Merck + Co., Inc.

Microcide Pharmaceuticals, Inc.

Meiji Seika Kaisha, Ltd.

Merck Gmbh

Burton G Christensen

Ronald W Ratcliffe

Lovji D Cama

David H Shih

Susan M Schmitt

William J Leanza

David B Johnston

Frank P DiNinno

Thomas N Salzmann

Meyer Sletzinger

Sandor Karady

Raymond A Firestone

James V Heck

Ravindra N Guthikonda

Scott J Hecker

Tomasz W Glinka

In-Seop Cho

John Hannah

Thomas R Beattie

John C Chabala

Kenneth J Wildonger

Seiji Shibahara

Ving J Lee

Edward Walton

W Alexander Andrus

Shunzo Fukatsu

Taro Niida

Yasushi Murai

Tsuneo Okonogi

Robert B Morin

Tadashi Wakazawa

F Aileen Bouffard

Arthur A Patchett

Michael H Fisher

Helmut H Mrozik

Zhijia J Zhang

Nathan G Steinberg

Shokichi Ohuchi

David A Muthard

Yasuyuki Ichimaru

Michael J Szymonifka

Michael W Fordice

Louis Barash

John L Fahey

Thomas N Salzman

Tsuneo Okonogy

Ronald W Ratcliff

Takashi Egawa

Seiji Tsutsumni

The present invention includes (7R)-7-(acylamino)-3-(substituted-pyridinyl)-3-cephem-4-carboxylic acids or their pharmacologically acceptable salts which exhibit antibiotic activity against methicillin-resistant bacteria and are therefore useful as antibacterial agents.

Substituted-pyridinyl cephalosporin antibiotics active against

The present invention includes novel (7R)-7-(acylamino)-3-(arylthio)-3-cephem-4-carboxylic acids or their pharmacologically acceptable salts which exhibit antibiotic activity against a wide spectrum of organisms including organisms which are resistant to .beta.-lactam antibiotics and are useful as antibacterial agents. The invention also relates to novel intermediates useful for making the novel compounds of the present invention and to novel methods for producing the novel compounds and intermediate compounds.

Cephalosporin antibiotics

The present invention includes novel compounds or their pharmacologically acceptable salts which exhibit antibiotic activity against a wide spectrum of organisms including organisms which are resistant to .beta.-lactam antibiotics and are useful as antibacterial agents. The invention also relates to novel intermediates useful for making the novel compounds of the present invention and to novel methods for producing the novel compounds and intermediate compounds.

.beta.-lactam antibiotics

The invention relates to derivatives of pyrrolidin-2-ylcarbonylheterocyclic compound of the general formula ##STR1## in which R.sup.1 represents C.sub.1-6 alkyl, C.sub.1-20 cycloalkyl, aryl or heteroaryl,

Derivatives of pyrrolidin-2-ylcarbonylheterocyclic compounds

Disclosed are 2-aza-substituted 1-carbadethiapen-2-em-3-carboxylic acids. I, where the generic 2-aza group includes azido, acylamino, amino, alkylamino, dialkylamino, triazolyl, triazolinyl, aziridinyl, and their pharmaceutically acceptable salt, ester, anhydride and amide derivatives which are useful as antibiotics. Also disclosed are processes for the preparation of I from the known, appropriately substituted bicyclic keto ester II via the 2-azido central intermediate III: ##STR1## wherein R.sup.16 is H or CH.sub.3, preferably beta-methyl; R.sup.6, and R.sup.7 are independently hydrogen, linear, branched or cyclic C.sub.1 -C.sub.5 alkyl, which can be substituted with fluoro, hydroxy, protected hydroxy, sulfoxy, amino, protected amino, wherein R.sup.6 and R.sup.7 taken together can also be C.sub.2 -C.sub.4 alkylidene, similarly substituted; with the proviso that both R.sup.6 and R.sup.7 are not unsubstituted alkyl, R.sup.1 and R.sup.2 are, inter alia, hydrogen, alkyl, acyl, and can be joined to form a ring comprising 3 to 7 atoms; R.sup.a is hydrogen, a salt cation, a removable protecting group, or a pharmaceutically acceptable ester moiety. Also disclosed are processes for the preparation of such compounds; pharmaceutical compositions comprising such compounds; and methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.

