Structurally modified glp-1 analogue and preparation method thereof

A technology of GLP-1 and 34GLP-1, which is applied in the preparation of exenatide derivatives and structurally modified exenatide derivatives, which can solve the problems of short efficacy and low toxicity

Active Publication Date: 2019-12-10
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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  • Structurally modified glp-1 analogue and preparation method thereof
  • Structurally modified glp-1 analogue and preparation method thereof
  • Structurally modified glp-1 analogue and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0135] The preparation of the compound shown in embodiment 1 formula 10

[0136]

[0137]

[0138] 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.

[0139] Add 55 ...

Embodiment 2

[0146] The preparation of the compound shown in embodiment 2 formula 13

[0147]

[0148] 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.

[0149] Post-reaction processing:

[0150] 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

[0151] The preparation of embodiment 3 compound 16

[0152]

[0153] 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.

[0154] 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.

[0155] 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.

[0156] Post-reaction processing:

[0157] 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 reduc...

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Abstract

The present invention involves structural modification of GLP‑1 analog and its preparation methods, which involves Essean peptide derivatives and their preparation methods; and the use of drug compositions containing them and their use in treating diseases such as II diabetes.The Essean peptide derivatives provided by the present invention are modified at the end of the Essean peptide C to prepare to obtain a compound that can significantly provide intracellular CAMP content, and animal experiments show that the Essean peptide derivative provided by the present invention provided by the inventionIt has a better biological activity that is equivalent to Essean peptides. At the same time, compounds provided by the present invention have good stability compared with Esseanptides, and the half -life in vivo is significantly prolonged.

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 RegistryNumber 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 prepara...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/605A61K38/26A61K47/60A61P3/10
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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