DPP4 inhibitor modified derivative of GLP-1 analogue

A technology of GLP-1 and DPP4, which can be applied in drug combinations, peptide preparation methods, animal/human proteins, etc., and can solve the problems of high clearance rate limiting effectiveness, etc.

Inactive Publication Date: 2016-11-23
ADLAI NORTYE BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, high clearance limits the effectiveness of th

Method used

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  • DPP4 inhibitor modified derivative of GLP-1 analogue
  • DPP4 inhibitor modified derivative of GLP-1 analogue
  • DPP4 inhibitor modified derivative of GLP-1 analogue

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Embodiment one: the synthesis of Palmitoyl-OSu activated lipid

[0086] Weigh 25.64g n-hexadecanoic acid (100mmol), add 13.81g HOSu (120mmol) into 200ml THF, add 24.76g DCC (120mmol) under ice-water bath, react for 1 hour, raise the temperature to room temperature for 3 hours, and filter the reaction solution. The mother liquor was spin-dried, dissolved in DCM, filtered, washed 3 times with saturated sodium bicarbonate, 2 times with pure water, back-extracted 2 times, combined organic phase, dried with anhydrous sodium carbonate, spin-dried, recrystallized with ice ethanol 3 times, filtered, The solid oil pump dried to 31.46g Palmitoyl-OSu activated fat, yield 89%.

Embodiment 2

[0087] Embodiment two: the synthesis of Palmitoyl-Glu-OtBu

[0088] Weigh 10.16g H-Glu-OtBu (50mmol) and 7.95g Na2CO3 (75mmol) into a mixed solution of 50ml water and 50ml THF to dissolve, weigh 17.68g Palmitoyl-OSu (50mmol) into 50ml THF, dissolve and drop Add it to the above mixed solution, react overnight at room temperature, adjust the pH to 7 with 10% dilute hydrochloric acid, remove THF by rotary evaporation, and then adjust the pH to 3. A large white precipitate was obtained which was filtered. The resulting white precipitate was recrystallized from ice ethanol. The solid oil pump was pulled dry to 19.21g Palmitoyl-Glu-OtBu, and the yield was 87%.

Embodiment 3

[0089] Example 3: Synthesis of Palmitoyl-Glu(OSu)-OtBu

[0090] Weigh 8.83g Palmitoyl-Glu-OtBu (20mmol), add 2.76g HOSu (24mmol) into 100ml THF, add 4.95g DCC (24mmol) under ice-water bath, react for 1 hour, warm up to room temperature for 3 hours, and filter the reaction solution. The mother liquor was spin-dried, dissolved in DCM, filtered, washed 3 times with saturated sodium bicarbonate, 2 times with pure water, back-extracted 2 times, combined organic phase, dried with anhydrous sodium carbonate, spin-dried, recrystallized with ice ethanol 3 times, filtered, The solid oil pump is pulled dry to 9.48g Palmitoyl-Glu(OSu)-OtBu activated fat, and the yield is 88%.

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Abstract

The invention relates to a GLP-1 analogue derivative modified with a DPP4 inhibitor and analogue thereof. The derivative has a longer half-life period than marketed GLP-1 medicine, such as exenatide and liraglutide, and has interesting pharmaceutical properties in treatment of diabetes mellitus type 2.

Description

Technical field [0001] The invention involves the new derivatives after the modification of the DPP4 inhibitors of the human pancreas-1 (GLP-1) and its fragments and the analogs of these fragments. They have a longer effect than before modification.The curve also involves the preparation of these substances. Background technique [0002] An important reason for the onset and progress of type 2 is the progressive recession of islet function, including insulin discharge caused by β -cell insulin secretion defects and the inappropriate secretion of alpha cells to increase sugar: the proportion of glucose is imbalance.Pancar-hybal-sample-1 (GLP-1) is a kind of intestinal insulin (incretin) that is synthesized by intestinal endocrine cells under the stimulation of food nutrients.By promoting insulin secretion of β -cells, inhibiting the secretion of inappropriate cells in cells, delaying gastric emptying, and suppressing appetite and other channels to participate in the body's blood g...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/107A61K38/26A61P3/10A61P3/04
CPCC07K14/605A61K38/00
Inventor 周俊杨东晖路杨
Owner ADLAI NORTYE BIOPHARMA CO LTD
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