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Preparation method of quinoline TGF-beta1 inhibitor

A catalyst and solvate technology, applied in the field of medicinal chemistry, can solve the problems of low target selectivity and specificity, off-target toxic and side effects, etc.

Pending Publication Date: 2021-10-22
NANJING SANHOME PHARM RES & DEV 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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  • Preparation method of quinoline TGF-beta1 inhibitor
  • Preparation method of quinoline TGF-beta1 inhibitor
  • Preparation method of quinoline TGF-beta1 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] 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

[0071]

[0072] Step 1: Preparation of 2-bromo-1-(tetrahydro-2H-pyran-4-yl)ethan-1-one

[0073]

[0074] 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 ...

experiment example 1

[0109] Experimental example 1 compound in vitro ALK5 kinase activity evaluation

[0110] 1. Experimental materials

[0111] 1.1 Compounds

[0112] The compound of formula (I) of the present invention in Example 1 was prepared to 10 mM with DMSO, and then diluted to 3.333 μM, 1.111 μM, 370 nM, 123 nM, 41 nM, 14 nM, 4.6 nM, 1.5 nM, 0.5 nM.

[0113] 1.2 Reagents and instruments

[0114] Reagents: ALK5, purchased from Carna Company, Cat.No.09-141; p38α was purchased from Carna Company, Cat.No.04-152; TGFβR1 peptide was purchased from SignalChem Company, Cat.No.T36-58; II Methyl sulfoxide (DMSO), purchased from Sigma, USA; EDTA, purchased from Sigma, USA; ADP-Glo ​​Kinase Assay, purchased from Promega, Cat.No.v9102 / 3, 1×kinase buffer ( 40mM Tris, pH 7.5, 0.10% BSA, 20mM MgCl 2 , 1mM DTT), prepared just before use.

[0115] Instrument: 2104Multilabel Reader, purchased from Perkin Elmer, USA.

[0116] 2. Experimental method

[0117] 2.1 Prepare 1x Kinase Buffer

[0118] 1x as...

experiment example 2

[0151] Experimental example 2 compound in vitro cell luciferase test evaluation

[0152] 1. Experimental materials

[0153] Test compound: the compound of formula (I) of the present invention in Example 1, prepared into 4mM with DMSO, and then diluted 4 times successively to 20000.00nM, 5000.00nM, 1250.00nM, 312.5nM, 78.125nM, 19.53nM, 4.88nM, 1.22 nM.

[0154] Luc-Smad2 / 3-NIH3T3 mouse fibroblasts (engineered to overexpress SMAD2, 3-responsive promoter) were donated by the laboratory of China Pharmaceutical University.

[0155] Reagents: DMEM, purchased from Invitrogen, USA; FBS, purchased from Invitrogen, USA; DMSO, purchased from Sigma, USA; Glo Lysis Buffer, purchased from Progema, USA; Bright-GloLuciferase assay system, purchased from USA Promega; TGFβ, purchased from PeproTech, USA.

[0156] Instrument: MD SpectraMax M3 multifunctional microplate reader, purchased from Molecular Devices, USA.

[0157] 2. Experimental method

[0158] 2.1 Cell culture:

[0159] Cell r...

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Abstract

The invention belongs to the field of medical chemistry, and relates to a preparation method of a quinoline TGF-beta1 inhibitor, in particular to a preparation method 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 as shown in a formula (I) or a salt, a hydrate, a solvate or a crystal thereof.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to 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 or its salts, Preparation of Hydrates, Solvates or Crystals. 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 endocrine functions, tumor form and develop. At the same time, these three isoforms have similar structures, and their amino acid sequences a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04C07B2200/13
Inventor 陈程杜爽赵立文陈宏雁
Owner NANJING SANHOME PHARM RES & DEV CO LTD
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