EP2010481A1 - Composes de type 1, 4-naphtoquinones, compositions les comprenant et utilisation de ces composes en tant qu'agents anti -cancereux - Google Patents

Composes de type 1, 4-naphtoquinones, compositions les comprenant et utilisation de ces composes en tant qu'agents anti -cancereux

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Publication number
EP2010481A1
EP2010481A1 EP07731362A EP07731362A EP2010481A1 EP 2010481 A1 EP2010481 A1 EP 2010481A1 EP 07731362 A EP07731362 A EP 07731362A EP 07731362 A EP07731362 A EP 07731362A EP 2010481 A1 EP2010481 A1 EP 2010481A1
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EP
European Patent Office
Prior art keywords
aryl
function
optionally substituted
carboxylic acid
radical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP07731362A
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German (de)
English (en)
French (fr)
Inventor
Gaëlle DEPIERRE
Jean Dessolin
Michel Laguerre
Claude Commandeur
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre National de la Recherche Scientifique CNRS
Universite Sciences et Technologies Bordeaux 1
FLUOFARMA
Original Assignee
Centre National de la Recherche Scientifique CNRS
Universite Sciences et Technologies Bordeaux 1
FLUOFARMA
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Publication of EP2010481A1 publication Critical patent/EP2010481A1/fr
Withdrawn legal-status Critical Current

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    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/18—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/31—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/22—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
    • 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 field of prevention and treatment of diseases involving abnormal cell proliferation.
  • 1,4-naphthoquinone type compounds especially as a drug, and the use of such compounds in the preparation of pharmaceutical compositions.
  • These pharmaceutical compositions may especially be intended to prevent or treat diseases involving abnormal cell proliferation, in particular cancer.
  • the invention also relates to pro-apoptotic and / or anti-proliferative compositions comprising compounds of this type, or the use of this type of compounds as a pro-apoptotic and / or anti-proliferative agent.
  • Apoptosis or programmed cell death is a physiological process that is essential for maintaining tissue homeostasis. It is the mechanism by which the body regulates the quantity of cells necessary for its well-being and development.
  • This process is particularly interesting because, unlike necrosis, it does not release mediators of inflammation in the extracellular medium. Thus, in the context of an application in anti-cancer therapy, it can induce a "clean death", compared with necrosis, at the level of tumor cells.
  • the pro-apoptotic compounds mention may be made of the peptides of SMAC (second mitochondria activator of caspases).
  • SMAC secondary mitochondria activator of caspases
  • the peptide fragments of SMAC can pose multiple problems when used in vivo, for example low bioavailability, too rapid degradation and / or too strong immunogenicity.
  • the inventors have now discovered that the compounds as defined below exhibit anticancer activity, especially related to a pro-apoptotic and / or antiproliferative activity, while at least partly solving the problems mentioned above.
  • the subject of the invention is the isolated compounds corresponding to the following formula (I) or a pharmaceutically acceptable salt thereof, as medicament:
  • - R1 represents a hydrogen atom; a halogen atom; a hydroxyl function, optionally substituted; an alkyl, alkene or alkyne radical comprising from 1 to 2 to 18 carbon atoms, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; an aryl radical, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; an arylalkyl or alkylaryl radical, optionally substituted, in particular with one or more amino acid groups, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy; a nitro function; or a function -X'-A'-Z 'in which:
  • X ' represents a divalent radical, in particular chosen from alkyls, alkenes, or alkynes, linear, branched or cyclic, substituted or unsubstituted, chiral or non-chiral, optionally interrupted by a heteroatom,
  • R2, R3, R4 and R5 represent independently of each other a hydrogen atom; a halogen atom; a hydroxyl function, optionally substituted; an alkyl, alkene or alkyne radical comprising from 1 to 2 to 18 carbon atoms, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; an aryl radical, optionally substituted, in particular with one or several amino groups, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy; an arylalkyl or alkylaryl radical, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; or a nitro function; or R2 and R3, R3 and R4 and / or R4 and R5 together form an optionally substituted ring or heterocycle,
  • X represents a divalent radical, in particular chosen from alkyls, alkenes or alkynes, linear, branched or cyclic, substituted or unsubstituted, chiral or non-chiral, optionally interrupted by a heteroatom,
  • R G1 , R G2 and R G3 is independently of the other occurrences of R G1 a hydrogen atom; a halogen atom; or a linear, branched or cyclic, optionally substituted alkyl, heteroalkyl, alkene or alkyne function; or an aryl, heteroaryl, heterocycle, alkylaryl or alkylheteroaryl group in which the aryl, heteroaryl or heterocyclic radical is optionally substituted; or else, when G represents -NR 02 -, R G1 and R 02 together with the nitrogen atom to which they are bonded form an optionally substituted heterocycle or heteroaryl
  • Z is linked to the radical X via its terminal carboxyl function
  • A is -O-, -S- or -NY- where the group Y represents a hydrogen atom or a protective group, in particular chosen among those described in TW Greene's Protective Groups in Organic Synthesis, PGM Wuts, Wiley-Interscience, New York, 4th Edition, 2007.
  • the terminal amine function of Z, and / or the possible lateral chemical functions of Z are free or possibly protected.
  • the terminal carboxyl function of Z, and / or the possible lateral chemical functions of Z are free or optionally protected.
  • the terminal amine function of Z may be in the form of a quaternary amine salt such as a hydrochloride, a hydrobromide, a trifluoroacetate (etc.).
  • the terminal amine function of Z as well as any functions carried by the side chain of the amino acid residue Z (hydroxyl, amine, guanidine, etc.), may be protected by a protective group of said function such as those described in the book “Protective Groups in Organic Synthesis” by TW Greene and PGM Wuts, Wiley-Interscience, New York, 4th edition 2007.
  • the terminal amine function of Z, and / or the possible lateral chemical functions of Z are free or possibly protected.
