4506-66-5

Basic information

• Product Name: 1,2,4,5-BENZENETETRAMINE TETRAHYDROCHLORIDE
• Synonyms: 1,2,4,5-TETRAAMINOBENZENE TETRAHYDROCHLORIDE;1,2,4,5-BENZENETETRAMINE TETRAHYDROCHLORIDE;1,2,4,5-Benzenetetraamine tetrahydrochloride;benzene-1,2,4,5-tetrayltetraamine tetrahydrochloride;1,2,4,5-BENZENETETRAMINE TETRAHYDRO-CHLO RIDE, TECH.;1,2,4,5-BenzenetetraminetetraHCl;1,2,4,5-Benzenetetramine tetrahydrochloride, 1,2,4,5-Tetraaminobenzene tetrahydrochloride;(2,4,5-triaminophenyl)amine tetrahydrochloride
• CAS NO: 4506-66-5
• Molecular Formula: C₆H₁₄N₄*4Cl
• Molecular Weight: 284.01
• EINECS: 224-822-6
• Product Categories: Selective focal adhesion kinase (FAK) inhibitor that displays no significant activity at a range of other kinases including EGFR, PDGFR and IGF-RI.
• Mol File: 4506-66-5.mol
• Article Data: 2

Chemical Properties

• Melting Point: ≥300 °C(lit.)
• Boiling Point: 400.9 °C at 760 mmHg
• Flash Point: 233.6 °C
• Appearance: , faint purple to dark brown/
• Density: 1.401g/cm³
• Vapor Pressure: 1.23E-06mmHg at 25°C
• Refractive Index: 1.827
• Storage Temp.: Desiccate at RT
• Solubility: H2O: soluble20mg/mL, clear
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO or distilled water may be stored at -20° for up to 1 month.
• BRN: 3701344
• CAS DataBase Reference: 1,2,4,5-BENZENETETRAMINE TETRAHYDROCHLORIDE(CAS DataBase Reference)
• NIST Chemistry Reference: 1,2,4,5-BENZENETETRAMINE TETRAHYDROCHLORIDE(4506-66-5)
• EPA Substance Registry System: 1,2,4,5-BENZENETETRAMINE TETRAHYDROCHLORIDE(4506-66-5)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36
• WGK Germany: 3
• F: 10
• Hazardous Substances Data: 4506-66-5(Hazardous Substances Data)

Usage

Description

FAK inhibitor 14 (4506-66-5) is a selective focal adhesion kinase (FAK) inhibitor that displays no significant activity at a range of other kinases including EGFR, PDGFR and IGF-R.1 Prevents FAK autophosphorylation at Y397 (IC50 = 1 μM), promotes cell detachment and inhibits cell adhesion in vitro. FAK inhibitor 14 exhibits antiproliferative activity in a variety of human tumor cell lines in vitro and in breast cancer cells in vivo. Induces regression of pancreatic tumors2 and glioblastoma3. Displays antiangiogenic activity.4

Uses

Different sources of media describe the Uses of 4506-66-5 differently. You can refer to the following data:
1. FAK Inhibitor 14 directly blocks phosphorylation of focal adhesion kinase (FAK) in a dose- and time-dependent manner and has also shown breast tumor regression in vivo. It has been suggested that targeting the Y397 site of FAK with FAK Inhibitor 14 can be effectively used in cancer therapy.
2. FAK Inhibitor 14 has been used in the metastasis assay. It is also used to study its effect on bone morphogenetic protein 7 (BMP-7)-induced cell crawling and adhesion.

General Description

A cell-permeable tetraamine compound that is identified from a computer-aided molecular docking screening based on Fak Y397 interaction and is shown to inhibit FAK (Cat. No. 324876) autophosphorylation as well as its kinase activity toward paxillin phosphorylation both in cell-free kinase assays (IC50<1 μM) and in BT474 breast cancer cultures, while exhibiting little activity against Pyk2 (Cat. No. 662067) autophosphorylation or the kinase activity of c-Raf, c-Src, EGFR, VEGFR-3, IGF-1, Met, PDGFR-α, Pyk2, and PI 3-K (p110δ/p85α). Reported to inhibit BT474 proliferation both in cultures in vitro (IC50 ~10 μM) and in mice in vivo (~25% of no treatment controls on day 23; 30 mg/kg via 5 i.p/wk).

