Polymyxin derivatives as antimicrobial compounds

Patent metadata

Field	Value
Publication number	US-RE48335-E
Application number	US-201516144967-A
Country	US
Kind code	E1
Filing date	Apr 1, 2015
Priority date	Apr 1, 2014
Publication date	Dec 1, 2020
Grant date	Dec 1, 2020

Abstract

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

First claim

The claims defining the invention are as follows:

1. A compound of formula (IIb):

wherein:
R 1 is selected from hexanoyl, hepatanoyl, octanoyl, nonanoyl, decanoyl, dodecanoyl, 7 methyloctanoyl, S-5-methylheptanoyl, R-5-methylheptanoyl, S,R-5-methylheptanoyl (racemic mixture), 4-biphenylcarboxyl, 4-trifluoromethylbenzoyl, 4-ethylbenzoyl, 3,4-dichlorobenzoyl, 4-chlorobenzoyl, 3-chlorobenzoyl, pentafluorobenzoyl, 4-methylbenzoyl, 4-ethylphenylacetyl, phenylacetyl, 4-methylphenylacetyl, 4-trifluoromethylphenylacetyl, pentafluorophenylacetyl, 3,4-dichlorophenylacetyl, 4-chlorophenylacetyl, 3-chlorophenylacetyl, 2-chlorobenzoyl, 2-fluorobenzoyl, 2-methylbenzoyl, 2-chlorophenylacetyl, 2-fluorophenylacetyl, 2-methylphenylacetyl, 2,3-dichlorobenzoyl, 2,3-dimethylbenzoyl, 2,4-dichlorophenylacetyl, 2,4-dichlorobenzoyl, 2,4-dimethylbenzoyl, 2-chloro-4-methylbenzoyl, 2-chloro-4-trifluoromethylbenzoyl, 3-fluorobenzoyl, 3-methylbenzoyl, 3-trifuoromethylbenzoyl, 3,4-dimethylbenzoyl, 3-fluoro-4-methylbenzoyl, 4-chloro-3-methylbenzoyl, 3,4-dimethylphenylacetyl, 3-chloro-4-methylbenzoyl, 4-chloro-3-fluorobenzoyl, 3-fluoro-4-trifluoromethylbenzoyl, 3-chloro-4-fluorobenzoyl, 4-methyl-3-trifluoromethylbenzoyl, 3-methyl-4-trifluoromethylbenzoyl, 3-methyl-5-trifluoromethylbenzoyl, 3,5-dimethylbenzoyl, 3,5-dichlorobenzoyl, 3,5-bis(trifluoromethyl) benzoyl, 3-fluoro-5-trifluoromethylbenzoyl, 3-chloro-5-methylbenzoyl, 3-chloro-5-fluorobenzoyl, 2,4,6-trimethylbenzoyl, 2,4,6-trichlorobenzoyl, 2-chloro-4-fluorobenzoyl, 4-chloro-2-fluorobenzoyl, 3,4,5-trifluoromethylbenzoyl, 4-chloro-2-trifluoromethylbenzoyl, 2-fluoro-4-trifluoromethylbenzoyl, 3-biphenylcarboxyl, 4-chlorobiphenyl-4-carboxyl, 3-phenylproponyl, 4-phenylbutanoyl, 2,4-dichlorophenylsulfonyl, 4-chloro-3-trifluoromethylbenzoyl, 4-isopropylbenzoyl, 4-chloro-3-fluorobenzoyl, and 3-chloro-4-trifluoromethylbenzoyl;
R 3 represents a side chain of an amino acid selected from leucine, phenylalanine, norleucine, norvaline or t-butylglycine;
R 4 represents a side chain of an amino acid selected from alanine, threonine, serine, valine, t-butylglycine, 2-aminobutyric acid or 2-aminoisobutyric acid; and
k and q are individually selected from 1, 2, or 3; or
pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 , wherein R 4 represents the side chain of an amino acid selected from alanine, threonine, serine, 2-aminobutyric acid, or 2-aminoisobutyric acid.

3. The compound of claim 2, wherein R 3 represents the side chain of D-leucine; R 4 represents the side chain of 2-aminobutyric acid; R 1 is 2,4-dichlorobenzoyl; k is 2; and q is 1.

4. The compound of claim 1, selected from the group consisting of:

Compound
R 1
R 3
R 4
k
q

29
4-BPC
D-Leu
Thr
2
2

30
PA
D-Leu
Thr
2
2

56
4-TFMB
D-Leu
Thr
2
1

57
3,4-DCB
D-Leu
Thr
2
1

61
3-CPA
D-Leu
Thr
2
1

62
2,4-DCPA
D-Leu
Thr
2
1

70
2,4-DCPA
D-Leu
Abu
2
1

71
3,4-DCB
D-Leu
Abu
2
1

72
2-CB
D-Leu
Abu
2
1

73
2-FB
D-Leu
Abu
2
1

74
4-TFMB
D-Leu
Abu
2
1

75
2-MB
D-Leu
Abu
2
1

76
2-MPA
D-Leu
Abu
2
1

77
4-CPA
D-Leu
Abu
2
1

78
PA
D-Leu
Abu
2
1

79
3-CPA
D-Leu
Abu
2
1

80
4-MPA
D-Leu
Abu
2
1

81
3,4-DCPA
D-Leu
Abu
2
1

82
2,4-DCB
D-Leu
Abu
2
1

83
3,4-DMB
D-Leu
Abu
2
1

84
2-CPA
D-Leu
Abu
2
1

85
2-FPA
D-Leu
Abu
2
1

86
3-FB
D-Leu
Abu
2
1

87
3-MB
D-Leu
Abu
2
1

88
3-CB
D-Leu
Abu
2
1

89
2,4-DMB
D-Leu
Abu
2
1

90
2,3-DCB
D-Leu
Abu
2
1

91

Assignees

• Univ Monash

Inventors

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

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

• A61K38/12

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C07K7/62 Primary

  Polymyxins; Related peptides · CPC title