WO2020017919A1 - Nouvel intermédiaire utilisé pour un polypeptide physiologiquement actif et son procédé de préparation - Google Patents

Nouvel intermédiaire utilisé pour un polypeptide physiologiquement actif et son procédé de préparation Download PDF

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WO2020017919A1
WO2020017919A1 PCT/KR2019/008935 KR2019008935W WO2020017919A1 WO 2020017919 A1 WO2020017919 A1 WO 2020017919A1 KR 2019008935 W KR2019008935 W KR 2019008935W WO 2020017919 A1 WO2020017919 A1 WO 2020017919A1
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trt
tbu
resin
boc
lys
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PCT/KR2019/008935
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Korean (ko)
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최원경
김나리
박종환
박성준
김남두
조영범
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한미정밀화학주식회사
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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
    • C07K1/06—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
    • C07K1/10—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using coupling agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F12/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring
    • C08F12/02—Monomers containing only one unsaturated aliphatic radical
    • C08F12/04—Monomers containing only one unsaturated aliphatic radical containing one ring
    • C08F12/06—Hydrocarbons
    • C08F12/08—Styrene
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/30—Introducing nitrogen atoms or nitrogen-containing groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
    • C08G81/02—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers at least one of the polymers being obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G85/00—General processes for preparing compounds provided for in this subclass
    • 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 present invention relates to novel intermediates used in physiologically active polypeptides and methods for their preparation. More specifically, the present invention relates to a method for producing a bioactive polypeptide more safely and efficiently, and to a novel polypeptide intermediate and a method for producing the same.
  • Diabetes-related diseases including obesity and type 2 diabetes, are one of the major metabolic diseases occurring in modern society and are recognized as an important threat to health around the world, and economic costs are increasing rapidly.
  • glucagon derivatives Glucagon is produced in the pancreas when blood sugar begins to drop due to medication or disease, hormone or enzyme deficiency. Glucagon signals the breakdown of glycogen in the liver to release glucose and raises blood sugar levels to normal levels. In addition, glucagon has been reported to exhibit anti-obesity effects by promoting lipolysis by activating hormone-sensitive lipase of appetite suppression and adipocytes in addition to the effect of increasing blood glucose. Various studies are in progress.
  • Korean Patent Laid-Open Publication No. 10-2017-0080521 discloses a triple activator having activity on both glucagon, GLP-1, and GIP receptor and use thereof.
  • Such peptides may be formed from substitution, addition, removal, modification, and combinations thereof of at least one or more amino acids in a native glucagon sequence, and more specifically, in Formula 1
  • An isolated peptide is disclosed comprising the indicated amino acid sequence.
  • the peptides can be prepared according to their length by methods known in the art, such as by synthetic peptide synthesizers, by genetic engineering techniques, or by any other method. In order to use the peptides prepared by such various manufacturing methods as pharmaceuticals, high purity quality, yield suitable for commercialization, and manufacturing process suitable for mass production are required.
  • Another object of the present invention is to provide an efficient method for preparing the novel polypeptide intermediate and resin complex compound.
  • Another object of the present invention is to provide an efficient method for preparing a bioactive polypeptide using the novel polypeptide intermediate.
  • one embodiment of the present invention provides a novel polypeptide intermediate of the formula (1).
  • R is H, straight or branched C 1-12 alkyl, straight or branched C 1-12 alkyloxycarbonyl, straight or branched C 2-12 alkenyl, C 3-10 Cycloalkyl, heterocycloalkyl, C 6-12 aryl, C 6-12 aryloxycarbonyl, C 1-6 alkylC 6-12 aryl, C 1-6 alkylC 6-12 aryloxycarbonyl and heteroaryl Selected from the group consisting of;
  • X is H, straight or branched C 1-12 alkyl, straight or branched C 1-12 alkyloxycarbonyl, straight or branched C 2-12 alkenyl, C 3-10 cycloalkyl , Heterocycloalkyl, C 6-12 aryl, C 6-12 aryloxycarbonyl, C 1-6 alkyl C 6-12 aryl, C 1-6 alkyl C 6-12 aryloxycarbonyl and heteroaryl Is selected from;
  • the aforementioned substituents may additionally be H, halogen, cyano, straight or branched C 1-6 alkyl, straight or branched C 2-10 alkenyl, C 3-10 cycloalkyl, haloC 1- 5 alkyl, hydroxyC 1-6 alkyl, amino, mono or diC 1-6 alkylamino, oxo, hydroxy, C 1-6 alkoxy, C 6-12 arylsulfonyl and C 1-6 alkylsulfonyl It may be substituted with one or more same or different substituents selected from the group consisting of.
  • one embodiment of the present invention provides a novel resin complex compound of Formula 3:
  • a to D are protecting groups
  • a to D are each independently triphenylmethyl (Trt), tertiary butyl (tBu), t-butyloxycarbonyl (Boc) and 2,2,4,6,7-pentamethyldihydrobenzofuran-5- Selected from the group consisting of sulfonyl (Pbf),
  • R is H, straight or branched C 1-12 alkyl, straight or branched C 1-12 alkyloxycarbonyl, straight or branched C 2-12 alkenyl, C 3-10 cycloalkyl , Heterocycloalkyl, C 6-12 aryl, C 6-12 aryloxycarbonyl, C 1-6 alkyl C 6-12 aryl, C 1-6 alkyl C 6-12 aryloxycarbonyl and heteroaryl Is selected from;
  • the aforementioned substituents may additionally be H, halogen, cyano, straight or branched C 1-6 alkyl, straight or branched C 2-10 alkenyl, C 3-10 cycloalkyl, haloC 1- 5 alkyl, hydroxyC 1-6 alkyl, amino, mono or diC 1-6 alkylamino, oxo, hydroxy, C 1-6 alkoxy, C 6-12 arylsulfonyl and C 1-6 alkylsulfonyl It may be substituted with one or more same or different substituents selected from the group consisting of.
