Three protein tyrosine phosphatase 1B (PTP1B) inhibitors and synthesis and application thereof

Abstract

The invention relates to a chemical complete synthesis method for three novel PTP1B inhibitors and application of the PTP1B inhibitors in medicines for treating type II diabetes. The chemical structural formulas of the PTP1B inhibitors are shown as follows: a compound 6 (4, 5-di-(2, 3-dibromo-4, 5-dimethoxybenzyl)-1, 2-dimethoxyphenyl): groups connected with C of 2', 3', 2'' and 3'' sites of a benzene ring are bromine atoms, and C of 1, 2, 4', 5', 4'' and 5' sites is connected with methoxyl; a compound 7 (3-bromo-4, 5-di-(2, 3-dibromo-4, 5-dimethoxybenzyl)-1): the groups connected with C of 3, 2', 3', 2'' and 3'' sites of the benzene ring are bromine atoms, and C of 1, 2, 4', 5', 4'' and 5' sites is connected with the methoxyl; and a compound 8 (3-bromo-4, 5-di-(2, 3-dibromo-4, 5-dyhydroxylbenzyl)-1, 2-dihydroxybenzene): the groups connected with C of 3, 2', 3', 2'' and 3'' sites of the benzene ring are bromine atoms, and C of 1, 2, 4', 5', 4'' and 5'' is connected with hydroxyl. The three compounds enhance the sensitivity of an insulin receptor through inhibiting the activity of protein tyrosine phosphatase 1B and have good therapeutic action on insulin resistant type II diabetes.

Description

technical field [0001] The present invention relates to biomedicine, specifically three brominated compounds 4,5-bis-(2,3-dibromo-4,5-dimethoxybenzyl)-1,2-dimethoxy Benzene, 3-bromo-4,5-bis-(2,3-dibromo-4,5-dimethoxybenzyl)-1,2-dimethoxybenzene, 3-bromo-4,5 - Di-(2,3-dibromo-4,5-dihydroxybenzyl)-1,2-diphenol and its chemical total synthesis method, pharmacological activity and pharmaceutical use. The above compounds and derivatives thereof are used as insulin sensitizers and can be used for treating insulin resistance type 2 diabetes. Background technique [0002] Diabetes (Diabetes Mellitus, DM) is a chronic endocrine and metabolic disease. Currently, the drugs used to treat type 2 diabetes (Type 2 Diabetes Mellitus, T2DM) mainly include biguanides, sulfonylureas, α-glucosidase inhibitors and thiazolidine diuretics. Ketones, etc., have various disadvantages because they are mostly designed for symptoms rather than molecular target drugs for etiology. Therefore, the market...

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Problems solved by technology

[0004] There are not many studies on PTP1B inhibitors in the world, mainly in the following categories: (1) Peptides: peptide substrates containing phosphorylated tyrosine residues (pTyr) have a higher affinity with PTP1B, But its chemical and biological stability are poor; (2), naphthoquinones Naphthnoquinone: inhibit the activity of enzyme by modifying the active site of PTPase; (3), thiazolidinediones Azolidinediones: increase the insulin sensitivity of target organ Improve blood sugar control, mainly including ciglitazone, troglitazone and rosiglitazone, but due to severe liver toxicity, ciglitazone has been withdrawn from the market; (4), Benzo[b]naphthol[2,3-d]furans and thiophenes: benzbromarone (PTP1B inhibitor, IC 50 =26μM) as the lead compound designed and synthesized as a series of Benzo[b]naphthol[2,3-d]furans and thiophenes compounds, which showed good hypoglycemic activity in mice, but it still needs to be used as a drug for treating diabetes. Overcoming many obstacles, such as high electronegativity, poor cell membrane permeability, and poor selective specificity, all of which make these inhibitors less druggable

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