CN107260729B - β-内酰胺化合物及其用途 - Google Patents
β-内酰胺化合物及其用途 Download PDFInfo
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- CN107260729B CN107260729B CN201710337816.7A CN201710337816A CN107260729B CN 107260729 B CN107260729 B CN 107260729B CN 201710337816 A CN201710337816 A CN 201710337816A CN 107260729 B CN107260729 B CN 107260729B
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Abstract
Description
本申请是申请日为2011年11月25日的题为“化合物及其用途”的中国专利申请No.201180056747.3的分案申请。
技术领域
本发明所述的是β-内酰胺化合物作为β-内酰胺酶抑制剂的用途,其类似物、衍生物、互变异构形式、立体异构体、多晶型物、溶剂合物、药学上可接受的盐、酯、前药及其代谢物用于与合适的抗生素组合治疗细菌感染的用途。本发明描述了用于治疗细菌感染的这些化合物的药物组合物。本文所描述的化合物用作检测β-内酰胺酶的诊断试剂。
背景技术
β-内酰胺类抗生素,即青霉素类,头孢菌素类,碳青霉烯类,单环β-内酰胺类是经常使用的抗生素。已知由微生物产生的β-内酰胺酶水解β-内酰胺环,从而使抗菌活性失活。为了抑制β-内酰胺酶,将β-内酰胺酶抑制剂与抗生素联合给药。这些抑制剂与β-内酰胺酶结合后比单独β-内酰胺抗生素能发挥更大的作用。这种组合帮助抗生素发挥其抗菌效果,而其抗菌效果不会因β-内酰胺酶而下降。几种抗生素/β-内酰胺酶抑制剂的组合在市场上已存在,例如,氨苄西林/舒巴坦,阿莫西林/克拉维酸,替卡西林/克拉维酸,哌拉西林/他佐巴坦等。这些β-内酰胺/β-内酰胺酶抑制剂组合抗生素用于在社区和在医院环境中治疗产β-内酰胺酶的细菌引起的感染-但除了碳青霉烯酶和抑制剂抗性的β-内酰胺酶。
抗菌药物,尤其是β-内酰胺抗生素的广泛使用带来的日益增长的问题是在抗生素耐药性方面的发展。抗生素耐药性的一个重要诱因在于β-内酰胺酶(例如,碳青霉烯酶,头孢菌素酶,青霉素酶,ESBL,抑制剂抗性的β-内酰胺酶,等)。在许多已知的β-内酰胺酶中,碳青霉烯酶(例如,KPC,Sme,NMC-A,IMI等) 是最近发现的,它们可水解所有类别的β-内酰胺抗生素(Drawz,S.M.和 Bonomo,R.A.Clin.Microbiol.Rev.2010,23(1),160-201)。已知这些酶有多药耐受性(MDR)的作用。考虑到开发有效抵抗不断变化的β-内酰胺酶的β-内酰胺酶抑制剂(BLI)方面的迫切需要,我们的研究工作致力于鉴定潜在的由式(I)的化合物得到的BLI。
为解决对于特定检测β-内酰胺酶的合适诊断方法的需要,使用式(I)化合物确定诊断方法。
已知许多β-内酰胺酶抑制剂在文献中公开,而式(A)的化合物公开于US 4, 562,073中,
其中R1为氢或三烷基甲硅烷基;R2为氢、三烷基甲硅烷基或COOR2',其中R2'为氢,C1-18烷基,C2-7烷氧基甲基,C3-8烷基羰基氧甲基,C4-9烷基羰基氧乙基、(C5-7环烷基)羰基氧甲基,C9-14苯甲基羰基氧甲基,C3-8烷氧基羰基甲基, C4-9烷氧基羰基乙基,酞基,2(5H)-呋喃酮-4-基,γ-丁内酯-4-基,被1至3个卤素原子取代的卤代C1-6烷基,C1-6烷氧基或硝基取代的或未取代的苯甲基,二苯甲基,四氢吡喃基,二甲基氨基乙基,二甲基氯硅烷基,三氯甲硅基,(5-取代的C1-6烷基或苯基或未取代的-2-氧代-1,3-二氧环戊烷(dioxoden)-4-基)甲基, C8-13苯甲酰基氧烷基或用于形成药学上可接受的盐的集团;且R3与以上R2'有相同的含义。
我们的专利,US 7,687,488 B2(印度同族IN 1217CHE2006)公开了式(B) 化合物。这些化合物被证明能够增强抗生素的活性。
式中,A=C或N;Het为三至七元杂环;R1代表羧酸根阴离子或-COOR4,其中R4代表氢,羧酸保护基团或药学上可接受的盐;R2和R3可以为相同或不同的,并各自独立地表示氢,卤素,氨基,保护的氨基或任选被取代的烷基,烯基,炔基等,R表示取代或未取代的烷基,烯基,芳基,芳烷基,环烷基,氧代基,杂环基,杂环烷基。
人们对于β-内酰胺酶抑制剂有广泛的需求,因为它们能抑制β-内酰胺酶等酶,特别是产碳青霉烯酶多药抗性细菌。此外,对于抗生素,特别是β-内酰胺类抗生素和克服了细菌耐药性的和β-内酰胺酶抑制剂的组合的需求仍未被满足。
发明目的
本发明的一个目的是使用式(Ⅰ)的β-内酰胺化合物作为β-内酰胺酶抑制剂与合适的抗生素组合用于治疗产β-内酰胺酶的细菌引起的感染,该β-内酰胺酶如碳青霉烯酶,头孢菌素酶,青霉素酶,ESBL,抑制剂抗性β-内酰胺酶,ESBL 等。
本发明的另一个目的是提供一种药物组合物,其将式(I)化合物与合适的抗生素组合。
本发明的还另一个目的是提供一种治疗或预防宿主的细菌感染的方法,该宿主通常是动物且最典型的是人,该方法包括向宿主将治疗量的式(I)化合物或药学上可接受的盐和/或其前药以及β-内酰胺抗生素一起施用。
本发明的另一目的是提供一种用于检测β-内酰胺酶的诊断试剂。所述β-内酰胺酶属于KPC家族(例如,KPC-2,KPC-3)及ESBL(例如,SHV18)生产肠杆菌。
本发明的另一目的是恢复/增强抗生素,尤其是β-内酰胺抗生素,如青霉素类,头孢菌素类,碳头孢烯、氧头孢烯,碳青霉烯类,青霉烷类,头霉素类,青霉烯类和单环β-内酰胺,通过与式(I)的化合物组合对于碳青霉烯酶和ESBL 的活性。
因此,本发明的一个目的是提供一种用于抑制β-内酰胺酶的化合物;和/或包含所述化合物的药物组合物;和/或用于抑制细胞中的β-内酰胺酶的改进的方法;和/或用于治疗和/或预防β-内酰胺酶介导的疾病的改进的方法,和/或与β- 内酰胺抗生素一起用于治疗和/或预防细菌感染的改进方法;和/或恢复/增强抗生素的活性的方法;或者至少向公众提供一种有用的选择。
发明内容
这里所描述的是式(I)化合物,其衍生物,类似物,互变异构形式,立体异构体,多晶型物,溶剂合物,药学上可接受的组合物,代谢物,前药,药学上可接受的盐和酯的方法或用途;
特别地,本文所提供的是式(Ⅰ)化合物,它们的衍生物,类似物,互变异构形式,立体异构体,多晶型物,溶剂合物,代谢物,前药,水合物,药学上可接受的盐和酯,用于抑制β-内酰胺酶的用途,该β-内酰胺酶包括碳青霉烯酶,头孢菌素酶,青霉素酶,ESBL,细菌所产生的抗抑制剂的β-内酰胺酶;增强/ 恢复抗生素的活性的用途,包括向有需要的受试者施用治疗有效量的式(I)化合物;
其中
A=C或N;
Het代表取代的或未取代的三至七元杂环;R1代表羧酸根阴离子或-COOR4,其中R4代表氢,C1-C6烷基,C6-C10芳基,C6-C10芳基C1-C6烷基甲氧基苯甲基,硝基苯甲基,甲硅烷基,二苯基甲基、普塞基、醋氧乙基、环庚塞基、匹伏基、海替基(hexetil)、达罗塞特或其药学上可接受的盐;R2和R3可以相同或不同,且独立地代表氢,卤素,氨基,选自三苯甲基氨基,酰氨基(如苯基乙酰基氨基),苯氧基乙酰氨基和苯甲酰基氨基的保护的氨基或任选取代的C1-C6烷基,C2-C6烯基和C2-C6炔基;
R表示取代或未取代的C1-C6烷基,C2-C6烯基,C6-C10芳基、C6-C10芳基 C1-C6烷基、C3-C12环烷基,氧代基,杂环基和杂环烷基,在基团R,R2和R3被取代时,该取代基可为选自以下的一种或多种:低级烷基(C1-C4烷基,如甲基,乙基,丙基和异丙基);低级烷氧基(C1-C4烷氧基,如甲氧基,乙氧基和丙氧基);低级烷硫基(C1-C4烷硫基,如甲硫基和乙硫基);低级烷氨基(C1-C4烷氨基,如甲氨基,乙氨基和丙氨基);环(低级)烷基(C5-C6环烷基,如环戊基和环己基);环(低级)烯基(C5-C6环烯基如环己烯基和环己二烯基);羟基;卤素(氯,溴,氟和碘);氨基;保护的氨基;氰基;硝基;氨基甲酰基;-CONHC1-C4烷基-COO-C1-C4烷基;羧基;保护的羧基;-COO-C1-C4烷基;-CO-杂环基;磺酰基;氨磺酰基;亚氨基;氧代基;氨基(低级)烷基,如氨基甲基,氨基乙基和氨基丙基;卤代(低级)烷基如三氟甲基(-CF3),氟甲基,氟乙基,溴甲基和二氟甲基;羧酸和羧酸衍生物,如异羟肟酸,酯和酰胺。优选的取代基为C1-C4烷基,C1-C4烷氧基,C1-C4烷硫基,C1-C4烷氨基,羟基,卤素及三卤甲基。该取代物任选进一步被C1-C4烷氧基羰基C1-C4烷基,羟基C1-C4烷基;C1-C4烷基,C6-C10芳基,杂环基和酯。
