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PTP1B inhibitors and synthesis thereof, and application of PTP1B inhibitors to preparation of medicines for treating type 2 diabetes

An inhibitor and compound technology, which can be used in the preparation of carbon-based compounds, the preparation of organic compounds, and the preparation of ethers by dehydration of hydroxyl-containing compounds, which can solve the problems of high electronegativity, poor selection specificity, and not much.

Active Publication Date: 2011-04-20
INST OF OCEANOLOGY - CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

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mainly including ciglitazone, troglitazone and rosiglitazone, but due to severe liver toxicity, ciglitazone has been withdrawn from the market; (4), Benzo[b]naphthol[2,3-d]furans and thiophenes: benzbromarone (PTP1B inhibitor, IC 50 =26μM) as the lead compound designed and synthesized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

Method used

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  • PTP1B inhibitors and synthesis thereof, and application of PTP1B inhibitors to preparation of medicines for treating type 2 diabetes
  • PTP1B inhibitors and synthesis thereof, and application of PTP1B inhibitors to preparation of medicines for treating type 2 diabetes
  • PTP1B inhibitors and synthesis thereof, and application of PTP1B inhibitors to preparation of medicines for treating type 2 diabetes

Examples

Experimental program
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Effect test

Embodiment 1

[0074] Example 1 "(2'-bromo-6'-dibromomethyl-3',4'-dimethoxyphenyl)-(2,3-dibromo-4,5-dimethoxyphenyl )-Methanone"Chemical Total Synthesis and Structure Identification

[0075] (1) Chemical Synthesis and Structure Identification of 5-Bromovanillin

[0076] At 0°C, add 2.8ml of Br dropwise to 60ml of methanol dissolved with 7.6g (0.05mol) of vanillin 2 , 2 hours to complete the addition, stirred at room temperature for 1 hour, then added dropwise 25ml of water (precipitation) at 0°C, added 20 minutes, continued to stir for 15 minutes, filtered the precipitate, washed the precipitate with ice water, and drained to obtain 10.7g of white crystals, after spectral analysis, it was confirmed that the compound was 5-bromovanillin;

[0077] The physical and chemical properties of the compound are as follows: white crystal, melting point 160-162°C; H NMR spectrum: 1 HNMR (500Hz, CDCl 3 ): δ9.78(s, 1H), 7.64(d, J=1.65, 1H), 7.36(d, J=1.65, 2H), 6.53(s, 1H), 3.98(s, 3H); NMR carbon Sp...

Embodiment 2

[0096] Example 2 "3,4-dibromo-5-[(2'-bromo-3',4'-dihydroxy-6'-n-propoxymethyl-phenyl)-methyl]-1,2 - Hydroquinone, 3,4-dibromo-5-[(2'-bromo-3',4'-dihydroxy-6'-isopropoxymethyl-phenyl)-methyl]-1, 2-benzenediol, 3,4-dibromo-5-[(2'-bromo-6'-n-butoxymethyl-3',4'-dihydroxy-phenyl)-methyl]-1 , 2-benzenediol, 3,4-dibromo-5-[(2′-bromo-3′,4′-dihydroxy-6′-isobutoxymethyl-phenyl)-methyl]- Chemical synthesis and structure identification of 1,2-benzenediol"

[0097] (1) Chemical synthesis and structure identification of 5,6-dibromo-3,4-dimethoxybenzyl alcohol

[0098] Under the ice-water bath, 2.2 grams of sodium borohydride were added to 72 grams of 5,6-dibromoveratraldehyde in the methanol (400ml) solution, stirred, and detected by TLC. After the raw material point disappeared, 10% of Dilute hydrochloric acid until the solution is weakly acidic, distill off methanol, extract the obtained solid with equal volumes of dichloromethane and water (200ml each), dry the organic phase with anhy...

Embodiment 3

[0118] Example 3 "2,3-dibromo-1-(2'-bromo-6'-(2"-bromo-4",5"-dimethoxybenzyl)-3',4'-di Chemical synthesis and structure identification of methoxybenzyl)-4,5-dimethoxybenzene"

[0119] (1) 2,3-dibromo-1-(2'-bromo-6'-(3",4"-dimethoxybenzyl)-3',4'-dimethoxybenzyl )-4,5-Dimethoxybenzene Chemical Synthesis and Structure Identification

[0120] The compound veratrole 0.69g and 3-bromo-2-[(2′,3′-dibromo-4′,5′-dimethoxy)-benzyl]-4,5-methoxybenzene Dissolve 2.78g of methanol in dichloromethane, add 0.8g of aluminum trichloride to the above mixed solution under ice-water bath conditions, detect by TLC, after the raw material point disappears, pour the reaction solution into ice water, extract and separate, organic The phase was washed 3 times with dilute hydrochloric acid with a mass concentration of 3%, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized from methanol to obtain 2.8 g of a white solid, which was confirmed to be 2,3-dibromo-1...

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Abstract

The invention relates to a chemical total synthesis method for six novel PTP1B inhibitors, and application of the PTP1B inhibitors to the preparation of medicines for treating type 2 diabetes. The active ingredients of the PTP1B inhibitors are one or more of six compounds with structural formulas shown in the specifications. The compound enhances the sensitivity of an insulin receptor by inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), and has good treatment effect on insulin-resistant type 2 diabetes.

Description

technical field [0001] The present invention relates to biomedicine, specifically six kinds of brominated compounds "(2'-bromo-6'-dibromomethyl-3',4'-dimethoxyphenyl)-(2,3-bis Bromo-4,5-dimethoxyphenyl)-methanone (1), 3,4-dibromo-5-[(2'-bromo-3',4'-dihydroxy-6'-n-propane Oxymethyl-phenyl)-methyl]-1,2-benzenediol (2), 3,4-dibromo-5-[(2'-bromo-3',4'-dihydroxy-6 '-isopropoxymethyl-phenyl)-methyl]-1,2-benzenediol (3), 3,4-dibromo-5-[(2'-bromo-6'-n-butoxy Methyl-3', 4'-dihydroxy-phenyl)-methyl]-1,2-benzenediol (4), 3,4-dibromo-5-[(2'-bromo-3' , 4'-dihydroxy-6'-isobutoxymethyl-phenyl)-methyl]-1,2-benzenediol (5), 2,3-dibromo-1-(2'-bromo -6'-(2"-bromo-4", 5"-dimethoxybenzyl)-3', 4'-dimethoxybenzyl)-4,5-dimethoxybenzene ( 6)" and its chemical total synthesis method, pharmacological activity and pharmaceutical use. The above compounds and their derivatives are used as insulin sensitizers and can be used to treat insulin-resistant type 2 diabetes. Background technique [0002] Di...

Claims

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Application Information

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IPC IPC(8): A61K31/12A61K31/075A61K31/09C07C49/84C07C45/63C07C43/178C07C41/09C07C43/225C07C41/22A61P3/10
Inventor 史大永郭书举范晓卢伟伸崔永超
Owner INST OF OCEANOLOGY - CHINESE ACAD OF SCI
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