Combination therapy involving a vascular disrupting agent and an agent which targets hypoxia

A technology of vascular disruptor and targeting agent, applied in the field of cancer treatment

Inactive Publication Date: 2015-06-10
BONOMICS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A difficulty with this however is that not all known antiproliferative agents provide useful or beneficial effects in combination, thus research in many laboratories is currently focused on developing new and useful antiproliferative combination partners

Method used

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  • Combination therapy involving a vascular disrupting agent and an agent which targets hypoxia
  • Combination therapy involving a vascular disrupting agent and an agent which targets hypoxia
  • Combination therapy involving a vascular disrupting agent and an agent which targets hypoxia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0241] Preparation of 2-methyl-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (BNC105)

[0242]

[0243] Preparation A

[0244] To 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methanol in 1,4-dioxane (2 mL) at 90°C A stirred solution of oxybenzofuran (20 mg, 0.042 mmol), methylboronic acid (40 mg, 0.67 mmol) was added tetrakis-triphenylphosphine palladium (11 mg, 0.01 mmol), followed by carbonic acid in distilled water (0.5 mL) Sodium hydrogen (40mg, 0.48mmol) solution. After 5 minutes, the reaction mixture turned red. After 2 hours (tlc), the reaction mixture was warmed to room temperature and saturated ammonium chloride (2 mL) was added and diluted with dichloromethane (20 mL). The organic layer was separated and washed with water, dried over magnesium sulfate and the solvent was removed by distillation under vacuum. The residue was purified by PTLC (eluent=dichloromethane / methanol, 1:1) to give the title compound as a fluffy white solid (acetate cleav...

Embodiment 2

[0249] Preparation of 6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzofuran-7-yl phosphate disodium ester

[0250]

[0251] Step 1: Dibenzyl 6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzofuran-7-ylphosphate:

[0252]To 0.081 g (0.22 mmol) (7-hydroxy-6-methoxy-2-methylbenzofuran-3-yl) (3,4 , 5-trimethoxyphenyl)methanone, a mixture of 0.086 g (0.261 mmol) carbon tetrabromide and 0.063 mL (0.283 mmol) dibenzyl phosphite was added dropwise with 0.046 mL of anhydrous triethylamine. The resulting mixture was stirred at room temperature for 2 hours, then diluted to 20ml with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (dichloromethane / ethyl acetate, 9:1) to give the title compound as a colorless foam, (0.13 g, 94%);

[0253] 1 H NMR (CDCl 3 )δ2.42(s, 3H, Me-2); 3.83(s, 1H, OMe); 3.93(s, 3H, OMe); 5.33(m, 4H, CH 2 Ph); 6.89 (d...

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Abstract

The present invention provides a method for treating a proliferative disease in a patient. The method comprises administering to a patient in need thereof: a) a vascular disrupting agent and (b) at least one hypoxia targeting agent. Preferred combinations are BNC105 and Pazopanib and BNC 105 and Bortezomib.

Description

[0001] submission date [0002] This application is related to and claims priority from Australian Patent Application no. 2012902291 filed 1 June 2012, the entire contents of which are incorporated herein by reference. field of invention [0003] The present invention generally relates to novel chemical combinations and methods of their use in the treatment of proliferative diseases and especially cancer. Background of the invention [0004] Cancer is usually treated with chemotherapy and / or radiation therapy. Although these therapies are often effective in destroying large numbers of tumor cells, they tend to leave behind many tumor cells that are resistant to the treatment. These resistant cells can proliferate to form new tumors that are in turn resistant to treatment. The use of known combinations of chemotherapeutic drugs has resulted in the development of multidrug resistant ('MDR') tumor cells. [0005] The pattern of proliferative diseases such as cancer is multif...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/343A61K31/381A61K31/404A61K31/44A61K31/506A61K31/53A61K31/69A61K31/661A61P35/00
CPCA61K31/343A61K31/404A61K31/506A61K31/53A61K31/661A61K45/06A61K31/436A61K31/395A61K31/41A61K31/416A61K31/665A61K31/675A61K31/7004A61K31/69A61P35/00A61K2300/00
Inventor 丹尼尔·J·英格利斯蒂娜·C·拉夫拉诺斯加布里埃尔·克雷米迪奥蒂
Owner BONOMICS LTD
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