Tetrahydrochysene isoquinoline derivant, its producing method and uses of the same

A technology of tetrahydroisoquinoline and its derivatives, which is applied in the direction of pharmaceutical formulations, drug combinations, and medical preparations containing active ingredients, etc., and can solve problems such as low specificity, low reversal activity, and cardiovascular side effects

Inactive Publication Date: 2008-04-02
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the MDR reversal agents in clinical research are mainly calcium antagonists, and the representative drug is verapamil. This type of reversal agent has a definite reversal effect, but it has the disadvantages of weak specificity, low reversal activity, and accompanying serious cardiovascular side effects

Method used

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  • Tetrahydrochysene isoquinoline derivant, its producing method and uses of the same
  • Tetrahydrochysene isoquinoline derivant, its producing method and uses of the same
  • Tetrahydrochysene isoquinoline derivant, its producing method and uses of the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] N-(3,4-dimethoxy)phenethyl-(3,4-dimethoxy)phenylacetamide (II 1 ) preparation

[0085] 3,4-dimethoxyphenylethylamine (dimethoxydistilled, 140-170 / 1mmHg fraction) 18.6g (0.103mol) mixed with 3,4-dimethoxyphenylacetic acid 18.9g (0.096mol), nitrogen, Slowly heat to 190°C, water vapor is generated, all solids melt, keep warm for 3 hours, let cool to 80°C, add 150ml of chloroform to dissolve, and wash the chloroform solution with 3% hydrochloric acid, water, 3% NaOH aqueous solution, and saturated saline to medium sex, anhydrous Na 2 SO 4 Dry, evaporate to near dryness under reduced pressure, cool slightly, add 100ml of diethyl ether, shake gently, precipitate white solid, filter, dry, crude product weighs 31.9g, yield: 84%, mp120-122°C (documentation mp122.5-123°C ).

[0086] 6,7-dimethoxy-1-(3,4-dimethoxy)benzyl-3,4-dihydroisoquinoline (III 1 ) preparation

[0087] II 1 24.4g (0.0213mol) dissolved in 40ml of anhydrous toluene, POCl 3 30ml (0.3266mol), mix well, bl...

Embodiment 2

[0111] 6,7-Dimethoxy-1-(3,4-dimethoxy)benzyl-2-[N[2-(3',4'-dimethoxy)ethyl]glycyl] -1,2,3,4-tetrahydroisoquinoline (VI 2 ) preparation

[0112] V 1 Dissolve 3.8g (9.058mmol) in 50ml of dichloromethane, add 3,4-dimethoxyphenethylamine 3.28ml (18.1mmol), triethylamine 1.4ml (10.05mmol), catalytic amount of potassium iodide, and stir at room temperature for 14h . Chloroform:methanol=14:1 was used as the developer column chromatography to separate the main spot to obtain 2.0 g of oil. Yield 39.1%.

[0113] MS (ESI, m / z): 565 ([M+H] + , base peak)

[0114] 6,7-Dimethoxy-1-(3,4-dimethoxy)benzyl-2-[(chloroglycyl)-N-[2-(3',4'-dimethoxy ) ethyl] glycyl] -1,2,3,4-tetrahydroisoquinoline (VII 2 ) preparation

[0115] VI 2 5.7g (10.11mmol) was dissolved in 50ml of dichloromethane, DCC 2.3g (11.15mmol), DMAP catalytic amount was added, chloroacetic acid 1.92g (20.3mmol) was added in batches, room temperature was stirred for 1h, petroleum ether: ethyl acetate = 1:4 is the develope...

Embodiment 3

[0131] 6,7-dimethoxy-1-(3,4-dimethoxy)benzyl-2-(N-cyclohexylglycyl)-1,2,3,4-tetrahydroisoquinoline ( VI 4 ) preparation

[0132] V 1 Dissolve 3g (7.15mmol) in 30ml of dichloromethane, add 1.64ml (14.3mmol) of cyclohexylamine, 1.1ml (7.865mmol) of triethylamine, and a catalytic amount of potassium iodide, and stir at room temperature for 14h. Chloroform:methanol=14:1 was used as the developer column chromatography to separate the main spot to obtain 2.0 g of oil. Yield 58.0%.

[0133] MS (ESI, m / z): 483 ([M+H] + , base peak)

[0134] 6,7-Dimethoxy-1-(3,4-dimethoxy)benzyl-2-[(chloroglycyl)-N-cyclohexylglycyl]-1,2,3,4 -Tetrahydroisoquinoline (VII 4 ) preparation

[0135] VI 4 3.6g (7.47mmol) was dissolved in 30ml of dichloromethane, DCC 1.7g (8.22mmol), DMAP catalytic amount was added, chloroacetic acid 1.4g (14.9mmol) was added in batches, room temperature was stirred for 1h, petroleum ether: ethyl acetate = 1:4 is the developer column chromatography to separate the ma...

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Abstract

The present invention relates to the field of medicinal chemistry, and specifically relates to a category of novel tetrahydrocannabinol isoquinoline compounds (I), the preparation method, the pharmaceutical preparations containing the compounds and the application as tumor multi-drug and drug-resistant reversal agents. Wherein, the R 1 , R 2 and X are defined in the specification.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a new class of tetrahydroisoquinoline derivatives (I), their preparation method, pharmaceutical preparations containing them and their use as tumor multidrug resistance reversal agents. Background technique [0002] As a systemic treatment, chemotherapy has an important position and development prospect in the comprehensive treatment of malignant tumors, a systemic disease. Drug resistance is one of the most common and most insurmountable problems in the failure of clinical cancer chemotherapy. There are many ways of tumor cell drug resistance, among which multidrug resistance (MDR) is more common. The characteristic of MDR is that tumor cells are resistant to one anti-tumor drug and also resistant to other anti-tumor drugs with different structures and mechanisms of action. MDR is an important reason for the failure of tumor chemotherapy. At present, the MDR reversa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/24A61K31/472A61P35/00
Inventor 黄文龙李煜张惠斌
Owner CHINA PHARM UNIV
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