Synthesis of 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones: selective antagonists of muscarinic (M3) receptors?

Organic & Biomolecular Chemistry Pub Date: 2008-04-18 DOI: 10.1039/B801206G

Abstract

Two approaches to tetrahydro-[1H]-2-benzazepin-4-ones of interest as potentially selective, muscarinic (M3) receptor antagonists have been developed. Base promoted addition of 2-(tert-butoxycarbonylamino)methyl-1,3-dithiane 5 with 2-(tert-butyldimethylsiloxymethyl)benzyl chloride 14 gave the corresponding 2,2-dialkylated 1,3-dithiane 15 which was taken through to the dithiane derivative 19 of the parent 2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one by desilylation, oxidation and cyclisation via a reductive amination. After conversion into the N-tert-butyloxycarbonyl, N-toluene p-sulfonyl and N-benzyl derivatives 20–22, hydrolysis of the dithiane gave the N-protected tetrahydro-[1H]-2-benzazepin-4-ones 23–25. However, preliminary attempts to convert these into 5-cycloalkyl-5-hydroxy derivatives were not successful. In the second approach, ring-closing metathesis was used to prepare 2,3-dihydro-[1H]-2-benzazepines which were hydroxylated and oxidized to give the required 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones. Following preliminary studies, ring-closing metathesis of the dienyl N-(2-nitrophenyl)sulfonamide 48 gave the dihydrobenzazepine 50 which was converted into the 2-butyl-5-cyclobutyl-5-hydroxytetrahydrobenzazepin-4-one 55 by hydroxylation and N-deprotection followed by N-alkylation via reductive amination, and oxidation. This chemistry was then used to prepare the 2-[(N-arylmethyl)aminoalkyl analogues 69, 72, 76 and 78. N-Acylation followed by amide reduction using the borane–tetrahydrofuran complex was also used to achieve N-alkylation of dihydrobenzazepines and this approach was used to prepare the 5-cyclopentyl-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one 103 and the 5-cyclobutyl-8-fluoro-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one 126. The structures of 2-tert-butyloxycarbonyl-4,4-propylenedithio-2,3,4,5-tetrahydro-[1H]-2-benzazepine 20 and (4RS,5SR)-2-butyl-5-cyclobutyl-4,5-dihydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepine 53 were confirmed by X-ray diffraction. The racemic 5-cycloalkyl-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones were screened for muscarinic receptor antagonism. For M3 receptors from guinea pig ileum, these compounds had log10KB values of up to 7.2 with selectivities over M2 receptors from guinea pig left atria of approximately 40.

Graphical abstract: Synthesis of 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones: selective antagonists of muscarinic (M3) receptors
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