Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output. Thus, linagliptin stimulates the release of insulin in a glucose-dependent manner and decreases the levels of glucagon in the circulation.
Starting from commercially available 8-bromo-3-methylxanthine 1 linagliptin was prepared in four steps. As part of a sequential alkylation sequence, xanthine derivative 1 was first N-alkylated with butyn-2-yl bromide in the presence of N,N-diisopropylethylamine followed by a second N-alkylation with (chloromethyl)-4-methylquinazoline 3 in the presence of potassium carbonate to furnish xanthine derivative 4. Subsequent nucleophilic aromatic substitution of the bromide in 4 with (R)-3-Boc-aminopiperidine followed by the Boc deprotection of the primary amine in 6 yielded linagliptin.
^"8-(3-(R)-Aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a Highly Potent, Selective, Long-Acting, and Orally Bioavailable DPP-4 Inhibitor for the Treatment of Type 2 Diabetes'". Eckhardt M, Langkopf E, Mark M, Tadayyon M, Thomas L, Nar H, Pfrengle W, Guth B, Lotz R, Sieger P, Fuchs H, Himmelsbach F Journal of Medicinal Chemistry; 2007; 50 pp 6450 - 6453; doi:10.1021/jm701280z