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Prodrugs of substituted polycyclic carbamoyl pyridone derivatives

A technology of substituents and alkyl groups, applied in the fields of polycyclic carbamoyl pyridone derivatives, prodrugs thereof and pharmaceutical compositions containing them, can solve the problem that there is no record of cap-dependent endonuclease, no record of previous medicine and other issues

Active Publication Date: 2016-03-16
SHIONOGI & CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The substances that have been reported to inhibit endonuclease of cap-dependent nuclease are: flutamide (flutimide, patent document 1 and non-patent document 1 and 2) or 4-substituted 2,4-dioxobutanoic acid (non-patent document 3 ~5), etc., but not yet clinically used as an anti-influenza drug
In addition, Patent Documents 2 to 16 and Non-Patent Document 6 describe compounds having a structure similar to the compound of the present invention as compounds having HIV integrase inhibitory activity, but there is no description about cap-dependent endonuclease
It should be noted that Patent Document 17 describes the invention of "substituted polycyclic carbamoyl pyridone derivatives" having cap-dependent endonuclease inhibitory activity filed by the present applicant, but there is no Describe the prodrugs involved in the present invention

Method used

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  • Prodrugs of substituted polycyclic carbamoyl pyridone derivatives
  • Prodrugs of substituted polycyclic carbamoyl pyridone derivatives
  • Prodrugs of substituted polycyclic carbamoyl pyridone derivatives

Examples

Experimental program
Comparison scheme
Effect test

reference example 1

[1309] 【Chemical 79】

[1310]

[1311] first step

[1312] A solution of compound 1A (12.8 g, 89.4 mmol) and pyridine (8.50 g, 107 mmol) in dichloromethane (90 mL) was cooled to 1-3° C., and benzyloxyacetyl chloride was added dropwise over 50 minutes while maintaining the same temperature ( 19.8 g, 107 mmol) in dichloromethane (90 mL). After stirring the reaction solution at the same temperature for 30 minutes, the temperature was gradually raised to 15° C. over 60 minutes, and ice water was added. The dichloromethane layer was separated, and the aqueous layer was extracted once with dichloromethane. The combined extracts were washed three times with water, washed with saturated brine, and then dried. The solvent was distilled off, and the obtained oil was purified by silica gel column chromatography. It was first eluted with n-hexane, followed by n-hexane-ethyl acetate (1:1, v / v). When the target fraction was concentrated, 22.2 g of Compound 1B was obtained as an oil....

reference example 2

[1339] 【Chemical 80】

[1340]

[1341] first step

[1342] Trifluoroacetic acid (40 ml) was added to (S)-tert-butyl 3-hydroxy-1,1-diphenylpropan-2-ylcarbamate (5.00 g, 15.3 mmol), followed by stirring under ice-cooling for 1 hour. After trifluoroacetic acid was distilled off, toluene was added and the mixture was again distilled off under reduced pressure to obtain crude (S)-2-amino-3,3-diphenylpropan-1-ol. To the obtained (S)-2-amino-3,3-diphenylpropan-1-ol, compound 1F (5.73 g, 15.3 mmol), toluene (50 ml), triethylamine (6.4 ml, 45.8 mmol) were added , stirred at 90° C. for 1 hour, and cooled to room temperature, and then the solvent was distilled off. Dichloromethane was added to the obtained residue, followed by washing with 2N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and saturated brine. After separating the organic layer, magnesium sulfate was added, Celite filtration was performed, and the filtrate was distilled off to obt...

reference example 3

[1357] 【Chemical 81】

[1358]

[1359] According to Reference Example 2, compound 3 was synthesized by the same method.

[1360] 1 H-NMR (DMSO-d 6 )δ: 3.15(1H, m), 3.26(3H, s), 3.52-3.70(4H, m), 3.70-3.80(2H, m), 4.10(1H, d, J=12.9Hz), 4.92(1H , brs), 6.98(1H, t, J=7.4Hz), 7.03(1H, brs), 7.08(1H, t, 7.6Hz), 7.34(1H, d, J=7.8Hz), 7.47(1H, d , J=7.3Hz), 7.80 (1H, s), 10.94 (1H, brs), 15.38 (1H, brs).

[1361] MS: m / z = 412.4 [M+H] + .

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Abstract

The present invention provides compounds having antiviral effects, particularly influenza virus growth-inhibiting activities, and more preferably pros of substituted 3-hydroxy-4-pyridone derivatives exhibiting cap-dependent endonuclease inhibitory activity. medicine.

Description

technical field [0001] The present invention relates to substituted polycyclic carbamoylpyridone derivatives exhibiting cap-dependent endonuclease inhibitory activity, prodrugs thereof and pharmaceutical compositions containing them. Background technique [0002] Influenza is an acute respiratory infection caused by influenza virus infection. In Japan, millions of influenza-like patients are reported every winter, and influenza is accompanied by high attack and mortality rates. It is a particularly important disease in high-risk groups such as infants and the elderly. Among the elderly, the complication rate of pneumonia is high, and the elderly account for the majority of deaths due to influenza. [0003] Known anti-influenza medicines are: Sinmetrel (Symmetrel, trade name: Amantadine (Amantadine)) or rimantadine hydrochloride (Flumadine, trade name: Rimantadine (Rimantadine)), Neuraminidase inhibitors Oseltamivir (trade name: Tamiflu) or Zanamivir (trade name: Relenza) t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/53A61P31/16A61P43/00
CPCC07D471/14A61K31/4738C07D471/04A61P31/00A61P31/16A61P43/00A61K31/541C07F9/65616A61K31/53C07D253/10C07F9/6561
Inventor 高桥知佳三神山秀勋秋山俊行富田健嗣垰田善之河井真阿南浩辅宫川雅好铃木尚之
Owner SHIONOGI & CO LTD
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