阅读说明：本技术 一种二氢吡唑磺酰胺类化合物及其制备方法和用途 (Dihydropyrazole sulfonamide compound and preparation method and application thereof ) 是由 李青山 徐陈 沈邦念 高仰哲 吴法浩 李钢 褚冠武 王志航 阮班锋 于 2020-05-18 设计创作，主要内容包括：本发明公开了一种二氢吡唑磺酰胺类化合物及其制备方法和用途,其中二氢吡唑磺酰胺类化合物具有如下通式：<Image he="381" wi="587" file="DDA0002495815060000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,R<Sup>1</Sup>选自OCH<Sup>3</Sup>、CH<Sup>3</Sup>、Cl或Br；R<Sup>2</Sup>选自OCH<Sup>3</Sup>、CH<Sup>3</Sup>或F；R<Sup>3</Sup>选自4-F、4-Cl、4-OCH<Sup>3</Sup>、4-NO<Sub>2</Sub>、3-Cl或3-CH<Sub>3</Sub>。本发明二氢吡唑磺酰胺类衍生物对vemurafenib有耐药性的人黑色素瘤细胞A375<Sup>R</Sup>和人结直肠癌细胞COLO 205<Sup>R</Sup>有良好的抗增殖活性。(The invention discloses a dihydropyrazole sulfonamide compound and a preparation method and application thereof, wherein the dihydropyrazole sulfonamide compound has the following general formula: wherein R is 1 Is selected from OCH 3 、CH 3 Cl or Br; r 2 Is selected from OCH 3 、CH 3 Or F; r 3 Selected from 4-F, 4-Cl, 4-OCH 3 、4‑NO 2 3-Cl or 3-CH 3 . The dihydropyrazole sulfonamide derivative has drug resistance to vemurafenib, namely human melanoma cell A375 R And human colorectal cancer cell CO L O205 R Has good antiproliferative activity.)

1. A pyrazoline sulfonamide compound is characterized in that the structural general formula is as follows:

wherein R is₁Is selected from OCH₃、CH₃Cl or Br; r₂Is selected from OCH₃、CH₃Or F; r₃Selected from 4-F, 4-Cl, 4-OCH₃、4-NO₂3-Cl or 3-CH₃。

2. The dihydropyrazole sulfonamide compound according to claim 1, wherein:

3. a process for producing a dihydropyrazolesulfonamide compound according to claim 1, characterized by comprising the steps of:

dissolving an acetophenone derivative A in absolute ethyl alcohol, slowly dropwise adding a 10% NaOH solution, adding a benzaldehyde derivative B, stirring and reacting at normal temperature, monitoring the reaction progress by using T L C, and separating out a product in a solid form;

the structural formula of the acetophenone derivative A is as follows:

the structural formula of the benzaldehyde derivative B is as follows:

the structural formula of the chalcone derivative C is as follows:

wherein R is₁Is selected from OCH₃、CH₃Cl or Br; r₂Is selected from OCH₃、CH₃Or F;

and 2, dissolving the dried chalcone derivative C in n-propanol, then adding 80% hydrazine hydrate, heating to reflux, monitoring the reaction progress by T L C, standing the reaction solution for 8-12H at 2-6 ℃ after the reaction is completed, automatically separating out a product, standing, performing suction filtration, and recrystallizing by using ethanol to obtain a compound D-3, 5-diaryl-4, 5-dihydro-1H-pyrazole derivative, wherein the structural formula is as follows:

wherein R is₁Is selected from OCH₃、CH₃Cl or Br; r₂Is selected from OCH₃、CH₃Or F;

step 3, dissolving the compound D in dichloromethane, adding triethylamine and different substituted benzene sulfonyl chloride, stirring at room temperature, detecting by using T L C, extracting the reaction liquid by using water after the reaction is finished, and using anhydrous Na as an organic phase₂SO₄Drying, vacuum concentrating, and finally performing column chromatography separation and purification to obtain a target compound;

the structural formula of the different substituted benzene sulfonyl chlorides is shown as follows:

wherein R is₃Selected from 4-F, 4-Cl, 4-OCH₃、4-NO₂3-Cl or 3-CH₃。

4. The production method according to claim 3, characterized in that:

in the step 1, the mass ratio of the acetophenone derivative A to the benzaldehyde derivative B is 1:1.

5. The production method according to claim 3, characterized in that:

in step 2, 0.2m L80% hydrazine hydrate was added per millimole of chalcone derivative C.

6. The production method according to claim 3, characterized in that:

in step 3, the mass ratio of compound D to the differently substituted benzenesulfonyl chlorides was 1: 1.2.

7. The production method according to claim 3, characterized in that:

in step 3, the eluent used in the column chromatography separation and purification is ethyl acetate: petroleum ether is 1: 4, v/v.

8. Use of a dihydropyrazolesulfonamide compound according to claim 1, characterized in that:

the application of the dihydropyrazole sulfonamide compound in preparing a P13K inhibitor.

9. Use according to claim 8, characterized in that:

the dihydropyrazole derivative has drug resistance to vemurafenib, namely human melanoma cell A375^RAnd human colorectal cancer cell CO L O205^RHas good antiproliferative activity.

Technical Field

The invention relates to a dihydropyrazole sulfonamide compound and a preparation method and application thereof. The dihydropyrazole sulfonamide derivative has drug resistance to vemurafenib, namely human melanoma cell A375^RAnd human colorectal cancer cell CO L O205^RHas good antiproliferative activity.

