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WO2009041841A1 - Complexes peptide-platine et leur procédé de préparation et d'utilisation - Google Patents

Complexes peptide-platine et leur procédé de préparation et d'utilisation Download PDF

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Publication number
WO2009041841A1
WO2009041841A1 PCT/PL2008/000068 PL2008000068W WO2009041841A1 WO 2009041841 A1 WO2009041841 A1 WO 2009041841A1 PL 2008000068 W PL2008000068 W PL 2008000068W WO 2009041841 A1 WO2009041841 A1 WO 2009041841A1
Authority
WO
WIPO (PCT)
Prior art keywords
peptide
phe
compound
formula
platinum complex
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.)
Ceased
Application number
PCT/PL2008/000068
Other languages
English (en)
Inventor
Aleksandra Misicka-Kesik
Andrzej W. Lipkowski
Agnieszka Glowinska
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.)
INSTYTUT MEDYCYNY DOSWIACZALNEJ I KLINICZNEJ
Uniwersytet Warszawski
Original Assignee
INSTYTUT MEDYCYNY DOSWIACZALNEJ I KLINICZNEJ
Uniwersytet Warszawski
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 INSTYTUT MEDYCYNY DOSWIACZALNEJ I KLINICZNEJ, Uniwersytet Warszawski filed Critical INSTYTUT MEDYCYNY DOSWIACZALNEJ I KLINICZNEJ
Publication of WO2009041841A1 publication Critical patent/WO2009041841A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K38/08—Peptides having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • 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
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • 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
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

  • the present invention relates to novel peptide-platinum complexes, to their preparation, pharmaceutical composition and to use the same as medicament for treatment of tumors, especially in the form of infusions, intravenous injections or implants.
  • the main used compounds include cisplatin or analogs thereof.
  • platinum complexes such as cisplatin has been shown to be effective in the treatment of most advanced forms of tumors (Rosenberg, Cancer 1985, 55, 2303 2316; Prestayko et al., Cancer Treat. Rev. 1979, 6, 17 39).
  • the present invention provides the new peptide-platinum complexes of the general formula I: Tyr-D-Ala-Gly-Phe-NH-NH ⁇ -Phe ⁇ - AA-PtX 2 wherein:
  • AA is a residue of methionine, cysteine, histidine, 1,3-diaminebutanoic acid or 1,4- diaminepentanoic acid,
  • X is halogen, or pharmaceutically acceptable salts thereof.
  • Cl is preferred halogen.
  • Tyr denotes tyrosine, preferably L-tyrosine
  • D-AIa denotes D-alanine
  • GIy denotes glycine
  • Phe denotes phenylalanine, preferably L-phenylalanine.
  • Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, lactic acid, malonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, lactic acid, malonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, and the like.
  • the present invention further relates to a method for the preparation of the new peptide-platinum complexes of general formula I, as defined above, comprising reacting peptide of general formula V: Tyr-D-Ala-Gly-Phe-NH-NH ⁇ — Phe «— AA, optionally in the form of an acid addition salt, with Pt(II) compound.
  • the obtained product may be, if necessary, converted into a desired pharmaceutically acceptable salt by a conventional method.
  • Pt(II) compound can be, for example, haloplatinate(II).
  • the reaction is preferably carried out in an aqueous medium.
  • the essential feature of the method according to the invention is that the amino acid residues of methionine, cysteine or histidine chemically linked to an opioid peptide, as shown by formulae II to IV, are the elements which directly complexes platinum.
  • the intermediate complexing peptide of formula V may be prepared by routine amino acids addition. It is novel compound. The method for the preparation of the opioid peptide was described by Lipkowski et al. Bioorg. Med. Chem. Lett. 1999, 2763-2766.
  • Novel peptide-platinum complexes are effective in the chemotherapy of tumors and they also exhibit analgesic effect, thereby simultaneously they control a pain associated with chemotherapy and neoplastic lesions.
  • the present invention also provides a pharmaceutical composition for the treatment of tumors comprising as an active ingredient the novel peptide-platinum complexes of general formula I, as defined above, or their pharmaceutically acceptable salts and a therapeutically acceptable carrier.
  • the compounds are preferably formulated in a suitable pharmaceutical composition using known additions such as a therapeutically acceptable carrier, diluent or auxiliaries.
  • the invention relates to novel peptide-platinum complexes of formula I, defined above, or to their pharmaceutically acceptable salts for use in the treatment of tumors with simultaneous complete or partial blocking a conduction of the pain impulses as the result of affinity to the opioid receptors of peptide complexes.
  • Novel compounds can take the form of intravenous infusions, subcutaneous implant or implant into body tissues that ensures the best access of released novel peptide-platinum complex to a site of treatment.
  • Novel compounds can be administered singly as a substance or as an ingredient of multi-drugs composition of medicaments used in the therapy.
  • the affinity to opioid receptors was evaluated accordingly to the test described by Misicka at al. in Life Sciences 51, 1025, 1992.
  • Affinity test Homogenate of a rat brain is saturated with a standard of the opioid ligand, then the tested compound is added and amount of labeled compound displaced with the tested compound is measured.
  • the anti-tumor activity was evaluated in the proliferation test. This test consists in counting proliferating tumor cells contained in culture comprising the tested compounds (and medium). The novel compounds resulted in distinct reduction of proliferation of the tumor cells T98G-human glioblastoma (about 50% after 4 days in comparison with the standard).
  • Proliferation test for assessment of the effect of peptides on cell growth T98G cells were seeded into 35 mm diameter culture dishes (3xl05/dish) and peptides dissolved in medium were added at the concentration lO ⁇ M or 20 ⁇ M. Cell numbers were measured every day from day 4 by harvesting the cells using 0.25% trypsin-0.02% EDTA and counting in a hemacytometer chamber.
  • Boc-Tyr-D-Ala-Gly-Phe-NH-NH ⁇ -Phe-NH 2 is coupled with Boc protected amino acids: Boc-Met-OH, Boc-Cys-OH and Boc-His-OH.
  • Boc-Tyr-D-Ala-Gly-Phe-NH-NH ⁇ Phe ⁇ -Met-Boc, Boc-Tyr-D-Ala-Gly-Phe-NH- NH ⁇ -Phe ⁇ -Cys-Boc and Boc-Tyr-D-Ala-Gly-Phe-NH-NH ⁇ -Phe ⁇ His-Boc are prepared. Double-sided Boc protecting group is then removed from all peptides.
  • the crude product is purified by a high performance liquid chromatography on C 18 column using system of solvents A and B H 2 O/ ACN: 0.05% TFA in H 2 O (A) and 0.05% TFA in ACN (B).
  • ACN - acetonitrile, TFA - trifluoroacetic acid Tyr-D-Ala-Gly-Phe-NH-NH*-Phe ⁇ -Met(N,5)PtCl 2
  • the crude product is purified by a high performance liquid chromatography on Ci g column using system of solvents A and B H 2 O/ACN: 0.05% TFA in H 2 O (A) and 0.05% TFA in ACN (B).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention porte sur de nouveaux complexes peptide-platine représentés par la formule générale I Tyr-D-Ala-Gly-Phe-NH-NH<- Phe<- AA-PtX2, dans laquelle AA est un résidu méthionine, cystéine, histidine, acide 1,3-diaminebutanoïque ou acide 1,4-diaminepentanoïque, X est halogène, ou sur des sels pharmaceutiquement acceptables de ces complexes. L'invention porte également sur un procédé de préparation de nouveaux complexes, comprenant la réaction d'un peptide représenté par la formule générale V : Tyr-D-Ala-Gly-Phe-NH-NH<- Phe<- A avec un composé Pt(II). L'invention porte sur l'utilisation des nouveaux complexes en tant que médicament pour le traitement de tumeurs, présentant simultanément une activité analgésique.
PCT/PL2008/000068 2007-09-24 2008-09-23 Complexes peptide-platine et leur procédé de préparation et d'utilisation Ceased WO2009041841A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PLP383412 2007-09-24
PL383412A PL208164B1 (pl) 2007-09-24 2007-09-24 Nowe peptydowe kompleksy platyny, sposób ich otrzymywania, kompozycja farmaceutyczna i zastosowanie

