• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
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    • 专利摘要:
    Ruthenium complexes for the treatment of cancer. The present invention is directed to the use of ruthenium (II) complexes for the preparation of a medicament for the treatment of cancer, especially of cancer comprising cancer stem cells. These ruthenium complexes are able to selectively metalate the guanine quadruplex, which causes an increase in the expression of the c-myc oncogene. This increase in the proportion of c-myc could promote the differentiation of cancer stem cells. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2594499A1
    申请号:ES201631426
    申请日:2016-11-10
    公开日:2016-12-20
    发明作者:Jessica RODRÍGUEZ VILLAR；José Luis Mascareñas Cid；José RODRÍGUEZ COUCEIRO；Jesús MOSQUERA MOSQUERA；Marcos Eugenio VÁZQUEZ SENTÍS；Bruno SAINZ ANDING
    申请人:Universidade de Santiago de Compostela；Universidad Autonoma de Madrid；
    IPC主号:
    专利说明:

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    β-actin expression was quantified by densitometry (lower panel). The experimental procedure was similar to that described in Figure 11.
    Figure 15. Levels of c-MYC protein expression determined by Western-blot in
    5 presence or absence of complex 5 (RuMet), complex 1 (RuCl), or complex 2 (here). Light bars correspond to c-MYC expression levels under irradiation conditions while dark bars correspond to dark conditions. The expression of c-MYC is represented as the change factor with respect to the expression in the untreated samples. Relative levels of protein with respect to levels of
    10 -actin expression was quantified by densitometry.
    Figure 16. Feasibility test of different cell lines treated with complex 5 (RuMet). The Vero and HeLa cell lines were incubated for 3 days with 100 µM complex 5. Cell viability was analyzed using a standard MTT assay. The
    15 light gray bars indicate the experimental values under irradiation conditions and the black bars the values determined in the dark. The values represent the factor of change with respect to untreated cells in the dark (control) and are the average of three different experiments each performed in triplicate. Error bars represent the standard deviation.
    20 Figure 17. Effects of complex 2 (RuH2O) on pancreatic ductal adenocarcinoma cells (PDAC). (A) Complex 2 (RuH2O) increases c-MYC expression in PDAC cells, as determined by Western blotting, in PDACs treated with different concentrations of complex 2 and during different times. (B) Complex 2 (RuH2O)
    25 reduces the ability to auto-renew PDAC cancer stem cells. The upper panel shows the experimental design The lower panel shows the quantification of the number of spheres / mL determined on day 7 after sowing by treatment group. Detailed Description of the Invention
    Researchers have found that the ruthenium complexes of formula (I) in which X is Cl are capable of selectively metalizing guanosine monophosphate (GMP) by prior transformation into the active aquo complex (X = H2O). This reaction can be done.
    35 accelerate by irradiation with light.
    7
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    The term "alkenyl" refers to a linear or branched hydrocarbon chain radical containing from 2 to 6 ("C2-C6 alkenyl"), more preferably from 2 to 3 ("C2-C3 alkenyl"), carbon atoms, which contains at least one double bond and joins the
    5 rest of the molecule through a single bond. Illustrative examples include ethenyl, propenyl, allyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
    The term "alkynyl" refers to a linear or branched hydrocarbon chain radical containing from 2 to 6 ("C2-C6 alkynyl"), more preferably from 2 to 3
    10 ("C2-C3 alkynyl"), carbon atoms, which contains at least one triple bond and is attached to the rest of the molecule by a single bond. Illustrative examples include ethynyl, propynyl, butynyl, and the like.
    The term "aryl" refers to an aromatic group having between 6 and 14, preferably
    15 between 6 and 10 carbon atoms, comprising 1 or 2 aromatic nuclei fused together. Illustrative examples of aryl groups include phenyl, naphthyl, indenyl, phenanthryl, etc.
    The term "heterocyclyl" refers to a monocyclic or bicyclic system that may be completely or partially saturated or aromatic ("heteroaryl") containing from 3 to
    10, preferably 5 to 10, more preferably 5 to 7, ring atoms containing one or more, specifically one, two, three or four ring heteroatoms independently selected from N, O and S, and the atoms being remaining carbon ring.
    The term "halogen" refers to bromine, chlorine, iodine or fluorine.
