Glycoclusters and their pharmaceutical use as antibacterials

Patent metadata

Field	Value
Publication number	US-2016287620-A1
Application number	US-201415023470-A
Country	US
Kind code	A1
Filing date	Sep 22, 2014
Priority date	Sep 23, 2013
Publication date	Oct 6, 2016
Grant date	—

Abstract

A molecule responding to formula (I)of the glycocluster type with galactose residues at their extremities. Simple and efficient methods for the preparation of these compounds. Medical use of compounds (I) as inhibitors of infections by Pseudomonas aeruginosa, more specifically as inhibitors of Pseudomonas aeruginosa 's virulence.

First claim

1 . A molecule responding to formula (II):

Wherein
K represents a carbohydrate selected from the group consisting of mannose, galactose, glucose, arabinose, xylose, ribose and lactose
Pho represents a phosphorous group selected from the group consisting of:

Wherein X represents O or S,
One or two oxygen atoms of the phosphate group being linked by a covalent link to a L1 linker arm,
L1 represents a linker arm selected from the group consisting of:
a linear or branched C 1 -C 3 alkyl di radical, a linear, branched or cyclic C 4 -C 6 alkyl di radical, a linear, branched or cyclic C 7 -C 12 alkyl di radical possibly comprising one or several ether bridges —O—,
a poly(ethylene glycol) di radical comprising 2, 3, 4, 5 or 6 ethylene glycol units,
a polypyleneglycol) di radical comprising 2, 3, 4, 5 or 6 propylene glycol units,
T represents a connecting group selected from:
a triazole di-radical

L2 represents a linker arm selected from the group consisting of

n and m represent an integer selected from 1, 2, 3, 4, or 5
Ar is selected from the group consisting of phenyl, naphtalenyl and 1,4-biphenyl

L3 represents O, S or —CH2

Gal represents the radical □-D-galactopyranosyl:

z is an integer selected from 1, 2 3, 4, 5, 6, 7, 8, 9 or 10

2 . The molecule according to claim 1 , wherein K represents the mannose under the form D-mannopyranosyl.

3 . The molecule according to claim 1 , wherein L1 represents a group Pro (1,3-n-propyl), EG2M (diethylene glycol methylene), EG3M (triethylene glycol methylene), EG4M (tetraethylene glycol methylene).

4 . The molecule according to claim 1 , wherein Ar is the phenyl group.

5 . The molecule according to claim 1 , wherein z is 3 or 4.

6 . The molecule according to claim 1 , selected from the group consisting of:
Man(POProTzAcNPhe-O-Gal) 4 Gal(POProTzAcNPhe-O-Gal) 4 Glc(POProTzAcNPhe-O-Gal) 4 Man(POEG 2 MTzAcNPhe-O-Gal) 4 Man(POProTzAcNPhe-O-Gal) 8 Man[POTHME (MTzAcNPhe-O-Gal) 2 ] 4 Man(PSEG2MTzAcNPhe-CH2-Gal) 4 Man(PSEG3MTzAcNPhe-CH2-Gal) 4 Man(EG2MTzAcNPhe-CH2-Gal) 4 Man(EG3MTzAcNPhe-CH2-Gal) 4 Man(EG2MTzAcNPhe-CH2-SGal) 4 Man(EG3MTzAcNPhe-CH2-SGal) 4 Man(PSEG3MTzAcNPh-Gal) 4 Man(PSEG3MTzAcNPhe-CH2-SGal) 4 Man(PSEG2MTzAcNPhe-CH2-SGal) 4 Man(PSEG3MTzAcNPh-SGal) 4 Man(PSEG2MTzAcNPh-Gal) 4 Man(PSEG2MTzAcNPh-SGal) 4 Man(EG2MTzAcNPh-SGal) 4 Man(EG3MTzAcNPh-SGal) 4 Man(EG3MTzproNCONapht-OGal) 4 Man(EG3MTzproNCOBisphe-OGal) 4 Man(PSEG3MTzproNCOBisphe-OGal) 4 Man(PSEG2MTzproNCOBisphe-OGal) 4 Man(EG2MTz AcNPh-Gal) 4 Man(PSEG3MTzproNCONapht-OGal) 4 Man(EG3MTz AcNPh-Gal) 4 Man(PSEG2MTzproNCONapht-OGal) 4 Man(EG2MTzproNCOBisphe-OGal) 4 Man(EG2MTzproNCONapht-OGal) 4 Wherein Man represents mannose, Gal represents galactose, Glc represents glucose.

7 . A pharmaceutical composition comprising at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or excipient.

8 . The pharmaceutical composition according to claim formulated to be inhaled or instilled in the respiratory tract.

9 . The pharmaceutical composition according to claim 7 , further comprising at least one or more other antibacterial agent(s) or one or more other antivirulence agent(s) or one or more drug(s) reinforcing the host innate immunity.

10 . The pharmaceutical composition according to claim 7 for use for the prevention, delaying, attenuating and therapeutical treatment of infections due to microbial pathogens, particularly bacterial pathogens.

11 . The pharmaceutical composition according to claim 10 , for treating, delaying, attenuating or preventing infections from Pseudomonas aeruginosa.

12 . A composition comprising at least one compound according to claim 1 for use for material able to capture Pseudomonas aeruginosa.

13 . The molecule according to claim 2 , wherein L1 represents a group Pro (1,3-n-propyl), EG2M (diethylene glycol methylene), EG3M (triethylene glycol methylene), EG4M (tetraethylene glycol methylene).

14 . The molecule according to claim 2 , wherein Ar is the phenyl group.

15 . The molecule according to claim 2 , wherein z is 3 or 4.

16 . The molecule according to claim 2 , selected from the group consisting of:
Man(POProTzAcNPhe-O-Gal) 4 Gal(POProTzAcNPhe-O-Gal) 4 Glc(POProTzAcNPhe-O-Gal) 4 Man(POEG 2 MTzAcNPhe-O-Gal) 4 Man(POProTzAcNPhe-O-Gal) 8 Man[POTHME(MTzAcNPhe-O-Gal) 2 ] 4 Man(PSEG2MTzAcNPhe-CH2-Gal) 4 Man(PSEG3MTzAcNPhe-CH2-Gal) 4 Man(EG2MTzAcNPhe-CH2-Gal) 4 Man(EG3MTzAcNPhe-CH2-Gal) 4 Man(EG2MTzAcNPhe-CH2-SGal) 4 Man(EG3MTzAcNPhe-CH2-SGal) 4 Man(PSEG3MTzAcNPh-Gal) 4 Man(PSEG3MTzAcNPhe-CH2-SGal) 4 Man(PSEG2MTzAcNPhe-CH2-SGal) 4 Man(PSEG3MTzAcNPh-SGal) 4 Man(PSEG2MTzAcNPh-Gal) 4 Man(PSEG2MTzAcNPh-SGal) 4 Man(EG2MTzAcNPh-SGal) 4 Man(EG3MTzAcNPh-SGal) 4 Man(EG3MTzproNCONapht-OGal) 4 Man(EG3MTzproNCOBisphe-OGal) 4 Man(PSEG3MTzproNCOBisphe-OGal) 4 Man(PSEG2MTzproNCOBisphe-OGal) 4 Man(EG2MTz AcNPh-Gal) 4 Man(PSEG3MTzproNCONapht-OGal) 4 Man(EG3MTz AcNPh-Gal) 4 Man(PSEG2MTzproNCONapht-OGal) 4 Man(EG2MTzproNCOBisphe-OGal) 4 Man(EG2MTzproNCONapht-OGal) 4 Wherein Man represents mannose, Gal represents galactose, Glc represents glucose.

17 . The molecule according to claim 3 , wherein Ar is the phenyl group.

18 . The molecule according to claim 3 , wherein z is 3 or 4.

19 . The molecule according to claim 4 , wherein z is 3 or 4.

Assignees

• Centre Nat Rech Scient
• Univ Montpellier 1

Inventors

• Morvan Francois
• Vasseur Jean-Jacques
• Ligeour Caroline
• Chevolot Yann
• Souteyrand Eliane
• Vidal Olivier
• Goudot Alice
• Vidal Sebastien

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• C07H15/26

  Acyclic or carbocyclic radicals, substituted by hetero rings · CPC title

• A61K45/06

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

• A61K31/70

  Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047) · CPC title

• A61K31/7056 Primary

  containing five-membered rings with nitrogen as a ring hetero atom · CPC title