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WO2021258173A1 - Ligands binucléants phénoliques, composés métalliques binucléaires, composition médico-vétérinaire, procédés de synthèse de ligands binucléants, procédé de synthèse de composés binucléaires, méthode de traitement de nélplasies et de maladies fongiques, et utilisation - Google Patents

Ligands binucléants phénoliques, composés métalliques binucléaires, composition médico-vétérinaire, procédés de synthèse de ligands binucléants, procédé de synthèse de composés binucléaires, méthode de traitement de nélplasies et de maladies fongiques, et utilisation Download PDF

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Publication number
WO2021258173A1
WO2021258173A1 PCT/BR2021/050266 BR2021050266W WO2021258173A1 WO 2021258173 A1 WO2021258173 A1 WO 2021258173A1 BR 2021050266 W BR2021050266 W BR 2021050266W WO 2021258173 A1 WO2021258173 A1 WO 2021258173A1
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Prior art keywords
copper
complexes
compounds
binuclear
treatment
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Portuguese (pt)
Inventor
Nicolás ADRIÁN REY
Marcos Dias Pereira
Jesica Paola RADA ARIAS
Rafaela DOS SANTOS MORAES FRANCISCO
Zeinab GHASEMISHAHRESTANI
André Luis SOUZA DOS SANTOS
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FACULDADES CATOLICAS
Universidade Federal do Rio de Janeiro UFRJ
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FACULDADES CATOLICAS
Universidade Federal do Rio de Janeiro UFRJ
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86—Hydrazides; Thio or imino analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/08—Copper compounds

Definitions

  • BINUCLEANT PHENOLIC BINDERS BINUCLEAR METALLIC COMPOUNDS, MEDICAL-VETERINARY COMPOSITION, BINUCLEANT BINDERS SYNTHESIS PROCESS, BINUCLEAR COMPOUNDS SYNTHESIS PROCESS, METHOD OF TREATMENT OF NEOPLES AND PHUGAL DISEASES
  • the present invention relates to new metallodrugs containing a copper(II) binuclear coordination center and the non-symmetrical binding ligands 2-hydroxy-3- ⁇ [(2-hydroxybenzyl)(2-pyridylmethyl)amino] -methyl ⁇ -5-methylbenzaldehyde isonicotinoyl hydrazone (H 3 L1 ) or 2-hydroxy-3- ⁇ bis[(2-pyridylmethyl)amino]-methyl ⁇ -5-methylbenzaldehyde isonicotinoyl hydrazone (H 2 L2) for treatment of neoplasms involving solid tumors and/or leukemias, as well as diseases of an opportunistic nature, such as diseases caused by pathogenic fungi.
  • the present invention falls within the field of application of chemistry, pharmacy, medicine, biology and biochemistry, more specifically in the area of drug preparations containing active ingredients.
  • the pharmaceutical composition described in this document deals with a group of macrophage inhibiting agents, among which one stands out. copper chelate.
  • the Brazilian reference deals with cancer therapy (breast, lung and/or prostate) through the adjuvant use of copper chelates, but does not propose the use of metallo-drugs based on the metal itself.
  • the intrinsic mechanism behind the antitumor action! is proposed to be improving the immune response or increasing the activity of an immune cell in a patient with a disease or condition.
  • the compounds have been proposed as antitumor agents with preferential therapeutic use for the treatment of solid and blood tumors (eg leukemia).
  • the tested copper mononuclear complex namely [Gu(4,7-dimethyl-1 ,10-phenanthroline)(glycinate)]NO 3 has a slightly higher activity than cisplatin, but lower than mitomycin, a reference drug used in cancer therapy
  • the tests with experimental animals showed that only at higher doses of the compound was po It is possible to verify an increase in the survival of animals affected by the inoculation of lymphoid leukemia cells.
  • krusei which are extremely important in situations of neoplasms and advanced tumors, and still others, such as Aspergillus spp, Cryptococcus spp, Scedosporium spp, Fusarium spp, Zygomycetes spp and Trichosporon spp, which are frequently found in immunocompromised patients due to chemotherapy.
  • compositions have antiseptic properties, being active against gram-positive and gram-negative bacteria, fungi, viruses and spores, and may be applied over a wide range of temperatures.
  • Methods of using the compositions of the present invention in the treatment and prevention of diseases caused by a variety of pathogens are described.
  • the invention does not address their effectiveness against cancer cells and still makes reference to complexes mononuclear cells whose antimicrobial activity depends on association with other molecules.
