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WO2017005954A1 - Analogues de la mélatonine pour le traitement du cancer - Google Patents

Analogues de la mélatonine pour le traitement du cancer Download PDF

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Publication number
WO2017005954A1
WO2017005954A1 PCT/ES2016/070497 ES2016070497W WO2017005954A1 WO 2017005954 A1 WO2017005954 A1 WO 2017005954A1 ES 2016070497 W ES2016070497 W ES 2016070497W WO 2017005954 A1 WO2017005954 A1 WO 2017005954A1
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Prior art keywords
cancer
mutated
compound
composition according
pharmaceutical composition
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PCT/ES2016/070497
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English (en)
Spanish (es)
Inventor
Josefa LEÓN LÓPEZ
Jorge CASADO RUÍZ
Javier SALMERÓN CASTELAR
Sergio Manuel JIMÉNEZ RUÍZ
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Universidad De Granada
Servicio Andaluz De Salud
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Publication of WO2017005954A1 publication Critical patent/WO2017005954A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide

Definitions

  • the present invention is within the field of medicine and pharmacy, and refers to the use of agomelatine (N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide) and pharmaceutical compositions comprising agomelatine for prevention, and / or treatment of cancer, and more specifically, of colon cancer.
  • agomelatine N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide
  • pharmaceutical compositions comprising agomelatine for prevention, and / or treatment of cancer, and more specifically, of colon cancer.
  • Colorectal cancer is a neoplasm whose frequency has been increasing in recent years and will be one of the most important malignant tumors at the population level in the near future. The genetic events that lead to the onset of colon cancer have been well characterized, however.
  • Melatonin is an indolamine derived from tryptophan, originally identified as the main product of the pineal gland, but which is also synthesized in other organs. This compound can carry out its effects through its membrane receptors (MT1 and MT2, belonging to the superfamily of G-protein coupled receptors) or nuclear (RZR / ROR). It can also interact directly with cytoplasmic proteins such as calmodulin or PKC.
  • MT1 and MT2 belonging to the superfamily of G-protein coupled receptors
  • RZR / ROR nuclear
  • cytoplasmic proteins such as calmodulin or PKC.
  • One of the best known actions of the Melatonin is your ability to purify free radicals.
  • antioxidant enzymes such as superoxide dismutase, glutathione oxidase and glutathione reductase
  • prooxidant enzymes such as NOS
  • This indolamine affects cell proliferation in a variety of tumor cell lines, both in physiological and pharmacological concentrations. The intracellular mechanism of these effects seems to vary from one system to another.
  • melatonin In some models it has been proposed as responsible for its membrane receptor, while in others it has been implicated in its ability to bind calmodulin.
  • incubation with pharmacological doses of melatonin inhibits growth and induces cell cycle arrest due to changes in the cellular redox state by inactivation of the RTK / PKC / Akt / NF-kappaB () pathway.
  • melatonin can inhibit the ability to invade and metastasize as well as the angiogenesis process.
  • prostate cancer cells it induces neuroendocrine differentiation by an independent mechanism of PKA (Sainz et al., 2004. Prostate. 63 (1): 29-43).
  • MCF-7 breast cancer cells In MCF-7 breast cancer cells and at physiological doses, it promotes cell differentiation and increases the expression of the ⁇ -l and E-caderin integrin subunit. In this type of cancer it inhibits proliferation and invasion due to its interaction with the signaling pathways of the estrogen receptor (Cos et al., 2008. Curr Cancer Drug Targets. 2008 Dec; 8 (8): 691-702).
  • melatonin induces apoptosis, both in vivo and in vitro, through a mechanism that involves its nuclear receptor (Winczyk et al., 2001. J Pineal Res .31 (2): 179-82) and MT1 membrane, while in HT-29 it does so through its antioxidant effects (Garc ⁇ a-Navarro et al., 2007. J Pineal Res. 43 (2): 195- 205) and can act synergistically with selective cholecystokinin-A receptor antagonists (CCK-A) (González-Puga et al., 2004).
  • CCK-A selective cholecystokinin-A receptor antagonists
  • Agomelatine is a specific agonist of MT1 / MT2 receptors. It also has 5-HT2C antagonistic activity. It is used in the treatment of the important depressive condition. Agomelatine increases the release of norepinephrine and dopamine specifically in the frontal cortex and has no influence on the extracellular levels of serotonin. Valdoxan is the first melatoninergic antidepressant. It works by blocking 5HT2C receptors, which are normally activated by the neurotransmitter serotonin When activated, they cause anxiety, depression, social anxiety and compulsive disorders. It also increases the levels of dopamine and norepinephrine in the brain, which are associated with depression, and this improves and elevates mood.
  • agomelatine would have the same effect against cancer as melatonin, since there are several molecular mechanisms associated with this effect. It is therefore necessary to determine whether agomelatine can act as an alternative to cancer treatment.
  • One aspect of the present invention relates to the use of a compound of general formula (I) (also referred to as the compound of the invention):
  • (I) or any of its salts preferably any pharmaceutically acceptable salt, esters, tautomers, polymorphs, pharmaceutically acceptable hydrates, or an isomer, prodrugs, derivatives, solvates or the like, or any combination thereof, in the preparation of a medicament for prevention, improvement, relief and / or treatment of cancer.
  • it refers to the compound of the invention or any of its salts, preferably any pharmaceutically acceptable salt, esters, tautomers, polymorphs, pharmaceutically acceptable hydrates, or an isomer, prodrugs, derivatives, solvates or the like, or any combination thereof, for its use in the prevention, relief and / or treatment of cancer in mammals, and more preferably in humans.
  • cancer is selected from the list consisting of: colon cancer, rectal cancer, breast cancer, digestive system cancers (among which are, but are not limited to, cancer anal, esophageal, pancreatic and gastric (stomach)), head cancer, neck cancer, ovarian and cervical cancer, and basal cell skin cancer and actinic keratosis, or any combination thereof.
  • the cancer is colon cancer.
  • the cancer is a non-mutated (wild) p53 cancer.
  • the cancer is a cancer with mutated p53.
