20028-80-2

Usage

Uses

Used in Pharmaceutical Industry:
1,2,4-Benzotriazin-3-amine is used as a potential intermediate in the synthesis of aminoindazole PDK1 inhibitors for the treatment of cancer. It has been identified through fragment-based drug discovery methods, which involve screening small molecular fragments to identify potential drug candidates.
In the pharmaceutical industry, 1,2,4-Benzotriazin-3-amine serves as a key building block for the development of novel therapeutic agents targeting the PDK1 enzyme. PDK1 (Phosphoinositide-dependent protein kinase-1) is an important enzyme involved in various cellular processes, including cell survival, growth, and metabolism. Inhibition of PDK1 has been shown to have potential anti-cancer effects, making it an attractive target for drug development.
By incorporating 1,2,4-Benzotriazin-3-amine into the molecular structure of aminoindazole PDK1 inhibitors, researchers can potentially enhance the potency, selectivity, and pharmacokinetic properties of these compounds. This, in turn, may lead to the development of more effective cancer treatments with fewer side effects.

Synthesis Reference(s)

The Journal of Organic Chemistry, 42, p. 542, 1977 DOI: 10.1021/jo00423a032

InChI:InChI=1/C7H6N4/c8-7-9-5-3-1-2-4-6(5)10-11-7/h1-4H,(H2,8,9,11)

Upstream product

• 5424-06-6 3-amino-1,2,4-benzotriazine 1-oxide 
• 50-01-1 guanidine hydrochloride 
• 98-95-3 nitrobenzene 
• 1493-27-2 ortho-nitrofluorobenzene 
• 331655-50-6 2-amino-N₁-(4-bromobenzylideneamino)benzimidazole 
• 1174221-44-3 2-amino-N₁-(4-chlorobenzylideneamino)benzimidazole 
• 331655-51-7 2-amino-N₁-(4-methoxybenzylideneamino)benzimidazole 
• 1174221-43-2 2-amino-N₁-(4-methylbenzylideneamino)benzimidazole 
• 99056-01-6 1,4-dihydro-benzo[e][1,2,4]triazine-3-carboxylic acid ethyl ester 
• 98556-75-3 benzo[e][1,2,4]triazine-3-carbonyl azide 
• 99185-60-1 ethyl benzo[e][1,2,4]triazine-3-carboxylate 
• 98555-24-9 benzo[e][1,2,4]triazine-3-carboxylic acid hydrazide 
• 27314-97-2 3-amino-1,2,4-benzotriazine-1,4-dioxide 
• 88-74-4 2-nitro-aniline 

Downstream Products

• 5424-06-6 3-amino-1,2,4-benzotriazine 1-oxide 
• 27238-43-3 3-amino-1,2,4-benzotriazine 2-oxide 
• 27314-97-2 3-amino-1,2,4-benzotriazine-1,4-dioxide 
• 251322-95-9 3-amino-1,2,4-benzotriazine 4-oxide 
• 916890-53-4 1-benzo[1,2,4]triazin-3-yl-3-[5-chloro-2-(3-dimethylaminopropoxy)phenyl]urea 
• 91669-21-5 3-chlorobenzo[e][1,2,4]triazine 
• 127845-06-1 3-phenylaminobenzo[e][1,2,4]triazine 
• 77475-32-2 ethyl 2-(benzo[e][1,2,4]triazin-3-yl)acetate 
• 67692-91-5 3-chloro-1,2,4-benzotriazine 1-oxide 
• 254-87-5 1,2,4-benzotriazene 
• 110422-84-9 2,3-diphenyl-benz[e]imidazo[1,2-b][1,2,4]triazine 

Relevant academic research and scientific papers

3-amino-1,2,4-benzotriazine 4-oxide: Characterization of a new metabolite arising from bioreductive processing of the antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine)