  • the terminal carboxyl function of Z When Z is bound to the radical X via its terminal amine function, the terminal carboxyl function of Z may be in the form of a salt such as a sodium or potassium salt.
  • the terminal carboxyl function of Z, as well as any functions carried by the side chain of the amino acid residue Z (hydroxyl, amine, guanidine, etc.) may be protected by a protecting group of said function such as those described in the book “Protective Groups in Organic Synthesis” by TW Greene and PGM Wuts, Wiley-Interscience, New York, 4th edition 2007.
  • the terminal carboxyl function of Z, and / or the possible lateral chemical functions of Z are free or possibly protected.
  • the group X represents a divalent radical of the type - (CH 2 ) n - in which n is an integer ranging from 1 to 10, in particular from 2 to 8.
  • the group X represents a branched divalent radical having the formula - (CH 2 ) p - CHR x - (CH 2 ) q - in which p and q are independently of each other an integer ranging from 0 to 12, and the sum p + q is an integer from 1 to 12, especially 1 to 7, and R x is a side chain of a natural amino acid; C x 6 alkyl; C1-heteroalkyl; ; C 6 _ 10 aryl; C 3 . 10 heteroaryl; ; C 1 -C 6 alkylC 3 _
  • R 01 , R 02 and R 03 is independently of the other occurrences of R 01 a hydrogen atom; a halogen atom; or a linear, branched or cyclic, optionally substituted alkyl, heteroalkyl, alkene or alkyne function; or an aryl, heteroaryl, alkylaryl or alkylheteroaryl group in which the aryl or heteroaryl radical is optionally substituted; or when G is - NR 02 -, R 01 and R G2 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle or heteroaryl.
  • A is -NY-, and the amino acid residue Z is linked to the radical X via an amide bond, in particular corresponding to the formula Z 'CONYX, in which the radical Z' CO- represents the residue amino acid Z, and X and Z are as defined above.
  • A is -CO-
  • the amino acid residue Z is linked to the radical X via a retro-inverso amide bond, in particular corresponding to the formula Z 'NYCOX, in which the radical Z' NY- represents the amino acid residue Z, and X and Z are as defined above.
  • A is -O-, and the amino acid residue Z is linked to the radical X via an ester bond, in particular corresponding to the formula
  • A is -SO 2 -, and the amino acid residue Z is linked to the radical X via a sulfonamide linkage, in particular corresponding to the formula Z 'NYSO 2 X, in which the radical Z' NY- represents the amino acid residue Z, and X and Z are as defined above.
  • the compounds described herein may be substituted with chemical substituents or functions, which may be as numerous and varied as the chemical valence of the compound allows.
  • substituents preceded or not by the term “optionally”, and the substituents described in the formulas herein refer to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent.
  • substituents may be the same or different at each position.
  • substituted covers all the substituents of the organic compounds that are possible and that can be envisaged by those skilled in the art.
  • the substituents contemplated include any carbon or heteroatom substituents of organic compounds, whether cyclic or non-cyclic, linear or branched, heterocyclic or carbocyclic, aromatic or non-aromatic.
  • heteroatoms such as the nitrogen atom, may carry hydrogen atoms and / or any permissible substituents of organic compounds described herein which satisfy the chemical valence of said heteroatoms.
  • the invention as described herein shall in no way be construed as being limited by the permissible substituents of organic compounds.
  • substituents and chemical groups contemplated in the present invention are preferably those which result in the formation of stable and usable compounds for the treatment and prevention of diseases, disorders and conditions, such as those described herein.
  • Substituents include, but are not limited to, alkyl; alkene, alkyne, cycloalkyl, cycloalkene, cycloalkyne, heteroalkyl; haloalkyl; aryl; heteroaryl; heterocycle; alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; heteroalkylthio; arylthio; heteroalkylthio; heteroarylthio; heteroarylthio; heteroarylthio; heteroarylthio; F; Cl; Br; I; -NO 2 ; - CN; -CF 3 ; -CH 2 CF 3 ; -CHCl 2 ; -CH 2 OH; -CH 2 CH 2
  • stable preferably refers to compounds which are stable enough to permit their preparation, and whose integrity is maintained for a time sufficient to permit their detection, and preferably for a time sufficient to be useful for the purposes detailed in the current.
  • Halogen atom denotes an atom chosen from fluorine, chlorine, bromine and iodine.
  • the alkyl radicals can comprise from 1 to 18 carbon atoms, especially from 1 to 12 carbon atoms, and in particular from 1 to 6 carbon atoms.
  • the alkenes may comprise from 2 to 18 carbon atoms, especially from 2 to 12 carbon atoms, and in particular from 2 to 6 carbon atoms. They may further comprise one or more double bonds.
  • the alkyne radicals can comprise from 2 to 18 carbon atoms, especially from 2 to 12 carbon atoms, and in particular from 2 to 6 carbon atoms. They may further comprise one or more triple bonds. Unless otherwise stated, the alkyl, alkenes and alkynes radicals may be linear, branched or cyclic.
  • heteroalkyl refers to an alkyl radical in which at least one carbon atom in the main chain has been replaced by a heteroatom.
  • a heteroalkyl denotes an alkyl radical comprising, in its main chain, at least one heteroatom selected from nitrogen, sulfur, phosphorus, silicon, oxygen or selenium atoms in place of a carbon atom.
  • a radical denotes a radical comprising 1 to 6 carbon atoms and at least one heteroatom selected from nitrogen, sulfur, phosphorus, silicon, oxygen or selenium.
  • aryl refers to a mono-, bi- or tricyclic hydrocarbon system comprising one, two or three rings satisfying Hekel's aromaticity rule.
  • an aryl radical may be phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and similar radicals.
  • the aryl radicals may comprise from 6 to 14 carbon atoms and in particular from 6 to 10 carbon atoms.
