Acrylamide derivatives as antimalarial agents

摘要

The invention relates to novel acrylamide derivatives of the formula I;wherein R1, R2, R3, X, and ring A are as defined in the description, and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including pharmaceutical compositions containing those compounds and their use as medicaments for the treatment or prevention of protozoal infections, such as especially malaria.

主权项

1. A compound of the formula I: wherein ring A is a phenylene or pyridin-diyl ring, wherein the group —X—R3 is attached to ring A in meta- or para-position with respect to the point of attachment of ring A to the —CH2— group; R1 represents phenyl, or 5- or 6-membered heteroaryl; wherein said phenyl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from (C1-5)alkyl, (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and (C1-3)alkyl-SO2—;
X represents —NR4— wherein R4 represents hydrogen or (C1-3)alkyl; —O—; or —(CO)—; andR3 represents
piperidin-4-yl which is optionally substituted on the nitrogen with (C1-4)alkyl;5- or 6-membered heteroaryl wherein said heteroaryl independently is unsubstituted, or mono-, or di-substituted wherein the substituents are independently selected from (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy;8- to 10-membered heteroaryl wherein said heteroaryl independently is unsubstituted, or mono-, or di-substituted wherein the substituents are independently selected from (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy;unsubstituted phenyl; or4-hydroxy-3-(diethylamino-methyl)-phenyl; or X represents a direct bond and
R3 represents
4-[(C1-4)alkyl]-piperazin-1-yl or pyrrolidine-1-yl; or5- or 6-membered heteroaryl, wherein said heteroaryl independently is unsubstituted, or mono-substituted with (C1-4)alkyl;or X represents —O— and R3 represents —(C2-4)alkylene-NR10R11, wherein R10 and R11 independently represent (C1-3)alkyl; and R2 represents
—(C2-4)alkylene-NR12R13, wherein R12 and R13 independently represent (C1-3)alkyl, or R12 and R13 together with the nitrogen atom to which they are attached to form a morpholine ring; or(C3-7)cycloalkyl which is mono-substituted with NR14R15, wherein R14 and R15 independently represent (C1-3)alkyl, or R14 and R15 together with the nitrogen atom to which they are attached to form a pyrrolidine ring; or—(C0-2)alkylene-heterocyclyl, wherein said heterocyclyl is a 4- to 7-membered saturated monocyclic or 7- to 11-membered saturated bicyclic carbocyclic ring containing one ring nitrogen atom; wherein said heterocyclyl may carry one optional substituent attached to a ring carbon atom wherein said substituent is selected from hydroxy and fluoro; and wherein said heterocyclyl is unsubstituted or substituted on said ring nitrogen atom with a substituent selected from:
(C1-6)alkyl,(C2-3)fluoroalkyl;—(C2-4)alkylene-(C1-4)alkoxy;—(C2-4)alkylene-NR16R17, wherein R16 and R17 independently represent (C1-3)alkyl;(C3-7)cycloalkyl;—(C1-3)alkylene-(C3-7)cycloalkyl;bicyclo [2.2.1]hept-5-en-2-ylmethyl;piperidin-4-yl, wherein said piperidin group is substituted at the nitrogen atom with (C1-4)alkyl;2,2-diphenylethyl;3-diethylaminomethyl-4-hydroxy-benzyl;—(C1-3)alkylene-phenyl wherein the phenyl group is optionally mono- or di-substituted wherein the substituents are independently selected from (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy; and—(C1-3)alkylene-heteroaryl, wherein the heteroaryl is a 5- to 10-membered heteroaryl, which is optionally mono- or di-substituted wherein the substituents are independently selected from (C1-4)alkyl, (C1-4)alkoxy, halogen, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, phenyl, and —(CO)—(C1-4)alkyl; with the exception of: N-[3-(4-morpholinyl)-propyl]-N-[(3-phenoxyphenyl)-methyl]-3-phenyl-2-propenamide; and N-[2-(4-morpholinyl)-ethyl]-N-[(3-phenoxyphenyl)-methyl]-3-phenyl-2-propenamide; or a pharmaceutically acceptable salt of such a compound.