含4-(吡唑基)哌啶侧链的人CCR5受体拮抗剂。第2部分：高效、选择性及口服生物可利用化合物的发现。

Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 2: Discovery of potent, selective, and orally bioavailable compounds.

作者信息

Shen Dong-Ming, Shu Min, Willoughby Christopher A, Shah Shrenik, Lynch Christopher L, Hale Jeffrey J, Mills Sander G, Chapman Kevin T, Malkowitz Lorraine, Springer Martin S, Gould Sandra L, DeMartino Julie A, Siciliano Salvatore J, Lyons Kathy, Pivnichny James V, Kwei Gloria Y, Carella Anthony, Carver Gwen, Holmes Karen, Schleif William A, Danzeisen Renee, Hazuda Daria, Kessler Joseph, Lineberger Janet, Miller Michael D, Emini Emilio A

机构信息

Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA.

出版信息

Bioorg Med Chem Lett. 2004 Feb 23;14(4):941-5. doi: 10.1016/j.bmcl.2003.12.005.

DOI:10.1016/j.bmcl.2003.12.005

PMID:15012998

Abstract

Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of alpha-(pyrrolidin-1-yl)-alpha,alpha-dialkyl acetic acid from a pyrrolidine and alpha-bromo-alpha,alpha-dialkyl acetic acid using silver triflate was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of alpha-(pyrrolidin-1-yl)acetic acid was also uncovered.

摘要

对我们的先导吡唑化合物1中吡咯烷上的烷基乙酸部分和苯基进行修饰，得到了异丙基化合物9。该化合物是一种有效的CCR5拮抗剂，对HIV-1显示出良好的体外抗病毒活性、出色的选择性以及在三种动物物种中良好的口服生物利用度。在这项研究中，发现了一种使用三氟甲磺酸银从吡咯烷和α-溴-α,α-二烷基乙酸制备α-(吡咯烷-1-基)-α,α-二烷基乙酸的新方法。这使我们首次能够制备诸如24和25之类的化合物。还发现了一种新型的钯介导的α-(吡咯烷-1-基)乙酸的N-脱烷基化反应。