CN109422765A - C类β-内酰胺酶抑制剂及其制备方法和应用 - Google Patents
C类β-内酰胺酶抑制剂及其制备方法和应用 Download PDFInfo
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- CN109422765A CN109422765A CN201710790073.9A CN201710790073A CN109422765A CN 109422765 A CN109422765 A CN 109422765A CN 201710790073 A CN201710790073 A CN 201710790073A CN 109422765 A CN109422765 A CN 109422765A
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- Prior art keywords
- acid
- hydroxyl
- reaction
- lactamase inhibitor
- propyl
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- 239000003781 beta lactamase inhibitor Substances 0.000 title claims abstract description 54
- 229940126813 beta-lactamase inhibitor Drugs 0.000 title claims abstract description 54
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims description 16
- 239000002253 acid Substances 0.000 claims abstract description 101
- 238000006243 chemical reaction Methods 0.000 claims description 70
- 102000006635 beta-lactamase Human genes 0.000 claims description 26
- 108090000204 Dipeptidase 1 Proteins 0.000 claims description 23
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 23
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 19
- 229910052794 bromium Inorganic materials 0.000 claims description 19
- 230000003115 biocidal effect Effects 0.000 claims description 18
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 17
- -1 (2- thiophene-yl) propyl Chemical group 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 16
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Substances [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 12
- 239000007818 Grignard reagent Substances 0.000 claims description 10
- 150000004795 grignard reagents Chemical class 0.000 claims description 10
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 claims description 10
- AZFNGPAYDKGCRB-XCPIVNJJSA-M [(1s,2s)-2-amino-1,2-diphenylethyl]-(4-methylphenyl)sulfonylazanide;chlororuthenium(1+);1-methyl-4-propan-2-ylbenzene Chemical compound [Ru+]Cl.CC(C)C1=CC=C(C)C=C1.C1=CC(C)=CC=C1S(=O)(=O)[N-][C@@H](C=1C=CC=CC=1)[C@@H](N)C1=CC=CC=C1 AZFNGPAYDKGCRB-XCPIVNJJSA-M 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- 235000010289 potassium nitrite Nutrition 0.000 claims description 8
