Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
• • 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
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • 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
  • C07D491/10—Spiro-condensed systems
  • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• • 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
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/10—Spiro-condensed systems

Definitions

• the present invention relates to griseofulvin derivatives and their use for the treatment of cancerous and pre-cancerous hyperproliferative pathologies.
• Griseofulvin 1 is a natural molecule isolated from filamentous fungus cultures Penicilium griseofulvum [J. Chem. Soc. 1958, 360-365]. It is used in the treatment of fungal diseases of the skin in humans and is also used in veterinary medicine. It is administered primarily orally at doses of 0.5 to 1.0 grams per day in humans.
• griseofulvin derivatives substituted at 2 'with oxygen or sulfur groups [J. Med. Chem. 2009, 3342-3347] have been synthesized. However, none of these products has demonstrated the potential to be used as a drug in the treatment of cancerous and pre-cancerous hyperproliferative diseases.
• the inventors have thus surprisingly found that the addition of particular rings or groups in 2 ', 3' and / or 4 'allowed to obtain more potent cytotoxic derivatives than griseofulvin and its analogs previously described.
• the present invention thus relates to a compound of general formula (I) below:
• rrrr represents a single or double bond, the X ⁇ and ⁇ Y bonds can not represent a double bond at the same time,
• X represents a single bond X
• ⁇ Y represents a single bond Y
• Z represents a hydrogen atom or an aryl group, -S (O) Ri 3 or
• X represents a group CH-R 14 when X ⁇ represents a single bond X or CR 14 when X ⁇ represents a double bond X, with:
• R 1 to R 5 and R 7 to Ru represent, independently of each other, a hydrogen atom or a (C 1 -C 6) alkyl, aryl, (C 1 -C 6) alkyl-aryl or aryl- (C 1 -C 6) group; 6 ) alkyl,
• ⁇ 5 and R 2 representing, independently of one another, a hydrogen atom or a (Ci-Ce) alkyl, aryl, (Ci-C6) alkyl-aryl, aryl- (Ci-C6) alkyl , C (O) NH 2 or C (S) NH 2
• ⁇ R 13 is a group (Ci-Ce) alkyl, aryl, (Ci-C 6) alkyl-aryl or aryl- (Cl- C6) alkyl,
• R M represents a group -R 5, -NHR 15, -CH 2 -NHRi 5, -CH 2 -NH-C (0) -R 5, -NH-CH 2 -R 5, -NH-NH-Ris , -NH-C (O) -Ri 5 , -NH-C (O) -CH 2 -Ri 5 , -NH-CH 2 -C (O) -Ri 5 , -NH-CH 2 -C (O) -O-R 5 , -NH-CH 2 -C (O) -O-R 5 , -NH-CH 2 -C (O) -NH-R 5 , -NH-S0 2 -Ri 5 , -S (O) -Ri 5 , -SO 2 -R 15 , -S (O) CH 2 -R 15 , -S0 2 -CH 2 -R 15 , or -NR 16 Riv,
• ⁇ R 15 representing a hydrogen atom or a (Ci-Ce) alkyl, carbocycle, heterocycle, biaryl, carbocycle- (Ci-C 6) alkyl or heterocycle (Ci-C 6) alkyl optionally substituted, and
• part Y of the molecule of formula (I) mentioned above may comprise one or more asymmetric carbon atoms which may each be present in the R or S configuration or in the form of a mixture of the two configurations R and S in all proportions, especially in equimolar proportions.
• the compound of formula (I) according to the invention will not be compounds 6 to 10 described in Oda et al.
• the compound of formula (I) according to the invention will not be the griseofulvin dimer (VI) described in Lesniewska et al.
• the compound of formula (I) according to the invention will not be the compound 2 described in Newman.
• the term "pharmaceutically acceptable” means that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for veterinary as well as pharmaceutical use. human.
• pharmaceutically acceptable salts of a compound are understood to mean salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity of the parent compound.
• These are in particular acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulphonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tar
• halogen atom means the fluorine, chlorine, bromine and iodine atoms.
• (Ci-C 6) alkyl is understood within the meaning of the present invention, a saturated hydrocarbon chain, linear or branched, having 1 to 6 carbon atoms. It may be in particular a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl group.
• (C 1 -C 6 ) alkoxy means a (C 1 -C 6 ) alkyl group as defined above bonded to the remainder of the molecule via a hydrogen atom. 'oxygen. It may be in particular a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy or n-hexoxy group.
• (C 2 -C 6 ) alkenyl is meant, in the sense of the present invention, a hydrocarbon chain, linear or branched, having at least one double bond and having 2 to 6 carbon atoms.
• (C 2 -C 6 ) alkynyl is meant, in the sense of the present invention, a hydrocarbon chain, linear or branched, having at least one triple bond and having 2 to 6 carbon atoms.
• aryl means a hydrocarbon aromatic group preferably comprising from 5 to 10 carbon atoms and comprising one or more contiguous rings, preferably 1 or 2 rings, for example a phenyl or naphthyl group.
• phenyl is phenyl.
• (Ci-C 6 ) alkyl-aryl means a (C 1 -C 6 ) alkyl group as defined above bonded to the remainder of the molecule via an aryl group as defined above. It may be in particular a tolyl group.
• aryl- (Ci-C 6) alkyl is understood within the meaning of the present invention, an aryl group as defined above bound to the rest of the molecule via a (Ci-C 6 ) alkyl as defined above. It may be in particular a benzyl group.
• biasing is meant, within the meaning of the present invention, an aryl group as defined above linked to the remainder of the molecule through an aryl group as defined above. It may be in particular a biphenyl group.
• heteroaryl group is meant, in the sense of the present invention, an aryl group as defined above in which one or more carbon atoms have been replaced by one or more heteroatoms, advantageously 1 to 4, preferably 1 to or 2.
• heteroaryl groups are pyridine, pyrimidine, pyrazine, pyridazine, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, tetrazole, benzofuran, benzothiophene, indole, benzimidazole, indazole , quinoline, isoquinoline, quinazoline or quinoxaline.
• heteroatom in particular an atom of sulfur, nitrogen or oxygen.
• the term "carbocycle” means one or more contiguous rings, preferably 1 or 2 fused, hydrocarbon, saturated, unsaturated or aromatic rings, each ring advantageously having 3 to 8 ring members, preferably 3, 5, 6 or 7 members, and more preferably 5 or 6 members. It may be in particular a cyclopentyl or a cyclohexyl.
• the term "unsaturated" means that the ring comprises one or more double bonds.
• the term "carbocycle- (C 1 -C 6 ) alkyl” is intended to mean a carbocycle group as defined above bonded to the remainder of the molecule via a (Ci-C) group. 6 ) alkyl as defined above, and preferably by through a group -CH 2 -. It may be in particular a cyclopentylmethyl or cyclohexylmethyl group.
• heterocycle means a carbocycle group as defined above in which one or more carbon atoms have been replaced by one or more heteroatoms, advantageously 1 to 4, preferably 1 or Examples of heterocycles comprising a single ring are epoxide, aziridine, furan, dihydrofuran, tetrahydrofuran, pyrrole, pyroline, pyrrolidine, thiophene, dihydrothiophene, tetrahydrothiophene, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imizadolidine, thiazole, dihydrothiazole, tétrahydrothiazole, oxazole, dihydrooxazole, tétrahydrooxazole, triazoles, dihydrotriazoles, tétrahydrotriazoles, pyridine, dihydropyridine, tetrahydropyridine, piper
• heterocycles comprising 2 fused rings are the aforementioned 1-ring heterocycles fused with 1 phenyl ring, such as indole, benzo-furan, benzopyrans including chromene and isochromene, and dihydrobenzopyrans including chroman and quinoline. , dihydroquinolines, tetrahydroquinoline, isoquinoline, dihydroisoquinolines and tetrahydroisoquinoline.