  • heteroaryl refers to an unsaturated heterocyclic system comprising at least one aromatic ring, and from 5 to 14 members, of which at least one member of the ring system is selected from S, O and N; zero, one or two members of the ring system are additional heteroatoms selected independently from each other from S, O and N; the remainder of the ring members of the ring system being carbon atoms; the heteroaryl radical being attached to the remainder of the molecule via any one of the ring members of the ring system (whether it is a carbon atom or a heteroatom).
  • a heteroaryl radical may be pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and similar radicals.
  • the arylalkyl and alkylaryl radicals may comprise from 7 to 25 carbon atoms, especially from 7 to 20 carbon atoms and in particular from 7 to 15 carbon atoms.
  • the alkylaryl radical may represent a benzyl.
  • heteroarylalkyl and alkylheteroaryl radicals may comprise from 7 to 25 carbon atoms, especially from 7 to 20 carbon atoms and in particular from 7 to 15 carbon atoms.
  • R 2 and R 3, R 3 and R 4 and / or R 4 and R 5 together form a ring or a heterocycle this may have from 4 to 10 ring members, and in particular from 6 to 8 ring members.
  • heterocycle refers to a 5- or 20-membered saturated or unsaturated and nonaromatic mono- or polycyclic ring system, optionally comprising one or more 5- or 6-membered rings having from 1 to 3 independently selected heteroatoms.
  • each 5-membered ring has from 0 to 2 double bonds, and each 6-membered ring has from 0 to 2 double bonds, (ii) the atoms sulfur and / or nitrogen are optionally oxidized, and (iii) the nitrogen atoms are optionally in the form of quaternary salt.
  • a heterocyclic radical may be pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, or tetrahydrofuryl.
  • a heterocycle comprises, in addition to carbon atoms, at least one heteroatom, chosen in particular from oxygen, nitrogen, sulfur, phosphorus, selenium and silicon.
  • amine or “amino” denotes a radical corresponding to the formula -N (R) 2 in which each occurrence of R is independently of one another a hydrogen atom; an alkyl, heteroalkyl, alkene, alkyne, aryl, heteroaryl, arylalkyl, alkylaryl, heteroarylalkyl or alkylheteroaryl radical, optionally substituted; or wherein the R groups together with the nitrogen atom to which they are attached form an optionally substituted heterocycle or heteroaryl.
  • the amine function can optionally be in the form of a quaternary amine salt.
  • the amino acid residues may be residues of natural amino acids or of synthetic amino acids, in particular of ⁇ , ⁇ or ⁇ amino acids.
  • the amino acid residues may be in racemic form or in enantiomerically enriched or even pure form, in D or L form.
  • the amine or terminal carboxyl function ie, not linked to X or X '
  • any chemical functions side amino acid residues can be protected or not.
  • ⁇ -, ⁇ - and ⁇ -amino acid residues natural (L) or non-(D, or synthetic) may be used.
  • ⁇ -amino acids such as ornithine or norleucine
  • ⁇ -amino acids such as ⁇ -alanine
  • ⁇ -amino acids such as the statin
  • more exotic structures used in peptidomimetic synthesis such as Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
  • amino acid residues may for example be chosen from the group comprising: - the natural amino acid residues, in particular glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, glutamic acid, glutamine, aspartic acid, Asparagine, Serine, Threonine, Methionine, Cysteine, Lysine, Arginine, Histidine, Proline,
  • the "rare" amino acid residues in particular hydroxyproline, hydroxylysine, allo-hydroxylysine, 6-N-methylsilyl, N-ethylglycine, N-methylglycine, N-ethylasparagine, allo-isoleucine, N-methylisoleucine, N-methylvaline, pyroglutamine, aminobutyric acid,
  • isolated when used to characterize compounds of the invention, refers to compounds that are (i) separated from at least one compound with which they are associated in nature, and / or (ii) products, prepared or manufactured by the care of man. According to a first definition of the invention, the compounds correspond to formula (I) as defined above, from which the following compounds are excluded:
  • the compounds correspond to the following formula (I), or a pharmaceutically acceptable salt thereof:
  • X ' represents a divalent radical, in particular chosen from alkyls, alkenes, or alkynes, linear, branched or cyclic, substituted or unsubstituted, chiral or non-chiral, optionally interrupted by a heteroatom
  • Y ' represents a hydrogen atom or a protective group, in particular chosen from those described in the book "Protective Groups in Organic Synthesis" by TW Greene, PGM Wuts, Wiley-Interscience, New York, 4th edition, 2007, and
  • Z ' represents an amino acid residue, in particular D or L, natural or synthetic residue, in particular an amino acid residue ⁇ , ⁇ or ⁇ , the amine or terminal carboxyl function (ie, not bound to X') as well as the any Z 'lateral chemical functions being protected or not, where Z' is linked to the radical X 'via an amide bond, a retro-inverso amide bond, an ester bond, or a sulfonamide bond, a thioester bond or a thioamide bond, or a bioisosteric bond of the amide bond resulting from the coupling of X 'with an aldehyde or terminal alcohol function of Z' resulting from the reduction of the carboxyl terminal function of the amino acid residue Z '; - R2, R3, R4 and R5 represent independently of each other a hydrogen atom; a halogen atom; a hydroxyl function, optionally substituted; an alkyl, alkene or alkyne
  • Z represents an amino acid residue, in particular D or L, natural or synthetic residue, in particular an amino acid residue ⁇ , ⁇ or ⁇ , the amine or terminal carboxyl function (ie, not linked to X) as well as any lateral chemical functions; Z being protected or not, where Z is linked to the radical X via a retro-inverso amide bond, an ester bond, or a sulfonamide bond, a thioester bond or a thioamide bond, or a bioisosteric bond of the amide bond, resulting coupling X with an aldehyde or terminal alcohol function of Z resulting from the reduction of the carboxyl terminal function of the amino acid residue Z;
  • R1 represents a hydrogen atom; a halogen atom; a hydroxyl function, optionally substituted; an alkyl, alkene or alkyne radical comprising from 1 to 2 to 18 carbon atoms, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; an aryl radical, optionally substituted, in particular with one or more amino groups, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy; an arylalkyl or alkylaryl radical, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; a nitro function; or a -X'-A'-Z 'function in which: (i) X' represents a divalent radical, in particular chosen from alkyls, alkenes, or alkynes, linear, branched or cyclic, substituted or un
