2- or 3-imidazolines as carbapenemases inhibitors
The present application relates to novel 3-imidazolines of formula (I′) and (I) below: (I′) (I) Wherein Ar 1 , Ar 2 , Ar 3 , and R 1 to R 6 are as defined in the claims. The 3-imidazolines of the invention are useful in antibiotic therapies, in particular as inhibitors of carbapenemases. They are also useful as antibiotics themselves. The present invention also concerns a method for preparing more specifically the 3-imidazolines of formula (I). The present invention further relates to conjugates of said compounds with known antibiotics.
1. A compound of formula (I):
wherein
represents a single or double bond, with the proviso that one of the two bonds
is a single bond and the other is a double bond;
Ar 1 and Ar 2 are identical or different and are independently a mono or polycyclic C 5 -C 12 aryl or mono or polycyclic C 3 -C 12 heteroaryl group, optionally substituted with:
one to three substituents independently selected from the group consisting of: a halogen atom, OH, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkoxy, nitro, cyano, formyl, amino-C 1 -C 10 alkoxy, (carboxylic acid)-C 1 -C 10 alkoxy, (carboxylic (C 1 -C 6 )alkyl ester)-C 1 -C 10 alkoxy, (1,2 diol)-C 2 -C 10 alkoxy, —O—(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl-OH, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl, C 2 -C 6 alkylcarbonyl, C 1 -C 6 alkylthio, C 1 -C 6 thioalkyl, (C 1 -C 6 )-alkylthio-(C 1 -C 6 )-alkyl, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkoxy alkyl, C 2 -C 6 haloalkylcarbonyl, C 1 -C 6 haloalkylthio, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 haloalkylsulfonyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkenyloxy, C 2 -C 6 haloalkynyloxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkenylthio, C 2 -C 6 alkynylthio, C 2 -C 6 haloalkenylthio, C 2 -C 6 haloalkynylthio, and a C 1 -C 6 alkoxy optionally substituted by a mono or polycyclic C 5 -C 12 aryl group,
a mono or polycyclic C 5 -C 12 aryl or mono or polycyclic C 3 -C 12 heteroaryl group optionally substituted with a halogen atom, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; and/or
a bridging group of formula —O—CH 2 —O— or —O—CH 2 CH 2 —O—;
Ar 3 is a mono or polycyclic C 5 -C 12 aryl group or mono or polycyclic C 3 -C 12 heteroaryl group, optionally substituted with substituents independently selected from the group consisting of:
halogen atoms, OH, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkoxy, cyano, formyl, nitro, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl, C 2 -C 6 alkylcarbonyl, C 1 -C 6 alkylthio, C 1 -C 6 thioalkyl, (C 1 -C 6 )-alkylthio-(C 1 -C 6 )-alkyl, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkoxy alkyl, C 2 -C 6 haloalkylcarbonyl, C 1 -C 6 haloalkylthio, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 haloalkylsulfonyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkenyloxy, C 2 -C 6 haloalkynyloxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkenylthio, C 2 -C 6 alkynylthio, C 2 -C 6 haloalkenylthio, C 2 -C 6 haloalkynylthio group, and a monocyclic C 5 -C 6 aryl group optionally substituted by a C 1 -C 6 alkyloxy group,
a mono or polycyclic C 5 -C 12 aryl or mono or polycyclic C 3 -C 12 heteroaryl group optionally substituted with a halogen atom, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; and/or
a bridging group of formula —O—CH 2 —O— or —O—CH 2 CH 2 —O—;
R 4 is present when the bond between the carbon 1 and the nitrogen atom is a single bond and is absent when the bond between the carbon 1 and the nitrogen atom is a double bond;
R 4a is present when the bond between the carbon 2 and the nitrogen atom is a single bond and is absent when the bond between the carbon 2 and the nitrogen atom is a double bond;
R 4a is a C 1 -C 6 alkyl group optionally substituted with substituents independently selected from the group consisting of: halogen atoms, hydroxyl (OH), oxo (═O), nitro, cyano, formyl, C 3 -C 7 cycloalkyl, C 1 -C 6 -alkoxy, amino, arylimido optionally substituted, C 1 -C 6 alkylamino, di(C 1 -C 6 )alkylamino, COOH, COO—(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, C 1 -C 6 thioalkyl, SH, S(C 1 -C 6 )alkyl, S(O)(C 1 -C 6 )alkyl, S(O 2 )(C 1 -C 6 )alkyl, and a mono or polycyclic C 5 -C 12 aryl group;
