Preparation of pyrrole gastric acid secretion inhibitor compound salt

A technology of pyrrole and organic acid salts, applied in anti-inflammatory agents, digestive system, organic chemistry, etc., can solve the problems of poor water solubility of compounds, limit acid suppression and treat gastric acid-related diseases, and achieve the treatment of gastric acid-related diseases , the effect of meeting the clinical drug demand

Inactive Publication Date: 2016-06-22
JIANGSU CAREFREE PHARM CO LTD
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] TAK438 (5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylaminofumarate) is a potassium Ion-competitive acid blocker (P-CAB), in vitro experiments show that the ability of this compound to inhibit proton pump (H+, ATPase) is 400 times that of lansoprazole, which can effectively inhibit gastric acid secretion and has a long-lasting effect advantages, but the compound has poor water solubility, and the oral bioavailability of animals is only 10%, which limits the compound's ability to suppress acid and treat gastric acid-related diseases

Method used

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  • Preparation of pyrrole gastric acid secretion inhibitor compound salt
  • Preparation of pyrrole gastric acid secretion inhibitor compound salt
  • Preparation of pyrrole gastric acid secretion inhibitor compound salt

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] In a 100 mL one-necked bottle, add 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylamine (5.0 g, 14.48 mmol) and acetic acid Ethyl ester (25mL) was stirred and dissolved at room temperature (15°C), sulfuric acid (0.5mL, 15.20mmol) was added dropwise to the reaction system, stirred at this temperature for 30 minutes, isopropanol (20mL) was added, and The temperature was lowered to 3°C, and stirred for 30 minutes, a solid precipitated, the solid was filtered out, and washed with ethyl acetate (10mL*2 times), and the obtained solid was dried in a vacuum oven (45°C) for 4 hours to obtain White solid 4.3g, yield 76%.

[0058] 1 HNMR (DMSO- d 6;500MHZ)δ(ppm)8.89(dd, J =4.8, J =1.3,1H),8.72(s,2H),8.56(d, J =2.0,1H),7.92(dd, J =8.1, J =2.1,1H),7.84(s,1H),7.64(m,1H),7.52(m,1H),7.22(m,2H),7.10(m,1H),6.54(d, J =1.5,1H),4.04(s,2H),2.57(s,3H)

[0059] Example 2

Embodiment 2

[0061] In a 100 mL one-necked bottle, add 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylamine (3.0 g, 6.1 mmol) and acetic acid Ethyl ester (15mL) was stirred and dissolved at room temperature (15°C), phosphoric acid (0.3mL, 4.6mmol, 85%) was added dropwise to the reaction system, stirred at this temperature for 30 minutes, and isopropanol (12mL) was added , and then lowered the temperature to 2°C and stirred for 30 minutes, a solid precipitated out, the solid was filtered out, and washed with ethyl acetate (8mL*2 times), and the obtained solid was dried in a vacuum oven (45°C) for 4 hours , to obtain 3.1 g of off-white solid with a yield of 91.0%.

[0062] 1 HNMR (DMSO- d 6;500MHZ)δ(ppm)8.86(d, J =4.6,1H),8.71(s,2H),8.55(d,J=1.9,1H),7.92(d, J =8.1,1H),7.83(s,1H),7.66(m,1H),7.53(m,1H),7.23(m,2H),7.11(m,1H),6.55(d, J =1.6,1H),3.92(s,2H),2.51(s,3H)

[0063] Example 3

Embodiment 3

[0065] In a 100 mL one-necked bottle, add 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylamine (6.0 g, 14.4 mmol) and acetic acid Ethyl ester (30mL) was stirred and dissolved at room temperature (15°C), methanesulfonic acid (1.2mL, 18.3mmol) was added dropwise to the reaction system, stirred at this temperature for 30 minutes, isopropanol (20mL) was added, After that, the temperature was lowered to 2°C and stirred for 30 minutes. A solid precipitated out. The solid was filtered out and washed with ethyl acetate (12 mL*2 times), and the obtained solid was dried in a vacuum oven (45°C) for 4 hours. 3.9 g of off-white solid was obtained with a yield of 55.8%.

[0066] 1 HNMR (DMSO- d 6;500MHZ)δ(ppm)8.89(d, J =4.7,1H),8.75(s,2H),8.57(s,1H),7.90(d, J =8.0,1H),7.83(s,1H),7.64(m,1H),7.53(m,1H),7.23(m,2H),7.10(m,1H),6.52(s,2H),6.39( s,4H),4.02(t,2H),2.55(t,3H),2.44(brs,6H)

[0067] Example 4

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Abstract

Belonging to the technical field of chemical drugs, the invention in particular relates to a 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methyl ammonia inorganic acid salt or organic acid salt compound with the effect of treating gastric acid related diseases. The invention makes water solubility and stability study on related salt compounds, also provides a preparation method of corresponding salts, and performs crystal form study on 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methyl ammonia acetate.

Description

technical field [0001] The invention belongs to the technical field of chemical medicine, and specifically relates to 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-methylammonia inorganic acid salt or organic acid Salt and water solubility, stability and preparation method of corresponding salt. 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, it affects the thera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61P1/00A61P29/00A61P1/04A61P31/04
Inventor 秦引林徐洋
Owner JIANGSU CAREFREE PHARM CO LTD
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