Il-8 inhibitors for use in the treatment and/or prevention of bacterial secondary infections

Patent metadata

Field	Value
Publication number	US-2025009719-A1
Application number	US-202418892729-A
Country	US
Kind code	A1
Filing date	Sep 23, 2024
Priority date	May 30, 2017
Publication date	Jan 9, 2025
Grant date	—

Abstract

The present invention relates to IL- 8 inhibitor compounds, preferably dual CXCR 1/ CXCR 2 receptor inhibitors, useful in the treatment and/or prevention of secondary bacterial infections, preferably secondary respiratory infections.

First claim

1 . A method of treating and/or preventing secondary respiratory bacterial infections associated with a preceding influenza infection in a subject in need thereof, comprising administration of an effective amount of an IL-8 inhibitor, wherein the IL-8 inhibitor is selected from small molecular weight molecules, and wherein the IL-8 inhibitor is administered alone or in combination with one or more pharmaceutically acceptable excipients and/or diluents.

2 . The method according to claim 1 , wherein the secondary respiratory bacterial infections are secondary pneumococcal infections.

3 . The method according to claim 1 , wherein the IL-8 inhibitor is an inhibitor of the activity of IL-8 mediated by the CXCR1 receptor or by both the CXCR1 and CXCR2 receptors.

4 . The method according to claim 1 , wherein the IL-8 inhibitor is selected from 1,3-thiazol-2-ylaminophenylpropionic acid derivatives, 2-phenyl-propionic acid derivatives and their pharmaceutically acceptable salts.

5 . The method according to claim 4 , wherein the 1,3-thiazol-2-ylaminophenylpropionic acid derivative is a compound of formula (I)

or a pharmaceutically acceptable salt thereof,
wherein
R1 is hydrogen or CH 3 ;
R2 is hydrogen or linear C 1 -C 4 alkyl;
Y is a heteroatom selected from S, O and N;
Z is selected from halogen, linear or branched C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, hydroxyl, carboxyl, C 1 -C 4 acyloxy, phenoxy, cyano, nitro, amino, C 1 -C 4 acylamino, halo C 1 -C 3 alkyl, halo C 1 -C 3 alkoxy, benzoyl, linear or branched C 1 -C 8 alkanesulfonate, linear or branched C 1 -C 8 alkanesulfonamide, and linear or branched C 1 -C 8 alkylsulfonylmethyl;
X is OH or a residue of formula NHR 3 , wherein R 3 is selected from:

hydrogen, hydroxyl, linear or branched C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 1 -C 5 alkoxy, C 1 -C 6 phenylalkyl, wherein the alkyl, cycloalkyl or alkenyl group can be substituted by a COOH residue, and a residue of formula SO 2 R4 wherein R4 is C 1 -C 2 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 haloalkyl.

6 . The method according to claim 5 , wherein:
R1 is hydrogen or CH 3 ; X is OH; R2 is hydrogen or linear C 1 -C 4 alkyl; Y is a heteroatom selected from S, O and N; and Z is selected from linear or branched C 1 -C 4 alkyl, linear or branched C 1 -C 4 alkoxy, halo C 1 -C 3 alkyl and halo C 1 -C 3 alkoxy.

7 . The method according to claim 5 , wherein R1 is hydrogen and the chiral carbon atom of the phenylpropionic group is in the S configuration.

8 . The method according to claim 5 , wherein the IL-8 inhibitor is selected from 2-methyl-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino} phenyl) propanoic acid and pharmaceutically acceptable salts thereof.

9 . The method according to claim 8 , wherein the 2-methyl-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino} phenyl) propanoic acid is in the form of its sodium salt.

10 . The method according to claim 5 , wherein the IL-8 inhibitor is (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl] amino} phenyl) propanoic acid or a pharmaceutically acceptable salt thereof.

11 . The method according to claim 10 , wherein the (2S)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl] amino} phenyl) propanoic acid is in the form of its sodium salt.

12 . The method according to claim 4 , wherein the 2-phenyl-propionic acid derivative is a compound of formula (II)

or a pharmaceutically acceptable salt thereof,
wherein:
R 4 is linear or branched C 1 -C 6 alkyl, benzoyl, phenoxy, trifluoromethanesulfonyloxy;
R 5 is H or linear or branched C 1 -C 3 alkyl; and
R 6 is linear or branched C 1 -C 6 alkyl or trifluoromethyl.

13 . The method according to claim 4 , wherein the 2-phenyl-propionic acid derivative is a compound of formula (III)

or a pharmaceutically acceptable salt thereof,
wherein
R′ is hydrogen and
R is H or a residue of formula SO 2 Ra wherein Ra is linear or branched C 1 -C 4 alkyl or halo C 1 -C 3 alkyl.

14 . The method according to claim 12 , wherein the chiral carbon atom of the phenylpropionic group is in the R configuration.

15 . The method according to claim 12 , wherein the IL-8 inhibitor is R-(−)-2-(4-isobutylphenyl)propionyl methanesulfonamide or a pharmaceutically acceptable salt thereof.

16 . The method according to claim 15 , wherein the R-(−)-2-(4-isobutylphenyl)propionyl methanesulfonamide is in the form of its lysine in situ salt.

17 . The method according to claim 13 , wherein the IL-8 inhibitor is R(−)-2-(4-trifluoromethanesulfonyloxy)phenyl]-N-methanesulfonyl propionamide or a pharmaceutically acceptable salt thereof.

18 . The method according to claim 17 , wherein the R(−)-2-(4-trifluoromethanesulfonyloxy)phenyl]-N-methanesulfonyl propionamide is in the form of its sodium salt.

19 . The method according to claim 13 , wherein the IL- 8 inhibitor is R(−)-2-[(4′-trifluoromethanesulfonyloxy)phenyl]propionamide.

Assignees

• Dompe Farm Spa

Inventors

• Brandolini Laura
• Allegretti Marcello
• Teixeira Mauro Martins

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K16/28

  against receptors, cell surface antigens or cell surface determinants · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61K31/18

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title