3β-羟基-孕甾-5-烯-20-酮衍生物(A,B环)的合成及其构—效关系的研究

本文报道3β-羟基-孕甾-5-烯-20-酮(孕甾烯醇酮)C₃-位羟基的酯及A,B环重排成6β-羟基-3,5-环孕甾烷-20-酮有关衍生物的合成。抗炎实验发现除水杨酸酯和苯甲酸酯有与临床应用的抗炎松(孕甾烯醇酮乙酰水杨酸酯)相当的抗炎作用外,其余酯类(三氯乙酸酯、氯乙酸酯、呋喃-2′-羧酸酯、对甲苯磺酸酯、邻苯二甲酸单酯)及重排产物6β-羟基-3,5-环孕甾烷-20-酮都有较抗炎松略强的抗炎作用,其作用为临床应用的琥珀酸单酯的两倍多。为了定量地阐明孕甾烯醇酮衍生物的脂溶性对抗炎活性的影响,我们用疏水性碎片常数估算了孕留烯醇酮衍生物的脂水分配系数log P,发现除孕甾烯醇酮3-甲醚和3β-氯-孕甾-5-烯-20-酮以外,当log P0时,随着logP增高,抗炎活性logA明显地加大,两者之间呈抛物线关系。

SYNTHESIS OF 5-PREGNEN-3β-OL-20-ONE DERIVATIVES (A, B RING) AND STUDIES ON THEIR STRUCTURE-ACTIVITY RELATIONSHIPS

The syntheses of 5-pregnen-3β-ol-20-one esters and 3,5-cyclo-pregnan-6β-ol-20-one derivatives are described. Animal tests (inflammatory granuloma pouch) gave the following results: the salicylate and benzoate of 5-pregnen-3β-ol-20-one possess significant anti-inflammatory action, equivalent to that of Antiflamisonum The other esters of 5-pregnen-3β-ol-20-one (chloroacetete, trichloroacetate, furan-2'-carboxylate, p-toluenesulfonate, phthalate)and 3,5-cyclo-pregnan-6β-ol-20-one were found to be somewhat more active than Antiflamisonum.In order to interpret quantitatively the relationship between the lipophilic properties and anti-inflammatory activities, partition coefficients of pregnenolone derivatives were calculated from the hydrophobic fragmental constants. It was noticed that when logP0 the anti-inflammatory activities of all compounds except those of 3-methoxy-5-pregnen-20-one and 3β-chloro-5-pregnen-20-one, increased correspondingly with the increase of their partition coefficients. It was found that the correlations of anti-inflammatory activities and partition coefficients of this series were of parabolic dependence.