Antimicrobial polymyxin derivative compounds

Patent metadata

Field	Value
Publication number	US-11225505-B2
Application number	US-201615763954-A
Country	US
Kind code	B2
Filing date	Sep 29, 2016
Priority date	Sep 29, 2015
Publication date	Jan 18, 2022
Grant date	Jan 18, 2022

Abstract

The present invention relates to antimicrobial polymyxin derivative compounds and their uses, and in particular to peptide polymyxin antibiotics which may be used in the treatment of bacterial infections such as Gram negative bacterial infections, particularly those caused by multidrug-resistant (MDR) Gram negative bacterial infections.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein
R 1 is selected from 5-chloronicotinoyl, 6-chloronicotinoyl, 2,6-dichloronicotinoyl, 4,6-dicloronicotinoyl, 5,6-dichloronicotinoyl, 6-(trifluoromethyl)nicotinoyl, 3,5-dichloropicolinoyl, 4,6-dichloropicolinoyl, 5-phenylpicolinoyl, 5-(4-chlorophenyl)picolinoyl, 4-(6-chloro-3-pyridinyl)benzoyl, 5-(4-chlorophenyl)thiophene-2-carboxyl, 2,6-dichloroisonicotinoyl, 5-(trifluoromethyl)nicotinoyl, 4-(trifluoromethyl)picolinoyl, 3,5-dibromopicolinoyl, 5-bromonicotinoyl, 2-chloroisonicotinoyl, 2-bromoisonicotinoyl, 4-chloropicolinoyl, 2-(trifluoromethyl)isonicotinoyl, 2,6-dibromoisonicotinoyl, 3,5-dibromopicolinoyl, 5-methylnicotinoyl, 2-fluoroisonicotinoyl, 2-(trifluoromethyl)isonicotinoyl, 5-bromo-3-chloropicolinoyl, 3-chloroisonicotinoyl, 3-chloro-5-(trifluoromethyl)picolinoyl, 3-chloropicolinoyl, 5-chloropicolinoyl, 5-(trifluoromethyl)picolinoyl, 2-chloro-6-methylisonicotinoyl, 2-chloro-6-(trifluoromethyl)nicotinoyl, 6-ethylnicotinoyl, 5-ethylpicolinoyl, 6-chloropicolinoyl, 6-(trifluoromethyl)picolinoyl, 2-(trifluoromethyl)pyrimidine-5-carboxyl, 2-quinoxalinecarboxyl, 1H-benzimidazole-2-carboxyl, 1-methylindole-2-carboxyl, 6-methyl-imidazo[1,2-α]pyridine-2-carboxyl, benzo[b]thiophene-2-carboxyl, 1-methylindazole-3-carboxyl, 3-quinolinecarboxyl, benzothiazole-6-carboxyl, 1H-indazole-3-carboxyl, quinaldoyl, 1H-indole-2-carboxyl, 1-methylbenzimidazole-2-carboxyl, 5-chloro-1-methylindole-2-carboxyl, 5-chloro-1H-indole-2-carboxyl, 5,6-difluoro-1H-indole-2-carboxyl, 3-chlorobezo[b]thiophene-2-carboxyl, 1-methylindole-3-acetyl, 1-methylindole-3-carboxyl, benzo[d]thiazole-2-carboxyl, 6-chlorobenzimidazole-2-carboxyl, benzo[b]thiazole-2-propanoyl, 2-phenylpyrimidine-5-carboxyl, benzooxazole-2-carboxyl, benzo[d]isooxazole-3-carboxyl, 2,5-dibromothiphene-3-carboxyl, 4,5-dibromopyrrole-2-carboxyl, 5-bromothiophene-2-carboxyl, 4,5-dibromofuran-2-carboxyl, 5-phenyl-1, 2-oxazole-3-carboxyl, 5-phenyl-1,2,4-oxadiazole-3-carboxyl, 2-phenyl-1H-imidazole-4-carboxyl, 4,5-dibromothiophene-2-carboxyl, 5-phenyl-1H-pyrazole-3-carboxyl, 3,5-dibromothiophene-2-carboxyl, 5-(trifluoromethyl)thiophene-2-carboxyl, 3-phenyl-1,2-oxazole-5-carboxyl, 4-bromothiophene-2-carboxyl, 3-chlorothiophene-2-carboxyl, 4H-thieno[3,2-b]pyrrole-5-carboxyl, 2-bromo-1,3-thiazole-5-carboxyl, benzofuran-2-carboxyl, 4-bromo-1-methylpyrrole-2-carboxyl, 5-(4-chlorophenyl)-1,2-oxazole-3-carboxyl, 5-bromothiophene-3-carboxyl, 4-bromopicolinoyl, 5-bromofuran-3-carboxyl and indole-3-propanoyl;
R 2 represents a side chain of an amino acid selected from D-Ser, L-Dab or L-Dap;
R 3 represents a side chain of an amino acid selected from leucine, phenylalanine, norleucine, or norvaline; and
R 4 represents a side chain of an amino acid selected from alanine, threonine, valine, or 2-aminobutyric acid; or
a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 represented by of formula (II):

