3-Amino-l,2,4-benzotriazines

A few interesting organic molecules may possess the ability to release hydroxyl radical under physiological conditions. The most extensively studied of these is 3-amino-l,2,4-benzotriazine 1,4-dioxide (tirapazamine, 95, Scheme 8.32). Tirapazamine is a bioreductively activated DNA-damaging agent that selectively kills the oxygen-poor (hypoxic) cells found in solid tumors. The biological activity of... 

Treatment of l,2,4-benzotriazin-3-one 1-oxide (131) with sodium hydroxide afforded benzotriazole (132a). Similarly, 3-amino-l,2,4-benzotriazine 1-oxide (133) with a base gave benzotriazole or 1 -acetylbenzotriazole (132b) while 3-amino-1,2,4-benzotriazine 2-oxide (134) was converted into benzotriazole and benzotriazole-1-carboxamine (132c) (62JOC185). 

The product of methylation of l,2,4-benzotriazin-3-one 1-oxide (210) with methyl iodide was identified as 4-methyl-1,2,4-benzotriazin-3-one 1-oxide (211) (59JOC813). Like the amines in the monocyclic series mentioned above, 3-amino-l,2,4-benzotriazine 1-oxides (133) are acylated on the amino group (54JA3551). 

Only a few examples of the formation of 1,2,4-triazines by this fragment combination have been published, all cases being 1,2,4-benzotriazine syntheses. 2-Nitroaniline reacts with cyanamides to give 2-nitrophenylguanidines (601) which cyclize under basic conditions to 3-amino-l,2,4-benzotriazine 1-oxides (602) <78HC(33)189, p.699). With benzoyl isothiocyanate it affords Ar-(2-nitrophenyl)-N -benzoylthiourea (603), which cyclizes to l,2,4-benzotriazine-3-thione 1-oxide (604) (80MI21900).. 

Cyclization of the 2-acylaminoazobenzenes (729) leads to 2-aryI-l,2,4-benzotriazinium salts (730) (74GEP2241259). When the azo compound (731) was heated without a solvent to 200°C 3-amino-l,2,4-benzotriazine (732) was isolated (27CB2598) this involves N(l)—C(8a) [N(l)—C(6)] bond formation, unusual in 1,2,4-benzotriazine syntheses. 

Amino-l,2,4-benzotriazine 1,2-dioxide Thin layer chromatography Thymidine-5 -phosphate iV,iV,iV, iV -Telramclhylphcnylcncdiamine Tetranitromethane 3,5,4 -Trihydroxy-frans-stilbene 2-Amino-2-hydroxy-l, 3-propanediol Time-resolved light-scattering p-[meso-5-5,10,15,20-Tetra(pyridyl)porphyrin]tetra kis[ (ns-(bipyridine) chloride ruthenium(II)]... 

Anderson, R.F., Shinde, S.S., Hay, M.P., Gamage, S.A. and Denny, W.A. (2003) Activation of 3-amino-l,2,4-benzotriazine 1,4-dioxide antitumor agents to oxidizing species following their one-electron reduction. Journal of the American Chemical Society, 125, 748-756. 

Dichlorophenyl)-l,2,4-triazine-3,5-diamine (13, Lamotrigine, LTG, BW430C, 430C78)27 and 3-amino-l,2,4-benzotriazine 1,4-dioxide (14, SR4233)440 are used as drugs. Cephalosporins and penicillins with a 1,2,4-triazine moiety have been prepared and found pharmaceutical applications.444... 

Treatment of 2-nitrophenylcarboximidamides with base affords 1,2,4-benzotriazine 1-oxides.15 5a c Similar treatment of the 2-nitrophenylureas, thioureas and guanidines leads to the 3-hydroxy-, 3-sulfanyl- and 3-amino-l,2,4-benzotriazine 1-oxides or their tautomers.155a c... 

Methyl-,242 3-phenyl-,450 or 3-amino-l,2,4-benzotriazine 1-oxide or -2-oxide afford benzo-triazoles 4 when treated with sodium hydroxide377 The same reaction is observed for pyrido-[2,3-e]-l,2,4-triazin-3-amine or pyrido[4,3-e]-l,2,4-triazin-3-amine 1-oxide in sodium hydroxide affording the corresponding products in 77 and 40% yield, respectively.370 379... 

K.I. Priyadarsini, M. Tracy and P. Wardman, The one-electron reduction potential of 3-amino-l,2,4-benzotriazine 1,4-dioxide (tirapazamine) a hypoxia-selective bioreductive drug. Free Radical Res., 25 (1996) 393. 

A mass spectrometric method was used to study protonation of 3-amino-l,2,4-benzotriazine and its A -oxides, such as the 1-oxide, 2-oxide, 4-oxide, and 1,4-dioxide (tirapazamine) <2001JOC107, 2003JAM881>. Protonation of tirapa-zamine in both the gas and liquid phases was shown to occur exclusively at the oxygen in the 4-position. The activation energy for loss of OH radical from O-protonated tirapazamine was estimated to be approximately 14kcal moPc Quantum-chemical calclulations of protonated A -oxides were performed to interpret the experimental results and identify intermediates <2003JAM881>. 

A recently reported synthesis of 3-amino-l,2,4-benzotriazines is also based on the [3+3] combination of fragments (Scheme 124) <2006RCB1243>. The feature of this approach is that in 3-fluoro-substituted nitrobenzenes, nucleophilic displacement of hydrogen at C-2 or C-6 by the action of guanidine takes place, followed by intramolecular cyclization into the isomeric 3-amino-l,2,4-benzotriazines (Scheme 124) <2006RCB1243>. 

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