  • a to D are protecting groups
  • a to D are each independently triphenylmethyl (Trt), tertiary butyl (tBu), t-butyloxycarbonyl (Boc) and 2,2,4,6,7-pentamethyldihydrobenzofuran-5- Selected from the group consisting of sulfonyl (Pbf),
  • R is H, straight or branched C 1-12 alkyl, straight or branched C 1-12 alkyloxycarbonyl, straight or branched C 2-12 alkenyl, C 3-10 cycloalkyl , Heterocycloalkyl, C 6-12 aryl, C 6-12 aryloxycarbonyl, C 1-6 alkyl C 6-12 aryl, C 1-6 alkyl C 6-12 aryloxycarbonyl and heteroaryl Is selected from;
  • the aforementioned substituents may additionally be H, halogen, cyano, straight or branched C 1-6 alkyl, straight or branched C 2-10 alkenyl, C 3-10 cycloalkyl, haloC 1- 5 alkyl, hydroxyC 1-6 alkyl, amino, mono or diC 1-6 alkylamino, oxo, hydroxy, C 1-6 alkoxy, C 6-12 arylsulfonyl and C 1-6 alkylsulfonyl It may be substituted with one or more same or different substituents selected from the group consisting of.
  • the step of preparing a deprotected resin by deprotecting the protecting group using a piperidine solution in the cyclized peptide compound prepared by the above method in a polar aprotic solvent (2) adding protected amino acid, 1-hydroxy-1H-benzotriazole and 1,3-diisopropylcarbodiimide in a polar aprotic solvent to activate the protected amino acid; (3) adding and coupling an activated protected amino acid solution to the deprotected resin in the reactor; (4) repeating steps (1)-(3) until the peptide is formed; (5) cleaving the desired peptide from the resin while simultaneously deprotecting the protected resin using the cleavage cocktail; And (6) filtering the cleavage mixture from the resin, to provide a method for producing a bioactive polypeptide and a pharmaceutically acceptable salt.
  • novel polypeptide intermediate and the manufacturing process thereof according to the present invention can provide a novel polypeptide intermediate that can be utilized in bioactive polypeptide pharmaceuticals, and can be reproducible production of high-quality products suitable for mass production There is an advantage.
  • the protecting groups of amino acids used in the present invention are stable under peptide condensation conditions, are easily removable and do not affect peptide chains and substituents in the elimination reaction, as well as the racemization of any chiral centers present in the peptide. Anything that can be used can be used.
  • suitable protecting groups include 9-fluorenylmethyloxycarbonyl (Fmoc), 2- (4-nitrophenyl-sulfonyl) ethoxycarbonyl (NSC), t-butoxycarbonyl (Boc), benzyloxycarbono Neyl (Cbz), biphenylisopropyl-oxycarbonyl, t-amyloxycarbonyl, isobornyloxycarbonyl, ( ⁇ , ⁇ ) -dimethyl-3,5-dimethoxybenzyloxycarbonyl, O-nitro Phenylsulphenyl, 2-cyano-t-butyloxycarbonyl, and the like, but are not limited to these and other suitable protecting groups known in the art for this purpose may also be used within the scope of the present invention.
  • fluorenylmethyloxycarbonyl (Fmoc) or tert-butyloxycarbonyl (Boc) groups can be used.
  • a solid-phase peptide synthesis method using 9-fluoroenylmethoxycarbonyl (Fmoc) as an amino acid protecting group may be used.
  • Resin used in the reaction of all the steps of the present invention is a polymer support treated with a suitable linker, polystyrene (PS) resin or polystyrene-polyethylene glycol copolymer (PS-PEG copolymer) resin is preferred, but without limitation, other suitable resins known in the art for this purpose may also be used within the scope of the present invention.
  • PS polystyrene
  • PS-PEG copolymer polystyrene-polyethylene glycol copolymer
  • the resins usable in the present invention are, for example, aminomethyl resin, aminoethyl resin, aminobutyl resin, linkamide aminomethyl resin, linkamide aminoethyl resin, linkamide aminobutyl resin, linkamide MBHA resin, linkamide for polystyrene series.
  • Polar aprotic solvents used in the reactions of all stages of the present invention include, for example, dimethylformamide, dimethylacetamide, and the like, but are not limited to these other suitable polar aprotic solvents known in the art for this purpose. It is also possible to use within the scope of the present invention.
  • the polar aprotic solvent used in the reaction of all stages of the present invention may preferably be selected from the group consisting of dimethylformamide, dimethylacetamide and mixtures thereof.
  • step (1) the resin is swollen in a polar aprotic solvent.
  • step (2) deprotected resin is prepared by deprotecting the protecting group using a piperidine solution in a polar aprotic solvent.