- 239000004304 potassium nitrite Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 235000010288 sodium nitrite Nutrition 0.000 claims description 7
- 239000012298 atmosphere Substances 0.000 claims description 6
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 5
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 claims description 4
- ITLHXEGAYQFOHJ-UHFFFAOYSA-N [diazo(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(=[N+]=[N-])C1=CC=CC=C1 ITLHXEGAYQFOHJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000013019 agitation Methods 0.000 claims description 4
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- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
- ZENKESXKWBIZCV-UHFFFAOYSA-N 2,2,4,4-tetrafluoro-1,3-benzodioxin-6-amine Chemical group O1C(F)(F)OC(F)(F)C2=CC(N)=CC=C21 ZENKESXKWBIZCV-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
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- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 2
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims description 2
- VOUGEZYPVGAPBB-UHFFFAOYSA-N penicillin acid Natural products OC(=O)C=C(OC)C(=O)C(C)=C VOUGEZYPVGAPBB-UHFFFAOYSA-N 0.000 claims description 2
- 235000010265 sodium sulphite Nutrition 0.000 claims description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 2
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- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 claims 1
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- 239000000243 solution Substances 0.000 description 26
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- 239000000047 product Substances 0.000 description 15
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- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 7
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 7
- 229960003324 clavulanic acid Drugs 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 6
- 229960003022 amoxicillin Drugs 0.000 description 6
