Synthesis of 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones:: selective antagonists of muscarinic (M3) receptors
Synthesis of 5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-ones:: selective antagonists of muscarinic (M3) receptors
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DOI：
10.1039/b801206g
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发表时间：
2008-01-01
影响因子：
3.2
通讯作者：
Escargueil, Christine
中科院分区：
文献类型：
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作者：
Bradshaw, Benjamin;Evans, Paul;Escargueil, Christine
已经开发了两种方法来获得作为潜在选择性毒蕈碱（M-3）受体拮抗剂的感兴趣的四氢-[1H]-2-苯并氮杂卓-4-酮。2-（叔丁氧羰基氨基）甲基-1，3-二噻烷5与2-（叔丁基二甲基甲酰基甲基）苄基氯14在碱促进下加成得到相应的2，2-二烷基化1，3-二噻烷15，该化合物通过脱甲硅烷基化、氧化和还原胺化环化为母体2，3，4，5-四氢-[1H]-2-苯并氮杂庚因-4-酮的二噻烷衍生物19。在转化成N-叔丁氧基羰基、N-甲苯对磺酰基和N-苄基衍生物20-22之后，二噻烷的水解得到N-保护的四氢-[1H]-2-苯并氮杂-4-酮23-25。然而，将这些转化为5-环烷基-5-羟基衍生物的初步尝试并不成功。在第二种方法中，使用闭环复分解来制备2，3-二氢-[1H]-2-苯并氮杂卓，其经羟基化和氧化得到所需的5-羟基-2，3，4，5-四氢-[1H]-2-苯并氮杂卓-4-酮。在初步研究之后，二烯基N-（2-硝基苯基）磺酰胺48的闭环复分解得到二氢苯并氮杂卓50，其通过羟基化和N-脱保护，随后通过还原胺化和氧化进行N-烷基化转化为2-丁基-5-环丁基-5-羟基四氢苯并氮杂卓-4-酮55。然后使用该化学方法制备2-[（N-芳基甲基）氨基烷基]类似物69、72、76和78。N-酰化后用硼烷-四氢呋喃络合物还原酰胺也用于实现二氢苯并氮杂卓的N-烷基化，该方法用于制备5-环戊基-5-羟基-2，3，4，5-四氢-[1H]-2-苯并氮杂卓-4-酮103和5-环丁基-8-氟-5-羟基-2，3，4，5-四氢-[1H]-2-苯并氮杂卓-4-酮126。2-叔丁氧羰基-4，4-亚丙基二硫代-2，3，4，5-四氢-[1H]-2-苯并氮杂卓20和（4 RS，5SR）-2-丁基-5-环丁基-4，5-二羟基-2，3，4，5-四氢-[1H]-2-苯并氮杂卓53的结构经X射线衍射确证。筛选外消旋5-环烷基-5-羟基-2，3，4，5-四氢- [1H]-2-苯并氮杂-4-酮的毒蕈碱受体拮抗作用。对于来自豚鼠回肠的M-3受体，这些化合物的log（10）K（B）值高达7.2，与来自豚鼠左心房的M-2受体相比的选择性约为40。
Two 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 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(10)K(B) values of up to 7.2 with selectivities over M-2 receptors from guinea pig left atria of approximately 40.