Isothiazolidine 1,1-dioxide and 1,4-butan sultone containing rapamycin derivatives and uses thereof
A compound and drug technology, applied in the field of rapamycin derivatives containing isothiazolidine 1,1-dioxide and 1,4-butane sultone and its application, can solve the problem of difficult to obtain galenic, Variable bioavailability, low availability, etc.
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[0247] This disclosure sets forth the following examples. The synthetic examples and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein, and these examples should not be construed as limiting the scope in any way.
[0248] The compounds provided herein can be prepared from readily available starting materials using modifications to the specific synthetic schemes listed below that are well known to those skilled in the art. It will be appreciated that where typical or preferred process conditions (ie, reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
[0249] Furthermore, as will be apparent...
example 1
[0301] Example 1. Synthesis of Compound 1
[0302]
[0303] Rapamycin (0.549 g, 0.601 mmol) was combined with isothiazolidine 1,1-dioxide (0.728 g, 6.01 mmol) in anhydrous acetonitrile (3.0 mL) in a reaction vial. TsOH (0.011 g, 0.060 mmol) was added and the reaction mixture was stirred at room temperature for 50 minutes. The reaction mixture was diluted with brine and extracted three times with EtOAc. The combined organic extracts were washed with Na 2 SO 4 Drying, decantation and concentration gave the crude product as a yellow oil (ca. 1 g). The crude product was purified by silica gel flash column chromatography (0 to 50% acetone-heptane, ISCO combiflash gradient elution, 40g Silicycle silica gel 15-40um FLH-R10017B-ISO40, TLC 40% acetone-heptane, visible under UV) . Product-containing fractions were checked by LCMS, and fractions with the highest purity were combined and concentrated to give Compound 1 (0.315 g, 0.298 mmol, 49.7% yield) as a white solid.
[030...
example 2
[0307] Example 2. Synthesis of Compounds 2 and 3
[0308] RAD001 (everolimus, 1.0 g, 1.044 mmol) was combined with isothiazolidine 1,1-dioxide (1.264 g, 10.44 mmol) in anhydrous dichloromethane (5.2 mL) in a reaction vial. TsOH (0.020 g, 0.104 mmol) was added in one portion. The reaction was stirred at room temperature for 22 minutes.
[0309] The reaction mixture was diluted with saturated aqueous NaHCO3, and then extracted four times with EtOAc. The organic extracts were combined, dried over Na2SO4, decanted and concentrated to give a crude orange tar (2.181 g).
[0310] A portion (1.436 g) of the crude product was subjected to silica gel flash column chromatography (15% to 50% acetone-heptane, ISCO combiflash gradient elution, 40 g Silicycle silica gel 15-40um FLH-R10017B-ISO40, TLC 40% acetone-heptane , visible under UV) purification. Two spots were observed via TLC elution.
[0311] Fractions containing product were checked by LCMS and the most pure fractions fro...
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