New cyclic octapeptides

摘要

The invention comprises an O-alkyl-tyrosine2 - lysine8 - vasopressin of the general formula in which X is a C1-4 alkyl group. The cyclic octapeptide is prepared by the known general methods for the synthesis of polypeptides for example by reacting an N-R-S-R1-L-cysteinyl O-alkyl-L-tyrosyl-L-phenylalanine azide with a hexapeptide L - glutaminyl - L - asparaginyl-S-R1-L-cysteinyl-L-prolyl-Ne - R11-lysyl glycin - amide or an N-R-S-R1-L-cysteinyl-O-alkyl-L-tyrosyl-L-phenylalanine with the above hexapeptide in the presence of a condensing agent, in which R, R1 and R11 are protecting groups such as the carbobenzyloxy, benzyl and benzene- or toluene-sulphonyl groups respectively, to form the nonapeptide N-R-S-R1-L-cysteinyl O-alkyl-L-tyrosyl-L- phenylalanyl - L - glutaminyl - L - asparaginyl - S-R1-L-cysteinyl - L - prolyl-Ne -R11-L-lysyl-glycinamide, or by acylating a heptapeptide L-phenylalanyl-L-glutaminyl - L - asparaginyl - S - R1-L-cysteinyl-L-prolyl-Ne -R1-L-lysyl-glycinamide with a reactive functional derivative of an N-R111-O-alleyl-L-tyrosine e.g. the nitrophenyl ester thereof) in which R111 represents a carbobenzyloxy radical to form the octapeptide N-R111-O-alkyl - L-tyrosyl-L-phenylalanyl-L-glutaminyl-L - asparaginyl - S-R1-L-cysteinyl-L-prolyl-Ne -R11-L-lysyl -glycinamide splitting off the radical R111 and acylating the free amino group with a reactive functional derivative of an N-R-S-U-R1-cysteine to give the nonapeptide above, and finally splitting off the groups R, R1 and R11 from the nonapeptide by treatment with an alkali metal in liquid ammonia and oxidising the free nonapeptide with air at room temperature in an aqueous medium at pH 6.5 to 8.5. N-Carbobenzyloxy- S-benzyl-L-cysteinyl-O-alkyl-L-tyrosyl-L -phenylalanine azide is prepared by reacting N-carbobenzyloxy-S-benzyl-L-cysteinyl-O-alkyl-tyrosine with L-phenylalanine methyl ester hydrochloride to form the tripeptide methyl ester, reacting this with hydrazine to give the hydrazide and this with nitrous acid. The free tripetide is prepared by hydrolysis of the methyl ester. Pharmaceutical compositions having vasopressor action comprise the cyclic octapeptides of the invention in admixture or in conjunction with a pharmaceutically suitable carrier and/or a stabilizer and may be in the form of a nasal spray or snuff powder or a solution for injection stabilized by the addition of trichloro-t-butanol.