Patent GB-917013-A (GB)
Title: Cyclic decapeptides and process for their manufacture
IPC: A01N37/44
Filed: 1959-04-29
Abstract: The invention comprises cyclo-(A-B-L-leucyl-D-phenylalanyl-L-prolyl)2 in which A represents the residue of glycine or of an L-a -amino acid of the formula <FORM:0917013/IV (b)/1> in which X represents a C1-5 alkyl group, and B represents the residue of a natural L-a -amino acid which contains 2-9 carbon atoms and, when it contains besides the a -amino group a further amino or a hydroxyl, carboxyl, or carbonamide group contains at least 6 carbon atoms, and their derivatives having protected amino groups, preferably cyclic (glycyl - L - (MZ) - lysyl - L-leucyl-D-phenylalanyl-L-prolyl)2 wherein MZ represents para(para-methoxy-phenylazo)-carbobenzoxy, and their acid addition salts, the preparation thereof by treating an acid addition salt of (a) an A - B - L - leucyl - D - phenylalanyl-L-proline carboxylic acid ester or (b) the linear decapeptide ester containing the same amino acid sequence twice, in which ester any free amino group in B is protected and which ester contains an electron-attracting substituent in the hydroxy component, (that is a meta-directing substituent or a halogen atom), with a basic agent and, if desired, converting any protected amino group present into the free amino groups and, if desired, free the resulting compound into an acid addition salt thereof.  The amino acid A is preferably L-valine, L-leucine or glycine and the acid B preferably, L-leucine, L-lysine, or L-tyrosine.  L - Leucyl-L-leucyl-L-leucyl-D-phenylalanyl-L-proline-para-nitro phenyl ester trifluoroacetate is prepared by converting carbobenzoxy-L-leucyl-L-leucine methyl ester into the hydrazide with hydrazine, treating this with sodium nitrite to give the azide, reacting this with L-leucyl-D-phenylalanyl-L-proline methyl ester to give carbobenzoxy-L-leucyl-L-leucyl-D-phenylalanyl-L-proline methyl ester, hydrogenating this to give the free amino peptide ester hydrochloride converting this to the N-trityl peptide ester with triphenyl methyl chloride, hydrolysing off the ester group to give the N-trityl pentapeptide, reacting the acid with di-(para-nitrophenyl)-sulphite to give the N-trityl pentapeptide nitrophenyl ester and detritylating the ester with trifluoroacetic acid.  Similarly, L - valyl - L - tyrosyl - L - leucyl-D-phenylalanyl - L - proline-paranitrophenyl ester trifluoracetate is prepared from carbobenzoxyL-valine-L-tyrosine-hydrazide through the corresponding azide, the carbobenzoxy-L-valyl-L-tyrosyl - L - leucyl - D-phenylalanyl-L-prolinemethyl ester, the free amino peptide ester, N - trityl-L-valine-O-trityl-L-tyrosine-L-leucine-D-phenylalanine-L -proline methyl ester, the free ditrityl peptide acid and the di-trityl pentapeptide-p-nitrophenyl ester.  Glycyl-(MZ) -L-lysyl-L-leucyl-D-phenylalanyl-L-proline-p-nitrophenyl ester trifluoroacetate wherein MZ is p-(p1-methoxyphenylazo)carbobenzoxy, is prepared from N-trityl-glycyl(MZ)-L-lysine hydrazide through the azide, N - trityl - glycyl - (MZ) - L-lysyl-L-leucyl-D-phenylalanyl-L-proline methyl ester, the Na -trityl-Ne -(MZ)-pentapeptide acid, and the Na -trityl-Ne -(MZ)-pentapeptide p-nitrophenyl ester.  L - Valyl - tosyl - L-lysyl-L-leucyl-D-phenylalanyl-L-proline p-nitrophenyl ester trifluoroacetate is prepared from carbobenzoxy-L-valyl-tosyl-L-lysine hydrazide through the azide, carbobenzoxy - L - valyl-tosyl-L-lysyl-L-leucyl-D-phenylalanyl-L-proline methyl ester, the Ne -tosyl pentapeptide ester hydrochloride, the Na -trityl-Ne -tosyl pentapeptide ester, the Na -trityl-Ne -tosyl pentapeptide free acid and the Na -trityl-Ne -tosyl pentapeptide p-nitrophenyl ester. The linear decapeptide di-(L-valyl-tosyl-L-lysyl-L-leucyl-D-phenylalanyl-L-prolyl) p-nitrophenyl ester trifluoroacetate is prepared by condensing L - valyl - tosyl-L-lysyl-L-leucyl-D-phenylalanyl-L-proline methyl ester hydrochloride with trityl - L - valyl-tosyl-L-lysyl-L-leucyl - D - phenylalanyl - L - proline in the presence of dicyclohexyl-carbodiimide to form the N-trityl decapeptide methyl ester hydrolysing this to form the N-trityl-decapeptide free acid, esterifying this to give the N-trityl decapeptide p-nitrophenyl ester and detritylating the ester with trifluoracetic acid.  Pharmaceutical compositions showing antibiotic activity comprise the cyclic decapeptides of the invention and their physiologically acceptable acid addition salts together with a pharmaceutical carrier suitable for enteral, parenteral or local administration. p  They may contain other therapeutically active substances, and may take the form of tablets, dragees, powders, ointments, creams, suppositories, solutions, suspensions or emulsions. Specification 917,014 is referred to.