1,2,3,4-tetrahydroisoquinoline derivatives having effects of preventing and treating degenerative and inflammatory diseases

A degenerative disease, tetrahydroisoquinoline technology, applied in bone diseases, organic active ingredients, nervous system diseases, etc., can solve the problem that no effective method for neurodegenerative diseases has been developed

Inactive Publication Date: 2009-10-07
UNIV OF ULSAN FOUND FOR IND COOPERATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although attempts have been made to develop various substances such as secretase inhibitors, no clinical trials have been conducted on such substances developed
In addition, effective treatments for other neurodegenerative diseases such as Lou Gehrig's disease, Gutsfeld-Jacob's disease, and Huntington's disease have not been developed

Method used

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  • 1,2,3,4-tetrahydroisoquinoline derivatives having effects of preventing and treating degenerative and inflammatory diseases
  • 1,2,3,4-tetrahydroisoquinoline derivatives having effects of preventing and treating degenerative and inflammatory diseases
  • 1,2,3,4-tetrahydroisoquinoline derivatives having effects of preventing and treating degenerative and inflammatory diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1: 2-acetyl-7-hydroxy-6-methoxy substituted with methyl or phenyl at the C1 position -Synthesis of 1,2,3,4-tetrahydroisoquinoline (AHMTIQ) derivatives and their structural analysis

[0071] [Chemical Equation 1]

[0072]

[0073] Preparation and Analysis of AHMTIQ(5a)

[0074] Acetaldehyde (15.7mmol, 692mg) was reacted with 3-O-methyldopamine hydrochloride (1.96mmol, 400mg) dissolved in 1M HCl solution (10ml) in a pressure tube at 100°C for 24 hours. The reaction tube was allowed to cool and the mixture was neutralized with sodium bicarbonate. Water and remaining solvent were removed under reduced pressure, and the resultant was dried in vacuo. Methanol was added to the residual precipitate on the filter and crude compound 4a was extracted by short column chromatography. Crude compound 4a was crystallized to obtain the hydrochloride salt (250 mg, 55%) as a white powder [ 1 HNMR (DMSO-d 6 , 400MHz) 89.93(br s, 1H), 9.40(br s, 1H), 9.06(s, 1H), 6.72(s,...

Embodiment 2

[0080] Example 2: AHMTIQ derivatives (6, 7a-h, 8a-h and 9a-g) synthetic methods and their structural analysis

[0081] [Chemical Equation 2]

[0082]

[0083] ①N-(2-(4-hydroxy-3-O-methylphenyl) ethyl)-tert-butyl carbonate (6) synthetic method and analysis analysis

[0084] Method a) tert-butoxycarbonyl anhydride (7.63mmol, 1.67g) and triethylamine (19.5mmol, 1.93g) and compound 3 (6.35mmol, 1.30g) were added into chloroform (20ml). The mixture was stirred at RT for 24 hours, to which was added aluminum chloride solution. The mixture was extracted with dichloromethane solvent, and the organic layer was washed twice with water. White crystalline compound (1.32 g, 59%) was obtained by column chromatography and recrystallization [ 1 H NMR (CDCl 3 , 200MHz) δ6.83(d, J=8.4Hz, 1H), 6.63-6.67(m, 2H), 5.83(s, 1H), 6.45(br s, 1H), 3.84(s, 3H), 3.35( q, J=6.6Hz, 2H), 2.70(t, J=7.0Hz, 2H), 1.43(s, 9H); 13 C NMR (CDCl 3 , 50MHz) δ155.9, 146.5, 144.1, 130.6, 121.2, 114.4, ...

Embodiment 3

[0141] Example 3: 7-Hydroxy-6-methoxy-1,2,3,4-tetrahydroiso Synthesis of Quinoline (HMTIQ) Derivatives (11a-e and 12a-f) and Their Structural Analysis

[0142] [Chemical Equation 3]

[0143]

[0144] ①Preparation and analysis of HMTIQ derivatives (11a-e) substituted with amides at the N2 position

[0145] Preparation a) and b): Compound 10 (1.0 mmol or 2.0 mmol) was dissolved in dichloromethane solvent (10-15 ml), and alkyl acid chlorides (propionic anhydride, butyryl chloride, cyclohexanoyl chloride, iso butyryl chloride or 3-methylbutyryl chloride). Triethylamine (3.0 mmol or 6.0 mmol) was added slowly and the mixture was stirred at RT for about 1 hour. The reaction was quenched with water, and the organic layer was washed with water. The solvent was removed under reduced pressure. The obtained compound was dissolved in methanol (10-20 ml), and calcium carbonate (3.0 mmol or 6.0 mmol) was added thereto, and then the mixture was refluxed for about 2-3 hours. The...

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Abstract

Provided are 7-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline derivatives and synthesis methods thereof. The compounds significantly inhibit the production of nitrogen monoxide (NO) and superoxide in an activated microglial cell and expressions of TNF-alpha, IL- 1beta inducive NO synthase and cyclooxygenase-2 genes. They also prevent NF-kB shift to a nucleus, decrease reactive oxygen species (ROS), inhibit expression of GTP cyclohydrolase I gene and over-production of tetrahydrobiopterin (BH 4 ), and protect dopaminergic neurons from injury due to activated microglial cells. Consequently, the compounds are effective in treating inflammatory and neurodegenerative diseases.

Description

technical field [0001] The invention relates to a 7-hydroxyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline derivative capable of preventing and treating degenerative diseases and inflammatory diseases. Background technique [0002] Recent studies have shown that inflammation is a key mechanism leading to neurodegenerative diseases. Microglia and immune cells in the central nervous system may be activated by exogenous or endogenous substances, thereby producing and releasing inflammatory cytokines, TNF-α or IL-1β, nitric oxide (NO), prostaglandins , peroxides and other substances. Although they induce an immune response within a short period of time, the substances are continuously produced in excess, thus leading to the loss of neighboring neurons and eventually to neurodegenerative diseases. In addition, substances released by dying neurons induce the reactivation of microglia, so that neurodegenerative diseases become more severe. Activation of microglia has been reported to...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/472
CPCA61K31/472A61P19/02A61P25/00A61P25/14A61P25/16A61P25/28A61P39/06A61P43/00
Inventor 黄温裕池大润孙孝真徐载雄
Owner UNIV OF ULSAN FOUND FOR IND COOPERATION
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