Tirapazamine (1) is a promising antitumor agent that selectively causes DNA damage in hypoxic tumor cells, following one-electron bioreductive activation. Surprisingly, after more than 10 years of study, the products arising from bioreductive metabolism of tirapazamine have not been completely characterized. The two previously characterized metabolites are 3-amino-1,2,4-benzotriazine 1-oxide (3) and 3-amino-1,2,4-benzotriazine (5). In this work, 3-amino-1,2,4-benzotriazine 4-oxide (4) is identified for the first time as a product resulting from one-electron activation of the antitumor agent tirapazamine by the enzymes xanthine/xanthine oxidase and NADPH:cytochrome P450 oxidoreductase. As part of this work, the novel N-oxide (4) was unambiguously synthesized and characterized using NMR spectroscopy, UV-vis spectroscopy, LC/MS, and X-ray crystallography. Under conditions where the parent drug tirapazamine is enzymatically activated, the metabolite 4 is produced but readily undergoes further reduction to the benzotriazine (5). Thus, under circumstances where extensive reductive metabolism occurs, the yield of the 4-oxide (4) decreases. In contrast, the isomeric two-electron reduction product 3-amino-1,2,4-benzotriazine 1-oxide (3) does not readily undergo enzymatic reduction and, therefore, is found as a major bioreductive metabolite under all conditions. Finally, the ability of the 4-oxide metabolite (4) to participate in tirapazamine-mediated DNA damage is considered.

Complete 1H, 13C and 15N NMR assignment of tirapazamine and related 1,2,4-benzotriazine N-oxides

1H, 13C and 15N NMR measurements (1D and 2D including 1H-15N gs-HMBC) have been carried out on 3-amino-1, 2,4-benzotriazine and a series of N-oxides and complete assignments established. N-Oxidation at any position resulted in large upfield shifts of the corresponding N-1 and N-2 resonances and downfield shifts for N-4 with the exception of the 3-amino-1,2,4-benzotriazine 1-oxide in which a small upfield shift of N-4 was observed. Density functional GIAO calculations of the 15N and 13C chemical shifts [B3LYP/6-31G(d)//B3LYP/6- 311+G(2d,p)] gave good agreement with experimental values confirming the assignments. The combination of 13C and 15N NMR provides an unambiguous method for assigning the 1H and 13C resonances of N-oxides of 1,2,4-benzotriazines. Copyright

ORGANIC COMPOUND AND ORGANIC ELECTROLUMINESCENT DEVICE USING THE SAME

The present invention relates to a novel organic compound and an organic electroluminescent device using the same. An organic electroluminescent device is provided to improve luminous efficiency, driving voltage and lifetime by including an organic compound having excellent luminous efficiency, electron transporting capability, electrochemical stability, and thermal stability.

3-Substituted Benzo[ e][1,2,4]triazines: Synthesis and Electronic Effects of the C(3) Substituent

A series of 19 structurally diverse C(3)-substituted derivatives of benzo[e][1,2,4]triazine were synthesized from 3-chloro- (1c) and 3-iodobenzo[e][1,2,4]triazine (1d) obtained in three steps from 2-nitroaniline in 37-55% yields. Nucleophilic aromatic substitution and metal-catalyzed (Pd, Cu) reactions led to functional derivatives that include alkyl (C5H11), (het)aryl (Ph, 2-thienyl, ferrocenyl), ArCC, amine (NHPh and morpholine), PO(OEt)2, sulfanyl (SBu-t), alkoxide (OEt, OMe), and CN. The synthesis of C(3)-CF3 derivative 1g via the Ruppert reaction with 1d and its 1-oxide analogue 2d led to the substitution followed by formal addition of HCF3 to the C?N bond. Pd-catalyzed carbonylation reactions of 1d and 2d did not give the corresponding C(3)-carboxylic acids. Therefore, acid 1f was obtained through hydrolysis of the CN. The substituent effect on the electronic structure of the benzo[e][1,2,4]triazine ring was investigated by spectroscopic methods (UV-vis and NMR) augmented with density functional theory calculations. Results show significant effect of the C(3) substituent on the (1) transition energy and good correlation of the 1H NMR chemical shift with the substituent constant σp. Molecular and crystal structures of six derivatives were established with the single-crystal X-ray diffraction method, and the substituent impact on the molecular geometry was investigated.

