Synthesis of certain N‐ and C‐alkyl purine analogs

Abstract

A number of N‐ and C‐alkyl derivatives of selected guanine analogs have been synthesized as potential antiviral agents. n‐Pentyl, n‐hexyl and 6‐hydroxyhexyl derivatives in the imidazo[1,2‐α]‐s‐triazine, 9–11, imid‐azo[1,2‐α]pyrimidine, 13–17, and thiazolo[4,5‐d]pyrimidine, 19–21, ring system have been prepared by the direct alkylation of the sodium salt of the appropriate aglycon with the respective alkylbromides. Dehydra‐tive coupling of 3‐amino‐6‐hydrazino‐1,2,4‐triazin‐5(4H)‐one (22) with either hexanoic acid or heptanoic acid, and further ring closure of the reaction products 24a and 24b provided the n‐pentyl and n‐hexyl derivatives of 6‐amino‐1,2,4‐triazolo[3,4‐f][1,2,4]triazin‐8(7H)‐one 25a and 25b, respectively. A similar condensation of 3‐amino‐6‐aminomethyl‐1,2,4‐triazin‐5(4H)‐one (23) with heptanoic acid, followed by ring annulation, readily gave 2‐amino‐7‐n‐hexylimidazo[5,1‐f][1,2,4]triazin‐4(3H)‐one (25c). Bromination of 25c with N‐bromosuccini‐mide afforded the corresponding 5‐bromo derivative 26. Alkylation of the in situ generated sodium salt of 4‐methoxycarbonylmethyl‐5‐methoxycarbonyl‐2‐oxo‐1H,3H‐imidazole (27) with 1‐bromohexane gave the N‐1 alkylated product 31. Manipulation of the functional groups in 31 and further hydrazine mediated ring annulation furnished 5,6‐diamino‐1‐n‐hexyl‐3‐methylimidazo[4,5‐c]pyridine‐2,4‐dione (39). Catalytic hydrogena‐tion of 39 gave 7‐methyl‐8‐oxo‐9‐hexyl‐3‐deazaguanine (40), a congener of the immunostimulator 7‐methyl‐8‐oxoguanosine.

Recent Advances in Imidazo[5,1‐f][1,2,4]triazin‐4(3H)‐ones Chemistry: An Overview of the Synthetic Routes to Vardenafil and Its Analogues

“…This debenzylated via hydrogenation over Pd–C in ethanol in HCl to afford the known 3‐amino‐6‐(aminomethyl)‐1,2,4‐triazin‐5(4 H )‐one dihydrochloride 154 . Condensation of 154 with the active ester 155 gave 156 ; subsequent cyclization of 156 with POCl 3 afforded imidazo‐[5,1‐ f ]‐1,2,4‐triazin‐4(3 H )‐one 157 . Iodination of 157 using 1.2 equiv of N ‐iodosuccinimide at room temperature afforded the iodo derivative 158 in 75% yield.…”

Synthesis andin vitro evaluation of the anticancer activity of novel fluorinated thiazolo[4, 5-d]pyrimidines

“…Three compounds were found active and their anticancer activity against 60 human tumor cell lines are described in detail. Introduction Thiazolo[4,pyrimidines can be considered as thiaanalogues of the naturally occurring purine bases, adenine and guanine, due to the insertion of a sulphur atom in the place of the nitrogen atom at position 7 of the purine ring.These compounds have acquired a growing importance as anticancer immunotherapeutic agents [1], antiviral agents used in the treatment of human cytomegalovirus (HCMV) [2][3][4][5][6], antitumour [7] and antibacterial agents [8]. Recently they have been found to strongly antagonise the activity of the corticotropin releasing factor (CRF) and thus have the potential to be CNS active agents [9,10].…”

“…Thiazolo [4,5-d]pyrimidines have also been reported to have antidepressive activity [11]. Many of these compounds are therefore of interest to major pharmaceutical companies [3][4][5][6][9][10][11]. …”

Salts of 5-Substituted Uracils with 1,8-Diazabicyclo[5.4.0]-undec-7-ene: Convenient Reagents for Nucleophilic Addition and Substitution Reactions

“…2,4-(1H,3H)-Pyrimidinediones and purines as NH-acids are characterized by low acidity. Sodium hydride, [10][11][12][13] tertiary amines 14 or potassium carbonate 15 are usually used as deprotonating agents. More recently, tetrabutylammonium salts of purines, which exhibit sufficient solubility in organic solvents, were introduced.…”