  • the p53 gene normally, when DNA mutations occur in any of the chromosomes, induces the G1 cell cycle to stop. This function apparently gives time for the repair of the mutation to take place. If repair is not possible, p53 induces apoptotic cell death. When both p53 copies mutate, the gene is not functional, and mutations throughout the genome persist and accumulate. The mutated (dysfunctional) p53 is present in 50% of all human cancers. Alterations of this gene can be studied at the level of its protein product with immunohistochemical techniques (Roa et al., 1997 .. Rev Méd Chil 125: 523-9), immunoprecipitation (Van Meir et al., 1994.
  • compositions comprising at least one compound of the invention, or a tautomer, a pharmaceutically acceptable salt, a derivative or a prodrug thereof, in the preparation of a medicament for prevention, improvement, relief and / or treatment of cancer in mammals, and more preferably in humans.
  • a pharmaceutical composition comprising at least one compound of the invention or any of its salts, preferably any pharmaceutically acceptable salt, is referred to, esters, tautomers, polymorphs, pharmaceutically acceptable hydrates, or an isomer, prodrugs, derivatives, solvates or the like, or any combination thereof, for use in the prevention, improvement, relief and / or treatment of cancer in mammals, and more preferably in humans.
  • the composition of the invention further comprises a pharmaceutically acceptable carrier or carrier, an excipient and / or
  • the pharmaceutical composition of the invention comprises as the only active ingredient a compound of the invention, or a tautomer, a pharmaceutically acceptable salt, a derivative or a prodrug thereof, although it may additionally comprise other pharmaceutically acceptable excipients and / or carriers.
  • cancer is selected from the list consisting of: colon cancer, rectal cancer, breast cancer, digestive system cancers (among which are, but not limited to, anal cancer , esophageal, pancreatic and gastric (stomach)), head cancer, neck cancer, ovarian and cervical cancer, and basal cell skin cancer and actinic keratosis, or any combination thereof.
  • the cancer is colon cancer.
  • agomelatine is useful in the treatment of both cancer with mutated p53 and cancer with non-mutated p53, presenting greater effectiveness in those cancers with non-mutated p53. Therefore, in another preferred embodiment of this aspect of the invention, colon cancer is a non-mutated (wild) p53 cancer. In another preferred embodiment of this aspect of the invention, the cancer is a cancer with mutated p53.
  • Another aspect of the invention relates to a food composition or a nutraceutical composition or a "medical food” type composition, hereafter referred to as the food composition of the invention, comprising at least the compound of the invention.
  • the food or nutraceutical composition of the invention comprises as the only active ingredient a compound of the invention, or a tautomer, a pharmaceutically acceptable salt, a derivative or a prodrug thereof, although it may additionally comprise other excipients. and / or nutraceutically acceptable vehicles.
  • Another aspect of the invention relates to the use of the food composition of the invention for the prevention, improvement, relief or treatment of cancer in mammals, and more preferably in humans.
  • the cancer refers to the use of the food composition of the invention, for the prevention and / or treatment of cancer in mammals, and more preferably in humans.
  • the cancer is selected from the list consisting of: colon cancer, rectal cancer, breast cancer, digestive system cancers (among which are, but are not limited to, anal, esophageal, pancreatic cancer and gastric (stomach)), head cancer, neck cancer, ovarian and cervical cancer, and basal cell skin cancer and actinic keratosis, or any combination thereof. Even more preferably, the cancer is colon cancer.
  • the cancer is a non-mutated (wild) p53 cancer. In another preferred embodiment of this aspect of the invention, the cancer is a cancer with mutated p53.
  • Another aspect of the invention relates to a method for the prevention, improvement, relief or treatment of a subject, preferably human, suffering from cancer, preferably colon cancer, and even more preferably non-mutated (wild) p53 colon cancer, which comprises the administration of the compound of the invention or of the pharmaceutical composition of the invention.
  • the cancer is a cancer with mutated p53. In another preferred embodiment of this aspect of the invention, the cancer is a cancer with mutated p53.
  • a component A which is selected from a compound of the invention, or a pharmaceutical composition of the invention as described herein, and
  • a component B comprising an active ingredient that is selected from the list consisting of a pyrimidine derivative, a platinum derivative, raltitrexed, paclitaxel, doxorubicin, a camptothecin derivative, or any combination thereof.
  • Another aspect of the invention relates to the use of the combined preparation of the invention for the prevention, improvement, relief or treatment of cancer in mammals, and more preferably in humans.
  • the combined preparation of the invention is referred to, for use in the prevention and / or treatment of cancer in mammals, and more preferably in humans.
  • the cancer is selected from the list consisting of: colon cancer, rectal cancer, breast cancer, digestive system cancers (among which are, but are not limited to, anal, esophageal, pancreatic cancer and gastric (stomach)), head cancer, neck cancer, ovarian and cervical cancer, and basal cell skin cancer and actinic keratosis, or any combination thereof.
  • the cancer is colon cancer.
  • the cancer is a non-mutated (wild) p53 cancer.
  • the cancer is a cancer with mutated p53.
  • FIGURES Figure 1 Inhibition of cell proliferation by melatonin (A) and agomelatine (B) in colon cancer cell lines HCT-1 16 and HCT-1 16 p53 - / -.
  • the data represent the mean ⁇ E.E.M of three experiments performed in triplicate. * P ⁇ 0.01 vs 0; ** P ⁇ 0.001 vs 0; #P ⁇ 0.01 vs HCT-1 16 p53 - / -; ## P ⁇ 0.001 vs HCT-1 16 p53 - / -.
  • FIG. 4 Alkaline phosphatase activity after treatments with melatonin (A) and agomelatine (B) of the HCT-1 16 and HCT-1 16 p53 - / - cell lines.
  • the data represent the mean ⁇ E.E.M of three experiments performed in triplicate. ** P ⁇ 0.001 vs control.
  • Figure 5 Percentage of apoptosis after treatment with melatonin (A) and agomelatine (C) in the HCT-1 16 and HCT-1 16 p53 - / - cell lines. Data represent the mean ⁇ E.E.M of three experiments performed in duplicate. * P ⁇ 0.01 vs control; ** P ⁇ 0.001 vs control. Figure 6. Expression of caspase 3 after treatment of the HCT-1 16 and HCT-1 16 p53 - / - cell lines with different doses of melatonin and agomelatine for 48 hours.
  • Figure 7 Expression of the genes of the circadian clock Perl, Per2, Per3 and Clock, after treatment with melatonin and agomelatine in the cell lines HCT-116 (A, B) and HCT-116 p53 - / - (C, D) . * P ⁇ 0.01 vs control; ** P ⁇ 0.001 vs control.
