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

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
formula
mmol
prostate cancer
pharmaceutical composition
diagnosing
Prior art date
Application number
PCT/KR2019/013635
Other languages
English (en)
Korean (ko)
Inventor
변영주
손상현
김결
권홍목
Original Assignee
고려대학교 세종산학협력단
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 고려대학교 세종산학협력단 filed Critical 고려대학교 세종산학협력단
Publication of WO2020080842A1 publication Critical patent/WO2020080842A1/fr

Links

Classifications

    • 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.

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 WO2020080842A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
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
KR10-2018-0123801 2018-10-17

Publications (1)

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

Family

ID=70282975

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2019/013635 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)

Country Link
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

Similar Documents

Publication Publication Date Title
EP0623606B1 (fr) Peptide-kétones comme inhibiteurs de l'interleukin-1bêta convertant enzyme
CA1244041A (fr) Procede de preparation du cis, endo-octahydrocyclopenta ¬b|pyrrole-2- carboxylate
EP0623592A1 (fr) Analogues de peptides à adivité inhibitrice de l'interleukin 1 bêta protéase
HUT60282A (en) Process for producing new beta-amino-alpha-hydroxycarboxylic acid derivatives and pharmaceutical compositions comprising such compounds
WO2021194318A1 (fr) Composé induisant une dégradation sélective de plk1
EP0308885A1 (fr) Dérivés de l'acide D-glutamine et de l'acide D-aspartique
US5767316A (en) Process for producing 3-amino-2-oxo-1-halogenopropane derivatives
WO2016085127A2 (fr) Dérivé d'acide ascorbique conjugué à un peptide stable, son procédé de préparation, et composition cosmétique le contenant
WO2018226053A1 (fr) Composé dérivé du cyclopropylamine et son utilisation
WO2016204376A1 (fr) Nouveaux intermédiaires pour la préparation d'inhibiteurs de la dpp-iv, procédé de préparation de ces intermédiaires et procédé de préparation d'inhibiteurs de la dpp-iv utilisant ces intermédiaires
WO2019168269A1 (fr) Composé organométallique chiral bifonctionnel ayant une excellente énantiosélectivité, son procédé de préparation et procédé pour produire de l'acide gamma-aminé non naturel à partir d'un composé nitré à l'aide de celui-ci
WO2021086069A1 (fr) Composé comprenant un inhibiteur d'ezh2 et un liant de ligase e3 et composition pharmaceutique pour prévenir ou traiter une maladie associée à ezh2 comprenant celui-ci en tant que principe actif
WO2010114291A2 (fr) Procédé amélioré d'élaboration d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
WO2020080842A1 (fr) 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
WO2010114292A2 (fr) Procédé amélioré de fabrication d'inhibiteur de dipeptidyl peptidase-iv et d'intermédiaire
WO2023018236A1 (fr) Nouveau composé induisant la dégradation de plk1
EP0210896B2 (fr) Dérivés d'acides amino-4 hydroxy-3 carboxyliques optiquement purs et procédé de synthèse stéréospécifique
US20040009923A1 (en) Peptide analogs as irreversible interleukin-1beta protease inhibitors
WO2019088800A9 (fr) Dérivé de polyéthylène glycol et son procédé de préparation
EP0024664B1 (fr) Amides de peptides et procédé pour leur préparation
US4847384A (en) Process for the preparation of certain nitrogen-containing mono- and bicyclic ace inhibitors, and novel intermediates useful therefor
TWI386395B (zh) 哌啶衍生物的立體有擇合成
AU8749398A (en) Stereoisomeric indole compounds, process for the preparation of the same, and use thereof
WO2023277583A1 (fr) Nouveau composé induisant la dégradation de la protéine plx1
WO2023101115A1 (fr) Procédé de préparation d'un isomère unique de 1-(1-(2-benzylphénoxy)propan-2-yl)-2-méthylpipéridine de pureté élevée

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19873259

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19873259

Country of ref document: EP

Kind code of ref document: A1