• (C 1 -C 6) -cyclo-heterocycle means a heterocycle group as defined above linked to the remainder of the molecule via a (C 1 -C 6) group. ) alkyl as defined above, and preferably via a group -CH 2 -.
• cycloalkyl is intended to mean a saturated hydrocarbon monocycle, advantageously comprising 3 to 8 carbon atoms, in particular 5 or 6. This may especially be cyclohexyl.
• the present invention relates to a compound of general formula (I) below:
• rrrr represents a single or double bond, the X ⁇ and ⁇ Y bonds can not represent a double bond at the same time,
• X represents a single bond X
• ⁇ Y represents a single bond Y
• X forms with Z and the carbon atom which carries them an optionally substituted carbocycle or heterocycle
• Z forms with Y or X and the carbon atom which carries them an optionally substituted carbocycle or heterocycle, preferably an optionally substituted heterocycle.
• the heterocycle will advantageously comprise 1 or 2 contiguous, saturated, unsaturated or aromatic rings, each cycle advantageously having 3 to 8 members, preferably 3, 5, 6 or 7 members, and more preferably 5 or 6 members.
• it will comprise 1 or 2 heteroatoms chosen from N, O and S, preferably chosen from N and O.
• it may be an epoxide, aziridine, furan, dihydrofuran, tetrahydrofuran, pyrrole, pyroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imizadolidine, pyridine, dihydropyridine, tetrahydropyridine, piperidine, pyrimidine or pyridazine ring.
• it will be a furan, dihydrofuran, tetrahydrofuran, pyrrole, pyroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, pyridine, dihydropyridine, tetrahydropyridine, piperidine, pyrimidine, pyridazine, pyrazine or dihydropyrimidine ring.
• it will be a furan ring, dihydrofuran, pyrrole, pyroline, pyrazole, pyrazoline, imidazole, imidazoline, pyridine, dihydropyridine, tetrahydropyridine, pyrimidine, pyridazine, pyrazine, dihydropyrimidine, dihydropyridazine, dihydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, tetrahydropyrazine, pyran, dihydropyran, indole, benzo furan, benzopyran including chromene and isochromene, quinoline, dihydroquinolines, isoquinoline, or dihydroisoquinolines.
• It may be in particular an epoxide ring, furan, dihydro furan, pyrrole, pyroline, pyrazole, pyridine, dihydropyridine, tetrahydropyridine, pyrimidine, tetrahydropyrimidine, dihydropyran, tetrahydroazepine, benzofuran, isochromene, isoquinoline, or dihydroisoquinolines.
• NR 4 4 6 sR NR 47, OR 48, and aryl, in particular selected from NR 4 SR 4 6, OR 48 and aryl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; and a carbocycle, heterocycle or biaryl (preferably an aryl, heteroaryl, saturated carbocycle, saturated heterocycle or biaryl such as phenyl, naphthyl, thiophene, thiazole, piperidine, morpholine, piperazine, tetrahydropyran, tetrahydrofuran or biphenyl) optionally substituted with one or several substituents chosen from a halogen atom (for example F or Cl), OR 49 , NR 50 R 51 , C (O) R 52 , C (O) OR 53 , C (O) NR 54 R 55 , an aryl and a group (Ci-C 6) alkyl optionally substituted with one
• R 8 to R 47 and R 49 to R 56 each independently of one another being a hydrogen atom or a (C 1 -C 6) alkyl, aryl, (C 1 -C 6) alkyl-aryl or aryl group;
• (Ci-Ce) alkyl preferably a hydrogen atom or a (Ci-C 6) alkyl or aryl,
• R 48 representing a hydrogen atom or a (C 1 -C 6 ) alkyl, aryl, (C 1 -C 6 ) alkyl-aryl, aryl- (C 1 -C 6 ) alkyl or -C (O) - (Ci group) -C 6 ) alkyl, advantageously a hydrogen atom or a (C 1 -C 6 ) alkyl or -C (O) - (C 1 -C 6) alkyl group, and
• R 57 and R 5 each representing 8 independently of one another, a hydrogen atom or a (Ci-C 6) alkyl, aryl, (Ci-C 6) alkyl-aryl or aryl (C - C 6 ) alkyl, advantageously a hydrogen atom or a (C 1 -C 6 ) alkyl or aryl group, or together forming, with the nitrogen atom which carries them, a heterocycle which may contain another heteroatom such as morpholine, piperazine and piperidine,
• N + -0 an oxygen atom
• its nitrogen atoms may optionally be substituted with an oxygen atom (to give an N + -0 ") where the N atom is engaged in a double bond or by an OH or (C 1 -C 6) alkyl group when the nitrogen atom is not engaged in a double bond.
