| 摘要 |
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. |
