Patent GB-997849-A (GB)
Title: Polypeptides
IPC: C07K7/22
Filed: 1964-01-20
Abstract: The invention comprises peptides of the formula X - L - alanyl - L - phenylalanyl - L - isoleucyl - glycyl - L - leucyl - methioninamide, where X represents L-lysyl-L-aspartyl, L-seryl-L-lysyl-L-aspartyl or L-propyl-L-seryl-L-lysyl-L-aspartyl, their salts and derivatives wherein any free amino or carboxylic group has been blocked by a protecting group capable of being removed by acidolysis or hydrogenolysis and the preparation thereof by reacting the hexapeptide L - alanyl - L - phenylalanyl - L - isoleucyl - glycyl - L -leucyl - L - methioninamide with a di-, tri- or tetra-peptide X-OH, wherein any amino or carboxylic group not involved in the reaction is protected, the reaction being carried out in the presence of an N,N-dialkyl formamide or lower aliphatic nitrile solvent and a carbodiimide condensing agent, and optionally removing the protecting groups.  Free amino groups are blocked by tosyl, carbobenzoxy, carbo-t-butoxy, trityl, formyl, trifluoroacetyl groups, and free carboxyl by methyl, ethyl, t.-butyl benzyl and p-nitrobenzyl groups. a ,e  - N - Dicarbo - t. - butoxy - L - lysyl - (b  - t. - butyl) - L - aspartate is prepared by reacting dicyclohexylammonium N-carbobenzoxy-(b -t.-butyl)-L-aspartate with diazomethane and hydrogenating the product to give a -methyl-b -t.-butyl-L-aspartat hydrochloride, then reacting this with a ,e -N-dicarbo-t.-butoxy-L-lysine to give a ,e  - N - dicarbo - t. - butoxy - L - lysine - (a  - methyl - b  - butyl) - L - aspartate, and hydrolysing to remove the methyl group.  a ,e  - N - dicarbo - t. - butoxy - L - lysine is prepared from L-lysine monohydrochloride and p-nitrophenyl-t.-butylcarbonate and converted into the dicyclohexylammonium salt.  N - Carbo - t. - butoxy - L - seryl - e - N - carbo - t. - butoxy - L - lysyl - (b  - t. - butyl) - L - aspartate is prepared by reacting a -methyl-b -t.-butyl-L-aspartate hydrochloride with a -N-carbobenzoxy - e  - N - carbo - t. butoxy - L - lysine to give a  - N - carbobenzoxy - e  - N - carbo - t. - butoxy - L - lysyl - (a  - methyl - b  - t. - butyl) - L -aspartate, hydrogenating this to give e  - N - carbo - t. - butoxy - L - lysy - (a  - methyl - b  - t. - butyl) - L - aspartate, reacting this with N - carbo - t. - butoxy - L - serinazide (from the hydrazide with nitrous acid) to give N -carbo-t.-butoxy - L - seryl - e  - N - carbo - t. - butoxy - L - lysyl (a  - methyl - b  - t. - butyl) - L - aspartate and selectively hydrolysing the methyl ester group.  N - Carbo - t. - butoxy - L - propyl - L - seryl - e  - N - carbo - t. - butoxy - L - lysyl - (b  - t. - butyl) - L-aspartate is prepared by condensing N-carbobenzoxy-L-serine with e -N-carbo-t.-butoxy-L-lysyl - (a  - methyl - b  - t. - butyl) - L - aspartate to give N - carbobenzoxy - L - seryl - e  - N - carbo - t. - butox - L - lysyl - (a  - methyl - b  - t. - butoxyl) - L - aspartate hydrogenating this to give L - seryl - e  - N - carbo - t. - butoxy - L - lysyl - (a  - b  - t. - butyl) - L - aspartate, condensing this with N-carbo-t.-butoxy-proline to give N - carbo - t. - butoxy - L - propyl - L - seryl - e  - N - carbo - t. - butoxy - L - lysyl - (a  - methyl - b  - t. - butyl - L - aspartate and selectively hydrolysing the methyl ester group.  Pharmaceutical compositions comprise one or more of the peptides of the invention in admixture with a therapeutically acceptable vehicle. The compounds are antihypertensive agents.  Specifications 872,332 and 984,810 are referred to.