Isolated darobactin A analog compounds and compositions thereof

Patent metadata

Field	Value
Publication number	US-11535648-B2
Application number	US-201917260934-A
Country	US
Kind code	B2
Filing date	May 17, 2019
Priority date	Jul 19, 2018
Publication date	Dec 27, 2022
Grant date	Dec 27, 2022

Abstract

Embodiments of the present invention relate to a novel compound of Formula (I) or stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, for use in treatment of infection caused by Gram-negative bacteria.

First claim

What is claimed is:

1. A compound of Formula (I):

and/or a pharmaceutically acceptable salt, stereoisomer, tautomer, or hydrate thereof, wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, hydroxyalkyl, halogen, —CN, —O-alkyl, —C(O)-alkyl, —C(O)O-alkyl, —C(O)OH, —C(O)NH 2 , —C(O)NH-alkyl, —NH 2 , —NO 2 , —CF 3 , —NH-alkyl, —N-(alkyl) 2 , —NHC(O)-alkyl and aryl, wherein said alkyl, alkenyl, alkynyl and aryl are each optionally substituted;
R 7 and R 8 are each independently selected from the group consisting of hydrogen, straight or branched C1-C5 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl; wherein said alkyl, alkenyl and alkynyl are each optionally substituted;
R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, haloalkyl, hydroxyl, hydroxyalkyl, halogen, —CN, —O-alkyl, —C(O)-alkyl, —C(O)O-alkyl, —C(O)OH, —C(O)N H 2 , —C(O)NH-alkyl, —NH 2 , —NO 2 , —CF 3 , —NH-alkyl, —NHC(O)-alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, haloalkyl are each optionally substituted; A is a bond or —(CH 2 ) n —, wherein n is an integer between 0 and 10; and X is —C(O)—, —CH 2 —, —C(OH)—, —C(O)O-alkyl, —C((O)alkyl)-, with the provision that the compound of formula (I) is isolated in a substantially pure form from a microorganism; is encoded by a darA gene comprising at least one non-natural nucleotide substitution; and is neither naturally occurring nor the compound of formula (II):

2. A pharmaceutical composition for treating infections in an animal caused by Gram-negative bacteria, comprising a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 2 , further comprising at least one pharmaceutically acceptable carrier, excipient or diluent.

4. The pharmaceutical composition according to claim 2 , in a form of topical administration, systemic administration, parenteral administration, subcutaneous administration, or transdermal administration, rectal administration, oral administration, intravaginal administration, intranasal administration, intrabronchial administration, intraocular administration, intra-aural administration, intravenous administration, intramuscular administration, or intraperitoneal administration.

5. The pharmaceutical composition according to claim 2 , further comprising at least one additional therapeutic agent.

6. The pharmaceutical composition according to claim 2 , obtained by culturing a microorganism having an ability to produce the compound in a nutrient medium.

7. The pharmaceutical composition according to claim 6 , wherein the microorganism is Photorhabdus khanii DSM 3369.

Assignees

• Univ Northeastern

Inventors

• Lewis Kim
• Imai Yu
• Favre-Godal Quentin
• Iinishi Akira
• Meyer Kirsten

Classifications

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C12N1/20

  Bacteria; Culture media therefor · CPC title

• A61K38/15

  Depsipeptides; Derivatives thereof · CPC title