WO2023275052A1 - Dérivés de bufaline utiles en thérapie - Google Patents

Dérivés de bufaline utiles en thérapie Download PDF

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Publication number
WO2023275052A1
WO2023275052A1 PCT/EP2022/067743 EP2022067743W WO2023275052A1 WO 2023275052 A1 WO2023275052 A1 WO 2023275052A1 EP 2022067743 W EP2022067743 W EP 2022067743W WO 2023275052 A1 WO2023275052 A1 WO 2023275052A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
substituted
phenyl
use according
Prior art date
Application number
PCT/EP2022/067743
Other languages
English (en)
Inventor
Yaping Hua
Karl-Henning KALLAND
Weidong Zhang
Xisong KE
Yunheng SHEN
Anne Margrete ØYAN
Original Assignee
Vestlandets Innovasjonsselskap As
Shanghai University Of Traditional Chinese Medicine
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
Priority claimed from GBGB2110150.6A external-priority patent/GB202110150D0/en
Application filed by Vestlandets Innovasjonsselskap As, Shanghai University Of Traditional Chinese Medicine filed Critical Vestlandets Innovasjonsselskap As
Publication of WO2023275052A1 publication Critical patent/WO2023275052A1/fr

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Classifications

    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • 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
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/001—Oxiranes
    • C07J71/0021—Oxiranes at position 14(15)

Definitions

  • Prostate cancer has the highest incidence of diagnosed cancer among men in Europe and the second-highest worldwide. Prostate cancer may be diagnosed based on prostate-specific antigen (PSA) screening, a digital rectal exam, multi-parametric magnetic resonance imaging (mpMRI) or gene-based tests, such as the transmembrane protease serine 2 (TMPRSS2) protein-ETS gene fusions, and the non-coding RNA, prostate cancer gene 3 (PCA3).
  • PSA prostate-specific antigen
  • mpMRI multi-parametric magnetic resonance imaging
  • gene-based tests such as the transmembrane protease serine 2 (TMPRSS2) protein-ETS gene fusions, and the non-coding RNA, prostate cancer gene 3 (PCA3).
  • Hua et al. discloses a small molecule compound (cinobufagin-3-acetate, referred to herein as compound 154) which inhibits AR and STAT3 transcriptional activity, reduces the expression of phosphorylation of STAT3 (Y705) and downregulates the mRNA levels of AR target genes.
  • the present inventors have identified a group of largely novel compounds which exhibit desirable properties as AR antagonists and therefore utility as anti-cancer drugs.
  • composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the present invention also provides the in vitro use of a compound or composition of the invention as a STAT3 inhibitor, preferably a STAT3 SH2 domain inhibitor.
  • the present invention also provides a method of treating cancer, preferably prostate cancer, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound or a composition of the invention.
  • Other preferred cancers and tumours to be treated are as described elsewhere herein.
  • the present invention provides a compound of Formula (I), or a solvate, a tautomer, a stereoisomer or a salt thereof, for use in therapy: wherein
  • Most preferred compounds according to the invention are the compounds listed in Table 1 below.
  • the most preferred compound of the invention is:
  • This compound is referred to herein as either compound 104A or compound 154c.
  • the cancers/patients treated according to the present invention are those which exhibit drug resistance to LBD binding domain inhibitors such as ENZ.
  • the cancers treated are those which express splice variants of full-length AR, in particular those splice variants which do not contain the full-length LBD of AR.
  • the cancers treated are those which express gain-of- function mutations in the AR, in particular within the LBD.
  • Particularly preferred cancers/tumours to be treated are those which have constitutively active AR splice variants with mutations in the AR LBD, such as ARv567 and AR-V3, 7 or 9.
  • a pharmaceutical pack comprising a compound of the invention (i.e. , a compound of Formula (I)) or a solvate, stereoisomer, tautomer, or salt thereof; and an AR ligand binding domain (LBD) inhibitor, such as abiraterone, hydroxyflutamide, apalutamide, darolutamide, bicalutamide, flutamide or enzalutamide (ENZ), preferably enzalutamide.
  • LBD AR ligand binding domain
  • Subjects or patients treated in accordance with the present invention will preferably be humans, but veterinary treatments are also contemplated.
  • compositions e.g., pharmaceutical compositions, according to the invention may be presented, for example, in a form suitable for oral, nasal, parenteral, intravenous, topical, intratumoural or rectal administration.
  • pharmaceutical includes veterinary applications of the invention.
  • the tablets may if desired consist of several layers.
  • Coated tablets may be produced by coating cores, obtained in a similar manner to the tablets, with agents commonly used for tablet coatings, for example, polyvinyl pyrrolidone or shellac, gum arabic, talcum, titanium dioxide or sugar.
  • the core may consist of several layers too.
  • the tablet-coat may also consist of several layers in order to obtain sustained release, in which case the excipients mentioned above for tablets may be used. Organ specific carrier systems may also be used.
  • the compounds of the invention are preferably administered by injection, more preferably intraperitoneal injection.
  • Example 1 - synthesis of the compounds Some of the compounds of the invention were synthesised as set out below.
  • Example 8 - compound 154c augmented the drug efficiency of Enzalutamide in vitro
  • Enzalutamide is currently used as one of the most important AR-targeted therapies for the treatment of the CRPC.
  • poor response within some patients or drug resistance caused by enzalutamide makes CRPC therapy challenging.
  • compound 154c could synergize with Enzalutamide to treat CRPC.
  • LNCaP cells transfected with AR reporter were treated with different doses of compound 154c or Enzalutamide (ENZ) in the presence of 1 nM R1881 for 24 hrs. The results are shown in Figure 8A.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (I) ou un solvate, un tautomère, un stéréoisomère ou un sel de ceux-ci, destinés à être utilisés en thérapie, par exemple dans le traitement du cancer. L'invention concerne également des compositions comprenant les composés de l'invention, ainsi que des méthodes de traitement du cancer à l'aide des composés de l'invention.
PCT/EP2022/067743 2021-06-28 2022-06-28 Dérivés de bufaline utiles en thérapie WO2023275052A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN2021102780 2021-06-28
CNPCT/CN2021/102780 2021-06-28
GBGB2110150.6A GB202110150D0 (en) 2021-07-14 2021-07-14 Compounds useful in therapy
GB2110150.6 2021-07-14

