C(8) substituted 1-azabicyclo[3.3.1]non-3-enes and C(8) substituted 1-azabicyclo[3.3.1]nonan-4-ones: novel muscarinic receptor antagonists.

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Kim MG, Bodor ET, Wang C, Harden TK, Kohn H

C(8) substituted 1-azabicyclo[3.3.1]non-3-enes and C(8) substituted 1-azabicyclo[3.3.1]nonan-4-ones: novel muscarinic receptor antagonists.

J Med Chem. 2003 May 22;46(11):2216-26.

PubMed ID
12747793 [ View in PubMed
]
Abstract

Expedient syntheses of C(8) substituted 1-azabicyclo[3.3.1]non-3-enes and C(8) substituted 1-azabicyclo[3.3.1]nonan-4-ones are reported to begin with 2,5-disubstituted pyridines. Catalytic reduction of the pyridine to the piperidine followed by treatment with ethyl acrylate and Dieckmann cyclization gave diastereomeric mixtures of C(8) substituted 3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-enes, which were separable by chromatography. We found that the catalytic reduction (PtO2, H2) procedure provided the cis-substituted piperidine but that pyridine reduction was accompanied by competitive cleavage of the C(2) pyridyl substituent. Accordingly, an alternative route was devised that afforded a diastereomeric mixture of the cis- and trans-2,5-disubstituted piperidine. Treatment of the substituted pyridine with m-CPBA gave the pyridine N-oxide, which was reduced to the piperidine by sequential reduction with ammonium formate in the presence of Pd-C followed by NaBH3CN. Addition of ethyl acrylate completed the synthesis of the substituted piperidine. The overall four-step reaction gave higher yields (57%) than the two-step procedure (13%) with little cleavage of the C(2) pyridyl substituent. Acid decarboxylation of the bicyclo[3.3.1]non-3-enes provided the C(8) substituted 1-azabicyclo[3.3.1]nonan-4-ones. Structural studies revealed diagnostic 13C NMR signals that permit assignment of the orientation of the C(8) substituent. Pharmacological investigations documented that 3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-enes efficiently bind to the human M1-M5 muscarinic receptors and function as antagonists. We observed that exo-8-benzyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene (3) displayed the highest affinity, exhibiting Ki values at all five muscarinic receptors that were approximately 10-50 times lower than carbachol and approximately 30-230 times lower than arecoline. Receptor selectivity was observed for 3. Compound 3 contained two different pharmacophores found in many muscarinic receptor ligands, and preliminary findings indicated the importance of both structural elements for maximal activity. Compound 3 serves as a novel lead compound for further drug development.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
ArecolineMuscarinic acetylcholine receptor M1Ki (nM)29000N/AN/ADetails
ArecolineMuscarinic acetylcholine receptor M3Ki (nM)43000N/AN/ADetails
CarbamoylcholineMuscarinic acetylcholine receptor M1Ki (nM)12000N/AN/ADetails
CarbamoylcholineMuscarinic acetylcholine receptor M2Ki (nM)1300N/AN/ADetails
CarbamoylcholineMuscarinic acetylcholine receptor M3Ki (nM)20000N/AN/ADetails
CarbamoylcholineMuscarinic acetylcholine receptor M4Ki (nM)7600N/AN/ADetails