Alpha, beta-unsaturated ketone compound containing 1,2,4-oxadiazoles heterocycle

Abstract

The invention relates to an alpha, beta-unsaturated ketone compound containing a 1,2,4-oxadiazoles, the structure of which is as shown in general formula 5, wherein R1 is hydrogen, methyl or chlorine; R2 is methyl, chlorine or bromine; R3 is methyl or ethyl; R4 is para-trifluoromethyl, ortho-methyl or para-nitro; and R5 is hydrogen or methyl. The invention also provides a preparation method of the compound and application thereof. The half-growth inhibitory concentration of the compound on HL-60 cells is less than or equal to 2.0 mu, and the activity is obviously improved, thus the compound can be used for preparing antileukemie medicaments.

Description

technical field

[0001] The invention relates to the fields of organic compounds and medical applications, in particular to α, β-unsaturated ketone compounds containing 1,2,4-oxadiazole heterocycle and their antitumor activity. Background technique

[0002] Malignant tumor is one of the major diseases that threaten human health in the world today. With the development of tumor biology, it provides a new molecular biological basis for the research and development of antitumor drugs. Most tumor cells highly express glutathione S-transferases (GSTs). GSTs are a multifunctional protein superfamily widely present in eukaryotes and are usually divided into cytosolic family, mitochondrial family and membrane-bound protein family. Microsomal family, see: Hayes, J.D.; Flanagan, J.U.; Jowsey, I.R. Glutathione transferases. Annu. Rev. Pharmacol. Toxicol. 2005, 45, 51-88. Mammalian cytosolic GSTs can be divided into seven subtypes: Alpha (α), Mu (μ), Pi (π), Sigma (σ), Omega (ω), Theta ...

Examples

preparation example Construction

[0034] The preparation method of the general formula 5 containing 1,2,4-oxadiazole α,β-unsaturated ketone compound of the present invention, the steps are as follows:

[0035] 1) Preparation of substituted amidoxime (2)

[0036] Add hydroxylamine hydrochloride to anhydrous methanol, add 0.8mL of anhydrous methanol to every millimole of hydroxylamine hydrochloride, then add anhydrous potassium carbonate, react at room temperature until no bubbles are formed, then add substituted benzonitrile (1). The molar ratio of hydroxylamine hydrochloride, anhydrous potassium carbonate and substituted benzonitrile is 5:5:1. Reflux reaction for 4-7h, filter while hot, wash the filter cake with anhydrous methanol, combine the washing liquid and filtrate, evaporate the solvent under reduced pressure, and separate the substituted amidoxime (2) by column chromatography, the elution system is petroleum ether / acetone 3:1 volume ratio.

[0037] 2) Preparation of 2-[2,3-disubstituted-4-(2-methylen...

Embodiment 1

[0051] 1) Preparation of substituted benzamide oxime compound (2)

[0052] Put 3.48g (50mmol) of hydroxylamine hydrochloride and 6.90g (50mmol) of anhydrous potassium carbonate in a 100mL round bottom flask, add 40mL of anhydrous methanol, and react at room temperature until no bubbles are generated, then add 1.71 g of p-substituted benzonitrile (5c) g (10 mmol). Slowly raise the temperature to 65°C, react for 4-7h, filter while hot, wash the filter cake with anhydrous methanol, combine the washing liquid and filtrate, remove the solvent by rotary evaporation, dry, and separate by column chromatography to obtain the intermediate substituted benzamide oxime, The elution system is petroleum ether / acetone 3:1 volume ratio.

[0053] Substituted benzonitrile selects 4-trifluoromethylbenzonitrile, 2-methylbenzonitrile or 4-nitrobenzonitrile respectively, obtains the following substituted benzamide oxime compound (2) respectively:

[0054] 2a: 4-trifluoromethylbenzamide oxime, whit...

Embodiment 2

[0080] Example 2. Compound GST P1-1 Inhibitory Activity Test and Determination of Growth Inhibition of HL-60 Cells

[0081] GST P1-1 inhibitory activity assay method: refer to CN1706789 "α, β-unsaturated ketone compound and its preparation method and its inhibition of GSTπ activity" 200510043573.3, Example 5 on page 11 of the specification.

[0082] HL-60 cell growth inhibitory activity assay method: refer to CN101108832 "Five-membered Heterocyclic Compounds, Preparation Method and Application", 200710015199.5, page 3 of the description. Human Acute Promyelocytic Leukemia Cell Line (HL-60)

[0083] Table 1. Determination data of compounds inhibiting GST P1-1 activity and inhibiting HL-60 cell growth activity

[0084]

[0085]

[0086] Experimental results show that most of the 1,2,4-oxadiazole α,β-unsaturated ketone compounds of the present invention have a half-inhibitory concentration of HL-60 cells less than or equal to 2.0 μM, and the activity is further improved. ...

technical field

[0001] The invention relates to the fields of organic compounds and medical applications, in particular to α, β-unsaturated ketone compounds containing 1,2,4-oxadiazole heterocycle and their antitumor activity. Background technique

[0002] Malignant tumor is one of the major diseases that threaten human health in the world today. With the development of tumor biology, it provides a new molecular biological basis for the research and development of antitumor drugs. Most tumor cells highly express glutathione S-transferases (GSTs). GSTs are a multifunctional protein superfamily widely present in eukaryotes and are usually divided into cytosolic family, mitochondrial family and membrane-bound protein family. Microsomal family, see: Hayes, J.D.; Flanagan, J.U.; Jowsey, I.R. Glutathione transferases. Annu. Rev. Pharmacol. Toxicol. 2005, 45, 51-88. Mammalian cytosolic GSTs can be divided into seven subtypes: Alpha (α), Mu (μ), Pi (π), Sigma (σ), Omega (ω), Theta ...

Examples

preparation example Construction

[0034] The preparation method of the general formula 5 containing 1,2,4-oxadiazole α,β-unsaturated ketone compound of the present invention, the steps are as follows:

[0035] 1) Preparation of substituted amidoxime (2)

[0036] Add hydroxylamine hydrochloride to anhydrous methanol, add 0.8mL of anhydrous methanol to every millimole of hydroxylamine hydrochloride, then add anhydrous potassium carbonate, react at room temperature until no bubbles are formed, then add substituted benzonitrile (1). The molar ratio of hydroxylamine hydrochloride, anhydrous potassium carbonate and substituted benzonitrile is 5:5:1. Reflux reaction for 4-7h, filter while hot, wash the filter cake with anhydrous methanol, combine the washing liquid and filtrate, evaporate the solvent under reduced pressure, and separate the substituted amidoxime (2) by column chromatography, the elution system is petroleum ether / acetone 3:1 volume ratio.

[0037] 2) Preparation of 2-[2,3-disubstituted-4-(2-methylen...

Embodiment 1

[0051] 1) Preparation of substituted benzamide oxime compound (2)

[0052] Put 3.48g (50mmol) of hydroxylamine hydrochloride and 6.90g (50mmol) of anhydrous potassium carbonate in a 100mL round bottom flask, add 40mL of anhydrous methanol, and react at room temperature until no bubbles are generated, then add 1.71 g of p-substituted benzonitrile (5c) g (10 mmol). Slowly raise the temperature to 65°C, react for 4-7h, filter while hot, wash the filter cake with anhydrous methanol, combine the washing liquid and filtrate, remove the solvent by rotary evaporation, dry, and separate by column chromatography to obtain the intermediate substituted benzamide oxime, The elution system is petroleum ether / acetone 3:1 volume ratio.

[0053] Substituted benzonitrile selects 4-trifluoromethylbenzonitrile, 2-methylbenzonitrile or 4-nitrobenzonitrile respectively, obtains the following substituted benzamide oxime compound (2) respectively:

[0054] 2a: 4-trifluoromethylbenzamide oxime, whit...

Embodiment 2

[0080] Example 2. Compound GST P1-1 Inhibitory Activity Test and Determination of Growth Inhibition of HL-60 Cells

[0081] GST P1-1 inhibitory activity assay method: refer to CN1706789 "α, β-unsaturated ketone compound and its preparation method and its inhibition of GSTπ activity" 200510043573.3, Example 5 on page 11 of the specification.

[0082] HL-60 cell growth inhibitory activity assay method: refer to CN101108832 "Five-membered Heterocyclic Compounds, Preparation Method and Application", 200710015199.5, page 3 of the description. Human Acute Promyelocytic Leukemia Cell Line (HL-60)

[0083] Table 1. Determination data of compounds inhibiting GST P1-1 activity and inhibiting HL-60 cell growth activity

[0084]

[0085]

[0086] Experimental results show that most of the 1,2,4-oxadiazole α,β-unsaturated ketone compounds of the present invention have a half-inhibitory concentration of HL-60 cells less than or equal to 2.0 μM, and the activity is further improved. ...

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