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WO2020080842A1 - Inhibiteur de l'antigène membranaire spécifique de la prostate pour le diagnostic et le traitement du cancer de la prostate, et composition pharmaceutique contenant celui-ci pour le diagnostic et le traitement du cancer de la prostate - Google Patents

Inhibiteur de l'antigène membranaire spécifique de la prostate pour le diagnostic et le traitement du cancer de la prostate, et composition pharmaceutique contenant celui-ci pour le diagnostic et le traitement du cancer de la prostate Download PDF

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Publication number
WO2020080842A1
WO2020080842A1 PCT/KR2019/013635 KR2019013635W WO2020080842A1 WO 2020080842 A1 WO2020080842 A1 WO 2020080842A1 KR 2019013635 W KR2019013635 W KR 2019013635W WO 2020080842 A1 WO2020080842 A1 WO 2020080842A1
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WO
WIPO (PCT)
Prior art keywords
formula
mmol
prostate cancer
pharmaceutical composition
diagnosing
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/KR2019/013635
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English (en)
Korean (ko)
Inventor
변영주
손상현
김결
권홍목
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Korea University Research and Business Foundation
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Korea University Research and Business Foundation
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Publication of WO2020080842A1 publication Critical patent/WO2020080842A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0446—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/0472—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the present invention provides a novel inhibitor having an inhibitory activity by binding to a prostate-specific membrane antigen (PSMA) and a pharmaceutical composition having excellent efficacy in the diagnosis and treatment of prostate cancer, including the same, for use in the treatment or diagnosis of prostate cancer I want to.
  • PSMA prostate-specific membrane antigen
  • the present invention provides a compound represented by the following [Formula 1] or [Formula 2], and the following compound is characterized by inhibiting activity by binding to a prostate specific membrane antigen (PSMA).
  • PSMA prostate specific membrane antigen
  • R is a bodyfi derivative or cyanine derivative fluorescent substance exhibiting fluorescence in the near-infrared fluorescence region 500 to 800 nm wavelength, or a benzoyl group substituted with a halogen group, m is an integer from 1 to 4, n is an integer from 1 to 2 .
  • the present invention is to provide a pharmaceutical composition for the diagnosis or treatment of prostate cancer containing the compound represented by the above [Formula 1] or [Formula 2] or a salt thereof as an active ingredient, the activity of the prostate specific membrane antigen (PSMA) It is characterized by inhibiting.
  • PSMA prostate specific membrane antigen
  • PSMA inhibitors according to the present invention are based on dipeptides derived from ⁇ - or ⁇ -amino acids, based on ⁇ - or ⁇ -amino acid analogs with different chiral properties, and also to increase the hydrophobic interaction with PSMA
  • a phosphor structure and a benzoyl group substituted with a halogen group are introduced into a ⁇ - or ⁇ -amino acid analog.
  • One aspect of the present invention is a compound represented by the following [Formula 1] or [Formula 2], characterized by binding to the prostate specific membrane antigen (PSMA) and inhibiting activity.
  • PSMA prostate specific membrane antigen
  • R is a phosphor that exhibits fluorescence in the near-infrared fluorescence region at a wavelength of 500 to 800 nm.
  • a phosphor When present in an aqueous solution that is a medium in which biomolecules are present, light bleaching and quenching are small, molar absorption coefficient and quantum efficiency are large, and stable under various pH conditions If it is a phosphor, it is not limited.
  • cyanine cyanine, bodipy, coumarins, fluoresceins, rhodamines, pyrenes, carbopyronin, oxazine, etc.
  • This preferably, may be a cyanine-based derivative, a bodypi-based derivative, or a benzoyl group substituted with a halogen group.
  • X 1 and X 2 may each be a halogen group or may be 18 F, 125 I, or 131 I substituted with a radioactive label element.
  • the compound represented by [Chemical Formula 1] or [Chemical Formula 2] may be a compound represented by the following [15a] to [18d], thereby limiting the scope of the present invention. no.
  • the amino acid skeleton is ⁇ -amino acid, and has an (S) -configuration sequence configuration
  • [16a] to [16d] is an amino acid skeleton ⁇ -amino acid, (R) -configuration sequence It has a composition.
  • [16a] to [16d] are amino acid backbones are ⁇ -amino acids, and have a (S) -configuration sequence configuration
  • [18a] to [18d] are amino acid backbones are ⁇ -amino acids
  • PSMA inhibitory properties of the synthetic compounds according to the present invention were confirmed through fluorescence analysis, and (S) -configuration configuration of the (R) -configuration configuration of ⁇ -amino acids was studied through a study of the structure-activity relationship. It was confirmed that having a (S) -configuration sequence configuration of ⁇ -amino acid and having a (R) -configuration sequence configuration more strongly inhibited PSMA than having.
  • the compound represented by [Chemical Formula 1] or [Chemical Formula 2] is a ⁇ -amino acid having an (R) -configuration sequence configuration or an amino acid skeleton having ⁇ - It may be an amino acid and have an (S) -configuration configuration.
  • Another aspect of the present invention relates to a pharmaceutical composition for diagnosing and treating prostate cancer containing the compound represented by the above Chemical Formula 1 or Chemical Formula 2 or a salt thereof as an active ingredient, and of prostate specific membrane antigen (PSMA) It is characterized by inhibiting activity.
  • PSMA prostate specific membrane antigen
  • the pharmaceutical composition according to the present invention may be administered in the form of a complex preparation together with drugs for diagnosis and treatment of prostate cancer, or may include other ingredients such as carriers, diluents, adjuvants and stabilizers.
  • Reagents and conditions i) Triphosgene, triethylamine, anhydrous CH 2 Cl 2 , -78 °C, room temperature, 30 minutes iii) TFA / CH 2 Cl 2 (1/4, v / v), room temperature, 2 hours iv) Boc-L-Dap-OH, triethylamine, room temperature, 24 hours v) Pd / C, MeOH, H 2
  • PSMA inhibitory activity was evaluated using a fluorescence-based assay, and the results are shown in Table 1 below using DCFPyL compounds represented by the following structures as comparative examples. Briefly, lysates (25 ⁇ L) of LNCaP cell extract were incubated with compound (12.5 ⁇ L), N-acetyl aspartyl glutamate (NAAG, 12.5 ⁇ L) for 2 hours. The amount of glutamate released by NAAG hydrolysis was measured by incubating in a solution of Amplex Red (50 ⁇ L) for 60 minutes. Fluorescence was measured at 490 nm and luminescence at 642 nm using a VICTOR3 V multi-label plate reader. The inhibition curve plot was obtained using 50% inhibition of enzyme activity and an enzyme inhibition constant (Ki value) using Cheng-Prusoff transformation.
  • Ki value enzyme inhibition constant
  • the present invention relates to a pharmaceutical composition for diagnosing or treating prostate cancer, and it is excellently bound to PSMA overexpressed in prostate cancer to inhibit enzymatic action or to obtain a clear image of a prostate cancer tumor site through strong binding. Cancer can be diagnosed or treated early.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne : un composé qui se lie à l'antigène membranaire spécifique de la prostate (PSMA) et inhibe son activité ; une composition pharmaceutique pour le diagnostic ou le traitement du cancer de la prostate, la composition pharmaceutique contenant le composé en tant que principe actif. Selon la présente invention, une activité enzymatique peut être inhibée par une excellente liaison au PSMA sur-exprimé dans le cancer de la prostate, ou des images claires de sites tumoraux du cancer de la prostate peuvent être obtenues par liaison forte, et, grâce à son utilisation, le cancer de la prostate peut être diagnostiqué ou traité précocement.
PCT/KR2019/013635 2018-10-17 2019-10-17 Inhibiteur de l'antigène membranaire spécifique de la prostate pour le diagnostic et le traitement du cancer de la prostate, et composition pharmaceutique contenant celui-ci pour le diagnostic et le traitement du cancer de la prostate Ceased WO2020080842A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2018-0123801 2018-10-17
KR1020180123801A KR20200043115A (ko) 2018-10-17 2018-10-17 전립선암의 진단과 치료를 위한 전립선 특이 막 항원 저해제 및 이를 포함하는 전립선암 진단 및 치료용 약학 조성물