  • Z ' represents an amino acid residue, in particular D or L, natural or synthetic residue, in particular an amino acid residue ⁇ , ⁇ or ⁇ , the amine or terminal carboxyl function (ie, not bound to X') as well as the any lateral chemical functions of Z being protected or not, where Z 'is linked to the radical X' via an amide bond, a retro-inverso amide bond, an ester bond, or a sulfonamide bond, a thioester bond or a thioamide bond, or a bioisosteric bond of the amide bond resulting from the coupling of X 'with an aldehyde or terminal alcohol function of Z' resulting from the reduction of the carboxyl terminal function of the amino acid residue Z '; - R3, R4 and R5 represent independently of each other a hydrogen atom; a halogen atom; a hydroxyl function, optionally substituted; an alkyl, alkene or alkyne radical comprising a atom,
  • R2 independently of R1, R3, R4 and R5 is hydrogen; a halogen atom; a substituted hydroxyl function; an alkyl, alkene or alkyne radical comprising from 1 to 2 to 18 carbon atoms, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; an aryl radical, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; an arylalkyl or alkylaryl radical, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; or a nitro function; or R2 and R3, R3 and R4 and / or R4 and R5 together form an optionally substituted ring or heterocycle, - X represents a divalent radical, in particular chosen from alkyls, alkenes or al
  • Y represents a hydrogen atom or a protective group, in particular chosen from those described in the book "Protective Groups in Organic Synthesis” by T. W. Greene, P.M. M. Wuts, Wiley-Interscience, New York, 4th edition, 2007, and
  • Z represents an amino acid residue, in particular D or L, natural or synthetic residue, in particular an amino acid residue ⁇ , ⁇ or ⁇ , the terminal amine function (ie, not linked to X); as well as the possible lateral chemical functions of Z being protected or not, where Z is linked to radical X via an amide bond;
  • R1 represents a hydrogen atom; a halogen atom; a hydroxyl function, optionally substituted; an alkyl, alkene or alkyne radical comprising from 1 to 2 to 18 carbon atoms, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; an aryl radical, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; an arylalkyl or alkylaryl radical, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; a nitro function; or a -X'-A'-Z 'function in which: (i) X ⁇ represents a divalent radical, in particular chosen from alkyls, alkenes, or alkynes, linear, branched or cyclic, substituted or
  • R3, R4 and R5 independently of one another are hydrogen; a halogen atom; a hydroxyl function, optionally substituted; an alkyl, alkene or alkyne radical comprising from 1 to 2 to 18 carbon atoms, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; an aryl radical, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; an arylalkyl or alkylaryl radical, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; or a nitro function;
  • R2 represents a hydroxyl function; or R3 and R4 and / or R4 and R5 together form an optionally substituted ring or heterocycle,
  • X represents a divalent radical, chosen in particular from unsubstituted linear or cyclic alkyls, alkenes or alkynes, optionally interrupted by a heteroatom,
  • Y represents a hydrogen atom or a protective group, in particular chosen from those described in the book
  • Z represents an amino acid residue, in particular D or L, natural or synthetic residue, in particular an amino acid residue ⁇ , ⁇ or ⁇ , the terminal amino function (ie, not linked to X) as well as the possible lateral chemical functions of Z being protected or not, where Z is linked to radical X via an amide bond;
  • R1 represents a halogen atom; a hydroxyl function, optionally substituted; an alkyl, alkene or alkyne radical comprising from 1 to 2 to 18 carbon atoms, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; an aryl radical, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; an arylalkyl or alkylaryl radical, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; a nitro function; or a -X'-A'-Z 'function in which: (i) X' represents a divalent radical, in particular chosen from alkyls, alkenes, or alkynes, linear, branched or cyclic, substituted or unsubstituted,
  • R2 represents a hydroxyl function
  • R3, R4 and R5 independently of one another are hydrogen; a halogen atom; a hydroxyl function, optionally substituted; an alkyl, alkene or alkyne radical comprising from 1 to 2 to 18 carbon atoms, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; an aryl radical, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; an arylalkyl or alkylaryl radical, optionally substituted, in particular with one or more amino, carboxylic acid, carboxylic acid derivative, alkoxy, aryl or hydroxy groups; or a nitro function; or R3 and R4 and / or R4 and R5 together form an optionally substituted ring or heterocycle, - X represents a divalent radical, in particular chosen from alkyls, alkenes or alkynes, linear
  • Y represents a hydrogen atom or a protective group
  • the compounds correspond to one of the following formulas:
  • n is an integer ranging from 1 to 12, in particular from 2 to 8; and Z represents an amino acid residue, in particular D or L, natural or synthetic residue, in particular an amino acid residue ⁇ , ⁇ or ⁇ , the terminal amine function (ie, not linked to -NH-) as well as any lateral chemical functions. Z being protected or not, where Z is linked to the -NH- radical via an amide bond.
  • the compounds correspond to one of the following formulas:
  • Z is as defined above; p and q are independently of one another integers ranging from 0 to 12, in particular from 0 to 7; R1 is as previously defined; and R x is a side chain of a naturally occurring amino acid; C 1 . 6 alkyl; C 6 _ 10 aryl; C 3 _ 10 heteroary C 1 -C 6 alkylC 3 _
  • the compounds correspond to one of the following formulas:
  • Z is as defined above; p and q are independently of one another integers ranging from 0 to 12, in particular from 0 to 7; except when R1 is a hydrogen atom, in which case p and q are independently of one another integers ranging from 1 to 12, in particular from 1 to 7; R1 is as previously defined; and R x is a side chain of a naturally occurring amino acid; C 1. 6 heteroalkyl; Cj.ghaloalkyle; C s _ lo aryl; C 3 - 10 heteroaryl; Ci.galkylCg.i o aryl; C 1 -C 6 alkylC 3 - 10 heteroaryl; C 1? AIkOXy; C 6 .
