Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
  • C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to new chemical compounds derived from the binary alkaloids of Catharanthus roseus, their preparation and their therapeutic use.
• the compounds of the invention have the general formula 1:
• n 1 or 2
• R 1 represents a methyl group or a vinyl group
• R 2 represents a methoxyl group or an amino group
• R 3 represents a hydrogen atom or an acetyl group.
• the invention also relates to the salts of the compounds of formula 1 with pharmaceutically acceptable mineral or organic acids.
• the acid used can be, by way of nonlimiting example, sulfuric acid or tartaric acid.
• the invention relates equally to mixtures of the diastereoisomers corresponding to the 20 'carbon configurations of the compounds of general formula 2, as well as their mixture in any proportion.
• the derivatives of the invention are prepared by reaction of a compound of general formula 2 in a superacid medium, originating from the association of a Bronsted acid such as hydrofluoric acid HF and a Lewis acid such as pentafluoride d antimony SbFs, in the presence of a halogenating reagent such as bromine, a hypochlorite such as calcium hypochlorite, or an N-halo imide such as N-corosuccinimide or N-bromosuccinimide.
• a Bronsted acid such as hydrofluoric acid HF and a Lewis acid such as pentafluoride d antimony SbFs
• a halogenating reagent such as bromine, a hypochlorite such as calcium hypochlorite, or an N-halo imide such as N-corosuccinimide or N-bromosuccinimide.
• n, Ri, R 2 and R 3 are defined as above, R represents a hydroxyl group and R 5 represents a hydrogen atom; or R 4 and R 5 together form a double bond.
• the reaction is carried out at a temperature between -60 ° C and -15 ° C in Teflon vessels according to the following scheme:
• IR, NMR, mass at high resolution confirm the structure of the compounds obtained according to the invention.
• the products are described using biogenetic numbering [J. LEMEN and WI TAYLOR, Experientia, 21, 508, (1965)].
• the crude reaction product is then quickly poured onto a liter of mixture (water + ice) added with 80 g of sodium carbonate in order to prevent the mixture from heating up. 15 ml of acetone are then added to promote the extraction, carried out with 3 times 500 ml of dichloromethane. The organic phase is separated and dried over MgSO 4 , and the solvent is evaporated under reduced pressure.
• This compound is dissolved in 3 ml of absolute EtOH, then salified by adding 1.8 ml of 2% solution of concentrated sulfuric acid in EtOH. The mixture is then poured dropwise with vigorous stirring into 20 ml of ethyl ether cooled in an ice bath. The white precipitate obtained, hygroscopic, is filtered and dried under vacuum.
• This derivative is obtained according to the procedure described in Example 1, by replacing N-bromosuccinimide with N-chlorosuccinimide during treatment in a superacid medium.
• the reaction time in superacid medium is 20 minutes at -50 ° C.
• the reaction time in superacid medium is 15 minutes at -30 ° C.
• the physico-chemical and spectroscopic characteristics of the isolated product are identical to those of the compound obtained in Example 1.
• This derivative is obtained according to the procedure described in Example 1, by replacing the N-bromosuccinimide with calcium hypochlorite during the treatment in superacid medium.
• the reaction time in superacid medium is 20 minutes at -50 ° C.
• reaction time in superacid medium is 15 minutes at -30 ° C.
• the reaction time in superacid medium is 15 minutes at -30 ° C.
• the physico-chemical and spectroscopic characteristics of the isolated product are identical to those of the derivative obtained in Example 5.
• the reaction time in superacid medium is 15 min at -30 ° C.
• reaction time in superacid medium is 15 minutes at -30 ° C.
• C 46 H54 F 2 N 4 0 9 : 844.92 Melting point: 228 - 233 ° C (dec.)
• the compounds of the invention have been subjected to pharmacological tests which have demonstrated their advantage as substances with therapeutic activity. Also, the cytotoxic activity of the products was evaluated using the MTT test [T. Mosman, J. Immunol. Method. £ 5.55 (1983)] on different tumor cell lines.
• the MTT test is based on the ability of living cells to reduce, by the action of their mitochondrial enzymes, a yellow tetrazolium salt to a blue violet compound, formazan, measurable by spectrophotometry after dissolution in dimethylsulfoxide. The amount of formazan formed (and therefore the intensity of the coloration obtained) is directly proportional to the number of living cells present in the culture medium at the time of the test.
• the lines used are of human origin, and are 15 marketed by the American Type Cell Collection (ATCC), a benchmark organization for the supply of standardized strains.
• ATCC American Type Cell Collection
• the results are expressed as a percentage of growth inhibition relative to the controls.
• Table 1 gives, by way of example, the results obtained for certain derivatives of the invention at the concentration of 1 ⁇ g / ml.
• REPLACEMENT LLE (RULE 2 ⁇ )
• the products prepared according to the invention are poisons of the mitotic spindle. This property was confirmed by measuring the inhibition of polymerization of tubulin into microtubules in the presence of the compounds of the invention, by following the method described by RC Weisenberg (Science 177, 1196-7, 1972). The results are expressed as the concentration of product which causes 50% inhibition of the polymerization. This phenomenon is easily monitored and quantified through variations in optical density.
• Table 2 shows the results obtained with some derivatives prepared according to the invention:
• the anti-tumor properties of the products of the invention have been confirmed by in vivo tests, in particular on the model of mammary adenocarcinoma MXT, a solid tumor particularly insensitive to anticancer agents [CS Watson, D. Medina, JH Clark, Cancer Res. 37. 3344 (1977); W.T. Bradner and C.A. Claridge, "Antineoplastic Agents", Wiley-Interscience (1984); T.W. Redding and AV. Schally, Proc. Natl. Acad. Sci. U.S.A., 80, 1459 (1983)].
• mice of the B6D2F1 type are grafted by the injection (subcutaneously) of a tumor fragment of approximately 10 mm 3 originating from an MXT tumor.
• the products to be tested are administered ip from the 17th day after the transplant.
• the MXT test provides two types of results: the effect exerted by the molecule studied on tumor growth, and the survival time of the treated animals compared to the control animals (T / C expressed as a percentage).
• REPLACEMENT SHEET S ⁇ -H 26 the compound of Example 1 causes a reduction in tumor size of 40% compared to the controls not treated according to a protocol of 9 x 40 mg / kg, while all the derivatives of this chemical family, vinblastine , vincristine, vindesine and vinorelbine, are devoid of activity on this model.
• the compounds of the present invention can be used in human therapy in the treatment of cancer pathology.
• compositions containing these active ingredients can be shaped for administration by the oral, intravenous or subcutaneous route.

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• General 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)
• Chemical Kinetics & Catalysis (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Plant Substances (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Saccharide Compounds (AREA)
• Compounds Of Unknown Constitution (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

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• 1993
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