Beta-carboline derivative containing hydroximic acid as well as preparation method and medical application thereof

A kind of derivative, carboline technology, used in the preparation of malignant tumor, β-carboline derivatives and their pharmaceutically acceptable salts, Alzheimer's and Parkinson's disease medicines

Active Publication Date: 2015-06-03
JIANGSU FANGSHIYUANLVE SCI & TECH CONSULTING CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In-depth research on the drug action mechanism and biological characteristics of this type of compound, the present invention discloses a class of hydroxamic acid β-carboline derivatives with medicinal value and pharmaceutically acceptable salts thereof. any reports of

Method used

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  • Beta-carboline derivative containing hydroximic acid as well as preparation method and medical application thereof
  • Beta-carboline derivative containing hydroximic acid as well as preparation method and medical application thereof
  • Beta-carboline derivative containing hydroximic acid as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Embodiment 1N-(2-(hydroxylamino)-2-oxaethyl)-1-methyl-9-Boc-β-carboline-3-formamide (Ⅰ 1 ) preparation

[0072] 1-Methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (2a)

[0073] Dissolve L-tryptophan (10.2g, 50mmol) in 20ml of 2.5mol / L H 2 SO 4 To the solution, 13.8ml of 40% acetaldehyde solution (115mmol) was added, and stirred at 60°C for 2h. After the reaction was completed, the reaction solution was adjusted to PH=5 with 2M HCl, and a large amount of white solid was precipitated, which was filtered by suction, washed with water, and dried in vacuo to obtain 9.8 g of white solid with a yield of 85.2%.

[0074] Methyl 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (3a)

[0075] Dissolve 2a (11.5g, 50mmol) in 100ml of methanol, and slowly add 10.9ml of SOCl dropwise under low temperature and vigorous stirring at -5°C 2 (17.85g, 150mmol), heat and reflux for 2h after half an hour, pressurize and concentrate to remove the solvent after the reaction is c...

Embodiment 2

[0086] Embodiment 2N-(2-(hydroxylamino)-2-oxaethyl)-1-methyl-β-carboline-3-formamide (I 2 ) preparation

[0087] Will I 1 (0.1g, 0.25mmol) dissolved in CF 3 COOH / CH 2 Cl 2 (v / v=1:1, 10mL in total), stirred overnight at room temperature, after the reaction was complete, evaporated the solvent to obtain I 2 , yield 94.9%. ESI-MS(m / z):299[M+H] + .

Embodiment 3

[0088] Embodiment 3N-(4-(hydroxylamino)-4-oxabutyl)-1-methyl-9-Boc-β-carboline-3-carboxamide (I 3 ) preparation

[0089] Preparation of N-(4-(methoxy)-4-oxabutyl)-1-methyl-9-Boc-β-carboline-3-carboxamide (7b)

[0090] Referring to the preparation method of 7a, a yellow oil was obtained from 6a and γ-butyric acid methyl ester with a yield of 73.8%.

[0091] N-(4-(hydroxylamino)-4-oxabutyl)-1-methyl-9-Boc-β-carboline-3-carboxamide (I 3 ) preparation

[0092] Refer to I 1 The preparation method of , a yellow solid was obtained from 7b and hydroxylamine, and the yield was 66.1%. 1 H NMR (CDCl 3 ,300MHz):δ8.76(s,1H,H-4),δ8.69(m,1H,N H CH 2 ),8.27(m,1H,H-5),8.08(m,1H,H-8),7.60(m,H,H-6),7.28(m,1H,H-7),3.79(m, 2H, NCH 2 ),2.92(s,3H,CH 3 ),2.67(m,2H,CH 2 C=O),2.01(s,1H,OH),1.91(m,2H,CH 2 C H 2 CH 2 ),1.26(s,9H,-C(CH 3 ) 3 ).ESI-MS(m / z):427[M+H] + .

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Abstract

The invention discloses a beta-carboline derivative containing hydroximic acid as well as a preparation method and a medical application thereof. The product has the structure as shown in the general formula I. The compound can be combined with other antitumor drugs such as alkylating agents, antimetabolites, topoisomerase inhibitors, mitotic inhibitors and DNA intercalating agents and additionally can be combined with radiotherapy. The invention also discloses a pharmaceutical composition containing the compound with the general formula I as well as medical application thereof, particularly application of preparation of antitumor medicines, Alzheimer disease medicines and Parkinson disease medicines. The other antitumor medicines or radiotherapy can be administrated with the compound at the same time or in different times. The combination therapy can generate the synergistic effect, so that the treatment effect is improved.

Description

technical field [0001] The present invention relates to the field of medicine, in particular to a class of β-carboline derivatives containing hydroxamic acid and pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions containing these derivatives and their medical use , especially in the preparation of drugs for malignant tumors, Alzheimer's and Parkinson's diseases. Background technique [0002] β-carboline derivatives are a class of natural indole alkaloids widely distributed in nature. This class of compounds has a wide range of biological activities, but their toxicity is very low, which has attracted the interest of medicinal chemists for their development research. Recent studies have shown that β-carbolines act on multiple biological targets, thus exhibiting a broad spectrum Pharmacological activity, especially in the application of antitumor activity. In recent years, studies have found that using β-carboline alkaloids to d...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/454A61P35/00A61P25/28A61P25/16
Inventor 凌勇杨宇民郭益冰王志强吴彩霞王雪敏颜森森陈悦
Owner JIANGSU FANGSHIYUANLVE SCI & TECH CONSULTING CO LTD
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