Despite the fact that it was put on the market more than 60 years ago, hydrochlorothiazide (HCT) is still one of the most important antihypertensive drugs. Due to its chemical structure, which ...contains the secondary aryl-alkyl-amino moiety, it is vulnerable to the formation of N-nitrosamine drug substance-related impurity (NDSRI) N-nitroso-hydrochlorothiazide (NO-HCT). In our study, we reveal that NO-HCT degrades rapidly at pH values 6 to 8. The main degradation products identified are formaldehyde, thiatriazine, and aminobenzenesulfonic acid derivative. Interestingly, degradation of NO-HCT at pH values from 5 to 1 is significantly slower and provides a different impurity profile when compared to the profile generated between pH 6 and 8. Specifically, between pH 1 and 5, HCT is observed as one of the key degradation products of NO-HCT in addition to formaldehyde and aminobenzenesulfonic acid. Moreover, at pH 1, the aminobenzenesulfonic acid derivative is transformed to the corresponding diazonium salt in approximately 3% yield with the nitrosyl cation, which is released during the decomposition of NO-HCT to HCT. This diazonium is highly unstable above pH 5. To verify that degradation of NO-HCT does not produce the corresponding diazonium salt that could be formed via metabolic activation of NO-HCT, this diazonium salt and its hydrolytic and reduction degradation products were synthesized and used as standards for the identification of species formed during the degradation of NO-HCT. This enabled us to confirm that the corresponding aryl diazonium salt, which would be obtained from metabolic activation of NO-HCT, is not observed in the NO-HCT degradation pathway. Our study also demonstrates that this diazonium salt is stable only in the presence of a large excess of strong mineral acid under anhydrous conditions. In the presence of water, it is instantaneously converted to an aminobenzenesulfonic acid derivative. These findings suggest that the NO-HCT should not be considered as a typical compound belonging to the cohort of the concern.
A facile method for the synthesis of 1,2,4triazolo4,3-
1,2,4,6thiatriazine 1-oxides
is presented. The approach involves a reaction between
-triazol-3-ylamidines
and thionyl chloride in the presence ...of pyridine. The structures of the synthesized compounds were confirmed by spectral studies including IR,
H NMR,
C NMR, MS and elemental analysis.
In the quest for discovery of novel bioactive molecules, new heterocyclic ring systems provide templates for exploration of uncharted chemical space. Herein, we describe the synthesis of a new ...benzo4,5imidazo1,2-b1,2,4,6thiatriazine derivative from readily available 1,2-diaminobenzimidazole and N,N-diethyl-N′-chlorosulfonyl chloroformamidine. The product structure, confirmed by X-ray crystallography, bears an exocyclic NH2 group, which should enable synthesis of an extended range of derivatives of this unusual scaffold.
A very short, effective and widely applicable synthesis of substituted 1-carbo-1λ
4
-1,2,4,6-thiatriazines is presented. The first step consisting of replacing the chlorine atom at the sulfur of ...trichlorothiatriazine by a carbon atom is described for the first time.
1?4,2,4,6-thiatriazines were identified as a novel class of herbicides. Their interesting effects on plants as well as their uncommon structures incited further studies. In addition to the initial ...sulfodiimine based preparation method, a flexible synthetic route was designed giving access to a larger array of compounds. The poor initial biological activity was improved and compounds with very high herbicidal activity were identified. Thiatriazines have been found to be unique and very potent inhibitors of the biosynthesis of cellulose, which is a major component of the plant cell wall. While the precise biochemical site of thiatriazine action is not yet known, they are known to induce the formation of a non-crystalline ?-1,4-glucan, as opposed to previously described herbicides which inhibit cellulose biosynthesis. Studies on the uptake, translocation and metabolism of a representative thiatriazine provided evidence for crop selectivity on the basis of differential rates of metabolism in various plant species.