R 4 is a hydrogen atom or a C 1 -C 6 alkyl group optionally substituted with substituents independently selected from the group consisting of: halogen atoms, hydroxyl (OH), nitro, cyano, formyl, C 3 -C 7 cycloalkyl, C 1 -C 6 -alkoxy, amino, C 1 -C 6 alkylamino, di(C 1 -C 6 )alkylamino, COOH, COO—(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, C 1 -C 6 thioalkyl, SH, S(C 1 -C 6 )alkyl, S(O)(C 1 -C 6 )alkyl, S(O 2 )(C 1 -C 6 )alkyl, and a mono or polycyclic C 5 -C 12 aryl group;
R 6 is a hydrogen atom, a halogen atom, a cyano, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkoxy, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkoxy-(C 1 -C 6 )-alkyl, C 1 -C 10 thioalkyl, (C 1 -C 6 )-alkylthio-(C 1 -C 6 )-alkyl, C 1 -C 10 alkylsulfinyl, C 1 -C 10 haloalkylsulfinyl, C 1 -C 10 haloalkylsulfonyl, C 1 -C 10 alkylsulfonyl, C 5 -C 12 arylsulfonyl, formyl, C 2 -C 10 alkylcarbonyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 2 -C 10 alkenyloxy, C 2 -C 10 alkynyloxy, C 2 -C 10 alkenylthio, C 2 -C 10 alkynylthio, C 1 -C 10 haloalkyl, C 2 -C 10 haloalkenyl, C 2 -C 10 haloalkynyl, C 2 -C 10 haloalkylcarbonyl, C 1 -C 10 haloalkylthio, C 2 -C 10 haloalkenyloxy, C 2 -C 10 haloalkynyloxy, C 2 -C 10 haloalkenylthio, C 2 -C 10 haloalkynylthio, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl ester or a mono or polycyclic C 5 -C 12 aryl or mono or polycyclic C 3 -C 12 heteroaryl group, each group being optionally substituted with substituents independently selected from the group consisting of: halogen atoms, hydroxyl (OH), nitro, cyano, formyl, C 3 -C 7 cycloalkyl, C 1 -C 6 -alkoxy, amino, C 1 -C 6 alkylamino, di(C 1 -C 6 )alkylamino, COOH, COO—(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, C 1 -C 6 thioalkyl, SH, S(C 1 -C 6 )alkyl, S(O)(C 1 -C 6 )alkyl, S(O 2 )(C 1 -C 6 )alkyl, and a mono or polycyclic C 5 -C 12 aryl group,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein:
R 4 is present and is a hydrogen atom, or
R 4a is present and is a group of formula —C(═X)R 7 with X representing O or N—R 8 , R 7 representing a C 1 -C 6 alkyl, and R 8 representing an aryl optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy.
3. The compound of claim 1 , wherein R 6 is a hydrogen atom, a halogen atom, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkoxy, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkoxy-(C 1 -C 6 )-alkyl, C 1 -C 10 thioalkyl, (C 1 -C 6 )-alkylthio-(C 1 -C 6 )-alkyl, C 1 -C 10 alkylsulfinyl, C 1 -C 10 haloalkylsulfinyl, C 1 -C 10 haloalkylsulfonyl, C 1 -C 10 alkylsulfonyl, C 5 -C 12 arylsulfonyl, formyl, C 2 -C 10 alkenyl, C 2 -C 10 alkenyloxy, C 2 -C 10 alkenylthio, C 1 -C 10 haloalkyl, C 2 -C 10 haloalkenyl, C 1 -C 10 haloalkylthio, C 2 -C 10 haloalkenyloxy, C 2 -C 10 haloalkenylthio, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl ester, a mono or polycyclic C 5 -C 12 aryl, or mono or polycyclic C 3 -C 12 heteroaryl group,
in which each C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkoxy, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkoxy-(C 1 -C 6 )-alkyl, C 1 -C 10 thioalkyl, (C 1 -C 6 )-alkylthio-(C 1 -C 6 )-alkyl, C 1 -C 10 alkylsulfinyl, C 1 -C 10 haloalkylsulfinyl, C 1 -C 10 haloalkylsulfonyl, C 1 -C 10 alkylsulfonyl, C 5 -C 12 arylsulfonyl, formyl, C 2 -C 10 alkenyl, C 2 -C 10 alkenyloxy, C 2 -C 10 alkenylthio, C 1 -C 10 haloalkyl, C 2 -C 10 haloalkenyl, C 1 -C 10 haloalkylthio, C 2 -C 10 haloalkenyloxy, C 2 -C 10 haloalkenylthio, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl ester, a mono or polycyclic C 5 -C 12 aryl, or mono or polycyclic C 3 -C 12 heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of: halogen atoms, hydroxyl (OH), C 1 -C 6 -alkoxy, amino, C 1 -C 6 _alkylamino, di(C 1 -C 6 )alkylamino, COOH, COO—(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, C 1 -C 6 thioalkyl, SH, S(O)(C 1 -C 6 )alkyl, S(O 2 )(C 1 -C 6 )alkyl, and a mono C 5 -C 6 aryl group.