一方面,本文提供的是式(Ⅱ)化合物,其衍生物,类似物,互变异构形式,立体异构体,多晶型物,溶剂合物,代谢物,前药,水合物,药学上可接受的盐和酯,用于抑制细菌所产生的碳青霉烯酶;增强/恢复抗生素活性,包括向有需要的受试者施用治疗有效量的式(II)化合物;
其中
L=C或N;
R,R1,R2和R3如上所述。
R5代表氢,C1-C6烷基,C1-C6烷氧基,C1-C6烷硫基,C1-C6烷氨基,羟基,卤素及三卤甲基;且
m为0,1或2。
另一方面,本文提供的是化合物,其用于治疗和/或预防由产碳青霉烯酶细菌引起的感染,包括向有需要的受试者给予治疗有效量的式(I)化合物。
在还另一方面,本文提供的是化合物,其用于治疗和/或预防产碳青霉烯酶细菌引起的感染,包括向有需要的受试者施用治疗有效量的式(I)化合物,并与合适的抗生素组合使用。
在还另一方面,本文提供的是化合物,其用于治疗由革兰氏阴性菌表达的β- 内酰胺酶引起的感染。
在还另一方面,本文提供的是用于使用的化合物,其中细菌选自肺炎克雷伯杆菌(Klebsiella pneumoniae)和大肠杆菌(E.coli)。
在还另一方面,本文提供的是用于使用的化合物,其中所述碳青霉烯酶选自KPC-2和KPC-3。
在还另一方面,本文提供的是用于治疗或预防产碳青霉烯酶细菌引起的感染的方法,该方法包括施用治疗有效量的式(I)化合物。
本文的另一方面包括肠杆菌和非肠杆菌表达的β-内酰胺酶的检测。
本文的还另一个方面包括式(I)化合物作为检测β-内酰胺酶的诊断试剂的用途。所述β-内酰胺酶属于KPC-2,KPC-3的家庭,以及ESBL例如产SHV18肠杆菌。
在一个实施例中,此处提供的是包含式(I)化合物的药物组合物,其作为治疗或预防产碳青霉烯酶细菌所引起的感染的活性成分。
在另一实施方案中,本文所提供的是包含式(I)化合物的药物组合物,其与以下组分一起作为治疗或预防产碳青霉烯酶细菌所引起的感染的活性成分:
a.一种或多种式(Ⅰ)化合物;
b.一种或多种抗生素,和
c.一种或多种药学上可接受的载体。
在还另一实施例中,该抗生素选自β-内酰胺抗生素类。
在还另一实施例中,本文提供的是以下化合物:(2S,3S,5R)-3-甲基-3-(3-甲基-咪唑-3-鎓-1-基甲基)-4,4,7-三氧代-4-硫杂-1-氮杂双环[3.2.0]庚烷-2-羧酸酯和 (2S,3S,5R)-3-甲基-3-(4-甲基-3-甲基-咪唑-3-鎓-1-基甲基)-4,4,7-三氧代-4-硫杂-1- 氮杂-双环[3.2.0]庚烷-2-羧酸酯,它们的衍生物、类似物,互变异构形式,立体异构体,多晶型物,溶剂合物,代谢物,前药,药学上可接受的盐和酯。
在还另一方面,化合物(2S,3S,5R)-3-甲基-3-(3-甲基-咪唑-3-鎓-1-基甲基)-4,4,7-三氧代-4-硫杂-1-氮杂双环[3.2.0]庚烷-2-羧酸酯;(2S,3S,5R)-3-甲基 -3-(4-甲基-3-甲基-咪唑-3-鎓-1-基甲基)-4,4,7-三氧代-4-硫杂-1-氮杂-双环[3.2.0] 庚烷-2-羧酸酯及其衍生物,类似物,互变异构形式,立体异构体,多晶型物,溶剂合物,代谢物,前药,药学上可接受的盐和酯,其用于抑制β-内酰胺酶,该β-内酰胺酶不限于,碳青霉烯酶,头孢菌素酶,青霉素酶,ESBL和抑制剂抗性β-内酰胺酶的用途。
在还另一些方面中,本文所描述的是式(I)化合物,其用于治疗和/或预防耐受抗生素的细菌。
附图说明:
图1:检测KPCβ-内酰胺酶的双纸片协同试验。图1示出了用于检测KPCβ-内酰胺酶双盘协同实验,其示出了化合物-1抗(A)肺炎克雷伯菌ATCC BAA 1705[KPC2生产者],(B)大肠杆菌233[KPC3生产者],(C)肺炎克雷伯菌ATCC 700603[SHV 18生产者],(D)大肠杆菌ATCC 25922。其中,I=亚胺培南;C=头孢他定;T=化合物-1;IT=亚胺培南+化合物-1;CT=头孢他定+化合物-1。
具体实施方式
式(I)的β-内酰胺化合物,
其衍生物,类似物,互变异构形式,立体异构体,多晶型物,溶剂合物,其药学上可接受的组合物,其药学上可接受的盐和酯,它们用于抑制由细菌产生的碳青霉烯酶;增强/恢复抗生素活性,其中:
Het为三至七元杂环,该杂环可具有合适的取代基,优选的杂环基如吡咯基,吡咯啉基,咪唑基,吡唑基,吡啶基,嘧啶基,吡嗪基,哌啶基,呋喃基,噻吩基,吡咯烷基,哌嗪基,噁唑烷基,噻唑基,哒嗪基,四唑基(例如1H-四唑基,2H-四唑基等),咪唑基,三唑基,1,2,4-噁二唑基,1,3,4-噁二唑基,1,2,5- 噁二唑基,1,2,3-噻二唑基,1,2,4-噻二唑基,1,3,4-噻二唑基和1,2,5-噻二唑基。
所定义的杂环基可任选地被一个或多个取代基取代,合适的取代基例如:低级烷基(C1-C4烷基,如甲基,乙基和丙基),低级烷氧基(C1-C4烷氧基如甲氧基,乙氧基和丙氧基),低级烷硫基(C1-C4烷硫基,如甲硫基和乙硫基),低级烷氨基(C1-C4烷氨基如甲氨基,乙氨基和丙氨基),环(低级)烷基(C5-C6环烷基,如环戊基和环己基);环(低级)烯基(C5-C6环烯基如环己烯基和环己二烯基),羟基,卤素(氯,溴,氟和碘);氨基;保护的氨基;氰基;硝基;羧基;保护的羧基,氨磺酰基;亚氨基;氧代基;氨基(低级)烷基(氨基甲基,氨基乙基和氨基丙基);卤素和三卤甲基(-CF3)。优选的取代基为C1-C4烷基,C1-C4烷氧基,C1-C4烷硫基,C1-C4烷氨基,羟基,卤素和三卤甲基。该取代物任选进一步被取代。
通常情况下,基团Het是未取代的或带有一个或多个如上文所定义的取代基。
优选地,Het表示包含一个或两个杂原子(包括季铵化的氮)的五到六元杂环。更优选Het选自吡咯基、吡咯啉基、咪唑基、三唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哌啶基、呋喃基、噻吩基、吡咯烷基、哌嗪基、噁唑烷基、噻唑基、哒嗪基、吡咯烷基和咪唑烷基。
优选地,Het是芳环。
更优选地,Het表示五元杂环;
R1代表羧酸根阴离子或-COOR4,其中R4表示氢,-C6烷基,C6-C10芳基, C6-C10芳基C1-C6烷基,甲氧基苯甲基,硝基苯甲基,甲硅烷基,二苯基甲基,普塞基,醋氧乙基、环庚塞基、匹伏基、海替基、达罗塞特根(daloxate)或其药学上可接受的盐;
R2和R3各自独立地表示氢,卤素,氨基,如三苯甲基氨基的保护的氨基,如苯基乙酰氨基的酰氨基,苯氧基乙酰氨基和苯甲酰基氨基,任选取代的烷基,烯基或炔基;
优选地,R选自-(CH2)n-CH3,-(CH2)nC6H5,-(CH2)n-CH=CH2,-CH2-CONH2,包括-CH2COOBut的-CH2-COO-(C1-C4烷基),-(CH2)nCO-杂环基, -CH2-CONH-(CH2)n-COOEt,其中n是从0到5的整数。
更优选地,R为-(CH2)n-CH3,-(CH2)nC6H5,-(CH2)n-CH=CH2,-CH2-CONH2或-CH2COOBut。
本文所使用的,C1-C6烷基基团或部分为直链或支链的含1至6个碳原子的烷基基团或部分。通常地,C1-C6烷基基团或部分为C1-C4烷基或部分。C1-C4烷基基团或部分是包含1至4个碳原子的直链或支链的烷基或部分。C1-C6烷基基团和部分的实例包括,但不限于、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、3-甲基-丁基、戊基和己基。C1-C4烷基基团和部分的实例包括,但不限于,甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。为免生疑问,在一组中存在两个烷基部分时,该烷基部分可以是相同或不同的,其可任选地被一个或多个取代基取代。
术语“C2-C6烯基”是指含有碳-碳双键,并且可以为具有约2至6个碳原子的直链或支链的脂肪族烃基,其可任选地被一个或多个取代基取代。优选的烯基包括,但不限于,乙烯基、1-丙烯基、2-丙烯基、异丙烯基、2-甲基-1-丙烯基、 1-丁烯基和2-丁烯基。
本文所使用的,C6-C10芳基基团或部分通常是苯基或萘基。苯基为优选的。
术语“C6-C10芳基C1-C6烷基”指直接键合至烷基的芳基,其可以任选被一个或多个取代基取代。优选的芳烷基包括,但不限于,-CH2C6H5,-C2H4C6H5, -CH(CH3)C6H5等。
