3-(5-fluoro-indol-3-yl)-pyrrolidine-2,5-dione

3-(5-fluoro-indol-3-yl)-pyrrolidine-2,5-dione Property

Melting point:

190-195 °C

Boiling point:

533.2±50.0 °C(Predicted)

Density 

1.464±0.06 g/cm3(Predicted)

storage temp. 

Inert atmosphere,Room Temperature

solubility 

Soluble in DMSO (up to at least 25 mg/ml)

form 

solid

pka

9.13±0.50(Predicted)

color 

White

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H302Harmful if swallowed

H315Causes skin irritation

H319Causes serious eye irritation

H335May cause respiratory irritation

Precautionary statements

P261Avoid breathing dust/fume/gas/mist/vapours/spray.

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P270Do not eat, drink or smoke when using this product.

P271Use only outdoors or in a well-ventilated area.

P280Wear protective gloves/protective clothing/eye protection/face protection.

P301+P312IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.

P302+P352IF ON SKIN: wash with plenty of soap and water.

P304+P340IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

P321Specific treatment (see … on this label).

P330Rinse mouth.

P332+P313IF SKIN irritation occurs: Get medical advice/attention.

P337+P313IF eye irritation persists: Get medical advice/attention.

P403+P233Store in a well-ventilated place. Keep container tightly closed.

P405Store locked up.

P501Dispose of contents/container to..…

3-(5-fluoro-indol-3-yl)-pyrrolidine-2,5-dione Chemical Properties,Usage,Production

Description

PF-06840003 (198474-05-4) is a potent (IC50?= 150 and 410 nM via two methods) and selective inhibitor of Indoleamine-2,3-dioxygenase (IDO1).1?In mice with syngeneic tumor grafts, it reduced intratumoral kynurenine levels by over 80%, inhibited tumor growth as monotherapy, and increased the efficacy of anti-PD-L1 therapy.2?PF-06840003 treatment combined with GM-CSF-secreting allogenic pancreatic tumor cell vaccine (GVAX) resulted in increased antitumor efficacy in a murine model of pancreatic ductal adenocarcinoma.3

Uses

PF-06840003 is a potential clinical candidate as a novel and selective Indoleamine 2,3-dioxygenase inhibitor. Highly selective and orally bioavailable IDO-1 inhibitor.

Synthesis

The general procedure for the synthesis of 3-(5-fluoro-1H-indol-3-yl)-2,5-pyrrolidinedione from maleimide and 5-fluoroindole was as follows: 5-fluoroindole (5.00 g, 35.5 mmol, 96 wt%) was mixed with maleimide (5.17 g, 53.3 mmol, 1.5 eq.) in a 50 mL reaction vessel followed by addition of acetonitrile ( 15.0 mL, 11.7 g, 286 mmol, 100 wt%) and zinc chloride (5.08 g, 37.3 mmol, 1.05 equiv). The reaction mixture was heated to 85 °C within 10 min and maintained at this temperature for 24 h. The reaction was carried out at a temperature of 0.5 °C. The reaction was carried out at a temperature of 0.5 °C. During the reaction, the temperature was maintained above 80 °C and water (30.0 mL, 30.0 g, 1670 mmol, 100 wt%) was slowly added and yellow solid precipitation was observed. Subsequently, the reaction mixture was cooled to 50 °C over 1 h and stirred at this temperature for 2 h, after which it continued to be cooled to 10 °C over 1 h and stirred at 10 °C for 1 h. The reaction mixture was then cooled to 50 °C over 1 h and stirred at 10 °C for 2 h. The reaction mixture was then The solid was collected by filtration and the filter cake was washed twice with 5 mL of a 1:1 acetonitrile/water mixture to give the crude product (6.85 g, 29.5 mmol, 83.1% yield). To purify the crude product, it (6.85 g, 29.5 mmol, 100 wt%) was dissolved in tetrahydrofuran (41.1 mL, 36.4 g, 505 mmol, 100 wt%) and heated to 66 °C to form a homogeneous solution. Heptane (27.4 mL, 18.7 g, 187 mmol, 100 wt%) was slowly added at 66 °C and the solid was observed to start precipitating. The mixture was cooled to 25 °C over 3 h, filtered and washed with heptane, followed by drying in a high vacuum oven overnight to give the purified product (4.93 g, 21.2 mmol, 100 wt%, 72.0% yield). For further purification, the above product (1.00 g, 4.3 mmol, 100 wt%) was mixed with tetrahydrofuran (6 mL, 100 wt%) and heptane (6 mL, 100 wt%) in a 50 mL vessel and stirred for 48 h at 25 °C. The product was purified by washing with a solvent and dried in a high vacuum oven overnight. The solid was collected by filtration and dried in a high vacuum oven overnight to give the final product (0.89 g, 3.83 mmol, 100 wt%, 89.00% yield).

in vivo

IC 50

IDO-1

References

[1] STEFANO CROSIGNANI*. Discovery of a Novel and Selective Indoleamine 2,3-Dioxygenase (IDO-1) Inhibitor 3-(5-Fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and Its Characterization as a Potential Clinical Candidate[J]. Journal of Medicinal Chemistry, 2017, 60 23: 9617-9629. DOI:10.1021/acs.jmedchem.7b00974
[2] BRUNO GOMES. Characterization of the Selective Indoleamine 2,3-Dioxygenase-1 (IDO1) Catalytic Inhibitor EOS200271/PF-06840003 Supports IDO1 as a Critical Resistance Mechanism to PD-(L)1 Blockade Therapy.[J]. Molecular Cancer Therapeutics, 2018, 17 12: 2530-2542. DOI:10.1158/1535-7163.mct-17-1104
[3] ALEX B BLAIR. IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma.[J]. Journal of Clinical Investigation, 2019, 129 4: 1742-1755. DOI:10.1172/jci124077