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WO2023279323A1 - Procédé de synthèse d'analogue de glp-1 - Google Patents

Procédé de synthèse d'analogue de glp-1 Download PDF

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Publication number
WO2023279323A1
WO2023279323A1 PCT/CN2021/105192 CN2021105192W WO2023279323A1 WO 2023279323 A1 WO2023279323 A1 WO 2023279323A1 CN 2021105192 W CN2021105192 W CN 2021105192W WO 2023279323 A1 WO2023279323 A1 WO 2023279323A1
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Prior art keywords
fmoc
glu
fragment
otbu
resin
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Ceased
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PCT/CN2021/105192
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English (en)
Chinese (zh)
Inventor
汪伟
黄嘉诚
尹传龙
唐洋明
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Hybio Pharmaceutical Co Ltd
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Hybio Pharmaceutical Co Ltd
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Priority to PCT/CN2021/105192 priority Critical patent/WO2023279323A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/08—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the technical field of polypeptide synthesis, in particular to a method for synthesizing GLP-1 analogues.
  • GLP-1 glucagon-like peptide-1
  • GLP-1 receptor binds to the GLP-1 receptor and acts on pancreatic ⁇ cells to increase the biosynthesis and secretion of insulin; at the same time Increase the number of islet ⁇ cells, inhibit the secretion of glucagon; inhibit appetite and food intake, delay the emptying of gastric contents, etc.
  • GLP-1 analogues are clinically developed for the treatment of type II diabetes and obesity, including liraglutide (Liraglutide), semaglutide (Semaglutide), etc.
  • the peptide sequence of liraglutide is:
  • the peptide sequence of semaglutide is:
  • the existing methods for preparing GLP-1 analogues can be roughly divided into two categories: genetic recombination methods and chemical synthesis methods.
  • Genetic recombination method Firstly, construct a recombinant expression vector, ferment, and purify the main chain fragment of the peptide, and then chemically connect the side chain fragment to the main chain fragment to obtain the crude peptide of the target product, such as patents CN1271086, CN105154498, etc.
  • the development cycle of this method is long, the technology is difficult, and the impurities are not easy to control.
  • Chemical synthesis methods including the following:
  • Fmoc/tBu strategy is used for solid-phase synthesis, temporary protecting groups such as Mtt, Aloc or ivDde are selected for lysine side chains, and the main chains are coupled one by one from the C-terminus to the N-terminus according to the peptide sequence, and then removed
  • the side chain amino acids are coupled in sequence according to the peptide sequence, and finally the target product crude peptide is obtained by trifluoroacetic acid cleavage, such as patents CN102286092, CN106928343, CN109369798, etc.
  • Patent CN106749613 first synthesizes the following three fragments by solid phase or liquid phase method: [1-16], [17-22] and [23-31], then condenses the fragments in the liquid phase to obtain a fully protected peptide, and finally trifluoroacetic acid Cleavage to obtain crude semaglutide peptide.
  • Patent CN109456401 first synthesizes six fragments by liquid phase or solid phase method: [1-4], [5-9], [10-16], [17-22], [23-27], [28-31], Then the fragments were coupled to a resin to obtain a peptide resin, and finally trifluoroacetic acid was cleaved to obtain a crude semaglutide peptide.
  • Patent CN11037278 firstly synthesized Oct- ⁇ -Glu(tBu)-AEEA-AEEA-OH side chain fragment and Fmoc-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(tBu)- Val-OH hexapeptide fragments, and then these two fragments and other amino acids are coupled to the resin to obtain a peptide resin, and finally trifluoroacetic acid is cleaved to obtain a crude semaglutide peptide.
  • Fragment [17-22] selected by patent CN106749613 in fragment condensation, fragment [5-9], [17-22] and [23-27] selected by patent CN109456401, fragment Fmoc-Thr(tBu)-Phe selected by patent CN11037278 -Thr(tBu)-Ser(tBu)-Asp(tBu)-Val-OH will racemize the C-terminal amino acid during coupling, resulting in more racemic impurities, and the purity of the crude peptide is low. At the same time, it is cumbersome to use liquid phase to synthesize fragments. Therefore, it is necessary to provide a synthetic method of GLP-1 analogs with high purity and yield of crude peptide and less Des-Thr 5 impurities to adapt to industrial production.
