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A compound for inhibiting collagen synthesis and deposition and application thereof

A technology of collagen synthesis and compounds, applied in organic chemistry, drug combination, respiratory diseases, etc., to achieve the effect of inhibiting collagen synthesis and collagen deposition, reducing secretion, and important social value

Active Publication Date: 2022-05-24
ZHEJIANG MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are no literature reports on the intervention of IPF by small molecular compounds that dually target P4H and LOX to inhibit collagen synthesis and deposition.

Method used

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  • A compound for inhibiting collagen synthesis and deposition and application thereof
  • A compound for inhibiting collagen synthesis and deposition and application thereof
  • A compound for inhibiting collagen synthesis and deposition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1CQ11

[0033]Example 1CQ11(Ⅰ, R=β-CN-CH 2 CH 2 Preparation of NH)

[0034] In the three-necked flask, PDCA (pyridine-2,5-dicarboxylic acid) 167 mg (1 mmol), BAPN 168 mg (2.4 mmol) and dichloromethane 40 mL were added successively and stirred, then EDC 400 mg (2 mmol) was added, and a catalytic amount of triethylamine was added, The reaction was stirred at room temperature and 25°C, and the end point of the reaction was monitored by TLC.

[0035] After the reaction was completed, the reaction solution was washed three times with an appropriate amount of saturated sodium bicarbonate solution, the layers were separated, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. Purification by silica gel column chromatography: DCM / MeOH gradient elution, the eluate was collected, concentrated and dried in vacuo to obtain 21 mg of white solid CQ11, mp: 188.0-189.0°C; purity: 99% (HPLC). 1 H-NMR (400MHz, DMSO-d 6 )δ9.2...

Embodiment 2CQ15

[0036] Example 2CQ15(I, R=OCH 3 ) preparation

[0037] 9.0g (0.05mol) of 5-(methoxycarbonyl)-2-picolinic acid and 400mL of dichloromethane were added to the flask; under stirring at room temperature, 10.0g (50mmol) of EDC, 4.2g (0.06mol) of BAPN and 1.5g of triethylamine were successively added. mL (0.01 mol), continue to stir at room temperature, and monitor the reaction end point by TLC. After the reaction was completed, the reaction solution was washed three times with water, and the dichloromethane layers were combined and collected, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a crude product. Recrystallization from ethanol aqueous solution gave CQ15 as a white solid, mp: 136.0-137.0°C; purity: 99% (HPLC). 1 H-NMR (400MHz, DMSO-d 6 )δ9.33(s,1H),9.15(dd,J=2.1,0.8Hz,1H),8.52(dd,J=8.1,2.1Hz,1H),8.22(dd,J=8.1,0.8Hz,1H ), 3.95(s, 3H), 3.59(q, J=6.5Hz, 2H), 2.84(t, J=6.6Hz, 2H). 13 C-NMR (100MHz, DMSO-d 6 )δ165.12,163.77,153.10,149.39,139.23,...

Embodiment 3C

[0038] Example 3 Preparation of CQ16 (I, R=OH))

[0039] 233 mg (1 mmol) of CQ15 was dissolved in 2 mL of methanol, poured into a round-bottomed flask containing 20 mL of NaOH aqueous solution, stirred for reaction at room temperature, and monitored by TLC until CQ15 disappeared completely. After the reaction was completed, the reaction solution was washed three times with an appropriate amount of ethyl acetate, the pH of the aqueous layer was adjusted to 2-3 with dilute hydrochloric acid, an appropriate amount of ethyl acetate was added for extraction three times, the ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 193 mg of light yellow Solid CQ16, mp: 196.0-197.0°C; purity: 99% (HPLC). 1 H-NMR (400MHz, DMSO-d 6 ),δ13.29(s,1H),9.12(s,1H),8.94(m,J=6Hz,1H),8.46(dd,J1=2.3Hz,J2=0.9Hz,1H),8.16(d, J=8.2Hz, 1H), 3.48(m, J=6.7Hz, 2H), 2.55(t, J=6.8Hz, 2H). 13 C-NMR (100MHz, DMSO-d 6 )δ166.08,163.88,152.79,149.61,139.24,124.98,1...

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Abstract

The present invention provides a compound for inhibiting collagen synthesis and deposition and application thereof. The small molecule compound for inhibiting collagen synthesis and deposition is formed by linking P4H inhibitors and LOX inhibitors by chemical means by applying the splicing principle. The invention discloses a preparation method of the small molecule compound I. The present invention also discloses the application of the small molecular compound and its pharmaceutically acceptable salts for inhibiting collagen synthesis and deposition in the treatment of idiopathic pulmonary fibrosis, and the new compound has better anti-pulmonary fibrosis Application prospect.

Description

technical field [0001] The present invention relates to a small molecule compound for inhibiting collagen synthesis and deposition and a pharmaceutically acceptable salt thereof, and its application in preventing or treating idiopathic pulmonary fibrosis. Background technique [0002] Organ fibrosis, such as pulmonary fibrosis, renal fibrosis, liver fibrosis, myocardial fibrosis, etc., is a major disease that seriously endangers human health and life. In recent years, with the global industrialization and changes in people's life and diet, the incidence of fibrotic diseases has increased significantly. [0003] Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic interstitial lung disease of unknown etiology limited to the lungs and characterized by common interstitial pneumonia. IPF invades the alveolar wall and alveolar space and develops into diffuse interstitial pulmonary fibrosis. The patient eventually died of respiratory failure. The statistics ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/81A61P11/00
CPCC07D213/81A61P11/00
Inventor 马臻王尊元沈正荣潘有禄
Owner ZHEJIANG MEDICAL COLLEGE
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