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Branched peg-modified glp-1 analogs and pharmaceutically acceptable salts thereof

A GLP-1, branched technology, applied in the field of branched PEG-modified GLP-1 analogs and their pharmaceutically acceptable salts, can solve the problem of inability to maintain blood sugar metabolism and endocrine regulation, loss of function, and ineffective long-term effects. First-class problems, to achieve the effect of low cost, optimized design, long-term activity

Active Publication Date: 2015-12-23
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The mechanism of action of these drugs may be different, but none of them has the effect of protecting the β-cells with the function of secreting insulin, so it is impossible to maintain normal blood sugar metabolism and endocrine regulation in the body
In many cases, the use of a single drug slowly wears off, forcing the use of combination therapy. Often patients are also taking blood pressure and cholesterol lowering drugs, so the long-term effect of such regimens is variable.

Method used

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  • Branched peg-modified glp-1 analogs and pharmaceutically acceptable salts thereof
  • Branched peg-modified glp-1 analogs and pharmaceutically acceptable salts thereof
  • Branched peg-modified glp-1 analogs and pharmaceutically acceptable salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: Synthesis of GLP-1 analogue SEQIDNO.95

[0026] The sequence of SEQ ID NO.95 is shown in formula (I): HdAEGTFTSDLSKQNleEEEAVRLFIEWLKQGGPSSGAPPPC-NH 2

[0027] (I)

[0028] According to the structural characteristics, it can be synthesized by relatively mature solid-phase synthesis technology.

[0029] 1.1 Amino acid derivatives used in the synthesis

[0030] Fmoc-His(Trt)-OH, Fmoc-D-Ala-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Ser (tBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Nle-OH, Fmoc-Ala-OH , Fmoc-Val-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Ile-OH, Fmoc-Trp(Boc)-OH, Fmoc-Pro-OH, Fmoc-Cys(Trt)-OH.

[0031] The above amino acid derivatives were purchased from Jill Biochemical.

[0032] 1.2 Resins and other reagents

[0033] Resin: RinkAmide-AM resin (Gill Biochemical).

[0034]Other reagents: N, N'-diisopropylcarbodiimide (DIC), hydroxybenzotriazole (HOBT), dimethylformamide (DMF), dichlorom...

Embodiment 2

[0040] Embodiment 2: the synthesis of maleimide-based active polyethylene glycol

[0041] This example is the synthesis of linear and branched maleimide-based active polyethylene glycol, in which the main raw materials are mPEG-OH (5kD), mPEG-OH (10kD), mPEG-OH (20kD), mPEG -OH (30kD) was purchased from Sunbio Company in South Korea, and other reagents such as ethylenediamine, N-hydroxysuccinimide (HOSu), Lys, toluene, and methylene chloride were commonly used reagents.

[0042] 2. Synthesis of 1mPEG-MAL (20kD)

[0043]

[0044] Put 20g (1mmol) mPEG-OH (20kD) into a 200ml single-necked bottle, add 100ml toluene, reflux to separate water; then distill off the toluene, cool to room temperature, add 100ml DCM, and then add 1.18g (4mmol) of triphosgene (triphosgene), stirred at room temperature and reacted overnight; the next day, the reaction solution was washed into 200ml of anhydrous ether in a fume hood, filtered and vacuum-dried to obtain 15g of a white solid. Put 15g of...

Embodiment 3

[0081] Example 3: Synthesis of Pegylated GLP-1 Analog SEQIDNO.95

[0082] Active polyethylene glycol mPEG-MAL (20kD), mPEG4-Lys-MAL (20kD), mPEG2-Lys-MAL (20kD), mPEG2-Lys-MAL (40kD), mPEG2-Lys respectively prepared in Example 2 -MAL (60kD) and mPEG2-glycerol-MAL (40kD) purchased from U.S. NEKTAR company (article number: 2D3Y0T01), react with the GLP-1 analog SEQIDNO.95, and form a thioether bond after the Michael addition reaction to make the polypeptide and Polyethylene glycol is covalently bound to obtain the pegylated GLP-1 analog SEQ ID NO.95.

[0083]

[0084] Structure of mPEG2-glycerol-MAL(40kD)

[0085] 3.1 Preparation of PEX-165

[0086] Weigh 5.0gmPEG-MAL (20kD) and 1.26g GLP-1 analog SEQIDNO.95 (1.2 times excess), add 300ml 0.1M sodium phosphate buffer (pH7.7), and stir at room temperature for 2 hours.

[0087] The reaction solution was separated and purified using a reverse-phase HPLC preparative column (Luna, C18), and lyophilized to obtain 2.5 g of a white...

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Abstract

Provided are branched PEG-modified GLP-1 analogs and pharmaceutically acceptable salts thereof, preparation methods thereof, pharmaceutical compositions containing therapeutically effective amounts of the analogs, and drugs for treating and / or preventing type 2 diabetes in the application.

Description

technical field [0001] The present invention relates to a branched PEG-modified GLP-1 analogue, a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing a therapeutically effective amount of the analogue, and its role in the treatment and / or prevention of type II diabetes aspects of application. Background technique [0002] In recent years, with the improvement of living standards, the modernization of life patterns and the aging of society, the prevalence of diabetes is increasing year by year all over the world, especially in developing countries that are changing from poor to rich. Diabetes has become the third serious chronic non-communicable disease after tumors and cardiovascular and cerebrovascular diseases, and is one of the main causes of death and disability. In 1997, WHO reported that there were 135 million people with diabetes in the world, and it is estimated that by 2000 it will reach 175 million people...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/605A61K38/26A61K47/48A61P3/10
CPCA61K38/26A61K47/60C07K14/605A61P3/10
Inventor 王瑞军赵军军
Owner JIANGSU HANSOH PHARMA CO LTD