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Substituted bisindolylmaleimides for inhibition of cell proliferation

A technology of indole and alkyl, applied in the field of substituted pyrrole compounds, which can solve the problems of poor solubility, unsuitability, inconvenient therapeutic application, etc.

Inactive Publication Date: 2005-11-30
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although many agents with desirable antiproliferative activity have been identified, many of them have various disadvantages including poor solubility, molecular complexity, etc., making them either unsuitable or inconvenient for therapeutic application in human patients

Method used

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  • Substituted bisindolylmaleimides for inhibition of cell proliferation
  • Substituted bisindolylmaleimides for inhibition of cell proliferation
  • Substituted bisindolylmaleimides for inhibition of cell proliferation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Example 1: 3-[2-(2-Methoxy-ethoxy)-ethoxy]-propionic acid 3-[4-(1-methyl-6-nitro-1H-indole-3 -yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-indol-1-ylmethyl ester

[0100] 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide·HCl ("EDC·HCL"; Aldrich, 77 mg, 0.40 mmol) in dry THF (12 ml) at 22°C The suspension in DMAP (Aldrich) (55 mg, 0.45 mmol) was treated for 2 min. To this was added 3-(1-hydroxymethyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5 - Diketone (110 mg, 0.26 mmol) (prepared below). The mixture was stirred for 20 minutes, to which was added 2-(2-methoxy-ethoxy)-ethoxy]-propionic acid (CAS: 209542-49-4) (120 mg, 0.62 mmol). Stirring was continued for 4 hours at 22°C. All solvents were evaporated and the product was purified by silica gel chromatography to give 130 mg of 3-[2-(2-methoxy-ethoxy)-ethoxy]-propionic acid 3-[4-(1-methyl-6-nitroso yl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-indol-1-ylmethyl ester. (80% yield)

[0101] 3-(1-...

Embodiment 2

[0102] Example 2: O-[2-[[2,5-dihydro-3-[4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo Sub-2,5-dihydro-pyrrol-3-yl]-indol-1-yl]methoxycarbonyl]ethyl]-O'-methylpolyethylene glycol 2000

[0103] To 3-(1-hydroxymethyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole at -78°C -2,5-Dione (200 mg, 0.5 mmol) (prepared as described in Example 1 above) in dichloromethane was added triethylamine (0.6 mmol) followed by O-(2-carboxyethyl) -O'-Methyl polyethylene glycol 2000 acid chloride (0.6 mmol) (prepared according to standard procedures for mono-methyl polyethylene glycol 2000 propionic acid). The solution was stirred at room temperature for 3 hours and the solvent was evaporated. The residue was purified by silica gel flash chromatography to give 1 g of O-[2-[[2,5-dihydro-3-[4-(1-methyl-6-nitro-1h-indol-3-yl)-2 , 5-dioxo-2,5-dihydropyrrol-3-yl]-indol-1-yl]methoxycarbonyl]ethyl]-O'-methyl polyethylene glycol 2000 (yield 80 %).

Embodiment 3

[0104] Example 3: The following compounds were prepared in the same manner as in Example 2:

[0105] a) 2,3-Dimethoxy-benzoic acid 3-[4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5 -Dihydro-1H-pyrrol-3-yl]-indol-1-ylmethyl ester;

[0106] b) 3-Diethylaminomethyl-benzoic acid 3-[4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5 -Dihydro-1H-pyrrol-3-yl]-indol-1-yl methyl ester hydrochloride.

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Abstract

Disclosed are novel substituted pyrroles having formula (I). These compounds and their pharmaceutically acceptable salts are suitable for administration to patients as continuous infusion solution and are useful in the treatment and / or control of cell proliferative disorders, in particular cancer. Also disclosed are pharmaceutical compositions containing the foregoing compounds and methods for the treatment and / or control of cancer.

Description

Summary of the invention [0001] This invention relates to certain substituted azoles as antiproliferative agents. These compounds and their pharmaceutically acceptable salts are useful in the treatment or control of cell proliferative diseases, especially cancer. The present invention also relates to a pharmaceutical composition containing the compound and its use in treating and / or preventing cancer, especially treating or controlling solid tumors. Background of the invention [0002] Uncontrolled cell proliferation is a hallmark of cancer. Typically, cancerous tumor cells have some form of damage to genes that directly or indirectly regulate the cell division cycle. Humans have done a lot of work in the research of antiproliferative agents. Although many agents with desirable antiproliferative activity have been identified, many of them suffer from various disadvantages including poor solubility, molecular complexity, etc., making them either unsuitable or inconvenient ...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61K31/40A61K31/404A61K31/454A61K31/664A61K31/77A61P35/00A61P43/00C07D403/14C07F9/572C07F9/6558
CPCC07D403/14C07F9/65583C07F9/5728A61P35/00A61P43/00
Inventor 纳德·佛投赫埃米莉·爱军·刘艾伦·约翰·勒韦伊约翰·吉尔福伊尔·吉尔·马林吉瑟普·费德里科·韦伯
Owner F HOFFMANN LA ROCHE & CO AG
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