Patent GB-984810-A (GB)
Title: Polypeptides
IPC: A61K38/22
Filed: 1962-10-01
Abstract: The invention comprises polypeptides R-L-alanyl - L - phenylalanyl - L - isoleucylglycyl- L - leucyl - L - methioninamide wherein R may be hydrogen, L-aspartyl, L-glutaminyl-L-prolyl - L - seryl - L - lipyl - L - aspartyl or L-pyroglutamyl - L - prolyl - L - seryl - L - lysyl-L-aspartyl, their salts and esters and protected derivatives e.g. the N-tosyl-, -carbobenzozy-, - carbo - t - butoxy -, - trifluoroacetyl, or - trityl - derivatives; or the methyl, ethyl, t-butyl; benzyl or p-nitrobenzyl esters, or hydrazides); the preparation thereof by condensing a derivative of L-alanyl-L-phenylalanyl-L-isoleucine having a protective group for an amino group with glycyl-L-leucyl-L-methioninamide, where appropriate condensing the hexapeptide with a derivative of aspartic acid having a protective group for an amino-group and b -carboxyl group and where appropriate condensing the resulting heptapeptide with a derivative of L - glutaminyl - L - prolyl - L-seryl - L - lysine having the amino - group protected, where appropriate eliminating ammonia from the resulting undecapeptide to yield L - pyroglutamyl - L - prolyl - L - seryl-L - lysyl - L - aspartyl - L - alanyl - L - phenyl-alanyl - L - isoleucyl - glycyl - L - leucyl - L-methioninamide and removing the protecting groups.  The removal of ammonia may be effected by carboxylic acid exchange resins or heating with water.  Tosyl - L - pyroglutamyl - L - proline is prepared from tosyl-L-pyroglutamyl chloride and L - proline and converted into tosyl - L - glutaminyl - L - proline by ammonia.  Carbobenzoxy - L - seryl - hydrazide is converted into the azide and this was converted into carbobenzoxy - L - seryl - (e  - N - tosyl) - L-lysine ethyl ester, the free dipeptide ester, N-tosyl-L - glutaminyl - L - prolyl - L - seryl - (e  - N-tosyl) - L - lysine ethyl ester and the N - tosyl-tetrapeptide in stages. Carbobenzoxy-L-phenylalanine and L-isoleucine methyl ester give carbobenzoxy - L - phenylalanyl - L - isoleucine methyl ester, and this is converted in stages, into the free dipeptide ester, carbobenzoxy-L-alanyl-L - phenylalanyl - L - isoleucine methyl ester and the N - carbobenzoxy - tripeptide.  Carbobenzoxyglycyl - L - leucine and methionine methyl ester give carbobenzoxyglycyl - L - leucyl - L-methionine methyl ester and in stages this is converted to the N-carboxytripeptamide and the free tripeptamide. N-Carbobenzoxy-L-pyroglutamyl-L-proline is prepared from N-carbobenzoxy - L - pyroglutamyl chloride and L - proline and is reacted with ammonia to give N-carbobenzoxy - L - glutaminyl - L - proline.  N - Trityl-L-serine is prepared by tritylating serine methyl ester and hydrolysing the N-trityl ester and is converted in stages into N-trityl-L-seryl-e  - N - carbobenzoxy - L - lysine methyl ester, L - seryl - e  - N - carbobenzoxy - L - lipine methyl ester, N-carbobenzoxy-L-glutaminyl-L-prolyl - L - seryl e  - N - carbobenzoxy - L - lipine methyl ester, and the hydrazide. N-Trityl-glycyl-L-leucine is prepared from N-trityl-glycine and L-leucine methyl ester and hydrolysing the dipeptide ester. Glycyl-L-leucyl-L-methionamide is also prepared by condensing L-methioninamide, from L-methionine ethyl ester and ammonia, with N-trityl-glycyl-L-leucine and detritylating the N-trityl-tripeptamide so formed.  Hypotensive compositions comprise the compounds of the invention together with an inert carrier or diluent in dosage unit form, preferably for parenteral administration.  Specification 872,332 is referred to.