Novel peptide derivatives and a process for the manufacture thereof

摘要

The invention comprises compounds of the general formula in which n1 and n2 each represent zero or unity, X represents a hydroxy, alkoxy, amino or hydrazino group or an alkylamino or dialkylamino group which may be long-chain in character (i.e. containing at least 10 carbon atoms) and each R represents a residue of an a -amino carboxylic acid devoid of its a -amino and carboxylic groups with at least one such residue carrying an amino and/or guanidino group which may in turn carry a long-chain aliphatic acyl substituent and in which A represents an amino group or an amino group which carries a long-chain acyl substituent, and acid addition salts thereof; there being at least one of said long-chain moieties present in the molecule and the preparation thereof by condensing the appropriate protected a -amino carboxylic acid with a protected a -amino acid or dipeptide or tripeptide or the appropriate protected dipeptide with an a -amino acid or dipeptide in the presence of a condensing agent, or reacting the appropriate protected a -amino carboxylic acid or dipeptide or tripeptide starting material in its mixed anhydride, azide, activated ester, or acid chloride form with the other component in the absence of a condensing agent, hydrolysing the terminal carboxyl function to a free carboxyl group or converting it into an amido, N-alkyl-amido, N,N-dialkylamido or hydrazido group, removing the protective groups, and, if desired, converting the resulting peptide into a salt; the long-chain acyl group, if not already present in the molecule, being effected by interchange with a protecting group which can be selectively split off. Carboxyl groups are protected prior to the condensation reaction involving them per se by conversion into their esters or amides or by salt formation. Free amino groups may be protected by conversion into benzyloxycarbonylamino groups by formylation, or by conversion into phthalyl derivatives or by the introduction of the long-chain acyl group. Compounds may contain more than one N-protecting group and if these are different the groups may be removed separately. Na - Palmitoyl - (Nd - carbobenzyloxy) - L-ornithine is prepared from the N-protected ornithine and palmitoyl chloride Na -palmitoyl-Ne -carbobenzyloxy-L, -D- and -DL-lysine; Na -stearyl-,-lauryl-, and -caproyl-Ne -carbobenzyloxy-L - lysine, and Na - palmitoyl - Na - carbobenzyloxy - L - diamino butyric acid. Ne -Palmitoyl-L-lysine methylester is prepared by reacting the copper complex of L-lysine with palmitoyl chloride to give Ne -palmitoyl-L-lysine and esterifying this with methanol. Similarly is prepared Na -palmitoyl L-diamino-butyric and its methyl ester. Ne -Phthaloyl-L-lysine ethyl ester hydrochloride prepared from the free acid is reacted with 10-andecenoic acid in the presence of dicyclohexyldicarbodimide to give Na - (10 - undecenoyl) - (Ne - phthaloyl) - L lysine ethyl ester and, on hydrolysis, the free acid. Na - Benzyloxycarbonyl - Ne - phthaloyl-L-lysine is prepared from the Ne -phthaloyl-L-lysine and benzyloxycarbonyl chloride. Specifications 1,000,899 and 1,000,900 are referred to.