Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/56—Ring systems containing three or more rings
  • C07D209/80—[b, c]- or [b, d]-condensed
  • C07D209/82—Carbazoles; Hydrogenated carbazoles
  • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to the preparation of hydroxy-9 ellipticine, as well as derivatives thereof substituted in positions 6 and / or 9, and / or quaternized on the nitrogen atom in position 2.
• the invention has more particularly relates to a process for the preparation of compounds of formula:
• R 1 is a hydrogen atom or an alkyl group
• R 2 is a hydrogen atom or an alkyl, acyl, benzyl or benzoyl group
• R and X when present, are respectively an alkyl group , substituted or not, and an appropriate quaternization anion.
• the essential object of the invention is therefore a process for the preparation of hydroxy-9 ellipticine, as well as derivatives thereof substituted in positions 6 and / or 9 and / or quaternized on the nitrogen atom. position 2, according to which:
• 5-methoxy indole is condensed on hexane-dione 2, 5 in order to prepare 6-methoxy-1,4-dimethyl carbazole,
• dimethyl-6-dimethyl-1,4 carbazole is dimethylated to prepare hydroxy-6 dimethyl-1,4 carbazole; 3. the hydroxy group is protected from the latter by benzylation or by benzoylation of 6-hydroxy dimethyl-1,4-carbazole,
• a metallation of the benzyl (or benzoyl) -oxy-6-1,4-dimethyl-1,4-carbazole thus prepared is carried out if desired, and the product of this metallation is treated with alkyl iodide to prepare the alkyl -9 benzyl (or benzoyl) -oxy-6 dimethyl-1,4-carbazole,
• step 3 or 4 is formulated to prepare the 3-forrayl benzyl (or benzoyl) - (oxy
• step 6 the product from step 6 is cyclized, and 8.
• step 8 the product of step 8 is treated with an alkyl halide in order to obtain the hydroxy-9-alkyl-2-ellipticinium halide, or the corresponding hydroxy-2,6-dialkyl-ellipticinium halide, and eventually,
• step 9 the substituted ellipticinium halide obtained in step 9 is converted into a corresponding water-soluble salt quaternized on the nitrogen atom in position 2.
• the alkyl halide used for the alkylation at position 2 of the ellipticinium structure may also be an unsubstituted alkyl halide, in particular an unsubstituted lower alkyl halide, that an alkyl halide in which the alkyl group is substituted, in particular, but not limited to, by at least one hydroxy group, or by a nitrogen atom, which can itself, in turn, be substituted by alkyl groups, in particular lower alkyl groups, or be part of a nitrogen heterocycle.
• R CH 3 , C 2 H 5 , or more generally an alkyl group, such as for example a C 1 -C 3 alkyl group.
• the product thus obtained is practically insoluble in water, but soluble in DMF.
• ion exchange resins which can be used for this purpose are the resins marketed under the respective names Amberlite and Bio-Rad (Analytical Grade Anion Exchange Resin Bio-Rad, Ag R l-X8, in acetate form, marketed by Bio-Rad Laboratories,
• the process according to the invention is very particularly suitable for obtaining compounds in which, depending on the compounds used and / or of the process step which is considered to be the final step:
• -X is a halogen atom, or an acyloxy group, in particular the CH 3 COO 'group.
• the method according to the invention leads to the obtaining of the desired compounds with a very good yield and a high degree of purity.
• This last factor above all is an important asset, since hydroxy-9 ellipticine and its derivatives substituted in positions 6 and / or 9 are intermediates for the synthesis of water-soluble salts (and the quaternized derivatives on the atom of nitrogen in position 2 are themselves water-soluble salts), which are in particular useful in the treatment of cancers and exhibit in this application an exceptionally low degree of toxicity, as described in patent GB 1,508,388, to which it should refer to this proposal.
• the compounds obtained according to the invention are therefore essentially useful for the production of pharmaceutical compositions with anticancer activity (their effectiveness in the treatment of leukemias and solid tumors of human beings have been established), or as intermediates in the preparation of such compounds.
• the toluene solutions were collected, washed twice with water, dried over anhydrous CaCl 2 , filtered and the excess toluene was removed in a water bath.