  • the purpose of the present invention is to provide a method for synthesizing GLP-1 analogues, the purity and yield of the crude peptide obtained by the method are high, the Des-Thr 5 impurity is less, and the operation is simple, which is suitable for industrial production.
  • the invention provides a method for synthesizing GLP-1 analogues, comprising the following steps:
  • Step 1 Synthesizing a fragment 1 coupled with a protecting group at the N-terminal of the amino acid sequence shown in SEQ ID NO: 1, on the His side chain, and on the Glu side chain;
  • Step 2 Synthesizing Fragment 2 with protective groups coupled to the N-terminal of the amino acid sequence shown in SEQ ID NO: 2, on the Thr side chain, on the Ser side chain, on the Asp side chain, on the Tyr side chain, and on the Glu side chain;
  • Step 3 sequentially coupling the amino acid shown in SEQ ID NO:3, Fragment 2 and Fragment 1 on the solid phase carrier in the order from the C-terminal to the N-terminal to obtain a peptide resin;
  • Step 4 Cleavage the peptide resin to obtain crude peptide.
  • the present invention firstly synthesizes the fragment 1 to 4 of the N-terminal of the GLP-1 analogue, the fragment 2 of the 5th to 12th position, and then sequentially couples SEQ ID NO:
  • the amino acid shown in 2 Fragment 2 and Fragment 1 are obtained from peptide resin, and cleaved to obtain crude peptide.
  • the crude peptide obtained by the synthesis method of the invention has high purity, high yield and less Des-Thr5 impurities.
  • the purity of the crude peptide is 80% to 82%, the yield is 38% to 40%, and the impurity of Des-Thr 5 is about 0.07 to 0.08%. .
  • the step 1 is specifically: sequentially coupling Fmoc-Gly-OH, Fmoc-Glu(OtBu)-OH, Fmoc-X-OH and Boc-His(Trt)-OH, piperidine removes the Fmoc protecting group, and fragment 1 is obtained by weak acid cleavage.
  • the peptide sequence of Fragment 1 is Boc-His(Trt)-X-Glu(OtBu)-Gly-OH.
  • X is Ala or Aib.
  • the step 2 is specifically: according to the sequence from the C-terminus to the N-terminus of the amino acid sequence shown in SEQ ID NO: 2, sequentially coupling Fmoc-Gly-OH, Fmoc-Glu(OtBu)- OH, Fmoc-Leu-OH, Fmoc-Tyr(Boc)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Val-Ser(psiMe, Mepro), Fmoc-Asp(OtBu)-OH, Fmoc-Ser( tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH and Fmoc-Thr(tBu)-OH, piperidine removes the Fmoc protecting group, and weak acid cleavage to obtain Fragment 2.
  • the weak acid used in the weak acid cracking is one or more of trifluoroethanol, hexafluoroisopropanol, acetic acid and trifluoroacetic acid.
  • step 3 of the present invention the coupling of the amino acids shown in SEQ ID NO:3 is specifically to couple the protected amino acids one by one in the order from the C-terminal to the N-terminal of the amino acid sequence shown in SEQ ID NO:3; the protected amino acid is the protected group protected amino acids.
  • the protected amino acid is Fmoc-Gly-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Gly-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Phe-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Lys(Y)-OH, Fmoc-Ala-OH , Fmoc-Ala-OH and Fmoc-Gln(Trt)-OH.
  • Y is Pal-Glu-OtBu or Oct(OtBu)-Glu-OtBu-AEEA-AEEA.
  • the peptide sequence of the GLP-1 analog is (N-terminal to C-terminal): H-His-X-Glu-Gly-Thr 5 -Phe-Thr-Ser-Asp-Val 10 -Ser-Ser-Tyr -Leu-Glu 15 -Gly-Gln-Ala-Ala-Lys 20 (Y)-Glu-Phe-Ile-Ala-Trp 25 -Leu-Val-Arg-Gly-Arg 30 -Gly-OH.