本文所用的,术语“杂环基”指5至10元杂环基团或部分为单环的非芳族,饱和或不饱和的C5-C10的碳环,其中一个或多个,例如1,2,3或4个碳原子被选自N,O,S,S(O)和S(O)2的杂原子取代。通常情况下,它是5至6元环。合适的杂环基团和部分包括吡唑烷基,哌啶基,哌嗪基,硫代吗啉基,S-氧代- 硫代吗啉基,S,S-二氧代-硫代吗啉基,吗啉基,吡咯烷基,吡咯啉基,咪唑烷基,咪唑啉基,1,3-二氧戊环基,1,4-二氧杂环戊烯基和吡唑啉基和部分。吡唑烷基,哌啶基,哌嗪基,吡唑烷基,吗啉基和咪唑基和部分是优选的。
术语“杂环基烷基”指与烷基直接键合的杂环基,其可以被取代或未被取代。
术语“C3-C12环烷基”指约3至12个碳原子的非芳族单环或多环系统,其可任选地被一个或多个取代基取代。优选的环烷基包括,但不限于,环丙基,环丁基,环戊基,环己基,环辛基和十氢萘基。
术语“类似物”包括通过一个或多个C,N,O或S原子与母体结构不同的化合物。因此,某一化合物中母体结构的N原子之一被S原子取代后为该化合物的类似物。
术语“衍生物”指从式(I)的化合物利用简单的化学处理过程,例如通过氧化,氢化,烷基化,酯化,卤化等转化一个或多个的官能团得到的化合物,类似物,互变异构形式,立体异构体,多晶型物,水合物,其药学上可接受的盐或药学上可接受的溶剂合物。
术语“立体异构体”包括在原子的空间排列上彼此不同但其化学式和结构都相同的异构体。立体异构体包括对映异构体和非对映异构体。
术语“互变异构体”包括可容易地相互转换的处于平衡状态的化合物的异构体形式。酮-烯醇互变异构现象是一个示例。
术语“多晶型物”包括晶型上不同形式,而在化学上具有相同结构的化合物。
术语“药学上可接受的溶剂合物”包括溶剂分子与溶质化合物的分子或离子的组合。
具有β-内酰胺酶抑制性质的代表性的化合物(1-13)包括但不限于:
1.l-{[(2S,3S,5R)-2-羧基-3-甲基-4,4,7-三氧代-4-硫杂-1-氮杂双环[3.2.0]庚-3- 基]甲基}-3-甲基-1H-1,2,3-三唑-3-鎓;
2.l-{[(2S,3S,5R)-2-羧基-3-甲基-4,4,7-三氧代-4-硫杂-l-氮杂双环[3.2.0]庚-3- 基]甲基}-3-乙基-1H-1,2,3-三唑-3-鎓;
3.l-{[(2S,3S,5R)-2-羧基-3-甲基-4,4,7-三氧代-4-硫杂-l-氮杂双环[3.2.0]庚-3- 基]甲基}-3-正丙基-1H-1,2,3-三唑-3-鎓;
4.l-{[(2S,3S,5R)-2-羧基-3-甲基-4,4,7-三氧代-4-硫杂-l-氮杂双环[3.2.0]庚-3- 基]甲基}-3-烯丙基-1H-1,2,3-三唑-3-鎓;
5.l-{[(2S,3S,5R)-2-羧基-3-甲基-4,4,7-三氧代-4-硫杂-l-氮杂双环[3.2.0]庚-3- 基]甲基}-3-(2-氨基-2-氧代乙基)-1H-1,2,3-三唑-3-鎓和对应的酸;
6.l-{[(2S,3S,5R)-2-羧基-3-甲基-4,4,7-三氧代-4-硫杂-l-氮杂双环[3.2.0]庚-3- 基]甲基}-3-(2-叔丁氧基-2-氧代乙基)-1H-1,2,3-三唑-3-鎓和对应的酸;
7.l-{[(2S,3S,5R)-2-羧基-3-甲基-4,4,7-三氧代-4-硫杂-l-氮杂双环[3.2.0]庚-3- 基]甲基}-3-(2-吗啉-4-基-2-氧代乙基)-1H-1,2,3-三唑-3-鎓和对应的酸;
8.l-{[(2S,3S,5R)-2-羧基-3-甲基-4,4,7-三氧代-4-硫杂-l-氮杂双环[3.2.0]庚-3- 基]甲基}-3-{2[(2-乙氧基-2-氧代乙基)氨基]-2-氧代乙基}-1H-1,2,3-三唑-3-鎓和对应的酸;
9.l-{[(2S,3S,5R)-2-羧基-3-甲基-4,4,7-三氧代-4-硫杂-l-氮杂双环[3.2.0]庚-3- 基]甲基}-3-{2-[(3-乙氧基-3-氧丙基)氨基]-2-氧乙基}-1H-1,2,3-三唑-3-鎓和对应的酸;
10.l-{[(2S,3S,5R)-2-羧基-3-甲基-4,4,7-三氧代-4-硫杂-l-氮杂双环[3.2.0]庚-3- 基]甲基}-3-(2-{[1-(乙氧基羰基)-2-羟基丙基]氨基}-2-氧代乙基)-1H-1,2,3-三唑-3- 鎓和对应的酸;
11.l-{[(2S,3S,5R)-2-羧基-3-甲基-4,4,7-三氧代-4-硫杂-l-氮杂双环[3.2.0]庚-3- 基]甲基}-3-苯甲基-1H-1,2,3-三唑-3-鎓和对应的酸;
12.(2S,3S,5R)-3-甲基-3-(3-甲基-咪唑-3-鎓-1-基甲基)-4,4,7-三氧代-4-硫杂-1- 氮杂双环[3.2.0]庚烷-2-羧酸酯和对应的酸;
13.(2S,3S,5R)-3-甲基-3-(4-甲基-3-甲基-咪唑-3-鎓-1-基甲基)-4,4,7-三氧代-4- 硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸酯和对应的酸。
这些化合物(1至11)通过US7,687,488(印度同族IN1217CHE2006)提供的如下方法制备。
化合物12和13根据如下所示反应方案制备:
式(IV)化合物通过在步骤1中将式(VI)化合物与式(V)化合物的反应获得。在步骤2中,式(IV)化合物转化为式(III)化合物。式(III)化合物向式(I)化合物的转化可使用选自六甲基二硅氮烷(HMDS),三甲基氯硅烷(TMCS),三甲基碘硅烷 (TMSI),N,O-双-(三甲基甲硅烷基)-乙酰胺(BSA),甲基三甲基甲硅烷基三氟乙酰胺(MSTFA),Ν,Ο-双(三甲基甲硅烷基)三氟乙酰胺(BSTFA),甲基二氯硅烷,二甲基二氯硅烷,二苯基二氯硅烷,N-甲基甲硅烷基乙酰胺(MSA),双三甲基甲硅烷基脲等的甲硅烷基化剂,在试剂存在下进行,该试剂例如丙酮,甲醇,四氢呋喃,氯仿,二氯甲烷,二氯乙烷,乙酸乙酯,N,N-二甲基甲酰胺(DMF),二甲基乙酰胺(DMAc)等或其混合物。式(I)化合物通过将式(III)化合物与合适的 R-X(X=卤素)反应获得。
本文所描述的β-内酰胺化合物优选形成为内盐。当R上的代表性取代为羧酸或氨基时,它可被进一步转化成药学上可接受的盐。用于制造羧酸基团的盐的碱选自以下的碱:氢氧化钠,甲醇钠,碳酸氢钠,碳酸钠,碳酸氢钾,碳酸钾,氢氧化钙,氢氧化镁等,在如醚,四氢呋喃,甲醇,叔丁醇,二噁烷,异丙醇,乙醇等溶剂中。也可使用溶剂的混合物。也可以使用合适的酸制备酸加成盐。
形成本发明的一部分的化合物的立体异构体可通过使用以其单一对映体形式的反应物,以所有可能的工艺制备,或通过将该反应在单一对映体形式的试剂或催化剂存在下进行,或利用常规方法将立体异构体的混合物解析。一些优选的方法包括利用微生物拆分(resolution),解析手性酸如扁桃酸,樟脑磺酸,酒石酸,乳酸等只要是可适用的手性酸形成的非对映异构体盐,或通过使用手性碱如马钱子碱,金鸡纳生物碱,它们的衍生物及其类似物进行。
式(I)化合物的前药也是本发明所考虑的。前药是一种有活性的或无活性的化合物,在向患者施用后其经体内生理学活性进行化学改性,如水解,代谢等处理成本发明的化合物。在制造,使用前药方面的适用性和涉及的技术为本领域技术人员熟知。
通式(I)的化合物的各种多晶型物可以通过将式(I)化合物在不同条件下的结晶制备,这些条件在现有技术中为已知。例如,使用不同的常用溶剂或它们的混合物进行重结晶,在不同温度下结晶,各种模式的冷却,其范围包括结晶过程中从非常快至非常慢的冷却。多晶型物也可以通过以下方式获得,将化合物加热或使其熔化,然后逐渐冷却或快速冷却。多晶型的存在可通过固体探针NMR 光谱,红外光谱,差示扫描量热法,粉末X射线衍射或此类其他技术检测。
式(I)化合物的药学上可接受的溶剂合物可通过常规方法制备,如将式(I)化合物溶解在溶剂,例如水,甲醇,乙醇中,以及以下的溶剂的混合物中,如丙酮:水,二噁烷:水,N,N-二甲基甲酰胺:水等,优选为水,并通过使用不同的结晶方法重结晶。
应注意,本文所描述的化合物可含有可以互变异构形式存在的基团,并且虽然本文中一种形式被命名,说明,显示和/或要求保护,但所有的形式应认为固有地包括在这样的名称,说明,显示和主张中。
