含(1-芳乙酰胺基-2-叔胺基)乙烷结构的六氢-1H-1,4-二氮(艹卓)类化合物的合成与镇痛活性

2-或5-取代的六氢-1H-1,4-二氮(艹卓)类化合物(1～3)经单酰化及酰化反应后,合成了16个带有(1-芳乙酰胺基-2-叔氨基)乙烷结构的六氢-1H-1,4-二氮(艹卓)类目标化合物(5～9,11～13,15～17,19～23),经元素分析、IR、MS和¹H NMR确证了其组成和结构。对所有目标化合物都进行了豚鼠回肠试验,初步药理试验表明,16个化合物对受试标本显示不同程度的抑制作用,对抑制率较高的两个化合物5和7测试了IC₅₀值。对在豚鼠回肠试验中显示较强激动作用的4个化合物进行了小鼠扭体法镇痛活性试验,测得了其ED₅₀值。

Synthesis of Hexahydro-1H-1,4-diazepine Analogues Carrying the Segment of(1-Arylacetamide-2-tertiary amide) Ethane and Their Analgesic Effects

In order to get some selective κ-opioid receptor agonists, which can relieve pain while lackingserious side effects, 16 target compounds of hexahydro-1H-1, 4-diazepine analogues carrying the segmentof (1-arylacetamide-2-tertiary amide) ethane were synthesized through single amidation and amidation ofthe basic modified structures of compounds 1-3, 2-(5-) substituted hexahydro-1H-1, 4-diazepine.Thestructures of these products were characterized by IR, EIMS, elementary analysis and ¹H NMR.All thetarget compounds were screened in vitro in the guinea pig ileum(GPI) for their receptor affinities.The pre-liminary pharmacology tests indicated that these compounds showed a certain agonist activity(presented inthe item of inhibition rate) respectively at 5 × 10^-6mol/Llevel and the IC₅₀ values(μmol/L) of compounds5, 7 were achieved.The antinociceptive potencies of the compounds with a higher potency(compounds 5,13, 22, 23) in the GPIstudy were further tested their in the mouse abdominal constriction model and their ED₅₀ values(mg/kg, s.c.) were also obtained.