Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—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
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
  • C07D491/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
  • C07D497/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D497/14—Ortho-condensed systems

Definitions

• the present invention relates to new tricyclic derivatives of dihydro-quinolines, their process of preparation, the pharmaceutical compositions which contain them as well as their use as anticancer.
• the compounds of the invention in addition to the fact that they are new, exhibit very advantageous antitumor properties.
• R ⁇ a - ôb and R f e identical or different, each represents a hydrogen atom or a linear or branched (Ci-C 6 ) alkyl group
• - R ô represents a linear or branched (C ⁇ -C 6 ) alkyl group when R 10 represents a hydrogen atom and a group selected from hydrogen and alkyl (C-. -C 6) linear or branched when R 10 represents an alkyl group (Cl- Ce) linear or branched
• - X represents an oxygen or sulfur atom or an NRe c group in which R ôc represents a hydrogen atom or a linear or branched (Ci-C 6 ) alkyl group,
• - Ri represents a hydrogen atom or a group chosen from:
• R 7a and R 7 b identical or different, each represent an alkyl group (Ci-C 6 ) linear or branched, optionally substituted by a hydroxy or amino group (itself optionally substituted by one or two alkyl groups (Ci-Ce) linear or branched), or else R 7a and R form together with the nitrogen atom who wear them a nitrogen heterocycle),
• R a and R 7b identical or different, each represent a group linear or branched (Ci-C 6 ) alkyl, optionally substituted by a hydroxy or amino group (itself optionally substituted by one or two linear or branched (Ci-C 6 ) alkyl groups, or else R 7a and R 7b form together with the nitrogen atom which carries them a nitrogen heterocycle, - or OR 9 in which R 9 represents a hydrogen atom or an aryl, or alkyl (Ci-C 6 ) linear or branched group optionally substituted by a group of formula NR 7a R7b in which R 7a and R 7b , identical or different, each represent a linear or branched (Ci-C 6 ) alkyl group, optionally substituted by a group of formula NR 7a R7b in which R 7a and R 7b , identical or different, each represent a linear or branched (Ci-C 6 ) alkyl group, optionally substituted by a
• R 2 , R 3 , Ri and R 5 identical or different, each represent: - a hydrogen atom, - a halogen atom, - a linear or branched alkyl group (C ⁇ -C 6 ),
• m represents an integer such that 1 ⁇ m ⁇ 4, or R 2 with R 3 , or R with IL-., or with R 5 , form together with the carbon atoms which carry them a mono- or bicyclic group of 5 to 12 members, aromatic or non-aromatic, optionally containing 1 or 2 heteroatoms chosen from O, S and N, and optionally substituted by one or more atoms or groups, identical or different, chosen from halogen atoms and alkyl groups (C ⁇ -C 6 ) linear or branched, hydroxy, alkoxy (C ⁇ -C 6 ) linear or branched, polyhaloalkyl (C ⁇ -C 6 ) linear or branched, amino (optionally substituted by one or more alkyl groups (C ⁇ -C 6 ) linear or branched), nitro , linear or branched acyl (C ⁇ -C 6 ) or alkylenedioxy (C -.- C),
• Rio represents a hydrogen atom or a linear or branched (Ci-Ce) alkyl group
• Ar represents a linear or branched aryl, heteroaryl or arylalkyl (C ⁇ -C 6 ) group
• hydrochloric hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic acids, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic, benzenesulfonic, camphoric.
• aryl group is understood to mean phenyl, biphenylyl, naphthyl or tetrahydronaphthyl, each of these groups being optionally substituted by one or more atoms or groups, identical or different, chosen from halogen atoms and alkyl groups (C ⁇ -C 6 ) linear or branched, hydroxy, alkoxy (Ci-Ce) linear or branched, polyhaloalkyl (C ⁇ -C 6 ) linear or branched, amino (optionally substituted by one or more alkyl groups (C ⁇ -C 6 ) linear or branched), nitro , acyl (C ⁇ -C 6 ) linear or branched or alkylenedioxy (C ⁇ -C 2 ).
• heteroaryl group is meant a mono- or bicyclic aromatic group of
• heteroaryl may be optionally substituted by one or more atoms or groups, identical or different, chosen from halogen atoms and groups linear or branched (C ⁇ -C 6 ), hydroxy, linear or branched (C ⁇ -C 6 ), linear or branched polyhaloalkyl (C ⁇ -C 6 ) or amino (optionally substituted by one or more alkyl groups (C--) C 6 ) linear or branched).
• heteroaryl groups non-limiting mention may be made of thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl and pyrimidinyl groups.
• nitrogen heterocycle is meant a saturated monocyclic group of 5 to 7 members containing one, two or three heteroatoms, one of these heteroatoms being the nitrogen atom, and the additional heteroatom (s) possibly present being chosen from the atoms oxygen, nitrogen or sulfur.
• the preferred nitrogen heterocycles are the pyrrolidinyl, piperidyl, morpholinyl or piperazinyl groups.
• aromatic or non-aromatic optionally containing 1 or 2 heteroatoms chosen from O, S and N
• An advantageous aspect of the invention relates to the compounds of formula (I) for which Rio represents a hydrogen atom.
• Another advantageous aspect of the invention relates to the compounds of formula (I) for which Rio represents a linear or branched alkyl group (C ⁇ -C 6 ).
• R 6a , Re, Re c and Re are as defined in formula (I).
• R 2 , R 3; R). and R 5 each represents a hydrogen atom or a linear or branched (Ci-Ce) alkyl or linear or branched alkoxy (C ⁇ -C 6 ) group, or alternatively R 2 and R 3; or R 3 and R, form together with the carbon atoms which carry them a mono- or bicyclic group of 5 to 12 members, aromatic or non-aromatic, optionally containing 1 or 2 heteroatoms chosen from O, S and N.
• R 3 and P form together, with the carbon atoms which carry them, a group of formula G 3 or G 4 as defined above, and those for which R and R 3 together form, with the carbon atoms which carry them, a phenylene group.
• An advantageous aspect of the invention relates to the compounds of formula (I) for which Ar represents an aryl group. Among these, very particularly preferred are those for which Ar represents an optionally substituted phenyl group.
• Another advantageous aspect of the invention relates to the compounds of formula (I) for which Ar represents a heteroaryl group.
• R * represents a hydrogen atom, a linear or branched (Ci-Ce) alkyl group or an arylalkyl group in which the alkyl part is (C ⁇ -C 6 ) linear or branched.
• the invention also extends to a process for preparing the compounds of formula (I) characterized in that a compound of formula (II) is reacted:
• R-, R 2 , R 3 , R 4 , R 5 , R 10 and Ar are as defined above,
• R ,, R 2 , R 3 , R 4 , R 5 , R 10 and Ar are as defined above, compounds of formula (la) or (Ib) which constitute all of the compounds of formula (I), which are purified, if necessary, according to a conventional purification technique, from which, if desired, they are separated optical isomers according to a conventional separation technique, and which, if desired, is converted into their addition salts with a pharmaceutically acceptable acid.
• the compounds of the present invention in addition to the fact that they are new, exhibit advantageous pharmacological properties. They have cytotoxic properties which make them useful in the treatment of cancers.
• the invention also extends to pharmaceutical compositions containing as active principle at least one compound of formula (I) with one or more inert excipients, not toxic and appropriate.
• pharmaceutical compositions according to the invention mention may be made more particularly of those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), nasal administration, simple or coated tablets, sublingual tablets, capsules, tablets, suppositories, creams, ointments, dermal gels, injections, oral suspensions, etc.
• the useful dosage is adaptable according to the nature and severity of the condition, the route of administration as well as the age and weight of the patient and any associated treatments. This dosage varies from 0.5 mg to 2 g per 24 hours in one or more doses.
• the starting materials used are known products or prepared according to known preparatory methods.
• the expected product is obtained according to the process described in Example 1 from 3,4-methylenedioxy-aniline, from 5,5-dimethyl-tetrahydrofuran-2,4-dione (the preparation of which is described in Chem. Pharm. Bull. 1984, 32, 3724) and 3,4,5-trimethoxybenzaldehyde. Melting point:> 260 ° C.
• the expected product is obtained according to the process described in Example 1 from 3,4-methylenedioxy-aniline, from 5,5-dimethyl-2,2-dioxo [1,2] oxathiolan-4-one (including the preparation is described in Tetral edron 1997, 17795) and 3,4,5-trimethoxybenzaldehyde. Drop point: 270-280 ° C.
• the expected product is obtained according to the process described in Example 5 from 3,4-methylenedioxy-aniline, tetronic acid and 3,4,5-trimethoxybenzaldehyde.
• the expected product is obtained according to the process described in Example 5 from 1-naphthylamine, tetronic acid and 3,4,5-trimethoxybenzaldehyde.
• Stage A N-methyl-3-methox aniline A solution of 3-methoxyaniline (10 mmol) in formic acid (36 ml) is heated at reflux for 1 hour. After removal of the excess formic acid, the residue obtained is diluted in water, then extracted with dichloromethane. The combined organic phases are evaporated. The residue obtained is dissolved in ether, then aluminum and lithium hydride (42 mmol) is added at 10 ° C, in small portions. After 3 hours of stirring at room temperature, water and 10% sodium hydroxide are added and the mixture is filtered through celite. The filtrate is dried, evaporated and the residue obtained is purified by chromatography on silica using dichloromethane as eluent to yield the expected product in the form of an oil.
• the expected product is obtained according to the process described in Example 5, replacing, in stage A, N-benzyl-3,4-methylenedioxyaniline with the compound obtained in the preceding stage. Drop point: 198-200 ° C
• PoinJ_deJusjon > 260 ° C.
• Miçro ttiçdyse elementaire _ C% H% N% calculated 71.02 4.70 4.36 found 70.93 4.84 4.20
• EXAMPLE 10 9-Methyl-6,7-methylenedioxy-9- (3,4,5-trimethoxyphenyl) -4,9- dihydrofuro [3,4-b] quinoline-1 (3jH) -one
• the cells are distributed in microplates and exposed to cytotoxic compounds. The cells are then incubated for 2 days (L1210) or
• the compounds of the invention exhibit cytotoxicity in vitro.
• the compound of Example 5 has an IC 50 (concentration of cytotoxic agent which inhibits the proliferation of the treated cells by 50%) of 0.19 ⁇ M (L1210).

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

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• 2002
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