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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

Inactive Publication Date: 2012-03-28
ENZON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, patients need to take anti-angiogenic agents for a long time, and this long-term treatment with angiogenesis inhibitors may have adverse effects on the immune system, reproductive system, heart, etc.

Method used

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  • Methods for inhibiting angiogenesis with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin
  • Methods for inhibiting angiogenesis with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin
  • Methods for inhibiting angiogenesis with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin

Examples

Experimental program
Comparison scheme
Effect test

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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Abstract

The present invention relates to methods of inhibiting angiogenesis in mammals. The present invention includes administering polymeric prodrugs of 07-ethyl-10-hydroxycamptothecin to the mammals in need thereof. The present invention also relates to methods of treating a disease associated with angiogenesis in mammals by administering polymeric prodrugs of 7-ethyl-10-hydroxycamptothecin to the mammals in need thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application 61 / 170,386, filed April 17, 2007, the contents of which are incorporated herein by reference. field of invention [0003] The present invention relates to a method for inhibiting angiogenesis or angiogenesis (angiogenesis) activity by administering (administering, administering) a polymeric prodrug of 7-ethyl-10-hydroxycamptothecin. In particular, the invention relates to a method of inhibiting angiogenesis by administering a polyethylene glycol conjugate of 7-ethyl-10-hydroxycamptothecin. Background of the invention [0004] Angiogenesis is a natural process in the body that involves the formation of new blood vessels. Healthy humans control angiogenesis by maintaining the balance between angiogenesis activators and angiogenesis inhibitors. [0005] Various diseases and pathological conditions are associated with angiogenesis (either under- or ove...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/44A61K47/48
CPCA61K47/48215A61K31/44A61K31/437A61K47/60A61P35/00A61P9/00A61K31/4738A61K31/4353
Inventor 法比奥·帕斯托里诺麦尔科·彭佐尼普加·萨普拉
Owner ENZON PHARM INC
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