Pyrazino thiazines

Of the possible 16 pyridazino-, pyrimido-, and pyrazino-oxazines, 10 are known with 19 benzo-fused derivatives. Literature over the past 10 years reports 10 bicyclic and 9 tricyclic systems and these are shown in Table 2. Of the possible 16 N-bridgehead pyridazino-, pyrimido-, and pyrazino-thiazines, 7 are known along with 13 benzo-fused derivatives. In this review five bicyclic and four tricyclic systems are discussed and these are shown in Table 3. One bicyclic system has been reported with a Se heteroatom and this is shown in Table 4. 

Conformational analysis using the Sybyl 6.8 program was performed on the proposed transition state structure of the pyrazino[2,l-A [l,3]thiazine 288 (R =Me, R2 = H, R3 = Arg-Trp-NH2) formed by solid-phase synthesis, to rationalize the stereochemical outcome of the ring formation <2004TL6333>. 

Pyrazino[2,l-A][l,3]thiazines of type 288-291 were synthesized on a solid support, with a stereoselective cycliza-tion step C1998JOC3162, 2001TL4453, 2004TL6333>. 

Diaryl-octahydro-pyra/ino[2,1 -c 1,4]thiazines are useful as melanine concentrating hormone receptor ligands <2002W02002/094799>. Pyrazino[2,l-f][l,4]oxazines 245 (Y = 0) and pyrazino[2,1 -c][ 1,4]thiazines 245 (Y = S) exert a tachykinin antagonistic effect <2002W0055518>. 

The one-step synthesis of further tri- and tetracyclic pteridine derivatives from 2-aminopyrazine 153 has also been described <2001JHC1173>. Cyclic analogues of A -[bis(methylthio)methylene]amino reagents such as 2-(methylthio)-2-thiazoline, 5,6-dihydro-2-(methylthio)-4//-l,3-thiazine, 2-(methylthio)-2-imidazoline, 2-(methylthio)-l,4,5,6-tetrahydro-pyrimidine, 2-(methylthio)-2-pyrazine, and 2-chloropyrimidine reacted with aminopyrazine 153 to afford thiazolo/thia-zino[2,3-3]- 159 ( = 1 (53%), n = 2 (42%)), imidazo/pyrimidino[2,l-/ ]- 160 ( = 1 (53%), = 2 (57%)), pyrazino[2,l-/ ]-161 (21%), and pyrimido[2,l-/ ]-pteridine 162 (42%) derivatives, respectively. 

Reactivity of pyrazino[2,3-3][l,3]thiazines was described in CHEC-II(1996) <1996CHEC-II(7)737>. The only recent report of reactions of this system, as summarized in Scheme 99 <2004CPB675>, describes N-protection followed by an ester reduction/homologation sequence. After further elaboration of the side chain, the ring nitrogen is deprotected by treatment with hydrochloric acid. 

A benzannulated pyrazino[2,3-,y][l,2]thiazine has been prepared by coupling of o-phenylenediamine with a thiazine-4,5-dione (Equation 179) <1992AP461>. 

Benzannulated pyrazino[2,3- ][l>2]thiazines have been prepared by the reaction of 3-ethoxycarbonyl-2-mercaptoqui-noxaline with active nitriles (Equation 180) <2001AEE335>. 

Published routes to pyrazino[2,3-3][l,4]thiazines, as reviewed in CHEC-II(1996) <1996CHEC-II(7)737>, involved the reaction of a 3-aminopyrazine-2-thiol with a biselectrophile and of a 3-chloropyrazin-2-amine with thioglycolate. In more recent work, the system is formed by condensation of a dichloropyrazine with a 2-aminothiophenol (Equation 182) <2002CPB922>. The same approach, using either 2-aminothiophenol or 2-aminoethanethiol, has been used to form oxadiazole-fused systems (Scheme 100) <1997CHE1352>. In studies toward the synthesis of ER-49890 151, benzannulated pyrazino[2,3-/ ][l,4]thiazines have also been accessed by an indirect sequence (Scheme 101)<2005H(65)403>. 

Although five pyridazinothiazine isomers are possible examples of only one, namely pyrid-azino[4,5-6][l,4]thiazine (Z) have been reported so far. Pyrazinothiazines could occur as two types but only the pyrazino[2,3-6][l,4]thiazines (AA) are known at present. Pyrimidothiazines are the best known diazinothiazines but derivatives of only three isomers (AB, AC, and AD) are currently known. 

Although there were many reports on pyrazino[2,3-A][l, 4]thiazines in the 1970s nothing has been published since 1980. No theoretical calculations or x-ray analyses have been reported and routine analytical data are the only information available on the structure of these molecules. 

Pyrazino[2,3-/>][l,4]thiazin-3-ones (224) have been converted into their 1,1 dioxides (225) using KMn04 as oxidative agent. All compounds were reported to be diuretics (Equation (32)) <71JAP32671>. 

Pyrazino[2,3-/)][l,4]thiazines (228) can easily be prepared by cyclization of the aminothiolpyrazine (226) with ethyl 4-chloroacetoacetate. The resulting 2,3-dihydro product (227) was dehydrated with... 

Pyrazino[2,3-6][ 1,4]thiazin-3-ones (232) have been obtained by cyclization of highly substituted aminopyrazines (231) using NaOEt—EtOH (Equation (33)) (75KGS66). 

The 3-amino-2-chloropyrazines (235) can be transformed into the thiols (236) by NaSH and cyclization with 2-chloroacetic acid or 2-chloropropionic acid gives 2,3-dihydro-(4//)-pyrazino[2,3-b][, 4]thiazin-3-ones (237) <71KGS230>. 

Amino-2-chloropyrazine upon treatment with sodium ethoxide in DMF saturated with H2S gave 3-amino-2-thiolpyrazine and cyclization to the pyrazino[2,3-6][ 1,4]thiazine was effected with phenacyl bromide in a similar way to that described above <70KGS1092>. 

Many 2,4-disubstituted pyrazino[2,3-6][l,4]thiazin-3-ones (244) show potent antipyretic, analgesic, and antiinflammatory activities <75MI 719-01). Another interesting group of pyrazino[2,3- ][l,4]thiazin-3-ones (245) are the 2-disubstituted 6,7-dimethyl derivatives which are claimed to have oncostatic activity <71KGS1498>. 

Pyrimidines fused to other six-membered rings, most frequently in the form of bicyclic structures, can be degraded to corresponding substituted monocyclic pyrimidines. Fused pyrimidine structures described are benzo- (quinazolines), pyrano[2,3-tf]-, pyrazino[2,3-i/j- (pteridines), pyrimido[l,2-u]-, pyrimido[4,5-i/]pyrimidines, and pyrimido[5,4-e]-a -triazines, pyrimido[5,4- f]-v-triazine, pyrim-ido[4,5-i/][l,3]oxazines, pyrimido[5,4-i/][l,3]oxazine, pyrimido[4,5- ][l,4]thiazines, pyrimido[5,4- ][l,4]thiazines, and pyrimido[4,5-e][l,2,4]thiadiazines. References to these reactions can be found in . 

Pyrazino]2,l-cJ] 1,4Jthiazines and their benzo derivatives Synthesis of Particular Classes of Compounds and Critical Comparison of the Routes Available Important Compounds and Applications. 8.1 Pyrimido] 1,2-hJ] 1,3Jthiazine derivatives. 8.2 Pyrimido] 4,3-b J] 1,3 J thiazine derivatives... 

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