Schering Corporation

Schering-plough Corporation

Peter J Daniels

Tattanahalli L Nagabhushan

Gerald H Wagman

Alan K Mallams

Joseph A Marquez

Dinanath F Rane

John J Wright

Stuart W McCombie

Marvin J Weinstein

Bong K Lee

Raymond T Testa

William N Turner

Raymond Testa

Mohammad Mehdi Nafissi Varchei

Mohammed M Varchei

The microorganisms Micromonospora inyoensis 1550F-1G and M. purpurea strain 1124 each microbiologically convert tobramycin, kanamycin A, kanamycin B and dibekacin to their respective 3'-N-methyl and 3'-N-methyl-4'-C-methyl derivatives. The derivatives exhibit significant activity against representative gram positive and gram negative bacteria and may also be converted to other derivatives which have significant antibacterial activity.

Microbiological methylation of aminoglycosyl-aminoglycosides

A novel process whereby 4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitols are reacted with a dialkylaminosulfur trifluoride to produce novel 5-fluoro-5-deoxy and 5-epi-fluoro-5-deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol antibacterial agents.

Process for the preparation of 5-fluoro-5-deoxy and

1-N-(R-.beta.-amino-.alpha.-hydroxypropionyl) gentamicin B, 1-N-(R-.gamma.-amino-.alpha.-hydroxybutyryl) gentamicin B, 1-N-(R-.delta.-amino-.alpha.-hydroxyvaleryl) gentamicin B and the corresponding diastereoisomers derived from the respective S-aminohydroxy acids and the acid addition salts thereof exhibit substantial antibacterial activity, especially against strains of bacteria which are resistant to gentamicin B and acid addition salts thereof.

1-N-aminohydroxyacyl derivatives of gentamicin B

2'-Hydroxy-2'-desamino-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitols having a 6'-amino function exhibit antibacterial activity and are prepared by reaction of the corresponding N-protected (except the 2'-amino)-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol with hydrogen peroxide in the presence of tungstate ion, followed by cleavage of the thereby formed 2'-oximino derivative, thence reduction of the resulting 2'-oxo derivative and removal of the N-protecting groups. Preferred compounds are 1-N-(.omega.-amino-.alpha.-hydroxyalkanoyl)-2'-hydroxy-2'-desamino-4,6-di- O-(aminoglycosyl)-1,3-diaminocyclitols which exhibit antibacterial activity against bacteria resistant to the parent aminoglycoside.

2'-Hydroxy-2'-desamino-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitols,

The aminocyclitol 2,5-dideoxystreptamine may be prepared by a novel two-step synthesis from cis-4,8-dioxatricyclo [5.1.0.0.sup.3,5 ]octane. The aminocyclitol and a novel intermediate in the synthesis thereof are utilized by a Micromonospora inyoensis (M. inoyensis strain 1550F-1G NRRL 5742) for the elaboration of a novel antibacterial agent designated Mutamicin 2.

Process for the preparation of 2,5-dideoxystreptamine and of a novel

Disclosed herein are novel 1-N-X-aminoglycoside anti-bacterial agents produced from antibiotics elaborated by species of the genus Micromonospora wherein X is a member selected from the group consisting of S-3-amino-2-hydroxypropionyl and S-4-amino-2-hydroxybutyryl and S-5-amino-2-hydroxypentanoyl. Also disclosed are novel intermediates in the production of the foregoing.

Aminoacyl derivatives of aminoglycoside antibiotics

The aminocyclitol 2,5-dideoxystreptamine may be prepared by a novel two-step synthesis from cis-4,8-dioxatricyclo [5.1.0.0.sup.3,5 ]octane. The aminocyclitol and a novel intermediate in the synthesis thereof are utilized by a Micromonospora inyoensis (M. inoyensis strain 155OF-1G NRRL 5742) for the elaboration of a novel antibacterial agent designated Mutamicin 2.

1,2'-di-N-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitols and 1,6'-di-N-alkyl-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitols and their acid addition salts are valuable as antibacterial agents. Also disclosed are 2'-N-alkyl-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol antibacterial agents which are also useful as intermediates in the preparation of the 1,2'-di-N-alkyl-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitols. Preferred compounds of this invention include 1,2'-di-N-ethylsisomicin and 1,6'-di-N-ethylsisomicin.