The reactions of (aryl)(chloro)methyl
p-tolyl sulfoxides
2 with tetrasulfur tetranitride (S
4N
4) in
p-dioxane at reflux gave 3,5-diaryl-1,2,4,6-thiatriazine 1-oxides, 3,5-diaryl-1,2,4-thiadiazoles, ...and 1-amino-3,5-diaryl-1,2,4,6-thiatriazine 1-oxides. For the first time, the structures of 3,5-diaryl-1,2,4,6-thiatriazine 1-oxides were unequivocally characterized based on X-ray crystallography of 3,5-di(3,4-dimethylphenyl)-1,2,4,6-thiatriazine 1-oxide. Treatment of the thiatriazine 1-oxides with
m-CPBA gave 2,6-diaryl-4-(3-chlorophenyl)-1,3,5-triazines. Mechanisms are proposed for the formation of thiatriazine 1-oxides and 1,3,5-triazines.
The EPR spectra of six 1,2,4,6-thiatriazinyls have been redetermined and simulated using modern computer simulation programs. The hyperfine coupling (hfc) constants determined from the simulations ...differ in some cases significantly from those reported previously. The presence of unresolved coupling also can be detected in some of the spectra. The hfc values to the two kinds of nitrogen atoms in the ring vary in a systematic fashion with the relative electron-withdrawing character of the substituents attached to the ring carbon atoms at the 3 and 5 positions.
4
+
2 addition reactions of the thiazyl derivatives FSN (
1) and (CF
3)
2NOSN (
4) to the 1,3-diazabutadiene Me
2C
6H
3NC(C
6H
5)–NC(CF
3)
2 (
3) give the corresponding 2,5-dihydro-1λ
...4,2,4,6-thiatriazines
3 and
5 in 67 and 76% yield, respectively. X-ray structures of
3 and
5 are reported.
5-Diazoimidazoles and 5-diazopyrazoles have been shown to react with acyl isothiocyanates yielding the imidazo- and pyrazolo5,1-d1,2,3,5thiatriazines stabilized by a nonbonded Sa=O interaction. In ...contrast to acyl isothiocyanates, alkyl-, aryl-, and arylsulfonyl isothiocyanates do not react with 5-diazoazoles. The nature and the strength of stabilizing intramolecular interaction between non-bonded S and O atoms have been studied by X-ray analysis for mono crystals and DFT calculations for selected azolo5,1-d1,2,3,5thiatriazines. The interaction was described in terms of Weinhold covalence ratio factors, NBO, and AIM schemes. The reaction discovered was used to develop an efficient approach toward the new 8-substituted 4-ethoxycarbonylimino-4-benzoyl- and 4-(3,4,5,6-tetrafluorobenzoyl)iminoimidazo(pyrazolo)5,1-d1,2,3, 5 thiatriazines.
Fluorine-containing compounds are at the leading edge of many new developments in the life science industry. In recent years a steady increase in the number of fluorinated organic molecules reaching ...commercial status as crop protection products and pharmaceutical drugs has been observed: in 1978, ca. 600 pesticides were known, but only approximately 25 (4%) contained fluorine. Today, fluorine-containing compounds account for more than 17% of all commercially available crop protection agents and many others are currently under development. The structures of the fluorine-containing development compounds proposed for ISO common names between 1997 and 2002 are highlighted in this paper. In the pharmaceutical area around 220 fluorinated drugs were on the market in 1990, representing ca. 8% of all synthetic drugs. Six years later already more than 1500 fluorine-containing drugs were under development. Fluorine-containing compounds have also been successful in the marketplace, such as the insecticides fipronil and lambda-cyhalothrin, the fungicides epoxiconazole and trifloxystrobin, the herbicides trifluralin and clodinafop, and the pharmaceutical blockbusters Fluoxetine (Prozac®), Paroxetine (Paxil®), Ciprofloxacin (Cipro®) and Cisaprid (Propulsid®). This success is mainly due to the fact that selectively fluorinated compounds can exhibit dramatically improved potency when compared to the non-fluorinated analogues. The incorporation of fluorine into a biologically active compound alters the electronic, lipophilic and steric parameters and can critically increase the intrinsic activity, the chemical and metabolic stability, and the bioavailability. The positive effects of fluorine on the biological efficiency is outlined by three examples: in the chemical class of herbicidal thiatriazines, the presence or the absence of fluorine leads to dramatic effects on the biological activity; the metabolic stability and the pharmacokinetics of aminopyrazinone acetamide thrombin inhibitors were improved by the introduction of fluorine, and in a novel class of insecticides/acaricides any modification of the gem -difluorovinyl group results in a strong decrease of biological activity.
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