US 6,632,825 B2Granted

Antipicornaviral compounds and compositions, their pharmaceutical uses, and materials for their synthesis

AssigneeAgouron Pharmaceuticals, Inc.

InventorsTheodore O. Johnson, Jr., Shao Song Chu, Brian Walter Eastman, Ye Hua, Hiep The Luu, Siegfried Heinz Reich, Donald James Skalitzky, Yi Yang, Thomas F. Hendrickson, Fora P. Chan

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Abstract

Compounds of the formula: where the formula variables are as defined in the disclosure, advantageously inhibit or block the biological activity of the picornaviral 3C protease. These compounds, as well as pharmaceutical compositions containing these compounds, are useful for treating patients or hosts infected with one or more picornaviruses, such as RVP. Intermediates and synthetic methods for preparing such compounds are also described.

Claims11

Dependent claims

A compound of formula:

wherein:
Ra1 is a heterocycloalkyl, or heteroaryl group, provided that Ra1 is not a substituted pyrrolidinyl, where the heterocycloalkyl, or heteroaryl group is unsubstituted or substituted with one or more suitable substituents;
Rc is a substituent having the formula:
wherein:
Rf and Rg are each independently H or lower alkyl;
m is 1;
p is 1;
A1 is CH;
A2 is C(Rh)(Ri), where each Rh, and Ri is independently H or a lower alkyl group;
each A3 present is C(Rh)(Ri);
where each Rh and Ri is independently H or lower alkyl;
when p is 1, A4 is N(Rk), where each Rk is H, alkyl, aryl, or acyl;
where each dotted line in the ring depicts a single bond;
Rd is H, halogen, hydroxyl or an alkyl, alkoxy or alkylthio group, where the alkyl, alkoxy or alkylthio group is unsubstituted or substituted with one or more suitable substituents;
Rb is H or an alkyl group, unsubstituted or substituted with one or more suitable substituents;
Z and Z1 are each independently H, F, an alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, where the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted with one or more suitable substituents, —C(O)Rn—CO2Rn—CN, —C(O)NRnRo, —C(O)NRnORo, —C(S)Rn, —C(S)ORn—C(S)NRnRo, —C(═NRn)Ro, —C(═NRn)ORo, —NO2, —SORo, —SO2Rn, —SO2NRnRo, —SO2(NRn)(ORo), —SONRn, —SO3Rn, —PO(OR)n)2, —PO(ORn)(ORo), —PO(NRnRo)(ORp), —PO(NRnRo)(NRpRq), —C(O)NRnNRoRp, or —C(S)NRnNRoRp, where Rn, Ro, Rp and Rq are each independently H or an alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group, where the alkyl, cycloalkyl, aryl, heterocycloalkyl, acyl or thioacyl group is unsubstituted or substituted with one or more suitable substituents, or where any two of the Rn, Ro, Rp and Rq, taken together with the atoms to which they are bonded, form a heterocycloalkyl group, which may be optionally substituted,
or Z and Rd, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Rd are as defined above except for moieties that cannot form the cycloalkyl or heterocycloalkyl group,
or Z and Z1, together with the atoms to which they are bonded, form a cycloalkyl or heterocycloalkyl group, where Z and Z1 are as defined above (except for moieties that cannot form the cycloalkyl or heterocycloalkyl group);
or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof.

16 more elements

A compound selected from the group:

4S-[(5-bromo-pyridine-3-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4S-[(3-hydroxyquinoxaline-2-carbonyl)-amino]-5-(2-oxopyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4S-[(5-ethyl-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4S-(3-benzo[1,3]dioxol-5-yl-acryloylamino)-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4-[(1H-benzoimidazole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4S-[(3-acetyl-2-phenyl-thiazolidine-4-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4S-[(5-bromo-benzofuran-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4S-[(5,6-dimethoxy-1-methyl-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4S-[(5-bromo-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid;
4S-[(5-bromo-1-methyl-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4S-[(benzo[b]thiophene-2-carbonyl)-amino]-6-carbamoyl-hex-2-enoic acid ethyl ester;
6-carbamoyl-4S-[(quinoxaline-2-carboxyl)-amino]-hex-2-enoic acid ethyl ester;
6-carbamoyl-4S-[(quinoline-2-carbonyl)-amino]-hex-2-enoic acid ethyl ester;
6-carbamoyl-4S-[(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-amino]-hex-2-enoic acid ethyl ester;
4S-[(2-benzyl-5-tert-butyl-2H-pyrazole-3-carbonyl)-amino]-6-carbamoyl-hex-2-enoic acid ethyl ester;
6-carbamyl-4S-[(1H-indole-2-carbonyl)-amino]-hex-2-enoic acid ethyl ester;]
4S-[(5-fluoro-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4S-[(5-chloro-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4S-[(5-methoxy-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4S-[(7-nitro-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4-[(5-methyl-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3-yl)-pent-2-enoic acid ethyl ester;
4S-[(6-chloro-2H-chromene-3-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4S-[(2-methyl-5-phenyl-furan-3-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4S-[(6-benzyloxy-5-methoxy-1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4S-[(1H-indole-2-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4S-[3-(6-bromo-benzo[1,3]dioxol-5-yl)-acryloylamino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
4S-[(6-bromo-2H-chromene-3-carbonyl)-amino]-5-(2-oxo-pyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
and 4S-[(2H-chromene-3-carbonyl)-amino]-5-2-oxopyrrolidin-3S-yl)-pent-2-enoic acid ethyl ester;
or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof.

26 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/882,345Filed 13 Jun 2001 · us provisional application
Priority: 14 Jun 2000
Published: US 2002/0061916 A123 May 2002
Granted: 14 Oct 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification18 codes

C07D 207/26
Oxygen or sulfur atoms: 2-Pyrrolidones
A61P 31/14
Antivirals: for RNA viruses
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07C 237/22
Having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton: having nitrogen atoms of amino groups…