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Beta-aryl thioether substituted alpha, beta-cycloenone derivative as well as preparation method and application thereof

A technology of aryl sulfides and derivatives, which is applied in the synthesis of cycloenone NF-κB inhibitors, α, β-cycloenone derivatives substituted by β-aryl sulfides and their preparation fields, capable of Solve the problems of high toxicity and easy drug resistance

Inactive Publication Date: 2015-02-18
EAST CHINA UNIV OF SCI & TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Currently clinically used anti-tumor chemotherapy drugs are generally highly toxic, and long-term use is prone to drug resistance

Method used

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  • Beta-aryl thioether substituted alpha, beta-cycloenone derivative as well as preparation method and application thereof
  • Beta-aryl thioether substituted alpha, beta-cycloenone derivative as well as preparation method and application thereof
  • Beta-aryl thioether substituted alpha, beta-cycloenone derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Synthesis of compound 1,5,5-dimethyl-3-((1-phenyl-1H-tetrazol-5-yl)thio)cyclohex-2-enone, starting from aniline and reacting with carbon disulfide Generate phenyl isothiocyanate, and then condense with sodium azide to obtain the intermediate 1-phenyl-5-mercaptotetrazolium. 5,5-Dimethyl-1,3-cyclohexanedione was chlorinated to obtain 3-chloro-5,5-dimethylcyclohex-2-enone. Compound 1 was obtained after alkylation of 1-phenyl-5-mercaptotetrazolium and 3-chloro-5,5-dimethylcyclohex-2-enone under basic conditions.

[0100] Step 1: Preparation of phenylisothiocyanate

[0101] Dissolve 5 milliliters of aniline and 42 milliliters of triethylamine in 60 milliliters of tetrahydrofuran, and add 4.1 milliliters of carbon disulfide dropwise under the protection of a nitrogen atmosphere. The temperature of the reaction solution is kept at 0-5 degrees during the addition process, and the temperature of the reaction solution rises naturally after the addition. to room temperature and ...

Embodiment 2

[0112] Synthesis of compound 2, 3-((1-phenyl-1H-tetrazol-5-yl)thio)cyclohex-2-enone, 1,3-cyclohexanedione was chlorinated to obtain 3-chloro Cyclohex-2-enone. Compound 2 was obtained after alkylation of 1-phenyl-5-mercaptotetrazole and 3-chlorocyclohex-2-enone under basic conditions.

[0113] Step 1: Preparation of 3-chlorocyclohex-2-enone

[0114] Dissolve 15 grams of 1,3-cyclohexanedione in 40 milliliters of chloroform, carefully add 28.7 milliliters of oxalyl chloride dropwise at room temperature within 30 minutes, reflux for 20 minutes after the addition, cool to room temperature, evaporate the solvent, and the residue 13.7 g of a colorless transparent liquid (20 mmHg, 110°C) was obtained by vacuum distillation with a yield of 79%.

[0115] 1 H NMR (400MHz, CDCl 3 ppm: 6.22 (s, 1H), 2.68 (t, J = 6.1 Hz, 2H), 2.40 (t, J = 6.8 Hz, 2H), 2.14-2.04 (m, 2H).

[0116] Step 2: Preparation of 3-((1-phenyl-1H-tetrazol-5-yl)thio)cyclohex-2-enone

[0117] 1-phenyl-5-mercapto-...

Embodiment 3

[0120] Synthetic compound 3,3-((1-(2-methyl)phenyl-1H-tetrazol-5-yl) thio)cyclohex-2-enone, with 2-methylaniline as raw material, and Carbon disulfide reacts to generate 2-methylphenylisothiocyanate, and then condenses with sodium azide to obtain the intermediate 1-(2-methyl)phenyl-5-mercaptotetrazolium. Compound 3 was obtained after alkylation of 1-(2-methyl)phenyl-5-mercaptotetrazolium and 3-chlorocyclohex-2-enone under basic conditions.

[0121] With reference to the method of Example 1, prepare 1-(2-methyl)phenyl-5-mercaptotetrazolium, then react with 3-chlorocyclohex-2-enone,

[0122] The synthesis process is the same as 1. Yield 65%.

[0123] 1 H NMR (CDCl 3 ) ppm: 7.53(m,1H),7.42(m,2H),7.22(d,1H,J=7.6Hz),6.17(s,1H),2.56(m,2H),2.40(t,2H,J =6.4Hz), 2.08(m,5H). 13 C-NMR (CDCl 3 ) ppm: 195.7, 145.9, 149.5, 135.0, 131.9, 131.8, 131.6, 128.1, 127.3, 126.7, 36.8, 30.4, 22.5, 17.4. HRMS (MALDI): C 14 h 15 N 4 OS, calculated: 287.0961, found: 287.0968.

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Abstract

The invention relates to a beta-aryl thioether substituted alpha, beta-cycloenone derivative. The derivative is characterized by having a structure represented by a formula (I) as shown in the specification, when m is equal to 0, R' is equal to H; when m is equal to 1, R' is equal to H or CH3; and R is aryl and has a group with a structure represented by a formula (II) as shown in the specification or a group with a structure represented by a formula (III) as shown in the specification. An alpha, beta-cycloenone NF (nuclear factor)-kappaB inhibitor adopts the beta-aryl thioether substituted alpha, beta-cycloenone derivative, thereby having good inhibition activity on NF-kappaB signal path and small toxicity, being capable of being used for treatment of diseases related to the NF-kappaB signal path and having good clinic application prospect.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to the synthesis of cycloenone NF-κB inhibitors, in particular to a β-aryl sulfide-substituted α,β-cycloenone derivative and its preparation method and application. Background technique [0002] Nuclear factor NF-κB (Nuclear factor-κB) is a dimeric transcription factor that can recognize and bind specific DNA sequence sites (GGRNNYYCC). The NF-κB signaling pathway is widely involved in a variety of biological effects, such as immune response, inflammatory response, apoptosis, etc., and is one of the most important signaling pathways in higher biological cells. More and more evidence shows that this signaling pathway regulates the occurrence and development of tumors. NF-κB is often highly expressed in malignant tumor cells, and NF-κB signaling is often persistent in different types of tumors including solid tumors such as breast cancer, liver cancer, head and neck cancer, lung cancer,...

Claims

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Application Information

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IPC IPC(8): C07D257/04C07D235/28C07D277/74C07D263/58A61P35/00
CPCC07D257/04C07D235/28C07D263/58C07D277/74
Inventor 郑剑斌李佳周宇波马磊彭延敏曹现超
Owner EAST CHINA UNIV OF SCI & TECH