A compound with ppar multiple agonistic activity and its preparation method and application

Abstract

The invention discloses a compound with PPAR multiple agonist activities and a preparation method and application thereof. The compound has the chemical structure as shown in the formula I. Research results show that the compound adopting the formula I can remarkably improve the transcriptional activities of PPAR alpha, beta and gamma, has the multiple agonist activities of PPAR alpha, beta band gamma, is expected to serve as an active ingredient to be used for preparing a drug or health food for preventing and / or treating metabolic syndromes, and is particularly expected to be used for preparing a drug or health food for preventing and / or treating abnormal glucose metabolism and / or abnormal lipids metabolism diseases. The compound has a wide application prospect and a remarkable medicinal value.

Description

technical field

[0001] The invention relates to a compound with multiple agonistic activities of PPAR and its preparation method and application, belonging to the technical field of chemistry and medicine. Background technique

[0002] According to the World Health Organization, about 20%-25% of adults worldwide suffer from metabolic syndrome, 70%-80% of diabetic patients suffer from metabolic syndrome, and up to 86% of type II diabetic patients are diagnosed with metabolic syndrome. disorder. Studies have shown that: people's weight gain and inactive lifestyle can cause insulin resistance in fat cells, leading to more and more people suffering from metabolic syndrome (Diabetes&Metabolic Syndrome Clinical Research&Reviews[J],2015,9(2):124 -126). Metabolic syndrome is related to the disturbance of glucose metabolism in the body (Journal of Diabetes & Metabolic Disorders[J],2014,13(1):1-7), and is a risk factor leading to obesity, central obesity, insulin resistance, dyslipi...

Examples

Embodiment 1

[0053] Embodiment 1: the preparation of formula II compound

[0054]

[0055] Add p-hydroxybenzaldehyde (3.7g, 30.0mmol) and potassium carbonate (12.4g, 90.0mmol) into DMF (40mL), stir and dissolve at room temperature, slowly drop p-methoxybenzyl chloride (3.5g, 30.0 mmol), react at room temperature (about 20-25° C.) for 12 hours, end the reaction, add saturated NaCl solution to quench the reaction, then add ethyl acetate for extraction until the extraction is complete, combine the organic phases, and dry the organic phases with anhydrous sodium sulfate. Suction filtration, concentrated under reduced pressure until no solution distilled off to obtain a white powder substance, which is the compound of formula II (named: 4-p-methoxybenzylhydroxy-benzaldehyde): 6.2g, 25.6mmol, molar yield was 85.3%.

Embodiment 2

[0056] Embodiment 2: the preparation of formula III compound

[0057]

[0058] Dissolve 3-methoxy-4-bromoaniline (6.0g, 30.0mmol) in dichloromethane (30mL), cool to 0°C in an ice bath, and slowly add BCl dropwise at 0°C 3 Dichloromethane solution (1.0mol / L, 33mL), keep stirring for half an hour, then slowly add AlCl 3 (4.4g, 33.0mmol) and CH 3 CN (3.2mL, 60.0mmol), after the addition is complete, stir the reaction at room temperature for half an hour, then rise to 70°C and keep the temperature for 12 hours, and then end the reaction. After the reaction solution is cooled, add 2N HCL to quench the reaction (the process of adding hydrochloric acid The reaction solution will have a lot of white bubbles, try to add it slowly in an ice bath at 0°C), then stir at 70°C for 2 hours, after cooling to room temperature, add 1N NaHCO 3 Adjust the solution to neutral, then add dichloromethane to extract until the extraction is complete, combine the organic phases, dry the organic phas...

Embodiment 3

[0061] Embodiment 3: the preparation of formula IV compound

[0062]

[0063] Add the compound of formula II (1.7g, 6.5mmol) and the compound of formula III (1.2g, 5.0mmol) into absolute ethanol (20mL), then add solid sodium hydroxide (800.0mg, 20.0mmol), after the addition is complete, the temperature is raised Reaction at 60°C for 12 hours, the reaction was terminated, the reaction solution was cooled to room temperature, filtered, the filter cake was washed with ethanol, and dried to obtain a yellow powder substance, which was the compound of formula IV (named: 1-(2'-amino-4 '-methoxy-5'-bromo)-3-(4'-methoxybenzylanisole)-2E-propen-1-one): 2.2 g, 4.66 mmol, and the molar yield is 93.2%.