  • X is Ala
  • Y is Pal-Glu-OtBu
  • the synthetic GLP-1 analogue is liraglutide, and its peptide sequence is:
  • X is Aib
  • Y is Oct(OtBu)-Glu-OtBu-AEEA-AEEA
  • the synthetic GLP-1 analog is semaglutide, and its peptide sequence is:
  • the type of solid resin is not particularly limited, and the types commonly used in the field are sufficient.
  • the solid resin used in steps 1-3 is 2-chlorotrityl chloride resin or Wang resin.
  • the removal agent used to remove the N-terminal Fmoc protecting group in the present invention is preferably piperidine solution. Including but not limited to this.
  • the coupling agent for coupling is DIPCDI/HOBt, PyBop/HOBt/DIPEA, HBTU/HOBt/DIPEA, DIPCDI/HOAt, HATU/HOAt/DIPEA and PyAop/HOAt/DIPEA one or several.
  • the lysate of the lysis is a trifluoroacetic acid solution containing a capture agent, and the capture agent is one or more of PhSMe, PhOH, H 2 O, TIS, PhOMe, and EDT.
  • the lysate is a combination of TFA, H 2 O and PhOH, wherein the volume ratio of TFA, H 2 O and PhOH is 90:5:5.
  • the present invention firstly synthesizes the fragment 1 of the 1st to 4th position of the N-terminal of the GLP-1 analogue, and the fragment 2 of the 5th to 12th position of the N-terminal, and then sequentially couples the SEQ ID NO on the solid phase carrier according to the order from the C-terminal to the N-terminal : amino acid shown in 3, fragment 2 and fragment 1, obtain peptide resin, crack, obtain crude peptide.
  • the crude peptide obtained by the synthesis method of the invention has high purity and high total yield.
  • Fig. 1 shows the preparation process flowchart of GLP-1 analogue
  • Figure 2 shows a typical chromatogram of liraglutide fragment one
  • Figure 3 shows a typical chromatogram of liraglutide crude peptide
  • Figure 4 shows a typical chromatogram of semaglutide fragment one
  • Fig. 5 shows the typical chromatogram of semaglutide crude peptide
  • Figure 6 shows a typical chromatogram of a refined peptide.
  • the present invention provides a method for synthesizing GLP-1 analogues, and those skilled in the art can refer to the content of this article and appropriately improve the process parameters to realize it.
  • all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.
  • the method and application of the present invention have been described through preferred embodiments, and relevant personnel can obviously make changes or appropriate changes and combinations to the method and application herein without departing from the content, spirit and scope of the present invention to realize and apply the present invention Invent technology.
  • the reagents and instruments used in the present invention are all common commercial products and can be purchased in the market.
  • the invention provides a method for synthesizing GLP-1 analogues, comprising the following steps:
  • Step 1 Synthesizing a fragment 1 coupled with a protecting group at the N-terminal of the amino acid sequence shown in SEQ ID NO: 1, on the His side chain, and on the Glu side chain;
  • Step 2 Synthesizing Fragment 2 with protective groups coupled to the N-terminal of the amino acid sequence shown in SEQ ID NO: 2, on the Thr side chain, on the Ser side chain, on the Asp side chain, on the Tyr side chain, and on the Glu side chain;
  • Step 3 sequentially coupling the amino acid shown in SEQ ID NO:3, Fragment 2 and Fragment 1 on the solid phase carrier in the order from the C-terminal to the N-terminal to obtain a peptide resin;
  • Step 4 Cleavage the peptide resin to obtain crude peptide.
  • the peptide sequence of the GLP-1 analog is (N-terminal to C-terminal): H-His-X-Glu-Gly-Thr 5 -Phe-Thr-Ser-Asp-Val 10 -Ser-Ser-Tyr -Leu-Glu 15 -Gly-Gln-Ala-Ala-Lys 20 (Y)-Glu-Phe-Ile-Ala-Trp 25 -Leu-Val-Arg-Gly-Arg 30 -Gly-OH (Formula I).
