TRIPEPTIDES AND PROCESS FOR THEIR PREPARATION

摘要

1463190 Tripeptides HOECHST AG 23 Aug 1974 [25 Aug 1973 4 April 1974] 37163/74 Heading C3H [Also in Division C2] Per se tripeptides of formula wherein X is an alkyl radical of 2-8 carbon atoms, a cycloalkyl radical of 5-7 carbon atoms, or an aralkyl radical having 1 or 2 carbon atoms in the alkyl portion, or the trifluoroacetate salt thereof may be prepared by either (i) the reaction of Z-histidine azide with a proline derivative of general formula wherein X is as above and Z is benzyloxycarbonyl, the radical Z is removed by hydrogenation, and the dipeptide is reacted with an active ester of pyroglutamic acid, or (ii) Z-Gln(4,41- dimethoxybenzhydryl)-His-OH is reacted with the proline derivative of (i) in the presence of dicyclohexylcarbodiimide and an acidic N- hydroxy compound (1-hydroxybenzotriazone), the protective groups are removed (by trifluoroacetic acid), and the glutamyl residue converted to pyroglutamyl. Examples illustrate the preparation wherein X is ethyl, n-propyl, isobutyl, #-phenylethyl, n-hexyl and cylcohexyl. Other peptide intermediates isolated are Z - Gln(Mbh) - His - Pro - ethylamide, nhexylamide, n - propylamide and isobutylamide. Dipeptide intermediates are the n-hexyl, cyclohexyl and #-phenylethyl derivatives of Z and H-His-Pro-NH 2 . Pharmaceutical compositions comprise peptides of Formula (I) in conjunction or admixture with a pharmaceutically suitable carrier for use as methods of increasing milk secretion in mammals by oral, subcutaneous, intramuscular or intravenous routes.