7-氨噻肟头孢菌素的聚合物分析

摘要：在头孢菌素类药物杂质谱的控制中，对聚合物类杂质的分析是其最薄弱环节。7-氨噻肟头孢菌素是第三代头孢菌素 的典型代表，也是当前仿制药一致性评价的热点品种。本文通过回顾近年来对7-氨噻肟头孢菌素聚合物分析取得的进展，归纳 总结该类头孢菌素的聚合反应特性、聚合物特性和常见的聚合物衍生物/降解物，试图解决LC-MS分析聚合物结构中的常见困 惑，形成对该类抗生素聚合物分析相对系统的策略与方法。     

氨噻肟头孢菌素合成中新酰化工艺探讨

氨噻肟头孢菌素(Cefotaxime Sodium,HR-756) (1)是一种抗菌谱广、抗菌活性强、对酶稳定的第三代头孢菌素。氨噻肟侧链(2)与7-ACA缩合时,以往     

头孢菌素结构和其聚合反应关系的探讨：Ⅰ.结构对反应类型的影响

头孢菌素的聚合反应可分为:只和母核结构有关的N型聚合反应和7位侧链参与聚合的L型聚合反应两类。7位侧链不具有自由氨基等活性基团的头孢菌素,只能发生N型聚合反应;所形成的聚合物中保留有7位侧链取代基结构,但3位侧链的取代基结构消失。7位侧链中含有自由氨基的头孢菌素,在酸性条件下一般主要以N型聚合反应为主,在碱性条件下N型聚合反应和L型聚合反应可以同时发生;两类聚合反应的相对强度与化合物本身的结构有关。     

新头孢菌素BMY—28232及其口服前药BMY—28271的合成与生物活性

自研制出头孢呋新甲酯(Cefuroximeaxetil)以来,已报道了许多前药——高效口服的头孢菌素酯类,该类化合物的特点是在头孢核C-7位接有一个氨噻侧链,而主要区别是C-3位取代基不同。我们曾在口服吸收良好的头孢氨节-头孢羟氨苄系列中开发出3-烯头孢菌素,并对3-(2)-丙烯衍生物BMY-28100进行了临床评价。在开发广谱口服头孢菌素的研究过程中,我们在氨噻头孢菌素的C-3位接上烯基侧链,并且确证是一种新的3-(2)-丙烯基头孢菌素BMY-28232(图1)BMY-28232抗菌谱广,对革蓝氏阳性与阴性菌(包括产生β-内酰胺酶的菌株)均有活性,     

氨噻三嗪头孢菌素在小儿科领域内的基础与临床研究

最近由于头孢菌素类药剂(CEPs)的使用量激烈增加,对头孢菌素的耐药菌也有所上升的趋势,因而迫切需要开发对β-内酰胺酶稳定的新头孢菌素药物,要在7ACA的7位侧链与3位侧链上进行化学结构改造,最近由瑞士罗氏制药公司开发的氨噻三嗪头孢菌素(Ceftriaxone,Ro-13-9904,商品名Rocephin,"菌必治")是属第三代头孢菌素,其     

头孢菌素类抗生素（Ⅱ）

(七)注射用第四代头孢菌素第三代氨噻肟头孢菌素,具有高效、广谱、耐酶的特性,但对假单胞菌的作用较差。第三代头孢菌素中的鎓基头孢菌素如头孢他啶具有抗假单胞菌的特点,但对革兰阳性菌作用较差,为了吸取两类第三代头孢菌素的优势,克服其缺点,所以第四代头孢菌素7β位采取头孢噻肟的氨噻肟基团,3位采取头孢他啶的鎓基进行最佳组合,从而得到抗革兰阳性和革兰阴性菌谱较为平衡的第四代头孢菌素类,它们兼备头孢噻肟和头孢他啶的双重优点。所以第四代头孢菌素对金葡菌和铜绿假单孢都有很好的抗菌活性,对β-内酰胺酶特别是AMPC酶也更加稳定。…     

