Patent GB-1007777-A (GB)
Title: Improvements in or relating to hendecapeptides
Inventor: BOISSONNAS ROGER
IPC: C07K7/08
Filed: 1962-06-29
Abstract: The invention comprises the hendecapeptide pyroglutamyl - prolyl - seryl - lysyl - aspartyl alanyl - phenylalanyl - isoleucyl - glycyl leucyl-methionine amide (wherein all the amino acid residues are of L-configuration), its acid addition salts, and peptide having a protective group on the e -amino radical of the lysine residue and, optionally, a protective group on the end amido group of the pyroglutamine residue and/or a protective group on the b -carboxyl radical of the aspartic acid residue, and the preparation thereof by condensing a suitably protected pyroglutamyl-prolyl-seryl-lysine having, optionally, the carboxyl radical of the lysine residue substituted with a radical reactive with amino radicals to form an amide link with aspartyl-alaryl - phenylalanyl - isoleucyl - glycyl - leucyl-methionine amide, optionally protected, and if desired removing the protecting groups in one or more stages.  Protecting groups for the pyroglutamyl residue are, for example, carbobenzoxy, carbo-tertiary-butoxy and p-nitrocarbo benzoxy; for the Ne  amino group of lysine, the aforementioned together with phthalyl and formyl; and for the b -carboxyl group benzoyl, p-nitrobenzyl, methyl, ethyl, tertiary-butyl and amido radicals. Groups in the tetrapeptide reactive with amino radicals to form amide linkages are azide, and p-nitrophenyl ester radicals; an asymmetric anhydride of the detetrapept or the reaction product of the tetrapeptide with dicyclohexylcarbodiimide.  Pyroglutamyl - prolyl - seryl - (Ne  - carbotertiary-butoxy) lysine hydrazide is prepared by condensing carbobenzoxypyroglutamine p-nitrophenyl ester with prolin to give carbobenzoxypyroglutamyl-proline, condensing this with seryl - Ne  - carbobenzoxylysine methyl ester to give carbobenzoxypyroglutamyl - prolyl - seryl-lysine methyl ester, hydrogenating this to give the free tetra peptide ester, forming the Ne -carbo - t - butoxy - lysine derivative and reacting the ester with hydrazine.  Seryl - Ne  - carbobenzoxylysine methyl ester is prepared by condensing N-tritylserine with Ne -carbobenzoxylysine methyl ester and detritylating the protected dipeptide.  Aspartyl - alanyl - phenylalanyl - isoleucyl-glycyl - leucyl - methioninamide is prepared from carbobenzoxyphenylalamine p-nitrophenyl ester and isoleucine methyl ester through carbo-benzoxyphenylalanyl - isoleucyl methyl ester, carbobenzoxy - o - benzyloxyaspartyl - isoleucine methyl ester, carbo - tert - butoxy - aspartyl-alanyl - phenylalanyl - isoleucine methyl ester and its hydrazide and carbo-tert-butyoxy-aspartyl - alanyl - phenylalanyl - isoleucyl - glycyl - leucyl - methioninamide, by stepwise addition of an amino acid with liberation of the free amino peptides, the last stage being condensation between a tetra- and a tri-peptide.  Glycyl - leucyl - methioninamide is prepared from trityl - glycyl - leucine and methionine amide through the trityl tripeptamide.  Pharmaceutical compositions showing hypotensive activity comprise the compounds of the invention with an inert pharmaceutical carrier.  Specifications 872,332 and 878,732 are referred to.