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Substituted indoline derivatives as dengue viral replication inhibitors

A technology of dengue fever and solvate, applied in the field of substituted indoline derivatives, can solve the problems of effective, inappropriate, and unavailable specific antiviral drugs for treating or preventing dengue virus infection, etc.

Active Publication Date: 2019-11-15
JANSSEN PHARMA NV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Despite these shortcomings, the vaccine is a game-changer in endemic areas, as it will provide protection for a large portion of the population, but may not protect very young infants, who carry the greatest burden of dengue
Furthermore, the dosing regimen and very limited efficacy in flavivirus-naive subjects makes it inappropriate and probably not worthwhile / cost-effective for travelers from non-endemic areas to dengue-endemic areas
The above disadvantages of dengue vaccines are the reasons why pre-exposure to prophylactic dengue antiviral agents is required
[0009] In addition, specific antiviral drugs for the treatment or prevention of dengue virus infection are not currently available
Clearly, there remains a large unmet medical need for therapeutic agents useful in the prevention or treatment of viral infections in animals, more particularly in humans, and especially against viral infections caused by flaviviruses, more specifically dengue viruses

Method used

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  • Substituted indoline derivatives as dengue viral replication inhibitors
  • Substituted indoline derivatives as dengue viral replication inhibitors
  • Substituted indoline derivatives as dengue viral replication inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0073] Example 1 : 2-(4-fluoro-2-(2-hydroxyethoxy)phenyl)-2-((3-methoxy-5-(1H-1,2,4-triazol-1-yl) Synthesis and chiral separation of phenyl)amino)-1-(6-(trifluoromethyl)indolin-1-yl)ethanone (compound 1) into enantiomers 1A and 1B.

[0074]

[0075] Synthesis of Intermediate 1a:

[0076] 4-Fluoro-2-methoxyphenylacetic acid [CAS 886498-61-9] (10 g, 54.3 mmol) was dissolved in EtOH (200 mL) and H 2 SO 4 (2 mL) was heated at reflux for 12 h. Water was added and the mixture was concentrated under reduced pressure to half the original volume. Add ice. The solution was treated with K 2 CO 3 Basified and extracted with EtOAc. The organic layer was washed with brine, washed with MgSO 4 Dry, filter and concentrate the solvent under reduced pressure to give ethyl 2-(4-fluoro-2-methoxyphenyl)acetate 1a (11.6 g). This compound was used directly in the next step.

[0077] Synthesis of intermediate 1b:

[0078] At -30°C, boron tribromide in CH 2 Cl 2 (109.3 mL, 109.3 mmol)...

example 2

[0108] Example 2 : 2-(4-fluoro-2-(2-hydroxyethoxy)phenyl)-2-((3-methoxy-5-(1H-1,2,4-triazol-1-yl) Synthesis and chiral separation of phenyl)amino)-1-(5-methoxy-6-(trifluoromethyl)indolin-1-yl)ethanone (compound 2) into enantiomers 2A and 2B.

[0109]

[0110] Synthesis of intermediate 2a:

[0111] At -10°C, 1-methoxy-4-nitro-2-(trifluoromethyl)benzene [CAS 654-76-2] (24.5g, 110.8mmol) and 4-chlorophenoxy A mixture of acetonitrile [CAS 3598-13-8] (20.4 g, 121.9 mmol) in DMF (100 mL) was added dropwise to a stirred solution of tBuOK (27.35 g, 243.7 mmol) in DMF (100 mL). After the addition, the purple solution was maintained at -10 °C for 1 h. 500 mL of ice water and 500 mL of 6N HCl were added, and the precipitate was filtered off, washed with water and dried under reduced pressure to obtain 40.4 g of 2-(5-methoxy-2-nitro-4-(trifluoro Methyl)phenyl)acetonitrile 2a (used as such in next step).

[0112] Synthesis of intermediate 2b:

[0113] 2-(5-Methoxy-2-nitro-4-(tri...

example 3

[0135] Example 3 : 2-(4-fluoro-2-(2-hydroxyethoxy)phenyl)-2-((3-methoxy-5-(1H-1,2,4-triazol-1-yl) Synthesis and chiral separation of phenyl)amino)-1-(6-(trifluoromethoxy)indolin-1-yl)ethanone (compound 3) into enantiomers 3A and 3B.

[0136]

[0137] Synthesis of intermediate 3a:

[0138] To 2-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-fluorophenyl)-2-((3-methoxy-5-(1H - To a solution of 1,2,4-triazol-1-yl)phenyl)amino)acetic acid 1f (1.02g, 1.974mmol) in DMF (10mL) was added HATU (1.13g, 2.96mmol), diisopropyl Ethylamine (979 μL, 5.92 mmol) and 6-(trifluoromethoxy)indoline [CAS 959235-95-1] (401 mg, 1.97 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water. The precipitate was filtered off, washed with water and taken up with EtOAc. The organic layer was washed with K 2 CO 3 10% solution in water, washed with water, over MgSO 4 Dry, filter and concentrate the solvent under reduced pressure to give 2-(...

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Abstract

The present invention relates to substituted indoline derivatives, methods to prevent or treat dengue viral infections by using said compounds and also relates to said compounds for use as a medicine,more preferably for use as a medicine to treat or prevent dengue viral infections. The present invention furthermore relates to pharmaceutical compositions or combination preparations of the compounds, to the compositions or preparations for use as a medicine, more preferably for the prevention or treatment of dengue viral infections. The invention also relates to processes for preparation of thecompounds.

Description

[0001] The present invention relates to substituted indoline derivatives, a method of preventing or treating dengue virus infection by using said compound, and also relates to said compound as a medicament, more preferably as a medicament for treating or preventing dengue virus infection . Furthermore, the present invention relates to pharmaceutical compositions or combined preparations of these compounds, to compositions or preparations for use as a medicament, more preferably for the prevention or treatment of dengue virus infection. The invention also relates to processes for the preparation of these compounds. Background technique [0002] Flaviviruses transmitted by mosquitoes or ticks cause life-threatening infections in humans, such as encephalitis and hemorrhagic fever. Four distinct but closely related serotypes of the flavivirus dengue are known, the so-called DENV-1, -2, -3 and -4. Dengue is endemic in most tropical and subtropical regions worldwide, mainly in urb...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61K31/41A61P31/14
CPCC07D403/12A61P31/12A61P31/14A61K45/06A61K31/4196Y02A50/30A61K2300/00
Inventor B.R.R.凯斯特莱恩J-F.邦方蒂E.科塞曼斯P.J-M.B.拉布瓦松A.D.M.马钱德D.A.M-E.巴迪奥特
Owner JANSSEN PHARMA NV
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