Biological Activity

Selective focal adhesion kinase (FAK) inhibitor that displays no significant activity at a range of other kinases including EGFR, PDGFR and IGF-RI. Prevents FAK autophosphorylation at Y397 (IC 50 = 1 μ M), promotes cell detachment and inhibits cell adhesion in vitro . Exhibits antiproliferative activity in a variety of human tumor cell lines in vitro and in breast cancer cells in vivo .

Biochem/physiol Actions

1,2,4,5-Benzenetetraamine tetrahydrochloride (FAK Inhibitor 14; Y15) is a cell-permeable, selective focal adhesion kinase (FAK) inhibitor. Focal adhesion kinase (FAK) is essential in regulating integrin signaling pathways responsible for cell survival, cell proliferation and motility. Phosphorylation of FAK tyrosine 397 (Y397) forms a high affinity binding site for the SH2 domain of the Src family kinases and PI3 kinase. FAK is overexpressed in a number of human tumors. 1,2,4,5-Benzenetetraamine tetrahydrochloride (FAK Inhibitor 14, Y15) blocks phosphorylation of Y397-FAK, which results in neuroblastoma cell detachment and apoptosis.

References

1) Golubovskaya et al. (2008), A small molecule inhibitor, 1,2,4,5-benzenetetraamine tetrahydrochloride, targeting the y397 site of focal adhesion kinase decreases tumor growth; J. Med. Chem., 51 7405 2) Hochwald et al. (2009), A novel small molecule inhibitor of FAK decreases growth of human pancreatic cancer; Cell Cycle, 8 2435 3) Golubovskaya et al. (2013), Pharmacologic blockade of FAK autophosphorylation decreases human glioblastoma tumor growth and synergizes with temozolomide; Mol. Cancer Ther., 12 162 4) Cabrita et al. (2011), Focal Adhesion kinase inhibitors are potent anti-angiogenic agents; Mol. Oncol., 5 517

InChI:InChI=1/C6H10N4/c7-3-1-4(8)6(10)2-5(3)9/h1-2H,7-10H2

Synthetic route

1,3-diamino-4,6-dinitrobenzene (4987-96-6) → 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5)

Conditions	Yield
Stage #1: 1,3-diamino-4,6-dinitrobenzene With tin; Degussa F101 catalyst; hydrogen In ethanol at 80.5℃; under 15514.9 Torr; for 2h; Autoclave; Inert atmosphere; Stage #2: With hydrogenchloride In ethanol; water at 15℃;	81%
Stage #1: 1,3-diamino-4,6-dinitrobenzene With hydrogenchloride In ethanol at 50℃; for 0.166667h; Schlenk technique; Inert atmosphere; Stage #2: With tin(ll) chloride In ethanol at 86℃; for 2h; Schlenk technique; Inert atmosphere;

dipotassium 2,5-dihydroxyterephthalate + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → 1,2,4,5-tetraminobenzene 2,5-dihydroxyterephthalic acid (957471-31-7)

Conditions	Yield
With tin; sodium dithionite; sodium hydroxide In water at 15 - 55℃; for 2.25h; Product distribution / selectivity; Inert atmosphere;	100%

1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) + 2-chloro-1,3-dimethylimidazolinium chloride (37091-73-9) → N1,N2,N4,N5-tetrakis(1,3-dimethylimidazolidin-2-ylidene)benzene-1,2,4,5-tetraamine (1258956-31-8)

Conditions	Yield
With triethylamine In acetonitrile at 0℃; for 1.5h; Inert atmosphere;	100%

1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) + oxalic acid (144-62-7) → C10H6N4O4

Conditions	Yield
In water for 7h; Reflux; Inert atmosphere;	100%

2,7-dibromo-phenanthrene-9,10-dione (84405-44-7) + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → 2,7,13,18-tetrabromodibenzo[a,c]dibenzo[5,6:7,8]quinoxalino-[2,3-i]phenazine

