Studies on anti-MRSA parenteral cephalosporins. I. Synthesis and antibacterial activity of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)- hydroxyiminoacetamido]-3-(substituted imidaz

In order to improve the antibacterial activity of cefozopran (CZOP) against methicillin-resistant Staphylococcus aureus (MRSA), we initiated chemical modification to introduce a 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-hydroxyimino acetyl group at the C-7 position and a 3- or 6-substituted imidazo[1,2-b]pyridazinium or 5-substituted imidazo[1,2-a]pyridinium group at the C-3' position. Although this approach successfully enhanced the anti-MRSA activity of CZOP two to eight times, a slight decrease in the activity against Gram-negative bacteria including Pseudomonas aeruginosa was involved. Among the novel derivatives, 3-(6-aminoimidazo[1,2-b]pyridazinium-1-yl)methyl-7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)hydroxyiminoacetamido]-3-cephem-4-carboxylate (44a) showed an excellent balance of activity against MRSA and Gram-negative bacteria.     

Studies on anti-MRSA parenteral cephalosporins. II. Synthesis and antibacterial activity of 7beta-[2-(5-amino-1,2,4- thiadiazol-3-yl)-2(Z)-alkoxyiminoacetamido]-3-(substituted imidaz

In an effort to discover a novel cefozopran (CZOP) derivative having excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), we performed chemical modification of the alkoxyimino moiety and imidazo[1,2-b]pyridazinium group of CZOP. Among the prepared compounds, the cyclopentyloxyimino derivative 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyloxyiminoacetamido]-3-(3,6-diaminoimidazo[1,2-b]pyridazinium-1-yl)methyl-3-cephem-4-carboxylate (20 g) showed the most potent anti-MRSA activity, reflecting its high affinity (IC50 = 1.6 microg/ml) for penicillin binding protein 2' (PBP2'), although its anti-MRSA activity was slightly inferior to that of vancomycin (VCM). In experimental systemic infection in mice, however, 20 g showed activity comparable to that of VCM against MRSA. In addition, 20 g showed activity similar or slightly inferior to that of CZOP against Pseudomonas aeruginosa both in vitro and in vivo. Considering its favorable antibacterial activity profile, 20 g was considered to be the most promising CZOP derivative for further studies.     

Studies on condensed-heterocyclic azolium cephalosporins. IV. Synthesis and antibacterial activity of 7 beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)- alkoxyiminoacetamido]-3-(condensed-heterocyclic azolium)methyl cephalosporins including SCE-2787.

The synthesis and in vitro antibacterial activity of 7 beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-alkoxyiminoacetami do] cephalosporins bearing various condensed-heterocyclic azolium groups at the 3 position in the cephalosporin nucleus are described. The thiadiazolyl cephalosporins showed good antibacterial activity against both Gram-positive and Gram-negative bacteria and the MICs of the thiadiazolyl cephalosporins against Pseudomonas aeruginosa was more potent than that of the corresponding 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-alkoxyiminoacetamido]-3- (condensed-heterocyclic azolium)methyl cephalosporins. Also, the thiadiazolyl cephalosporins bearing (imidazo[1,2-b]-pyridazinium-1-yl)methyl groups at the 3 position showed antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Among the cephalosporins tested, 7 beta-[2-(5- amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetamido]-3-(imidaz o[1,2- b]pyridazinium-1-yl)methyl-3- cephem-4-carboxylate (4, SCE-2787) which exhibited the most potent antibacterial activity and the broadest antibacterial spectrum was selected as a parenteral cephalosporin candidate for further biological evaluation.     

Studies on condensed-heterocyclic azolium cephalosporins. III. Synthesis and antibacterial activity of 7 beta-[2-(2-amino-5-substituted-thiazol-4-yl)-2 (Z)-alkoxyiminoacetamido]-3-(condensed-heterocyclic azolium)methyl-3-cephem-4- carboxylates.

As a part of our research on the synthesis of cephalosporins bearing condensed-heterocyclic azolium groups at the 3 position in the cephalosporin nucleus, we describe herein the synthesis of 7 beta-[2-(2-amino-5-halogeno-, methylthio-, methylsulfinyl-, methylsulfonyl- and sulfothiazol-4-yl)-2(Z)-alkoxyiminoacetamido] cephalosporins and their antibacterial activity. Among the compounds prepared, 7 beta-[2-(2-amino-5-chlorothiazol-4-yl)-2(Z)- methoxyiminoacetamido]-3-(imidazo[1,5-a]-pyridinium-1-yl)methyl-3-cephem -4-carboxylate (14) showed good antibacterial activity against both Staphylococcus aureus including methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, whereas the antibacterial activity against other Gram-negative bacteria was a slightly lower than that of 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(im ida zo [1,2-a]pyridinium (I-1) and imidazo[1,5-a]pyridinium (I-4)-1-yl)methyl-3-cephem-4-carboxylates.     

