Pyrazino thiadiazine 2,2-dioxides

Condensation of triamine (171) with arylaldehydes in dimethylformamide at room temperature affords 4-amino-6-aryl-l,5-dihydroimidazo[4,5-c][l,2,6]thiadiazine 2,2-dioxides (177) in 63-95% yield. The reaction is also successful with ethanal, but proceeds in lower yield (45%) <87H(26)3123). Studies in the late 1980s, revealed that under anhydrous conditions and with electron rich aldehydes, mixtures of the imidazo[4,5-c]-thiadiazine dioxides (177) and pyrazino[2,3-c]thiadiazine dioxides (180) are produced <88JHC89i, 89MI616-01). The latter products arise by electrocyclization of the bis-anils (178), formed by condensation of the triamine with two equivalents of aldehyde, followed by... 

Pyrazino[2,3-c]-l,2,6-thiadiazine 2,2-dioxides useful in medicinal chemistry 97F283. 

The tautomerism of 4-amino-1 //-pyrazino[2,3-c]-1,2,6-thiadiazine 2,2-dioxides 213 has been investigated in the gas phase and in solution by different solvent simulations (Scheme 139) [98JCS(P2)1889]. 

The tautomerism of the pyrazino[2,3-f]-l,2,6-thiadiazine 2,2-dioxide ring present in compound 21 has been studied in solution <1998J(P2)1889>, particularly with reference to the acidity (p 1 ) of the H-N(l) (21, R = H) proton. Further advances in the study of the tautomeric forms of the systems that appear in this chapter have not appeared since CHEC-II(1996), and the detailed and interesting discussion contained therein remains pertinent <1996CHEC-II(7)785>. 

Pyrazino[2,3-f]-l>2,6-thiadiazine 2,2-dioxides 21 have attracted reasonable attention in recent years and are typically stable solids, which are isolated by recrystallization from methanol-water or ethanol-water <1999JME1698, 2000JME4219, 2003HCA139>, often with melting points in excess of 200/250°C. 

The pyrazino[2,3- ][l>2,6]thiadiazine-2,2-dioxides 60 have been the subject of detailed study, and are readily substituted at the thiadiazine ring sp nitrogen as shown in Equation (9) to give the 1-substituted systems 61 in the yields shown in the accompanying table <2000JME4219, 1999JME1698>. 

The reaction of pyrazino[2,3-r-][l,2,6]thiadiazine-2,2-dioxides 61 with secondary amines proceeds very readily and allows access to, for example, the 4-pyrrolidinyl derivative 62 as shown in Equation (10). A similar reaction with primary amines allowed access to a range of 4-amino-pyrazino[2,3-r-][l,2,6]thiadiazine-2,2-dioxides 63, as shown in Equation (11) <2000JME4219>. 

Nucleophilic displacement of the 4-amino group of pyrazino[2,3-r-][1,2,6]thiadiazine-2,2-dioxides 61 with water gives the 4-oxo derivatives 64, giving a very versatile entry to this system. The corresponding 4-thioxo analogues 65 were easily accessed by the treatment of compounds 64 with P2SS, as shown in Scheme 9 <2003HCA139>. 

Alkylation of the exocyclic amino group of the 4-amino-6-phenylpyrazino[2,3-c][l,2,6]thiadiazine 2,2-dioxide 95, shown in Equation (14), with ethyl iodide and potassium carbonate in acetone gave the corresponding 4-ethyl-amino derivative 96 in a clean and efficient manner, although the researchers noted that the procedure is not general due to competitive formation of dialkylated products <2000JME4219>. The procedure described in Section 10.20.6.3 (Equations 10 and 11) is, in fact, a more efficient entry to 4-alkylamino pyrazino[2,3-c] [ 1,2,6]thiadiazine 2,2-dioxide. 

Three classes of compound dominate this section, namely the 6-azapteridines or pyrimido[4,5- ][l,2,4]triazines, the 7-azapteridines or pyrimido[5,4-i ][l,2,4]triazines, and the pyrazinothiadiazines, particularly the pyrazino[2,3-r ][l,2,6]thiadiazine 2,2-dioxides. None of the other systems that have appeared in this chapter show important applications. 

The 6- or 7-phenyl-substituted l-ethyl-pyrazino[2,3-r-][l,2,6]thiadiazine 2,2-dioxides 187 were found to show significant platelet aggregation inhibition comparable to other antithrombotic agents. Strong evidence was found that this activity was due to interference with the platelet arachidonic acid pathway <1999JME1698>. 