  • R and R are independently of other occurrences of R 'G1 a hydrogen atom; a halogen atom or a alkyl, heteroalkyl, alkene or alkyne function, linear, branched or cyclic, optionally substituted; or an aryl, heteroaryl, alkylaryl or alkylheteroaryl group in which the aryl or heteroaryl radical is optionally substituted.
  • the compounds correspond to one of the following formulas:
  • Z is as defined above; p and q are independently of one another integers ranging from 0 to 12, in particular from 0 to 7; and R x is a side chain of a naturally occurring amino acid; Ci.galkyle; C 1 . 6 haloalkyl; C 6 _ 10 aryl; C 3 - 10 heteroaryl; C 1 -C 6 alkylaryl; C 1 -C 6 alkylC 3 - 10 heteroaryl; C 1? AIkOXy; C 6 _ 10 aryloxy; C 3.
  • the compounds correspond to one of the following formulas:
  • Z is as defined above; p and q are independently of one another integers ranging from 1 to 12, in particular from 1 to 7; and R x is a side chain of a naturally occurring amino acid; is Ci.galkyl; Ci.ghcieroalkyle; C 1 . 6 haloalkyl; C 6 _ 10 aryl; C 3 - 10 heteroaryl; ; C 1 -C 6 alkylC 3 - 10 heteroaryl; C 1? AIkOXy; C 6 _ 10 aryloxy; C 3. 10 heteroalkoxy; C 3 - 10 heteroaryloxy; ; C 6 . 10 arylthio; ; C 3 - 10 heteroarylthio; F;
  • the compounds correspond to one of the following formulas:
  • Z is as defined above; p and q are, independently of one another, integers ranging from 0 to 12, in particular from 0 to 7; and R x is a side chain of a naturally occurring amino acid; ; C 1 . 6 haloalkyl; C 6 _ 10 aryl; C 3 - 10 heteroaryl; ; ; C 6 _ 10 aryloxy; C 3 . 10 heteroalkoxy; C 3 - 10 heteroaryloxy; C1-heteroalkylthio; C 6 . 10 arylthio; C j .
  • heteroalkylthio C 3 - 10 heteroarylthio; F; Cl Br; I; -NO2 / -CN; -CF 3 ; -CH 5 CF3 / -CHCl, -CH, OH
  • the compounds correspond to one of the following formulas:
  • Z and Z ' are, independently of one another, an amino acid residue, in particular D or L, natural or synthetic residue, in particular an amino acid residue ⁇ , ⁇ or ⁇ , the terminal amine function (ie, no linked to -NH-) as well as the possible lateral chemical functions of Z / Z 'being protected or not, where Z and Z' are linked to the radical -NH- via an amide bond.
  • the compounds according to the invention may correspond to the following formula (II) or to one of its pharmaceutically acceptable salts:
  • ni represents an integer ranging from 1 to 12, in particular from 1 to 6, more particularly from 1 to 5, and in particular from 1 to 2, and
  • Y and Y ' represent, independently of one another, a hydrogen atom or a protective group
  • Z and Z ' represent independently of each other an amino acid residue, in particular D or L, natural or synthetic residue, in particular an amino acid residue ⁇ , ⁇ or ⁇ , the terminal amine function (ie, unrelated to - NY- or -NY'-) as well as the possible lateral chemical functions of Z and Z 'being protected or not, where Z and Z' are linked to the radical -NY- or -NY'-, respectively, via an amide bond;
  • X represents a group - (CH 2 J n -, n represents an integer ranging from 1 to 12, in particular from 1 to 6, more particularly from 1 to 5, and in particular from 1 to 2, and
  • R5 represents a hydrogen atom, a halogen atom, or an optionally substituted hydroxyl function.
  • the compound according to the invention corresponds to formula (II) in which R 1 represents an alkyl radical comprising from 1 to 6 carbon atoms, especially from 1 to 4 carbon atoms, in particular from 1 to 2 carbon atoms, or even is the methyl radical.
  • these compounds belong to the family Plumbagones, they then correspond to the formula (II) wherein R1 represents a methyl radical, and R5 represents a hydroxyl function.
  • these compounds belong to the Ménadiones family, they then correspond to formula (II) in which R1 represents a methyl radical, and R5 represents a hydrogen atom.
  • the compound according to the invention corresponds to formula (II) in which R1 represents a hydrogen atom.
  • these compounds belong to the family of simple substitution Juglones, when they correspond to the formula (II) in which R1 represents a hydrogen atom and R5 represents a hydroxyl function.
  • the compound according to the invention corresponds to formula (II) in which R1 represents a group - (CH 2 ) nl -NY '-COCHRNH 2 , where
  • -COCHRNH 2 represents a natural or synthetic amino acid residue, D or L, wherein R denotes the side chain of said amino acid residue,
  • -ni represents an integer ranging from 1 to 5, and in particular from 1 to 2, and
  • Y represents a hydrogen atom or a protective group, in particular chosen from those described in the book "Protective Group in Organic Synthesis” by T. W. Greene, PGM Wuts, Wiley-Interscience, New York, 4th Edition, 2007.
  • these compounds belong to the family of double substitution Juglones when they correspond to the formula (II) in which R1 represents a - (CH 2 ) nl -NY '-COCHRNH 2 group and R5 represents a hydroxyl function.
  • the compounds of formula (I) or (II) may optionally be in solvated form, salt, or other physiologically acceptable derivatives.
  • Salts and solvents that are acceptable for pharmaceutical use are generally those in which the counterion or the associated solvent is pharmaceutically acceptable.
  • the salts that can be used can be organic or inorganic acids or bases.
  • acceptable acid addition salts mention may be made of those formed from hydrochloric, hydrobromic, sulfuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, phenylacetic or triphenylacetic acid.
