头霉素关键中间体7-MAC的合成方法改进

目的改进头霉素关键中间体7α-甲氧基-7β-氨基-3-[（1-甲基-1H-四氮唑-5-基）硫甲基]头孢-3-烯4-羧酸二苯甲酯（7-MAC）的合成方法。方法以7-氨基-3-乙酰氧甲基头孢烯酸（7-ACA）为原料,经亲核取代反应合成3-（1-甲基-1胁四氮唑-5-基）硫甲基-7-氨基头孢烯酸（2）,2经取代．消除反应、酯化反应制得7-甲硫亚胺-3-[（1-甲基-1H-四氮唑-5-基）硫甲基]头孢-3-烯4-羧酸二苯甲酯（5）,在中间体5的7α位引入甲氧基制得目标化合物7-MAC。结果与结论目标化合物的结构经质谱、核磁共振氢谱确证,总收率为60％以上,纯度为99．1％,透光率高于75％。该方法反应条件温和,得到的产品质量好,有利于工业化生产。     

头孢菌素Ⅳ

[答]青霉素过敏反应和过敏休克的发生,目前尚有些问题没有研究清楚。现已知青霉素特别是它的代谢产物,在机体内与蛋白质形成共价键结合而具有免疫原性,刺激机体免疫机制产生抗体。第二次这种药物再次进入体内,即可发生抗体抗原结合反应(过敏反应)。青霉素及其代谢产物与蛋白质结合所产生的     

Synthesis and antimicrobial activity of 7 alpha-methoxypyrimidinyl-ureidocephalosporins

The synthesis of a series of 7 alpha-methoxy-7-[(R)-2-[3-[5-pyrimidinyl]ureido]-2-(4-hydroxyphenyl) acetamido]-3-cephem-4-carboxylates 2 is described. 7-[(R)-2-[3-[2-(p-Aminosulfonyl)-anilino-4-hydroxy-5-pyrimidinyl]ureido- 2-(4-hydroxyphenyl)acetamido]-7 alpha-methoxy-3-[(1-methyl-1H-tetrazol-5 -yl)thio]methyl-3-cephem-4-carboxylic acid, sodium salt (2k, UG-FA 132), has exhibited a broad range of antimicrobial activity. UG-FA 132 is highly active against Gram-positive and Gram-negative organisms, including Pseudomonas and lactamase producers, and shows potent activity against anaerobes. The high efficacy of UG-FA 132 was confirmed by in vivo experiments in mice.     

Orally absorbable cephalosporin antibiotics. 1. Structure-activity relationships of benzothienyl- and naphthylglycine derivatives of 7-aminodeacetoxycephalosporanic acid

A structure-activity relationship study of a number of orally absorbed cephalosporins together with their syntheses is described. These new cephalosporins are benzothienyl- and naphthylglycine derivatives of 7-aminodeacetoxycephalosporanic acid. Several different synthetic methods for the glycine side chains, their protection, and the final acylations are reported. Several of these analogues were more active than cephalexin both in vitro and in vivo against commonly encountered Gram-positive bacteria. (R)-7-(3-Benzothienylglycylamido)-3-methyl-3-cephem-4-carboxylic acid (1R) has emerged as a potent antibacterial agent and is currently undergoing preclinical evaluation.     

Synthesis and antimicrobial activities of some new tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives of cefadroxil.

Eleven new 7-[2-(dihydro-5-substituted-6-thioxo-2H-1,3,5-thiadiazine-3( 4H)-yl)-2- (4-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid derivatives were synthesized by the reaction of cefadroxil monohydrate, formaldehyde and substituted potassium dithiocarbamate. Their structures have been elucidated by spectral data and elementary analysis. The title compounds were tested for antimicrobial activity in vitro against gram-positive bacteria (Staphylococcus aureus, Streptococcus faecalis), gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and yeast-like fungi (Candida albicans, C. parapsilosis, C. stellatoidea, C. pseudotropicalis) in comparison with cefadroxil monohydrate. The activity of compounds 1 and 10 against S. aureus (MBC: 37.5 micrograms/ml) and compound 1 against E. coli (MBC: 75 micrograms/ml) were found to be the same as cefadroxil monohydrate. Compounds 1 and 10 were more effective than cefadroxil monohydrate against S. faecalis with 25 and 37.5 micrograms/ml MBC values, respectively. None of the compounds and cefadroxil monohydrate proved to be effective against P. aeruginosa (MBC: greater than 100 micrograms/ml). While cefadroxil monohydrate had no activity against yeast-like fungi, compounds 9 and 10 were significantly effective against yeast-like fungi (MFC: 37.5 micrograms/ml).     