    The term aza-aromatic ligand N, N-bidentate or N, N, N-tridentate refers to aromatic molecules that can take two (bidentate) or three (tridentate) coordination sites of the metal core of Ru (II) by coordination only through the nitrogen atoms. Preferably, this aromatic molecule is a stable heteroaryl having 10 to 32,
    30 preferably from 12 to 28, more preferably from 12 to 20, members (bidentate) or having 15 to 32, preferably from 18 to 30, more preferably from 18 to 26, members (tridentate), formed by carbon atoms and from two (bidentate) or three (tridentate) to six, preferably 2, 3, 4 or 5, nitrogen atoms. The term "heteroaryl having 10 to 32 members or having 15 to 32 members" as used herein
    35 document means a heteroaryl group having a skeleton of from 10 to 32 atoms or
    9
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    Optionally substituted C6-C14, optionally substituted 5-10 membered heteroaryl and halogen.
    In a particular embodiment, the Ru (II) complex has the following formula:
    image11 n +
    image12 N
    image13
    N
    image14 N
    image15 image16 Y
    Ru
    image17 n
    N
    image18 X
    N
    image19
    image20
    image21
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    where X, Y-y n are as defined in this document.
    The value of n is determined by the chemical structure and electrical charge of the ligands
    10 selected and the 2+ electric charge of the central Ru (II) atom. Thus, when X represents OH2 or SR1R2, then n is 2. When X represents Cl, Br or I, then the value of n is 1. The complex of formula (I) is neutral, that is, its overall charge is zero.
    In a particular embodiment, X represents OH2. Preferably, N1-N1-N1 represents
    15 2.2 ’: 6’, 2 ’’ - optionally substituted terpyridine as previously defined, N2-N2 represents optionally substituted 2,2’-bipyridine as previously defined and X represents OH2.
    In another particular embodiment, X represents Cl, Br or I, preferably Cl. In one embodiment
    In particular, N1-N1-N1 represents optionally substituted 2,2 ': 6', 2 '' - terpyridine as defined previously, N2-N2 represents optionally substituted 2,2'-bipyridine as defined previously and X represents Cl, Br or I, preferably Cl.
    In one embodiment, X represents SR1R2, where R1 and R2 are independently selected.
    Optionally substituted C1-C12 alkyl. Preferably, R1 and R2 are independently selected from C1-C12 alkyl, preferably C1-C6 alkyl optionally substituted with one or more groups selected from halogen, OR '', N (R '') 2, N (R '') COR ' ', CN, NO2, COR' ', CO2R' ', OCOR' ', OCO2R' ', OCONHR' ', OCON (R' ') 2, CONHR' ', CON (R' ') 2, C1-C6 alkyl , C2-C6 alkenyl, C2-C6 alkynyl, C6-C14 aryl, and 3-10 heterocyclyl
    30 members, where each R 'group is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C14 aryl and 3-heterocyclyl
    14
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    Pharmaceutical compositions
    The Ru complexes of the invention can be used to prepare a pharmaceutical composition for the treatment of cancer. Therefore, another aspect of the invention is a pharmaceutical composition comprising a ruthenium complex of formula (I) as defined herein, for use in the treatment of cancer.
    As used herein, the term "pharmaceutical composition" refers to a formulation that has been adapted to deliver a predetermined dose of one or more useful therapeutic agents to a cell, a group of cells, an organ, a tissue. or an organism.
    Ruthenium complexes are administered in a therapeutically effective amount. A "therapeutically effective amount" is understood as an amount that can provide a therapeutic effect and that can be determined by one skilled in the art by commonly used means. The effective amount will vary with the particular disorder being treated, the age and physical condition of the subject being treated, the intensity of the disorder, the duration of treatment, the nature of the simultaneous or combination therapy (if any), the specific route of administration and similar factors within the knowledge and experience of the healthcare professional. It is generally preferred that a maximum dose be used, that is, the highest safe dose according to reasonable medical criteria. For example, if the subject has a tumor, an effective amount may be the amount that reduces the volume or tumor burden (as determined, for example, by imaging the tumor). Effective amounts can also be evaluated by the presence and / or frequency of cancer cells in the blood or other fluid or body tissue (eg, a biopsy). If the tumor affects the normal functioning of a tissue or organ, then the effective amount can be evaluated by measuring the normal functioning of the tissue or organ. Those skilled in the art will appreciate that dosages can also be determined with the guidelines of Goodman and Goldman’s The Pharmacological Basis of Therapeutics, ninth edition (1996), appendix II, p. 1707-1711 and from Goodman and Goldman’s The Pharmacological Basis of Therapeutics, Tenth Edition (2001), Appendix II, p. 475-493.
