WO2013092556A1 - Composés chélateurs de métal présentant au moins une chaîne polyaminée - Google Patents
Composés chélateurs de métal présentant au moins une chaîne polyaminée Download PDFInfo
- Publication number
- WO2013092556A1 WO2013092556A1 PCT/EP2012/075907 EP2012075907W WO2013092556A1 WO 2013092556 A1 WO2013092556 A1 WO 2013092556A1 EP 2012075907 W EP2012075907 W EP 2012075907W WO 2013092556 A1 WO2013092556 A1 WO 2013092556A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carbon atoms
- iron
- quilamine
- equal
- compound according
- Prior art date
Links
- 0 C*(C)CNCCCNCCCCNCCCNCc1nc(c(O)ccc2)c2cc1 Chemical compound C*(C)CNCCCNCCCCNCCCNCc1nc(c(O)ccc2)c2cc1 0.000 description 1
- GINSRQLMFUPOMZ-UHFFFAOYSA-N NCCCCNCCCCNCCCNCc1nc(c(O)ccc2)c2cc1 Chemical compound NCCCCNCCCCNCCCNCc1nc(c(O)ccc2)c2cc1 GINSRQLMFUPOMZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
-
- 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
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
Definitions
- Metal chelating compounds having at least one polyamine chain.
- the present invention relates to chimeric molecules associating one or more 8-hydroxyquinoline metal chelator groups with at least one polyamine chain. These compounds are hereinafter referred to by the acronym "Quilamine”.
- the invention also relates to the use in the therapeutic field of such Quilamines, in particular in the treatment or prevention of proliferative and / or metal-overload-related diseases such as cancers and neurodegenerative diseases in humans or in humans. animal.
- metal ions from iron, copper, manganese, zinc are involved in several biochemical and metabolic reactions of the body.
- the needs of the body generally vary according to the type of metal ions and the location of the biochemical and metabolic reactions involved. To ensure proper functioning of the body, these metal ions must be present at certain levels. to avoid overloads or deficiencies for example.
- overloads of metal ions such as iron and copper are harmful even toxic to the body because they catalyze the formation of reactive oxygen species.
- Overloads of metal ions can have various origins: genetic, metabolic, exogenous nutritional contributions or repeated blood transfusions. In particular, they can be linked to diseases such as cancers or tumors, neurodegenerative diseases, in which an imbalance in the homeostasis of metal ions occurs.
- tumor cells proliferate uncontrollably and require abnormally high amounts of metal ions such as iron and copper, for their growth, compared to healthy cells.
- Desferal® inhibits the growth of melanoma cells in vitro and in vivo (Richardson, D., P. Ponka, and E. Baker, The ejfect of the iron (III) chelator, desferrioxamine, on iron and transferrin uptake by the human malignant melanoma cell. Cancer Res, 1994. 54 (3): p. 685-9) and hepatoma (Yamasaki, T., Terai S. and I. Sakaida, Deferoxamine for advanced hepatocellular carcinoma, The New England Journal of Medicine, 201 1, 365 (6): 576-77). In preliminary clinical trials, this chelator has been shown to be effective in the treatment of leukemias and neuroblastomas.
- cytotoxic chemotherapeutic agents such as doxorubicin and Bleomycin
- doxorubicin and Bleomycin partially interferes with their chelating ability of iron and copper, as well as clioquinol, a derivative of 8-hydroxyquinoline (Ding, WQ, et al. Anticancer activity of the antibiotic clioquinol, Cancer Res, 2005. 65 (8): 3389-95).
- the biosynthesis and uptake of these ubiquitous molecules by the polyamine transport system (PTS) is strongly activated in tumor cells.
- the activity Antiproliferative treatment of iron chelators such as deferasirox® and O-trensox is associated with the intracellular iron depletion they cause and the inhibition of polyamine metabolism (Gaboriau, F., et al., Modulation of Cell Proliferation and polyamine metabolism in rat liver cell cultures by the iron chelator O-trensox, Biometals, 2006. 19 (6): 623-32).
- the reactive oxygen species produced in iron and / or copper overload at the cerebral level cause alterations of the membrane lipids, proteins and DNA of the nerve cells involved in the etiology of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Elevated iron levels are observed in the central nervous system (CNS). Regardless of their involvement in the catalysis of reactive oxygen species, metals such as iron and copper also appear to play an important role in protein aggregation. They are therefore likely to provide a link between the two pathological processes of protein aggregation and oxidative damage characterizing neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD) and those with prions.
- PD Parkinson's disease
- AD Alzheimer's disease
- Clioquinol which is currently in clinical trial, has the best protective efficacy in animal models of AD and PD.
- chelators of these metal ions is an interesting research pathway in the treatment of proliferative diseases and / or related to metal overload in the body, such as cancers or certain neurodegenerative diseases.
- Chelators capable of inducing metal depletion in the cell large enough to create intracellular metal deficiency and to reduce cell proliferation and local production of reactive oxygen species are sought.
- Cancer cells have a particularly amplified metabolism (biosynthesis and uptake) of polyamines.
- the Polyamine Transport System which transports polyamines, is particularly active in these cells.
- PBS Polyamine Transport System
- these chelators have a low affinity for iron and are not entirely satisfactory for the development of a therapeutic treatment, for example in the treatment of cancers.
- the antiproliferative action of these chelators on cultured liver cells is not very effective.
- the Applicant has now discovered a new family of compounds associating metal chelators and polyamine (s), called quilamines. These compounds effectively and selectively exert an antiproliferative action on the diseased cells and remedy the aforementioned drawbacks.
- the quilamines according to the invention are compounds comprising at least one 8-hydroxyquinoline unit substituted in the 2-position, that is to say in the alpha position of the constituent nitrogen atom of the 8-hydroxyquinoline ring, by at least one polyamine chain.
- the Quilamines according to the invention are capable of treating, in a targeted, less toxic and more efficient manner, proliferative diseases and / or related to a metal overload in human or animal cells, such as cancers. or neurodegenerative diseases compared to known chelators.
- a quilamine according to the invention has a strong antiproliferative activity that can even be greater than that of conventional iron chelators, for the same concentration of chelators.
- the quilamines according to the invention exhibit enhanced or at least unchanged antiproliferative activity in the presence of exogenous iron, compared to classical chelators of iron. They are therefore particularly effective for treating diseases related to sideroid overload in human or animal cells.
- the Quilamines according to the invention have the advantage of being low in toxicity and suitable for various applications in the therapeutic field. They have a low cytotoxicity for healthy cells, particularly thanks to their high selectivity of recognition by the polyamine transport system, allowing them to selectively target the tumor cells.
