Patent GB-980383-A (GB)
Title: Synthesis of bradykinin
IPC: A61K38/00
Filed: 1961-05-12
Abstract: The invention comprises:  (1) synthetic bradykinin having the formula <FORM:0980383/C2/1> (wherein each of the symbols R, R1, R11 and R111 represents a hydrogen atom) and pharmaceutical compositions containing it together with an inert carrier; (2) the preparation of the compound of (1) by splitting off the protective group or groups from a corresponding compound containing such group or groups in place of at least one of the aforesaid hydrogen atoms; (3) the combination of the process of (2) with the preparation of the starting material by condensing a tetrapeptide of the general formula <FORM:0980383/C2/2> or a reactive derivative thereof (wherein R1 represents a protective grouping and R1 represents a hydrogen atom or a protective grouping) with a pentapeptide of the general formula <FORM:0980383/C2/3> (wherein R11 and R111 each represent a hydrogen atom or a protective grouping).  In one embodiment of the process, N-carbobenzoxynitro - L - arginine is condensed with the methyl ester of L-proline and the product is saponified to give N-carbobenzoxy-nitro-L-arginyl-L-proline. This is condensed with the t.-butyl ester of L-prolyl-glycine and the product is saponified to give N - carbobenzoxy - nitro - L - arginyl - L - prolyl - L - prolyl - glycine <FORM:0980383/C2/4> in the second general formula above). Furthermore the p-nitrobenzyl ester of nitro-L-arginine is condensed with N-carbobenzoxy-L-phenylalanine to form N-carbobenzoxy-L-phenylalanyl - nitro - L - arginine p - nitrobenzyl ester. The carbobenzoxy group is then selectively split off and the product condensed with N-carbobenzoxy-L-proline, the carbobenzoxy group is split off and the product condensed with N-carbobenzoxy - L - phenylalanine - L - serine azide, and again the carbobenzoxy group is split off, forming L-phenylalanyl - L - seryl - L - prolyl - L - phenylalanyl - nitro - L - arginine p-nitrobenzyl ester (R11=NO2 and R111=p-nitrobenzyl in the third general formula above). This pentapeptide and the foregoing tetrapeptide are then condensed together and the protective groupings removed by hydrogenolysis. Starting materials for this and other embodiments are prepared as follows:-  L-Prolylglycine t-butyl ester by condensing N-carbobenzoxy-L-proline with glycine t-buty-ester and hydrogenolysing the product.  Nitro-L-arginine p-nitrobenzyl ester by condensing N-carbobenzoxy-nitro-L-arginine with p-nitrobenzyl chloride and treating the product with a solution of hydrogen bromide in glacial acetic acid.  N - Carbobenzoxy - L - phenylalanyl - L - serine azide by condensing N-carbobenzoxy-L-phenylalanine with L-serine methyl ester hydrochloride, reacting the product with hydrazine hydrate and treating the resulting hydrazide with nitrous acid.  L - Phenylalanyl - L - seryl - L - prolyl - L - phenylalanyl - L - arginine by hydrogenating N - carbobenzoxy - L - phenylalanyl - L - seryl - L - propyl - L - phenylalanyl - nitro - L - arginine p-nitrobenzyl ester.  The pharmaceutical compositions lower the blood pressure and have a high vascular activity useful in the treatment of peripheral circulation troubles and hypertony.