Quaternary bis-ammonium salt precursors and their uses as prodrugs having an antiparasitic activity
申请人:Vial Henri
公开号:US06972343B1
公开(公告)日:2005-12-06
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.
该发明涉及具有抗疟疾作用的药物前体,其特征在于它由通式(I)的季铵双盐组成,其中A和A′,相同或不同,分别是通式(1)的A1和A′1基团,其中n=2至4;R′1是氢,C1-C5烷基,可选地被芳基、羟基、烷氧基(其中烷基包括1至5个碳)、芳氧基取代,W是卤素或亲核离去基;或者是代表甲酰基-CHO或乙酰基-COCH3的A2基团。B和B′,相同或不同,分别代表A和A′分别表示A1、A′1、B1、B′1的情况下的B1和B′1基团,其中B1、B′1代表与上述R′1相同定义的R1基团,但不能是氢原子;或者分别代表A和A′表示A2的情况下的B2和B′2基团,其中B2或B′2是如上定义的R1基团,或者是通式(2)的基团,其中-Ra是RS-或RCO-,其中R是C1-C6烷基,必要时取代,苯基或苄基,其中苯基在必要时取代,后者是可选地取代的;R2是氢、C1-C5烷基,或者是—CH2-COO-(C1-C5)烷基;R3是氢、C1-C5烷基或烯烃基,必要时取代,磷酸酯、烷氧基(其中烷基是C1-C3烷基)或芳氧基;或者是烷基(或芳基羰基氧基;或者R2和R3共同形成一个含有5或6个碳的环;R和R3可以结合形成一个环。±表示:当A和A′表示A1和A′1时,是单键;或者当A和A′表示A2,B2和B′2表示(3)时,当A和A′为—CHO或—COCH3,B2和B′2为R1时,是通式(4)的基团或通式(5)的基团,其中(a)表示朝向Z的键,(b)表示朝向氮原子的键。Z是C9-C21烷基,必要时插入一个或多个键,和/或一个或多个杂原子O和/或S,和/或几个芳香环,以及所述化合物的药学上可接受的盐。所述前体和环化噻唑衍生物作为抗寄生虫药物,特别是抗疟疾和抗巴贝斯病的药物是有用的。