Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C335/04—Derivatives of thiourea
  • C07C335/24—Derivatives of thiourea containing any of the groups, X being a hetero atom, Y being any atom
  • C07C335/26—Y being a hydrogen or a carbon atom, e.g. benzoylthioureas
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • 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
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C275/46—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylureas
  • C07C275/48—Y being a hydrogen or a carbon atom
  • C07C275/54—Y being a carbon atom of a six-membered aromatic ring, e.g. benzoylureas
• • 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
  • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
  • C07D235/14—Radicals substituted by nitrogen atoms
• • 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
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
  • C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
  • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
  • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C335/04—Derivatives of thiourea
  • C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
  • C07C335/08—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms of a saturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2

Definitions

• the present invention relates to the use of acyl-thiourea derivatives or acyl-ureas for the treatment of pathologies involving tissue dysfunction related to deregulation of the hedgehog signaling pathway, as well as to new ones.
• acyl-thiourea derivatives or acyl-ureas as such for their use as medicaments, and pharmaceutical compositions containing them.
• Hedgehog signaling molecule is a secreted self-proteolytic protein that activates the signaling pathway of hedgehog proteins, a signaling pathway that plays a fundamental role in the morphogenesis of many tissues, particularly in the formation of the endoderm and the embryonic axis, the development of the brain and hair follicles, as well as in cell proliferation, and would be involved in maintenance and tissue repair in adults (For a review see: Ingham et al, Genes Dev. , 2001, 15, 3059-3087, Marti et al, Trends Neurosci., 2002, 25, 89-96, Weschler et al., Annu Rev. Neurosci., 2001, 24, 385-428).
• Hedgehog protein and the associated transduction pathway are conserved in vertebrates and invertebrates. Only one homologue of Hh is present in Drosophila, while three homologues of Hh: Sonic (Shh), Indian (Ihh) and Desert (Dhh) are present in mammals. Of these three counterparts, Shh was the most studied because of its extended expression profile during development. Shh participates in the ventralization of the neural tube by specifying the early phenotype of several neuronal types along the ventral midline (spinal cord motoneurons, dopaminergic or cholinergic neurons) and inducing the generation of oligodendrocyte precursors from the spinal cord. ventral.
• Shh induces the survival of gabaergic and dopaminergic neurons, orients the fate of serotoninergic precursors and prevents the death of dopaminergic neurons caused by MPP toxin. It finally induces the proliferation of precursors of granular cells in the early postnatal cerebellum.
• the other members of the Hedgehog family participate respectively in the development of bone tissue (Ihh), testes and nerves peripherals (Dhh).
• the results obtained with Shh also apply to Dhh and Ihh.
• Hh has been associated with normal tissue maintenance and repair processes, spatiotemporal regulation of proliferation and differentiation, allowing Developing tissues achieve their correct size with the appropriate cell types and appropriate degrees of vascularization and innervation.
• the essential role of the Hh signaling function is demonstrated by the dramatic consequences of defects in this signaling pathway in the human fetus, such as holoprosencephaly observed with Sonic Hedgehog mutants.
• the Shh pathway has been identified in the adult brain, where the amino-terminal active form of the molecule is expressed in many regions of the mature nervous system at a higher level than that seen during the postnatal period.
• early Traiffort et al., Eur J. Neurosci., 1999, 11, 3199-3214 and 2001, 14, 839-850.
• Shh the role of Shh in adults are not fully understood, it first appeared, like other neurotrophic molecules, as a factor capable of promoting the survival and maintenance of the phenotype of the cells of the system. nerve (Reilly et al., Mol., Neurosci., 2002, 19, 88-96, Charytoniuk et al, Eur J. Neurosci., 2002, 16, 2351-2357).
• Shh is able to preserve the axonal projections of dopaminergic neurons in the striatum or to improve the time required for subsequent motor recovery. crushing of the sciatic nerve (Tsuboi et al., Exp Neurol., 2002, 173, 95-104, Pepinski et al, J. Pharm Sci., 2002, 91, 371-387).
• Hh proteins are synthesized as immature precursors of approximately 45 kDa which are subjected to intramolecular cleavage catalyzed by the C-terminal region of the precursor. This cleavage produces a 25 kDa C-terminal fragment with no known additional function and a 19 kDa active amino-terminal fragment (called HhNp for N-terminal processed domain) bound at its C-terminus to a cholesterol molecule, sufficient for all known signaling activities of hedgehog proteins.
• HhNp active amino-terminal fragment
• the signaling pathway of Hedgehog proteins comprises three main components; Hh ligand, a transmembrane receptor circuit, composed of the Patched Negative Regulator (Ptc) and the Smoothed Activator (Smo) and a cytoplasmic complex that regulates the transcriptional effectors.
• Hh ligand a transmembrane receptor circuit
• Ptc Patched Negative Regulator
• Smo Smoothed Activator
• the cellular response to the hedgehog morphogen is controlled by the expression products of the Patched gene (Ptc), a tumor suppressor gene, and Smoothened proto-oncogene (Smo); however, the exact mechanism of regulation of the hedgehog pathway is not fully understood.
• Patched gene Ptc
• Trc tumor suppressor gene
• Smo Smoothened proto-oncogene
• the Smo gene product which encodes a protein of the G protein coupled receptor family has no known endogenous ligand.
• Ptc would block the constitutive activity of Smo.
• Hedgehog binding to Ptc would remove this inhibition and allow signal transduction via Smo.
• the mechanism of regulation of Smo activity by Ptc in mammals could involve a molecule transported by Ptc and interacting with Smo (Taipale et al., Nature, 2002, 418, 892-896). Activation of GIi transcription factors is involved in the cascade of events resulting from Smo activity.