新头孢烯衍生物(6R,7R)-7-[(2-(2-对氨基苯磺酰胺基噻唑-4-)-Z-2-甲氧基亚胺)-乙酰胺基]—头孢烯酸的合成及体外抑菌试验

氨噻肟类头孢菌素是目前β-内酰胺类抗生素研究中最热门的课题之一,许多研究者们通过氨噻唑头孢菌素的3—位、4—位、6—位取代基及肟基氧上R取代基的改变,制备了一些有很好抑菌活性的衍生物。但是,在氨噻肟的氨基上取代的衍生物尚未见报道。因此,我们设计并合成了(6R、7R)-7-[(-2-(2-对氨基苯磺酰胺基噻唑-4-)-Z-2-甲氧基亚胺)—乙酰胺基]—头孢烯酸[Ⅷ]。并进行了体外抑菌试验。结果如下:     

氨噻肟头孢菌素的生物测定

最近的氨噻肟头孢菌素(Cefotaxime)专题论文集中指出:虽然氨噻肟头孢菌素(新的耐β-内酰胺酶的广谱头孢菌素)是临床上相当有效的抗生素,但应用微生物方法测定它在体液内的浓度,结果均不理想。因为在体内有部分氨噻肟头孢菌素代谢为去乙酰氨噻肟头孢菌素,而代谢物本身也是一种有效的抗生素,其活性低于氨噻肟头孢菌素,抗菌谱也狭窄。由于这种代谢作用,微生物测定法就不能单独测得氨噻肟头孢菌素,除非使用一株     

氨噻肟唑头孢菌素的合成

氨噻肟唑头孢菌素(Cefmenoxime)为第三代头孢菌素,1978年开始有报道、其抗菌谱广、抗菌活性强,具有耐β-内酰胺酶的作用,特别是对革蓝氏阴性菌有高效,临床用于治疗各种较严重的感染。 氨噻肟唑头孢菌素的合成,Ochiai M.氏报道了氯乙酰基保护侧链氨基以酰氯法缩合的合成方法,法国专利报道了以三苯甲基保护侧链并使用DCC缩合的合成方法。其中酰氯法酸性过强有促使产品异构化的可能,而三苯氯甲烷作为保护基来源困难不适于生产。因此我们设计了以氯乙酰基保     

氨噻肟头孢菌素钠在水溶液中的降解机理和动力学

本文报道氨噻肟头孢菌素钠在水溶液中的稳定性的动力学。研究阐明了氨噻肟头孢菌素钠的降解机理,测定了动力学参数。实验所用材料为氨噻肟头孢菌素钠,去乙酰基氨噻肟头孢菌素和去乙酰基氨噻肟头孢菌素内酯。研究动力学所用的各种缓冲剂是盐酸—氯化钾缓冲剂(pH0.10,0.48,1.15     

头孢菌素类抗生素结构修饰的研究

细菌的耐药性问题日益严峻,给临床治疗带来极大困难。研发新型抗耐药菌药物成为目前的研究热点。头孢菌素作为重要的抗生素药物,在筛选新抗生素困难重重的情况下,对其进行适当的结构修饰成为创制新药的有效途径。本文简单介绍了头孢菌素类构效关系,并对头孢菌素分子结构中的C-2、C-3、C-7等部位的修饰改造以及相关母核来源进行了综述。     

Studies on cephalosporin antibiotics. I. Synthesis, antibacterial activity and oral absorption of new 3-(O-substituted)-7 beta-[D-alpha-amino-alpha-(4-hydroxyphenyl)acetamido]cephalosporins

The synthesis, antibacterial activity and oral absorption of new 7 beta-[D-alpha-amino-alpha-(4-hydroxyphenyl)acetamido]cephalosporins (1) with various O-substituents at the C-3 position of a cephalosporin nucleus are described. Of these, the cephalosporins (1b-1e) having an alkoxycarbonylmethoxy group at the C-3 position showed good oral absorption in rats as well as potent activity against Gram-positive bacteria. The structure-activity relationships of 1 are also presented.     

Synthesis and activity of 3-(isoxazolin-5-yl)- and 3-(isoxazol-4-yl)cephalosporins.