Reaction of N-Nitro-benzotriazole with nucleophiles

N-Nitro-benzotriazole 1 reacts with various C-nucleophiles 2 in tetrahydrofuran at room temperature to afford o-nitramidophenylazo-compounds 3a-f and o-nitramidophenyl hydrazones 3g-l, respectively. Reaction of 1 with sodium azide in aqueous acetonitrile gives a reactive 2-azidophenylnitramide intermediate 4 which is trapped by Cu-catalyzed 1,3-dipolar cycloadition with phenyl acetylene to afford 1-o-nitramidophenyl-4-phenyl-1,2,3-triazole 5. Reaction of 1 with trimethylsilylcyanide affords 3-amino-benzo[e][1,2,4]triazine 6. Copyright Taylor & Francis Group, LLC.

Hypervalent iodine mediated oxidation of 1,2-diaminobenzimidazole and its schiff bases: Efficient synthesis of 3-amino-1,2,4-benzotriazine and 2-aryl-1,2,4-triazolo[1,5-a]benzimidazoles

Hypervalent iodine mediated oxidation of 1,2-diaminobenzimidazole and its Schiff bases is described. The reaction produces 3-amino-1,2,4-benzotriazine and 2-aryl-1,2,4-triazolo[1,5-a]benzimidazoles efficiently. Georg Thieme Verlag Stuttgart.

HETEROCYCLIC TRIAZINES AS HYPOXIC SELECTIVE PROTEIN KINASE INHIBITORS

The invention relates to novel heterocyclic triazines which are useful as hypoxic selective cytotoxic agents that mediate and/or inhibit cell proliferation, for example, through the activity of protein kinases. The invention is further related to pharmaceutical compositions containing such compounds and compositions, and to methods of treating cancer as well as other disease states associated with unwanted angiogenesis and/or cellular proliferation by administering effective amounts of such compounds.

Methods of synthesizing 3-amino-1,2-4-benzotriazines

An improved method of producing 3-amino-1,2,4-benzotriazines using nitrobenzene or a derivative thereof, a guanidine salt and a base as reactants is provided. The method is carried out at a moderate reaction temperature without producing halide wastes derived from nucleophilic substitution and acid byproducts.

Time-resolved spectroscopy of the excited singlet states of tirapazamine and desoxytirapazamine

Laser flash photolysis (LFP, 400 nm excitation) of the anti-cancer drug tirapazamine (TPZ) in acetonitrile produces the singlet excited-state S 1 with λmax = 544 nm. The lifetime of this state is 130 ps, in good agreement with the reported fluorescence lifetime. The excited state is reduced to the corresponding radical anion by KSCN or KI. The spectrum of the radical anion is in good agreement with previously reported pulse radiolysis studies and time-dependent density functional theory (TD-DFT) calculations. LFP of desoxytirapazamine (dTPZ) also produces the first excited singlet state, S1. The fluorescence quantum yield and lifetime (5.4 ns) of the dTPZ singlet excited state are both much greater than the corresponding values of TPZ. This is explained by DFT calculations that predict that cyclization of TPZ to form an oxaziridine is thermodynamically facile but that cyclization of dTPZ to form an oxadiaziridine is not. Thus, the S 1 state of TPZ has a short lifetime and low fluorescence quantum yield due to ready cyclization whereas the cyclization of the S1 state of dTPZ is unimportant and does not limit either the fluorescence quantum yield or the fluorescence lifetime. This conclusion is confirmed by studies of dTPZ', an isomer of dTPZ containing the C=N-O moiety which has a low quantum yield and short fluorescence lifetime similar to that of TPZ.

Benzoazine mono-N-oxides and benzoazine 1,4 dioxides and compositions therefrom for the therapeutic use in cancer treatments

The present invention relates to a synergetistic composition comprising one or more benzoazine-mono-N-oxides, and one or more benzoazine 1,4 dioxides for use in cancer therapy. The invention also provides a range of novel 1,2,4 benzoazine-mono-N-oxides and related analogues. These can be used as potentiators of the cytotoxicity of existing anticancer drugs and therapies for cancer treatment.