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Tetrahydroisoquinoline derivative, preparation method and application thereof

A technology of tetrahydroisoquinoline and tetrahydroisoquinoline hydrochloride, applied in the field of tumor multidrug resistance reversal agent, tetrahydroisoquinoline derivatives and pharmaceutically acceptable salts, can solve the problem of specific action Weakness, cardiovascular side effects, high fat solubility, etc.

Inactive Publication Date: 2011-05-18
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 derivative, preparation method and application thereof
  • Tetrahydroisoquinoline derivative, preparation method and application thereof
  • Tetrahydroisoquinoline derivative, preparation method and application thereof

Examples

Experimental program
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Embodiment approach

[0048] Embodiment: according to tetrahydroisoquinoline derivatives of the present invention, its general formula I compound can be prepared according to the following method:

[0049] (1) The compound of general formula I can be prepared according to the following method: 3,4-dimethoxyphenethylamine (compound 2) is reacted with substituted acetic acid under 190 DEG C of solvent-free compound 3, and compound 3 is prepared in trichloroxy In the presence of phosphorus, reflux in anhydrous toluene to obtain compound 4, compound 4 is under the condition of anhydrous methanol as a solvent, add a catalytic amount of diethylamine, and be reduced by potassium borohydride to obtain compound 5, compound 5 and oxadiazole (II) In acetonitrile, use anhydrous potassium carbonate as an acid-binding agent to reflux for 2 to 8 hours to obtain compound I, compound 5 and substituted phenoxyalkyl bromide (III) in acetonitrile, use anhydrous potassium carbonate as an acid-binding agent to reflux for...

Embodiment 1

[0112] Example 1: 6,7-dimethoxy-3,4-dihydroisoquinoline (4a)

[0113] Mix 40g (0.22mol) of 3,4-dimethoxyphenethylamine with 18.4g of 36% (0.22mol) formaldehyde, gradually heat up to 100°C, reflux for 30 minutes, stop heating, and after a little cooling (yellow oil-water mixture) pipette Suck off 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 45ml of concentrated ammonia water to the crystals, 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 28.5 g of yellow solid powder, yield: 67.9%, which was directly used in the following step response.

Embodiment 2

[0114] Example 2: 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5a)

[0115] 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.

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Abstract

The invention relates to a novel tetrahydroisoquinoline derivative which is a compound with the general formula (I), and pharmaceutically acceptable salts thereof. The invention also provides the application of the novel tetrahydroisoquinoline derivative, particularly the application for reversing the multidrug resistance of tumors. The novel tetrahydroisoquinoline derivative and the pharmaceutically acceptable salts thereof can be used for improving the treatment effect of antineoplastic drug.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to tetrahydroisoquinoline derivatives and pharmaceutically acceptable salts, their preparation methods and their use as tumor multidrug resistance reversal agents. 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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/04C07D217/16C07D217/20C07D413/06A61K31/472A61K31/4725A61P35/00
Inventor 黄文龙邹志红刘保民钱海蓝晓步唐春雷朱孝云
Owner CHINA PHARM UNIV
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