• the bond ⁇ Y will preferably be a double bond Y.
• the compounds of formula (I) may have the following formula (I-YZ):
• a 4 represents:
• the compounds of formula (I) may in particular meet one of the following formulas (I-YZ-A and (I-YZ-B):
• I-YZ-1 preferably (I-YZ-1), (I-YZ-2), (I-YZ-3), (I-YZ-9), (I-YZ-10), or (I-YZ-12), for which :
• Ra represents a hydrogen atom or an OH, (C 1 -C 6) alkyl, aryl, aryl- (C 1 -C 6 ) alkyl or C (O) O- (C 1 -C 6 ) alkyl group, and
• halogen in particular a hydrogen atom; a halogen atom; -CN; -ORis; -NR19R20; -C (O) R 24 ; -C (O) OR 25 ; -C (0) NR 26 R 2 7; (Ci-C 6) alkyl optionally substituted with one or more substituents selected from halogen (e.g.
• NR 4 4 6 sR NR 4 6 sR
• aryl in particular selected from NR 4 4 6 sR, OR 4 8 and aryl; or an aryl, heteroaryl, saturated carbocycle, saturated heterocycle or biaryl (such as phenyl, naphthyl, thiophene, thiazole, piperidine, morpholine, piperazine, tetrahydropyran, tetrahydrofuran or biphenyl) optionally substituted by one or more substituents chosen from a halogen atom (eg F or Cl), OR 49 , NR 50 R 51 , C (O) R 52 , C (O) OR 53 , C (O) NR 54 R 55 , aryl and optionally substituted (C 1 -C 6 ) alkyl by one or more substituents selected from a halogen atom, OR56 and NR57R58.
• a halogen atom eg F or Cl
• OR 49
• the X ⁇ bond will preferably be a double X bond.
• the compounds of formula (I) may have the following formula (I-XZ):
• n3 and n4 valle independently of each other, 0 or 1,
• a 9 represents:
• Ra, Rb, Rb ', Rc, Rc', Rd, Rd ', Re, Rf, Rz, and Rz' as defined below
• NR 4 4 6 sR NR 47, OR 48, and aryl, in particular selected from NR 4 SR 4 6, OR 48 and aryl; (C 2 -C 6 ) alkenyl; (C 2 -C 6 ) alkynyl; or a carbocycle, heterocycle or biaryl (preferably an aryl, heteroaryl, saturated carbocycle, saturated heterocycle or biaryl such as phenyl, naphthyl, thiophene, thiazole, piperidine, morpholine, piperazine, tetrahydropyran, tetrahydrofuran or biphenyl) optionally substituted by one or more substituents selected from halogen (e.g.
• a hydrogen atom in particular a hydrogen atom; a halogen atom; -CN; -ORi 8 ; -NR 1 R 20 ; -C (O) R 24 ; -C (O) OR 25 ; -C (O) NR 26 R 27 ; (dC 6 ) optionally alkyl substituted by one or more substituents chosen from a halogen atom (for example F), a group NR45R46, OR48 and aryl, especially chosen from NR45R46, OR48 and aryl; or an aryl, heteroaryl, saturated carbocycle, saturated heterocycle or biaryl (such as phenyl, naphthyl, thiophene, thiazole, piperidine, morpholine, piperazine, tetrahydropyran, tetrahydrofuran or biphenyl) optionally substituted by one or more substituents chosen from a halogen atom (e.g.
• the compounds of formula (I) may in particular meet one of the following formulas (I-XZ-A and (I-XZ-B):
• the compounds of formula (I) may respond advantageously to the formula
• n5 is 0 or 1
• Ra, Rb, Rb ', Rc, Rc', Rd, Rd ', Re, Rf, Rz, and Rz' as defined below and Re 'as defined above.
• the compounds of formula (I) may meet one of the general formulas (I-XZ-1) to (I-XZ-19) below:
• Ra represents a hydrogen atom or an OH, (C 1 -C 6) alkyl, aryl, aryl- (C 1 -C 6 ) alkyl or C (O) O- (C 1 -C 6 ) alkyl group, and
• NR 4 4 6 sR NR 4 6 sR
• aryl in particular selected from NR 4 4 6 sR, OR 4 8 and aryl; or an aryl, heteroaryl, saturated carbocycle, saturated heterocycle or biaryl (such as phenyl, naphthyl, thiophene, thiazole, piperidine, morpholine, piperazine, tetrahydropyran, tetrahydrofuran or biphenyl) optionally substituted by one or more substituents chosen from a halogen atom (eg F or Cl), OR 49 , NR 50 R 51 , C (O) R 52 , C (O) OR 53 , C (O) NR 54 R 55 , aryl and optionally substituted (C 1 -C 6 ) alkyl by one or more substituents selected from a halogen atom, OR56 and NR57R58.
• a halogen atom eg F or Cl
• OR 49
• neither X and Z, nor Y and Z form a carbocycle or a heterocycle with the carbon atom that carries them.
• Z will advantageously represent a hydrogen atom, a group -SO-Ri 3 , or a group -SO 2 -Ri 3 .
• X-r-r will advantageously represent a double X bond.
• R 4 represent in particular a carbocyclic group such as aryl, heterocycle as heteroaryl, -NHR 15, -CH 2 -NHRi 5, -CH 2 -NH-C (0) -R 5, -NH-CH 2 -R 5 , -NH-NH-Ris, -NH-C (O) -Ri 5 , -NH-C (O) -CH 2 -Ri 5 , -NH-CH 2 -C (O) -Ri 5 , -NH-CH 2 -C (O) -Ri 5 , -NH- CH 2 -C (O) -O-R 5 , -NH-CH 2 -C (O) -NH-R 5 , -NH-S0 2 -Ri 5 , -SO 2 -Ri 5 , -SO 2 -CH 2 -Ri 5 , or -NRigRiv-
• R 1 4 will advantageously represent a carbocycle group such as aryl, heterocycle such as heteroaryl, -NHR 15 , -NH-CH 2 -Ri 5 , -NH-NH-R 15, -NH-C (O) -Ri 5 , -NH- C (O) -CH 2 -Ri 5 , -NH-CH 2 -C (O) -Ri 5 , -NH-CH 2 -C (O) -O-R 5 , -NH-CH 2 -C (0 ) -NH-Ris, -NH-S0 2 -Ri 5 , or -NRieRiv-Ri 4 will in particular represent a carbocycle group such as aryl, heterocycle such as heteroaryl, -NH-CH 2 -Ri 5 , -NH-NH-R15 , -NH-C (O) -Ri 5 , -NH-C (O) -CH 2 -Ri 5
• Ri4 particularly represent -NH-CH2-R15, -NH-NH-R 15, -NH-C (0) -R 5, -NH-C (0) -CH 2 -R 5, -NH-CH 2 -C (O) -Ri 5 , -NH-CH 2 -C (O) -O-Ri 5 , or
• R14 may also represent a group -NHR 15 , -NH-CH 2 -Ri 5 , -NH-NH-Ris, -NH-C (O) -Ri 5 , -NH-C (O) -CH 2 -Ri 5 , -NH-CH 2 -C (O) -Ri 5 , -NH-CH 2 -C (O) -O-R 5 , -NH-CH 2 -C (O) -NH-R 5 , -NH- S0 2 -Ri 5 , or -NRi 6 Riv.