  • Figure 8. Antioxidant activity of the HCT-1 16 (A, B) and HCT-1 16 p53 - / - (C, D) cell lines after treatment with melatonin and agomelatine. In each situation the experiment was performed three times and 6 samples were analyzed per group.
  • HCT-1 16 (A) and HCT-1 16 p53 - / - (B) were treated with agomelatine (5 mg / kg), melatonin (5 mg / kg) and 5-FU (50 mg / kg) three times a week for two weeks. 8 animals were used per treatment group.
  • Agomelatine inhibits tumor growth, induces cell cycle arrest and caspase-dependent apoptosis.
  • the cell cycle stop is associated with an increase in cell differentiation.
  • the effect obtained is 10 times higher than that produced by 5- FU, the first line of chemotherapy treatment against CRC in the clinic.
  • agomelatine has fewer side effects than 5-fluorouracil, which could be considered for the treatment of this type of cancer and others in which 5-fluorouracil is used as a treatment.
  • the invention relates to the use of N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide in the preparation of a medicament for the prevention and / or treatment of cancer, preferably colon cancer, and even more preferably a cancer with p53 not mutated.
  • a first aspect of the present invention relates to the use of a compound of general formula (I) (also referred to as the compound of the invention):
  • (I) or any of its salts preferably any pharmaceutically acceptable salt, esters, tautomers, polymorphs, pharmaceutically acceptable hydrates, or an isomer, prodrugs, derivatives, solvates or the like, or any combination thereof, in the preparation of a medicament for the prevention, relief and / or treatment of cancer.
  • it refers to the compound of the invention or any of its salts, preferably any pharmaceutically acceptable salt, esters, tautomers, polymorphs, pharmaceutically acceptable hydrates, or an isomer, prodrugs, derivatives, solvates or the like, or any combination thereof, for its use in the prevention, relief and / or treatment of cancer in mammals, and more preferably in humans.
  • the cancer is selected from the list consisting of: colon cancer, rectal cancer, breast cancer, digestive system cancers (among which are, but are not limited to, the anal, esophageal, pancreatic and gastric (stomach) cancer, head cancer, neck cancer, ovarian and cervical cancer, and basal cell skin cancer and actinic keratosis, or any combination thereof.
  • the cancer is colon cancer.
  • the cancer is a non-mutated (wild) p53 cancer, although agomelatine is also effective, in cases of mutated p53 cancer, so in another preferred embodiment, the cancer is a cancer with mutated p53.
  • the p53 gene normally, when DNA mutations occur in any of the chromosomes, induces the G1 cell cycle to stop. This function apparently gives time for the repair of the mutation to take place. If repair is not possible, p53 induces apoptotic cell death. When both p53 copies mutate, the gene is not functional, and mutations throughout the genome persist and accumulate. The mutated (dysfunctional) p53 is present in 50% of all human cancers.
  • Alterations of this gene can be studied at the level of its protein product with immunohistochemical techniques (Roa et al., 1997 .. Rev Méd Chil 125: 523-9), immunoprecipitation (Van Meir et al., 1994. Cancer Res 54: 649-52) 9; at the chromosomal level (in situ hybridization, FISH) (Williams et al., 1999. Exp Mol Pathol 67: 135-43); at the gene level with molecular biology techniques based on the polymerase chain reaction (PCR). Among the latter are simple chain conformational polymorphism (SSCP) (Tamura et al., 1991. Cancer Res 51: 3056-8; Lang et al., 1999.
  • SSCP simple chain conformational polymorphism
  • DGGE gradient gel electrophoresis of Denaturation
  • Oncogene 8: 2213-20 Van Orsouw et al., 1999. Genet Anal 14: 205-13
  • heteroduplex analysis Tesongalis et al., 1994. Clin Chem 40: 485-6
  • sequencing of the amplified gene segments King et al., 1995. Cancer 1995; 75: 2700-5.
  • cancer is understood as a wide range of conditions caused by an excessive proliferation of malignant cells (also known as cancerous or cancerous), with typical behavioral and uncontrolled growth traits (growth and division beyond normal limits). , invasion of surrounding tissue and, sometimes, metastasis).
  • cancer comprises any disease of an organ or tissue in a mammal, preferably man, characterized by a poorly controlled, or uncontrolled, multiplication of normal or abnormal cells in said tissue, and their effect on the entire body.
  • cancer within this definition, includes benign neoplasms, dysplasias, hyperplasias, as well as neoplasms that show metastases, or any other transformation such as, for example, leukoplasias that often precede the outbreak of cancer.
  • Cells and tissues are cancerous when they grow and replicate more quickly than normal, moving or dispersing in the surrounding healthy tissue or any other body tissue, what is known as metastasis, assumes abnormal shapes and sizes, shows changes in its Nucleocytoplasmic ratio, nuclear polychromasia, and finally ceases.
  • Cancer cells and tissues can affect the body as a whole causing paraneoplastic syndromes, or if cancer occurs in a vital organ or tissue, its normal function being interrupted or damaged, with possible fatal results.
  • the end result of the evolution of a cancer that involves a vital organ, whether primary or metastatic, is the death of the affected mammal.
  • the cancer tends to spread, and its extent is normally related to changes in disease survival.
  • the cancer is in one of three growth stages: early or localized, when the tumor is still confined in the tissue of origin, or in its primary location; direct extension, when the cancer cells of the tumor have invaded adjacent tissue or have spread only to regional lymph nodes; or metastasis, when cancer cells have migrated to distant parts of the body from the primary location, through the circulatory or lymphatic system, and have been established in secondary locations.
  • cancer is malignant because of its tendency to cause death if it is not treated. Benign tumors do not usually cause death, although they can do so if they interfere with the normal function of the body due to its characteristics or location, size or paraneoplastic effects. Here malignant tumors fall within the definition of cancer within the scope of this definition as well.
  • cancer cells divide at a higher rate than normal cells, but the distinction between the growth of normal and cancerous tissues is not so much that cell division is much faster, such as the partial or complete loss of stopping your growth and differentiate into a useful and limited tissue, of the type that characterizes the functional balance of normal tissue growth.
  • Cancer tissue can express certain receptor molecules and are probably influenced by susceptibility and immunity, and it is known that certain prostate and breast cancers, for example, depend on certain hormones.