  • the deprotected resin can be washed with a polar solvent.
  • the polar solvent used herein may be selected from the group consisting of dimethylformamide, dimethylacetamide, methanol, ethanol and mixtures thereof.
  • protected amino acids, 1-hydroxy-1H-benzotriazole and 1,3-diisopropylcarbodiimide are added in a polar aprotic solvent to activate the protected amino acids.
  • step (4) an activated protected amino acid solution is added to the deprotected resin in the reactor to perform a coupling reaction.
  • the coupled resin can be washed using a polar solvent.
  • the polar solvent used herein may be selected from the group consisting of dimethylformamide, dimethylacetamide, methanol, ethanol and mixtures thereof.
  • steps (2)-(6) are repeated until a peptide is formed.
  • step (5) may be carried out repeatedly 2 to 100 times until a desired length of peptide is formed, preferably 10 to 50 times, most preferably 14 to 30 times Can be.
  • step (6) the synthesized peptide is reacted with tetrakispalladium, N-methylaniline and penicsilane in a solvent to prepare a partially deprotected resin.
  • the solvent used in the reaction of step (6) may be selected from the group consisting of dichloromethane, chloroform and mixtures thereof.
  • a polypeptide intermediate is prepared by adding a coupling reagent and a coupling reagent in a polar aprotic solvent to perform a cyclization reaction.
  • the coupling reagent used in the reaction of step (7) is 1-hydroxy-1H-benzotriazole / 1,3-diisopropylcarbodiimide or HATU (1- [bis (dimethylamino) methylene] -1H -1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate, hexafluorophosphate azabenzotriazole tetramethyl uronium) / N, N-diisopropylethyl
  • Other coupling reagents known in the art for this purpose may also be used within the scope of the present invention, although it may be selected from amines.
  • step (1) the deprotected resin is prepared by deprotecting the protecting group using the piperidine solution of the cyclized peptide compound prepared by the above method in a polar aprotic solvent.
  • step (2) protected amino acids, 1-hydroxy-1H-benzotriazole and 1,3-diisopropylcarbodiimide are added in a polar aprotic solvent to activate the protected amino acids.
  • step (3) an activated protected amino acid solution is added to the deprotected resin in the reactor to carry out the coupling reaction.
  • step (4) steps (1)-(3) are repeated until a peptide is formed.
  • step (4) may be performed repeatedly 1 to 50 times, preferably 1 to 30 times, until a peptide of a desired length is formed.
  • step (5) above the cleavage cocktail is used to deprotect the protected resin while simultaneously cleaving the desired peptide from the resin.
  • the cleavage cocktail of step (5) may comprise a solution of trifluoroacetic acid (TFA), one or more scavengers and dichloromethane.
  • TFA trifluoroacetic acid
  • scavengers one or more scavengers and dichloromethane.
  • the scavenger of step (5) is said scavenger is triisopropylsilane (TIPS), triethylsilane (TES), phenol, anisole, thioanisole, water, ethanedithiol (EDT), 1-dodecane Thiol, dithiothreitol (DTT) and indole may be selected from the group consisting of, but not limited to, other suitable scavengers known in the art for this purpose are also available within the scope of the present invention.
  • TIPS triisopropylsilane
  • TES triethylsilane
  • phenol anisole
  • thioanisole water
  • EDT ethanedithiol
  • DTT 1-dodecane Thiol
  • DTT dithiothreitol
  • indole may be selected from the group consisting of, but not limited to, other suitable scavengers known in the art for this purpose are also available within the scope
  • step (6) there is provided a method of preparing a bioactive polypeptide and a pharmaceutically acceptable salt comprising filtering the cleavage mixture from the resin.
  • novel polypeptide intermediate provided by the present invention and a pharmaceutical intermediate of high purity can be provided through the preparation method thereof, and the bioactive polypeptide prepared by using the same can also be used for the manufacture of high-quality pharmaceutical products with high purity and easy purification. This is possible.
  • a physiologically active polypeptide can be prepared by linear synthesis of the polypeptide followed by a cyclization reaction.
  • linearly synthesize 16 to 30 amino acids sequentially and perform a cyclization reaction of each linear synthesized polypeptide (16mer to 30mer).
  • the purity tends to decrease rapidly as the length of the linearly synthesized polypeptide increases.
  • the purification process becomes very difficult and thus yields tend to decrease rapidly.
  • the novel polypeptide intermediate and the physiologically active polypeptide prepared through the preparation method according to the present invention undergo a step of preparing a linear polypeptide up to 15mer, performing a cyclization reaction, and further synthesizing the remaining amino acids. Therefore, it has the advantage of synthesizing a high purity product compared to the existing manufacturing method.
  • the manufacturing method of the present invention not only facilitates the purification process after synthesis, but also has the advantage that the final manufacturing yield is greatly improved and is an efficient process suitable for commercial production.
  • amino acids referred to herein as abbreviations are described according to the IUPAC-IUB nomenclature.
  • Methionine-Met M; Phenylalanine-Phe, F; Proline-Pro, P;
  • Solid phase peptide synthesis methods including deprotection of amino acids, methods of cleaving peptides from resins, and SPPS methods, including purification thereof), as well as methods of detecting and characterizing the resulting peptides (LCMS, MALDI, and UPLC) Method).
