67692-91-5

Basic information

• Product Name: 3-chloro-1,2,4-benzotriazine 1-oxide
• CAS NO: 67692-91-5
• Molecular Formula: C₇H₄ClN₃O
• Molecular Weight: 181.5792
• Mol File: 67692-91-5.mol

Chemical Properties

• Boiling Point: 392.2°C at 760 mmHg
• Flash Point: 191°C
• Density: 1.57g/cm³
• Vapor Pressure: 5.26E-06mmHg at 25°C
• Refractive Index: 1.716
• CAS DataBase Reference: 3-chloro-1,2,4-benzotriazine 1-oxide(CAS DataBase Reference)
• NIST Chemistry Reference: 3-chloro-1,2,4-benzotriazine 1-oxide(67692-91-5)
• EPA Substance Registry System: 3-chloro-1,2,4-benzotriazine 1-oxide(67692-91-5)

Safety Data

• Hazardous Substances Data: 67692-91-5(Hazardous Substances Data)

Upstream product

• 27446-08-8 3-oxo-3,4-dihydrobenzo-1,2,4-triazine 1-oxide 
• 1493-27-2 ortho-nitrofluorobenzene 
• 5424-06-6 3-amino-1,2,4-benzotriazine 1-oxide 
• 3320-86-3 2-nitrophenyl isocyanate 
• 2273-04-3 1-(2-nitrophenyl)urea 
• 88-74-4 2-nitro-aniline 
• 20028-80-2 SR 4330 
• 27446-08-8 3-hydroxybenzo[e][1,2,4]triazine-1-oxide 

Downstream Products

• 106321-20-4 3-(4-methoxy-phenyl)-benzo[e][1,2,4]triazine-1-oxide 
• 51110-86-2 3-phenyl-1,2,4-benzotriazine 1-oxide 
• 121745-82-2 N-phenyl-1,2,4-benzotriazin-3-amine 1-oxide 
• 77475-32-2 ethyl 2-(benzo[e][1,2,4]triazin-3-yl)acetate 
• 96583-60-7 3-(4-nitrophenyl)-1,2,4-benzotriazine 1-oxide 
• 1383844-70-9 (R)-3-((1-cyclohexylethyl)amino)benzo[e][1,2,4]triazine-1,4-dioxide 
• 1383844-69-6 3-((4-(tert-butyl)cyclohexyl)amino)benzo[e][1,2,4]triazine 1,4-dioxide 
• 916890-49-8 4-[4-(1-oxybenzo[1,2,4]triazin-3-ylamino)phenyl]piperazine-1-carboxylic acid tert-butyl ester 
• 906004-85-1 methyl 2-({[1-(1-oxido-1,2,4-benzotriazin-3-yl)-4-piperidinyl]acetyl}amino)benzoate 
• 906004-80-6 methyl 2-({[1-(1-oxido-1,2,4-benzotriazin-3-yl)-4-piperidinyl]carbonyl}amino)benzoate 
• 763131-62-0 Methyl {4-[(1-oxido-1,2,4-benzotriazin-3-yl)amino)phenyl}acetate 
• 108954-09-2 toluene-4-sulfonic acid-[N'-(1-oxy-benzo[e][1,2,4]triazin-3-yl)-hydrazide] 
• 1016-90-6 7-nitro-1,2,4-benzotriazin-3-amine 1-oxide 
• 27314-97-2 3-amino-1,2,4-benzotriazine-1,4-dioxide 

Relevant articles and documents

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.

Putative electron-affinic radiosensitizers and markers of hypoxic tissue: Synthesis and preliminary in vitro biological characterization of C3-amino-substituted benzotriazine dioxides (BTDOs)

