WO2023203535A1 - DÉRIVÉS DE 4-CHROMONE EN TANT QU'INHIBITEURS DE POLYMÉRASE ɳ DESTINÉS À ÊTRE UTILISÉS DANS LE TRAITEMENT D'UN NÉOPLASME MÉTASTASIQUE RÉSISTANT AU PLATINE - Google Patents

DÉRIVÉS DE 4-CHROMONE EN TANT QU'INHIBITEURS DE POLYMÉRASE ɳ DESTINÉS À ÊTRE UTILISÉS DANS LE TRAITEMENT D'UN NÉOPLASME MÉTASTASIQUE RÉSISTANT AU PLATINE Download PDF

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Publication number
WO2023203535A1
WO2023203535A1 PCT/IB2023/054098 IB2023054098W WO2023203535A1 WO 2023203535 A1 WO2023203535 A1 WO 2023203535A1 IB 2023054098 W IB2023054098 W IB 2023054098W WO 2023203535 A1 WO2023203535 A1 WO 2023203535A1
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Prior art keywords
compounds
compound
mmol
medical use
gradient
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PCT/IB2023/054098
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English (en)
Inventor
Marco DE VIVO
Nicoletta BRINDANI
Federico MUNAFO'
Michela NIGRO
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Fondazione Istituto Italiano Di Tecnologia
Alma Mater Studiorum-Universita' Di Bolona
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Publication of WO2023203535A1 publication Critical patent/WO2023203535A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention applies to the medical field, and in particular for the treatment of tumors.
  • DNA polymerases are enzymes involved in important cellular processes such as gene expression, regulation, transcription, and DNA damage repair.
  • Y-Family Pols is an important group of enzymes capable of conducting the synthesis of translesion DNA (TLS): a biological process that involves the replication of damaged DNA, with good precision.
  • TLS translesion DNA
  • Such enzymes are capable of bypassing damaged bases, which would otherwise block the normal progression of the replication fork.
  • Each Y-family polymerase is unique and has different "preferences" for lesions to bypass and for deoxyribonucleoside triphosphate (dNTP) to be incorporated.
  • dNTP deoxyribonucleoside triphosphate
  • DNA polymerase p (Pol) is capable of bypassing UV-induced cyclobutane pyrimidine (CPD) cis-syn dimers, suppressing the mutagenic effect of UV- induced DNA damage (Yang, 2014).
  • CPD UV-induced cyclobutane pyrimidine
  • Aurintricarboxylic acid and ellagic acid known inhibitors of Pol ⁇ , show very promising nanomolar IC50 values (Dorjsuren et al., 2009), but are characterized by poor selectivity and with an unspecific action mechanism that therefore limits the use thereof mainly to biological experiments only.
  • N- benzoyl indolylbarbituric acid (ITBA) derivatives which show IC50s in the low micromolar range (Coggins et al., 2013) and act on the allosteric site of the enzyme.
  • cisplatin and the analogues thereof react with DNA bases to cross-link adjacent purines.
  • the inventors of the present patent application have surprisingly found that the compounds characterized by the general formula (I) can be employed for treating diseases or disorders represented by primary and/or metastatic neoplasms, which have developed resistance after previous treatment with chemotherapeutic compounds.
  • the present patent application describes compounds for medical use in treating diseases or disorders represented by primary and/or metastatic neoplasms, which have developed resistance after previous treatment with chemotherapeutic compounds.
  • such compounds are described for treating tumors in combination with other chemotherapeutic compounds.
  • the present patent application describes a method for treating diseases or disorders represented by primary and/or metastatic neoplasms, which have developed resistance after previous treatment with chemotherapeutic compounds comprising the administration of a pharmaceutically effective amount of a compound or formulation according to the invention. According to an even more particular aspect, such a method is carried out in association with other chemotherapeutic compounds.
