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Tetralin isoquinoline compounds as well as preparation methods and applications thereof

A compound, tetrahydrofuran technology, applied in the field of drug synthesis, can solve the problems of prolonging the time of microtubules and changing the "mechanical instability of microtubules"

Inactive Publication Date: 2011-07-27
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] 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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  • Tetralin isoquinoline compounds as well as preparation methods and applications thereof
  • Tetralin isoquinoline compounds as well as preparation methods and applications thereof
  • Tetralin isoquinoline compounds as well as preparation methods and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] 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)

[0077] (1) Preparation of N-(4,5-methylenedioxy)phenethyl-4,5-dimethoxy-3-oxo-isobenzofuran-1-amide (104)

[0078] 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), DMAP 0.12g (1.0mmol) and dichloromethane 40.0mL mixed liquid. 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), and dried...

Embodiment 2

[0083] 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)

[0084] The preparation method is the same as that of compound 1, and the yield is 57.6%.

[0085] 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

[0086] Example 3: 6,7-dimethoxy-3-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinyl)-1(3H)-iso Preparation of Benzofuranone Hydrochloride (3)

[0087] The preparation method is the same as that of compound 1, and the yield is 49.8%.

[0088] 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 relates to tetralin isoquinoline compounds and synthesis thereof as well as applications of the tetralin isoquinoline compounds in the aspect of inhibiting tumor cell proliferation. In the invention, the structure of natural (-)-alpha-(1R, 9S)-narcotine is modified, so as to synthesize a series of novel tetralin isoquinoline compounds (I). In vitro antitumor activity screening indicates that the tetralin isoquinoline compounds have activities of inhibiting the tumor cell proliferation, thus the compounds can be further developed into novel antitumor medicaments.

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. 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] [0004] In 1998, Joshi's research group (Joshi et al., Proc Natl Acad Sci USA, 1998, 95, 1601) found that narcotin has good antitumor activity. Noscapine can arrest cell mitosis in M ​​phase and induce tumor cell apopt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/056C07D405/04C07D217/20C07D405/06C07D217/14C07D217/04C07D498/04C07D498/14A61K31/4745A61K31/4741A61K31/4725A61K31/472A61P35/00
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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