[0064] Tested:

[0065] 1 H NMR (300MHz, CDCl 3 )δ8.00(s,1H,ArH),7.70(d,J=15.3Hz,1H,=H),7.59(d,J=8.4Hz,2H,ArH),7.44–7.33(m,3H,= H / ArH), 6.96(dd, J=21.1, 8.3Hz, 4H, ArH), 6.59(s, 2H, NH2), 6.13(s, 1H, ArH), 5.04(s, 2H, OCH 2 ),3.89(s,3H,ArOCH 3 ),3.82(s,3H,ArOCH 3 ).

technical field

[0001] The invention relates to a compound with multiple agonistic activities of PPAR and its preparation method and application, belonging to the technical field of chemistry and medicine. Background technique

[0002] According to the World Health Organization, about 20%-25% of adults worldwide suffer from metabolic syndrome, 70%-80% of diabetic patients suffer from metabolic syndrome, and up to 86% of type II diabetic patients are diagnosed with metabolic syndrome. disorder. Studies have shown that: people's weight gain and inactive lifestyle can cause insulin resistance in fat cells, leading to more and more people suffering from metabolic syndrome (Diabetes&Metabolic Syndrome Clinical Research&Reviews[J],2015,9(2):124 -126). Metabolic syndrome is related to the disturbance of glucose metabolism in the body (Journal of Diabetes & Metabolic Disorders[J],2014,13(1):1-7), and is a risk factor leading to obesity, central obesity, insulin resistance, dyslipi...

Examples

Embodiment 1

[0053] Embodiment 1: the preparation of formula II compound

[0054]

[0055] Add p-hydroxybenzaldehyde (3.7g, 30.0mmol) and potassium carbonate (12.4g, 90.0mmol) into DMF (40mL), stir and dissolve at room temperature, slowly drop p-methoxybenzyl chloride (3.5g, 30.0 mmol), react at room temperature (about 20-25° C.) for 12 hours, end the reaction, add saturated NaCl solution to quench the reaction, then add ethyl acetate for extraction until the extraction is complete, combine the organic phases, and dry the organic phases with anhydrous sodium sulfate. Suction filtration, concentrated under reduced pressure until no solution distilled off to obtain a white powder substance, which is the compound of formula II (named: 4-p-methoxybenzylhydroxy-benzaldehyde): 6.2g, 25.6mmol, molar yield was 85.3%.

Embodiment 2

[0056] Embodiment 2: the preparation of formula III compound

[0057]

[0058] Dissolve 3-methoxy-4-bromoaniline (6.0g, 30.0mmol) in dichloromethane (30mL), cool to 0°C in an ice bath, and slowly add BCl dropwise at 0°C 3 Dichloromethane solution (1.0mol / L, 33mL), keep stirring for half an hour, then slowly add AlCl 3 (4.4g, 33.0mmol) and CH 3 CN (3.2mL, 60.0mmol), after the addition is complete, stir the reaction at room temperature for half an hour, then rise to 70°C and keep the temperature for 12 hours, and then end the reaction. After the reaction solution is cooled, add 2N HCL to quench the reaction (the process of adding hydrochloric acid The reaction solution will have a lot of white bubbles, try to add it slowly in an ice bath at 0°C), then stir at 70°C for 2 hours, after cooling to room temperature, add 1N NaHCO 3 Adjust the solution to neutral, then add dichloromethane to extract until the extraction is complete, combine the organic phases, dry the organic phas...

Embodiment 3

[0061] Embodiment 3: the preparation of formula IV compound

[0062]

[0063] Add the compound of formula II (1.7g, 6.5mmol) and the compound of formula III (1.2g, 5.0mmol) into absolute ethanol (20mL), then add solid sodium hydroxide (800.0mg, 20.0mmol), after the addition is complete, the temperature is raised Reaction at 60°C for 12 hours, the reaction was terminated, the reaction solution was cooled to room temperature, filtered, the filter cake was washed with ethanol, and dried to obtain a yellow powder substance, which was the compound of formula IV (named: 1-(2'-amino-4 '-methoxy-5'-bromo)-3-(4'-methoxybenzylanisole)-2E-propen-1-one): 2.2 g, 4.66 mmol, and the molar yield is 93.2%.

[0064] Tested:

[0065] 1 H NMR (300MHz, CDCl 3 )δ8.00(s,1H,ArH),7.70(d,J=15.3Hz,1H,=H),7.59(d,J=8.4Hz,2H,ArH),7.44–7.33(m,3H,= H / ArH), 6.96(dd, J=21.1, 8.3Hz, 4H, ArH), 6.59(s, 2H, NH2), 6.13(s, 1H, ArH), 5.04(s, 2H, OCH 2 ),3.89(s,3H,ArOCH 3 ),3.82(s,3H,ArOCH 3 ).

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