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.     

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.     

Studies on monocyclic beta-lactam antibiotics. V. Synthesis and antibacterial activity of 3-[2-(2-aminothiazol-4-yl)-(Z)-2-(O-substituted oxyimino)-acetamido]-1-(1H-tetrazol-5-yl)-2-azetidinones having various functional groups at C-4 position of beta-lactam

The synthesis and antibacterial activity of the 3-[2-(2-aminothiazol-4-yl)-(Z)-2-(O-substituted oxyimino)acetamido]-1-(1H-tetrazol-5-yl)-2-azetidinones++ + having various functional groups at C-4 position of beta-lactam are described. These compounds exhibited a strong activity against a variety of Gram-negative bacteria including beta-lactamase-producing strains. Among various C-4 substituents explored, the fluoromethyl and carbamoyloxymethyl moiety were found to increase the activity.     

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.     

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.     

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.     

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.     

Chemical modification of sulfazecin. Synthesis of 4-(substituted methyl)-2-azetidinone-1-sulfonic acid derivatives

In expectation of improving the antibacterial activity of sulfazecin by chemical modification at the 3- and 4-positions, a number of 3-[2-(2-aminothiazol-4-yl)-(Z)-2-(substituted oxyimino)-acetamido]-4-(substituted methyl)-2-azetidinone-1-sulfonic acids were synthesized. Among various 4-substituents explored, the carbamoyloxymethyl group was found to provide a good effect to the antibacterial activity of these 2-azetidinone derivatives. An extensive study of structure-activity relationships led to selecting (3S,4S)-3-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxymethoxyiminoace tamido]-4- carbamoyloxymethyl-2-azetidinone-1-sulfonic acid, AMA-1080 (Ro 17-2301), which has highly potent antibacterial activity against Gram-negative bacteria including Pseudomonas aeruginosa, for further biological and subsequent clinical evaluation.     

Semisynthetic beta-lactam antibiotics. I. Synthesis and antibacterial activity of 7 beta-[2-aryl-2-(aminoacetamido)acetamido]-cephalosporins

The synthesis and in vitro structure-activity relationships of cephalosporins having dipeptides substituted with various aryl groups as the side chain at the C-7 position have been outlined. Of these compounds, 2-aminothiazol derivatives showed a broad spectrum of enhanced antibacterial activity, and 7 beta-[DL-2-(D-aminopropionamido)-2-(2-aminothiazol-4-yl)acet amido]-3- [(1-methyl-1H-tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxyli c acid was the most balanced of these active derivatives with respect to both Gram-positive and Gram-negative strains.     

Synthesis of a new series of cephalosporins having 3-substituted-ammonio-1-propenyl group as the C-3 side chain

The synthesis and antimicrobial activity of eight derivatives of 7-[(Z)-2-(2-aminothiazol-4-yl)- and 7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido] cephalosporins having an (E) or (Z)-3-ammonio-1-propenyl group in the C-3 side chain are described. The (E)-propenyl derivatives were more active than their corresponding Z-isomers and showed well-balanced, broad antibacterial activity against both Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa.     

Synthesis and activity of potent 3-(isoxazolidin-5-yl)- and 3-(isoxazolidinium-5-yl)cephalosporins.

The syntheses and in vitro antibacterial activities of 3-(isoxazolidin-5-yl)- and 3-(isoxazolidinium-5-yl)cephalosporins are described. 1,3-Dipolar cycloaddition of 3-vinylcephalosporin with nitrone gave diastereomeric isomers of 3-(isoxazolidin-5-yl)cephalosporin. The antibacterial activities of 3'-(S)-isomers were superior to those of 3'-(R)-isomers. The quaternarization of isoxazolidine ring increased the antibacterial activity. Among them, compound 10b with a hydroxyimino group in the C-7 side chain showed potent activities against staphylococci and compound 10f with an N-hydroxypyridone exhibited an excellent antipseudomonal activity.     

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. 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 FK482 (Cefdinir). IV. Synthesis and structure-activity relationships of 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]- 3-substituted cephalosporin derivatives

The synthesis of 7 beta-[(Z)-2-(aminothiazol-4-yl)-2-hydroxyiminoacetamido] cephalosporins (Ia-i) modified at the C-3 position of a cephem nucleus and the effect of the C-3 substituents on the antibacterial activity and oral absorbability are discussed. The cephems (Ie, h and i) having a C-3 substituent such as 1-propenyl, ethylthio and vinylthio group as well as FK482 (cefdinir) exhibited excellent antibacterial activities against both gram-positive and gram-negative bacteria. However, those compounds showed poor absorption rate after oral administration in rats. It is concluded that the vinyl moiety at the 3-position is necessary to display fairly oral absorptivity in a series of 7 beta-[(Z)-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]c eph ems.     

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.     

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.     

A new cephalosporin. SCE-963: 7-[2-(2-aminothiazol-4-yl)-acetamido]-3-[[[1-(2-dimethylaminoethyl)-1h-tetrazol-5-yl]-thio]methyl]ceph-3-em-4-carboxylic acid. Chemistry and structure-activity relationships.

The synthesis and the in vitro and in vivo antimicrobial activities of a series of 7-[2-(2-aminothiazol-4-yl)acetamido]cephalosporins (1) having varied 3-substituents, such as methyl, hydroxymethyl, acetoxymethyl, pyridiniomethyl and heterocyclicthiomethyls, are described. The derivatives having five membered heterocyclicthiomethyls exhibited strong inhibitory activities against Gram-negative organisms including some strains of Escherichia coli and Proteus morganii which are insensitive to cefazolin and cephaloridine. Pronounced activities were noted with 7-[2-(2-aminothiazol-4-yl)-acetamido]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylic acid (1y; SCE-963).     

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.     

Monocyclic beta-lactam antibiotics: synthesis and antibacterial activity of 4-(substituted ethyl)-2-azetidinone-1-sulfonic acid derivatives

The synthesis and antibacterial activity of sodium (3S,4R)-3-[2-(2-aminothiazol-4-yl)-(Z)-2-(O-substituted oxyimino)acetamido]-2-azetidinone-1-sulfonates having various substituted ethyl groups at the C-4 position are described. Among various substituents explored, the (substituted isothiuronio)ethyl groups were found to have strong antibacterial activity against a variety of Gram-negative bacteria, and moreover, the ethylene isothiuronium derivative exhibited moderate antibacterial activity against Staphylococcus aureus.     

Synthesis and structure-activity relationships of 2-azetidinone-1-sulfonic acid derivatives with a heteroatom-bound substituent at the 4-position

The synthesis and antibacterial activity of 3-[(Z)-2-alkoxyimino-2-(2-aminothiazol-4-yl)-acetamido] -2-azetidinone-1-sulfonic acid derivatives with a heteroatom-bound substituent at the 4-position are described. The effect of various 4-substituents on the antibacterial activity was examined. Some of these compounds showed excellent antibacterial activity especially against Gram-negative bacteria, including beta-lactamase-producing strains.