Pyrazino thiadiazines

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-chlorosuccin-imide to the give 6-bromo and 6-chloropyrazinothiadiazines 34 <1999JME1698>. 

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. 

Condensation reaction between the 3,4,5-triamino-l,2,6-thiadiazine 135 and a symmetrical 1,2-diketone 136 (Scbeme 23) gave the pyrazino[2,3-( ][l,2,6]thiadiazines 137. When the dicarbonyl used was the nonsymmetric... 

The same researchers later extended the scope of the process and Equation (20) and Table 8 show a typical range of pyrazino[2,3-f][l,2,6]thiadiazines 142 that is available from thiadiazine 135 using these methods <2000JME4219>. 

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 same type of synthesis affords pyrazino[2,3-e]-1,2,4-triazines (329) and (330) from the diamino precursor (328), by reaction of the latter with glyoxal or phenylglyoxal, respectively. Product (329) is a dihydrate. The fully aromatic intermediate could not be isolated. Formation of (330) involves not only covalent solvation, but also an unusual TV-methylation of the presumed first-formed intermediate, and the suggested mechanism is outlined in Scheme 24 <86JHC33,93H(36)2577>. Reversing the order of polarities of the components allows [4 + 2] cyclization of pyrimidine (331) with orr/io-phenylenediamine (332), giving the benzo fused pyrazino[2,3-c][l,2,6]thiadiazine (333) (a [l,2,6]thiadiazino[3,4-6]quinoxaline]) (Equation (52)) <72ZN(B)1471>. 

Reaction of a 1,2-dihalo heterocycle, such as compounds (464) and (467), with a suitable acylhy-drazine or thioacylhydrazine leads to derivatives of four different ring systems, namely pyrazino[2,3-e][l,3,4]-thiadiazine (463), pyrazino[2,3-e][l,3,4]oxadiazine (465), pyrimido[4,5-e][l,3,4]thiadiazine (466), and pyrimido[4,5-e][l,3,4]oxadiazine (468) (Schemes 38 and 39) (80JOC3677, 81JHC799, 91IJC(B)936>. 

Bifunctional nucleophilic compounds can add to TV-alkylpyrazinium salts, and the benzo fused pyrazino[2,3-e][l,3,4]thiadiazine (471) as well as the benzo fused pyrazino[2,3-e]-l,2,4-oxadiazine (472) can be made by this method (Scheme 40). A closely related reaction is exemplified by the preparation of the pyrazino[2,3-e]-1,2,4-triazine (473) (Equation (94)) <87KGS557, 87KGS1118). The pyrimido[5,4-c][l,2,5]oxadiazine (475) can be prepared by treatment of the uracil derivative (474) with isoamyl nitrite (Equation (95)). Presumably the reaction proceeds by cyclization of an initially formed 5-nitrosopyrimidine intermediate (64ZC454). 

JCS(P1)1747>, and also the benzo fused pyrazino[2,3-< ][l,3,4]thiadiazine (500) (Equation (106)) <89JIC124>, more properly named as a thiadiazine[5,6- ]quinoxaline. 

This synthesis is also represented by only one example. 3-Ethoxycarbony-lamino-l//-pyrazino[2,3-e][l,3,4]thiadiazine (125) in methanolic hydrogen chloride under reflux during 2 h furnished 3-(4-ethoxycarbonylsemicarbazido)-2(l//)-pyrazinethione (126) in 32% yield.284... 

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]

---