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. doi: 10.1021/jm020572p.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Line
  • Crystallography, X-Ray
  • Humans
  • Inositol Phosphates / biosynthesis
  • Magnetic Resonance Spectroscopy
  • Membranes
  • Muscarinic Antagonists / chemical synthesis*
  • Muscarinic Antagonists / chemistry
  • Muscarinic Antagonists / pharmacology
  • Radioligand Assay
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 8-benzyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo(3.3.1)non-3-ene
  • Bridged Bicyclo Compounds, Heterocyclic
  • Inositol Phosphates
  • Muscarinic Antagonists