5-Deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitols, methods for their manufacture, method for their use as antibacterial agents and compositions useful therefor
AssigneeSchering Corporation
InventorsPeter J. L. Daniels, Stuart W. McCombie
Life of this patent
Estimating the term…
Abstract
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.
Claims15
A 5-deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of
- 5-deoxygentamicin B,
- 5-deoxygentamicin B.sub.1,
- 5-deoxygentamicin C.sub.1a,
- 5-deoxygentamicin C.sub.2,
- 5-deoxygentamicin C.sub.2a,
- 5-deoxygentamicin X.sub.1,
- 5-deoxygentamicin X.sub.2,
- 5-deoxy-Antibiotic 66-40B,
- 5-deoxy-Antibiotic 66-40D,
- 5-deoxy-Antibiotic G-418,
- 5-deoxy-Antibiotic JI-20A,
- 5-deoxy-Antibiotic JI-20B,
- 5-deoxyverdamicin,
- 5-deoxykanamycin B,
- 5-deoxykanamycin C,
- 5,3',4'-trideoxykanamycin B,
- 5-deoxy-Aminoglycoside XK-88-5,
- 5-deoxytobramcyin;
- the 1-N-X derivatives thereof wherein X is a substituent selected from the group consisting of --CH.sub.2 Z and ##STR8## wherein Z is a member selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl, alkylaminohydroxyalkyl, phenyl, benzyl, and tolyl, said substituent Z having up to 7 carbon atoms and, when substituted by amino and hydroxy, bearing the substituents on different carbon atoms;
- the 2'-N-CH.sub.2 Z, 6'-N-CH.sub.2 Z, 1,2'-di-N-CH.sub.2 Z and the 1,6'-di-N-CH.sub.2 Z derivatives thereof wherein Z is as hereinabove defined;
- 5-deoxy-Antibiotic G-52 and the 1-N-X derivatives thereof wherein X is as hereinabove defined;
- and the pharmaceutically acceptable acid addition salts thereof.
The process for the preparation of a 5-deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol which comprises the reaction of the corresponding 5-O-thioformyl-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol having all amino functions protected by an amino protecting group, Y, and all primary and secondary hydroxyl groups protected by a hydroxy protecting group, R;
- with at least a molar equivalent of an organotin hydride in an inert aprotic solvent at a temperature of at least about 100.degree. C and under an inert atmosphere;
- followed by removal of said amino protecting groups, Y, and said hydroxyl protecting groups R.
The method of eliciting an antibacterial response in a warm-blooded animal having a susceptible bacterial infection which comprises administering to said animal a non-toxic, antibacterially effective amount of a member selected from the group consisting of a 5-deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of
- 5-deoxygentamicin B,
- 5-deoxygentamicin B.sub.1,
- 5-deoxygentamicin C.sub.1a,
- 5-deoxygentamicin C.sub.2,
- 5-deoxygentamicin C.sub.2a,
- 5-deoxygentamicin X.sub.1,
- 5-deoxygentamicin X.sub.2,
- 5-deoxy-Antibiotic 66-40B,
- 5-deoxy-Antibiotic 66-40D,
- 5-deoxy-Antibiotic G-418,
- 5-deoxy-Antibiotic JI-20A,
- 5-deoxy-Antibiotic JI-20B,
- 5-deoxyverdamicin,
- 5-deoxykanamycin B,
- 5-deoxykanamycin C,
- 5,3',4'-trideoxykanamycin B,
- 5-deoxy-Aminoglycoside XK-88-5,
- 5-deoxytobramycin;
- the 1-N-X derivatives thereof wherein X is a substituent selected from the group consisting of --CH.sub.2 Z and ##STR10## wherein Z is a member selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl, alkylaminohydroxyalkyl, phenyl, benzyl, and tolyl, said substituent Z having up to 7 carbon atoms and, when substituted by amino and hydroxy, bearing the substituents on different carbon atoms;
- the 2'-N-CH.sub.2 Z, 6'-N-CH.sub.2 Z, 1,2'-di-N-CH.sub.2 Z and the 1,6'-di-N-CH.sub.2 Z derivatives thereof wherein Z is as hereinabove defined;
- 5-deoxy-Antibiotic G-52 and the 1-N-X derivatives thereof wherein X is as hereinabove defined;
- and the pharmaceutically acceptable acid addition salts thereof.
A pharmaceutical composition comprising an antibacterially effective amount of a member selected from the group consisting of a 5-deoxy-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of
- 5-deoxygentamicin B,
- 5-deoxygentamicin B.sub.1,
- 5-deoxygentamicin C.sub.1a,
- 5-deoxygentamicin C.sub.2,
- 5-deoxygentamicin C.sub.2a,
- 5-deoxygentamicin X.sub.1,
- 5-deoxygentamicin X.sub.2,
- 5-deoxy-Antibiotic 66-40B,
- 5-deoxy-Antibiotic 66-40D, 5-deoxy-Antibiotic G-418,
- 5-deoxy-Antibiotic JI-20A,
- 5-deoxy-Antibiotic JI-20B,
- 5-deoxyverdamicin,
- 5-deoxykanamycin B,
- 5-deoxykanamycin C,
- 5,3',4'-trideoxykanamycin B,
- 5-deoxy-Aminoglycoside XK-88-5,
- 5-deoxytobramycin;
- the 1-N-X derivatives thereof wherein X is a substituent selected from the group consisting of --CH.sub.2 Z and ##STR11## wherein Z is a member selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl, alkylaminohydroxyalkyl, phenyl, benzyl, and tolyl, said substituent Z having up to 7 carbon atoms and, when substituted by amino and hydroxy, bearing the substituents on different carbon atoms;
- the 2'-N-CH.sub.2 Z, 6'-N-CH.sub.2 Z, 1,2'-di-N-CH.sub.2 Z and the 1,6'-di-N-CH.sub.2 Z derivatives thereof wherein Z is as hereinabove defined;
- 5-deoxy-Antibiotic G-52 and the 1-N-X derivatives thereof wherein X is as hereinabove defined;
- and the pharmaceutically acceptable acid addition salts thereof;
- together with a non-toxic pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.