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2-substituted-6,7-dimethoxy tetralin isoquinoline derivative, preparation method thereof, medicinal composition and application thereof

The technology of a drug and a compound is applied in the application field of preparing a drug for treating diabetes, and can solve problems such as inactivation of GLP-1

Inactive Publication Date: 2012-02-22
江西省隆南药化有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, DPP-4 can rapidly and specifically cleave the second proline or alanine at the N-terminal of the GLP-1 peptide chain in vivo, leading to the inactivation of GLP-1

Method used

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  • 2-substituted-6,7-dimethoxy tetralin isoquinoline derivative, preparation method thereof, medicinal composition and application thereof
  • 2-substituted-6,7-dimethoxy tetralin isoquinoline derivative, preparation method thereof, medicinal composition and application thereof
  • 2-substituted-6,7-dimethoxy tetralin isoquinoline derivative, preparation method thereof, medicinal composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, English translation: 6,7-dimethoxy-1,2,3,4-tetrahydr roisoquinoline

[0063] 9.05g (0.05mol) of 3,4-dimethoxyphenethylamine and 1.8g of paraformaldehyde were respectively dissolved in 30ml of absolute ethanol, stirred at room temperature for 1-2h, TLC detected the formation of Schiff base, and then added 6N concentrated After adjusting the pH to 3 with hydrochloric acid, the reaction was heated under reflux for 6 hours, a large amount of white solids precipitated, cooled and filtered, and recrystallized from 95% ethanol to obtain 7.92 g of colorless flaky crystals, mp: 254°C. Add the colorless crystals obtained above into 50 ml of 2M sodium hydroxide solution, stir, extract three times with dichloromethane, combine the organic layers, wash the organic layer three times with saturated brine, and dry over anhydrous sodium sulfate. Concentrate to obtain 6.6g of yellow-white solid, yield 68.3%, mp: 81-83°C, literature: 84-85°C ...

Embodiment 2

[0076] 6,7-dimethoxy-2-[N-(N-(4-methylphenyl)acetamide)aminoethyl]-1,2,3,4-tetrahydroisoquinoline (Ia 2 ), English translation: 2-((2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)amino)-N-(p-tolyl)acetamide

[0077] 0.4g (0.0015mol) 2-(2-aminoethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, anhydrous potassium carbonate 0.42g (0.003 mol), 0.18g (0.001mol) N-chloroacetyl-4-methylaniline, according to (Ia 1 ) method to obtain 0.15 g of white solid, yield 39.1%, mp: 92-94°C.

[0078] IR (cm -1 ): 3281, 2972, 1726, 1298, 1189 1 HNMR (CDCl 3 , 500MHz) δ: 9.48 (s, 2H, -NH), 7.43-7.46 (d, 2H, Ar-H), 7.03-7.06 (d, 2H, Ar-H), 6.60 (s, 1H, Ar-H ), 6.47(s, 1H, Ar-H), 3.81-3.85(2s, 6H, 2-OCH 3 ), 3.70 (s, 2H, C1-CH 2 ), 3.44 (s, 2H, -CH 2 ), 2.88-2.93 (m, 6H, -N-CH 2 -CH 2 -NH, C4-CH 2 ), 2.77-2.79(t, 2H, C3-H), 2, 28(s, 3H, -CH 3 )

[0079]MS (ESI, m / z): 384 ([M+1] + , basepeak)

Embodiment 3

[0081] 6,7-dimethoxy-2-[N-(N-4-fluorophenyl)acetamide)aminoethyl]-1,2,3,4-tetrahydroisoquinoline (Ia 3 ), English translation: 2-((2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)amino)-N-(4-fluorophenyl)acetamide

[0082] 0.4g (0.0015mol) 2-(2-aminoethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, anhydrous potassium carbonate 0.42g (0.003 mol), 0.19g (0.001mol) N-chloroacetyl-4-fluoroaniline, according to (Ia 1 ) method to obtain white solid 0.16g, yield 41.3%, mp: 88-90°C.

[0083] IR (cm -1 ): 3290, 2928, 1685, 1405, 1222 1 HNMR (CDCl 3 , 300MHz) δ: 9.63 (s, 1H, -NH), 7.44-7.49 (m, 2H, Ar-H), 6.88-6.94 (m, 2H, Ar-H), 6.59 (s, 1H, Ar-H ), 6.47(s, 1H, Ar-H), 3.82-3.86(2s, 6H, 2-OCH 3 ), 3.58(s, 2H, C1-CH 2 ), 3.40 (s, 2H, -CH 2 ), 2.76-2.89 (m, 6H, -N-CH 2 -CH 2 -NH, C4-CH2), 2.64-2.68 (t, 2H, C3-H) MS (ESI, m / z): 388 ([M+1] + , basepeak)

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Abstract

The invention discloses a 2-substituted-6,7-dimethoxy tetralin isoquinoline derivative, a preparation method thereof, a medicinal composition and application thereof, which relate to compounds shown as a general formula (I) and pharmaceutically acceptable salts thereof. The type of compounds has a good blood sugar lowering effect. The invention further relates to a preparation method of the type of compounds and a medicinal preparation containing the compounds. Due to the adoption of the method, a series of compounds shown as the general formula (I) and pharmaceutically acceptable salts are synthesized.

Description

technical field [0001] The invention relates to 2-substituted-6,7-dimethoxytetrahydroisoquinoline derivatives, a preparation method thereof, a pharmaceutical composition containing the compound as an active ingredient and its application in the preparation of medicines for treating diabetes. Background technique [0002] Diabetes is a chronic progressive lifelong disease caused by the disorder of sugar, protein and fat metabolism in the body. Clinically, diabetes can be divided into insulin-dependent diabetes (type 1) and non-insulin-dependent diabetes (type 2), wherein type 1 diabetes accounts for about 10% of diabetic patients, and type 2 diabetes accounts for about 90%. At present, about 246 million people in the world suffer from type 2 diabetes, and it is estimated that the number of people suffering from type 2 diabetes will reach 380 million within 20 years, seriously threatening human health. Diabetes has become the third common frequently-occurring disease after ca...

Claims

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Application Information

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IPC IPC(8): C07D217/04C07D401/12C07D217/06A61K31/4725A61K31/472A61P3/10
Inventor 张惠斌刘庆森周金培
Owner 江西省隆南药化有限公司