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Broad spectrum antiviral compositions and methods

A technology of compositions and compounds, applied in the field of broad-spectrum antiviral compositions and methods, capable of solving problems such as reducing transplantation, infected organs, nephrotoxic side effects, and increased drug resistance rates

Pending Publication Date: 2020-10-23
艾弗里斯生物有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Cytomegalovirus (HCMV) is the most prevalent post-transplant pathogen; HCMV can infect most organs, and despite the availability of HCMV antiviral agents, such as ganciclovir, nephrotoxic side effects and increased rates of drug resistance are significant Reduced transplant and patient survival

Method used

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  • Broad spectrum antiviral compositions and methods
  • Broad spectrum antiviral compositions and methods
  • Broad spectrum antiviral compositions and methods

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0269] Preparation of intermediates

[0270] Preparation of Intermediate 1

[0271]

[0272] 1. 1 (Key Organics, 15g, 48.08mmol), 2,4-dimethyl-1H-imidazole (13.8g, 144.23mmol), (S,S)-N,N'-dimethyl-1, A mixture of 2-diaminocyclohexane (1.37g, 9.62mmol), t-BuOK (16.15g, 144.23mmol) and CuI (4.58g, 24.04mmol) in NMP (150mL) was heated at 160°C under N 2 Stir overnight. The mixture was cooled to RT and NaHCO was added 3 Saturated aqueous solution (50mL) and Boc 2 O (26.2 g, 120 mmol), and the resulting mixture was stirred overnight at RT. The mixture was concentrated and the residue was purified by chromatography on silica gel to provide material which was purified by prep-HPLC to afford 2 (6 g, 38% yield) as a pale yellow oil. MS (ESI): C 19 h 25 N 3 o 2 Theoretical molecular weight: 327.43, m / z experimental molecular weight: 327.9[M+H] + .

[0273] 2. To a solution of 2 (6 g, 18.35 mmol) in DCM (50 mL) was added TFA (50 mL). The resulting mixture was stirred overn...

Embodiment 1

[0436] 1. To a solution of Intermediate 7 (346 mg, 1.09 mmol) in DMSO (10 mL) was added Intermediate 9 (329 mg, 1.31 mmol) and K 2 CO 3 (300 mg, 2.18 mmol). The mixture was stirred overnight at 120 °C and cooled to RT. The mixture was treated with water and extracted with EA. The combined organic extracts were washed with water, brine, washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to provide a crude oil. The crude product was purified by silica gel chromatography to provide 90.36 mg of Example 1. 1 HNMR (CDCl 3 ,300MHz)δ:δ:1.3-1.4(d,6H),3.0-3.1(m,2H),3.6-3.8(m,2H),4.1(s,2H),4.2-4.3(s,2H), 4.8-4.9(s,2H),6.5(s,1H),7.0-7.1(s,1H),7.1-7.2(s,1H),7.4-7.5(s,1H),7.5-7.6(s,1H ), 7.7.6-7.7(d,1H), 7.7-7.8(s,1H), 7.8-7.9(s,1H), 7.9-8.0(s,1H). LC-MS: m / z=496.5(M+1) + .

Embodiment 2

[0438] 1. Intermediate 9 (100mg, 0.40mmol), Intermediate 3 (121mg, 0.44mmol), Pd 2 (dba) 3 (36.6mg, 0.04mmol), SPhos (16.4mg, 0.04mmol) and t-BuOK (123mg, 1.10mmol) in dioxane (2.00mL) was stirred at 95°C for 2h. The reaction was quenched with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, washed with Na 2 SO 4 Dried and concentrated. The residue was purified by prep-HPLC to afford Example 2 (45.9 mg, 25% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 )δ2.91(2H,t,J=5.6Hz),3.67(2H,t,J=5.6Hz),4.04(2H,s),4.08(3H,s),4.60(2H,s),6.53( 1H,t,J=2.0Hz),7.03(1H,s),7.25(1H,d,J=8.0Hz),7.36(2H,d,J=8.4Hz),7.63-7.73(3H,m), 7.77 (2H, d, J = 8.4 Hz), 8.46 (2 H, d, J = 2.0 Hz). MS theoretical value: 453.2; MS experimental value: 454.2 [M+H] + .

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Abstract

Novel thiazole- and isoquinoline- containing compounds are presented that are useful for treating and / or preventing broad-spectrum viral infections. Methods of treating and / or preventing broad-specturm viral infections are also presented. These compounds have shown inhibitio of HCMV, influenza viruses, Zika virus, BK Virus and RSV replication in cell-based assays.

Description

[0001] Statement of Federally Funded Research [0002] The U.S. Government has a paid-up license in this invention and, in limited circumstances, the right to require the patent owner to license others under reasonable terms established by the National Institute of Allergy and Infectious Diseases. of Allergy and Infectious Diseases under the terms of Contract No. 1R44AI122488-01 awarded by technical field [0003] The present application relates to compounds for preventing, treating or ameliorating viral infections. [0004] References to related applications [0005] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 574,067, filed October 18, 2017, which is incorporated herein by reference in its entirety. Background technique [0006] According to the Viral Disease Branch of the Walter Reed Army Institute of Research, non-adenoviral respiratory infections "account for 25-30 percent of infectious disease hospitalizations in the military and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14A61K31/427A61K31/4709A61P31/12
CPCA61K45/06A61K31/4725A61K31/4741A61K31/496A61K31/506A61K31/5355A61K31/5377A61K31/541C07D417/14A61P31/12C07D491/056Y02A50/30A61K31/427A61K31/4709
Inventor 斯泰西·雷米谢夫斯基莉莲·W·希昂艾尼·安东尼·墨菲弗兰克·凯泽孙群萨拉·乔斯林·芬克
Owner 艾弗里斯生物有限责任公司
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