| Identification | Back Directory | [Name]
Basmisanil | [CAS]
1159600-41-5 | [Synonyms]
RG 1662
RG-1662
CS-2342
RO5186582
Ladarixin
Basmisanil
RG1662;RO5186582
Basmisanil (RG1662)
RG 1662; RG-1662; RG1662; RO5186582; RO-5186582; RO 5186582; BASMISANIL
(1,1-Dioxo-4-thiomorpholinyl)[6-[[3-(4-fluorophenyl)-5-methylisoxazol-4-yl]methoxy]pyridin-3-yl]methanone
(1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone
Methanone, (1,1-dioxido-4-thiomorpholinyl)[6-[[3-(4-fluorophenyl)-5-methyl-4-isoxazolyl]methoxy]-3-pyridinyl]-
(1,1-dioxo-1λ6-thiomorpholin-4-yl)-{6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-methanone | [Molecular Formula]
C21H20FN3O5S | [MDL Number]
MFCD28902245 | [MOL File]
1159600-41-5.mol | [Molecular Weight]
445.46 |
| Chemical Properties | Back Directory | [Melting point ]
141-144°C | [Boiling point ]
726.6±60.0 °C(Predicted) | [density ]
1.388±0.06 g/cm3(Predicted) | [storage temp. ]
-20°C Freezer | [solubility ]
DMSO (Slightly), Methanol (Slightly) | [form ]
Solid | [pka]
2.07±0.22(Predicted) | [color ]
White | [InChI]
InChI=1S/C21H20FN3O5S/c1-14-18(20(24-30-14)15-2-5-17(22)6-3-15)13-29-19-7-4-16(12-23-19)21(26)25-8-10-31(27,28)11-9-25/h2-7,12H,8-11,13H2,1H3 | [InChIKey]
VCGRFBXVSFAGGA-UHFFFAOYSA-N | [SMILES]
C(N1CCS(=O)(=O)CC1)(C1=CC=C(OCC2=C(C)ON=C2C2=CC=C(F)C=C2)N=C1)=O |
| Hazard Information | Back Directory | [Uses]
Basmisanil is a highly selective GABAAα5 negative allosteric modulator. | [Synthesis]
1) 6-[3-(4-fluorophenyl)-5-methylisoxazol-4-ylmethoxy]nicotinic acid (23.0 g, 70.1 mmol) and 1,1'-carbonyldiimidazole (15.3 g, 94.6 mmol, 1.35 eq.) were dissolved in THF (120 mL), and the reaction mixture was stirred for 1 hour at room temperature.
2) The above solution was slowly added to a suspension of THF (120 mL) containing thiomorpholine-1,1 -dioxide hydrochloride (16.9 g, 98.5 mmol), DMAP (400 mg, 3.27 mmol) and triethylamine (9.78 g, 96.7 mmol).
3) The reaction mixture was heated to reflux temperature and stirred continuously at this temperature for 50 hours.
4) Upon completion of the reaction, the mixture was cooled to room temperature and then water (300 mL) was slowly added over a period of 1 hour.
5) THF was removed by distillation under reduced pressure at 60 °C, while solvent replacement was carried out by successive addition of ethanol (426 g) in a constant volume.
6) The resulting suspension was cooled to room temperature and stirring was continued for 2 hours.
7) The crystals were collected by filtration and washed with a mixture of ethanol (100 mL) and water (100 mL).
8) Drying to constant weight at 55 °C/<25 mbar afforded 28.9 g (92% yield) of the target product (1,1-dioxothiomorpholine)(6-((3-(4-fluorophenyl)-5-methylisoxazol-4-yl)methoxy)pyridin-3-yl)methanone as a colorless solid with a purity of 99.7% (area) as determined by HPLC. | [in vivo]
Basmisanil (3-100 mg/kg, p.o.) occupies GABAA-α receptor in dose-dependent in rat brain[1].
Basmisanil (3-600 mg/kg p.o.) improves cognition in rats and non.human primates and not show anxiogenic or proconvulsant effects[1].
| Animal Model: | Sprague Dawley rats[1]
(180 g; female)
| | Dosage: | 3-100 mg/kg | | Administration: | p.o. | | Result: | Decreased the binding of [3H]-Ro 15-4513 in a dose-dependent manner.
Reduced specific binding in the hippocampus by 70% at the highest dose (100 mg/kg).
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| Animal Model: | Lister Hooded rats, Wistar rats and F-344 Fischer rats [1]
(Lister Hooded rats: 220-250 g; male)
(Wistar rats: 200-220 g; male and female)
(F-344 Fischer rats: 170-180 g; male)
| | Dosage: | 3-600 mg/kg | | Administration: | p.o. | | Result: | Significantly attenuated the diazepam-induced deficit.
Showed plasma concentrations in dose- and time-dependent manner and reached a maximal level of 903 ng/mL (379 nM free plasma) 30 min after the administration at 10 mg/kg.
|
| Animal Model: | Male cynomolgus macaques[1]
(Macaca fascicularis; 7-10 kg)
| | Dosage: | 1-600 mg/kg | | Administration: | p.o. | | Result: | Significantly improved the percentage of correct first reaches during difficult trials of the object retrieval task at the 3 and 10 mg/kg doses.
Exhibited an inverted U-shaped dose response in this paradigm with the 1 and 30 mg/kg doses producing no marked improvement on performance.
Increased the total plasma exposure in dose-dependent.
|
| [References]
[1] Patent: US2013/102778, 2013, A1. Location in patent: Paragraph 0280; 0281; 0282
[2] Patent: WO2013/57123, 2013, A1. Location in patent: Page/Page column 51; 52
[3] Patent: US2013/172329, 2013, A1. Location in patent: Paragraph 0263
[4] Patent: WO2013/57124, 2013, A1. Location in patent: Page/Page column 38; 39
[5] Patent: EP2792360, 2014, A1. Location in patent: Paragraph 0176 |
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