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US 5,962,487 AGranted
Antipicornaviral compounds and methods for their use and preparation
AssigneeAgouron Pharmaceuticals, Inc.
InventorsStephen E. Webber, Peter S. Dragovich, Thomas J. Prins, Ethel S. Littlefield, Joseph T. Marakovits, Robert E. Babine
Life of this patent
Estimating the term…
Abstract
Picornaviral 3C protease inhibitors, obtainable by chemical synthesis, inhibit or block the biological activity of picornaviral 3C proteases. These compounds, as well as pharmaceutical compositions that contain these compounds, are suitable for treating patients or hosts infected with one or more picornaviruses. Several novel methods and intermediates can be used to prepare the novel picornaviral 3C protease inhibitors of the present invention.
Claims34
A compound of formula (I):
- ##STR99## wherein:
- M is O or S;
- R.sub.1 is H, F, an alkyl group, OH, SH, or an O-alkyl group;
- R.sub.2 and R.sub.5 are independently selected from H, ##STR100## or an alkyl group, wherein said alkyl group is different from ##STR101## with the proviso that at least one of R.sub.2 or R.sub.5 must be ##STR102## and wherein, when R.sub.2 or R.sub.5 is ##STR103## X is .dbd.CH or .dbd.CF and Y.sub.1 is .dbd.CH or .dbd.CF, or X and Y.sub.1 together with Q' form a three-membered ring in which Q' is --C(R.sub.10)(R.sub.11)-- or --O--, X is --CH-- or --CF--, and Y is --CH--, --CF--, or --C(alkyl)--,
- where R.sub.10 and R.sub.11 independently are H, a halogen, or an alkyl group, or, together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group,
- or X is --CH.sub.2 --, --CF.sub.2 --, --CHF--, or --S--, and Y.sub.1 is --O--, --S--, --NR.sub.12 --, --C(R.sub.13)(R.sub.14)--, --C(O)--, --C(S)--, or --C(CR.sub.13 R.sub.14)--,
- wherein R.sub.12 is H or alkyl, and R.sub.13 and R.sub.14 independently are H, F, or an alkyl group, or, together with the atoms to which they are bonded, form a cycloalkyl group or a heterocycloalkyl group;
- A.sub.1 is C, CH, CF, S, P, Se, N, NR.sub.15, S(O), Se(O), P--OR.sub.15, or P--NR.sub.15 R.sub.16,
- wherein R.sub.15 and R.sub.16 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, or, together with the atom to which they are bonded, form a heterocycloalkyl group;
- D.sub.1 is a moiety with a lone pair of electrons capable of forming a hydrogen bond;
- and B.sub.1 is H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, --OR.sub.17, --SR.sub.17, --NR.sub.17 R.sub.18, --NR.sub.19 NR.sub.17 R.sub.18, or --NR.sub.17 OR.sub.18,
- wherein R.sub.17, R.sub.18, and R.sub.19 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group;
- and with the provisos that when D.sub.1 is the moiety .tbd.N with a lone pair of electrons capable of forming a hydrogen bond, B.sub.1 does not exist;
- and when A.sub.1 is an sp.sup.3 carbon, B.sub.1 is not --NR.sub.17 R.sub.18 when D.sub.1 is the moiety --NR.sub.25 R.sub.26 with a lone pair of electrons capable of forming a hydrogen bond, wherein R.sub.25 and R.sub.26 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- and wherein D.sub.1 --A.sub.1 --B.sub.1 optionally forms a nitro group where A.sub.1 is N;
- and further wherein, when R.sub.2 or R.sub.5 is ##STR104## X is .dbd.CH or .dbd.CF and Y.sub.2 is .dbd.C, .dbd.CH or .dbd.CF, or X and Y.sub.2 together with Q' form a three-membered ring in which Q' is --C(R.sub.10)(R.sub.11)-- or --O--, X is --CH-- or --CF--, and Y.sub.2 is --CH--, --CF--, or --C(alkyl)--, where R.sub.10 and R.sub.11 independently are H, a halogen, or an alkyl group, or, together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group,
- or X is --CH.sub.2 --, --CF.sub.2 --, --CHF--, or --S--, and Y.sub.2 is --O--, --S--, --N(R'.sub.12)--, --C(R'.sub.13)(R'.sub.14)--, --C(O)--, --C(S)--, or --C(CR'.sub.13 R'.sub.14)--,
