| Identification | Back Directory | [Name]
(R)-2-((R)-6,7-diMethoxy-1-(4-(trifluoroMethyl)phenethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-N-Methyl-2-phenylacetaMide | [CAS]
913358-93-7 | [Synonyms]
CS-942
Almorexant HCI
ACT078573 hydrochloride
AlMorexant (hydrochloride)
Almorexant HCl (Act-078573)
ACT-078573;ACT 078573;ACT078573;ACT-078573 HYDROCHLORIDE;ACT 078573 HYDROCHLORIDE;ACT078573 HYDROCHLORIDE
(R)-2-((R)-6,7-diMethoxy-1-(4-(trifluoroMethyl)phenethyl)-3,4-dihydroisoquinolin-2(1H)-yl)-N-Methyl-2-phenylacetaMide USP/EP/BP
(R)-2-((S)-1-(4-(trifluoromethyl)phenethyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-methyl-2-phenylacetamide hydrochloride
(alphaR,1S)-3,4-Dihydro-6,7-dimethoxy-N-methyl-alpha-phenyl-1-[2-[4-(trifluoromethyl)phenyl]ethyl]-2(1H)-isoquinolineacetamide monohydrochloride | [Molecular Formula]
C29H31F3N2O3 | [MDL Number]
MFCD11110686 | [MOL File]
913358-93-7.mol | [Molecular Weight]
512.563 |
| Chemical Properties | Back Directory | [Melting point ]
196-200°C | [storage temp. ]
-20°C Freezer | [solubility ]
Chloroform (Slightly), Methanol (Slightly) | [form ]
Solid | [color ]
White | [Stability:]
Stable under recommended storage conditions., Stable Under Recommended Storage C |
| Hazard Information | Back Directory | [Uses]
Almorexant Hydrochloride is an orally active orexin antagonist (OX1 and OX2 dual receptor antagonist) used in the treatment of insomnia. | [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). | [in vivo]
Almorexant hydrochloride (1.8 μmol/kg, 100 μL; IP, daily) reduces the volume of tumors[2].
Almorexant hydrochloride (300 mg/kg, PO, once) can help rats to be fully capable of spatial and avoidance learning[4].
Almorexant hydrochloride (30-300 mg/kg) dose-dependently increases rapid eye movement (REM) and non-REM (NREM) sleep and decreases wakefulness apparently without inducing either cataplexy or deficits in next-day performance[3]. | Animal Model: | Mice xenografted with AsPC-1 cells[2] | | Dosage: | 1.8 μmol/kg, 100 μL | | Administration: | IP, daily, starting at day 0 or day 38 | | Result: | Resulted in a significant decrease in tumor volume when treatment starting at day 0. Started after AsPC-1 tumors were developed (day 38), rapidly and strongly reduced the volume of established tumors. |
| Animal Model: | Long-Evans rats (24, male, 16-18 weeks of age)[4] | | Dosage: | 300 mg/kg | | Administration: | PO, once | | Result: | Successfully learned the spatial task, established spatial memory. |
| Animal Model: | Male C57BL/6 mice (Orexin/ataxin-3 transgenic (TG) mice and WT mice, 32 ± 0.9 g, age 15 ± 0.5 week)[3] | | Dosage: | 30, 100, 300 mg/kg (3, 10, and 30 mg/mL; 10 mL/kg) | | Administration: | IP, once every 3 days | | Result: | Exacerbated cataplexy in TG mice and increased nonrapid eye movement (NREM) sleep with heightened sleep/wake fragmentation in both genotypes during the 12-h dark period after dosing. Showed greater hypnotic potency in WT mice than in TG mice. |
| [target]
OX2 | [IC 50]
human OX2R: 0.17 nM (Kd); human OX1R: 1.3 nM (Kd); Caspase-3 | [storage]
Store at -20°C | [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. |
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