- Another object of the present application relates to the quilamines according to the invention as therapeutic treatment agents.
- the subject of the invention is also the Quilamines according to the invention as agents for treating proliferative diseases and / or neurodegenerative diseases linked to an overload of metal, for example iron and / or copper.
- Quilamines according to the invention are particularly useful as antiproliferative agents and / or cytotoxic agents of cancer or tumor cells.
- the compounds according to the invention may be obtained according to preparation processes in which the polyamine chain (s) is (or are) coupled to the 8-hydroxyquinoleic motif (s) by steps of reductive amination, nucleophilic substitution or addition of Micka ⁇ l to give a quilamine according to the invention.
- These preparation methods have the advantage of being simple to perform. In particular, they make it possible to synthesize the quilamines according to the invention in less than fifteen steps, and preferably in less than twelve steps.
- the invention relates to compounds comprising at least one 8-hydroxyquinoline unit having in the 2-position, that is to say in the alpha position of the constituent nitrogen atom of the 8-hydroxyquinoline ring, at least one polyamine chain. .
- quilamines according to the invention correspond to the following general formula (I), or to one of its conjugated forms, its salts or solvates:
- R 1 , R 2 , R 3 , R 4 and R 5 are chosen independently from one another from a hydrogen atom, a linear or branched, saturated, unsaturated, cyclic or aromatic hydrocarbon group comprising from 1 to 10 carbon atoms, carbon, a cyclic hydrocarbon group, aliphatic or aromatic, comprising from 4 to 12 carbon atoms, a halogen, a thiol, a hydroxyl, an amine preferably secondary or tertiary, an ether, a thioether;
- R 6 is a hydroxyl
- a is equal to 0 or 1 with:
- M is a group corresponding to the following formula ( ⁇ ):
- R 11 , R 12 , R 13 and R 14 are chosen independently from each other from hydrogen atoms, linear or branched, saturated, unsaturated, cyclic or aromatic hydrocarbon groups comprising from 1 to 12 carbon atoms, and protective groups of amino function,
- B 1 , B 2 and B 3 are chosen independently of one another from linear or branched, saturated or unsaturated hydrocarbon groups comprising from 2 to 6 carbon atoms
- i and j identical or different, are equal to 0 or 1
- h is an integer from 0 to 4.
- R '11, R 12, R' 13, R '14, R 15, R 16 and R 17 are independently selected from each other from linear hydrocarbon groups or branched, saturated, unsaturated, cyclic or aromatic containing from 1 to 12 carbon atoms, and amino function protecting groups.
- B and B are independently selected from linear or branched, saturated or unsaturated hydrocarbon groups having from 2 to 6 carbon atoms
- B ' 3 is chosen from linear or branched, saturated or unsaturated hydrocarbon-based groups comprising from 2 to 6 carbon atoms, which can be interrupted by one or more secondary amino functions -NH- and / or one or more tertiary amino functions -NR 11 -,
- i and j identical or different, are equal to 0 or 1
- h is an integer from 0 to 4.
- M is a group corresponding to the following formula (I "): in which :
- D 1 and D 2 identical or different, representing a hydrocarbon group, linear or branched, comprising from 1 to 5 carbon atoms
- a 2 being the same as or different from A 1 and having the formula (X) or (Y);
- R ' 1 , R' 2 , R ' 3 , R' 4 , R ' 5 and R' 6 are chosen independently from each other from a hydrogen atom, a saturated or unsaturated linear or branched hydrocarbon group, comprising: from 1 to 10 carbon atoms, a cyclic hydrocarbon group, aliphatic or optionally substituted aromatic, comprising from 4 to 12 carbon atoms, a halogen, a thiol, a hydroxyl, an amine preferably secondary or tertiary, an ether, a thioether.
- the quilamine according to the invention is a metal chelator. It is capable of binding with a metal atom or metal ion by forming several (at least two) chelator-metal coordination bonds to form a metal complex, especially with a metal atom of the 3d series of transition metals, particularly the iron, copper, manganese and / or zinc.
- the quilamine according to the invention is especially capable of chelating an iron ion having a degree of oxidation equal to two (Fe (II) or Fe 2+ ) or three (Fe (III) or Fe 3+ ), an ion of copper having an oxidation state of two (Cu (II) or Cu 2+ ), a manganese ion having an oxidation state of two (Mn (II) or Mn 2 ) or a zinc ion having a oxidation degree equal to two (Zn (II) or Zn 2+ ).
- quilamine is an iron chelator.
- the complexing affinity of quilamine with the metal ion in the body reflects the chelating or chelating ability of quilamine.
- This affinity can be evaluated by measuring the value of pW corresponding to -log of the concentration of free metal ion W, that is to say non-complexed by quilamine, for a ratio of the respective concentrations of Quilamine (10 micromoles per liter). ) and metal ion (1 micromole per liter) equal to 10 at 25 ° C and pH 7.4.
- the quilamine according to the invention has a pFe 2+ and / or pFe 3+ value at physiological pH which is strictly greater than that measured under identical conditions for the ligands of low molecular weight usually present in human cells. or animal complexing labile iron pool (Labil Iron Pool or LIP).
- the pFe 2+ or pFe 3+ of the quilamine-iron complex is strictly greater than 20, and preferably ranging from 25 to 27 physiological pH.
- quilamine forms a quilamine-Fe (III) complex preferably having a ligand / metal stoichiometry of 2/1.
- the ligand / metal stoichiometry can for example be determined by the continuous variations method using the transition. characteristic in the absorption spectrum of Quilamine-Fe (III) complex at 580nm, for chelating and iron concentrations ranging from 0 to 500 micromoles per liter.
- the polyamine chain (s) of the quilamine is or are recognized by the polyamine transport system of the cells and allows Quilamine to be transported to the cells.
- the polyamine chain or chains of the quilamine according to the invention is or are cationic or cationizable.
- Cationic means that which comprises one or more quaternary amino functions, such that the global ionic charge carried by the amine chain is positive.
- the polyamine chain may be mono or polycationic.
- cationizable means that which comprises one or more primary and / or secondary amine functional groups, in particular in salt form, spontaneously ionizing into cation (s) in the medium for using quilamine, at physiological pH.
- the polyamine chain or chains may comprise a putrescine, spermine, spermidine, or non-natural analog of these compounds such as homospermine, homospermidine, norspermine,
- the polyamine chain or chains comprise a similar non-natural motif to putrescine, spermine or spermidine, such as homospermine, homospermidine, norspermine, allowing them to be recognized by the polyamine transport system, but without being degraded by the enzymes. of the oxidative retroconversion pathway.
- a is zero and b is one.
