Synthesis of 7,9-diazabicyclo[4.2.2]decanes as conformationally restricted κ receptor agonists: Fine tuning of the dihedral angle of the ethylenediamine pharmacophore

Abstract

In order to slightly modify the orientation of the pharmacophoric structural elements of the potent κ agonists 7 and 8, the three-membered bridge of these compounds was enlarged to four carbon atoms. Reductive amination of the bicyclic ketone 11 with pyrrolidine and NaBH(OAc)3 provided the pyrrolidine 12 with excellent diastereoselectivity (>99:1). The diastereomeric pyrrolidine 24 was established by a stepwise strategy, involving an unselective nucleophilic substitution of the triflate 20 with NaN3 as key step. The synthesis of 9 and 10 was completed by LiAlH4 reduction, replacement of the PMB group at N-9 with a (3,4-dichlorophenyl)acetyl residue and the N-7-benzyl group with the methoxycarbonyl moiety. The κ receptor affinity of the new compounds is strongly dependent on the stereochemistry and the N-7-substituent. The (1RS,2SR,6SR)-configured pyrrolidine 9 with a methoxycarbonyl moiety at N-7 represents the most potent κ ligand (Ki = 65 nM) of this series. The 65fold lower κ affinity of 9 compared with its smaller homologue 7 is partly explained by 9 being a racemic mixture, and the slightly modified dihedral angle of the pharmacophoric N(pyrrolidine)–C–C–N(dichlorophenylacetyl) substructure. However, the additional methylene moiety, which enlarges the size of the bridge, is assumed to be responsible for the reduced κ affinity.