Background

The dihydropyrazole is an extremely important nitrogenous five-membered heterocyclic compound and has stronger biological activity, such as anticancer, antiviral, antifungal, antituberculosis, insecticidal activity and the like. In nature, it can be biotransformed from appropriately substituted unsaturated ketones, and naturally occurring, biologically active flavonoids and isoflavones serve as ideal synthetic units therefor. It is a structural subunit with various pharmacological properties, and an active compound lead with general medicinal biological activity. More importantly: because it is chiral, the substitution on the ring and the conformation of the molecule have more variability and better bioactivity potential.

Targeted inhibitors play an important role in tumor therapy, but drug resistance to drugs also becomes the biggest limiting factor in achieving long-term clinical benefit of inhibitors. The major mechanism of resistance independent of the MAPK signaling pathway is activation of PI3K as a compensatory signaling pathway and involvement of Receptor Tyrosine Kinases (RTKs). The direct medicine design method based on the three-dimensional structure of the target biomacromolecule can screen the molecules in the database before pharmacological activity, the biological sample in the pharmacological experiment in the virtual screening is replaced by the three-dimensional image of the biomacromolecule such as enzyme or receptor of a computer, the compound sample is replaced by the compound in the database, and the molecular docking replaces the in-vitro pharmacological screening. The method greatly shortens the time of drug development and improves the efficiency, and is a conventional means for pharmaceutical chemistry research at present.

In the invention, according to a method of computer-aided drug design, a design strategy of 'combined pharmacophore' is adopted, the pharmacophore playing an important role in a combined model is selected and introduced to a3, 5-diaryl-4, 5-dihydropyrazole skeleton with good activity, and a new structure with good space complementarity and combining capacity is screened and synthesized to be used as a compound for resisting drug-resistant tumor cells.

Disclosure of Invention

The invention aims to provide a novel dihydropyrazole sulfonamide compound and a preparation method and application thereof. The dihydropyrazole sulfonamide compound has drug resistance to vemurafenib, namely human melanoma cell A375^RAnd human colorectal cancer CO L O205^RHas good antiproliferative activity.

The human melanoma cell A375^RAnd human colorectal cancer cell CO L O205^RCan generate drug resistance to vemurafenib inhibitor.

The dihydropyrazole sulfonamide compound has the following general formula:

wherein R is₁Is selected from OCH₃、CH₃Cl or Br; r₂Is selected from OCH₃、CH₃Or F; r₃Selected from 4-F, 4-Cl, 4-OCH₃、 4-NO₂3-Cl or 3-CH₃。

Further, the structural formula of the dihydropyrazole sulfonamide compound is preferably as follows:

the preparation method of the dihydropyrazole sulfonamide compound comprises the following steps:

step 1, dissolving acetophenone derivative A (16mmol) in 30m L anhydrous ethanol, slowly dropwise adding 5m L% NaOH solution with the concentration of 10%, adding benzaldehyde derivative B (16mmol), stirring at normal temperature for reaction, monitoring the reaction progress by using T L C, and after about 3 hours, precipitating a product in a solid form;

the structural formula of the acetophenone derivative A is as follows:

the structural formula of the benzaldehyde derivative B is as follows:

the structural formula of the chalcone derivative C is as follows:

wherein R is₁Is selected from OCH₃、CH₃Cl or Br; r₂Is selected from OCH₃、CH₃Or F.

And 2, dissolving the dried chalcone derivative C (10mmol) in n-propanol of 25m L, adding hydrazine hydrate of 2m L80%, heating to 90 ℃ for reflux, continuously monitoring the reaction progress by T L C, standing the reaction solution at 2-6 ℃ for 8-12H after the reaction is completed, automatically separating out a product, standing, performing suction filtration, and recrystallizing by using ethanol to obtain the compound D-3, 5-diaryl-4, 5-dihydro-1H-pyrazole derivative.

Wherein R is₁Is selected from OCH₃、CH₃Cl or Br; r₂Is selected from OCH₃、CH₃Or F.

Step 3, dissolving the compound D (2mmol) in 15m L dichloromethane, adding 3m L triethylamine and different substituted benzene sulfonyl chloride (2.4mmol), stirring at room temperature, detecting with T L C, extracting the reaction solution with water after the reaction is finished, and using anhydrous Na for an organic phase₂SO₄Drying, vacuum concentrating, and separating and purifying by column chromatography (ethyl acetate: petroleum ether: 1: 4, v/v)A target compound.

The structural formula of the different substituted benzene sulfonyl chlorides is shown as follows:

wherein R is₃Selected from 4-F, 4-Cl, 4-OCH₃、4-NO₂3-Cl or 3-CH₃。

In the step 1, the mass ratio of the acetophenone derivative A to the benzaldehyde derivative B is 1:1.

In step 2, 0.2m L80% hydrazine hydrate was added per millimole of chalcone derivative C.

In step 3, the mass ratio of compound D to the differently substituted benzenesulfonyl chlorides was 1: 1.2.

The application of the dihydropyrazole sulfonamide compound is application in preparing a P13K inhibitor. In particular, the dihydropyrazole derivatives have drug resistance to vemurafenib, namely human melanoma cells A375^RAnd human colorectal cancer cell CO L O205^RHas good antiproliferative activity.

Detailed Description

The present invention is further illustrated in detail by the following examples, but it should be noted that the scope of the present invention is not limited by these examples at all.