Synthesis of new antiinflammatory steroidal 20-carboxamides: (20R)- and (20S)-21-(N-substituted amino)-11 beta,17,20-trihydroxy-3,21-dioxo-1,4- pregnadiene.
Synthesis of new antiinflammatory steroidal 20-carboxamides: (20R)- and (20S)-21-(N-substituted amino)-11 beta,17,20-trihydroxy-3,21-dioxo-1,4- pregnadiene.
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合成新型抗炎类固醇 20-甲酰胺：(20R)- 和 (20S)-21-(N-取代氨基)-11 beta,17,20-三羟基-3,21-二氧代-1,4-孕二烯。
DOI：
10.1021/jm00395a011
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发表时间：
1987
影响因子：
7.3
通讯作者：
Lee,HJ
中科院分区：
文献类型：
--
作者：
Kim,HP;Bird,J;Heiman,AS;Hudson,GF;Taraporewala,IB;Lee,HJ
The synthesis and antiinflammatory activities of new steroidal 20-carboxamides,(201?)-and (20S)-21-(TV-substituted amino)-ll/3, 17, 20-trihydroxy-3, 21-dioxo-l, 4-pregnadiene (5-8) are described. These compounds were prepared from the respective isomer of 20-dihydroprednisolonic acid,(20/?)-and (20S)-ll/J, 17, 20-trihydroxy-3-oxo-l, 4-pregnadien-21-oic acid (4a and 4b), by coupling with primary amines after the activation of the steroid acid with TV. TVLdicyclo-hexylcarbodiimide (DCC) and 1-hydroxybenzotriazole. Confirmation of the configurational assignment at C-20 of the 20-carboxamides was achieved by reductionof methyl (201?)-and (20S)-ll/3, 17, 20-trihydroxy-3-oxo-l, 4-preg-nadien-21-oate (3a and 3b) to the known stereochemistry at C-20 of (20/?)-and (20S)-ll/3, 17, 20, 21-tetrahydroxy-3-oxo-l, 4-pregnadiene (2a and 2b). 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 (/?)-hydroxy configurations exhibit higher potency than those with the 20-(S)-hydroxy configurations. The amides of steroidal 21-oic acids with highlocal antiinflammatory potency exhibited systemic activities unlike the corresponding esters of steroidal 21-oic acids, which are devoid of systemic activities. active metabolite. 2· 3 Compounds that have at least one active intermediary metabolite can be considered as partial antedrugs. It has recently been established that methyl lld, 17-dihydroxy-3, 20-dioxo-l, 4-pregnadien-21-oate and the isomers of methyl (20/?)-and (20S)-ll/3, 17, 20-trihydroxy-3-oxo-l, 4-pregnadien-21-oate (3a and 3b) retain significant local antiinflammatory activity, but are devoid of prednisolone-like side effects, such as pituitary adrenal suppression and thymus involution. 2-4 It has been sug-
