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Substitutive (S)-benaldehyde sulfonyl pyrrolidine-3-amino derivative, and preparation method and application thereof

A double-substitution and multi-substitution technology is applied in the field of substituted (S)-phenylmethylsulfonylpyrrolidine-3-amino derivatives and their preparation and application, which can solve the problem that it is difficult to find dual inhibitors and achieve structural The effect of correctness, easy access to raw materials, and easy operation

Active Publication Date: 2012-05-30
SHENZHEN GRADUATE SCHOOL TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This makes it difficult to find dual inhibitors among known tyrosine kinase inhibitors and PI3K inhibitors

Method used

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  • Substitutive (S)-benaldehyde sulfonyl pyrrolidine-3-amino derivative, and preparation method and application thereof
  • Substitutive (S)-benaldehyde sulfonyl pyrrolidine-3-amino derivative, and preparation method and application thereof
  • Substitutive (S)-benaldehyde sulfonyl pyrrolidine-3-amino derivative, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1, (S)-2-[(1-benzylsulfonyl)pyrrolidine-3-amino]-1-(4-benzylpiperazine)ethanone (in formula I, R1 is H, R2 is Compounds of H) Synthesis

[0043] Step (1): Dissolve 60 mmol potassium carbonate in 20 mL water and stir until completely dissolved, add 30.6 mmol (S)-Boc-3-aminopyrrolidine in ethyl acetate (70 mL), and stir at room temperature for 25 minutes. 33mmol of benzylsulfonyl chloride was dissolved in 60mL of ethyl acetate and tetrahydrofuran (1:1, v / v), added dropwise under an ice-water bath, and reacted at room temperature for one day after dropping. The reaction solution was concentrated under reduced pressure, then diluted with 30 mL of water and 50 mL of ethyl acetate, and then the organic phase was separated and collected, washed successively with saturated sodium bicarbonate solution, water, and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain Yellow solid (S)-tert-butyl-1-benzylsulfonylpy...

Embodiment 2

[0051] Example 2, Preparation of differently substituted (S)-phenylmethylsulfonylpyrrolidine-3-amino derivatives

[0052] According to the method of Example 1, replace "benzylsulfonyl chloride" in step 1) with "substituted benzylsulfonyl chloride", and replace "benzylpiperazine" in step 3) with "substituted benzylpiperazine" The following corresponding substituted (S)-benzenemethylsulfonylpyrrolidine-3-amino derivatives can be obtained.

[0053] (S)-2-[(1-Benzylsulfonyl)pyrrolidine-3-amino]-1-[4-(2-methylbenzyl)piperazine]ethanone

[0054] The structural confirmation data are as follows: 1 H NMR (400MHz, CDCl 3 ) δ7.41-7.43 (m, 2H), δ7.35-7.39 (m, 3H), δ7.30 (d, J=7.2Hz, 2H), δ7.14-7.21 (m, 3H), δ4. 25(s, 2H), δ3.61(br s, 2H), δ3.48(s, 2H), δ3.34-3.38(m, 1H), δ3.31-3.33(m, 4H), δ3. 28(d, J=6.0Hz, 2H), δ3.27(br s, 1H), δ2.96-3.00(m, 1H), δ2.44(t, J=4.8Hz, 4H), δ2.37 (s, 3H), δ1.96-2.04 (m, 2H), δ1.73 (dt, J=18.0, 6.4Hz, 1H); 13 C NMR (100.6MHz, CDCl 3 )δ168.75,137.60,135...

Embodiment 3

[0103] Example 3, MTT method cell proliferation inhibitory activity screening

[0104] Human liver cancer cell HepG-2 (catalogue number: TChu 72), breast cancer cell MCF-7 (catalogue number: TCHu 74) and leukemia cell K562 (catalogue number: TCHu191) in logarithmic growth phase were taken, (the above cells were purchased from In the Cell Bank of the Typical Culture Collection Committee of the Chinese Academy of Sciences, and the Cell Resource Center of the Shanghai Institutes for Biological Sciences, the Chinese Academy of Sciences) with 2×10 5 Seed / mL density in 96-well plate, 99 μL / well, at 37 ° C, 5% CO 2 After culturing in the incubator for 4 hours, the compounds prepared in the examples of the present invention were added to each well so that the final concentrations were 50 μmol / L, 25 μmol / L, 10 μmol / L, 5 μmol / L, 2.5 μmol / L, 1 μmol / L, 10 concentration gradients of 0.5μmol / L, 0.25μmol / L, 0.1μmol / L, 0.05μmol / L. Three replicate wells were set up for each compound, and bot...

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Abstract

The invention discloses a substitutive (S)-benaldehyde sulfonyl pyrrolidine-3-amino derivative, and a preparation method and application thereof. The structure of the compound is shown in an equation I. The preparation method includes: different substitutive alpha-toluenesulfonyl chloride and (S)-3-tert-butoxycarbonyl amino pyrrolidine are reacted, deprotection of a reaction product is performed so that an important intermediate is generated; and another intermediate can be prepared from different substitutive benzylpiperazine via 2-chloromethylation. The two intermediates are reacted in tetrahydrofuran in a backflow manner overnight, and the structure as shown in the equation I can be obtained by thin layer chromatography. A compound has an excellent tumor activity inhibiting effect, and has important practical value and application prospect in the field of preparation of anti-tumor medicines.

Description

technical field [0001] The invention relates to a substituted (S)-phenylmethylsulfonylpyrrolidine-3-amino derivative and its preparation method and application. Background technique [0002] Protein tyrosine kinases (PTK) are extremely important substances in the process of cell signal transduction, and have a variety of cellular functions. Overexpression of protein tyrosine kinases activates their downstream signaling pathways, leading to cell transformation, proliferation, resistance to apoptosis, promotion of cell survival, and ultimately tumor formation. Molecular design targeting tyrosine kinase ABL has promoted the successful marketing of drugs such as Imatinib, but clinical drug resistance has always existed. Studies have shown that the compensatory effect of the PI3K / AKT / mTOR signaling pathway is one of the mechanisms leading to Imatinib resistance; preclinical studies have found that the combined use of tyrosine kinase inhibitors and PI3K inhibitors can achieve ver...

Claims

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Application Information

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IPC IPC(8): C07D207/48A61K31/496A61P35/00A61P35/02
Inventor 蒋宇扬张存龙谭春燕刘红霞刘峰高春梅孙钦生
Owner SHENZHEN GRADUATE SCHOOL TSINGHUA UNIV
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