    16

    The pharmaceutical compositions of the invention may include at least one pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" means a filler, diluent, encapsulation material or adjuvant of solid, semi-solid or liquid, inert, non-toxic formulation of any type that is acceptable to the patient since a pharmacological / toxicological point of view and for the manufacturing pharmaceutical chemist from a physical / chemical point of view regarding the composition, formulation, stability, acceptance by the patient and bioavailability. Remington’s Pharmaceutical Sciences. Ed. By Gennaro, Mack Publishing, Easton, Pa., 1995 describes various vehicles used in the formulation of pharmaceutical compositions 10 and known techniques for preparing them. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum tragacanth powder; malt; jelly; talcum powder; 15 excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; Sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as TWEEN ™ 80; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen free water; isotonic saline solution; Ringer's solution; ethyl alcohol; and phosphate buffer solutions, as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants in the composition,
    25 according to the formulator's criteria. If filtration or other terminal sterilization methods are not viable, the formulations can be manufactured under aseptic conditions.
    Pharmaceutical compositions of the invention include any solid composition (tablets, pills, capsules, granules, etc.), semi-solid (creams, ointments, etc.) or liquid (solution, suspension or emulsion).
    The pharmaceutical compositions of this invention can be administered to a patient by any means known in the art including oral and parenteral routes. According to such embodiments, the compositions of the invention can be administered by injection (for example, intravenous, subcutaneous or intramuscular injection,
    17

    intraperitoneal). In a particular embodiment, the ruthenium complexes of the invention are administered systemically, for example by infusion or injection iv. Injectable preparations may be formulated, for example, sterile injectable aqueous or oleaginous suspensions according to the known technique using suitable suspending agents and dispersing agents or humectants. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic diluent or solvent, parenterally acceptable, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as the solvent or suspending medium. For this purpose, any mild fixed oil including synthetic mono or diglycerides can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectable products. Injectable formulations can be sterilized, for example, by filtration through a filter that retains bacteria, or by
    Incorporation of sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.
    The compositions may comprise the ruthenium complex as the sole agent or in
    20 combination with another therapeutic agent, such as an anticancer drug. In one embodiment, the pharmaceutical composition or medicament of the invention comprises the combination of a ruthenium complex of formula (I) and an anticancer drug formulated for simultaneous, separate or sequential administration. This implies that the combination of the two compounds can be administered:
    25 -like a combination that is part of the same pharmaceutical formulation or medication, administering the two compounds simultaneously; or
    -like a combination of two dosage forms, each containing one of the 30 substances, giving rise to the possibility of simultaneous, sequential or separate administration.
    In a particular embodiment, the ruthenium complex of formula (I) and the anticancer drug are administered independently (i.e., in two forms of
    35 dosage) but at the same time.
    18

    In another particular embodiment, the ruthenium complex of formula (I) is administered first, and then the other anticancer drug is administered separately or sequentially.
    In a further particular embodiment, the other anticancer drug is administered first and then the compound of formula (I) is administered, separately or sequentially, as defined.
    The term "anti-cancer drug", as used herein, also
    10 called "anticancer agent", "antitumor agent" or "antineoplastic agent" refers to an agent that is useful in the treatment of cancer. Antitumor agents according to the present invention include, without limitation, alkylating agents, antimetabolites, topoisomerase inhibitors and anthracyclines.
    The term "alkylating agent", as used herein, also referred to as "alkylating antineoplastic agent", refers to an agent that mediates the transfer of an alkyl group from a molecule to DNA. The alkyl group can be transferred as an alkyl carbocation, a free radical, a carbanion or a carbine (or its equivalents). Alkylating agents are used in chemotherapy to damage the DNA of cancer cells. The agents
    20 alkylating agents are generally separated into six classes: nitrogen nitrogen, such as mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, etc .; -ethylenamine and methylenamine derivatives, including altretamine, thiotepa and the like; -alkyl sulphonates, such as busulfan, etc .;
    25-nitrosoureas, such as carmustine, lomustine, etc .; -triazenes, such as dacarbazine, procarbazine, temozolomide, etc .; and antineoplastic agents containing platinum, such as cisplatin, carboplatin and oxaliplatin, which are usually classified as alkylating agents, although they do not rent the DNA, but cause the formation of covalent metal adducts with the
    30 DNA through a different medium, etc.
    The term "antimetabolite," as used herein, refers to a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances often have a structure similar to that of the metabolite with which they interfere, such as antifolates that interfere with the use of folic acid. The
    19

    Presence of antimetabolites can have toxic effects on cells, such as stopping cell growth and cell division, so that these compounds are used as cancer chemotherapy. The antimetabolites are passed through a purine or a pyrimidine, preventing their incorporation into the DNA during the S phase (of the cell cycle), stopping normal development and division. They also affect the synthesis of RNA. However, since thymidine is used in DNA but not in RNA (in which uracil is used instead), inhibition of thymidine synthesis by thymidylate synthase selectively inhibits DNA synthesis with respect to synthesis of RNA. Antimetabolites can be selected from:
    - purine analogues, such as azathioprine, mercaptopurine, thioguanine, fludarabine,
    pentostatin, cladribine, etc .; - Pyrimidine analogues, such as 5-fluorouracil (5FU), floxuridine (FUDR), arabinoside
    cytosine (cytarabine), 6-azauracil (6-AU), etc .; or -antifolates, such as methotrexate, pemetrexed, proguanyl, pyrimethamine, trimethoprim,
    etc.
