Pyridine sulfonamide phosphate compound as well as preparation method and application thereof

A technology for pyridine sulfonamide phosphate and compounds, which is applied in the field of pyridine sulfonamide phosphate compounds, can solve the problems of not effectively improving water solubility and difficulty in preparation production, and achieve the advantages of convenient preparation of preparations, high stability and high solubility Effect

Active Publication Date: 2019-12-24
SHANGHAI XUNHE PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with torasemide, although the phenolic hydroxyl group has been introduced into the benzene ring, the water solubility of M3 has not been effectively improved, and the preparation production is difficult

Method used

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  • Pyridine sulfonamide phosphate compound as well as preparation method and application thereof
  • Pyridine sulfonamide phosphate compound as well as preparation method and application thereof
  • Pyridine sulfonamide phosphate compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The preparation of embodiment 1 formula I compound

[0028] Step 1: Preparation of the compound of formula 3

[0029] Add absolute ethanol (300mL) and compound 2 (18.5g, 0.15mol, 1.05eq) into a 500mL reaction flask, stir and heat to about 75°C, add compound 1 (27.5g, 0.143mol, 1.0eq) in batches, add After the completion, keep the temperature and stir the reaction for 1h, and a solid precipitates out. The temperature was lowered to 20-25° C., sodium carbonate (15.9 g, 0.15 mol, 1.5 eq) was added, and paraformaldehyde (15 g, 0.5 mol, 5 eq) was added in batches under stirring. After the addition, the temperature was raised to an internal temperature of 80-85°C for 2 hours, then slowly lowered to an internal temperature of 20-25°C, filtered, and dried to obtain a light yellow filter cake as the compound of formula 3 (36.5g, yield 81%), MS :280[M+1].

[0030] Step 2: Preparation of the compound of formula M3

[0031] Acetone (200mL), compound of formula 3 (35g, 0.11mol, ...

Embodiment 14

[0083] Embodiment 14 solubility comparison

[0084] Solubility comparison of torasemide, M3, I, I-1, I-2, I-3, I-4, II, II-1, II-2, III, III-1 and III-2 , the result is as follows:

[0085] Table 2. Comparison of water solubility of compounds

[0086]

[0087]

[0088] The results of the solubility experiment show that the solubility of the pyridine sulfonamide phosphate compounds in Examples 1-11 is better than that of torasemide and M3, and has better druggability.

Embodiment 15

[0089] Embodiment 15 diuretic effect comparison

[0090] SD male rats (body weight 180±20g) were randomly divided into 14 groups, 3 rats in each group, and each rat was given 30 mL / kg normal saline by intragastric administration. After intragastric administration of normal saline, except for the blank control group, each group was given a drug (10mg / kg, ig, 1mg / mL, formulation prescription: dissolved in normal saline), and the 4h urination was collected. The results are shown in Table 3:

[0091] Table 3. Comparison of urine output of different compounds

[0092] compound Dosage and method of administration Urine output (mL / kg, 4h) blank control -- 19.2 torsemide 10mg / kg, ig 105.3 M3 10mg / kg, ig 107.2 Compound I 10mg / kg, ig 121.4 Compound I-1 10mg / kg, ig 127.6 Compound I-2 10mg / kg, ig 119.8 Compound I-3 10mg / kg, ig 123.4 Compound I-4 10mg / kg, ig 125.6 Compound II 10mg / kg, ig 119.3 Compound ...

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Abstract

The invention relates to the technical field of biological medicines, and particularly relates to a pyridine sulfonamide phosphate compound as well as a preparation method and application thereof. Thestructure of the pyridine sulfonamide phosphate compound is shown as a formula I shown in the specification. The pyridine sulfonamide phosphate compound has the beneficial effects that the pyridine sulfonamide phosphate compound has the characteristics of high solubility, high stability, convenience in preparation of preparations and the like, is easy to industrially amplify and is used for medical application.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a pyridine sulfonamide phosphate compound, its preparation method and its application. Background technique [0002] The chemical name of torasemide is 1-[4-(3-methylphenyl)aminopyridin-3-yl]sulfonyl-3-isopropylurea, which is a new generation of high-efficiency loop diuretic, and its pKa value is 6.44, almost insoluble in water, slightly soluble in 0.1mol / L sodium hydroxide solution. More than 20 years of clinical application have proved that torasemide has a wide range of indications, and its diuretic effect is rapid, strong and long-lasting. It is a class of high-efficiency diuretics worthy of clinical promotion. [0003] Currently, torasemide is available in the form of injections, tablets, and capsules. In the preparation process of injection, it is hoped that the raw material drug has high water solubility. Torsemide is very slightly soluble in water (European Journal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/58A61K31/675A61P7/10
CPCC07F9/58A61P7/10A61K31/675A61K31/6615C07F9/09
Inventor 郑永勇魏农农金华周峰黄美花
Owner SHANGHAI XUNHE PHARMA TECH CO LTD
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