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New racemic or achiral dual molecules comprising cyclic peroxide linked to antimalarially active and/or bioavailability improving residue, useful as broad-spectrum antimalarial agents
New racemic or achiral dual molecules comprising cyclic peroxide linked to antimalarially active and/or bioavailability improving residue, useful as broad-spectrum antimalarial agents
New racemic or achiral dual molecules (I) consist of coupling products of (a) a cyclic peroxide having a spiro-bonded azacyclic ring and (b) a molecule with antimalarial activity and/or a residue for improving bioavailability, (a) and (b) being linked by a coupling arm bonded to the N-atom of (a). New racemic or achiral dual molecules consist of coupling products of formula (I) or their acid addition salts. Corresponding molecules in the form of pure optical isomers or their mixtures in all proportions are also claimed. [Image] A : residue of a molecule with antimalarial activity and/or a residue for improving bioavailability, the latter comprising one or more N, O or S heteroatoms in a 6-18C saturated or unsaturated cyclic moiety or in an optionally substituted (os) 1-18C linear chain; p, p', p'' : 0 or 1, provided that at least one of p and p'' is 1; Y 1, Y 21-5C alkylene, optionally containing one or more amine, amide, sulfonamide, carboxy, thiocarboxy, carbonyl, ether, thioether or thiocarbonyl radicals and os by 1-5C alkyl; U : amine, amide, thioamide, sulfonyl, carbonyl, thiocarbonyl, carboxy, thiocarboxy, ether, thioether or sulfonate function; Z 1, Z 2linear, branched or cyclic, saturated or unsaturated 1-4C alkylene, one of Z 1 and Z 2 optionally being absent; Z 1 + Z 2polycyclic structure including N and the junction carbon C j; R 1, R 2H or water-solubilizing group (specifically COOH, OH or NR aR b); R a, R bH or 1-5C linear, branched or cyclic alkyl; R x + R ygroup completing a 4-8 membered cyclic peroxide containing 1 or 2 additional O atoms in the ring structure and including C j in the ring structure, the ring being substituted by 1-4 groups R 3; R 3H, halo, OH, CF 3, NO 2, aryl, heteroaryl, Q, OQ or 3-18C mono-, bi- or tricyclic structure (optionally containing one or more O, N or S heteroatoms and os by Q), provided that at least one R 3 group other than H is present; or two adjacent R 3 groups together for a 5- or 6-membered saturated or unsaturated cyclic structure, os by one or more groups R 3 as defined above; Q : 1-5C linear, branched or cyclic alkyl. An independent claim is included for the preparation of (I). ACTIVITY : Antimalarial. Racemic 7-chloro-N-(2-(6-isopropyl-8a-methyl-4a,7,8,8a-tetrahydro-1'H-spiro-(1,2,4-benzotrioxin-3,4'-piperidine)-1'-yl)-ethyl)-quinoline-4-amine (Ia) (designated 'PA 1010') had IC 5 0 less than 0.1 MicroM against Plasmodium falciparum strains FcB1-Columbia (moderately resistant to chloroquine) and FcM29-Cameroon (highly resistant to chloroquine), cultured in vitro in media containing human erythrocytes. MECHANISM OF ACTION : Parasite heme and/or protein alkylating agent.
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机译：新的外消旋或非手性双分子（I）由（a）具有螺旋键合的氮杂环的环状过氧化物和（b）具有抗疟活性的分子和/或用于改善生物利用度的残基的偶联产物组成，（a）和（ b）通过与（a）的N原子键合的耦合臂连接。新的外消旋或非手性双分子由式（I）的偶合产物或其酸加成盐组成。也要求保护纯旋光异构体形式的相应分子或其所有比例的混合物。 [图像] A：具有抗疟疾活性的分子的残基和/或用于提高生物利用度的残基，后者在6-18C饱和或不饱和环状部分或任选取代的（os ）1-18C线性链; p，p'，p''：0或1，前提是p和p''中的至少一个为1; Y 1，Y 21-5C亚烷基，任选地含有一个或多个胺，酰胺，磺酰胺，羧基，硫代羧基，羰基，醚，硫醚或硫代羰基基团和在1-5C烷基上的os。 U：胺，酰胺，硫代酰胺，磺酰基，羰基，硫代羰基，羧基，硫代羧基，醚，硫醚或磺酸盐官能团; Z 1，Z 2直链，支链或环状，饱和或不饱和的1-4C亚烷基，Z 1和Z 2中的一个不存在。 Z 1 + Z 2包括N和连接碳C j的多环结构; R 1，R 2H或水溶性基团（特别是COOH，OH或NR aR b）; R a，R bH或1-5C直链，支链或环状烷基; R x + R y基团完成在环结构中含有1或2个额外的O原子并在环结构中包括C j的4-8元环过氧化物;该环被1-4个基团R 3取代; R 3H，卤素，OH，CF 3，NO 2，芳基，杂芳基，Q，OQ或3-18C单环，双环或三环结构（可选地包含一个或多个O，N或S杂原子和Q的os），前提是存在至少一个除H以外的R 3基团;或两个相邻的R 3基团一起形成5或6元饱和或不饱和环状结构，o为一个或多个如上定义的基团R 3; Q：1-5C直链，支链或环状烷基。包括独立权利要求用于制备（I）。活动：抗疟疾。外消旋7-氯-N-（2-（6-异丙基-8a-甲基-4a，7,8,8a-四氢-1'H-螺-（1,2,4-苯并三恶英-3,4'-哌啶）-1'-基）-乙基）-喹啉-4-胺（Ia）（命名为'PA 1010'）对恶性疟原虫菌株FcB1-Columbia（中度耐氯喹）和FcM29-的IC 5小于0.1 MicroM喀麦隆（对氯喹具有高度抗性），在含有人红细胞的培养基中体外培养。作用机理：寄生血红素和/或蛋白质烷基化剂。
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