Anti-picornaviral agents

Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Tripeptides – e.g. – tripeptide thyroliberin – etc.

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Details

530330, 514 18, 514 19, A61K 3806

Patent

active

058213317

ABSTRACT:
The present invention provides a group of novel compounds that inhibit the proteolytic activity of 3C proteases which are found in picornaviruses, particularly rhinoviruses. In picornaviruses the RNA genome is translated into a single large viral polyprotein precursor. The precursor demonstrates auto-proteolytic activity, cleaving itself into mature viral gene products. Therefore, compounds of the current invention are particularly useful in treating picornaviral infections by interrupting the processing of the viral gene products into mature and infectious viral particles. The current invention also provides a novel process the preparation of compounds of the current invention. The process entails the selective reduction of an imide intermediate representing a marked improvement over processes known in the art for making peptidyl-aldehydes.

REFERENCES:
Skiles, et al., Tetrahedron Letters, "Spiro Indolinone Beta-Lactams, Inhibitors of Poliovirus and Rhinovirus 3C-Proteinases", 31:50, 7277-7280 (1990).
Cordingley, et al., The Journal of Biological Chemistry, "Substrate Requirements of Human Rhinovirus 3C Protease for Peptide Cleavage in Vitro", 265:16, 9062-9065 (1990).
Orr, et al., J. Gen. Virol., "Hydrolysis of a Series of Synthetic Peptide Substrates by the Human Rhinovirus 14 3C Proteinase, Cloned and Expressed in Escherichia coli", 70, 2931-2942 (1989).
Nicklin, et al., Biotechnology, 4, (1986).
Takeda, et al., Tetrahedron Letters, "A Convenient Synthesis of Peptide Using Oxalates", 24, 4451-4455 (1983).
Witiak, et al., J. Med. Chem, "Para-Substituted N-Acetyl-L(S)- and -D(R)-alpha-amino-N-phenylsuccinimides and -glutarimides. Substituent Effects on Stereoselective Anticonvulsant Activity", 15, 1117-1123 (1972).
Stuart, et al., Tetrahedron Letters, "Isolation and Synthesis of Glutamine and Glutarimide Derivatives from Corton Humilis", 29, 4071-4075 (1973).
Wijnberg, et al., Tetrahedron Letters, "A Regioselective Reduction of Gem-Disubstituted Succinimides", 34, 179-187 (1978).
Hubert, Tetrahedron, 31, 1437 (1975).
Araki, Tetrahedron Letters, 29, 351 (1988).
Chamberlin, Tetrahedron Letters, 23, 2619 (1982).

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