  • the present invention provides, in this way, new metallodrugs, synthesis process, method of treatment, use in the manufacture of drugs for the treatment of tumors and fungal diseases in humans and other mammals, as well as pharmaceutical and veterinary composition, based on binuclear copper(II) complexes, non-symmetric, with cytotoxic effect on cell lines of prostate, breast and lung cancer, which also show antifungal activity and low toxicity to healthy cells.
  • a first mode of invention is the development of new technological alternatives, aimed at new compounds/binuclear copper complexes with antitumor activity, with potentially great impact on current cancer chemotherapy, whose arsenal of substances could be replaced or even optionally combined with the new compounds.
  • biotechnological potential presented by these new complexes is not limited to antitumor activity, as they were also shown to be active against pathogenic fungi (eg Candida aibicans, Candida parapsiiosis, Candida tropicaiis and Candida krusei), showing great versatility of application for use in cancer therapy and opportunistic pathologies caused by fungi.
  • pathogenic fungi eg Candida aibicans, Candida parapsiiosis, Candida tropicaiis and Candida krusei
  • the present invention therefore provides, in this first modality, four metallodrugs derived from two new non-symmetric hydrazonic precursors, namely: 2-hydroxy-3- ⁇ [(2-hydroxybenzyl)(2-pyridylmethyl)amino]- methyl ⁇ -5-methylbenzaldehyde isonicotinoyl hydrazone (H 3 L1), according to the structural formula below and illustrated in figure 1 , and 2-hydroxy-3- ⁇ bis[(2-pyridylmethyl)amino]-methyl ⁇ -5-methylbenzaldehyde isonicotinoyl hydrazone (H 2 L2), according to the structural formula below and illustrated in Figure 1 , belonging to the broad group of binucleating ligands, that is, capable of forming binuclear complexes by providing coordination environments suitable to accommodate two metallic centers in close proximity, such that a cooperative effect between them is possible, and even expected.
  • Binuclear copper complexes generated from H 3 L1 and H 2 L2, both those with an exogenous hydroxide bridge (postulated as the active form) and those with exogenous acetate bridges (pro-drugs that would generate the biologically active form by reaction of hydrolysis in the organism), have unsaturated copper(II) centers or contain labile ligands, such as the water molecule, which enables their interaction with biological macromolecules such as, for example, DNA, RNA and/or proteins.
  • a fifth and last modality would correspond to the use of synthesized compounds in the manufacture of drugs aimed at treating neopiasias. Drugs that present, concomitantly, little toxicity to healthy human cells, high efficacy against malignant cell lines of prostate, breast and lung, in addition to an antifungal effect.
  • FIG. 4 Survival assay of cells from human tumor lines MCF-7, A549 and PC-3 treated for 24 h in the presence of complexes 1 (A) and 3 (B); human non-tumor lineage, MGF10A, treated with complexes 1 and 3 (C) and; cell lines MCF-7, A549, PC-3 and MCF10A submitted to treatment with the antitumor metallo drug cisplatin, used as reference.
  • FIG. 9 Analysis of cell cycle inhibition (cell proliferation) during treatment with complexes 1 and 3 and the anti-tumor metallodrug cisplatin in MCF-7 (A and C) and A549 (B and C) cancer cells. Representative histograms (C) of the cell population distributed throughout the cell cycle, corresponding to the mean ⁇ standard error of 3 independent experiments.
  • - Figure 11 Synthetic route used in the preparation of binuclear copper(ll) 1 and 3 complexes, including the synthesis conditions and yields obtained.
  • the steps highlighted in the gray box correspond to the intrinsic processes related to the synthesis of new compounds (H 3 L1 ligand and complexes 1 and 3), and differentiate this synthetic route from others existing in the literature.
  • - Figure 12 Synthetic route used in the preparation of binuclear copper(ll) 2 and 4 complexes, including the synthesis conditions and yields obtained.
  • the steps highlighted in the gray box correspond to the intrinsic processes related to the synthesis of new compounds (H 2 L2 ligand and complexes 2 and 4), and differentiate this synthetic route from others existing in the literature.
  • the present invention therefore describes "Binuclear copper(ii) complexes with potent antitumor activity, composition, chemical synthesis process and use in the preparation of drugs and in the treatment of cancer and infections by pathogenic fungi", which seek meet the growing demand for new treatments for neoplasms, both those involving solid tumors and leukemia, as well as fungal diseases.
