JTE052;JTE-052;LEO124249;Digotinib;LEO 124249;Delgocitinib;Delgocitinib(JTE-052);Corectim（Delgocitinib）;Delgocitinib (LEO124249;Delgocitinib, 10 mM in DMSO
The lead compound to delgocitinib was tofacitinib, a potent pan-JAK inhibitor. To maintain the overall pan-JAK inhibition profile of tofacitinib, the pyrrolopyrimidine hinge binder, and the cyanoacetyl group were kept fixed. At the same time, the central aminopiperidine linker was replaced by a variety of spirocyclic scaffolds to maintain comparable binding patterns. This effort identified the three-dimensional diazaspiro[3.4]octane scaffold as the optimal linker, and further SAR studies led to delgocitinib, which demonstrates better selectivity against JAK3 compared to tofacitinib and its selectivity for the JAK family over LCK is also improved. Delgocitinib exhibits no significant inhibition of non-JAK kinases under 1 μM except ROCK2.
Clinical Use
Delgocitinib is a pan-JAK inhibitor that inhibits all Janus Kinase (JAK) family members. Topical delgocitinib 0.5% ointment received its first approval in Japan in 2020 for treating adults with atopic dermatitis. The FDA has granted delgocitinib cream fast-track designation for chronic hand eczema.
Synthesis
Bromolactone 128 reacted with benzylamine via SN2 reaction to generate α-aminolactone 129, which was acylated with optically pure acid chloride 131 (prepared by treatment of commercial acid 130 with thionyl chloride) to give lactone 132. Lactone 132 was treated with LHMDS to generate the enolate anion. The enolate anion removed the chlorine atom via SN2 substitution to form spirolactone 133, with two stereogenic centers established in a 98:2 diastereomeric ratio (dr) and 96% enantiomeric purity. The γ-carbon of spirolactone 133 was attacked by potassium phosphoanhydride to open the lactone ring, and the resulting carboxylic acid was converted to the ethyl ester by reaction with ethyl iodide. Finally, treatment with diethylenetriamine liberated the anhydride group to provide a free amine, which cyclized via the corresponding ethyl ester intermediate to form spirolactam 134. The carbonyl group in spirolactam 134 was reduced using lithium aluminum hydride and aluminum chloride in tetrahydrofuran (THF) to give diamine 135, which was crystallized as a succinate salt in 86% yield. Diamine 135 was subjected to SNAr reaction with chloropyrimidopyrrole. The benzyl protecting group was removed by catalytic hydrogenation, and the amine 137 was obtained in 92% overall yield after these two steps. Amine 137 was amidated with cyanoacetylpyrazole. The product of the reaction of amine 137 with cyanoacetylpyrazole was recrystallized from n-butanol and 3 wt% BHT (butylated hydroxytoluene) was added as an antioxidant to give the final product, digaotinib, in 86% yield with enantiomeric purity (ee) and diastereomeric purity (de) greater than 99%.
