Antibacterial compounds

Patent metadata

Field	Value
Publication number	US-10857110-B2
Application number	US-201716324509-A
Country	US
Kind code	B2
Filing date	Aug 9, 2017
Priority date	Aug 11, 2016
Publication date	Dec 8, 2020
Grant date	Dec 8, 2020

Abstract

An antibacterial compound of formula I, wherein X is selected from fluoro or bromo, effective against Gram negative and Gram positive bacteria, and in particular against non-fermenting multiresistant bacteria affecting patients suffering from cystic fibrosis and which are responsible of severe hospital-acquired infections in immunodepressed patients; its preparation process and pharmaceutical composition comprising said compound.

First claim

The invention claimed is:

1. An antibacterial compound of formula I

wherein X is selected from fluoro or bromo.

2. A process for preparing the antibacterial compound of claim 1 , said process comprising the steps of:
a) adding an amine and trietilamine to an acyl thiourea in solvent;
b) slowly adding HgCl 2 to the mixture of step a); and
c) allowing the reaction to proceed at room temperature for at least 6 hours.

3. The process of claim 2 , wherein the acyl thiourea has the formula II

wherein R is the adamantyl group C 10 H 15 ; R1 is H and R2 is 2-Br-4,6-F 2 —C 6 H 2 .

4. The process of claim 2 , wherein the solvent comprises dimethylformamide.

5. The process of claim 2 , wherein steps a) and b) are carried out under agitation and overheating is avoided using refrigeration means.

6. The process of claim 2 , wherein the amine of step a) is R 3 —NH 2 , wherein R 3 is selected from the group comprising 2-bromo-4,6-difluoro-phenyl (2-Br-4,6-F 2 —C 6 H 2 ) and 2,6-dibromo-4-fluoro-phenyl (2,6-Br 2 -4-F—C 6 H 2 ).

7. The process of claim 2 , wherein after step c) the obtained guanidine is purified by performing the additional steps of:
d) removing by filtration the HgS formed during the reaction, which is an highly insoluble solid;
e) removing by filtration the Et 3 NH + Cl − salt, which is the other solid formed during the reaction, by an extraction process consisting of water addition and ethyl acetate to the reaction mixture under vigorous agitation;
f) allowing to settle and separating the ethyl acetate organic layer;
g) optionally, repeating the extraction process of steps e) and f);
h) drying the organic phase by adding MgSO 4 or CaCl 2 and removing the solvent under negative pressure;
i) the obtained solid is purified by standard ethanol re-crystallization methods.

8. A bactericidal pharmaceutical composition comprising the compound of claim 1 .

9. A bactericidal pharmaceutical composition against Gram positive bacteria comprising the compound of claim 1 .

10. A bactericidal pharmaceutical composition for the treatment of infections affecting patients suffering from cystic fibrosis, said composition comprising the compound of claim 1 .

11. A bactericidal pharmaceutical composition for the treatment of infections caused by non-fermenting multiresistant Gram negative bacteria, said composition comprising the compound of claim 1 .

Assignees

• Consejo Nacional De Investigaciones Cientificas Y Tecn Conicet
• Univ Nacional De La Plata Unlp
• Quaid I Azam Univ
• Consejo Nacional De Investigaciones Cientificas Y Tecn Conicent

Inventors

• Saeed Bhatti Aamer
• BOSCH María Alejandra Nieves
• Lamberti Yanina Andrea
• Erben Mauricio Federico

Classifications

• C07C279/18

  having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings · CPC title

• A61K31/155 Primary

  Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2) · CPC title

• A61P31/04

  Antibacterial agents · CPC title