  • binuclear copper(ll) compounds different from those existing in the prior art, as they present changes in the chemical structure, toxic activity against human cancer cells and, at the same time, less toxicity to non- carcinogens in the body. Thus, they show greater efficacy and fewer side effects, offering patients undergoing chemotherapy for cancer a better quality of life and survival.
  • the binuclear copper coordination compounds! i) and preferred non-symmetric linkers of the present invention are: 2-hydroxy-3- ⁇ [(2-hydroxybenzyl)(2-pyridylmethyl)amino]-methyl ⁇ -5-methylbenzaldehyde isonicotinoyl hydrazone (H 3 L 1 ) as per formula structural below and illustrated in figure 1 and 2-hydroxy-3- ⁇ bis[(2-pyridylmethyl)amino]-methyl ⁇ -5-methylbenzaldehyde isonicotinoyl hydrazone (H 2 L2) as structural formula below and illustrated in figure 1 , as well as their respective binuclear copper(II) complexes containing exogenous acetate-type bridges: compound 1 and compound 2 according to the structural formulas below and shown in figure 2 or hydrox: compound 3 and compound 4 according to the structural formulas below and illustrated in figure 3 .
  • Figure 5 graphically represents the induction of the production of reactive oxygen species (or ROS), a critical factor for the induction of the process endogenous apoptosis in cancer cells, during treatment with the new complexes 1 and 3, and with the chemotherapeutic used as control of the experiment, which is also applied in cancer therapy, doxorubicin.
  • ROS reactive oxygen species
  • Figure 5 shows the representative results of a series of at least three independent experiments performed on MCF-7 (A, B and C) and A549 (D, E and F) lines and represents the mean ⁇ standard error of the mean.
  • the symbols (#) and ( *** ) represent a statistical difference in relation to the control treatments.
  • Figure 6 graphically represents the alteration/loss of the mitochondrial membrane potential ( ⁇ m), target of reactive oxygen species and the first step in inducing the endogenous process of apoptosis, during the treatment of cancer cells with the new complexes copper 1 and 3, and the metallochemotherapeutic used in cancer therapy, cisplatin.
  • This figure presents a graphical representation of the level of mitochondrial membrane potential, expressed as arbitrary fluorescence units in the MCF-7 ( Figure 6 ⁇ and C) and A549 ( Figure 6E and G) lines.
  • Figure 7 graphically represents the activation of caspase enzymes 8 (Figure 7A and C) and 9 ( Figure 7B and D), which are key in the activation of the apoptosis process, during cell treatment of cancer with complexes 1 and 3 and the anti-tumor chemotherapy cisplatin.
  • the results obtained are expressed as mean ⁇ standard error of the mean of at least three independent experiments and are shown as a relationship between the activity of cells treated with the novel complexes 1 and 3 or cisplatin and untreated cells.
  • the symbol ( * ) represents statistical difference from cells not treated with copper or cisplatin compounds.
  • Figure 8 graphically represents the induction of the apoptosis process through the analysis of DNA breakage / fragmentation of cancer cells by the TUNEL technique [Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling] during treatment with the new complexes 1 and 3, and the anti-tumor chemotherapy cisplatin.
  • TUNEL Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling
  • a and B representative TUNEL histograms can be seen showing the percentage of cells in apoptosis after treatment with cisplatin or copper(ll) complexes in the A549 (A) and MCF-7 (B) lines, respectively .
  • Figure 8C represents the mean ⁇ standard error of the mean of at least three independent experiments with A549 and MCF-7 cells treated with cisplatin or copper(II) complexes.
  • the symbol ( * ) represents statistical difference in relation to cells not treated with copper or cisplatin compounds.
  • Figure 9 represents the analysis of cell cycle inhibition (cell proliferation) during treatment with complexes 1 and 3 in A549 and MCF-7 cancer cells.
  • Figure 9 A and B
  • Figure 10 graphically represents the toxicity of complex 1 and the chemotherapeutic used in cancer therapy, cisplatin in an alternative animal model, Galeria mellonei ⁇ a.
  • the experiment was performed by injecting 1 or cisplatin, both at the same concentrations (1.0 mg/mL), directly into the hemocele of G. mellonei ⁇ a larvae.
  • the complex did not show toxicity and did not interfere with the developmental stages (larva, pupa and moth) of the alternative animal model used in the study, showing a significantly different profile from that observed for treatment with the chemotherapy used in cancer treatment, cisplatin.
