Alpha-configuration nucleoside and application in treating cat coronavirus infection

A configuration, nucleoside technology, applied in the treatment of coronavirus infection in cats or other animals, α-configuration nucleosides and corresponding prodrugs, and the field of solvates

Inactive Publication Date: 2020-11-20
李小冬
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In terms of treatment, there is currently no specific drug for FIP

Method used

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  • Alpha-configuration nucleoside and application in treating cat coronavirus infection
  • Alpha-configuration nucleoside and application in treating cat coronavirus infection
  • Alpha-configuration nucleoside and application in treating cat coronavirus infection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Synthesis of Example 1 Compound 1

[0038]

[0039] Under nitrogen protection, compound 1A (25.16 g, 45.53 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (55 mL, 2.1 times), stirred at 0°C, and TfOH (8.1 mL, 91.06 mmol, 2.0 eq), after the dropwise addition was completed, stir for 10 minutes. Then TMSOTf (17.3 mL, 95.61 mmol, 2.1 eq) was slowly added dropwise. After the dropwise addition was completed, the reaction was stirred at this temperature for 30 minutes. Slowly add TMSCN (22.8 mL, 182.11 mmol, 4.0 eq) dropwise, and after the dropwise addition, stir below 0°C for 2 hours. TLC detected that the reaction of the raw materials was complete, and slowly added 22 mL of triethylamine dropwise. After the drop, the reaction solution rose to room temperature, then added sodium bicarbonate (34.42 g), added dropwise 120 mL of water, stirred for 10 minutes after the drop, and separated the liquid , collected the organic phase, extracted the aqueous phase with dic...

Embodiment 2

[0044] Synthesis of Example 2 Compound 2

[0045]

[0046]Compound 1 (0.5 g, 1.72 mmol, 1.0 eq) was suspended in 10 mL of pyridine, DMAP (21 mg, 0.17 mmol, 0.1 eq) was added, and isobutyric anhydride (870 mg, 5.49 mmol, 3.2 eq ). After the dropwise addition, stir overnight at room temperature, TLC shows that the reaction of the raw materials is complete, spin the reaction solution to dryness, add 20 mL of dichloromethane to dissolve, add 20 mL of saturated sodium bicarbonate solution and stir for 10 minutes, separate the liquids, and use dichloromethane for the aqueous phase Extraction (20 mL×1), combined organic phases, dried over anhydrous sodium sulfate, filtered, spin-dried, and column chromatography gave compound 2 as a white solid (689 mg, yield: 79.9%).

[0047] 1H NMR (500 MHz, DMSO-d6) : 8.03 (s, 1H), 7.93 – 7.81 (m, 2H), 6.93(d, J = 3.5 Hz, 1H), 6.72 (d, J = 3.5 Hz, 1H) , 4.95 (s, 1H), 4.53 (s, 1H),4.12 (s, 1H), 3.96 – 3.94 (m, 1H), 3.77 – 3.75 (m, 1H), 2.63 – 2...

Embodiment 3

[0049] Synthesis of Example 3 Compound 3

[0050]

[0051] Compound 1 (0.5 g, 1.72 mmol, 1.0 eq) was suspended in 10 mL of pyridine, TMSCl (653 mg, 6.01 mmol, 3.5 eq) was slowly added dropwise, and stirred at room temperature for 1 hour. Then octanoyl chloride (307 mg, 1.89 mmol, 1.1 eq) was slowly added dropwise, and stirred at room temperature until TLC showed that the reaction of the starting material was complete. Spin the reaction solution to dryness, add 20 mL of dichloromethane to dissolve, add 20 mL of saturated sodium bicarbonate solution and stir for 10 minutes, separate the layers, extract the aqueous phase with dichloromethane (20 mL×1), combine the organic phases, and anhydrous sulfuric acid Sodium-dried, filtered, spin-dried, and column chromatography gave compound 2 as a white solid (480 mg, yield: 67.0%).

[0052] 1H NMR (500 MHz, DMSO-d6): 8.32 (br, 1H), 8.13 (s, 1H), 7.02 (d, J =3.5 Hz, 1H), 6.81 (d, J = 3.5 Hz, 1H), 5.50 (d, J = 4.5 Hz, 1H), 5.30 (d, J ...

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Abstract

The present invention provides a method for treating coronavirus infections in cats or other animals by administering a nucleoside represented by a formula (I) and a corresponding prodrug, solvate, orpharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the compound, wherein the nucleoside and the prodrug thereof in the formula (I) are in alpha configuration, and R1, R2, R3 and R4 are all defined in the specification. The formula (I) is defined in the specification.

Description

technical field [0001] The present invention relates to the field of veterinary medicine, in particular to an α-configuration nucleoside and a corresponding prodrug, a solvate thereof, or a pharmaceutically acceptable salt, a pharmaceutical composition comprising the compound, and a method for treating cats or other animals Application for coronavirus infection. Background technique [0002] Feline coronavirus (FCoV) is widespread in cats, with an estimated 40-80% of cats worldwide carrying the virus. In nature, FCoV exists as two distinct biotypes: feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV), which is a mutated form of the former. [0003] Most cats with FECV infection are asymptomatic, but FIPV infection can easily invade other organs and develop infectious peritonitis (FIP). The disease occurs in young cats of 3-9 months, especially in cats raised in groups. The course may be sudden (more common in young cats) or indolent and last f...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07F9/6561A61P31/14A61K31/4196A61K31/675
CPCA61P31/14C07D487/04C07F9/65616
Inventor 不公告发明人
Owner 李小冬
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