Search

CN-115894587-B - Preparation of nucleoside derivative and application of nucleoside derivative in antiviral drug field

CN115894587BCN 115894587 BCN115894587 BCN 115894587BCN-115894587-B

Abstract

The invention relates to a compound shown as a formula I, a preparation method and application thereof. The compound of the invention is suitable for developing into novel antiviral drugs by having good antiviral activity.

Inventors

  • LIU JUN
  • LI XIANGYANG
  • FU HAIJIAN

Assignees

  • 知和(山东)大药厂有限公司

Dates

Publication Date
20260505
Application Date
20220930
Priority Date
20210930

Claims (9)

  1. 1. A compound which is a compound of formula I or a stereoisomer of a compound of formula I, or a pharmaceutically acceptable salt thereof: In structural formula I: m represents 1; R a is halogen, or hydrogen; When R a is halogen, -OR 3 is absent; R b is hydrogen; R c is hydrogen; r 1 represents hydrogen; R 2 represents hydrogen, - (CO) R 6 、-(CO)-OR 6 、-(CO)-NHR 6 ; r 3 、R 4 independently of one another represents hydrogen, -COR 6 、-(CO)-OR 6 ; R 5 represents 、 、 ; W represents O or S; Q represents O, or-NH-; R x 、R y independently represents hydrogen, alkyl of any 1-8 carbon atoms, alkoxy of any 1-8 carbon atoms, or R x 、R y are connected into a ring; R 6 represents any one of alkyl of 1 to 8 carbon atoms, carbocyclyl of 3 to 8 carbon atoms, heterocyclyl of 2 to 8 carbon atoms, aryl of 6 to 12 carbon atoms, heteroaryl of 3 to 12 carbon atoms, optionally substituted with one or more of hydrogen, amino; R 7 represents any one of an alkyl group of 1 to 8 carbon atoms, an alkoxy group of 1 to 8 carbon atoms, an alkylamino group of 1 to 8 carbon atoms, a carbocyclyl group of 3 to 8 carbon atoms, a heterocyclyl group of 2 to 8 carbon atoms, an aryl group of 6 to 12 carbon atoms, a heteroaryl group of 3 to 12 carbon atoms, optionally substituted with one or more R 12 ; R 8 represents hydrogen, deuterium, alkyl of any 1-8 carbon atoms, aryl of any 6-12 carbon atoms; R 9 represents hydrogen, alkyl of any 1-8 carbon atoms, alkoxy of any 1-8 carbon atoms, carbocyclyl of any 3-8 carbon atoms, heterocyclyl of any 2-8 carbon atoms, aryl of any 6-12 carbon atoms, heteroaryl of any 3-12 carbon atoms, optionally substituted with one or more of hydrogen, deuterium, halogen, hydroxy, mercapto, cyano, amino, trifluoromethyl, acetyl, carboxyl, alkyl of 1-8 carbon atoms, alkoxy of 1-8 carbon atoms, carbocyclyl of 3-8 carbon atoms, heterocyclyl of 2-8 carbon atoms, aryl of 6-12 carbon atoms, heteroaryl of 3-12 carbon atoms; R 10 、R 11 independently represents hydrogen, alkyl of any 1-8 carbon atoms, aryl of any 6-12 carbon atoms.
  2. 2. The compound of claim 1 having the structure of formula II: the definition of substituents in formula II is as defined in formula I of claim 1.
  3. 3. The compound of claim 1 having the structure of formula III: the definition of substituents in formula III is as defined in formula I of claim 1.
  4. 4. The compound of claim 1 having the structure of formula IV: the definition of substituents in formula IV is as defined in formula I of claim 1.
  5. 5. The compound of claim 1 having the structure: 。
  6. 6. Use of a compound according to any one of claims 1 to 5 for the preparation of a medicament for the treatment or prophylaxis of orthomyxoviridae, paramyxoviridae, coronaviridae, filoviridae in a human or other animal body.
  7. 7. An antiviral agent pharmaceutical composition comprising a compound of any one of claims 1-5 and a pharmaceutically acceptable adjuvant.
  8. 8. The antiviral agent pharmaceutical composition of claim 7, wherein the dosage form is selected from the group consisting of an injectable dosage form, a respiratory tract dosage form, a skin dosage form, a mucosal dosage form, a luminal dosage form, and an oral dosage form.
  9. 9. The pharmaceutical composition according to claim 7, comprising the compound according to any one of claims 1 to 5 in an amount ranging from 0.01% to 80% (W/W%).

