391198-75-7Relevant academic research and scientific papers
Synthesis of 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones: Selective antagonists of muscarinic (M3) receptors
Bradshaw, Benjamin,Evans, Paul,Fletcher, Jane,Lee, Alan T. L.,Mwashimba, Paul G.,Oehlrich, Daniel,Thomas, Eric J.,Davies, Robin H.,Allen, Benjamin C. P.,Broadley, Kenneth J.,Hamrouni, Amar,Escargueil, Christine
experimental part, p. 2138 - 2157 (2009/02/01)
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 M 3 receptors from guinea pig ileum, these compounds had log 10KB values of up to 7.2 with selectivities over M 2 receptors from guinea pig left atria of approximately 40. The Royal Society of Chemistry 2008.
1,2,3,5-tetrahydrobenzo'c!azepin-4-one derivatives having muscarinic antagonist activity
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, (2008/06/13)
There is disclosed a compound having the formula or a pharmaceutically acceptable salt thereof, wherein: R1a, R1b and R1c are independently fluorine or hydrogen; R2 is C1 to C12 alkyl being
