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Compound, compositions and methods for preventing neurodegeneration in acute and chronic injuries in central nervous system

A technology of central nervous system and compounds, applied in the field of nervous system diseases

Inactive Publication Date: 2006-08-02
GNT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the pathogenesis of ALS has not been elucidated, excitotoxicity is thought to be involved in the ALS process

Method used

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  • Compound, compositions and methods for preventing neurodegeneration in acute and chronic injuries in central nervous system
  • Compound, compositions and methods for preventing neurodegeneration in acute and chronic injuries in central nervous system
  • Compound, compositions and methods for preventing neurodegeneration in acute and chronic injuries in central nervous system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 5

[0057]

[0058] Reagent (a) N,N-methylformamide (DMF), triethylamine, room temperature, 4 hours.

[0059] Specific compounds of interest in formula (I) are as follows:

[0060] 5-Benzylaminosalicylic acid

[0061] 5-(4-nitrobenzyl)aminosalicylic acid (NBAS)

[0062] 5-(4-Chlorobenzyl)aminosalicylic acid (CBAS)

[0063] 5-(4-Trifluoromethylbenzyl)aminosalicylic acid (TBAS)

[0064] 5-(4-Fluorobenzyl)aminosalicylic acid (FBAS)

[0065] 5-(4-Methoxybenzyl)aminosalicylic acid (MBAS)

[0066] 5-(Pentafluorobenzyl)aminosalicylic acid (PBAS)

[0067] 5-(4-Nitrobenzyl)amino-2-hydroxybenzoic acid ethyl ester (NAHE)

[0068] 5-(4-Nitrobenzyl)-N-acetamido-2-hydroxybenzoic acid ethyl ester (NNAHE)

[0069] 5-(4-Nitrobenzyl)-N-acetamido-2-acetoxy-ethyl benzoate (NNAAE)

[0070] 5-(4-Nitrobenzoyl)aminosalicylic acid (NBAA)

[0071] 5-(4-Nitrobenzenesulfonyl)aminosalicylic acid (NBSAA)

[0072] 5-[2-(4-Nitrophenyl)-ethyl]aminosalicylic acid (NPAA)

[0073] 5-[3-(4-nitrophenyl)n...

experiment Embodiment 1

[0123] Experimental Example 1: Antioxidative Effect of 5-Aminosalicylic Acid

[0124] The neuroprotective effects of 5-aminosalicylic acid (AS) were tested in primary cortical cell cultures. Containing 10-300 μM AS did not reduce neuronal death induced by 10 min exposure to 300 μM NMDA over 24 hours (Fig. 1.a). Interestingly, adding 10-100 μM AS dose-dependently prevented free radical neurotoxicity induced by exposure to ferrous ions for 24 h (Fig. 1b). Continuous addition of AS during and after zinc ion treatment did not reduce neuronal death 24 hours after exposure to 300 micromolar zinc ions for 30 min. The neuroprotective effect of AS against free radical neurotoxicity is attributed to the direct antioxidant properties of the compound AS reducing the level of DPPH, a stable free radical. Compared to trolox, a membrane permeable form of vitamin E, AS is a weak oxidizing agent.

[0125] Reactant

Concentration of Trolox or AS (micromolar)

0

3...

experiment Embodiment 2

[0128] Experimental Example 2: Neuroprotective Effects of 5-Benzylaminosalicylic Acid and Its Derivatives

[0129] Neuroprotective effects of 1.5-benzylaminosalicylic acid

[0130] BAS was synthesized and tested for its ability to resist nerve damage induced in cortical cell cultures. Simultaneous addition of 300 micromolar 5-benzylaminosalicylic acid (BAS) was able to reduce NMDA-induced neuronal death by approximately 50% (Fig. 2a). In the presence of 1 μM BAS, there was a considerable decrease in neuronal death induced by exposure to 50 μM ferrous ions (Fig. 2b) or 10 mmol BSO (Fig. 2c), adding 3 μM molar BAs, neuronal death was essentially completely blocked. Addition of 30-300 micromolar BAS dose-dependently reduced neuronal death induced by exposure to 300 micromolar zinc ions for 30 minutes over 24 hours. Like AS or trolox, BAS is a direct antioxidant (Table 2). The antioxidant properties of BAS were observed at doses as low as 1 micromolar.

[0131] [BAS]...

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Abstract

The present invention provides a compositions and methods for prevention and prophylaxis of neurological diseases accompanied by neuronal death. The invention includes synthesis of 5-benzylamino salicylic acid (BAS) and its derivatives. BAS and its derivatives protect cortical neurons from toxic insults by N-methyl-D-aspartate, Zn2+, and reactive oxygen species. Thus, the present invention provides compositions and methods for treating stroke, traumatic brain and spinal cord injury, epilepsy, and neurodegenerative diseases that are accompanied by severe neuronal loss via excitotoxicity, Zn2+ neurotoxicity, and free radical neurotoxicity.

Description

technical field [0001] The present invention relates to novel salicylic acid compounds, compositions, and methods for preventing and preventing neurological diseases accompanied by neuronal death. technical background [0002] Excitotoxicity and Brain Disease [0003] Hyperactivation of ionotropic glutamate receptors sensitive to N-methyl-D-aspartate (NMDA receptors) causes neuronal death and is known to mediate a variety of neurological disorders [Choi , Neuron 1:623-634 (1988)]. Glutamate is an excitatory neurotransmitter, which accumulates in large quantities in the brain and is susceptible to hypoxic-ischemic damage, which activates ionized glutamate receptors, making them accessible to calcium and sodium ions Infiltration, followed by neuronal death [Choi and Rothman, Annu Rev Neurosci: 13: 171-182 (1990)]. NMDA receptor antagonists significantly reduced hypoglycemia, hypoxia, and hypoxic-ischemia induced by brain injury [Simon, Swan, Griffiths, and Meldrum. Science...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/64C07C311/21A61K31/196C12M3/00A61BA61B17/42A61B17/435A61B19/02A61D19/02A61D19/04A61K31/606A61K31/618A61K31/621A61P3/10A61P7/06A61P19/08A61P21/04A61P25/08A61P25/14A61P25/16A61P25/28A61P43/00C07C233/54C07C233/81
CPCC07C229/64C07C233/54C07C311/21A61P19/08A61P21/04A61P25/00A61P25/08A61P25/14A61P25/16A61P25/28A61P43/00A61P7/06A61P9/10A61P3/10
Inventor 郭秉周李英爱柳宝凛尹性和文镐相
Owner GNT PHARMA
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