Biological Activity
almorexant is an antagonist of orexin 1 receptor (ox1r) and orexin 2 receptor (ox2r) with kd values of 1.3nm and 0.17nm, respectively [1].almorexant is a dual ox antagonist. it inhibits the binding of orexin-a to both ox1r and ox2r with ic50 values of 6.6nm and 3.4nm, respectively. in the inositol phosphates assay, almorexant acts as a competitive antagonist of hox1r but a noncompetitive-like antagonist of hox2r. besides that, almorexant is found to block the increase in locomotor activity induced by icv orexin in c57bl/6 mice. furthermore, almorexant shows effects on sleep in multiple species, including man. it reduces the time spent awake and increased the time spent in nrem and rem sleep dose-dependently in normal c57bl/6 mice. these effects on sleep caused by almorexant are mediated by ox2rs as almorexant has no effect in mice lacking both ox1r and ox2r but has effects in mice lacking only ox1r [1, 2].
Synthesis
Synthesis of (R)-2-((S)-6,7-dimethoxy-1-(4-(trifluoromethyl)phenylethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-N-methyl-2-phenylacetamide from compound (CAS:1296659-30-7) and (S)-2-(methylamino)-2-oxo-1-phenylethyl 4-methylbenzenesulfonate The general procedure for hydrochloride is as follows:
1. suspend (16)-6,7-dimethoxy-1-[2-(4-trifluoromethylphenyl)ethyl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (50 g) in 2-butanone (250 ml) at room temperature and stir for 5 min.
2. Na2CO3 (30.3 g) was added and stirring was continued for 10 minutes at room temperature.
3. (S)-2-(methylamino)-2-oxo-1-phenylethyl 4-methylbenzenesulfonate (51.7 g) was added and heated to reflux and kept at reflux while stirring for 16 hours.
4. Most of the solvent (about 200 ml) was removed by distillation.
5. The residue was co-distilled with ethyl acetate (3 x 50 ml) and the mixture was diluted with 150 ml of ethyl acetate.
6. Aspirate the solid fraction and wash with 100 ml of ethyl acetate.
7. Wash the solution with water (2 x 100 ml) and brine (50 ml).
8. dried with MgSO4 and heated the solution to 60°C.
9. Add ethyl acetate (8.9%, 51 g) solution of HCl (g) dropwise over 30 min.
10. After heating to reflux and stirring for 30 min, the solution was cooled to 0 °C and aspirated.
11. 63 g (92%) of almorexant hydrochloride of form A was obtained (confirmed by XRPD analysis).
References
[1] malherbe p, borroni e, pinard e, wettstein jg, knoflach f. biochemical and electrophysiological characterization of almorexant, a dual orexin 1 receptor (ox1)/orexin 2 receptor (ox2) antagonist: comparison with selective ox1 and ox2 antagonists. mol pharmacol. 2009 sep;76(3):618-31.
[2] mang gm1, dürst t, bürki h, imobersteg s, abramowski d, schuepbach e, hoyer d, fendt m, gee ce. the dual orexin receptor antagonist almorexant induces sleep and decreases orexin-induced locomotion by blocking orexin 2 receptors. sleep. 2012 dec 1;35(12):1625-35.
