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Bicyclic fused pyrazole derivatives for the treatment of rsv

A compound, bicyclic heteroaryl technology, applied in the field of small molecule therapeutics, can solve unmet problems, high cost, preventing large-scale implementation, etc.

Active Publication Date: 2022-07-29
GEORGIA STATE UNIV RES FOUND INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Adoption of the humanized neutralizing antibody palivizumab for immunoprophylaxis in high-risk pediatric patients, but high cost prevents large-scale implementation
[0013] Therefore, there is still an urgent unmet need for new compounds that can be used to treat and prevent RSV infection

Method used

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  • Bicyclic fused pyrazole derivatives for the treatment of rsv
  • Bicyclic fused pyrazole derivatives for the treatment of rsv
  • Bicyclic fused pyrazole derivatives for the treatment of rsv

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0194] Process for the preparation of series A compounds

[0195] In all experimental data reported below, the following abbreviations are used:

[0196] rt: room temperature

[0197] UV: Ultraviolet

[0198] HPLC: High Pressure Liquid Chromatography

[0199] Rt: retention time

[0200] LCMS: Liquid Chromatography Mass Spectrometry

[0201] NMR: Nuclear Magnetic Resonance Spectroscopy

[0202] CC: Column chromatography

[0203] TLC: Thin Layer Chromatography

[0204] sat: saturated

[0205] aq: water-based

[0206] DCM: dichloromethane

[0207] DCE: Dichloroethane

[0208] DMF: Dimethylformamide

[0209] DIPEA: Diisopropylethylamine

[0210] EtOAc: ethyl acetate

[0211] TEA: Triethylamine

[0212] THF: Tetrahydrofuran

[0213] TFA: trifluoroacetic acid

[0214] t-BuOK: Potassium tert-butoxide

[0215] n-BuOH: n-butanol

[0216] EtOH: Ethanol

[0217] HOAc: acetic acid

[0218] o / n: overnight

[0219] MW: microwave

[0220] h: hours

[0221] min: minutes...

Embodiment 1A

[0224] Example 1A: Conventional Synthesis Method A1

[0225]

[0226] Exemplary experimental procedure for conventional method A1

[0227] 1.4-(3-(Cyclopentyloxy)-4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-b]pyridine-6(7H )-keto (AVG-065) was synthesized as follows:

[0228]

[0229] Compound M2 (200 mg, 1.3 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (272 mg, 1.9 mmol) and 3-(cyclopentyloxy)-4- A mixture of methoxybenzaldehyde (415 mg, 1.9 mmol) in EtOH (10 mL) was refluxed for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc (30 mL x 2). The organic layer was washed with water and brine, filtered through Na 2 SO 4 Drying, filtration and concentration gave crude product, which was purified by preparative TLC to give compound AVG-065 (50 mg, 10% yield) as a white solid.

[0230]Agilent LCMS1200-6110, column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); column temperature...

Embodiment 1B

[0239] Example 1B: Conventional Synthesis Method A2

[0240]

[0241] Exemplary experimental procedure for conventional method A2

[0242] 1. Synthesis of 3-(2-(2,4-dimethoxybenzylidene)hydrazino)propionitrile (F2-2)

[0243]

[0244] Hydrazine hydrate (80%, 5.0 g, 124 mmol) was added to a stirred solution of acrylonitrile (6.0 g, 113 mmol) in THF (50 mL) cooled to 0°C over a period of about 20 min, then the reaction mixture was stirred at room temperature 2h. 2,4-Dimethoxybenzaldehyde (19.7 g, 119 mmol) was added to the reaction mixture over a period of about 15 min, and the reaction mixture was stirred at room temperature for 4 h. Crude oil was then obtained by concentration, which was used directly in the next step.

[0245] Agilent LCMS1200-6110, column: Waters X-Bridge C18 (50mm*4.6mm*3.5μm); column temperature: 40°C; flow rate: 2.0mL / min; mobile phase: from 95% [water+0.05% in 1.6min] TFA] and 5% [CH 3 CN+0.05%TFA] to 0%[Water+0.05%TFA] and 100%[CH 3 CN+0.05%...

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Abstract

Disclosed herein are compounds and compositions for the treatment or inhibition of RSV and related members of the Pneumoviridae and Paramyxoviridae families, such as human metapneumovirus, mumps virus, human parainfluenza virus, and Nipah and Hendra viruses , and methods of treating or preventing it.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims the benefit of US Provisional Application No. 62 / 359,894, filed July 8, 2016, and US Provisional Application No. 62 / 333,992, filed May 10, 2016, the disclosures of which are incorporated herein in their entirety. . [0003] Statement Regarding Federally Funded Research and Development [0004] This invention was made with government support under grants HD079327 and AI071002 awarded by the National Institutes of Health (NIH). The government has certain rights in this invention. technical field [0005] The present invention relates to small molecule therapeutic agents for the treatment of respiratory syncytial virus (RSV) and related members of the families Pneumoviridae and Paramyxoviridae such as human metapneumovirus, mumps virus, human parainfluenza virus and Nipah and Hender pull virus). Background technique [0006] Respiratory syncytial virus (RSV) is a member of the Paramyxoviridae fa...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K39/155C07K14/135
CPCA61K31/437A61K31/444C12N2760/18511A61P31/12C07D471/04C07D519/00
Inventor 理查德·K·普莱佩尔艾迪·李约翰·维纳乔艾丽丝·布尔克
Owner GEORGIA STATE UNIV RES FOUND INC
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