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- WZOZEZRFJCJXNZ-ZBFHGGJFSA-N cefoxitin Chemical compound N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)CC1=CC=CS1 WZOZEZRFJCJXNZ-ZBFHGGJFSA-N 0.000 description 6
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- 229930182555 Penicillin Natural products 0.000 description 4
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
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Abstract
本发明提供了一种C类β‑内酰胺酶抑制剂,所述C类β‑内酰胺酶抑制剂为6α‑(1R‑羟基‑3(2‑噻吩‑基)丙基)青霉素酸,具有如下式1所示结构,
Description
技术领域
本发明属于药物合成技术领域,尤其涉及一种C类β-内酰胺酶抑制剂及其制备方法和应用。
背景技术
产生β-内酰胺酶是细菌对β-内酰胺类抗生素耐药的最重要途径。β-内酰胺酶根据序列同源性可分为A、B、C、D四类,A类和C类是目前临床上最为常见的两类β-内酰胺酶,这两类的β-内酰胺酶,特别是其中超广谱β-内酰胺酶可以令大多数的抗生素失效,从而给医院及社区健康带来巨大威胁。很长时间以来,临床上可用的β-内酰胺酶抑制剂只有三种,克拉维酸、舒巴坦、他唑巴坦,但这三种仅适用于A类β-内酰胺酶。而对于另一类更具广谱活性的C类β-内酰胺酶,仅最新上市的阿维巴坦具有抑制效果。因此对于C类β-内酰胺酶抑制剂的开发有着迫切的市场需求。
发明内容
本发明的目的在于提供一种C类β-内酰胺酶抑制剂及其制备方法,旨在解决现有C类β-内酰胺酶抑制剂市场需求窘迫的问题。
本发明的另一目的在于提供一种含有上述C类β-内酰胺酶抑制剂的C类β-内酰胺酶抑制药物。
本发明是这样实现的,一种C类β-内酰胺酶抑制剂,所述C类β-内酰胺酶抑制剂为6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸,具有如下式1所示结构,
相应的,一种C类β-内酰胺酶抑制剂的制备方法,包括以下步骤:
步骤(1).将第一非质子性溶剂进行冷却处理后,在搅拌条件下加入液溴、硫酸、亚硝酸钠或亚硝酸钾,然后加入6-氨基青霉素酸,在4-10℃条件下进行恒温反应,获得6,6-二溴青霉素酸;
步骤(2).将所述6,6-二溴青霉素酸溶于第二非质子性溶剂中,室温条件下添加二苯基重氮甲烷,反应制备二苯甲基6,6-二溴青霉素酸;
步骤(3).将所述二苯甲基6,6-二溴青霉素酸溶于四氢呋喃中,冷却至-70~-50℃,加入格氏试剂,反应制备二苯甲基-6α-溴-6β-(1R-羟基-3(2-噻吩基)丙基)青霉素酸;
步骤(4).将所述二苯甲基-6α-溴-6β-(1R-羟基-3(2-噻吩基)丙基)青霉素酸溶解后,冷却至0-5℃,加入三丁基膦,反应制备二苯甲基-6α-(1R-羟基-3(2-噻吩基)丙基)青霉素酸;
步骤(5).将所述二苯甲基-6α-(1R-羟基-3(2-噻吩基)丙基)青霉素酸与间甲苯酚在惰性气氛下反应,制备得到6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸。
以及,一种C类β-内酰胺酶抑制药物,所述C类β-内酰胺酶抑制药物中含有上述的C类β-内酰胺酶抑制剂。
本发明提供的C类β-内酰胺酶抑制剂,能够特异性地抑制C类β-内酰胺酶P99,其抑制效果相比克拉维酸和苏巴坦有2-5倍的提升。此外,所述6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸还能抑制A类β-内酰胺酶PenP(IC50>1mM),相比克拉维酸和苏巴坦而言,是有效的A类β-内酰胺酶抑制剂(IC50<2μM)。
本发明提供的C类β-内酰胺酶抑制剂的制备方法,反应条件温和易控,且制备得到的产品纯度高,产率可达46%以上。
本发明提供的C类β-内酰胺酶抑制药物,含有上述C类β-内酰胺酶抑制剂,能与其他抗生素一起作用,有效促进抗生素的抑菌活性。
附图说明
图1是本发明实施例4提供的β-内酰胺酶与6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸酰化反应0分钟的质谱图;
图2是本发明实施例4提供的β-内酰胺酶与6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸酰化反应5分钟的质谱图;
图3是本发明实施例4提供的β-内酰胺酶与6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸酰化反应15分钟的质谱图;
