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Alpha, beta-unsaturated ketone compound and its prepn process and GST-Pi inhibiting activity

A ketone compound and unsaturated technology, which is applied in the field of organic compound synthesis and pharmaceutical application, can solve the problems of low activity of ethacrynic acid, restricting clinical application, large toxic and side effects, etc. simple effect

Inactive Publication Date: 2005-12-14
QINGDAO HUANGHAI PHARM CO LTD
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AI Technical Summary

Problems solved by technology

[0007] Wherein, α, β-unsaturated ketone compound ethacrynic acid is an effective GSTπ inhibitor, and shows better GSTπ inhibitory activity in vivo and in vitro, see: "Biochemical Pharmacology" 1990, 40 (7): 1631, Ploemen JH, van Ommen B, van Bladeren PJ.Inhibition of ratand human glutathione S-transferase isoenzymes by ethacrynic acid and its glutathione conjugate. Biochem Pharmacol, 1990, 40 (7): 1631.), its Combining with tesepai to treat advanced tumors has entered Phase I clinical trials, but its severe diuresis, ototoxicity, hyperglycemia, hypocalcemia and hypomagnesemia and other toxic and side effects have seriously affected and restricted its clinical application
[0008] After searching, at present, etaconic acid is used as the lead compound at home and abroad, and its structure is modified and modified, and a series of α, β-unsaturated ketone derivatives are designed and synthesized to improve the low activity and toxicity of ethacrynic acid. The research and application of disadvantages such as large side effects have not been reported yet

Method used

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  • Alpha, beta-unsaturated ketone compound and its prepn process and GST-Pi inhibiting activity
  • Alpha, beta-unsaturated ketone compound and its prepn process and GST-Pi inhibiting activity
  • Alpha, beta-unsaturated ketone compound and its prepn process and GST-Pi inhibiting activity

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] The preparation of embodiment 1.2-(2-methylphenoxy group) propionic acid (III)

[0036] Dissolve sodium hydroxide (15g, 375mmol) in 20ml of water, add it to a 250ml round bottom flask, stir at room temperature, add o-cresol (10.8, 100mmol), and add 2-chloropropionic acid (18.4g , 170mmol), reacted at 85-90°C for 2 hours, cooled, added 200ml of water, filtered, and the filtrate was acidified to pH 2.0 with concentrated hydrochloric acid to produce a brown oil, which was extracted with ether (100ml×2), and the ether solution was washed with 5% NaHCO 3 Extract (75ml×2), NaHCO 3 The extract was acidified with concentrated hydrochloric acid to pH 2.0 to produce a solid, which was filtered and dried to obtain 2-(2-methylphenoxy)propionic acid, yellow powder, yield 32.2%, mp: 86-89°C, TLC Rf=0.49 (n-hexane / ethyl acetate 2:1). 1 H-NMR (DMSO-d 6 )δ: 12.9(s, 1H), 7.13(d, J=7.3Hz, 1H), 7.10(t, J=7.7Hz, 1H), 6.83(t, J=7.3Hz, 1H), 6.75(d, J=8.2Hz, 1H), 4.78(q, J=6.7Hz, 1H), 2.18...

Embodiment 2

[0046] Example 2. Preparation of 2-[2-methyl-4-(1-oxygen-propyl)phenoxy]propionic acid (II)

[0047] 2-(2-Methylphenoxy)propanoic acid (4.3 g, 24 mmol) was added to CS 2 (70ml), stirred at room temperature, added anhydrous aluminum trichloride powder (10g, 75mmol) in batches, and then slowly added propionyl chloride (2.6ml, 30mmol) dropwise to produce a yellow viscous substance, reacted at 55-60°C for 4 hours , cooling, the CS 2 Pour out, add 100g of ice water containing 3ml of concentrated hydrochloric acid, stir, produce oil, extract with ether (100ml×2), ether solution with 5% NaHCO 3 Extract (50ml×2), NaHCO 3 The extract was acidified to pH 2.0 with concentrated hydrochloric acid to produce a precipitate, which was filtered and dried to obtain 2-[2-methyl-4-(1-oxo-propyl)phenoxy]propionic acid as a yellow powder with a yield of 72.7% , mp: 129~131°C, TLC Rf=0.33 (n-hexane / ethyl acetate 2:1). 1 H-NMR (DMSO-d 6 )δ: 13.05(s, 1H), 7.84(m, 2H), 6.92(m, 1H), 5.01(q, J=6.7Hz...

Embodiment 3

[0063] Example 3. Preparation of 2-[2-methyl-4-(2-methylene-1-oxygen-propyl)phenoxy]propionic acid (I)

[0064] Dissolve 2-[2-methyl-4-(1-oxo-propyl)phenoxy]propionic acid (4.0g, 17mmol) in ethanol (34ml), add 30% formaldehyde (1.7ml, 17mmol), shake Evenly, K 2 CO 3 (2.3g, 17mmol) was dissolved in a mixed solution of water (17ml) and ethanol (10ml), and these two solutions were slowly added to refluxing ethanol (24ml) at the same time, reacted at 85-90°C for 3 hours, cooled, The product was poured into hydrochloric acid solution (5ml concentrated hydrochloric acid, 340ml water) to produce light yellow oil, which was extracted with diethyl ether (150ml×2), evaporated under reduced pressure to remove diethyl ether, separated by column chromatography, eluent petroleum ether: chloroform: methanol =10:10:1, 2-[2-methyl-4-(2-methylene-1-oxygen-propyl)phenoxy]propionic acid was obtained, brown oil, yield 28.6%, TLC Rf= 0.54 (petroleum ether / acetone 2:1). 1 H-NMR (DMSO-d 6 )δ: 13...

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Abstract

The present invention relates to alpha, beta-unsaturated ketone compound shown in general expression (I) and its preparation process. The preparation process includes the reaction between substituted phenol as material and 2-chlorocarboxylic acid to obtain 2-(2, 3-substituent phenoxy) carboxylic acid; the subsequent Friedel-Crafts reaction with acyl chloride to obtain 2-[2, 3-substituent-4-(1-oxy-substituent)phenoxy] carboxylic acid; and further reaction with formaldehyde to obtain 2-[2, 3-substituent-4-(2-methylene-1-oxy-substituent)phenoxy] carboxylic acid. The present invention also relates to the application of the compound as tumor drug resistance reversing agent.

Description

technical field [0001] The invention relates to the field of organic compound synthesis and medical application, in particular to α, β-unsaturated ketone compounds and their preparation method and their activity of inhibiting GSTπ. Background technique [0002] Tumor is one of the major diseases that threaten human health. Chemotherapy is the main treatment method, and the generation of multidrug resistance (MDR) of tumor cells is the main reason for the failure of chemotherapy. The drug resistance of human malignant tumors to chemotherapy can be divided into natural drug resistance (natural resistance) and acquired drug resistance (acquired resistance); according to the drug resistance spectrum, it can be divided into primary drug resistance (PDR) and multidrug resistance Drug resistance (multidrug resistance, MDR). PDR only produces resistance to the induced original drug, but does not produce cross-resistance to other drugs. Multidrug resistance is induced by one drug, b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/90
Inventor 赵桂森于韬张林娜王小兵袁玉梅景永奎
Owner QINGDAO HUANGHAI PHARM CO LTD
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