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Substituted n-aryl benzamides and related compounds for treatment of amyloid diseases and synucleinopathies

A compound and substituent technology, applied in drug combination, organic chemistry, neurological diseases, etc., can solve problems such as harmfulness to patients, no obvious treatment method or effective treatment plan, etc.

Inactive Publication Date: 2007-06-20
普罗塔医药公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For most of these amyloid lesions, there is no apparent cure or effective treatment options and the consequences of amyloid deposition are detrimental to the patient

Method used

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  • Substituted n-aryl benzamides and related compounds for treatment of amyloid diseases and synucleinopathies
  • Substituted n-aryl benzamides and related compounds for treatment of amyloid diseases and synucleinopathies
  • Substituted n-aryl benzamides and related compounds for treatment of amyloid diseases and synucleinopathies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0300] Synthesis of 3-methylsulfonylamino-4-hydroxybenzoic acid 3,4-dihydroxyaniline (DC-0051-S1, also known as DC-0051-CB)

[0301]

[0302] The formation of the methanesulfonylamino derivative of amide DC-0051 can be carried out as follows: first form the well-known 3-nitro-4-methoxybenzoic acid, and then use 3,4-methylenedioxyaniline to prepare Aniline products of the preceding compounds give 3-nitro-4-methoxy-amides. This is followed by catalytic reduction via intermediate mesylation to give mesylamide, which is demethylated in a simple reaction with boron tribromide to give 3-methanesulfonylamino-4-hydroxybenzoic acid 3, 4-Dihydroxyaniline (DC-0051-S1; also known as DC-0051-CB).

[0303] A) 3-nitro-4-methoxybenzoic acid

[0304] To a suspension of p-anisic acid (3 g) in anhydrous acetic acid (20 ml) at 0°C was added concentrated nitric acid (6 ml) dropwise. The resulting clear solution was brought to room temperature and then maintained for 30 minutes. The mixture wa...

Embodiment 2

[0317] 3-Hydroxy-4-methanesulfonylamino-N-(3,4-dihydroxyphenyl)benzamide

[0318] (DC0051-S8; also known as DC-0051-DB)

[0319]

[0320] 3,4-Methylenedioxyaniline reacts with 3-methoxy-4-nitrobenzoic acid to form 3-nitro-4-methoxy-amide. Catalytic hydrogenation followed immediately by mesylation yields the mesylamino group. 3-Hydroxy-4-methanesulfonylamino-N-(3,4-dihydroxyphenyl)benzamide (DC0051-S8; also known as DC-0051) by demethylation by reaction with boron tribromide -DB).

[0321] A) 3-methoxy-4-nitro-N-(3,4-methylenedioxyphenyl)benzamide

[0322] A suspension of 3-methoxy-4-nitrobenzoic acid (0.5g) in thionyl chloride (10ml) was heated at reflux for 1 hour. The solvent was removed under vacuum to give the acid chloride as a white solid. The acid chloride was dissolved in dry dichloromethane (10ml), and pyrimidine (0.5ml) and 3,4-methylenedioxyaniline (0.4g) dissolved in dichloromethane (5ml) were added dropwise solution of the mixture. The mixture was left a...

Embodiment 3

[0333] N-(3-Methanesulfonylamino-4-hydroxyphenyl)-3,4-dihydroxybenzamide

[0334] (DC0051-S6; also known as DC-0051-AE)

[0335]

[0336]Treatment of commercially available 2-methoxy-5-nitroaniline with methylsulfonyl chloride yields the methylsulfonylamino group. Catalytic reduction of the nitro group yields the desired anilino group, while condensation with 3,4-methylenedioxybenzoyl chloride yields the aniline. Removal of the methoxy and methylenedioxy groups with boron tribromide affords N-(3-methanesulfonylamino-4-hydroxyphenyl)-3,4-dihydroxybenzamide (DC0051-S6; also known as DC0051-AE).

[0337] A) 2-Methoxy-5-nitro-methanesulfonylaminobenzene.

[0338] To a solution of 2-methoxy-5-nitroaniline (5g) in pyrimidine (25ml) at 0°C was added dropwise methanesulfonyl chloride (3.5ml) followed by pyridine (0.5ml). The mixture was maintained at 0 °C for 1 hour, then the temperature was raised to room temperature and maintained for 2 hours. The mixture was poured on ice (...

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PUM

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Abstract

Substituted diaryl compounds of the Formulae (I, II, III), where the variables are as defined in the claims, and their pharmaceutically acceptable derivatives, their synthesis, pharmaceutical compositions containing them, and their use in the treatment of amyloid diseases, including Ass amyloidosis, such as observed in Alzheimer's disease, IAPP amyloidosis, such as observed in type 2 diabetes, and synucleinopathies, such as observed in Parkinson's disease, and the manufacture of medicaments for such treatment are provided.

Description

[0001] related application [0002] This application, filed May 12, 2004 by Snow et al. under 35 U.S.C. § 119(e), is entitled "Substituted N-arylbenzamides and related Compounds", U.S. Provisional Patent Application 60 / 570,669, and Snow et al., filed November 18, 2004, entitled "Substituted N-arylbenzamides and related Compounds” of U.S. Provisional Patent Application 60 / 629,525, the contents of which are incorporated herein by reference in their entirety. technical field [0003] The present invention provides substituted N-arylbenzamides and related compounds, pharmaceutical compositions and methods for the treatment of amyloid diseases including beta-amyloid (Aβ), as in Alzheimer's disease beta-amyloid as observed in type 2 diabetes; Down syndrome; islet amyloid polypeptide (IAPP), as observed in type II diabetes; Alpha-synuclein observed in Kinson's disease. Background technique [0004] Alzheimer's disease is characterized by the aggregation of a 39-43 amino acid pol...

Claims

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Application Information

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IPC IPC(8): C07C311/08C07C235/56C07C237/40C07D235/26A61K31/167A61P25/28
Inventor 亚伦·D·斯诺贝丝·P·阮托马斯·P·莱克杰拉多·M·卡斯蒂罗曼弗雷德·韦格勒
Owner 普罗塔医药公司
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