- a is zero, b is one, and L is CH 2 '
- a is zero, b is one, and L is CH 2 -CH 2 '.
- c and c ' are identical, L and L' are identical, D 1 and D 2 are identical, and / or R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are identical to R ' 1 , R' 2 , R ' 3 , R' 4 , R ' 5 and R' 6 respectively.
- R ' 6 is a hydroxyl.
- the quilamine according to the invention meets the general formula (the exclusion of
- B 1 , B 2 , B 3 are chosen from n-propyl and n-butyl groups and B ' 3 is chosen from n-propyl and n-butyl groups which may be interrupted by one or more secondary amino functions - NH- and / or one or more tertiary amino functions -NR 11 -, -NR 12 -.
- group or groups A 1 and A 2 mentioned above can be chosen from:
- B 3 and B ' 3 do not denote an n-propyl group and R 13 , R 14 , R' 13 , R '14 and R 17 do not denote simultaneously a hydrogen atom.
- the polyamine chain does not terminate with a primary n-propylamine group.
- Such polyamine chains are likely to be degraded by amine oxidase enzymes present in the serum (polyamine oxidase and semicarbazide sensitive amine oxidase) and generate a cytotoxic aldehyde and hydrogen peroxide.
- These Quilamines have a particularly important chelating power.
- R 1 to R 5 are chosen independently from each other from a hydrogen atom, a saturated or unsaturated linear or branched hydrocarbon group comprising from 1 to 10 carbon atoms;
- R 6 is a hydroxyl; a is zero; b is equal to one;
- L is a C 1 -C 2 alkyl group; and the group A 1 corresponds to the formula (X) in which R 11 , R 12 , R 13 and R 14 are chosen independently from each other among hydrogen atoms, and amino protecting groups;
- B 1 , B 2 and B 3 which may be identical or different, are n-propyl and / or n-butyl groups; i and j identical or different being equal to one or zero; h being equal to one.
- the preferred quilamine is HQ 1-44 and its conjugated forms, salts or solvates.
- HQ1-44 describes the chelating unit HQ hydroxyquinoline, indexed 1 for the number of C3 ⁇ 4 group linked to the polyamine chain.
- the number 44 (and respectively 444, 443, 43, 434, 433, 33, 334, 333, 34, 344, 343) specifies the number of carbon between each nitrogen atom of the polyamine chain.
- the quinolines can be selected from any pharmaceutically acceptable salt.
- pharmaceutically acceptable salt is meant in particular a salt with a pharmaceutically acceptable inorganic acid, such as hydrochloric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic or hydrobromic acids; or a salt with a pharmaceutically acceptable organic acid, such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic or oxalic acids, phenylacetic, methanesulfonic, toluenesulfonic, benzenesulfonic, salicylic, sulfanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric.
- a pharmaceutically acceptable inorganic acid such as hydro
- treatment refers to the ability of Quilamines to decrease the pool of excess metal ion (iron and / or copper) and / or to reduce polyamine levels in tumor cells and consequently to decrease and and / or inhibit the development of these cancerous or tumor cells and / or their symptoms.
- the solvates of Quilamines consist of complexes or aggregates formed by one or more Quilamines or one of its salts as defined above, with one or more solvent molecules.
- the solvents may be, for example, water, methanol, ethanol, isopropanol or acetic acid.
- the solvent is water
- the solvate is a hydrate.
- the solvates of Quilamines are hydrates such as hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates.
- the conjugated forms of Quilamines correspond to the forms of resonances due to the delocalization of one or more electronic doublets.
- the quilamine according to the invention can be used as a therapeutic agent in humans and animals, in particular as an agent for treating proliferative diseases, neurodegenerative diseases, and / or linked to iron overload, copper , zinc and / or manganese, in human or animal cells.
- Quilamine can be used as an anti-tumor agent, for example in the treatment of hepatocarcinomas, lymphomas, melanomas, renal, ovarian carcinomas, breast, colon, and / or prostate carcinomas. , bladder, pancreas, and lungs in humans or animals. It can also be used to treat neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases.
- the quilamine according to the invention can be used as an inhibitory agent for the endogenous synthesis of polyamines by the body.
- the polyamines result from the degradation of arginine, either directly by arginine decarboxylase which converts it to agmatine, or via the urea cycle which starts with arginine catalyzed transformation of arginine into ornithine. .
- the polyamines are then synthesized sequentially from ornithine which is decarboxylated initially by ornithine decarboxylase (ODC) to form putrescine.
- ODC ornithine decarboxylase
- Spermidine is synthesized by spermidine synthase which makes the addition putrescine of an aminopropyl group provided by S-adenosyl methionine, decarboxylated by S-adenosyl methionine decarboxylase (SAMDC).
- SAMDC S-adenosyl methionine decarboxylase
- Spermine is formed in the same way from spermidine by the addition of a second aminopropyl group.
- the main inhibitors of polyamine synthesis act at the ODC ( ⁇ -difluoromethyl ornithine or DFMO), or SAMDC (CGP 48664).
- Another subject of the invention relates to a composition comprising at least one quilamine as defined above.
- composition according to the invention may further comprise at least one excipient.
- excipient (s) that can be used are chemically inert and pharmacologically inactive auxiliary substances, in particular they do not influence the effects of quilamine and any additional active ingredients present in the composition.
- the excipient serves to formulate the composition of the invention in the form most suitable for the desired route of administration and optionally, where appropriate, to modulate the rate of release of the active substance (s) to the organism.
- excipients include: water and sucrose are the two excipients constituting the simple syrup - or, for dry forms, the modified starch (s) and the modified cellulose (s) are disintegrating agents used in dry forms (tablets, capsules, etc.) to accelerate the disintegration (or disintegration) of these once arrived in the stomach.
- the excipient may be an aqueous, sterile, isotonic to blood, pharmaceutically acceptable solvent or diluent, such as phosphate or saline acetate buffers, water, 5% dextrose solution. These formulations can be prepared as defined doses contained in a sterile glass vial and sealed according to the proven methods of the pharmacy.
- the excipient is preferably a phosphate buffered saline.
- composition according to the invention may be administered by any route of administration conventionally used in the therapeutic field, applied to humans or animals.
- it can be administered orally, sublingually, parenterally, subcutaneously, intramuscularly, intravenously, transdermally, locally, rectally or inhaled.
- it is administered orally in a formulation in syrup, capsules or tablets.
- composition according to the invention preferably comprises a therapeutically effective quilamine content, that is to say such that the composition can be used as a therapeutic agent, in particular as a treatment agent for proliferative diseases and neurodegenerative and / or related to an overload of iron, copper, zinc and / or manganese, especially as antitumor agent, anti Parkinsonian or anti-Alzheimer, in humans or animals.
