Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/402—1-aryl substituted, e.g. piretanide
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• • 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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • 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
  • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

• aminopeptidase inhibitors or azaindole compounds for the prevention or treatment of cancer metastases of epithelial origin
• the present invention relates to the field of therapeutic treatment of cancers, and more particularly to the prevention or treatment of metastases, in the case of cancer in humans or animals.
• the treatment of this other part of the patients is generally a systemic treatment including, for example, the administration of chemotherapeutic drugs that interfere with the growth of the cancer cells.
• Tumor invasion processes are the main cause of death in cancer patients.
• tumor cells not only have a strong ability to proliferate, but also a strong ability to destroy tissue and infiltrate into nearby tissues, including blood vessels and lymphatics, then to migrate through the bloodstream or lymphatic circulation to tissues located at parts of the body far removed from the primary tumor.
• tumor cells have the ability to circulate and then form secondary tumors, also called metastases, in tissues distant from the primary tumor.
• metastases is a multi-stage physiological phenomenon, in which tumor cells break away from the primary tumor, invade the extracellular matrix, enter through the blood vessels, enter the vasculature by intravasation, and then stop migration into the blood or lymphatic circulation at a distant site, extravasate out of the circulation, then attach to a distant tissue and proliferate to form a secondary tumor.
• epithelium is the most abundant tissue type in the human or animal body. This is probably one of the reasons why more than 90% of human cancers originate from the malignant transformation of epithelial cells. In particular, colorectal epithelial cancer is the second leading cause of cancer death in industrialized countries.
• the mortality is not due to the primary tumor, but to metastases that spread systemically in the body, from the primary tumor.
• This malignant progression that leads to tumor invasion which is clinically manifested by the generation of metastases, is initially conditioned by the loss of cellular adhesion of certain tumor cells as well as an increase in cell motility, which results in these Invasive tumor cells leave the tissue of the primary tumor and then colonize one or more target tissues, sometimes very distant from the site of the primary tumors, in the human or animal body.
• epithelial cancers the malignant progression is accompanied by a loss of inter-cellular junctions made by E-cadherin, at the level of the primary tumor.
• colorectal cancers represent the second most common cancers in industrialized countries.
• the evolution of colorectal cancer is a succession of events that begins with an initiation phase due to a genomic dysregulation affecting the proliferative properties of cells.
• the second phase is a phase of tumor progression that leads to changes in cell morphology and the emergence of transformed cell clones.
• the last phase consists of the invasion phase following the epithelio-mesenchymal transition, defined as the ability of an epithelial cell to separate from neighboring cells and migrate to other sites in the body.
• systemic anti-cancer therapeutics have little effect on metastases, and particularly on macro-metastases, which reside in organs distant from the primary tumor site, such as the lung, the liver, bone marrow or brain.
• metastases and particularly on macro-metastases, which reside in organs distant from the primary tumor site, such as the lung, the liver, bone marrow or brain.
• cancer patients often die due to metastatic cancers caused by metastases of cancer cells.
• the search for anti-invasive molecules has generally been based on (i) the ability of candidate compounds to inhibit the growth of tumor cells, (ii) the ability of the candidate compounds to inhibit cell migration.
• the selected compounds have no effect on the spread of invasive cells and therefore no effect on the metastatic process itself.
• the compounds may have an activity of inhibiting the ability of cells to migrate into the body and forming metastases, but have no effect on metastatic cells that have already migrated.
• the present invention relates to the use of a compound selected from an aminopeptidase inhibiting compound and an aza-indole compound for the manufacture of a medicament for the prevention or treatment of cancer metastases in the man or the animal.
• an anti-metastatic compound chosen from compounds of formula ( I), (II), (III), (IV), (V) and (Vl) which are described in detail later in the present description.
• the invention relates to the use defined above, for the prevention or treatment of metastases in the case of epithelial cancers, including in the case of colorectal cancer, mammary cancer, liver, pancreas, prostate and uterus.
• FIG. 1 is a diagram illustrating the anti-metastatic effect of each of the compounds of formulas (I); (II), (III), (IV), (V) and (VI) of the invention.
• Figure 3 is a digraph illustrating the anti-metastatic effect of each of the compounds of formulas (I); (II), (III), (IV), (V) and (VI) of the invention.