  • Figure 1 shows the structure of compounds known in the art.
  • FIGS 2, 3 and 4 show Schemes 1, 2 and 3 mentioned in the present patent application, respectively.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are, independently of each other, -H, -OH, -R 7 , -x, -OR 7 , -R 7 (X)n, -NO 2 , -NH 2 , -NHR 7 , where
  • R 7 is a linear or branched C 1-4 alkyl optionally substituted with one or more groups selected from -OH, -X, -NO 2 , -NH 2 , -NHR 8 , where R 8 is a linear or branched C 1-4 alkyl, or where
  • A is preferably a single bond or, alternatively, is one of:
  • the described compounds have the following formula: wherein
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are, independently of each other, -H, -OH, -R 7 , -X, -OR 7 , —R 7 (X) n , -NO 2 , -NH2, -NHR 7 , wherein
  • R 7 is a linear or branched C 1-4 alkyl optionally substituted with one or more groups selected from -OH, -X, -NO 2 , -NH 2 , -NHR 8 , where R 8 is a linear or branched C 1-4 alkyl, or wherein
  • R 1 , R 2 , R 3 , R 4 and R 7 are as described above and R 5 and R 6 form, together with the benzene ring to which they are bound, a (2,2- difluorobenzo[d][1,3]dioxol cycle: , and
  • A is preferably a single bond or alternative
  • the compounds above are described for medical use in the treatment of diseases or disorders associated with increased activity and/or expression of DNA polymerase ⁇ .
  • Objects of the present invention are also prodrugs of the above compounds capable of increasing the bioavailability thereof in the body, such as boronates and hyaluronic acid polymers.
  • neoplasms such as neoplasms. More in particular, such neoplasms are represented by primary and/or metastatic neoplasms.
  • such a medical use is described for treating primary and/or metastatic neoplasms, which have developed resistance after a prior treatment with chemotherapeutic compounds.
  • chemotherapeutics are represented by nucleoside analogs or alkylating agents derived from platinum, e.g., Cis platinum or analog compounds.
  • neoplasms are represented by: ovarian cancer, breast cancer, pancreatic cancer, lung cancer, gastric adenocarcinoma, mucosa-derived squamous cell carcinoma of the neck.
  • the compounds of the present patent application are described for medical use in association with chemotherapeutic compounds.
  • chemotherapeutic compounds are represented by nucleoside analogs or alkylating agents derived from platinum, such as Cis platinum or analog compounds, such as carboplatin or oxaliplatin.
  • the compounds of the present patent application are described for medical use in association with other compounds having another mechanism of action, possibly in association with or as an alternative to radiotherapy.
  • the compounds of the present patent application are described for medical use so as to avoid the occurrence of treatment resistance phenomena conducted against a primary and/or metastatic neoplasia.
  • association means a not necessarily simultaneous therapeutic association, where the simultaneous association represents a preferred aspect.
  • R 1 , R 2 , R 4 , R 5 and R 6 are, independently of each other, -H, -R 7 , -X, -OH, -OR 7 , -R 7 (X)n, -NO 2 , -NH 2 , -NHR 7 , wherein
  • R 7 is a linear or branched C 1-4 alkyl optionally substituted with one or more groups selected from -OH, -X, -NO 2 , -NH 2 , -NHR 8 , where R 8 is a linear or branched C 1-4 alkyl,
  • R 3 is H
  • A is a single bond, provided that the compounds of formula (I) do not include:
  • the compounds of formula (I) are represented by the following compounds:
  • formulations comprising the compounds of the invention.
  • Such formulations can be administered orally, nasally, subcutaneously or intramuscularly.
  • such formulations comprise one or more pharmaceutically acceptable excipients being suitable for the route of administration.