  • Acceptable basic salts may also include alkali metal salts, such as sodium or potassium, alkaline earth metal salts, such as calcium and magnesium, and salts formed from organic bases, such as mono-, di- or tri-substituted amines.
  • alkali metal salts such as sodium or potassium
  • alkaline earth metal salts such as calcium and magnesium
  • salts formed from organic bases such as mono-, di- or tri-substituted amines.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active agent at least one compound as defined above in a pharmaceutically acceptable carrier.
  • the composition may be anticancerous and / or proapoptotic and / or antiproliferative.
  • the compounds are employed in an effective amount. This will be determined by those skilled in the art, according to various parameters, in particular with respect to the substance used, the age, the weight, and the physical state of the patient, the mode of administration, and the required diet. . The skilled person will be able to determine the mode of administration and dosage for each patient.
  • the compound according to the invention can be administered at a dose ranging from 0.1 to 5000 mg per day and per patient.
  • the pharmaceutical composition may comprise a quantity of compound according to the invention ranging from 0.1 mg to 5 g.
  • the pharmaceutical composition may be administered in any form, topical or systemic, especially in parenteral or enteral form.
  • composition or the drug When the composition or the drug are administered enterally, it may be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, microspheres.
  • composition in the case of parenteral administration, may be in the form of solutions or suspensions for infusion or for injection.
  • composition may further comprise at least one additive, chosen especially from color agents, flavor, and preservatives.
  • additive chosen especially from color agents, flavor, and preservatives.
  • those skilled in the art will take care to choose the additive (s) so that the advantageous properties intrinsically attached to the invention are not, or not substantially impaired by the envisaged addition.
  • composition according to the invention may further comprise another compound intended to treat cancer.
  • compounds useful according to the invention include doxorubicin, whose trade name is adriamycin ®, epothilone, paclitaxel, which is the tradename Taxol ® and cisplatin.
  • the subject of the invention is the use of at least one compound as defined above for the preparation of a pharmaceutical composition intended to treat and / or to prevent an abnormal proliferation of cells. .
  • Said composition may be intended for human and / or veterinary medicine, and in particular it may be intended to treat or prevent at least one cancer chosen from pancreatic cancer, oropharyngeal cancers, cancer of the pancreas stomach, cancer of the esophagus, colon and rectal cancer, brain cancer, especially gliomas, ovarian cancer, liver cancer, kidney cancer, laryngeal cancer, cancer of the thyroid cancer, lung cancer, bone cancer, multiple myeloma, mesothelioma and melanoma, skin cancer, breast cancer, prostate cancer, bladder cancer, cancer of the lung uterus, testicular cancer, non-Hodgkin's lymphoma, leukemia, Hodgkin's disease, and soft tissue cancers, as well as metastatic secondary locations of the cancers mentioned above.
  • cancer chosen from pancreatic cancer, oropharyngeal cancers, cancer of the pancreas stomach, cancer of the esophagus, colon and rectal cancer, brain cancer, especially gli
  • abnormal proliferation is meant a proliferation which is independent of normal regulatory mechanisms, for example the arrest of cell proliferation due to the activation of apoptosis (programmed cell death).
  • the invention also relates to a pro-apoptotic and / or anti-proliferative composition comprising at least one compound as defined above.
  • the subject of the invention is the use of at least one compound as defined above as a pro-apoptotic and / or antiproliferative agent.
  • H 2 O water
  • HBTU O-benzotriazolyl-N, N, N, N '-tetramethyluronium hexafluorophosphate
  • HOBt N-hydroxybenzotriazole
  • NaCl sodium chloride
  • the protected amino acids come from Novabiochem, including Boc-L-Ala-OH, Boc-L-Ser (OtBu) -OH, Boc-L-Thr (OtBu) -OH, Boc-D-Val-OH, Boc-L- D-Trp-OH, Boc-L-Thr (OBn) -OH and Boc-D-Tyr (OBn) -OH. All other chemical compounds used are from Aldrich, Fluka or Acros and are of standard quality.
  • the solvents are distilled before use.
  • Example 5 Synthesis of 2-methyl-3- (methylammonium) -1,4-naphthoquinone trifluoroacetate
  • a 25 mL flask immersed in an ice bath 1.277 g (1 eq; 4.23 ⁇ mol) of the compound of Example 3 is dissolved in a trifluoroacetic acid mixture: dichloromethane (1: 1 ratio) or 8.5 mL of each solvent.
  • the reaction medium is stirred for six hours under nitrogen and at room temperature.
  • the TFA and CH 2 Cl 2 are then evaporated and the residue is taken up in toluene to remove the excess of TFA.
  • the carboxylic acid function of the commercial serine must be deprotected.
  • BocSer (tBu) OH.DCHA is introduced (0.38 mmol), to which 3 ml of AcOEt, 3 ml of water and 0.4 ml of H 2 SO 4 (2M) are added.
  • the aqueous phase is extracted with AcOEt once and the organic phase is washed 3 times with water. It is evaporated and 0.077 g of a colorless oil is obtained which is the serine residue in carboxylic acid form.
  • the DCHA salt allowing crystallization of the serine residue must be hydrolysed: for this in a A small separating funnel is charged with 0.075 g of BocSer (tBu) OH.DCHA (0.17 mmol), to which 2 ml of AcOEt, 2 ml of water and 0.2 ml of H 2 SO 4 (2M) are added. ). The aqueous phase is extracted with AcOEt once and the organic phase is washed 3 times with water. It is evaporated and 0.045 g of a colorless oil is obtained which is the serine residue in carboxylic acid form.
  • Example 35 a 10 ml flask, 0.183 mol of Example 35 is dissolved (1 0.55 mmol) in 5.5 ml of CH 2 Cl 2 o argon. 0.3 mL Et 3 N (3.9 eq .;
  • EXAMPLE 37 Synthesis of 3-aminoethyl-O-acetylplumbagone hydrochloride According to the operating procedure previously described for the compound of Example 5, in a 10 ml flask, 0.190 g of the compound of Example 36 is introduced (1 eq, 0.509 mmol), and 2 ml of CH 2 Cl 2 and 2 ml of TFA (in an ice bath) are added. During evaporation, the medium is taken up several times in toluene, and then the brown solid obtained is taken up in a solution of 1M HCl in Et 2 O for 30 minutes. The solvent is evaporated and the operation is repeated with the hydrochloric acid solution in ether twice.
  • this intermediate can give rise to a compound of formula I where Z is linked to the radical X via an amide bond, by coupling with a suitable amino acid.
  • the compound obtained would, for example, correspond to the following formula if the aforementioned intermediate is coupled with an ⁇ -amino acid: designating the side chain of the amino acid).
  • Example 39 Synthesis of 2,3-bis- (N-tert-butyloxycarbonylaminoethyl) -5-hydroxy-1,4-naphthoquinone In a 5 ml flask containing 0.100 g of the mixture of compounds of Example 38
  • AO is (1 eq, 0.315 mmol), introduced 0.179 g of Boc- ⁇ Ala (Aldrich Co.) (3 eq, 0.95 mmol) and 0.016 g of AgNO 3 (0.3 eq, 0.095 mmol).
  • Example 40 Synthesis of 2-methyl- (N'-acetyl-the-methyl-aminomethyl) -1, 4-naphthoquinone in a flask of 10 mL, containing 0.200 g of menadione either (1 eq .; 1 16 mmol) was charged with 0.456 g of N-Ac-D, L-Ala (Aldrich Co.) (3 eq, 3.48 mmol) and 0.059 g of AgNO 3 (0.3 eq, 0.035 mmol).
  • the addition of 0.344 g of 5 (NH 2 S 2 O 8 (1.3 eq, 1.51 mmol) dissolved in 3.0 mL of a CH 3 CN: H 2 O mixture is carried out for 2 hours.
  • the reaction medium is then stirred for one hour at 65 ° C., then extracted with CH 2 Cl 2 three times and the organic phases are washed once with H 2 O.
  • this intermediate can give rise to a compound of Formula I wherein Z is linked to radical X via an amide bond, by coupling with an acid
  • this intermediate can give rise to a compound of formula I wherein Z is linked to the radical X via an amide bond, by coupling with a suitable amino acid.
  • the compound obtained would, for example, correspond to the following formula if the aforementioned intermediate is coupled with an ⁇ -amino acid:
  • Example 42 Synthesis of methyl 2-propanoate of 2-methyl-1,4-naphthoquinone
  • a 100 ml flask containing 1,000 g of menadione (Aldrich Co.), (1 ⁇ g, 5.81 mmol), 2,300 g of the succinic acid methyl ester (Aldrich Co.) (3 eq, 17.40 mmol) and 0.300 g of AgNO 3 (0.3 eq, 1.80 mmol).
  • the mixture CH 3 CN: water (2: 1) is added, ie 30.0 ml of CH 3 CN and 15.0 ml of H 2 O and the temperature of the mixture is brought to 65 ° C.
  • Example 43 Synthesis of methyl 3-propanoate of 1,4-naphthoquinone
  • a 10 ml flask containing 0.097 g of 1,4-naphthoquinone (Acros Co.) is (1 eq., 0.61 mmol)
  • introduced 0.242 g of the succinic acid methyl ester (Aldrich Co.) is (3 eq, 1.83 mmol) and 0.031 g of AgNO 3 (0.3 eq, 0.18 mmol).
  • the mixture CH 3 CN: water (2: 1) is added, ie 3.0 mL of CH 3 CN and 1.5 mL of H 2 O, and the temperature of the mixture is brought to 65 ° C.
  • Example 47 Synthesis of 3-propanol-1,4-naphthoquinone
  • 0.100 g of the compound of Example 43 (1 eq, 0.41 mmol) is weighed and dissolved in 5 ml. ethanol.
  • 0.100 g of sodium borohydride (6.7 eq, 2.6 mmol) are added at 0 ° C. and the mixture is stirred at reflux for 7 h.
  • the reaction medium is cooled to room temperature before being poured into 10 ml of ice water, then acidified with an aqueous solution of 1% sulfuric acid and extracted with CHCl 3 .
  • the intermediates of Examples 46 and 47 may give rise to compounds of Formula I wherein Z is linked to radical X via an ester linkage. by coupling with a suitable amino acid.
  • the compounds obtained would, for example, correspond to the following formulas if the aforementioned intermediates were coupled with an ⁇ -amino acid:
  • Example 48 Synthesis of 3- (N'-ierfc-butyloxycarbonyl-2-aminomethyl) -1,4-naphthoquinone
  • 0.950 g of 1,4-naphthoquinone (1 eq. ) 3.150 g (3 eq; 18.0 mmol) of Boc-Gly (Aldrich Co.), and 0.306 g of AgNO 3 (0.3 eq, 1.8 mmol).
  • the mixture acetonitrile: water (ratio 7: 3) is added, ie 30.0 ml of CH 3 CN and 15.0 ml of H 2 O and the temperature of the mixture is raised to 65 ° C.
  • Method A In a 100 mL flask, 0.475 g of 1,4-naphthoquinone (1 eq, 3.0 mmol), 1.580 g (3 eq, 9.0 mmol) of
  • Method B In a 25 mL flask, 0.300 g of the compound of Example 48 (1.0q mmol), 0.549 g (3 eq, 3.13 mmol) of Boc-Gly (Aldrich Co.), and 0.053 g of AgNO 3 (0.3 eq, 0.31 mmol). The mixture acetonitrile: water (ratio 7: 3) is added, ie 7.0 mL of CH 3 CN and 3.0 mL of H 2 O, and the temperature of the mixture is brought to 65 ° C. The addition of 0.30 (NH 4 ) S 2 O 8 (1.3 eq, 1.36 mmol) dissolved in 5 mL of a CH 3 CN: H 2 O mixture is made for 2 hours.
