Conformationally constrained backbone cyclized peptide analogs

A method for the preparation of cyclic peptides of the general Formula (I):

• 46
• wherein:
• a and b each independently designates an integer from 1 to 8 or zero;
• d, e, and f each independently designates an integer from 1 to 10;
• (AA) designates an amino acid residue wherein the amino acid residues in each chain may be the same or different;
• E represents a hydroxyl group, a carboxyl protecting group or an amino group, or CO—E can be reduced to CH2—OH;
• R and R′ each designates an amino acid side-chain optionally bound with a specific protecting group;
• and the lines designate a bridging group of the Formula:
• -X-M-Y-W-Z- (i) or -X-M-Z- (ii)
• wherein:
• one line may be absent;
• M and W are independently selected from the group consisting of disulfide, amide, thioether, thioester, imine, ether, and alkene;
• and X, Y and Z are each independently selected from the group consisting of alkylene, substituted alkylene, arylene, homo- or hetero-cycloalkylene and substituted cycloalkylene;
• comprising the steps of incorporating at least one Nα-ω-functionalized derivatives of amino acids of Formula (VI):
• 47
• wherein X is a spacer group selected from the group consisting of alkylene, substituted alkylene, arylene, cycloalkylene and substituted cycloalkylene;
• R′ is an amino acid side chain, optionally bound with a specific protecting group;
• B is a protecting group selected from the group consisting of alkyloxy, substituted alkyloxy, or aryl carbonyls;
• and G is a functional group selected from the group consisting of amines, thiols, alcohols, carboxylic acids and esters, aldehydes, alcohols and alkyl halides;
• and A is a specific protecting group of G;
• into a peptide sequence and subsequently selectively cyclizing the functional group with one of the side chains of the amino acids in said peptide sequence or with another ω-functionalized amino acid derivative.

A method for the preparation of cyclic peptides of the general Formula (II):

• 48
• wherein d, e and f each independently designates an integer from 1 to 10;
• (AA) designates an amino acid residue wherein the amino acid residues in each chain may be the same or different;
• E represents a hydroxyl group, a carboxyl protecting or an amino group, or CO—E can be reduced to CH2—OH;
• R is an amino acid side chain optionally bound with a specific protecting group;
• and the line designates a bridging group of the Formula:
• -X-M-Y-W-Z- (i) or -X-M-Z- (ii)
• wherein M and W are independently selected from the group consisting of disulfide, amide, thioether, thioester, imine, ether, and alkene;
• X, Y and Z are each independently selected from the group consisting of alkylene, substituted alkylene, arylene, homo- or hetero-cycloalkylene and substituted cycloalkylene;
• comprising the steps of:
• incorporating at least one ω-functionalized amino acid derivative of the general Formula (VI):
• 49
• wherein X is a spacer group selected from the group consisting of alkylene, substituted alkylene, arylene, cycloalkylene and substituted cycloalkylene;
• R is the side chain of an amino acid;
• B is a protecting group selected from the group consisting of alkyloxy, substituted alkyloxy, or aryloxy;
• and G is a functional group selected from the group consisting of amines, thiols, alcohols, carboxylic acids and esters or alkyl halides and A is a protecting group thereof;
• into a peptide sequence and subsequently selectively cyclizing the functional group with one of the side chains of the amino acids in said peptide sequence.