Synthetic routes to treprostinil N-acyl methylsulfonamide

被引：1
|
作者：
Picken, Christina [1 ,2 ]
Laing, Peter [1 ,2 ]
Shen, Lei [1 ]
Clapp, Lucie H. [1 ]
Brocchini, Steve [2 ]
机构：
[1] UCL, Inst Cardiovasc Sci, Gower St, London WC1E 6BT, England
[2] UCL, Sch Pharm, 29-39 Brunswick Sq, London WC1N 1AX, England
来源：
TETRAHEDRON LETTERS | 2020年 / 61卷 / 05期
基金：
英国生物技术与生命科学研究理事会;
关键词：
Prostacyclin; Treprostinil; Acylsulfonamide; Prodrug; PULMONARY ARTERIAL-HYPERTENSION; PROSTACYCLIN RECEPTOR AGONIST; PROSTANOID RECEPTORS; POTENT; PHARMACOKINETICS; ACYLSULFONAMIDES; EPOPROSTENOL; INFLAMMATION; SELEXIPAG; PRODRUGS;
D O I：
10.1016/j.tetlet.2019.151428
中图分类号：
O62 [有机化学];
学科分类号：
070303 ; 081704 ;
摘要：
The synthesis of the prodrug candidate, treprostinil N-acyl methylsulfonamide 5 was accomplished from treprostinil 2 utilising protecting group strategies. A more direct synthesis for the prodrug was also achieved using a treprostinil triol precursor 12 and bromoacetyl acylmethylsulfonamide 14. The overall yield of treprostinil N-acyl sulfonamide 5 directly from the triol precursor 12 is similar to the protecting group strategies because deprotonation of the acidic proton in the bromoacetyl acylmethylsulfonamide 14 reduces electrophilicity. However, the more direct route using the treprostinil triol precursor holds greater promise as a strategy to prepare a wide range of treprostinil prodrug candidates. Treprostinil N-acyl methylsulfonamide prodrug 5 exhibited a 30-fold decrease in the potency at the human prostacydin (IP) receptor compared to treprostinil 2 in an in vitro cyclic AMP assay. (C) 2019 Elsevier Ltd. All rights reserved.
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页数：5
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