  • cancer herein is not simply limited to benign neoplasms, but also includes other benign or malignant neoplasms such as: 1) Carcinoma, 2) Sarcoma, 3) Carcinosarcoma, 4) Blood-forming tissue cancers, 5) nerve tissue tumors, including the brain, 6) skin cell cancer.
  • Carcinosarcoma occurs in the epithelial tissues, which cover the outer face of the body (the skin) and the mucous membranes and the internal cavity of the structure of the organs, such as the breasts, the lung, the digestive and gastrointestinal tract, the glands endocrine, and the genitourinary system.
  • Ductal or glandular elements may persist in epithelial tumors, as well as in adenocarcinomas, such as thyroid adenocarcinoma, gastric adenocarcinoma, uterine adenocarcinoma.
  • Cancers of the epithelium of paved skin cells and certain mucous membranes as for example, cancer of the tongue, lips, larynx, urinary bladder, uterine cervix, or penis, can be called squamous or squamous cell carcinoma of the respective tissues, and they are also within the definition of cancer herein.
  • Sarcoma develops in connective tissues, including fibrous, adipose tissue, muscle, blood vessels, bone, and cartilage such as osteogenic sarcoma, liposarcoma, fibrosarcoma, and synovial sarcoma.
  • Carcionosarcomas develop in both epithelial and connective tissue.
  • the cancer can be primary or secondary. Primary indicates that the cancer has originated in the tissue that has been found, rather than having been established after metastasis from another region.
  • Cancer and tumor diseases can also be benign or malignant, and can affect the anatomical structures of a mammalian body.
  • they can be: I) cancer and bone marrow tumor diseases, and bone marrow derived cells (leukemia); II) endocrine and exocrine glands, such as thyroid, parathyroid, pituitary, adrenal glands, salivary glands, pancreas; III) breast, such as benign and malignant tumors in the mammary glands of both men and women, mammary ducts, adenocarcinoma, medullary carcinoma, carcinoma carcinoma.
  • Bone, and its connective and supportive tissues such as malignant or benign bone tumor, for example, osteogenic malignant sarcoma, benign osteoma, cartilage tumors; such as malignant chondrosarcoma or benign chondroma; bone marrow tumors, such as malignant myeloma, or benign eosinophilic granuloma, as well as metastatic tumors of bone tissues at other locations in the body;
  • the cancer is selected from the list consisting of: colon cancer, rectal cancer, breast cancer, digestive system cancers (among which are, but not limited to, anal, esophageal, pancreatic and gastric (stomach) cancer, head cancer, neck cancer, ovarian and cervical cancer, and basal cell skin cancer and actinic keratosis, or any combination thereof. Even more preferably, it is colon cancer.
  • Agomelatine is a compound with CAS number 138112-76-2, formula C15H17N02, IUPAC name: N- [2- (7-methoxynaphthalen-1-yl) ethyl] acetamide, and Formula (I):
  • the compounds of the present invention represented by formula (I) may include isomers, depending on the presence of multiple bonds, including optical isomers or enantiomers, depending on the presence of chiral centers.
  • the individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention, that is, the term isomer also refers to any mixture of isomers, such as diastereomers, racemic, etc., even their optically isomers. assets or mixtures in different proportions thereof.
  • the individual enantiomers or diastereoisomers, as well as mixtures thereof, can be separated by conventional techniques.
  • prodrugs of the compounds of formula (I) include any derivative of a compound of formula (I) - for example and not limited to: esters (including esters of carboxylic acids, amino acid esters, phosphate esters, esters of sulphonate of metal salts, etc.), carbamates, amides, etc. - which when administered to an individual can be transformed directly or indirectly into said compound of formula (I) in said individual.
  • said derivative is a compound that increases the bioavailability of the compound of formula (I) when administers to an individual or that enhances the release of the compound of formula (I) in a biological compartment.
  • the nature of said derivative is not critical as long as it can be administered to an individual and provides the compound of formula (I) in a biological compartment of an individual.
  • the preparation of said prodrug can be carried out by conventional methods known to those skilled in the art.
  • derivative includes both pharmaceutically acceptable compounds, that is, derivatives of the compound of formula (I) that can be used in the manufacture of a medicament or food compositions, as pharmaceutically unacceptable derivatives, and that these may be useful in the preparation of pharmaceutically acceptable derivatives.
  • the compounds of the invention may be in crystalline form as free compounds or as solvates.
  • solvate includes both pharmaceutically acceptable solvates, that is, solvates of the compound of formula (I) that can be used in the manufacture of a medicament, as pharmaceutically acceptable solvates, which may be useful in the preparation of pharmaceutically acceptable solvates or salts.
  • the nature of the pharmaceutically acceptable solvate is not critical as long as it is pharmaceutically acceptable.
  • the solvate is a hydrate.
  • Solvates can be obtained by conventional solvation methods known to those skilled in the art.
  • the compounds of formula (I), their salts, prodrugs or solvates will preferably be found in a pharmaceutically acceptable or substantially pure form, that is, having a pharmaceutically acceptable level of purity excluding pharmaceutical additives. normal such as diluents and carriers, and not including material considered toxic at normal dosage levels.
  • the purity levels for the active ingredient are preferably greater than 50%, more preferably greater than 70%, and still more preferably greater than 90%. In a preferred embodiment, they are greater than 95% of the compound of formula (I), or of its salts, solvates or prodrugs.
  • a second aspect of the invention relates to the use of a composition, hereinafter composition of the invention, preferably a pharmaceutical comprising at least one compound of the invention, or a tautomer, a pharmaceutically acceptable salt, a derivative or a prodrug. thereof, together with a carrier or carrier pharmaceutically acceptable, an excipient or a vehicle, in the preparation of a medicament for the prevention, improvement, relief and / or treatment of cancer in mammals, and more preferably in humans.
  • a composition, hereinafter referred to as a composition of the invention preferably a pharmaceutical composition comprising at least one compound of the invention or any of its salts, preferably any pharmaceutically acceptable salt, esters, tautomers, polymorphs, pharmaceutically acceptable hydrates is referred to.
  • composition of the invention further comprises a pharmaceutically acceptable carrier or camer, an excipient and / or a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the invention comprises as the only active ingredient a compound of the invention, or a tautomer, a pharmaceutically acceptable salt, a derivative or a prodrug thereof, although it may additionally comprise other excipients and / or pharmaceutically acceptable vehicles.