  • reaction medium is then stirred for one hour at 65 ° C. and then extracted with CH 2 Cl 2 three times and the ethereal phases are washed once with H 2 O. The organic phases are dried over MgSO 4 and evaporated.
  • Example 51 Synthesis of 2- (N '-tert-butyloxycarbonyl-2-aminomethyl) -3- (N'-tert-butyloxycarbonyl-2-aminoethyl) -1,4-naphthoquinone lon of 25 mL, Weigh 0.287 g of example 48 or (Leq. °? 568 9 (3 é ⁇ 3- 3 '° mmo l) e Aldrich Co.) / and 0.051 g of
  • Method A In a 100 mL flask, 0.475 g of 1,4-naphthoquinone (1 eq;
  • Method B In a 25 mL flask, 0.300 g of the compound of Example 49 (0.99 ⁇ gol), 0.565 g (3 eq; 2.99 mmol) of Boc- ⁇ Ala (0.35 g Aldrich Co.), and 0.051 g of AgNO 3 (0.3 eq, 0.30 mmol). The mixture acetonitrile: water (ratio 7: 3) is added, ie 7.0 mL of CH 3 CN and
  • Example 55 Synthesis of 2-Aminomethyl-1,4-naphthoquinone hydrochloride previously omitted procedure of Example 5, 10 ml is introduced 0.100
  • the sulfonamide bond is interesting because isostere of the amide.
  • the formation of the sulfonamide linkage can be achieved using a functionalized naphthoquinone in the form of a terminal amine (or ammonium salt form) as the compounds of Examples 5-6 or 55- 56, which can react with a sulfonyl chloride to yield a sulfonamide.
  • the retro-inverso bond contains the same functional groups, and thus remains very similar to the classical amide.
  • the naphthoquinone compound is functionalized in the form of a carboxylic acid (as in Examples 44 or 45), which can be activated according to the procedure described for Example 7, and then brought into contact with a suitably functionalized amine, or of an amino acid protected on its carboxylic function to give a retro-inverso amide.
  • this amino acid is an alanine
  • R 6 is CH-CO 2 GP, where GP is a protecting group for the carboxylic acid function
  • the amide bond is reversed relative to the compound of the example 7.
  • R 6 OH may be the side chain of an amino acid such as Ser or Thr whose amino and carboxylic acid functions would be protected, or R 6 could be of the CH-NHGP type, and would therefore be an amino acid derivative previously reduced.
  • R 6 could be an amino acid derivative (or something else), according to the formula Naphthoquinone -fixer-O- (CO) -O-R 6 .
  • the formation of the thioamide linkage can be achieved by the transformation of an amide (or retro-inverso amide) linkage in the presence of sulfur pentasulfide.
  • This same type of binding may also be carried out according to other methods, for example by generating a thioaldehyde in the presence of a suitably substituted amine (an amino acid protected on its carboxylic function, and on its side chain, for example).
  • the biological activity tests concern the measurement of apoptosis.
  • a fluorescent tracer interposing DNA, makes it possible to visualize the fragmentation of the DNA. This fragmentation of the DNA results from the induction of the apoptotic phenomenon in the cells.
  • the cells are incubated in the presence of different concentrations of the compounds presented above.
  • the measurement of apoptosis in the cells is monitored by measuring the fluorescence, thus making it possible to determine the activity of the compounds in microMolaires ( ⁇ M).
  • ⁇ M microMolaires
  • Example 61 Biological tests
  • the activities are measured by flow cytometry multiplex tests, by coupling the measurement of apoptosis and cell proliferation.
  • the measurement of cell proliferation is performed by monitoring the dilution of a specific fluorescent tracer during cell divisions:
  • the cells are incubated in the presence of several concentrations of compounds, then the apoptosis and cell proliferation measurements are carried out simultaneously by the flow cytometry technique; dose-response curves of the action of the compounds on apoptosis and cell proliferation are obtained.

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  • Organic Chemistry (AREA)
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  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP07731362A 2006-04-25 2007-04-25 Composes de type 1, 4-naphtoquinones, compositions les comprenant et utilisation de ces composes en tant qu'agents anti -cancereux Withdrawn EP2010481A1 (fr)

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FR0651461A FR2900150B1 (fr) 2006-04-25 2006-04-25 Composes de type 1,4-naphtoquinones, compositions les comprenant et utilisation de ces composes en tant qu'agent anti-cancereux
PCT/FR2007/000703 WO2007125196A1 (fr) 2006-04-25 2007-04-25 Composés de type 1, 4-naphtoquinones, compositions les comprenant et utilisation de ces composés en tant qu'agents anti -cancéreux

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EP2093207A1 (en) * 2008-02-06 2009-08-26 Julius-Maximilians-Universität Würzburg Antiinfective and antitumoral compounds isolated from tropical lianas
AU2013232208B2 (en) * 2012-03-14 2017-04-27 Indiana University Research And Technology Corporation Compounds and methods for treating leukemia
US10011549B2 (en) * 2015-07-06 2018-07-03 Robert Bosch Gmbh Electrochemically active agents for pH modulation in biological buffers
TWI738334B (zh) * 2019-10-22 2021-09-01 國立清華大學 萘醌衍生物用於抑制癌細胞的增殖及轉移的用途
WO2024085824A1 (en) * 2022-10-19 2024-04-25 İsti̇nye Üni̇versi̇tesi̇ An antimetastatic agent effective on prostate cancer cells and suitable for use in the treatment of these diseases

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AU2007245621A1 (en) 2007-11-08
US20090247472A1 (en) 2009-10-01
WO2007125196A1 (fr) 2007-11-08
FR2900150B1 (fr) 2012-07-06
CA2650480A1 (fr) 2007-11-08
JP2009534449A (ja) 2009-09-24

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