4-piperazinemethyl-7-hydroxybenzofuran compound and medical application thereof

Abstract

The invention provides a 4-piperazinemethyl-7-hydroxybenzofuran compound and medical application thereof, and relates to a compound and medical application thereof. The compound comprises the 4-piperazinemethyl-7-hydroxybenzofuran compound shown as a formula I as well as stereoisomers and pharmaceutically acceptable salts of the compound. The formula I is shown in the description, wherein Ar is independently selected from phenyl, C1-C4 alkyl-substituted phenyl, C1-C4 alkoxy-substituted phenyl, halogen-substituted phenyl and cyano-substituted phenyl. The compound provided by the invention can be applied to effective lipase inhibition medicines, is especially used as a novel nutrient absorption reducing agent, can act on gastrointestinal tract, is capable of inhibiting catalysis and decomposition of lipase and inhibiting absorption of part of fat from dietary intake, is applicable to obesity, and is suitable for obese people including healthy obese people and obese people with non-insulin-dependent diabetes mellitus.

Description

technical field

[0001] The invention relates to a compound and its medical use, in particular to a 4-piperazinemethyl-7-hydroxybenzofuran compound and its medical use. Background technique

[0002] Obesity is a common disease worldwide. In recent years, the incidence of obesity has been increasing all over the world, especially in developed countries. Due to the rapid development of the economy and the continuous improvement of living standards, the problems of insufficient exercise and relative excess energy intake have always existed in the lifestyle of modern people, which has led to the energy intake of many modern people exceeding energy consumption, and the excess energy Part of it will be stored as fat in adipose tissue, leading to obesity, and obesity can cause a variety of metabolic abnormalities, which is one of the main risk factors for diabetes and cardiovascular diseases, and is associated with increased morbidity and mortality of cardiovascular diseases . At ...

Examples

Embodiment 1

[0054] Example 1: Preparation of 4-[(4-phenylpiperazin-1-yl)methyl]-7-hydroxybenzofuran (B01)

[0055] Add 4.0 g (0.030mol) of 7-hydroxybenzofuran, 4.9 g (0.030mol) of 1-phenylpiperazine, 2.4 mL (0.033mol) of 37% aqueous formaldehyde solution, and 1 mL of glacial acetic acid into the reaction flask, and use an appropriate amount of ethanol as a solvent. Heat to reflux for 4~8h, TLC monitors the reaction process, after the reaction is completed, cool down, and remove ethanol by rotary evaporation to obtain a yellow oil, which is separated and purified by column chromatography with ethyl acetate:petroleum ether (1:5) as eluent , the solvent was removed by rotary evaporation, and 3.0 g of a light yellow solid was precipitated by freezing, with a yield of 32.5%. ESI-MSm / z: 309.2; 1H-NMR (CDCl3) δ(ppm): 2.62-2.67 (4H, m), 3.16-3.20 (4H, m), 3.56(2H, s), 6.70(1H, m) , 6.80(1H, d, J=8.1 Hz), 6.98-7.08(2H, m), 7.16-7.22 (4H, m), 7.68(1H, d, J=8.1 Hz).

Embodiment 2

[0056] Example 2: Preparation of 4-{[4-(4-methylphenyl)piperazin-1-yl]methyl}-7-hydroxybenzofuran (B02)

[0057]According to the preparation method of Example 1, a light yellow solid was obtained with a yield of 22.7%. ESI-MS m / z: 351.4; 1H-NMR(CDCl3) δ(ppm): 2.28 (3H, s), 2.67-2.72 (4H, m), 3.20-3.35 (4H, m), 3.60 (2H, s ), 6.70(1H, d, J=8.1 Hz), 6.96 (2H, d, J = 8.2 Hz), 7.00-7.06(2H, m), 7.16(2H, d, J=8.2 Hz), 7.72(1H , d, J=8.1 Hz).

