Merck + Co., Inc.

William J Leanza

Burton G Christensen

Ronald W Ratcliffe

Kenneth J Wildonger

Frank P DiNinno

David H Shih

John Hannah

Richard L Tolman

Raymond A Firestone

Stephen Marburg

Thomas N Salzmann

Robert R Wilkening

James V Heck

Emilio A Emini

Kothandaraman Shankaran

David A Muthard

Michael J Szymonifka

Louis Barash

Compounds of the formula: ##STR1## where R is hydrogen, hydroxyl, alkyl or acyl, R' and R' together are oxo, hydroxyimino or alkoxyimino, and R' and R' independently are hydrogen, hydroxyl, acyloxy, or amino substituted by any of hydrogen, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylsulfonyl or arylsulfonyl, and n is 0 or 1, and the pharmaceutically acceptable salts thereof. The compounds are macrolide antibiotics and are also useful as intermediates to the synthesis of other macrolide antibiotics. Pharmaceutical compositions and methods of their use are also provided for.

Homoerythromycin A derivatives modified at the 4'-and 8A-positions

A novel coconjugate comprising an immunogenic protein or protein complex having a first set of covalent linkages to low molecular weight moieties, --a.sup.--, which have an anionic or polyanionic character at physiological pH, and a second set of covalent linkages to peptides comprising Human Immunodeficiency Virus (HIV) Principal Neutralizing Determinants (PNDs), or peptides immunologically equivalent therewith, is useful for inducing anti-peptide immune responses in mammals, for inducing HIV-neutralizing antibodies in mammals, for formulating vaccines to prevent HIV infection or disease, including the Acquired Immune Deficiency Syndrome (AIDS), or for treating humans afflicted with HIV infection or disease.

Coconjugates of OMPC, HIV related peptides and anionic moieties

Homocysteine thiolactone derivatives in which the nitrogen is acylated with groups containing acidic functionalities have been synthesized. These include the succinyl, the carboxymethylglutaryl, the 3-phosphonopropionyl and the 3-sulfopropionyl derivatives. These thiolactones can be used to introduce a thiol functionality into proteins such as the outer membrane protein complex of Neisseria meninioitidis (OMPC) allowing conjugation with electrophilic ligands. This chemistry is similar to known N-acetyl-homocysteine thiolactone chemistry, but the pK.sub.a values are such that at pH 7, concomitant negative charge is introduced into the conjugate. Such negative charge neutralizes excess positive charge introduced when arginine- and lysine-rich peptides are bonded as ligands. In the case of OMPC, introduction of positive charge commonly effects irreversible precipitation of the conjugate. Conjugates prepared with the anionic thiolactones have improved solubility.

Acidic derivatives of homocysteine thiolactone

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 are 6-substituted-2-carbamimidoyl-pen-2-em-3-carboxylic acids (I) having the representative structure: ##STR1## wherein R.sup.6, and R.sup.7 are, inter alia, independently selected from the group consisting of hydrogen, alkyl, alkoxyl, halo, OH, COOH, 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, cycloalkyl, aryl, heteroaryl, heteroalkyl; R.sup.1 and R.sup.2, which define the carbamimidoyl function, are, 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 carbamimidoyl. 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-substituted-2-carbaminidoyl-pen-2-em-3-carboxylic acids

Crystalline dimethyliminothienamycin having the formula ##STR1## and its preparation are disclosed.

Crystalline dimethyliminothienamycin

Disclosed are 6- and 6,6-disubstituted-2-substituted thio-pen-2-em-3-carboxylic acids of the following structure: ##STR1## wherein: R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently selected from: hydrogen; substituted and unsubstituted: alkyl, cycloalkyl, halo, alkoxyl, alkenyl, aralkyl, aryl, heterocyclyl, heteroaryl, and heterocyclylalkyl; W is an electron withdrawing group, and, for example, is selected from: --COR.sup.5, --CN, SO.sub.2 C.sub.6 H.sub.5 ; R.sup.5 is hydrogen; substituted and unsubstituted: alkyl, aryl, aralkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl; or R.sup.5 may be --OR.sup.6, --NR.sup.7 R.sup.8, and --SR.sup.9 ; wherein R.sup.6 is H; substituted and unsubstituted: alkyl, alkenyl, or a group which defines --CO.sub.2 R.sup.6 as a pharmaceutically acceptable ester wherein R.sup.6 is, for example, phthalidyl, or 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl; R.sup.7 and R.sup.8 are independently selected from: hydrogen; substituted and unsubstituted: alkyl, aralkyl, aryl, heterocyclyl, and heterocyclylalkyl; R.sup.9 is substituted and unsubstituted: alkyl, aralkyl, aryl, heterocyclyl, and heterocyclyclalkyl; R.sup.3 may also be W; n is 0 or 1; when the unsaturated moiety attached to the exocyclic sulfur atom is acetylenic, then R.sup.3 and R.sup.4 are nonexistent and W is as previously defined. Such compounds I are new and they and their pharmaceutically acceptable salt and ester derivatives are useful as antibiotics.

