Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents

Authors:
  • JAJohn E. Arrowsmith
    John E. Arrowsmith
  • SCSimon F. Campbell
    Simon F. Campbell
  • PCPeter E. Cross
    Peter E. Cross
  • JSJohn K. Stubbs
    John K. Stubbs
  • RBRoger A. Burges
    Roger A. Burges
  • DGDonald G. Gardiner
    Donald G. Gardiner
  • KBKenneth J. Blackburn
    Kenneth J. Blackburn
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Abstract
A series of dihydropyridines substituted at the 2-position by basic side chains are described and their potencies as calcium antagonists listed. One compound, 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl-6-methyl-1,4-dihydropyridine (17, amlodipine) was found to be comparable in potency to nifedipine and to have an elimination half-life of 30 h in dogs. Oral bioavailability approached 100%, and hemodynamic responses were gradual in onset and long-lasting in effect. The two enantiomers have been prepared, and the bulk of the activity was found to reside with the (-) isomer, 18. X-ray crystallographic studies, carried out on a close analogue of 17, suggest the existence of a weak hydrogen bond between the side-chain oxygen and the proton on the ring nitrogen.

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