  • the synthesis strategy provided by the present invention is: the main chain peptide sequence of the above-mentioned GLP-1 analog is divided into three parts, fragment one (SEQ ID NO:1), fragment two (SEQ ID NO:2) and the remaining amino acids (SEQ ID NO: 3).
  • SEQ ID NO:1 fragment one
  • SEQ ID NO:2 fragment two
  • SEQ ID NO: 3 the remaining amino acids
  • the amino acid sequence shown in SEQ ID NO: 1 N terminal ⁇ C terminal
  • the specific sequence is: His-X-Glu-Gly, wherein, X is Ala or Aib.
  • amino acid sequence shown in SEQ ID NO: 2 is (N-terminal ⁇ C-terminal), which is the sequence numbered 5-16 in the peptide sequence shown in formula I, and the specific sequence is: Thr-Phe-Thr-Ser-Asp- Val-Ser-Ser-Tyr-Leu-Glu-Gly.
  • amino acid sequence (N-terminal ⁇ C-terminal) shown in SEQ ID NO:3 is the sequence numbered 17th to 31st in the peptide sequence shown in formula I, and the specific sequence is: Gln-Ala-Ala-Lys(Y)- Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly.
  • Y is Pal-Glu-OtBu or Oct(OtBu)-Glu-OtBu-AEEA-AEEA.
  • Fragment 1 The peptide sequence of Fragment 1 is Boc-His(Trt)-X-Glu(OtBu)-Gly-OH, wherein X is Ala or Aib. Using 2-chlorotrityl chloride resin as a carrier, according to the polypeptide solid-phase synthesis method, Fmoc-Gly-OH, Fmoc-Glu(OtBu)-OH, Fmoc-X-OH and Boc-His(Trt)-OH.
  • Fragment 2 The peptide sequence of Fragment 2 is Fmoc-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Val-Ser(psiMe,Mepro)-Ser(tBu) -Tyr(tBu)-Leu-Glu(OtBu)-Gly-OH.
  • 2-chlorotrityl chloride resin as a carrier, according to the polypeptide solid-phase synthesis method, Fmoc-Gly-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Leu-OH, Fmoc-Tyr(Boc)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Val-Ser(psiMe, Mepro), Fmoc-Asp(OtBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr (tBu)-OH, Fmoc-Phe-OH and Fmoc-Thr(tBu)-OH.
  • Synthesis of peptide resin use 2-chlorotrityl chloride resin or Wang resin as the carrier, according to the peptide solid-phase synthesis method, according to the peptide sequence, sequentially couple Fmoc-Gly-OH, Fmoc from C-terminal to N-terminal -Arg(Pbf)-OH, Fmoc-Gly-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Ala-OH, Fmoc-Ile-OH, Fmoc-Phe-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Lys(Y)-OH, Fmoc-Ala-OH, Fmoc-Ala-OH, Fmoc-Gln(Trt)-OH , fragment two and fragment one, wherein Y is Pal-Glu
  • Embodiment 2 the synthesis of fragment two
  • Embodiment 6 the synthesis of semaglutide peptide resin
  • Embodiment 7 the synthesis of semaglutide
  • the crude peptide obtained in Example 4 or 7 was prepared and purified by high performance liquid chromatography, with tetraalkylsilane bonded silica gel as the stationary phase, 0.2% acetic acid solution as the mobile phase A, and acetonitrile as the mobile phase B , monitoring wavelength 280nm, gradient elution to collect target peak fractions, concentrated, freeze-dried to obtain liraglutide or semaglutide fine peptide, purity 99.7%, (chromatogram shown in Figure 6).
  • the purity of the obtained crude peptide was 58%, and the total yield was about 15%.