Conditions	Yield
With acetic acid; triethylamine In ethanol at 100 - 130℃; for 6h; Inert atmosphere;	100%
With acetic acid; triethylamine In ethanol at 100 - 130℃; for 6h; Inert atmosphere;

formic acid (64-18-6) + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → Benzo<1,2-d;4,5-d'>diimidazole (50738-59-5)

Conditions	Yield
With hydrogenchloride In water for 16h; Reflux;	98%
at 100℃; for 36h;	96%
at 100℃; for 24h;	96%

hexaketocyclohexane (527-31-1) + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → C24H18N12*6ClH

Conditions	Yield
With hydrogenchloride In ethanol; water at 160℃; for 0.75h; Microwave irradiation;	98%

2,2-dimethylbutanoyl chloride (5856-77-9) + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → 1,2,4,5-tetra(2,2-dimethylbutyrylamido)benzene (1184267-92-2)

Conditions	Yield
Stage #1: 2,2-dimethylbutanoyl chloride; 1,2,4,5-benzenetetraamine tetrahydrochloride In dichloromethane for 0.0833333h; Stage #2: With triethylamine at 20℃; for 18h; Inert atmosphere;	97%

1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) + di(2-azulenyl)ethanedione (476692-34-9) → 6,7-diamino-2,3-(2-azulenyl)quinoxaline (1145777-29-2)

Conditions	Yield
With pyridine In ethanol for 1h; Reflux;	94%

1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) + 2-acetoxy-2-methylpropanoyl chloride (40635-66-3) → 1,2,4,5-tetrakis(2-acetoxy-2-methylpropanamido)benzene

Conditions	Yield
With triethylamine In 1,2-dichloro-ethane for 1h; Heating;	93.5%

1,5-difluoro-2,4-dinitrobenzene (327-92-4) + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → 4,6,16,18-tetranitro-10,12,22,24-tetraamino-2,8,14,20-tetraazacalix[4]arene (1446420-46-7)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 0℃; for 21h; Inert atmosphere; Reflux;	92%
With N-ethyl-N,N-diisopropylamine In acetonitrile Buchwald-Hartwig Coupling;	92%

3,5-di-tert-butyl-2-hydroxybenzaldehyde (37942-07-7) + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → 2,4-di-tert-butyl-6-((2,4,5-tri-[(3,5-di-tert-butyl-2-hydroxy-benzylidene)-amino]-phylimino)-methyl)-phenol

Conditions	Yield
In methanol for 18h; Inert atmosphere; Schlenk technique;	92%
In methanol; dimethyl sulfoxide at 50℃; for 16h;

3,5-bis(3,4-diethyl-5-formyl-1H-pyrrol-2-ylmethyl)-1H-pyrazole (934505-48-3) + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) + trifluoroacetic acid (76-05-1) → C2HF3O2*C52H62N12

Conditions	Yield
Stage #1: 3,5-bis(3,4-diethyl-5-formyl-1H-pyrrol-2-ylmethyl)-1H-pyrazole; 1,2,4,5-benzenetetraamine tetrahydrochloride In methanol at 50℃; for 0.25h; Inert atmosphere; Stage #2: trifluoroacetic acid In methanol for 30h; Inert atmosphere; Reflux;	91%

6-pyrazol-1-ylpyridine-2-carboxylic acid + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → 2,6-bis(6-(pyrazol-1-yl)pyridin-2-yl)-1,5-dihydrobenzo[1,2-d:4,5-d’]diimidazole

Conditions	Yield
With polyphosphoric acid at 200℃; for 4h;	91%
Stage #1: 6-pyrazol-1-ylpyridine-2-carboxylic acid; 1,2,4,5-benzenetetraamine tetrahydrochloride at 130 - 200℃; for 4h; Inert atmosphere; Schlenk technique; Stage #2: With hydrogenchloride In water pH=4;	73%

C34H44F2N8O8 + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → C56H84N12O8

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile Reflux;	90%

1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) + 5,10,15,20-tetrakis(3,5-di-tert-butylphenyl)porphyrin-2,3-dione → H2(P)-TA-(P)H2

