Novel Arylpyrazino[2,3-c][1,2,6]thiadiazine 2,2-Dioxides as Platelet Aggregation Inhibitors. 2. Optimization by Quantitative Structure−Activity Relationships

Abstract

In the previous paper (Part 1), we described the synthesis and antiplatelet activity of a series of phenyl- and heteroarylpyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides. In this paper, we report the optimization of the platelet aggregation inhibitory activity by an iterative sequence of quantitative structure-activity relationship studies which encompassed synthesis and evaluation of the effects of structure variations at the 1-, 6-, and 7-positions of the heterocyclic system. A model has been established that correctly correlates antiplatelet activity in this series with the partial atomic charges calculated by a local density functional ab initio method. As a result of this study, the experimental platelet aggregation inhibitory activity of the lead compound was improved 300-fold.

Unconventional Alkoxylation of Pyrazino[2,3-c][1,2,6]thiadiazine 2,2-Dioxides Mediated by N-Halosuccinimides

“…However, the electrophilic substitution of pyrazino[2,3- c] [1,2,6]thiadiazine is possible at position 6 and thus 6-bromopyrazino[2,3-c][1,2,6]thiadiazine 6 was prepared from the unsubstituted derivative 7 [6] by reaction with NBS or pyridinium bromide perbromide. (Scheme 2).…”

“…This 7-chloro derivative has previously been obtained by a different procedure in our group. [9] In the alkoxylation of pyrazino [2,3-c] [1,2,6]thiadiazines there is some evidence that the reaction may be mediated by the presence of freeradicals (Table 1). Thus, the reaction is initiated or accelerated by typical free-radical sources such as tert-butyl hydroperoxide when NCS is used (compare yields of entry 4 with 5) and the reaction of 1 with NCS and ethanol fails in the darkness (entry 6).…”

“…Different 7-methoxy and 7-ethoxy derivatives of 6-arylpyrazino[2,3-c]-[1,2,6]thiadiazines 8؊10 were prepared using the corresponding derivative in methanol or ethanol with NCS and tert-butyl hydroperoxide (Scheme 1). The 7-methoxy-6-(4-nitrophenyl) derivative 8 was formed from the reaction of 11 [2] with NCS and methanol and the 7-ethoxy derivatives of the 6-(tolyl)-(9) and 6-(4-chlorophenyl)-(10) derivatives were obtained by reaction of compounds 12 [2] and 13, [2] respectively, with ethanol and NCS.…”

“…The interest in pyrazino [2,3-c] [1,2,6]thiadiazine 2,2-dioxides bearing a 7-alkoxy substituent, an important functional group in medicinal chemistry, is based on the pharmacological properties shown by some derivatives as platelet aggregation inhibitors. [1,2] In general, the introduction of an alkoxy group in a heterocyclic compound can be carried out by the direct displacement of hydrogen or by the displacement of other substituents.…”

“…[1,2] In general, the introduction of an alkoxy group in a heterocyclic compound can be carried out by the direct displacement of hydrogen or by the displacement of other substituents. The most often used procedures to obtain 7-alkoxy derivatives involve the nucleophilic substitution of chloro derivatives or the direct alkoxylation from appropriate N-oxides.…”