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STAT3 (Signal Transducer and Activator of Transcription 3)-targeting small molecular compound as well as preparation method and application thereof

A compound and reaction technology, applied in the field of STAT3 inhibitors, small molecule compounds targeting STAT3 and its preparation, can solve the problems of poor physical and chemical properties, affecting clinical development, low anti-tumor activity of biochemical properties, etc., to achieve the goal of treating tumors effect of disease

Inactive Publication Date: 2014-04-16
FUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

One of the main factors hindering the entry of effective STAT3 small molecule inhibitors into the clinic is poor druggability, such as poor physicochemical properties (such as poor water solubility) and unsatisfactory biochemical properties (such as low antitumor activity) of polypeptides or peptoids; Small-molecule non-peptide compounds have poor pharmacokinetic properties, are prone to adverse reactions or have large toxic and side effects; several types of small-molecule non-peptide compounds that have entered phase I / II clinical trials, such as OPB-31121, have relatively high cLogP value and molecular weight, affecting its further clinical development

Method used

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  • STAT3 (Signal Transducer and Activator of Transcription 3)-targeting small molecular compound as well as preparation method and application thereof
  • STAT3 (Signal Transducer and Activator of Transcription 3)-targeting small molecular compound as well as preparation method and application thereof
  • STAT3 (Signal Transducer and Activator of Transcription 3)-targeting small molecular compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: 5-chloro-2-hydroxy- N -(1-Methyl-6-indole)benzamide (preparation of compound IIa)

[0033] Step 1: 1-methyl-6-nitroindole (intermediate 2): 800 mg of 60% NaH was added to 20 mL of DMF solution, and 4 g of 6-nitroindole was added in batches at 0°C. The mixture was stirred at 0°C for 10 minutes, and then 1.86 mL of methyl iodide was added dropwise. After the mixture was stirred at room temperature for 24 hours, it was slowly added to 100 mL of ice water and then 100 mL of ethyl acetate. After the extracted organic phase was washed with saturated sodium chloride, the organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain 4.50 g of intermediate 2. 1 H NMR (400 MHz, CDCl 3 ) δ 8.27 (d, 1H), 7.97 (d, 1H), 7.61 (d, 1H), 7.33 (d, 1H), 6.56 (d, 1H), 3.87 (s, 3H).

[0034] Step 2: 1 g of intermediate 2 was dissolved in 20 mL of methanol, and 100 mg of zinc powder was added. Add 20 mL of saturated ammonium chloride aqueous solution at 0°C,...

Embodiment 2

[0036] Example 2: (E)-3-(6-bromopyridine-2)-2-cyano- N -(1-methyl-6-indole)acrylamide (preparation of compound IIIa)

[0037] Step 1 and step 2 are the same as for the synthesis of compound IIa, and the 5-chlorosalicylic acid in step 3 is replaced with 2-cyanoacetic acid. Specifically, 146 mg of intermediate 3 was dissolved in 10 mL of DMF, 100 mg of 2-cyanoacetic acid was added, 500 mg of HBTU and 0.5 mL of DIPEA were added, after stirring at room temperature for 24 hours, 10 mL of water and 30 mL of ethyl acetate were added, and the organic phase obtained by extraction was extracted with 10 mL of water. After the extracted organic phase was washed with saturated sodium chloride, the organic phase was dried with anhydrous sodium sulfate and spin-dried, and the crude product was passed through a silica gel column to obtain 120 mg of intermediate 4. 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.83 (s, 1H), 8.26 (d, 1H), 7.95 (d, 1H), 7.60 (d, 1H), 7.32 (d, 1H), 6.55(d, 1H), 3.97 (s, ...

Embodiment 3

[0039] Example 3: N -(1-methyl-6-indole)-2-phenylquinoline-4-carboxamide (preparation of compound IVa)

[0040] Step 1 and step 2 are the same as the synthesis of compound IIa, and the 5-chlorosalicylic acid in step 3 in the preparation of compound IIa is replaced by 2-phenylquinoline-4-acetic acid. Specifically, 146 mg of intermediate 3 was dissolved in 10 mL of DMF, 300 mg of 2-phenylquinoline-4-acetic acid was added, 500 mg of HBTU and 0.5 mL of DIPEA were added, after stirring at room temperature for 24 hours, 210 mL of water and 50 mL of ethyl acetate were added, and the organic phase obtained by extraction was then Extracted with 20mL of water, the organic phase obtained by the extraction was washed with saturated sodium chloride, dried with anhydrous sodium sulfate and then spin-dried, the crude product was passed through a silica gel column to obtain 220 mg of the final product IVa. 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.31 (s, 1H), 8.45 (s, 1H), 8.39 (d, 2H), 8.35 (s...

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Abstract

The invention discloses an STAT3 (Signal Transducer and Activator of Transcription 3)-targeting small molecular compound as well as a preparation method and application thereof. The STAT3 inhibitor is a compound shown as a general formula I in the specification, wherein R<1> is 5-chloro-2-hydroxyphenyl, (E)-3-(6-bromo-2-pyridine)-2-cyan or 4-(2-phenylquinoline); R<2> is hydrogen or C1-C6 linear alkyl or branched alkyl. The compound has the advantages that the proliferation and the survival of various tumor cells of breast cancer, lung cancer, liver cancer, cervical cancer, prostate cancer and the like can be remarkably inhibited; the STAT3 signal channel of the tumor cells is inhibited; therefore, the tumor cell apoptosis is induced and the effect of treating the tumor diseases is achieved.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to STAT3 inhibitors, in particular to a small molecular compound targeting STAT3 and its preparation method and application. Background technique [0002] The Signal Transducers and Activators of Transcription (STATs) family is a class of cytoplasmic proteins with a molecular weight of 79-113kDa, which are widely expressed in different types of cells and tissues in the body and participate in cell growth, differentiation, apoptosis It regulates various physiological functions such as death, and is closely related to the pathophysiological functions of inflammation, tumor and immune response. As a bifunctional cytoplasmic protein, this kind of STATs family protein has both signal transduction and transcriptional activation functions. It can bind to different cytokine receptors, transmit extracellular signals to the nucleus, and interact with specific DNA in the nucleus. The promoter ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/08C07D401/12A61K31/404A61K31/4439A61K31/4709A61P35/00
CPCC07D209/08C07D401/12
Inventor 陈海军周小斌王爱兰俞雪梅胡子旋郑小梅欧敏锐高瑜
Owner FUZHOU UNIV
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