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Straightforward entry to pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones and their ADME properties
Affiliation:1. Research Group SynBioC, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium;2. Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Faculty of Pharmaceutical Sciences, KU Leuven, O&N II Herestraat 49—box 921, 3000 Leuven, Belgium;1. Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520 Recife, PE, Brazil;2. Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, CEP 31270-901 Belo Horizonte, MG, Brazil;3. Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, CEP, 40296-750 Salvador, BA, Brazil;4. Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, CEP, 50670-420 Recife, PE, Brazil;5. School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane 4072, Australia;1. Key Laboratory of Structure-Based Drug Design & Discovery, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China;2. Chem-Pharm R&D Institute, Tianjin Tasly Group Co., Ltd, Tasly TCM Garden, No. 2, Pujihe East Road, Beichen District, Tianjin 300402, PR China;3. Zhuhai Oxforston PharmTech Co., Ltd, Zhuhai, Guangdong 519085, China;1. Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran;2. Institute of Biotechnology, Shiraz University, Shiraz, Iran;3. Department of Chemistry, College of Sciences, Shiraz University, Shiraz, Iran;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskisehir, Turkey;2. Department of Chemistry, Faculty of Science & Letters, Eskisehir Osmangazi University, 26480 Eskisehir, Turkey;3. Department of Pharmaceutical Chemistry, School of Pharmacy, Medipol University, 34083 Istanbul, Turkey;4. Department of Microbiology, Faculty of Pharmacy, Anadolu University, 26470 Eskisehir, Turkey;1. İstanbul Medipol University, School of Pharmacy, Department of Pharmaceutical Chemistry, 34083 İstanbul, Turkey;2. İstanbul Medipol University, School of Pharmacy, Department of Pharmaceutical Microbiology, 34083 İstanbul, Turkey;3. Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 26470 Eskişehir, Turkey;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, 26470 Eskisehir, Turkey;2. Department of Pharmaceutical Chemistry, School of Pharmacy, Medipol University, 34083 Istanbul, Turkey;3. Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Anadolu University, 26470 Eskisehir, Turkey
Abstract:A straightforward synthesis of pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones was developed starting from 2-chloropyridine-3-carboxylic acid by esterification, nucleophilic aromatic substitution and amide formation in one step, and ring closure allowing their synthesis with two identical or two different group attached to nitrogen. The structural diversity of these [2,3-d]pyrimidine-2,4(1H,3H)-diones resulted in significant variation in the biopharmaceutical properties. This was reflected by the broad range in fasted state simulated intestinal fluid solubility values (12.6 μM to 13.8 mM), Caco-2 permeability coefficients (1.2 × 10−6 cm/s to 90.7 × 10−6 cm/s) and in vitro-predicted human in vivo intrinsic clearance values (0 to 159 ml/min/kg).
Keywords:Pyridopyrimidines  Pyrimidinediones  Pyrimidines  ADME
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