Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
  • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • 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
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C43/00—Ethers; Compounds having groups, groups or groups
  • C07C43/02—Ethers
  • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
  • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/78—Separation; Purification; Stabilisation; Use of additives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2602/00—Systems containing two condensed rings
  • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
  • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
  • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

• the present invention relates to 3- (3-hydroxy-4-methoxy-benzyl) -7-methylene-1-vinyl-2,3,3a, 4,7,7a-hexahydro-indene-4-one of formula :
• 3- (3-hydroxy-4-me oxy-r ⁇ rLzyl) -7-me ylene-1-vinyl-2,3,3a, 4,7,7a- hexahydro-indene-4-one and 3- (3-hydroxy-4-methoxy-benzyl) -4-hydroxy-7-methyl-1-vinyl-indane can be obtained from the plant Ottelia alismoides by extraction with a suitable solvent followed by separation of the 3- (3- hydroxy-4-methoxy-ber-zyl) -7-methylene-lv-nyl-2,3,3a, 4,7,7a-hexahydro-indene-4- one or 3- (3- hydroxy-4-methoxy-benzyl) -4-hydroxy-7-methyl-1-vinyl-indane of the extract obtained.
• Ottelia alismoides which belongs to the hydrocharitaceae family, is a submerged or partially floating aquatic plant.
• the leaves of Ottism alismo ⁇ des are radical forming, for the submerged part, a narrowed crown.
• the long floating part is petiolate, oval and lanceolate, oblong or cordate.
• the flowers are hermaphrodite and solitary, sessile with a long pedunculate mandate, and consist of three linear and oblong sepals and three large ovoid or orbicular petals.
• Ottelia alismoides in the form of the whole plant, generally dried and finely ground, is treated one or more times with a solvent chosen from aliphatic alcohols containing 1 to 4 carbon atoms and aliphatic ethers containing 1 to 6 carbon atoms to provide, after concentration, a dry extract which is taken up by an aliphatic hydrocarbon containing 5 to 8 carbon atoms or a cycloaliphatic hydrocarbon containing 5 to 7 carbon atoms to obtain a solution from which the insolubles are separated by filtration and which , after concentration, provides a dry extract from which the 3- (3-hydroxy-4-methoxy-benzyl) -7-methylene-1-vinyl-2,3,3a, 4,7,7a-hexahydro-mdene-4 are separated. -one or 3- (3- hydroxy-4-methoxy-benzyl) -4-hydroxy-7-methyl-1-vinyl-indane by application of chromatographic techniques.
• 2,3,3a, 4,7,7a-hexahydro-indene-4-one or 3- (3-hydroxy-4-methoxy-benzyl) -4- hydroxy-7-methyl-1-vinyl-indane from extract from treatment with an aliphatic hydrocarbon optionally combined with a nitrile is generally carried out by high performance liquid chromatography or by centrifugal partition chromatography.
• 3- (3-hydroxy-4-methoxy-benzyl) -7-methylene-1-vinyl- 2,3,3a, 4,7,7a-hexahydro-indene-4-one and 3- ( 3-hydroxy-4-methoxy-benzyl) -4- hydrOxy-7-methyl-1-vinyl-indane have the property of inhibiting the polymerization of tubulin.
• Tubulin obtained from pig brains, is purified by three cycles of polymerization-depolymerization according to the method of ML SHELANSKI et al., Proc. Natl. Acad. Sci. USA, 7Q, 765-768 (1973) followed by chromatography on phosphocellulose according to the method of MD WEINGARTEN et al., Proc. Natl. Acad. Sci. USA, 22, 1858-1862 (1975).
• Tubulin assembly into microtubules results in an increase in turbidity observed at 350 nm using a spectrophotometer.
• 3- (3-hyd-Oxy-4-methoxy-benzyl) -7-methylene-1-vinyl-2,3,3a, 4,7,7a- hexahydro-indene-4-one and 3- (3 -hydroxy-4-methoxy-benzyl) -4-hydroxy-7-methyl-1-vinyl-indane cause an inhibition of tubulin polymerization which results in an increase in latency, a decrease in the rate of polymerization as well as a lower turbidity in the stationary state.
• the product thus obtained is taken up in 5 cm3 of a dichloromethane-methanol mixture (99-1 by volume) and chromatography on a column of 50 g Merck 60H silica, for which the diameter / height ratio is equal to 15, prepared with the same solvent. Eluted with a dichloromethane-methanol mixture (99-1 by volume), collecting fractions of 2 cm3. Fractions 41 to 68 are combined and concentrated to dryness under reduced pressure.
• the ethereal solution thus obtained is concentrated to a volume of 15 liters in a thermosiphon evaporator, then concentrated to dryness under reduced pressure at 40 ° C.
• the product obtained can be viewed by chromatography on a thin layer of Merck F254 silica, eluting with a dichloromethane-methanol mixture (99-1 by volume) and development by the GIBBS reagent specific for phenols.
• 3- (3-hydroxy-4-me oxy-ber-2yl) -7-methylene-1-vinyl-2,3,3a, 4,7,7a-hexa- hydro-indene-4-one and 3 - (3-hydroxy-4-methoxy-benzyl) -4-hydroxy-7-methyl-1-vinyl-indane exhibit significant inhibitory activity on abnormal cell proliferation and has therapeutic properties allowing the treatment of patients with conditions pathologies associated with abnormal cell proliferation.
• Pathological conditions include abnormal cell proliferation of malignant or non-malignant cells of various tissues and / or organs, including, but not limited to, muscle, bone or connective tissue, skin, brain, lungs, sexual organs, the lymphatic or renal systems, the mammary or blood cells, the liver, the digestive system, the pancreas and the thyroid or adrenal glands.