Studies on cephalosporin antibiotics. III. Synthesis, antibacterial activity and oral absorption of new 3-(substituted-alkylthio)-7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2- (carboxymethoxyimino)acetamido]cephalosporins

The synthesis, antibacterial activity and oral absorption in rats of new 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(carboxymethoxyimino)ace tamido] cephalosporins (1) having various substituted-alkylthio groups at the C-3 position of the cephem nucleus are described. Of these, the cephalosporins with a cyanomethylthio group (1d) and fluoroethylthio group (1p) at the C-3 position showed a potent in vitro antibacterial activity against Gram-positive and Gram-negative bacteria as well as good oral absorption in rats. When administered orally to mice infected with Klebsiella pneumoniae, 1d had stronger protective effect than 1p. The structure-activity relationships of 1 are also presented.     

Studies on condensed-heterocyclic azolium cephalosporins. II. Synthesis and antibacterial activity of 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-alkoxyiminoacetamido]-3-(condensed- heterocyclic azolium)methyl-3-cephem-4-carboxylates.

From our series of studies on cephalosporins bearing condensed-heterocyclic azolium methyl groups at the 3 position in the cephalosporin nucleus, we describe here the synthesis and antibacterial activity of 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-alkoxyiminoacetamido]ceph alosporins containing imidazo[1,5-a]pyridinium, imidazo[1,2-b]pyridazinium, imidazo[1,2-a]pyrimidinium, imidazo[1,2-c]pyrimidinium, and pyrazolo[1,5-a]pyridinium methyl groups at the 3 position. Among the cephalosporins tested, 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3- (imidazo[1,5-a]pyridinium-2-yl) (1), (imidazo[1,2-b]pyridazinium-1-yl) (2), and (pyrazolo[1,5-a]-pyridinium-1-yl) (3)methyl-3-cephem-4-carboxylates showed potent antibacterial activity and broad antibacterial spectrum. The antibacterial activity of these cephalosporins (1 approximately 3) was superior to that of ceftazidime (CAZ). These results imply that the delocalization of the positive charge of the imidazo[1,5-a]pyridinium, pyrazolo[1,5-a]pyridinium and imidazo[1,2-b]pyridazinium groups leads to an expanded antibacterial spectrum and increased activity and that these condensed-heterocyclic compounds as well as imidazo[1,2-a]pyridine are effective moieties for improving antibacterial activity and spectrum.     

Semisynthetic beta-lactam antibiotics. III. Synthesis and antibacterial activity of 7 beta-[2-(2-aminothiazol-4-yl)-2-(substituted carbamoylmethoxyimino)acetamido]cephalosporins

Syntheses of cephalosporins modified with a 7 beta-[2-(2-aminothiazol-4-yl)-2-(substituted carbamoylmethoxyimino)acetamido] group at the C-7 position and with various hetero aromatics at the C-3 position are described. The effects of substituents on the carbamoyl group in the 7-side chain were investigated in order to improve antibacterial activity. Some of these compounds exhibited high antibacterial activity against Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa, as well as good resistance to beta-lactamase.     

Studies on condensed-heterocyclic azolium cephalosporins. I. Synthesis and antibacterial activity of 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)- alkoxyiminoacetamido]-3-(imidazo[1,2-a]pyridinium-1-yl)methyl-3- cephem-4-carboxylates.

In our study of the structure-activity relationships of cephalosporins bearing quaternary ammonium groups at the 3 position, we postulated that delocalization of the azolium positive charge would lead to an expanded antibacterial spectrum and increased activity. Since quaternization of condensed-heterocyclic compounds such as imidazo[1,2-a]pyridine gives positive charge delocalization, 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-alkoxyiminoacetamido] cephalosporin derivatives (1-53) bearing various (imidazo[1,2-a]pyridinium-1-yl)methyl moieties at the 3 position were prepared and their antibacterial activity was determined. As expected, these cephalosporins exhibited potent activity against both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa. These results imply that imidazo[1,2-a]pyridine is a quite useful substituent for improving antibacterial activity and spectrum. The structure-activity studies revealed that a favorable substituent on the imidazo[1,2-a]pyridine is the cyano radical at the 6 position of the ring, and ethoxyimino or 1-carboxy-1-methylethoxyimino groups are suitable for the alkoxyimino substituent. Among the cephalosporins tested, 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)- ethoxyiminoacetamido]-3-(6-cyanoimidazo[1,2-a]pyridinium -1-yl)methyl-3-cephem-4-carboxylate (45) and 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-(1- carboxy-1-methylethoxyiminoacetamido]-3-(6-cyanoimidazo[1,2- a] pyridinium-1-yl)methyl-3-cephem-4-carboxylate (49) showed good antibacterial activity.     

