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Liraglutide analogue and preparation method thereof

A technology of liraglutide and liraglutidyl, applied in the field of pharmaceutical peptides, can solve problems such as long action time, and achieve the effects of lowering blood sugar, reducing inflammation, and improving glucose metabolism

Active Publication Date: 2022-02-11
浙江湃肽生物股份有限公司深圳分公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Liraglutide belongs to a new generation of incretin hypoglycemic drugs with a long duration of action and may have positive effects on various cardiovascular risk factors

Method used

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  • Liraglutide analogue and preparation method thereof
  • Liraglutide analogue and preparation method thereof
  • Liraglutide analogue and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] The synthetic method of formula I compound, the route of its synthetic method sees figure 1 ,include,

[0073] Step I-a, add 0.1 mol of o-phenylenediamine and 0.12 mol of pyruvic acid into 80 mL of 5 M HCl solution, stir and reflux at 85°C for 3.5 h, cool to room temperature after the reaction, and then use 3.2 M NaOH solution to adjust the pH to 9.5, suction filtration, collect solid, wash 3 times with distilled water, dry, obtain formula Ia compound, productive rate is 74.6%, the molecular formula of Ia compound is C 9 h 8 N 2 O, 1 HNMR (DMSO-d 6 , 300 MHz) δ: 12.18 (s, 1H, NH), 7.25-7.61(m, 4H, Ar-H), 2.85(m, 3H, CH 3 );

[0074] Step I-b, add 0.1 mol of the compound of formula Ia and 0.12 mol of formic acid into 100 mL of acetonitrile, stir and reflux at 85°C for 4 h, and distill under reduced pressure to obtain the compound of formula Ib with a yield of 71.5%. The molecular formula of compound Ib is C 10 h 8 N 2 o 2 , 1 HNMR (DMSO-d 6 , 300 MHz) δ: 9.55...

Embodiment 2

[0078] The synthetic method of formula II compound, the route of its synthetic method sees figure 2 ,include

[0079] Step II-a, add 0.1 mol o-phenylenediamine and 0.12 mol lipoic acid into 80 mL 5 M HCl solution, stir and reflux at 85°C for 3.5 h, cool to room temperature after the reaction, and then adjust with 3.2 M NaOH solution pH to 9.5, suction filtration, collect solid, wash 3 times with distilled water, dry, obtain formula IIa compound, productive rate is 72.8%, the molecular formula of IIa compound is C 14 h 18 N 2 S 2 , 1 HNMR (DMSO-d 6 , 300 MHz) δ: 12.36 (s, 1H, NH), 7.29-7.64(m, 4H, Ar-H), 2.97(t, 2H, CH 2 ), 2.52-2.65(t, 3H, S-CH, S-CH 2 ), 1.79-1.94(t, 2H, CH 2 ),1.25-1.68(t, 6H, CH 2 );

[0080] Step II-b, add 0.1 mol of the compound of formula IIa and 0.12 mol of formic acid into 100 mL of acetonitrile, stir and reflux at 85°C for 4 h, and distill under reduced pressure to obtain the compound of formula IIb with a yield of 71.2%, the molecular form...

Embodiment 3

[0084] A preparation method of liraglutide analogue-I, comprising,

[0085] Add 1 mmol liraglutide, 2.4 mmol formula I compound, 1.3 mmol EDCI and 0.25 mmol DMAP into 220 mL dichloromethane, react at room temperature, TLG traces the reaction process, after the reaction, the solvent is distilled off under reduced pressure, and then Slowly pour into 100 mL of 1.5 M HCl solution, extract 3 times with 50 mL of dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and distill off the solvent under reduced pressure to obtain liraglutide analogue-I.

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Abstract

The invention discloses a liraglutide analogue and a preparation method thereof, and belongs to the technical field of pharmaceutical peptides. According to the liraglutide analogue, acylation modification is carried out on the N terminal and / or the 15 site of the N terminal of liraglutide by utilizing a modifier, and the modifier is a compound shown in a formula I or a formula II. The preparation method of the liraglutide analogue comprises the step of carrying out acylation reaction on liraglutide and the modifier to obtain the liraglutide analogue. The liraglutide is modified by adopting the compound shown in the formula I or the formula II, so that the blood sugar reducing effect, the blood fat reducing effect and the weight losing effect of the liraglutide analogue can be improved, the liraglutide analogue can have the anti-inflammatory property and the analgesic property, and in addition, the half-life period of the liraglutide can be prolonged.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical peptides, and in particular relates to a liraglutide analog and a preparation method thereof. Background technique [0002] Liraglutide is a modified human glucagon-like-1 (GLP-1) used for the treatment of type II diabetes. It has GLP-1 receptor agonistic effect. And immunogenicity and other aspects are similar to GLP-1. Liraglutide belongs to a new generation of incretin hypoglycemic drugs with a long duration of action and may have positive effects on various cardiovascular risk factors. The listing of liraglutide has added a more humane hypoglycemic treatment option for patients, and its structural formula is: His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr -Leu-Glu-Gly-Gln-Ala-Ala-Lys(Nα-PAL-γ-Glu)-Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH. The molecular structure of liraglutide has 97% homology with GLP-1 (7-37). The difference is that Lys 34 is replaced by Arg; the side c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605C07K1/107A61K38/26A61P3/10A61P3/06A61P3/04A61P29/00
CPCC07K14/605A61P3/10A61P3/06A61P3/04A61P29/00A61K38/00
Inventor 魏祝宇涂仕前马奔叶有志
Owner 浙江湃肽生物股份有限公司深圳分公司
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