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Targeted polymeric prodrugs containing multifunctional linkers

A linker and water-soluble polymer technology, applied in the direction of carbohydrate active ingredients, medical preparations containing active ingredients, drug combinations, etc., can solve the problems of anticancer drug toxicity and achieve the effect of enhancing bioavailability

Inactive Publication Date: 2009-09-23
ENZON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] It is well known that many small doses of anticancer drugs have significant toxicity

Method used

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  • Targeted polymeric prodrugs containing multifunctional linkers
  • Targeted polymeric prodrugs containing multifunctional linkers
  • Targeted polymeric prodrugs containing multifunctional linkers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0094] Preferred embodiments include:

[0095]

[0096]

[0097] C. Substantially non-antigenic water-soluble polymers (R 1 )

[0098] The prodrugs of the present invention include polymer residues R 1 , preferably a water-soluble and substantially non-antigenic polymer. Suitable examples of such polymers include polyalkylene oxides (PAOs) such as polyethylene glycols. Some preferred polymers are polyethylene glycols such as mPEG. Thus, non-limiting examples of such polymers include polyalkylene oxide homopolymers such as polyethylene glycol (PEG) or polypropylene glycol, polyoxyethylenated polyols, copolymers thereof, and block copolymers thereof.

[0099] The polymer portion of the compounds described herein has an average molecular weight of from about 2,000 to about 100,000 Daltons, preferably from about 5,000 to about 60,000 Daltons. In some aspects, the polyalkylene oxide may be from about 5,000 to about 25,000, preferably from about 12,000 to about 20,000 dal...

Embodiment 1

[0483] Example 1: N-(methoxycarbonyl)maleimide (Compound 1).

[0484] Add methyl chloroformate (4.4 mL, 56.7 mmol, 1 eq) to maleimide (5.5 g, 56.7 mmol, 1 eq) and NMM (6.2 mL, 56.7 mmol, 1 eq) in 200 mL at 0 °C solution in EtOAc. The suspension was stirred at 0 °C for 30 min, filtered and washed with EtOAc. The filtrate and washings were combined, washed with cold water, and washed with anhydrous Na 2 SO 4 dry. After filtration and evaporation in vacuo, a pink solid was obtained. Purification by silica gel column chromatography (hexane-EtOAc, 1:1, v / v) afforded the product (4.8 g, 55%).

Embodiment 2

[0485] Example 2: Nε-maleoyl-α-(Boc)-L-lysine (Compound 2).

[0486] Add N-(methoxycarbonyl)maleimide (315 mg, 2.03 mmol, 1 equiv) to Boc-L-lysine (500 mg, 2.03 mmol, 1 equiv) in 10 mL of saturated NaHCO at 0 °C 3 in solution in aqueous solution. The mixture was stirred vigorously at 0°C for 40 minutes and at room temperature for a further 1 hour. After cooling to 0°C, use concentrated H 2 SO 4 The solution was acidified to pH 3.0, then extracted with ethyl acetate. The organic layers were combined and washed with anhydrous MgSO 4 dry. After removing the solvent in vacuo, the residue was purified by silica gel column chromatography using CHCl 3 - MeOH mixture (5:1, v / v) to give the product (458 mg, 69%): 1 H NMRδ1.39-1.87 (6H, m, (CH 2 ) 3 ), 1.44 (9H, s, Boc), 3.52 (2H, t, J=7.2Hz, NCH 2 ), 4.25-4.30 (1H, m, CH), 5.15 (1H, d, NH), 6.70 (2H, s, maleimide).

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Abstract

The present invention provides single chain antibody-directed polymeric prodrugs containing multifunctional linkers. Methods of making the polymeric delivery systems and methods of treating mammals using the same are also disclosed.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application 60 / 844943, filed September 15, 2006, the contents of which are incorporated herein by reference. Background technique [0003] It is well known that many small doses of anticancer drugs have significant toxicity. Over the years, many attempts have been made to reduce the toxicity and increase the efficacy of small doses of anticancer drugs. [0004] One of the attempts to reduce the toxicity and improve the efficacy of small doses of anticancer drugs has focused on targeting agent-directed drug delivery systems. For example, single-chain antibodies, RGD peptides, or folate-targeting agents can direct drug delivery and enhance its therapeutic effect. At the same time, targeted delivery of highly potent chemotherapeutic agents would reduce their toxicity. Formal FDA approval confirms, for example, Wyeth's Gemtuzumab zogamicin, a humanized anti-CD33 ...

Claims

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Application Information

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IPC IPC(8): A61K31/70A61K38/16
CPCC07K5/0815A61K47/48407C07K5/06086C07K5/0215A61K47/48107C07K5/0819A61K47/48338C08G65/329C08G73/121A61K47/48315A61K47/48092A61K47/48215A61K47/48246C07K5/06052A61K47/65A61K47/60A61K47/549A61K47/551A61K47/64A61K47/645A61K47/6809A61P35/00A61P35/02A61P35/04A61P43/00C08G65/48C08G64/28C08L71/02A61K31/785
Inventor 赵洪玛丽亚·B·鲁比奥普拉桑纳·雷迪
Owner ENZON PHARM INC
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