Treatment of ciliopathies using inhibitors of glucosylceramide synthase (GCS)
A disease and cilia technology, which can be applied to medical preparations, drug combinations, and pharmaceutical formulations containing active ingredients, and can solve problems such as no reported ciliary effects.
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Embodiment 1
[0493] Embodiment 1: the synthesis of quinucidine compound
[0494] 1-Azabicyclo[2.2.2]oct-3-yl[2-(4'-fluorobiphenyl-3-yl)propan-2-yl]carbamate (compound 1)
[0495] Using general procedure C, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromophenyl)propan-2-yl]carbamate (600 mg, 1.63 mmol), 4-fluoro Phenylboronic acid (457 mg, 3.27 mmol) and palladium(II) acetate gave the title compound (373 mg; 60%) as a white solid. 1 H NMR (400MHz, CDCl 3 )δ7.56(s,1H),7.52(dd,J=5.4,8.4Hz,2H),7.42-7.38(m,3H),7.12(m,2H),5.18(5,1H),4.62(s ,1H), 2.66(m,6H), 1.72(s,6H), 2.01-0.83(m,5H)ppm. 13 C NMR (100MHz, CDCl 3 ) δ 125.0, 124.0, 123.8, 116.0, 116.0, 71.3, 55.9, 55.5, 47.6, 46.7, 29.6, 25.6, 24.8, 19.8ppm. Purity: 98.0% UPLCMS (210nm); retention time 0.95min; (M+1) 382.9. C 23 h 27 FN 2 o 2 0.37 (CHCl 3 ) for: C, 65.86; H, 6.47; N, 6.57. Found: C, 65.85; H, 6.69; N, 6.49.
[0496] (S)-Quinuclidin-3-yl 2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-ylcarbamate (Compound 2)
[0497] To a s...
Embodiment 2
[0554] Example 2: (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)prop-2-yl)carbamate Preparation of alkali
[0555] Step 1: Dimethylation with iodomethane
[0556]
[0557] A 3N RB flask was equipped with a thermometer, addition funnel and nitrogen inlet. The flask was flushed with nitrogen and potassium tert-butoxide (MW 112.21, 75.4 mmol, 8.46 g, 4.0 equiv, white powder) was weighed and added to the flask via a powder funnel followed by THF (60 mL). Most of the potassium tert-butoxide was dissolved to give a cloudy solution. The mixture was cooled to 0-2 °C (internal temperature) in an ice-water bath. In a separate flask, the starting ester (MW 265.3, 18.85 mmol, 5.0 g, 1.0 equiv) was dissolved in THF (18 mL + 2 mL as rinse) and transferred to an addition funnel. This solution was added dropwise to the cooled mixture over a period of 25-30 min, keeping the internal temperature below 5 °C during the addition. The reaction mixture was cooled back to 0-2 °C....
Embodiment 3
[0574] Example 3: (S)-Quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate salt Preparation of crystalline forms of
[0575] (S)-Quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate can be prepared as described in Example 23 crystallized salt.
[0576] For example, (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate (about 50mmol) at room temperature Dissolved in IPA (140ml) and filtered. The filtrate was added to a 1 L r.b. flask equipped with overhead stirrer and nitrogen in / out. L-malic acid (about 50 mmol) was dissolved in IPA (100+30 ml) at room temperature and filtered. The filtrate was added to the above 1 liter flask. The resulting solution was stirred at room temperature (with or without seeding) under nitrogen for 4 to 24 hours. Crystals formed during this time period. The product was collected by filtration and washed with a little IPA (30ml). The crystalline solid was dried in a vacuum o...
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