1035555-63-5

Basic information

• Product Name: TAK-733
• Synonyms: TAK-733;TAK-733/TAK733;(R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;(R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione TAK 733;(R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrim
• CAS NO: 1035555-63-5
• Molecular Formula: C₁₇H₁₅F₂IN₄O₄
• Molecular Weight: 504.2266764
• Product Categories: MAPK;Inhibitors
• Mol File: 1035555-63-5.mol
• Article Data: 4

Chemical Properties

• Boiling Point: 530.5±60.0 °C(Predicted)
• Appearance: /
• Density: 1.91±0.1 g/cm3(Predicted)
• Solubility: ≥25.2 mg/mL in DMSO; insoluble in EtOH; insoluble in H2O
• PKA: 13.72±0.20(Predicted)
• CAS DataBase Reference: TAK-733(CAS DataBase Reference)
• NIST Chemistry Reference: TAK-733(1035555-63-5)
• EPA Substance Registry System: TAK-733(1035555-63-5)

Safety Data

• Hazardous Substances Data: 1035555-63-5(Hazardous Substances Data)

Usage

Description

TAK-733 is a potent and selective MEK allosteric site inhibitor for MEK1 with IC50 of 3.2 nM, inactive to Abl1, AKT3, c-RAF, CamK1, CDK2, c-Met, etc. Phase 1.

In vitro

TAK-733 is highly potent and selective MEK allosteric site inhibitor with IC50 of 3.2 nM. TAK-733 shows potent enzymatic and cell activity with an EC50 of 1.9 nM against ERK phosphorylation in cells.

In vivo

TAK-733 demonstrates broad antitumor activity in mouse xenograft models of human cancer including models of melanoma, colorectal, NSCLC, pancreatic and breast cancer. TAK-733 is well tolerated with pharmacokinetics and pharmacodynamics that support once-daily oral dosing in humans. TAK-733 shows maximally efficacious doses at once daily orally doses of 10 mg/kg.

Biological Activity

tak-733 is a potent, atp-noncompetitive and selective inhibitor of mek allosteric site with the ic50 value of 3.2nm [1].tak-733 has been shown potent enzymatic and cell activity with an ic50 value of 3.2nm against constitutively active mek enzyme and an ec50 of 1.9nm against erk phosphorylation in cells. in addition, tak-733 has also shown the low clearance and high oral bioavailability based on the pharmacokinetics of tak-733 in all species (mouse, rat, dog and monkey). furthermore, tak-733 has been reported to broad inhibit tumor activity in mouse xenograft models of human cancer (melanoma, colorectal, nsclc, pancreatic and breast cancer) [1].

references

[1] dong q1, dougan dr, gong x, halkowycz p, jin b, kanouni t, o'connell sm, scorah n, shi l, wallace mb, zhou f. discovery of tak-733, a potent and selective mek allosteric site inhibitor for the treatment of cancer. bioorg med chem lett. 2011 mar 1;21(5):1315-9. doi: 10.1016/j.bmcl.2011.01.071. epub 2011 jan 22.

Upstream product

• 1227054-01-4 (R)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido-[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1227053-99-7 5-chloro-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1227053-98-6 2-amino-4-chloro-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile 
• 1402613-56-2 C₇H₆FN₃O₂ 
• 1227053-96-4 C₇H₅FN₂O₃ 
• 1227053-97-5 2-amino-5-fluoro-4-hydroxy-1-methyl-6-oxo-1,6-dihydropyridine-3-carbonitrile 
• 1035556-26-3 5-(4-amino-2-fluorophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1035556-24-1 3-benzyl-5-chloro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1035556-22-9 3-benzyl-6-(methylamino)pyrimidin-4(3H)-one 
• 1035556-27-4 5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1035555-88-4 3-benzyl-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1035556-25-2 3-benzyl-5-(2-fluoro-4-nitrophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 
• 1035555-51-1 (R)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 

Downstream Products

• 1035555-67-9 (R)-3-(2,3-dihydroxypropyl)-5-(4-ethynyl-2-fluorophenylamino)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 

Relevant articles and documents

Process research and kilogram synthesis of an investigational, potent MEK inhibitor

TAK-733 (1) is an investigational, novel MEK kinase inhibitor that bears a 6-fluoropyridopyrimidone core. Process research of 1 was conducted, and an efficient, scalable route was developed. The key intermediate, a multisubstituted fluoropyridone, was formed in one pot via a three-step cascade reaction: condensation between a-fluoromalonate and malononitrile, methyl amide formation, and intramolecular cyclization. Chlorination of the hydroxyl functionality and cyclization with formic acid provided the desired pyridopyrimidone core in high yield. Subsequent N-alkylation with the nosylate of (R)-glycerol acetonide and displacement of the chlorine with 2-fluoro-4-iodoaniline proceeded successfully with good yields. Final acid-catalyzed deprotection of the acetonide functionality followed by a controlled crystallization protocol afforded the active pharmaceutical ingredient (API) with the desired polymorph. Compared to the initial synthesis, this route was more concise (six steps compared to the original nine steps), and the overall yield was improved significantly (from 3% to 25%). These improvements allowed for production of multikilograms of 1.

PROCESS FOR MAKING (R)-3-(2,3-DIHYDROXYPROPYL)-6-FLUORO-5-(2-FLOURO-4-IODOPHENYLAMINO)-8-METHYLPYRIDO[2,3-d]PYRIMIDINE-4,7(3H,8H)-DIONE AND INTERMEDIATES THEREOF

The present invention relates generally to processes of making (R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione, intermediates thereof, and a process for making a particular polymorph of (R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione.