Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
  • C07D493/18—Bridged systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
  • A61P33/06—Antimalarials
• • 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
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
  • C07D493/20—Spiro-condensed systems

Definitions

• the present invention relates to new artemisinin derivatives, their preparation process and the pharmaceutical compositions containing them.
• Artemisinin is an active ingredient isolated from Artemisia annual. L., well known for its activity against malaria.
• the compounds of the present invention are new, and have particularly advantageous pharmacological properties as anti-tumor agents
• R represents the radical of formula (II)
• A represents
• CN a group of formula (III) -CR (m) R in which - R 1 represents an aryl, substituted aryl, heteroaryl or substituted heteroaryl group,
• R 2 represents a hydrogen atom, or a linear or branched alkyl group (Ci -Ce) substituted or not,
• - Y represents a linear or branched alkylene (C 2 -C ⁇ ) group substituted or not, alkenylene (C 2 -C ⁇ 4 ) linear or branched substituted or not, alkynvlene (C 2 -C ⁇ ) linear or branched substituted or not, phenylene, substituted phenvlene, naphthylene, or substituted naphthylene, - Z represents an oxygen or sulfur atom, or a group NR ' 2 or R' 2 can take the same values as R 2 ,
• aryl means a phenyle, naphthyl, phenanthryl, fluorenyl or anthryl group, - by heteroaryl, we mean any mono or bicyc group that aromatic containing from 5 to
• 10 atoms and may contain from 1 to 3 heteroatoms chosen from oxygen, nitrogen or sulfur,
• aryl "," heteroaryl “,” phenylene “,” naphthylene “ means that these groups are substituted by one or more radicals, identical or different, chosen from linear or branched (CC 6 ) alkyl , hydroxy, linear or branched alkoxy (C r C 6 ), alkoxycarbonyl (d-C ⁇ ), linear or branched polyhalogenoalkyl (C ⁇ -C 6 ), aryloxy (not substituted or substituted by one or more groups, identical or different, chosen from hydroxy, alkyl (C ⁇ -C6) linear or branched alkoxy (C ⁇ -C6) linear or branched, polyhaloalkyl (C ⁇ -C6) linear or branched, or halogen atoms), nitro, amino, alkylamino (-C Ce) linear or branched, dialkylamino (C ⁇ -C 6 ) linear or branched, alkylcarbonylamino c
• substitute affecting the expressions "alkyl”, “alkylene”, “alkenylene”, “alkynylene” means that these groups are substituted by one or more radicals, identical or different, chosen from hydroxy, alkoxy (C ⁇ -C 6 ) linear or branched, polyhalogenoalkyle, amino or halogen atoms (fluorine, chlorine, bromine or iodine), their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base
• hydrochloric bromide, sulphonic, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, succinic malonic, glutinic, fumaic, tartic, maleic, citric, ascorbic, oxalic, methane sulfonic acids. , camphoric, etc
• the preferred compounds of the invention are those for which - A represents a group of formula (III),
• Z represents a group NR ' 2 ,
• - Y represents an alkylene or alkenylene chain (C 2 -Cj), substituted or not, - Y represents a phenvlene or a naphthylene, substituted or not,
• the invention relates to the compounds of formula (I) for which A represents a group of formula (III) or R 1 represents a substituted or unsubstituted phenyl group and R 2 represents a hydrogen atom or a methyl group, or a group of formula (IV) or Y represents a chain - (CH 2 ) n - or n is such that 2 ⁇ n ⁇ 7, Z represents an oxygen atom or a group NR ' 2 and R 3 represents a group of formula (III) where R 1 represents a substituted or unsubstituted phenyl or naphthyl group and R 2 represents a hydrogen atom or a methyl group
• the invention also extends to the process for preparing the compounds of formula (I) characterized in that the compound of formula (V) is used as starting material:
• R and Y are defined as above, on which it is reacted under acid catalysis conditions, in the presence of a coupling agent, or after transformation into the corresponding acid chloride,
• the compound of formula (V) is easily accessible to those skilled in the art by conventional reduction of artemisinin (commercial).
• the compounds of formula (VI) are obtained by conventional condensation of a cyanide salt on the ketone of formula (XI):
• R 1 and R 2 are defined as above.
• the compounds of formula (X) are obtained by the action of H 2 S in the presence of a catalyst such as Al O 3 for example on the compound of formula (VI).
• Another advantageous process of the invention relates to the preparation of the compounds of formula (I) for which A represents a group of formula (IV), characterized in that a compound of formula (VII) is used as starting material :
• R, Y, R 1 . R 2 and R ' 2 are as defined above,
• the compounds of formula (I) have interesting pharmacological properties They have excellent cytotoxicity m vitro not only on leukemic lines but also on solid tumor lines, and also have an action on the cell cycle These properties allow their use in therapeutic as anti-tumor agents
• the present invention also relates to pharmaceutical compositions containing the products of formula (I) their optical isomers or one of their addition salts with a base or a pharmaceutically acceptable acid, alone or in combination with one or more inert non-toxic excipients or vehicles
• compositions according to the invention particular mention will be made of those which are suitable for oral, parenteral, nasal, rectal, perhnal, ocular or respiratory administration and in particular simple or coated tablets, sublingual tablets, sachets, packets , capsules, glossettes, tablets, suppositories creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nasal drops
• the useful dosage varies according to the age and weight of the patient, the route of administration, the nature of the therapeutic indication and any associated treatments and ranges from 0.1 to
• Examples 4 to 16 are obtained according to the same process from the appropriate nitriles.
• the title product is conventionally obtained by condensation of succinic acid or its anhydride on dihydroartemisinin.
• Stage B 1, 4-Succinate of [(2-kromophenyl) (cyano) methyl] and of dihydroartemisininyl
• Examples 18 to 27 are obtained according to the same process by replacing in stage B 2- (2-bromophenyl) -2-hydroxyacetonitrile with the appropriate reagent.
• EXAMPLE 34 4- (E) -2-Butenedioate of [(2-chlorophenyl) (cyano) methyl] and of dihydroartemisininyl
• EXAMPLE 35 1, 4- (2.3-Dichloro) succinate of
• EXAMPLE 40 4 - ( ⁇ [Cyano] [(3-methoxy-4-benzyloxy) phenyl] methyl ⁇ amino) -4- dihydroartemisininyl oxobutanoate
• Examples 45 to 48 are obtained by proceeding as in Example 1, replacing 2- (4-bromophenyl) -2-hydroxy acetonitrile with the appropriate nitrile.
• Examples 49 to 56 are obtained by proceeding as in Example 42, replacing: - in stage .A benzaldehyde with the appropriate reagent, - in stage B. succinic anhydride with the appropriate reagent.
• Stage A 4-Bromobenzaldehyde
• Stage B Succinic anhydride
• EXAMPLE 50 4 - ⁇ [(Cyano [phenyl] methyl) (methyl) amino] carbonyl ⁇ dihydroartemisininyl benzoate
• Stage A Benzaldehyde
• Stage B 2-Butenedioic acid
• Stage A 2- Bromobenzaldehyde
• Stage B Succinic anhydride
• Examples 57 to 67 are obtained by proceeding as in Example 16, replacing in Step B 2- (2-bromophenyl) -2-hydroxyacetonitrile with the appropriate acetonitrile.
• the cells are cultured in complete RPMI 1640 culture medium containing 10% of fetal calf serum 2 mM of glutam e, 50 units / ml of penicillin, 50 ⁇ g / ml of streptomycin and 10 mM of Hepes
• the cells are distributed in microplates and exposed to cytotoxic compounds. They are then incubated for the time necessary for cell doubling. The number of viable cells is then quantified by a colo ⁇ met ⁇ que test, the Minoculture Tetrazo um Assay (Carmichael J De Graff WG, Gazdar AF , Mmna JD and Mitchell JR, Evaluation of a tetrazo um-based semi-automated colo ⁇ met ⁇ c assay assessment of chemosensitivity testing, Cancer Res, 47 936-942, 1987)
• the L1210 cells are incubated for 21 hours at 37 ° C. in the presence of different concentrations of test products.
• the cells are then fixed with 70% ethanol (V / V), washed twice in PBS and incubated for 30 minutes.
• the percentage in phase G2 + M is calculated and the results are expressed according to a classification determined according to the percentage of cells accumulated in phase G2 + M after 21 hours compared to the control (control 20%)
• the compounds of the invention show an accumulation of more than 60% of the cells in G2-M phase after 21 hours for product concentrations ranging from 0.5 to
• the compounds of the invention show an induction of apoptosis at cytotoxic doses

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (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)
• Tropical Medicine & Parasitology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=5224325

Family Applications (1)

Country Status (14)

Families Citing this family (17)

Family Cites Families (7)

• 1998
  • 1998-06-17 CN CN98114788A patent/CN1084333C/zh not_active Expired - Fee Related
• 1999
  • 1999-06-09 HU HU0102599A patent/HUP0102599A3/hu unknown
  • 1999-06-09 JP JP2000554739A patent/JP2002518398A/ja active Pending
  • 1999-06-09 CN CN99807416A patent/CN1111162C/zh not_active Expired - Fee Related
  • 1999-06-09 PL PL99344984A patent/PL344984A1/xx not_active Application Discontinuation
  • 1999-06-09 NZ NZ508388A patent/NZ508388A/en unknown
  • 1999-06-09 BR BR9911274-4A patent/BR9911274A/pt not_active IP Right Cessation
  • 1999-06-09 CA CA002342990A patent/CA2342990A1/fr not_active Abandoned
  • 1999-06-09 AU AU40474/99A patent/AU748798B2/en not_active Ceased
  • 1999-06-09 US US09/719,767 patent/US6307068B1/en not_active Expired - Fee Related
  • 1999-06-09 EP EP99923702A patent/EP1086107A1/de not_active Withdrawn
  • 1999-06-09 WO PCT/FR1999/001359 patent/WO1999065914A1/fr not_active Application Discontinuation
• 2000
  • 2000-11-30 ZA ZA200007070A patent/ZA200007070B/en unknown
  • 2000-12-08 NO NO20006257A patent/NO20006257L/no not_active Application Discontinuation
• 2001
  • 2001-11-12 HK HK01107929A patent/HK1036985A1/xx not_active IP Right Cessation

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events