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Phosphodiesterase-4 inhibitor

A technology of -ra and q-ra, applied in the field of phosphodiesterase-4 inhibitors, can solve the problems of limiting the dosage, not significantly reducing the acute exacerbation of the disease, and improving the quality of life

Inactive Publication Date: 2013-07-03
SHANDONG XUANZHU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Oral administration of roflumilast for more than 4 weeks in COPD patients can significantly reduce the number of neutrophils in sputum, and it can slightly improve lung function after taking roflumilast for more than 6-12 months, but it cannot significantly reduce the acute exacerbation of the disease or improve the quality of life. The reason may be Drug side effects limit its dosage

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] Example 1 N-cyclopropyl-4-oxo-1-(3-(pyridin-3-yloxy)phenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound 1) Preparation

[0144]

[0145] (1) Preparation of 2-chloro-3-pyridyl chloride

[0146]

[0147] Dissolve 2-chloro-3-pyridinecarboxylic acid (15g, 0.095mol) in thionyl chloride, add DMF (N,N-dimethylformamide) (0.5mL), react at 70°C for 3 hours, and depressurize Concentrate, cool and precipitate to obtain the product (13g, yield 78%).

[0148] (2) Preparation of 2-(2-chloronicotinoyl)-3-(dimethylamino)ethyl acrylate

[0149]

[0150] Dissolve 2-chloro-3-pyridine acid chloride (10g, 0.057mol) in toluene (200mL), add TEA (triethylamine) (10.5g, 0.10mol), (E)-3-dimethylaminoacrylic acid Ethyl ester (10g, 0.07mol) was reacted at 90°C for 3 hours, extracted with DCM (dichloromethane) and water, and purified by silica gel column chromatography to obtain the product (13g, yield 81%).

[0151] (3) Preparation of ethyl 1-(3-bromophenyl)-4-oxo-1,4-dih...

Embodiment 2

[0165] Example 2 3-(3-(3-(cyclopropylcarbamoyl)-4-oxo-1,8-naphthyridin-1(4H)-yl)phenoxy)pyridine 1-oxide (C The preparation of nitrogen oxides of compound 1)

[0166]

[0167] The N-cyclopropyl-4-oxo-1-(3-(pyridin-3-yloxy)phenyl)-1,4-dihydro-1,8-naphthyridine- 3-Carboxamide (0.6g, 1.5mmol) and m-chloroperbenzoic acid (m-CPBA) (778mg, 4.5mmol) were dissolved in DCM (200mL) and reacted at 40°C for 3 hours. After the reaction is complete, wash with water, extract with dichloromethane, take the organic phase, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation. The residue is separated and purified by silica gel column chromatography (dichloromethane:methanol=50:1) to obtain the product ( 100mg, yield 16%).

[0168] Molecular formula: C 23 h 18 N 4 o 4 Molecular weight: 414.41LC-MS: 415.2 (M+H) +

[0169] 1 H-NMR (400MHz, CDCl 3 )δ: 9.75(s,1H), 9.02(s,1H), 8.79(dd,1H), 8.75(dd,1H), 8.16(s,1H), 8.02(d,1H), 7.60(m,1H ),7.50-7.47(m,1H),7.3...

Embodiment 3

[0170] Example 3 N-cyclopropyl-4-oxo-1-(3-(pyridin-3-ylthio)phenyl)-1,4-dihydro-1,8-naphthyridine-3-carboxamide (compound 2) Preparation

[0171]

[0172] (1) Preparation of 3-nitrothiophenol

[0173]

[0174] Dissolve 1,2-di(3-nitrophenyl)disulfane (20g, 65mmol) in tetrahydrofuran (200mL), add sodium borohydride (8g, 211mmol) dropwise at 0°C, and react at room temperature for 10 After 1 hour, it was quenched with dilute hydrochloric acid, diluted with ethyl acetate, washed with saturated sodium chloride, the organic phase was taken, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the product (10 g, yield 99%).

[0175] (2) Preparation of 3-((3-nitrophenyl)thio)pyridine

[0176]

[0177] Under nitrogen, cuprous bromide (758 mg, 5.3 mmol), ethyl 2-oxocyclohexanecarboxylate (1.8 mg, 10.6 mmol) and cesium carbonate (33 g, 0.1 mol) were dissolved in dimethyl sulfoxide (100mL), after stirring at room temperature for 0...

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Abstract

The invention belongs to the technical field of medicines and particularly relates to a phosphodiesterase-4 inhibitor as shown in a general formula (I) and a pharmaceutically acceptable salt, a stereoisomer or a solvent compound thereof. In the formula, R1, R2, R3, R4, R5, R6, R7, R8, R9, R7', R8', R9', L and a ring A are as defined in the specification. The invention further relates to a preparation method for the compound, a pharmaceutical composition with the compound, and an application of the compound and the pharmaceutical composition to preparation of drugs for treating and / or preventing inflammatory diseases, disease symptoms and disease conditions characterized by or related with undesired inflammatory immune reaction and all diseases induced by or related with TNF-alpha (tumor necrosis factor-alpha) and PDE-4 (phosphodiesterase-4) hypersecretion.

Description

technical field [0001] The present invention relates to phosphodiesterase-4 inhibitor, its pharmaceutically acceptable salt, its stereoisomer or its solvate, their preparation method, the pharmaceutical composition containing said compound, and said compound and medicine Compositions are useful in the manufacture of treatments and / or prophylaxis of inflammatory diseases, disorders and conditions characterized by or associated with an undesired inflammatory immune response and induced by oversecretion of TNF-α and PDE-4 Application in the medicine of all diseases of or associated with excessive secretion of TNF-α and PDE-4. Background technique [0002] Hormones are a class of compounds that affect cellular activity in different ways. In many cases, hormones act as messengers that trigger specific cellular responses and activities. However, many of the effects produced by hormones are not caused solely by the specific effects of the hormone. Instead, the hormone first bind...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/506A61K31/444A61P29/00A61P37/02A61P11/06A61P11/00A61P11/02A61P37/08A61P19/02A61P1/00A61P17/06A61P17/00A61P27/02
Inventor 吴永谦孙亮
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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