Di-N-alkylaminoglycosides, methods for their manufacture and novel

5-Deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitols, useful antibacterial agents, are prepared by the reaction of the corresponding 5-O-thioformyl-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol having all amino functions and all primary and secondary hydroxyl groups protected, with an organotin hydride (preferably tri-n-butylstannane) in an inert aprotic solvent under an inert atmosphere at temperatures of at least about 100.degree. C, followed by removal of said hydroxyl and amino protecting groups.

5-Deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitols, methods for their

Micromonospora inyoensis strain 155OF-1G NRRL 5742 is incapable of producing antibiotics unless an aminocyclitol is added to the fermentation medium. When such a compound is added, antibiotics are produced, said antibiotics being analogs of known aminoglycoside antibiotics differing therefrom with respect to the aminocyclitol subunit.

Methods for the preparation of semi-synthetic aminocyclitol

Described are 6'-N-alkyl derivatives of antibacterially active 4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitols having a primary carbinamine at C-5' of which a preferred group are 6'-N-alkyl derivatives having 2 to 4 carbon atoms of 4-O-aminoglycosyl-6-O-garosaminyl-2-deoxystreptamines having a primary carbinamine at C-5', a particularly preferred compound being 6'-N-ethylsisomicin. The 6'-N-alkyl derivatives are prepared by the reaction of the corresponding 6'-N-unsubstituted aminoglycoside having protecting groups on all other amino functions with an aldehyde or a ketone, followed by the reaction in situ of the 6'-N-substituted intermediate thereby formed with a hydride reducing agent, then removal of any N-protecting groups. Pharmaceutical formulations comprising 6'-N-alkylaminoglycosides of the invention are described and the method for their use in treating bacterial infections.

6'-N-alkyl-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitols, methods for

Micromonospora inyoensis strain 1550F-1G NRRL 5742 is incapable of producing antibiotics unless an aminocyclitol is added to the fermentation medium. When such a compound is added, mutamicins are produced, said mutamicins being analogs of known aminoglycoside antibiotics differing therefrom with respect to the aminocyclitol subunit.

Semi-synthetic aminocyclitol aminoglycoside antibiotics and methods for

1-N-Alkyl-4,6-di-(aminoglycosyl)-1,3-diaminocyclitols, valuable as antibacterial agents, are prepared by treating an acid addition salt of a 4,6-di-(aminoglycosyl)-1,3-diamonocyclitol antibacterial agent in an inert solvent, preferably a protic solvent containing water, with one equivalent of a hydride donor reducing agent and with at least one equivalent of an aldehyde. The 1-N-alkyl-4,6-di-(aminoglycosyl)-1,3-diaminocyclitols are also prepared by treating the corresponding 1-N-acyl-4,6-di-(aminoglycosyl)-1,3-diaminocyclitol with an amide-reducing hydride reagent in an inert organic solvent. Other methods of preparing 1-N-alkyl-4,6-di-(aminoglycosyl)-1,3-diaminocyclitols include carrying out the foregoing processes with partially N-protected intermediates. Another useful process involves preparing a Schiff base of the 1-amino function of a partially N-protected 4,6-di-(aminoglycosyl)-1,3-diaminocyclitol followed by reduction of said Schiff base and removal of the N-protecting groups. Pharmaceutical compositions comprising 1-N-alkyl-4,6-di-(aminoglycosyl)-1,3-diaminocyclitols are described as well as the method of using said compositions to elicit an antibacterial response in a warm blooded animal having a susceptible bacterial infection.

1-N-alkyl-4,6-di-(aminoglycosyl)-1,3-diaminocyclitols, methods for their

1-N-Alkyl-Aminoglycoside-XK-88 derivatives, valuable as antibacterial agents, are prepared by the reaction of an acid addition salt of the corresponding 1-N-unsubstituted-Aminoglycoside-XK-88 antibacterial derivative or of a 2'-N-alkanoyl-Aminoglycoside-XK-88-5 derivative in an inert solvent, preferably a protic solvent containing water, with one equivalent of a hydride-donor reducing agent and with at least one equivalent of an aldehyde. The 2'-N-alkanoyl-Aminoglycoside-XK-88-5 intermediates are prepared by the reaction of a partially neutralized acid addition salt of Aminoglycoside-XK-88-5 with an acylating agent, and isolating the 2'-N-alkanoyl-Aminoglycoside-XK-88-5.

Growing community of inventors

Cedar Grove, NJ, United States of America

Peter J Daniels