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
  • A61K31/33—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
• • 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
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to new combinations of pyridoindolone derivatives with anticancer agents, and the pharmaceutical compositions containing them.
• pyridoindolone derivatives which can be used in the present invention are the compounds of formula:
• - R represents a hydrogen atom or a methyl or ethyl group
• - R.2 represents a methyl or ethyl group
• - 1 represents either a phenyl group optionally substituted by a halogen atom or a methyl or methoxy group, or a thienyl group;
• R4 represents a hydrogen or chlorine atom or a methyl or methoxy group.
• Preferred pyridoindolone derivatives are the compounds of formula:
• - R represents a hydrogen atom, a methyl or ethyl group
• R2 represents a methyl or ethyl group
• - R and R2 together form a group (CH2) 3;
• - R 3 represents a hydrogen or halogen atom or a methyl or methoxy group;
• R4 represents a hydrogen or chlorine atom or a methyl or methoxy group.
• Particularly preferred pyridoindolone derivatives are the compounds of formula:
• - R represents a hydrogen atom, a methyl or ethyl group
• R2 represents a methyl or ethyl group
• R3 represents a hydrogen or halogen atom or a methyl or methoxy group
• R4 represents a hydrogen or chlorine atom or a methyl or methoxy group.
• More particularly preferred pyridoindolone derivatives are the compounds of formula:
• Rj represents a methyl or ethyl group
• R2 represents a methyl or ethyl group
• R3 represents a hydrogen or halogen atom or a methyl or methoxy group
• R4 represents a hydrogen or chlorine atom or a methyl or methoxy group.
• pyridoindolone derivatives according to the invention are:
• the compounds of formula (I) were tested in vitro on a human breast cancer cell line: the line MDA-MB-231 available from the American
• the inhibitory concentration 50 is defined as the concentration which inhibits cell proliferation by 50%.
• the compounds of formula (I) have an IC50 generally less than 10 ⁇ M on the MDA-MB-231 line.
• MDR line from the English multi-drag-resistant
• MDA-Ai MDA-Ai
• multi-resistant which qualifies this line, means that said line is generally insensitive to the chemotherapy drugs commonly used and in particular to antimitotics of natural origin such as paclitaxel, vincristine, vinblastine.
• the compounds of formula (I) have an IC50 generally less than 10 ⁇ M on the multi-resistant line MDA-A1.
• the compounds of formula (I) inhibit the proliferation of tumor cells including the proliferation of cells exhibiting multi-resistance.
• Several compounds of formula (I) have also been evaluated in vivo on a xenograft model of human tumors implanted subcutaneously on the immunosuppressed mouse SCDD (from the English: Severe Combined __mmuno Deficiency).
• the treatment of animals with a compound of formula (I) begins 6 to 7 days after implantation, when the tumor reaches a tumor mass of approximately 60 mg.
• the compound in solution in a solvent, is then administered orally.
• the antitumor activity is evaluated when the average tumor mass reaches approximately 1000 mg in the control animals, treated with the solvent only: the T / C ratio is measured, T representing the average weight of the tumors in the treated animals and C representing the weight by means of tumors in control animals.
• a T / C ratio less than or equal to 42% is considered to be an indicator of significant antitumor activity according to Stuart T et al., In J. Med. Chem., 2001, 44 (11), 1758-1776.
• certain compounds of formula (I) have led to a T / C ratio of less than 20%.
• the antiproliferative effects of the association of a compound of formula (I) with another anticancer agent were measured on the MDA-Aj line, called the multi-resistant line cited above, according to the technique referenced (JM Derocq et al .).
• the IC50 obtained for the anticancer agent alone was compared to that obtained for the association of the same anticancer agent with a compound of formula (I). A clear decrease in the IC50 was observed.
• the IC50s can be divided by a factor ranging from 2 to 100 and even beyond 100 for certain pyridoindolone derivatives of formula (I) combined with another anticancer agent.
• the IC50 obtained for paclitaxel alone was compared to that obtained for the association of paclitaxel with 1,6,9-trimethyl-3-phenyl-1,9-dihydro-2H-pyrido [2 , 3-b] indol-2-one.
• the IC50 is divided by a factor ranging from 14 to 100 depending on the concentrations of 1,6,9-trimethyl-3- ⁇ henyl-1,9-dihydro-2H-pyrido [2,3- b] indol-2-one used .
