Methods and compounds for treatment of clostridium based infection
Methionyl tRNA synthetase inhibitors (MetRS) are provided for use in therapy as antibacterial agents in Clostridium based infection.
1. A method of treating a Clostridium difficile based infection in a mammal comprising administering to the mammal an effective amount of a MetRS inhibitor compound represented by a compound of formula (IIa):
in which:
X is selected from the group consisting of NH, O, S, SO, SO 2 , or CH 2 ;
n is 1, 2 or 3;
* indicates an asymmetric carbon atom, wherein when n is 2 or 3, then * is R configuration; wherein when n is 1 and X is CH 2 , then * is R configuration; and wherein when n is 1 and X is selected from the group consisting of NH, O, S, SO, or SO 2 , then * is S configuration;
m is 0, 1, 2, 3, or 4;
R 1 is independently selected from halo, cyano, hydroxyl, (C 1-6 )alkyl (optionally substituted by halo, hydroxyl, amino, carboxy, or (C 1-6 )alkoxycarbonyl), (C 3-7 )cycloalkyl, C( 1-6 )alkoxy, amino, mono- or di-(C 1-6 )alkylamino, acylamino, carboxy, (C 1-6 )alkoxycarbonyl, carboxy(C 1-6 )alkyloxy, (C 1-6 )alkylthio, (C 1-6 )alkylsulphinyl, (C 1-6 )alkylsulphonyl, sulphamoyl, mono- and di-(C 1-6 )alkylsulphamoyl, carbamoyl, mono- and di-(C 1-6 )alkylcarbamoyl and heterocyclic;
R 2 is independently selected from halo, cyano, hydroxyl, (C 1-6 )alkyl (optionally substituted by halo, hydroxyl, amino, carboxy, or (C 1-6 )alkoxycarbonyl), (C 3-7 )cycloalkyl, C( 1-6 )alkoxy, amino, mono- or di-(C 1-6 )alkylamino, acylamino, carboxy, (C 1-6 )alkoxycarbonyl, carboxy(C 1-6 )alkyloxy, (C 1-6 )alkylthio, (C 1-6 )alkylsulphinyl, (C 1-6 )alkylsulphonyl, sulphamoyl, mono- and di-(C 1-6 )alkylsulphamoyl, carbamoyl, mono- and di-(C 1-6 )alkylcarbamoyl and heterocyclic; and
when Z 1 is S, Z 2 and Z 3 are CH; when Z 2 is S, Z 1 and Z 3 are CH; and when Z 3 is S, Z 1 and Z 2 are CH.
2. The method of claim 1 wherein the MetRS inhibitor is selected from the group consisting of:
5-[3-((R)(−)-5,7-Dibromo-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-propylamino]-4H-thieno[3,2-b]pyridine-7-one;
5-[3-((R)(+)-8-Bromo-6-chloro-chroman-4-ylamino)-propylamino]-4H-thieno[3,2-b]pyridine-7-one;
5-[3-((R)(+)-6,8-Dibromo-1,2,3,4-tetrahydro-quinolin-4-ylamino)-propylamino]-4H-thieno[3,2-b]pyridine-7-one;
5-[3-((R)(+)-6,8-Dibromo-chroman-4-ylamino)-propylamino]-4H-thieno[3,2-b]pyridine-7-one;
and
5-[3-((S)-5,7-Dibromo-2,3-dihydro-benzofuran-3ylamino)-propylamino]-4H-thieno[3,2-b]pyridine-7-one.