2- or 3-imidazolines as carbapenemases inhibitors

Patent metadata

Field	Value
Publication number	US-11285133-B2
Application number	US-201816492502-A
Country	US
Kind code	B2
Filing date	Mar 8, 2018
Priority date	Mar 9, 2017
Publication date	Mar 29, 2022
Grant date	Mar 29, 2022

Abstract

The present application relates to novel 3-imidazolines of formula (I′) and (I) below: (I′) (I) Wherein Ar1, Ar2, Ar3, and R1 to R6 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.

First claim

The invention claimed is:

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

Assignees

• Centre Nat Rech Scient
• Univ Paris Sud
• Assist Publique—Hopitaux De Paris

Inventors

• Cariou Kevin
• Dodd Robert
• Romero Eugénie
• Benchekroun Mohamed
• Iorga Bogdan
• Naas Thierry
• Oueslati Saoussen

Classifications

• C07D233/20 Primary

  with substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C07D233/22

  Radicals substituted by oxygen atoms · CPC title

• A61K47/552

  one of the codrug's components being an antibiotic · CPC title

• A61K31/4164 Primary

  1,3-Diazoles · CPC title