2-unsaturated alkylthio-pen-2-em-3-carboxylic acids

Disclosed are 6-(1-hydroxyethyl)-2-carbamimidoyl-pen-2-em-3-carboxylic acids (I) having the representative structure: ##STR1## wherein: 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, cycloalkyl, aryl, heteroaryl, heteroalkyl; R.sup.1 and R.sup.2, which define the carbamimidoyl function, are, inter alia, independently selected from hydrogen, alkyl, aryl, alkoxy, amino; 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 quaternization of one of the nitrogen atoms of said carbamimidoyl. 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-hydroxyethyl)-2-carbamimidoyl-pen-2-em-3-carboxylic acids

Disclosed is a synthesis for preparing substituted 2-thioxopenams which are useful in the synthesis of penem antibiotics 7 which may be conducted in an enantiospecific manner; said process proceeds from azetidinone 1 via the azetidinone acetic ester 2, the 4-metallothiozetidinone 3, and the 4-dithiocarbonylazetidinone 4 to the substituted 2-thioxopenam 5: ##STR1## wherein: R.sup.6 and R.sup.7 are independently selected from: hydrogen; R.sup.6 NH-- (R.sup.6 is acyl or H); substituted and unsubstituted: alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein said substituents are, inter alia: halo (chloro, bromo, fluoro, iodo), hydroxyl, cyano, carboxyl, amino, and the above-recited values for R.sup.6 and R.sup.7 ; in functional terms,

Process for preparing substituted 2-thioxopenams and 2-substituted

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 substituted N-methylene derivatives of thienamycin which may be represented by the following structural formula: ##STR1## wherein X and Y are selected from the group consisting of hydrogen, R, OR, SR, and NR.sup.1 R.sup.2 wherein, inter alia, R is substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; R.sup.1 and R.sup.2 are hydrogen or R. Such compounds and their pharmaceutically acceptable salt, ether, 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.

Substituted N-methylene derivatives of thienamycin

Disclosed are substituted N-methylene derivatives of thienamycin having the formula: ##STR1## wherein: (1.) X.dbd.--NR.sup.1 R.sup.2, and Y.dbd.--R'--N.dbd.CRNR.sup.1 R.sup.2, and

Disclosed are N-alkyl-N-iminomethyl derivatives of thienamycin which may be represented by the following structural formula: ##STR1## wherein R.sup.5 is, inter alia, alkyl, alkenyl, aryl, or aralkyl, R.sup.6 is selected from R, OR, SR and NR.sup.1 R.sup.2 wherein R is, inter alia, hydrogen and substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, and heterocyclylalkyl; and R.sup.1 and R.sup.2 are hydrogen or R. Such compounds, including their O-- and carboxyl derivatives are useful as antibiotics. Also dislosed 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.

N-Alkyl-N-iminomethyl derivatives of thienamycin

Disclosed are N-alkyl- N-acyl derivatives of the antibiotic thienamycin having the following structural formula: ##STR1## wherein R.sup.1 is, inter alia, alkyl, alkenyl, aryl or aralkyl; and R.sup.2 is acyl. Such compounds, including their O- and carboxyl 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.

N-Alkyl-N-acyl derivatives of thienamycin

Disclosed are N-alkylated derivatives of the antibiotic thienamycin, which has the following structure: ##STR1## Such compounds and their pharmaceutically acceptable salt, ester and amide 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.

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Berkeley Heights, NJ, United States of America

William J Leanza