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Compositions and methods for reducing the risk of epileptic occurrence and/or for treatment of seizure disorders

A composition and technology of antiepileptic drugs, which can be applied in drug combinations, nervous system diseases, active ingredients of heterocyclic compounds, etc., and can solve problems such as discomfort treatment

Inactive Publication Date: 2006-11-22
迪-药品有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the pharmacologic approach suggested in the literature for the treatment of pyridoxine-dependent epilepsy is not suitable for the treatment of other forms of epilepsy

Method used

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  • Compositions and methods for reducing the risk of epileptic occurrence and/or for treatment of seizure disorders
  • Compositions and methods for reducing the risk of epileptic occurrence and/or for treatment of seizure disorders
  • Compositions and methods for reducing the risk of epileptic occurrence and/or for treatment of seizure disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] Example 1: Synthesis of [5-hydroxy-6-methyl-4-(hydroxymethyl)-pyridin-3-yl]methyl-4-aminobutyrate, dihydrochloride (=B6-GABA)

[0107] The chemical structure of [5-hydroxy-6-methyl-4-(hydroxymethyl)-pyridin-3-yl]methyl-4-aminobutyrate, dihydrochloride is:

[0108]

[0109] The synthesis of [5-hydroxy-6-methyl-4-(hydroxymethyl)-pyridin-3-yl]methyl-4-aminobutyrate, dihydrochloride was a five-step process. All synthesized compounds were characterized by NMR and mass spectrometry.

[0110] 1.3, the synthesis of 4-bis(bromomethyl)-5-hydroxyl-6-methylpyridine (2):

[0111]

[0112] In the first step, pyridoxine (1) (20 g, 0.097 mol) was refluxed in 48% hydrobromic acid (150 ml) for 1 hour. After crystallization at -15°C the precipitate was isolated, washed with acetone and dried. Yield 25 g (68%).

[0113] MS(ES): m / z295.95; 297.93(M+H) + .

[0114] 2. Synthesis of 3-bromomethyl-5-hydroxy-4-hydroxymethyl-6-methylpyridine hydrobromide (3).

[0115]

[0116] 4,5...

Embodiment 2

[0131] Example 2: [3-(5-hydroxyl-6-methyl-4-(hydroxymethyl)pyridyl]methyl-2-[(4-hydroxyl)quinoline formate (=B6-Kyn) synthesis

[0132] The chemical structure of [3-(5-hydroxy-6-methyl-4-(hydroxymethyl)pyridyl]methyl-2-[(4-hydroxy)quinolinecarboxylate is:

[0133]

[0134] Under argon, a mixture of 4-hydroxyquinoline-2-carboxylic acid hydrate (kynurenic acid (7)) (1.80 g, 8.70 mmol) and cesium carbonate (4.25 g, 13.05 mmol) was stirred at room temperature in Stir in dry DMSO (70ml) for 1.5 hours. 3-Bromomethyl-5-hydroxy-4-hydroxymethyl-6-picoline hydrobromide (3) (3.58 g, 11.42 mmol) was then added. The resulting brown solution was kept at room temperature for 18 hours, then diluted with water (200ml) and extracted with ethyl acetate (12x150ml). After crystallization at 5°C the precipitate was isolated, washed with ethyl acetate, ether and dried. Yield 0.25 g (7.8%).

[0135] 1 H NMR (DMSO-d 6 )δ: 2.36(s, 3H), 4.77(s, 2H), 5.47(s, 2H), 6.60(s, 1H), 7.37(t, 1H), 7.69(...

Embodiment 3

[0137] Example 3: [4-(4-hydroxyquinoline-2-carbonamido)]butanoic acid 5-hydroxyl-4-hydroxymethyl-6-methyl-pyridin-3-yl)methyl ester (B6- GABA-Kyn) synthesis

[0138] The chemical structure of [4-(4-hydroxyquinoline-2-carbonylamino)]butanoic acid 5-hydroxy-4-hydroxymethyl-6-methyl-pyridin-3-yl)methyl ester is:

[0139]

[0140] 1. Synthesis of 4-(4-hydroxyquinoline-2-carbonylamino)butanoic acid (10).

[0141]At 50°C, BSA (N, O-bis(trimethylsilyl)acetamide) (3.26ml, 13.20mmol) was added to 4-aminobutyric acid (GABA) (0.62g, 6.00mmol) in a dry dichloromethane (10ml) and the mixture was stirred for 6 hours. The resulting solution was added in the mixed anhydride which was prepared from kynurenic acid (7) (0.95g, 5.00mmol), Et 3 N (1 ml), EtOCOCl (0.5 ml, 5.25 mmol) was prepared in dry DMF (10 ml) at -20°C for 20 minutes. The reaction mixture was stirred at -5°C for 2 hours and kept at 4°C for a further 18 hours. Water (50ml) and ethyl acetate (30ml) were then added. A mix...

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Abstract

The present invention relates to compounds and compositions useful for reducing the risk of epileptic occurrences and / or for alleviating epileptic phenomena in patients. In accordance with the invention, the compounds and compositions have at least the following two components: a) vitamin B6-based component selected from pyridoxal, pyridoxamine, pyridoxine, their pharmaceutically acceptable functional derivatives and salts; and b) at least one antiepileptic drug (AED) or anticonvulsive, neuro-protective drug or nootrope compound or moiety. The invention further relates to methods for preventing epileptic episodes and for alleviating epileptic episodes, as well as methods for reducing side effects of antiepileptic drugs.

Description

field of invention [0001] The present invention relates to compositions and methods of using such compositions for the treatment and prevention of epilepsy and related disorders. Background of the invention [0002] Epilepsy is one of the most common chronic neurological disorders. The disease is characterized by recurrent seizures that arise from abnormal and excessive brain neuronal activity and result in episodic disturbances of brain function. Types of epilepsy include partial (symptomatic) and generalized spontaneous seizures. Partial epilepsy is "locally related" and occurs in a limited area of ​​the brain. The general development of epilepsy is not caused by a specific brain lesion or disease, apart from a possible genetic predisposition to produce seizures. Generalized or grand mal seizures include tonic-clonic seizures in which the entire body experiences convulsions. Epilepsy left untreated can become status epilepticus, a potentially fatal neurological emergen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/02A61KA61K31/44A61P25/08C07D
CPCC07D213/63C07D401/12A61P25/08A61P43/00
Inventor S·多林纳V·舒太曼M·维尼科弗I·沙皮洛
Owner 迪-药品有限公司
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