symmetrically and unsymmetrically bridged methylenebis(allopurinols) synthesis of dimeric potential anti-gout drugs对称和偏压地段桥梁制(别嘌呤醇)的合成二聚的潜在anti-gout药物.pdfVIP

Molecules 2007, 12, 563-575 molecules ISSN 1420-3049 Full Paper Symmetrically and Unsymmetrically Bridged Methylenebis(allopurinols): Synthesis of Dimeric Potential Anti-Gout Drugs Helmut Rosemeyer 1,*, Martina Anders 1 and Frank Seela 1,2 1 Organische Chemie I – Bioorganische Chemie, Institut für Chemie, Fachbereich Biologie/Chemie, Universität Osnabrück, Barbarastr. 7, D-49069 Osnabrück, Germany 2 Laboratory of Bioorganic Chemistry and Chemical Biology, Center for Nanotechnology, Heisenbergstr. 11, D-48149 Münster, Germany *Author to whom correspondence should be addressed; E-mail: Helmut.Rosemeyer@uos.de Received: 9 March 2007; in revised form: 19 March 2007 / Accepted: 19 March 2007 / Published: 21 March 2007 Abstract: Liquid-liquid phase transfer alkylation of 4-methoxy-pyrazolo[3,4-d]- pyrimidine (1a) with a dichloromethane/dibromomethane mixture (3:1, v/v) gave the regioisomeric methylenebis(heterocycles) 3a–5a. These were converted by dilute aqueous sodium hydroxide containing dimethylsulfoxide (DMSO) at concentrations between 0 and 60 vol-% into the methylenebis(allopurinols) 3b–5b by nucleophilic SNAr reactions at C(4). The effect of DMSO on the reaction kinetics was investigated. Keywords: Allopurinol, dimethylsulfoxide, dimeric drugs. Introduction 1,5-Dihydro-4H-pyrazolo[3,4-d]pyrimidine = 8-aza-7-deazahypoxanthine (allopurinol, 1b, Figure 1; IUPAC numbering is used throughout the manuscript) [1,2] is a progressive inhibitor of xanthine oxidase with alloxanthine – a 6-oxo derivative of 1b – being the actual inhibitor [3]. This has led