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HIV protease inhibitor derivative, preparation thereof and use in antineoplastic medicament preparation

A protease inhibitor and anti-tumor drug technology, which is applied in chemical synthesis and pharmaceutical fields, can solve the problem of low anti-tumor activity of HIV protease inhibitors, achieve the effect of inhibiting tumor cell activity, and have broad application prospects

Active Publication Date: 2011-11-09
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the antitumor activity of HIV protease inhibitors is low

Method used

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  • HIV protease inhibitor derivative, preparation thereof and use in antineoplastic medicament preparation
  • HIV protease inhibitor derivative, preparation thereof and use in antineoplastic medicament preparation
  • HIV protease inhibitor derivative, preparation thereof and use in antineoplastic medicament preparation

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1: the synthesis of compound CH05-05

[0043] Synthesis of compound CH05-01 (C 9 h 10 o 2 )

[0044] In a 500ml three-necked round bottom flask, add 180ml88% formic acid solution, under stirring, the H 2 o 2 (30%) 42ml was added dropwise, after dropping, stirred at 35°C for 15min. Then, 34.8g of indene (CH05-SM1) was added slowly, the rate of addition was controlled, and the temperature was kept at 35-40°C. After dropping, the mixture was stirred at 40° C. for 1 h and reacted overnight. Concentrate under reduced pressure, remove formic acid and water, add 50ml NaOH aqueous solution (10mol / L), stir for 10min, extract 6 times with ethyl acetate while hot, combine organic phases, and dry over anhydrous sodium sulfate. The solvent was removed and recrystallized to obtain 22.6 g of a white powdery solid with a yield of 50%. CH05-01:

[0045] ESI-MS: 151 (M+H) + ;

[0046] 1 H NMR (400MHz, CDCl 3 )d: 2.26 (brs, 2H), 2.93-2.99 (m, 1H), 3.10-3.16 (m, 1H)...

Embodiment 2

[0063] Embodiment 2: the synthesis of compound CH05-08

[0064] Synthesis of compound CH05-07 (C 27 h 38 N 4 o 4 )

[0065] Add 2.4g indinavir (CH05-06), 30ml ethanol, 2g KOH into a 100ml round bottom flask, heat to reflux for 3h, TLC (dichloromethane:methanol=10:1, v / v) shows that the raw material disappears. Concentrate, add water and ethyl acetate, separate layers, extract the aqueous layer with ethyl acetate 3 times, the combined solution is concentrated after drying over anhydrous sodium sulfate, and then go through silica gel column chromatography (dichloromethane:methanol=10:1, v / v) Separate and purify to obtain 1.2 g of white solid (compound CH05-07), with a yield of 75%. CH05-07:

[0066] ESI-MS: 505(M+H) + ;

[0067] 1 H NMR (400MHz, MeOD)d: 1.09(s, 9H), 1.63(m, 1H,), 2.01-2.30(m, 5H), 2.31-2.51(m, 3H), 2.52-2.62(m, 2H) , 2.63-2.74(m, 1H), 2.75-2.88(m, 3H), 2.89-2.94(m, 2H), 3.29(s, 2H), 3.65(d, 1H, J=8.0Hz), 6.83-6.92 (m, 1H), 6.95-7.10(m, 4H), 7.15-7.23...

Embodiment 3

[0072] Embodiment 3: the synthesis of compound CH05-10

[0073] Synthesis of compound CH05-09 (C 45 h 65 N 5 o 5 Si)

[0074] In a 25ml round bottom flask, add 200mg compound CH05-08, 77mg compound CH05-05, 84mg EDCI, 59mg HOBT, 101mg Et 3 N, 2 mL of anhydrous DMF, stirred at room temperature for 3 hours, TLC (petroleum ether:THF=1.5:1, v / v) tracking showed that the starting material disappeared. The solvent was removed by rotary evaporation, 40 mL of dichloromethane was added, 20 mL of saturated NaHCO 3 Washing, washing with saturated brine, drying over anhydrous sodium sulfate, and rotary evaporation to remove the solvent, the resulting solid was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1, v / v) to obtain a foamy off-white solid (compound CH05- 09) 160 mg, yield 61%.

[0075] CH05-09:

[0076] ESI-MS: 784(M+H) +

[0077] 1 H NMR (400MHz, CDCl 3 )d: 0.07(s, 3H), 0.09(s, 3H), 0.88(s, 9H), 1.01(s, 3H), 1.26(s, 3H), 1.32(s, 9H), 2...

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Abstract

The invention discloses HIV protease inhibitor derivatives, a preparation method thereof and application thereof in preparing anticancer drugs. The HIV protease inhibitor derivatives have a structure as shown by a genera formula X, the preparation for the HIV protease inhibitor derivatives adopts cheap and easily obtained indene as an initial raw material, the indene is dihydroxylated and protected, and then a carbonyl group is introduced through benzylic oxidation and then is converted into an amino group to obtain a needed reaction intermediate CH05-05. Another molecular building block is prepared from indinavir sulfate (CH05-05), the indinavir sulfate is subjected to hydrolysis reaction firstly, hydroxide radical is protected and then performs the condensation of acid amide with the CH05-05, and the obtained product is deprotected to obtain a target product. The HIV protease inhibitor derivatives can inhibit the activity of tumor cells and inhibit the growth of various tumor cell strains at the micromolar level, can be used for developing broad-spectrum anti-tumor drugs, and have broad application prospect.

Description

technical field [0001] The invention relates to the fields of chemical synthesis and medicine, in particular to a class of HIV protease inhibitor derivatives, a preparation method thereof and an application in the preparation of antitumor drugs. Background technique [0002] Malignant tumor is a disease that seriously endangers human life. Its mortality rate is second only to cardiovascular and cerebrovascular diseases, and its incidence is increasing year by year. Therefore, cancer prevention and treatment has received widespread attention from all walks of life. Tumor chemotherapy (hereinafter referred to as chemotherapy) is one of the three basic methods of tumor treatment. After more than 50 years of development, the drugs used for tumor treatment have made great achievements, and a large number of clinical anti-tumor drugs with different mechanisms of action have been obtained. Unfortunately, these anticancer drugs have different degrees of toxic and side effects, so m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/14A61K31/496A61P35/00A61P35/02
Inventor 陈小平邱发洋游剑岚邓刚何正祥刘薇
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI