Use of dantrolene and dantrolene prodrugs to treat radiation exposure
A radiation exposure and dantrolene technology, applied in the field of application of dantrolene and dantrolene prodrugs for the treatment of radiation exposure, can solve the problems of reduced survival rate of patients with hematopoietic syndrome
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Embodiment 1
[0180] Embodiment 1. Radiation dose research
[0181] Research objectives. To evaluate the efficacy of intravenous administration of Ryanodex to prevent or attenuate acute radiation syndrome in a whole-body irradiated C57BL / 6 male mouse model of hematopoiesis.
[0182] Radiation and dosimetry. For whole body irradiation dose administration, animals were irradiated in an RS-2000 X-ray bioirradiator (Rad Source, Suwanee, GA) according to SNBL USA SOP.
[0183] target dose. 6.0Gy (Ld50 / 30 calculated from institutional lethality curve)
[0184] target dose rate. About 1.325Gy / min
[0185] energy. 160kV at 25mA (on floor of RS-2000 room with circular RAD+)
[0186] Copper filter size. 0.3mm Cu
[0187] ion chamber. RadCal 2086 Ion Chamber Dosimeter
[0188] calculate. Dose (Gy) = dose rate (Gy / min) x time (min)
[0189] Test and Control
[0190] test object. for injectable suspension (Dantrolene Sodium) (Eagle Pharmaceutical, Inc.). Store at room temperature (15 t...
Embodiment 2
[0283]
[0284] Sodium dantrolene (1 equivalent) was dissolved in anhydrous dimethylformamide. Reagent 3 (1 eq) was added and the reaction mixture was stirred at 60°C under nitrogen. After 4 hours, another equivalent of reagent 3 was added and the reaction was stirred overnight at 60°C. The reaction was then diluted with ethyl acetate and washed twice with saturated sodium chloride. Separate the layers. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified using silica gel chromatography. The desired product was isolated in 90-95% purity. 1 H NMR was consistent with the predicted value of the desired product.
[0285] Embodiment 2, Method A : 1a with P 2 o 5Let dry overnight. To a mixture of 1a (500 mg, 1.48 mmol) in DMF (10 mL) was added 3 (0.84 mL, 3.72 mmol) followed by NaI (245 mg, 1.63 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 64 hours. The mixture was diluted with EtOAc (30 ...
Embodiment 3
[0288]
[0289] A sample of compound 4 was treated with 1 ml of a 9 / 1 mixture of trifluoroacetic acid / water for 20-30 minutes at ambient temperature. Excess TFA was immediately removed using high vacuum and the resulting solid was collected by filtration, washed with water (5ml) and air dried. The starting material, reaction mixture and final product were analyzed by LC / MS to determine whether 2 reverted to dantrolene during the deprotection conditions. No reversion of 2 to dantrolene was observed. product of 1 H NMR was in agreement with the prediction of the expected product.
[0290] Example 3, Method A : To 4 (886mg, 1.65mmol) in CH 2 Cl 2 To the mixture in (9 mL) was added TFA (9 mL). The resulting mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness on a rotary evaporator. The resulting residue was triturated with hexane for 1 hour, and the yellow solid was filtered and dried to give the desired compound 2 (660 mg, 94%). ...
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