Improved process for the preparation of diamidic d

专利名称：Improved process for the preparation of

diamidic derivatives of the tripeptid KPV

发明人：GENARD, SYLVIE申请号：EP04300039.7申请日：20040122公开号：EP1440977A1公开日：20040728

摘要：A multi-stage, solution-phase synthesis of KPV (lysine-proline-valine) tripeptidediamide derivatives (I) is claimed, starting from an N,N'-diprotected lysine compound (II)and an optionally carboxy-protected proline compound (III) and utilizing specificcombinations of protecting groups. Some compounds (I) are new. Solution-phasesynthesis of KPV (lysine-proline-valine) tripeptide diamide derivatives of formula (I) ortheir 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 optionallyprotected proline compound of formula (III) (optionally salified with a mineral or organicacid) in presence of an activating or coupling reagent in a solvent to give a protecteddipeptide of formula (IV) (in either order); (b) coupling the C-terminal of the prolineresidue 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 thealpha-amino group of the N-terminal proline residue of (IV) with an acid chloride oranhydride of formula CR1R'1R''1-CO-Cl (VIA) or (CR1R'1R''1-CO)2-O (VIB); and (c) cleavingthe 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 ofhalo 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 aheteroatom such as O, S or N); R2, R3 = 1-24C alkyl (optionally interrupted by aheteroatom 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 andoptionally containing an additional heteroatom such as O, S or N); P1, P2 = differentprotecting groups; P3 = protecting group (different from P1 and P2) or OH; Providedthat neither of CR1R'1R''1-CO- and NR2R3 is the residue of an aminoacid or peptide. AnIndependent claim is included for (I) and their salts as new compounds, provided that atleast one of R1, R'1 and R''1 is other than H and at least one of R2 and R3 is other than H.

申请人：L'OREAL

地址：14, rue Royale 75008 Paris FR

国籍：FR

代理机构：Catherine, Alain

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