4. The compound of claim 3 , wherein R 6 is a hydrogen atom.
5. The compound of claim 1 , wherein Ar 1 and Ar 2 are independently a mono or polycyclic C 5 -C 12 aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of OH, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkoxy, (1,2 diol)-C 2 -C 10 alkoxy, —O—(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl-OH, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkoxy alkyl, a C 1 -C 6 alkoxy optionally substituted by a mono or polycyclic C 5 -C 12 aryl group, and a bridging group of formula —O—CH 2 —O— or —O—CH 2 CH 2 —O—.
6. The compound of claim 1 , wherein Ar 3 is substituted with 1 to 3 substituents selected from the group consisting of halogen atoms, OH, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkoxy, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl, C 2 -C 6 alkylcarbonyl, C 1 -C 6 alkylthio, C 1 -C 6 thioalkyl, (C 1 -C 6 )-alkylthio-(C 1 -C 6 )-alkyl, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkoxyalkyl, C 2 -C 6 haloalkylcarbonyl, C 1 -C 6 haloalkylthio, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 haloalkylsulfonyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkenyloxy, C 2 -C 6 haloalkynyloxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkenylthio, C 2 -C 6 alkynylthio, C 2 -C 6 haloalkenylthio, C 2 -C 6 haloalkynylthio group, and a monocyclic C 5 -C 6 aryl group optionally substituted by a C 1 -C 6 alkyloxy group.
7. The compound of claim 1 , wherein
R 4 is present and is a hydrogen atom or R 4a is present and is a group of formula —C(═X)R 7 with X representing O or N—R 8 , R 7 representing a C 1 -C 6 alkyl, and R 8 representing an aryl optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy;
R 6 is a hydrogen atom; and
Ar 1 , Ar 2 and Ar 3 are independently a mono or polycyclic C 5 -C 12 aryl, optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, and a bridging group of formula —O—CH 2 —O— or —O—CH 2 CH 2 —O—, or selected from the group consisting of a halogen atom, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
8. The compound of claim 1 , wherein the compound is a compound of formula (Ia):
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , wherein the compound is selected from the group consisting of:
and the pharmaceutically acceptable salts thereof.