2-aza-substituted 1-carbadethiapen-2-em-3-carboxylic acids

N-tetrazolyl beta-lactams of the Formula: ##STR1## and the pharmaceutically acceptable salts thereof wherein R.sup.2 is hydrogen, alkyl having 1 to 6 carbon atoms or carboalkoxy having 2 to 7 carbon atoms; and

N-tetrazolyl beta-lactams

##STR1## wherein R.sup.1, R.sup.2 and R.sup.3 are, inter alia, independently selected from the group consisting of hydrogen, alkyl, aryl, and aralykl. Such compounds as well as their pharmaceutically acceptable salt, ester and amide derivatives are useful as antibiotics. Also disclosed are processes for the preparation of such compounds, pharmaceutical compositions comprising such compounds and methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.

Process for preparing 1-carba-2-penem-3-carboxylic acid

Disclosed are 6- and 6,6-disubstituted-3-substituted-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carbo xylic acids (I): ##STR1## wherein R.sup.1 and R.sup.2 are, inter alia, independently selected from the group consisting of hydrogen (both are not hydrogen at the same time), substituted and unsubstituted: alkyl, aryl and aralkyl; X is halo, oxygen (the 2-3 bond is saturated and the species I exists as carboxylate salt or ester), or --OR wherein R is, inter alia, acyl, alkyl, or aralkyl. Such compounds and their pharmaceutically acceptable salt, ester and amide derivatives are useful as antibiotics. Also disclosed are processes for the preparation of such compounds, pharmaceutical compositions comprising such compounds and methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.

6- and

Disclosed are 2- and 6-substituted-1-carbadethiapen-2-em-3-carboxylic acids having the structure: ##STR1## wherein R.sup.6, and R.sup.7 are, inter alia, independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl and aralkyl; A is a direct, single bond connecting the indicated S and C atoms, or A is a cyclic or acyclic connecting group selected, inter alia, from alkyl, cyclalkyl, aryl, heteroaryl, heteroalkyl; R.sup.1 and R.sup.2 inter alia, independently selected from hydrogen, alkyl, aryl; additionally, said carbamimidoyl is characterized by cyclic structures achieved by the joinder of the two nitrogen atoms via their substituents and by their joinder to connecting group A; additionally, 'carbamimidiums' are disclosed by quarternization of one of the nitrogen atoms of said carbammidoyl. Such compounds as well as their pharmaceutically acceptable salt, ester and amide derivatives are useful as antibiotics. Also disclosed are processes for the preparation of such compounds; pharamaceutical compositions comprising such compounds; and methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.

2-carbamimidoyl-6-substituted-1-carbadethiapen-2-em-3-carboxylic acids

Disclosed are 6- and 4-substituted-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylic acid esters and salts (I) which are useful in the preparation of 6-, 1- and 2-substituted carbapenem antibiotics. ##STR1## wherein R.sup.5 is a pharmaceutically acceptable ester moiety or a removable protecting group or an alkali or alkaline earth metal cation such as sodium or potassium and wherein R.sup.1, R.sup.2, Rhu 3 and R.sup.4 are, inter alia, independently selected from the group consisting of hydrogen, alkyl, aryl and aralkyl. Another embodiment disclosed is a group of compounds having the formula ##STR2## where X is a leaving group.

6- and 4-substituted-1-azabicyclo(3.2.0)heptan-3, 7-dione-2-carboxylates

Disclosed are 2- and 6-substituted-1-carbadethiapen-2-em-3-carboxylic acids having the structure: ##STR1## wherein R.sup.6, R.sup.7 and R.sup.8 are inter alia, independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl and aralkyl. Such compounds as well as their pharmaceutically acceptable salt, ester and amide derivatives are useful as antibiotics. Also disclosed are processes for the preparation of such compounds, pharmaceutical compositions comprising such compounds and methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.

2-substituted-6-carbadethiapen-2-em-3-carboxylic acids

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Scotch Plains, NJ, United States of America

Burton G Christensen