Richard F. Heier

An asymmetric synthesis of (R)‐5‐(methylamino)‐5,6‐dihydro‐4H‐imidazo‐[4,5,1‐ij]quinolin‐2(1H)‐one (1) and its [2‐14C]‐ and [6,7‐3H2]‐labeled forms

(R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (1) is a dopamine agonist which shows selectivity for the D2 receptor subtype, and is of interest as a potential drug for the treatment of Parkinsons disease. An asymmetric epoxidation approach has been used to prepare 1 in eleven steps (15% overall yield) from 8-nitroquinoline. An advanced intermediate in this synthesis, tert-butyl (R)-methyl(8-amino-1,2,3,4-tetrahydro-3-quinolinyl)carbamate (10), has been reacted with [ 14 C]phosgene to provide a two-step synthesis of 1 labeled with carbon-14 at the C-2 position (236 μCi/mg). Bromination of 1 gave the dibromo analogue 12b which was reduced in the presence of tritium gas to give 1 labeled with tritium at the C-6 and C-7 positions (28.5 Ci/mmol). In addition to providing syntheses for labeled forms of the drug which are useful in drug disposition and receptor binding studies, this approach also provides a convenient synthesis for the unlabeled form of drug

α‐Methyl analogues of acetylenic amines as striatal muscarinic antagonists

Abstract— The effect of acetylenic amines, with or without α‐methyl substitution, on striatal acetylcholine (ACh) concentration in rats was investigated. Oxotremorine, oxotremorine‐1, and U‐77053 (trimethyl (4‐(1‐pyrrolidinyl)‐2 butynyl)‐urea), the unsubstituted amines, increased striatal ACh concentration. On the other hand, the corresponding α‐methyl substituted analogues, α‐methyl‐oxotremorine, BM‐5, and α‐methyl U‐77053, decreased the concentration of ACh in the striatum. The results indicate that substitution of α‐methyl in acetylenic amines converts compounds from agonists to antagonists for striatal muscarinic receptors.