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

• Vinca alkaloids Pink Catharanthus dimer alkaloids and their derivatives, commonly called Vinca alkaloids, have been widely used in cancer chemotherapy for around thirty years. They are represented by four products:
• vindesin obtained from vinblastine, and vinorelbine, synthesized from the alkaloid precursor monomers, catharanthine and vindoline.
• the present invention carried out at the Pierre Fabre Research Center, relates to new derivatives of Vinca alkaloids, their method of preparation and their therapeutic application.
• Rj represents a hydrogen or fluorine atom
• the invention also relates to the salts of the compounds of general 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 both to the isomers corresponding to the R and S configurations of the 4 'and 20' carbons of the compounds of general formula 1, as well as their mixtures 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 mixture of a strong Bronsted acid such as hydrofluoric acid, and a strong Lewis acid such as pentafluoride d 'antimony, in the presence of a species-generating reagent of the superelectrophilic type, according to the name proposed by G. Olah (Ang. Chem. Int. Ed. Engl., 32, 767-88, 1993).
• This reagent can consist of a chlorinated derivative such as methylene chloride, chloroform, carbon tetrachloride, 2,2-dichloropropane or a mixture of these derivatives in all proportions.
• the reactions in superacid medium are carried out in containers resistant to hydrofluoric acid such as Tefion® or a steel of suitable composition.
• the derivative of formula 2, in which R3 and R4 are defined as above, is dissolved in hydrofluoric acid or in a chlorinated derivative defined as above serving as solvent, and added to the superacid mixture, which may possibly already contain a fraction of chlorinated derivative. This addition is carried out while maintaining the temperature of the medium at a chosen value, between -80 and -30 ° C.
• AgBF4 silver tetrafluoroborate
• the subject of the invention is also a new process for the synthesis of 4'-deoxy-20 ', 20'-difluorovinblastine, as well as 20', 20'-difluoro - 3 ', 4'- dihydrovinorelbine or vinflunine, compounds claimed in patent FR 2,707,988 of July 21, 93 (WO 95/033 12).
• NBS N-(n-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-(n-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
• the derivative of formula 2 is dissolved in the chlorinated derivative, preferably chloroform or 2,2-dichloropropane, or a mixture containing chloroform or 2,2-dichloropropane, and added to the superacid medium, maintaining the temperature of this last between -45 and -35 ° C.
• the difluorinated derivative, 4'-deoxy-20 ', 20'-difluorovinblastine then constitutes the majority final product of the reaction.
• the assay by analytical HPLC indicates a proportion of this compound of the order of 50%>.
• This method therefore constitutes a new process for the preparation of 4'-deoxy-20 ', 20'-difluorovinblastine, with a higher yield than that obtained by the prior art.
• the intermediate compound 9'-bromoindolenine of 4'-deoxy-20 ', 20'- difluorovinblastine, not very stable and not isolated, undergoes hydrolysis preferably in a mixture [methylene chloride: water: tetrahydrofuran], whether or not tetrafluoroborate is present.
• methylene chloride: water: tetrahydrofuran a mixture
• AgBF4 makes it possible to increase the speed of the reaction.
• the major compound obtained with a yield of about 80%> is the 20, 20'-difluoro-3 ', 4'-dihydrovinorelbine or vinflunine.
• reaction medium is poured with great care into 1.5 liters of a 3M aqueous suspension of Na2C ⁇ 3 containing 200 ml of methylene chloride. After decantation, the aqueous phase is extracted with 100 ml of methylene chloride. The organic phases are combined, washed with saturated NaCl solution, dried over MgS ⁇ 4 and evaporated.
• the two diastereoisomers of 20'-chloro-4'-deoxyvinblastine are salified in the form of ditartrate by addition of two equivalents (mole) of tartaric acid in water, and lyophilized.
• This compound is isolated from the reaction mixture obtained in Example 1 or in Example 2, from other less polar fractions originating from chromatography on a silica column. The final purification is carried out by preparative HPLC in reverse phase.
• the 20'-chloro-4'-deoxy-4'-fluorovinblastine is salified in the form of ditartrate by addition of two equivalents (mole) of tartaric acid in water, and lyophilized.
