Tri-fused ring compound as PDE3/PDE4 dual inhibitor

A compound and heterocyclic group technology, applied in the field of tricyclic compounds as PDE3/PDE4 dual inhibitors, can solve the problems of unsatisfactory anti-inflammatory effect and unsatisfactory PDE4 inhibitory activity.

Pending Publication Date: 2022-06-21
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Victoria Boswell et al, J.Pharmaco.Experi.Therap.2006,318,840-848 and WO200005830 reported compounds RPL554 and RPL565, which have long-acting bronchodilation and anti-inflammatory effects, as well as poor solubility and high plasma clearance. , suitable for inhalation administration, but the data also show that its PDE4 inhibitory activity is unsatisfactory, and the anti-inflammatory effect is not ideal, so it is necessary to develop compounds with good PDE3 / 4 inhibitory activity

Method used

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  • Tri-fused ring compound as PDE3/PDE4 dual inhibitor
  • Tri-fused ring compound as PDE3/PDE4 dual inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0147] Under nitrogen atmosphere, a mixture of compound BB-1-1 (21.10 g) and ethyl cyanoacetate (11.00 g, 10.38 mL) was stirred at 100° C. for 16 hours. After the reaction was completed, the mixture was cooled to 70° C., and ethanol (30 mL) was slowly added dropwise, and a large amount of solids precipitated out. After filtration, the filter cake was dried under reduced pressure to obtain the product BB-1-2.

[0148] 1 H NMR (400MHz, DMSO-d6) δ=8.26(t, J=5.2Hz, 1H), 6.86(d, J=8.0Hz, 1H), 6.79(br s, 1H), 6.71(d, 8.0Hz, 1H), 4.00(q, J=6.8Hz, 2H), 3.72(s, 3H), 3.59(s, 2H), 3.31-3.23(m, 2H), 2.64(t, J=7.2Hz, 2H), 1.32(t,J=6.8Hz,3H).MS–ESI m / z:263.1[M+H] + .

[0149] Step 2: Synthesis of compound BB-1-3

[0150]Under nitrogen atmosphere, phosphorus oxychloride (379.50 g, 230.00 mL) was heated to 85° C., and compound BB-1-2 (26.00 g) was added in batches. The reaction mixture was stirred at 85°C for 2 hours. After the reaction was completed, most of the phosphorus oxychloride...

Embodiment 2

[0166] Compound BB-2-1 (8g) and urea (9.18g) were dissolved in water (80mL) at room temperature, concentrated hydrochloric acid (12mol / L, 9.56mL) was added dropwise, heated to 110°C and stirred for 24 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, filtered, and the filter cake was washed with water (50 mL x 2), and dried in vacuum to obtain compound BB-2-2.

[0167] 1 H NMR (400MHz, DMSO-d 6 )δ=6.84(br d,J=8.0Hz,1H),6.78(br s,1H),6.69(brd,J=8.0Hz,1H),6.02(br t,J=5.2Hz,1H),5.43 (br s,2H),4.04-3.94(m,2H),3.71(s,3H),2.95(q,J=6.4Hz,2H),2.50-2.40(m,2H),1.66-1.59(m, 2H),1.35-1.25(m,3H).MS–ESI m / z:253.2[M+H] + .

[0168] Step 2: Synthesis of compound BB-2-3

[0169] Under a nitrogen atmosphere, sodium (6.38 g) was added to absolute ethanol (150 mL) in batches, and stirred until the sodium was completely dissolved to obtain a fresh sodium ethoxide solution. Compound BB-2-2 (7 g) and diethyl malonate (11.11 g) were added thereto, foll...

Embodiment 3

[0179] Compound BB-3-1 (2 g) was dissolved in 1,2-dichloroethane (20 mL) at room temperature, trimethylsilylisocyanate (3.82 g) was added dropwise, and then heated to 90° C. and stirred for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was slurried with methyl tert-butyl ether (10 mL) to obtain compound BB-3-2.

[0180] MS–ESI m / z:255.1[M+H] + .

[0181] Step 2: Synthesis of compound BB-3-3

[0182]Under a nitrogen atmosphere, sodium (1.13 g) was added to absolute ethanol (85 mL) in batches, and stirred until the sodium was completely dissolved to obtain a fresh sodium ethoxide solution. Compound BB-3-2 (2.5 g) and diethyl malonate (3.94 g) were added thereto, followed by heating under reflux for 12 hours. The reaction solution was cooled to room temperature, concentrated to remove ethanol, the residue was dissolved in water, 2 mol / L hydrochloric acid was added ...

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Abstract

The invention discloses a tri-fused-ring compound serving as a PDE3 / PDE4 dual inhibitor, and application of the tri-fused-ring compound in preparation of drugs for treating PDE3 / PDE4 related diseases, particularly medicinal functions of the tri-fused-ring compound in the aspects of chronic obstructive pulmonary disease (COPD) and the like. Specifically disclosed are compounds represented by formula (I) and pharmaceutically acceptable salts thereof.

Description

[0001] This application is a divisional application of the following application: filing date: July 12, 2019; application number 201980045308.9; title of invention: "Tricyclic compounds as PDE3 / PDE4 dual inhibitors". [0002] This application claims the following priority: [0003] This application claims the rights and priority of the Chinese Invention Patent Application No. 201810772374.3 submitted to the State Intellectual Property Office of the People's Republic of China on July 13, 2018, the entire contents of which are hereby incorporated herein by reference. technical field [0004] This application relates to a tricyclic compound as a PDE3 / PDE4 dual inhibitor, its preparation method, a pharmaceutical composition containing the compound, and its application in the treatment of diseases related to PDE3 / PDE4, specifically related to chronic obstructive pulmonary disease ( COPD). Background technique [0005] Phosphodiesterase (PDE) belongs to the superfamily of enzymes...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D487/04C07D498/04A61K31/519A61K31/55A61K31/553A61P11/06A61P11/00
CPCC07D471/04C07D487/04C07D498/04A61P11/06A61P11/00A61P11/08A61K31/519C07D513/04A61K31/55A61K31/553A61K31/517
Inventor 罗云富潘建峰张国利苏胜王勇陈曙辉
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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