Publications (1)

Publication Number Publication Date
WO2020080842A1 true WO2020080842A1 (fr) 2020-04-23

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PCT/KR2019/013635 Ceased WO2020080842A1 (fr) 2018-10-17 2019-10-17 Inhibiteur de l'antigène membranaire spécifique de la prostate pour le diagnostic et le traitement du cancer de la prostate, et composition pharmaceutique contenant celui-ci pour le diagnostic et le traitement du cancer de la prostate

Country Status (2)

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KR (1) KR20200043115A (fr)
WO (1) WO2020080842A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003060523A1 (fr) * 2002-01-10 2003-07-24 Johns Hopkins University Agents d'imagerie et procedes d'imagerie de naaladase et psma
WO2013028664A1 (fr) * 2011-08-22 2013-02-28 Siemens Medical Solutions Usa, Inc. Agents d'imagerie du psma
WO2016065142A2 (fr) * 2014-10-22 2016-04-28 The Johns Hopkins University Nouveaux échafaudages et intermédiaires multifonctionnels pour l'imagerie de et le traitement du cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003060523A1 (fr) * 2002-01-10 2003-07-24 Johns Hopkins University Agents d'imagerie et procedes d'imagerie de naaladase et psma
WO2013028664A1 (fr) * 2011-08-22 2013-02-28 Siemens Medical Solutions Usa, Inc. Agents d'imagerie du psma
WO2016065142A2 (fr) * 2014-10-22 2016-04-28 The Johns Hopkins University Nouveaux échafaudages et intermédiaires multifonctionnels pour l'imagerie de et le traitement du cancer

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEN, Y.: "2-(3-{I-Carboxy-5-[(6-[18F]Fluoro-Pyridine-3-Carbonyl)-Amino]- Pentyl}-Ureido)-Pentanedioic Acid, [18F]DCFPyL, a PSMA-Based PET Imaging Agent for Prostate Cancer", CLIN CANCER RES., vol. 17, no. 24, 15 December 2011 (2011-12-15), pages 7645 - 7653, XP055278472 *
CHEN, Y.: "Synthesis and Biological Evaluation of Low Molecular Weight Fluorescent Imaging Agents for the Prostate-Specific Membrane Antigen", BIOCONJUG CHEM., vol. 23, no. 12, 19 December 2012 (2012-12-19), pages 2377 - 2385, XP055280710, DOI: 10.1021/bc3003919 *
PAVLICEK, J.: "Structural characterization of P10-diversified urea-based inhibitors of glutamate carboxypeptidase II", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 24, no. 10, 28 March 2014 (2014-03-28), pages 2340 - 2345, XP028646746 *

Also Published As

Publication number Publication date
KR20200043115A (ko) 2020-04-27

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