11. A method for preparing a compound of formula (I) according to claim 1 , comprising:
a) adding a compound of formula (II):
where
LG represents a leaving group;
Ar 3 is a mono or polycyclic C 5 -C 12 aryl group or mono or polycyclic C 3 -C 12 heteroaryl group, optionally substituted with substituents independently selected from the group consisting of:
halogen atoms, OH, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkoxy, cyano, formyl, nitro, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl, C 2 -C 6 alkylcarbonyl, C 1 -C 6 alkylthio, C 1 -C 6 thioalkyl, (C 1 -C 6 )-alkylthio-(C 1 -C 6 )-alkyl, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkoxy alkyl, C 2 -C 6 haloalkylcarbonyl, C 1 -C 6 haloalkylthio, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 haloalkylsulfonyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkenyloxy, C 2 -C 6 haloalkynyloxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkenylthio, C 2 -C 6 alkynylthio, C 2 -C 6 haloalkenylthio, C 2 -C 6 haloalkynylthio group, and/or a monocyclic C 5 -C 6 aryl group optionally substituted by a C 1 -C 6 alkyloxy group,
a mono or polycyclic C 5 -C 12 aryl or mono or polycyclic C 3 -C 12 heteroaryl group optionally substituted with a halogen atom, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; and/or
a bridging group of formula —O—CH 2 —O— or —O—CH 2 CH 2 —O—;
R 6 is a hydrogen atom, a halogen atom, a cyano, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkoxy, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkoxy-(C 1 -C 6 )-alkyl, C 1 -C 10 thioalkyl, (C 1 -C 6 )-alkylthio-(C 1 -C 6 )-alkyl, C 1 -C 10 alkylsulfinyl, C 1 -C 10 haloalkylsulfinyl, C 1 -C 10 haloalkylsulfonyl, C 1 -C 10 alkylsulfonyl, C 5 -C 12 arylsulfonyl, formyl, C 2 -C 10 alkylcarbonyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 2 -C 10 alkenyloxy, C 2 -C 10 alkynyloxy, C 2 -C 10 alkenylthio, C 2 -C 10 alkynylthio, C 1 -C 10 haloalkyl, C 2 -C 10 haloalkenyl, C 2 -C 10 haloalkynyl, C 2 -C 10 haloalkylcarbonyl, C 1 -C 10 haloalkylthio, C 2 -C 10 haloalkenyloxy, C 2 -C 10 haloalkynyloxy, C 2 -C 10 haloalkenylthio, C 2 -C 10 haloalkynylthio, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl ester or a mono or polycyclic C 5 -C 12 aryl or mono or polycyclic C 3 -C 12 heteroaryl group, each group being optionally substituted with substituents independently selected from the group consisting of: halogen atoms, hydroxyl (OH), nitro, cyano, formyl, C 3 -C 7 cycloalkyl, C 1 -C 6 -alkoxy, amino, C 1 -C 6 alkylamino, di(C 1 -C 6 )alkylamino, COOH, COO—(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, C 1 -C 6 thioalkyl, SH, S(C 1 -C 6 )alkyl, S(O)(C 1 -C 6 )alkyl, S(O 2 )(C 1 -C 6 )alkyl, a mono or polycyclic C 5 -C 12 aryl group, to a compound of formula (III):
where
Ar 1 and Ar 2 are identical or different and are independently a mono or polycyclic C 5 -C 12 aryl or mono or polycyclic C 3 -C 12 heteroaryl group, optionally substituted with:
one to three substituents independently selected from the group consisting of: a halogen atom, OH, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkoxy, nitro, cyano, formyl, amino-C 1 -C 10 alkoxy, (carboxylic acid)-C 1 -C 10 alkoxy, (carboxylic (C 1 -C 6 )alkyl ester)-C 1 -C 10 alkoxy, (1,2 diol)-C 2 -C 10 alkoxy, —O—(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl-OH, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl, C 2 -C 6 alkylcarbonyl, C 1 -C 6 alkylthio, C 1 -C 6 thioalkyl, (C 1 -C 6 )-alkylthio-(C 1 -C 6 )-alkyl, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkoxy alkyl, C 2 -C 6 haloalkylcarbonyl, C 1 -C 6 haloalkylthio, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 haloalkylsulfonyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkenyloxy, C 2 -C 6 haloalkynyloxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkenylthio, C 2 -C 6 alkynylthio, C 2 -C 6 haloalkenylthio, C 2 -C 6 haloalkynylthio and/or a C 1 -C 6 alkoxy optionally substituted by a mono or polycyclic C 5 -C 12 aryl group,