  • the cancer is selected from the list consisting of: colon cancer, rectal cancer, breast cancer, digestive system cancers (among which are, but are not limited to, anal, esophageal, pancreatic cancer and gastric (stomach)), head cancer, neck cancer, ovarian and cervical cancer, and basal cell skin cancer and actinic keratosis, or any combination thereof.
  • the cancer is colon cancer.
  • the cancer is a non-mutated (wild) p53 cancer, although, it is also effective, in cases of mutated p53 cancer, so in another preferred embodiment, the cancer is a cancer. with mutated p53.
  • Methods to detect if a cancer has mutated p53 are known in the state of the art, among which are, but not limited to, those that have been previously described herein.
  • compositions are the adjuvants and vehicles known to those skilled in the art and commonly used in the elaboration of therapeutic compositions.
  • the pharmaceutical composition of the invention will comprise at least one compound of the invention, and preferably will comprise a therapeutically effective amount of the compound of the invention.
  • therapeutically effective amount refers to the amount of the agent or compound capable of developing the therapeutic action determined by its pharmacological properties, calculated to produce the desired effect and, in general, will be determined, among other causes, by the characteristics of the agents. compounds, including the age, condition of the patient, the severity of the disorder or disorder, and the route and frequency of administration.
  • the compounds described in the present invention, their salts, prodrugs and / or solvates as well as the pharmaceutical compositions containing them can be used together with other drugs, or additional active ingredients, to provide a combination therapy.
  • Said additional drugs may be part of the same pharmaceutical composition or, alternatively, they may be provided in the form of a separate composition for simultaneous or non-simultaneous administration to the pharmaceutical composition comprising a compound of formula (I), or a salt, prodrug or solvate thereof.
  • the pharmaceutical composition further comprises another active ingredient.
  • the active ingredient is selected from the list consisting of: a pyrimidine derivative, a platinum derivative, raltitrexed, paclitaxel, doxorubicin, a camptothecin derivative, or any combination thereof.
  • the "pyrimidine analogues” constitute a well defined group in the ATC code or System of Anatomical, Therapeutic, Chemical Classification (instituted by the World Health Organization, and adopted in Europe). They belong to section ATC L01, section of the ATC classification system within group L, corresponding to antineoplastic and immunomodulating agents.
  • L01 BC Pyrimidine analogues are classified as L01 BC Pyrimidine analogues, and in the last update of 2011 includes: L01 BC01 cytarabine; L01 BC02 fluoruracil; L01 BC03 tegafur; L01 BC04 carmofur; L01 BC05 gemcitabine; L01 BC06 Capecitabine; L01 BC07 azacitidine; L01 BC08 decitabine; L01 BC52 fluoracil, combinations; L01 BC53 tegafur, combinations.
  • the pyrimidine derivative is selected from the list consisting of cytarabine, fluoruracil (5-fluoruracil or 5-FU), tegafur, carmofur, gemcitabine, capecitabine, azacitidine, decitabine, or any of its salts, isomers , corresponding prodrugs, derivatives or analogs, and combinations thereof.
  • the pyrimidine analog is 5-fluorouracil (5-FU), or any of its salts, isomers, prodrugs, derivatives or the like.
  • the platinum derivative is selected from the list consisting of carboplatin, cisplatin and oxiplatin, or any of its salts, isomers, corresponding prodrugs, derivatives or analogs, and combinations thereof.
  • the pyrimidine analog is oxiplatin or any of its salts, isomers, prodrugs, derivatives or the like.
  • CPT is a phytotoxic alkaloid isolated for the first time from the extracts of an ornamental plant of Chinese origin, as described in Wall et al., J. Am. Chem. Soc, vol. 88 (16), pp. 3888-3890, (1966).
  • initial studies focusing on the mechanism of action of CPT, determined that the cytotoxic activity of the alkaloid could occur due to the ability to inhibit the synthesis of DNA and RNA. It was observed that such inhibition occurred reversibly, but increasing the concentration and exposure time of the CPT blockade of the sequences became irreversible.
  • the general conclusions determined that CPT is selective in the S phase of the cell cycle, stops the G 2 phase and induces fragmentation of chromosomal DNA.
  • the CPT has a pentacyclic structure with an asymmetric center in the E ring and a 20 (S) configuration.
  • the molecule is formed by a quinoline nucleus (rings A and B) attached to a pyridone ring (ring D) and with a lactone ring of 6 carbon atoms (ring E) that has a hydroxyl group of configuration S.
  • the camptothecin derivative is selected from the list consisting of topotecan, iridotecan or any of its corresponding salts, isomers, prodrugs, derivatives or analogs, and their combination.
  • Platinum derivatives form covalent bonds with guanine and DNA adenine. Most of these unions are intracatenary, although they can also be intercatenary.
  • the most important drugs in this group are: cisplatin, carboplatin and oxaliplatin. They are used for the treatment of lung cancer, bladder cancer, germ tumors, ovarian cancer, head and neck cancer, esophageal cancer, stomach cancer, etc.
  • Oxaliplatin is a third generation analog of cisplatin. Its mechanism of action is similar to this, but it also binds to nuclear and cytoplasmic proteins. Its main indication is the treatment of colorectal cancer.
  • the platinum derivative is selected from cisplatin, carboplatin and oxaliplatin, or any of its corresponding salts, isomers, prodrugs, derivatives or analogs, and their combination. Even more preferably, the Platinum derivative is oxaliplatin or any of its salts, isomers, prodrugs, derivatives or the like.
  • active substance means any component that potentially provides a pharmacological activity or other different effect on the diagnosis, cure, mitigation, treatment, or prevention of a disease, or that affects the structure or function of the body of man or other animals.
  • the term includes those components that promote a chemical change in the preparation of the drug and are present therein in a modified form intended to provide the specific activity or effect.
  • a third aspect of the invention relates to a pharmaceutical form, hereinafter pharmaceutical form of the invention, comprising the compound of the invention or the composition of the invention.
  • pharmaceutical form means the mixture of one or more active ingredients with or without additives that have physical characteristics for proper dosage, preservation, administration and bioavailability.
  • compositions and pharmaceutical forms of the invention are suitable for oral administration, in solid or liquid form.
