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Tetrahydroisoquinoline derivatives and preparation method and application thereof

A technology of tetrahydroisoquinoline and its derivatives, which is applied in the direction of drug combinations, pharmaceutical formulas, and medical preparations containing active ingredients, etc. It can solve the problems of low reversal activity, high fat solubility, and weak specificity of action.

Inactive Publication Date: 2011-05-25
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 severe side effects. cardiovascular side effects of
Among the tetrahydroisoquinoline MDR reversal agents developed in the past, most of the compounds with better activity showed higher fat solubility, poor pharmacokinetic properties, and poor druggability, etc.

Method used

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  • Tetrahydroisoquinoline derivatives and preparation method and application thereof
  • Tetrahydroisoquinoline derivatives and preparation method and application thereof
  • Tetrahydroisoquinoline derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] Example 1: 6,7-dimethoxy-3,4-dihydroisoquinoline (4a)

[0126] 40g (0.22mol) 3,4-dimethoxyphenethylamine (compound 2) mixed with 18.4g 36% (0.22mol) formaldehyde, gradually warming up to 100 ° C, reflux for 30 minutes, stop heating, after a little cooling (yellow oil-water mixture) suction pipette to remove the upper aqueous solution, then add 4 times the amount of 23% hydrochloric acid, evaporate the reaction solution to dryness to obtain a brownish yellow solid, recrystallize with 200ml of 95% ethanol to obtain 35g of white needle crystals, add the crystals to Concentrated ammonia water 45ml, slightly heated until completely dissolved without viscous matter, extracted with dichloromethane, washed with saturated brine until neutral, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to obtain 28.5g of yellow solid powder, yield: 67.9%, used directly in the next reaction.

Embodiment 2

[0127] Example 2: 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5a)

[0128] 28.5g (0.15mol) of compound 4a was dissolved in 160ml of methanol, 16g (0.38mol) of potassium borohydride was added in batches under an ice-water bath, and stirred at room temperature for 22h. The reaction solution was slowly poured into 500ml of ice-cold brine, and allowed to stand overnight to fully hydrolyze the potassium borohydride. Extracted with dichloromethane (100ml×3), washed with saturated brine until neutral, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to obtain 26.1g of white solid 5a, yield: 92%. mp: 74-76°C.

Embodiment 3

[0129] Example 3: N-(3,4-dimethoxy)phenethyl-(3,4-dimethoxy)phenylacetamide (3b)

[0130] 3,4-dimethoxyphenylethylamine (dimethoxyphenethylamine (distilled under reduced pressure, 140-170 / 1mmHg cut) 19.7g (0.106mol) is mixed with 3,4-dimethoxyphenylacetic acid 20.0g (0.102mol), pass Nitrogen, slowly heated to 190 ° C, water vapor is generated, all solids melt, keep warm for 3 hours, let cool to room temperature, add 150ml of chloroform to dissolve, and wash the chloroform solution with 3% hydrochloric acid, clear water, 3% NaOH aqueous solution, and saturated saline successively until Neutral, 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 to obtain 32g of white solid, yield: 87%, mp: 121-123°C.

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Abstract

The invention relates to novel tetrahydroisoquinoline derivatives, namely compounds shown as a general formula (I) and pharmaceutically acceptable salts thereof. The invention also provides application of the novel tetrahydroisoquinoline derivatives, and in particular relates to application to the reversion of multi-medicine resistance of tumors. The derivatives are used for improving the curative effects of anti-tumor medicines.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a tetrahydroisoquinoline derivative (I) compound, a preparation method thereof and an application as a tumor multidrug resistance reversal agent. Background technique [0002] Chemical drugs have a very important position and development prospects in the comprehensive treatment of malignant tumors, a systemic disease. At present, drug resistance has become one of the most common and most insurmountable problems in clinical tumor chemotherapy failure. Among the various ways of tumor cell drug resistance, 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 has become an important reason for the failure of many chemotherapy drugs. At present, the MDR reversal agents in clinical research are mainly calcium ...

Claims

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Application Information

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IPC IPC(8): C07D217/04C07D401/12C07D413/12A61K31/472A61K31/4725A61K31/473A61K31/4245A61P35/00
Inventor 黄文龙邹志红钱海蓝晓步唐春雷朱孝云刘保民
Owner CHINA PHARM UNIV
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