Method for producing peptides and their salts which have an agonist activity of luteinizing hormone releasing hormones secreted from the hypothalamus

摘要

A peptide of the formula:; $PTEXTPDAT5-oxo\—Pro\—R/PDATHILSPPDAT1/PDAT/SP/HILPDAT\—Trp\—Ser\—R/PDATHILSPPDAT2/PDAT/SP/HILPDAT\—R/PDATHILSPPDAT3/PDAT/SP/HILPDAT\—R/PDATHILSPPDAT4/PDAT/SP/HILPDAT\—Arg\—Pro\—R/PDATHILSPPDAT6/PDAT/SP/HILPDAT\ \ (I)\; /PDAT/PTEXT$ ;wherein R¹ represents His, Tyr, Trp or p—NH₂—Phe, R² represents Tyr or Phe, R³ represents an optionally substituted Gly or an optionally substituted &agr;-D-amino acid residue, R⁴ represents Leu, Ile or Nle, R⁶ represents (1) Gly—NH—R⁷, wherein R⁷ represents a hydrogen atom or an alkyl group which may optionally be substituted with a hydroxyl group, or (2) NH—R⁸, wherein R⁸ represents a hydrogen atom, an alkyl group which may optionally be substituted with a hydroxyl group or an ureido group (—NH—CO—NH₂), is produced advantageously in an industrial scale by reacting a peptide of the formula:; $PTEXTPDAT5-oxo\—Pro\—R/PDATHILSPPDAT1/PDAT/SP/HILPDAT\—Trp\—Ser\—R/PDATHILSPPDAT2/PDAT/SP/HILPDAT\—R/PDATHILSPPDAT3/PDAT/SP/HILPDAT\—OH\ \ (II)\; /PDAT/PTEXT$ ;wherein R¹, R² and R³ have the same meanings as defined above or its salts, with a peptide of the formula:; $PTEXTPDATH\—R/PDATHILSPPDAT4/PDAT/SP/HILPDAT\—R/PDATHILSPPDAT5/PDAT/SP/HILPDAT\—Pro\—R/PDATHILSPPDAT6/PDAT/SP/HILPDAT\ \ (III)\; /PDAT/PTEXT$ ;wherein R⁴ and R⁶ have the same meaning as defined above and R⁵ represents Arg which has been protected or its salts, to produce a peptide of the formula:; $PTEXTPDAT5-oxo\—Pro\—R/PDATHILSPPDAT1/PDAT/SP/HILPDAT\—Trp\—Ser\—R/PDATHILSPPDAT2/PDAT/SP/HILPDAT\—R/PDATHILSPPDAT3/PDAT/SP/HILPDAT\—R/PDATHILSPPDAT4/PDAT/SP/HILPDAT\—R/PDATHILSPPDAT5/PDAT/SP/HILPDAT\—Pro\—R/PDATHILSPPDAT6/PDAT/SP/HILPDAT\ \ (I\′)\; /PDAT/PTEXT$ ;wherein R¹, R², R³, R⁴, R⁵ and R⁶ have the same meanings as defined above or its salt, and then subjecting thus obtained peptide (I′) to a de-protecting group reaction.