• On the abscissa from left to right: (i) cells of the colo-rectal metastatic SK-CoI line (ATCC No. HTB-77) incubated with the culture medium alone or supplemented with each of the compounds of formula (I), ( II), (III), (IV), (V) and (VI).
• the results shown in Figure 3 are an average of three experiments.
• Figure 4 is a digraph illustrating the anti-metastatic effect of each of the compounds of formulas (I); (II), (III), (IV), (V) and (VI) of the invention.
• the present invention provides novel means for preventing or treating metastasis in various cancers, particularly in epithelial cancers, including colorectal cancers, breast cancers, liver cancers, pancreatic cancers, Prostate and cancers of the uterus.
• aminopeptidase inhibiting compounds and compounds of the azaindole family have the ability to inhibit or block invasive properties. of cancer cells initially capable of generating metastases.
• aminopeptidase inhibiting compounds and compounds of the azaindole family have the capacity to inhibit or block the migration properties of metastatic cells originating from various epithelial cancers, such as colo-rectal cancers or breast cancers.
• the identification of the anti-metastatic properties of these compounds has enabled the applicant to develop pharmaceutical compositions for preventing or treating cancer metastases in humans or animals, comprising as active ingredient at least one selected compound. from an aminopeptidase inhibitor compound and an azaindole compound.
• This identification of new preventive or therapeutic properties has made possible the use of these compounds for the manufacture of pharmaceutical compositions with anti-metastatic activity.
• the present invention relates to a compound selected from an aminopeptidase inhibiting compound and an aza-indole compound for the prevention or treatment of cancer metastasis in humans or animals.
• the present invention also relates to the use of a compound selected from an aminopeptidase inhibiting compound and an aza-indole compound for the manufacture of a medicament for the prevention or treatment of cancer metastases in humans or the animal.
• the aminopeptidase inhibiting compounds and the aza-indole compounds identified according to the invention have the capacity to induce a reversion of the invasive phenotype of cancer cells such as metastatic colorectal carcinoma cells and metastatic mammary adenocarcinoma cells.
• the Applicant has shown that the aminopeptidase inhibiting compounds and the azaindole compounds identified according to the invention are not cytotoxic.
• the applicant believes that the anti-metastatic properties of the aminopeptidase inhibiting compounds and of the aza-indole compounds identified according to the invention are due to the common ability of all these compounds to induce the restoration of cellular junctions associated with the expression of E-cadherin on the surface of metastatic cancer cells.
• an anti-metastatic compound which is used according to the invention, consists of an aminopeptidase inhibiting compound of formula (I) below:
• the compound of formula (I) is also referred to herein as the compound 2- (4 - [(4-amino-1, 2,5-oxadiazol-3-yl) (hydroxyimino) methyl] -1-piperazinyl) ethanol .
• the compounds of formula (I) can be synthesized according to any synthesis method known to those skilled in the art. In order to synthesize a compound of formula (I), those skilled in the art may in particular refer to the method described in the following document: Synthesis of secondary and tertiary aminofurazans. Sheremetev, AB; Andrianov, VG; Mantseva, EV; Shatunova, EV; Aleksandrova, NS; Yudin, I. L .;
• an anti-metastatic compound which is used according to the invention, consists of an azaindole compound of formula (II) below:
• R 1 group is a linear or branched alkyl having from 1 to 8 carbon atoms
• Alkyl means a linear or branched aliphatic hydrocarbon group optionally interrupted by a heteroatom, the alkyl may be unsubstituted or substituted on the carbon atoms by one or more identical or different substituents, the substituents being chosen from: aryl, hydroxy, alkoxy, aryloxy, alkyloxy, aralkyloxy.
• branched alkyl is meant lower alkyl, having
• alkyl groups consist of alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
• alkyl groups are methyl, ethyl, n-propyl, n-butyl, heptyl, decyl or cyclohexylmethyl.
• alkoxy is meant an alkyl-O- group in which the alkyl group is as previously defined.
• Alkoxy groups include methoxy, ethoxy, n-propoxy, n-propoxy, n-butoxy and heptoxy.
• aryloxy is meant an aryl-O group in which the aryl group is as previously defined.
• Aryloxy groups include phenoxy and naphthoxy.
• aralkyl is meant an alkyl group substituted with one or more aryl groups.
• aralkyloxy is meant an aralkyl-O- group in which the aralkyl group is as previously defined.
