Methods for inhibiting angiogenesis with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin
An angiogenesis and compound technology, applied in the direction of active ingredients of heterocyclic compounds, cardiovascular system diseases, medical preparations of non-active ingredients, etc., can solve problems such as immune system, reproductive system, and adverse effects of the heart
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Embodiment 140k4
[0367] Example 1. 40k 4arm-PEG-tert-butyl ester (compound 2):
[0368] Make 40k 4arm-PEG-OH (12.5 g, 1 eq.) was azeotroped with 220 mL toluene to remove 35 mL toluene / water. The solution was cooled to 30° C. and a 1.0 M solution of potassium tert-butoxide in tert-butanol (3.75 mL, 3 eq×4=12 eq.) was added. The mixture was stirred at 30°C for 30 minutes and then tert-butyl bromoacetate (0.975 g, 4 eq. x 4 = 16 eq.) was added. The reaction was maintained at 30°C for 1 hour and then cooled to 25°C. 150 mL of diethyl ether was slowly added to precipitate the product. The resulting suspension was cooled to 17°C and kept at 17°C for half an hour. The crude product was filtered and the wet cake was washed twice with ether (2 x 125 mL). The isolated wet cake was dissolved in 50 mL DCM and the product was precipitated with 350 mL diethyl ether and filtered. The wet cake was washed twice with ether (2 x 125 mL). The product was dried under vacuum at 40°C (Yield = 98%, 12.25 g). ...
Embodiment 240k4
[0369] Example 2. 40k 4arm-PEG acid (Compound 3):
[0370] Will 40k 4arm-PEG-tert-butyl ester (compound 2, 12 g) was dissolved in 120 mL DCM and then 60 mL TFA was added. The mixture was stirred at room temperature for 3 hours and then the solvent was removed under vacuum at 35°C. The resulting oily residue was dissolved in 37.5 mL DCM. The crude product was precipitated with 375 mL of ether. Dissolve the wet cake in 30 mL 0.5% NaHCO 3 middle. The product was extracted twice with DCM (2 x 150ml). The combined organic layers were washed with 2.5g MgSO 4 dry. The solvent was removed under vacuum at room temperature. The resulting residue was dissolved in 37.5 mL of DCM and the product was precipitated with 300 mL of ether and filtered. The wet cake was washed twice with ether (2 x 125 mL). The product was dried under vacuum at 40°C (Yield = 90%, 10.75 g). 13 C NMR (75.4MHz, CDCl 3 ): δ67.93-71.6 (PEG), 170.83.
Embodiment 3
[0371] Example 3.TBDPS-(10)-(7-ethyl-10-hydroxycamptothecin) (compound 5):
[0372] To a suspension of 7-ethyl-10-hydroxycamptothecin (compound 4, 2.0 g, 5.10 mmol, 1 eq.) in 100 mL of dry DCM was added Et 3 N (4.3 mL, 30.58 mmol, 6 eq.) and TBDPSCl (7.8 mL, 30.58 mmol, 6 eq.). The reaction mixture was heated to reflux overnight and then washed with 0.2N HCl solution (2×50 mL), saturated NaHCO 3 solution (100 mL) and brine (100 mL) washed. The organic layer was treated with MgSO 4 Dry, filter and evaporate under vacuum. The residue was dissolved in anhydrous DCM and precipitated by addition of hexane. The precipitation with DCM / hexane was repeated to remove excess TBDPSCl. The solid was filtered and dried under vacuum to obtain 2.09 g of product. (65% yield). 1 HNMR (300MHz, CDCl 3 ): δ0.90(3H, t, J=7.6Hz), 1.01(3H, t, J=7.3Hz), 1.17(9H, s), 1.83-1.92(2H, m), 2.64(2H, q, 6.9Hz), 3.89(1H, s, OH), 5.11(2H, s), 5.27(1H, d, J=16.1Hz), 5.72(1H, d, J=16.4Hz), 7.07(2H, d, J...
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