SYNTHESIS OF FUSED 1,2,5-TRIAZEPINE-1,5-DIONES AND SOME N-2-SUBSTITUTED AND N-3-SUBSTITUTED DERIVATIVES - POTENTIAL CONFORMATIONAL MIMETICSFOR CIS-PEPTIDYL PROLINAMIDES

The synthesis of a new fused 1,2,5-triazepine-1,5-dione heterocycle, w hich is expected to mimic structural features of cis-peptidyl prolinam ides, is described, The required parent heterocycle, corresponding to cis-glycyl-(2S)-prolinamide, has been prepared in good yield by the cy clisation of N-(2-bromoacetylprolyl)hydrazine which Is itself generate d in situ from the bromoacetyl proline methyl ester. Analogues corresp onding to cis-(2R)-alanyl- and cis-(2S)alanyl-(2S)-prolinamide have be en similarly prepared from the appropriate N-(2-bromopropionyl)proline methyl esters and hydrazine hydrate where the cyclisation step, invol ving the displacement of bromide, has been shown to occur with inversi on of configuration at C-2 of the propionyl moiety, Acylation at the N -3 position of the triazepine is equivalent to N-terminal acylation of the residue preceding the proline residue in cis-aminoacyl prolinamid es, This has been achieved without incident using standard peptide cou pling procedures, Extension at the 'C-terminal' has been achieved by p reparing elaborated hydrazine precursors which are reacted with suitab ly activated esters of N-alpha-halogenoacylprolines, prior to cyclisat ion, to give the required fused triazepine dione. Thus it is possible to prepare constrained cis-peptidyl prolyl peptide mimetics of defined stereochemistry based upon this new triazepine dione in which all of the non-proline residues can be varied.