Patent NZ-501315-A (NZ)
Title: Carbonyl-ethyl-carboxamidyl-alkane and carbonyl-ethyl-thiocarboxamidyl-alkane derivatives useful as antipicornaviral agents
Inventor: DRAGOVICH PETER S
IPC: C07D209/08
Filed: 1998-03-26
Abstract: A compound, a pharmaceutically acceptable prodrug, salt, active metabolite or solvate thereof has the formula (I) wherein: M is O or S; R1 is H, F, alkyl, OH, SH or O-alkyl; R2 and R5 are independently H, a group of formula 2a or formula 2b or alkyl provided that the alkyl is different from formula 2a or 2b further provided that at least one of R2 or R5 must be a group of formula 2a or 2b; R3 and R6 are independently H, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C(O)R17, -OR17, -SR17, -NR17R18, -NR19NR17R18 or -NR17OR18 or R3 and R6 together with the carbon atom to which they are attached form cycloalkyl or heterocycloalkyl; R7 is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR17, -SR17, -NR17R18, -NR19NR17R18 or -NR17OR18 or R7 together with R3 or R6 and the atoms to which they are attached forms heterocycloalkyl; Z and Z1 are independently H, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C(O)R21, -CO2R21, -CN, -C(O)NR21R22, -C(O)NR21OR22, -C(S)R21, -C(S)NR21R22, -NO2, -SOR21, -SO2R21, -SO2NR21R22, -SO(NR21)(OR22), -SONR21, -SO3R21, -PO(OR21)2, -PO(R21)(R22), -PO(NR21R22)(OR23), -PO(NR21R22)(NR23R24), -C(O)NR21NR22R23 or -C(S)NR21NR22R23 or Z1 together with R1 and the atoms to which Z1 and R1 are bonded form cycloalkyl or heterocycloalkyl or Z and Z1 together with the atoms to which they are bonded form cycloalkyl or heterocycloalkyl; in formula 2a: a) X is -CR2-, -CF2-, -CHF- or -S- and Y1 is -O-, -S-, -NR12-, -C(R13)(R14)-, -C(O)-, -C(S)- or -C(CR13R14)-; b) X is =CH or =CF and Y1 is =CH or =CF or c) X and Y1 together with Q' form a three- membered ring in which Q' is -C(R10)(R11)- or -O-,  X is -CH- or -CF- and Y1 is -CH-, -CF- or -C(alkyl)-; A1 is C, CH, CF, S, P, Se, N, NR15, S(O), Se(O), P-OR15 or P-NR15R16; D1 is a moiety with a lone pair of electrons capable of forming a hydrogen bond; B1 is H, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR17, -SR17, -NR17R18, -NR19NR17R18 or -NR17OR18 or together D1 - A1 - B1 optionally forms a nitro group where A1 is N provided that i) when D1 is the moiety ºN with a lone pair of electrons capable of forming a hydrogen bond, B1 does not exist; and ii) when A1 is an sp3 carbon, B1 is not -NR17R18 when D1 is the moiety -NR25R26 with a lone pair of electrons capable of forming a hydrogen bond; In formula 2b: d) X is -CR2-, -CF2-, -CHF- or -S- and Y2 is -O-, -S-, -NR'12-, -C(R'13)(R'14)-, -C(O)-, -C(S)-, or -C(CR'13R'14)-; e) X is =CH or =CF and Y2 is =CH or =CF or f) X and Y2 together with Q' form a three- membered ring wherein Q' is -C(R10)(R11)- or -O-,  X is -CH- or -CF- and Y2 is -CH-, -CF- or - C(alkyl); A2 is C, CH, CF, S, P, Se, N, NR15, S(O), Se(O), P-OR15 or P-NR15R16; D2 is a moiety with a lone pair of electrons capable of forming a hydrogen bond and B2 is H, F, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR17, -SR17, -NR17R18, -NR19NR17R18 or -NR17OR18 or any combination of Y2, A2, B2, and D2 optionally can form cycloalkyl, heterocycloalkyl, aryl or heteroaryl provided that when D2 is the moiety ºN with a lone pair of electrons capable of forming a hydrogen bond, B2 does not exist; R10 and R11 independently are H, halogen or alkyl or together with the carbon atom to which they are attached form cycloalkyl or heterocycloalkyl; R12 is H or alkyl; R'12 is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR'13, -NR'13R'14, C(O)R'13, -SO2-R'13 or -C(S)R'13; R13 and R14 independently are H, F or alkyl or together with the atoms to which they are bonded form a cycloalkyl group or a heterocycloalkyl group; R'13 and R'14 independently are H, F or alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or together with the atoms to which they are bonded form cycloalkyl or heterocycloalkyl; R15 and R16 independently are alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl or together with the atom to which they are bonded form a heterocycloalkyl group; R17, R18 and R19 independently are H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or acyl; R20 is H, OH, or any suitable organic moiety; R21, R22, R23 and R24 are independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl, or thioacyl or any two of R21, R22, R23 and R24 together with the atom(s) to which they are bonded form heterocycloalkyl and R25 and R26 are independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. The compound of formula (I) has antipicornaviral activity with an EC50 less than or equal to 10 mM in the HI-HeLa cell culture assay. A pharmaceutical composition thereof is useful for treating a disease condition mediated by picornaviral protease activity or for inhibiting the activity of a picornaviral 36 protease or rhinoviral protease.