• pathological conditions may also include psoriasis, solid tumors, ovarian, breast, brain, prostate, colon, stomach, kidney or testicular cancer, Kaposi's sarcoma, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms tumor, Hodgkin's disease, melanomas, multiple myelomas, chronic lymphocytic leukemias, acute or chronic granulocytic lymphomas.
• the new product according to the invention is particularly useful for the treatment of breast, ovarian, colon or kidney cancer.
• the product according to the invention can be used to prevent or delay the onset or recurrence of pathological conditions or to treat these pathological conditions.
• the products according to the invention can be administered to a patient in different forms adapted to the chosen route of administration which, preferably, is the parenteral route.
• Parenteral administration includes intravenous, intraperitoneal, intramuscular or subcutaneous administration. More particularly preferred is intraperitoneal or intravenous administration.
• the present invention also includes pharmaceutical compositions which contain 3- (3-hydroxy-4-methoxy-benzyl) -7-methylene-1-vinyl-2,3,3a, 4, 7,7a-hexahydro-indene-4 -one or 3- (3-hydroxy-4-methoxy-benzyl) - 4-hydroxy-7-methyl-1-vinyl-indane in a sufficient amount suitable for use in human or veterinary therapy.
• the compositions can be prepared according to the usual methods using one or more pharmaceutically acceptable adjuvants, carriers or excipients. Suitable carriers include diluents, sterile aqueous media and various non-toxic solvents.
• the compositions are in the form of aqueous solutions or suspensions, injectable solutions which may contain emulsifying agents, dyes, preservatives or stabilizers.
• adjuvants or excipients can be determined by the solubility and chemical properties of the product, the particular mode of administration and good pharmaceutical practices.
• aqueous or non-aqueous sterile solutions or suspensions are used.
• nonaqueous solutions or suspensions can be used natural vegetable oils such as olive oil, sesame oil or paraffin oil or injectable organic esters such as ethyl oleate .
• the aqueous solutions are suitable for intravenous administration as long as the pH is suitably adjusted and the isotonicity is achieved, for example, by a sufficient amount of sodium chloride or glucose. Sterilization can be carried out by heating or by any other means which does not alter the composition. It is understood that all the products entering into the compositions according to the invention must be pure and non-toxic for the quantities used.
• compositions can contain at least 0.001% of therapeutically active product.
• the amount of active ingredient in a composition is such that a suitable dosage can be prescribed.
• the compositions are prepared in such a way that a unit dose contains from 0.01 to 100 mg approximately of active product for parenteral administration.
• Therapeutic treatment can be carried out concurrently with other therapeutic treatments including antineoplastic drugs, monoclonal antibodies, immunological therapies or radiotherapy or modifiers of biological responses.
• Response modifiers include, but are not limited to, lymphokines and cytokines such as interleukins, interferons ( ⁇ , ⁇ or ⁇ ) and TNF.
• chemotherapeutic agents useful in the treatment of disorders due to abnormal cell proliferation include, but are not limited to, alkylating agents such as nitrogen mustards such as mechloretamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, lomustine, semustin and streptozocin, triazenes such as dacarbazine, antimetabolites such as folic acid analogs such as methotrexate, pyrimidine analogs such as fluorouracil and cytarabine, analogs of purines like mercaptopurine and tm ⁇ guanine, natural products such as vinca alkaloids like vinblastine, vincristine and vendesine, epipodophyllotoxins like etoposide and teniposide, antibiotics like dactinomycin, daunorubicin, doxorubicin, ble
• the doses used to implement the methods according to the invention are those which allow a prophylactic treatment or a maximum response. therapeutic.
• the doses vary according to the form of administration and the specific characteristics of the subject to be treated. In general, the doses are those which are therapeutically effective for the treatment of disorders due to abnormal cell proliferation.
• the product according to the invention can be administered as often as necessary to obtain the desired therapeutic effect. Some patients may respond quickly to relatively large or low doses and may require low or no maintenance doses. Generally, low doses will be used at the start of treatment and, if necessary, increasing doses will be administered until an optimum effect is obtained. For other patients it may be necessary to administer maintenance doses 1 to 8 times a day, preferably 1 to 4 times, depending on the physiological needs of the patient concerned. It is also possible that for some patients it is necessary to use only one or two daily administrations.
• the doses are generally between 0.05 and 50 mg / kg and, preferably between 0.01 and 5 mg / kg and, even more specifically between 0.1 and 2 mg kg. It is understood that, in order to choose the most appropriate dosage, the route of administration, the patient's weight, his general state of health, his age and all the factors which may influence the effectiveness of the treatment must be taken into account. .
• Example 2 40 mg of the product obtained in Example 1 are dissolved in 1 cm 3 of Emulphor EL 620 and 1 cm 3 of ethanol then the solution is diluted by adding 18 cm 3 of physiological saline.
• composition is administered by infusion for 1 hour by introduction into physiological saline.