• R 14 represents a group -NR 18 R 17, this will advantageously be a heterocycle chosen from piperidine, piperazine and morpholine optionally substituted with a -R 15 , -OR 15 or -NHR 15 group .
• R 15 will advantageously represent a (C 1 -C 6) alkyl, carbocycle, heterocycle, biaryl, carbocycle- (C 1 -C 6) alkyl or optionally substituted (C 1 -C 6) alkyl heterocycle, in particular an alkyl, carbocycle, heterocycle or biaryl optionally group; substituted, and in particular an optionally substituted carbocycle, heterocycle or biaryl group,
• the carbocycle being advantageously a cycloalkyl such as cyclohexyl or an aryl such as phenyl or naphthyl,
• the heterocycle being advantageously pyridine, pyrimidine, pyridazine, pyrazine, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, oxazole, triazoles, benzo furan, benzothiophene, indole, 1,3-benzodioxolane, piperidine, morpholine or piperazine; more particularly pyridine, furan, thiophene, pyrrole, benzofuran, benzothiophene, indole, 1,3-benzodioxolane or piperidine; and especially pyridine, furan, thiophene, benzofuran, 1,3-benzodioxolane or piperidine, and
• the biaryl being advantageously biphenyl.
• heterocycles being optionally substituted by an oxo, (C 1 -C 6 ) alkyl or C0 2 - (C 1 -C 6 ) alkyl group.
• the compounds of the invention may be selected from Examples 1 to 261 described in the experimental part below.
• the subject of the present invention is also a compound according to the invention of formula (I) as defined above, for its use as a medicament, in particular intended for the treatment of cancerous and precancerous hyperproliferative pathologies.
• the present invention also relates to the use of a compound of formula (I) as defined above, for the manufacture of a medicament, in particular for the treatment of cancerous and pre-cancerous hyperproliferative pathologies.
• the present invention also relates to a method for treating cancerous and pre-cancerous hyperproliferative pathologies, comprising administering to a person in need of an effective dose of a compound of formula (I) as defined above.
• cancerous or precancerous hyperproliferative pathologies is intended to mean all types of cancerous or pre-cancerous hyperproliferative pathologies, in particular cancer of the lung, breast, brain and cutaneous cancers.
• the term "skin cancer” is intended to mean, in particular, actinic keratosis, solar keratosis, keratinocyte intraepithelial neoplasia, cutaneous papillomas, squamous cell carcinomas in situ, squamous cell carcinomas, precancerous skin lesions, basal cell carcinoma including superficial and nodular forms, Bowen's disease, Dubreuilh's melanoma, condylomas, Merkel's tumor, Paget's disease, or mucocutaneous lesions induced by the human papillomavirus.
• the present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined above, and at least one pharmaceutically acceptable excipient.
• compositions according to the invention may be formulated especially for oral administration, for topical administration or by injection, said compositions being intended more particularly for mammals, including humans.
• the active ingredient can be administered in unit dosage forms, in admixture with conventional pharmaceutical carriers, to animals including humans.
• the compounds of the invention as active ingredients can be used at doses of between 0.01 mg and 1000 mg per day, given as a single dose once a day or administered in several doses throughout the day, for example twice a day in equal doses.
• the dose administered per day is advantageously between 5 mg and 500 mg, more advantageously between 10 mg and 200 mg. It may be necessary to use doses out of these ranges which the skilled person can realize himself.
• compositions according to the invention may also comprise at least one other active ingredient, such as an anticancer agent.
• the present invention also relates to a pharmaceutical composition as defined above for its use as a medicament, in particular for the treatment of cancerous and pre-cancerous hyperproliferative pathologies.
