CN113912605A

CN113912605A - Influenza virus inhibitor

Info

Publication number: CN113912605A
Application number: CN202010661979.2A
Authority: CN
Inventors: 熊国裕; 许铮
Original assignee: Beijing Kawin Technology Share Holding Co ltd
Current assignee: Beijing Kawin Technology Share Holding Co ltd
Priority date: 2020-07-10
Filing date: 2020-07-10
Publication date: 2022-01-11

Abstract

The present invention relates to an influenza virus inhibitor and the therapeutic effect of the inhibitor in patients after influenza virus infection.

Description

Influenza virus inhibitor

Technical Field

The invention belongs to the field of chemical drugs, and particularly relates to a compound with cap-dependent endonuclease inhibitory activity and application of the compound in influenza treatment.

Background

Influenza virus causes an infectious disease every year, 29 to 65 million people die worldwide, and 300 to 500 million people have severe disease. In addition, epidemics caused by newly emerging recombinant viruses may have devastating global effects. Therefore, there is a continuing effort to improve vaccines and antiviral drugs as a strategy. Two classes of antiviral drugs are currently available for clinical use, neuraminidase inhibitors (NAIs: oseltamivir, zanamivir, peramivir) and M2 ion channel inhibitors (amantadine, rimantadine). However, the currently circulating influenza viruses are largely resistant to the M2 inhibitor s 3. In addition, NAIs are relatively weak against viruses, and another concern with this class of drugs is the emergence of resistance, as in the H1N1 influenza pandemic season of oseltamivir resistance from 2008 to 2009. Therefore, the treatment and prevention of influenza virus infection requires more effective antiviral drugs with new mechanisms of action.

Heterotrimeric RNA-dependent RNA polymerase (RdRp) of influenza virus consists of PA, PB1 and PB2 subunits. It is responsible for the replication and transcription of the segmented single-stranded viral RNA genome (vRNA) in the nucleus of infected cells. Transcription of viral mRNA is by a unique "cap robbing" mechanism. This involves high hijacking of the host RNA polymerase by binding the nascent capped transcript to the PB2 subunit, followed by cleavage at the nucleotide by a cap-dependent endonuclease (CEN) in the PA subunit. Short, cap enzyme-bearing oligomers, produced by the RdRp function of PB1 subbunit 1, serve as primers for viral mRNA transcription. Viral transcripts are polyadenylated in a conserved rich region of the template vRNA by a mechanism to convert to functional proteins upon nuclear export. Since cap snatching is a necessary condition for viral replication, cap-binding, endonuclease and RdRp activities are attractive targets for small molecule inhibitors, and indeed several new compounds against polymerases are actively under clinical development. In 2014, favipiravir (avigan), an RNA synthesis inhibitor, was approved in japan, although this indication was limited to the treatment of novel influenza viruses that do not respond to other drugs. Pimodivir (JNJ-63623872, VX-787) is a PB2 cap-binding inhibitor that is used alone in combination with oseltamivir for virological efficacy against simple influenza, but only against influenza A viruses. Thus, there is a continuing effort to find and develop better performing influenza drugs.

Disclosure of Invention

The invention aims to provide a brand-new compound with cap-dependent endonuclease inhibition activity, which has the following structure:

wherein P is^aIs hydrogen, deuterium, or a substituent group that forms a prodrug;

r is selected from CH₂O, S or NR¹Wherein R is¹Independently hydrogen, halogen, hydroxy, carboxy, formyl, lower alkyl, halogenated lower alkyl, lower alkyloxy, halogenated lower alkyloxy, lower alkyloxy lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, lower alkylsulfonylamino.

R²Each independently of the others is hydrogen, deuterium, halogen,Hydroxy, alkyl, haloalkyl, or alkoxy;

m is an integer of 0 to 2

A preferred embodiment is a compound of the present invention, or a pharmaceutically acceptable salt thereof, wherein R is²Preferably halogen, R is N.

Specifically, the present invention relates to compounds having the structure:

wherein said P^aIs hydrogen or a substituent group that forms a prodrug.

The substituent groups forming the prodrug are selected from the following structures:

(1)-C(＝O)-P^R0、-C(＝O)-L-P^R0、-C(＝O)-L-O-P^R0、-C(＝O)-L-O-L-P^R0；

(2)-C(＝O)-O-P^R1、-C(＝O)-O-L-P^R1、-C(＝O)-N-P^R1；

(3)-C(P^R2)2-O-P^R3、-C(P^R2)2-O-C(＝O)-O-P^R3

l is a linear or branched alkylene group, or a linear or Chilean-mounted Hilen group;

the P is^R0Is hydrogen or alkyl optionally substituted with a substituent Q, alkenyl optionally substituted with a substituent Q, carbocyclyl optionally substituted with a substituent Q, heterocyclyl optionally substituted with a substituent Q, alkylamino optionally substituted with a substituent Q, or alkylthio optionally substituted with a substituent Q;

P^R1、P^R3each independently is hydrogen, deuterium, or an alkyl group substituted with a substituent Q, a carbocyclyl group optionally substituted with a substituent Q, a heterocyclyl group optionally substituted with a substituent Q, a carbocycloalkyl group optionally substituted with a substituent Q, a heterocycloalkyl group optionally substituted with a substituent Q, or an alkylsilyl group optionally substituted with a substituent Q;

P^R2is hydrogen, deuterium or alkyl;

substituent Q is hydrogen, deuterium, oxo, alkyl, hydroxyalkyl, amino, alkylamino, carbocyclyl, heterocyclyl, carbocycloalkyl, alkylcarbonyl, halogen, hydroxy, carbonyl, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyloxy, alkylaminocarbonyloxy, alkylaminoalkyl, alkoxy, cyano, nitro, azido, alkylsulfonyl, trialkylsilyl or phosphoryl.

