A kind of benzoxazole-2-ethyl oxime derivative, its preparation method and application

A technology of benzoxazole and ethyl oxime, applied in the pharmaceutical field, can solve the problems of many side effects, intolerance of patients, acute attack of gout without therapeutic effect and the like

Active Publication Date: 2021-02-12
SUZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, these drugs not only have serious side effects, but also have no therapeutic effect on the acute attack of gout
In December 2015, the FDA just approved Zurampic, a new drug for the treatment of gout. Although its combination with xanthine oxidase inhibitors can well control the content of serum uric acid, it also has renal and cardiovascular safety risks
In terms of anti-inflammatory drugs, clinically commonly used western medicines such as colchicine, non-steroidal anti-inflammatory drugs and glucocorticoids can be used to relieve acute gouty arthritis, but these drugs are used in large amounts and have many side effects. intolerable
Although the emerging interleukin-1 (IL-1) receptor blocker Rilonacept and anti-IL-1β monoclonal antibody Canakinumab can significantly relieve the joint symptoms of gout patients who are ineffective or intolerable to conventional anti-inflammatory analgesic treatment, but Its research and development costs are expensive, the way of administration is limited, and there are serious safety problems

Method used

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  • A kind of benzoxazole-2-ethyl oxime derivative, its preparation method and application
  • A kind of benzoxazole-2-ethyl oxime derivative, its preparation method and application
  • A kind of benzoxazole-2-ethyl oxime derivative, its preparation method and application

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preparation example Construction

[0041] The present invention also provides a method for preparing the above-mentioned benzoxazole-2-ethyloxime derivatives, comprising:

[0042] Carry out oximation reaction with the compound shown in formula (1) and hydroxylamine hydrochloride, obtain the compound shown in formula (2);

[0043] The compound shown in the formula (2) and R 2 COCl reaction, obtains the compound shown in formula (I);

[0044] Or the compound shown in formula (3) and R 4 SO 2 NHNH 2 Reaction, obtains the compound shown in formula (II);

[0045]

[0046] Among them, X 1 with X 2 each independently selected from NH or O;

[0047] R 1 with R 3 each independently selected from H, F, Br or Cl;

[0048] R 2 Selected from C1~C10 alkyl, substituted C1~C10 alkyl, phenyl or substituted phenyl; the substituent of the substituted C1~C10 alkyl is selected from phenyl or halogen; the substituted phenyl The substituents are selected from C1~C10 alkyl, C1~C10 alkoxy, halogen or nitro;

[0049] R ...

Embodiment 1

[0058] Embodiment 1: the synthesis of 1-(benzoxazol-2-ethyl)-1-alcohol

[0059] Add 6g of 2-aminophenol, 5ml (D / L) lactic acid, 20ml of p-toluenesulfonic acid, and 25ml of toluene into a 50ml round-bottom flask, use a water trap, and heat to reflux at 142°C for 8h. After the reaction was finished, wait for the mixture to cool to room temperature, add 100ml of water, extract with ethyl acetate, extract 3 times with 20ml each time, dry with anhydrous magnesium sulfate, and spin evaporate. The crude product was passed through the column with petroleum ether: ethyl acetate (4:1 ~ 2:1) gradient to obtain a viscous tan product.

[0060] Utilize nuclear magnetic resonance to analyze the product obtained in embodiment 1, obtain: 1 H NMR (600MHz, DMSO-d 6 )δ7.72(t, J=8.6Hz, 2H), 7.37(qd, J=10.3, 6.9, 6.0Hz, 2H), 5.93(d, J=5.0Hz, 1H), 4.96(p, J=5.9 Hz, 1H), 1.54 (t, J=4.2Hz, 3H).

[0061] 13 C NMR (151MHz, DMSO-d 6 ) δ 168.78, 150.50, 140.91, 125.56, 124.81, 120.18, 111.26, 62.93,...

Embodiment 2

[0062] Embodiment 2: Synthesis of 1-(benzoxazol-2-ethyl)-1-ketone

[0063]Dissolve 1g of compound 1-(benzoxazol-2-ethyl)-1-ol in 50ml of dichloromethane, mix 1.3g of pyridinium chlorochromate with 6.5g of silica gel powder, add the above solution, and stir overnight at room temperature , filtered after the reaction, and rinsed the residue with acetone, collected the filtrate and rotary evaporated. The crude product was separated by column with petroleum ether: dichloromethane (1:1) to obtain a white to light yellow product.

[0064] Utilize nuclear magnetic resonance to analyze the product obtained in embodiment 2, obtain: 1 H NMR (600MHz, Chloroform-d) δ7.90 (dt, J=8.0, 1.0Hz, 1H), 7.68–7.64 (m, 1H), 7.54 (ddd, J=8.3, 7.2, 1.2Hz, 1H), 7.46 (ddd, J = 8.3, 7.3, 1.1 Hz, 1H), 2.82 (s, 3H).

[0065] 13 C NMR (151MHz, DMSO-d 6 )δ 152.6, 150.0, 140.1, 110.6, 119.1, 123.8, 124.8, 185.0, 26.1.

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Abstract

The present invention provides a kind of benzoxazole-2-ethyl oxime derivative, as shown in formula (I) or formula (II); Wherein, X 1 with X 2 each independently selected from NH or O; R 1 with R 3 each independently selected from H, F, Br or Cl; R 2 selected from C1-C10 alkyl, substituted C1-C10 alkyl, phenyl or substituted phenyl; the substituent of the substituted C1-C10 alkyl is selected from phenyl or halogen. Compared with the prior art, the benzoxazole-2-ethyloxime derivatives shown in the formula (I) or formula (II) provided by the invention can significantly reduce the acute gouty arthritis rat ankle joint Swelling degree and serum uric acid level, with good dual inhibitory activity of NLRP3 and TLR4, the effect is higher than that of the positive control dexamethasone, and can be used to prepare drugs for the treatment of hyperuricemia or acute gouty arthritis, with few side effects and high safety .

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and in particular relates to a benzoxazole-2-ethyloxime derivative, a preparation method and application thereof. Background technique [0002] Hyperuricemia is a common metabolic disease that seriously endangers human health caused by increased uric acid synthesis or decreased uric acid excretion. Recent studies have found that elevated blood uric acid is an independent risk factor for kidney disease, and may be a pathogenic factor for kidney disease. Among them, gout is a crystal-associated arthropathy caused by the deposition of monosodium urate (MSU), which is directly related to hyperuricemia caused by purine metabolic disorders and / or decreased uric acid excretion, and belongs to the category of metabolic disorders. In the category of sexual rheumatism, it mainly manifests as recurrent acute and chronic gouty arthritis, tophi, uric acid stones, uric acid nephropathy, etc., and acute gouty...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/56C07D235/14A61P19/06A61P19/02A61P29/00
Inventor 李环球周泽浩黄俊陈喜华
Owner SUZHOU UNIV
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