Bioorganic & Medicbud Chemistry Letters, Vo1.2. No.10. pp. 1247-1250. 1992 Priitcd in Great Britain 096&894X/92 $5.00 + .OO 0 1992 Pqamon Pms Ltd COMPETITIVE NMDA ANTAGONISTS THAT BASE THELR ACTIVITY ON A UNIQUE CONFORMATIONAL EFFECT Alf Claesson, B&t-Marie Swahn, Karin M. Pdvinsson, HrIkan Molin and Mats Sandberg Preclinical Research, Astra Pain Control, 151 85 SGdertZlje, Sweden (Received 26 June 1992) zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJ Abstract: The synthesis of two NMDA antagonists, cis -3-( 1-oxi-2-phosphonoethyl)-2-piperidine- carboxylic acid and cis -3-(l-hydroxy-2-phosphonoethyl)-2-piperidinecarboxylic acid (1 and 2), is reported. The enantiomers of 1 were also prepared. NMR analysis showed that 1 prefers a 3=, 2,, chair conformation due to internal hydrogen bonding. The most potent competitive antagonists at the NMDA subtype of excitatory amino acid receptors belong to the o-phosphono substituted a-amino acid type. With a starting point in the prototypical AP5 and AP7,t whose R-forms are more active, the receptor affinity has been improved at least a twenty fold with compounds like CGS 19755.2 The pharmacological activity of this class of compounds is of interest in potential therapy of epilepsy, neurodegeneration associated with stroke, and in pain treatment.3 R , P03H2 - i I m R 1 ;HJ03”2 H2 C&H AP5, AP7 CGS 19755 3 CH2/ POstI While exploring the effects of structural modifications of antagonists based on the piperidine nucleus we discovered, and report here, that the 3-substituted compounds 1 and 2 are among the better antagonists found so far. We have also found that the receptor affinity most likely stems from a unique conformational effect caused by an internal hydrogen bond, that differentiates 1 and 2 from their less active” non-oxygenated congener 3. The synthesis of 1, Scheme 1, started with a reaction of the known4 acid chloride 4 with lithiated dimethyl methanephosphonate which produced moderate yields of the /3-ketophosphonate 5. Hydrogenation over Pt and BOC protection gave an intermediate that could be chromatographically purified. However, after facile removal of the phosphonate esters and the BOC group with bromotrimethylsilane the subsequent basic hydrolysis always caused some cis-tram isomerization. By careful ion-exchange chromatography on a H+ -saturated 1 Scheme LlC+bP03~ L- THF, 23% zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 0 qw ‘)H2.P% 3) (Bw30 l 3) TMS-Br 4) LIOH m3H2 1247