Benzoxazole-2-ethyl oxime derivate, preparation method and application thereof

A technology of benzoxazole and ethyl oxime, which is applied in the field of pharmaceuticals, can solve problems such as serious side effects, expensive research and development costs, hidden dangers of kidney and cardiovascular safety, etc.

Active Publication Date: 2018-03-06
SUZHOU UNIV
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  • Summary
  • 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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  • Benzoxazole-2-ethyl oxime derivate, preparation method and application thereof
  • Benzoxazole-2-ethyl oxime derivate, preparation method and application thereof
  • Benzoxazole-2-ethyl oxime derivate, preparation method and application thereof

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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 HNMR (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 HNMR (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 invention provides a benzoxazole-2-ethyl oxime derivate. The benzoxazole-2-ethyl oxime derivate is as shown in a formula (I) or a formula (II), wherein X1 and X2 are independently selected from NHor O; R1 and R3 are independently selected from H, F, Br or C1; R2 is selected from C1-C10 alkyl, substituted C1-C10 alkyl, phenyl or substituted phenyl; the substituted group of the substituted C1-C10 alkyl is selected from phenyl or halogen. Compared with the prior art, the benzoxazole-2-ethyl oxime derivate as shown in the formula (I) or the formula (II) is capable of obviously reducing anklejoint swelling degree and serum uric acid level of a rat with acute gouty arthritis, and is high in NLRP3 and TLR4 dual inhibition activity; the effect of the benzoxazole-2-ethyl oxime derivate is obviously prior to that of positive control dexamethasone; the benzoxazole-2-ethyl oxime derivate is applicable to preparation of drugs for treating hyperuricemia or acute gouty arthritis, and is small in side effect, and high in safety. (The formula is shown in the description).

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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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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