Description

Preparation of nucleoside derivative and application of nucleoside derivative in antiviral drug field Technical Field The invention relates to the technical field of medicines, in particular to a compound which improves the antiviral effect of drug molecules by introducing carbon-sulfur double bond groups and has better drug development prospect. Background Orthomyxovirus (Orthomyxoviuses) is a virus with affinity for mucin on the surface of human or some animal erythrocytes, with a single-stranded RNA genome, and influenza virus belongs to one of the orthomyxoviruses. Orthomyxoviruses mainly comprise three types of influenza a virus, influenza b virus and influenza c virus, wherein the influenza a virus is the strongest among the three, the number of people infected in multiple seasons of influenza is the largest, and serious respiratory tract infection diseases can be induced, so that more than 30 tens of thousands of people die from influenza every year worldwide. In China, tens of millions of people are infected with influenza virus each year, especially the prevalence rate and the mortality rate of infants and the elderly are high, and diseases such as pneumonia and the like can be caused. Therefore, development of antiviral drugs effective in treating influenza a virus is particularly important. Currently, the major anti-influenza drugs on the market are amantadine (AMANTADINE), the neuraminidase inhibitor oseltamivir (Oseltamivir) or Zanamivir (Zanamivir). However, these compounds also exhibit poor physicochemical properties such as low solubility, low bioavailability, etc., which make them undesirable as influenza therapeutics. Disclosure of Invention The first aspect of the invention is to provide a preparation method of nucleoside derivatives with novel structures and application thereof in the field of antiviral drugs. The second aspect of the present invention is that the compounds of the present invention have a high antiviral activity in vitro and in vivo. In a third aspect, the invention provides compounds useful for treating individuals infected with orthomyxoviridae, paramyxoviridae, coronaviruses, and filoviridae. In a fourth aspect of the present invention, compounds are provided that exert potent antiviral effects in cells and in individuals infected with the aforementioned viruses, achieving unexpected results. Unless specifically stated otherwise herein, the terms used herein are all the basic meanings commonly understood by those skilled in the art. The invention provides a compound which is a compound shown in a formula I or a stereoisomer, a tautomer, an oxide, a solvate, a metabolite or a pharmaceutically acceptable salt of the compound shown in the formula I: In structural formula I: M represents 1, 2, 3, or 4; R a is halogen, or hydrogen; When R a is halogen, -OR 3 is absent; R b is halogen, methyl, or hydrogen; r c is azido, cyano, or hydrogen; r 1 represents hydrogen, halogen, alkyl of any 1-8 carbon atoms, alkoxy of any 1-8 carbon atoms, alkenyl of any 2-8 carbon atoms, alkynyl of any 2-8 carbon atoms, carbocyclyl of any 3-8 carbon atoms, heterocyclyl of any 2-8 carbon atoms, aryl of any 6-12 carbon atoms, heteroaryl of any 3-12 carbon atoms; R 2 represents hydrogen, deuterium, alkyl of any 1-8 carbon atoms, alkoxy of any 1-8 carbon atoms, - (CO) R 6、-(CO)-OR6、-(CO)-NHR6; R 3、R4 independently represents hydrogen, deuterium, -COR 6、-(CO)-OR6 or R 3、R4, and are connected to form a ring; R 5 represents 、、; W represents O or S; Q represents O, or-NH-; R x、Ry independently represents hydrogen, alkyl of any 1-8 carbon atoms, alkoxy of any 1-8 carbon atoms, or R x、Ry are connected into a ring; R 6 represents any one of an alkyl group of 1 to 8 carbon atoms, an alkoxy group of 1 to 8 carbon atoms, a carbocyclyl group of 3 to 8 carbon atoms, a heterocyclyl group of 2 to 8 carbon atoms, an aryl group of 6 to 12 carbon atoms, a heteroaryl group of 3 to 12 carbon atoms, optionally substituted with one or more of hydrogen, deuterium, halogen, hydroxy, mercapto, cyano, methylthio, ethylthio, amino, trifluoromethyl, acetyl, carboxyl, alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, carbocyclyl of 3 to 8 carbon atoms, heterocyclyl of 2 to 8 carbon atoms, aryl of 6 to 12 carbon atoms, heteroaryl of 3 to 12 carbon atoms; r 7 represents any one of an alkyl group of 1 to 8 carbon atoms, an alkoxy group of 1 to 8 carbon atoms, an alkylamino group of 1 to 8 carbon atoms, a carbocyclyl group of 3 to 8 carbon atoms, a heterocyclyl group of 2 to 8 carbon atoms, an aryl group of 6 to 12 carbon atoms, a heteroaryl group of 3 to 12 carbon atoms, optionally substituted with one or more R 12; R 8 represents hydrogen, deuterium, alkyl of any 1-8 carbon atoms, alkoxy of any 1-8 carbon atoms, alkylamino of any 1-8 carbon atoms, carbocyclyl of any 3-8 carbon atoms, heterocyclyl of any 2-8 carbon atoms, aryl of any 6-12 carbon atoms, heteroaryl of any 3-12 carbon atoms, optionally substituted by one