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DOI: 10.1055/s-0029-1218442
Parallel Solid-Phase Synthesis of Iodinated Analogues of Rimonabant
Contributor(s):Yasuhiro Uozumi, Yoichi M. A. Yamada, Maki MinakawaImperial College, London and Sanofi-Aventis, Alnwick, UK
A Method for Parallel Solid-Phase Synthesis of Iodinated Analogues of the CB1 Receptor Inverse Agonist Rimonabant
Org. Lett. 2009, 11: 4760-4763
Publication History
Publication Date:
21 December 2009 (online)
Key words
solid-phase synthesis - HypoGel - germane linker - rimonabant
Significance
A novel method for the parallel solid-phase synthesis of iodinated analogues of the CB1 receptor inverse agonist rimonabant was described. HypoGel-bound 1,5-diarylpyrazole tert-butyl ester 6 was prepared by employing HypoGel-bound gelmanium bromide 4 via transmetalation. Parallel amidation of 6 with hydrazines and amines gave HypoGel-bound 1,5-arylpyrazolyl hydrazides/amides 7a-e. Cleavage of the Ge linker with concomitant ipso-iodination afforded iodinated rimonabant analogues 1a-e (5 examples, 42-63% yield, 1-6 h).
Comment
Rimonabant (marketed as Acomplia) is a CB1 receptor inverse agonist first approved for the treatment of obesity by European Medicines Agency in 2006, and then withdrawn from the market in 2008 following the emergence of psychiatric disorders among patients. Various ¹¹C-labeled, ¹8F-labeled, and ¹²³/¹²4I-labeled rimonabant derivatives (e.g., 1a: [¹²³I] AM281 and 1b: [¹²³I] AM251) have proved to be viable for positron emission tomography (PET) and single photon emission computerized tomography (SPECT) imaging of central nervous system (CNS) activity.