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Derivative or pharmaceutically acceptable salt of GLP-1 analogue and application of derivative or pharmaceutically-acceptable salt of a GLP-1 analogue

A technology of GLP-1 and analogues, applied in the field of derivatives of GLP-1 analogues or their pharmaceutically acceptable salts and applications, which can solve the problem of reduced activity of GLP-1 derivatives, suspension of clinical research, and unsuitability for chronic dosage strategies And other issues

Active Publication Date: 2011-03-23
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In September 2005, after analyzing the results of existing trials, ConjuChem believed that CJC-1131 might not be suitable for chronic dosing regimens (chronic dosing regimens), thus suspending the clinical research of CJC-1131
WO9943705 discloses a chemically modified derivative at the N-terminus of GLP-1, but it has been reported in the literature that modification of the amino acid at the N-terminus will greatly reduce the activity of the entire GLP-1 derivative (J.Med.Chem.2000, 43, 1664 1669)

Method used

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  • Derivative or pharmaceutically acceptable salt of GLP-1 analogue and application of derivative or pharmaceutically-acceptable salt of a GLP-1 analogue
  • Derivative or pharmaceutically acceptable salt of GLP-1 analogue and application of derivative or pharmaceutically-acceptable salt of a GLP-1 analogue
  • Derivative or pharmaceutically acceptable salt of GLP-1 analogue and application of derivative or pharmaceutically-acceptable salt of a GLP-1 analogue

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] The solid phase synthesis method of embodiment 1 HS-20001

[0050] (1) Drying and swelling of solid phase synthetic resin

[0051] Weigh 50g (20mmol) of Fmoc-Lys(Mtt)-HMPA-AM resin (0.4mmol / g) which was vacuum-dried for 24 hours and place it in a 2L bubbler bottle, add 500mL N,N-dimethylformamide (DMF) Swell the resin for 30 minutes, then remove the DMF solution;

[0052] (2) Fmoc-Lys(Mtt)-HMPA-AM resin removes 4-methyltrityl (Mtt) protecting group

[0053] Wash the resin with 200mL DCM, repeat once, add 1200mL 1% TFA / DCM (TFA about 8 times excess) to remove the Mtt protecting group, reaction time 30 minutes, use 200mL 5% N, N-diisopropylethylamine (DIEA) / DMF and DMF were washed 3 times, and DMF was washed three times.

[0054] (3) Condensation of palmitic acid

[0055] Weigh 50mmol each of palmitic acid and 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4-one (DEPBT), add 400mL DMF to dissolve, then add 100mmol DIEA and stir the reaction at room temperature After 3...

Embodiment 2

[0070] The solid phase synthesis method of embodiment 2 HS-20002

[0071] (1) Drying and swelling of solid phase synthetic resin

[0072] Weigh 50g (20mmol) of Fmoc-Lys(Mtt)-HMPA-AM resin (0.4mmol / g) dried under vacuum for 24 hours and place it in a 2L bubbler bottle, add 500mL DMF to swell the resin for 30 minutes, and drain the DMF solution;

[0073] (2) Fmoc-Lys(Mtt)-HMPA-AM resin removes Mtt protecting group

[0074] Wash the resin with 200mL DCM, repeat once, add 1200mL 1% TFA / DCM (TFA about 8 times excess) to remove the Mtt protecting group, reaction time 30 minutes, wash 3 times with 200mL 5% DIEA / DMF and DMF, and wash 3 times with DMF .

[0075] (3) Condensation of palmitic acid

[0076] Weigh 50mmol each of palmitic acid and DEPBT, add 400mL DMF to dissolve, then add 100mmol DIEA, stir and react at room temperature for 3 minutes, add the above solution to the resin, and pass N 2 React for 2 hours. After the reaction was finished, the reaction solution was sucked ...

Embodiment 3

[0090] The solid-phase synthesis method of embodiment 3 HS-20003

[0091] (1) Drying and swelling of solid phase synthetic resin

[0092] Weigh 50g (20mmol) of Fmoc-Lys(Mtt)-HMPA-AM resin (0.4mmol / g) that was vacuum-dried for 24 hours and place it in a 2L bubbler bottle, add 500mL of DMF to swell the resin for 30 minutes, and remove the DMF solution;

[0093] (2) Fmoc-Lys(Mtt)-HMPA-AM resin removes Fmoc protecting group

[0094] Add 200mL of 20% piperidine / DMF solution to the bubble bottle filled with Fmoc-Lys(Mtt)-HMPA-AM resin, take it out after reacting for 5 minutes, then add 200mL of 20% piperidine / DMF solution and react at room temperature for 20 minutes. After the reaction, the resin was washed four times with 200 mL of DMF.

[0095] (3) Condensation of palmitic acid

[0096]Weigh 50mmol each of palmitic acid and DEPBT, add 400mL DMF to dissolve, then add 100mmol DIEA, stir and react at room temperature for 3 minutes, add the above solution to the resin, and pass N ...

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Abstract

The invention relates to a derivative or pharmaceutically-acceptable salt of a GLP-1 analogue containing an amino acid sequence shown in a formula (I). The derivative of the GLP-1 analogue has the function of human GLP-1 analogue, and compared with the human GLP-1 analogue, the derivative has a longer half-life period in vivo. The derivative or pharmaceutically-acceptable salt of the GLP-1 analogue, or the pharmaceutical composition of derivatives containing the GLP-1 analogue or pharmaceutically-acceptable salts thereof can be widely used for treating non-insulin-dependent diabetes mellitus,insulin-dependent diabetes mellitus and obesity. The formula (1) is as follows: X1-X2-Glu-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-X12-X13-X14-Glu-X16-X17-Ala-X19-X20-X21-Phe-Ile-X24-Trp-Leu-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36-X37-X38-X39-Lys (I).

Description

technical field [0001] The present invention relates to derivatives of human glucagon-like peptide-1 (GLP-1) analogs or pharmaceutically acceptable salts thereof. The derivatives of GLP-1 analogs provided by the present invention have the function of human GLP-1, and Compared with human GLP-1, it has a longer half-life in vivo. The present invention also relates to derivatives of GLP-1 analogs or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing derivatives of GLP-1 analogs or pharmaceutically acceptable salts thereof for the treatment of non-insulin-dependent diabetes mellitus, insulin-dependent Uses for diabetes and obesity. Background technique [0002] Diabetes is a global epidemic. It is a syndrome of glucose, protein, and lipid metabolism disorders caused by absolute or relative insulin deficiency (Chen Ruijie. Research status of diabetes treatment drugs. Journal of Guangdong Pharmaceutical College, 2001, 7( 2): 131-133), according t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605A61K38/26A61P3/10A61P3/04
CPCA61K38/00C07K14/605A61P3/04A61P3/10
Inventor 王亚里吕爱锋孙长安袁恒立
Owner JIANGSU HENGRUI MEDICINE CO LTD
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