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Cycloalkane thiophthene derivative as well as preparation method and medical application thereof
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A technology of thiophene derivatives and cycloalkanes, applied in the field of medicine, can solve the problems of unstable metabolism, difficult-to-clinical compounds, toxicity, etc.
Inactive Publication Date: 2018-09-21
EAST CHINA NORMAL UNIV
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[0008] Through the structural analysis and clinical performance analysis of the above-mentioned small molecule STAT3 inhibitors, it is found that the current small molecule STAT3 inhibitors have obvious defects: Among them, small molecule inhibitors represented by STA-21, Cryptotanshinone, Stattic, BBI608 and JMC-9 Because they all contain quinones or quinone-like structures, they show great toxicity clinically; in addition, some compounds such as S3I-201, SH5-07 and BP-1-102 are mostly peptidomimetic compounds. Metabolism in the body is unstable, making it difficult to develop into clinical compounds. There is no report of this type of small molecule STAT3 inhibitor entering clinical research
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Embodiment 1-14
[0188] Example 1-1 Synthesis of 4-cyano-5-(1-methyl-4-pyrazole)-carboxamido-cyclobutyl[2,3]thiophene (1a).
[0189] Target products 1a-1e, 2a-2j are shown in formula 1-1, cyclobutanone (or other cycloalkanones), malononitrile, solidsulfur and proline are dissolved in DMF, stirred at 60°C for 10 The reaction was completed in 1 hour; the reaction solution was slowly added dropwise to stirred ice water, and a large amount of crude product containing the intermediate 2-amino-3-cyano-thiophene derivative intermediate was precipitated, and after filtration, drying and purification; the intermediate Body, 1-methylpyrazole-4-carboxylic acid, 2-chloro-1-methylpyridiniumiodide and DMAP were dissolved in dichloromethane, triethylamine was added dropwise under stirring and then heated to reflux overnight to obtain the target Products 1a-1e, 2a-2j.
[0190]
[0191] Synthetic steps of formula 1-1 1a-1e, 2a-2j
[0193] Example 1-2 Synthesis of 4-cyano-5-(1-methyl-4-pyrazole)-carboxamido-cyclopentyl[2,3]thiophene (1b).
[0194] Using the same method for preparing compound 1a, replacing cyclobutanone with cyclopentanone, finally obtained 1b with a yield of 67%. 1 HNMR(500MHz,DMSO)δ11.32(s,1H),8.43(s,1H),8.05(s,1H),3.91(s,3H),2.85(t,J=6.5Hz,2H),2.75( t,J=6.4Hz,2H),2.40-2.36(m,2H).
Embodiment 1-3
[0195] Example 1-3 Synthesis of 2-(1-methyl-4-pyrazole)-carboxamido-3-cyano-4,5,6,7-tetrahydrobenzothiophene (1c).
[0196] Using the same method for preparing compound 1a, replacing cyclobutanone with cyclohexanone, finally obtained 1c with a yield of 63%. 1 HNMR(500MHz,DMSO)δ11.31(s,1H),8.44(s,1H),8.05(s,1H),3.90(s,3H),2.61-2.60(m,2H),2.51-2.50(m ,2H),1.76-1.75(m,4H).
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technical field [0001] The invention relates to the technical field of medicine, in particular to a cycloalkanethiophene derivative and its preparation method and medical application, especially the application in the preparation of antitumor drugs and autoimmune diseases. Background technique [0002] Signal transducers and activators of transcription 3 (STAT3) is a transcription factor for signal transduction mediated by some cytokines and growth factors, and regulates growth, proliferation, differentiation and apoptosis in normal cells. A series of physiological functions. The STAT protein family includes 7 members: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6. The overexpression and activation of STAT3 are highly expressed in many malignant tissue types of tumors, and have a positive effect on many solid tumors and hematological tumors. Facilitate the occurrence of cancer, including ovarian cancer, endometrial cancer, cervical cancer, breast cancer, colon cance...
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