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Preparation method of uralipide

A technology of ularitide and peptide resin, which is applied in the field of polypeptide drug preparation, can solve the problems of inability to bring about clinical prognosis, achieve the effects of shortening the preparation process cycle, wide practical value and application prospect, and improving product purity and yield

Pending Publication Date: 2020-02-11
CHENGDU SHENGNUO BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Uralitide may not lead to better clinical outcomes because uralitide acts through the same receptor pathway as nesiritide, however, earlier treatment targeting deleterious pathological mechanisms may translate into better long-term outcomes

Method used

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  • Preparation method of uralipide
  • Preparation method of uralipide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The synthesis of embodiment 1 ularitide resin

[0035] Ularitide peptide resin is:

[0036] Boc-Thr(tBu)-Ala-Pro-Arg(Pbf)-Ser(tBu) 5 -Leu-Arg(Pbf)-Arg(Pbf)-Ser(tBu)-Ser(tBu)10 -Cys(Trt)-Phe-Gly-Gly-Arg(Pbf) 15 -Met-Asp(OtBu)-Arg(Pbf)-Ile-Gly 20 -Ala-Gln(Trt)-Ser(tBu)-Gly-Leu 25 -Gly-Cys(Trt)-Asn(Trt)-Ser(tBu)-Phe 30 -Arg(Pbf)-Tyr(tBu)-resin

[0037] Using Fmoc-Gly-resin as the starting resin, Fmoc deprotection and coupling reactions were performed, followed by coupling with the protected amino acids shown in Table 2 to prepare ularitide resin. The protected amino acids or fragments corresponding to the protected amino acids used in this example are shown in the table below:

[0038] Table 2

[0039]

[0040] 1. Access to the second protected amino acid

[0041] Take 0.09 mol of the second protected amino acid and 0.09 mol of HOBt, and dissolve it with an appropriate amount of DMF; take another 0.09 mol of DIC, slowly add it to the protected amino acid DMF sol...

Embodiment 2

[0046] Example 2 Preparation of Ularitide Crude Product

[0047] Get the Liularitide resin obtained in Example 1, add a cleaving reagent (cracking reagent 10mL / gram resin) with a volume ratio of TFA:water:EDT=95:5:5, stir evenly, stir at room temperature for 3 hours, and react The mixture was filtered with a sand core funnel, the filtrate was collected, the resin was washed 3 times with a small amount of TFA, the combined filtrates were concentrated under reduced pressure, anhydrous diethyl ether was added to precipitate, and anhydrous diethyl ether was used to wash the precipitate 3 times, and dried under reduced pressure at 35-45°C to obtain Off-white powder.

[0048] The obtained off-white powder was dissolved in 30% acetic acid solution to make a solution of about 3 mg / ml, and a saturated solution of iodine / ethanol was added dropwise with stirring until complete cyclization, and concentrated under reduced pressure at 35-40°C to obtain a concentrated solution of atosiban cr...

Embodiment 3

[0049] Example 3 Purification of Ularitide Crude Product

[0050] Take the crude ularitide obtained in Example 2, add water and stir, adjust the pH to 8.5 with ammonia water until completely dissolved, filter the solution with a 0.45 μm mixed microporous membrane, and purify it for later use;

[0051] High-performance liquid chromatography was used for purification, and the chromatographic filler for purification was 10 μm reversed-phase C18. Two mobile phase systems were used for purification alternately. The first mobile phase system was 0.1% TFA / water solution-0.1% TFA / acetonitrile solution, and the second mobile phase system was 0.1% TFA / water solution-0.1% TFA / acetonitrile solution. The two mobile phase systems are 50mmol ammonium acetate / water solution-acetonitrile. The flow rate of the 77mm*250mm chromatographic column is 90mL / min, the gradient system is used for elution, and the sample is injected and purified in a circular manner. The crude product solution is loaded ...

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Abstract

The invention provides a preparation method of high-purity urelipide. The preparation method adopts a special protected amino acid fragment, that is, Boc-Thr(tBu)-Ala-Pro-Arg(Pbf)-Ser(tBu)-Leu-Arg(Pbf)-Arg(Pbf)-Ser(tBu)-Ser(tBu)-Cys(Trt)-Phe-Gly-OH, the preparation process cycle is shortened, and the purity and yield of products in large-scale production are improved.

Description

technical field [0001] The invention belongs to the technical field of polypeptide drug preparation methods, in particular to a preparation method of ularitide. Background technique [0002] Ularitide is one of the endogenous natriuretic peptide family members present in plasma and urine, which includes ANP, BNP, CNP, DNP, vasodilator and uraritide. ANP, BNP and ularitide can exert physiological and pharmacological effects through the atrial natriuretic peptide receptor (NPRA), activate guanylate cyclase, increase the level of cyclic guanosine phosphate (cGMP), trigger RAAS system inhibition, vasodilation, Fibrosis and lusitropy. ANP, BNP and CNP can combine with atrial natriuretic peptide receptor 3 (NPR-C) to control the level of ularitide in plasma. The heart, kidney, vascular smooth muscle cells and other organs all express NPR-A receptors, and the distal tubules of the kidneys can synthesize uralitide in response to the increase in serum sodium concentration. Uraliti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/58C07K1/20C07K1/06C07K1/04
CPCC07K14/58Y02P20/55
Inventor 董华建郭德文文永均
Owner CHENGDU SHENGNUO BIOPHARM
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