Patent GB-876570-A (GB)
Title: Peptides and the preparation thereof
IPC: C07C233/00
Filed: 1957-09-05
Abstract: The invention comprises L-asparaginyl-L-arginyl-L-valyl-L-tyrosyl-L-valyl- L-histidyl-L -prolyl-L-phenylalanyl-L-histidyl -L- leucine of the formula <FORM:0876570/IV (b)/1> <FORM:0876570/IV (b)/2> and derivatives thereof having an esterified carboxyl group and free amino groups, or having an esterified carboxyl group, an arginyl group in which a nitro group protects the amino group in the amidino group and a protected amino group, the protecting group being capable of being split off by hydrogenation or hydrolysis and salts of these compounds, and the preparation thereof by reacting amino-acids so that there are linked together in an amide-like manner the residues of an L-asparagine having a protected amino group, said protecting amino group being capable of being split off by hydrogenation or hydrolysis of an L-arginine having the amino group in the amidino group protected by a nitro group, of valine, of an L-tyrosine having a free or substituted hydroxyl group, of L-valine, of L-histidine, of L-proline, of L-phenylalanine, of L-histidine and of an L-leucine ester to form a decapeptide having the aforesaid series of amino-carboxylic residues in the sequence referred to above, then in the decapeptide so obtained liberating the free carboxyl group from the esterified carboxyl group in the leucine residue, the free amino group from the protected amino group of the asparagine residue and the nitro group in the arginine residue and, when required, liberating the hydroxyl group from a substituted hydroxyl group in the tyrosine residue.  The process may be extended by converting the carbonyl amide group in the asparagine residue to a free carboxyl group by hydrolysis with an alkali hydroxide or a mineral acid such as hydrochloric acid to form hypertensin which differs from the decapeptide of the above formula in that the first residue is an aspartic acid residue and not an asparagine residue.  The invention also includes L-asparaginyl-nitro-L-arginine the free amino group of which is protected by a radical capable of being split off by hydrogenation or hydrolysis and esters thereof, and salts of these compounds; L-valyl-L-tyrosyl-L-valyl-L-histidyl-L-prolyl-L-phenylalanyl- L -histidyl -L-leucine and esters thereof having a free or protected amino group, the protecting group being capable of being split off by hydrogenation or hydrolysis, and salts of these compounds; L-valyl-L-typosyl-L-valyl-L-histidine and derivatives thereof having an esterified carboxyl group and a free or protected amino group or a free carboxyl group and a protected amino group, the protecting group being capable of being split off by hydrogenation or hydrolysis, and salts of these compounds; L-asparaginyl-nitro-L-arginyl-L-valyl-L-tyrosyl-L-valyl-L-histidin the free amino group of which is protected by a radical capable of being split off by hydrogenation or hydrolysis and esters thereof, and salts of these compounds; L-prolyl-L-phenylalanyl-L-histidyl-L-leucine ester the free amino group of which may be protected by a radical capable of being split off by hydrogenation or hydrolysis, and salts of these compounds; L-valyl-L-tyrosine and derivatives thereof having a free or esterified carboxyl group and a protected amino group or an esterified carboxyl group, a protected amino group or an esterified carboxyl group, a protected amino group and an O-acyl group, the protecting group being capable of being split off by hydrogenation or hydrolysis, and salts of these compounds; L-valyl-histidine and esters thereof having a free or protected amino group, the protecting group being capable of being split off by hydrogenation or hydrolysis, and salts of these compounds; L-valyl-L-tyrosyl-L-valine and derivatives thereof having a protected amino group, or an esterified carboxyl group and a protected amino group, the protecting group being capable of being split off by hydrogenation or hydrolysis, and salts of these compounds; L-prolyl-L-phenylalanylhistidine the free amino group of which is protected by a radical capable of being split off by hydrogenation or hydrolysis and esters thereof, and salts of these compounds; and L-prolyl-L-phenylalanine having a protected amino group, the protecting group being capable of being split off by hydrogenation or hydrolysis and esters thereof, and salts of these compounds. Radicals that may be used to protect the free amino groups are the carbobenzyloxy and trityl radicals.  