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Cycloalkane thiophthene derivative as well as preparation method and medical application thereof

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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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[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

Method used

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  • Cycloalkane thiophthene derivative as well as preparation method and medical application thereof
  • Cycloalkane thiophthene derivative as well as preparation method and medical application thereof
  • Cycloalkane thiophthene derivative as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

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, solid sulfur 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-methylpyridinium iodide 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

[0192] Weigh cyclobutanone (210mg, 3.0mmol), malononitrile (218mg, 3.3mm...

Embodiment 1-2

[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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PUM

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Abstract

The invention discloses a cycloalkane thiophthene derivative and pharmaceutically acceptable salts, metabolic products or prodrugs thereof. A compound can be used for treating diseases related with STAT3 (Signal Transducer and Activator of Transcription 3) activation, such as ovarian cancer, endometrial cancer, cervical cancer, breast cancer, colon cancer, pancreatic cancer, lung cancer, brain cancer, prostate cancer, kidney cancer, liver cancer, bladder cancer, oral cancer, sarcoma, prostate cancer, head and neck squamous cell carcinoma, neuroglioma, melanoma, lymphoma, leukemia, and renal fibrosis, pulmonary fibrosis, rheumatoid arthritis, hair growth, arthritis, psoriasis, lupus erythematosus, inflammatory lung diseases and inflammatory bowel diseases. (The formula is shown in the description.).

Description

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...

Claims

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Application Information

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IPC IPC(8): C07D409/12C07D409/14C07D495/04C07D413/12C07D417/12C07D333/68A61K31/4155A61K31/4365A61K31/4709A61K31/4725A61K31/444A61K31/496A61K31/5377A61K31/4178A61K31/422A61K31/427A61K31/506A61K31/381A61P35/00A61P35/02A61P13/12A61P11/00A61P19/02A61P29/00A61P17/06A61P1/00A61P17/14A61P37/06
CPCA61P1/00A61P11/00A61P13/12A61P17/06A61P17/14A61P19/02A61P29/00A61P35/00A61P35/02A61P37/06C07D333/68C07D409/12C07D409/14C07D413/12C07D417/12C07D495/04
Inventor 陈益华刘明耀周文波陈煌胡盼易正芳
Owner EAST CHINA NORMAL UNIV
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