  • formulations of the invention are also described for the medical use and uses reported above.
  • the present patent application describes a method for treating diseases or disorders associated with increased activity and/or expression of DNA polymerase p comprising administering a pharmaceutically effective amount of a compound or formulation according to the invention.
  • neoplasms are represented by primary and/or metastatic neoplasms.
  • such a method for treating primary and/or metastatic neoplasms, which have developed resistance after a prior treatment with chemotherapeutic compounds.
  • chemotherapeutics are represented by nucleoside analogs or alkylating agents derived from platinum, e.g., Cis platinum or analog compounds.
  • neoplasms are represented by: ovarian cancer, breast cancer, pancreatic cancer, lung cancer, gastric adenocarcinoma, mucosa-derived squamous cell carcinoma of the
  • the treatment method is described in association with chemotherapeutic compounds.
  • chemotherapeutic compounds are represented by nucleoside analogs or alkylating agents derived from platinum, such as Cis platinum or analog compounds.
  • the treatment method of the present patent application is described in association with other compounds having a different mechanism of action, possibly in association with or as an alternative to radiotherapy.
  • the method of the present patent application is described to avoid the occurrence of treatment resistance phenomena conducted against a primary and/or metastatic neoplasia.
  • association means a not necessarily simultaneous therapeutic association, where the simultaneous association represents a preferred aspect.
  • the intermediates la and lb can be synthesized according to the procedure shown in European Journal of Medicinal Chemistry 180 (2019) 350-366.
  • the intermediate 1c can be synthesized according to the procedure shown in prior art document WO 2017/132928 Al.
  • the anhydrous solvents were purchased from Sigma-Aldrich.
  • Spectra were acquired at 300 K, using deuterated dimethylsulfoxide (DMSO-d 6 ) or deuterated chloroform (CDCI 3 ) as solvents.
  • DMSO-d 6 deuterated dimethylsulfoxide
  • CDCI 3 deuterated chloroform
  • UPLC/MS analyses were run on a Waters Acquity UPLC/MS system consisting of a SQD (single quadrupole detector) mass spectrometer equipped with an electrospray ionization interface and a photodiode array detector. The PDA range was 210-400 nm. The analyses were performed on an ACQUITY UPLC BEH C18 column (100x2.1 mmID, 1.7 pm particle size) with a VanGuard BEH C18 pre-column (5x2.1 mmID, 1.7 pm particle size).
  • the mobile phase was 10 mM NH 4 OAC in H 2 O at pH 5 adjusted with CH 3 COOH (A) and 10 M NH 4 O C in CH 3 CN-H2O (95:5) at pH 5.0.
  • Two types of gradients were applied depending on the analysis, gradient 1 (5% to 100% mobile phase B in 3 min) or gradient 2 (50% to 100% mobile phase B in 3 min).
  • Electrospray ionization in positive and negative mode was applied.
  • ESI was applied in positive and negative mode. All tested compounds showed ⁇ 95% purity by UPLC/MS analysis.
  • the intermediate 3bb was prepared according to general procedure A described above using: ketone lb (200 mg, 1.00 mmol), 2,2- Difluoro-1,3-benzodioxol-5-carboxaldehyde 2b (210 g, 1.1 mmol), KOH (1680 mg, 20 mmol) in anhydrous MeOH (8.5 mL). The crude product was purified by trituration with EtOH (3 mL) to give the title intermediate 3bb (200 mg, 55% yield).
  • the title compound 5df was prepared following general procedure D using: compound 4df (181 mg, 0.49 mmol), Pd/C (40 mg), Et 3 SiH (0.5 mL, 2.35 mmol) in a 1:1 mixture of MeOH/DCM (10 mL). Purification by silica (elution by gradient from 100 to 0 cyclohexane/EtOAc) gave the pure intermediate 5df (69 mg, 50% yield).
  • Step 4 Synthesis of 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-(3- hydroxypropoxy)-4H-chromen-4-one (compound 9, Scheme 2).