图4是本发明实施例4提供的P99-PC-1(6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸)复合物的活性中心结构示意图;
图5是本发明实施例4提供的PC-1(6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸)与活性中心氨基酸的相互作用示意图;
图6是本发明实施例4提供的P99-PC-1(6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸)结构与AmpC_amoxicillin(阿莫西林)(PDB ID:1LL9)、AmpC_cephalothin(头孢噻吩)(PDB ID:1KVM)复合物结构的重叠图。
具体实施方式
为了使本发明要解决的技术问题、技术方案及有益效果更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
本发明实施例提供了一种C类β-内酰胺酶抑制剂,所述C类β-内酰胺酶抑制剂为6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸,具有如下式1所示结构,
本发明实施例提供的C类β-内酰胺酶抑制剂,是一种新型结构的C类β-内酰胺酶抑制剂(6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸),经实验研究,所述6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸能够特异性地抑制C类β-内酰胺酶P99,其抑制效果相比克拉维酸和苏巴坦有2-5倍的提升。此外,所述6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸还能抑制A类β-内酰胺酶PenP(IC50>1mM),相比克拉维酸和苏巴坦而言,是有效的A类β-内酰胺酶抑制剂(IC50<2μM)。
本发明实施例所述C类β-内酰胺酶抑制剂,可以通过下述方法制备获得。
相应的,本发明实施例还提供了一种C类β-内酰胺酶抑制剂的制备方法,包括以下步骤:
步骤(1).将第一非质子性溶剂进行冷却处理后,在搅拌条件下加入液溴、硫酸、亚硝酸钠或亚硝酸钾,然后加入6-氨基青霉素酸,在4-10℃条件下进行恒温反应,获得6,6-二溴青霉素酸;
步骤(2).将所述6,6-二溴青霉素酸溶于第二非质子性溶剂中,室温条件下添加二苯基重氮甲烷,反应制备二苯甲基6,6-二溴青霉素酸;
步骤(3).将所述二苯甲基6,6-二溴青霉素酸溶于四氢呋喃,加入格式试剂和3-(2-噻吩基)丙醛,反应制备二苯甲基-6α-溴-6β-(1R-羟基-3(2-噻吩基)丙基)青霉素酸;
步骤(4).将所述二苯甲基-6α-溴-6β-(1R-羟基-3(2-噻吩基)丙基)青霉素酸溶解后,冷却至0-5℃,加入三丁基膦,反应制备二苯甲基-6α-(1R-羟基-3(2-噻吩基)丙基)青霉素酸;
步骤(5).将所述二苯甲基-6α-(1R-羟基-3(2-噻吩基)丙基)青霉素酸与间甲苯酚在惰性气氛下反应,制备得到6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸。
具体的,上述步骤(1)中,所述第一非质子性溶剂作为反应介质,对所述液溴、亚硝酸钠或亚硝酸钾、6-氨基青霉素酸均具有较好的分散溶解性能。具体优选的,所述第一非质子性溶剂包括但不限于二氯甲烷、乙酸乙酯。
在搅拌条件下液溴、硫酸、亚硝酸钠或亚硝酸钾,其中,所述硫酸与亚硝酸盐反应生成亚硝酸(反应方程式H2SO4+2NaNO2→2HNO2+Na2SO4)。进一步的,加入6-氨基青霉素酸,所述亚硝酸与液溴、6-氨基青霉素酸反应生成6,6-二溴青霉素酸。本发明实施例中,由于亚硝酸与液溴、6-氨基青霉素酸反应生成6,6-二溴青霉素酸的反应为放热反应,且反应过程中会产生气体。为了使温度保持恒定,且利于生成的气体缓慢排出,优选的,所述6-氨基青霉素酸采用分批加入的方式,优选的,在4-6min内分批次加入所述6-氨基青霉素酸,加入方式优选滴加。本发明实施例中,生成6,6-二溴青霉素酸的反应反应分为两步,首先,6-氨基青霉素酸上的氨基与生成的亚硝酸发生重氮化反应;接着,重氮基被溴取代得到溴代产物,放出氮气。优选的,在4-10℃条件下进行恒温反应,防止温度过高时发生副反应如偶合反应;而温度过低,也不利于反应的进行。反应时间优选为20-60min,具体优选的,在5℃条件下进行恒温反应30min。
进一步优选的,所述液溴、6-氨基青霉素酸的摩尔比为2.4:1~3:1(液溴稍微过量,有利于反应完全),所述亚硝酸钠或亚硝酸钾、6-氨基青霉素酸的摩尔比为1.5:1~2:1,从而有利于反应的充分进行,且减少副反应的产生。若所述亚硝酸钠或亚硝酸钾的含量偏低,容易发生偶合反应。在上述实施例的基础上,优选的,所述硫酸的浓度为1.25mol/L,所述硫酸的体积为所述有机溶剂体积的30~50%,以保证反应的充分进行,当然,所述硫酸的浓度和体积百分含量,可以根据所述亚硝酸盐的用量进行对应调整。具体优选的,所述硫酸的浓度为1.25mol/L,所述硫酸的体积为所述有机溶剂体积的40%。
