Preparation of dipeptide inhibitors of dipeptidyl peptidase IV.

Abstract

The invention relates to ArCR7R8CH(NH2)CR5R6C(O)NHCR3R4C(O)NR1R2 (I; variables defined below; e.g. 2-[[(3R)-3-amino-4-(2-fluorophenyl)butanoyl]amino]-N-benzylindan-2-carboxamide hydrochloride (free base shown as II)) or pharmaceutically-acceptable salts thereof, which possess dipeptidyl peptidase IV (DPP-IV) inhibitory activity and accordingly have value in the treatment of disease states assocd. with DPP-IV activity, such as diabetes mellitus (not claimed). Processes for the prepn. of said compds., intermediates in said processes, pharmaceutical compns. contg. said compds. or salts, and the use of said compds. or salts are also described. Using a fluorescence assay the compds. I generally show activity with IC50 < 100 μM; II showed an IC50 = 0.46 μM, and (R)-3-amino-4-(2-fluorophenyl)-N-((R)-1-methyl-1-methylcarbamoyl-2-phenylethyl)butanamide hydrochloride showed an IC50 = 0.45 μM. For I: Ar is Ph (un)substituted with 1-5 halo, (1-6C)alkyl ((un)substituted with 1-5 halo), (1-6C)alkoxy ((un)substituted with 1-5 halo) and cyano; R1 = H and (1-6C)alkyl; R2 = H, (1-6C)alkyl, (3-8C)cycloalkyl, (5-12C)bicycloalkyl, etc. or R1 and R2 may together with the N to which they are attached form a ring; R3 and R4 = H, (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkenyl, (5-12C)bicycloalkyl, etc. or R3 and R4 together form a ring; R5, R6, R7 and R8 = H and (1-6C)alkyl; addnl. details are given in the claims. A method of prepn. is claimed and ∼70 example prepns. and/or characterization data are included. For example, 96 % of II was prepd. by deprotection of tert-Bu [(1R)-3-[[2-[(benzylamino)carbonyl]-2,3-dihydro-1H-inden-2-yl]amino]-1-(2-fluorobenzyl)-3-oxopropyl]carbamate, which was prepd. (86 %) by condensation of benzylamine with 2-[(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2-fluorophenyl)butanoyl]indan-2-carboxylic acid (prepn. described). [on SciFinder(R)]