Imidazolo-heteroaryl derivatives with antibacterial properties
The invention relates to Imidazolo-heteroaryl derivatives of formula (I). The compounds inhibit the activity of the Dlta enzyme of Gram-positive bacteria and are useful to treat Gram-positive bacterial infections. Furthermore the application discloses method for assessing the Dlta inhibitory activity of tested molecules and a method for measuring the efficacy of molecules in inhibiting bacteria proliferation in vitro.
1. An imidazolo-heteroaryl derivative of formula (I)
wherein,
Y=N and W is C
or
Y=C and W=N,
R1 is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, CO 2 R a , COR a , CONR a R b ; CR a ═NOR b , S(O) n R a , phenyl or heterocycle, all being optionally substituted by one or several identical or different R, or R1 is H, halogen or CN;
R 2 is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl OR a , S(O) n R a , phenyl or heterocycle, all being optionally substituted by one or several identical or different R, or R2 is H or halogen;
R 3 is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, CO 2 R a , COR a , CR a , NR a R b , NR a COR b , CONR a R b , CR a ═NOR b , S(O) n R a , SO 2 NR a R b , phenyl or heterocycle, all being optionally substituted by one or several identical or different R, or R3 is H, halogen or CN;
R4 is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, phenyl or heterocycle all being optionally substituted by one or several identical or different R, or R4 is H, halogen or CN;
R5 is H, COR a , CO 2 R a , P(O)(OH) 2 or COCHR a NR b R c ;
R a , R b and R c identical or different are selected from the group consisting of H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, phenyl and heterocycle;
R is selected from the group consisting of C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, phenyl, heterocycle, CO 2 R a , COR a , CONR a R b , OCOR a , OR a , NR a R b , CR a ═NOR b , NR a CORb, NR a COOR b , OCONR a R b , NR a CONR b R c , NR a SO 2 R b , S(O) n R a , and
SO 2 NR a R b , all being optionally substituted by one or several identical or different R′, or R is halogen; CN or NO 2 , Ra, Rb and Rc are such as described above;
R′ is selected from the group consisting of C 1 -C 10 alkyl, CO 2 R″, COR″, C0NR″R′″, OCOR″, OR″, NR″R″OR″═NOR″NR″COR′″, NR″COOR′″, OCONR″R′″, NR″C0NR″R″NR″SO 2 R″S(O) n R″, SO 2 NR″R″ halogen, CN and NO 2 ;
R″ and R′″ being identical or different are H or C 1 -C 10 alkyl or form together a 3 to 6 membered nitrogenous heterocycle;
n is 0, 1 or 2;
with the proviso that R5 is not H, when R2=F or SO 2 CH 3 ; R1, R3 and R4=H; and W=C, and
with the proviso that R1, R2, R3, R4 and R5 are not all H when W is C and Y is N, or
a pharmaceutically acceptable salt thereof.
2. The derivative of claim 1 , wherein Y=N and W is C and R1 is selected from the group consisting of H, halogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, CO 2 R a , COR a , CONR a R b S(O) n R a phenyl, R substituted phenyl, 5 or 6-membered heterocycle, and R substituted heterocycle.
3. The derivative of claim 1 , wherein Y=C and W is N and R1 is selected from the group consisting of H, C 1 -C 10 alkyl, R substituted alkyl, phenyl and R substituted phenyl.
4. The derivative of claim 2 , wherein R1 is H.
5. The derivative of claim 2 , wherein R1 is C 1 -C 10 alkyl.
6. The derivative of claim 2 , wherein R1 is C 2 -C 10 alkenyl.
7. The derivative of claim 2 , wherein R1 is C 2 -C 10 alkynyl.
8. The derivative of claim 2 , wherein R1 is an halogen selected between Br and I.
9. The derivative of claim 2 , wherein R1 is phenyl.
10. The derivative of claim 2 , wherein R1 represents a phenyl group substituted by R which is selected from the group consisting of C 1 -C 10 alkyl-CO—NH—, NH 2 —SO 2 —, C 1 C 10 alkyl-O—C 1 -C 10 alkyl-SO 2 —NH, non aromatic heterocycle, C 1 -C 10 alkyl-NH—CO—, HO—C 1 C 10 -alkyl-, and NH 2 —C 10 alkyl-, or R1 is a phenyl group substituted by two R.