  • binuclear complexes are the result of a very complex preparatory route (Figure 11), developed in the search for new agents with greater effectiveness to eliminate or reduce the proliferation of tumor cells.
  • Figure 11 some works on binuclear copper compounds with a diverse range of applications have already been published in international scientific journals. However, in all of them, the structures presented are different from the ones we are proposing in this study. [041] From these works, we will highlight two references, discussed in more depth here, thus complementing the background of the invention. Although they may appear similar, these documents are essentially different in terms of the structure of the ligands used, effectiveness against human cancer cells, and selectivity.
  • the compounds of the present invention have an advantage, which is characterized by the six-membered 4-pyridine ring, whose presence results from the use of isomyazide, known as an anti-tuberculosis agent, as a starting hydrazide in the preparation of new ligands.
  • Proteomic data obtained by the group of the present study demonstrate that the direct activation of apoptosis occurs through the apoptosis-inducing factor (AIF), through the down-regulation of the RAS-ERK pathway, [049]
  • AIF apoptosis-inducing factor
  • casein kinase, calpain, well as the catalytic and regulatory subunits of the proteosome they also promote the activation of DNA degradation pathways.
  • the down-regulation of the glycolytic enzyme pyruvate kinase indicates a down-regulation of glycolysis, forcing tumor cells to carry out respiratory metabolism through oxidative phosphorylation.
  • This non-symmetric linker was prepared from the synthetic intermediate hbpamff, that is, from the compound 2-hydroxy-3- ⁇ [(2-hydroxybenzyl)(2-pyridylmethyl)amino]-methyl ⁇ -5-methylbenzaldehyde.
  • a methanolic solution (5 ml) of the isonicotinic acid hydrazide, ssonsazide (0.138 g; 1 mmol) was dropped, under constant stirring, onto a solution of hbpamff (0.333 g, 0.9 mmol) in 10 ml of a mixture 1: 1 MeOH:Et 2 0, previously prepared in a 50 ml flask. The mixture was refluxed for 2 hours.
  • This linker was prepared from the synthetic intermediate bpmamff, ie, 2-hydroxy-3- ⁇ bis[(2-pyridylmethyl)amino]-methyl ⁇ -5-methylbenzaldehyde. Isoniazid, previously dissolved in 5 ml of a mixture (v/v) 1:1 dichloromethane/MeOH (0.277 g, 2 mmol) was slowly dropped onto a solution containing bpmamff (0.703 g, 2 mmol) dissolved in 10 ml of the same mixing using ultrasound. The solution (50 ml flask) was then refluxed for 3 hours. Over the course of the reaction, the initially bright yellow mixture turned orange. The solvent was subsequently removed under reduced pressure and the oil obtained, left to stand in 1:1 MeCN/MeOH. After two weeks, light yellow microcrystalline needles were isolated.
  • the non-symmetrical binuclear copper(li) complexes comprised in the present invention can be synthesized by the following process steps: 1. dissolution of an amount of the binucleating ligand, H 3 L1 or H 2 L2, in a pure organic solvent or mixture of solvents; 2. Slow addition of 2 equivalents of copper(II) salt, previously dissolved in methanol or a mixture of solvents.
  • the counterion present in this salt can be coordinating (such as, for example, acetate, propionate or, more generally, a carboxylate anion capable of generating a prodrug) or not (as well as perchlorate, whale, among other capable counterions to generate a final drug in its active form);
  • reaction mixture is then stirred, under moderate heating, for a period that may vary from 10 minutes to 24 hours - moderate heating is understood here as the use of a temperature lower than the boiling point of the solvent or mixture of solvents used;
  • the solid obtained is filtered, washed with ice-cold organic solvent and dried in a vacuum.
  • a greater mass of product and, eventually, crystals suitable for the process of structural determination by X-ray diffraction can be obtained by the slow evaporation of the mother liquor.
  • Example 3 COMPLEXES synthesized using ACETATE
  • the solution was filtered through paper and transferred to a 50 mL beaker, so that the solvent was completely evaporated by heating to 60 °C.
  • the resulting solid was washed with ice-cold methanol, filtered on a Buchner funnel and stored under vacuum in a desiccator containing silica.
  • the present study deals with the effects caused by a series of novel binuclear copper(ll) complexes ( Figures 2 and 3) in breast (MCF-7), lung (A549) and prostate (PC) cancer cell lines -3).
