Anhydro-and isomer-a-21978c cyclic peptides
AssigneeEli Lilly and Company
InventorsPatrick J. Baker, Manuel Debono, Khadiga Z. Farid, R. Michael Molloy
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Abstract
Two new groups of A-21978C cyclic peptides, anhydro- and isomer-A21978C peptide derivatives, have antibacterial activity and are useful as intermediates. The two groups are prepared via transpeptidation of the parent cyclic peptides. Pharmaceutical formulations containing the new peptides as active ingredients and methods of treating infections caused by susceptible Gram-positive bacteria with the formulations are also provided. The invention also provides an antibacterial composition containing the new drug substance LY 146032 in substantially pure form.
Claims31
A An isolated compound of the formula 1
- in which R is C5-C14-alkanoyl;
- R1, R2, R3, R4 and R5 are hydrogen;
- or a pharmaceutically acceptable salt thereof;
- and wherein the alanine is D-alanine and the serine is D-serine.
A An isolated compound of the formula 2
- in which R is C5-C14-alkanoyl;
- R1, R2, R3, R4 and R5 are hydrogen;
- or a pharmaceutically acceptable salt thereof;
- and wherein the alanine is D-alanine and the serine is D-serine.
An antibiotic composition comprised of a combination of a compound of formula 1, a compound of formula 2 and a compound of formula 3, or pharmaceutically acceptable salts thereof, wherein the formula 1 compound is
- in which R is a C10 alkanoyl;
- R1, R2, R3, R4 and R5 are hydrogen, and wherein the alanine is D-alanine and the serine is D-serine;
- the formula 2 compound is
- in which R is a C10 alkanoyl;
- R1, R2, R3, R4 and R5 are hydrogen, and wherein the alanine is D-alanine and the serine is D-serine;
- and the formula 3 compound is an A21978C cyclic peptide of
- wherein RN is n-decanoyl;
- and wherein the total amount of the compound of formula 1 and the compound of formula 2, or salts thereof, in the combination is less than 6 weight percent.
An antibiotic composition useful for the treatment of bacterial infections comprising a combination of a compound of formula 1, a compound of formula 2 and a compound of formula 3, or pharmaceutically acceptable salts thereof, wherein the formula 1 compound is
- in which R is a C10 alkanoyl;
- R1, R2, R3, R4 and R5 are hydrogen, and wherein the alanine is D-alanine and the serine is D-serine;
- the formula 2 compound is
- in which R is C10 alkanoyl;
- R1, R2, R3, R4 and R5 are hydrogen, and wherein the alanine is D-alanine and the serine is D-serine;
- and the formula 3 compound is an effective antibacterial amount of an A21978C cyclic peptide compound of
- wherein RN is n-decanoyl, in substantially pure form.
A pharmaceutical formulation comprising a combination of a compound of formula 1, a compound of formula 2 and a compound of formula 3, or pharmaceutically acceptable salts thereof, wherein the formula 1 compound is
- in which R is a C10 alkanoyl;
- R1, R2, R3, R4 and R5 are hydrogen, and wherein the alanine is D-alanine and the serine is D-serine;
- the formula 2 compound is
- in which R is a C10 alkanoyl;
- R1, R2, R3, R4 and R5 are hydrogen, and wherein the alanine is D-alanine and the serine is D-serine;
- and the formula 3 compound is an A21978C cyclic peptide of
- wherein RN is n-decanoyl;
- and wherein the total amount of the compound of formula 1 and the compound of formula 2, or salts thereof, in the combination is less than 6 weight percent, and the pharmaceutical formulation further comprises from about 0.1 to about 90 weight percent of the A21978C cyclic peptide of formula 3.
A pharmaceutical composition comprised of a combination of a compound of formula 1, a compound of formula 2 and a compound of formula 3, or pharmaceutically acceptable salts thereof, wherein the formula 1 compound is
- in which R is a C10 alkanoyl;
- R1, R2, R3, R4 and R5 are hydrogen, and wherein the alanine is D-alanine and the serine is D-serine;
- the formula 2 compound is
- in which R is a C10 alkanoyl;
- R1, R2, R3, R4 and R5 are hydrogen, and wherein the alanine is D-alanine and the serine is D-serine;
- and the formula 3 compound is an A21978C cyclic peptide of
- wherein RN is n-decanoyl;
- and the total amount of the compound of formula 1 and the compound of formula 2, or salts thereof, in the combination is less than 6 weight percent;
- and wherein an effective dose of the compound or salt of formula 3 is between about 0.1 and about 100 mg/kg of the compound;
- or its pharmaceutically acceptable salt.
Dependencies are inferred from the claim text.