本文公开的β-内酰胺化合物与β-内酰胺抗生素组合可用于治疗人和其他温血动物的微生物感染,它们可同时经肠胃外,局部和/或口服给药。除了式(I)化合物,该药物组合物也可包含一种或多种已知药物或与之共同施用,其中该已知药物选自其它临床上有用的抗生素制剂,如青霉素类(哌拉西林,替卡西林等),头孢菌素类(头孢他定,头孢美唑,头孢噻肟等),青霉烯类(法罗培南,美罗培南,厄他培南等),碳头孢烯(洛拉卡比等),氧头孢烯(拉氧头孢,拉他头孢,氟氧头孢等),头霉素类(头孢替坦等)单酰胺菌素类(氨曲南、替吉莫南等),氨基糖苷类(链霉素,庆大霉素,阿米卡星等),细菌素类(大肠杆菌素,小菌素等),喹诺酮类(环丙沙星,莫西沙星等),磺胺类(磺胺甲噁唑等),大环内酯类(红霉素,罗红霉素,阿奇霉素等),四环素类(多西环素,米诺环素等),甘氨酰环素类(替加环素(Tigecycline)等),噁唑烷酮类(利奈唑来,特里唑来(Torezolid),雷得唑来 (Radezolid)等),脂肽类(达托霉素等),多肽类(放线菌素,杆菌肽,粘菌素,多粘菌素B等),多烯抗真菌剂类(那他霉素,制霉菌素,两性霉素B等),利福霉素类(利福平,利福布汀,利福喷汀等),氯霉素等,或它们的衍生物。
抗生素包括青霉素类,头孢菌素类,碳头孢烯类,氧头孢烯类、碳青霉烯类,青霉烷类,头霉素类,表霉烯(penem)类、单酰胺菌素类或它们的组合。
青霉素类包括,但不限于,氮卓西林(美西林)、阿莫西林,氨苄西林,戊青霉素、阿帕西林,阿扑西林,阿度西林,阿洛西林,巴氨西林,羧苄青霉素,卡茚西林、氯甲西林、氯唑西林、环西林(环己西林),双氯西林,依匹西林、芬贝西林、氟氯青霉素(氟氯西林),海他西林,仑氨西林、美坦西林,甲氧西林,美洛西林,萘夫西林,苯唑西林,培那西林、青霉素G乙胺酯(Penethecillin),青霉素G(普鲁卡因青霉素),青霉素N,青霉素O,青霉素V(苯氧甲基青霉素),青霉素B、哌拉西林,匹氨西林,丙匹西林、喹那西林、磺苄西林、酞氨西林、替莫西林,替卡西林,匹美西林,苄星青霉素,苄青霉素,复合阿莫西林克拉维酸(Co-amoxiclav)、仑氨西林或它们的组合。
头孢菌素类包括,但并不限于头孢噻啶,头孢雷定,头孢西丁,头孢乙腈,头孢哌酮,头孢甲肟(Cefinenoxime),头孢甘酸(Cephaloglycin),头孢尼西,头孢地嗪,头孢匹罗,头孢匹胺,头孢唑兰,头孢噻利,头孢瑞南、头孢咪唑、头孢克定、头孢泊肟酯,头孢特仑,头孢卡品,头孢吡普(Ceftobiprole),头孢洛林 (ceftaroline)、头孢喹肟,头孢噻呋,头孢维星(Cefovecin),头孢羟氨苄,头孢洛宁,头孢吡肟,头孢噻肟,头孢他啶,头孢他美,头孢托仑,头孢噻啶,头孢他啶,头孢曲松、头孢拉宗,头孢噻吩,头孢唑林,头孢匹林,头孢替唑,头孢孟多,头孢替安,头孢替安己酯,头孢呋辛,头孢唑肟,头孢甲肟,头孢唑喃,头孢磺啶,头孢美唑,头孢米诺,头孢氨苄,头孢拉定,头孢克洛,头孢羟氨苄,头孢洛宁,头孢丙烯,头孢呋肟酯,头孢克肟,头孢泊肟酯,头孢布烯,头孢地尼,CXA-101(FR264205)或它们的组合;
青霉烯类包括,但不限于,法罗培南和碳青霉烯类包括但不限制于美罗培南,厄他培南(Ertapenem),多利培南,比阿培南,帕尼培南,利替培南、替比培南、头茂培南(Tomopenem)、硫培南、阿祖培南(Razupenem),亚胺培南, ME1036、SM216601,或它们的组合。
单酰胺菌素类包括但不限于,氨曲南、卡芦莫南、替吉莫南BALI 9764, BAL30072或它们的组合。
与式(I)化合物组合使用的β-内酰胺类抗生素也可与氨基糖苷类、杆菌素类,喹诺酮类,磺胺类,大环内酯类,四环素类,甘氨酰环素类,噁唑烷酮类,脂肽类,多肽类,利福霉素,氯霉素,多烯抗真菌剂类和它们的衍生物共同给药。
式(I)化合物也可包含杀菌性/通透性增加蛋白产物(BPI)或流出泵抑制剂或与之共同给予,以改善抗革兰氏阴性菌和耐抗微生物剂的细菌的活性。抗病毒剂,抗寄生虫剂,抗真菌剂和其他抗生素也可与式(I)化合物组合给予。以合适的抗生素的组合方式的式(I)化合物可用于治疗患者的细菌感染,术前患者,术后患者,重症监护病房(ICU)患者的,医院感染患者和兽医的患者。
该药物组合物可以为常用的形式,如片剂,胶囊剂,丸剂,颗粒剂,散剂,糖浆剂,锭剂,溶液,悬浮液,气雾剂,透皮贴剂,外用药膏,软膏等,可在合适的固体或液体载体或稀释剂中包含矫味剂,甜味剂等,,或在适宜的无菌介质中包含上述物质以形成可注射溶液或悬浮液。该药物组合物还可包含现有技术中已知的药学上可接受的载体。
本发明化合物可以单独或与如上所述包含任何试剂的抗生素化合物/试剂一起冷冻干燥。该试剂包括配位剂或抗凝血剂,抗氧化剂,稳定剂,氨基糖苷类,药学上可接受的盐等或它们的混合物。可对稀释的溶液或浓缩的溶液进行冷冻干燥,这根据最终产品所要求的品质进行。在冷冻干燥或冻干或解冻之前,可将冷冻干燥物进行脱气以达到最佳气体浓度。该化合物可以在无菌条件下过滤。也可使用适当的过滤器,如超滤,以充分减少半乳甘露聚糖的水平。式(I)化合物也可与合适的抗菌剂物理共混。
式(I)化合物也可用于治疗产β-内酰胺酶(特别是KPC-2)细菌引起的感染。
除了式(I)化合物,该药物组合物还可能包含缓冲液,如柠檬酸钠,乙酸钠,酒石酸钠,碳酸钠,碳酸氢钠,吗啉丙磺酸,其他的磷酸盐缓冲液等,和螯合剂,如乙二胺四乙酸(EDTA),二亚乙基三胺五乙酸,羟基乙二胺三乙酸,次氮基三乙酸,1,2-二氨基环己烷四乙酸,双(2-氨基乙基)乙二醇四乙酸,1,6-丙二胺四乙酸等或它们的药学上可接受的盐。式(I)化合物可用于治疗或预防宿主中的细菌感染,该宿主通常是动物且最典型为人,包括向宿主给予治疗量的式(I)化合物或其药学上可接受的盐和/或其前药,以及β-内酰胺抗生素。
术语“预防”或“防止”是指防止疾病,即,使疾病的临床症状不发展。
术语治疗(“treatment'/'treating”)是指对于哺乳动物疾病的任何治疗,包括:(a) 抑制疾病,即,减缓或阻止临床症状的发展,和/或(b)缓解疾病,即,引起临床症状消退。
术语“治疗有效量”或“有效量”是指,如下文定义的,在单独或与其他治疗方法组合施用于需要这种治疗的哺乳动物时,足以有效治疗的式(I)化合物的化合物或混合物的量。
术语“增强”是指由一种试剂增强另一种试剂的作用效果,使得总体效果大于两种试剂的任一种的效果总和。
本文使用的术语“用于使用的化合物”包含任何一个或多个以下的情况:(1) 化合物的使用,(2)化合物的使用方法,(3)用于治疗的用途,(4)制造用于治疗的药物组合物/药剂的用途或(5)治疗/预防/减少/抑制的方法,其包括向有需要的受试者给予有效量的式(I)化合物。
术语“受试者”是指有细菌感染的患者,术前患者,术后患者,处于ICU的患者,医院内感染的患者,社区获得的感染和兽医。
从前面的描述中,本领域技术人员可以很容易地确定本发明的本质特征而在不会脱离本发明的精神和范围的情况下对本发明进行各种变化和修改,以使其适应各种用途和症状。
术语一旦被描述,则对于该术语的相同含义适用于整个专利。
参考化合物1(化合物1)
l-{[(2S,3S,5R)-2-羧基-3-甲基-4,4,7-三氧代-4-硫杂-1-氮杂双环[3.2.0]庚-3-基] 甲基}-3-甲基-1H-1,2,3-三唑-3-鎓;
于25-30℃下,向(2S,3S,5R)-3-甲基-7-氧代-3-(1H-1,2,3-三唑-1-基甲基)-4-硫杂-1-氮杂双环-[3.2.0]庚烷-2-羧酸4,4-二氧化物(25g)的丙酮(100mL)悬液中在搅拌条件下缓慢加入N,O-双(甲硅烷基)乙酰胺(18.6g)。将反应混合物在该温度 (25-30℃)下搅拌15-20分钟。向所得的澄清溶液中以15分钟的时长加入甲基碘 (100ml),并在25-30℃搅拌24小时。通过过滤分离沉淀的固体,然后用丙酮(25mL) 洗涤。得到的固体的湿重为30g。
上述湿固体用纯化水(300mL)在10-15℃下搅拌2.5小时。向所得的反应混合物中加入硫代硫酸钠(0.1g),并在10-15℃下搅拌10-15分钟。向该反应混合物中加入二氯甲烷(300mL),搅拌并分离有机层。将水层用安伯莱特(Amberlite)LA-2 树脂溶液(在二氯甲烷中的5%的溶液)洗涤两次,然后用二氯甲烷洗涤两次。向该水溶液中,加入活性炭(1g),搅拌15分钟,过滤,并用纯化水(25mL)洗涤。将该溶液过滤并冷冻干燥以得到纯的形式的标题化合物(10g)。
1H NMR(400MHz,DMSO-d6)δppm:1.39(S,3H),3.14(dd,J=16.0,1.3 Hz,1H),3.55(dd,J=16.0,4,2Hz,1H),3.97(s,1H),4.34(s,3H),5.05(dd,J=4.2, 1.3Hz,1H),5.29(d,J=14.7Hz,1H),5.42(d,J=14.7Hz,1H),8.91(d,J=1.3Hz, 1H),8.99(d,J=1.3Hz,1H).
