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Protein-tyrosine-phosphatase 1B inhibitor and its preparation method and use

A C1-C6, halogen atom technology, applied in the delay or treatment of diseases mediated by PTP1B, type II diabetes and obesity drugs, insulin sensitizers, can solve difficult drug candidate compounds and other problems

Inactive Publication Date: 2008-09-10
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The research on PTP1B selective inhibitors has made some progress, but most of them are limited to some peptides or peptidoids, such as the inhibitor EEDE(F2PMP)M (Ki=7.2nM) designed based on the substrate sequence of PTP1B dephosphorylation , Glu-F2PMP-F2PMP (IC50=40nM), although these peptide inhibitors have strong inhibitory activity and high selectivity, the fact that they are peptide phosphate compounds makes it difficult to become drug candidate compounds

Method used

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  • Protein-tyrosine-phosphatase 1B inhibitor and its preparation method and use
  • Protein-tyrosine-phosphatase 1B inhibitor and its preparation method and use
  • Protein-tyrosine-phosphatase 1B inhibitor and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097]

[0098] step one:

[0099] Suspend 55mmol tyrosine in 100mL water and 100mL 1,4-dioxane, add 110mmol triethylamine, react for 1h, then add 83mmol (Boc) 2 O, react for 20h, spin dry. Dilute with ice water, extract and wash with ethyl acetate, adjust the pH of the aqueous phase to 2, and extract with ethyl acetate. The concentrated product was dissolved in 100 mL DME, 0.22 mol imidazole was added, and after stirring for 10 minutes, 0.1 mol TBSCl was added and reacted overnight. Quench with ice water, extract with ether, and concentrate to obtain compound 14 (yield 80%).

[0100] Dissolve 32 mmol of compound 14 in 200 mL of redistilled DME, add 32 mmol of N-methylmorpholine and 32 mmol of isobutyl chloroformate at -13°C, react at room temperature for 1 h, bubbling in ammonia gas for 4 h, quench with ice water, and extract with chloroform. The concentrated product was dissolved in 200 mL of redistilled DME, added 16 mmol Lawesson reagent, reacted for 5 hours, quenched with i...

Embodiment 2～13

[0114] The final products of Examples 2-13 in Table 1-1 were prepared by a method similar to Example 1.

[0115] Table 1-1 Final product (R 5 =R 7 =Me)

[0116]

[0117]

[0118]

Embodiment 14

[0120]

[0121] The preparation method of compound 21 is the same as in Example 1.

[0122] Dissolve 0.05mmol of compound 21 in 1mL of dichloromethane, add 0.3mL of trifluoroacetic acid dropwise, react for 2h, spin off the solvent and trifluoroacetic acid. Add 0.06mmol F 3 CCOOH, 0.12mmol EDCI, 0.01mmol DMAP and 2mL DMF were reacted overnight, quenched with ice water, extracted with ethyl acetate, concentrated, and passed through the column with petroleum ether: ethyl acetate=4:1 to obtain compound 23 (yield 50-90% ).

[0123] Compound 23 (WY558f)

[0124] 1 H NMR(CDCl 3 , 300MHz) data: δ 1.26 (t, 3H), 2.04 (s, 3H), 2.17 (s, 3H), 3.26 (dq, 2H), 4.21 (q, 2H), 5.02 (s, 2H), 5.47 (q, 1H), 6.27(s, 1H), 6.48(s, 1H), 6.88(d, 2H), 6.98(d, 2H), 7.04(s, 1H), 7.32-7.44(5H), 7.48( d, 1H).

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Abstract

The invention provides a PTP1B inhibitor. The concrete structure is as follows. The test shows that the inhibitor can effectively inhibit the activity of protein tyrosine phosphatase 1B (PTP1B), can be taken as insulin sensitizer, and is used to prevent, postpone or treat the related diseases resisted by insulin mediated by the PTP1B (particularly type II diabetes and obesity). The invention also provides a preparation method for the inhibitor.

Description

Technical field [0001] The present invention relates to a class of PTP1B inhibitors, specifically a class of novel small molecule organic compounds that can be used as protein tyrosine phosphatase 1B (PTP1B) inhibitors, and also relates to a preparation method of the inhibitor and as an insulin sensitizer , In the prevention, delay or treatment of diseases mediated by PTP1B, especially type II diabetes and obesity drugs. Background technique [0002] Diabetes (Diabetes Mellitus) is a group of clinical syndromes caused by the interaction of genetic and environmental factors. Due to absolute or relative insufficient insulin secretion and decreased sensitivity of target tissue cells to insulin, it causes sugar, protein, fat, water, electrolytes, etc. A series of metabolic disorders. Clinically, hyperglycemia is the main common sign. Prolonged illness can lead to various complications such as blindness, cardiovascular and cerebrovascular diseases, and renal failure. Acute metabolic d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/30C07D417/12A61K31/426A61K31/427A61P3/10A61P3/06
CPCC07D277/30C07D417/12A61P3/10A61P3/04A61P3/06A61P43/00
Inventor 南发俊李佳韦轶张薇李静雅石磊
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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