wherein
R 1 is selected from 5-chloronicotinoyl, 6-chloronicotinoyl, 2,6-dichloronicotinoyl, 4,6-dicloronicotinoyl, 5,6-dichloronicotinoyl, 6-(trifluoromethyl)nicotinoyl, 3,5-dichloropicolinoyl, 4,6-dichloropicolinoyl, 5-phenylpicolinoyl, 5-(4-chlorophenyl)picolinoyl, 4-(6-chloro-3-pyridinyl)benzoyl, 5-(4-chlorophenyl)thiophene-2-carboxyl, 2,6-dichloroisonicotinoyl, 5-(trifluoromethyl)nicotinoyl, 4-(trifluoromethyl)picolinoyl, 3,5-dibromopicolinoyl, 5-bromonicotinoyl, 2-chloroisonicotinoyl, 2-bromoisonicotinoyl, 4-chloropicolinoyl, 2-(trifluoromethyl)isonicotinoyl, 2,6-dibromoisonicotinoyl, 3,5-dibromopicolinoyl, 5-methylnicotinoyl, 2-fluoroisonicotinoyl, 2-(trifluoromethyl)isonicotinoyl, 5-bromo-3-chloropicolinoyl, 3-chloroisonicotinoyl, 3-chloro-5-(trifluoromethyl)picolinoyl, 3-chloropicolinoyl, 5-chloropicolinoyl, 5-(trifluoromethyl)picolinoyl, 2-chloro-6-methylisonicotinoyl, 2-chloro-6-(trifluoromethyl)nicotinoyl, 6-ethylnicotinoyl, 5-ethylpicolinoyl, 6-chloropicolinoyl, 6-(trifluoromethyl)picolinoyl, 2-(trifluoromethyl)pyrimidine-5-carboxyl, 2-quinoxalinecarboxyl, 1H-benzimidazole-2-carboxyl, 1-methylindole-2-carboxyl, 6-methyl-imidazo[1,2-α]pyridine-2-carboxyl, benzo[b]thiophene-2-carboxyl, 1-methylindazole-3-carboxyl, 3-quinolinecarboxyl, benzothiazole-6-carboxyl, 1H-indazole-3-carboxyl, quinaldoyl, 1H-indole-2-carboxyl, 1-methylbenzimidazole-2-carboxyl, 5-chloro-1-methylindole-2-carboxyl, 5-chloro-1H-indole-2-carboxyl, 5,6-difluoro-1H-indole-2-carboxyl, 3-chlorobezo[b]thiophene-2-carboxyl, 1-methylindole-3-acetyl, 1-methylindole-3-carboxyl, benzo[d]thiazole-2-carboxyl, 6-chlorobenzimidazole-2-carboxyl, benzo[b]thiazole-2-propanoyl, 2-phenylpyrimidine-5-carboxyl, benzooxazole-2-carboxyl, benzo[d]isooxazole-3-carboxyl, 2,5-dibromothiphene-3-carboxyl, 4,5-dibromopyrrole-2-carboxyl, 5-bromothiophene-2-carboxyl, 4,5-dibromofuran-2-carboxyl, 5-phenyl-1, 2-oxazole-3-carboxyl, 5-phenyl-1,2,4-oxadiazole-3-carboxyl, 2-phenyl-1H-imidazole-4-carboxyl, 4,5-dibromothiophene-2-carboxyl, 5-phenyl-1H-pyrazole-3-carboxyl, 3,5-dibromothiophene-2-carboxyl, 5-(trifluoromethyl)thiophene-2-carboxyl, 3 -phenyl-1,2-oxazole-5-carboxyl, 4-bromothiophene-2-carboxyl, 3-chlorothiophene-2-carboxyl, 4H-thieno[3,2-b]pyrrole-5-carboxyl, 2-bromo-1,3-thiazole-5-carboxyl, benzofuran-2-carboxyl, 4-bromo-1-methylpyrrole-2-carboxyl, 5-(4-chlorophenyl)-1,2-oxazole-3-carboxyl, 5-bromothiophene-3-carboxyl, 4-bromopicolinoyl, 5-bromofuran-3-carboxyl and indole-3-propanoyl;
R 3 represents a side chain of an amino acid selected from leucine, phenylalanine, norleucine, or norvaline; and
R 4 represents a side chain of an amino acid selected from alanine, threonine, valine, or 2-aminobutyric acid; or
a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or pharmaceutically acceptable salts thereof, together with at least one pharmaceutically acceptable carrier or diluent.

4. A method of preventing or treating a Gram-negative bacterial infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

5. A method according to claim 4 , wherein the Gram-negative bacterial infection is a multidrug-resistant (MDR) Gram-negative bacterial infection.

6. A method according to claim 4 , further comprising administering a second antibacterial agent to said subject.

7. A method according to claim 4 , wherein the one or more compounds is administered to the subject in need thereof orally, intravenously or intramuscularly.

Assignees

• Univ Monash

Inventors

• Roberts Kade D
• Li Jian
• Velkov Tony
• Nation Roger L
• Thompson Philip E

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K45/06

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

• C07K7/62 Primary

  Polymyxins; Related peptides · CPC title

• A61P31/04

  Antibacterial agents · CPC title