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Condensed ring compound and preparation method and application thereof

A technology of compounds and oxides, applied in the direction of active ingredients of heterocyclic compounds, drug combinations, organic chemistry, etc., can solve problems such as reducing the degradation of aggrecan

Pending Publication Date: 2021-12-07
CHENGDU KANGHONG PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in 2007, Song et al. (Arthritis Rheum 2007,56(2):575-585) found that in human chondrocytes, siRNA transfection to interfere with the expression of ADAMTS-5 or ADAMTS-4 can reduce aggrecan degradation, however, simultaneous inhibition of ADAMTS-4 and ADMTS-5 exhibited comparable effects to ADAMTS-5 alone

Method used

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  • Condensed ring compound and preparation method and application thereof
  • Condensed ring compound and preparation method and application thereof
  • Condensed ring compound and preparation method and application thereof

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specific Embodiment approach

[0252] In order to make the purpose and technical solution of the present invention clearer, the present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. Moreover, the specific experimental methods not mentioned in the following examples are all carried out according to conventional experimental methods.

[0253] Abbreviations in this document have the following meanings:

[0254] Abbreviation meaning

[0255] TLC thin layer chromatography

[0256] LC-MS liquid chromatography-mass spectrometry

[0257] DMF N,N-Dimethylformamide

[0258] DMSO dimethyl sulfoxide

[0259] EA ethyl acetate

[0260] PE petroleum ether

[0261] THF Tetrahydrofuran

[0262] LDA lithium diisopropylamide

[0263] LiHMDS lithium bistrimethylsilylamide

[0264] NaHMDS lithium bistrimethylsilylamide

[026...

Embodiment 1

[0320] Example 1: (S)-5-cyclopropyl-5-[3-(1,2,3,4-tetrahydroisoquinolin-2-yl)-3-oxopropane]imidazoline-2, Preparation of 4-diketones

[0321]

[0322] 3-[(4S)-4-cyclopropyl-2,5-dioximidazolidin-4-yl]propionic acid (70mg, 0.33mmol), EDCI (76mg, 0.396mmol), HOBT (54mg, 0.396mmol ) and DIPEA (128mg, 0.99mmol) were dissolved in 2mL of dichloromethane, stirred at room temperature for half an hour, then added 1,2,3,4-tetrahydroisoquinoline (44mg, 0.33mmol), and continued to stir for 12 hours. After the completion of the reaction monitored by TLC, 22 mg of the target compound (white solid, yield 20.4%) was separated by preparative TLC.

[0323] 1 H NMR (400MHz, DMSO-d 6 )δ:10.63(s,1H),7.74(s,1H),7.20-7.18(m,4H),4.61-4.59(m,2H),3.63-3.59(m,2H),2.88-2.85(t, J=6.0Hz, 1H), 2.77-2.74(t, J=6.0Hz, 1H), 2.47-2.43(m, 1H), 2.36-2.28(m, 1H), 2.03-1.91(m, 2H), 1.14 -1.04(m,1H),0.46-0.44(m,1H),0.35-0.28(m,2H),0.13-0.07(m,1H). ESI-MS(m / z)328.1[M+H] + .

[0324] Compounds shown in Table ...

Embodiment 18

[0334] Example 18: (S)-5-cyclopropyl-5-(3-(2-(3,5-difluorophenyl)-2,6-dihydropyrrolo[3,4-c]pyrazole Preparation of -5(4H)-yl)-3-oxopropyl)imidazoline-2,4-dione

[0335]

[0336] step 1 : Preparation of tert-butyl 2-(3,5-difluorophenyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (Int18-2)

[0337] To a solution of starting material Int18-1 (500mg, 2.39mmol) and 3,5-difluoroiodobenzene (574mg, 2.39mmol) in DMF (6mL) were added sequentially potassium phosphate (1.01g, 4.78mmol), phosphide Copper (92 mg, 0.48 mmol) and (1S,2S)-(+)-1,2-cyclohexanediamine (55 mg, 0.48 mmol). Under a nitrogen blanket, the reaction was stirred at 120°C for 18 hours. Subsequently, the reaction solution was diluted with 50 mL of water, and extracted with ethyl acetate (50 mL×2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and finally separated by silica gel column chromatography (EA:PE=15:85) to obtain 250 mg of the target compou...

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Abstract

The present invention provides a condensed ring compound and a preparation method and application thereof, the compound has a good inhibitory effect on ADAMTS-5 and / or ADAMTS-4, particularly, the compound exhibits excellent selectivity and bioavailability.

Description

technical field [0001] The present invention relates to fused ring compounds for treating diseases mediated by ADAMTS-5 and / or ADAMTS-4 (such as osteoarthritis), more specifically to biscyclic inhibitors and their stereoisomers and interconversions Isomers, polymorphs, solvates (such as hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxygen compounds, isotope labels, prodrugs, etc. The present invention also relates to the preparation method, intermediate, pharmaceutical preparation, pharmaceutical composition and therapeutic use of the compound. Background technique [0002] Articular cartilage is a nonvascular tissue, 95% of its volume is occupied by extracellular matrix, which mainly consists of two components: type II collagen and aggrecan. Type II collagen is an extracellular matrix protein that forms a cross-linked rigid triple helix structure that ensures the mechanical strength of cartilage. Aggrecan is an extensively glycosylated extracellular...

Claims

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Application Information

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IPC IPC(8): C07D401/06C07D495/04C07D403/06C07D487/04C07D471/14C07D403/14C07D403/12A61K31/4725A61K31/437A61K31/4178A61K31/4375A61K31/4985A61K31/55A61P19/08A61P17/06A61P31/04A61P19/06
CPCC07D401/06C07D495/04C07D403/06C07D487/04C07D471/14C07D403/14C07D403/12A61P19/08A61P17/06A61P31/04A61P19/06
Inventor 孙启正吴红丽柯尊洪
Owner CHENGDU KANGHONG PHARMA GRP
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