  • Possible forms for oral administration are tablets, capsules, syrups or solutions and may contain conventional excipients known in the pharmaceutical field, as aggregating agents (eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinyl pyrrolidone), fillers (eg lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), disintegrants (eg starch, polyvinyl pyrrolidone or microcrystalline cellulose) or a pharmaceutically acceptable surfactant such as sodium lauryl sulfate.
  • Other pharmaceutical forms may be colloidal systems, which include nanoemulsions, nanocapsules and polymeric nanoparticles.
  • compositions for oral administration can be prepared by conventional methods of Galenic Pharmacy, as mixing and dispersion.
  • the tablets can be coated following methods known in the pharmaceutical industry.
  • the compositions and pharmaceutical forms can be adapted for parenteral administration, such as sterile solutions, suspensions, or lyophilisates of the products of the invention, using the appropriate dose.
  • Suitable excipients such as pH buffering agents or surfactants, can be used.
  • the aforementioned formulations can be prepared using conventional methods, such as those described in the Pharmacopoeias of different countries and in other reference texts.
  • medication refers to any substance used for prevention, diagnosis, improvement, relief, treatment or cure of diseases in man and animals.
  • the administration of the compounds, compositions or pharmaceutical forms of the present invention can be performed by any suitable method, such as intravenous infusion and oral, topical or parenteral routes. Oral administration is preferred for the convenience of patients and for the chronic nature of the diseases to be treated.
  • the amount administered of a compound of the present invention will depend on the relative efficacy of the compound chosen, the severity of the disease to be treated and the weight of the patient. However, the compounds of this invention will be administered one or more times a day, for example 1, 2, 3 or 4 times daily, with a total dose between 0.001 and 1000 mg / kg / day, or between 0.1 and 500 mg / Kg / day It is important to keep in mind that it may be necessary to introduce variations in the dose, depending on the age and condition of the patient, as well as modifications in the route of administration.
  • the compounds and compositions of the present invention can be used together with other medicaments in combination therapies.
  • the other drugs may be part of the same composition or of a different composition, for administration at the same time or at different times.
  • a third aspect of the invention relates to a food composition such as a nutraceutical composition or a "medical food” type composition, hereinafter food composition of the invention, comprising at least one of the compounds of formula (I ).
  • the food or nutraceutical composition of the invention comprises as the only active ingredient a compound of the invention, or a tautomer, a pharmaceutically acceptable salt, a derivative or a prodrug thereof, although it may additionally comprise other excipients. and / or nutraceutically acceptable vehicles.
  • the food composition of the invention comprises the compound of the invention in an amount effective for the prevention, improvement, relief and / or treatment of cancer, and preferably for the prevention, relief and treatment of colon cancer, in mammals, including a human being.
  • Preferred food compositions are selected from the list consisting of: a beverage, milk, yogurt, cheese, fermented milk, flavored milk beverage, soy milk, pre-cooked cereals, bread, cakes, butter, margarine, sauces, frying oils , vegetable oils, corn oil, olive oil, soybean oil, palm oil, sunflower oil, cottonseed oil, condiments, salad dressings, fruit juices, syrups, desserts, glazes and fillings, frozen products Soft, sweet, gum and intermediate foods.
  • the food composition of the invention can be a nutritional or dietary supplement.
  • the nutritional or dietary supplement comprises a sterile composition containing the compound of the invention, preferably provided with a gastric acid resistant coating, being a delayed release composition.
  • the food composition, including the compound of the invention and / or the nutritional or dietary supplement comprises appropriate "carriers" such as diluents, adjuvants, excipients or carriers with which the compound of the invention is administered.
  • Suitable suitable excipients include, but are not limited to starch, glucose, fructose, lactose, sucrose, gelatin, malt, rice, flour, calcium sulfate, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, glycol, water, ethanol, and the like.
  • Such nutritional supplements can be used to combat liver problems, and help maintain health or a healthy lifestyle for the mammal, preferably a human being.
  • a fourth aspect of the invention relates to the use of the food composition of the invention for the prevention, relief or treatment of cancer, preferably colon cancer in mammals, and more preferably in humans.
  • it refers to the use of the food composition of the invention, for the prevention of relief and / or treatment of cancer, preferably of colon cancer in mammals, and more preferably in humans.
  • treatment refers to combating the effects caused as a result of a disease or pathological condition of interest in a subject (preferably mammal, and more preferably a human) that includes:
  • prevention is to prevent the onset of the disease, that is, to prevent the disease or pathological condition from occurring in a subject (preferably mammal, and more preferably a human), in particularly, when said subject has a predisposition for the pathological condition.
  • Another aspect of the invention relates to a pharmaceutical form, hereafter referred to as the pharmaceutical form of the invention, comprising agomelatine, the composition of the invention or components a) and / or b) of the combined preparation of the invention as and as defined below herein.
  • the pharmaceutical form is the individualized arrangement to which drugs (active ingredients) and excipients (pharmacologically inactive matter) are adapted to constitute a medicament.
  • liquid pharmaceutical forms can be solutions, (oral solutions), aromatic waters, syrups, elixirs, mouthwashes, mouthwashes, potions, mucilages, emulsions, suspensions, eye drops, lotions, tinctures, fluid extracts, injections, gargles, plasters, ointments , pastes, creams, lotions, liniments, gels, foams, powders, etc.
  • compositions comprising one or more compounds of the invention described above together with a pharmaceutically acceptable carrier.
  • the compounds are normally combined with one or more adjuvants appropriate for the indicated route of administration.
  • the compounds may be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide sodium and calcium salts of phosphoric and sulfuric acids, acacia, gelatin, sodium alginate , polyvinylpyrrolidone, and / or polyvinyl alcohol.
  • the compounds of this invention can be dissolved in saline, water, polyethylene glycol, propylene glycol, colloidal solutions of carboxymethyl cells, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and / or various buffers.
  • Other adjuvants and modes of administration are well known in the pharmaceutical art.
  • the carrier or diluent may include temporary delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
  • a fifth aspect of the invention relates to a combined preparation, hereafter combined preparation of the invention, comprising two components:
  • Component A agomelatine or any of its pharmaceutically acceptable salts, isomers, prodrugs, derivatives or analogs, where the agomelatine has the formula (I):
  • Component B another active ingredient that is selected from a derivative of pyrimidine, a derivative of platinum, raltitrexed, paclitaxel, doxorubicin, a derivative of camptothecin, or any combination thereof.
