| 摘要 |
<p>A multi-stage, solution-phase synthesis of KPV (lysine-proline-valine) tripeptide diamide derivatives (I) is claimed, starting from an N,N'-diprotected lysine compound (II) and an optionally carboxy-protected proline compound (III) and utilizing specific combinations of protecting groups. Some compounds (I) are new. Solution-phase synthesis of KPV (lysine-proline-valine) tripeptide diamide derivatives of formula (I) or their salts involves: (a) reacting a diprotected lysine compound of formula P2-N-(CH2)4-C(NH-P1)-CO2H (II) (optionally salified with a mineral or organic base) and an optionally protected proline compound of formula (III) (optionally salified with a mineral or organic acid) in presence of an activating or coupling reagent in a solvent to give a protected dipeptide of formula (IV) (in either order); (b) coupling the C-terminal of the proline residue of (IV; P3 = OH) with a valinamide compound of formula Me2CH-CH(NH2)-CONR2R3 (V) (optionally salified with a mineral or organic acid) and (b) coupling the alpha-amino group of the N-terminal proline residue of (IV) with an acid chloride or anhydride of formula CR1R'1R''1-CO-Cl (VIA) or (CR1R'1R''1-CO)2-O (VIB); and (c) cleaving the protecting group P2 in the obtained protected tripeptide of formula (XII). R1, R'1, R''1 = H; 1-22C alkyl (optionally interrupted by a heteroatom such as O, N, S or Si); 4-10C cycloalkyl; 1-22C per- or polyfluoroalkyl; aryl (optionally substituted by one or more of halo and/or 1-4C alkyl); or aralkyl; or CR1R'1R''1 = 3-7 membered saturated ring (optionally substituted by one or more 1-4C alkyl and optionally containing a heteroatom such as O, S or N); R2, R3 = 1-24C alkyl (optionally interrupted by a heteroatom such as O, N, S or Si); 4-10C cycloalkyl; 1-22C per- or polyfluoroalkyl; aryl (optionally substituted by one or more of halo and/or 1-4C alkyl); or aralkyl; or NR2R3 = 5- or 6-membered saturated ring (optionally substituted by one or more 1-4C alkyl and optionally containing an additional heteroatom such as O, S or N); P1, P2 = different protecting groups; P3 = protecting group (different from P1 and P2) or OH; Provided that neither of CR1R'1R''1-CO- and NR2R3 is the residue of an aminoacid or peptide. An Independent claim is included for (I) and their salts as new compounds, provided that at least one of R1, R'1 and R''1 is other than H and at least one of R2 and R3 is other than H.</p> |