Introduction: The redox characteristics of 1,2,4-benzotriazine-1,4-dioxides (BTDOs) make them potential radiosensitizing agents for hypoxic cells in solid human cancers. Tirapazamine (TPZ) is the most clinically tested BTDO radiosensitizer, despite its toxicity at effective doses. To date, no BTDOs have been developed as diagnostic markers of tissue hypoxia. Hypothesis: TPZ analogues with appropriate reporting groups can act as potential radiosensitizers and hypoxia selective diagnostics. Experimental and results: 3-Chloro-1,2,4-benzotriazine 1-oxide was substituted at the C3 position to afford 3-(2-hydroxyethoxyethyl)-amino-1,2,4-benzotriazine-1-oxide, which was oxidized to 3-(2-hydroxyethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (HO-EOE-TPZ) or converted to 3-(2-tosyloxyethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (Tos-EOE-TPZ). Tos-EOE-TPZ was intended for use as a synthon for preparing 3-(2-azidoethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (N3-EOE-TPZ) and 3-(2-iodoethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (I-EOE-TPZ). The logP values (?0.69 to 0.61) for these molecules bracketed that of TPZ (?0.34). Cell line dependent cytotoxicities (IC50) in air were in the 10–100 μM range, with Hypoxia Cytotoxicity Ratios (HCR; IC50-air/IC50-hypoxia) of 5–10. LUMO calculations indicated that these molecules are in the optimal redox range for radiosensitization, offering cell-line-specific Relative Radiosensitization Ratios (RRSR; SER/OER) of 0.58–0.88, compared to TPZ (0.67–0.76). Conclusion: The LUMO, IC50, HCR and RRSR values of 3-(2-substituted ethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxides are similar to the corresponding values for TPZ, supporting the conclusion that these TPZ analogues are potentially useful as hypoxia-activated radiosensitizers. Further studies into their biodistributions in animal models are being pursued to determine the in vivo potential in hypoxia management.

Application of Suzuki–Miyaura and Buchwald–Hartwig Cross-coupling Reactions to the Preparation of Substituted 1,2,4-Benzotriazine 1-Oxides Related to the Antitumor Agent Tirapazamine

Many 1,2,4-benzotriazine 1,4-dioxides display the ability to selectively kill the oxygen-poor cells found in solid tumors. As a result, there is a desire for synthetic routes that afford access to substituted 1,2,4-benzotriazine 1-oxides that can be used as direct precursors in the synthesis of 1,2,4-benzotriazine 1,4-dioxides. Here we describe the use of Suzuki–Miyaura and Buchwald–Hartwig cross-coupling reactions for the construction of various 1,2,4-benzotriazine 1-oxide analogs bearing substituents at the 3-position, 6-position, and 7-position.

COMPOUNDS USEFUL IN DELIVERING ANTI-NEOPLASTIC THERAPY AND DIAGNOSTIC IMAGING TO HYPOXIC CELLS AND METHODS OF USE THEREOF

Described herein are compounds that permeate cell membranes via specific hypoxia-upregulated transporters in hypoxic cells, get bioreductively activated intracellularly, and bind selectively to subcellular macromolecules to demonstrate hypoxia-specific ac

Synthesis, structure and hypoxic cytotoxicity of 3-amino-1,2,4- benzotriazine-1,4-dioxide derivatives

A series of novel 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives were synthesized and screened for their in vitro cytotoxicity against promyelocyte leukemia HL-60, androgen-independent prostate tumor PC3, hepatocellular carcinoma Bel-7402, human esop

Synthesis and hypoxic-cytotoxic activity of some 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives

A series of 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives 1 have been synthesized and evaluated for their cytotoxic activity in vitro against human leukemia cell lines: Molt-4, K562, HL60, human liver cancer cell Hep-G2, human prostate cancer cell PC-3 in hypoxia. Most of the compounds showed more potent activity than TPZ. Compounds 1i and 1m displayed encouraging superior activity against Molt-4 and HL-60 cell lines. Three potential derivatives received the test of the activity in hypoxia and in normoxia against Molt-4 and HL-60 cell lines and showed obvious hypoxia selectivity. Further mechanism study revealed that the cytotoxic activities of compounds 1i and 1k in Molt-4 cells might be mediated by modulation of p53 protein expression and mitochondrial membrane potential (ΔΨm).

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

Stille coupling reactions in the synthesis of hypoxia-selective 3-alkyl-1,2,4-benzotriazine 1,4-dioxide anticancer agents

The introduction of a 3-alkyl substituent is a key step in the synthesis of 1,2,4-benzotriazine 1,4-dioxide hypoxia-selective anticancer agents, such as SN29751. The Stille reaction of 3-chloro-1,2,4-benzotriazine 1-oxides (BTOs) 5 was inhibited by the presence of electron donating substituents on the benzo ring, thus limiting the range of compounds available for SAR studies. The use of 3-iodo-BTOs 8 did not provide a significant improvement in the yields of 3-ethyl-BTOs 6. Microwave-assisted Stille coupling of chlorides 5 gave dramatically improved yields, which were consistently superior to those from the corresponding iodides 8. The application of microwave-assisted synthesis extended the range of substituted BTOs available for SAR studies and provided an efficient, scalable synthesis of the investigational anticancer agent, SN29751 (1).

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.

DNA-TARGETED BENZOTRIAZINE 1,4-DIOXIDES AND THEIR USE IN CANCER THERAPY

The present invention relates to DNA-targeted 1,2,4-benzotriazine- 1,4-dioxides and related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.