• Aralkyloxy groups include benzyloxy.
• a compound of formula (II) which is preferred according to the invention is the compound in which the group R 1 denotes a propyl group, which may also be designated in the present description as the compound methyl 4 - [([3- (4-fluorophenyl) 4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene) methyl) benzoate.
• the compounds of formula (II) can be synthesized according to any synthesis method known to those skilled in the art.
• those skilled in the art can in particular refer to the process described in the following document: quinazolinone compounds. (Tanabe Seiyaku Co., Ltd., Japan). Jpn. Kokai Tokkyo Koho (1982), 5 pp. CODEN: JKXXAF JP 5701 1970 To 19820121 Showa. Patent written in Japanese. Application: JP 80-86044 19800624. Priority:. CAN 97: 72383 AN 1982: 472383 CAPLUS
• said compound consists of an azaindole compound of formula (III) below:
• R 1 , R 2 , R 3 and R 4 each represent, independently of one another, an alkyl of 1 to 8 carbon atoms, the definition of which is identical to that of the R 1 group of the compound of formula (II).
• a preferred compound of formula (III) is the compound wherein R 1 is methyl and R 2 , R 3 and R 4 are ethyl, said compound may be designated as 3,4 5-triethoxy-N- (2-methyl-4-nitrophenyl) benzamide.
• the compounds of formula (III) can be synthesized according to any synthesis method known to those skilled in the art.
• a person skilled in the art can in particular refer to the process described in the following document: Microwave-assisted synthesis of salicylamide via BCI3 mediated coupling. Zhang, Lei; Zhang, John Y. CytRx Laboratories, Inc., Worcester, MA, USA. Journal of Combinatorial Chemistry (2005), 7 (4), 622-626. Publisher: American Chemical Society, CODEN: JCCHFF ISSN: 1520-4766. Journal written in English. CAN 143: 21 1699 YEAR 2005: 538799 CAPLUS According to a fourth embodiment of an antimetastatic compound which is used according to the invention, said compound consists of an azaindole compound of formula (IV) below:
• R 1, R 2 and R 3 represent, independently of one another, a halogen selected from a fluorine (F), chlorine (C) I, iodine (I) and bromine atom; (B) r.
• a compound of formula (IV) which is preferred according to the invention is the compound in which the groups R 1 and R 3 each signify a chlorine atom and the group R 2 signifies a bromine atom, which compound can also be designated as the compound 5 - (5-Bromo-3-chloro-2-hydroxybenzylidene) -1- (4-chlorophenyl) -2,4,6 (1H, 3H, 5H) -pyrimidinetrione.
• the compounds of formula (IV) can be synthesized according to any synthesis method known to those skilled in the art.
• those skilled in the art may in particular refer to the method described in the following document: Synthesis of pyrimidine derivatives possessing an antioxidative property and their inhibitory effects on picryl chloride-induced contact hypersensitivity reaction. Isobe, Yoshiaki; Hirota, Kosaku. Pharmaceutical and Biotechnology Laboratory, Japan Energy Corporation, Saitama, Japan. Chemical & Pharmaceutical Bulletin (2003), 51 (12), 1451-1454. Publisher: Pharmaceutical Society of Japan, CODEN: CPBTAL ISSN: 0009-2363. Journal written in English. CAN 140: 174446 YEAR 2003: 989349 CAPLUS
• an anti-metastatic compound which is used according to the invention, consists of an azaindole compound of formula (V) below:
• the group R 1 is a halogen selected from a fluorine (F), chlorine (C) I, iodine (I) and bromine (B) r atom
• the group R 2 is a linear or branched alkyl having from 1 to 8 carbon atoms, the definition of which is identical to that of the R 1 group of the compound of formula (II).
• a preferred compound of formula (V) is the compound in which the group R 1 means a bromine atom and the group R 2 signifies an ethyl group, which compound can also be designated as the 5-bromo-N- (4-butoxyphenyl) compound nicotinamide.
• the compounds of formula (V) can be synthesized according to any synthesis method known to those skilled in the art.
• a person skilled in the art can in particular refer to the method described in the following document: Application of organolithium and related reagents in synthesis, 30. Behavior of N-pyridylbenzamides versus benzanilides in the ortho-directed lithiation of masked aromatic carboxylic acids. Jozwiak, Andrzej; Brzezinski, Jacek Z .; Plotka, Mieczyslaw W .; Szczesniak, Aleksandra K.; Malinowski, Zbigniew; Epsztajn, Jan.