本发明实施例中,为了避免残余的溴对后续反应造成影响,反应结束后,在反应液中加入还原剂,将反应液中过量的溴还原,优选为还原剂溶液。但是,并非任意的还原剂均能用于本发明。除了考虑还原剂本身与溴之间的还原性能外,还要考虑还原剂对步骤(1)得到的产物6,6-二溴青霉素酸的影响,不能还原产物6,6-二溴青霉素酸,或引入其他杂副反应。优选的,所述还原剂为亚硫酸氢钠、亚硫酸钠、硫代硫酸钠中的至少一种。优选在5-15℃条件下反应(温度偏低会导致反应不完全或不反应,温度过高则会导致副反应的发生),可以看到液溴的颜色逐渐褪去,反应液呈现淡黄色,即呈现6,6-二溴青霉素酸的颜色,产物生成。
在反应结束后,还包括对产物6,6-二溴青霉素酸进行提纯处理。优选的,将反应体系萃取分离得到有机相,水相用二氯甲烷萃取两次,合并的有机相再用饱和食盐水洗涤,减压浓缩得到黄色固体,即为6,6-二溴青霉素酸。
上述步骤(1)方法获得的6,6-二溴青霉素酸,产率在83%以上。
上述步骤(2)中,将所述6,6-二溴青霉素酸溶于第二非质子性溶剂中,所述第二非质子性溶剂为乙酸乙酯、二氯甲烷、四氢呋喃中的至少一种。所述6,6-二溴青霉素酸与所述二苯基重氮甲烷在室温条件下反应生成二苯甲基6,6-二溴青霉素酸。本发明实施例中,所述室温是指室内温度,包括10-35℃的温度范围。其中,优选的,所述二苯基重氮甲烷采用滴加的方式进行添加,有利于反应生成的氮气,缓慢排出,提高安全性。
本发明实施例可以通过TLC(液相薄层色谱)检测反应液,监控反应是否完全。待反应结束后,还包括对反应液进行纯化处理。具体的,将上述步骤(2)反应后的反应液进行减压蒸馏除去溶剂,然后通过硅胶柱色谱进行分离,最终得到纯化的二苯甲基6,6-二溴青霉素酸,经过上述步骤(2)后获得的产物产率为61%。
上述步骤(3)中,在格氏试剂作用下,3-(2-噻吩基)丙醛与二苯甲基6,6-二溴青霉素酸反应生成二苯甲基-6α-溴-6β-(1R-羟基-3(2-噻吩基)丙基)青霉素酸。其中,优选的,先加入格氏试剂包括但不限于乙基溴化镁、甲基溴化镁、异丙基溴化镁,添加是优选采用格氏试剂的***或四氢呋喃溶液,有利于控制滴加量和反应的均匀性。本发明实施例中,先在-70~-50℃条件下反应2~3小时,该步骤中,通过格氏试剂交换反应得到二苯甲基6,6-二溴青霉素酸的格氏试剂;然后在相同的温度下加入3-(2-噻吩基)丙醛,在-70~-50℃条件下反应1~2小时,此时,二苯甲基6,6-二溴青霉素酸的格氏试剂与和3-(2-噻吩基)丙醛加成反应生成二苯甲基-6α-溴-6β-(1R-羟基-3(2-噻吩基)丙基)青霉素酸。进一步优选的,所述格氏试剂和所述3-(2-噻吩基)丙醛均通过滴加方式加入。
反应结束后,包括对得到的产物进行提纯处理,具体的,在先反应液加入饱和氯化铵淬灭反应,反应液放置到室温;然后通过减压蒸馏除去有机溶剂如四氢呋喃。再加入水和乙酸乙酯进行萃取分液,分得的有机相先后用5%碳酸氢钠和饱和食盐水洗,经浓缩获得油状物。将得到的油状物通过硅胶柱分离得到目标产物二苯甲基-6α-溴-6β-(1R-羟基-3(2-噻吩基)丙基)青霉素酸。该步骤反会存在杂副反应,产生下述结构所示同向异构体的副产物,该副产物可以在柱层析中分离除去。
步骤(3)获得的二苯甲基-6α-溴-6β-(1R-羟基-3(2-噻吩基)丙基)青霉素酸的产率为49%。
上述步骤(4)中,将所述二苯甲基-6α-溴-6β-(1R-羟基-3(2-噻吩基)丙基)青霉素酸溶解后,冷却至0-5℃,以防止反应过程中发生杂副反应,生成难于去除的产物的其他立体构型。其中,溶解二苯甲基-6α-溴-6β-(1R-羟基-3(2-噻吩基)丙基)青霉素酸的溶解优选为有机醇,包括但不限于甲醇、乙醇或异丙醇。进一步的,加入三丁基膦,与二苯甲基-6α-溴-6β-(1R-羟基-3(2-噻吩基)丙基)青霉素酸反应制备二苯甲基-6α-(1R-羟基-3(2-噻吩基)丙基)青霉素酸,反应条件为:在-0-5℃条件下反应1~2小时。
将反应产物进行提纯处理,具体的,将反应液进行减压蒸馏,然后通过硅胶柱色谱纯化,得到二苯甲基-6α-(1R-羟基-3(2-噻吩基)丙基)青霉素酸。步骤(4)获得的二苯甲基-6α-(1R-羟基-3(2-噻吩基)丙基)青霉素酸的产率59%。
上述步骤(5)中,将所述二苯甲基-6α-(1R-羟基-3(2-噻吩基)丙基)青霉素酸与间甲苯酚混合,在惰性气氛下反应,制备目标产物6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸,即C类β-内酰胺酶抑制剂。其中,所述惰性气氛包括但不限于氮气气氛;反应的条件为:在50-60℃条件下反应3~5小时。
将反应产物进行纯化处理,具体的,反应液降温至室温,然后减压蒸馏,将得到的油状物经薄板层析分离,得到终产物6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸(PC-1),产率为46%。
