Substituted polycyclic pyridone compound and prodrug thereof

A compound and solvent compound technology, applied in heterocyclic compound isotope introduction, isotope introduction into organic compounds, organic chemistry, etc., can solve problems such as limited application range, poor patient compliance, and unmet clinical needs

Active Publication Date: 2019-10-11
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Poor absorption, distribution, metabolism and / or excretion (ADME) properties are known to be a major reason for failure of many drug candidates in clinical trials
Many currently marketed drugs also limit their application range due to poor ADME properties
The rapid metabolism of drugs will cause many drugs that can treat diseases with high efficiency to be eliminated from the body too quickly, making it difficult to become a drug
Although frequent or high-dose medication may solve the problem of rapid drug clearance, this method will bring problems such as poor patient compliance, side effects caused by high-dose medication, and increased treatment costs
In addition, rapidly metabolizing drugs may also expose patients to undesirable toxic or reactive metabolites
[0009] Although Baloxavir Marboxil is effective in the treatment of influenza, there are still serious clinical unmet needs in this area, and it is still challenging to find new compounds with good oral bioavailability and druggability

Method used

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  • Substituted polycyclic pyridone compound and prodrug thereof
  • Substituted polycyclic pyridone compound and prodrug thereof
  • Substituted polycyclic pyridone compound and prodrug thereof

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0140] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and selection of appropriate protecting groups can be readily determined by those skilled in the art. The chemistry of protecting groups can be found in, eg, Wuts and Greene, Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.

[0141] The compounds of the present invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. isomer. Enantiomeric resolution may be performed using diastereomeric derivatives of the compounds of the invention, preferentially dissociable complexes (eg, crystalline diaster...

Embodiment 1

[0224] Example 1 (((12aR)-12-((11S)-7,8-difluoro-6,11-dihydrodibenzo(B,E)thiepin-11-yl- 11-d)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-(1,4)oxazine(3,4-C)pyrido(2,1 -F)(1,2,4) Preparation of triazin-7-yl)oxy)methyl carbonate (compound T-1)

[0225]

[0226] The synthetic route is as follows

[0227]

[0228] Synthesis of step 1 compound 25

[0229] Compound 9 (0.5g, 1.5mmol), compound 24 (0.45g, 1.5mmol) and T3P (0.73g, 2.3mmol) were added to ethyl acetate (6ml) in turn, and then methanesulfonic acid (0.29g , 3.0mmol), the reaction solution was reacted at 70°C for 6 h, then 10ml of water was added, and then extracted with ethyl acetate (20ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation ( Eluent: petroleum ether / ethyl acetate (v / v)=1:2), 0.6 g of white solid was obtained with a yield of 69%.

[0230] Synthesis of step 2 compound 26

[0231] Compound 25 (0.6g, 1.0mmol) and...

Embodiment 2

[0236] Example 2 (((12aR)-12-((11S)-7,8-difluoro-6,11-dihydrodibenzo(B,E)thiepin-11-yl- 11-d)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-(1,4)oxazine(3,4-C)pyrido(2,1 -F)(1,2,4) Triazin-7-yl-3,3,4,4-d 4 ) Oxygen group) the preparation of methyl carbonate (compound T-2)

[0237]

[0238] The synthetic route is as follows

[0239]

[0240] Synthesis of step 1 compound 28

[0241] Compound 17 (0.5g, 1.5mmol), compound 24 (0.45g, 1.5mmol) and T3P (0.73g, 2.3mmol) were added to ethyl acetate (6ml) solution in turn, and then methanesulfonic acid (0.29g , 3.0mmol), the reaction solution was reacted at 70°C for 6h, then 10ml of water was added, and then extracted with ethyl acetate (20ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated solution was subjected to column separation (washing Removing agent: petroleum ether / ethyl acetate (v / v)=1:2), 0.55 g of white solid was obtained, yield 60%.

[0242] Synthesis of step 2 compound...

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PUM

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Abstract

The invention provides a deuterium-substituted polycyclic pyridone compound, a prodrug thereof, a composition containing the compound and application of the composition. The deuterium-substituted polycyclic pyridone compound is the compound shown in the formula (I) or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent compound thereof. The compound and the composition show the cap-dependent endonuclease inhibitory activity and have superior pharmacokinetic properties.

Description

technical field [0001] The present invention relates to a substituted polycyclic pyridone compound and its prodrug, a composition containing the compound and its application. More specifically, the present invention relates to certain deuterium-substituted (((12aR)-12-((11S)-7,8-difluoro-6,11-dihydrodibenzo(B,E)thiaheptine -11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-(1,4)oxazine(3,4-C)pyrido(2, 1-F) (1,2,4) triazin-7-yl) oxy) methyl methyl carbonate and parent drug thereof, these deuterium-substituted compounds and compositions thereof exhibit cap-dependent endonuclease ( Cap-dependent endonuclease) inhibitory activity, and these deuterium-substituted compounds have better pharmacokinetic properties. Background technique [0002] Influenza is called influenza (influenza or flu) for short, is the acute respiratory infectious disease that is caused by the infection of influenza virus, has become the viral infectious disease with the highest fatality rate. Elderly people o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/14A61K31/5383A61P31/16C07B59/00
CPCC07D498/14A61P31/16C07B59/002C07B2200/05
Inventor 王义汉刘志强李焕银
Owner SHENZHEN TARGETRX INC
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