• said compound consists of an azaindole compound of formula (VI) below:
• group R 1 is a halogen selected from a fluorine (F), chlorine (C) I, iodine (I) and bromine (B) r.
• the compound of formula (VI) may also be designated the compound 3-chloro-1-phenyl-4 - [(2-phenylethyl) amino] -1 Hpyrrole-2,5-dione.
• the compounds of formula (VI) can be synthesized according to any synthesis method known to those skilled in the art.
• the compounds of formula (VI) consist of compounds readily available commercially. There may be mentioned in particular the compound of formula VI consisting of 3-chloro-1-phenyl-4 - [(2-phenylethyl) amino] -1H-pyrrole-2,5-dione, which is marketed by the company Chembridge ( San Diego, United States of America) under the reference ID 6137235.
• the preferred active ingredients which are used to manufacture a medicament for the prevention or treatment of cancerous metastases in humans or animals are chosen from: - methyl 4 - [([3- (4-fluorophenyl) -4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene) methyl) benzoate; 3,4,5-triethoxy-N- (2-methyl-4-nitrophenyl) benzamide; 5- (5-bromo-3-chloro-2-hydroxybenzylidene) -1- (4-chlorophenyl) -
• the aminopeptidase inhibiting compounds and the azaindole compounds of interest according to the invention are used for the manufacture of a medicament intended for the prevention or treatment of epithelial cancers.
• the aminopeptidase inhibiting compounds and the azaindole compounds of interest according to the invention are used for the manufacture of a medicament intended for the prevention or treatment of an epithelial carcinoma chosen from a colon cancer. rectal and breast cancer.
• compositions according to the invention mention may be made more particularly of those which are suitable for oral, parenteral, nasal, percutaneous, transcutaneous, rectal, perlingual or respiratory administration and in particular simple or coated tablets, sublingual tablets, capsules , tablets, suppositories, creams, ointments, dermal gels, and oral or injectable ampoules.
• the dosage varies according to the sex, the age and the weight of the patient, according to the route of administration, and according to the type of cancer, the state of progression of the cancer, in particular according to whether metastases have been detected or not in the patient.
• the dosage may also vary depending on the type of the associated anti-cancer treatment (s).
• an anti-metastatic compound as defined in the present description is used in amounts ranging from 0.01 mg to 1 g per 24 hours for a man or an adult woman with an average weight of 80 kg, in one or more catches.
• a pharmaceutical composition according to the invention comprises the anti-metastatic compound in combination with at least one excipient selected from the group consisting of pharmaceutically acceptable excipients.
• a pharmaceutical composition according to the invention comprises from 0.01% to 99% by weight, and advantageously from 1% to 90% by weight, of an antimetastatic compound, relative to the total weight of said composition.
• a pharmaceutical composition according to the invention comprises from 1% to 99.99% by weight, and preferably from 10% to 99% by weight, of an excipient or a combination of pharmaceutically acceptable excipients.
• the pharmaceutical composition of the present invention can be used for parenteral, topical or local administration and prophylactically and / or therapeutically.
• the anti-metastatic compound according to the present invention is prepared in a form adapted to the type of administration chosen, for example in liquid form or in freeze-dried form.
• the pharmaceutical compositions comprising an anti-metastatic compound according to the invention may contain an excipient and / or a pharmaceutically acceptable vehicle, preferably an aqueous vehicle.
• compositions for example, water, buffered water, saline solution, glycine solution and their derivatives as well as agents necessary to reproduce physiological conditions such as buffering agents and pH adjusters, surfactants such as sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, this list not being limiting.
• the pharmaceutical composition can be sterilized by sterilization techniques well known to those skilled in the art.
• excipients or inert, non-toxic, pharmaceutically acceptable vehicles mention may also be made, by way of indication and without limitation, of diluents, solvents, preservatives, wetting agents, emulsifiers, dispersing agents, binders, blowing agents, disintegrants, retardants, lubricants, absorbents, suspending agents, dyes, flavoring agents, etc.
• the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
• a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
• the tablets may be coated with sucrose or other suitable raw materials or may be treated so that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient.