- a therapeutically effective quilamine content that is to say such that the composition can be used as a therapeutic agent, in particular as a treatment agent for proliferative diseases and neurodegenerative and / or related to an overload of iron, copper, zinc and / or manganese, especially as antitumor agent, anti Parkinsonian or anti-Alzheimer, in humans or animals.
- composition according to the invention may further comprise at least one additional active ingredient different from the Quilamines and having in particular a marketing authorization.
- chemotherapeutic agents such as alkylating agents (Cis-Platinum), plant alkaloids (paclitaxel, epothilones), topoisomerase inhibitors (campthotecin, taxanes, alkaloids). Vinca family (Vinblastine, Vincristine, 7)), microtubule inhibitors (Bleomycin) and anti-metabolites (5-Fluoro uracil) and polyamine-like inhibitors such as Eflornithine ( ⁇ -Difluoromethylornithine) and CGP 48664.
- composition according to the invention may also comprise at least one additive chosen from preservatives such as methyl methylhydroxybenzoate, chlorocresol, metacresol, phenol and benzalkonium chloride.
- the composition may be a ready-to-use composition or a composition obtained by extemporaneous mixing of the quilamine (s) with one or more excipients and / or one or more additional active ingredients and / or one or more additives as mentioned above.
- the composition may be a combination product for simultaneous, separate or spread over time use of these various active principles and quilamines.
- the additional active principle is chosen from an endogenous polyamine synthesis inhibiting agent and a chemotherapeutic agent.
- said endogenous polyamine synthesis inhibiting agent is an inhibitor of ornithine decarboxylase, S-adenosylmethionine decarboxylase, spermidine synthase or spermine synthase.
- polyamine synthesis inhibiting agent is meant a molecule capable of completely or partially blocking, directly or indirectly, at least one of the enzymes involved in the synthesis of polyamines in the human or animal body.
- Ornithine decarboxylase (EC 4.1.1.17) is a target enzyme for compounds that inhibit the biosynthesis of polyamines.
- the role of the inhibitor of polyamine biosynthesis is to stop or significantly reduce the endogenous production of polyamines in the organism treated with the product according to the present invention. Co-treatment with such inhibitors of the endogenous synthesis of polyamines makes it possible to enhance the antiproliferative activity of the quilamines according to the present invention by a conjugated deficiency of polyamines and of intracellular iron.
- chemotherapeutic agent have meant a chemical molecule to treat diseases such as cancer, neurodegenerative diseases or autoimmune diseases.
- diseases such as cancer, neurodegenerative diseases or autoimmune diseases.
- the majority of chemotherapeutic substances work by stopping mitosis (cell division), effectively targeting dividing cells too rapidly or the synthesis and function of DNA.
- Some new agents do not act directly on DNA but directly target a molecular abnormality (leukemia, colon cancer).
- composition according to the invention as defined above can be used as a therapeutic agent in humans and animals, especially as an agent for treating proliferative diseases, neurodegenerative diseases and / or related to metal overload. in human or animal cells.
- it can be used as an agent for the treatment of hepatocarcinomas, lymphomas, melanomas, renal, ovarian carcinomas, breast, colon, and / or carcinomas of the prostate, bladder, prostate pancreas, and lungs in humans or animals.
- neurodegenerative diseases such as Parkinson's and Alzheimer's diseases.
- the compounds according to the invention can be obtained by a process in which the polyamine chain (s) is (are) coupled to the 8-hydroxyquinoleic unit (s) by a reductive amination step, nucleophilic substitution. or addition of Mickael.
- the method used comprises:
- a reductive amination step between an aldehyde reagent and an amino reactant, one of the reagents being able to carry a precursor of the 8-hydroxyquinoline unit and the other being able to carry a precursor of the polyamine chain,
- nucleophilic substitution step of an amino reactant carrying a precursor of the polyamine chain, on an electrophilic reagent carrying a precursor of the 8-hydroxyoxynoleic motif
- said precursors of the 8-hydroxyquinoline unit comprise in position alpha of the constituent nitrogen atom of the 8-hydroxyquinoline ring a functional group suitable for reacting with the second reactant carrying the precursor of the polyamine chain.
- the preparation process comprises the following steps:
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in formula (I), and whose thiol, hydroxyl, primary and secondary amine functions, which may be present, are optionally protected by appropriate protective groups and a carboxaldehyde carrying a polyamine chain, of formula ( ⁇ )
- a ' 1 represents an amino hydrocarbon group corresponding to A 1 as defined above, and whose primary and secondary amine functions are protected by appropriate protecting groups;
- the reducing agent is chosen from hydrogen (H 2 ) in the presence of a catalyst (palladium on activated carbon for example), a hydride (NaBH 4 , NaBH 3 CN or triacetoxyborohydride sodium NaBH (OAc) 3 for example), and a hydrogen donor (formic acid, or a salt thereof for example).
- a catalyst palladium on activated carbon for example
- a hydride NaBH 4 , NaBH 3 CN or triacetoxyborohydride sodium NaBH (OAc) 3 for example
- OAc triacetoxyborohydride
- hydrogen donor formic acid, or a salt thereof for example.
- sodium triacetoxyborohydride is used.
- the thiol, hydroxyl, primary and secondary amine functions can be protected by means of well-known protective groups making them inactive with respect to the reductive amination reaction.
- the deprotection reactions corresponding to the various protected functions are also known per se by those skilled in the art.
- protective groups of the hydroxyl functions mention may be made of acetyl group (Ac), silyl derivatives or methyl. These functions can be deprotected respectively by an acid treatment, a fluoride anion or boron tribromide.
- protective groups of the primary and secondary amine functions of the polyamine chains there may be mentioned, for example, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl or benzyl group. These functions can be deprotected respectively by acid treatment with trifluoroacetic acid or hydrochloric acid, by hydrogenolysis in the presence of dihydrogen and palladium.
- the 8-hydroxyquinole unit has primary or secondary amine functions, they can be protected and deprotected in the same way.
- the carboxaldehyde bearing a polyamine chain, of formula ( ⁇ ) can be obtained from a hydrocarbon monomer constituting the polyamine chain (for example B 1 , B 2 , B 3 in the case of formula (X)) comprising a terminal hydroxyl primary function and a terminal amine primary function, that is to say at the end of the chain.
- the polyamine chain may be obtained by an N-substitution on the primary amine of the first monomer, a second constituent monomer of the polyamine chain and bearing a nitrile function; reduction of nitrile function to primary amine; protection of the appropriate functions (secondary amine in particular); and then possibly repeating these steps until the desired polyamine chain is obtained.
