Solid phase synthesis of cyclic amino acid molecules
AssigneesEncycle Therapeutics, The Governing Council of the University of Toronto, Universite de Sherbrooke
InventorsJennifer L. Hickey, John Mancuso, Eric Marsault, Andrew L. Roughton, Adam P. Treder, Marie-Claude J. Trembley, Andrei K. Yudin, Serge Zaretsky
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Abstract
The present invention relates to cyclic amino acid molecules and methods of preparing the same, and in particular the macrocyclization of amino acids or linear peptides bound to a solid support.
Claims34
A process to produce a cyclic molecule bound to a solid support comprising reacting a peptide, having an amino terminus and a carboxyl terminus and bound to the solid support by a side chain of the peptide, with an isocyanide and a compound having formula (Ia) and/or (Ib):
- wherein:
- R1, R2 and R3 are independently selected from H;
- lower alkyl;
- alkenyl;
- heterocycle;
- cyckoalkyl;
- esters of the formula —C(O)OR* wherein R* is selected from alkyl and aryl;
- amides of the formula —C(O)NR**R***, wherein R** and R*** are independently selected from alkyl and aryl;
- —CH2C(O)R, wherein R is selected from —OH, lower alkyl, aryl, -lower alkyl-aryl, or —NRaRb, where Ra and Rb are independently selected from H, lower alkyl, aryl or -lower alkyl-aryl;
- —C(O)Rc, wherein Rc is selected from lower alkyl, aryl or -lower alkyl-aryl;
- or -lower alkyl-ORd, wherein Rd is a suitable protecting group or OH group;
- all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents;
- and
- the aldehyde component thereof may optionally be in its bisulfite adduct form;
- and the compound comprises an aziridine chiral center proximal to the aldehyde with stereochemistry that is homochiral with respect to the carbon atom proximal to the amino terminus of the peptide.
A process for preparing a cyclic molecule of formula [(III)] bound to a solid support:
- wherein,
- R1, R2 and R3 are independently selected from H;
- lower alkyl;
- aryl;
- heteroaryl;
- alkenyl;
- heterocycle;
- esters of the formula —C(O)OR* wherein R* is selected from alkyl and aryl;
- amides of the formula —C(O)NR**R***, wherein R** and R*** are independently selected from alkyl and aryl;
- —CH2C(O)R, wherein R is selected from —OH, lower alkyl, aryl, -loweralkyl-aryl, or —NRaRb, where Ra and Rb are independently selected from H, lower alkyl, aryl or -loweralkyl-aryl;
- —C(O)Rc, wherein Rc is selected from lower alkyl, aryl or -lower alkyl-aryl;
- or -lower alkyl-ORd, wherein Rd is a suitable protecting group or OH group;
- all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents,
- Z is an amino terminus of a peptide;
- —C=O— is the carboxy terminus of the peptide;
- L, along with Z and —C=O— is the peptide;
- R″ is an optionally substituted amide;
- R4 is a nucleophile;
- wherein the peptide is bound to the solid support by a side chain of the peptide;
- comprising reacting a compound having formula [II] bound to the solid support with a nucleophile:
A process for preparing a cyclic molecule of formula [(IV)]:
- wherein,
- R1, R2 and R3 are independently selected from H;
- lower alkyl;
- aryl;
- heteroaryl;
- alkenyl;
- heterocycle;
- esters of the formula —C(O)OR* wherein R* is selected from alkyl and aryl;
- amides of the formula —C(O)NR**R***, wherein R** and R*** are independently selected from alkyl and aryl;
- —CH2C(O)R, wherein R is selected from —OH, lower alkyl, aryl, -loweralkyl-aryl, or NRaRb, where R and Rb are independently selected from H, lower alkyl, aryl or -loweralkyl-aryl;
- —C(O)Rc, wherein Rc is selected from lower alkyl, aryl or -lower alkyl-aryl;
- or -lower alkyl-ORd, wherein Rd is a suitable protecting group or OH group;
- all of which are optionally substituted at one or more substitutable positions with one or more suitable substituents;
- Z is an amino terminus of a peptide;
- —C=O— is the carboxy terminus of the peptide;
- L, along with Z and —C=O— is the peptide;
- R″ is an optionally substituted amide;
- R4 is a nucleophile;
- comprising cleaving a solid support from a cyclic molecule of formula [(III)] bound to the solid support:
- and optionally deprotecting one or more side chains of the peptide if one or more of said side chains are protected with protecting groups.
-35. (canceled)
Dependencies are inferred from the claim text.