NEW BETA-LACTAMASE INHIBITORS TARGETING GRAM NEGATIVE BACTERIA
The present invention relates to a compound of the following formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, notably for use as β-lactamase inhibitors, notably in the treatment of a disease caused by gram negative bacteria, in particular enterobacteria, as well as pharmaceutical compositions containing such a compound and a process to prepare such a compound.
1 . A compound of the following general formula (I):
or a pharmaceutically acceptable salt and/or solvate thereof, wherein:
X is O or S;
Y is SO 3 H or PO 3 H; and
R 1 is:
H
a tri-(C 1 -C 6 )alkylsilyl group,
a (C 1 -C 6 )alkyl group, optionally substituted with one or several groups selected from halo, cyano (CN), OR 2 , SR 3 , NR 4 R 5 , COR 6 , CO 2 R 7 , CONR 8 R 9 and NO 2 , or
an aryl, heteroaryl, aryl-(C 1 -C 6 )alkyl, heteroaryl-(C 1 -C 6 )alkyl, cycloalkyl, cycloalkyl-(C 1 -C 6 )alkyl, heterocycle or heterocycle-(C 1 -C 6 )alkyl group, optionally substituted with one or several groups selected from halo, cyano (CN), (C 1 -C 6 )alkyl, OR 10 , SR 11 , NR 12 R 13 , COR 14 , CO 2 R 15 , CONR 16 R 17 and NO 2 ,
wherein R 2 to R 17 are, independently of each other, H, a (C 1 -C 6 )alkyl group or a C(═O)O(C 1 -C 6 )alkyl.
2 . The compound according to claim 1 , wherein said compound is of the following general formula (Ia):
3 . The compound according to claim 1 , wherein X is O.
4 . The compound according to claim 1 , wherein Y is SO 3 H.
5 . The compound according to claim 1 , wherein R 1 is:
a tri-(C 1 -C 6 )alkylsilyl group, notably a trimethylsilyl group,
a (C 1 -C 6 )alkyl group, optionally substituted with one or several groups selected from halo, OR 2 , NR 4 R 5 , CO 2 R 7 and CONR 8 R 9 , or
an aryl, heteroaryl, aryl-(C 1 -C 6 )alkyl, heteroaryl-(C 1 -C 6 )alkyl, heterocycle or heterocycle-(C 1 -C 6 )alkyl group, optionally substituted with one or several groups selected from halo, (C 1 -C 6 )alkyl, OR 10 , NR 12 R 13 , CO 2 R 15 and CONR 16 R 17 .
6 . The compound according to claim 1 , wherein:
the aryl moiety in the aryl and aryl-(C 1 -C 6 )alkyl groups is a phenyl;
the heteroaryl moiety in the heteroaryl and heteroaryl-(C 1 -C 6 )alkyl groups is a 5- or 6-membered heteroaryl comprising one or two heteroatoms chosen from O and N, preferably selected from furan, pyrrole, imidazole, pyridine, pyrazine and pyrimidine, more preferably pyridine;
the heterocycle moiety in the heterocycle and heterocycle-(C 1 -C 6 )alkyl groups is a 5- or 6-membered, saturated or unsaturated, preferably saturated heterocycle comprising one or two heteroatoms chosen from O and N, preferably selected from pyrrolidine, piperidine, morpholine and piperazine.
7 . The compound according to claim 1 , wherein it is chosen among the following compounds 1a.i and 2a.i:
and the pharmaceutically acceptable salts, such as the sodium salts, and solvates thereof.
8 . A compound according to claim 1 for use as β-lactamase inhibitors.
9 . A compound according to claim 1 for use as a β-lactamase inhibitor in combination with β-lactam antibiotics.
10 . A compound according to claim 1 for use in the treatment of a disease caused by gram negative bacteria, in particular enterobacteria.
11 . A pharmaceutical composition comprising at least one compound according to claim 1 and at least one pharmaceutically acceptable excipient.
12 . A pharmaceutical composition comprising:
(i) at least one compound according to claim 1 , and
(ii) at least another active principle, such as an antibiotic, notably a β-lactam antibiotic, as a combination product for a simultaneous, separate or sequential use.
13 . A process to prepare the compound according to claim 1 , comprising a reaction converting the OH group of a compound of the following formula (II) into a OY group to obtain the corresponding compound of formula (I):
wherein X is O or S, and R 1 is as defined in claim 1 , R 1 being optionally in a protected form, wherein:
when Y is SO 3 H, said reaction is a sulfonation reaction, and
when Y is PO 3 H, said reaction is a phosphorylation reaction,
followed by a deprotection of the R 1 group when it is in a protected form,
optionally followed by a salt-forming step.
14 . The process according to claim 13 , wherein the compound of formula (II) is obtained by a coupling reaction between:
a compound of the following formula (III):
wherein X is O or S, and Y p is a hydroxyl protecting group, such as a benzyl group, and
a compound of the following formula (IV):
wherein R 1 is as defined in claim 1 , optionally in a protected form,
followed by a deprotection of the OY p group.