a mono or polycyclic C 5 -C 12 aryl or mono or polycyclic C 3 -C 12 heteroaryl group optionally substituted with a halogen atom, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; and/or
a bridging group of formula —O—CH 2 —O— or —O—CH 2 CH 2 —O—;
R 4 is present when the bond between the carbon 1 and the nitrogen atom in the compound of formula (I) is a single bond and is absent when the bond between the carbon 1 and the nitrogen atom in the compound of formula (I) is a double bond;
R 4a is present when the bond between the carbon 2 and the nitrogen atom in the compound of formula (I) is a single bond and is absent when the bond between the carbon 2 and the nitrogen atom in the compound of formula (I) is a double bond;
R 4a is a C 1 -C 6 alkyl group optionally substituted with substituents independently selected from the group consisting of: halogen atoms, hydroxyl (OH), oxo (═O), nitro, cyano, formyl, C 3 -C 7 cycloalkyl, C 1 -C 6 -alkoxy, amino, arylimido optionally substituted, C 1 -C 6 alkylamino, di(C 1 -C 6 )alkylamino, COOH, COO—(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, C 1 -C 6 thioalkyl, SH, S(C 1 -C 6 )alkyl, S(O)(C 1 -C 6 )alkyl, S(O 2 )(C 1 -C 6 )alkyl, a mono or polycyclic C 5 -C 12 aryl group;
R 4 is a hydrogen atom or a C 1 -C 6 alkyl group optionally substituted with substituents independently selected from the group consisting of: halogen atoms, hydroxyl (OH), nitro, cyano, formyl, C 3 -C 7 cycloalkyl, C 1 -C 6 -alkoxy, amino, C 1 -C 6 alkylamino, di(C 1 -C 6 )alkylamino, COOH, COO—(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, C 1 -C 6 thioalkyl, SH, S(C 1 -C 6 )alkyl, S(O)(C 1 -C 6 )alkyl, S(O 2 )(C 1 -C 6 )alkyl, a mono or polycyclic C 5 -C 12 aryl group;
in the presence of a base B1 selected from the group consisting of hydroxide salts, C1-C6 alkoxide salts, and phenoxide salts,
wherein optionally (a) is carried out under pressure and/or at a temperature above 50° C.; and
b) isolating the compound of formula (I).
12. A conjugate of a compound of formula (I) or (I′) with an antibiotic through a linker, represented by formula (IV):
Inhibitor-Linker-Antibio (IV)
wherein Inhibitor is a compound of formula (I) as defined in claim 1 , or a compound of formula (I′)
wherein
represents a single or double bond, with the proviso that one of the two bonds
is a single bond and the other is a double bond;
R 1 , R 2 , and R 3 are identical or different, and are independently one from each other a hydrogen, halogen, nitro, cyano, formyl, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 3- to 8-membered heterocycle, C 1 -C 10 alkoxy, C 2 -C 10 alkylcarbonyl, a C 6 -C 13 arylcarbonyl, a C 4 -C 13 heteroaryl carbonyl, C 1 -C 10 haloalkoxy, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkoxy-(C 1 -C 6 )-alkyl, C 1 -C 10 thioalkyl, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl ester, (C 1 -C 6 )-alkylthio-(C 1 -C 6 )-alkyl, C 1 -C 10 alkylsulfinyl, C 1 -C 10 haloalkylsulfinyl, C 1 -C 10 haloalkylsulfonyl, C 1 -C 10 alkylsulfonyl, C 5 -C 12 arylsulfonyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 2 -C 10 alkenyloxy, C 2 -C 10 alkynyloxy, C 2 -C 10 alkenylthio, C 2 -C 10 alkynylthio, C 1 -C 10 haloalkyl, C 2 -C 10 haloalkenyl, C 2 -C 10 haloalkynyl, C 2 -C 10 haloalkylcarbonyl, C 1 -C 10 haloalkylthio, C 2 -C 10 haloalkenyloxy, C 2 -C 10 haloalkynyloxy, C 2 -C 10 haloalkenylthio, C 2 -C 10 haloalkynylthio, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl, a (C 1 -C 6 )alkyl-(C 5 -C 12 )aryl, a (C 1 -C 6 )alkyl-(C 5 -C 12 )heteroaryl, a mono or polycyclic C 5 -C 12 aryl or mono or polycyclic C 3 -C 12 heteroaryl fragments, wherein