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Acid addition salt of pyrimethamine

A technology of acid addition salt and pyrimethamine base, applied in the direction of organic active ingredients, resistance to vector-borne diseases, medical preparations containing active ingredients, etc., can solve problems such as solubility without mentioning

Pending Publication Date: 2021-03-16
GLG PHARMA SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the synthesis and crystallographic characterization of pyrimethamine salts of some common acids (maleic, succinic, phthalic, fumaric, glutaric or formic) were described (Crystal Growth and Design, 2002, 2 / 6,631; 2003,3 / 5,823) but does not mention their solubility in water

Method used

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  • Acid addition salt of pyrimethamine
  • Acid addition salt of pyrimethamine
  • Acid addition salt of pyrimethamine

Examples

Experimental program
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Effect test

Embodiment 1

[0094] Pyrimethamine (30g) (purity 99.83%, containing 0.16% impurity, R f =2.53) was crystallized in ethylene glycol (3 x 60 mL). The obtained crystals were refluxed in ethanol (50 mL), filtered and dried at 60°C under reduced pressure. 25 g of pyrimethamine containing 0.09% R f= 2.53 impurities. The obtained product (24.9 g, 0.1 mol) was suspended in acetone (250 mL), and methanesulfonic acid (24.0 g, 0.25 mol) was added to the suspension. The reaction was stirred at room temperature for 60 minutes, then the white precipitate was collected and washed with acetone (500 mL). The product was suspended in ethanol (250 mL) and refluxed with stirring for 15 minutes. Then, the suspension was cooled to room temperature, and the precipitate was collected, washed with ethanol (250 mL), and dried at 60° C. under reduced pressure (20 mmHg). The product was obtained as white crystals in a yield of 24.0 g (70%). The acid content of the salt was determined by potentiometric titration:...

Embodiment 2

[0100] Pyrimethamine (24.9 g, 0.1 mol) was dissolved in hot ethylene glycol (100 mL), methanesulfonic acid (24.0 g, 0.25 mol) was added to the solution, and the reaction mixture was cooled to room temperature. Then, acetone (200 mL) was added, and the mixture was left at room temperature for 12 hours. The precipitate was collected, washed with acetone (50 mL), and dried at 60° C. under reduced pressure (20 mm Hg). The product was obtained as white crystals in a yield of 18.0 g (52%). The acid content of the salt was determined by potentiometric titration: 28.20% (calculated: 27.87%).

Embodiment 3

[0102] Pyrimethamine (249 g, 1 mol) was suspended in 96% ethanol (1 L), and methanesulfonic acid (240 g = 162 mL, 2.5 mol) was added. The reaction mixture was stirred at room temperature for 60 minutes. Then reflux for 30 minutes. After cooling, the white precipitate was collected and washed with ethanol (500 mL). The product was suspended in ethanol (1 L) and refluxed for 15 minutes with stirring. The mixture was then cooled to room temperature and the precipitate was collected and washed sequentially with ethanol (200 mL), acetone (1 L) and again with ethanol 10 (200 mL). The product was dried at 60°C under reduced pressure (20 mm Hg) to give white crystals in a yield of 278 g (81%). Acid content: 27.92% (calculated: 27.87%).

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Abstract

Acid addition salt of pyrimethamine (5-4-chlorophenyl)-6-ethyl-2,4- pyrimidinediamine) and methane sulfonic acid, process for its preparation and pharmaceutical compositions comprising the acid addition salt are disclosed.

Description

technical field [0001] The present invention relates to a novel addition salt of pyrimethamine, a preparation method thereof and a pharmaceutical composition containing the same. Background technique [0002] Pyrimethamine (5-(4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine) is a dihydrofolate reductase (DHFR) inhibitor with antiparasitic properties approved for use in for the treatment of malaria. Its activity against Plasmodium and Toxoplasma is based on selective inhibition of folate conversion, leading to failure of folinic acid synthesis, which is critical for nucleic acid formation. Recently, this compound was evaluated in a phase I / II clinical study for the treatment of chronic lymphocytic leukemia. Preclinical studies for the treatment of autosomal dominant polycystic kidney disease are also underway, as are phase I / II clinical studies for the treatment of familial amyotrophic lateral sclerosis. In the United States, the compound is designated as an orphan drug for ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48A61K31/505C07C309/04
CPCC07B2200/13C07C309/04C07D239/48A61K9/00Y02A50/30A61K9/20A61K9/48C07D239/49
Inventor 武卡乌什·卡兹玛瑞克玛尔塔·瓦什奇格热戈日·胡什恰马乌戈热塔·斯卡日尼克玛尔塔·泽祖拉亚历山德拉·格罗曼埃尔兹别塔·斯托拉奇克马雷克·库比塞斯基金加·奇钦斯卡克日什托夫·库扎克
Owner GLG PHARMA SA
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