Conditions	Yield
In pyridine for 216h; Ambient temperature;	89%
In pyridine for 216h; Inert atmosphere;

1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → 2,3,7,8-phenazine tetramine sesquihydrochloride

Conditions	Yield
With sodium acetate In water for 5h; Reflux; Schlenk technique; Inert atmosphere;	89%
With sodium acetate In water at 100℃;

3-Aminomethylpyridine (3731-52-0) + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → 2,6-di(3-pyridyl) benzo[1,2-d:4,5-d’]bisimidazole

Conditions	Yield
With air In methanol at 20℃;	89%

propylamine (107-10-8) + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → N1,N2,N4,N5-tetrapropyl-2,5-diamino-1,4-benzoquinonediimine

Conditions	Yield
In methanol; water at 20℃;	88%

1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) + dicyclohexyl-carbodiimide (538-75-0) → C58H98N12*4ClH

Conditions	Yield
With dimethylaluminum chloride In tetrahydrofuran; hexane at 20℃; for 40h; Inert atmosphere; Schlenk technique;	87%

5-dodecyl-2-hydroxy-3-methylbenzaldehyde (1228010-48-7) + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → C86H130N4O4 (1373212-90-8)

Conditions	Yield
In ethanol for 16h;	85%

1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) + 4,4'-bis(trifluoromethyl)benzil (73790-20-2) → 2,3,7,8-tetra(4′-trifluoromethylphenyl)pyrazino[2,3-g]quinoxaline (1158741-25-3)

Conditions	Yield
In butan-1-ol at 120℃; for 16h;	85%
With acetic acid for 24h; Reflux; Inert atmosphere;	60%

1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) + 2-chloro-1,3-dimethyl-1H-benzo[d]imidazol-3-ium hexafluorophosphate → N1,N2,N4,N5-tetrakis(1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-ylidene)benzene-1,2,4,5-tetraamine

Conditions	Yield
With triethylamine In acetonitrile at 20℃; for 20h; Inert atmosphere;	85%

1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) + benzylamine (100-46-9) → 2,6-diphenyl-1,5-dihydrobenzo[1,2-d:4,5-d′]diimidazole

Conditions	Yield
With air In methanol at 20℃;	85%

N1,N5-bis(5-fluoro-2,4-dinitrophenyl)-N2,N4-bis(3,4,5-trimethoxyphenyl)benzene-1,2,4,5-tetraamine + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → C42H40N12O14

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 20℃; Inert atmosphere; Reflux;	85%

1,2-bis-(4-methoxycarbonylphenyl)-ethane-1,2-dione (66553-02-4) + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → C42H30N4O8

Conditions	Yield
Stage #1: 1,2,4,5-benzenetetraamine tetrahydrochloride With triethylamine In ethanol for 0.05h; Stage #2: 1,2-bis-(4-methoxycarbonylphenyl)-ethane-1,2-dione With acetic acid In ethanol for 20h; Reflux;	84%

1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) + C15H11N3O2 → C36H24N10*ClH

Conditions	Yield
Stage #1: 1,2,4,5-benzenetetraamine tetrahydrochloride; C15H11N3O2 at 120 - 200℃; for 4h; Inert atmosphere; Schlenk technique; Stage #2: With hydrogenchloride In water pH=3;	83%

6-(3,5-dimethyl-1H-pyrazol-1-yl)picolinic acid + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → C28H24N10*2ClH

Conditions	Yield
Stage #1: 6-(3,5-dimethyl-1H-pyrazol-1-yl)picolinic acid; 1,2,4,5-benzenetetraamine tetrahydrochloride at 120 - 200℃; for 4h; Inert atmosphere; Schlenk technique; Stage #2: With hydrogenchloride In water pH=3;	83%

1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) + 6-(indazol-1-yl)picolinic acid → C32H20N10*2ClH

