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WO2025169163A1 - Procédé de synthèse de trofinétide et de ses analogues - Google Patents

Procédé de synthèse de trofinétide et de ses analogues

Info

Publication number
WO2025169163A1
WO2025169163A1 PCT/IB2025/051364 IB2025051364W WO2025169163A1 WO 2025169163 A1 WO2025169163 A1 WO 2025169163A1 IB 2025051364 W IB2025051364 W IB 2025051364W WO 2025169163 A1 WO2025169163 A1 WO 2025169163A1
Authority
WO
WIPO (PCT)
Prior art keywords
trofinetide
tag
coupling
amino acid
synthesis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2025/051364
Other languages
English (en)
Inventor
Veeranjaneyulu Avula
Selvakumar Balaraman
Umamaheswar SIRIPURAPU
Akshitha D N
Nagendra G
Ranjithkumar M
Surya Prakash Rao H
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Reva University
Teadus Pharma Private Ltd
Original Assignee
Reva University
Teadus Pharma Private Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Reva University, Teadus Pharma Private Ltd filed Critical Reva University
Publication of WO2025169163A1 publication Critical patent/WO2025169163A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala

Definitions

  • the present invention relates to a method for synthesizing Trofinetide (1) and its analogues. It further introduces a novel approach for the synthesis of Trofinetide (1) and its analogues using the TAG approach, involving sequential amino acid coupling through solid-phase peptide synthesis. Additionally, the invention provides a commercially viable purification method for producing high-purity Trofinetide (1) and its analogues. BACKGROUND OF THE INVENTION The tripeptides are used to treat the main symptoms of Rett syndrome (RTT). RTT is a genetically induced neurological disorder.
  • Trofinetide is a tripeptide synthetic compound indicated for the treatment of Rett syndrome in people two years of age and older.
  • Trofinetide is designated chemically as (2S)-2- ⁇ [(2S)-1-(2-aminoacetyl)-2- methylpyrrolidine-2-carbonyl] amino ⁇ pentane dioic acid (IUPAC). Its empirical formula is C 13 H 21 N 3 O 6 and its molecular weight is 315.33 g/mol.
  • the chemical structure is: Trofinetide is the first drug approved by the US Food and Drug Administration in March 2023. It is an oral medication sold under the brand name Daybue. Like its parent tripeptide Glypromate, Trofinetide is also tripeptide in which proline has been modified.
  • Tripeptide Glypromate (glycine-proline glutamate) is a naturally occurring small- molecule neuroprotectant derived from IGF-1 which inhibits caspase III dependent apoptosis, for the potential treatment of neurodegenerative diseases by IV infusion.
  • Tetrahedron 61 (2005) 10018–10035, Neuren Pharmaceuticals Medicinal Chemistry Group provides a method for the synthesis of ten analogues of GPE modified at proline residue.
  • US 2003/0055004 A1 patent application reported the synthesis of GPE by modifying glutamic acid and glycine residue on solid-phase peptide synthesis.
  • US 2023023114 A1 patent application provided the pharmaceutical composition of crystalline forms of Trofinetide and Trofinetide hydrates.
  • suitable base used herein the present invention until unless specified is selected from inorganic bases like “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert-butoxide, potassium tert- butoxide, lithium tert-butoxide and the like; organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine (DIPEA), diisobutylamine, trimethyl
  • Coupler used herein the present invention until unless specified is selected from the group consisting of Benzotriazole- 1 -yl-oxy-tris- (dimethylamino)- phosphonium hexafluorophosphate (BOP), Benzotriazole- 1-yl-oxy-tris-pyrrolidino- phosphonium hexafluorophosphate (PyBOP), O-(IH-Benzotriazol-l-yl)-N,N, N,N- tetramethyluronium tetrafluoroborate (TBTU), O-(7-Azabenzotriazole- 1 -yl)-N,N,N,N- tetramethyluronium tetrafluoroborate (TATU), O-(lH-Benzotriazole-l-yl)-N, N, N, N- tetramethyluronium hexafluorophosphate,(HBTU), 2-(7
  • the present invention provides a novel method for the synthesis of Trofinetide and its analogues using tagging approach.
  • the tagging approach is cost-efficient compared to solid and solution phase peptide synthesis methods.
  • the preparation method provides a commercially scalable, cost-efficient method with improved yield and impurities are controlled within the ICH limits.
  • the solvent used in stap a) is selected from the list as defined above, preferably THF.
  • the step a) reaction is carried out at a suitable temperature of about 0°C to about 5°C for a sufficient period till completion of the reaction.