  • the pyrimidine derivative is selected from the list consisting of cytarabine, fluoracil (5-fluoruracil or 5-FU), tegafur, carmofur, gemcitabine, capecitabine, azacitidine, decitabine, or any of its salts, isomers , corresponding prodrugs, derivatives or analogs, and combinations thereof.
  • the pyrimidine analog is 5-fluorouracil (5-FU), or any of its salts, isomers, prodrugs, derivatives or the like.
  • the platinum derivative is selected from the list consisting of carboplatin, cisplatin and oxiplatin, or any of its corresponding salts, isomers, prodrugs, derivatives or analogs, and combinations thereof.
  • the pyrimidine analog is oxiplatin or any of its salts, isomers, prodrugs, derivatives or the like.
  • the camptothecin derivative is selected from the list consisting of topotecan, iridotecan or any of its corresponding salts, isomers, prodrugs, derivatives or analogs, and their combination.
  • Platinum derivatives form covalent bonds with guanine and DNA adenine. Most of these unions are intracatenary, although they can also be intercatenary.
  • the most important drugs in this group are: cisplatin, carboplatin and oxaliplatin. They are used for the treatment of lung cancer, bladder cancer, germ tumors, ovarian cancer, head and neck cancer, esophageal cancer, stomach cancer, etc.
  • Oxaliplatin is a third generation analog of cisplatin. Its mechanism of action is similar to this, but it also binds to nuclear and cytoplasmic proteins. Its main indication is the treatment of colorectal cancer. Therefore, in another preferred embodiment the platinum derivative is selected from cisplatin, carboplatin and oxaliplatin, or any of its corresponding salts, isomers, prodrugs, derivatives or analogs, and their combination. Even more preferably, the platinum derivative is oxaliplatin or any of its salts, isomers, prodrugs, derivatives or the like.
  • the term “combined preparation” or also called “juxtaposition”, herein, means that the components of the combined preparation need not be present as a joint, for example in a true composition, in order to be available for combined application. , separate or sequential. In this way, the expression “juxtaposed” implies that it is not necessarily a true combination, in view of the physical separation of the components.
  • All compounds of the present invention include pharmaceutically acceptable salts, esters, amides and prodrugs, including but not limited to carboxylic salts, addition salts. of amino acids, esters, amides, and prodrugs of the compounds of the present invention that are, within the scope of medical judgment, suitable for use in patients without excessive toxicity, irritation, allergic response, and the like, with a benefit / reasonable risk, and effective for its intended use, as well as hybrid ion forms (zwitterionic forms, in English), where possible, of the compounds of the present invention.
  • salts refers to the relatively harmless, inorganic and organic acid addition salts of the compounds of the present invention.
  • salts can be prepared in situ during the final isolation and purification of the compounds or by reacting separately the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative examples of such salts include the salts hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobsonate, lauryl sulphonate, and the like.
  • alkali and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, and ammonium such as, as well as harmless ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium , methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like (see for example, Berge SM, et al, "Pharmaceutical Salts," J.Pharm.Sci., 1977; 66: 1-19, the content of which is incorporated in this application by reference).
  • HCT-1 16wt and HCT-116p53 - / - (Horizon Discovery Ltd.) colorectal cancer cell lines have been used. These cell lines have been maintained in culture in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% antibiotics (pelicillin and streptomycin). All cell culture reagents were purchased from Gibco-BRL (Gibco; Invitrogen, Carisbad, CA, USA). The cells were grown at 37 ° C, in a humidified environment and at 5% C02. For the experiments with different treatments, the cells were seeded and the next day the medium was changed, in this case for a serum-free medium, for 6 hours.
  • FBS fetal bovine serum
  • antibiotics pelicillin and streptomycin
  • the cells were seeded in 6-well plates, and after appropriate treatments, a population among were collected with trypsin and centrifuged for 5 minutes at 300 g. TO The supernatant was then removed and fixed by adding 200 ⁇ of 70% ethanol, stirring slowly. The cells were allowed to stand at -4 ° C for 30 minutes. Then, they were washed in 2 ml of PBS solution with 2% BSA. They were subsequently resuspended in 0.5 ml of PI / RNase solution, and incubated for 15 minutes at room temperature. After incubation, the content was analyzed by flow cytometry (BDFACSAria II).
  • Alkaline phosphatase activity was determined using a commercial kit (Sensolyte pNPP Alkaline Phosphatase Assay Kit, Anaspec, Fremont, CA, USA). About 10 5 cells were lysed in 50 ⁇ of buffer to which 50 ⁇ g / ml aprotinin, 1 mM PMSF, and 50 ⁇ leupeptin were added, at 4 ° C for 10 min. The absorbance was measured at 405 (end point) after the addition of 50 ⁇ of p-nitrophenyl phosphate as the reaction substrate. The activity was expressed in ng / ml ⁇ 10 6 cells.
  • apoptotic cells The proportion of apoptotic cells was determined by a commercial kit (BD Lifesciences, UK). Briefly, cells were washed with cold PBS, trypsinized and resuspedieron in buffered solution at a concentration of 1 x 10 6 cells ⁇ / ml. 100 ⁇ of solution (1 x 10 ⁇ 5 cells) were transferred to a tube of 5 ml, to which was added 5 ⁇ FITC Annexin V and 5 ⁇ Pl. After gentle agitation, the cells were incubated for 15 minutes at room temperature (25 ° C) and in darkness. After this time, 400 ⁇ of buffered solution was added and each cell sample was analyzed within one hour after flow cytometry (BDFACSAria II).
  • AAPH 3'M 2,2'-Azobis (2-amidinopropane) dihydrochloride
  • the total RNA of the samples was prepared using the TRIzol rectifier (Invitrogen). The amount of total RNA was determined by UV spectrophotometry, and the integrity of the misto by agarose gel electrophoresis.
  • the Cdna was prepared by RT-PCR with oligo-dT primers and starting from 2 ⁇ g of total RNA in 50 ⁇ of total volume using a commercial kit (AccuScriptTM High Fidelity Ist Strand cDNA Synthesis Kit, Stratagene). Real-time PCR
  • the cells were resuspended in 50 ⁇ lysis buffer (RIPA buffer with phosphatase and protease inhibitors) per 500,000 cells, for 30 minutes at 4 ° C.
