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Cap-dependent endonuclease inhibitors

An alkyl and compound technology, applied in the field of influenza treatment, can solve the problems of inability to act as an influenza treatment agent, poor pharmacological properties, and poor efficacy

Active Publication Date: 2019-10-01
TAIGEN BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these heterocyclic compounds exhibit poor pharmacological properties, such as poor potency, solubility, and bioavailability, making them unsuitable as therapeutic agents for influenza

Method used

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  • Cap-dependent endonuclease inhibitors
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  • Cap-dependent endonuclease inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Embodiment 1: Preparation and characteristics of compound 1 to compound 39

[0078] Synthesis and Characterization of Compound 1

[0079] 1-(1-fluoro-5,11-dihydro-10-thia-dibenzo[a,d]cyclohepten-5-yl)-5-hydroxy-3,3-cyclopropyl-2, 3-Dihydro-1H-pyrido[1,2-b]pyridazine-4,6-dione (Compound 1)

[0080] Compound I-3 was first prepared from commercially available 3-benzyloxy-4-oxyl-4H-pyran-2-carbaldehyde and intermediates I-1 and I-2 in the manner shown below .

[0081]

[0082] Pyrrolidine (30.9g, 434mmole) was added to 3-(benzyloxy)-4-oxyl-4H-pyran-2-carbaldehyde (100g, 434mmole) and cyclopropanaldehyde (91.3g, 1.30mmole) in solvent DMSO (1 L), and the mixture was stirred at 50°C for 23 to 24 hours, then cooled to room temperature. The resulting mixture was dissolved in CH 2 Cl 2 (1 L) with 1N HCl (aq) (1 L) and saturated NaHCO 3 (1 L) aqueous solution, followed by washing with saturated brine (1 L). The organic phase was separated and dried over anhydrous magne...

Embodiment 2

[0160] Example 2: Cytopathic Effect (CPE) Inhibition Test)

[0161] CPE inhibition assays were performed as follows to assess the potency of test compounds to inhibit cap-dependent endonuclease activity.

[0162] MDCK cells in 96-well tissue culture plates were incubated with test compounds and influenza A or influenza B virus at low infection rates at 37°C for 72 hours. Plates were fixed by adding 0.5% formaldehyde and then stained with 0.5% crystal violet. Subsequently, the absorbance at a wavelength of 570 nm was measured with a microdisk analyzer (Multiskan Ascent, Thermo). Relative to the virus control group, the concentration required for the test compound to reduce the virus-induced CPE by 50%, expressed as the 50% effective dose (EC 50 ).

[0163] Compounds 1 to 39 were evaluated using the CPE inhibition assay, where, for influenza A virus infection, 30 test compounds (i.e. compounds 1 to 10, 13, 16 to 22, 25, 27 to 30, 32 to 33, 35 to 38 and 39) Unexpectedly exhib...

Embodiment 3

[0170] Embodiment 3: Survival rate test after infecting influenza virus 24 hours

[0171] The following experiment was performed to evaluate the effect of the compound of formula (I) on the survival rate at 24 hours after infection in a mouse model of influenza A virus.

[0172] First, mice were infected with 100 or 500 pfu using mouse influenza A virus, and then the compound of formula (I) was administered 24 hours after infection. Dosing was twice daily for 5 days. Each compound was orally administered to mice at doses of 5, 10 or 20 mg / kg. Mice infected with 100 or 500 pfu of virus showed extremely high mortality. Unexpectedly, it was observed that the mice treated with oseltamivir showed a survival rate of 16.7% and the mice treated with Comparative Example Compound B1 showed a survival rate of 14.3%. Compound (eg Compound 1 and Compound 2) treated mice exhibited 80 to 100% survival. Oseltamivir is a commercial drug used to treat influenza, and Compound B1 of Comparati...

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Abstract

Provided is a compound of Formula (I) below, or a pharmaceutically acceptable salt, metabolite, or prodrug thereof; wherein Formula (I): A1 is CR4 or N; A2 is CR5' R6'or NR7'; A3 is CR5' R6'or NR7'; each of R1, R2, R2', R3, R3', R4, R5, R5', R6, R6', R7, and R7', independently, is hydrogen, deuterium, halogen, cyano, hydroxyl, carboxyl, amino, formyl, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,C1-6 alkoxy, C2-6 alkenyloxy, C1-6 alkylcarbonyl, C1-6 alkyloxycarbonyl, C1-6 alkylamine, C3-20 carbocyclyl, or C3-20 heterocyclyl; or R5 and R6, R5' and R6', or R5 and R5', together with the adjacent atom to which they are each attached, form C3-10 carbocyclyl or C3-10 heterocyclyl. Further provided are a method of using the above- described compound, or the pharmaceutically acceptable salt, metabolite, or prodrug thereof for treating influenza and a pharmaceutical composition containing same.

Description

[0001] Cross References to Related Applications [0002] This application claims priority from US Provisional Application: 62 / 620,065, filed January 22, 2018. technical field [0003] The present invention relates to a heterocyclic compound with cap-dependent endonuclease inhibitory activity, its prodrug, and its use for influenza treatment. Background technique [0004] The RNA polymerase of influenza virus contains a cap-dependent endonuclease (cap-dependent endonuclease) domain, which cleaves host mRNA to generate a capped RNA fragment, which serves as a primer for priming viral mRNA synthesis. [0005] Translation of viral mRNA by host ribosomes requires the 5' cap of the mRNA, which can be achieved in influenza virus-infected cells by a cap-snatching mechanism whereby a cap-dependent endonuclease extracts a cap from the host The 5' capped ends of the mRNA are then used as transcription primers (10 to 13 nucleotides), and these capped RNA primers are used to synthesize ...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCA61P31/16A61K31/5025C07D471/04
Inventor 许明珠林助强陈宏铨蒋佳颖严启峰
Owner TAIGEN BIOTECHNOLOGY CO LTD
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