Kim H P, Bird J, Heiman A S, Hudson G F, Taraporewala I B, Lee H J
Center for Anti-inflammatory Research, College of Pharmacy, Florida A&M University, Tallahassee 32307.
J Med Chem. 1987 Dec;30(12):2239-44. doi: 10.1021/jm00395a011.
The synthesis and antiinflammatory activities of new steroidal 20-carboxamides, (20R)- and (20S)-21-(N-substituted amino)-11 beta,17,20-trihydroxy-3,21-dioxo-1,4-pregnadiene are described. These compounds were prepared from the respective isomer of 20-dihydroprednisolonic acid, (20R)- and (20S)-11 beta,17,20-trihydroxy-3-oxo-1,4-pregnadien-21-oic acid, by coupling with primary amines after the activation of the steroid acid with N,N1-dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole. Confirmation of the configurational assignment at C-20 of the 20-carboxamides was achieved by reduction of methyl (20R)- and (20S)-11 beta,17,20-trihydroxy-3-oxo-1,4-pregnadien-21-oate to the known stereochemistry at C-20 of (20R)- and (20S)-11 beta,17,20,21-tetrahydroxy-3-oxo-1,4-pregnadiene The topical antiinflammatory activities of these steroidal 20-carboxamides were assessed by the croton oil induced ear edema assay and their local and systemic antiinflammatory activities by the cotton pellet granuloma bioassay. Results of these investigations suggest a structure-activity relationship where carboxamide derivatives with the 20(R)-hydroxy configurations exhibit higher potency than those with the 20-(S)-hydroxy configurations. The amides of steroidal 21-oic acids with high local antiinflammatory potency exhibited systemic activities unlike the corresponding esters of steroidal 21-oic acids, which are devoid of systemic activities.
本文描述了新型甾体20-羧酰胺，即(20R)-和(20S)-21-(N-取代氨基)-11β,17,20-三羟基-3,21-二氧代-1,4-孕二烯的合成及其抗炎活性。这些化合物是由20-二氢泼尼松龙酸的相应异构体，即(20R)-和(20S)-11β,17,20-三羟基-3-氧代-1,4-孕二烯-21-酸，在甾体酸用N,N'-二环己基碳二亚胺（DCC）和1-羟基苯并三唑活化后与伯胺偶联制备而成。通过将(20R)-和(20S)-11β,17,20-三羟基-3-氧代-1,4-孕二烯-21-酸甲酯还原为已知立体化学结构的(20R)-和(20S)-11β,17,20,21-四羟基-3-氧代-1,4-孕二烯，实现了对20-羧酰胺C-20构型归属的确认。通过巴豆油诱导的耳肿胀试验评估了这些甾体20-羧酰胺的局部抗炎活性，并通过棉球肉芽肿生物测定法评估了它们的局部和全身抗炎活性。这些研究结果表明了一种构效关系，即具有20(R)-羟基构型的羧酰胺衍生物比具有20-(S)-羟基构型的衍生物表现出更高的活性。甾体21-酸的酰胺具有较高的局部抗炎活性，与甾体21-酸的相应酯不同，后者没有全身活性。
