Di-N-alkylaminoglycosides, methods for their manufacture and novel intermediates useful therein, method for their use as antibacterial agents and pharmaceutical compositions useful therefor
AssigneeSchering Corporation
InventorsJohn J. Wright, Peter J. L. Daniels, Alan K. Mallams, Tattanahalli L. Nagabhushan
Life of this patent
Estimating the term…
Abstract
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.
Claims23
A 1,2'-di-N-X and a 1,6'-di-N-X derivative of a 4,6-di-O-aminoglycosyl-1,3-diaminocyclitol having antibacterial activity, said 4-O-aminoglycosyl having amino groups, all of which are primary, said primary amino groups being on one or both of positions 2' and 6';
- wherein X is a substituent selected from the group consisting of alkyl, alkenyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl and alkylaminohydroxyalkyl, said substituent having 2 to 8 carbon atoms, the carbon in said substituent adjacent to the aminoglycoside nitrogen being unsubstituted, and when said substituent is substituted by both amino and hydroxyl functions, only one of said functions can be attached at any one carbon atom;
- wherein the substituents, X, in said 1,2'-di-N-X- and in said 1,6'-di-N-X derivatives may be the same or different;
- and the pharmaceutically acceptable acid addition salts thereof.
A 2'-N-X-4,6-di-O-(aminoglycosyl)-1,3-diaminocyclitol selected from the group consisting of:
- 2'-N-X-gentamicin A,
- 2'-n-x-sisomicin,
- 2'-N-X-verdamicin,
- 2'-N-X-tobramycin,
- 2'-N-X-Antibiotic 66-40B,
- 2'-n-x-antibiotic 66-40D,
- the 5-epi, 5-epi-azido-5-deoxy, 5-epi-amino-5-deoxy analogs of the foregoing and the following;
- 2'-N-X-gentamicin C.sub.1a,
- 2'-N-X-gentamicin C.sub.2,
- 2'-n-x-gentamicin C.sub.2a,
- 2'-N-X-gentamicin X.sub.2,
- 2'-n-x-antibiotic G-418,
- 2'-n-x-antibiotic JI-20A,
- 2'-n-x-antibiotic JI-20B,
- and 2'-N-X-Antibiotic Mu-1, 2'-N-X-Antibiotic Mu-2, 2'-N-X-Antibiotic Mu-4and 2'-N-X-Antibiotic Mu-5;
- wherein X is a substituent selected from the group consisting of alkyl, alkenyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alklaminoalkyl, aminohydroxyalkyl, and alkylaminohydroxyalkyl, said substituent having 2 to 8 carbon atoms, the carbon in said substituent adjacent to the aminoglycoside nitrogen being unsubstituted and when said substituent is substituted by both hydroxyl and amino functions, only one of said functions can be attached at any one carbon atom.
The method of eliciting an antibacterial response in a warm blooded animal having a susceptible bacterial infection which comprises administering to saidd animal a non-toxic antibacterially effective amount of a 1,2'-di-N-X and a 1,6'-di-N-X derivative of a 4,6-di-O-aminoglycosyl-1,3-diaminocyclitol having antibacterial activity, said 4-O-aminoglycosyl having amino groups all of which are primary, said primary amino groups being on one or both of positions 2' and 6';
- wherein X is a substituent selected from the group consisting of alkyl, alkenyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl and alkylaminohydroxyalkyl, said substituent having 2 to 8 carbon atoms, the carbon in aid substituent adjacent to the aminoglycoside nitrogen being unsubstituted, and when said substituent is substituted by both amino and hydroxyl functions only one of said functions can be attached at any one carbon atom;
- wherein the substituents, X, in said 1,2'-di-N-X-and in said 1,6'-di-N-X derivatives may be the same or different;
- and the pharmaceutically acceptable acid addition salts thereof.
A pharmaceutical composition comprising an antibacterially effective amount of a 1,2'-di-N-X and a 1,6'-di-N-X derivative of a 4,6-di-O-aminoglycosyl-1,3-diaminocyclitol having antibacterial activity, said 4-O-aminoglycosyl having amino groups all of which are primary, said primary amino groups being on one or both of positions 2' and 6';
- wherein X is a substituent selected from the group consisting of alkyl, alkenyl, cycloalkylalkyl, aralkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, aminohydroxyalkyl and alkylaminohydroxyalkyl, said substituent having 2 to 8 carbon atoms, the carbon in said substituent adjacent to the aminoglycoside nitrogen being unsubstituted, and when said substituent is substituted by both amino and hydroxyl functions only one of said functions can be attached at any one carbon atom;
- wherein the substituents, X, in said 1,2'-di-N-X- and in said 1,6'-di-N-X derivatives may be the same or different;
- and the pharmaceutically acceptable acid addition salts thereof;
- together with a non-toxic pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.