  • Step b) of the foregoing process involves deprotecting the Fmoc group in the TAG-linked amino acid (5) using a deprotecting agent in the presence of a base and solvent, followed by coupling with the N-protected second amino acid (4) in the presence of a coupling reagent, base, and solvent under appropriate reaction condition to obtain the dipeptide compound in situ.
  • the deprotecting agent used in step b) is piperidine.
  • the N-protected first amino acid is having a structure of Fmoc- ⁇ -Glu-O t Bu (6); N-protected second amino acid is having a structure of Fmoc- ⁇ -CH3-Pro-OH (4); and N-protected third amino acid is having a structure of Boc-Gly-OH (3).
  • the synthesis of linear peptide backbone is carried out on TAG-OH.
  • TAG-OH referred herein is (2,4- bis(octadecyloxy)phenyl) methanol (7).
  • the TAG linked amino acid is Fmoc- Glu-(OCH 2 -TAG)-O t Bu (5) and the TAG linked tripeptide is Boc-Gly- ⁇ -CH 3 -Pro-Glu- (OCH 2 -TAG)-O t Bu (2).
  • the present synthetic approach allows the introduction of TAG ((2,4-bis-octadecyl oxy-phenyl)-methanol) to the C- C-terminus end of ⁇ -glutamic acid at the first step.
  • the above-mentioned compounds are prepared by liquid phase easily by using the Tagging technique on an industrial scale without any difficulty with good purity and in high yield.
  • the compounds were prepared with an acid-labile Tagging technique to provide the desired protected tripeptide and subsequently desired final Trofinetide with good yield and purity.
  • the present invention provides a preparation method for fragment synthesis on less expensive Tags instead of costly resins. This provides better yield and less impurity wherein the peptides can be easily purified using simple non-expensive techniques.
  • the method described herein in the present invention can provide Trofinetide and its analogues with good yield and high purity on an industrial scale.
  • the present invention provides a facile purification method for the preparation of high pure tripeptide and its analogues.
  • Step 2 Preparation of H-Glu-(O-TAG)-OtBu (Fmoc deprotection of the TAG attached amino acid)
  • DBU 0.26 mL
  • piperidine 0.26 mL
  • the reaction mass was cooled to 0-5 °C, and the mixture pH was adjusted with 1 M aq. HCl to ⁇ 7.0.
  • the reaction mass was washed with purified water (5V x 2).
  • Step 3 Preparation of Boc-Gly- ⁇ -CH3-Pro- ⁇ -Glu-(OCH2-TAG)-O t Bu (2) [2 nd and 3 rd amino acids coupling]: To the step 2 solution having H-Glu-(O-TAG)-O t Bu (0.5 g), Fmoc- ⁇ -CH3-Pro-OH (4) (0.232 g), COMU (0.35 g) and DIPEA (0.31 mL) in THF (5.0 mL) were added at 0-5°C and stirred for 1 hour.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biophysics (AREA)
  • Epidemiology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Neurology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne un procédé de synthèse de trofinétide (1) et de ses analogues. La présente invention concerne également une nouvelle approche pour la synthèse de trofinétide (1) et de ses analogues par approche TAG par couplage séquentiel d'acides aminés à l'aide d'une synthèse peptidique en phase solide. L'invention concerne en outre un procédé de purification commercialement viable pour la synthèse de trofinétide (1) de haute pureté et de ses analogues. Formule (1)
PCT/IB2025/051364 2024-02-10 2025-02-10 Procédé de synthèse de trofinétide et de ses analogues Pending WO2025169163A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202441009099 2024-02-10
IN202441009099 2024-02-10

Publications (1)

Publication Number Publication Date
WO2025169163A1 true WO2025169163A1 (fr) 2025-08-14

Family

ID=96699410

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2025/051364 Pending WO2025169163A1 (fr) 2024-02-10 2025-02-10 Procédé de synthèse de trofinétide et de ses analogues

Country Status (1)

Country Link
WO (1) WO2025169163A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014085480A1 (fr) * 2012-11-28 2014-06-05 Neuren Pharmaceuticals Limited Traitement de troubles du spectre autistique à l'aide de l'acide glycyl-l-2-méthylprolyl-l-glutamique
WO2021026066A1 (fr) * 2019-08-05 2021-02-11 Neuren Pharmaceuticals Limited Compositions de trofinétide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014085480A1 (fr) * 2012-11-28 2014-06-05 Neuren Pharmaceuticals Limited Traitement de troubles du spectre autistique à l'aide de l'acide glycyl-l-2-méthylprolyl-l-glutamique
WO2021026066A1 (fr) * 2019-08-05 2021-02-11 Neuren Pharmaceuticals Limited Compositions de trofinétide

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