Pyrazolo[1,5-a][1,3,5]triazines (5-Aza-9-deazapurines): Synthesis and Biological Activity

Abstract

The present review gives an account on the synthetic routes to pyrazolo [1,5-a] [1,3,5]triazine system, which is an isostere of purine, and polyfused systems bearing this heterocyclic core. Data concerning biological activity of compounds with pyrazolo[1,5-a] [1,3,5]triazine skeleton are also discussed. CONTENTS 1. INTRODUCTION 2. SYNTHESIS BY ANNELATION OF THE 1,3,5-TRIAZINE RING ONTO A PYRAZOLE SCAFFOLD 2.1. Four-bond formation (3+1+1+1) through cyclization of 3(5)-aminopyrazoles with two carbon and one nitrogen atoms.2.2. Three-bond formation (3+2+1) through cyclization of 3(5)-aminopyrazoles with reagents introducing C-N fragment and one carbon atom.2.3. Two-bond formation (3+3) through cyclization of 3(5)-aminopyrazoles with reagents introducing C-N-C fragment. Two-bond formation (3+3) through cyclization of 1-acylpyrazolidinediones with reagentsintroducing N-C-N fragment. Two-bond formation (4+2) through cyclization of 5-aminopyrazoles having carbon atom at N1with reagents introducing C-N fragment.2.6. Two-bond formation (4+2) through cyclization of pyrazoles having N-C appendage at C3(5) with reagents introducing C-N fragment.2.7. Two-bond formation (5+1) through cyclization of 5-aminopyrazoles having C-N appendage at N1 with one carbon atom. HETEROCYCLES, Vol. 75, No. 7, 2008 15752.8. Two-bond formation (5+1) through cyclization of pyrazoles having N-C-N appendage at C3 (5) with one carbon atom.2.9. One bond formation through intramolecular cyclization of 5-aminopyrazoles having C-N-C appendage at N1.2.10. One bond formation through intramolecular cyclization of pyrazoles having N-C-N-C appendage at C3(5). SYNTHESIS BY ANNELATION OF THE PYRAZOLE RING ONTOA 1,3,5-TRIAZINE SCAFFOLD 4. SYNTHESIS BY CONCURRENT FORMATION OF BOTH THE 1,3,5-TRIAZINE AND PYRAZOLE RINGS 5. SYNTHESIS VIA RING TRANSFORMATION REACTIONS 6. BIOLOGICAL ACTIVITY OF PYRAZOLO[1,5-a][1,3,5]TRIAZINE DERIVATIVES 6.1. Enzyme inhibitors 6.2. Receptor ligands 6.3. Miscellaneous biological activities 7. CONCLUSION 1576 HETEROCYCLES, Vol. 75, No. 7, 2008 syntheses and pharmacological data on the more interesting examples of bioactive compounds are discussed separately in the Section 6 of this review. Within the review we collectively categorized the common approaches to the synthesis of pyrazolo[1,5-a][1,3,5]triazines into: (A) annelation of the 1,3,5-triazine ring onto a pyrazole scaffold; (B) annelation of the pyrazole ring onto a 1,3,5-triazine scaffold; (C) concurrent formation of both the 1,3,5-triazine and pyrazole ring; (D) syntheses via ring transformation reactions. SYNTHESIS BY ANNELATION OF THE 1,3,5-TRIAZINE RING ONTO A PYRAZOLE SCAFFOLDThe 1,3,5-triazine ring annelation strategy is a very versatile synthetic approach for the preparation of pyrazolo[1,5-a][1,3,5]triazines. This strategy represents the most frequently utilized route to the formation of the pyrazolo[1,5-a][1,3,5]triazine ring system. Suitably functionalized pyrazoles can be cyclized to pyrazolo[1,5-a][1,3,5]triazines according to the following schematically represented p...

Microwave-Assisted Sequential One-Pot Synthesis of 8-Substituted Pyrazolo[1,5-a][1,3,5]triazines

“…Based on literature data, three steps are required for the synthesis of the target heterocyclic systems. The first step started from 5-aminopyrazole or its 4-substituted analogs (1) which were reacted with ethoxycarbonyl isothiocyanate in various solvents (e.g., ethyl acetate, [10], ethyl acetate/benzene [13,21] or dimethylformamide DMF [14]) to give the intermediate N-carbetoxythioureas (2). The latest were heated in basic conditions (e.g., ammonium hydroxide in methanol [10], aqueous sodium hydroxide [13][14][15]21,22,25,29], sodium methoxide [5] and sodium ethoxide in ethanol [7,14,15]) and then cyclized, giving the 2-thioxo-1H-pyrazolo [1,5-a] [1,3,5]triazin-4-ones (3).…”

“…The pyrazolo [1,5-a] [1,3,5]triazine is a heterocyclic system which has generated considerable interest in the communities of academic and industrial medicinal chemists [1,2]. This nitrogen-rich heterocyclic core was intensively developed as a bioisosteric substitute of biogenic purines (e.g., adenine, guanine, and xanthine in Figure 1) for the conception of potentially bioactive compounds in a wide range of biological applications [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21].…”

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

“…Purine scaffolds, such as allopurinol (106) used as the first choice of drug in gout therapy and temozolomide (107) used in the treatment of brain cancer are well-known examples [93,94]. Among the purine scaffolds, 5-aza-9-deazapurine and 5-azapurine have been identified as a favorable skeleton for the construction of new compounds such as 108 and 109 (Figure 8) [95,96].…”

New heteroatom-rich ring systems from N,N-dialkyl-N’-chlorosulfonyl chloroformamidines

“…[52][53][54] A small set of 4-substituted pyrazolo-triazines 62 was prepared from one-carbon di-electrophiles, most conveniently with either orthoesters or carboxylic anhydrides (Scheme 37, Table 15). …”