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Quinoline compound as well as preparation method and application thereof

A compound, quinoline technology, applied in the field of medicinal chemistry, can solve the problems of off-target toxicity and side effects, low target selectivity and specificity

Pending Publication Date: 2021-10-22
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Research on drugs targeting the TGF-β pathway has been carried out for many years, but TGFβR1 inhibitors such as Galunisertib have shown certain cardiotoxicity (such as bleeding, functional degradation, inflammatory damage, etc.) in animal models. The reason is that Due to the low target selectivity and specificity of this type of drug, while the drug inhibits the activation site of the TGFβR1 kinase, it also has a strong inhibitory effect on other proteins with the same kinase region (such as p38α), resulting in many non- Anticipated off-target toxicities

Method used

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  • Quinoline compound as well as preparation method and application thereof
  • Quinoline compound as well as preparation method and application thereof
  • Quinoline compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoro Preparation of methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline

[0048]

[0049] Step 1: Preparation of 2-bromo-1-(tetrahydro-2H-pyran-4-yl)ethan-1-one

[0050]

[0051]Under nitrogen protection, add methanol (100mL) and 1-(tetrahydro-2H-pyran-4-yl)ethanone (20.0g, 156mmol) in sequence to a 1000mL three-necked flask, cool down to below -15°C, and slowly drop Enter liquid bromine and keep the temperature below -15°C. After dropping, raise the temperature to 0°C, react for 45 minutes, then raise the temperature to 10°C, react for 45 minutes, keep the internal temperature below room temperature and slowly add 11mol / L sulfuric acid (55mL) dropwise, and react overnight at room temperature. Monitor the completion of the reaction, add ethyl acetate and sodium chloride aqueous solution for extraction, combine the organic layers, adjust the pH value of the o...

Embodiment 2

[0086] Example 2: 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)quinoline

[0087]

[0088] 7-bromo-4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)quinoline (1.00g, 2.41 mmol), Pd / C (0.20g) were dissolved in methanol (20mL), replaced by hydrogen, and kept stirring at room temperature under hydrogen atmosphere for 4-5hrs. LC-MS monitored that the reaction was complete, filtered, and concentrated the mother liquor to dryness to obtain the title compound, a total of 0.92g . ESI-MS[M+H] + m / z:336.2, 1 H NMR (500MHz, DMSO-d 6 )δ9.14-9.15(1H, J=6.5Hz,d),8.55-8.57(1H,J=6.5Hz,dd),8.30-8.32(1H,J=8.5Hz,d),8.20-8.23(1H ,J=8Hz,t),8.10(1H,s),7.98-8.02(1H,J 1 =8Hz,t),7.29-7.30(1H,J=6.5Hz,d),3.74-3.75(1H,m),3.25-3.30;3.76-3.80(4H,m),2.78-2.84(1H,m) ,1.62-1.71(4H,m),0.97-1.11(4H,m).

Embodiment 3

[0089] Example 3: 4-((1-cyclopropyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)-7-(3-(tri Fluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)quinoline

[0090]

[0091] Step 1: Preparation of 1-cyclopropyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ol

[0092]

[0093] The reaction mother liquor of 1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ol in Step 6 of Example 1 was subjected to column chromatography to obtain 15 g of crude product. Take 10 g of the crude product and add ethyl acetate (50 mL), heat up and reflux to dissolve, slowly add petroleum ether (50 mL), turn off heating and cooling to crystallize to 40°C, heat filter, and dry the filter cake under vacuum for 3 hours to obtain the title compound, the yield is 35.0 %. ESI-MS[M+H] + m / z:209.1, 1 H NMR (500MHz, DMSO-d 6 )δ7.97(1H,s),6.85(1H,s),3.43-3.46; 3.92-3.95(4H,m),3.36-3.41(1H,m),3.11-3.18(1H,m),1.56- 1.59; 2.02-2.10(4H,m),0.92-0.97(4H,m).

[0094] Step 2: Preparation o...

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Abstract

The invention belongs to the field of medical chemistry, and particularly relates to a quinoline compound, a preparation method thereof and application of the quinoline compound as a reference substance in qualitative and / or quantitative analysis of related impurities in quality research of 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl) oxy)-7-(3-(trifluoromethyl)-5, 6-dihydro-[1, 2, 4] triazolo [4, 3-a] pyrazine-7 (8H)-yl) quinoline bulk drug.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to quinoline compounds, their preparation methods and their use as reference substances in 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl) )-1H-pyrazol-4-yl)oxy)-7-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a ]Pyrazin-7(8H)-yl)quinoline bulk drug quality research related impurity qualitative and / or quantitative analysis purposes. Background technique [0002] TGF-β (transforming growth factor β) is an important class of cytokines. So far, 6 different subtypes (TGF-β1-6) have been found, and their homology is different. In mammals Only three subtypes are expressed, namely TGF-β1, TGF-β2 and TGF-β3. It is a multifunctional growth factor superfamily with a wide range of biological activities involved in early embryonic development, cartilage and bone formation, extracellular matrix synthesis, inflammation, interstitial fibrosis, regulation of immune and endocri...

Claims

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Application Information

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IPC IPC(8): C07D405/14C07D487/04A61P35/00G01N30/02G01N30/06G01N21/64
CPCC07D405/14C07D487/04A61P35/00G01N30/02G01N30/06G01N21/6428G01N21/6486
Inventor 陈程杜爽赵立文马宁
Owner NANJING SANHOME PHARMACEUTICAL CO LTD
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