PD168393 Chemical Properties

Melting point:

279℃

Boiling point:

571.1±50.0 °C(Predicted)

Density 

1.558±0.06 g/cm3(Predicted)

storage temp. 

room temp

solubility 

insoluble in H2O; ≥1 mg/mL in EtOH with gentle warming and ultrasonic; ≥18.45 mg/mL in DMSO

form 

powder

pka

12.19±0.43(Predicted)

color 

white to beige

InChI

InChI=1S/C17H13BrN4O/c1-2-16(23)21-13-6-7-15-14(9-13)17(20-10-19-15)22-12-5-3-4-11(18)8-12/h2-10H,1H2,(H,21,23)(H,19,20,22)

InChIKey

HTUBKQUPEREOGA-UHFFFAOYSA-N

SMILES

C(NC1C=CC2C(C=1)=C(NC1=CC=CC(Br)=C1)N=CN=2)(=O)C=C

PD168393 Usage And Synthesis

Uses

PD 168393, is an irreversible epidermal growth factor receptor (EGFR) inhibitor.

Uses

PD168393 has been used in the acute inhibition of ErbB4.

Definition

ChEBI: A member of the class of quinazolines carrying bromoanilino and acrylamido substituents at positions 4 and 6 respectively.

Biochem/physiol Actions

PD168393 is a 6-acrylamido-4-anilinoquinazoline compound. It increases apoptosis in malignant peripheral nerve sheath tumor cells, stimulated by lysosomal dysfunction.

Synthesis

Acrylic acid (12.7 mmol, 0.87 mL) was added to an anhydrous N,N-dimethylformamide (DMF, 20 mL) solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (2.0 g, 6.35 mmol) under nitrogen protection. The reaction mixture was cooled to 0 °C, followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI-HCl, 7.62 mmol, 1.46 g). The reaction was stirred at 0 °C for 15 min and then gradually warmed up to room temperature and continued stirring for 2 h. The reaction was carried out at 0 °C for 1 h. The reaction was then stirred for 2 h. After that, acrylic acid (0.30 mL) and EDCI-HCl (0.30 g) were added supplementally. The reaction continued to stir for 2 h. After the reaction was continued, the completion of the reaction was confirmed by thin layer chromatography (TLC). The solvent was removed under reduced pressure and the residue was diluted with saturated sodium bicarbonate (NaHCO3) solution and extracted several times with ethyl acetate (EtOAc). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure. The crude product was purified by chromatography on a class III alumina column using ethyl acetate/methanol (95:5, v/v) as eluent, followed by recrystallization with ethyl acetate/hexane to give a spongy white solid. After drying in high vacuum for several hours, N-[4-[(3-bromophenyl)amino]quinazolin-6-yl]acrylamide (1.06 g, 45% yield) was obtained as a cream-colored powder with a melting point of 258-261 °C. 1H NMR ((CD3)2SO, 200 MHz): δ 10.51 (s, 1H, CONH), 9.93 (s, 1H, NH), and 8.83 (br s, 1H, H-5), 8.59 (s, 1H, H-2), 8.18 (br s, 1H, H-2'), 7.94-7.78 (m, 3H, H-6', 8,5'), 7.40-7.27 (m, 2H, H-7,4'), 6.54 (dd, J = 9.8 Hz, J = 17.0 Hz, 1H CH2CHCO), 6.36 (dd, J = 2.1 Hz, J = 16.9 Hz, 1H, CH2CHCO), 5.85 (dd, J = 2.0 Hz, J = 9.7 Hz, 1H, CH2CHCO). Mass spectrum (CI): m/z 371 (95, 81BrMH+), 370 (53, 81BrM+), 369 (100, 79BrMH+), 368 (33, 79BrM+). Elemental analysis (C17H13BrN4O) Calculated values: C, 55.30; H, 3.55; N, 15.17%. Measured values: C, 55.19; H, 3.34; N, 14.88%.

in vivo

target

EGFR

IC 50

EGFR: 0.7 nM (IC₅₀)

References

[1] Journal of Medicinal Chemistry, 1999, vol. 42, # 10, p. 1803 - 1815
[2] Patent: US6344459, 2002, B1. Location in patent: Page column 48

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