Publications (1)

Publication Number Publication Date
WO2009041841A1 true WO2009041841A1 (fr) 2009-04-02

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/PL2008/000068 Ceased WO2009041841A1 (fr) 2007-09-24 2008-09-23 Complexes peptide-platine et leur procédé de préparation et d'utilisation

Country Status (2)

Country Link
PL (1) PL208164B1 (fr)
WO (1) WO2009041841A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106699847A (zh) * 2017-01-04 2017-05-24 陕西慧康生物科技有限责任公司 一种低成本纯化六胜肽的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004014943A2 (fr) * 2002-08-13 2004-02-19 Lipkowski Andrzej W Composes, et leurs applications analgesiques
US20060205677A1 (en) * 2005-02-23 2006-09-14 Xenoport, Inc. Platinum-containing compounds exhibiting cytostatic activity, synthesis and methods of use
US20070010427A1 (en) * 2005-07-07 2007-01-11 Cancure Laboratories, Llc Use of one or more metal carriers to selectively kill mammalian cells

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004014943A2 (fr) * 2002-08-13 2004-02-19 Lipkowski Andrzej W Composes, et leurs applications analgesiques
US20060205677A1 (en) * 2005-02-23 2006-09-14 Xenoport, Inc. Platinum-containing compounds exhibiting cytostatic activity, synthesis and methods of use
US20070010427A1 (en) * 2005-07-07 2007-01-11 Cancure Laboratories, Llc Use of one or more metal carriers to selectively kill mammalian cells

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIPKOWSKI A W ET AL: "Biological activity of fragments and analogues of the potent dimeric opioid peptide, biphalin", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 9, no. 18, 20 September 1999 (1999-09-20), pages 2763 - 2766, XP004179967, ISSN: 0960-894X *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106699847A (zh) * 2017-01-04 2017-05-24 陕西慧康生物科技有限责任公司 一种低成本纯化六胜肽的方法
CN106699847B (zh) * 2017-01-04 2020-08-14 陕西慧康生物科技有限责任公司 一种低成本纯化六胜肽的方法

Also Published As

Publication number Publication date
PL383412A1 (pl) 2009-03-30
PL208164B1 (pl) 2011-03-31

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