  • Compound 9 was prepared following general procedure D using: compound 8 (365 mg, 0.58 mmol), Pd/C (72 mg), Et 3 SiH (2.2 mL, 10.5 mmol) in a 1:1 mixture of MeOH/DCM (14 mL). Purification by silica (elution by gradient from 100 to 40/60 Cyclohexane/EtOAc) gave the pure compound 9 (33 mg, 15% yield in two steps).
  • HATU (170 mg, 0.43 mmol) and DIPEA (0.23 mL, 1.3 mmol) were sequentially added to a solution of intermediate 11 (60 mg, 0.29 mmol) in a 3:1 mixture of DMF/DCM (4 mL) under argon.
  • the reaction mixture was stirred at room temperature for 15 minutes, after that 3,4-dimethoxyaniline (44 mg, 0.29 mmol) was added and the reaction mixture was stirred for another 4 hours until complete consumption of the starting material.
  • Compound 13 was prepared following general procedure C, method A using: intermediate 12 (45 mg, 0.13 mmol), BBrs (1 M in DCM) (0.59 mL, 0.59 mmol) in anhydrous CH2CI2 (2.6 mL). The crude product was purified by silica (elution by gradient from 100:0 to 98:2 DCM/MeOH) to give product 13 (0.016 g, 40% yield).
  • Pol ⁇ activity was assessed by quantification of the final product of DNA synthesized with the enzyme in the presence of all four dNTPs/nucleotides.
  • the double strand of DNA used in the reaction was created by annealing an IRD700-labeled primer to a template strand.
  • a mixture of DNA template and Pol ⁇ was placed on ice in an assay buffer solution and then added in test tubes containing the inhibitors or DMSO (as vehicle; the final concentration in the assay is 1%).
  • the reaction was started with the addition of 5 mM Mg 2+ and immediately transferred to 37°C. After 60 minutes of incubation, the reaction was stopped with the addition of 5X loading buffer for the sample and incubation for 5 minutes at 70°C.
  • the Pol ⁇ extension products were then separated by denaturing electrophoresis (15% polyacrylamide/tbe/urea gel; BioRad) and scanned using the ChemiDoc imaging system (BioRad Laboratories).
  • Compound 9 was evaluated for the inherent antiproliferative activity thereof, individually and together with cisplatin on the cancer cell lines A549, A375 and OVCAR3.
  • the antiproliferative activity of compound 9 was evaluated using the MTT cell viability assay.
  • the cells were seeded at a density of 5000 cells/well (A549), 3000 cells/well (A375) and 10000 cells/well (OVCAR3). After 24 hours, the cells were first treated with Cisplatin (0.4-50 ⁇ M) alone and compound 9 (0.046-100 ⁇ M), then with Cisplatin (0.4-50 ⁇ M) with compound 9 at 50 ⁇ M, 75 ⁇ M and 100 ⁇ M for 48 hours.
  • the MTT solution was added to a final concentration of 0.5 mg/ml and the cells were further incubated for 4 hours.
  • the insoluble formazan crystals were solubilized by the addition of a 10% 0.01 N SDS/HC1 solution and the absorbance measured at 570 nm (reference 690 nm) in a plate reader (Tecan Spark).
  • the inhibition curves were 8 serial dilutions in triplicate in each case, and the results were analyzed as sigmoidal dose-response curves using GraphPad Prism software. The values are reported as meaniSD of three experiments. a The concentration of compound 9 is 100 ⁇ M b The concentration of compound 9 is 50 ⁇ M c The concentration of compound 9 is 75 ⁇ M
  • the compounds described have been shown to be very active in inhibiting human polymerase eta (Pol ⁇ ) representing a potential tool for the therapy of chemo-resistant tumors in combination with current therapies, for example comprising the use of Cis platinum.
  • the data obtained show the effectiveness in inhibiting the proliferation of cancer cells and the low cell toxicity.
  • the main structure and substructures define scaffolds which allow a good chemical diversity, allowing many compounds with similar structure to be investigated.
  • the compounds described are referred to as small molecules, thus being molecules of small size capable of being easily synthesized.