  • the membranous and DNA residues were removed by centrifugation and in the supernatant the protein concentration was quantified by the Bradford method.
  • protein loading buffer (0.125 M Tris-HCL pH 6.8, 10% ⁇ -mercaptoethanol, 4% Sodium Dodecyl Sulfate, 20% Glycerol, Bromophenol Blue 0.004%) was added and the samples were heated at 95 ° C for 3-5 minutes. Subsequently, an SDS-polyacrylamide gel electrophoresis was performed to separate the proteins, which were then transferred to a PVDF membrane (Bio-Rad Laboratories, Inc., USA) using the semi-dry transfer technique with the Trans-Blot SD system ( Bio-Rad Laboratories, Inc., USA) at 100 mA for 45 minutes.
  • PVDF membrane Bio-Rad Laboratories, Inc., USA
  • the membrane was blocked with a 5% milk powder solution in 0.1% Tween-20 TBS buffer for 30 minutes and subsequently incubated overnight at 4 ° C with the corresponding antibody : caspase 3 (1: 3000, Immunostep) and ⁇ -actin (1: 200, Santa Cruz Biotechnology). After this incubation, the primary antibody was removed and the membrane was washed 3 times for 5 minutes with 0.1% TBS / Tween buffer. Finally, the membrane was incubated for 1 hour at room temperature with the corresponding secondary antibody labeled with HRP peroxidase (Bio-Rad Laboratories, Inc., USA). Subsequently, a three wash cycle was carried out with 0.1% TBS / Tween buffer, and the bands were visualized using the Quantity One 4.6.8 program (Bio-Rad Laboratories, Inc., USA).
  • mice of the four-six week strain balb / c athymic were used (Charles River Laboratories). The animals were kept in quarantine for a week before injecting them subcutaneously 2.5 x 10 6 cells HCT-1 16wt and HCT-1 16p53 - / -, on the right and left flanks respectively, resuspended in 100 ⁇ of complete medium. Once the tumors reached sizes between 100-150 mm 3 , the animals were randomly divided into 4 groups (8 animals per group).
  • HCT-1 16 and HCT-1 16 p53 - / - have been used, which have been cultured in the presence of increasing concentrations of melatonin (0-1 mM) and agomelatine for three days.
  • the MTT assay shows that both drugs inhibit the growth of these tumor cells in culture ( Figure 1).
  • HCT-1 16 an inhibitory effect is observed by melatonin from 0.25 mM and at the maximum concentration (1 mM) the inhibition is close to 50%.
  • Luzindole (10 ⁇ ), non-selective antagonist of the two membrane receptors of melatonin.
  • HCT-1 line 16 there are no differences in the inhibitory capacity of melatonin and agomelatine after co-incubation with luzindole ( Figure 2A and 2B).
  • agomelatine acts through serotonin 5- HT2C receptors
  • cells were incubated in the presence of agomelatine and Ro 60-0175
  • Treatment with melatonin also resulted in a decrease in the number of G2 / M cells in HCT-1 16 (7.20 ⁇ 0.84% in the group treated with melatonin versus 12.50 ⁇ 0.13% in control cells) and HCT-1 16 p53 - / - (12.69 ⁇ 1.21% in the group treated with melatonin versus 25.60 ⁇ 1.42% in the control cells).
  • Other concentrations of melatonin did not produce any variation in the distribution of the cell cycle in either of the two lines analyzed.
  • Treatment with melatonin also produced a decrease in the number of G1 phase cells in HCT-1 16 (39.36 ⁇ 5.24% in the group treated with melatonin versus 69.47 ⁇ 1.72% in control cells) and HCT-1 16 p53 - / - (46.40 ⁇ 2.07% in the group treated with melatonin versus 73.00 ⁇ 2.68% in the control cells).
  • Other concentrations of agomelatine produced similar variations in the distribution of the cell cycle in the two lines analyzed.
  • Agomelatine induces caspase-dependent apoptosis in colon cancer cell lines HCT-116 and HCT-116 p53 - / -.
  • both melatonin and agomelatine are regulators of the circadian rhythm at the central level
  • the cells have been incubated with melatonin and agomelatine for 48 hours at the dose of 1 mM. To ensure that these are synchronized cultures, before treatment, the cells were kept in culture medium without serum for 6 hours.
  • HCT-1 16 and HCT-1 16 p53 - / - cell lines were injected into the flanks of immunosuppressed mice.
  • Melatonin and agomelatine were injected at a dose of 5 mg / kg of weight three times a week.
  • a group of animals were also used in which 5-fluorouracil (5-FU) was injected at a dose of 50 mg / kg twice weekly.
  • melatonin and agomelatine produce an increase in blood glucose and ALT
  • treatment with 5-FU induces an increase in ALT levels only.
  • the latter also induces a decrease in the average weight of animals because it produces diarrhea in them.

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Abstract

Selon la présente invention, le composé: N-[2-(7-méthoxynaphtalène-1-il)éthyle]acétamide (agomélatine), inhibe la croissance de lignées cellulaires du cancer du côlon in vitro, et engendre aussi l'inhibition in vivo, ce qui suggère le rôle oncostatique/cytotoxique de ce composé. Les lignées qui présentent un p53 sauvage ont des niveaux plus élevés d'inhibition que celles qui ont un p53 muté. Son effet dépend de l'état, muté ou non muté de p53, même si, et à la différence de la mélatonine ou du 5-fluorouracil, il est également capable d'inhiber la croissance dans le cas où p53 a été muté, et de ce fait, le nombre de patients pouvant être traités augmente.
PCT/ES2016/070497 2015-07-03 2016-07-02 Analogues de la mélatonine pour le traitement du cancer WO2017005954A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070197829A1 (en) * 2004-02-13 2007-08-23 Les Laboratoires Servier Process for the synthesis and crystalline form agomelatine
US20130259800A1 (en) * 2010-12-15 2013-10-03 Biovista, Inc. Compositions and methods for cancer treatment

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070197829A1 (en) * 2004-02-13 2007-08-23 Les Laboratoires Servier Process for the synthesis and crystalline form agomelatine
US20130259800A1 (en) * 2010-12-15 2013-10-03 Biovista, Inc. Compositions and methods for cancer treatment

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