Patent ES-272025-A1 (ES)
Title: Heneicosapeptides and intermediates for the manufacture thereof
IPC: C07K14/695
Filed: 1961-11-15
Abstract: The invention comprises the heneicosa peptides H - Ser - Tyr - Ser - Met - Glu(NH2) - His - Phe - Arg - Try - Gly - Lys - Pro - Val - Gly - Lys - Lys - Arg - Arg - Pro - Val - Lys OH, and the corresponding compound which has the radical of glutamic acid (-Glu-) instead of the glutamine (-Glu(NH2)-) radical, their derivatives in which the amino and carboxylic acid groups are protected (e.g. by tertiary butoxycarbonyl(BOC), carbobenzoxy (Z), p-phenylazobenzyloxycarbonyl (PZ). p-(p-methoxyphenylazo)-benzyloxycarbonyl (MZ) groups, benzyl (Bzy), or p-nitrobenzyl (NB) esters, amides or hydrazides) and acid addition salts, and the preparation thereof by condensing a nonadecapeptide BOC -Ser - Tyr - Ser - Met - Glu(NH2) - (or Glu - g - ester) - His - Phe - Arg - Try - Gly - BOC - Lys -Pro - Val - Gly - BOC - Lys - BOC - Lys - Arg - Arg - ProOH with an ester, amide or hydrazide of H - Val - BOC - LysOH and, if desired, removing the amino and carboxyl protecting groups. The peptide may also be prepared by stepwise synthesis from H - (Ne - PZ) - LysOBzy (or H(Ne - MZ - ) LysOBzy or H - (Ne - MZ - ) - LysONB), and through the following intermediates and their terminally N - unprotected analogues, BOC - Val - PZ - LysOBzy, BOC - Pro - Val - Lys(PZ) - OBzy, BOC - Arg -(Z2) - Pro - Val - Lys(PZ)OBzy, BOC - Arg(Z2) - Arg(Z2) - Pro - Val - Lys(PZ)OBzy, BOC - Lys(Z) - Arg(Z2) - Arg(Z2) - Pro - Val - Lys(PZ) OBzy, BOC - Lys(Z) - Lys(Z) - Arg(Z2) - Arg (Z2) - Pro - Val - Lys(PZ)OBzy, BOC - Val - Gly - Lys(Z) - Lys(Z - Arg(Z2) - Arg(Z2) - Pro - Val - Lys(PZ)OBzy, BOC - Pro - Val - Gly - Lys(Z) - Lys(Z) - Arg(Z2) - Arg(Z2) - Pro - Val - Lys(PZ)OBzy, BOC - Lys(Z) - Pro - Val - Gly - Lys(Z) - Lys(Z) - Arg(Z2) - Arg(Z2) - Pro - Val - Lys(PZ) - OBzy, BOC - Gly - Lys(Z) - Pro - Val - Gly - Lys(Z) - Lys(Z) - Arg(Z2) - Arg(Z2) - Pro - Val - Lys(PZ)OBzy, BOC - Try - Gly - Lys(Z) - Pro - Val - Gly - Lys(Z) - Lys(Z) - Arg(Z2) - Arg(Z2) - Pro - Val - Lys(PZ-)OBzy, BOC - Arg(Z2) - Try - Gly - Lys(Z) - Pro - Val - Gly - Lys(Z) - Lys(Z) - Arg(Z2) - Arg(Z2) - Pro - Val - Lys(PZ)OBz, BOC - Phe - Arg(Z2) - Try - Gly - Lys(Z) - Pro - Val - Gly - Lys(Z) - Lys(Z) - Arg - (Z2) - Arg(Z2) - Pro - Val - Lys(PZ)OBzy, BOC - His - Phe - Arg(Z2) - Try - Gly - Lys(Z) - Pro - Val - Gly - Lys(Z) - Lys(Z) - Arg(Z2) - Arg(Z2) - Pro - Val - Lys - (PZ)Obzy, BOC - Glu(Obzy) - His - Phe - Arg(Z2) - Try - Gly - Lys(Z) - Pro - Val - Gly - Lys(Z) - Lys(Z) - Arg(Z2) - Arg(Z2) - Pro - Val - Lys - (PZ)OBzy, BOC - Met - Glu(OBZY) - His - Phe - Arg(Z2) - Try - Gly - Lys(Z) - Pro - Val - Gly - Lys(Z) - Lys(Z) - Arg(Z2) - Arg(Z2) - Pro - Val - Lys(PZ)-OBzy, BOC - Ser(OBzy) - Met - Glu(OBzy) - His - Phe - Arg(Z2) - Tty - Gly - Lys(Z) - Pro - Val - Gly - Lys(Z) - Lys(Z) - Arg(Z2) - Arg(Z2) - Pro - Val - Lys(PZ)OBzy), BOC - Try - Ser(OBzy) - Met - Glu(OBzy) - His - Phe - Arg(Z2) - Try - Gly - Lys(2) - Pro - Val - Gly - Lys(Z) - Lys(Z) - Arg(Z2) - Arg(Z2) - Pro - Val - Lys(PZ)OBzy, and BOC - Ser(OBzy) - Tyr - Ser(OBzy) - Met - Glu(OBzy) - His - Phe - Arg(Z2) - Try - Gly - Lys(Z) - Pro - Val - Gly - Lys(Z) - Lys(Z) - Arg(Z2) - Arg(Z2) - Pro - Val - Lys(PZ)OBzy. L-Val-BOC-LysOMe is prepared from Z-Val-OH and Ne -BOC-LysOMe through Z-Val-BOC-LysOMe from which the carbobenzoxy group is removed BOC-Val-Gly-OH and its dicyclohexylamine salt from BOC-valine and glycine ethyl ester to form BOC-Val-GlyO Et and hydrolysing the ester group Na -BOC-N o ,N o -(Z2)-ArgOH, BOC-HisOH, BOC-Glu(OBzy)OH, and BOC-O(Bzy)-SerOH, from BOC-azide and the amino acid O-Bzy-SerOH from the methyl ester D-hydrogen tartrate and Na -BOC-Ne -Z-LysONP and BOC-PheONP from the free acid and p-nitrophenol. Pharmaceutical compositions comprise the heneicosa peptides of the invention in admixture with a pharmaceutical carrier suitable for enteral or parenteral administration. The preparations may be formulated as tablets, dragees, powders, ointments, creams, suppositories, solutions, suspensions or emulsions and may be compounded with other therapeutically active substances. They have adrenocorticotropic activity. Specifications 872,332, 957,892 and 992,958 are referred to.