本发明实施例提供的C类β-内酰胺酶抑制剂的制备方法,反应条件温和易控,且制备得到的产品纯度高,产率可达46%以上。
以及,本发明实施例还提供了一种C类β-内酰胺酶抑制药物,所述C类β-内酰胺酶抑制药物中含有上述的C类β-内酰胺酶抑制剂。
本发明实施例提供的C类β-内酰胺酶抑制药物,含有上述C类β-内酰胺酶抑制剂,能与其他抗生素一起作用,有效促进抗生素的抑菌活性。
进一步优选的,所述C类β-内酰胺酶抑制药物中还含有抗生素。所述C类β-内酰胺酶抑制剂本身不具备抑菌作用,但与所述抗生素联合使用后,可以有效增强抗生素的抑菌活性。
下面结合具体实施例进行说明。
实施例1
一种C类β-内酰胺酶抑制剂,所述C类β-内酰胺酶抑制剂为6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸,具有如下式1所示结构,
所述C类β-内酰胺酶抑制剂的制备方法,包括以下步骤:
S11.将60mL二氯甲烷冷却至5℃,搅拌条件下加入14.4g(90mmol)液溴,24mL 2.5N(1.25mol/L)硫酸和4.14g(60mmol)亚硝酸钠,在大约5分钟内分批次加入6.5g(30mmol)6-氨基青霉素酸,保持温度在4-10℃,在5℃条件下反应30分钟。然后将50mL 1M的亚硫酸氢钠溶液逐滴加入反应液中,保持温度在5-15℃,可以看到液溴的颜色逐渐褪去,反应液呈现淡黄色。萃取分离得到有机相,水相再用二氯甲烷萃取两次,合并的有机相再用饱和食盐水洗涤,减压浓缩得到黄色固体。以该方法获得9g 6,6-二溴青霉素酸,产率为83%。
S12.将步骤S11获得的7.18g(20mmol)6,6-二溴青霉素酸溶于100mL乙酸乙酯中,室温下慢慢滴加二苯基重氮甲烷,滴加完毕后室温反应过夜,TLC检测原料反应完全。反应液减压蒸馏除去溶剂,然后通过硅胶柱分离得到目标产物二苯甲基6,6-二溴青霉素酸(6.2g),产率为61%。
S13.将步骤S12获得的2g(3.8mmol)二苯甲基-6,6-二溴青霉素酸溶于无水四氢呋喃(40mL)中,冷却至-50℃,逐滴加入0.61mL(3M,1.82mmol)乙基溴化镁的***溶液,反应液在-50℃反应2小时。然后在相同的温度下滴加3-(2-噻吩基)丙醛,-50℃条件下再反应2小时。加入饱和氯化铵淬灭反应,反应液放置到室温,然后通过减压蒸馏除去四氢呋喃;加入水和乙酸乙酯进行萃取分液,分得的有机相先后用5%碳酸氢钠和饱和食盐水洗,并浓缩获得油状物;将油状物通过硅胶柱分离得到目标产物二苯甲基-6α-溴-6β-(1R-羟基-3(2-噻吩基)丙基)青霉素酸(1.1g),产率为49%。
S14.将步骤S13得到的0.92g(1.57mmol)二苯甲基-6α-溴-6β-(1R-羟基-3(2-噻吩基)丙基)青霉素酸溶于40mL甲醇中,冷却到0-5℃,加入0.59mL(2.35mmol)三丁基膦,反应液在相同温度下反应1小时。减压蒸馏,然后通过硅胶柱色谱纯化得到苯甲基-6α-(1R-羟基-3(2-噻吩基)丙基)青霉素酸0.47g,产率59%。
S15.将200mg苯甲基-6α-(1R-羟基-3(2-噻吩基)丙基)青霉素酸与3mL间甲苯酚混合,将反应液在氮气保护条件下,50℃条件下反应3小时。反应液降温至室温,然后减压蒸馏,得到的油状物再经薄板层析分离得到终产物6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸60mg(PC-1),产率为46%。
上述方法的反应式如下所示:
将步骤S15得到的产物进行质谱和核磁分析。
1、采用负离子喷雾技术测得m/z:[M-H]-340.3。
2、以CDCl3为试剂,400MHz测试得到的核磁数据如下:
1H-NMR:δ1.55(s,3H,C(CH3)2),1.68(s,3H,C(CH3)2),1.86-1.98(m,2H,CH2-CH2-CH),2.91-3.05(m,2H,Ar-CH2-CH2),3.33(d,1H,CH-CHCO-CH),4.15-4.18(m,1H,CH2-CHOH-CH),4.39(s,1H,C-CHN-COOH),5.32(s,1H,CH-CHS-N),6.83(d,1H,CH-CHS-CH2),6.91-6.94(m,1H,CH=CH-CH),7.12-7.14(d,1H,CH=CH-S)。
13C-NMR:δ25.9,26.8,30.6,37.1,61.5,65.5,65.6,66.5,70.9,123.4,124.6,126.9,143.8,172.4,174.0。
实施例2
体外测试实施例提供的6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸进行C类β-内酰胺酶的抑制活性。
