ES416516A1 - A PROCEDURE FOR THE PREPARATION OF NONAPEPTIDES. - Google Patents

Abstract

A procedure for the preparation of nonapeptides that constitute active ingredients in pharmaceutical compositions with natriuretic properties, of the general formula **(See formula)** in which Q means the radical of arginine or lysine, Mpr means the beta-mercaptopropionyl group and all amino acids with an asymmetric carbon atom have the L configuration, and their non-toxic and pharmaceutically usable acid addition salts, the process of which comprises a) dissociate the protecting groups of a peptide of the general formula **(See formula)** in which R1 means a hydrogen atom or an amide protecting group and Q'means a grouping of the formula -NH-CH [- (CH2) 3-NH-C (= NH) -NHR2] -CO- or -NH-CH [- (CH2) 4-NH-R3] -CO, where R2 means a hydrogen atom or a guanidine radical protecting group and R3 means a hydrogen atom or a protecting group from the lysine epsilon-amine group, provided that at least one of the radicals R1 and R2 or R3 signifies a protecting group and where all amino acids with an asymmetric carbon atom have L-configuration, and convert, if desired, the obtained free peptide, by reaction with an organic or inorganic acid, into a pharmaceutically usable non-toxic acid addition salt, or b) oxidizing a peptide of the general formula **(See formula)** in which Q has the meaning attributed to it in claim 1 and, R4 and R5 each represent a hydrogen atom or a sulfhydryl protecting group, and where all amino acids with an asymmetric carbon atom have an L configuration, with simultaneous or preliminary dissociation of any protecting group that may be present and convert the product obtained, if desired, by reaction with an organic or inorganic acid, in a pharmaceutically usable non-toxic acid addition salt, O well c) oxidizing a peptide of the general formula **(See formula)** in which R1 means a hydrogen atom or an amide protecting group, Q'means a grouping of the formula -NH-CH [- (CH2) 3-NH- C (= NH) -NHR2] -CO- or -NH-CH [- (CH2) 4-NH-R3] -C0- where R2 means a hydrogen atom or a guanidine radical protecting group and R3 means a hydrogen atom or a protecting group from the lysine epsilon-amine group, provided that at least one of the radicals R1 and R2 or R3 represents a protecting group and R4 and R5 each represent a hydrogen atom or a protecting group and where all amino acids with an asymmetric carbon atom have an L configuration, with simultaneous dissociation of the protecting group or groups, and convert the product obtained, if desired, by reaction with an organic or inorganic acid, in a pharmaceutically usable non-toxic acid addition salt, or d) amidating a peptide of the general formula **(See formula)** in which means the radical of lysine or arginine, Mpr means the beta-mercaptopropionyl group and R6 means a hydroxy group or a carboxylic group activating radical, O well e) reacting a hexapeptide of the general formula **(See formula)** with a tripeptide of the general formula H-Pro-Q-Gly-NH2 0 react a heptapeptide of the general formula **(See formula)** with a dipeptide of the general formula H-Q-Gly-NH2 or react an octapeptide of the general formula **(See formula)** with glycine amide and convert, if desired, the resulting nonapeptide into a pharmaceutically usable non-toxic acid addition salt. In formulas VII to XI, R6 represents a hydroxylic group or an activator group of the boxyl group, q means the arginine or lysine radical and all amino acids with an asymmetric carbon atom have an L configuration. (Machine-translation by Google Translate, not legally binding)