- wherein R'.sub.12 is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, --OR'.sub.13, --NR'.sub.13 R'.sub.14, --C(O)--R'.sub.13, --SO.sub.2 R'.sub.13, or --C(S)R'.sub.13, and R'.sub.13 and R'.sub.14, independently are H, F, or an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group or, together with the atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group;
- A.sub.2 is C, CH, CF, S, P, Se, N, NR.sub.15, S(O), Se(O), P--OR.sub.15, or P--NR.sub.15 R.sub.16,
- wherein R.sub.15 and R.sub.16 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group or, together with the atom to which they are bonded, form a heterocycloalkyl group;
- D.sub.2 is a moiety with a lone pair of electrons capable of forming a hydrogen bond;
- and B.sub.2 is H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, --OR.sub.17, --SR.sub.17, --NR.sub.17 R.sub.18, --NR.sub.19 NR.sub.17 R.sub.18, or --NR.sub.17 OR.sub.18,
- wherein R.sub.17, R.sub.18, and R.sub.19 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group;
- and further wherein any combination of Y.sub.2, A.sub.2, B.sub.2, and D.sub.2 forms a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- R.sub.3 and R.sub.6 are independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an ayl group, a heteroaryl group, --C(O)R.sub.17, --OR.sub.17, --SR.sub.17, --NR.sub.17 R.sub.18, --NR.sub.19 NR.sub.17 R.sub.18, or --NR.sub.17 OR.sub.18,
- wherein R.sub.17, R.sub.18, and R.sub.19 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group;
- or, R.sub.3 and R.sub.6, together with the carbon atom to which they are attached, form a cycloalkyl group or a heterocycloalkyl group;
- R.sub.4 is any suitable organic moiety, or R.sub.4 and R.sub.3 or R.sub.6, together with the atoms to which they are attached, form a heterocycloalkyl group;
- R.sub.7 is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, --OR.sub.17, --SR.sub.17, --NR.sub.17 R.sub.18, --NR.sub.19 NR.sub.17 R.sub.18, or --NR.sub.17 OR.sub.18,
- wherein R.sub.17, R.sub.18, and R.sub.19 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group;
- or R.sub.7, together with R.sub.3 or R.sub.6 and the atoms to which they are attached, forms a heterocycloalkyl group;
- R.sub.8 is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, --NR.sub.29 R.sub.30, --OR.sub.29, or --C(O)R.sub.29,
- wherein R.sub.29 and R.sub.30 each independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- or R.sub.8, together with R.sub.4 and the nitrogen atom to which they are attached, forms a heterocycloalkyl group or a heteroaryl group, or R.sub.8 and R.sub.3 or R.sub.6, together with the atoms to which they are attached, forms a heterocycloalkyl group;
- Z and Z.sub.1 are independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, --C(O)R.sub.21, --CO.sub.2 R.sub.21, --CN, --C(O)NR.sub.21 R.sub.22, --C(O)NR.sub.21 OR.sub.22, --C(S)R.sub.21, --C(S)NR.sub.21 R.sub.22, --NO.sub.2, --SOR.sub.21, --SO.sub.2 R.sub.21, --SO.sub.2 NR.sub.21 R.sub.22, --SO(NR.sub.21)(OR.sub.22), --SONR.sub.21, --SO.sub.3 R.sub.21, --PO(OR.sub.21).sub.2, --PO(R.sub.21)(R.sub.22), --PO(NR.sub.21 R.sub.22)(OR.sub.23), --PO(NR.sub.21 R.sub.22)(NR.sub.23 R.sub.24), --C(O)NR.sub.21 NR.sub.22 R.sub.23, or --C(S)NR.sub.21 NR.sub.22 R.sub.23,
- wherein R.sub.21, R.sub.22, R.sub.23, and R.sub.24 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or wherein any two of R.sub.21, R.sub.22, R.sub.23, and R.sub.24, together with the atom(s) to which they are bonded, form a heterocycloalkyl group;
- or Z.sub.1, as defined above, together with R.sub.1, as defined above, and the atoms to which Z.sub.1 and R.sub.1 are bonded, form a cycloalkyl or heterocycloalkyl group,
- or Z and Z.sub.1, both as defined above, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group;
- with the proviso that when R.sub.7 is H, R.sub.8 is a moiety other than H;
- or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof;
- and wherein said compound, pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof has antipicornaviral activity with an EC.sub.50 less than or equal to 100 .mu.M in the HI-HeLa cell culture assay.