(1)将P99和PenP的DNA序列分别通过分子克隆方法***一个修饰的pET30a的载体中,这一载体包含6个组氨酸的标签和HRV3C蛋白酶的酶切位点,通过这一方法构建出含有P99或PenP基因序列的质粒,然后将两种质粒分别转化到大肠杆菌BL21(DE3)中。接下来,不管是PenP还是P99,蛋白的表达和纯化都采用相同的步骤。细菌接种过夜后,以1:100的倍数稀释到2.4L的LB营养基中,在37℃培养2.5小时直至OD600达到0.6-0.8,然后加入异丙基硫代-β-D-半乳糖苷(IPTG)诱导蛋白表达,再在30℃培养5小时后离心收获菌体。
通过上述方法表达的融合蛋白含有6个组氨酸的标签,因此蛋白纯化可以采用镍亲和柱分离得到纯的融合蛋白。再通过蛋白酶HRV 3C切掉标签,通过第二轮的镍亲和柱分离除去标签,再经过进一步的凝胶过滤色谱得到纯的目标蛋白。最后P99或PenP蛋白经过浓缩后,液氮中速冻保存在-80℃冰箱中。
(2)β-内酰胺酶活性的测定
该方法使用头孢硝噻吩作为β-内酰胺酶的底物,头孢硝噻吩水解前后从黄色变成红色,产物在500nm会有显著的吸收,由此通过紫外可见分光光度计记录底物水解引起的吸收度变化来测定PenP或P99β-内酰胺酶的水解活性。
(3)β-内酰胺酶抑制活性的测定
将PC-1与P99或PenP混合10分钟,然后加入头孢硝噻吩,用紫外可见分光光度计记录吸收度变化来测定水解的初始速度;改变PC-1的浓度,在6-8个浓度下一式两份的对水解速度进行测试,获得PC-1浓度[S]和不同浓度下的水解速度[v],通过GraphPad软件处理数据,算出IC50。临床上常用的β-内酰胺酶抑制剂克拉维酸和苏巴坦作为对照分别进行相同的实验来得到他们对于PenP或P99的IC50,结果如下表1所示。
表1
上述结果表明,PC-1不能抑制A类β-内酰胺酶PenP(IC50>1mM),相比而言,克拉维酸和苏巴坦是有效的A类β-内酰胺酶抑制剂(IC50<2μM)。可是,PC-1可以比较有效而且特异性的抑制C类β-内酰胺酶P99,其抑制效果相比克拉维酸和苏巴坦有2-5倍的提升。
实施例2
一种C类β-内酰胺酶抑制药物,所述C类β-内酰胺酶抑制药物中含有实施例1提供的C类β-内酰胺酶抑制剂6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸和抗生素。
体外测试上述C类β-内酰胺酶抑制药物的抑菌活性,包括:
(1)PC-1的抑菌浓度测试
将PC-1溶于300μL LB培养基中,达到终浓度512μg/mL,然后取其中150μL稀释两倍制备浓度为256μg/mL的PC-1溶液,接下来用同样的方法先后配制浓度分别为128,64,32,16,8,4,2,1μg/mL的PC-1的LB溶液。大肠杆菌BL21(DE3)接种培养过夜后,稀释至OD6000.08-0.1,取5μL,加入之前配制的150μL含PC-1的培养基中,在37℃培养过夜,读取最小的无细菌生长时的PC-1浓度,即为最小抑菌浓度(MIC),测试结果如表2所示。
表2
表2结果表明,PC-1不能像抗生素一样,具备抑菌的效果。
(2)药物联用测试
该方法测试PC-1与抗生素联用对表达P99的大肠杆菌BL21(DE3)的最小抑菌浓度。混合不同浓度的PC-1(终浓度1,2,4~512μg/mL,10个浓度,相邻两个浓度后者是前者的2倍)和抗生素包括青霉素G,氨苄西林,头孢噻吩,头孢西丁(终浓度1,2,4~512μg/mL),测试不同浓度下PC-1对应的抗生素的最小抑菌浓度MIC,结果如下表3所示。
表3
表3结果表明,跟没有PC-1时相比,当PC-1浓度为512μg/mL时,青霉素G的MIC从512μg/mL减少到16μg/mL,达到32倍的提升;当联合PC-1与其他抗生素如氨苄西林,头孢噻吩,头孢西丁合用时,相应的MIC也有4-8倍的提升。由此可见,PC-1充当了C类β-内酰胺酶抑制剂的作用,加强了抗生素的抑菌活性。抑菌实验证实PC-1与抗生素合用时,可以提升抗生素的最小抑菌浓度达4-32倍。
实施例4
通过质谱和X-射线晶体学阐述PC-1抑制P99的内在分子机制。
(1)质谱分析证实PC-1与P99形成稳定的酰化产物。
将35μL 5μM P99β-内酰胺酶与35μL 20μM PC-1混合,在室温下反应,在不同的时间点用70μL含1%甲酸的乙腈溶液淬灭反应,然后采用电子喷雾电离质谱(ESI-MS)分析混合物的组成,反应0、5、15分钟的质谱图分别如图1、2、3所示。在所获得的质谱图中,E代表酶,而EI*代表酶跟PC-1发生酰化反应的产物。
质谱结果证实PC-1与C类β-内酰胺酶P99发生缓慢的酰化反应,在反应发生15分钟后趋于平衡,而没有检测到脱酰化反应的发生。
(2)P99与化合物PC-1的复合物结构解析
将纯化得到的P99蛋白采用悬滴气相扩散法结晶,1μL P99蛋白与1μL结晶液(0.1MBis-Tris pH 6.5,25%PEG3350)混合,晶体在16℃生长,大约两周长到~100μm大小。为了获得P99与PC-1的复合物结构,将P99晶体浸泡于含PC-1结晶液中(浓度约50mM)约20分钟,接下来把复合物晶体放入Rigaku X-射线衍射仪中,收集360℃的衍射数据。