• the mixture is then neutralized by the addition of 5 ml of a saturated solution of NaPIC03, then immediately of a solution of 21 1 mg (1.08 mmol) of silver tetrafioroborate in a mixture of 5 ml of tetrahydrofuran and 2 ml of water.
• the mixture is left to return to ambient temperature with magnetic stirring for approximately two hours.
• This compound is obtained by following the procedure described in Example 7, replacing 2,2-dichloropropane with dibromomethane CH2Br2 during the treatment in superacid medium.
• the mixture is neutralized by the addition of 300 ml of a 10% solution of NaHCO3, then immediately a solution of 23.4 g (0.12 mole) of silver tetrafioroborate in a mixture of 300 ml of tetrahydrofuran and 100 ml of water. The mixture is left to return to ambient temperature with stirring for approximately two hours.
• Vinflunine in solution in toluene, is extracted with an aqueous solution containing exactly two equivalents (mole) of tartaric acid. The aqueous phase is then lyophilized to obtain the vinflunine ditartrate.
• the pharmaceutical preparations containing these active ingredients can be shaped for administration by the oral, intravenous or subcutaneous route, in a conventional manner, well known to those skilled in the art.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Public Health (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Steroid Compounds (AREA)
• Saccharide Compounds (AREA)
• Other In-Based Heterocyclic Compounds (AREA)
• Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 1997
  • 1997-04-10 FR FR9704398A patent/FR2761990B1/fr not_active Expired - Lifetime
• 1998
  • 1998-04-10 EP EP06124480A patent/EP1764368B1/fr not_active Expired - Lifetime
  • 1998-04-10 DE DE69824840T patent/DE69824840T2/de not_active Expired - Lifetime
  • 1998-04-10 AT AT06124480T patent/ATE473987T1/de active
  • 1998-04-10 AU AU73408/98A patent/AU737549C/en not_active Expired
  • 1998-04-10 US US09/402,678 patent/US6127377A/en not_active Expired - Lifetime
  • 1998-04-10 EP EP20030017052 patent/EP1357125A3/fr not_active Ceased
  • 1998-04-10 BR BRPI9816177-6A patent/BR9816177B1/pt not_active IP Right Cessation
  • 1998-04-10 JP JP54247098A patent/JP4401440B2/ja not_active Expired - Lifetime
  • 1998-04-10 CA CA2665949A patent/CA2665949C/fr not_active Expired - Lifetime
  • 1998-04-10 DK DK98920607T patent/DK0975640T3/da active
  • 1998-04-10 EP EP98920607A patent/EP0975640B1/fr not_active Expired - Lifetime
  • 1998-04-10 DE DE69841766T patent/DE69841766D1/de not_active Expired - Lifetime
  • 1998-04-10 ES ES98920607T patent/ES2222588T3/es not_active Expired - Lifetime
  • 1998-04-10 PT PT06124480T patent/PT1764368E/pt unknown
  • 1998-04-10 CA CA002286560A patent/CA2286560C/fr not_active Expired - Lifetime
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  • 1998-04-10 AT AT98920607T patent/ATE270297T1/de active
  • 1998-04-10 WO PCT/FR1998/000730 patent/WO1998045301A1/fr not_active Ceased
  • 1998-04-10 PT PT98920607T patent/PT975640E/pt unknown
  • 1998-04-10 DK DK06124480.2T patent/DK1764368T3/da active
  • 1998-04-10 CA CA2455416A patent/CA2455416C/fr not_active Expired - Lifetime
  • 1998-04-10 DE DE122010000054C patent/DE122010000054I1/de active Pending
  • 1998-04-10 BR BRPI9807944-1A patent/BR9807944B1/pt not_active IP Right Cessation
• 2004
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• 2009
  • 2009-03-11 JP JP2009058098A patent/JP2009167196A/ja active Pending
• 2010
  • 2010-09-27 FR FR10C0045C patent/FR10C0045I2/fr active Active
  • 2010-10-14 CY CY20101100917T patent/CY1111476T1/el unknown
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