The 1,3-dipolar cycloaddition of nitrile oxide with 3-vinylcephalosporin provided diastereomeric isomers of 3-(isoxazolin-5-yl)cephalosporin. Cycloaddition of nitrile oxide with 3-(dimethylamino-vinyl)cephalosporin gave 3-(isoxazol-4-yl)cephalosporin. These semisynthetic cephalosporins with an aminothiazole in the C-7 side chain showed moderate antibacterial activities.     

Structure-binding relationship and binding sites of cephalosporins in human serum albumin.

The binding of some cephalosporins to human serum albumin (HSA) was studied by an ultrafiltration technique. Changes in C-3 side chain resulted in marked changes in the binding to HSA, but changes in C-7 side chain did not. Cephalosporins were classified into three groups by C-3 side chain: (i) Cationic side chain with low affinity for HSA; (ii) anionic side chain with high affinity for HSA; (iii) non ionized side chain, in which binding to HSA was dependent on lipophilicity. These findings suggest that electrostatic and hydrophobic forces play a role in the binding affinity of cephalosporins for HSA. The binding of cephalosporins with high HSA affinity was displaced significantly by warfarin but not by phenylbutazone, L-tryptophan, or diazepam. The interaction of the cephalosporins with high affinity for HSA with chemically modified HSA was investigated to clarify the amino acid residues of HSA involved in the cephalosporin binding sites. The binding of the cephalosporins decreased remarkably with the modification of the tyrosine residues. These results suggest that the binding site of cephalosporins is located in the vicinity of warfarin binding site rather than benzodiazepine binding site and that tyrosine residues are involved in the cephalosporin binding site.     

Studies on beta-lactam antibiotics. X. Synthesis and structure-activity relationships of 7 beta-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino)acetamido] cephalosporin derivatives

The synthesis of 7 beta-([Z) -2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino) acetamido]-cephalosporins (2a-h) modified at the C-3 position of a cephem nucleus and the effect of the C-3 substituents on the antibacterial activity, oral absorptivity and therapeutic activity are discussed. The cephems (2a and 2b) having a C-3 substituent such as hydrogen or vinyl were more potent than other cephalosporins against Gram-negative bacteria. However, the cephalosporin (2f) having methylthio group at the 3-position showed the highest absorption rate in rats. These three cephalosporins (2a, b and f) exhibited equally good protective activities in mice infected. Furthermore, the serum levels of these cephalosporins (2a, b and f) were examined in dogs, and 2b and 2f showed outstanding high and prolonged serum levels.     

Characterization and activity of cephalosporin metal complexes

Semi-synthetic cephalosporin antibiotics have structures similar to that of penicillins, and both groups of compounds are characterized by similar properties and determined by the same methods. Most antibiotics, including cephalosporins and their decomposition products, contain electron donor groups that can bind naturally occurring metal ions in vivo. Cephalosporin antibiotics exhibit a change in their toxicological properties and biological performance when they were tested as metal complexes. The proposed reason for such a behavior is the capability of chelate binding of the cephalosporins to the metals. In an attempt to understand the coordination mode of metals with cephalosporins, different spectroscopic techniques such as IR, UV-visible, NMR spectroscopy and voltammetric measurements were carried out to elucidate the structure of the metal-cephalosporin complexes. Synthesis, characterization and biological screening of the cephalosporins and of the cephalosporin-metal complexes are discussed in this review. However, little information is available on the influence of the metal ions on the pharmacokinetics of the cephalosporin derivatives.     