• the results of the tests show a synergistic effect and a potentiation of the antiproliferative effects of the components of the associations of the invention.
• the compound or compounds of formula (I) are administered in combination with one (or more) active principle (s) anticancer.
• active ingredients can in particular be anti-tumor compounds such as alkylating agents, alkylsulfonates (busulfan), dacarbazine, procarbazine, nitrogen mustards (chlormethine, melphalan, chlorambucil), cyclophosphamide, ifosfamide; nitrosoureas such as carmustine, lomustine, semustine, streptozocin; antineoplastic alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel; antineoplastic antibiotics such as actinomycin; intercalating agents, antineoplastic antimetabolites, folate antagonists, methotrexate; inhibitors of purine synthesis; purine analogs such as mercaptopurine, 6-thioguanine; inhibitors of pyrimidine synthesis, aromatase inhibitors, capecitabine, pyrimidine analogs such as fluorouracil, gemcitabine, cytarabine and cyto
• antitopoisomerases such as etoposide, antracyclines including doxorubicin, bleomycin, mitomycin and methramycin; metal anticancer complexes, platinum complexes, cisplatin, carboplatin, oxaliplatin; interferon alpha, triphenylthiophosphoramide, altretamine; antiangiogenic agents; immunotherapy adjuvants.
• the combinations of the invention are useful for the prevention and treatment of diseases caused or exacerbated by the proliferation of tumor cells, such as primary or metastatic tumors, carcinomas and cancers, in particular: breast cancer; lung cancer ; cancer of the small intestine, cancer of the colon and rectum; cancer of the respiratory tract, oropharynx and hypopharynx; esophageal cancer; liver cancer, stomach cancer, bile duct cancer, gallbladder cancer, pancreatic cancer; urinary tract cancers including kidney and urothelium, bladder cancer; cancers of the female genital tract including cancer of the uterus, cervix, ovaries, chloriocarcinoma and trophoblastoma; cancers of the male genital tract including cancer of the prostate, seminal vesicles, testes, germ cell tumors; cancers of the endocrine glands including cancer of the thyroid, pituitary gland, adrenal glands; skin cancers including hemangiomas, melanomas, sar
• the present invention also relates to pharmaceutical compositions containing, as active principle (s), a therapeutically effective amount. at least one compound of formula (I) or a pharmaceutically acceptable salt, a hydrate or a solvate of said compound, and a therapeutically effective amount of one (or more) other (s) active principle (s) anticancer , as well as one or more pharmaceutically acceptable excipients.
• Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known in the prior art.
• compositions of the present invention can be prepared for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, or any other suitable route, to animals and humans. for the prevention or treatment of the above diseases.
• the compounds of formula (I) above can be used in daily doses of 0.002 to 2000 mg per kilogram of body weight of the mammal to be treated, preferably in daily doses of 0.1 to 300 mg / kg.
• the dose may preferably vary from 0.02 to 10,000 mg per day, more particularly from 1 to 3000 mg, depending on the age of the subject to be treated or the type of treatment (prophylactic or curative).
• the anti-cancer active ingredients, with which the compounds of formula (I) are associated, are used at the usual doses.
• Suitable administration forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, forms for sublingual, oral, intratracheal, intraocular, intranasal, inhalation, forms for topical, tr_msdem_ique, subcutaneous, intramuscular or intravenous administration, forms for rectal administration and implants.
• oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions
• forms for sublingual, oral, intratracheal, intraocular, intranasal, inhalation forms for topical, tr_msdem_ique, subcutaneous, intramuscular or intravenous administration, forms for rectal administration and implants.
• the combinations according to the invention can be used in creams, gels, ointments or lotions.
• the appropriate dosage for each patient is determined by the doctor according to the mode of administration, the age, the weight and the response of said patient.
• the compound (s) of formula (I) and one (or more) other (s) active principle (s) anticancer can be administered simultaneously, sequentially or spread over time , for the treatment of diseases caused or exacerbated by the proliferation of tumor cells.
• the combinations of the invention can be presented in the form of a kit containing at least one compound of formula (I), on the one hand, and one (or more) other (s) active principle (s) anticancer, d 'somewhere else.
• the invention also relates to a method for the treatment of diseases caused or exacerbated by the proliferation of tumor cells which consists in administering to a subject in need a therapeutically effective amount of at least one compound of formula (I) in association with one (or more) other active principle (s) anticancer.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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