Synthetic cephalosporins. V. Synthesis and antibacterial activity of 3-alkylthio-7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(O-substituted oxyimino)acetamido]cephalosporins and related compounds

3-Alkylthio-7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(O-substituted oxyimino)acetamido]cephalosporins (6 and 7) and the 3-methoxy analogues (10) were prepared by coupling diphenylmethyl 7-amino-3-alkylthio-3-cephem-4-carboxylate (1 and 2) or diphenylmethyl 7-amino-3-methoxy-3-cephem-4-carboxylate with (Z)-2-(2-tritylaminothiazol-4-yl)-2-(O-substituted oxyimino)acetic acid (4), followed by deprotection and subjected to examination of antibacterial activities. The pivaloyloxymethyl esters (8 and 9) of the compounds (6 and 7) were also prepared and oral activities of these esters were compared with those of the parent compounds (6 and 7). The cephalosporins (6a-j and 7a-c) had potent and wide antibacterial spectra against Gram positive and Gram negative bacteria which were comparable to those of cefixime or cefteram. Among them, the cephalosporins (6f and 7c) and the pivaloyloxymethyl esters (8b and 9b) had good in vivo efficacy in mice against infections of Escherichia coli No. 29 and especially 8b showed high urinary recovery in mice.     

2-（5-氨基-1，2，4-噻二唑-3-基）-2-（Z）-甲氧亚氨基乙酸S-苯并噻唑硫酯的合成

2-(5-氨基-1,2,4-噻二唑-3-基)-2-(Z)-甲氧亚氨基乙酰胺与2-巯基苯并噻唑为原料,哌啶为溶剂,在三乙胺催化下反应制得头孢菌素中间体2-(5-氨基-1,2,4-噻二唑-3-基)-2-(Z)-甲氧亚氨基乙酸S-苯并噻唑硫酯,收率约76%。     

Studies on cephalosporin antibiotics. II. Synthesis, antibacterial activity and oral absorption of 3-alkoxycarbonylmethoxy-7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(O-substituted oxyimino)-acetamido]cephalosporins

The synthesis, antibacterial activity and oral absorption in rats of 3-alkoxycarbonyl-methoxy-7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(O-substituted oxyimino)acetamido]cephalosporins (1) are described. In this cephalosporin series, 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(carboxy-methoxyimino)acetamid o] cephalosporins (1b, 1i and 1j) with a lower alkoxycarbonylmethoxy group at the C-3 position of a cephem nucleus exhibited not only potent activity against Gram-negative bacteria but also good oral absorption in rats. Structure-activity relationships of 1 are also presented.     

Semisynthetic beta-lactam antibiotics. II. Synthesis and antibacterial activity of 7beta-[2-(acylamino)-2- (2-aminothiazol-4-yl)acetamido]cephalosporins

Cephalosporin derivatives (I) substituted with a neutral, acidic or basic amino acid group as the terminal group attached to the 2-amino-2-(2-aminothiazol-4-yl)acetamido side chain at the C-7 position were synthesized, and the effect of each group on antibacterial activity was examined. The derivatives bearing an amidino or guanidino group showed broad spectra of antibacterial activity similar to those of cefotaxime, but they were relatively sensitive to beta-lactamases.     

(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基乙酸的合成

目的 合成头孢唑兰中间体(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基乙酸。方法 以氰乙酰胺为起始原料,依次经甲氧亚氨化、加成、酯化、与硫氰化钾反应、构型转换和水解共6步反应制得目标化合物。结果和结论 目标化合物的结构经¹H-NMR和MS谱确证。该工艺路线原料易得,操作简便,总收率为29.8%,具有一定的工业化价值。     

Studies on cephalosporin antibiotics. IV. Synthesis, antibacterial activity and oral absorption of new 3-(2-substituted-vinylthio)-7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2- (carboxymethoxyimino)acetamido]cephalosporins.

A series of new 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(carboxymethoxyimino)ace tamido] cephalosporins (1) having various substituted-vinylthio groups at the C-3 position of the cephen nucleus was synthesized and evaluated for antibacterial activity and oral absorption in rats in comparison with cefixime. Of these, the cephalosporins (1a and 1c) with a lower alkoxycarbonylvinylthio group (Z-form) at the C-3 position showed a potent antibacterial activity against Gram-negative bacteria, improved activity against Staphylococcus aureus as well as good oral absorption in rats. The structure-activity relationships of 1 are also presented.     

