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Hydroxamic acid compound and preparation method as well as application thereof

A compound and hydroxime technology, applied in the field of hydroxamic acid compounds, can solve the problems of apoptosis of cancer cells, abnormal inhibition of genes, etc.

Active Publication Date: 2012-09-12
CHENGDU DIAO JIUHONG PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In general, increased histone acetylation levels are associated with increased gene transcription activity, while low acetylation levels are associated with gene expression suppression (Forsberg EC, Bresnick EH. Histone acetylation beyond promoters: long-range acetylation patterns in the chromatin world[ J]. Bioessays, 2001, 23 (9): 820-830). Studies have found that HDAC is overexpressed and recruited by transcription factors, leading to abnormal suppression of specific genes, leading to tumors and other diseases; and inhibiting the activity of HDAC will Cause growth inhibition and apoptosis of many cancer cells (Somech R, Izraeli S, J Simon A. Histone deacetylase inhibitors-a new tool to treat cancer [J]. Cancer Treat Rev, 2004, 30(5): 461-472)

Method used

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  • Hydroxamic acid compound and preparation method as well as application thereof
  • Hydroxamic acid compound and preparation method as well as application thereof
  • Hydroxamic acid compound and preparation method as well as application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] The preparation of embodiment 12-[4-benzamide cyclohexylidene] methyl acetate:

[0076] Step 1, utilize the witting reaction principle to prepare 2-[4-(N-tert-butoxycarbonylamino) cyclohexylidene] methyl acetate:

[0077] In the there-necked flask with drying tube, reflux condenser and thermometer, add 2.13g (10mmol) 4-N-tert-butoxycarbonylaminocyclohexanone, 2.73g (15mmol) trimethyl phosphonoacetate and 100ml tetrahydrofuran, After stirring and dissolving, add 0.42g (17.5mmol) lithium hydroxide and 15g 4A molecular sieve, stir at room temperature for a few minutes, then raise the temperature and reflux for 10 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid product with a yield of 95%.

[0078] Step 2, prepare 2-(4-aminocyclohexylene) methyl acetate:

[0079] In a single-necked bottle with a drying tube, add 2.69g (10mmol) methyl 2-[4-(N-tert-butoxycarbonylamino)cyclohexylene]acetate, 50ml dich...

Embodiment 2

[0082] The preparation of embodiment 22-[4-(2-quinoline carboxamide) cyclohexylidene] methyl acetate

[0083] Step 1 and Step 2 refer to Example 1.

[0084] Step 3: Add 5.19g (30mmol) quinoline 2-carboxylic acid and 200ml tetrahydrofuran to a single-necked bottle with a drying tube, stir and dissolve, then add 8.92g HBTU (23.54mmol) and 60ml N,N-dimethylformamide , stirred at room temperature for half an hour, then added 3.62 g (21.4 mmol) of methyl 2-(4-aminocyclohexylene) acetate, adjusted the pH to ≥ 8 with diisopropylethylamine, and continued to stir at room temperature for 8 hours. The reaction mixture was concentrated in vacuo, 100 ml of water was added to the residue, and a milky white solid was precipitated by shaking and shaking. The milky white solid was dissolved in ethyl acetate, washed twice with water, 5% potassium carbonate, 2% hydrochloric acid, and saturated brine, and dried over anhydrous sodium sulfate. After suction filtration, the solvent was evaporated ...

Embodiment 3

[0085] Example 3 Preparation of methyl 2-[4-(8-quinolinesulfonamide)cyclohexylene]acetate

[0086] Step 1 and Step 2 refer to Example 1.

[0087] Step 3, in the three-necked flask, add 3.38g (20mmol) 2-(4-aminocyclohexylene) methyl acetate and 6.06g (60mmol) triethylamine, stir and dissolve with 80ml dichloromethane, and cool in an ice bath to At 0° C., a dichloromethane solution of 6.83 g (30 mmol) quinoline 8-sulfonyl chloride was added dropwise. During the dropwise addition, the temperature was kept at 0-5°C, and then gradually raised to room temperature and stirred for three hours. The reaction mixture was concentrated in vacuo, washed successively with saturated sodium bicarbonate solution and saturated brine twice, and dried over anhydrous sodium sulfate. After suction filtration, the solvent was evaporated under reduced pressure, and the pure product was obtained by column chromatography with a yield of 65%.

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Abstract

The invention discloses a hydroxamic acid compound and a preparation method as well as application of the compound. The invention also discloses a medicine combination for restraining the activity of histone deacetylase. The hydroxamic acid compound provided by the invention has good inhibitory effect on the HDAC in vitro, can also enter tumor cells to inhibit the activity of the HDAC in the tumor cells and enhance the expression of acetylated histone and cycle-related proteins and has the anti-tumor effect; and the anti-tumor effect of the hydroxamic acid compound is obviously superior to that of SAHA.

Description

technical field [0001] The invention relates to a hydroxamic acid compound, its preparation method and application. Background technique [0002] Inactivation of genes that control cell growth in the body is a hallmark of tumorigenesis. The epigenetic mechanisms that cause gene inactivation mainly include DNA methylation, histone acetylation, and modifications of other components in the higher-order structure of chromatin. These modifications change the chromatin configuration, resulting in changes in the regulation of gene transcription. Improper cell proliferation, leading to tumors. [0003] 40 years ago, Allfrey et al realized that the acetylation process of histones is closely related to the regulation of gene transcription in eukaryotic cells (Allfrey VG, Faulkner R, Mirsky AE.Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis[J ]. Proc Natl Acad Sci USA, 1964, 51:786-794). Histone acetylation plays a central role in t...

Claims

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Application Information

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IPC IPC(8): C07C259/06C07D215/48C07D209/42C07D307/85C07D215/36C07D217/02C07D317/68A61K31/166A61K31/343A61K31/404A61K31/47A61K31/472A61K31/36A61P35/00A61P35/02
CPCY02P20/55
Inventor 王学超张萧洁吴逢伟余飞江邓林根杜勇华朱学军
Owner CHENGDU DIAO JIUHONG PHARMA FACTORY
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