  • N-terminal amino acids have an alpha amino group protected with Boc (eg Boc-His (Boc) -OH, or Boc-His (Trt) -OH for peptides having His at the N-terminus).
  • Boc eg Boc-His (Boc) -OH
  • Boc-His (Trt) -OH for peptides having His at the N-terminus.
  • link amide MBHA resin 80.0 g (0.31 mmol / g) of link amide MBHA resin and 480 ml of dimethylformamide were added to the vessel, stirred for 15 minutes, and filtered to remove dimethylformamide. This process was carried out twice. Through the above procedure, link amide MBHA resin was prepared.
  • Cys (Trt) -Fmoc activated in step (2) was added to the Fmoc deprotected link amide MBHA resin prepared in step (1), stirred at room temperature for 3 hours or more, and filtered. 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. Methanol 480ml was added to the filtered resin, stirred for 2 minutes, and filtered. This process was carried out three times in total. 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. This process was carried out three times in total. Through the above procedure, a target compound, Resin-Cys (Trt) -Fmoc, was obtained.
  • Step (2) Activation of Thr (tBu) -Fmoc (T)
  • Thr (tBu) -Fmoc activated in step (2) was added to the Fmoc deprotected resin-Cys (Trt) prepared in step (1), followed by stirring at room temperature for 3 hours or more, followed by filtration.
  • 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration.
  • Methanol 480ml was added to the filtered resin, stirred for 2 minutes, and filtered. This process was carried out three times in total.
  • 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. This process was carried out three times in total.
  • Step (2) Activation of Asn (Trt) -Fmoc (N)
  • Asn (Trt) -Fmoc activated in step (2) was added to the Fmoc deprotected resin-Cys (Trt) -Thr (tBu) prepared in step (1), followed by stirring at room temperature for 3 hours or more, followed by filtration. . 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. Methanol 480ml was added to the filtered resin, stirred for 2 minutes, and filtered. This process was carried out three times in total. 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. This process was carried out three times in total. Through the above procedure, a target compound, Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Fmoc, was obtained.
  • Step (3) Preparation of Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Fmoc (Poly 4mer Synthesis)
  • step (2) After adding the activated Met-Fmoc in step (2) to the Fmoc deprotected resin-Cys (Trt) -Thr (tBu) -Asn (Trt) prepared in step (1) and stirred at room temperature for 3 hours or more. Filtered. 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. Methanol 480ml was added to the filtered resin, stirred for 2 minutes, and filtered. This process was carried out three times in total. 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. This process was carried out three times in total. Through the above procedure, a target compound, Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Fmoc, was obtained.
  • Step (3) Preparation of Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Leu-Fmoc (Poly 5mer Synthesis)
  • Lemo-Fmoc activated in step (2) was added to the Fmoc deprotected resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met prepared in step (1), followed by stirring at room temperature for 3 hours or more. And then filtered. 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. Methanol 480ml was added to the filtered resin, stirred for 2 minutes, and filtered. This process was carried out three times in total. 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. This process was carried out three times in total. Through the above procedure, the target compound Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Leu-Fmoc was obtained.
  • Trp (Boc) -Fmoc 39.2 g of Trp (Boc) -Fmoc, 1H-benzotriazole, 16.7 g, 16.7 g of hydrate, and 480 ml of dimethylformamide were added to the vessel, followed by complete dissolution. 15.5 ml of 1,3-diisopropylcarbodiimide was added to the dissolved reaction solution, followed by stirring at room temperature for 30 minutes. Through the above process, the target compound Trp (Boc) -Fmoc was activated.
  • Step (3) Preparation of Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Leu-Trp (Boc) -Fmoc (Poly 6mer Synthesis)
  • step (2) The Tmo (Boc) -Fmoc activated in step (2) was added to the Fmoc deprotected Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Leu prepared in step (1).
  • the mixture was stirred at least 3 hours and filtered.
  • 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration.
  • Methanol 480ml was added to the filtered resin, stirred for 2 minutes, and filtered. This process was carried out three times in total.
  • 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. This process was carried out three times in total.
  • Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Leu-Trp (Boc) -Fmoc was obtained.
  • Step (2) Activation of Gln (Trt) -Fmoc (Q)
  • Step (3) Preparation of Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Leu-Trp (Boc) -Gln (Trt) -Fmoc (Poly 7mer Synthesis)
  • Val-Fmoc 1H-benzotriazole, 1-hydroxy, 16.7 g of hydrate, and 480 ml of dimethylformamide were added to the vessel, followed by stirring to completely dissolve it. 15.5 ml of 1,3-diisopropylcarbodiimide was added to the dissolved reaction solution, followed by stirring at room temperature for 30 minutes. Through the above process, Val-Fmoc, the target compound, was activated.
  • Step (3) Preparation of Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Leu-Trp (Boc) -Gln (Trt)-Val-Fmoc (Poly 8mer Synthesis)
  • step (1) The Fmoc deprotected Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Leu-Trp (Boc) -Gln (Trt) prepared in step (1) was activated in step (2). Val-Fmoc was added thereto, stirred at room temperature for 3 hours or more, and filtered. 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. Methanol 480ml was added to the filtered resin, stirred for 2 minutes, and filtered. This process was carried out three times in total.
