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Grain lactone derivative as well as preparation method, pharmaceutical composition and application thereof

A derivative, the technology of glutaractone, which is applied in the field of chemical medicine, can solve the problems of no anti-tumor activity of glutaractone derivatives and insufficient killing ability of cancer cells, and achieve excellent anti-leukemia cell activity, strong tumor cell proliferation, and obvious anti-tumor activity. The effect of tumor activity

Pending Publication Date: 2022-08-05
HEBEI KANGTAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although it is used to synthesize a large number of natural products with a variety of biological activities, there are still no reports on the antitumor activity of glutaractone derivatives. For example, glutaractone can kill most cancer cells in the in vitro tumor cell proliferation test. Insufficient capacity, IC 50 Values ​​are greater than 100μM

Method used

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  • Grain lactone derivative as well as preparation method, pharmaceutical composition and application thereof
  • Grain lactone derivative as well as preparation method, pharmaceutical composition and application thereof
  • Grain lactone derivative as well as preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1: Preparation of Compound 4

[0020] The structure of compound 4 is as follows:

[0021]

[0022] (1) Preparation of compound 1

[0023] The structure of compound 1 is as follows:

[0024] The preparation process is as follows:

[0025] Trifluoroacetic acid (66.6 mL, 900 mmol) was dissolved in dichloromethane (300 mL), and sodium borohydride (4.54 g, 120 mmol) was slowly added to the reaction system at -10 °C. g, 30.0 mmol) in dichloromethane (10 mL) was slowly added dropwise to the above reaction system, reacted at 0°C for 20 minutes, then slowly added sodium carbonate to neutralize the reaction system, washed with dichloromethane and washed with saturated sodium chloride solution , the organic phase was collected, concentrated and dried, and purified by column chromatography (dichloromethane:methanol=40:1) to obtain compound 1 (white solid, 5.61 g, 83%).

[0026] (2) Preparation of compound 2

[0027] The structure of compound 2 is as follows:

[0...

Embodiment 2

[0034] Example 2: Preparation of Compound 5

[0035] The structure of compound 5 is as follows:

[0036] The preparation process is as follows:

[0037] To a solution of compound 4 (236 mg, 1.00 mmol) in dichloromethane (5 mL) at 0 °C, imidazole (340 mg, 5.00 mmol) and trimethylchlorosilane (327 mg, 3.00 mmol) were added, and the organic phase was collected after filtration for 1 h. Concentrated and dried, and purified by column chromatography (petroleum ether:ethyl acetate=60:1) to obtain compound 5 (white solid, 256 mg, 83%).

[0038] Compound 5 is detected, and its detection results are as follows: 1H NMR(400MHz, Chloroform-d)δ6.42(s,1H),5.54(d,J=2.7Hz,1H),4.62(d,J=3.6Hz,1H),3.59(t,J=7.5Hz , 1H), 2.71–2.47 (m, 2H), 2.28 (d, J=6.5Hz, 1H), 2.05–1.70 (m, 4H), 1.55–1.22 (m, 5H), 0.75 (d, J=5.3 Hz,3H),0.05(s,9H). 13 C NMR (100MHz, CDCl 3 ) δ166.2, 132.2, 128.8, 81.1, 79.9, 43.1, 39.5, 34.2, 31.3, 31.1, 30.1, 27.6, 22.3, 10.5, 0.3.

Embodiment 3

[0039] Example 3: Preparation of Compound 6

[0040] The structure of compound 6 is as follows:

[0041] The preparation process is as follows:

[0042] Using tert-butyldimethylsilyl chloride (453 mg, 3.00 mmol), following the synthetic procedure for compound 5 described in Example 2, the title compound 6 (white solid, 302 mg, 61%) was obtained.

[0043] Compound 6 is detected, and its detection results are as follows: 1 H NMR (400MHz, Chloroform-d) δ6.41(s,1H), 5.53(s,1H), 4.61(s,1H), 3.60(t, J=8.8Hz,1H), 2.79–2.46(m, 2H), 1.98(d, J=15.2Hz, 2H), 1.89-1.73(m, 1H), 1.55(m, 2H), 1.46-1.38(m, 1H), 1.33(m, 2H), 1.26(m ,2H),0.86(s,9H),0.75(s,3H),-0.02(s,6H). 13 C NMR (100MHz, CDCl 3 )δ166.1,132.1,128.6,81.0,79.8,43.3,39.3,34.1,30.1,29.7,27.5,25.8,22.3,18.1,10.5,-4.5,-4.9.

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Abstract

The invention discloses a valerolactone derivative and a preparation method, a pharmaceutical composition and application thereof, the structure of the valerolactone derivative is as shown in formula I, and R1 is alkyl or silyl. The novel valerolactone derivative is obtained by means of semi-synthesis modification, the preparation process is simple and easy to implement, pharmacological experiments find that the valerolactone derivative provided by the invention has strong activity of inhibiting proliferation of various tumor cells, and particularly, the valerolactone derivative has a good application prospect. The valerolactone derivative shows excellent and powerful anti-leukemia cell activity, has obvious in-vitro and in-vivo anti-tumor activity, and is suitable for development of anti-tumor drugs.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and in particular relates to a glutaractone derivative and a preparation method, pharmaceutical composition and application thereof. Background technique [0002] In recent years, the morbidity and mortality of malignant tumors in the world have been increasing year by year, and malignant tumors have become the main cause of human death. Acute myeloid leukemia (AML) is one of the most common hematological malignancies in adults, with a median survival of 4 months and a one-year overall survival rate of less than 10%. Most AML patients eventually die of drug resistance and relapse, and the incidence tends to increase with age. Despite advanced biological therapies, the primary treatment regimen for AML has remained virtually unchanged and faces the challenge of relapse and drug resistance. At present, the lack of better low-toxicity and high-efficiency effective drugs and feasible alternatives i...

Claims

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Application Information

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IPC IPC(8): C07F7/18C07F7/04C07D311/94A61P35/02A61P35/00A23L33/10
CPCC07F7/1804C07F7/188C07F7/04C07D311/94A61P35/00A61P35/02A23L33/10A23V2002/00A23V2200/308Y02P20/55
Inventor 李金岭李金波杨光
Owner HEBEI KANGTAI PHARMA
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