the C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 3- to 8-membered heterocycle, C 1 -C 10 alkoxy, C 2 -C 10 alkylcarbonyl, a C 6 -C 13 arylcarbonyl, a C 4 -C 13 heteroaryl carbonyl, C 1 -C 10 haloalkoxy, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkoxy-(C 1 -C 6 )-alkyl, C 1 -C 10 thioalkyl, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl ester, (C 1 -C 6 )-alkylthio-(C 1 -C 6 )-alkyl, C 1 -C 10 alkylsulfinyl, C 1 -C 10 haloalkylsulfinyl, C 1 -C 10 haloalkylsulfonyl, C 1 -C 10 alkylsulfonyl, C 5 -C 12 arylsulfonyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 2 -C 10 alkenyloxy, C 2 -C 10 alkynyloxy, C 2 -C 10 alkenylthio, C 2 -C 10 alkynylthio, C 1 -C 10 haloalkyl, C 2 -C 10 haloalkenyl, C 2 -C 10 haloalkynyl, C 2 -C 10 haloalkylcarbonyl, C 1 -C 10 haloalkylthio, C 2 -C 10 haloalkenyloxy, C 2 -C 10 haloalkynyloxy, C 2 -C 10 haloalkenylthio, C 2 -C 10 haloalkynylthio, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl, a (C 1 -C 6 )alkyl-(C 5 -C 12 )aryl, a (C 1 -C 6 )alkyl-(C 5 -C 12 )heteroaryl, a mono or polycyclic C 5 -C 12 aryl or mono or polycyclic C 3 -C 12 heteroaryl fragment is optionally substituted with:
one or several (1 to 3) halogen atoms, hydroxyl (OH), nitro, cyano, formyl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, 3- to 8-membered heterocycle, amino-C 1 -C 10 alkoxy, (carboxylic acid)-C 1 -C 10 alkoxy, (carboxylic (C 1 -C 6 )alkyl ester)-C 1 -C 10 alkoxy, (1,2 diol)-C 2 -C 10 alkoxy, —O—(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl-OH, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl, C 2 -C 6 alkylcarbonyl, C 1 -C 6 alkylthio, C 1 -C 6 thioalkyl, (C 1 -C 6 )-alkylthio-(C 1 -C 6 )-alkyl, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkoxy alkyl, C 2 -C 6 haloalkylcarbonyl, C 1 -C 6 haloalkylthio, C 1 -C 6 haloalkylsulfinyl, C 1 -C 6 haloalkylsulfonyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkenyloxy, C 2 -C 6 haloalkynyloxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkenylthio, C 2 -C 6 alkynylthio, C 2 -C 6 haloalkenylthio, C 2 -C 6 haloalkynylthio and/or a C 1 -C 6 alkoxy optionally substituted by a mono or polycyclic C 5 -C 12 aryl group,
a mono or polycyclic C 5 -C 12 aryl or mono or polycyclic C 3 -C 12 heteroaryl group optionally substituted with a halogen atom, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; and/or
a bridging group of formula —O—CH 2 —O— or —O—CH 2 CH 2 —O—, said bridging group being useable when the fragment contains an aryl or heteroaryl moiety, or when the fragment is a C 6 -C 13 arylcarbonyl, a C 4 -C 13 heteroaryl carbonyl, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl ester, C 5 -C 12 arylsulfonyl, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl, a (C 1 -C 6 )alkyl-(C 5 -C 12 )aryl, a (C 1 -C 6 )alkyl-(C 5 -C 12 )heteroaryl, a mono or polycyclic C 5 -C 12 aryl or mono or polycyclic C 3 -C 12 heteroaryl fragment;
R 4 is present when the bond between the carbon 1 and the nitrogen atom is a single bond and is absent when the bond between the carbon 1 and the nitrogen atom is a double bond;
R 4a is present when the bond between the carbon 2 and the nitrogen atom is a single bond and is absent when the bond between the carbon 2 and the nitrogen atom is a double bond;
R 4 is a hydrogen atom or a C 1 -C 6 alkyl group optionally substituted with substituents independently selected from the group consisting of: halogen atoms, hydroxyl (OH), nitro, cyano, formyl, C 3 -C 7 cycloalkyl, 3- to 8-membered heterocycle, C 1 -C 6 -alkoxy, amino, C 1 -C 6 alkylamino, di(C 1 -C 6 )alkylamino, COOH, COO—(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, C 1 -C 6 thioalkyl, SH, S(C 1 -C 6 )alkyl, S(O)(C 1 -C 6 )alkyl, S(O 2 )(C 1 -C 6 )alkyl, and a mono or polycyclic C 5 -C 12 aryl group;
