Tetrahydroisoquinoline compounds and preparation method and application thereof

A technology of tetrahydroisoquinoline and compounds, applied in organic chemistry, drug combination, pharmaceutical formulation, etc., can solve the problems of prolonging the microtubule time and changing the "mechanical instability of microtubule"

Inactive Publication Date: 2010-06-16
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Different from the mechanism of action of paclitaxel and vinblastine drugs, although narcotin acts on tubulin, it does not promote or inhibit the polymerization of microtubules, nor does it change the ratio of tubulin polymers to monomers. It binds to tubulin at a stoichiometric ratio (norcidine molecule: tubulin dimer = 0.95±0.02), changes the "mechanical instability" of microtubules, and causes microtubules to be in a state of attenuation (in this state, microtubules length constant) time extension

Method used

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  • Tetrahydroisoquinoline compounds and preparation method and application thereof
  • Tetrahydroisoquinoline compounds and preparation method and application thereof
  • Tetrahydroisoquinoline compounds and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1: 6,7-dimethoxy-3-(5,6,7,8-tetrahydro-1',3'-dioxole[4',5'-g]-5 Preparation of -isoquinolyl)-1(3H)-isobenzofuranone hydrochloride (1)

[0060] (1) Preparation of N-(4,5-methylenedioxy)phenethyl-4,5-dimethoxy-3-oxo-isobenzofuran-1-amide (104)

[0061] Under argon protection and stirring, a mixture of piperonylethylamine 1.65g (10.0mmol) and dichloromethane 20.0mL was slowly dropped into 4,5-dimethoxy-3-oxoisobenzofuran-1-carboxylate Acid 2.38g (10.0mmol), DCC 2.17g (10.5mmol), DMAP0.12g (1.0mmol) and dichloromethane 40.0mL of the mixed solution. After dropping, react at room temperature for 12.0h. The insoluble matter was filtered off, 50 mL of water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (30 mL×2). The organic layers were combined, washed successively with 1.0 mol / L hydrochloric acid (50 mL×1), 1.0 mol / L sodium bicarbonate solution (50 mL×1) and saturated brine (50 mL×1), a...

Embodiment 2

[0066] Example 2: 5,6-dimethoxy-3-(5,6,7,8-tetrahydro-1',3'-dioxole[4',5'-g]-5 Preparation of -isoquinolyl)-1(3H)-isobenzofuranone hydrochloride (2)

[0067] The preparation method is the same as that of compound 1, and the yield is 57.6%.

[0068] MS(m / z): 370.1[M+H] + . 1 H NMR (D 2 O) δ2.98~3.02(m, 2H), 3.43~3.47(m, 2H), 3.88(s, 3H), 3.94(s, 3H), 5.35(d, 1H, J=2.4), 5.96(d , 2H, J = 10.9), 6.21 (d, 1H, J = 2.4), 6.29 (s, 1H), 6.68 (s, 1H), 6.85 (s, 1H), 7.37 (s, 1H).

Embodiment 3

[0069] Example 3: 6,7-dimethoxy-3-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinyl)-1(3H)-iso Preparation of Benzofuranone Hydrochloride (3)

[0070] The preparation method is the same as that of compound 1, and the yield is 49.8%.

[0071] MS(m / z): 386.2[M+H] + . 1 H NMR (D 2 O) δ3.00(d, 2H, J=6.0), 3.28(s, 3H), 3.45~3.47(m, 1H), 3.65~3.68(m, 1H), 3.73(s, 3H), 3.74(s , 3H), 3.89(s, 3H), 5.15(s, 1H), 5.72(s, 1H), 6.17(s, 1H), 6.84(s, 1H), 7.28(d, 1H, J=8.4), 7.54 (d, 1H, J = 8.4).

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Abstract

The invention belongs to the technical field of medicament synthesis and in particular relates to synthesis of tetrahydroisoquinoline compounds and initial application of the tetrahydroisoquinoline compounds in inhibiting tumor cell proliferation. Through the modification of a structure of natural (-)-alpha-(1R,9S)-narcotine, a series of novel tetrahydroisoquinoline compounds (I) are synthesized. Through the screening of anti-tumor activity in vitro, the novel tetrahydroisoquinoline compounds have remarkable effect of inhibiting the tumor cell proliferation activity and can be further developed into a novel anti-tumor medicament.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to tetrahydroisoquinoline compounds and a preparation method thereof, and the first application of such compounds in inhibiting tumor cell proliferation. The research on the anti-tumor cell proliferation activity of these compounds is the first of the present invention, and this research is of great significance to the development of new anti-tumor drugs. Background technique [0002] (-)-α-(3S, 5R)-Narcotine is an opioid alkaloid, English name (-)-α-(3S, 5R)-Noscapine or Narcotine, molecular formula C 22 h 23 NO 7 , chemical name (-)-(3S,5R)-6,7-dimethoxy-3-(5,6,7,8-tetrahydro-4-methoxy-6-methyl-1', 3'-dioxole[4',5'-g]-5-isoquinolinyl)-1(3H)-isobenzofuranone is a classic antitussive drug with low toxicity and side effects, and is resistant to Good acceptance, wide safety range and so on. At the same time, Narcidine can be used to treat stroke and edema. [0003] In 1998, Joshi's...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/153C07D491/056C07D405/06C07D217/20A61K31/4741A61K31/472A61K31/4725A61P35/00
CPCC07D217/04C07D491/04C07D405/06C07D217/22A61P35/00
Inventor 许佑君魏秀岩从俊杰张青扬倪积智林禄清肖和平韩福庆王哲
Owner SHENYANG PHARMA UNIVERSITY
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