质量m/z:M+1峰于315处。或者可对该溶液进行喷雾干燥以得到标题化合物。
化合物-12
(2S,3S,5R)-3-甲基-3-(3-甲基-咪唑-3-鎓-1-基甲基)-4,4,7-三氧代-4-硫杂-1-氮杂双环[3.2.0]庚烷-2-羧酸酯
步骤1:(2S,3S,5R)-3-(咪唑-1-基甲基)-3-甲基-7-氧代-4-硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸二苯甲基酯的制备
向咪唑(1.696g,24.9mmol)的乙腈(75mL)和水(25mL)的搅拌溶液中加入碳酸氢钠(4.18g,49.8mmol),并将所得物质搅拌15分钟。将(2S,3S,5R)-3-氯甲基-3- 甲基-7-氧代-4-硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸二苯甲基酯(10g,24.8mmol) 加入到上述混合物中,并在25-30℃下搅拌24小时。反应完成后,将反应物用乙酸乙酯和水的混合液稀释。分离有机层。将水层再次用乙酸乙酯提取。用无水硫酸钠干燥合并的有机层,并在真空条件下浓缩以得到粗品(2S,3S,5R)-3-(咪唑 -1-基甲基)-3-甲基-7-氧代-4-硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸二苯甲基酯。产量:10g。
步骤2:制备(2S,3S,5R)-3-(咪唑-1-基甲基)-3-甲基-4,4,7-三氧代-4-硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸二苯甲基酯
在先前步骤中得到的粗品(2S,3S,5R)-3-(咪唑-1-基甲基)-3-甲基-7-氧代-4-硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸二苯甲基酯(10g)溶解于乙腈(50mL)中。将乙酸和水的混合液加入到上述溶液中,并冷却至0-5℃。向该均相反应混合物中加入高锰酸钾(14.59g,92.3mmol)。在0-5℃下再连续搅拌2小时。将反应物用偏亚硫酸氢钠溶液骤冷。将反应物用乙酸乙酯和水的混合液稀释。分离有机层,将水层用乙酸乙酯提取。将合并的有机层用饱和的碳酸氢钠溶液中和。将有机层用无水硫酸钠干燥,并减压浓缩。向得到的残余物中加入丙酮,并搅拌30分钟。有白色固体析出,将其过滤并干燥。产量:2.60g(22.4%)。
1H NMR(400MHz,DMSO-d6)δppm:1.09(s,3H),3.35(d,J =16.0Hz,1H),3.76(dd,J=16.0,2.0Hz,1H),4.42(d,J=15.6Hz,1H),4.90(d,J= 15.6Hz,1H),5.10(s,1H),5,26(m,1H),6.89(s,2H),6.98(s,1H),7.33-7.50(m, 11H).质量m/z:466(M+1).
步骤3:制备(2S,3S,5R)-3-(咪唑-1-基甲基)-3-甲基-4,4,7-三氧代-4-硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸(化合物-M)
向(2S,3S,5R)-3-(咪唑-1-基甲基)-3-甲基-4,4,7-三氧代-4-硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸二苯甲基酯(900mg,1.9mmol)的甲醇(20mL)溶液中加入10%的Pd/C(900mg w/w)并在氢气气氛下搅拌2小时。将反应物过滤,并用甲醇洗涤。将滤液在减压下蒸发。向残余物中加入乙醚(30mL),并搅拌15分钟。将析出的白色固体过滤并用乙醚洗涤。产量:530mg(91.3%)。
1H MMR(400 MHz,DMSO-d6)δppm:1.38(s,3H),3.28(d,J=16.4Hz,1H),3.68(dd,J=16.4,4.4 Hz,1H),4.51(d,15.2Hz,1H),4.53(s,1H),4.84(d,J=15.2Hz,1H),5.14-5.15(m, 1H),7.02(s,1H),7.25(s,1H),7.85(s,1H).质量m/z:300(M+1).
步骤4:制备(2S,3S,5R)-3-甲基-3-(3-甲基-咪唑-3-鎓-1-基甲基)-4,4,7-三氧代 -4-硫杂-1-氮杂双环[3.2.0]庚烷-2-羧酸酯
向(2S,3S,5R)-3-(咪唑-1-基甲基)-3-甲基-4,4,7-三氧代-4-硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸(450mg,1.5mmol)在无水丙酮(1.8mL)中的悬液中缓慢加入 N,O-双(甲硅烷基乙酰胺)(0.93mL,3.7mmol),同时搅拌。将反应物再搅拌15分钟。向得到的澄清溶液中加入甲基碘(1.8mL)并在25-30℃下搅拌2天。将反应物浓缩,并用二氯甲烷-水稀释。分离有机层。将水层用安伯莱特LA-2树脂溶液(在二氯甲烷中的30%溶液)洗涤,接着用二氯甲烷洗涤。将水层进行脱气,并冷冻干燥得到标题化合物。熔点:161.37℃。
1H NMR(400MHz,D2O)δppm:1.53(s,3H),3,47(dd,J=16.7,1.36Hz,1H), 3.70(dd,J=16.7,4.2Hz,1H),3.94(s,3H),4.41(s,1H),4.99(ABquartet,J=15.4Hz,2H),5.09(m,1H),7.53(s,1H),7.64(s,1H),8.99(s,1H).质量m/z:314(M+1).
化合物13
(2S,3S,5R)-3-甲基-3-(4-甲基-3-甲基-咪唑-3-鎓-1-基甲基)-4,4,7-三氧代-4-硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸酯。
步骤1:制备(2S,3S,5R)-3-(4-甲基-咪唑-1-基甲基)-3-甲基-7-氧代-4-硫杂-双环[3.2.0]庚烷-2-羧酸二苯甲基酯
向(2S,3S,5R)-3-氯甲基-3-甲基-7-氧代-4-硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸二苯甲基酯(3g,7.4mmol)在乙腈(22.5mL))的搅拌溶液中加入碳酸氢钠(628mg,7.4mmol),水(7.5mL)和4-甲基-咪唑(1.22g,7.4mmol)。将所得物在25-30℃下搅拌42小时。将反应物用乙酸乙酯和水的混合液稀释。分离有机层。将水层再次用乙酸乙酯提取。对合并的有机层用无水硫酸钠干燥,并真空浓缩,得到粗 (2S,3S,5R)-3-(4-甲基咪唑-1-基甲基)-3-甲基-7-氧代-4-硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸二苯甲基酯。产量:3.5g。
步骤2:制备(2S,3S,5R)-3-(4-甲基-咪唑-1-基甲基)-3-甲基-4,4,7-三氧代-4-硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸二苯甲基酯。
将前一步骤获得的粗(2S,3S,5R)-3-(4-甲基-咪唑-1-基甲基)-3-甲基-7-氧代-4- 硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸二苯甲基酯(3.5g,7.8mmol)溶解于乙腈(18mL)中。然后向上述溶液中加入乙酸(18mL)和水(9mL)混合液并冷却至0-5℃。向该均质反应混合物中加入高锰酸钾(2.47g,15.6mmol)。0-5℃再继续搅拌2小时。然后将反应物用偏亚硫酸氢钠溶液淬火,并用乙酸乙酯和水稀释。分离有机层,将水层用乙酸乙酯提取。将合并的有机层用饱和的碳酸氢钠溶液中和。将有机层用无水硫酸钠干燥并减压浓缩。使用硅胶柱色谱法(用40-50%乙酸乙酯的己烷溶液梯度洗脱)纯化粗化合物得到纯化合物,为无色固体。产量:350mg(10%)。
1H NMR(400MHz,CDCl3,6ppm):1.00(s,3H),2.17(s,3H),3.50(dd,J=16.2Hz,1.8Hz,1H),3.57(dd,J=16.2Hz,4.1Hz,1H),4.24(d,J=15.3Hz,1H),4.50(s,1H), 4.61-4.62(m,1H),6.53(s,1H),6.99(s,1H),7.05(s,1H)7.32-7.49(m,10H).