In a more preferred embodiment, R1 is hydrogen and P is^RThe base is as follows:

-C(＝O)-CH₃、-C(＝O)-O-(CH₂)₂-O-CH₃、-CH₂-O-C(＝O)-CH₃、-CH₂-O-C(＝O)-O-CH₃、

-CH₂-O-C(＝O)-O-CH₂CH₃、-CH(CH₃)-O-C(＝O)-O-CH₃、

-CH₂-O-C(＝O)-CH(CH₃)-NH-C(＝O)-O-C(CH₃)₃、CH₂C₆H₅。

one specific embodiment relates to the following structure:

more preferably, when it is a prodrug, P^aHas the specific structure that

Such as the following prodrug structures

The invention also relates to a pharmaceutical composition, which comprises the compound or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In the invention, besides the compound or the pharmaceutically acceptable salt thereof, the compound can also comprise other anti-influenza virus compounds, such as oseltamivir.

In another aspect, the present invention relates to the use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating influenza, and the use of a composition comprising the compound of the present invention in treating influenza, wherein the composition may further comprise other anti-influenza virus compounds, such as oseltamivir.

Detailed Description

In vitro cell inhibition assay

CPE inhibition assays were performed as follows to evaluate the efficacy of test compounds to inhibit the activity of cap-dependent endonuclease.

MDCK cells in 96-well tissue culture plates were cultured with the test compound and influenza A (IFV A/WSN/33(H1N1)) at low infectivity for 72 hours at 37 ℃, the plates were fixed by adding 0.5% formaldehyde and then stained with 0.5% crystal violet, and subsequently, absorbance at 570nm was measured with a microplate analyzer (Multiskan Ascent, Thermo), and the concentration required for the test compound to reduce virus-induced CPE by 50% relative to the virus control group, representing 50% effective dose (EC)₅₀) And CC₅₀The value is obtained.

Each compound was evaluated in a CPE-inhibition assay, wherein compounds 2, 3 and 4 had CE50 values of less than 10nM, while compound 6 was almost inactive against IFV A/WSN/33 influenza virus.

TABLE 1 inhibitory Activity of each candidate Compound on IFV A/WSN/33

CPD No.	CPD ID	EC₅₀(nM)	CC₅₀(nM)
				1	kw028-24	15.72	>1000
2	kw028-25	7.802	>1000
				3	kw028-26	7.502	>1000
4	kw028-27	7.586	>1000
				5	kw028-21	31.880	>1000
6	kw028-30	>1000	>1000

Claims

1. A compound having the following formula (I) or a pharmaceutically acceptable salt thereof,

r is selected from CH₂O, S or NR¹Wherein R is¹Independently hydrogen, halogen, hydroxy, carboxy, formyl, lower alkyl, halogenated lower alkyl, lower alkyloxy, halogenated lower alkyloxy, lower alkyloxy lower alkyl, lower alkyloxy, lower alkylcarbonyl, lower alkyloxycarbonyl, lower alkylamino, lower alkylcarbonylamino, lower alkylaminocarbonyl, lower alkylsulfonyl, lower alkylsulfonylamino.

R²Each independently is hydrogen, deuterium, halogen, hydroxy, alkyl, haloalkyl, or alkoxy;

m is an integer of 0 to 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is O, -NOH, -NOCH₃or-NOCH₂OCH₃。

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R²Is halogen.

4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is one of:

wherein said P^aIs hydrogen or a substituent group that forms a prodrug.

5.The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein said P is^aIs hydrogen, or a substituent group selected from the following to form a prodrug:

(1)-C(＝O)-P^R0、-C(＝O)-L-P^R0、-C(＝O)-L-O-P^R0、-C(＝O)-L-O-L-P^R0；

(2)-C(＝O)-O-P^R1、-C(＝O)-O-L-P^R1、-C(＝O)-N-P^R1；

(3)-C(P^R2)2-O-P^R3、-C(P^R2)2-O-C(＝O)-O-P^R3

P^R2is hydrogen, deuterium or alkyl;

6. A compound according to claim 5, or a pharmaceutically acceptable salt thereof, whereinThe P is^aIs hydrogen, or a substituent group selected from the following to form a prodrug: :

-C(＝O)-CH₃、-C(＝O)-O-(CH₂)₂-O-CH₃、-CH₂-O-C(＝O)-CH₃、-CH₂-O-C(＝O)-O-CH₃、-CH₂-O-C(＝O)-O-CH₂CH₃、-CH(CH₃)-O-C(＝O)-O-CH₃、-CH₂-O-C(＝O)-CH(CH₃)-NH-C(＝O)-O-C(CH₃)₃、CH₂C₆H₅。

7. a pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prophylaxis or treatment of influenza.