• a preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
• a pharmaceutical composition in the form of a syrup or elixir may contain the active ingredient together with a sweetener, preferably a calorie-free sweetener, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and a suitable colorant.
• a sweetener preferably a calorie-free sweetener, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and a suitable colorant.
• the water-dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents or suspending agents, such as polyvinylpyrrolodinone, as well as with sweeteners or scavengers. taste.
• the active ingredient may also be formulated in the form of microcapsules, optionally with one or more supports or additives.
• a person skilled in the art can advantageously refer to the latest edition of the European Pharmacopoeia, for example at the 5th edition of the Pharmacopoeia. European published in January 2005, or even the 6th edition of the European Pharmacopoeia, available to the public in June 2007.
• a pharmaceutical composition as defined above is suitable for oral, parenteral or intravenous administration.
• the pharmaceutical composition according to the invention comprises at least one pharmaceutical or physiologically acceptable excipient
• it is in particular a suitable excipient for administration of the composition orally or of a suitable excipient for administration of the composition parenterally.
• the invention also relates to a method for preventing or treating a disorder related to an imbalance of bone metabolism, particularly a disorder associated with loss of bone mass, said method comprising a step in which patients are administered a therapeutically therapeutic amount. effective of an anti-metastatic compound as defined in the present description or a pharmaceutical composition containing said anti-metastatic compound.
• a pharmaceutical composition comprising an antimetastatic compound according to the invention is indifferently in a solid form or in a liquid form.
• a solid pharmaceutical composition in the form of tablets, capsules or capsules, will be preferred.
• a pharmaceutical composition in the form of an aqueous suspension or a non-aqueous suspension, or in the form of a water-in-oil or oil-in-water emulsion, is preferred.
• Solid pharmaceutical forms may include, as carriers, adjuvants or excipients, at least one diluent, flavor, solubilizer, lubricant, suspending agent, binder, disintegrating agent, and agent. encapsulation.
• diluent for example, magnesium carbonate, magnesium stearate, talc, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, cocoa butter, and the like.
• compositions in liquid form may also comprise water, optionally mixed with propylene glycol or polyethylene glycol, and optionally also coloring agents, flavors, stabilizers and thickeners.
• Example 1 Anti-invasive properties of the anti-metastatic compounds of the invention.
• OPD o-Phenylenediamine
• the compounds of formula (I) to (VI) were tested for their ability to induce the restoration of inter-cellular junctions in in vitro cultures of SW620 igneous cells, using the E-cadherin labeling assay described in US Pat. Part Material and Methods.
• As a negative control the cells of the SW620 line incubated in the culture medium alone were used in the absence of an anti-metastatic compound. An average O.D. of 0.147 was obtained.
• the tests were carried out by incubating the cells of the SW620 line with each of the compounds (I) to (VI).
• the average OD obtained with each of the compounds (I) to (VI) has always been greater than 0.300, which means that the compounds (I) to (VI) are capable of inducing cell spreading, formation of compact cell islands, and to induce the generation of E-cadherin-type inter-cellular neo-junctions.
• the cells of the SW620 metastatic line incubated in the absence of anti-metastatic compound were used as a negative control, whose control value was arbitrarily set at 100%.
• Cells of the non-metastatic cancerous line HCT116 were used as a positive control.
• FIG. 1 it is shown that all the compounds of formula (I) to (VI) are capable of blocking the invasive properties of the cells of the metastatic colo-rectal cancer cell line, since the treated cells have a similar invasive activity or lower than that of the HCT1 line 16 of non-metastatic colorectal cancer.
• FIGS. 2, 3 and 4 show that the anti-invasive properties of each of the compounds of formula (I) to (VI) are demonstrated on various types of metastatic human cancer cells, including cells originating from breast cancer ( Figure 4).

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• 2008
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  • 2009-01-21 JP JP2010542670A patent/JP2011509982A/ja active Pending
  • 2009-01-21 US US12/812,501 patent/US20110046154A1/en not_active Abandoned
  • 2009-01-21 CA CA2712339A patent/CA2712339A1/fr not_active Abandoned
  • 2009-01-21 EP EP09706702A patent/EP2234610A2/de not_active Withdrawn
  • 2009-01-21 WO PCT/FR2009/050081 patent/WO2009095583A2/fr active Application Filing
  • 2009-01-21 CN CN2009801053395A patent/CN101951905A/zh active Pending

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