Triadyncyclic compounds as dual pde3/pde4 inhibitors

A compound and heterocyclyl technology, applied in the field of chronic obstructive pulmonary disease, can solve the problems of unsatisfactory anti-inflammatory effect and unsatisfactory PDE4 inhibitory activity

Active Publication Date: 2022-02-18
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] 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, poor solubility, high plasma clearance, etc. Physical and chemical properties, suitable for inhalation administration, but the data also show that its PDE4 inhibitory activity is not satisfactory, 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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  • Triadyncyclic compounds as dual pde3/pde4 inhibitors
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  • Triadyncyclic compounds as dual pde3/pde4 inhibitors

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0143] Embodiment 1: the synthesis of compound BB-1

[0144]

[0145] Step 1: Synthesis of compound BB-1-2

[0146] 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.

[0147] 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] + .

[0148] Step 2: Synthesis of compound BB-1-3

[0149]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 r...

Embodiment 2

[0162] Embodiment 2: the synthesis of compound BB-2

[0163]

[0164] Step 1: Synthesis of compound BB-2-2

[0165] 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.

[0166] 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(brt, 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] + .

[0167] Step 2: Synthesis of compound BB-2-3

[0168] Under a nitrogen atmosphere, sodium (6.38 g) was added to absolute ethanol (150 mL) in batches, and stirred until the sodium was c...

Embodiment 3

[0175] Embodiment 3: the synthesis of compound BB-3

[0176]

[0177] Step 1: Synthesis of compound BB-3-2

[0178] Compound BB-3-1 (2 g) was dissolved in 1,2-dichloroethane (20 mL) at room temperature, trimethylsilyl isocyanate (3.82 g) was added dropwise, and the temperature was raised 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.

[0179] MS-ESI m / z: 255.1[M+H] + .

[0180] Step 2: Synthesis of compound BB-3-3

[0181]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 c...

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Abstract

Disclosed are a class of trihecyclic compounds as PDE3/PDE4 dual inhibitors, and their application in the preparation of drugs for PDE3/PDE4-related diseases, especially their medicinal functions in aspects such as chronic obstructive pulmonary disease (COPD) . Specifically disclosed are compounds represented by formula (I) and pharmaceutically acceptable salts thereof.

Description

[0001] This application claims the following priority: [0002] 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 [0003] 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 [0004] Phosphodiesterase (PDE) belongs to the superfamily of enzymes, including 11 families, each of which is involved in different signal transduction and regulates different physiological processes. Among them, PDE3 is the main phosphodiesterase in human airway smooth muscle (ASM), an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/517A61K31/519A61P11/08
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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