  • the study carried out analyzed: (i) the survival (through the MTT assay) of the cancer cells; (ii) the intracellular production of reactive oxygen species (ROS) (through the DCFH2-DA probe assay); (iii) the mitochondrial membrane potential (via the assay with the fluorescent probe JC-1); (iv) the enzymatic activity for caspases 8 and 9; (v) DNA fragmentation (through the TUNNEL technique [Gravrieli et al, 1992 - Gavrieli Y, Sberman Y, Ben-Sasson SA, Identification of programmed death in situ via specific iabeling of nuciear DNA fragmentation.
  • Cisplatin was used as a chemotherapy control because it is a drug widely used in the clinic and also because it is, until today, the reference for coordination compounds with antitumor activity.
  • the cytotoxicity test was performed by the MTT method, which after metabolized by living cells is converted into purple formazan crystals. Cell survival was calculated as the percentage of living cells relative to cells not treated with any of the compounds.
  • caspase 8 and 9 activities showed that only the activity of caspase 9 enzyme was altered, having its levels increased in cell lines treated with complexes 1 and 3. The result clearly indicates that complexes 1 and 3 activate the intrinsic pathway that triggers the apoptosis process in human cancer cells ( Figure 7).
  • the metallodrugs of the present invention can constitute pharmaceutical compositions, being used alone or in combination with each other, adding them to pharmaceutically acceptable vehicles and excipients.
  • Cancer therapy presents high treatment difficulty, due to its different origins, and may present an intrinsic and/or acquired resistance to available treatments. Furthermore, the excessive use of the same drug/medication can cause serious side effects to the patient.
  • the metallodrugs described in the present invention can be combined/associated with any other drugs used in the treatment of neoplasms and related diseases.
  • anti-tumor drugs such as copper chelators and chemotherapy drugs, particularly those based on platinum, such as cisplatin [c/s-diaminodichloroplatinum(ll)].
  • Another possibility of combining the metallodrugs of the present invention comprises the one that can be performed with other copper complexes, however mononuclear. Different from those presented in this invention, the compounds may demonstrate synergistic effects during treatment.
  • Treatment includes administering an amount of the complexes alone or in combination that is effective to alleviate, alter, remedy, ameliorate or affect the disease, disease symptoms or diseases resulting from opportunistic infections caused by pathogenic fungi, in order to prevent the aggravation of the main disease, cancer.
  • the necessary dosages of the compounds and their compositions comprising the isolated complexes or in combination may vary in each case, being different for each individual treated.
  • the definition of the ideal dosage will be determined by balancing the therapeutic benefit and any risk or side effects of the treatments described herein.
  • the in vivo administration of these metallopharmaceuticals can be carried out in continuous dose or even intermittently (for example, in divided doses at appropriate intervals), throughout the course of treatment.
  • the most effective administration protocols of chemotherapeutics used in the therapy of various types of cancer are well known to those skilled in the art and will vary with the formulation used for the therapy, the purpose of therapy, the target cell and the subject to be treated.
  • An adequate dose of a platinum-based therapy may be a standard dose; a standard dosage of cisplatin for the treatment of testicular cancer is 20 mg/m 2 intravenously (IV) daily for 1 to 5 consecutive days every 3 weeks for 3-4 cycles of therapy when used in combination therapy; on the other hand, a standard dosage of cisplatin for the treatment of advanced ovarian carcinoma ranges from 75 to 100 mg/m 2 IV once every 3-4 weeks for 6 cycles when cisplatin is used in combination therapy. For the treatment of advanced bladder cancer, a standard dosage of cisplatin is 70 to 100 mg/m 2 IV once every 3-4 weeks for 4 cycles when cisplatin is used in combination therapy.
  • a standard dosage for the treatment of recurrent or advanced head and neck cancer is 80 to 120 mg/m 2 IV once every 3 weeks or 20 to 100 mg/m 2 IV when used in combination chemotherapy regimens, with frequency of administration depending on the specific regime employed.
  • a standard dosage of cisplatin for the treatment of cervical cancer is 40 mg/m 2 given. weekly for 6 weeks when combined with radiotherapy or 40 to 80 mg/m 2 every 3 weeks for 3-4 cycles when given in combination with other chemotherapy agents.
  • a standard dosage of cispiatin in combination therapy is 75 to 100 mg/m 2 IV once every 3-4 weeks for 4-8 cycles, depending on the specific regimen used.
