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dc.contributor.authorBenjamin Bradshaw
dc.contributor.authorPaul Evans
dc.contributor.authorJane Fletcher
dc.contributor.authorAlan T L Lee
dc.contributor.authorPaul G Mwashimba
dc.contributor.authorDaniel Oehlrich
dc.contributor.authorEric J Thomas
dc.contributor.authorRobin H Davies
dc.contributor.authorBenjamin C P Allen
dc.contributor.authorKenneth J Broadley
dc.contributor.authorAmar Hamrouni
dc.date.accessioned2012-10-22T15:39:54Z
dc.date.available2012-10-22T15:39:54Z
dc.date.issued2008-06-21
dc.identifier.citation2008 Jun 21;6(12):2138-57. Epub 2008 Apr 18.en_US
dc.identifier.urihttp://hdl.handle.net/123456789/326
dc.descriptionThe original publication is available at http://www.ncbi.nlm.nih.gov/pubmed/18528576en_US
dc.description.abstractTwo approaches to tetrahydro-[1H]-2-benzazepin-4-ones of interest as potentially selective, muscarinic (M(3)) receptor antagonists have been developed. Base promoted addition of 2-(tert-butoxycarbonylamino)methyl-1,3-dithiane with 2-(tert-butyldimethylsiloxymethyl)benzyl chloride gave the corresponding 2,2-dialkylated 1,3-dithiane which was taken through to the dithiane derivative 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 , hydrolysis of the dithiane gave the N-protected tetrahydro-[1H]-2-benzazepin-4-ones . 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 gave the dihydrobenzazepine which was converted into the 2-butyl-5-cyclobutyl-5-hydroxytetrahydrobenzazepin-4-one 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 , , and . 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 and the 5-cyclobutyl-8-fluoro-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one . The structures of 2-tert-butyloxycarbonyl-4,4-propylenedithio-2,3,4,5-tetrahydro-[1H]-2-benzazepine and (4RS,5SR)-2-butyl-5-cyclobutyl-4,5-dihydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepine 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 M(3) receptors from guinea pig ileum, these compounds had log(10)K(B) values of up to 7.2 with selectivities over M(2) receptors from guinea pig left atria of approximately 40.en_US
dc.description.sponsorshipPwani Universityen_US
dc.language.isoenen_US
dc.publisherPubMeden_US
dc.subjectantagonistsen_US
dc.subjectSynthesisen_US
dc.subjectreceptors.en_US
dc.titleSynthesis of 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones: selective antagonists of muscarinic (M3) receptors.en_US
dc.typeArticleen_US


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