Full Paper Synthesis of Novel Pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine Derivatives: Potent and Selective Adenosine A 3 Receptor Antagonists Veeraswamy Banda 1 , Balakumar Chandrasekaran 2 , Meryem Köse 3 , Christin Vielmuth 3 , Christa E. Müller 3 , Kurumurthy Chavva 1 , Santhosh Kumar Gautham 1 , Sambasivarao Pillalamarri 1 , Raghuprasad Mylavaram 4 , Raghuramarao Akkinepally 5 , Shanthanrao Pamulaparthy 1 , and Narsaiah Banda 1 1 Fluoroorganic Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad, Andhra Pradesh, India 2 University Institute of Pharmaceutical Sciences and UGC Centre of Advanced Study in Pharmaceutical Sciences (UGC-CAS), Panjab University, Chandigarh, Punjab, India 3 PharmaCenter Bonn, University of Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Bonn, Germany 4 Vishnu College of Pharmacy, Bhimavaram, West Godavari, Andhra Pradesh, India 5 University College of Pharmaceutical Sciences, Warangal, Andhra Pradesh, India A series of novel pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 5 was prepared from 2-amino-3- cyano-4-trifluoromethyl-6-phenylpyridine 1 in two steps via formation of iminoether 3 followed by reaction with different aroylhydrazides 4. Representative products 5 were evaluated for their affinity towards all four subtypes of human adenosine receptors. Compounds 2-(3-fluorophenyl)-8-phenyl-10- (trifluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5b), 2-(furan-2-yl)-8-phenyl-10-(trifluoro- methyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5d), and 2-(furan-2-yl)-5-methyl-8-phenyl-10-(tri- fluoromethyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine (5j) showed high affinity for the A 3 receptors, with K i values of 8.1, 10.4, and 12.1 nM, respectively, and were >1000-fold selective versus all other adenosine receptor subtypes. Keywords: Adenosine receptors / 2-Aminonicotinonitrile / Aroyl hydrazide / Orthoacetate / Orthoformate Received: January 11, 2013; Revised: July 18, 2013; Accepted: July 19, 2013 DOI 10.1002/ardp.201300003 Introduction Adenosine receptors (ARs) designated as A 1 ,A 2A ,A 2B , and A 3 , belong to the superfamily of G protein-coupled receptors (GPCRs), which modulate a wide range of biological functions including CNS, cardiac, and immune suppressive functions [1, 2]. A 2A ARs, for example, are present in high density in the basal ganglia of the brain where they are co- expressed with dopamine receptors forming heteromeric receptor complexes [3]. A 2A receptors are also present on tissues of the peripheral system, e.g., on platelets [4], lymphocytes [5], neutrophils [6, 7], monocytes, macrophages, and mast cells. A 1 and A 2A ARs are generally 60% identical within the transmembrane domains [8–10] and represent potential pharmacological targets for the treatment of asthma, psychosis, chronic inflammation, anxiety, and neurodegenerative disorders [11–13]. Thus, discovery and development of adenosine receptor antagonists have been an attractive field of research from the perspective of identifying new drugs for the treatment of widespread disorders such as inflammation, asthma, and Parkinson’s disease. Efforts to find selective ligands for A 2A receptors led to the identification of pyrazolotriazolopyrimidines such as SCH 58261 (5-amino-7- (2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]py- rimidine) and SCH 63390 (5-amino-7-(3-phenylpropyl)-2-(2- furyl)pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine) [14]. Com- pounds which possess hydrophilic groups in the para- and ortho-position of the aromatic ring have been found to be potent and selective for A 2A ARs [15, 16]. Like A 2A ARs, A 2B ARs Correspondence: Dr. Narsaiah Banda, Fluoroorganic Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad, Andhra Pradesh, India. E-mail: narsaiah@iict.res.in Fax: þ91 40 27160387 Arch. Pharm. Chem. Life Sci. 2013, 346, 699–707 699 ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim