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Harmine derivative anti-tumor prodrug with target characteristic

A technology of dehydrohalamine and its derivatives, which is applied in the fields of antineoplastic drugs, sugar derivatives, sugar derivatives, etc.

Inactive Publication Date: 2013-03-20
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Targeted therapy of dehydrohalamine antineoplastic drugs has not been reported yet

Method used

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  • Harmine derivative anti-tumor prodrug with target characteristic
  • Harmine derivative anti-tumor prodrug with target characteristic
  • Harmine derivative anti-tumor prodrug with target characteristic

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of I-1:

[0038] Step A: Mix harmine (1.06g, 5mmol), N,N-dimethylformamide (25ml), sodium hydrogen (0.192g, 8mmol), stir at room temperature for 10min, add 3-phenylpropyl bromide ( 10mmol), stirring for 0.5-3h, TLC tracking detection (petroleum ether / acetone=1:1), the reaction is completed, the reaction mixture solution is poured into 50ml ice water, stirred for 30min, filtered, and washed with a lot of water. The solid was dissolved in absolute ethanol, adjusted to pH 3-4 with hydrochloric acid, and concentrated to dryness under reduced pressure. The absolute ethanol was carried with water several times to obtain an oil, which was recrystallized with acetone to obtain white crystals as the hydrochloride salt of the product.

[0039] ESI-MS m / e(M+1)331.2

[0040] 1 H-NMR (500MHz, CDCl 3 )δ8.23-8.24 (1H, d, J=5.1Hz); 7.81-7.82 (1H, d, J=5.13Hz); 8.10-8.08 (1H, d, J=8.6Hz); 7.11-7.12 (1H , M); 6.86-6.88 (1H, m); 7.11-7.30 (5H, m); 3.90 (3H, s); 3.15 (3H, s); 2.01-2...

Embodiment 2

[0048] Preparation of I-2:

[0049] Step A: The preparation method is the same as in Example 1. In the step, bromoethane is used as the alkylating agent.

[0050] ESI-MS m / e(M+1)241.3

[0051] 1 H-NMR (500MHz, CDCl 3 )δ8.23-8.24 (1H, d, J=5.1Hz); 7.81-7.82 (1H, d, J=5.13Hz); 8.10-8.08 (1H, d, J=8.6Hz); 7.11-7.12 (1H , M); 6.86-6.88 (1H, m); 3.90 (3H, s); 3.15 (3H, s); 4.46-4.53 (2H, m); 1.29-1.34 (3H, m)

[0052] Step B: The preparation method is the same as in Example 1.

[0053] ESI-MS m / e(M+1)227.2

[0054] 1 H-NMR (500MHz, CDCl 3 )δ9.70 (1H, s, OH); 8.23-8.24 (1H, d, J = 5.1 Hz); 7.81-7.82 (1H, d, J = 5.13 Hz); 8.10-8.08 (1H, d, J = 8.6Hz); 7.11-7.12 (1H, m); 6.86-6.88 (1H, m); 3.15 (3H, s); 4.46-4.53 (2H, m); 1.29-1.34 (3H, m)

[0055] Step C: The preparation method is the same as in Example 1.

[0056] ESI-MS m / e(M+1)313.3

[0057] 1 H-NMR (500MHz, CDCl 3 )δ8.23-8.24 (1H, d, J=5.1Hz); 7.81-7.82 (1H, d, J=5.13Hz); 8.10-8.08 (1H, d, J=8.6Hz); 7.11-7.12 (1H , M); 6.86-6.88 (1H, m); 3....

Embodiment 3

[0059] Preparation of I-3:

[0060] Step A: The preparation method is the same as in Example 1. In the step, bromobutane is used as the alkylating agent.

[0061] ESI-MS m / e(M+1)269.3

[0062] 1 H-NMR (500MHz, CDCl 3 )δ8.23-8.24(1H, d, J=5.1Hz); 7.81-7.82(1H, d, J=5.13Hz); 8.10-8.08(1H, d, J=8.6Hz); 7.11-7.12(1H , M); 6.86-6.88 (1H, m); 3.90 (3H, s); 3.15 (3H, s); 3.84-3.86 (2H, m); 1.76-1.78 (2H, m); 1.32-1.34 (2H , M); 0.95-0.97 (3H, m)

[0063] Step B: The preparation method is the same as in Example 1.

[0064] ESI-MS m / e(M+1)255.7

[0065] 1 H-NMR (500MHz, CDCl 3 )δ9.74 (1H, s, OH); 8.23-8.24 (1H, d, J=5.1Hz); 7.81-7.82 (1H, d, J=5.13Hz); 8.10-8.08 (1H, d, J= 8.6Hz); 7.11-7.12 (1H, m); 6.86-6.88 (1H, m); 3.15 (3H, s); 3.84-3.86 (2H, m); 1.76-1.78 (2H, m); 1.32-1.34 (2H, m); 0.95-0.97 (3H, m)

[0066] Step C: The preparation method is the same as in Example 1.

[0067] ESI-MS m / e(M+1)341.3

[0068] 1 H-NMR (500MHz, CDCl 3 )δ8.23-8.24 (1H, d, J=5.1Hz); 7.81-7.82 (1H, d, J=5.13Hz); 8....

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Abstract

The invention relates to the field of tumor target treatment, and in particular relates to a harmine derivative anti-tumor prodrug with target characteristic. The invention discloses a junctional complex for structuring 2-deoxidation-D-deoxyglucose (II) and the harmine derivative anti-tumor drug which have tumor targets. Pharmacodynamic tests prove that the compound (II) is targeted to tumors, the water solubility of a tumor drug is improved, so that an anti-tumor effect is increased, and neurotoxicity is reduced.

Description

Technical field [0001] The invention relates to the field of tumor targeted therapy. Specifically for the construction of tumor-targeted 2-deoxy-D-deoxyglucose (2DG) and harmine derivatives (harmine derivatives) anti-tumor drug linker. A variety of tumor-targeted 2DG-harmaine derivatives anti-tumor composite drugs are prepared. Background technique [0002] The death rate caused by malignant tumors is second only to cardiovascular diseases, and it is the second killer of human beings. It is seriously endangering human health and survival. The incidence rate has always been high, and it has shown a clear trend of younger people. There are about 2.2 million new cancer patients in my country every year. Therefore, improving the cure rate of cancer is an important means to improve the health and quality of life of all human beings. [0003] Chemotherapy is the most important, most commonly used and effective treatment method in the treatment of malignant tumors. There are a wide ran...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07H5/06C07H1/00A61K31/437A61K31/706A61P35/00
Inventor 顾月清王阿琴陈玉祺
Owner CHINA PHARM UNIV
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