL酶的体外抑制活性
1、实验方法
通过以下方法测试本发明化合物1~38对SBL类β-内酰胺酶(TEM-1,KPC-2,Ampc,OXA-48)和MBL类β-内酰胺酶(GOB-18,SFH-1,NDM-1,VIM-2)的体外抑制活性,以市售的β-内酰胺酶抑制剂Avibactam为对照。
(1)蛋白的制备:
(1.1)制备VIM-2蛋白。利用PCR仪扩增VIM-2基因(蛋白残基序列:27-266),并克隆到N端带有His标签和TEV蛋白酶切位点的PET28载体当中。将VIM-2蛋白在大肠杆菌(DE3)中表达,37℃培养2-4小时,直至OD600达到0.6~0.8,加入终浓度为0.3mM异丙基β-D-1-硫代吡喃半乳糖苷(IPTG)诱导VIM-2蛋白表达,20℃摇菌过夜。4000r/min离心15min收集菌体,并重悬于裂解缓冲液(20mM Tris-HCl,250mM NaCl,pH8.0),使用高压破菌仪破碎细胞,15,000r/min离心30min除去细胞碎片,收集上清并加入Ni-NTA柱(Roche)中,用含5mM咪唑的Wash buffer(20mM Tris-HCl pH 8.0,250mM NaCl,5mM咪唑)大量冲洗,以除去非特异性结合的蛋白。最后用含250mM咪唑的洗脱buffer(20mM Tris-HCl pH 8.0,250mM NaCl,250mM咪唑)洗脱目的蛋白。收集并浓缩目的蛋白,使用脱盐柱将VIM-2蛋白脱盐到20mM Tris-HClpH7.5,200mM NaCl的缓冲液中。收集VIM-2蛋白并浓缩至15mg/ml,并加入1mM三(2-羧乙基)膦(TCEP)储存于-80℃。通过SDS-PAGE监测纯化过程,蛋白浓度由Nanno Drop 2000光谱光度计(Thermo Scientific)测定。
(1.2)采用类似的方法制得其余蛋白(TEM-1,KPC-2,Ampc,OXA-48,GOB-18,SFH-1,NDM-1蛋白)。
(2)抑制活性的测试:
(2.1)测试化合物对VIM-2蛋白的抑制活性。将受试化合物分别溶解于100%的DMSO溶剂中配成100mM的母液,再用VIM-2缓冲溶液分别将其稀释成3.6mM、1.2mM、400μM等三倍稀释的化合物工作液。每个测试孔中加入10μL化合物工作液,30μL VIM-2缓冲溶液,10μL VIM-2蛋白(200pM),于25℃下反应10分钟,在每个测试孔加入10μL VIM-2底物后,立即使用Thermo VARIOSKAN LUX酶标仪在激发光波长为380nM和发射光波长为460nM测试以上反应液的动力学反应过程的荧光强度。化合物浓度从600μM至0.03μM 3倍稀释测定IC50,每个浓度设置3个平行组。抑制率使用以下公式计算:其中ΔFa为相同时间不含受试化合物的荧光强度的变化值,ΔFc为相同时间含受试化合物的荧光强度的变化值。使用Graphpad Prism软件(La Jolla,CA)获得受试化合物对VIM-2蛋白的半数有效抑制浓度(IC50)值。
(2.2)采用类似的方法,将VIM-2蛋白分别替换为其余蛋白,测得受试化合物对TEM-1,KPC-2,Ampc,OXA-48,GOB-18,SFH-1,NDM-1蛋白的IC50值。
2、实验结果
各化合物对SBL类β-内酰胺酶(TEM-1,KPC-2,Ampc,OXA-48)和MBL类β-内酰胺酶(GOB-18,SFH-1,NDM-1,VIM-2)的IC50值见表1。
表1、本发明化合物对临床β-内酰胺酶的抑制活性
表1中“+++”表示IC50<0.1μM;“++”表示0.1μM<IC50<10.0μM;“+”表示10.0μM<IC50<100.0μM;“-“表示IC50>100.0μM。
由表1可以看出,本发明化合物对SBL类β-内酰胺酶具有良好的抑制活性,特别是化合物3、11、15、18、23,其对KPC-2的IC50低至0.1μM以下。
此外,本发明化合物还对MBL类β-内酰胺酶具有良好的抑制活性,特别是化合物23,29,其对GOB-18的IC50低至0.1μM以下。
由表1还可以看出,本发明的化合物1~15、17~30、32、35~37同时对SBL类β-内酰胺酶和MBL类β-内酰胺酶都具有良好的抑制活性,可以用来制备MBL/SBL的双重抑制剂。
而市售的β-内酰胺酶抑制剂Avibactam虽然能够有效抑制多种SBL类β-内酰胺酶,但是,其对MBL类β-内酰胺酶的抑制效果不佳,对SFH-1、NDM-1的IC50>100.0μM。
上述实验结果表明,本发明提供的化合物可以用来制备SBL抑制剂,可以用来制备MBL抑制剂,甚至可以用来制备MBL/SBL的双重抑制剂。
综上,本发明提供了一种对MBL具有抑制作用,对SBL具有抑制作用,甚至对MBL和SBL具有双重抑制作用的3-取代五元环状硼酸酯衍生物及其药物组合物和制药用途。实验结果表明,该3-取代五元环状硼酸酯衍生物不仅对SBL类β-内酰胺酶具有良好的抑制活性,还对MBL类β-内酰胺酶具有良好的抑制活性,可以作为丝氨酸β-内酰胺酶抑制剂、金属β-内酰胺酶抑制剂、金属β-内酰胺酶和丝氨酸β-内酰胺酶双重抑制剂,在制备抗耐药菌的药物中具有广阔的应用前景。
Claims (11)
3.根据权利要求2所述的化合物、或其药学上可接受的盐、或其同位素化合物、或其立体异构体,其特征在于:n为1或2;
R1各自独立的选自卤代或未卤代的C1~4烷基、卤代或未卤代的C1~4烷氧基、卤素、硝基、氰基,或者两个R1连接形成5~6元环。
8.一种抑制β-内酰胺酶的药物组合物,其特征在于:它是以权利要求1~6任一项所述化合物、或其药学上可接受的盐、或其同位素化合物、或其立体异构体为活性成分,加上药学上可接受的辅料制得的制剂。
9.权利要求1~6任一项所述化合物、或其药学上可接受的盐、或其同位素化合物、或其立体异构体在制备β-内酰胺酶抑制剂中的用途。
10.根据权利要求9所述的用途,其特征在于:所述β-内酰胺酶抑制剂为金属β-内酰胺酶抑制剂、丝氨酸β-内酰胺酶抑制剂、金属β-内酰胺酶和丝氨酸β-内酰胺酶双重抑制剂。
11.根据权利要求9所述的用途,其特征在于:所述β-内酰胺酶抑制剂为抗菌药物;所述抗菌药物优选为抗耐药细菌的药物,更优选为抗多重耐药细菌的药物、抗广泛耐药细菌的药物或抗全耐药细菌的药物。
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