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Ambroxol derivative and application

A derivative, ambroxol technology, applied in the field of medicinal chemistry, can solve problems such as incompatibility and incompatibility, and achieve the effects of enhanced drug efficacy, wide pH dissolution range, and improved oral bioavailability

Active Publication Date: 2016-06-22
CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Its reason is mainly: the pH value of ambroxol hydrochloride after dissolving with sterile water for injection is 5.0, and the raising of pH value can cause the generation and precipitation of ambroxol free base, therefore, cannot mix with other solutions of pH>6.3 mix
Most of the weak acid and strong base salt drugs, such as: the sodium salts of penicillins, cephalosporins, sulfonamides, barbiturates, etc. are basically alkaline, and there is a compatibility taboo with ambroxol hydrochloride

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] The preparation of embodiment 1 compound 1

[0038]

[0039] The preparation scheme is shown in the following reaction formula:

[0040]

[0041] The starting material a (105mg, 0.28mmol) was dissolved in pyridine (5ml), and phosphorus oxychloride (46.5mg, 0.31mmol) was added dropwise, and reacted overnight at room temperature. Thin-layer chromatography tracked the reaction process. After the reaction was complete, it was quenched with ice water, dropped into dilute sodium hydroxide solution (0.56mmol), concentrated under reduced pressure, added acetone to precipitate a solid, and obtained compound 1 (105mg, off-white solid). The yield : 80.1%.

[0042] MSm / z(ES):502.9[M+1]

[0043] 1 HNMR (300MHz, D2O): δ (ppm) 7.33 (1H, m), 6.99 (1H, m), 3.60 (3H, brs), 2.50 (1H, brs), 1.77 (4H, brs), 1.02 (4H, brs);

[0044] Elemental Analysis: C, 31.1; H, 3.4; Br, 31.8; N, 5.6; Na, 9.1;

Embodiment 2

[0045] The preparation of embodiment 2 compound 2

[0046]

[0047] The preparation scheme is shown in the following reaction formula:

[0048] The starting material a (105mg, 0.28mmol) was dissolved in pyridine (5ml), and phosphorus oxychloride (46.5mg, 0.31mmol) was added dropwise, and reacted overnight at room temperature. Thin-layer chromatography tracked the reaction process. After the reaction was complete, it was quenched with ice water, dropped into dilute sodium hydroxide solution (0.28mmol), concentrated under reduced pressure, added acetone to precipitate a solid, and obtained compound 2 (100mg, off-white solid). The yield : 74.1%.

[0049] MSm / z(ES):480.9[M+1]

[0050] 1 HNMR (300MHz, D2O): δ (ppm) 7.34 (1H, m), 6.95 (1H, m), 3.54 (3H, brs), 2.30 (1H, brs), 1.87 (4H, brs), 1.12 (4H, brs),4.10-4.20(2H,m);

[0051] Elemental Analysis: C, 32.53; H, 3.78; Br, 33.29; N, 5.84; Na, 4.79;

Embodiment 3

[0052] The preparation of embodiment 3 compound 3

[0053]

[0054] The preparation method is shown in the following reaction formula:

[0055]

[0056] The starting material a (105mg, 0.28mmol) was dissolved in pyridine (5ml), and phosphorus oxychloride (46.5mg, 0.31mmol) was added dropwise, and reacted overnight at room temperature. Thin-layer chromatography tracked the reaction process. After the reaction was complete, it was quenched with ice water, dropped into dilute potassium hydroxide solution (0.56mmol), concentrated under reduced pressure, added acetone to precipitate a solid, and obtained compound 3 (105mg, off-white solid). The yield : 76.8%.

[0057] MSm / z(ES):534.8[M+1]

[0058] 1 HNMR (300MHz, D2O): δ (ppm) 7.31 (1H, m), 6.93 (1H, m), 3.65 (3H, brs), 2.53 (1H, brs), 1.79 (4H, brs), 1.22 (4H, brs);

[0059] Elemental Analysis: C, 29.23; H, 3.21; Br, 29.91; K, 14.64; N, 5.24;

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Abstract

The invention relates to the field of medicinal chemistry, in particular to an ambroxol derivative and a preparation method thereof and application of the ambroxol derivative in drugs for eliminating phlegm. The ambroxol derivative is a compound shown in a structure in the description or a stereoisomer, and please refer to figure 1 for the specific structure, wherein R1 represents H or alkali metal ions or organic amine, and R2 represents H or alkali metal ions or organic amine. The ambroxol derivative has good solubility, the solution pH is larger than 7, no sediment is separated out, the ambroxol derivative can be used concomitantly with cefoperazone sodium, a wider pH solubility range is achieved, the oral bioavailability is high, and the drug efficacy is greatly strengthened.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of ambroxol derivatives and a preparation method thereof, and their application in expectorant medicines. Background technique [0002] Ambroxol, also known as bromcyclohexylamine alcohol, is 2-amino-3,5-dibromo-N-(4-hydroxycyclohexyl)benzylamine. It is an organic raw material with a molecular formula of C13H18Br2N2O and a molecular weight of 378.1028 , the structural formula is: [0003] [0004] Ambroxol (Ambroxol) is a metabolite of bromhexine in vivo, which can promote the secretion of pulmonary surfactant and airway fluid secretion, break the mucopolysaccharide protein fibers in sputum, promote the dissolution of mucus sputum, significantly reduce sputum viscosity, and strengthen bronchial flow. Mucociliary movement promotes sputum discharge. Improve ventilatory function and dyspnea. Its expectorant effect is significantly higher than that of bromhexine, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/117C07C215/10C07C213/08A61P11/10
CPCC07C215/10C07F9/117
Inventor 杨茂廷张永斌谭少军牟长海
Owner CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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