  • Step (3) Preparation of Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Leu-Trp (Boc) -Gln (Trt)-Val-Phe-Fmoc (Poly 9mer Synthesis)
  • Step (3) Preparation of Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Leu-Trp (Boc) -Gln (Trt)-Val-Phe-Glu (OtBu) -Fmoc (Poly 10mer compound)
  • Step (2) Activation of Lys (Boc) -Fmoc (K)
  • Glu (OAll) -Fmoc Into the vessel, 30.5 g of Glu (OAll) -Fmoc, 1H-benzotriazole, 1-hydroxy, 16.7 g of hydrate, and 480 ml of dimethylformamide were added and stirred to dissolve completely. 15.5 ml of 1,3-diisopropylcarbodiimide was added to the dissolved reaction solution, followed by stirring at room temperature for 30 minutes. Through the above process, the target compound Glu (OAll) -Fmoc was activated.
  • Step (2) -1 Preparation of Cyclic Polypeptide (cyclic Poly 15mer Synthesis)
  • Step (2) -2 Preparation of Cyclic Polypeptide (cyclic Poly 15mer Synthesis)
  • HATU 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate, hexafluorophosphate azabenzo in a container 56.6 g of triazole tetramethyl uronium,) and 480 ml of dimethylformamide were added and stirred to dissolve completely. 51.8 mL of N, N-diisopropylethylamine was added to the dissolved reaction solution, and the mixture was stirred at room temperature for 5 minutes.
  • reaction solution prepared in the polypeptide (partial deprotection 15mer) prepared in step (1) was added thereto, stirred at room temperature for 3 hours, and filtered.
  • 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration.
  • Methanol 480ml was added to the filtered resin, stirred for 2 minutes, and filtered. This process was carried out three times in total.
  • 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. This process was carried out three times in total.
  • 480 ml of 20% piperidine was added to the cyclized polypeptide (cyclic poly 15mer synthesis) prepared in Example 3, stirred for 20 minutes, and filtered to remove 20% piperidine. This process was carried out twice. 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. Methanol 480ml was added to the filtered resin, stirred for 2 minutes, and filtered. This process was carried out three times in total. 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. This process was carried out three times in total.
  • Step (2) Activation of Asp (OtBu) -Fmoc (D)
  • Methanol 480ml was added to the filtered resin, stirred for 2 minutes, and filtered. This process was carried out three times in total. 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. This process was carried out three times in total.
  • Methanol 480ml was added to the filtered resin, stirred for 2 minutes, and filtered. This process was carried out three times in total. 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. This process was carried out three times in total.
  • Step (2) Activation of Lys (Boc) -Fmoc (K)
  • Step (2) Activation of Ser (tBu) -Fmoc (S)
  • Step (2) Activation of Asp (OtBu) -Fmoc (D)
  • Step (2) Activation of Ser (tBu) -Fmoc (S)
  • Step (2) Activation of Thr (tBu) -Fmoc (T)
  • Step (2) Activation of Thr (tBu) -Fmoc (T)
  • Step (2) Activation of Gln (Trt) -Fmoc (Q)
  • Step (2) Activation of Aib-Fmoc
  • Example 5 NH 2 CO-Cys-Thr-Asn-Met-Leu-Trp-Gln-Val-Phe-Glu-cyclo- [Lys-Ala-Arg-Lys-Glu] -Asp-Leu-Tyr-Lys-Ser- Preparation of Tyr-Asp-Ser-Thr-Phe-Thr-Gly-Gln-Aib-His-NH2, TFA (protector and resin cleavage, cleavage)
  • vessel 2 165 ml of trifluoroacetic acid, 10 ml of phenol, 10 ml of distilled water, 10 ml of thioanisole, and 5 ml of 1,2-ethanedithiol were added to the vessel 2 and stirred for 10 minutes. 20 g of the dried cyclocyclized polypeptide 30mer was added to the vessel 1, and the prepared reaction solution was added to the vessel 1, followed by stirring at room temperature for 1 hour 30 minutes. 3.0 L of methyl tertiary butyl ether was put into the container 3, and it cooled to 0-1 degreeC under nitrogen atmosphere.
  • the reaction liquid temperature of the vessel 1 was cooled to 5 ° C., 2.0 L of the cooled reactant methyl tertiary butyl ether of the vessel 3 was added thereto, and stirred for 10 minutes.
  • the reaction solution is filtered and washed twice with 400 ml of cooled methyl tertiary butyl ether. Crystals of the filter were dried under nitrogen atmosphere for 10 minutes. Dried crystals were added to the vessel 1, 400 ml of distilled water was added thereto, followed by stirring at room temperature for 10 minutes.
  • the reaction was filtered and washed with distilled water 600ml to give the target compound NH 2 CO-Cys-Thr-Asn-Met-Leu-Trp-Gln-Val-Phe-Glu-cyclo- [Lys-Ala-Arg-Lys-Glu] -Asp-Leu-Tyr-Lys-Ser-Tyr-Asp-Ser-Thr-Phe-Thr-Gly-Gln-Aib-His-NH 2 , TFA was obtained.
  • Rink amide MBHA resin 80.0g (0.31 mmol / g) and 480 ml of dimethylformamide were added to the vessel, stirred for 15 minutes, and filtered to remove dimethylformamide. This process was carried out twice.
  • Rink amide MBHA resin was prepared by the above procedure.
  • Cys (Trt) -Fmoc activated in step (2) was added to the Fmoc deprotected Rink amide MBHA resin prepared in step (1), stirred at room temperature for 3 hours or more, and filtered. 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. Methanol 480ml was added to the filtered resin, stirred for 2 minutes, and filtered. This process was carried out three times in total. 480 ml of dimethylformamide was added to the filtered resin, followed by stirring for 2 minutes, followed by filtration. This process was carried out three times in total. Through the above procedure, the target compound Resin-Cys (Trt) -Fmoc was obtained.
  • Step (2) Activation of Thr (tBu) -Fmoc (T)
  • Step (2) Activation of Asn (Trt) -Fmoc (N)
  • Trt Promote Fmoc deprotected Resin-Cys (Trt) -Thr (tBu) -Asn () as the target compound by the same method as in step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 3). Trt was obtained.
  • Met-Fmoc 18.4g was carried out in the same manner as in step (2) of Synthesis 1) to activate Met-Fmoc as a target compound.
  • Step (3) Preparation of Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Fmoc (Poly 4mer Synthesis)
  • Trt Promote Fmoc deprotected Resin-Cys (Trt) -Thr (tBu) -Asn () as the target compound by the same method as in step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 4). Trt) -Met was obtained.
  • Leu-Fmoc 17.5g was synthesized in the same manner as in step (2) of Synthesis 1) to activate the target compound Leu-Fmoc.
  • Step (3) Preparation of Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Leu-Fmoc (Poly 5mer Synthesis)
  • Trt Promote Fmoc deprotected Resin-Cys (Trt) -Thr (tBu) -Asn () as the target compound by the same method as step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 5). Trt) -Met-Leu was obtained.
  • Trp (Boc) -Fmoc 26.1g Synthesis 1) was carried out in the same manner as in step (2) to activate the target compound Trp (Boc) -Fmoc.
  • Step (3) Preparation of Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Leu-Trp (Boc) -Fmoc (Poly 6mer Synthesis)
  • Trt Promote Fmoc-deprotected Resin-Cys (Trt) -Thr (tBu) -Asn (target compound) in the same manner as in step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 6). Trt) -Met-Leu-Trp (Boc) was obtained.
  • Step (2) Activation of Gln (Trt) -Fmoc (Q)
  • Gln (Trt) -Fmoc 30.3g was synthesized in the same manner as in step (2) of Synthesis 1) to activate Gln (Trt) -Fmoc.
  • Step (3) Preparation of Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Leu-Trp (Boc) -Gln (Trt) -Fmoc (Poly 7mer Synthesis)
  • Trt Promote Fmoc-deprotected Resin-Cys (Trt) -Thr (tBu) -Asn (target compound) in the same manner as step (1) of Synthesis 1) with the polypeptide (poly 7mer synthesis) prepared in Synthesis 7). Trt) -Met-Leu-Trp (Boc) -Gln (Trt) was obtained.
  • Val-Fmoc 16.8g into the container was carried out in the same manner as in step (2) of synthesis 1) to activate the target compound Val-Fmoc.
  • Step (3) Preparation of Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Leu-Trp (Boc) -Gln (Trt)-Val-Fmoc (Poly 8mer Synthesis)
  • Trt Promote Fmoc deprotected Resin-Cys (Trt) -Thr (tBu) -Asn () as the target compound by the same method as in step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 8). Trt) -Met-Leu-Trp (Boc) -Gln (Trt) -Val was obtained.
  • Phe-Fmoc 19.2g was synthesized in the same manner as in step (2) of Synthesis 1) to activate Phe-Fmoc.
  • Step (3) Preparation of Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Leu-Trp (Boc) -Gln (Trt)-Val-Phe-Fmoc (Poly 9mer Synthesis)
  • Trt Promote Fmoc deprotected Resin-Cys (Trt) -Thr (tBu) -Asn () as the target compound by the same method as step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 9). Trt) -Met-Leu-Trp (Boc) -Gln (Trt) -Val-Phe was obtained.
  • Step (3) Preparation of Resin-Cys (Trt) -Thr (tBu) -Asn (Trt) -Met-Leu-Trp (Boc) -Gln (Trt)-Val-Phe-Glu (OtBu) -Fmoc (Poly 10mer compound)
  • Lys (Alloc) -Fmoc 22.4g Synthesis 1) was carried out in the same manner as in step (2) to activate the target compound Lys (Alloc) -Fmoc.
  • Trt Promote Fmoc deprotected Resin-Cys (Trt) -Thr (tBu) -Asn () as the target compound by the same method as step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 11). Trt) -Met-Leu-Trp (Boc) -Gln (Trt) -Val-Phe-Glu (OtBu) -Lys (Alloc) was obtained.
  • Ala-Fmoc 15.4g was activated in the same manner as in step (2) of Synthesis 1) to activate Ala-Fmoc, the target compound.
  • Trt Promote Fmoc-deprotected Resin-Cys (Trt) -Thr (tBu) -Asn () as the target compound by the same method as in step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 12). Trt) -Met-Leu-Trp (Boc) -Gln (Trt) -Val-Phe-Glu (OtBu) -Lys (Alloc) -Ala was obtained.
  • Arg (Pbf) -Fmoc 32.2g was synthesized in the same manner as in step (2) of Synthesis 1) to activate the target compound Arg (Pbf) -Fmoc.
