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Hydroxypyridinone [1, 2-b] [1, 2, 5] triazepine derivative as well as preparation and application thereof

A technology of hydroxypyridone and 2-b, which is applied in the production of bulk chemicals, organic chemistry, antiviral agents, etc., and can solve the problems of restricting the clinical use of drugs

Active Publication Date: 2020-12-11
ZHEJIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the teratogenicity and embryotoxicity of Favipiravir, it is only suitable for patients with new types of influenza who are ineffective or not effective enough for other anti-influenza drugs or patients with re-emerging pandemics; Pimodivir-resistant influenza virus mutants, which limit the drug's clinical use

Method used

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  • Hydroxypyridinone [1, 2-b] [1, 2, 5] triazepine derivative as well as preparation and application thereof
  • Hydroxypyridinone [1, 2-b] [1, 2, 5] triazepine derivative as well as preparation and application thereof
  • Hydroxypyridinone [1, 2-b] [1, 2, 5] triazepine derivative as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1 (R)-3-benzyl-1-(10,11-dihydro-5H-dibenzo[a,d][7]cyclo-5-yl)-6-hydroxyl-1,2, 3,4-Tetrahydropyrido[1,2-b][1,2,5]triazepine-5,7-dione hydrochloride;

[0065] Starting material 1: Commercially available.

[0066] Step 1: Preparation of 2-methyl-3-benzyloxy-4H-pyran-4-one:

[0067]

[0068] Dissolve 100g of commercially available benzyl maltol in 80mL of 95% ethanol, then add 83mL of benzyl chloride and 115mL of 30% aqueous sodium hydroxide solution, and let it react at 60°C for 6-18 hours. Ethanol was distilled off under reduced pressure, extracted with 300 mL of dichloromethane, the dichloromethane layer obtained by liquid separation was washed with 30 mL of 4% sodium hydroxide solution, and then washed with 30 mL of saturated brine, and the crude product obtained by evaporation under reduced pressure at 45°C was added to 60 mL of ethyl acetate and 120 mL of petroleum ether were recrystallized to obtain 145.3 g of compound 2 (yield: 84%). Pale yellow solid,...

Embodiment 2

[0109] Example 2 (S)-3-benzyl-1-(10,11-dihydro-5H-dibenzo[a,d][7]cyclo-5-yl)-6-hydroxyl-1,2, 3,4-Tetrahydropyrido[1,2-b][1,2,5]triazepine-5,7-dione hydrochloride

[0110]

[0111] Referring to the method of Example 1, just replace Boc-D-phenylalanine with Boc-L-phenylalanine, off-white powder, m.p.245.1-246.0°C. 1 H NMR (500MHz, DMSO) δ8.54(s, 1H), 8.06(s, 1H), 7.36(d, J=7.5Hz, 1H), 7.31-7.09(m, 13H), 6.11(s, 1H) ,5.71(s,1H), 3.90-3.83(m,1H),3.78(s,1H),3.69-3.63(m,1H),3.46-3.40(m,1H),3.22-3.17(m, 1H) ,2.89-2.83(m,1H),2.79-2.73(m,1H),2.64-2.58(m,3H). 13 C NMR (125MHz, DMSO) δ162.3, 140.0, 139.2, 137.9, 136.0, 135.5, 131.4, 131.1, 130.8, 129.0, 128.9, 128.8, 128.3, 126.5, 126.0, 110.1, 52.4, 35.7, 31.5 ):m / z calcd for (C 30 h 27 N 3 o 3 +H) + :478.2125; found: 478.2131.

Embodiment 3

[0112] Example 3 (S)-11-(10,11-dihydro-5H-dibenzo[a,d][7]cyclo-5-yl)-6-hydroxyl-1,2,3,11,12 ,12a-Hexahydropyrido[1,2-b]pyrrolo[1,2-e][1,2,5]triazepine-5,7-dione hydrochloride

[0113]

[0114] Referring to the method of Example 1, just replace Boc-D-phenylalanine with Boc-L-proline, off-white powder, m.p.276.6-277.5°C. 1 H NMR (500MHz, CHCl 3 )δ7.31(td, J=7.5,1.5Hz, 1H),7.23-7.18(m,2H),7.16(d,J=7.0Hz,1H),7.11(td,J=7.5,1.5Hz,1H ),7.05 (d,J=7.0Hz,1H),7.00(t,J=7.5Hz,2H),6.9(t,J=7.5Hz,1H),5.91(d,J=7.5Hz,1H), 5.39(s,1H),4.06-3.98(m,2H),3.95-3.88(m,1H),3.72-3.66(m,1H), 3.64-3.58(m,1H),3.40(dd,J=14.0 ,5.0,1H),3.30(s,1H),3.03-2.95(m,2H), 2.88-2.83(m,1H),2.09-2.02(m,1H),2.01-1.95(m,1H),1.74 -1.64(m,1H), 1.56-1.52(m,1H). 13 C NMR (125MHz, CHCl 3 )δ171.5, 160.6, 148.4, 141.1, 141.0, 138.7, 135.9, 135.1, 131.4, 131.2, 131.2, 131.1, 129.5, 129.1, 126.9, 126.6, 125.9, 110.0, 77.6, 55.92, 9.3, 55.3 , 22.8.HRMS(ESI):m / zcalcd for (C 26 h 25 N 3 o 3 +H) + :428.1969; found: 428.19...

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Abstract

The invention discloses a hydroxypyridinone [1, 2b] [1, 2, 5] triazepine derivative as well as preparation and application thereof. Experiments prove that the hydroxypyridinone [1, 2b] [1, 2, 5] triazepine derivative (as shown in the general formula I) has a relatively good inhibition effect on the activity of influenza A virus RNA polymerase, and can be used as an influenza virus RNA polymerase inhibitor for treating cold caused by influenza viruses. The structural general formula I is shown in the specification,.

Description

technical field [0001] The invention belongs to the field of pharmacy, and specifically relates to a hydroxypyrido[1,2-b][1,2,5]triazepine derivative, a preparation method and application thereof. Background technique [0002] Influenza (Influenza), referred to as influenza, is an acute respiratory infectious disease caused by influenza virus invading the body. Influenza virus, that is, influenza virus (Influenza virus), is a representative species of Orthomyxoviridae (Orthomyxoviridae), divided into four types: A (A), B (B), C (C), and D (D). Influenza A virus is more prone to antigenic variation, and generally causes an influenza pandemic every 10-15 years; the scale of influenza B caused by influenza B virus is relatively small, and its spread among the population is relatively limited; Influenza C caused by Influenza C virus has the characteristics of sporadic epidemics, causing relatively mild illness in the body; Influenza D virus mainly affects some animals and is no...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P31/16
CPCA61P31/16C07D471/04Y02P20/55
Inventor 陈文腾俞永平柯迪王思函刘祖东袁鑫
Owner ZHEJIANG UNIV
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