Quaternary bis-ammonium salt precursors and their uses as prodrugs having an antiparasitic activity

Abstract

The invention concerns drug precursors with antimalarial effect, characterised in that it consists in quaternary bis-ammonium salts of general formula (I) wherein A and A', identical or different, are respectively either a group A1 and A′1 of formula (1) wherein n=2 to 4; R′1 is hydrogen, C1-C5 alkyl, optionally substituted by an aryl, a hydroxy, an alkoxy, wherein the alkyl comprises 1 to 5 C, or aryloxy and W is halogen or a nucleofuge group; or a group A2 which represents formyl-CHO, or acetyl-COCH3. B and B′, identical or different, represent respectively either the group B1 and B′1, if A and A′ respectively represent A1, A′1, B1, B′1 representing a group R1 which has the same definition as R′1 above, but cannot be a hydrogen atom; or respectively the groups B2 and B′2, if A and A′ represent A2, B2 or B′2 being the group R1 as defined above, or a group of formula (2) wherein —Ra is RS— or RCO—, wherein R is a C1-C6 alkyl, substituted if required, a phenyl or benzyl, wherein the phenyl is substituted if required, the latter being optionally substituted; R2 is hydrogen, C1-C5 alkyl, or a —CH2-COO— (C1-C5)alkyl group; and R3 is hydrogen, C1-C5 alkyl or alkenyl, substituted if required, a phosphate, an alkoxy wherein the alkyl is a C1-C3 alkyl, or aryloxy; or an alkyl (or arylcarbonyloxy; or R2 and R3 form together a cycle with 5 or 6 C; R and R3 can be bound to form a cycle. ± represents: either a single bond when A and A′ represent A1 and A′1: or when A and A′ represent A2, and B2 and B′2 Represent (3) either, when A and A′ are —CHO or —COCH3 and B2 and B′2 are R1, a group of formula (4) or a group of formula (5) wherein (a) represents a bond towards Z and (b) a bond towards the nitrogen atom. Z is a C9-C21 alkyl, if required with insertion of one or several bonds, and/or one or several heteroatoms O and/or S and/or several aromatic cycles, and the pharmaceutically acceptable salts of said compounds. Said precursors and cyclized thiazolium derivatives are useful as antiparasitic medicines in particular antimalarial and antibabesiosis.