Synthesis and preliminary antimicrobial evaluation of new 7-(N-pyrrolyl) derivatives of cephalosporins

A series of seven new cephalosporins was prepared for preliminary microbiological evaluation by N-acylation of 7-aminocephalosporanic acid with substituted N-pyrrolylcarboxylic acids via mixed anhydrides. The chemical structure of the compounds were confirmed by IR, 1H-NMR and mass spectral data. The 7-(N-pyrrolyl) cephalosporin derivatives were tested in vitro by the disc diffusion method upon 3 strains and subsequent determination of the minimal inhibitory concentration (MIC) of the most active ones upon 29 strains. The products of the series exhibited antibacterial activity. They showed selective potency against gram-positive and were practically inactive against gram-negative microorganisms. The compound 3-[(acetyloxy)methyl]-7-([2-[3-(ethoxycarbonyl)-2-methyl-5-phenyl-1H-1-pyrrolyl]acetyl]amino)-6-oxo-7,7a-dihydro-2H,6H-aceto[2,1-b][1,3]thiazine-4-carboxylic acid (4a) was outlined as more active than the reference cefazolin (CAS 23325-78-2) in regard to S. pyogenes and some strains of S. aureus, the MIC of 4a against S. pyogenes were at least 4-fold lower. The toxicological evaluations of the starting N-pyrrolylcarboxylic acids showed no acute toxicity.     

7-酰氨基-3-(1,2,3-三唑甲基)头孢菌素衍生物的合成及其抗菌活性

本文以青霉素G扩环而得的7-苯乙酰氨基-3-甲基-3-头孢烯-4-羧酸(Ⅰ)为原料,合成了12个C₃位上有1,2,3-三唑甲基取代的新头孢菌素衍生物(Ⅷ_1～12),并经分析确证了各化合物的结构。体外抑菌试验结果表明,其中6个化合物,即Ⅶ_2～4,9～11,不仅对革兰氏阳性菌有较高的抑制作用。而且对革兰氏阴性菌也有高度敏感性。     

Synthesis and antibacterial activity of 6315-S, a new member of the oxacephem antibiotic

The synthesis and in vitro activity of 7 beta-difluoromethylthioacetamido-7 alpha-methoxy-3-[[1-(hydroxyethyl)-1H- tetrazol-5-yl]thiomethyl]-1-oxa-3-cephem-4-carboxylic acid sodium salt, 6315-S, are described. 6315-S shows good antibacterial activity against Gram-positive and Gram-negative bacteria, being especially highly active against clinical isolates of Staphylococcus aureus resistant to either ampicillin or methicillin. The structure-activity relationship of related 1-oxa and 1-thia cephems is also presented.     

Stereo-specific synthesis of 3-trifluoromethylcephalosporin derivative by microbial acylase.

Cephalosporin acylase (EC 3.5.1.11) obtained from Kluyvera citrophila ATCC 21285 was found to catalyze synthesis of 7-[2-(2-thienyl)acetamido]-3-trifluoromethyl-3-cephem-4-carboxylic acid from methyl thienylacetate and dl-7-amino-3-trifluoromethyl-3-cephem-4-carboxylic acid. The enzymatically-synthesized compound showed [alpha]25 D + 42.7 degrees (c 0.058, MeOH) and its biological activity was about twice as much as that of racemic 7-[2-(2-thienyl)acetamidol]-3-trifluoromethyl-3-cephem-4-carboxylic acid chemicall synthesized. As a result, N-acylation by this enzyme was demonstrated to be asymmetric synthesis.     