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

Abstract

La présente invention concerne des composés dérivés de 4-chromone de formule générale (I) et leur utilisation médicale en tant qu'agents anticancéreux.
PCT/IB2023/054098 2022-04-22 2023-04-21 DÉRIVÉS DE 4-CHROMONE EN TANT QU'INHIBITEURS DE POLYMÉRASE ɳ DESTINÉS À ÊTRE UTILISÉS DANS LE TRAITEMENT D'UN NÉOPLASME MÉTASTASIQUE RÉSISTANT AU PLATINE WO2023203535A1 (fr)

Applications Claiming Priority (2)

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IT102022000007988 2022-04-22
IT102022000007988A IT202200007988A1 (it) 2022-04-22 2022-04-22 Derivati del 4-cromone come inibitori della polimerasi ¿ come agenti antitumorali e metodo per la loro preparazione

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006076863A1 (fr) * 2005-01-20 2006-07-27 Shanghai Gloriayx Biopharmaceuticals Co., Ltd Composition pharmaceutique synergique destinee a inhiber une tumeur
WO2011099978A1 (fr) * 2010-02-12 2011-08-18 N30 Pharmaceuticals, Llc Inhibiteurs de la s-nitrosoglutathione réductase à base de chromone
WO2019008537A1 (fr) * 2017-07-05 2019-01-10 Vera Salus Ricerca S.R.L. Composés médicaux

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009008906A2 (fr) 2007-02-06 2009-01-15 The Trustees Of The University Of Pennsylvania Composés thérapeutiques pour un blocage de la synthèse d'adn de poxvirus
SI3411036T1 (sl) 2016-02-04 2022-03-31 Pharmaengine, Inc. 3,5-disubstituirani pirazoli, uporabni kot kontrolne točke inhibitorjev kinaze 1 (CHK1), ter njihovi pripravki in uporaba

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006076863A1 (fr) * 2005-01-20 2006-07-27 Shanghai Gloriayx Biopharmaceuticals Co., Ltd Composition pharmaceutique synergique destinee a inhiber une tumeur
WO2011099978A1 (fr) * 2010-02-12 2011-08-18 N30 Pharmaceuticals, Llc Inhibiteurs de la s-nitrosoglutathione réductase à base de chromone
WO2019008537A1 (fr) * 2017-07-05 2019-01-10 Vera Salus Ricerca S.R.L. Composés médicaux

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CATANZARO DANIELA ET AL: "Cell Cycle Control by Natural Phenols in Cisplatin-Resistant Cell Lines", NATURAL PRODUCT COMMUNICATIONS, vol. 9, no. 10, 1 October 2014 (2014-10-01), US, XP093003570, ISSN: 1934-578X, DOI: 10.1177/1934578X1400901015 *
LUO HAITAO ET AL: "Kaempferol enhances cisplatin's effect on ovarian cancer cells through promoting apoptosis caused by down regulation of cMyc", CANCER CELL INTERNATIONAL, BIOMED CENTRAL, LONDON, GB, vol. 10, no. 1, 11 May 2010 (2010-05-11), pages 16, XP021077239, ISSN: 1475-2867, DOI: 10.1186/1475-2867-10-16 *
PAPACHRISTOU FOTINI ET AL: "Differential effects of cisplatin combined with the flavonoid apigenin on HepG2, Hep3B, and Huh7 liver cancer cell lines", MUTATION RESEARCH. GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS, vol. 866, 1 June 2021 (2021-06-01), NL, pages 503352, XP093003646, ISSN: 1383-5718, DOI: 10.1016/j.mrgentox.2021.503352 *
SUN LEI ET AL: "Synthesis, characterization and antioxidant activity of quercetin derivatives", SYNTHETIC COMMUNICATIONS, vol. 51, no. 19, 23 August 2021 (2021-08-23), US, pages 2944 - 2953, XP055943921, ISSN: 0039-7911, DOI: 10.1080/00397911.2021.1942059 *
ZHANG YU ET AL: "Flavonoids from Chinese bayberry leaves induced apoptosis and G1 cell cycle arrest via Erk pathway in ovarian cancer cells", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 147, 1 March 2018 (2018-03-01), AMSTERDAM, NL, pages 218 - 226, XP093003652, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2018.01.084 *

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