Peptides containing an aliphatic-aromatic ketone side chain

Claim 1

L. A peptide or a nontoxic salt thereof, said peptide having the formula: X-R 1 -R 2 -R 3 -R 4 -R 5 -R 6 (V)-R 7 -Arg-Pro-R 10 wherein X is hydrogen or an acyl group having 7 or less carbon atoms; R 1 is pGlu, dehydro-Pro, Pro, D-pGlu, D-Phe, D-Trp or β-D-NAL; R 2 is (W)D-Phe or His; W is F, C1, Cl 2 Br, NO 2 or C α Me/Cl; R 3 is β-D-NAL, Trp, D - T rp, D-PAL, (N in For)D-Trp or D-Trp which is substituted in the 5- or 6-position with N0 2 , NH 2 , OCH 3 , F, Cl, Br or CH 3 ; R 4 is Ser, Orn, AAL or aBu; R 5 is Tyr, Arg, (3F)Phe, (2F)Phe, (3I)Tyr, (3CH 3 )Phe, (2CH 3 )Phe, (3Cl)Phe or (2Cl)Phe; R 6 is D-Glu, D-Hgl or D-Asp; R 7 is Leu, NML, Nle or NVa; R 10 is Gly-NH 2 , D-Ala-NH 2 or NH-Y, with Y being lower alkyl, cycloalkyl, fluoro lower alkyl or NHCONHQ, where Q is H or lower alkyl; and V is an aromatic moiety portion of a ketone formed from the carboxylic group side chain of R 6 and a compound selected from Class Z' as defined herein.

Claim 10

A method of making a GnRH analog peptide having a glutamic acid, a homoglutamic acid or an aspartic acid residue in the 6-position of the main chain thereof, the side chain of which residue constitutes a mixed alkyl ketone terminating in an aromatic group, which method comprises forming a nonapeptide or decapeptide intermediate wherein said main peptide chain contains a glutamic acid, a homoglutamic acid or an aspartic acid residue in the 6-position, the side chain carboxyl group of which is . protected with a protecting group selected from the class consisting of benzyl ester, 2,6-dichlorobenzyl, dinitrophenyl, 1-hydroxy-benzotriazole benzyl ester, 8-hydroxy-quinoline ester, p-nitrobenzyloxy, phenylazophenyl and tertiary butoxy; treating said peptide intermediate with HF and an aromatic compound selected from Class Z' (as defined herein) under conditions so that said protecting group is removed and an acylium ion intermediate is formed which ion reacts with said aromatic compound to form a mixed alkyl ketone therewith, and removing said HF and recovering said desired GnRH analog peptide.

Claim 11

A method of making a peptide hormone of not greater than about fifty residues having a glutamic acid, a homoglutamic acid or an aspartic acid residue at a nonterminus position in the main chain thereof, the side chain of which residue constitutes a mixed alkyl ketone terminating in an aromatic group, which method comprises forming a peptide intermediate wherein said main peptide chain contains a glutamic acid, a homoglutamic acid or an aspartic acid residue in the desired position, the side chain carboxyl group of which is protected with a protecting group selected from the class consisting of benzyl ester, 2,6-dichlorobenzyl, dinitrophenyl, 1-hydroxy-benzotriazole benzyl ester, 8-hydroxy-quinoline ester, p-nitrobenzyloxy, phenylazophenyl and tertiary butoxy; treating said peptide intermediate with HF and an aromatic compound selected from Class Z' (as defined herein) under conditions so that said protecting group is removed and an acylium ion intermediate is formed which ion reacts with said aromatic compound to form a mixed alkyl ketone therewith, and removing said HF and recovering said desired peptide hormone which has increased binding affinity to the receptor in question as a result of the inclusion of said aromatic ketone side chain.

Claim 20

A method in accordance with Claim I wherein said treatment is carried out at a temperature of about 20°C. or above.