1.3.4- Thiadiazin-5 -ones

Thiadiazines are prepared best by cyclocondensation of thiohydrazides with a-halo ketones (Section 9.08.8.2.2). Pharmacologically interesting 2,3-dihydro-l,3,4-thiadiazin-2-ones are obtained by cyclocondensation of 0-alkyl thiocarbazates (Section 9.08.8.2.2). By the reactions of a-halo carboxylic acids or a-halo carbonic esters, 1,3,4-thiadiazin-5-ones are formed (Section 9.08.8.2.2). Hydrazonyl chlorides react with ethyl sulfanylacetate to afford... 

Two Nitrogen Atoms and One Sulfur Atom Synthesis of 1,3,4-thiadiazines 98H(49)557. 

A precursor in the synthesis of a promising calcium sensitizing agent from E. Merck [33], a chiral thiadiazin-2-one EMD 53986, 3,6-Dihydro-5-[l,2,3,4-tetrahy-dro-6-quinolyl]-6-methyl-2H-l,3,4-thiadiazin-2-one [26]. The study was performed using Celluspher , a CSP prepared from cellulose tri(p-methylbenzoate) according to a patent from Ciba-Geigy [34]. The spherical particles had a mean particle diameter of 20 3 pm and the mobile phase was pure methanol. 

Another cyclisation involving 4-amino-6-methyl-3-thioxo-l,2,4-tiiazin-5-one 82 is the reaction with propargyl bromide followed by palladium(II) catalysis to yield a [1,2,4] triazino[3,4-f ][l,3,4]thiadiazine 83, or with phenacyl bromide to give 84 <96MI03 96CA(125)195597 96MI04 96CA(125)247767 >. 

Reports of bicyclic systems with one nitrogen atom containing two additional heteroatoms in each ring are scant in the literature. Fourteen such ring systems have been reported previously 1-14 <1996CHEC-II(8)733>. The literature examples available during the last decade include 1,2,4-triazino[3,4-Z ][ l,3,4]thiadiazine-4,7-dione 15, [l,2,4]tri-azino[3,4-/d [ 1,3,4]thiadiazinc 16, l,9a-dihydro-8//-l, 2,4-triazino-[3,4-Z ] [1,3,4] thiadiazine-4-oncs 17, [l,3,5]tria-... 

A series of 4//.8//-1,2-4-triazino[3,4-//]-l,3,4-thiadiazin-4-ones 17 <2001IJB475> has been reported and obtained by condensation of 4-amino-6-substituted-3-mercapto-l,2,4-triazin-5(4//)-ones 35 with various phenacyl bromides (Equation 2) <2001IJB475>. 

The compound 7-(4-chloro-benzyl)-2-(4-chloro-phenyl)-3,8a-dihydro-pyridazino[4,3-( ][l,3,4] thiadiazin-8-one 42 has been reported to be active against Bacillus Escherchia coli, Staphylococcus aureus, and Pseudomonas aeruginosa by a serial dilution method <2001IJB475>. Triazino-thiadiazines 24f, 25b, 25c, and 25f <2002IJH287> have been reported to be active against S. aureus-, sydnone derivatives of triazino-thiadiazine 24f <2002IJH287> are more reactive than coumarin derivatives. 

Benzamides e.g. MS-275 8 are one of the more common hydroxamic acid alternatives but are often less potent. Recent exceptions to this pattern include substituted pyridyl [29] and thiazolyl [30] benzamides, such as 9 and 10 with HDAC1 enzyme IC50s of 19nM and 29 nM, respectively and series of benzamides substituted with other heterocycles, such as indazoles [31] and benzo [l,2,4]thiadiazines [32], many with HDAC2 IC50s of <50 nM. The addition of... 

Liu et al. elaborated an efficient synthetic route to [l,2,4][5,l-A][l,3,5]thiadiazine-7-ones 122 <2000M953, 2000JFC111> starting from 3-mercapto[l,2,4]triazoles 121. These compounds were treated with N-substituted A-chloromethylcarbamoyl choride in dimethylformamide (DMF) solution at room temperature for 1-2 h to give the ring-closed products in high yield (>80%) (Scheme 22). 

Replacement of carbonyl by sulfonyl led to the benzo-2,l,3-thiadiazin-4-one 2,2-dioxide ring system, in particular bentazon (7) (68SAP6705164). It can be synthesized by reaction of 2-aminobenzoic acid, or ester, with isopropylsulfamoyl chloride, followed by cyclization with carbonyl chloride in the case of the acid, or sodium hydroxide in the case of the ester. 

Only one kind of six-membered ring system containing two nitrogens and one sulfur has been prepared from thiourea-type starting materials, namely 1,3,5-thiadiazines. The first report of this sort of preparation is that of Fromm and Weller,65 who in 1908 found that the thiourea... 

Apart from the various tautomeric forms, there are four kinds of parent thiadiazine structures, having molecular formula C3H4N2S, in which the sulfur atom is adjacent to at least one ring nitrogen atom (structures I-IV). In order to name a particular tautomer, the extra hydrogen requires designation. Thus, using Chemical Abstracts nomenclature, structure I is named as 6//-1,2,3-thiadiazine, and structures V, VI and VII are named as... 

Not much is known about the properties of 1,2,5-thiadiazines. However, there is one outstanding property the contraction of the 1,2,5-thiadiazine ring, which is shown both by monocyclic 1,2,5-thiadiazines and 2,1,4-benzothiadiazines. For instance, 1,2,5-thiadiazine 187, which is stable at low temperatures, tends to revert to 1,2,5-thiadiazolium cyanide 185 on standing at room temperature for several days (79TL1281). In this contraction, the ring sulfur atom is retained. Usually the sulfur atom is extruded to give imidazole derivatives, e.g., 1,2,5-thiadiazine 184 (R = i-Pr), when heated, yields thiazolidinethione 194 (49JOC946). In the 2,1,4-... 

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