步骤3:制备(2S,3S,5R)-3-甲基-3-(4-甲基-3-甲基-咪唑-3-鎓-1-基甲基)-4,4,7- 三氧代-4-硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸二苯甲基酯
向(2S,3S,5R)-3-(4-甲基-咪唑-1-基甲基)-3-甲基-4,4,7-三氧代-4-硫杂-1-氮杂- 双环[3.2.0]庚烷-2-羧酸二苯甲基酯(350mg,0.6mmol)在无水丙酮(4mL)中的悬液中加入碘甲烷(4mL)在25-30℃下搅拌15小时。将反应物浓缩并用硅胶柱色谱纯化(用0-10%MeOH的二氯甲烷溶液梯度洗脱)得到产物,为浅黄色固体,产量:320mg(96%)。
1H NMR(400MHz,CDCl3,δppm):1.35(s,3H),2.30(s,3H),3.47(dd,J=16.4Hz,1.7Hz 1H),3.58(dd,J=16.4Hz,4,4Hz 1H),3.89(s,3H),4.6(s,1H),4.69(m,1H), 4.89(ABquartet,J=15.9Hz,2H),7.01(s,1H),7.26(s,1H),7.32-7.49(m,10H), 9.83(s,1H).
步骤4:制备(2S,3S,5R)-3-甲基-3-(4-甲基-3-甲基-咪唑-3-鎓-1-基甲基)-4,4,7- 三氧代-4-硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸酯
向(2S,3S,5R)-3-甲基-3-(4-甲基-3-甲基-咪唑-3-鎓-1-基甲基)-4,4,7-三氧代-4- 硫杂-1-氮杂-双环[3.2.0]庚烷-2-羧酸二苯甲基酯(310mg,0.62mmol)的悬液中加入间甲酚(3mL),并在室温搅拌过夜。向反应混合物中加入己烷(3×25mL)并搅拌 5分钟,然后倾析。向其中加入乙醚(15mL)中。将得到的固体用水稀释,并用安伯莱特LA-2树脂(在二氯甲烷中的30%溶液)处理,接着用二氯甲烷处理。将水层冷冻干燥得到产物,为浅黄色固体。产量:130mg(75%)。
1H NMR(400MHz, D2O)δppm:1.52(s,3H),2.31(s,3H),3.47(dd,J=16.7Hz,1.3Hz1H),3.71(dd,J= 16.7Hz,4.1Hz 1H),3.80(s,3H),4.39(s,1H),4.92(ABquartet,J=15.4Hz,2H), 5.08(m,1H),7.38(s,1H),8.86(s,1H).质量m/z:328(M+1).
以下示例仅以说明性方式提供,且不应被视为限制本发明的范围。对于本领域技术人员显而易见的变动和改变将处于本发明的范围和性质中。
生物学:
产KPC/ESBL肠杆菌的检测
在本实验中,化合物-1用作诊断试剂,用于检测属于KPC&ESBL家族(例如,SHV18)的β-内酰胺酶生产肠杆菌的诊断试剂。一套简单的在琼脂培养基上的浸渍有抗生素的吸收纸盘用于该检测。当该菌株表达β-内酰胺酶时,与化合物-1组合的抑菌圈将明显大于单独的抗生素时的情况。
方法1:
·0.5麦克法兰的试验菌以1:10稀释接种于穆勒-海顿琼脂平板上
试验菌:肺炎克雷伯菌(Klebsiella pneumoniae)(K.p)ATCC BAA-1705,肺炎克雷伯菌(Klebsiella pneumoniae)(K.p)ATCC 700603,大肠杆菌(E.c)Ecoli233
·碳青霉烯(例如,亚胺培南[IPM]10μg)和头孢菌素(例如,头孢他啶 [CAZ]30μg)纸盘(7mm)放置在接种的琼脂平板上。
·化合物-1(60μg)盘放置在距离碳青霉烯和头孢菌素纸盘为7和10mm处。
·由于化合物-1存在的协同作用亚胺培南或头孢他啶的抑菌圈扩大,以此测量表达的碳青霉烯酶或ESBL的存在。
结果:
观察到协同作用,因为邻近含化合物-1纸盘的亚胺培南或头孢他啶抑菌圈增加(图1)。
方法2:
除了以下改变,该方法与方法1相同:
·向相同的纸盘上加入化合物-1(60μg)与碳青霉烯(例如,亚胺培南10μg)或头孢菌素(例如,头孢他定30μg)的组合并放在接种的琼脂平板上。
·以亚胺培南或头孢他啶与10化合物1组合的抑菌圈直径与单独的抗生素情况的比较的增加来测量表达的碳青霉烯酶或ESBL的存在。
结果
化合物-1对碳青霉烯酶或ESBL的抑制活性通过亚胺培南或头孢他啶与化合物-1的组合与单独抗生素相比抑菌圈直径(表1)增加来证明(图1)。图1中的 (A),(B)及(C)中的方法1显示了在位于10mm和7mm的距离时邻近含化合物-1 的盘的亚胺培南或头孢他啶的抑菌圈增加。图1中的(A),(B)和(C)中的方法2 显示了亚胺培南或头孢他啶与化合物-1(IT&CT)组合而不是单独的抗生素(I&C) 的抑菌圈的增加。(D)中的两种方法都没有显示抑菌圈的增加,且化合物-1不显示任何的抑菌圈,这是由于菌株中没有β-内酰胺酶。
有KPC酶的分离株(isolate)的结果显示于表1中。
表1:具有A类碳青霉烯酶和ESBL的临床分离株的抑菌圈(ZOI)
·化合物-1增加了头孢他啶分别抗测试的产KPC2和KPC3菌株的抑菌圈,分别从12增加至18.5mm,从11增加至22.5mm。
·化合物-1增加了亚胺培南分别抗测试的产KPC2和KPC3菌株的抑菌圈,分别从14.5增加至20mm,且从14mm增加至20mm。
·化合物-1增加了头孢他啶抗测试的产SHV18菌株的抑菌圈,从12mm增加至23mm,而在有或没有化合物-1存在的亚胺培南的直径没有变化,这表明亚胺培南自身具有抗这种菌株的活性。
·对β-内酰胺酶阴性菌株的抗性,化合物-1对头孢他啶或亚胺培南都没有任何影响,因为这两种抗生素自身都具有抗这种菌株的活性。
结论:
化合物-1可以用作一种诊断工具,用于检测包括KPC的β-内酰胺酶。
体外试验
本文描述的式(I)的β-内酰胺化合物与β-内酰胺抗生素类组合用于对它作为抗碳青霉烯酶的β-内酰胺酶抑制剂的作用进行评估。在此对本文所述化合物进行了体外评估,对于抗例如产KPC及表达KPC细菌的革兰氏阴性菌株的抗菌活性进行了评估,用这些酶进行了β-内酰胺酶抑制测定。在杂环氮原子上被取代的β-内酰胺化合物显示出显著的β-内酰胺酶抑制性。对于对比研究,他唑巴坦,克拉维酸和舒巴坦与β-内酰胺抗生素类一起使用。碳青霉烯类,头孢菌素类,单酰胺菌素和青霉烯类(包括兽医使用的那些)被选中作为抗菌试剂。
通过确定最小抑制浓度(MIC)进行的体外抗菌试验:肉汤微稀释法
通过肉汤微量稀释或琼脂稀释法对β-内酰胺化合物针对体外抗菌活性进行测试,该方法于美国临床和实验室标准化研究所(CLSI),(原NCCLS)公布的文件中描述。批准的标准M7-A7,2006年1月,CLSI,Wayne,宾夕法尼亚州,美国和M100-S18,2008年1月,CLSI,Wayne,宾夕法尼亚州,美国。
协同肉汤微量稀释MIC以棋盘格形式进行,采用一系列浓度的抗菌剂与几种浓度的BLI化合物和其他比较BLI试剂在96孔微量滴定板中进行。简要地说,β-内酰胺抗生素类的储液(例如,2560&1280μg/mL)是由水,0.1M的磷酸盐缓冲液,pH 6.0或pH 7.0或相应的合适的溶剂制成。同样地,制备了包含化合物-1 的BLI试剂的储液,β-内酰胺抗生素浓度设定为0.06-128μg/mL。包含BLI化合物的BLI试剂在浓度为1-64μg/mL的范围内被测试。所有的工作溶液都用阳离子调整的穆勒海顿肉汤(caMHB)进行适当的稀释。在96孔微量滴定板的孔中连续地用caMHB从工作溶液对抗菌剂进行2倍稀释。含有BLI化合物的BLI剂也被连续稀释然后将各待测试的浓度加入到每个不同的抗菌浓度中。BLI化合物,其他比较BLI和所有的抗菌剂也单独进行测试。通过挑选3至5个孔具有相同形态外观的菌落制备细菌接种物,该菌落来自于18-24h时长培养基,并调整生理盐水悬浮液的浊度为0.5麦氏浊度标准,其相当于细菌数量为1x 108菌落形成单位(CFU)每mL悬浮液。用caMHB对悬浮液以1:100稀释以得到约l x l06CFU/mL的菌群作为接种物。将该细菌接种物加入到含caMHB以及抗菌剂或抗菌剂+BLI剂的微量滴定板的孔中,并且细菌接种物体积与caMHB以及抗菌剂或抗菌剂+BLI剂的总体积相同。因此,最终接种物变成一半(约5x 105 CFU/mL)并且所测试的抗菌剂和组合的浓度也变成一半。将接种的板在35℃在环境气氛下孵育18-20小时。在光学镜辅助下用肉眼观察孵育后的板,并将MIC 记录为浓度,其显示了接种培养物没有生长或视觉的浊度。