• 6-benzoyl-oxy-1,4-dimethyl carbazole 21 g (0.10 mole) of 6-hydroxy-1,4-dimethyl-carbazole were dissolved in a mixture of 200 ml of anhydrous acetone and 50 ml of triethylamine (dried on potassium hydroxide pellets).
• the product was again crystallized from a minimum amount of CHC1 3 .
• reaction mixture was poured into 3 liters of water. ice cold, and neutralization was carefully carried out with ammonia up to a pH of about 7.
• the product was dried and washed with anhydrous ether and then recrystallized from absolute ethanol.
• step 9 The product from step 9 was dissolved in DMF, while adding water in fractions, so as to form a solvent composed of DMF and water in equal parts and to obtain a final concentration of approximately 2 at 10 mg per ml. This solution was then degassed carefully.
• a column of suitable anion exchange resin was prepared as follows:
• Quantity of resin used the exchange capacity of this resin was 1.4 meq / ml of resin, or 3.2 meq / g of dry weight of resin, i.e. in this case 0.78 g of resin / g of product.
• the amount of resin respectively used was 3 times the amount strictly necessary.
• Elution medium 50/50 mixture of DMF / H 2 O
• the resin was suspended in this mixture.
• the column was then fed and equilibrated, and the iodine derivative (prepared as described above) was eluted on this column, thus obtaining a solution of 9-hydroxy-2,6-diethyl ellipticinium acetate.
• the water and the DMF were completely removed therefrom.
• Precipitation was carried out in ether and, after filtration, the precipitated product was prepared by filtration, dried with ether, and dried in vacuo in a desiccator. An orange powder, perfectly soluble in water, was obtained (yield: 95% by weight), from which an aqueous solution containing 4 mg per ml of this acetate could be easily prepared.
• 6-hydroxy-1,4-dimethyl carbazole was prepared by following the procedure of steps 1 and 2 of Example 1.
• the synthesis of 9-hydroxy ellipticine was then carried out by following the reaction sequences below, and working in accordance with the operating methods, the details of which are given below. Under each of the formulas of the compounds considered in the reaction schemes appears the molecular weight of the compound.
• Dimethyl-4,4-benzyloxy-6 carbazole obtained by the action of benzyl chloride on 1,4-dimethyl-6 hydroxy-carbazole
• 1,4-Dimethyl-hydroxy-6-carbazole In a three-necked flask, 790 g (10 moles) of pyridine were charged and then 112.5 g (5 moles) of gaseous hydrochloric acid were bubbled through a dip tube. It was topped off by distillation until a mass temperature of 192-195 ° C was obtained. It was cooled to around 130 ° C and 112.5 (0.5 mole) of 1,4-dimethyl-6-methoxy-carbazole was introduced. The temperature was raised to 192-195 ° C and kept at this temperature for 0.50 hours. Hydrolysis was carried out on 1000 g of ice water. 300 cm3 of sulfuric ether were extracted with three times. The combined ethereal layers were washed with twice 100 cm3 of water and then dried over anhydrous sodium sulfate. The ether was removed by concentration under atmospheric pressure. We collected the product:
• the crude product is composed of a mixture of 70% of benzyl derivative and 30% of hydroxyl derivative coming from a cleavage in an acid medium. It can be recrystallized from 200 volumes of acetone, to yield a product containing less than 5% of hydroxylated derivative which does not constitute an impurity, since it is the product prepared in the following phase. Hydroxy-9 ellipticine

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Indole Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Hydrogenated Pyridines (AREA)

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• 1978
  • 1978-09-15 US US05/942,793 patent/US4310667A/en not_active Expired - Lifetime
• 1979
  • 1979-09-14 ES ES484181A patent/ES484181A1/es not_active Expired
  • 1979-09-14 EP EP79400646A patent/EP0009445B1/fr not_active Expired
  • 1979-09-14 AT AT79400646T patent/ATE3427T1/de not_active IP Right Cessation
  • 1979-09-14 JP JP54501503A patent/JPS5951956B2/ja not_active Expired
  • 1979-09-14 HU HU79AA936A patent/HU183081B/hu not_active IP Right Cessation
  • 1979-09-14 DE DE7979400646T patent/DE2965444D1/de not_active Expired
  • 1979-09-14 WO PCT/FR1979/000080 patent/WO1980000564A1/fr not_active Ceased
• 1980
  • 1980-05-14 SU SU802924050A patent/SU1053753A3/ru active
• 1984
  • 1984-07-24 JP JP59153892A patent/JPS6045579A/ja active Granted

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