- the carboxaldehyde is finally obtained by oxidizing the primary hydroxyl function of the resulting hydroxypolyamine intermediate.
- X is a leaving group such as
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in formula (I), and whose thiol, hydroxyl, primary and secondary amine functions, which may be present, are optionally protected by appropriate protective groups;
- a 1 is as defined in formula ( ⁇ );
- the reducing agent may be chosen from those used in the preparation process described above.
- sodium triacetoxyborohydride is used.
- Thiol, hydroxyl, primary and secondary amine functions can be protected and deprotected as indicated in the previous preparation method.
- the primary amine carrying a polyamine chain of formula ( ⁇ ) can be obtained by a process of preparation similar to the carboxaldehyde of formula ( ⁇ ) described above, from a hydrocarbon monomer constituting the polyamine chain (by example B 1 , B 2 , B 3 in the case of formula (X)) having two primary amine functions.
- a hydrocarbon monomer constituting the polyamine chain by example B 1 , B 2 , B 3 in the case of formula (X) having two primary amine functions.
- One of the amine functions is protected by a protective group beforehand.
- the polyamine chain can be obtained by an N-substitution on the unprotected primary amine of the first monomer, a second constituent monomer of the polyamine chain and carrying a nitrile function, reduction of the nitrile function to primary amine ; then protection of the appropriate functions (secondary amine in particular) before possible repetition of these steps until the desired polyamine chain is obtained.
- X is a betting group such as
- the process for preparing quilamine HQ'2 comprises the following steps:
- SUBSTITUTE SHEET (RULE 26) thiol, hydroxyl, primary and secondary amine functions which may be present are optionally protected by appropriate protective groups;
- the reducing agent may be chosen from those used in the preparation process described above.
- sodium triacetoxyborohydride is used.
- Thiol, hydroxyl, primary and secondary amine functions can be protected and deprotected as indicated in the previous preparation method.
- the process for preparing quilamine HQ'2 comprises the following steps:
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in formula (I), and whose thiol, hydroxyl or amine functions that may be present are optionally protected by appropriate protective groups ;
- the reducing agent may be chosen from those used in the preparation process described above.
- sodium triacetoxyborohydride is used.
- the primary and secondary thiol and amine functions can be protected and deprotected as indicated in the previous preparation method.
- the process for preparing quilamine HQ'2 comprises the following steps:
- X represents a good leaving group, such as tosylate (OTs) or mesylate (OMs), or a halogen;
- the hydroxymethylation of compound 6 can be obtained by reacting it with butyllithium and then paraformaldehyde.
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in formula (I), and whose thiol, hydroxyl, primary and secondary amine functions which may be present are optionally protected by appropriate protective groups,
- Useful cutting agents include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC or EDCI) and N, N'-dicyclohexylcarbodiimide (DCC). N-Hydroxybenzotriazole (HOBt) may be added to the reaction medium in order to activate the reaction.
- EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
- DCC N, N'-dicyclohexylcarbodiimide
- HBt N-Hydroxybenzotriazole
- a quilamine of formula (I) wherein a is zero, b is one and L is C S (denoted as HQ '(CS))
- this may be obtained by i) thionation, using Lawesson's reagent or diphosphorus pentasulfide (P 4 S 10 ), of a quilamine HQ '(CO) whose thiol, hydroxyl, primary and secondary amine functions that may be present are optionally protected by appropriate protective groups, and then (ii) deprotection of the protected functions.
- the thiol, hydroxyl, primary and secondary amine functions are preferably protected and deprotected as indicated in the previous preparation method.
- the process of the invention relates to the preparation of a quilamine of formula (I) in which a is equal to 1, c and c 'are identical, L and L' are identical, D 1 and D 2 are identical, and / or R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are identical to R ' 1 ,
- Said quilamine according to the invention can be obtained by (i) reductive amination of two equivalents of a carbaldehyde bearing an 8-hydroxyquinoleic unit with one equivalent of a primary diamine carrying a polyamine chain whose primary amine functions and secondary antibodies have been protected, and then (ii) deprotection of the protected functions, said carbaldehyde being in position 2 of the 8-hydroxyquinoline unit.
- the primary and secondary amino functions of the polyamine chain can be protected and deprotected as previously taught.
- Raney nickel (50% by weight in aqueous solution) is washed in ethanol (and permanently stored in the wet state in solvent because the compound is pyrophoric).
- the intermediate product obtained in the preceding step (2.00 g, 5.6 mmol) and NH 4 OH are added.
- Argon is bubbled for 20 minutes.
- the suspension is hydrogenated at 20 bar for 24 hours, Raney nickel is filtered on celite (Raney nickel is permanently stored in the wet state with ethanol).
- Ethanol and NH 4 OH are evaporated under vacuum and the oily residue is dissolved in CH 2 Cl 2 and washed with a 10% aqueous solution by weight of NaOH (3 * 50ml).
- the organic phase is dried with Na 2 S0 4 , filtered and the solvent is evaporated under vacuum to give the 5 'product (98%).
- Reagent 7 is a commercially available reagent. It can be obtained from product 6 according to the following reaction scheme:
- FIRE ILLE DE REM PLACEM ENT (RULE 26) The mixture is stirred for 12 hours until the aldehyde is consumed (followed by thin layer chromatography). The reaction is stopped by adding 10 ml of an aqueous solution of NaOH (1 mol / liter). The mixture is stirred for a further 20 minutes and the product is extracted with dichloromethane (3 times), dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (chloroform / methanol / ammonia: (94: 5: 1)). A pale yellow oil is obtained (91%).
- IR (KBr): ⁇ 3053, 2982, 2934, 1706, 1683, 1575, 1507, 1475, 1455, 1420, 1391, 1366, 1265, 1168, 1047 cm -1 .
- the diprotected compound is dissolved in 5 ml of ethanol and then 6 ml of an aqueous hydrochloric acid solution (6 mol / l) is added at 0 ° C. The mixture is stirred for 24 hours and the solvent is evaporated. The solid is taken up in a minimum of ethanol and the precipitate is filtered under vacuum and dried for 6 hours in a pump (73%).
- the protected product (100 mg, 0.188 mmol) is dissolved in 1 ml of ethanol and then an excess of an aqueous solution of hydrochloric acid (6 mol / l) is added. The solution is mixed at room temperature for 24 hours, the solvents are evaporated under vacuum. The product obtained is a yellow solid (60 mg, 96% yield).
