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1-(3',4',5'- trisubstituted phenyl)- tetrahydroisoquinoline compound and its use

A technology of tetrahydroisoquinoline and compounds, applied in the field of medicinal chemistry and pharmacology, can solve problems such as limiting the universal applicability of drugs, low selectivity, and malignant killing of normal cells

Inactive Publication Date: 2009-05-27
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the specific drugs for the treatment of tumor diseases are not satisfactory, and the malignant killing of normal cells caused by the low selectivity of cytotoxic drugs currently used in anti-tumor clinics limits the general applicability of such drugs

Method used

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  • 1-(3',4',5'- trisubstituted phenyl)- tetrahydroisoquinoline compound and its use
  • 1-(3',4',5'- trisubstituted phenyl)- tetrahydroisoquinoline compound and its use
  • 1-(3',4',5'- trisubstituted phenyl)- tetrahydroisoquinoline compound and its use

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0128] Preparation example 1: Preparation of compound IV-1 [N-(3-benzyloxy)phenethyl-(3',5'-dimethoxy-4'-benzyloxy)benzamide]:

[0129]

[0130] Dissolve 4.4g (16.0mmol) of 3,5-methoxy-4-benzyloxy-benzoic acid in 200ml of dry dichloromethane, add 20ml (230mmol) of oxalyl chloride dropwise under ice-cooling conditions, and complete the reaction at room temperature After 2 hours, excess oxalyl chloride was distilled off under reduced pressure. The residue was redissolved in 50ml of dry dichloromethane, and added dropwise to a solution of 4.5g (19.8mmol) of 3-benzyloxyphenethylamine and 0.5ml of triethylamine in 200ml of dichloromethane under ice-cooling conditions After stirring at room temperature overnight, add 50ml of 10% sodium hydroxide solution, stir for 30 minutes, separate the organic phase, and wash with saturated sodium carbonate (50ml×2), water (50ml×2) and saturated saline (50ml×2) respectively. )washing. After drying over anhydrous magnesium sulfate and evapor...

preparation example 2—13

[0134] Preparation example 2-13: Preparation 2-13 compounds shown in the following table 1 are prepared according to the method with the above preparation example 1:

[0135]

[0136] Table I

[0137]

[0138] Listed below is the physicochemical data of each compound in Table 1:

[0139] IV-2: jelly, Rf (ethyl acetate / petroleum ether 2:1): 0.12; 1 H NMR (400Mz, CD 3 OD): δ 2.82 (t, 2H, J=7.7, 7.0Hz, CH 2 -Ar), 3.55(t, 2H, J=7.3, 7.4Hz, CH 2 -NH), 3.87(s, 6H, OCH 3 ×2), 6.62-6.72(m, 3H, H-2, H-6), 7.08(d, 1H, J=7.7Hz, H-5), 7.12(s, 2H, H-2′, H- 6').

[0140] IV-3: white solid, Rf (ethyl acetate / petroleum ether 1:1): 0.73; 1 H NMR (400MHz, CDCl 3 ): δ 2.89 (t, 2H, J=6.9, 6.5Hz, CH 2 -Ar), 3.66(q, 2H, J=6.4, 6.9, 6.2Hz, CH 2 -NH), 3.82(s, 6H, OCH 3 ×2), 5.04(s, 2H, OCH 2 Ph), 5.05(s, 2H, OCH 2 Ph), 6.20 (brs, 1H, NH), 6.89 (s, 2H, H-2′, H-6′), 6.94 (dd, 2H, J=6.5, 2.0Hz, H-3, H-5) , 7.17 (dd, 2H, J=6.6, 2.0Hz, H-3, H-5), 7.27-7.47 (m, 10H, OCH 2 Ph-H×2).

...

preparation example 14

[0151] Preparation Example 14: Preparation of compound III-A1 [6-benzyloxy-1-(3',5'-dimethoxy-4'-benzyloxyphenyl)-3,4-dihydroisoquinoline]:

[0152]

[0153] Suspend 638 mg (1.28 mmol) of compound (IV-1) (see Preparation 1) in 50 ml of toluene, add 0.25 ml (2.6 mmol) of phosphorus oxychloride, reflux for 4 hours, cool to room temperature, and evaporate the toluene under reduced pressure , dissolve the residue in 30ml ethyl acetate, adjust the pH to 8-9 with concentrated ammonia water under ice-bath cooling, separate the water layer, extract with ethyl acetate (10ml×2), combine the organic phases, and successively water (10ml×2) 2), washed with saturated brine (10ml×2), dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was separated and purified by column chromatography (eluent: ethyl acetate / petroleum ether 1:2) to obtain 370 mg of solid with a yield of 60.3%.

[0154] III-A1 compound:

[0155] Rf (ethyl acetate / petroleum ether 1...

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Abstract

The invention relates to a 1-(3', 4', 5'-trisubstituted phenyl)-isoquinolin compound with tumor cytotoxicity shown in a formula (1) and intermediate compounds thereof or pharmaceutical salts or solvates thereof, The invention also relates to a method for preparing the compounds in the formula (1), pharmaceutical compositions and medicinal application thereof. The compounds have certain activity of inhibiting growth of tumor cells, and can be expected to be used as anti-tumor drugs. A structural formula (1) of the invention is shown in a figure.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of July 11, 2005 and an application number of 200510082721.2. technical field [0002] The invention belongs to the technical field of medicinal chemistry and pharmacology. Specifically, the present invention relates to four series of isoquinoline compounds and their preparation methods and for these series of compounds on six tumor cell lines such as human prostate cancer cells (PC-3), nasopharyngeal carcinoma cells (CNE), oral cavity Tumor cell growth inhibitory activity screening of epithelial cancer cells (KB), human lung cancer cells (A549), human liver cancer cells (BEL-7404), and human cervical cancer cells (Hela). The compounds are found to have a certain activity of inhibiting the growth of tumor cells, and can be expected to be used as antitumor drugs. Background technique [0003] At present, due to environmental pollution and other problems brought about ...

Claims

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Application Information

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IPC IPC(8): C07D491/056C07D217/14A61K31/47A61K31/4738A61P35/00
Inventor 赵昱丁红霞吕伟
Owner ZHEJIANG UNIV
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