The above process may include any of the following steps:-(1) nitro-L-arginine may be acylated with an L-asparagine containing the protected amino group to form L-asparaginyl-nitro-L-arginine having a protected amino group in the asparaginyl residue which may then be used in the above step-wise process to form the decapeptide or may be condensed with L-vayl-L-tyrosyl-L-valyl- L-histidyl- L-prolyl-L-phenylalanyl-L -histidyl-L-leucine ester to form the desired decapeptide; (2) the L-asparaginyl-nitro-L-arginine containing the protected amino group as in (1) may be condensed with L-vayl-L-tyrosyl-L-valyl-L-histidine to form an L-asparaginyl-nitro-L-arginyl-L-valyl-L-tyrosyl-L-valyl- L -histidine which is then reacted with an L-prolyl-L-phenylalanyl-L-histidyl-L-leucine ester to form the desired decapeptide; and (3) L-valyl-L-tyrosyl-L-valyl-histidine may be condensed with L-asparaginyl-nitro-L-arginine containing the protected amino group to form L-asparaginyl-nitro-L-arginyl-L-valyl-L-tryrosyl-L-valyl-histidine which is then condensed with L-prolyl-L-phenylalanine to form the octapeptide L-asparaginyl-nitro-L-arginyl-L-valyl-L-tyrosyl-L-valyl- L-histidyl - L-prolyl-L-phenylalanine and the octapeptide is then then condensed with L-histidyl-L-leucine ester to form the desired decapeptide.  In the steps (1) to (3) above, L-valine may be condensed with L-tyrosine to form an L-valyl-L-tyrosine, L-valine may be condensed with L-histidine to form an L-valyl-L-histidine, L-proline may be condensed with L-phenylalanine to form an L-prolyl-L-phenylalanine, and finally L-histidine may be condensed with an L-leucine ester to form an L-histidyl-L-leucine ester; the L-valyl-L-histidine may then be acylated with L-valyl-L-tyrosine to form an L-valyl-L-tyrosyl-L-valyl-L-histidine, or alternatively L-valine may be condensed with the L-valyl-L-tyrosine to form L-valyl-L-tyrosyl-L-valine which is then condensed with histidine to form the same product; L-prolyl-L-phenylalanine may be condensed with an L-histidyl-L-leucine ester to form an L-prolyl-L-phenylalanyl-L-histidyl- L-leucine ester which may also be prepared by a process in which L-histidine is acylated with L-prolyl-L-phenyl-alanine to form L-prolyl-L-phenylalanyl-histidine which is then reacted with an L-leucine ester; and L-valyl-L-tyrosyl-L-valyl-L-histidyl-L-prolyl- L-phenylalanyl-L -histidyl-L-leucine ester is prepared from the reaction of an L-valyl-L-tyrosyl-L-valyl-L-histidine and an L-prolyl-L-phenylalanyl-L-histidyl-L-leucine ester.  In all the steps (1) to (3) above and the processes by which reactants for these steps may be prepared, free amino groups not taking part in the reaction must be protected by radicals capable of being split off by hydrogenation or hydrolysis, and amino acids to be acylated are advantageously used in the form of their esters, e.g. the methyl or ethyl esters.  In addition an intermediate compound obtainable at any stage of the process may be used as the starting material for carrying out the remaining steps of the process.  As methods of acylation there are mentioned the reaction of a protected amino-acid with the appropriate phosphite amide, e.g. the phosphite amide obtained by reacting diethylchlorophosphite and nitro-L-arginine methyl ester to form the diethylphosphite amide of nitro-L-arginine methyl ester of the formula <FORM:0876570/IV (b)/3> The reaction of an acid and amine in the presence of a carbo-diimide such as 1-cyclo-hexyl-3-(2-morpholinyl-(4)- ethyl)- carbo-diimide; and particularly the reaction of an amine with an activated ester in which the acitvating substituent present in the alcohol component is advantageously a cyano or nitro group.  In the examples the following compounds are prepared (some of the compounds are converted in salts such as the hydrochloride and hydrobromide salts):-N-carbobenzyloxy-L-asparaginyl-nitro- L-arginine and the methyl ester thereof, N-carbobenzyloxy-L-asparaginyl-nitro- L-arginyl- L-valyl-L-tyrosyl - L-valyl-histidine and the methyl ester thereof, N-carbobenzyloxy-L-asparaginyl-nitro-L-arginyl- L-valyl- L-tyrosyl -L-valyl- L-histidyl- L-prolyl- L-phenylalanyl-L-histidyl-L -leucine methyl ester, L-asparaginyl-L-arginyl-L-valyl-L-tyrosyl- L-valyl-L-histidyl-L -prolyl-L-phenylalanyl-L-histidyl-L-leucine and the methyl esters thereof, hypertensin, N-carbobenzyloxy- L-valyl-L-tyrosyl-L-valyl-L-histidyl-L-prolyl-L - phenyl-alanyl-L-histidyl-L-leucine methyl ester, L-valyl-L-tyrosyl-L-valyl-L-histidyl- L-prolyl-L-phenylalanyl-L -histidyl- L-leucine and the methyl ester thereof, N-carbobenzyloxy-L-valyl-L-tyrosine ethyl ester, N-carbobenzyloxy-L-valyl-O-benzoyl-L-tyrosine ethyl ester, N-carbobenzyloxy- L-valyl- L-tyrosine, L-valyl-L-tyrosine, N-carbobenzyloxy- L-valyl-L-histidine and the methyl ester thereof, L-valyl-L-histidine and the methyl ester thereof, N-carbobenzyloxy- L-valyl- L-tyrosyl-L-valine methyl ester, N-carbobenzyloxy-L-valyl-L-tyrosyl-L-valine, L-valyl-L-tyrosyl-L-valine, N-carbobenzyloxy-L-valyl-L (and D)-tyrosyl-L-valyl-L-histidine methyl ester, N-carbobenzyloxy-L-valyl- L-tyrosyl- L-valyl-L-histidine, L-valyl-L-tyrosyl-L-valyl-L-histidine and the methyl ester thereof, N-carbobenzyloxy-L-valyl- L-tyrosyl-L-valyl- L-histidine, L-valyl-L-tyrosyl-L-valyl-L-histidine and the methyl ester thereof, N-carbobenzyloxy-L-prolyl-L-phenylalanine and the methyl and p-nitrophenyl ester thereof, N-carbobenzyloxy- L-prolyl- L-phenylalanyl- L-histidyl- L-leucine and L-p