5-pyrimidine-6-oxygen-pyrazolopyridine derivative and preparation method and application thereof

A technology of azolopyridines and derivatives, which is applied in the field of application as a drug for the treatment of pulmonary fibrosis, and can solve problems such as not having the ability to activate sGC

Active Publication Date: 2019-10-08
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the compound of general formula (I) does not have the function of activating sGC

Method used

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  • 5-pyrimidine-6-oxygen-pyrazolopyridine derivative and preparation method and application thereof
  • 5-pyrimidine-6-oxygen-pyrazolopyridine derivative and preparation method and application thereof
  • 5-pyrimidine-6-oxygen-pyrazolopyridine derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] 2-(6-((2-fluorobenzyloxy)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)pyrimidine-4,6-di Phenol (compound 1)

[0085]

[0086] Weigh 0.22g of sodium methoxide (4mmol) into a 100mL eggplant-shaped bottle, then measure 40mL of methanol into the reaction flask, stir at room temperature, weigh 0.5g of compound 6-(2-fluorobenzyloxy)-3- Add methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamidine (1.33mmol) into the reaction bottle, and weigh 0.18g of malonic acid with a plastic dropper by the reduction method Dimethyl ester (1.33 mmol) was slowly added dropwise into the reaction bottle, and finally 10 mL of methanol was added to rinse the bottle mouth. After transferring the reaction device to reflux at 70°C for 12 hours, TLC monitored the raw material 2-(6-((2-fluorobenzyloxy)-3-methyl-1-phenyl-1H-pyrazol[3,4- B] pyridine-5-pyridyl) formamidine is not completely reacted. TLC monitors raw material 2-(6-((2-fluorobenzyloxy)-3-methyl-1-phenyl-1H-pyridine after conti...

Embodiment 2

[0088] 2-(6-((2-fluorobenzyloxy)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-morpholinopyrimidine -4,6-diphenol (compound 2)

[0089]

[0090] According to the synthetic method of compound 1, the compound 6-(2-fluorobenzyloxy)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamidine and morphine Diethyl linylmalonate was used as starting material to obtain a yellow solid. Yield: 34%, melting point: 221.7-221.9°C, HPLC: 96.98%. 1 H NMR (400MHz, DMSO-d 6 ):δ12.03(br s,1H,-OH),8.63(s,1H),8.12(d,J=7.7Hz,2H,Ar-H),7.65~7.57(m,1H,Ar-H) ,7.54(t,J=8.0Hz,2H,Ar-H),7.41(m,1H,Ar-H),7.32(m,1H,Ar-H),7.21(t,J=7.4Hz,1H, Ar-H),5.66(s,2H,-CH 2 -),3.71~3.65(m,4H,-CH 2 -),3.09~3.02(m,4H,-CH 2 -),2.58(s,3H,-CH 3 ). 13 C NMR (101MHz, DMSO-d 6 ):δ160.44(d, 1 J C,F =244.0Hz),160.06,151.65(2C),148.57,144.80,139.12,135.22,130.59,130.51,130.40,129.68(2C),126.16,124.97,124.07(d, 2 J C,F =14.0Hz), 120.14(2C), 115.83(d, 2 J C,F =21.0Hz),113.65,112.48,112.35,66.91(2C),63.18,49....

Embodiment 3

[0092] 2-(6-((2-fluorobenzyloxy)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-piperidinylpyrimidine -4,6-Diphenol (Compound 3)

[0093]

[0094] According to the synthetic method of compound 1, the compound 6-(2-fluorobenzyloxy)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamidine and piperidine Diethyl pyridyl malonate was used as starting material to obtain a white solid. Yield: 41%, melting point: 230.0-231.5°C, HPLC: 97.34%. 1 H NMR (400MHz, DMSO-d 6 ):δ11.38(br s,1H,-OH),8.62(s,1H),8.17~8.07(d,J=7.8Hz,2H,Ar-H),7.66~7.58(m,1H,Ar- H), 7.53(t, J=7.9Hz, 2H, Ar-H), 7.44~7.35(m, 1H, Ar-H), 7.34~7.26(dd, J=16.0, 8.1Hz, 2H, Ar-H ), 7.20(t, J=7.4Hz, 1H, Ar-H), 5.66(s, 2H, -CH 2 -),3.34(m,4H,-CH 2 -),2.58(s,3H,-CH 3 ),1.76(m,4H,-CH 2 -),1.50(m,2H,-CH 2 -). 13 C NMR (101MHz, DMSO-d 6 ):δ160.44(d, 1 J C,F =244.0Hz),160.04,152.76(2C),148.51,144.85,139.05,135.14,130.58,130.50,130.32,129.64(2C),126.15,124.94,124.03(d, 2 J C,F =14.0Hz), 120.11(2C), 115.79...

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Abstract

The invention relates to a 5-pyrimidine-6-oxygen-pyrazolopyridine derivative and a pharmaceutically acceptable salt thereof, and a preparation method and application thereof. The chemical structural formula (II) of the 5-pyrimidine-6-oxygen-pyrazolopyridine derivative is shown in specification. The derivative and pharmaceutically acceptable salts thereof play anti-fibrotic effects by blocking theTGF-beta / ERK signaling pathway by activating a sGC-cGMP pathway. Therefore, as a novel sGC agonist, the 5-pyrimidine-6-oxygen-pyrazolopyridine derivative plays anti-fibrosis and anti-tissue remodeling effects by up-regulating cGMP levels, and becomes a new drug treatment strategy for pulmonary fibrosis diseases.

Description

technical field [0001] The present invention relates to 5-pyrimidine-6-oxo-pyrazolopyridine derivatives and pharmaceutically available salts thereof, the present invention also relates to their preparation method and application as medicine, especially as application of medicine for treating pulmonary fibrosis . Background technique [0002] Pulmonary fibrosis is a fatal lung disease characterized pathologically by damage and abnormal proliferation of alveolar epithelial cells, as well as deposition of extracellular matrix and proliferation and activation of fibroblasts, characterized by scarring-induced changes in the lung structure. Progressive and irreversible damage, culminating in organ dysfunction, leading to structural destruction of the lungs and loss of respiratory function. Pulmonary fibrosis can be caused by factors such as viral infection, exposure to radiation therapy, chemotherapeutic drugs, and aerosolized environmental toxins. Meanwhile, pulmonary fibrosis ...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61P11/00
CPCA61P11/00C07D471/04
Inventor 李乾斌胡高云胡立庆陈卓
Owner SHANDONG XINHUA PHARMA CO LTD
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