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Thieno-ring compound and synthesis method and application thereof

A compound and hydrate technology, applied in the field of biomedicine, can solve problems such as deficiency, increased expression of synthetase COX2, and increased PGE2 level

Active Publication Date: 2019-06-04
SHANGHAI YUYAO BIOTECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Transcription factor HIF1 in tumor tissue α The expression of PGE2 synthetase COX2 regulated by SP1 and SP1 was significantly increased, while the PGE2 metabolizing enzyme 15-PGDH was highly expressed in normal tissues, but it was lacking in colon cancer, gastric cancer, lung cancer and breast cancer tissues, which further led to the tumor microenvironment Increased levels of PGE2

Method used

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  • Thieno-ring compound and synthesis method and application thereof
  • Thieno-ring compound and synthesis method and application thereof
  • Thieno-ring compound and synthesis method and application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0182] The preparation of formula I compound

[0183] Exemplary formula I compound preparation process is shown in following table 1:

[0184] Table 1

[0185]

[0186]

[0187]

[0188]

[0189] Pharmaceutical composition and its use

[0190] Another aspect of the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of the compound selected from the above general formula (I), its pharmaceutically acceptable salts, enantiomers, diastereoisomers or racemate, and optionally, one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and / or diluents. The excipients are, for example, flavoring agents, flavoring agents, sweetening agents, and the like.

[0191] The pharmaceutical composition provided by the present invention preferably contains active ingredients in a weight ratio of 1-99%, and its preferred ratio is that the compound of general formula I accounts for 65wt%-99wt% of the to...

Embodiment 1-1

[0197] Example 1-1 , (S)-4-(1-(2-((4-fluorophenyl)ethynyl)-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide ) ethyl) the preparation of benzoic acid (YJ101)

[0198]

[0199] Tetrahydro-4H-pyran-4-one (2.00g, 20.0mmol), ethyl cyanoacetate (2.50g, 22.0mmol) and sulfur (704mg, 22.0mmol) were dissolved in 30.0mL ethanol, and then added to the solution Morpholine (1.74 g, 20.0 mmol) was added to it, and stirred overnight at 50°C. Use TLC to detect the reaction, after the reaction is completed, the reaction solution is extracted with ethyl acetate and water, the upper organic phase is taken and evaporated to dryness, and purified by column chromatography to obtain a light yellow solid, namely 2-amino-5,7-dihydro -4H-Thieno[2,3-c]pyran-3-carboxylic acid ethyl ester (4.38 g, yield 96%). Dissolve ethyl 2-amino-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (450 mg, 2.0 mmol) in 1.5M HCl (10.0 mL) at room temperature Stir for 20 min, then lower the temperature to 0 °C under ice...

Embodiment 1-2

[0200] Example 1-2 , (S)-4-(1-(2-((4-fluorophenyl)ethynyl)-5,6-dihydro-4H-cyclopentadiene[b]thiophene-3-carboxamide)ethyl Base) Preparation of Benzoic Acid (YJ102)

[0201]

[0202] Using the same reaction route as for the preparation of compound YJ101, replacing tetrahydro-4H-pyran-4-one with cyclopentanone, compound YJ102 was finally obtained (the yield of the last step reaction was 62%). 1 H NMR (500MHz, DMSO) δ8.59(d, J=7.5Hz, 1H), 7.81(d, J=7.6Hz, 2H), 7.52(d, J=7.7Hz, 2H), 7.45-7.43(m ,2H),7.23(t,J=8.4,8.8Hz,2H),5.18–5.13(m,1H),1.80(m,6H),1.45(d,J=6.8Hz,3H).

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Abstract

The invention discloses a thieno-ring compound as shown in the formula (I), a pharmaceutically acceptable salt, or a hydrate thereof, a composition containing the thieno-ring compound, and a preparation method thereof. The invention also discloses application of the thieno-ring compound as a prostaglandin EP4 receptor antagonist for preventing and treating prostaglandin PGE2 mediated diseases, including malignant tumors, autoimmune diseases, inflammation, pain or osteoarthritis.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a class of thienocyclic compounds and their synthesis methods and applications. The thienocyclic compounds of the present invention are used as prostaglandin receptor EP4 antagonists for preventing and treating diseases mediated by prostaglandin PGE2. Including malignancy, autoimmune disease, inflammation, pain, etc. Background technique [0002] The function of prostaglandin E2 in the regulation of acute and chronic inflammation has a long history of research, and the mechanism of action is also described in detail. In recent years, the regulatory mechanism of prostaglandin E2 on inflammatory cells and cytokines involved in tumor immunity has also been revealed more and more. [0003] Among all prostaglandin subtypes, prostaglandin E2 (PGE2) is the most abundant and widely distributed in the human body. It is involved in the regulation of many physiological and pathological processes ...

Claims

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Application Information

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IPC IPC(8): C07D495/04C07D333/78C07D333/80C07D333/68A61K31/381A61P37/00A61P37/08A61P29/00A61P19/00A61P35/00A61P35/02
CPCA61K31/381A61P19/00A61P29/00A61P35/00A61P35/02A61P37/00A61P37/02A61P37/08C07D333/68C07D333/78C07D333/80C07D495/04
Inventor 章涵堃卢伟强刘明耀杨俊杰于薇薇胡龙龙张昕沛林仙花刘文娟
Owner SHANGHAI YUYAO BIOTECH LTD
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