38 more elements
A compound having the formula II:
- ##STR107## wherein:
- R.sub.51 is H, F, or an alkyl group;
- R.sub.52 is selected from one of the following moieties:
- ##STR108## wherein:
- R.sub.35 is H, an alkyl group, an aryl group, --OR.sub.38, or --NR.sub.38 R.sub.39,
- wherein R.sub.38 and R.sub.39 independently are H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group;
- and
- R.sub.36 is H or an alkyl group,
- or R.sub.35 and R.sub.36, together with the nitrogen atom to which they are attached, form a heterocycloalkyl group or a heteroaryl group;
- R.sub.37 is an alkyl group, an aryl group, or --NR.sub.38 R.sub.39, wherein R.sub.38 and R.sub.39 are as defined above;
- R.sub.41 is H, an alkyl group, an aryl group, --OR.sub.38, --SR.sub.39, --NR.sub.38 R.sub.39, --NR.sub.40 NR.sub.38 R.sub.39, or --NR.sub.38 OR.sub.39, or R.sub.41 and R.sub.36, together with the atoms to which they are attached, form a heterocycloalkyl group, and
- wherein R.sub.38 and R.sub.39 are as defined above and R.sub.40 is H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or an acyl group;
- and
- n is 0, 1 or 2;
- R.sub.53 is H or an alkyl group;
- R.sub.54 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an O-alkyl group, an O-cycloalkyl group, an O-heterocycloalkyl group, an O-aryl group, an O-heteroaryl group, an S-alkyl group, an NH-alkyl group, an NH-aryl group, an N,N-dialkyl group, or an N,N-diaryl group;
- or R.sub.54, together with R.sub.58 and the nitrogen atom to which they are attached, forms a heterocycloalkyl group or a heteroaryl group;
- R.sub.57 is H or an alkyl group;
- R.sub.58 is H, an alkyl group, a cycloalkyl group, --OR.sub.70, or --NR.sub.70 R.sub.71, wherein R.sub.70 and R.sub.71 are independently H or an alkyl group;
- and
- Z and Z.sub.1 are independently H, F, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, --C(O)R.sub.21, --CO.sub.2 R.sub.21, --CN, --C(O)NR.sub.21 R.sub.22, --C(O)NR.sub.21 OR.sub.22, --C(S)R.sub.21, --C(S)NR.sub.21 R.sub.22, --NO.sub.2, --SOR.sub.21, --SO.sub.2 R.sub.21, --SO.sub.2 NR.sub.21 R.sub.22, --SO(NR.sub.21)(OR.sub.22), --SONR.sub.21, --SO.sub.3 R.sub.21, --PO(OR.sub.21).sub.2, --PO(R.sub.21)(R.sub.22), --PO(NR.sub.21 R.sub.22)(OR.sub.23), --PO(NR.sub.21 R.sub.22)(NR.sub.23 R.sub.24), --C(O)NR.sub.21 NR.sub.22 R.sub.23, or --C(S)NR.sub.21 NR.sub.22 R.sub.23,
- wherein R.sub.21, R.sub.22, R.sub.23, and R.sub.24 are independently H, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an acyl group, or a thioacyl group, or wherein any two of R.sub.21, R.sub.22, R.sub.23, and R.sub.24, together with the atom(s) to which they are bonded, form a heterocycloalkyl group,
- or wherein Z and Z.sub.1, together with the atoms to which they are bonded, form a heterocycloalkyl group;
- with the proviso that when R.sub.57 is H, R.sub.58 is a moiety other than H;
- or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof.
22 more elements
Dependencies are inferred from the claim text.