  • Trt Promote Fmoc deprotected Resin-Cys (Trt) -Thr (tBu) -Asn () as the target compound by the same method as in step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 13). Trt) -Met-Leu-Trp (Boc) -Gln (Trt) -Val-Phe-Glu (OtBu) -Lys (Alloc) -Ala-Arg (Pbf) was obtained.
  • Step (2) Activation of Lys (Boc) -Fmoc (K)
  • Lys (Boc) -Fmoc 23.2g Synthesis 1) was carried out in the same manner as in step (2) to activate the target compound Lys (Boc) -Fmoc.
  • Trt Promote Fmoc deprotected Resin-Cys (Trt) -Thr (tBu) -Asn () as the target compound by the same method as step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 14). Trt) -Met-Leu-Trp (Boc) -Gln (Trt) -Val-Phe-Glu (OtBu) -Lys (Alloc) -Ala-Arg (Pbf) -Lys (Boc) was obtained.
  • Glu (OAll) -Fmoc 20.3g Synthesis 1) was carried out in the same manner as in step (2) to activate the target compound Glu (OAll) -Fmoc.
  • Trt Promote Fmoc deprotected Resin-Cys (Trt) -Thr (tBu) -Asn () as the target compound by the same method as in step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 15). Trt) -Met-Leu-Trp (Boc) -Gln (Trt) -Val-Phe-Glu (OtBu) -Lys (Alloc) -Ala-Arg (Pbf) -Lys (Boc) -Glu (OAll).
  • Step (2) Activation of Asp (OtBu) -Fmoc (D)
  • Asp (OtBu) -Fmoc 20.4g was synthesized in the same manner as in step (2) of Synthesis 1) to activate Asp (OtBu) -Fmoc as a target compound.
  • Trt Promote Fmoc deprotected Resin-Cys (Trt) -Thr (tBu) -Asn () as the target compound by the same method as in step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 16). Trt) -Met-Leu-Trp (Boc) -Gln (Trt) -Val-Phe-Glu (OtBu) -Lys (Alloc) -Ala-Arg (Pbf) -Lys (Boc) -Glu (OAll) -Asp ( OtBu) was obtained.
  • Leu-Fmoc 17.5g was synthesized in the same manner as in step (2) of Synthesis 1) to activate the target compound Leu-Fmoc.
  • Trt Promote Fmoc-deprotected Resin-Cys (Trt) -Thr (tBu) -Asn () as the target compound by the same method as in step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 17).
  • Trt -Met-Leu-Trp (Boc) -Gln (Trt) -Val-Phe-Glu (OtBu) -Lys (Alloc) -Ala-Arg (Pbf) -Lys (Boc) -Glu (OAll) -Asp ( OtBu) -Leu was obtained.
  • Tyr (tBu) -Fmoc 22.8g was synthesized in the same manner as in step (2) of Synthesis 1) to activate the target compound Tyr (tBu) -Fmoc.
  • Trt Promote Fmoc-deprotected Resin-Cys (Trt) -Thr (tBu) -Asn () as a target compound by the same method as in step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 18).
  • Trt -Met-Leu-Trp (Boc) -Gln (Trt) -Val-Phe-Glu (OtBu) -Lys (Alloc) -Ala-Arg (Pbf) -Lys (Boc) -Glu (OAll) -Asp ( OtBu) -Leu-Tyr (tBu) was obtained.
  • Step (2) Activation of Lys (Boc) -Fmoc (K)
  • Lys (Boc) -Fmoc 23.2g Synthesis 1) was carried out in the same manner as in step (2) to activate the target compound Lys (Boc) -Fmoc.
  • Trt -Met-Leu-Trp (Boc) -Gln (Trt) -Val-Phe-Glu (OtBu) -Lys (Alloc) -Ala-Arg (Pbf) -Lys (Boc) -Glu (OAll) -Asp ( OtBu) -Leu-Tyr (tBu) -Lys (Boc) was obtained.
  • Step (2) Activation of Ser (tBu) -Fmoc (S)
  • Ser (tBu) -Fmoc 19.0g was synthesized in the same manner as in step (2) of Synthesis 1) to activate Ser (tBu) -Fmoc as a target compound.
  • Trt Promote Fmoc-deprotected Resin-Cys (Trt) -Thr (tBu) -Asn (target compound) in the same manner as step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 20).
  • Trt -Met-Leu-Trp (Boc) -Gln (Trt) -Val-Phe-Glu (OtBu) -Lys (Alloc) -Ala-Arg (Pbf) -Lys (Boc) -Glu (OAll) -Asp ( OtBu) -Leu-Tyr (tBu) -Lys (Boc) -Ser (tBu) was obtained.
  • Tyr (tBu) -Fmoc 22.8g was synthesized in the same manner as in step (2) of Synthesis 1) to activate the target compound Tyr (tBu) -Fmoc.
  • Trt Promote Fmoc deprotected Resin-Cys (Trt) -Thr (tBu) -Asn () as a target compound by the same method as in step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 21).
  • Trt -Met-Leu-Trp (Boc) -Gln (Trt) -Val-Phe-Glu (OtBu) -Lys (Alloc) -Ala-Arg (Pbf) -Lys (Boc) -Glu (OAll) -Asp ( OtBu) -Leu-Tyr (tBu) -Lys (Boc) -Ser (tBu) -Tyr (tBu) was obtained.
