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4'-substituted benzyloxy-phenyl butadiene derivatives and preparation and uses thereof

A technology of dimethoxyphenyl and benzyloxy is applied in the field of preparing antitumor drugs, and can solve the problems of unsatisfactory, low selectivity, malignant killing of normal cells and the like

Inactive Publication Date: 2010-03-31
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • 4'-substituted benzyloxy-phenyl butadiene derivatives and preparation and uses thereof
  • 4'-substituted benzyloxy-phenyl butadiene derivatives and preparation and uses thereof
  • 4'-substituted benzyloxy-phenyl butadiene derivatives and preparation and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 : Preparation of isomer 5-(4'-p-ethoxybenzyloxy-3',5'-dimethoxyphenyl)penta-2,4-dienoic acid ethyl ester (I-a~I-c)

[0035]

[0036]This example relates to a class of 5-(4'-substituted benzyloxy-3',5'-dimethoxyphenyl)penta-2,4-bis having cytotoxic activity as shown in formula (I). General synthesis of ethyl enoate derivatives. Specifically, it relates to the synthesis of ethyl 5-(4'-p-ethoxybenzyloxy-3',5'-dimethoxyphenyl)penta-2,4-dienoate. Sodium (85 mg, 3.67 mmol) and absolute ethanol (2 ml) were stirred and reacted under argon protection. When the mixed solution was uniform, it was lowered to room temperature, 10 ml of tetrahydrofuran was added, and ethyl bromocrotonate was added. Ester triphenylphosphine salt (1.84 g, 4.04 mmol) was a yellow turbid liquid, and then added 3,5-dimethoxy-4-p-ethoxybenzylbenzaldehyde (1.16 g, 3.67 mmol) under stirring ), stirred at room temperature for 2 hours, added a small amount of water to quench the reaction, adjus...

Embodiment 2

[0041] Example 2 : Compound II-a is (2E,4E)-5-(4'-p-ethoxybenzyloxy-3',5'-dimethoxyphenyl)penta-2,4-diene-1- Preparation of Alcohol

[0042]

[0043] This example relates to a class of 5-(4'-substituted benzyloxy-3',5'-dimethoxyphenyl)penta-2,4-bis having cytotoxic activity as shown in formula (II) General synthesis of en-1-ol derivatives. Specifically it relates to the synthesis of 5-(4'-p-ethoxybenzyloxy-3',5'-dimethoxyphenyl)penta-2,4-dien-1-ol. Under ice-cooling, lithium aluminum hydride (160 mg, 4.2 mmol) and aluminum trichloride (196 mg, 1.4 mmol) were added to anhydrous tetrahydrofuran, stirred for 5 minutes, and then raw material I-a (486 mg, 1.2 mmol mol) of anhydrous tetrahydrofuran solution was added dropwise to the reaction system, the temperature was controlled below 10°C, stirred for 2 hours, and a small amount of water was added dropwise to quench the reaction. The recovered tetrahydrofuran was added to dilute the reaction system and filtered, and the fi...

Embodiment 3

[0045] Example 3 : Preparation of Compounds II-b, II-c and II-d

[0046] According to the method of Example 2, using the compound of formula (I) of the corresponding configuration as a raw material, the conjugated diene compounds II-b and II-c were obtained through reduction, and the product II in which one of the double bonds was reduced was obtained. -d.

[0047] Compound II-b: yield: 51.3%; white solid; mp 93-95°C; Rf (n-hexane / ethyl acetate 5:2) 0.18; 1 H NMR (400MHz, CDCl 3 ): δ7.00 (2H, d, J=8.4Hz, H-3″, 7″), 6.90 (1H, d, J=15.2Hz, H-3), 6.74 (1H, d, J=8.8Hz , H-4″, 6″), 6.56 (2H, s, H-2′, 6′), 6.39 (1H, d, J=11.2Hz, H-5), 6.18 (1H, d, J=11.2 Hz, H-4), 5.91 (1H, dt, J=15.2Hz, H-2), 5.65 (2H, s, H-1′), 4.12 (2H, d, J=7.6Hz, H-1) , 3.95 (2H, q, J=7.6Hz, OCH 2 CH 3 -5″), 3.87 (6H, s, OCH 3 -3', 5'), 1.36 (3H, t, J=7.2Hz, OCH 2 CH 3 -5″); ESI-MS m / z[M+H] + 371.

[0048] Compound II-c: yield: 43.4%; white solid; mp 66-68°C; Rf (n-hexane / ethyl acetate 5:2) 0.20; ...

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Abstract

The present invention provides a 4'-substituted benzyloxy -3',5'-dimethoxyphenyl-butadiene type derivatives and the medical salt or solvent thereof with the above general formula , wherein 4'-subsituted benzyloxy -3',5'-dimethoxyphenyl-benaldehyde and bromoethylcrotonate-triphenylphosphonium are mixed, and the mixture is reduced by a complex of lithium aluminium hydride and aluminium chloride to obtain the corresponding chemical compound. The chemical compound provided by the present invention has important biological activity, cytotoxicity experiments in vitro on human lung cancer cells (A549), human chronic myeloid leukemia cell Line (K562), human karyotype leukemia cell(HL-60), and mice lymph-type tumor (P388D1) tumor cells indicate that the derivatives of 4'-substrate benzyloxy -3',5'-dimethoxyphenyl-butadiene has the suppressive function on both the growth of tumor cells and multiple tumors in vitro, and can be applied to preparation of drugs for tumor prevention and treatment.

Description

field of invention [0001] The invention belongs to the fields of organic chemistry, medicinal chemistry and pharmacology, and relates to 4'-substituted benzyloxy-3,5-dimethoxyphenyl-butadiene derivatives and their preparation methods, and the preparation of such compounds in the preparation of anti- Use in tumor medicine. Background of the invention [0002] At present, due to environmental pollution and other problems brought about by industrial development, the quality of human living environment continues to decline, and the incidence and mortality of tumor diseases are also increasing. 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. Therefore, searching for and discovering new highly selective cytotoxic antitumor drugs is a worldwide research hotspot. We are ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/734C07C43/23A61P35/00A61K31/085A61K31/216
Inventor 邹宏斌吴昊约阿施·史托克希特赵昱张勇民俞永平曾苏
Owner ZHEJIANG UNIV
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