7β-[2-(2-取代氨基噻唑-4-基)-(Z)-2-甲氧亚氨乙酰氨基]-3-季铵基甲基头孢菌素的合成及抗菌活性

为了寻找抗菌谱更广,抗菌活性更强的新型头孢菌素类化合物,本研究以2-(2-氨基噻唑-4-基)-(Z)-2-甲氧亚氨基乙酸乙酯（1）为原料,经酰化、取代、水解、活泼酯化、缩合、成盐得到目标化合物（N₁-N₉）。所合成的9个新型第四代头孢菌素的结构经红外、核磁共振氢谱、质谱和元素分析确证。体外抗菌实验结果表明, 所合成的化合物具有不同程度的抗菌活性,它们对革兰氏阳性菌的活性总体上相当于或优于硫酸头孢匹罗,特别是对金葡菌、表皮葡球菌表现出比硫酸头孢匹罗更好的活性。
     

Studies on cephalosporin antibiotics. V. Synthesis, antibacterial activity and oral absorption of new 3-[(Z)-2-methoxycarbonylvinylthio]-7 beta- [(Z)-2-(2-aminothiazol-4-yl)-2-(oxyimino)acetamido]cephalosporins.

A series of new 3-[(Z)-2-methoxycarbonylvinylthio]-7 beta-[(2- aminothiazol-4-yl)acetamido]-cephalosporins (1) having various oxyimino groups (Z-form) at the alpha position of the C-7 side chain was synthesized and evaluated for antibacterial activity and oral absorption in rats. Of these, the cephalosporin (1a) with a hydroxyimino group in the C-7 side chain showed a potent antibacterial activity against Gram-negative bacteria and Gram-positive Staphylococcus aureus as well as good oral absorption in rats. The structure-activity relationships of 1 are also presented.     

The synthesis and biological evaluation of 7 beta-[2-(5-amino-[1,2,4] oxadiazol-3-yl)-2-Z-methoximinoacetamido]-cephalosporin derivatives

A series of 7 beta-[2-(5-aminooxadiazol-3-yl)-2-Z-methoximinoacetamido] -3-cephem-4-carboxylic acids (7a-g) were synthesized and evaluated microbiologically Although somewhat less active than cefotaxime 7a-g showed good antimicrobial activity against a wide variety of Gram-positive and Gram-negative bacteria. The beta-lactamase stability of 7a and 7f was also discussed.     

(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基乙酸合成路线图解

（Z）-2-（5-氨基-1，2，4-噻二唑-3-基）-2-甲氧亚氨基乙酸（1）是合成头孢唑兰（cefozopran）和头孢克定（cefclidin）㈨等头孢菌素的关键中间体。1的合成路线按噻二唑环形成前或后引入甲氧亚氨基可分为两类，现分述如下：     

Studies on cephalosporin antibiotics. VI. Synthesis, antibacterial activity and oral efficacy in mice of new 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)-acetamido]-3- (substituted alkylthio)cephalosporins.

A series of new 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido] cephalosporins (1) having various substituted alkylthio groups at the C-3 position of the cephem nucleus were prepared and evaluated for antibacterial activity and oral absorption in rats. Of these, the cephalosporin with a cyanomethylthio group (1a) showed the greatest activity against Staphylococcus aureus and Gram-negative bacteria. Its pivaloyloxymethyl ester (6a), a representative prodrug, exhibited good in vivo efficacy in mice by oral administration. The structure-activity relationships of 1 are also presented.     

Synthetic cephalosporins. III. Synthesis and antibacterial activity of 7-[2-(2-Aminothiazol-4-yl)-3-carboxy-2-propenoamido]cep hal osporins and related compounds

Synthesis and antibacterial activity of 7-[2-(2-aminothiazol-4-yl)-3-carboxy-2-propenoamido]cepha los porins and their derivatives are described. These compounds are of interest as carbon analogues of oximecephalosporins, 7-[2-(2-aminothiazol-4-yl)-2(Z)-oxyiminoacetamido]cephalo spo rins having remarkable antibacterial activity. The synthesized 7-[2-(2-aminothiazol-4-yl)-3(Z)-carboxy-2-propenoamido]-c eph alosporins (14, 19) show improved activity especially against the beta-lactamase-producing strains. A 7-[2-(2-aminothiazol-4-yl) maleimido]cephalosporin (15) has been also prepared by cyclization of 7-[3-(2-aminothiazol-4-yl)-2-ethoxycarbonyl-2(Z)-propenoamido++ +]cephalosporin.