R 4a is a C 1 -C 6 alkyl group optionally substituted with substituents independently selected from the group consisting of: halogen atoms, hydroxyl (OH), oxo (═O), nitro, cyano, formyl, C 3 -C 7 cycloalkyl, C 1 -C 6 -alkoxy, amino, arylimido optionally substituted, C 1 -C 6 alkylamino, di(C 1 -C 6 )alkylamino, COOH, COO—(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, C 1 -C 6 thioalkyl, SH, S(C 1 -C 6 )alkyl, S(O)(C 1 -C 6 )alkyl, S(O 2 )(C 1 -C 6 )alkyl, and a mono or polycyclic C 5 -C 12 aryl group;
R 5 is a hydrogen atom, a halogen atom, a cyano, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 3-to 8-membered heterocycle, C 1 -C 10 alkoxy, C 1 -C 10 haloalkoxy, (C 1 -C 6 )-alkoxy-(C 1 -C 6 )-alkyl, (C 1 -C 6 )-haloalkoxy-(C 1 -C 6 )-alkyl, C 1 -C 10 thioalkyl, (C 1 -C 6 )-alkylthio-(C 1 -C 6 )-alkyl, C 1 -C 10 alkylsulfinyl, C 1 -C 10 haloalkylsulfinyl, C 1 -C 10 haloalkylsulfonyl, C 1 -C 10 alkylsulfonyl, C 5 -C 12 arylsulfonyl, formyl, C 2 -C 10 alkylcarbonyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 2 -C 10 alkenyloxy, C 2 -C 10 alkynyloxy, C 2 -C 10 alkenylthio, C 2 -C 10 alkynylthio, C 1 -C 10 haloalkyl, C 2 -C 10 haloalkenyl, C 2 -C 10 haloalkynyl, C 2 -C 10 haloalkylcarbonyl, C 1 -C 10 haloalkylthio, C 2 -C 10 haloalkenyloxy, C 2 -C 10 haloalkynyloxy, C 2 -C 10 haloalkenylthio, C 2 -C 10 haloalkynylthio, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl, (C 5 -C 12 )-aryl-(C 1 -C 6 )-alkyl ester, a (C 1 -C 6 )alkyl-(C 5 -C 12 )aryl, a (C 1 -C 6 )alkyl-(C 5 -C 12 )heteroaryl, a C 5 -C 12 aryl or a C 3 -C 12 heteroaryl group, each group being optionally substituted with substituents independently selected from the group consisting of: halogen atoms, hydroxyl (OH), nitro, cyano, formyl, C 3 -C 7 cycloalkyl, C 1 -C 6 -alkoxy, amino, C 1 -C 6 alkylamino, di(C 1 -C 6 )alkylamino, COOH, COO—(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, C 1 -C 6 thioalkyl, SH, S(C 1 -C 6 )alkyl, S(O)(C 1 -C 6 )alkyl, S(O 2 )(C 1 -C 6 )alkyl, and a mono or polycyclic C 5 -C 12 aryl group;
Linker is a covalent linking group or a bond; and
Antibio is an antibiotic.
13. The compound as defined in claim 1 wherein said compound is an inhibitor of a carbapenemase enzyme.
14. The compound according to claim 13 , wherein said compound is in combination with an antibiotic.
15. A pharmaceutical composition comprising at least one compound of formula (I) as defined in claim 1 and a pharmaceutically acceptable carrier.
16. The pharmaceutical composition of claim 15 , further comprising an antibiotic.
17. A drug comprising a compound of formula (I) as defined in claim 1 .
18. The drug according to claim 17 , wherein the drug is an antibiotic.
19. The compound according to claim 14 , wherein the antibiotic is a specific antibiotic for gram-negative bacteria.
20. A kit comprising:
at least one first container containing a first therapeutically active compound of formula (I) as defined in claim 1 , and
at least one second container containing a second therapeutically active substance which is an antibiotic,
as a combination product for simultaneous, sequential, or separate use.
21. The compound according to claim 13 , wherein the carbapenemase enzyme is selected from the group consisting of class A enzyme, a class B enzyme, and a class D enzyme.
22. The compound according to claim 13 wherein the carbapenemase enzyme is selected from the group consisting of a NDM-1 type enzyme, OXA-48 type enzyme, and a KPC-type enzyme.
23. A kit comprising:
at least one first container containing a first therapeutically active compound of at least a compound of formula (I′) or at least one conjugate of formula (IV) as defined in claim 12 , and
at least one second container containing a second therapeutically active substance which is an antibiotic,
as a combination product for simultaneous, sequential, or separate use.