R-406

Uses

Intermediate used for preparation of prodrugs of pyrimidine-2,4-diamines as anticancer agents.

Uses

R406 is a potent ATP-competitive inhibitor of spleen tyrosine kinase (Syk, Ki = 30 nM). Through this action, R406 blocks FcεRI-dependent mast cell activation (EC50 = 43 nM) and, at 3 μM, reduces the release of IL-10, -12, and -13 by immune complex-pulsed dendritic cells. R406 is orally available and can reduce immune complex-mediated inflammation. In cancers characterized by over-expression of Syk, R406 can prevent signaling downstream of Syk and induce apoptosis. R406 also inhibits Syk-dependent signaling through c-Jun N-terminal kinase in rheumatoid arthritis synoviocytes, suggesting a therapeutic intervention in this autoimmune disease.[Cayman Chemical]

Definition

ChEBI: 6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)-4-pyrimidinyl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one is a member of methoxybenzenes and a substituted aniline.

Biological Activity

r406 is a potent syk inhibitorspleen tyrosine kinase (syk) is a non-receptor tyrosine kinase mainly expressed in hematopoietic cells. it transmits signals from a variety of cell surface receptors including cd74, fc receptor and integrins. it is crucial for adaptive immune response, and also very important for cellular adhesion, innate immune recognition, osteoclast maturation, platelet activation and vascular development. [1]functional abnormality of syk has been implicated in several blood malignancies. constitutively active syk can transform b cells. syk inhibition can be beneficial for patients with blood cancers and autoimmune diseases.r406 is a potent inhibitor of ige and igg mediated fc receptor activation with ec50 for degranulation of 56-64 nm. [2] r406 targets syk and inhibits phosphorylation of syk substrates by binding to its atp binding pocket and competing with atp. r406 strongly inhibits syk kinase activity with an ic50 of 41 nm.r406 induces apoptosis in diffuse large b-cell lymphoma cell lines. it blocks b cell receptor signaling through inhibiton of syk autophosphorylation of y525/y526 and syk-dependent phosphorylation of the b-cell linker protein. [3]r406 can be administrated orally.

Synthesis

575484-83-2

24313-88-0

841290-80-0

Step B: Preparation of 6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one Under nitrogen protection, 6-[(2-chloro-5-fluoropyrimidin-4-yl)amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (product of step A, 568 kg, 1.00 mol eq.) was mixed with 3,4,5-trimethoxyaniline (402 kg, 1.25 mol eq.) in N-methylpyrrolidin-2-one ( 2835 kg) were mixed and stirred. After addition of water (11 kg), the reaction mixture was heated to 120 °C and maintained at this temperature with stirring for 10 hours. Upon completion of the reaction, the mixture was cooled to 65 °C and the pH was adjusted to 8.5 with a 4% w/w aqueous sodium hydroxide solution.Subsequently, the slurry was further cooled to 20 °C with continuous stirring for at least 6 hours and then filtered. The solid obtained by filtration was washed sequentially twice each with water (2 x 1440 kg) and acetone (2 x 1140 kg), and finally dried under vacuum at 40 °C to obtain the target compound 6-[[5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H )-one (754 kg, 91% yield) as a colored solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 1.42 (s, 6H), 3.59 (s, 3H), 3.66 (s, 6H), 7.04 (s, 2H), 7.32 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 8.13 (d, J = 3.4 Hz, 1H), 9.10 (br.s, 1H), 9.14 (br.s, 1H), 11.06 (br.s, 1H). Mass spectral data: m/z 471 [MH]+.

in vivo

target

Syk

References

[1]mocsai a, ruland j, tybulewicz vl. the syk tyrosine kinase: a crucial player in diverse biological functions. nat rev immunol 2010. 10(6): 387-402.
[2]braselmann s, taylor v, zhao h, et al. r406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. j pharmacol exp ther 2006. 319(3): 998-1008.
[3]chen l, monti s, juszczynski p, et al. syk-dependent tonic b-cell receptor signaling is a rational treatment target in diffuse large b-cell lymphoma. blood 2008. 111(4): 2230*2237.