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Pyrrolotriazine compounds, compositions and applications thereof

A technology of triazines and compounds, applied in the field of virus infection drugs, can solve problems such as incurable, low enzyme activity, and large side effects

Active Publication Date: 2021-02-05
GUANGZHOU LIUSHUN BIO TEC CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Feline coronavirus is an RNA virus that is prone to mutations. During the replication process, the enzyme activity of its error repair mechanism is very low, so it will mutate very quickly, and the vaccine is based on the fixed genes or proteins of the virus. development research, so its vaccine is more difficult to develop
At present, the treatment of feline infectious peritonitis is mainly conservative treatment, combined with the use of broad-spectrum antibiotics and antiviral drugs to prevent secondary infection, but these drugs have large side effects and cannot be cured
Since there is no effective symptomatic treatment for feline infectious peritonitis, there is a need to develop corresponding therapies

Method used

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  • Pyrrolotriazine compounds, compositions and applications thereof
  • Pyrrolotriazine compounds, compositions and applications thereof
  • Pyrrolotriazine compounds, compositions and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Preparation of Intermediate 1

[0094] (2R)-Isopropyl 2-((perfluorophenoxy)(phenoxy)phosphoryl)alanine was prepared as follows:

[0095]

[0096] Add 10g (0.6mol) L-alanine isopropyl ester hydrochloride, 100ml dichloromethane (DCM) and 12g triethylamine (Et 3 N), cooled to -78°C, stirred for 10 minutes, and then slowly added dropwise a dichloromethane solution of phenyl dichlorophosphate (13g / 50ml). After dropping, the temperature was raised to -20°C, and the reaction was continued to stir for 1 hour. Then 13g of pentafluorophenol and 50ml of dichloromethane were added dropwise to the above reaction solution. After the dropwise addition was completed, the temperature was raised to 25°C and the reaction was stirred, and the reaction was monitored by thin-layer chromatography. After the reaction was completed, the precipitate was removed by suction filtration. The organic phase was concentrated under reduced pressure to obtain 26 g of crude product. The crude prod...

Embodiment 2

[0098] Preparation of intermediate 2

[0099] (3R,4R,5R)-2-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-(benzyloxy)-5-(benzyl The preparation of oxymethyl)-3-fluorotetrahydrofuran-2-alcohol is specifically as follows:

[0100]

[0101] Add 3.4 g of 7-bromopyrrolo[2,1-f][1,2,4]-triazin-4-amine, 4.5 mL of trimethylchlorosilane (TMSCl) and 70 mL of tetrahydrofuran (THF) to the reaction flask , stirred at room temperature for 2 hours. Then the reaction solution was cooled to -78°C, 55mL, 1.0M n-butyllithium hexane solution (n-BuLi) was added dropwise, stirred for 30 minutes after the addition, and then added dropwise with 5.4g (3R, 4R, 5R)- 4-(Benzyloxy)-5-(benzyloxymethyl)-3-fluorodihydrofuran-2(3H)-one in 70 mL THF. After the dropwise addition, the reaction was stirred for 30 minutes, and then 42 mL of acetic acid was added to quench the reaction. The reaction solution was concentrated, diluted with 500 mL of ethyl acetate and washed with 250 mL of saturated NaCl solution...

Embodiment 3

[0109] Preparation of Intermediate 3

[0110] 7-((2S, 3R, 4R, 5R)-4-(benzyloxy)-5-((benzyloxy)methyl)-3-fluoro-2-methyltetrahydrofuran-2-yl)pyrrole[2 ,1-f][1,2,4]The preparation of triazin-4-amine is as follows:

[0111]

[0112] Add 3.6g of starting nucleosides and 200mL of anhydrous THF to the reaction flask, stir and cool to 0°C, add 20mL of 3N methyl magnesium chloride THF solution, and stir the reaction solution overnight. After the reaction was completed, 70 mmol of acetic acid was added to quench the reaction, and concentrated under reduced pressure to obtain a viscous liquid. The crude material was dissolved in 150 mL of anhydrous dichloromethane, 2 mL of methanesulfonic acid was added, stirred at room temperature for 12 hours, and then quenched by adding 35 mmol of triethylamine. The mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to obtain 1.53 g of a methyl-substituted nucleoside.

[0113] 1 H NM...

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Abstract

The invention relates to a pyrrolotriazine compound, a composition and an application thereof, the pyrrolotriazine compound has a structure as shown in a formula (I), and the definitions of R1-R11 areas defined in claim 1. The pyrrolotriazine compound has an excellent antiviral effect, and particularly can be used for preparing drugs for treating feline coronavirus infection-resistant diseases, such as feline infectious peritonitis.

Description

technical field [0001] The invention relates to the field of virus infection drugs, in particular to pyrrolotriazine compounds, compositions and applications thereof. Background technique [0002] Feline coronavirus (FCoV) is a positive-strand RNA virus with a diameter of 80-160 nm. It is an enveloped single-tube RNA. As a common infectious virus, it is transmitted through feces of cats. FCoV-infected cats have a 5-10% chance of mutating into infectious peritonitis (FIP). Feline infectious peritonitis is a chronic, progressive, infectious disease of cats, mainly characterized by peritonitis and a large amount of pleural effusion. . The fatality rate of sick cats is high, and most drugs have no therapeutic effect on them. Feline coronavirus is an RNA virus that is prone to mutations. During the replication process, the enzyme activity of its error repair mechanism is very low, so it will mutate very quickly, and the vaccine is based on the fixed genes or proteins of the vir...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/23C07H1/00A61K31/706A61P31/14
CPCA61P31/14C07H1/00C07H19/23
Inventor 不公告发明人
Owner GUANGZHOU LIUSHUN BIO TEC CO LTD
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