N-substituted pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxides. A new class of diuretics

Abstract

The synthesis and evaluation of a new class of diuretic agents derived from the pyrazino[2,3-c][1,2,6]thiadiazine 2,2-dioxide ring system are described. Preliminary structure-activity relationships indicate that the nature and location of the substituents at different positions of the heterocycle are crucial for activity. Thus, a novel synthetic methodology has been developed to selectively introduce the desired substituents at different positions. From the study of the pharmacological properties (dose-response curves, duration of action, and acute toxicity) of the most active compounds, 4-amino-1,7-diethyl-6-methylpyrazino[2,3-c][1,2,6]thiadiazine++ + 2,2-dioxide (9) was selected for further investigation. Compound 9 (C10H15N5O2S) crystallizes in space group P21/a with unit cell dimensions a = 16.482 (1), b = 9.3484 (3), c = 8.333 (3) A, beta = 103.003 (3) degrees, Z = 4.

On the Reactivity of 1H‐Pyrazino[2,3‐c][1,2,6]thiadiazine 2,2‐Dioxide and Derivatives: Nucleophilic Substitution, Amination, Aldol‐Type Condensation, Oxidation, and Hydrolysis

“…± The 1H-pyrazino [2,3-c] [1,2,6]thiadiazine 2,2-dioxide system, first synthesized in our laboratory [1] and structurally related to pteridine, is of considerable pharmaceutical interest since some of its derivatives have shown interesting properties as diuretics, platelet aggregation inhibitors, and bronchodilator agents [2] [3]. Particular structural features of this heterocycle are the lack of planarity, as shown by the three different X-ray structures of compounds incorporating this ring system (code CSD [4]: LICZOM [5], SAJWOP [6], WUNTON [7]) and the remarkable acidic character of HÀN (1) with pKa values ranging from 1 ± 4 [1] [8]. Tautomerism is also an interesting aspect of this heterocycle that we have studied in solution and theoretically by ab initio calculations [9].…”

“…Thus, we have previously described N(1) alkylation and transamination of the 4-amino group, and we have also studied regioselective syntheses of C(6)-and C(7)-substituted compounds [7] [11] [12]. In this paper, we wish to report novel reactions of this particular heterocycle at the C(6) and C(7) positions, including S N displacements of halogen atoms, amination, aldol-type condensations, and oxidation of Me groups.…”

“…± Reactions with NH 3 and MeNH 2 . Nucleophilic attack of NH 3 and primary amines at 1-substituted 6-halopyrazinothiadiazine derivatives can occur at three different positions, affording the products of transamination at C(4), aminolysis at C (6), and amination at C (7). Thus, reaction of 6-chloro-1-methyl-7phenyl-1H-pyrazino [2,3-c] [1,2,6]thiadiazin-4-amine (1) with NH 3 , under pressure, afforded the corresponding aminolysis compound, 1H-pyrazino [2,3-c] [1,2,6]thiadiazine-4,6-diamine 3.…”

“…These compounds were obtained by taking advantage of the acidic character of the 7-Me group of the 7-methyl-1Hpyrazino [2,3-c] [1,2,6]thiadiazines, which can be conveniently deprotonated to afford the synthetically useful carbanions a to the aromatic pyrazine ring. Thus, 7-methyl-1Hpyrazino [2,3-c] [1,2,6]thiadiazinamines 9a [7], 9b [1], and 9c [12] reacted with benzaldehyde and 4-chlorobenzaldehyde in NaOH solution (EtOH/H 2 O) to afford the corresponding 7-styryl derivatives 10a ± c in good yields (Scheme 3).…”

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

“…Under similar conditions, the 1-methyl-6-phenyl compound 2 [5] afforded the 7-methoxy derivative 5. The reaction can be achieved with NCS or NBS (Table 1), although yields are higher when NCS is used.…”