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Targeted EP4 receptor micromolecule antagonist and application thereof in treatment of osteoarthritis and cartilage defects

A technology selected from and compounds, applied in the biological field, to achieve the effect of repairing articular cartilage damage, inhibiting catabolism, and reducing osteophyte formation

Pending Publication Date: 2022-04-01
EAST CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Existing studies on the treatment of osteoarthritis with EP4 antagonists mainly focus on their anti-inflammatory effects and pain relief. There are no reports or patent documents mentioning the correlation between the activity of the EP4 signaling pathway in cartilage and cartilage anabolism. For Effects on repair of cartilage damage and regulation of subchondral bone homeostasis

Method used

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  • Targeted EP4 receptor micromolecule antagonist and application thereof in treatment of osteoarthritis and cartilage defects
  • Targeted EP4 receptor micromolecule antagonist and application thereof in treatment of osteoarthritis and cartilage defects
  • Targeted EP4 receptor micromolecule antagonist and application thereof in treatment of osteoarthritis and cartilage defects

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0128] Example 1-1, Compound (S)-4-(1-(1-(2-(4-fluorophenoxy)ethyl)-4-phenyl-1hydrogen-1,2,3-triazole - Preparation of 5-formylamino) ethyl) benzoic acid

[0129]

[0130] Add 1-(2-bromoethoxy)-4-fluorobenzene (657mg, 3.00mmol) and sodium azide (215mg, 3.30mmol) to anhydrous dimethylsulfoxide (8ml), stir at room temperature for 12 hour, add water and ethyl acetate to extract after the reaction is over, take the organic layer and add a certain amount of anhydrous sodium sulfate, filter, and evaporate the organic solvent to dryness under reduced pressure without further purification to obtain the crude product 1-(2-azidoethyl Oxy)-4-fluorobenzene (516 mg, 95% yield).

[0131] 1-(2-azidoethoxy)-4-fluorobenzene (516mg, 2.85mmol) was added to the toluene solution (15ml), then ethyl phenylpropiolate (496mg, 2.85mmol) was added, at 120 Reflux at ℃ for 8 hours, cool to room temperature after the reaction, evaporate the organic solvent to dryness under reduced pressure, and purify...

Embodiment 1-2

[0135] Example 1-2, Compound 4-(1-1-(2-(4-fluorophenoxy)ethyl)-4-phenyl-1hydrogen-1,2,3-triazole-5-formyl Preparation of amino)cyclopropyl)benzoic acid

[0136]

[0137] Substitute (S)-methyl 4-(1-aminoethyl)benzoate with methyl 4-(1-aminocyclopropyl)-benzoate, and prepare according to the method of Example 1-1. 1 H NMR (500MHz, DMS0) δ12.86(s, 1H), 9.69(s, 1H), 7.81(d, J=8.5Hz, 2H), 7.66(d, J=8.2Hz, 2H), 7.45(dd J=15.6,8.2Hz,3H),7.36(d,J=8.5Hz,2H),7.09(t,J=8.8Hz,2H),6.92(dd,J=9.2,4.4Hz,2H),4.84( t, J=5.0Hz, 2H), 4.37(t, J=5.0Hz, 2H), 1.36(t, J=6.4Hz, 2H), 1.30(t, J=5.8Hz, 2H).

Embodiment 1-3

[0138] Example 1-3, Compound (S)-4-(1-(1-(2-(3-(trifluoromethyl)phenoxy)ethyl)-4-phenyl-1hydrogen-1,2 , the preparation of 3-triazole-5-carboxamido) ethyl) benzoic acid

[0139]

[0140] Replace 1-(2-bromoethoxy)-4-fluorobenzene with 1-(2-bromoethoxy)-3-(trifluoromethyl)benzene, and prepare according to the method of Example 1-1. 1 H NMR (500MHz, DMS0) δ12.80(s, 1H), 9.57(d, J=7.7Hz, 1H), 7.88(d, J=8.1Hz, 2H), 7.65(d, J=5.3Hz, 2H ), 7.48(t, J=9.8Hz, 3H), 7.39(d, J=2.4Hz, 3H), 7.29(d, J=7.5Hz, 1H), 7.17(d, J=7.1Hz, 2H) , 5.31-5.21 (m, 1H), 4.89-4.77 (m, 2H), 4.51-4.38 (m, 2H), 1.42 (d, J=6.9Hz, 3H).

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Abstract

The invention discloses a triazole compound as shown in a formula (I), as well as a medicinal derivative and a hydrate thereof, and a composition containing the triazole compound. The invention also discloses a series of small molecule antagonists of the targeted prostaglandin receptor EP4, and the antagonists can be used for treating cartilage degeneration, subchondral bone lesion and pain caused by cartilage defect and / or osteoarthritis, promoting chondrogenesis of articular cartilage, inhibiting hypertrophy of the articular cartilage, and improving the cartilage degeneration and subchondral bone lesion caused by osteoarthritis. Anabolism of cartilage is promoted, catabolism is inhibited, cartilage regeneration is promoted, and then articular cartilage injury is repaired; meanwhile, the stable state of the subchondral bone can be maintained, and the activity of osteoclast in the subchondral bone at the early stage of osteoarthritis is inhibited, so that uncoupled bone remodeling of the subchondral bone is inhibited, and osteophyte formation is reduced. The micromolecule provided by the invention can also be used for researching in-vitro or in-vivo treatment of osteoarthritis.

Description

technical field [0001] The invention belongs to the technical field of drug application in the field of biotechnology, and relates to small molecule antagonists targeting prostaglandin receptor EP4 and derivatives thereof. The maintenance of state to treat related small molecule drugs, and its use in the preparation of drugs for the treatment of osteoarthritis-related diseases. Background technique [0002] Injuries to joints and articular cartilage occur frequently, with more than 6 million visits to U.S. hospitals each year for a variety of knee, wrist, and ankle conditions. Cartilage defects occur frequently in middle-aged and elderly people and athletes, and are the main cause of pain and disability. Divided into partial thickness cartilage defect and full thickness cartilage defect. Full-thickness cartilage defect destroys cartilage and subchondral bone, which will cause bone marrow mesenchymal stem cells to migrate to the defect, and some mesenchymal stem cells will ...

Claims

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Application Information

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IPC IPC(8): C07D249/06C07D249/04C07D409/04C07D405/04A61K31/4192A61P19/02A61P19/08A61P29/00A61P19/00
Inventor 罗剑金蕴韵姜文浩章涵堃卢伟强王维刘明耀
Owner EAST CHINA NORMAL UNIVERSITY
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