Conditions	Yield
Stage #1: 1,2,4,5-benzenetetraamine tetrahydrochloride; 6-(indazol-1-yl)picolinic acid at 120 - 200℃; for 4h; Inert atmosphere; Schlenk technique; Stage #2: With hydrogenchloride In water pH=3;	82%

1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) + (4Z,10Z,15Z,19Z)-5,10,20-Tris-(3,5-di-tert-butyl-phenyl)-15-(4-iodo-phenyl)-22,24-dihydro-porphine-2,3-dione + {2,3-dioxo-5,10,15,20-tetrakis(3,5-di-tert-butylphenyl)chlorinato}nickel(II) → C142H152I2N12 + C150H167IN12(2-)*Ni(2+) + C158H182N12(4-)*2Ni(2+)

Conditions	Yield
Stage #1: 1,2,4,5-benzenetetraamine tetrahydrochloride; (4Z,10Z,15Z,19Z)-5,10,20-Tris-(3,5-di-tert-butyl-phenyl)-15-(4-iodo-phenyl)-22,24-dihydro-porphine-2,3-dione With pyridine for 1h; Condensation; Cyclization; Heating; Stage #2: {2,3-dioxo-5,10,15,20-tetrakis(3,5-di-tert-butylphenyl)chlorinato}nickel(II) With pyridine for 16h; Condensation; Cyclization; Heating; Further stages.;	A 7% B 81% C 9%

H2(C(C6H4I)C4H2N)(((CH3)3C)2C6H3C(C4H2N))2C(C6H3(C(CH3)3)2)C4O2N + [2,3-dioxo-5,10,15,20-tetrakis(3'',5''-di-tert-butylphenyl)chlorinato]nickel(II) (171010-00-7) + 1,2,4,5-benzenetetraamine tetrahydrochloride (4506-66-5) → trans,exo-bis(4'-iodophenyl)hexakis(3'',5''-di-tert-butylphenyl)bisporphyrin + exo-(4'-iodophenyl)heptakis(3'',5''-di-tert-butylphenyl)bisporphyrin nickel(II) + oktakis(3',5'-di-tert-butylphenyl)bisporphyrin dinickel(II)

Conditions	Yield
In pyridine (Ar); a soln. of porphyrine and amine refluxed for 1 h, mixed with Ni-complex, refluxed for 16 h; cooled, added CH2Cl2, washed (water), dried (Na2SO4), filtered, solvent removed, chromy. (silica, dichloromethane/light petroleum); elem. anal.;	A 7% B 81% C 9%

Upstream product

• 4987-96-6 1,3-diamino-4,6-dinitrobenzene 

Downstream Products

• 96677-95-1 1,2,4,5-tetraacetamidobenzene 
• 321895-45-8 2,2-dimethyl-N-[2,4,5-tris-(2,2-dimethyl-propionylamino)-phenyl]-propionamide 
• 429693-76-5 2,2-dimethyl-propionic acid 2,4-bis-(2,2-dimethyl-propionylamino)-5-(2,2-dimethyl-propionyloxy)-phenyl ester 
• 321895-46-9 N,N',N'',N'''-tetraneopentyl-2,5-diamino-1,4-benzoquinonediimine 
• 111076-21-2 2,7-Diphenyl-1,2,3,4-tetrahydro-pyrazino[2,3-g]quinoxaline 
• 266994-71-2 octakis(3',5'-di-tert-butylphenyl)bis-porphyrin dizinc(II) 
• 1184267-92-2 1,2,4,5-tetra(2,2-dimethylbutyrylamido)benzene 

Relevant articles and documents

Benzobisimidazole Cruciform Fluorophores

A series of 11 cross-conjugated cruciform fluorophores based on a benzobisimidazole nucleus has been synthesized and characterized. Like in their previously reported benzobisoxazole counterparts, the HOMOs of these new fluorophores are localized along the vertical bisethynylbenzene axes, while their LUMOs remain relatively delocalized across the molecule, except in cruciforms substituted with electron-withdrawing groups along the vertical axis. Benzobisimidazole cruciforms exhibit a pronounced response to deprotonation in their UV/vis absorption and emission spectra, but their response to protonation is significantly attenuated. (Chemical Equation Presented).