Publications (1)

Publication Number Publication Date
WO2023275052A1 true WO2023275052A1 (fr) 2023-01-05

Family

ID=82492867

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2022/067743 WO2023275052A1 (fr) 2021-06-28 2022-06-28 Dérivés de bufaline utiles en thérapie

Country Status (1)

Country Link
WO (1) WO2023275052A1 (fr)

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
HUA ET AL., PHARMACOLOGY RESEARCH & PERSPECTIVES, vol. 6, 2018
HUA ET AL., PHARMACOLOGY RESEARCH & PERSPECTIVES, vol. 6, 2018, XP002807691 *
JUN-SHAN LIU ET AL.: "ANTI-TUMOR EFFECT AND 3D-QUANTITAVIE STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS OF BUFADIENOLIDES FROM TOAD VENOM", FILOTERAPIA, vol. 134, 12 March 2019 (2019-03-12), pages 362 - 371, XP002807693 *
LIU ET AL., CHEM BIOL., vol. 21, no. 10, 23 October 2014 (2014-10-23), pages 1415
YANG ZHOU ET AL.: "DESIGN, SYNTHESIS AND ANTI-TUMOR ACTIVITIES OF CARBAMATE DERIVATIVES OF CINOBUFAGIN", STEROIDS, vol. 164, no. 108749, 13 October 2020 (2020-10-13), XP002807692 *
YOSHIAKI KAMANO ET AL: "QSAR evaluation of the Ch'an Su and related bufadienolides against the colchicine-resistant primary liver carcinoma cell line PLC/PRF/5(1)", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 45, no. 25, 5 December 2002 (2002-12-05), pages 5440 - 5447, XP002491722, ISSN: 0022-2623, [retrieved on 20021105], DOI: 10.1021/JM0202066 *
YOSHIAKI KAMANO ET AL: "Synthesis and separation of 3ß-acetoxy-)6ß-hydroxy- 14,15ß-epoxy-5ß,14ß-bufa-20,22-dienolide 16-esters", TOKYO IKA DAIGAKU KIYO [MINUTES OF TOKYO MEDICAL UNIVERSITY],, no. 4, 30 November 1977 (1977-11-30), pages 159 - 168, XP009537935, ISSN: 0385-1303 *
ZHENG ET AL., FEBS LETT., vol. 592, no. 8, April 2018 (2018-04-01), pages 1445 - 1457

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