Carbon-13 NMR assignments have been made for some of the ring systems under review. Comprehensive data are available for the 2,2-dioxides of pyrazino[2,3-c][l,2,6]thiadiazines (19)... 

Pyrazino[2,3-c][l,2,6]thiadiazines are 2-thiapteridines, and their 2,2-dioxide derivatives (276) have been used in the preparation of 7-folic acid analogues (279). The latter had no biological activity, however. In the synthesis, the 7-methyl group of derivatives (276) is first brominated with pyridinium... 

The nucleophilic substitution, amination, aldol-type condensation, oxidation, and hydrolysis of the l//-pyrazino[2,3-c][l,2,6]thiadiazine 2,2-dioxide system, structurally related to pteridine, were studied in detail <03HCA139>. Chlorinated pyrazines were directly oxidized to their corresponding iV-oxides using dimethyldioxirane in a completely regioselective fashion <03HEC221 >. 1,6-Dibenzoyl-5//, 10//-diimidazo[ 1,5-a 1, 5 -[Pg.374]

Pyrazino[2,3-c]-l,2,6-thiadiazine 2,2-dioxides 15 have been glycosylated to give monoribosides at N-1 and N-8 and diribosides at N-1, N-4 (86LA1872). The fully deblocked N-1-glucosides (15c-e) exist at room temperature as a mixture of rotationally restricted syn- and mili-rotamers (Section II,A,4,c). 

UV Spectroscopy has been instrumental in determining not only the tautomeric nature of 1,2,6-thiadiazine 1,1-dioxides and their oxo-derivatives, but also the site of alkylation and glycosylation of these systems and of 1,2,6-thiadiazine 1,1-dioxides fused to other heterocyclic rings, for example pyrazino[2,3-c][l,2,6]thiadiazine 2,2-dioxides. A detailed account of these studies is available <88AHC(44)8l>, as is a brief review on the UV spectra of 1,2,6-thiadiazine 1,1-dioxides <70CRV593>. 

With a-keto-esters, 3,4,5-triamino-2//-1,2,6-thiadiazine 1,1 -dioxide (171) yields only the 4-amino-l/7-pyrazino[2,3-c][l,2,6]thiadiazin-7(8//)-one 2,2-dioxides (176), as a result of regioselective attack of the more nucleophilic 4-aminosubstituent at the ketone carbonyl centre <88LA121). 

Rate equations with temporal, spectral, and spatial dependence were derived to obtain characteristics of the laser emission of the monoprotonated species of 4-amino-7-phenyl-8//-pyrazino[3,2-f][l,2,6]thiadiazine 2,2-dioxide 42 in acetonitrile. The phenomenology indicated the possibility of observing simultaneous laser emissions at two different frequencies of both acid-base species <1995OQE1027>. 

Hydrolysis of the 4-amino group provided entry to the corresponding 4-oxo derivatives and, so, 157 was converted readily to the l//-pyrazino[2,3-H[l,2,6]thiadiazin-4(3//)-ones 158 (X = 0) by reaction with potassium carbonate in aqueous methanol. The parent system was prepared previously by reaction of 4,5-diamino-2//-l,2,6-thiadiazin-3(6//)-one 1,1-dioxide with 1,2-dicarbonyl compounds <1984JHC861>, but the starting diamine was difficult to prepare, so this is a more versatile method for preparation of the 4-oxo compounds. The 4-oxo compounds 158 (X = O) were converted to the corresponding 4-thioxo derivatives 158 (X = S) by reaction with phosphorus pentasulfide (Scheme 10) <2003HCA139>. 

Pyrazino[2.3-f][l,2,6]thiadiazine 2,2-dioxides were prepared by condensation of 4,5,6-triamino-l,2,6-thiadiazine 1,1-dioxide with 1,2-diketones. Regioselectivity was achieved as the more reactive carbonyl reacted with the 4-amino group. Alternately, selectivity could be attained by use of a-oximino ketones (Section 9.07.7.2). 

A new class of platelet aggregation inhibitors that are pyrazino[2,3-f][l,2,6]thiadiazine 2,2-dioxides having aryl substituents on the pyrazine ring 326 was described <1999JMC1698, 1999JMC3279>. 

Standard procedures were used to prepare the pyrazino[2,3-c]-1,2,6-thiadiazine -2,2-dioxide riboside (6), together with the N -rxbosyl isomer and an N ... 

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