- FIG. 1 shows the contribution of the polyamine chain in the iron chelation by the Quilamines according to the invention
- FIG. 3 shows the effects of quilamine HQ1-44 () and reference chelators, 8-hydroxyquinoline (HQ, ⁇ ) and deferasirox TM (ICL670, ⁇ ) on the viability of hamster ovary cells, the line wild (CHO, solid curves) and the mutant strain deficient for the Polyamine Transport System (CHOMG, dashed lines);
- FIG. 4 shows the influence of the exogenous micromolar iron (dashed lines) on the viability of hamster ovary cells (CHO), exposed to different concentrations of compounds, namely the quilamine HQ1-44 () and the chelators of reference, 8-hydroxyquinoline (HQ, ⁇ ) and deferasirox TM (ICL670, ⁇ );
- FIG. 5 shows the effects of Quilamines and the reference chelator, 8-hydroxyquinoline (8-HQ) on the viability of tumor cells from human hepatocarcinoma (HepG2);
- FIG. 6 shows the influence of STP on the viability of human hepatocarcinoma cells (HepG2) treated with quilamine HQ1-44;
- FIG. 7 shows the effects of Quilamines and reference chelators, 8-hydroxyquinoline (8-HQ) and deferasirox TM (ICL670) on the viability of tumor cells derived from human colon adenocarcinoma (Caco-2);
- FIG. 8 shows the effect of quilamine HQ 1-44 and the reference chelator, deferasirox TM (ICL670) on the expression of iron metabolism genes of human colon adenocarcinoma cells (Caco-2)
- FIG. 10 shows the effect of the quilamine HQ1-44 and the reference chelator, deferasirox TM (ICL670) on the expression of genes of the polyamine metabolism of human colon adenocarcinoma cells (Caco-2);
- Figure 1 1 shows the effect of quilamine HQ1-44 and the reference chelator, deferasirox TM (ICL670) on the polyamine metabolism of human colon adenocarcinoma cells (Caco-2).
- the fluorescence of calcein is detected in a microplate, at a concentration of 0.1 micromol per liter, in solution in a HEPES (4- (2-hydroxyethyl) -1- piperazine ethanesulfonic acid) at pH 7.4, in a Fusion-type fluorescence fluorescence reader (Packard), under excitation at 450 nanometers and analysis of the fluorescence emission at 515 nanometers.
- the fluorescence of calcein is quenched in the presence of iron (III) in hydrochloride (chloride) form at a concentration of 1 micromole per liter.
- the tests showed that the Quilamines according to the invention have a better chelating capacity with respect to the two chelators tested for chelator concentrations of less than 0.2 micromole per liter.
- HQ1-3 type quilamines HQ1-34, HQ1-344, HQ1-343, HQ1-33, HQ1-333
- the interaction of quilamine HQ1-44 with iron (Fe3 +) was evaluated, thanks to the characteristic transition at 580nm observed in the absorption spectrum of the quilamine complex HQ1-44 with Fe (III).
- the continuous variation method consists of measuring the amount of complex formed between quilamine and Fe (III), deduced from the value of the absorption at 580 nm, by varying the ratio of quilamine / quilamine concen trations. + Fe (III) for a total Quilamine + Fe (III) concentration constant and equal to 100 micromoles per liter (Tris / HCl buffer 100 millimoles per liter, pH 7.4).
- the continuous variations method showed that quilamine HQ1-44 forms a complex with Fe (III) with ligand / iron stoichiometry of 2/1 at physiological pH.
- Potentiometric measurements were made in thermostatically controlled titration cells at 25 ⁇ 0.1 ° C, using a Metrohm 702 SM Titrino connected to a Metrohm 6.0233.100.
- the ligand solution is prepared at a concentration of ⁇ 1.5 x 10 3 moles per liter
- the Fe 3+ solution is made from FeCl 3 and titrated by complexation with a standard solution of EDTA (ethylenediaminetetraacetic acid).
- the sample for the measurement contains approximately 0.03 millimoles per liter of ligand in a volume of 30 ml or the ionic strength is maintained at 0.1 mol per liter using KN0 3 as the supporting electrolyte.
- Fe 3+ is added to 0.45 or 0.9 equivalents of ligand.
- Each titration consists of 150-200 equilibrium points at a pH ranging from 2.0 to 1.5, and is repeated at least twice.
- the thermodynamic constants are calculated with the HYPERQUAD software and the species speciation diagram is made by the Hyss program.
- the in vitro efficacy of different Quilamines was tested on a wild-type hamster ovary (CHO) cell line with PBS, and a CHO-MG mutant line lacking PBS.
- the two CHO and CHO-MG cell types were treated 24h after their seeding in 96-well microplates by concentrations of the different Quilamines of between 0.1 and 400 micromoles per liter.
- the cytostatic (antiproliferative) and cytotoxic effects of quilamine after 72 h of cell treatment were evaluated respectively by counting the cell nuclei after labeling the DNA with the Hoescht 33342 fluorescent intercalator and by analyzing the membrane damage, detected by the assay for lactate dehydrogenase (LDH) activity in the supernatants).
- LDH lactate dehydrogenase
- the IC50 inhibitory concentration corresponding to the concentration of Quilamines for 50% inhibition of cell proliferation, was deduced from the dose-response counting curves of living cell nuclei on the CHO and CHO-MG lines. These dose-effect curves are sometimes biphasic, as in the case of quilamine HQ1-44 which has an antiproliferative component (without concomitant release of LDH in the supernatant) in the range of concentrations between 0.4 and 3 micromoles per liter and second cytotoxic component accompanied by a membrane toxicity resulting in a release of LDH, for concentrations greater than 2 micromoles per liter.
- the lower the IC50 value the more effective the anti-proliferative effect of the tested chelators.
- Table 2 Influence of the Polyamine Transport System on the selectivity of the antiproliferative action of Quilamines compared to that of the reference chelators, 8-hydroxyquinoline (8-HQ) and deferasirox TM (ICL670).
- the compound HQ1-44 is characterized by an IC50 of 1.4 micromoles per liter on the CHO line and 344 micromoles per liter on the CHO-MG line. This compound has the most effective antiproliferative effect and is best recognized by STP.
- poly (n-butylamine) chains (HQ1-44 and HQ 1-444) appear to be more selectively recognized by PBS than poly (n-propylamine) chains (HQ1-33).
- the quilamines of the invention tested all have excellent recognition by the STP compared to the known chelators 8-hydroxyquinoline and ICL670.
- 8-hydroxyquinoline causes a decrease in the number of viable cells associated with LDH release (cytotoxic effect).
- 8-hydroxyquinoline exerts a cytotoxic effect from a chelating concentration greater than or equal to 5 micromoles per liter.
- iron Exogenous there is no change in the cytotoxic action of 8-hydroxyquinoline.