• the manganese acetate dihydrate (9.45 mmol, 2.0 equiv) is dissolved in acetic acid (50 mL) at 80 ° C until a dark brown solution is formed. The temperature is reduced to 40 ° C., griseofulvic acid (1.6 g, 4.72 mmol, 1.0 equiv) and styrene (5.67 mmol, 1.2 equiv) are then added successively. The reaction medium is stirred until the dark brown color disappears (1 hour in this case, from 1 hour to 24 hours).
• the acetic acid is evaporated under vacuum, the residue obtained is diluted in ethyl acetate (150 mL) and the organic phase is successively washed with a saturated aqueous solution of bicarbonate (100 mL), sodium hydroxide and brine ( 100 mL). The organic phase is dried over magnesium sulfate, filtered and the solvents are evaporated under reduced pressure. The residue is purified on silica gel (CELCyAcOEt 98/2 to 90/10) to give the four isomers of the reaction with yields ranging from 12 to 22%.
• NBS (48.0 mg, 1.3 equiv) is added at 0 ° C to a solution of the alcohol to be brominated (100.0 mg, 1.0 equiv) and triphenylphosphine (81.0 mg; 1.5 equiv) in tetrahydrofuran (2.0 mL). The temperature is raised to room temperature. After stirring for 1 hour, water is added (15 mL) and the mixture is diluted with AcOEt (15 mL). The organic phase is extracted with brine, dried over MgSO 4, filtered and evaporated. The residue is purified on silica gel CELCylcohexane / AcOEt 10/10/1 to give the brominated derivative in the form of white foam with a yield of 58%.
• This acid (1.3 g, 1.0 equiv) is diluted in CH 2 C1 2 (15 mL), the solution is maintained at 0 ° C, oxalyl chloride is then added (1.62 mL; 6.2 equiv.) followeded by a few drops of DMF. As soon as the evolution of gas is complete, the medium is evaporated under vacuum and then taken up again (400 mg) in CH 2 C1 2 (5 mL) and then added dropwise to a solution of benzylamine (5.0 equiv.), Triethylamine ( 8.0 equiv) and DMAP (0.3 equiv) at 0 ° C. The temperature is then raised to room temperature and the mixture stirred for 4 hours.
• reaction medium is diluted with ethyl acetate (20 mL) and the organic phase is washed with brine solution (15 mL). The organic phase is dried over magnesium sulfate, filtered and the solvents are evaporated under reduced pressure. The residue is purified on silica gel CELCyMeOH 99/1 to give the pyridone with an overall yield of 20%.
• the reaction medium is then heated at 40 ° C. for 2 hours.
• the medium is diluted with dichloromethane and neutralized with sodium hydroxide (1.0 M).
• the organic phase is washed with a brine solution.
• the organic phase is dried over magnesium sulphate, filtered and the solvents are evaporated under reduced pressure.
• the residue is purified on silica gel CH 2 Cl 2 / AcOEt 98/2 to give chloropyridine with an overall yield of 56%.
• Example: R 2-BrBn Dichlorobis (triphenylphosphine) palladium (355 mg, 0.4 equiv) is added to the solution degassed under benzyl derivative nitrogen (640 mg, 1.0 eq.iv) and sodium acetate (176 mg; equiv.) in dimethylacetamide (20 mL). The mixture is stirred at 90 ° C for 18 hours. The crude is directly filtered on a silica cake with AcOEt. The solvents are evaporated and the residue purified on silica gel CH 2 Cl 2 / AcOEt 85/15 to give the pyridine as a beige solid with a yield of 13%.
• Dichlorobis (triphenylphosphine) palladium (55 mg, 0.2 equiv) is added to a solution degassed under benzyl derivative nitrogen (200 mg, 1.0 eq) and sodium acetate (65 mg; 0 equiv.) In dimethylacetamide (3 mL). The mixture is stirred at 90 ° C for 5 hours. The crude is directly filtered on a silica cake with AcOEt. The solvents are evaporated and the residue purified on silica gel CH 2 Cl 2 / AcOEt 85/15 to give the coupled derivative in the form of a green solid with a yield of 24%.