Embodiment 3

[0058] Example 3: Preparation of 4-{[4-(2-methylphenyl)piperazin-1-yl]methyl}-7-hydroxybenzofuran (B03)

[0059] According to the preparation method of Example 1, a light yellow solid was obtained with a yield of 23.8%. ESI-MS m / z: 351.4; 1H-NMR(CDCl3) δ(ppm): 2.30 (3H, s), 2.60-2.68 (4H, m), 3.28-3.36 (4H, m), 3.66 (2H, s ), 6.56-6.64 (1H, m), 6.77(1H, d, J=8.1 Hz), 6.94-7.03(3H, m), 7.08-7.13(2H, m), 7.82(1H, d, J=8.1 Hz).

technical field

[0001] The invention relates to a compound and its medical use, in particular to a 4-piperazinemethyl-7-hydroxybenzofuran compound and its medical use. Background technique

[0002] Obesity is a common disease worldwide. In recent years, the incidence of obesity has been increasing all over the world, especially in developed countries. Due to the rapid development of the economy and the continuous improvement of living standards, the problems of insufficient exercise and relative excess energy intake have always existed in the lifestyle of modern people, which has led to the energy intake of many modern people exceeding energy consumption, and the excess energy Part of it will be stored as fat in adipose tissue, leading to obesity, and obesity can cause a variety of metabolic abnormalities, which is one of the main risk factors for diabetes and cardiovascular diseases, and is associated with increased morbidity and mortality of cardiovascular diseases . At ...

Examples

Embodiment 1

[0054] Example 1: Preparation of 4-[(4-phenylpiperazin-1-yl)methyl]-7-hydroxybenzofuran (B01)

[0055] Add 4.0 g (0.030mol) of 7-hydroxybenzofuran, 4.9 g (0.030mol) of 1-phenylpiperazine, 2.4 mL (0.033mol) of 37% aqueous formaldehyde solution, and 1 mL of glacial acetic acid into the reaction flask, and use an appropriate amount of ethanol as a solvent. Heat to reflux for 4~8h, TLC monitors the reaction process, after the reaction is completed, cool down, and remove ethanol by rotary evaporation to obtain a yellow oil, which is separated and purified by column chromatography with ethyl acetate:petroleum ether (1:5) as eluent , the solvent was removed by rotary evaporation, and 3.0 g of a light yellow solid was precipitated by freezing, with a yield of 32.5%. ESI-MSm / z: 309.2; 1H-NMR (CDCl3) δ(ppm): 2.62-2.67 (4H, m), 3.16-3.20 (4H, m), 3.56(2H, s), 6.70(1H, m) , 6.80(1H, d, J=8.1 Hz), 6.98-7.08(2H, m), 7.16-7.22 (4H, m), 7.68(1H, d, J=8.1 Hz).

Embodiment 2

[0056] Example 2: Preparation of 4-{[4-(4-methylphenyl)piperazin-1-yl]methyl}-7-hydroxybenzofuran (B02)

[0057]According to the preparation method of Example 1, a light yellow solid was obtained with a yield of 22.7%. ESI-MS m / z: 351.4; 1H-NMR(CDCl3) δ(ppm): 2.28 (3H, s), 2.67-2.72 (4H, m), 3.20-3.35 (4H, m), 3.60 (2H, s ), 6.70(1H, d, J=8.1 Hz), 6.96 (2H, d, J = 8.2 Hz), 7.00-7.06(2H, m), 7.16(2H, d, J=8.2 Hz), 7.72(1H , d, J=8.1 Hz).

Embodiment 3

[0058] Example 3: Preparation of 4-{[4-(2-methylphenyl)piperazin-1-yl]methyl}-7-hydroxybenzofuran (B03)

[0059] According to the preparation method of Example 1, a light yellow solid was obtained with a yield of 23.8%. ESI-MS m / z: 351.4; 1H-NMR(CDCl3) δ(ppm): 2.30 (3H, s), 2.60-2.68 (4H, m), 3.28-3.36 (4H, m), 3.66 (2H, s ), 6.56-6.64 (1H, m), 6.77(1H, d, J=8.1 Hz), 6.94-7.03(3H, m), 7.08-7.13(2H, m), 7.82(1H, d, J=8.1 Hz).

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