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US 5,514,777 AGranted
Methods of synthesis of peptidyl argininals
AssigneeCorvas International, Inc.
InventorsThomas R. Webb, John E. Reiner, Susan Y. Tamura, William C. Ripka, Raymond Dagnino, Jr.
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Abstract
This invention provides solution-phase methods for the synthesis of peptidyl argininals and to novel reagents useful therein.
Claims79
A compound having the formula:
- ##STR51## wherein R.sub.1 is selected from the group consisting of hydrogen, benzyloxycarbonyl, isonicotinyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, t-butoxycarbonyl, t-amyloxycarbonyl, isobornyloxycarbonyl, adamantyloxycarbonyl, 2-(4-biphenyl)-2-propyloxycarbonyl, 9-fluorenylmethoxycarbonyl and methylsulfonylethoxycarbonyl;
- R.sub.2 is selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and alkyl of about 2 to about 12 carbon atoms substituted with a hydroxy, carbomethoxy or carboethoxy;
- R3 is selected from the group consisting of nitro, benzyloxycarbonyl, t-butoxycarbonyl and adamantyloxycarbonyl;
- and
- R.sub.4 is selected from the group consisting of hydrogen, alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms and aralkyl of about 7 to about 15 carbon atoms;
- or salts thereof.
3 more elements
A method of making a peptidyl argininal comprising the steps of:
- (a) reacting a first intermediate having the formula:
- ##STR53## wherein R.sub.5 is selected from the group consisting of benzyloxycarbonyl, isonicotinyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, t-butoxycarbonyl, t-amyloxycarbonyl, isobornyloxycarbonyl, adamantyloxycarbonyl, 2-(4-biphenyl)-2-propyloxycarbonyl, 9-fluorenylmethoxycarbonyl and methylsulfonylethoxycarbonyl;
- R.sub.6 is selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and alkyl of 2 to about 12 carbon atoms substituted with a hydroxy, carbomethoxy or carboethoxy;
- R.sub.7 is selected from the group consisting of nitro, benzyloxycarbonyl, t-butoxycarbonyl and adamantyloxycarbonyl;
- and
- R.sub.8 is selected from the group consisting of hydrogen, alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, and aralkyl of about 7 to about 15 carbon atoms;
- with a R.sub.5 removing reagent which chemically removes the R.sub.5 group from said first intermediate to give a second intermediate of the formula:
- ##STR54## (b) chemically coupling to the second intermediate of step (a), a protected amino acid, a protected amino acid analog or a protected peptide of about 2 to about 30 amino acids, amino acid analogs, or a combination of amino acids and amino acid analogs, using a coupling reagent to give a third intermediate having the formula:
- ##STR55## wherein X is a protecting group,
- k is an integer from 1 to 30, and
- AA.sub.1 -AA.sub.2 . . . AA.sub.k is an amino acid, amino acid analog or peptide comprised of k amino acids, amino acid analogs or combination of amino acids and amino acid analogs;
- (c) reacting the third intermediate with a R.sub.7 removing reagent which chemically removes the R.sub.7 group to give a fourth intermediate having the formula:
- ##STR56## and (d) reacting the fourth intermediate with a hydrolyzing reagent which comprises an aqueous acid to chemically hydrolyze said fourth intermediate to give said peptidyl argininal.
10 more elements
Dependencies are inferred from the claim text.