Sila-venlafaxine, a sila-analogue of the serotonin/noradrenaline reuptake inhibitor venlafaxine: Synthesis, crystal structure analysis, and pharmacological characterization
Sila-venlafaxine, a sila-analogue of the serotonin/noradrenaline reuptake inhibitor venlafaxine: Synthesis, crystal structure analysis, and pharmacological characterization
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DOI：
10.1021/om058051y
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发表时间：
2006-02-27
期刊：
影响因子：
2.8
通讯作者：
Tacke, R
中科院分区：
文献类型：
--
作者：
Daiss, JO;Burschka, C;Tacke, R
5 -羟色胺/去甲肾上腺素再摄取抑制剂rac-1-[2-（二甲胺）-1-（4-甲氧基苯基）乙基]环己烷-1-（racc -文拉法辛，rac-1a）作为抗抑郁药在临床使用。硅类似物rac1 -[2-（二甲氨基）-1-（4-甲氧基苯基）乙基]-1-硅环己烷-1-(rac1 -1b)，以四氯硅烷或四甲基氧基硅烷为起始原料，经多步合成。衍生物rac-2的相应的1-硅环戊烷-1被类似地制备。以(+)-或(-)-10-樟脑磺酸为拆分剂，对rac-1b进行拆分，得到sila-文拉法辛对映体(R)-1b和(S)-1b。化合物rac-1b、(R)-1b、(S)-1b、rac-1b中心点HCl、(R)-1b中心点HCl、(S)-1b-HCl、(R)-1b中心点HBr、rac-2和rac-2中心点HCl通过多核磁共振和元素分析进行了表征，rac-1b中心点HCl、(R)-1b中心点HBr和rac-2中心点HCl通过晶体结构分析进行了表征。化合物rac-1a、rac-1b、rac-2、(R)-1a、(S)-1a、(R)-1b和(S)-1b作为它们的氢氯化物，在血清素、去甲肾上腺素和多巴胺再摄取抑制试验中测试其有效性。化合物rac-1a， (R)-1a和(S)-1a (-rac-1b, （R)-1b, (S)-1b）的硅烷取代（C/Si开关）被发现显著影响其在5 -羟色胺，去甲肾上腺素和多巴胺再摄取抑制方面的药理学选择性谱。(R)-Sila-venlafaxine （(R)-1b）被认为具有与选择性去甲肾上腺素再摄取抑制一致的精细选择性。具有这种特征的化合物可能在治疗各种神经系统疾病中提供治疗益处。
The serotonin/noradrenaline reuptake inhibitor rac-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-of (rac-venlafaxine, rac-1a) is in clinical use as an antidepressant. The silicon analogue, rac-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-of (rac-sila-venlafaxine, rac-1b), was synthesized in multistep syntheses, starting from tetrachlorosilane or tetramethoxysilane. The corresponding 1-silacyclopentan-1-of derivative rac-2 was prepared analogously. The sila-venlafaxine enantiomers (R)-1b and (S)-1b were obtained by resolution of rac-1b, using (+)- or (-)-10-camphorsulfonic acid as the resolving agent. Compounds rac-1b, (R)-1b, (S)-1b, rac-1b center dot HCl, (R)-1b center dot HCl, (S)-1b-HCl, (R)-1b center dot HBr, rac-2, and rac-2 center dot HCl were characterized by multinuclear NMR studies and elemental analyses, and rac-1b center dot HCl, (R)-1b center dot HBr, and rac-2 were additionally characterized by crystal structure analyses. Compounds rac-1a, rac-1b, rac-2, (R)-1a, (S)-1a, (R)-1b, and (S)-1b were tested as their hydrochlorides for their efficacy in serotonin, noradrenaline, and dopamine reuptake inhibition assays. Sila-substitution (C/Si switch) of compounds rac-1a, (R)-1a, and (S)-1a (-rac-1b, (R)-1b, (S)-1b) was found to dramatically influence their pharmacological selectivity profiles with respect to serotonin, noradrenaline, and dopamine reuptake inhibition. (R)-Sila-venlafaxine ((R)-1b) was identified to have a refined selectivity profile consistent with selective noradrenaline reuptake inhibition. Compounds with this profile may provide therapeutic benefit in the treatment of various nervous system disorders.