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Abstract

La présente invention relève du domaine technique de la synthèse de polypeptides, en particulier un procédé de synthèse d'un analogue de GLP-1. Dans la présente invention, le fragment 1 et le fragment 2 respectivement aux positions 1-4 et les positions 5-12 d'une extrémité N-terminale d'un analogue de GLP-1 sont d'abord synthétisés, puis les acides aminés restants, le fragment 2 et le fragment 1 sont séquentiellement couplés sur un support en phase solide dans une séquence allant d'une extrémité C-terminale à une extrémité N-terminale pour obtenir une résine peptidique qui est clivée pour obtenir un peptide brut. Les analogues de GLP-1, à savoir le liraglutide et le semaglutide, sont synthétisés à l'aide d'une stratégie de synthèse spécifique selon la présente invention, de sorte que la pureté et le rendement total du peptide brut sont élevés, le procédé de synthèse est simple, et le procédé est approprié pour une production à grande échelle.
PCT/CN2021/105192 2021-07-08 2021-07-08 Procédé de synthèse d'analogue de glp-1 Ceased WO2023279323A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117024528A (zh) * 2023-07-07 2023-11-10 杭州信海医药科技有限公司 一种Retatrutide的制备方法
CN118666988A (zh) * 2024-08-20 2024-09-20 深圳佳肽生物科技有限公司 用于合成Trizepatide的组合物及Trizepatide的合成方法
WO2025094036A1 (fr) * 2023-10-30 2025-05-08 Piramal Pharma Limited Procédé de préparation de liraglutide

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016046753A1 (fr) * 2014-09-23 2016-03-31 Novetide, Ltd. Synthèse de peptides glp-1
CA3046425A1 (fr) * 2016-12-10 2018-06-14 Biocon Limited Synthese de liraglutide
WO2020074583A1 (fr) * 2018-10-09 2020-04-16 Fresenius Kabi Ipsum S.R.L. Procédé de fabrication d'analogues de glp-1
WO2020188510A2 (fr) * 2019-03-19 2020-09-24 Enzene Biosciences Limited Procédé de préparation d'agonistes du récepteur du peptide-1 de type glucagon (glp-1) et de leurs analogues
WO2021007701A1 (fr) * 2019-07-12 2021-01-21 Shanghai Space Peptides Pharmaceutical Co., Ltd. Procédé de préparation de liraglutide par synthèse de peptides en phase solide
WO2021070202A1 (fr) * 2019-10-09 2021-04-15 Prasad Alaparthi Lakshmi Procédé de préparation d'un analogue du glp-1 par synthèse de peptides en phase solide

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016046753A1 (fr) * 2014-09-23 2016-03-31 Novetide, Ltd. Synthèse de peptides glp-1
CA3046425A1 (fr) * 2016-12-10 2018-06-14 Biocon Limited Synthese de liraglutide
WO2020074583A1 (fr) * 2018-10-09 2020-04-16 Fresenius Kabi Ipsum S.R.L. Procédé de fabrication d'analogues de glp-1
WO2020188510A2 (fr) * 2019-03-19 2020-09-24 Enzene Biosciences Limited Procédé de préparation d'agonistes du récepteur du peptide-1 de type glucagon (glp-1) et de leurs analogues
WO2021007701A1 (fr) * 2019-07-12 2021-01-21 Shanghai Space Peptides Pharmaceutical Co., Ltd. Procédé de préparation de liraglutide par synthèse de peptides en phase solide
WO2021070202A1 (fr) * 2019-10-09 2021-04-15 Prasad Alaparthi Lakshmi Procédé de préparation d'un analogue du glp-1 par synthèse de peptides en phase solide

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117024528A (zh) * 2023-07-07 2023-11-10 杭州信海医药科技有限公司 一种Retatrutide的制备方法
CN117024528B (zh) * 2023-07-07 2024-03-22 杭州信海医药科技有限公司 一种Retatrutide的制备方法
WO2025094036A1 (fr) * 2023-10-30 2025-05-08 Piramal Pharma Limited Procédé de préparation de liraglutide
CN118666988A (zh) * 2024-08-20 2024-09-20 深圳佳肽生物科技有限公司 用于合成Trizepatide的组合物及Trizepatide的合成方法

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