Patent FR-2619813-B1 (FR)
Inventor: VINCENT MICHEL
IPC: C07K5/06
Filed: 1987-08-28
Granted: 1991-05-03
Abstract: 1. Claims for the contracting states : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE Compounds of formula (I) :   see diagramm : EP0305297,P29,F1   in which E is a hydrogen atom or a lower alkyl radical, as well as their addition salts with a pharmaceutically acceptable base or acid. 1. Claims for the contracting states : ES, GR Process for preparing the compounds of formula (I) :   see diagramm : EP0305297,P25,F3   in which E is a hydrogen atom or a lower alkyl radical, as well as their addition salts with a pharmaceutically acceptable base or acid, characterised in that a derivative of formula (III) :   see diagramm : EP0305297,P26,F1   in which E' denotes a lower alkyl or benzyl group, is subjected to hydrogenation in the presence of a catalyst such as palladinized charcoal, to obtain : - the compound of formula (I) for which E = H, in the case where E' denotes a benzyl group, - a compound of formula (I) for which E is a lower alkyl group, in the case where E' denotes a lower alkyl group, which compound can optionally be subjected to alkaline hydrolysis to obtain the compound of formula (I) for which E = H, it being possible, if so desired, for the compound of formula (I) thereby obtained to be salified with a therapeutically compatible inorganic or organic acid or base ; the compound of formula (III) itself being obtained : - either by subjecting a 2-oxo-4-phenylbutyrate of formula (IV) :   see diagramm : EP0305297,P26,F2   or (sic) E' has the same meaning as in the formula (III), to reductive amination in the presence of an alkali metal mixed hydride or an alkali metal mixed cyanohydride, such as sodium cyanoborohydride, with a lysine derivative in which the epsilon-amino and carboxyl groups are protected by suitable groups, such as tert-butyl (S)-N**epsilon-benzyloxycarbonyllysinate of formula (V) :   see diagramm : EP0305297,P26,F3   to obtain a derivative of formula (VI) :   see diagramm : EP0305297,P27,F1   in which E' has the same meaning as in the formula (III), the (S, R) and (S, S) isomers of which are isolated by a customary separation technique such as chromatography on a silica column, the (S, S) isomer thereby obtained then being subjected to a deprotection of the carboxylic acid group of the lysine in acid medium to obtain a derivative of formula (VII) :   see diagramm : EP0305297,P27,F2   in which E' has the meaning as in the formula (III), which is then condensed with a (3S)-2-azabicyclo[2.2.2]oc-tane-3-carboxylic acid ester, and preferably with the benzyl ester of formula (VIII) :   see diagramm : EP0305297,P27,F3   in the presence of a peptide coupling agent such as dicyclohexycarbodiimide (sic) in the presence of hydroxybenzotriazole, to obtain a derivative of formula (III), - or by coupling a (3S)-2-azabicyclo[2.2.2]octane-3-carboxylic acid ester and preferably the benzyl ester of the above formula designated (VIII), with a lysine derivative in which the alpha- and epsilon-amino groups are protected by suitable groups, such as (S)-N**alpha-tert-butoxycarbonyl-N**epsilon- -benzyloxycarbonyllysine of formula (IX) :   see diagramm : EP0305297,P27,F4   in the presence of a peptide coupling agent such as dicyclohexylcarbodiimide in the presence of hydroxybenzotriazole, to obtain a derivative of formula (X) :   see diagramm : EP0305297,P28,F1   which is subjected to a deprotection of the alpha-amino group of the lysyl residue in acid medium, to obtain a derivative of formula (XI) :   see diagramm : EP0305297,P28,F2   which is subjected to reductive amination in the presence of an alkali metal mixed hydride or an alkali metal mixed cyanohydride, such as sodium cyanoborohydride, with a derivative of formula (IV) designated above, to obtain the derivative of formula (III) in racemic form (III, R, S) :   see diagramm : EP0305297,P28,F3   in which E' has the same meaning as in the formular (III), the (S, S, S) isomer of which is isolated by a customary separation technique such as chromatography on a silica column.