数据处理采用CCP4程序套件,然后通过分子置换法获得初步的结构信息,接下来进行结构精修,最终获得复合物的结构。
P99与化合物PC-1的复合物结构,如附图4-6所示。在这一复合物结构中,2fo-fc电子密度图清楚地显示PC-1的β-内酰胺环打开,与丝氨酸64共价结合(图4,2Fo-Fc电子密度图以网状格式显示)。结合位点羰基有着保守的构型,位于由丝氨酸64和丝氨酸318主链氮原子组成的氧阴离子穴中;侧链C8上的羟基与天冬酰胺152形成氢键作用,末端噻吩跟酪氨酸221构成π-π重叠效应(图5,虚线表示氢键作用)。
值得注意的是,在所得的复合物结构中,PC-1整体保持一种独特的近似“水平”的构型,这在以往报道的复合物结构中从没出现过。P99-PC-1(6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸)结构与AmpC_amoxicillin(阿莫西林)(PDB ID:1LL9)、AmpC_cephalothin(头孢噻吩)(PDB ID:1KVM)复合物结构的重叠图如附图6所示。在已报道的AmpC与阿莫西林或头孢噻吩的复合物结构中,酰化加合物采取了“弯曲”的构型,阿莫西林的四氢噻唑环和头孢噻吩的二氢噻嗪环都弯曲而指向溶剂端,与β-内酰胺环的主链结构形成大约90℃的夹角,而关键的脱酰化水分子位于活性中心,便于对酰化加合物亲核进攻。相比而言,PC-1的四氢噻唑环保持在活性中心,支链的羧酸基团直接占据了脱酰化水分子的位置,与赖氨酸315,丝氨酸316和天冬酰胺346发生氢键作用,所导致的后果就是PC-1占据活性位点而不能被脱酰化,从而抑制了酶的活性。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (9)
1.一种C类β-内酰胺酶抑制剂,其特征在于,所述C类β-内酰胺酶抑制剂为6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸,具有如下式1所示结构,
2.一种C类β-内酰胺酶抑制剂的制备方法,其特征在于,包括以下步骤:
步骤(1).将第一非质子性溶剂进行冷却处理后,在搅拌条件下加入液溴、硫酸、亚硝酸钠或亚硝酸钾,然后加入6-氨基青霉素酸,在4-10℃条件下进行恒温反应,获得6,6-二溴青霉素酸;
步骤(2).将所述6,6-二溴青霉素酸溶于第二非质子性溶剂中,室温条件下添加二苯基重氮甲烷,反应制备二苯甲基6,6-二溴青霉素酸;
步骤(3).将所述二苯甲基6,6-二溴青霉素酸溶于四氢呋喃中,冷却至-70~-50℃,加入格氏试剂溶液和3-(2-噻吩基)丙醛,反应制备二苯甲基-6α-溴-6β-(1R-羟基-3(2-噻吩基)丙基)青霉素酸;
步骤(4).将所述二苯甲基-6α-溴-6β-(1R-羟基-3(2-噻吩基)丙基)青霉素酸溶解后,冷却至0-5℃,加入三丁基膦,反应制备二苯甲基-6α-(1R-羟基-3(2-噻吩基)丙基)青霉素酸;
步骤(5).将所述二苯甲基-6α-(1R-羟基-3(2-噻吩基)丙基)青霉素酸与间甲苯酚在惰性气氛下反应,制备得到6α-(1R-羟基-3(2-噻吩-基)丙基)青霉素酸。
3.如权利要求2所述的C类β-内酰胺酶抑制剂的制备方法,其特征在于,所述步骤(1)中,所述液溴、6-氨基青霉素酸的摩尔比为2.4:1~3:1,所述亚硝酸钠或亚硝酸钾、6-氨基青霉素酸的摩尔比为1.5:1~2:1;和/或
在所述恒温反应结束后,还包括在反应液中加入还原剂,其中,所述还原剂为亚硫酸氢钠、亚硫酸钠、硫代硫酸钠中的至少一种。
4.如权利要求2所述的C类β-内酰胺酶抑制剂的制备方法,其特征在于,所述步骤(2)中,所述二苯基重氮甲烷采用滴加的方式进行添加。
5.如权利要求2所述的C类β-内酰胺酶抑制剂的制备方法,其特征在于,所述步骤(3)中,反应制备二苯甲基-6α-溴-6β-(1R-羟基-3(2-噻吩基)丙基)青霉素酸的条件为:在-70~-50℃条件下反应2~3小时;
所述格式试剂为乙基溴化、甲基溴化镁、异丙基溴化镁中的至少一种。
6.如权利要求2所述的C类β-内酰胺酶抑制剂的制备方法,其特征在于,所述步骤(4)中,反应制备二苯甲基-6α-(1R-羟基-3(2-噻吩基)丙基)青霉素酸的条件为:在-0-5℃条件下反应1~2小时。
7.如权利要求2所述的C类β-内酰胺酶抑制剂的制备方法,其特征在于,所述步骤(5)中,将所述二苯甲基-6α-(1R-羟基-3(2-噻吩基)丙基)青霉素酸与间甲苯酚在惰性气氛下反应的条件为:在50~60℃条件下反应3~5小时。
8.一种C类β-内酰胺酶抑制药物,其特征在于,所述C类β-内酰胺酶抑制药物中含有权利要求1所述的C类β-内酰胺酶抑制剂。
9.如权利要求8所述的C类β-内酰胺酶抑制药物,其特征在于,所述C类β-内酰胺酶抑制药物中还含有抗生素。
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