Patent GB-895345-A (GB)
Title: Polypeptides
IPC: A61K38/00
Filed: 1959-07-03
Abstract: The invention comprises L-glutamyl- or L-glutaminyl - L - histidyl - L - phenylalanyl - L - a  a  - (lower aminoalkyl) - a  - aminoacetyl - L - tryptophylglycine (in which the lower alkyl groups contain up to 4 carbon atoms and the amino group may be unsubstituted or amidinosubstituted), esters thereof and derivatives in which the primary amino group is protected by a group which can be split off by hydrogenation, such as triphenylmethyl (trityl), carbobenzyloxy (Cbo-) and p1-(p-methoxyphenylazo)benzyloxy-carbonyl-(MZ-) groups. The polypeptide may be prepared by methods known per se for building up peptides from amino acid and/or smaller peptide molecules.  The compounds are prepared by a series of condensations wherein the following intermediates are formed in the given sequence and where the blocking and ester groups are removed by hydrolysis or hydrogenolysis accordingly: (1) N-trityltryptophane methyl ester, N-trityltryptophane, N-trityltryptophylglycine p-nitrobenzyl ester, tryptophylglycine p-nitrobenzyl ester (also Cbo-tryptophylglycine benzyl ester and MZ-tryptophylglycine benzyl ester); MZ-phenylalanylarginine methyl ester (also Cbo-phenylalanylarginin methyl ester), phenylalanylarginine methyl ester, Na -Cbo-N-(im)-benzyl-histidylphenylalanylarginine methyl ester, the free acid, Na -Cbo-N(im)-benzylhistidylphenylalanylarginyltryptophylglycine p-nitrobenester, N - (im) benzylhistidylphenylalanylarginyltryptophylglycine p-nitrobenzyl ester, Cbo-g -benzyl - glutamyl - N(m) - benzylhistidylphenylalanylarginyltryptophylglycine p-nitrobenzyl ester and the free unprotected hexapeptide.  (2) Cbo-phenylalanyl-nitro-arginine methyl esters, phenylalanylarginine methyl ester, di-Cbo-histidylphenylalanyl-nitro-arginine methyl ester, histidyl phenylalanylarginine methyl ester, Cbo-glutaminylhistidylphenylalanylarginine methyl ester, the free acid, Cbo-glutaminylhistidylphenylalanylarginyltryptophylglycine p - nitro - benzyl ester, Cbo - glutaminylhistidylphenylalanylarginyltryptophylglycine and the free hexapeptide.  (3) Cbo-glutaminylhistidine methyl ester, and Cbo - glutaminylhistidine; MZ - glutamine, MZ - glutaminylhistidine methyl ester and MZ - glutaminylhistidine; Cbo - phenylalanyl - nitro - arginyltryptophylglycine methyl ester, phenylalanylarginyltryptophylglycinemethylester and MZ - glutaminylhistidylphenylalanylarginyltryptophylglycine.  The Cbo-hexapeptide methyl ester is also prepared from Cbo-glutaminylhistodylphenylalanylarginine and tryptophylglycine methyl ester or from Cbo-glutaminylhistidine and phenylalanylarginyltryptophylglycine methyl ester.  Specification 895,344 is referred to.ALSO:Pharmaceutical compositions comprise the hexapeptides L-glutaminyl- or L-glutamyl-L-histidyl - L - phenylalanyl - L - a  - (lower aminoalkyl) - a  - aminoacetyl - L - tryptophylglycine, esters thereof and derivatives in which the primary amino group is protected by a protecting group which can be split off by hydrogenation and acid addition salts thereof, in admixture or in conjunction with a carrier suitable for enteral or parenteral administration.  In the foregoing "lower alkyl" indicates a group containing 1-4 carbon atoms, "amino" includes amidino-substituted amino, and groups removable by hydrogenation include triphenyl-methyl, carbobenzyloxy, -benzyl, p-nitrobenzyl, and p - (p1 - methoxyphenylazo) - benzoyloxycarbonyl.  The preparations may be in the form of tablets, dragees, powders, ointments, creams, suppositories, solutions, suspensions or emulsions, using conventional excipients; the preparations may contain further therapeutically useful substances.  Specification 895,344 is referred to.