3-acetylcoumarin compound having PTP 1b inhibitory activity

Abstract

The invention relates to a 3-acetylcoumarin compound having PTP 1B inhibitory activity. The 3-acetylcoumarin compound has the PTP 1B inhibitory activity, and can be used for treating the PTP 1B ?Cmediated diseases, especially diabetes and obesity, the invention belongs to the pharmaceutical chemistry field, and the compound has a structural general formula (I) shown as follows.

Description

Technical field

[0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of 3-acetyl coumarin compounds and applications thereof. Background technique

[0002] Diabetes and obesity are endocrine disorders and metabolic diseases that seriously threaten people’s health. They are often accompanied by decreased sensitivity of peripheral tissues to insulin and disturbances in the regulation of insulin signaling pathways. The phosphorylation level of protein tyrosine is an intracellular signal transduction. It is an important regulator of protein tyrosine kinase PTK and protein tyrosine phosphatase PTP. PTP 1B (protein tyrosine phosphatase 1B) can dephosphorylate protein tyrosine, weaken insulin and leptin signal transduction, and cause abnormal lipid metabolism, which is a key link in leading to insulin resistance and obesity. In the insulin signaling pathway, when insulin binds to IR, PTP 1B dephosphorylates the tyrosine of IRb in this pa...

Examples

preparation example Construction

[0047] The starting materials used in the preparation of the compounds of the present invention are known, can be prepared according to known methods, or are commercially available.

[0048] Both the intermediate and the final product can be post-processed and / or purified according to conventional methods, including pH adjustment, extraction, filtration, drying, concentration, chromatography, grinding, crystallization, and the like.

[0049] In addition, the compounds of the present invention can also be prepared by various methods known in the art or variations of the methods described herein.

[0050] The following various preparations are used to prepare synthetic intermediates for the compounds of the present invention.

[0051] Preparation 1 Preparation of 2-hydroxy-5-iodo-benzaldehyde

[0052]

[0053] Add iodine monochloride (162g, 1.0mol) dissolved in dry THF (100ml) to salicylaldehyde (12.2g, 0.1mol) and I 2 (25.38g, 0.1mol) mixed solution, stirred at room temperature for 48h...

Embodiment 1

[0058] Example 1 Preparation of 3-acetyl-6-N-morpholinocoumarin

[0059]

[0060] In a 50ml three-necked round bottom flask, the compound 3-acetyl-6-iodocoumarin (314mg, 1mmol) and CuI (190mg, 1mmol) obtained in Preparation 2 and CsCO 3 (650mg, 2mmol) was mixed and dissolved in 10ml of dry DMSO. After strict nitrogen protection on the reaction device, morpholine (100mg, 1.1mmol) was injected into the reaction vessel with a syringe, and the temperature was controlled at 90℃ to react for 24h, with acetic acid Ethyl (3*10ml) was used to extract the reaction solution, the organic phase was separated, washed with saturated brine 3*10ml, dried over anhydrous sodium sulfate, filtered, the solvent in the filtrate was distilled, and the residue was passed through silica gel Purification by column chromatography (petroleum ether:ethyl acetate=20:1) gave the title compound 3-acetyl-6-N-morpholinocoumarin.

Embodiment 2

[0061] Example 2 Preparation of 3-acetyl-6-(4-phenylpiperazin-1-yl) coumarin

[0062]

[0063] The morpholine in Example 1 was replaced with N-phenylpiperazine, and the compound was prepared using the same procedure as in Example 1.

Technical field

[0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of 3-acetyl coumarin compounds and applications thereof. Background technique

[0002] Diabetes and obesity are endocrine disorders and metabolic diseases that seriously threaten people’s health. They are often accompanied by decreased sensitivity of peripheral tissues to insulin and disturbances in the regulation of insulin signaling pathways. The phosphorylation level of protein tyrosine is an intracellular signal transduction. It is an important regulator of protein tyrosine kinase PTK and protein tyrosine phosphatase PTP. PTP 1B (protein tyrosine phosphatase 1B) can dephosphorylate protein tyrosine, weaken insulin and leptin signal transduction, and cause abnormal lipid metabolism, which is a key link in leading to insulin resistance and obesity. In the insulin signaling pathway, when insulin binds to IR, PTP 1B dephosphorylates the tyrosine of IRb in this pa...

Examples

preparation example Construction

[0047] The starting materials used in the preparation of the compounds of the present invention are known, can be prepared according to known methods, or are commercially available.

[0048] Both the intermediate and the final product can be post-processed and / or purified according to conventional methods, including pH adjustment, extraction, filtration, drying, concentration, chromatography, grinding, crystallization, and the like.

[0049] In addition, the compounds of the present invention can also be prepared by various methods known in the art or variations of the methods described herein.

[0050] The following various preparations are used to prepare synthetic intermediates for the compounds of the present invention.

[0051] Preparation 1 Preparation of 2-hydroxy-5-iodo-benzaldehyde

[0052]

[0053] Add iodine monochloride (162g, 1.0mol) dissolved in dry THF (100ml) to salicylaldehyde (12.2g, 0.1mol) and I 2 (25.38g, 0.1mol) mixed solution, stirred at room temperature for 48h...

Embodiment 1

[0058] Example 1 Preparation of 3-acetyl-6-N-morpholinocoumarin

[0059]

[0060] In a 50ml three-necked round bottom flask, the compound 3-acetyl-6-iodocoumarin (314mg, 1mmol) and CuI (190mg, 1mmol) obtained in Preparation 2 and CsCO 3 (650mg, 2mmol) was mixed and dissolved in 10ml of dry DMSO. After strict nitrogen protection on the reaction device, morpholine (100mg, 1.1mmol) was injected into the reaction vessel with a syringe, and the temperature was controlled at 90℃ to react for 24h, with acetic acid Ethyl (3*10ml) was used to extract the reaction solution, the organic phase was separated, washed with saturated brine 3*10ml, dried over anhydrous sodium sulfate, filtered, the solvent in the filtrate was distilled, and the residue was passed through silica gel Purification by column chromatography (petroleum ether:ethyl acetate=20:1) gave the title compound 3-acetyl-6-N-morpholinocoumarin.

Embodiment 2

[0061] Example 2 Preparation of 3-acetyl-6-(4-phenylpiperazin-1-yl) coumarin

[0062]

[0063] The morpholine in Example 1 was replaced with N-phenylpiperazine, and the compound was prepared using the same procedure as in Example 1.

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