CEP 33779

Description

Janus kinases (JAKs) are non-receptor kinases that mediate signaling through cytokine receptors, often to members of the signal transducer and activator of transcription family. CEP-33779 is a potent, orally available inhibitor of JAK2 (IC₅₀ = 1.3 nM). It shows 65-fold selectivity for JAK2 over JAK3. In mouse models of systemic lupus erythematosus, CEP-33779 reduces the production of inflammatory cytokines, decreases splenomegaly and lymphomegaly, and extends survival. It also diminishes inflammatory signaling and improves clinical scores in mice during collagen antibody-induced arthritis and collagen type II-induced arthritis. CEP-33779 induces regression of established colorectal tumors in mice, reducing angiogenesis and proliferation of tumor cells.

Uses

CEP-33779 acts as an orally available inhibitor of JAK2 reducing the production of inflammatory cytokines and decreasing splenomegaly. Anti-arthritic agent. Anticancer agent.

Synthesis

747413-17-8

1257704-13-4

1257704-57-6

GENERAL STEPS: To an oven-dried reaction tube was added palladium acetate (10 mg), 2,2'-bis(dicyclohexylphosphino)biphenyl (30 mg), 8-[4-(methylsulfonyl)phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-amine (75 mg), 1-(3-bromophenyl)-4-methylpiperazine (80 mg), cesium carbonate (270 mg) and 1 ,4-dioxane (5 mL). The reaction tube was evacuated and backflushed three times with nitrogen and then sealed. The reaction mixture was heated at 80°C for 72 hours. After completion of the reaction, the mixture was cooled to room temperature. The cooled mixture was diluted with dichloromethane (10 mL), filtered through a diatomaceous earth plug and rinsed with dichloromethane. The filtrate was concentrated by evaporation and purified by column chromatography (using an ISCO automated purification system, an amine-modified silica gel column, and an eluent of 5% to 100% ethyl acetate in hexane solution). The target compound N-[3-(4-methyl-1-piperazinyl)phenyl]-8-[4-(methylsulfonyl)phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Compound A) was obtained as a yellow solid (70 mg). Melting point: 232-234 °C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 7.5 Hz, 2H), 8.08 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 7.7 Hz, 1H), 7.38 (s, 1H), 7.27- 7.20 (m, 1H), 7.04-6.95 (m, 2H), 6.84 (s, 1H), 6.60 (d, J = 8.0 Hz, 1H), 3.30-3.25 (m, 4H), 3.10 (s, 3H), 2.63-2.58 (m, 4H), 2.38 (s, 3H). MS: MS = 463 (MH)+.

in vivo

target

JAK2

IC 50

JAK2: 1.8 nM (IC₅₀); JAK3: 150 nM (IC₅₀)

References

[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5243 - 5254
[2] Organic Process Research and Development, 2016, vol. 20, # 12, p. 2085 - 2091
[3] Patent: EP2648728, 2016, B1. Location in patent: Paragraph 0047