在简要琼脂稀释法中,用于兽医用途(例如,2mg/mL)的头孢菌素的储液用水,0.1M磷酸盐缓冲剂或合适的溶剂制备,并将溶液连续2倍稀释。化合物-1 溶解于水中且他唑巴坦(比较BLI)溶解于0.1M磷酸盐缓冲液中,其pH为6.0,以得到1mg/mL的溶液。头孢菌素浓度限定为0.5-32μg/mL。对于组合,本文所述的他唑巴坦或化合物-1以固定的4μg/mL的浓度,与浓度范围为0.5至32μg/mL 的头孢菌素类一起测试。将单独的头孢菌素和与化合物-1或各浓度的他唑巴坦组合的头孢菌素加入至20mL的熔融的已冷却至40-50℃的穆勒海顿琼脂中,并倒在陪替氏(petri)培养皿中。式(I)化合物和他唑巴坦也单独进行了测试。通过从18-24h时长培养物中选取3至5孔具有相同的形态外观的分离的菌落制备细菌接种物,并将生理盐水悬液的浊度调节至0.5麦克法兰浊度标准,其相当于约1 ×108CFU/mL悬液。用盐水将该悬液以1:10稀释,得到约1x 107CFU/mL的菌群作为接种物。将该细菌接种物用多点接种器接种到所制备的陪替氏培养皿上,其中每个接种点含有1x l04CFU的菌株。接种的陪替氏培养皿在35℃环境气氛下孵育18-20小时。孵育后,将该陪替氏培养皿放置在暗的非反射表面,且 MIC记录为浓度,其显示接种的培养没有生长。
表2:亚胺培南与β-内酰胺酶抑制剂(BLI)化合物-12组合时抗肺炎克雷伯氏菌碳青霉烯酶(KPC)生产菌株的最小抑菌浓度(MIC)
NA:不能获得
*表型上观察到AmpC的存在
化合物-12显示了在与化合物-1类似的范围内具有增强的抗KPC(2&3)产生菌株的活性,而化合物-M仅有中等活性活性,且不在预期活性范围内。
表3a:青霉烯类或单菌霉素/化合物-1抗产KPC-2肺炎克雷伯菌(ATCC BAA-1705)的MIC
IMP:亚胺培南,MER:美罗培南,ERT:厄他培南,FAR:法罗培南&AZT:氨曲南。
在≥4μg/mL浓度时化合物-1与亚胺培南和美罗培南协同作用优于他唑巴坦或克拉维酸或舒巴坦抗产KPC-2菌株ATCC BAA 1705。与上述比较物相比,在 64μg/mL的浓度,它也表现出与厄他培南,法罗培南和氨曲南的更好的协同作用(表3a)。同样地,该系列中以下化合物显示了恢复亚胺培南和美罗培南的抗菌活性的作用(表3b)。
表3b:青霉烯类BLI化合物抗KPC-2生产肺炎克雷伯菌(ATCC BAA-1705)
表4:人头孢菌素/化合物-1对产KPC-2肺炎克雷伯菌(ATCC BAA-1705-L) 抗性
CEF:头孢吡肟,CTX:头孢噻肟,CTZ:头孢他啶&CTB:头孢吡普
在>16μg/mL浓度时,化合物-1与头孢吡肟协同作用,比他唑巴坦或克拉维酸或舒巴坦更好地抗产KPC-2菌株ATCC BAA 1705。它也表现出与头孢噻肟和头孢他啶在64μg/mL时的协同作用比以上比较物更好的效果。头孢吡普在该测试浓度对所有的对比化合物相比并未显示出任何的协同效应(表4)。
表5:兽医的头孢菌素/化合物-1抗产KPC-2肺炎克雷伯菌(ATCC BAA-1705)
CFQ:头孢噻呋,CFF:头孢喹肟,CFD:头孢羟氨苄&CFL:头孢洛宁 (Cefalonium)
在≥32g/mL的浓度时化合物-1与兽医用头孢菌素头孢噻呋和头孢喹肟协同比他唑巴坦更好地抗产KPC-2菌株ATCC BAA 1705。头孢羟氨苄和头孢洛宁在测试的浓度没有显示所需的协同效应(表5)。
表6a:碳青霉烯类&人头孢菌素/化合物-1抗表达KPC-3大肠杆菌(J53 R6206)
IMP:亚胺培南,MER:美罗培南,CEF:头孢吡肟,CTX:头孢噻肟, CTZ:头孢他啶&CTB:头孢吡普
在≥2μg/mL的浓度,化合物-1与亚胺培南,美罗培南,头孢吡肟,头孢噻肟,头孢他啶和头孢吡普协同比他唑巴坦或克拉维酸或舒巴坦更好地抗表达 KPC-3大肠杆菌菌株J53R6206(表-6a)。同样地,该系列中的下列化合物显示了对于亚胺培南和美罗培南的抗菌活性的恢复(表6b)。
表6b:碳青霉烯类BLI化合物抗表达KPC-3大肠杆菌(J53R6206)
表-7:兽用头孢菌素/化合物-1抗表达KPC-3表达大肠杆菌(J53 R6206)
CFQ:头孢噻呋,CFF:头孢喹肟,CFD:头孢羟氨苄&CFL:头孢洛宁
在4μg/mL浓度时,化合物-1与兽用头孢菌素类头孢喹肟、头孢噻呋和头孢洛宁协同作用比他唑巴坦更好地抗表达KPC-3大肠杆菌菌株J53R6206。在测试浓度时头孢羟氨苄没有显示所需的协同作用(表7)。
用碳青霉烯酶类对β-内酰胺酶抑制分析
对化合物1进行β-内酰胺酶抑制分析,以测定IC50值,并将其与比较物BLI 剂进行比较,如其他地方所描述(Bebrone等人,Antimicrob.Agents.Chemother,2001,45(6):1868-1871;Jamieson等人,Antimicrob.Agents.Chemother,2003, 47(5):1652-1657)。简要地说,来自产KPC-2和表达KPC-3细菌的革兰氏阴性菌株的酶提取物用于研究β-内酰胺酶的抑制活性,并使用CENTA作为β-内酰胺酶的底物测定IC50值。
表8:化合物-1及碳青霉烯酶类的β-内酰胺酶抑制分析
化合物-1的IC50低于抗粗KPC-2&3酶提取物的比较BLI,这表明式(I)的化合物1的BLI的优越的结合后效力(表8)。
表9:哌拉西林与标准泰舒(Tazo)组合与新型抑制剂化合物抗来自ATCC的特定的产广谱β-内酰胺酶(ESBL)革兰氏阴性分离物抗性的比较
化合物-1抗产KPC碳青霉烯酶菌株的体内作用
化合物1是ESBL的有效抑制剂,其抗KPC酶的抑制活性已经在体外被证明。在此评估了在小鼠全身性感染和大腿感染的药学模型中化合物-1对产KPC2 肺炎克雷伯菌ATCCBAA 1705的抗性,用于体内转换为其对KPC2的抑制活性。在这些模型中,由于KPC2介导的水解,β-内酰胺类作为单一试剂的疗效衰退。通过将化合物-1与β-内酰胺类组合,对其恢复或增强β-内酰胺类的作用效果进行了评估。
方法:
小鼠全身感染模型
雌性瑞士小白鼠,重量为18-22g,它们用于所有的研究。对于每个剂量组,都包括5或6只小鼠。研究方案被研究院动物伦理委员会,兰花研究实验室有限公司审查和批准。将小鼠单独放置在通风笼中,在整个研究期间随意供应食物和水。从脑心浸液琼脂培养基的过夜培养物中,用含猪胃粘蛋白的常规生理盐水制备具有所需的细菌密度的检验接种物。在涉及多利培南的研究中,使用洗涤过的细菌细胞。每只小鼠腹腔注射检验接种物以使其感染。
哌拉西林与β-内酰胺酶抑制剂(BLI)组合:用水性琼脂(细菌用琼脂)制备增加浓度的哌拉西林和BLI(化合物-1或他唑巴坦)作为单一试剂或哌拉西林与BLI 以1:1的比例的组合。对感染的小鼠在感染后三个不同的时间点用药物制剂皮下给药。
亚胺培南与BLI的组合:增加浓度的亚胺培南作为单一试剂或与固定浓度的BLI组合使用,用于向感染的小鼠皮下给药。在这个实验中,亚胺培南总是与西司他汀一起施用。
多利培南与BLI组合:增加浓度的多利培南作为单一试剂或与固定浓度的 BLI组合用于向感染的小鼠皮下给药。
经过处理的小鼠的存活每天监测两次,直到感染后7天。用Reed和Muench 法计算有效剂量50(ED50)(Reed,L.J.;Muench,H..“一种估计百分之五十端点的简单方法”。TheAmerican Juournal of Hygiene,1938,27:493-497)。
中性粒细胞减少小鼠大腿感染模型(人类适用的模型)
雌性瑞士小白鼠,重24-30g,用于所有研究。研究方案经研究院动物伦理委员会,兰花研究实验室有限公司审查和批准。通过腹腔注射环磷酰胺使小鼠出现中性粒细胞减少的情况。将脑心浸液肉汤中的对数期培养物注入到小鼠大腿中。亚胺培南或多利培南单独或以组合形式以减少的分开(fractionated)剂量每 15分钟皮下给药,总时间为5.5h((Flü ckiger,U.等人.“Integration of pharmacokinetics and pharmacodynamics ofImipenem in a human-adapted mouse model′.Antimicrobial Agents and Chemother,1991,35(9):1905-1910)。在给药的开始将化合物-1或他唑巴坦皮下大剂量给药。疗效终点为:亚胺培南研究为6 小时,多利培南研究为8小时。
在小鼠全身感染模型中化合物-1恢复的哌拉西林的抗KPC2肺炎克雷伯菌 ATCCBAA 1705抗性的功效
哌拉西林单独没有什么功效,甚至高达800mg/kg。化合物-1恢复了哌拉西林的功效,因为哌拉西林与化合物-1以1∶1的比例的组合表现出ED50为 50mg/kg。因为化合物-1单独没有功效,因此哌拉西林以组合方式的功效归因于化合物-1的KPC2酶抑制活性。然而,临床使用的他唑巴坦不能恢复哌拉西林的功效,因为它与哌拉西林以1∶1的比例结合时高至>200∶>200mg/kg仍未显示功效(表10)。
