Process for systhesizing cyclic peptides

A process for synthesizing a cyclic peptide represented by the following formula I:

• ##STR7## wherein X1 is 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylbutanoate or 2,4-dihydroxy-3-methylpentanoate;
• X2 is MeVal;
• X3 is Phe or oFPhe;
• X4 is MePhe, oFMePhe, MeGly, MeTyr, .beta.HOMePhe, or .beta.R.sub.1 OMePhe, in which R.sub.1 is CO(CH.sub.2).sub.3 COOH, COCH.sub.3 or CO(CH.sub.2).sub.2 NHCOCH.sub.3 ;
• X5 is Pro, 4Hyp or SPro;
• X6 is aIle, Leu, Val, Nle, GluOR.sub.2, in which R.sub.2 is benzyl, C1-12 alkyl or C1-12 alkenyl, HONva or R.sub.3 ONva, in which R.sub.3 is n-hexanoyl;
• X7 is MeVal, MeaIle, MeLeu, 2-hydroxy-3-methylbutanoate, HOMeNva or R.sub.4 OMeNva, in which R.sub.4 is benzyl;
• X8 is Leu, Nva, AIle, HONva or GluOR.sub.5, in which R.sub.5 is cHex;
• X9 is .beta.HOMeVal or MeThr;
• and the dotted lines represent intramolecular hydrogen bonds;
• which process comprises:
• (a) cyclizing a linear peptide having a sequence represented by the following formula II:
• X6.fwdarw.X7.fwdarw.X8.fwdarw.X9.fwdarw.X1.fwdarw.X2.fwdarw.X3.fwdarw.X4.fw darw.X5 II
• wherein
• X1 is 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylbutanoate or 2,4-dihydroxy-3-methylpentanoate;
• X2 is MeVal;
• X3 is Phe or oFPhe;
• X4 is MePhe, oFMePhe, MeGly, O-protected MeTyr, O-protected .beta.HOMePhe or .beta.R.sub.1 OMePhe, in which R.sub.1 is CO(CH.sub.2).sub.3 COOH, COCH.sub.3 or CO(CH.sub.2).sub.2 NHCOCH.sub.3 ;
• X5 is Pro, O-protected 4Hyp, SPro or a reactive derivative having a activated carboxyl group thereof;
• X6 is aIle, Leu, Val, Nle, GluOR.sub.2, in which R.sub.2 is benzyl, C1-12 alkyl or C1-12 alkenyl, O-protected HONva or R.sub.3 ONva, in which R.sub.3 is n-hexanoyl;
• X7 is MeVal, MeaIle, MeLeu, 2-hydroxy-3-methylbutanoate, O-protected HOMeNva or R.sub.4 OMeNva, in which R.sub.4 is benzyl;
• X8 is Leu, Nva, aIle, O-protected HONva or GluOR.sub.5, in which R.sub.5 is cHex;
• X9 is .beta.HOMeVal, O-protected .gamma.HOMeVal or O-protected MeThr;
• and
• (b) deprotecting the O-protected cyclic peptide obtained in step (a), if the cyclic peptide contains an O-protected amino acid.