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Medicinal Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Oncology (AREA)
• Hematology (AREA)
• Urology & Nephrology (AREA)
• Endocrinology (AREA)
• Reproductive Health (AREA)
• Dermatology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Medicines Containing Plant Substances (AREA)

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• 1995
  • 1995-06-20 WO PCT/FR1995/000814 patent/WO1996000205A1/fr not_active Application Discontinuation
  • 1995-06-20 CZ CZ963806A patent/CZ380696A3/cs unknown
  • 1995-06-20 JP JP8502860A patent/JPH10504536A/ja active Pending
  • 1995-06-20 AU AU27980/95A patent/AU2798095A/en not_active Abandoned
  • 1995-06-20 CA CA002192711A patent/CA2192711A1/fr not_active Abandoned
  • 1995-06-20 CN CN95193728A patent/CN1151154A/zh active Pending
  • 1995-06-20 MX MX9606534A patent/MX9606534A/es unknown
  • 1995-06-20 BR BR9508364A patent/BR9508364A/pt unknown
  • 1995-06-20 PL PL95317895A patent/PL317895A1/xx unknown
  • 1995-06-20 US US08/750,838 patent/US5716994A/en not_active Expired - Fee Related
  • 1995-06-20 HU HU9603541A patent/HUT76337A/hu unknown
  • 1995-06-20 SK SK1667-96A patent/SK166796A3/sk unknown
  • 1995-06-20 EP EP95923415A patent/EP0767773A1/fr not_active Ceased
  • 1995-06-22 TW TW084106425A patent/TW374764B/zh active
• 1996
  • 1996-12-20 BG BG101071A patent/BG101071A/xx unknown
  • 1996-12-20 NO NO965504A patent/NO965504D0/no unknown
  • 1996-12-20 FI FI965166A patent/FI965166A/fi not_active Application Discontinuation

Non-Patent Citations (1)

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