表10:与化合物-1组合的哌拉西林对比他唑巴坦功效的比较
剂量组 | ED<sub>50</sub>(mg/kg) |
哌拉西林 | >800 |
化合物-1 | >64 |
他唑巴坦 | >200 |
哌拉西林:化合物-1以1∶1比例 | 50∶50 |
哌拉西林:他唑巴坦以1∶1比例 | >200∶>200 |
在小鼠全身感染模型中化合物-1增强亚胺培南的抗KPC2肺炎克雷伯菌 ATCC BAA1705抗性的功效
亚胺培南单独显示出ED50为8.9mg/kg。结合固定的64mg/kg的化合物-1使得功效增强,其ED50为2.2mg/kg。他唑巴坦与亚胺培南以相同的剂量组合添加得到的ED50为4mg/kg。化合物-1引起亚胺培南疗效的显著增加是由于其对于 KPC2酶的抑制活性(表11)。
表11:亚胺培南与化合物1的组合对比他唑巴坦的功效比较
剂量组 | ED<sub>50</sub>(mg/kg) |
亚胺培南 | 8.9 |
亚胺培南+化合物-1(64mg/kg) | 2.2 |
亚胺培南+他唑巴坦(64mg/kg) | 4 |
在小鼠全身感染模型中化合物-1增强的多利培南抗KPC2肺炎克雷伯菌 ATCC BAA1705的功效
对多利培南单独或多利培南与化合物-1或他唑巴坦组合进行评估。化合物-1 或他唑巴坦在20mg/kg和64mg/kg进行测试。多利培南单独具有的ED50为 14.14mg/kg。其功效被20mg/kg的化合物-1显著提高至ED50为1.4mg/kg,且被 64mg/kg的化合物-1显著提高至ED50为1.62mg/千g。他唑巴坦略微提高了多利培南的功效,其中他唑巴坦的剂量分别为20和64mg/kg时,其ED50分别为 11.89mg/kg和6.48mg/kg(表12)。
这些结果表明,化合物-1对于KPC2的有效抑制活性导致防止多利培南被 KPC2介导的水解分解,从而恢复多利培南的功效。
表12:多利培南与化合物-1的组合对比他唑巴坦的功效的比较
剂量组 | ED<sub>50</sub>(mg/kg) |
多利培南 | 14.14 |
多利培南+化合物-1(20mg/kg) | 1.4 |
多利培南+化合物-1(64mg/kg) | 1.62 |
多利培南+他唑巴坦(20mg/kg) | 11.89 |
多利培南+他唑巴坦(64mg/kg) | 6.48 |
在中性粒细胞减少小鼠大腿感染模型中化合物-1增强的亚胺培南抗KPC2 肺炎克雷伯菌ATCC BAA 1705的抗性
在治疗开始时的平均初始细菌负荷为1.8E+06CFU/大腿。亚胺培南 140mg/kg,以分开的剂量给药,总时间为5.5h,其没有效果;6小时的治疗后细菌生长至6.8E+06CFU/大腿。将亚胺培南与化合物-1以140mg/kg大剂量组合恢复了功效,此时细菌负荷减少至2.1E+05CFU/大腿(表13)。该实验结果表明,化合物-1在强韧的小鼠大腿感染模型中表现出抑制的能力。
表13:亚胺培南与化合物-1的组合的体内药效学(大腿感染模型)
剂量组 | 细菌负荷(CFU/大腿) |
初始细菌负荷 | 1.81E+06 |
感染对照 | 4.6E+07 |
亚胺培南140mg/kg处理 | 6.8E+06 |
亚胺培南(140mg/kg)+化合物-1(140mg/kg) | 2.1E+05 |
在中性粒细胞减少小鼠大腿感染模型中通过化合物-1增强的多利培南抗KPC2 肺炎克雷伯菌ATCC BAA 1705的功效
进行了三个实验,对多利培南单独或与化合物-1或他唑巴坦组合(两个实验) 进行评估。多利培南70mg/kg以分开的剂量经5.5h时长给予(Flückiger,U.等人. ″Integration of pharmacokinetics and pharmacodynamics of Imipenem in a human-adapted mouse model′.Antimicrobial Agents and Chemother,.1991,35(9): 1905-1910))。化合物-1或他唑巴坦在治疗开始时以大剂量给予。治疗终点是开始治疗后8小时。
最初的细菌负荷范围为从1.4E+07-3.1E+07CFU/大腿。多利培南70mg/kg对于细菌负荷单独发挥抑制效果。用多利培南单独处理的小鼠的细菌负荷为 5.4E+06-2.6E+07CFU/大腿。将35mg/kg的化合物-1与多利培南组合使细菌负荷下降到7.9E+05-1.3E+06CFU/大腿。在两个实验中还将多利培南与35mg/kg的他唑巴坦结合。他唑巴坦对多利培南的功效没有影响,因为小鼠细菌负荷显示为 1.2E+07-1.6E+07CFU/大腿(表14)。
表14:多利培南与化合物-1的组合(大腿感染模型)的体内药效学
剂量组 | 细菌负荷(范围)(CFU/大腿) |
初始细菌负荷 | 1.4E+07-3.1E+07 |
感染对照 | 7.3E+07-1.6E+08 |
多利培南70mg/kg处理的 | 5.4E+06-2.6E+07 |
多利培南(70mg/kg)+化合物-1(35mg/kg) | 7.9E+05-1.4E+06 |
多利培南(70mg/kg)+他唑巴坦(35mg/kg) | 1.19x10<sup>7</sup>-1.6x10<sup>7</sup> |
结论
在所有这些实验中,作为单一试剂的β-内酰胺类的功效下降,因为他们对于 KPC2是不稳定的。作为KPC2的抑制剂,化合物-1恢复或显著增强了β-内酰胺类的功效。
Claims (5)
1.一种药物组合物,包括:作为活性成分的l-{[(2S,3S,5R)-2-羧基-3-甲基-4,4,7-三氧代-4-硫杂-1-氮杂双环[3.2.0]庚-3-基]甲基}-3-甲基-1H-1,2,3-三唑-3-鎓或其药学上可接受的盐,连同选自头孢吡肟、头孢噻肟或它们的组合的抗生素;以及一种或多种药学上可接受的载体。
2.如权利要求1所述的药物组合物,其中,所述活性成分以2-64μg/mL的浓度存在。
3.如权利要求1或2所述的药物组合物,其中,所述抗生素为头孢吡肟。
4.如权利要求1或2所述的药物组合物,其中,所述抗生素为头孢噻肟。
5.如权利要求1或2所述的药物组合物,其中,所述活性成分以2-8μg/mL的浓度存在。
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TWI660972B (zh) * | 2012-09-10 | 2019-06-01 | 愛爾蘭商尼歐托普生物科學公司 | 抗mcam抗體及相關使用方法 |
US20140128364A1 (en) * | 2012-11-05 | 2014-05-08 | Rempex Pharmaceuticals | Therapeutic uses of tigemonam and carumonam |
GB201319776D0 (en) * | 2013-11-08 | 2013-12-25 | Allecra Therapeutics Sas | Compound |
GB201408649D0 (en) * | 2014-05-15 | 2014-07-02 | Allecra Therapeutics Sas | Method |
JP2016010399A (ja) * | 2014-06-03 | 2016-01-21 | 日水製薬株式会社 | カルバペネマーゼ産生耐性菌検出用組成物 |
FR3024465B1 (fr) * | 2014-07-30 | 2018-03-23 | Biomerieux | Caracterisation de micro-organismes par maldi-tof |
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SI25892A (sl) * | 2019-09-05 | 2021-03-31 | Gorenje Gospodinjski Aparati, D.O.O. | Pralni stroj, ki se polni s sprednje strani, z električnim svetlobnim telesom |
US11040987B2 (en) | 2019-09-11 | 2021-06-22 | Tennor Therapeutics Limited | Penam derivatives for treating bacterial infections |
CN110840897B (zh) * | 2019-11-28 | 2023-08-08 | 河北旺发生物科技有限公司 | 金属β-内酰胺酶抑制剂 |
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