Designing new β-lactams: implications from their targets, resistance factors and synthesizing enzymes

Penicillins and cephalosporins are β-lactam antibiotics widely used to treat bacterial infectious diseases. They mainly target the cell wall biosynthesis pathway to inhibit bacterial growth. The targets, known as penicillin-binding proteins, are enzymes involved in the polymerization of glycan chains, cross-linking them during bacterial cell wall formation. However, the dispensation of these antibiotics has been concomitant with increasing incidence of resistance to them. Reportedly, this is due to the evolvement of two resistance mechanisms in the bacterial pathogens. One is the production of β -lactamases that cleave the β -lactam rings of penicillin and cephalosporin antibiotics, rendering them ineffective against the pathogens. Another is the modification of the targets, resulting in their inability to bind β -lactam antibiotics. Nevertheless, β -lactam antibiotics remain clinically relevant due to their high target specificity in bacteria and low toxicity to humans. Thus, to overcome the continuing emergence of resistance in pathogens, more efficacious β -lactams have to be developed and cephalosporins are often preferred over penicillins due to two alkyl sites in the cephalosporin core structure amenable for modification. Transformed β -lactams are expected to have improved antimicrobial spectra and pharmacokinetics. This is illustrated by the development of two cephalosporins, namely ceftobiprole and ceftaroline, which have shown good antimicrobial activities and are currently undergoing clinical trials. This review will discuss computer-aided studies of three enzymes closely related to cephalosporins: (1) its synthesizing enzyme, deacetoxycephalosporin C synthase, (2) its targets, the penicillin-binding proteins, and (3) its degrading enzyme, the β -lactamases, and their implications in the development of new cephalosporins.     

Synthetic approach to gain insight into antigenic determinants of cephalosporins: in vitro studies of chemical structure-IgE molecular recognition relationships

Cephalosporins, after penicillins, are the most widely used antibacterial agents in infectious diseases and the cause of adverse immune reactions in the world. Whether a patient with a suspected allergy to a β-lactam can safely take a cephalosporin is often a matter of debate. However, there are no tests with enough sensitivity to detect allergy to cephalosporins. Understanding the way in which the drug metabolizes after protein conjugation is important if we are to make advances in the diagnosis of clinical allergy. Structural studies of cephalosporin-protein adducts have never been addressed successfully and are difficult to investigate. Our approach to determine the requirements involved in antigenic determinant structures consisted of designing and synthesizing a proposed skeleton that remains linked to the carrier protein after chemical degradation in cephalosporin conjugated to carrier proteins. In this study, a series of proposed epitopes were efficiently synthesized following a versatile methodology, involving the condensation of the R(1) acyl side chains of native cephalosporins, with the nuclear fragment structures (derived from amino acids or other aminofunctionalized molecules). The final well-defined structures 1-4 (a-f), representing a fragment from the proposed cephalosporin-Lys(protein) adduct intermediate, consist of closely related low-molecular-weight molecules, differing only in the functional group at C-3 and the R(1) side chains. They were assessed with sera from patients allergic to cephalosporins to study structure-IgE molecular recognition relationships. These IgE showed an enhanced recognition to proposed new skeleton epitopes with adequate functionality at C-3, with the specifities mainly related to the R(1) acyl side chain. Thus, this study led us to refine the model haptenic structures of cephalosporins and gain insight into the chemical mechanism of epitope formation.     

3-Substituent effect and 3-methylene substituent effect on the structure-reactivity relationship of 7 beta-(acylamino)-3-cephem-4-carboxylic acid derivatives studied by carbon-13 and IR spectroscopies

Relationships between the chemical reactivity of 3-substituted cephalosporins or 3-methylene-substituted cephalosporins and several parameters observed by 13C NMR and IR spectroscopies are described. Among 3-substituted cephalosporins, the values of delta (C-3) and delta (COO) of 13C NMR spectra are correlated with the logarithms of the rate constants for alkaline hydrolysis (log kobsd) when substituents at the 3-position are classified into two groups, i.e., OR substituents and others. Among the 3-methylene-substituted cephalosporins, the difference values of the 13C chemical shifts for C-3 and C-4, delta delta (4-3), are correlated with log kobsd. The beta-lactam vC = O value of the solution IR spectra is a good index for the prediction of a significant change of the beta-lactam reactivity resulting from modification of a 3-substituent or a 3-methylene substituent. From analysis of these observed parameters, both resonance and inductive effects of the substituent at the 3-position were found to affect the chemical reactivity of the beta-lactam ring in cephalosporin, while only the inductive effect of the substituent at the 3'-position was found to affect the beta-lactam reactivity.