- the dose-response curves for ICL670 are biphasic, like that of quilamine HQ1-44.
- a cytostatic effect is observed without membrane alteration for chelating concentrations of between 3 and 10 micromoles per liter and a cytotoxic effect for chelating concentrations of greater than 10 micromoles per liter, resulting in the release of LDH.
- an inhibition of the cytostatic and cytotoxic effects induced by this chelator is observed.
- Quilamine HQl-44 is therefore less toxic than 8-hydroxyquinoline and retains an antiproliferative action even in case of sideric overload unlike ICL670, which is of some interest for treating proliferative diseases and / or related to an overload.
- iron in the cells The absence of inhibition of the antiproliferative effect of quilamine in the presence of exogenous iron suggests that the antiproliferative action of quilamine is not associated solely with its iron depletion capacity in cells. It could also be associated with the HQ1-44 inhibition capacity of polyamine metabolism, as shown below in Caco-2 cells ( ⁇ 4).
- the efficacy of Quilamines was analyzed on hepatocyte cells of the HepG2 tumor line derived from a human hepatocarcinoma, and compared with that of ICL670, in the presence or absence of exogenous iron.
- the proliferating HepG2 cell cultures were treated 24h after their seeding in 96-well microplates by concentrations of the different Quilamines ranging from 0.1 to 400 micromoles per liter.
- the cytostatic (antiproliferative) and cytotoxic effects of quilamine after 72 hours of treatment cells were evaluated respectively by counting the cell nuclei after labeling the DNA with the Hoescht 33342 fluorescent intercalator or the mitochondrial succinate dehydrogenase (SDH) activity and by analyzing the membrane damage detected by the activity assay. lactate dehydrogenase (LDH) in the supernatants. The results obtained on the SDH activity are given in FIG.
- Table 3 Antiproliferative effect of Quilamines compared to that of the reference chelator, deferasirox TM (ICL670), in human hepatocarcinoma cells (HepG2).
- HQ1-44 The antiproliferative efficacy of HQ1-44 is highest after ICL670, followed by the compounds HQ1-443, HQ1-333 and HQ1-343.
- ODC ornithine decarboxylase
- the competitive inhibition of PBS by spermidine is caused by co-treatment of cells with Quilamines in the presence of spermidine at a concentration of 50 micromol per liter.
- the effect of Quilamines on cell viability was analyzed on the enterocyte cells of the Caco-2 tumor line, derived from a carcinoma of the human colon and compared with the action of ICL670, in the presence or absence of exogenous iron. after activation (DFMO) or competitive inhibition by spermidine, of STP.
- the operating conditions used are identical to those used for the CHO / CHO-MG and HepG2 cells.
- the dose-response curves of the action of Quilamines on the number of viable cells are biphasic with a cytostatic component for concentrations of less than 30 micromoles per liter and a cytotoxic component with release of LDH for concentrations greater than 30 micromoles per liter. Only this second cytotoxic component is observed when the cells of the Caco-2 line are treated after confluence (cessation of proliferation).
- Table 4 Antiproliferative effect of Quilamines compared to those of the reference chelators, 1 to 8-hydroxyquinoline (8-HQ) and deferasirox TM (ICL670), in human colon adenocarcinoma cells (Caco-2).
- cDNAs (Deoxyribonucleic Acid Complementary) synthesized during reverse transcription are amplified by qPCR (amount of polymerase chain reaction) to quantify the expression of mRNA (messenger ribonucleic acid) genes involved in the metabolism of iron.
- quilamine HQ1-44 and ICL670 at a concentration of 10 micromoles per liter do not significantly modify the expression of genes coding for the iron storage protein, L -ferritin (L-Fer), and for the main route of entry of iron into the cell, the transferrin receptor (RTrf). Exposure of cells to iron-saturated transferrin (holotransferrin) does not alter the expression of L-Ferritin and reduces transferrin receptor expression.
- the iron overload induced by exposure for 72 h to 20 micromoles per liter of iron-citrate is accompanied by a small increase in the expression of L-ferritin (not significant) and an inhibition of expressing of the transferrin receptor, in accordance with the IRL7IRP regulation of these two genes.
- the treatment for 72 hours of Caco-2 proliferating cells, by the chelators HQ1-44 and ICL670 at the concentration of 10 micromoles per liter has no effect on the expression of the genes involved in the regulation of polyamine metabolism, such as that of the ODC of antizyme (OAZ1), S-adenosyl methionine decarboxylase (SAMDC) and that of polyamine oxidase (PAO).
- Citrate alone causes the reduction of the expression of genes involved in the polyamine biosynthesis pathway (ODC and SAMDC).
- ODC and SAMDC S-adenosyl methionine decarboxylase
- PAO polyamine oxidase
- Citrate alone causes the reduction of the expression of genes involved in the polyamine biosynthesis pathway (ODC and SAMDC).
- ODC and SAMDC the iron overload caused by holotransferrin or iron-citrate has no effect on the expression of the genes of the polyamine metabolism.
- Iron overload does not alter the concentrations of natural polyamines (Putrescine, spermidine and spermine).
- the intracellular concentrations of putrescine (Put) and spermidine (Spd) are lowered after treatment with Quilamine HQ1-44 (-73% Put, -55% Spd) and to a lesser degree by ICL670 (-34 % Put, -15% Spd).
