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Water soluble salts of organic acid 5-(2-fluorophenyl)-N-methyl-1-(3-pyridyl sulfonyl)-1H-pyrrole-3-methylamine and injection and preparation method thereof

A technology of pyridylsulfonyl and organic acid salts, which is applied in the fields of medical preparations containing active ingredients, organic chemistry, organic active ingredients, etc. It can solve problems related to poor water solubility, inability to meet medical needs for swallowing, restriction of acid suppression, and treatment of gastric acid Diseases and other problems, to achieve the effect of rapid onset of action, improvement of absorption kinetic parameters and bioavailability, and rapid oral absorption

Active Publication Date: 2014-07-30
DONGYING DAOYI BIOLOGICAL MEDICINE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the compound has poor water solubility, and its oral bioavailability to animals is only 10%, which limits the compound's ability to suppress acid and treat gastric acid-related diseases. See J Pharmacol Exp Ther 2011, 337(3): 797-804
Moreover, the dosage form of TAK438 is only tablets, which cannot meet the medical needs of patients with dysphagia and other patients who are not suitable for tablets.

Method used

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  • Water soluble salts of organic acid 5-(2-fluorophenyl)-N-methyl-1-(3-pyridyl sulfonyl)-1H-pyrrole-3-methylamine and injection and preparation method thereof
  • Water soluble salts of organic acid 5-(2-fluorophenyl)-N-methyl-1-(3-pyridyl sulfonyl)-1H-pyrrole-3-methylamine and injection and preparation method thereof
  • Water soluble salts of organic acid 5-(2-fluorophenyl)-N-methyl-1-(3-pyridyl sulfonyl)-1H-pyrrole-3-methylamine and injection and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylamine pyroglutamate

[0021] Put 6.0 g (17.3 mmol) of 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylamine into a 100 mL three-necked flask, and add Ethyl acetate 15 mL, isopropanol 15 mL, stirred at room temperature to dissolve. Heat the mixture to an internal temperature of 50-60 o C, add 2.24 g (17.3 mmol) of L-pyroglutamic acid. Inner temperature 50-60 o After stirring at C for 30 minutes, 15 mL of ethyl acetate was added dropwise, and the inner temperature was 50-60 o C and stirred for another 30 minutes. The mixture was cooled to room temperature and stirred in an ice bath for 1 hour. Filter, wash the filter cake with 10 mL of ethyl acetate:isopropanol (2:1), and 10 mL of ethyl acetate, respectively. Collect filter cake, reduce pressure, 45 o C was dried to give crude product 6.5 g.

[0022] Refining: Put 6.5 g of the above crude product into a 100 mL three-necked f...

Embodiment 2

[0025] 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylamine lactate

[0026] Put 7.6 g (22.0 mmol) of 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylamine in a 100 mL three-necked flask, and add Ethyl acetate 30 mL, stirred at room temperature to dissolve. Heat the mixture to an internal temperature of 50-60 o C, add 1.98 g (22.0 mmol) of L-lactic acid. Inner temperature 50-60 o C was stirred for 1 hour. The mixture was cooled to room temperature and stirred for 2 hours in an ice bath. Filter and wash the filter cake with 10 mL of ethyl acetate. Collect filter cake, reduce pressure, 45 o C was dried to give crude product 6.3 g.

[0027]Refining: put 6.3 g of the above crude product into a 100 mL three-necked flask, and add 20 mL of ethanol. Stir and heat the mixture to an internal temperature of 60-70 o C was dissolved, and 190 mg of activated carbon was added. Bring the mixture to an internal temperature of 60-70 o C was...

Embodiment 3

[0030] 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylaminoethanesulfonate

[0031] Put 1.3 g (3.76 mmol) of 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylamine in a 25 mL three-necked flask, and add Ethyl acetate 6 mL, stirred at room temperature to dissolve. Heat the mixture to an internal temperature of 50-60 o C, add 0.41 g (3.76 mmol) of ethanesulfonic acid. Inner temperature 50-60 o C was stirred for 1 hour. The mixture was cooled to room temperature and stirred for 2 hours in an ice bath. Filter and wash the filter cake with 6 mL of ethyl acetate. Collect filter cake, reduce pressure, 45 o C was dried to obtain 0.79 g of the product, with a yield of 46.2%.

[0032] 1 H-NMR (DMSO-d 6 , 400MHz) δ (ppm): 8.91-8.90 (d, 1H), 8.71 (s, 2H), 8.58 (s, 1H), 7.90-7.89 (d, 1H), 7.82 (s, 1H), 7.66-7.63 (dd, 1H), 7.57-7.52 (q, 1H), 7.26-7.23 (t, 2H), 7.12-7.10 (t, 1H), 6.52 (s, 1H), 4.03 (s, 2H), 2.57 (s , 3H), 2.42-2.38 (q, 2H...

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Abstract

The invention belongs to the technical field of chemical synthetic medicines and particularly relates to water soluble salts of an organic acid of 5-(2-fluorophenyl)-N-methyl-1-(3-pyridyl sulfonyl)-1H-pyrrole-3-methylamine and an injection thereof for treating gastric acid related diseases and a preparation method thereof. The invention discloses the salts of the organic acid of 5-(2-fluorophenyl)-N-methyl-1-(3-pyridyl sulfonyl)-1H-pyrrole-3-methylamine shown as the following general formula in the specification, wherein n is 1 or 1 / 2 and HA is an organic acid. According to the salts of the organic acid, which are disclosed by the invention, the solubility of the salts in water or an artificial gastric and intestinal juice is far greater than TAK438, and the solubility of pyroglutamate and lactate in water is greater than 1g / mL.

Description

technical field [0001] The invention belongs to the technical field of chemically synthesized medicines, and in particular relates to 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole capable of treating gastric acid-related diseases -3-Methylamine water-soluble organic acid salt and injection and their preparation method. Background technique [0002] Gastric acid-related disease is the most common type of disease in the digestive system. It refers to a general term for a type of digestive tract disease caused by excessive gastric acid secretion or being particularly sensitive to gastric acid. The common one is gastroesophageal reflux disease. , peptic ulcer, Zollinger-Ellison syndrome and digestive system diseases caused by non-steroidal anti-inflammatory drugs. PPIs are currently the class of drugs with the strongest acid-suppressing effect, such as omeprazole, lansoprazole, pantoprazole, rabeprazole, etc. Due to the phenomenon of acid rebound at night in PPI...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K9/08A61K31/4439A61P1/04
CPCC07D401/12
Inventor 徐文方宋建伟王学健黄永学侯金宁
Owner DONGYING DAOYI BIOLOGICAL MEDICINE TECH CO LTD
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