11. The derivative of claim 2 , wherein R1 is an heterocycle selected from the group consisting of pyrazolyl, triazolyl, pyridyl, and pyrimidinyl.
12. The derivative of claim 2 , wherein R1 is an aromatic or non aromatic heterocycle substituted by R which is selected from the group consisting of C 1 -C 10 alkyl-O—, NH 2 , C 1 -C 10 alkyl-CO—, C 1 -C 10 alkyl-SO 2 —, C 1 -C 10 alkyl-O—C 6 H 4 —, phenyl, pyridyl, C 6 H 4 —CH 2 — and R a OOC—.
13. The derivative of claim 2 , wherein R1 is CHO.
14. The derivative of claim 2 , wherein R1 is COOR a —.
15. The derivative of claim 2 , wherein R1 is COOR a R b —.
16. The derivative of claim 2 , wherein R1 is S(O) n R a —.
17. The derivative of claim 3 , wherein R1 is H, or C 1 -C 10 alkyl substituted by R.
18. The derivative of claim 3 , wherein R1 represents a phenyl group substituted or not by R.
19. The derivative according to claim 2 , wherein R3 is H, NR a R b , halogen, or C 1 -C 10 alkyl.
20. The derivative according to claim 2 , wherein R4 is H or a phenyl substituted by R.
21. The derivative according to claim 2 , wherein R2 is CF 3 —, CF 3 O—CF 3 —C 6 H 4 —, CH 3 S—, CH 3 —CH 2 —S—, Br or H.
22. The derivative according to claim 2 , wherein R5 is H.
23. The derivative according to claim 2 , wherein R5 is COR a , CO 2 Ra, P(O)(OH) 2 or COCHR a NR b R c .
24. The derivative of claim 1 , wherein
R1=H, Br, CH 2 ═CH—, phenyl, phenyl substituted by CH 3 —CO—NH—, NH 2 —SO, CH 3 O—, CH 3 —SO 2 —NH—, morpholino, CH 3 —NH—CO—, HOCH 2 —, NH 2 —CH 2 —, both NH 2 — and CH 3 —O—, or R1 is pyrazolyl, pyrazolyl substituted by CH 3 —O—C 6 H 4 —, pyridyl substituted by CH 3 —O—, triazolyl, triazolyl substituted by C 6 H 4 —CH 2 —, pyrimidinyl substituted by NH 2 or piperazinyl substituted by CH 3 SO 2 —, or CH 3 CO;
R2=CF 3 , CF 3 —C 6 H 4 —, CF 3 —O—;
R3=R4=R5=H;
Y=N and W=C;
said derivative having an IC 50 lower than or equal to 2.5 μM.
25. The derivative of claim 1 , further characterized by the following properties: it is able to inhibit the activity of de DltA enzyme, it is able to render resistant bacteria sensitive to antibacterial cationic peptides and peptides mimicking said cationic peptides in vitro, and it is active in preventing bacterial multiplication in an experimental model of infection in mice model by rendering the bacteria avirulent.
26. A composition comprising at least a derivative of formula (I) as defined in claim 1 , for use as drug.
27. The composition of claim 26 for use as antibacterial agent to treat Gram-positive bacterial infections in human and animals due to bacteria of a genus selected from the group consisting of Staphylococcus, Bacillus, Listeria, Enterococcus, Streptococcus, Mycobacterium, Bacteroides and Clostridium.
28. A pharmaceutical composition comprising an effective amount of at least one derivative of formula (I) as defined in claim 1 , in combination with a pharmaceutically acceptable carrier.
29. A pharmaceutical composition comprising an effective amount of at least one derivative of formula (I) as defined in claim 1 , in combination with an antibacterial molecule and a pharmaceutically acceptable carrier.
30. The pharmaceutical composition according to claim 28 , which is formulated to be administered under oral, injectable, or parenteral routes, with individual doses appropriate for the patient to be treated.
31. The composition of claim 27 for use as antibacterial agent to treat Gram-positive bacterial infections in human and animals due to bacteria selected from the group consisting of Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Mycobacterium tuberculosis, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus agalactiae, Bacteroides fragilis , and Clostridium difficile.