• reaction mixture is then cooled to room temperature, washed with 2x100 mL of saturated sodium bicarbonate solution and then 100 mL of brine.
• the organic phase is dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure.
• a white solid (5.2 g) is obtained with 93% yield.
• griseofulvic acid 10 g, 29.5 mmol, 1.0 eq.
• methylhydrazine 20 mL, 5.0 eq.
• the reaction mixture is stirred and heated at 78 ° C for 16 h.
• the reaction medium is concentrated under reduced pressure, and the residue is purified by chromatography on silica gel (AcOEt / EP 1/5). A yellow solid (5 g) is then obtained with a yield of 46%.
• the mixture is heated at 100 ° C. for 16 hours.
• the reaction mixture is then cooled to room temperature and diluted with water and dichloromethane.
• the organic phase is washed with saturated NaHCO 3 solution , dried over MgSO 4, filtered and concentrated under reduced pressure.
• the residue is purified by chromatography on silica gel (eluent dichloromethane / methanol).
• the mixture is heated at 80 ° C for 2 hours and then concentrated under reduced pressure.
• the residue is purified by chromatography on silica gel. At most 3 isomers are isolated with yields of 1% to 13%.
• the mixed fractions are pooled and used in the next oxidation step.
• Carbonyl reduction The carbonyl derivative (1.0 g, 1.0 equiv) is diluted in 1/1 THF / MeOH (20 mL). NaBH 4 (100 mg, 1.0 eq) is added to the solution at room temperature. The reaction mixture thus obtained is stirred at 25 ° C. for 1 h. The reaction medium is diluted with ethyl acetate (100 mL) and the organic phase is successively washed with a saturated aqueous solution of bicarbonate (100 mL), sodium hydroxide and brine (100 mL). The organic phase is dried over magnesium sulfate, filtered and the solvents are evaporated under reduced pressure. The residue is purified on silica gel CH 2 Cl 2 / AcOEt 1/1 to give the desired alcohol with a yield of 86%. Inversion of alcohol:
• Lines N1E115 (ATCC, CRL2263), MDA-MB-231 (ATCC, HTB26) and HSC-1 (Health Science Research Resources Bank, JCRB1015) were cultured in DMEM (Dulbecco's Modified Eagle medium) supplemented with 2 mM L Glutamine (Sigma, G7513) and 10% fetal calf serum (Hyclone, SH30109.03) or 20% in the case of HSC-1 cells.
• Lines HCC-1937 (ATCC, CRL2336) and A549 (ATCC, CCL185) were cultured in RPMI medium (Roswell Park Memorial Institute medium) supplemented with 10% fetal calf serum and 2 mM L-Glutamine.
• the SCC114 (DSMZ, ACC662) line was cultured in MEM (Essential Essential Medium Eagle) supplemented with 10% fetal calf serum and 2 mM L-Glutamine.
• MEM Essential Essential Medium Eagle
• the cells are seeded into their respective culture media with 750 cells per well for N1E115; 1000 cells per well for SCC114 and A549; 2000 cells per well for HCC-1937 and HSC-1; 2500 cells per well for MDA-MB-231.
• a cascade dilution of each compound was made in dimethylsulfoxide (DMSO) (Sigma, D8418) from stock solutions at 10 mM in 100% DMSO.
• DMSO dimethylsulfoxide
• the cytotoxic properties of some compounds of the invention evaluated on lines A549 lung cancer cell line
• MDA-MB-231 mimmary adenocarcinoma cell line
• N1E115 neuroroblastoma cell line
• murine brain HCC-1937
• HSC-1 cutaneous squamous cell carcinoma cell line
• SCC114 squamous cell carcinoma squamous cell line
• the concentration values are expressed in micromolar units ( ⁇ ).

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• 2013
  • 2013-08-01 WO PCT/EP2013/066165 patent/WO2014020101A1/fr active Application Filing
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