Merck + Co., Inc.

David H Shih

Burton G Christensen

John Hannah

William J Leanza

Ronald W Ratcliffe

Thomas N Salzmann

Frank P DiNinno

James V Heck

Kenneth J Wildonger

Louis Barash

Carbapenems having the formula: ##STR1## are useful antibacterial agents.

2-(heteroarylsubstituted)phenyl carbapenem antibacterial agents

Disclosed are N-acyl derivatives of the antibiotic thienamycin having the following structural formula: ##STR1## wherein R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen and acyl. Such derivatives and their pharmaceutically acceptable salts, are useful as antibiotics. Also disclosed are processes for the preparation of such derivatives, pharmaceutical compositions comprising such derivatives, and methods of treatment comprising administering such derivatives and compositions when an antibiotic effect is indicated.

N-acyl derivatives of thienamycin

Disclosed is crystalline 5R,6S,8R-1.beta.-methyl-2-(N,N-dimethyl-carbaminidoylmethylthio)-6-(1-hydr oxyethyl)-1-carbapen-2-em-3-carboxylic acid and a process for its preparation.

Crystalline

Carbapenems having the formula: ##STR1## wherein ##STR2## is mono- or bicyclic quaternary heteroaryl, their preparation and antibiotic use are disclosed.

Carbapenems and 1-methylcarbapenems having an externally alkylated mono-

Disclosed are antibiotic 6-[1-hydroxyethyl]-2-SR.sup.8 -1-methyl-1-carbadethiapen-2-em-3-carboxylic acids and their pharmaceutically acceptable salts and esters (I): ##STR1## wherein: R.sup.8 is ##STR2## and ##STR3## wherein: R.sup.8 is ##STR4## and wherein n and m are independently selected from 0, 1, 2, 3, 4 and 5; X is --NR; and Y is --R, or --NRR; and wherein R is independently selected from hydrogen, alkyl, alkenyl, alkynyl, (having 1-6 carbon atoms); cycloalkyl and cycloalkenyl (having 3-6 carbon atoms); and heterocyclyl, heteroaryl (having 3-6 ring atoms, one or more of which is N, O or S).

6-[1-hydroxyethyl]-2-SR.sup.8

Disclosed are 1-, 6- and 2-substituted-1-carba-2-penem-3-carboxylic acids of the following structure: ##STR1## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are, inter alia, independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, spirocycloalkyl, heterocyclyl, heteroaryl, 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.

1-, 6- and 2-substituted-1-carba-2-penem-3-carboxylic acids

Disclosed are 1-substituted-6-(1-hydroxyethyl)-2-(2-aminoethylthio)-1-carbadethiapen-2-e m-3-carboxylic acids (I) and their pharmaceutically acceptable salts and esters which are useful as antibiotics; such compounds are prepared by total synthesis. ##STR1## wherein R.sup.1 and R.sup.2 are, inter alia, substituted and unsubstituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the spiro substituent formed by the joinder of R.sup.1 and R.sup.2.

6-(1-hydroxyethyl)-2-(2-amin

Disclosed are 1-, 6- and 2-substituted-1-carba-2-penem-3-carboxylic acids of the following structure: ##STR1## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are, inter alia, independently selected from the group consisting of hydrogen, alkyl, 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.

Process for preparing 1-6-and 2-substituted-1-carba-2-penem-3-carboxylic

Disclosed is a process for the total synthesis of thienamycin from descysteaminylthienamycin 1 ##STR1## via thienamycin sulfoxide 4: ##STR2## R.sup.3, R.degree., R' are blocking groups.

Process for the preparation of thienamycin

Disclosed are N-acyl and carboxyl derivatives of the antibiotic thienamycin, which has the following structure: ##STR1## Such derivatives are useful as antibiotics. Also disclosed are processes for the preparation of such derivatives, pharmaceutical compositions comprising such derivatives and methods of treatment comprising administering such derivatives and compositions when an antibiotic effect is indicated.

N- And carboxyl derivatives of thienamycin

Disclosed are S-oxides of 6-, 1- and 2-substituted-1-carbadethiapen-2-em-3-carboxylic acids having the structure: ##STR1## wherein: n is 1 or 2; and R.sup.1, 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.

6-, 1- And 2-substituted-thio-1-carbadethiapen-2-em-3-carboxylic acid

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, R.sup.3 and R.sup.4 are, inter alia, independently selected from the group consisting of hydrogen, alkyl, aryl and aralkyl.

6- and 4-Substituted-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylates

Disclosed are S-oxides of 6-, 2- and 1,1-disubstituted-1-carbadethiapen-2-em-3-carboxylic acids having the structure: ##STR1## wherein: n is 1 or 2; and R.sup.1, R.sup.2, 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.

6-, 2- and 1,1-Disubstituted-1-carbadethiapen-2-em-3-carboxylic acid

Disclosed is a process for the synthesis of carbapenem antibiotics I and their pharmaceutically acceptable salts and esters from 1: ##STR1## wherein: R.sup.7, R.sup.6, R.sup.1, R.sup.2 and R.sup.8 are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, spirocycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroalkyl, heteroaralkyl, heterocyclyl and heterocyclyalkyl.

Process for the preparation of carbapenem antibiotics

Disclosed is a process for the total synthesis of thienamycin from descysteaminylthinamycin 1 ##STR1## via thienamycin sulfoxide 4: ##STR2## R.sup.3, R.degree., R' are blocking groups.

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Edison, NJ, United States of America

David H Shih