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Structure-modified GLP-1 analogs and preparation method thereof

A technology of GLP-1 and analogs, which is applied in the field of preparation of exenatide derivatives and structurally modified exenatide derivatives, which can solve the problems of low toxicity and short drug effect

Active Publication Date: 2015-09-30
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, despite the progress in this field, Exendin-4 and some modified Exendin-4 drugs currently on the market have short drug effects, and there is still an urgent need to develop new exenatide derivatives to make them act for a long time in vivo and have good stability. , good hypoglycemic effect while maintaining low toxicity and good activity

Method used

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  • Structure-modified GLP-1 analogs and preparation method thereof
  • Structure-modified GLP-1 analogs and preparation method thereof
  • Structure-modified GLP-1 analogs and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] Example 1 The preparation of compound shown in formula 10

[0135]

[0136]

[0137] Under nitrogen protection, add 200 mL of pyridine and 120 g of the compound shown in formula 1 (1.0eq) into a 1000ml three-necked flask, stir to cool down to 0°C, add 151.8g of TsCl (1.0eq) in batches, stir for 1h, and then slowly raise the temperature to At room temperature, continue to stir for 3-4h. After the reaction is over, pour the reaction solution into ice dilute hydrochloric acid solution, solids are produced, add EA for extraction, wash the EA layer with dilute hydrochloric acid once, wash with saturated sodium bicarbonate, and wash with saturated brine, then anhydrous Na 2 SO 4 After drying, the solvent was evaporated under reduced pressure to obtain 119 g of the crude product, which was subjected to silica gel column chromatography (eluent: petroleum ether: ethyl acetate: acetic acid = 4:1:0.1) to obtain 55 g of the pure product of formula 2.

[0138] Add 55 g (...

Embodiment 2

[0145] Example 2 The preparation of compound shown in formula 13

[0146]

[0147] Compound 12 was prepared in a similar manner to compound 9. Add 1.0g compound 7, 15ml water, 0.7g NaHCO into 100mL three-neck flask 3 , 1.32 g of compound 12 and 15 ml of DME solution were added dropwise, stirred overnight, and the progress of the reaction was detected by TLC.

[0148] Post-reaction processing:

[0149] Add water to adjust the pH to about 3, extract with EA, wash the EA layer with dilute sodium hydroxide solution, adjust the pH to about 2 in the water layer, add EA for extraction, wash with water, wash with saturated saline, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, About 1.2 g of compound 13 was obtained.

Embodiment 3

[0150] Example 3 Preparation of compound 16

[0151]

[0152] Add 6.3g HOSU, 10g compound 14 and 60ml DMF to a 100mL three-neck flask, control the temperature below 0°C, add 11.3g DCC and stir overnight.

[0153] Post-reaction treatment: suction filtration, add water to the filtrate, extract with EA, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure to obtain compound 15.

[0154] Add 1.0g of compound 7, 15ml of water and 0.7g of NaHCO into a 100mL three-neck flask 3 , a solution of 1.5 g of compound 15 and 15 ml of DME was added dropwise, and stirred overnight.

[0155] Post-reaction processing:

[0156] Add water to adjust the pH value to about 3, extract with EA, wash the EA layer with dilute sodium hydroxide solution, adjust the pH of the water layer to about 2, add EA for extraction, wash with water, wash with saturated saline, dry over anhydrous sodium sulfate, and evaporate under reduced pr...

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Abstract

The invention relates to structure-modified GLP-1 analogs and a preparation method thereof, particularly exenatide derivatives and a preparation method thereof, and a pharmaceutical composition containing the analogs and application thereof in treating diseases, such as Type II diabetes. The exenatide derivatives are obtained by carrying out structure modification on the C terminal of exenatide. The prepared compounds can obviously provide intracellular cAMP (cyclic adenosine monophosphate) content. The animal experiment indicates that the exenatide derivatives have equivalent and even higher bioactivity than the exenatide. Meanwhile, compared with the exenatide, the compounds provided by the invention have the advantages of high stability and obviously longer in-vivo half life.

Description

technical field [0001] The present invention relates to the field of therapeutic peptides, in particular to structurally modified GLP-1 analogs and preparation methods thereof, further to structurally modified exenatide derivatives, and the present invention also relates to structurally modified exenatide derivatives method of preparation. Background technique [0002] Exenatide (also known as Exenatide or Exendin-4, trade name Byetta) is a polypeptide composed of 39 amino acids with a molecular weight of 4186.6 and a molecular formula of C 184 h 282 N 50 o 60 S, CAS Registry Number is 141758-74-9, amino acid sequence is: [0003] His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp- Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 ; manufactured and marketed by Amylin Pharmaceuticals and Eli Lilly and Company. Exenatide was approved for marketing by the FDA in April 2005. It is a subcutaneous injection prepar...

Claims

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Application Information

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IPC IPC(8): C07K14/605A61K38/26A61K47/48A61P3/10
CPCC07K14/47A61K38/00C07K14/605A61K47/542A61P3/10
Inventor 袁建栋黄仰青宋云松顾家宁杨晴铖朱锐季南南方程姚翠萍
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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