    The term "topoisomerase inhibitor", as used herein, refers to an agent designed to interfere with the action of topoisomerase enzymes (topoisomerase I and II). It is thought that topoisomerase inhibitors block the ligation stage of the cell cycle, generating single and double stranded tears that damage genome integrity. The introduction of these tears subsequently leads to apoptosis and cell death. Illustrative, non-limiting examples of topoisomerase inhibitors include etoposide, teniposide, topotecan, irinotecan, diflomotecan or elomotecan.
    The term "anthracycline," as used herein, refers to a class of drugs (CCNS or non-cell cycle specific) used in cancer chemotherapy derived from strains of Streptomyces bacteria. Illustrative, non-limiting examples of anthracyclines include daunorubicin, doxorubicin, epirubicin, idarubicin, valrubicin, mitoxantrone, etc.
    Other anticancer agents according to the present invention include, without limitation, the following agents:
    - angiogenesis inhibitors, such as angiostatin, endostatin, fumagiline, genistein, minocycline and staurosporine;
    twenty

    - DNA synthesis inhibitors, such as aminopterin, ganciclovir and hydroxyurea; -enzyme inhibitors, such as S (+) - camptothecin, curcumin, 2-imino-1imidazolidinacetic acid (cyclocreatin), hispidine, formestane and mevinoline; - microtubule inhibitors, such as colchicine and dolastatin 15; and 5 -other antitumor agents, such as 17- (allylamino) -17-demethoxyigeldanamicin, apigenin, cimetidine, leutinizing hormone releasing hormone, and pifitrin α.
    Applications
    An aspect of the invention is the use of a ruthenium complex as defined herein for the preparation of a medicament for the treatment of cancer.
    Another aspect of the invention relates to a ruthenium complex as defined herein for use in the treatment of cancer.
    Another aspect of the invention relates to a method of cancer treatment comprising administering to a patient in need of such treatment a therapeutically effective amount of a ruthenium complex as defined herein.
    20 As used herein, the terms "treat", "treating" and "treatment" generally include eradication, elimination, reversal, relief, modification
    or cancer control after its onset.
    The term "cancer", as used herein, also referred to as
    25 "carcinoma" refers to a disease characterized by an uncontrolled proliferation of abnormal cells capable of invading adjacent tissues and spreading to distant organs. Within the context of the present invention, this term includes any type of cancer or tumor. Illustrative, non-limiting examples of such cancers or tumors include hematological cancers (e.g., leukemia or lymphomas), neurological tumors (e.g.,
    30 astrocytomas or glioblastomas), melanoma, breast cancer, lung cancer, head and neck cancer, gastrointestinal tumors (eg, stomach, pancreas or colorectal cancer (RCC)), liver cancer (eg, hepatocellular carcinoma), cancer of renal cells, genitourinary tumors (eg, ovarian cancer, vaginal cancer, cervical cancer, bladder cancer, testicular cancer, prostate cancer), bone tumors, tumors
    35 vascular, etc.
    twenty-one
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    权利要求:
    Claims (1)
    [1]
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    同族专利:
    公开号 | 公开日
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    CA3045885A1|2018-05-17|
    EP3539971A1|2019-09-18|
    JP2019535699A|2019-12-12|
    MX2019005512A|2019-08-29|
    WO2018087413A1|2018-05-17|
    AU2017359398A1|2019-06-20|
    AU2017359398B9|2021-12-09|
    US20200054647A1|2020-02-20|
    ES2594499B2|2017-06-21|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB201017546D0|2010-10-18|2010-12-01|Univ Leiden|Light inducing drug release|
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    MX2019005512A| MX2019005512A|2016-11-10|2017-11-10|Ruthenium complexes for treating cancer which comprises cancer stem cells.|
    AU2017359398A| AU2017359398B9|2016-11-10|2017-11-10|Ruthenium complexes for treating cancer which comprises cancer stem cells|
    PCT/ES2017/070745| WO2018087413A1|2016-11-10|2017-11-10|Ruthenium complexes for treating cancer which comprises cancer stem cells|
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