- This reduction in Put associated with a smaller decrease in Spd and no effect on intracellular Spm, is comparable to the effect of DFMO, an inhibitor of ODC.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP12810215.9A EP2794570A1 (fr) | 2011-12-20 | 2012-12-18 | Composés chélateurs de métal présentant au moins une chaîne polyaminée |
CA2860520A CA2860520A1 (fr) | 2011-12-20 | 2012-12-18 | Composes chelateurs de metal presentant au moins une chaine polyaminee |
US14/367,493 US20140364454A1 (en) | 2011-12-20 | 2012-12-18 | Metal-chelating compounds having at least one polyamino chain |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1162108 | 2011-12-20 | ||
FR1162108A FR2984317B1 (fr) | 2011-12-20 | 2011-12-20 | Composes chelateurs de metal presentant au moins une chaine polyaminee. |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2013092556A1 true WO2013092556A1 (fr) | 2013-06-27 |
Family
ID=47504922
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2012/075907 WO2013092556A1 (fr) | 2011-12-20 | 2012-12-18 | Composés chélateurs de métal présentant au moins une chaîne polyaminée |
Country Status (5)
Country | Link |
---|---|
US (1) | US20140364454A1 (fr) |
EP (1) | EP2794570A1 (fr) |
CA (1) | CA2860520A1 (fr) |
FR (1) | FR2984317B1 (fr) |
WO (1) | WO2013092556A1 (fr) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105949120B (zh) * | 2016-05-27 | 2018-07-24 | 广东工业大学 | 一种四齿螯合型单喹啉衍生物及其制备方法和作为神经退行性疾病的金属离子调节剂的应用 |
CN116410132B (zh) * | 2023-02-23 | 2024-07-09 | 广东工业大学 | 一种8-羟基喹啉类化合物及其制备方法和在制备抗肿瘤药物上的应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS421872B1 (fr) * | 1964-11-26 | 1967-01-27 | ||
EP1667727A2 (fr) | 2003-09-09 | 2006-06-14 | University of Florida Research Foundation, Inc. | Conjugues polyamine-chelateur de metal |
WO2007068316A1 (fr) * | 2005-12-13 | 2007-06-21 | Merck Patent Gmbh | Derives d’hydroxyquinoleine |
WO2007147217A1 (fr) * | 2006-06-22 | 2007-12-27 | Prana Biotechnology Limited | Procédé de traitement d'une tumeur cérébrale gliome |
-
2011
- 2011-12-20 FR FR1162108A patent/FR2984317B1/fr not_active Expired - Fee Related
-
2012
- 2012-12-18 CA CA2860520A patent/CA2860520A1/fr not_active Abandoned
- 2012-12-18 EP EP12810215.9A patent/EP2794570A1/fr not_active Withdrawn
- 2012-12-18 WO PCT/EP2012/075907 patent/WO2013092556A1/fr active Application Filing
- 2012-12-18 US US14/367,493 patent/US20140364454A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS421872B1 (fr) * | 1964-11-26 | 1967-01-27 | ||
EP1667727A2 (fr) | 2003-09-09 | 2006-06-14 | University of Florida Research Foundation, Inc. | Conjugues polyamine-chelateur de metal |
WO2007068316A1 (fr) * | 2005-12-13 | 2007-06-21 | Merck Patent Gmbh | Derives d’hydroxyquinoleine |
WO2007147217A1 (fr) * | 2006-06-22 | 2007-12-27 | Prana Biotechnology Limited | Procédé de traitement d'une tumeur cérébrale gliome |
Non-Patent Citations (6)
Title |
---|
DING, W.Q. ET AL.: "Anticancer activity of the antibiotic clioquinol", CANCER RES, vol. 65, no. 8, 2005, pages 3389 - 95, XP002371610, DOI: doi:10.1158/0008-5472.CAN-04-4385 |
GABORIAU, F. ET AL.: "Modulation of cell proliferation and polyamine metabolism in rat liver cell cultures by the iron chelator O-trensox", BIOMETALS, vol. 19, no. 6, 2006, pages 623 - 32, XP019447388, DOI: doi:10.1007/s10534-006-6888-y |
RICHARDSON, D.; P. PONKA; E. BAKER: "The effect of the iron(III) chelator, desferrioxamine, on iron and transferrin uptake by the human malignant melanoma cell", CANCER RES, vol. 54, no. 3, 1994, pages 685 - 9 |
RICHARDSON, D.R.: "Potential of iron chelators as effective antiproliferative agents", CAN J PHYSIOL PHARMACOL, vol. 75, no. 10-11, 1997, pages 1164 - 80 |
SEILER N.: "Thirty years of polyamine- related approaches to cancer therapy. Retrospect and prospect. Part 1. Selective enzyme inhibitors", CURRENT DRUG TARGETS., vol. 4, 2003, pages 537 - 64 |
YAMASAKI, T.; S. TERAI; I. SAKAIDA: "Deferoxamine for advanced hepatocellular carcinoma", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 365, no. 6, 2011, pages 576 - 77 |
Also Published As
Publication number | Publication date |
---|---|
US20140364454A1 (en) | 2014-12-11 |
CA2860520A1 (fr) | 2013-06-27 |
FR2984317B1 (fr) | 2015-02-27 |
FR2984317A1 (fr) | 2013-06-21 |
EP2794570A1 (fr) | 2014-10-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Kizek et al. | Anthracyclines and ellipticines as DNA-damaging anticancer drugs: recent advances | |
JP7221227B2 (ja) | 発毛を調節するための組成物及び方法 | |
US6391895B1 (en) | Nitric oxide releasing chelating agents and their therapeutic use | |
US20080096974A2 (en) | Polyamine-Metal Chelator Conjugates | |
AU2016334396B2 (en) | (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid, and related compounds as GABA aminotransferase inactivators for the treatment of epilepsy, addiction and hepatocellular carcinoma | |
JP7045985B2 (ja) | Ezh2阻害剤を用いた髄芽腫の処置方法 | |
JP5295652B2 (ja) | 光障害の軽減剤 | |
CN107353313B (zh) | 新化学实体钙锰福地吡和其他混合金属配合物、制备方法、组合物以及治疗方法 | |
JP5367377B2 (ja) | 炎症性疾患治療のためのランチオニン関連化合物 | |
WO2013092556A1 (fr) | Composés chélateurs de métal présentant au moins une chaîne polyaminée | |
US10688087B2 (en) | Pharmaceutical compositions and therapeutic methods employing a combination of a manganese complex compound and a non-manganese complex form of the compound | |
US9815777B2 (en) | Metformin salts to treat Type2 diabetes | |
CN111201018A (zh) | 用于治疗与改变的tca循环代谢相关的病状的组合物和方法 | |
EP2139860A2 (fr) | Dérivés de la classe des hydroxyquinoléines aminées pour le traitement de cancers. | |
JP5611339B2 (ja) | 3−ヒドロキシピリジン‐4−オンのフッ素化誘導体 | |
Zhang et al. | Formation of hydroxyltetrahydropyrimidine conjugates from the reaction of heterocyclic guanines with α, β-unsaturated aldehydes | |
US20190144377A1 (en) | Reactive Oxygen Species-Sensitive Nitric Oxide Synthase Inhibitors for the Treatment of Ischemic Stroke | |
JP2019535823A (ja) | 化学療法で誘発されたpsnを防止および処置するための非遷移金属配位ジピリドキシル化合物の使用 | |
WO2022043265A1 (fr) | Compositions et méthodes comprenant de la d-cystéine ou un dérivé d de celle-ci | |
Wu | Biotransformation and Neurotoxicity of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and Its Two-electron Oxidation Product, The1-methyl-4-phenyl 1-2, 3,-dihydropyridinium (MPDP+) Species |
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: 12810215 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14367493 Country of ref document: US |
|
REEP | Request for entry into the european phase |
Ref document number: 2012810215 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012810215 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2860520 Country of ref document: CA |