Development of Synthetic Strategies for the Construction of Pyrido[4,3‐d]pyrimidine Libraries – the Discovery of a New Class of PDE‐4 Inhibitors

Abstract

The synthesis of a pyrido[4,3‐d]pyrimidine library from 4,6‐diamino‐2‐bromonicotinamide and 4,6‐diaminonicotinamide is described. A systematic variation of the substituents at positions 2, 4, 5 and 7 of the pyrido[4,3‐d]pyrimidine scaffold was carried out, leading to a wide variety of structural analogues. This strategy led to the discovery of a new structural class of PDE‐4 inhibitors. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Synthesis and in vitro evaluation of 2-amino-4-N-piperazinyl-6-(3,4-dimethoxyphenyl)-pteridines as dual immunosuppressive and anti-inflammatory agents

“…The exocyclic amino group was protected as an acetyl group and the tautomeric hydroxyl group was activated for a nucleophilic displacement reaction by preparing the corresponding 4-(1,2,4-triazolyl)-pteridine derivative 18 using POCl 3 and 1,2,4-triazole. 14 This key intermediate was sufficiently stable to be kept on the bench for several months. Reaction of this 4-N-triazolyl-pteridine derivative 18 with a number of nucleophiles, followed by alkaline deprotection of the acetyl group, afforded a series of 4-N-substituted pteridine analogues 19a-i (Table 2).…”

Synthesis of 8-aryl-substituted 4-(5-chloropyrido[4,3-d]pyrimidine-2-yl)morpholines as intermediates of potential PI3K inhibitors via selective Suzuki-Miyaura cross-coupling reaction

“…2 Several derivatives of pyrido [4,3-d]pyrimidine also possess a wide spectrum of biological activities, including PI3K inhibition, 3 tyrosine kinase inhibition, 4 and PDE-4 inhibition. 5 During the course of the search for novel PI3K inhibitors, compounds possessing simple alkylamino, alkylthio or alkoxy groups at the C-5 position and aryl groups at the C-8 position of the 4-(pyrido [4,3-d]pyrimidin-2-yl)morpholine scaffold, shown in Figure 1, were designed based on the lead compound LY294002. The Suzuki-Miyaura cross-coupling reaction would be preferred to introduce an aryl group into the key intermediate І 8-bromo-2-morpholinopyrido [4,3-d]pyrimidin-5(6H)-one or 8-iodo-2-morpholinopyrido [4,3-d]pyrimidin-5(6H)-one due to its mild reaction conditions, environmentally benign approaches and commercially available boronic acids and so on.…”

Transformations of dimethyl acetone-1,3-dicarboxylate. The synthesis of (4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)thiazole-5-carboxylates

“…[1][2][3] Recently, they have been prepared from 4-amino-6-chloro-5-phenyl-2-methylthiopyrimidine, 4 and from 4-amino-1-benzyl 1,2,5,6-tetrahydropyridine-3-carboxylate. 5 They are well-known pharmacophores, 6,7 PDE-inhibitors, 8 and inhibitors of tyrosine kinase activity in the epidermal growth factor receptor. 9,10 In connection with our interest in enaminones and related compounds as building blocks for the preparation of various heterocyclic systems, 11 including also some natural products, 12,13 dialkyl acetone-1,3-dicarboxylates have recently been employed for the synthesis of hetero-aryl substituted pyrimidines, 14 dialkyl 1-substituted 4-oxo-1,4-dihydropyridine-3,5-dicarboxylates,…”