Patent Evaluation: Highly Potent Carbapenems Resistant to DHP-I

Summary

Novelty: 7-Oxo-1-aza-bicyclo[3.2.0]hept-2-en-2-carboxylic acids (carbapenems) with novel 2-(2-alicyclic heterocyclic (alkyl)pyrrolidin-4-ylthio) substituents are disclosed. The compounds have good antibacterial activity against Gram-positive bacteria such as Staphylococcus aureus and Gram-negative bacteria including Pseudomonas aeruginosa and additionally exhibit excellent DHP-I stability.

Biology: Antibacterial activity (MIC or relative potency) against MRSA and Ps. aeruginosa is compared to meropenem and imipenem for selected compounds. The preferred compounds are significantly more active than the reference compounds with MIC values of 0.1–1.56 μg/ml compared to 1.56–6.25 for imipenem against Pseudomonas strains.

Chemistry: Representative experimental procedures for the synthesis of the C-2 substituent thio precursor and subsequent elaboration to the required carbapenems are fully documented (forty-four detailed examples; one thousand thirty-three compounds claimed). Preferred compounds are (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(pyrrolidin-3-yl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid and (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-(piperidin-4-yl)pyrrolidin-4-ylthio]-1-carbepen-2-em-3-carboxylic acid.     

Studies on beta-lactam antibiotics. III. Syntheses and antibacterial activities of new 3-(1,3-dithiolan-2-yl)cephalosporins, YM-22508, YM-16457 and their prodrug-type esters

The syntheses and biological activities of new 7-beta-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxy-iminoacetamido]-3-(1 ,3- dithiolan-2-yl)-3-cephem-4-carboxylic acid (YM-22508, 1a), 7-beta-[(Z)-2-(2-amino-4-thiazolyl)-2- methoxyiminoacetamido]-3-(1,3-dithiolan-2-yl)-3-cephem-4-carboxyli c acid (YM-16457, 1d) and their prodrug-type esters are described. Among them, YM-22561 (1c), the 1-acetoxyethyl ester of 1a, showed good in vivo efficacy in mice against infections of Staphylococcus aureus Smith, Streptococcus pyogenes S 23 and Escherichia coli NY-17 and a long plasma T1/2 in mice.     

Antimicrobial evaluation of cefoxitin: a new semisynthetic cephamycin. Comparative studies with cefazolin and cefalotin

Antimicrobial activity of 3-carbamoyloxymethyl-7-alpha-methoxy-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylic acid (cefoxitin), a new semisynthetic cephamycin antibiotic, was studied in comparison with that of cefazolin and cefalotin. Cefoxitin exhibited antibacterial activity against both gramnegative and gram-positive bacteria, and its action was bactericidal. Against gram-negative bacteria, cefoxitin was highly active as well as cefazolin, and more active than cefalotin. Especially, cefoxitin was highly active not only against strains of clinical isolates of indole-positive Proteus and S. marcescens but also against those of E. coli and P. mirabilis which were resistant to cefazolin and/or cefalotin, respectively. In addition, cefoxitin was effective against the strains resistant to beta-lactam antibiotics including cefazolin and cefalotin. Cefoxitin was hardly active against the strains of E. cloacae and P. aeruginosa, similar to cefazolin and cefalotin. Against gram-postive bacteria, cefoxitin was less active than cefazolin and cefalotin. In protection tests in mice, cefoxitin and cefazolin were more effective against infection with E. coli than cefalotin. Furthermore, cefoxitin was more active against infections with S. marcescens and P. morgani than the other antibiotics. Cefoxitin, like cefalotin, was less effective against infection with S. aureus than cefazolin. Cefoxitin was highly resistant to hydrolysis by beta-lactamases derived from the organisms insusceptible to the antibiotic. This fact revealed that the resistance of the organisms to cefoxitin may be in part due to factors other than beta-lactamase inactivation.     

Synthesis and structure-activity relationships of 7 beta-[2-(2-aminothiazol-4-yl)acetamido]cephalosporin derivatives. V. Synthesis and antibacterial activity of 7 beta-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-cephalosporin derivates and related compounds

In order to improve the antibacterial activity of 7 beta-[2-(2-aminothiazol-4-yl)acetamido]-cephalosporins new derivatives having a methoxyimino moiety in the 7-acyl side chain and related compounds were synthesized. Of these, 7 beta-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-cephalosporins were found to possess excellent activity against a variety of Gram-positive and Gram-negative bacteria including beta-lactamase-producing strains. An extensive study of structure-activity relationships led to the selection of 7 beta-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-methyl-1H-tetrazol-5-yl) thiomethyl]-ceph-3-em-4-carboxylic acid, SCE-1365, for further biological and clinical evaluation.     

Pyrrolnitrin analogues. IX. Synthesis and biological activity of 1-tolyl-3-nitrophenyl-5-methylpyrazole-4-carboxylic acids and 1-tolyl-3-methyl-5-nitrophenylpyrazole-4-carboxylic acids

The syntheses of all the possible 1-tolyl-3-nitrophenyl-5-methylpyrazole-4-carboxylic acids, 1-tolyl-3-methyl-5-nitrophenylprazole-4-carboxylic acids and of the corresponding carboxylates are reported. Several 1,3- and 1,5-diarylpyrazole derivatives were subjected to in vitro antibacterial screenings. Some acids showed activity against some strains of gram-positive bacteria. The results are discussed on the basis of structure-activity relationships.     

Structural identification and characterization of impurities in ceftizoxime sodium

Ceftizoxime sodium is a parenteral beta-lactamic antibacterial drug. In the synthesis of ceftizoxime sodium, eight process related impurities were detected in HPLC analysis. Pure impurities obtained by both synthesis and preparative HPLC were co-injected with ceftizoxime sample to confirm the retention times in HPLC. The impurities were characterized as, (6R,7R)-7-amino-3-cephem-4-carboxylic acid (impurity I); (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-cephem-1-oxo-4-carboxylic acid (impurity II); (4RS,6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetamido]-3,4-dihydro-3-cephem-4-carboxylic acid (impurity III); (6R,7R)-7-[(E)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-cephem-4-carboxylic acid (impurity IV); (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-cephem-N-(3-cephem-4-carboxy-7-yl)-4-carboxamide (impurity V); (6R,7R)-7-[(Z)-2-[[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetylamino]thiazol-4-yl]-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (impurity VI); 2-mercaptobenzothiazole (impurity VII) and 2-mercapto benzothiazolyl [(Z)-2-(2-amino-4-thiazolyl)-2-methoxyimino] acetate (impurity VIII). Structural elucidation of all impurities by spectral data ((1)H NMR, (13)C NMR, MS and IR) has been discussed.     

Preparation, identification, and quantitative NMR determination of silyl derivatives of 6-aminopenicillanic acid, 7-amino-3-methyl-delta3-cephem-4-carboxylic acid, and 7-amino-3-acetoxymethyl-delta3-cephem-4-carboxylic acid.

A rapid and accurate method for the quantitative determination of the extent and ratio of amino and carboxyl group trimethylsilylation of 6-aminopenicillanic acid, 7-amino-3-methyl-delta3-cephem-4-carboxylic acid, and 7-amino-3-acetoxymethyl-delta3-cephem-4-carboxylic acid is presented. The method utilizes NMR spectroscopy and is based on the difference in chemical shifts between N-trimethylsilyl and O-trimethylsilyl groups or, in cephalosporin derivatives, between the methyl group in the 3-position and free amino resonances. The spectra of the N,O-bis(trimethylsilyl) derivatives are discussed.     

Studies on beta-lactam antibiotics. I. Synthesis and in vitro anti-pseudomonal activity of 3-isothiazole-cephalosporin derivatives

The synthesis and in vitro activity of 7 beta-[(Z)-2-(2-amino-4-thiazolyl)-2-(2-carboxy-2- alkoxyimino)acetamido]cephalosporins with a (4-carboxy-3-hydroxy-5-isothiazolyl)thiomethyl group at the 3-position are described. These cephalosporins (9a approximately 9i) showed excellent activity against Gram-negative bacteria including beta-lactamase producing strains. The most interesting compound of the series was 7 beta-[(Z)-2-(2-amino-4-thiazolyl)-2- (2-carboxy-2-propoxyimino)acetamido]-3-cephem-4-carboxylic acid (9g, YM-13115) because of its outstanding inhibitory potency against Pseudomonas aeruginosa and highly prolonged plasma half-life in rats.     

Synthesis and antibacterial activity of new tetracyclic quinolone antibacterials.

A series of 8-substituted-9,1-(epoxymethano)-7-fluoro-5-oxo-5H- thiazolo[3,2-a]quinoline-4-carboxylic acids having a novel tetracyclic structure was synthesized and tested for antibacterial activity. The nature of the heteroatom (N, O, or S) substituted at the 8-position had little influence on the antibacterial activity. Among the six pyrrolidinyl derivatives and the five piperazinyl derivatives, the 8-(3-hydroxy-1-pyrrolidinyl) derivative 6h and the hydrochloride of the 8-(4-methyl-1-piperazinyl) derivative 6l showed the most potent activity against both Gram-positive and Gram-negative bacteria. Against nalidixic acid resistant strains, isolated from Escherichia coli KC-14, compound 6h was less potent than 6l. Replacement of the piperazinyl nitrogen atom by a carbon atom, an oxygen atom, or a sulfur atom (corresponding to the piperidino, morpholino, or thiomorpholino group, respectively) enhanced the activity against Gram-positive bacteria, but reduced the activity against Gram-negative bacteria. Compound 6l also showed potent in vivo antibacterial activity against Gram-positive and Gram-negative bacteria, and did not cause convulsions in mice with the concomitant administration of fenbufen. Replacement of the carboxy group by a sulfonic acid group in 6l resulted in a complete loss of antibacterial activity.     

New broad-spectrum cephalosporins with anti-pseudomonal activity. III. Synthesis and antibacterial activity of 7 beta-[D-2-(4-hydroxy-6-methylpyridine-3-carbonylamino)-2-(4-hydroxyphenyl) acetamido]-3-(methyl or substituted methyl)-ceph-3-em-4-carboxylic acids

The influence of various 3-substituents on the antibacterial activity of 7 beta-[D-2-(4-hydroxy-6-methylpyridine-3-carbonylamino)-2-(4-hydroxyphenyl) acetamido]ceph-3-em-4-carboxylic acids (III) was investigated. Introduction of an acidic substituent, such as a sulfo or a carboxyl group, to a 3-(1-methyl-1H-tetrazolyl)thiomethyl substituent (IIIf--i) resulted in a marked loss of activity against Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus faecalis, Escherichia coli, Klebsiella pneumoniae, and Enterobacter aerogenes, in contrast to an in crease of activity against Proteus mirabilis. Displacement of the acetoxy group of IIIb with pyridines (IIIm--p) enhanced the activity against P. aeruginosa and E. aerogenes: their activity against those strains were superior to that of the cephalosporin IIId having a 3-(1-methyl-1H-tetrazolyl)thiomethyl substituent. As a result of extensive studies in addition to the study of in vitro activity in this series, 7 beta-[D-2-(4-hydroxy-6-methylpyridine-3-carbonylamino)-2-(4-hydroxyphenyl) acetamido]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acid, code No. SM-1652, cefpiramide (generic name), was selected as a candidate for further biological and clinical investigations.     

Investigations on the synthesis and pharmacological properties of amides of 7-methyl-3-phenyl-1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl]-2,4- dioxo-1,2,3,4-tetrahydropyrido[2,3-d]-pyrimidine-5-carboxylic acid

Synthesis of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4- tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid (6-10) and their 1-[2-hydroxy-3(4-phenyl-1-piperazinyl)propyl] derivatives (11-15) are described. Some of them displayed strong analgesic activity.