  • a standard dosage of cispiatin is 50 to 120 mg/m 2 IV once every 3-4 weeks in combination chemotherapy regimens or 10 to 50 mg/m 2 IV every 3 weeks for 2 cycles when combined with radiation.
  • a standard dosage of cispiatin is 50 to 100 mg/m 2 IV once every 3-4 weeks in single or combined chemotherapy regimens.
  • the dose of the combination between the binuclear copper complexes of the present invention and another chemotherapeutic agent, such as cispiatin, but not limited exclusively to cispiatin, should be between 20 to 120 mg/m 2 of the drug's body surface antitumor, plus 10 to 480 mg/m 2 of body surface of binuclear copper(ll) complexes in a single intravenous infusion, every 3-4 weeks for the necessary number of cycles, obviously respecting the standard protocol used in specific chemotherapy for the cancer being treated.
  • the dilution rates of the new composition will be comprised between 1 part of the antitumor drug: 0.5 - 4.0 parts of the binuclear copper complex or, alternatively, 0.5 part of the antitumor drug: 0.5 - 4.0 parts of the binuclear copper complex.
  • composition is used in the preparation of an injectable solution or pharmaceutical formulation for oral use composed of both drugs and should be administered exclusively by intravenous infusion or orally.
  • Binuclear copper(II) complexes can be given in combination with an agent or procedure to reduce any possible side effects (eg, diarrhea, nausea, and vomiting).
  • antitumor agents examples include: pemetrexed, vinorelbine, gemcitabine, vinblastine, dacarbazine, temozolomide, 5FU (5-fluorouracil), cyclophosphamide , bleomycin, etoposide, ifosfamide, paclitaxel, methotrexate, doxorubicin, adriamycin, vincristine, mitomycin, docetaxel, and combinations of the above agents. These agents can also be administered in conjunction with performing surgical procedures and/or applying radiation.

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Abstract

La présente invention concerne de nouveaux métallomédicaments contenant un centre de coordination binucléaire de cuivre (II) et les ligands binucléants non symétriques 2-hydroxy-3-{[(2-hydroxybenzyl)(2-pyridylméthyl)amino]-méthyl}-5-méthylbenzaldéhyde isonicotinoyl hydrazone (H3L1 ) ou 2-hydroxy-3-{bis[(2-pyridylméthyl)amino]-méthyl}-5-méthylbenzaldéhyde isonicotinoyl hydrazone (H2L2), appropriés pour traiter des néoplasies, y compris des tumeurs solides et/ou des leucémies, ainsi que des maladies de nature opportuniste, telles que les maladies causées par des champignons pathogènes.
PCT/BR2021/050266 2020-06-26 2021-06-21 Ligands binucléants phénoliques, composés métalliques binucléaires, composition médico-vétérinaire, procédés de synthèse de ligands binucléants, procédé de synthèse de composés binucléaires, méthode de traitement de nélplasies et de maladies fongiques, et utilisation Ceased WO2021258173A1 (fr)

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BR1020200132407 2020-06-26
BR102020013240A BR102020013240A8 (pt) 2020-06-26 2020-06-26 Ligantes binucleantes fenólicos, compostos metálicos binucleares, composição médico-veterinária, processos de síntese de ligantes binucleantes, processo de síntese de compostos binucleares, e uso

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Non-Patent Citations (3)

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Title
MORAES RAFAELA DOS SANTOS: "Síntese e caracterização de ligantes binucleantes derivados da isoniazida e seus complexos binucleares de cobre (II)", MASTER DISSERTATION, 23 February 2011 (2011-02-23), Brazil, pages 1 - 106, XP055955750 *
MORAES, R. S.: "COMPLEXOS HOMO E HETEROBINUCLEARES DE LIGANTES DERIVADOS DA ISONIAZID/X COMO POTENCIES AGENTES ANTITUMORAIS", THESIS (DUTORADO EM QUIMICA -PROGRAMA DE POS GRADUATE EM QUIMICA DA PUC-RIO), 1 January 2016 (2016-01-01), Brazil, pages 1 - 163, XP009537922, DOI: 10.17771/PUCRio.acad.33320 *
RADA ARIAS, JESICA PAOLA: "Binucleating aroylhydrazonic ligands and their dicopper(II) complexes as new classes of potential anticancer agents syntheses, chemical characterization and biological activity", PHD THESIS, 16 August 2019 (2019-08-16), Brazil, pages 1 - 316, XP009538594 *

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