Inhibitors of HSP90

A kind of CH2, low-level technology, applied in the field of benzimidazolone derivatives in the preparation of pharmaceutical compositions for the treatment of the disease, the pharmaceutical compositions for the treatment of the diseases, and the preparation of new intermediate compounds of the benzimidazolone derivatives, Can solve problems such as poor solubility, difficult formulation/application, difficult synthesis, etc.

Inactive Publication Date: 2007-08-29
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The poor solubility of 17-AAG makes it difficult to formulate / administer and its synthesis is also difficult (typically obtained by fermentation)

Method used

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  • Inhibitors of HSP90
  • Inhibitors of HSP90
  • Inhibitors of HSP90

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0067]In the following preferred embodiments, general expressions may be replaced by corresponding more specific definitions provided above and below, thereby resulting in more preferred embodiments of the invention.

[0068] Preference is given to the use of compounds of formula (I) or (IA) or pharmaceutically acceptable salts thereof for the treatment of proliferative diseases.

[0069] Especially preferred is the use of a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof in the treatment of proliferative diseases, wherein the disease to be treated is a disease dependent on Hsp90 and / or hsp90 client protein or an overexpression of Hsp90 tumor.

[0070] Also preferred is the use of a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical preparation for the treatment of proliferative diseases, which pharmaceutical preparation comprises a compound of formula (I) and optionally a pharmaceu...

Embodiment 1

[0153] The synthesis of substituted anilines is carried out by nitrating the corresponding alkyl-resorcinols of formula (v) or 2,4-dimethoxy-acetophenone derivatives of formula (vi) to obtain formulas (iii) and 2,4-Dimethoxy-1-nitro-benzene derivatives of (iv). Friedel-Crafts acylation of 2,4-dimethoxy-1-nitro-benzene (vii) was performed using copper triflate as catalyst. Reduction of the corresponding The nitro derivatives (iii) and (iv) give 2,4-dimethoxy-5-substituted anilines. For simultaneous hydrogenation of nitro and keto groups, hydrochloric acid is added. 2,4-Dimethoxy-1-alkyl-benzenes (v) are obtained by hydrogenation of the corresponding 2,4-dimethoxy-acetophenones (vi).

[0154] Step 1.1: 5-Ethyl-2,4-dimethoxy-phenylamine

[0155] A solution of 1-ethyl-2,4-dimethoxy-5-nitro-benzene (Step 1.2) (6.1 g, 29 mmol) in ethanol (200 mL) was hydrogenated over Pd(C) (600 mg) for 1 h . The catalyst was filtered, the solvent was evaporated under reduced pressure and the ...

Embodiment 2

[0159]Example was synthesized from 5-chloro-2,4-dimethoxy-phenylamine and 1-fluoro-2-nitro-4-trifluoromethyl-benzene following a procedure similar to that described in the Synthetic Methods section 2 compounds.

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PUM

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Abstract

The invention relates to the use of benzoimidazolone compounds and salts thereof in the treatment of proliferative diseases and for the manufacture of pharmaceutical preparations for the treatment of said diseases, pharmaceutical preparations comprising benzoimidazolone compounds, novel benzoimidazolone compounds, and a process for the preparation of the novel benzoimidazolone compounds.

Description

Summary of the invention [0001] The present invention relates to a method for using benzimidazolone derivatives to treat proliferative diseases, a pharmaceutical preparation comprising benzimidazolone derivatives for treating said diseases, or a benzimidazolone derivative in the preparation of a medicament for treating said diseases use in compositions. The present invention also relates to novel benzimidazolone derivatives, pharmaceutical preparations comprising these benzimidazolone derivatives, processes for preparing novel benzimidazolone derivatives and pharmaceutical preparations, and methods for the preparation of benzimidazolone derivatives new intermediate compounds. Background of the invention: [0002] The chaperones of the Hsp90 family consist of 4 known members: Hsp90α and Hsp90β in the cytosol, grp94 in the endoplasmic reticulum and trap-1 in the mitochondria. Hsp90 is a highly abundant cellular chaperone protein required for the ATP-dependent refolding of de...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4184C07D239/70A61P35/00A61P35/02
CPCC07D235/26A61K31/4184A61P35/00A61P35/02A61P43/00
Inventor P·谢纳A·弗劳尔舍默P·菲雷J·舍普费尔
Owner NOVARTIS AG
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