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Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers

A kind of technology of camptothecin and compound, applied in the field of multi-arm polymerization prodrug, can solve the problem that the therapeutic agent cannot be dissolved in aqueous liquid and the like

Inactive Publication Date: 2009-04-29
ENZON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The problem is that the required therapeutic agent is not soluble in the aqueous liquid

Method used

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  • Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers
  • Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers
  • Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0147] Example 1 40k Four-arm-PEG-tert-butyl ester (compound 2):

[0148] Will 40k Fourarm-PEG-OH (12.5 g, 1 equiv) was azeotroped with 220 mL of toluene to remove 35 mL of toluene / water. The solution was cooled to 30°C and 1.0 M potassium tert-butoxide dissolved in tert-butanol (3.75 mL, 3 eq.times.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.×4=16 eq.) was added. React at 30°C for 1 hour and then cool to 25°C. 150 mL of ether was slowly added to precipitate the product. The resulting suspension was cooled to 17°C and allowed to stand for half an hour. The crude product was filtered and the wet cake was rinsed twice with ether (2 x 125 mL). The separated wet cake was dissolved in 50ml of DCM and the product was precipitated with 350ml of ether and filtered. The wet cake was rinsed twice with ether (2 x 125 mL). The product was dried under vacuum at 40°C (yield 98%, 12.25 g). 13 C NMR (75.4MHz, C...

Embodiment 240k

[0149] Example 2 40k Four Arm-PEG Acid (Compound 3):

[0150] Will 40k Fourarm-PEG tert-butyl ester (compound 2, 12 g) was dissolved in 120 mL of DCM and then 60 mL of TFA was added. The mixture was stirred at room temperature for 3 hours then the solvent was removed in vacuo at 35°C. The resulting oily residue was dissolved in 37.5 mL of DCM. The crude product was precipitated with 375 mL of ether. Dissolve wet cake in 30 mL of 0.5% NaHCO 3 middle. The product was extracted twice with DCM (2 x 150 mL). The combined organic layers were washed with 2.5 g of MgSO 4 dry. The solvent was removed in vacuo at room temperature. The resulting residue was dissolved in 37.5 mL of DCM to precipitate the product with 300 mL of ether and filtered. The wet cake was rinsed 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

[0151] Example 3 TBDPS-(10)-(7-ethyl-10-hydroxycamptothecin) (compound 5):

[0152] Et 3 N (4.3 mL, 30.58 mmol, 6 equiv) and tert-butyldiphenylchlorosilane (TBDPSCl) (7.8 mL, 30.58 mmol, 6 equiv). The reaction mixture was heated to reflux overnight, 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 in vacuo. The residue was dissolved in anhydrous DCM and precipitated by adding hexane. The precipitation was repeated with DCM / hexanes to remove excess TBDPSCl. The solid was filtered and dried in vacuo to afford 2.09 g of product (65% yield). 1 H NMR (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=2.63Hz), 7.36-7.49(7H, m), 7.58(1H, s), 7.75-7.79(4H, m), 8.05(1H, d, J=9.4Hz). 13 C NMR (75.4MH...

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Abstract

The present invention discloses a four-arm- polyethylene glycol-7-ethyl-10-hydroxy-camptothecin conjugate (formula I), method for preparing the conjugate and method for treating mammal using the conjuagate.

Description

[0001] Cross-references to related applications [0002] This application claims the benefit of U.S. Provisional Patent Applications Serial No. 60 / 772,464 filed February 9, 2006, Serial No. 60 / 804,391 filed June 9, 2006, and Serial No. 60 / 844,938 filed September 15, 2006 and priority of Serial No. 60 / 864,516 filed November 6, 2006, the contents of each of which are hereby incorporated by reference. technical field [0003] The present invention relates to multi-armed polymeric prodrugs of 7-ethyl-10-hydroxycamptothecin. In particular, the present invention relates to four-armed polyethylene glycol conjugates of 7-ethyl-10-hydroxycamptothecin and uses thereof. Background of the invention [0004] Several methods of administering biologically active materials to mammals have been proposed in recent years. The problem is that the desired therapeutic agent is not soluble in aqueous liquids. Often alkaloids are especially difficult to dissolve. [0005] Camptothecin is a wate...

Claims

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Application Information

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IPC IPC(8): A61K31/765A61K31/785A61K9/14
CPCA61K47/48215A61K47/60A61P35/00A61P35/02A61P35/04A61P43/00C07D491/147A61K31/38
Inventor 赵洪玛丽亚·B·鲁比奥普贾·萨普拉乌德春
Owner ENZON PHARM INC
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