  • Step (2) Activation of Asp (OtBu) -Fmoc (D)
  • Asp (OtBu) -Fmoc 20.4g was synthesized in the same manner as in step (2) of Synthesis 1) to activate Asp (OtBu) -Fmoc as a target compound.
  • Trt Promote Fmoc-deprotected Resin-Cys (Trt) -Thr (tBu) -Asn () as a target compound by the same method as step (1) of Synthesis 1) using the polypeptide prepared in Synthesis 22).
  • Trt -Met-Leu-Trp (Boc) -Gln (Trt) -Val-Phe-Glu (OtBu) -Lys (Alloc) -Ala-Arg (Pbf) -Lys (Boc) -Glu (OAll) -Asp ( OtBu) -Leu-Tyr (tBu) -Lys (Boc) -Ser (tBu) -Tyr (tBu) -Asp (OtBu) was obtained.
  • Step (2) Activation of Ser (tBu) -Fmoc (S)
  • Ser (tBu) -Fmoc 19.0g was synthesized in the same manner as in step (2) of Synthesis 1) to activate Ser (tBu) -Fmoc as a target compound.
  • Step (2) Activation of Thr (tBu) -Fmoc (T)
  • Phe-Fmoc 19.2g was synthesized in the same manner as in step (2) of Synthesis 1) to activate Phe-Fmoc.
  • Step (2) Activation of Thr (tBu) -Fmoc (T)
  • Gly-Fmoc 14.7g was synthesized in the same manner as in step (2) of Synthesis 1) to activate Gly-Fmoc.
  • Trt Promote Fmoc-deprotected Resin-Cys (Trt) -Thr (tBu) -Asn () with the polypeptide prepared in Synthesis 27) in the same manner as in step (1) of Synthesis 1). Trt) -Met-Leu-Trp (Boc) -Gln (Trt) -Val-Phe-Glu (OtBu) -Lys (Alloc) -Ala-Arg (Pbf) -Lys (Boc) -Glu (OAll) -Asp ( OtBu) -Leu-Tyr (tBu) -Lys (Boc) -Ser (tBu) -Tyr (tBu) -Asp (OtBu) -Ser (tBu) -Thr (tBu) -Phe-Thr (tBu) -Gly .
  • Step (2) Activation of Gln (Trt) -Fmoc (Q)
  • Gln (Trt) -Fmoc 30.3g was synthesized in the same manner as in step (2) of Synthesis 1) to activate Gln (Trt) -Fmoc.
  • Step (2) Activation of Aib-Fmoc
  • Aib-Fmoc 16.1g was synthesized in the same manner as in step (2) of Synthesis 1) to activate Aib-Fmoc as a target compound.
  • His (Trt) -Boc 30.7g was synthesized in the same manner as in step (2) of Synthesis 1) to activate His (Trt) -Boc as a target compound.

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Abstract

La présente invention concerne un nouvel intermédiaire utilisé pour un polypeptide physiologiquement actif et son procédé de préparation. Le nouvel intermédiaire peut être utilisé efficacement comme intermédiaire pour la préparation de produits pharmaceutiques polypeptidiques physiologiquement actifs, et peut être utilisé efficacement pour la préparation de produits pharmaceutiques de haute qualité en fournissant un intermédiaire polypeptidique de rendement élevé et de pureté élevée.
PCT/KR2019/008935 2018-07-19 2019-07-19 Nouvel intermédiaire utilisé pour un polypeptide physiologiquement actif et son procédé de préparation WO2020017919A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7928058B2 (en) * 2006-02-22 2011-04-19 Merck Sharp & Dohme Corp. Pharmaceutical composition comprising oxyntomodulin derivatives and a method for reducing body weight using the composition
KR20140018462A (ko) * 2012-07-25 2014-02-13 한미약품 주식회사 옥신토모듈린 유도체를 포함하는 고지혈증 치료용 조성물
KR20140058104A (ko) * 2012-11-06 2014-05-14 한미약품 주식회사 옥신토모듈린 유도체를 포함하는 당뇨병 또는 비만성 당뇨병 치료용 조성물
KR20140113696A (ko) * 2011-12-23 2014-09-24 입센 메뉴팩츄링 아일랜드 리미티드 치료 펩티드의 합성 방법
KR20170003466A (ko) * 2015-06-30 2017-01-09 한미약품 주식회사 신규 글루카곤 유도체 및 이의 지속형 결합체를 포함하는 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7928058B2 (en) * 2006-02-22 2011-04-19 Merck Sharp & Dohme Corp. Pharmaceutical composition comprising oxyntomodulin derivatives and a method for reducing body weight using the composition
KR20140113696A (ko) * 2011-12-23 2014-09-24 입센 메뉴팩츄링 아일랜드 리미티드 치료 펩티드의 합성 방법
KR20140018462A (ko) * 2012-07-25 2014-02-13 한미약품 주식회사 옥신토모듈린 유도체를 포함하는 고지혈증 치료용 조성물
KR20140058104A (ko) * 2012-11-06 2014-05-14 한미약품 주식회사 옥신토모듈린 유도체를 포함하는 당뇨병 또는 비만성 당뇨병 치료용 조성물
KR20170003466A (ko) * 2015-06-30 2017-01-09 한미약품 주식회사 신규 글루카곤 유도체 및 이의 지속형 결합체를 포함하는 조성물

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