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Cefixime derivative and its preparation method and use

A technology of cefixime double salt and cephalosporin, which is applied in the field of medicinal chemistry, can solve the problems of low bioavailability of oral preparations, slow onset of drug effect, and is not suitable for emergency treatment, and achieves improved bioavailability, high antibacterial activity and good heat resistant effect

Active Publication Date: 2016-05-25
GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The drug used in clinical treatment is cefixime trihydrate, which has very little solubility in water, and the dosage form is administered in the form of oral solid preparations, such as tablets, capsules, dispersible tablets and granules. These oral formulations have low bioavailability due to poor solubility in water
In addition, compared with injections, oral solid preparations have a slower onset of action and are not suitable for emergency treatment of patients with severe infections or multidrug-resistant patients. Therefore, it is urgent to convert oral solid preparations of cefixime into injections for emergency treatment. However, as an injection, the drug must have excellent water solubility and stability

Method used

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  • Cefixime derivative and its preparation method and use
  • Cefixime derivative and its preparation method and use
  • Cefixime derivative and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 (6R,7R)-7-{[(Z)-2-(2-aminothiazol-4-yl)-2-[(sodium carboxylate methoxy)imino]acetamido]} -3-vinyl-8-oxo-5-thia-1-azabicyclo[4,2,0]-2-octene-2-sodium carboxylate trihydrate (cefixime disodium trihydrate hydrate) preparation

[0042] Take (6R,7R)-7-{[(Z)-2-(2-aminothiazol-4-yl)-2-[(carboxymethoxy)imino]acetamido]}-3-ethylene Base-8-oxo-5-thia-1-azabicyclo[4,2,0]-2-octene-2-carboxylic acid trihydrate (10.0 g) was dissolved in methanol at room temperature, after Cool to 10°C, slowly add methanol solution of sodium methoxide (1mol / L), adjust the pH to 7.0, then cool down to 5°C, slowly add absolute ethanol (200ml), stir at the same temperature for 1h, filter, wash with absolute ethanol, Vacuum drying afforded 4.59 g of solid, with a yield of 42%.

[0043] 1 HNMR (400MHz, DMSO-d 6 )δ:11.80(d,J=8.5Hz,1H),7.16(s,2H),7.04(dd,J=17.8,11.2Hz,1H),6.84(s,1H),5.59(dd,J=8.5 ,4.9Hz,1H),5.11(d,J=17.6Hz,1H),5.03(d,J=4.9Hz,1H),4.90(d,J=11.7Hz,1H),4.25(s,2H), 3.44(s,1H),3.3...

Embodiment 2

[0046] Example 2 (6R,7R)-7-{[(Z)-2-(2-aminothiazol-4-yl)-2-[(sodium carboxylate methoxy)imino]acetamido]} -3-vinyl-8-oxo-5-thia-1-azabicyclo[4,2,0]-2-octene-2-sodium carboxylate trihydrate (cefixime disodium trihydrate hydrate) preparation

[0047] Take (6R,7R)-7-{[(Z)-2-(2-aminothiazol-4-yl)-2-[(carboxymethoxy)imino]acetamido]}-3-ethylene Base-8-oxo-5-thia-1-azabicyclo[4,2,0]-2-octene-2-carboxylic acid trihydrate (10.0 g) was dissolved in methanol at room temperature, after Cool to 10°C, slowly add methanol solution of sodium methoxide (1mol / L), adjust the pH to 7.0, then cool down to 5°C, slowly add anhydrous ether (200ml), stir at the same temperature for 1h, filter, wash with anhydrous ether, Vacuum drying afforded 8.51 g of solid, with a yield of 78%.

[0048] 1 HNMR (400MHz, DMSO-d 6 )δ:11.82(d,J=8.5Hz,1H),7.14(s,2H),7.06(dd,J=17.8,11.2Hz,1H),6.88(s,1H),5.57(dd,J=8.5 ,4.9Hz,1H),5.12(d,J=17.6Hz,1H),5.06(d,J=4.9Hz,1H),4.92(d,J=11.7Hz,1H),4.23(s,2H), 3.47(s,1H),3.38(...

Embodiment 3

[0051] Example 3 (6R,7R)-7-{[(Z)-2-(2-aminothiazol-4-yl)-2-[(sodium carboxylate methoxy)imino]acetamido]} -3-vinyl-8-oxo-5-thia-1-azabicyclo[4,2,0]-2-octene-2-sodium carboxylate trihydrate (cefixime disodium trihydrate hydrate) preparation

[0052] Take (6R,7R)-7-{[(Z)-2-(2-aminothiazol-4-yl)-2-[(carboxymethoxy)imino]acetamido]}-3-ethylene Base-8-oxo-5-thia-1-azabicyclo[4,2,0]-2-octene-2-carboxylic acid trihydrate (10.0 g) was dissolved in methanol at room temperature, after Cool to 10°C, slowly add ethanol solution of sodium ethoxide (1mol / L), adjust the pH to 7.0, then cool down to 5°C, slowly add acetone (200ml), stir at the same temperature for 1h, filter, wash with ethanol, and vacuum dry to obtain a solid 3.85 g, 35% yield.

[0053] 1 HNMR (400MHz, DMSO-d 6 )δ:11.79(d,J=8.5Hz,1H),7.15(s,2H),7.03(dd,J=17.8,11.2Hz,1H),6.83(s,1H),5.58(dd,J=8.5 ,4.9Hz,1H),5.10(d,J=17.6Hz,1H),5.07(d,J=4.9Hz,1H),4.94(d,J=11.7Hz,1H),4.23(s,2H), 3.45(s,1H),3.40(s,1H).

[0054] Elemental ...

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Abstract

The invention discloses a cefixime dual-salt hydrate or cefixime dual-salt solvate good in water solubility and a manufacturing method and purpose of the cefixime dual-salt hydrate or cefixime dual-salt solvate. The compound has the good water solubility and stability relative to cefixime trihydrate, can be independently used and can also be used by being combined with other beta-lactamase inhibitors, or compound preparation can be formed by the compound, the beta-lactamase inhibitors and the like, drug administration is carried out in the mode of injections, and the high bioavailability and good stability are achieved.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a novel cefixime double-salt hydrate or cefixime double-salt solvate, a preparation method thereof and an application in drugs for treating bacterial infectious diseases. Background technique [0002] Cefixime is the third generation of oral cephalosporin antibiotics, which was successfully developed by Japan Fujisawa Company. In 1987, it was first listed in Japan by Japan Fujisawa Pharmaceutical Co., Ltd. with the trade name cefixime. The chemical name of cefixime is: (6R,7R)-7-{[(Z)-2-(2-aminothiazol-4-yl)-2-[(carboxymethoxy)imino]acetamido ]}-3-vinyl-8-oxo-5-thia-1-azabicyclo[4,2,0]-2-octene-2-carboxylic acid trihydrate. my country began to import raw materials and preparations in 1994. The clinical effect of this product is remarkable, the curative effect is exact and the adverse reaction is small, and the dosage is on the rise. [0003] As a broad-spectrum third-generati...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/22C07D501/04A61K31/546A61P31/04
CPCC07D501/04C07D501/22
Inventor 陈矛朱少璇黄小光王健松卢丹张小娜张琳
Owner GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY