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US 8,889,826 B2Granted
Peptide antibiotics and methods for making same
AssigneeBioSource Pharm, Inc.
InventorsRichard A. Leese, Noreen Francis, William V. Curran, Donald B. Borders, Howard Jarolmen
Life of this patent
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Abstract
Disclosed herein are novel peptides and protected peptides. These compounds can be derived from naturally occurring peptides, such as those selected from colistin, circulin A, polymyxin A, polymyxin B, polymyxin D, octapeptin B, octapeptin C, and [Ile7]polymyxin B1. Also disclosed are pharmaceutical compositions containing the new peptides, as well as methods for preparing the novel peptides and protected peptides.
Claims64
An antibiotic compound of the formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- A is selected from R′—(C═O)-(p-aminophenylacetyl)-, R′—(C═O)-Lys-, R′—(C═O)-Phe-, R′—NH—(C═O)—, R′—NH(C═S)—, R′—SO2—, R′—(C═NH)—, R′—O—CH2—(C═O)—, R′—, R′-alkyl, R′—P(O)OH, R′—O—(C═S)—, R′—NH—(C═NH)—, and R′—(C═S)—;
- R′ is selected from aryl, heteroaryl, alkyl, alkenyl, heterocyclyl and cycloalkyl, wherein each aryl, heteroaryl, alkyl, alkenyl, heterocyclyl and cycloalkyl is optionally substituted with one or more groups selected from halogen, (C1-C20) alkyl, aryl, heteroaryl and aryloxy;
- x and y are each independently 0 or 1;
- z is 1;
- X1 is selected from Dab, Phe, Ala, Lys and Gly;
- X2 is Thr;
- X3 is Dab;
- and
- R6, R7 and R10 are each independently selected from isopropyl, benzyl, isobutyl, sec-butyl, 1-hydroxy-1-ethyl, and hydroxymethyl.
7 more elements
An antibiotic compound of the formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- A is selected from R′—(C═O)-(p-aminophenylacetyl)-, R′—(C═O)-Lys-, R′—(C═O)-Phe-, R′—NH—(C═O)—, R′—NH(C═S)—, R′—SO2—, R′—(C═NH)—, R′—O—CH2—(C═O)—, R′—, R′-alkyl, R′—P(O)OH, R′—O—(C═S)—, R′—NH—(C═NH)—, and R′—(C═S)—;
- R′ is selected from aryl, heteroaryl, alkyl, alkenyl, heterocyclyl and cycloalkyl, wherein each aryl, heteroaryl, alkyl, alkenyl, heterocyclyl and cycloalkyl is optionally substituted with one or more groups selected from halogen, aryl, heteroaryl and aryloxy;
- x, y, and z are each 1;
- X1 is Dab;
- X2 is Thr;
- X3 is Dab;
- and
- R6, R7 and R10 are each independently selected from isopropyl, benzyl, isobutyl, sec-butyl, 1-hydroxy-1-ethyl, and hydroxymethyl.
6 more elements
An antibiotic compound of the formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- A is R′—O—(C═O)— and R′ is selected from aryl, heteroaryl, alkyl, alkenyl, heterocyclyl and cycloalkyl, wherein each aryl, heteroaryl, alkyl, alkenyl, heterocyclyl and cycloalkyl is optionally substituted with one or more groups selected from halogen, (C1-C20) alkyl, (C6-C10) aryl, heteroaryl and aryloxy;
- or
- A is R′—O—(C═O)— and R′ is selected from unsubstituted, linear alkyl having at least 9 carbon atoms cycloalkyl, alkenyl, aryl, heteroaryl, heterocyclyl, and substituted alkyl, wherein at least one hydrogen on said substituted alkyl is replaced by a substituted group selected from halogen, aryl, heteroaryl, alkoxy and aryloxy;
- x and y are each independently 0 or 1;
- z is 1;
- X1 is Thr;
- X2 is Dab;
- and
- R6, R7 and R10 are each independently selected from isopropyl, benzyl, isobutyl, sec-butyl, 1-hydroxy-1-ethyl, and hydroxymethyl,
- provided that when R6 and R7 are each isobutyl and R10 is 1-hydroxy-1-ethyl, then x and Y are each 1 and X1 is Dab.
8 more elements
An antibiotic compound of the formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- A is R′—(C═O)— and R′ is selected from unsubstituted, linear alkyl having at least 9 carbon atoms, cycloalkyl, alkenyl, aryl, heteroaryl, heterocyclyl, and substituted alkyl, wherein at least one hydrogen on said substituted alkyl is replaced by a substituent group selected from halogen, aryl, heteroaryl, alkoxy, and aryloxy;
- x, y, and z are each 1;
- X1 is Dab;
- X2 is Thr;
- X3 is Dab;
- and
- R6, R7 and R10 are each independently selected from isopropyl, benzyl, isobutyl, sec-butyl, 1-hydroxy-1-ethyl, and hydroxymethyl.
5 more elements
A method for preparing a compound, the method comprising:
- (a) treating a polymyxin peptide having a sidechain comprising an amino group with an amino protecting group reagent to form a protected polymyxin peptide,
- wherein the polymyxin peptide comprises a cyclic heptapeptide attached to an exocyclic peptide chian comprising an acyl group, and the protecting group comprises at least one acidic substituent;
- (b) reacting the protected peptide with a deacylase enzyme in an aqueous solution to form a protected, deacylated peptide comprising a free amino terminus on the exocyclic peptide chain;
- and
- (c) reacting the free amino terminus on the exocyclic peptide chain of the protected, deacylated peptide with an addition reagent and removing the protecting group to form a peptide antibiotic having the following formula:
- wherein
- A is R′—O—(C═O)— and R′ is selected from aryl, heteroaryl, alkyl, alkenyl, heterocyclyl and cycloalkyl, wherein each aryl, heteroaryl, alkyl, alkenyl, heterocyclyl and cycloalkyl is optionally substituted with one or more groups selected from halogen, (C1-C20) alkyl, (C6-C10) aryl, heteroaryl and aryloxy;
- A is R′—(C═O)— and R′ is selected from unsubstituted, linear alkyl having at least 9 carbon atoms cycloalkyl, alkenyl, aryl, heteroaryl, heterocyclyl, and substituted alkyl, wherein at least one hydrogen on said substituted alkyl is replaced by a substituted group selected from halogen, aryl, heteroaryl, alkoxy and aryloxy;
- x and y are each independently 0 or 1;
- z is 1;
- X1 is Thr;
- X2 is Dab;
- and
- R6, R7 and R10 are each independently selected from isopropyl, benzyl, isobutyl, sec-butyl, 1-hydroxy-1-ethyl, and hydroxymethyl,
- provided that when R6 and R7 are each isobutyl and R10 is 1-hydroxy-1-ethyl, then x and Y are each 1 and X1 is Dab.
12 more elements
Dependencies are inferred from the claim text.