• HIP Hethog Intercating Protein
• HIP has been proposed as a negative regulator of the pathway (Ingham et al., Cited above, Ho et al., Curr Opin Neurobiol., 2002, 12, 57-63, Taipale et al, Nature, 2001, 411, 349). -354).
• products of the dispatched (disp) gene, including DispA would be involved in the release and accumulation in the extracellular medium of hedgehog proteins in soluble form (Ma et al., Cell, 2002, 111, 63-75).
• tumors Apart from basal cell carcinomas and medulloblastomas, other types of tumors have been associated with a defect in the Hedgehog signaling pathway; the location of these tumors is closely correlated with the expression sites of the pathway components during embryonic development.
• Shh has been associated with psoriasis.
• the components of this pathway such as Smoothened, Patched (Patched 1 and Patched 2) proteins, Dispatched proteins (Dispatched 1 and Dispatched 2) or even the HIP protein represent targets for the development of new molecules capable of modulating (activating or inhibiting) this pathway and thus of positively or negatively regulating the development [proliferation, differentiation, migration, survival (apoptosis)] and / or the activity of differentiated cells and cells in vitro and / or in vivo in embryos or adults.
• Such molecules are useful in the treatment of tumors associated with hyperactivation of the hedgehog pathway: nerve tissue tumors (medulloblastomas, primary neuroectodermal tumors, glioblastomas, meningiomas and oligodendrogliomas), cutaneous tumors (basal cell carcinomas, trichoepitheliomas), tumors muscle and bone tissue (rhabdomyosarcomas, osteosarcomas) and tumors of other tissues (kidney, bladder).
• nerve tissue tumors medulloblastomas, primary neuroectodermal tumors, glioblastomas, meningiomas and oligodendrogliomas
• cutaneous tumors basal cell carcinomas, trichoepitheliomas
• tumors muscle and bone tissue rhabdomyosarcomas, osteosarcomas
• tumors of other tissues Kidney, bladder.
• Such molecules are also useful in the treatment of neuro-degenerative pathologies requiring a blockade of the Hedge
• the hedgehog pathway to induce the formation, regeneration, repair and / or increase of tissue activity such as, but not limited to: nerve tissue [central (brain) and peripheral nervous system (sensory neurons, motor, sympathetic)], bone, cartilage, testes, liver, spleen, intestine, pancreas, kidneys, smooth and skeletal muscles, heart, lungs, skin and hair system , mucous membranes, blood cells and cells of the immune system.
• nerve tissue central (brain) and peripheral nervous system (sensory neurons, motor, sympathetic)
• bone cartilage, testes, liver, spleen, intestine, pancreas, kidneys, smooth and skeletal muscles, heart, lungs, skin and hair system , mucous membranes, blood cells and cells of the immune system.
• hedgehog proteins and derived polypeptides fragments, variants, etc.
• hedgehog protein antagonists PCT International Application WO 01/98344 in the name of BIOGEN
• these proteins and the derived polypeptides can not pass the blood brain barrier and therefore can not be administered systemically, especially for the treatment of brain tumors related to hyperactivation of the signaling pathway of hedgehog proteins.
• such molecules are difficult to produce and purify and are unstable;
• mifepristone (17 ⁇ -hydroxy 11 ⁇ - (4-dimethylamino phenyl) 17 ⁇ - (prop-1-ynyl) estra-4,9-dien-3-one), also known as RU-486 or RU-38486 (French patent) FR 03 00646 in the name of the CNRS) for which an inhibitory activity of the activity of the signaling pathway of hedgehog proteins has been demonstrated.
• the inventors have set themselves the goal of providing new compounds inhibitors of the signaling pathway of hedgehog proteins that better meet the needs of the practice, in particular in that they are simple to synthesize and potentially used in human therapy .
• the present invention relates to the use for the manufacture of a medicament for the treatment of tumors associated with hyperactivation of the signaling pathway of hedgehog proteins or neurodegenerative pathologies of the compounds of formula (I ) next :
• R 1, R 2 and R 3 which are identical or different and independently of each other, represent a hydrogen or halogen atom, a hydroxyl radical, an alkyl, perfluoroalkyl, alkoxy, alkylthio or nitrile group, a substituted alkoxy, or a fused heterocycle obtained from two adjacent radicals R 1, R 2 and R 3 which, together with the carbon atoms of the phenyl ring to which they are bonded, can form a fused heterocycle, X represents a sulfur atom or a oxygen,
• R 4 and R 5 which may be identical or different and independently of one another, represent a hydrogen or halogen atom, an alkoxy, alkylthio, alkyl, perfluoroalkyl, nitrile or nitro group.
• R 4 and R 5 which may be identical or different and independently of one another, represent a hydrogen or halogen atom, an alkoxy, alkylthio, alkyl, perfluoroalkyl, nitrile or nitro group.
• R 4 and / or R 5 represent a nitro group
• said heterocycle is a polycyclic heterocycle.
• said polycyclic heterocycle is chosen from indole, benzoimidazole, imidazopyridine and imidazothiazole groups.
• the compounds of formula (I) according to the invention has an inhibitory activity of the signaling pathway of hedgehog proteins and are therefore useful for the treatment of tumors associated with hyperactivation of the signaling pathway of hedgehog proteins or pathologies. neuro-degenerative type.
• the compounds of formula (I) according to the present invention may be divided into subunits A, B, C, (or C or C ") and D (or D 'or D") and represented by formulas (Ia) , (I-a '), (Ib), (I-b'), (Ic), (I-c '), (Id) and (I-d') as follows:
• R 1 to R 6 radicals have the same meanings as those indicated above, and the Z group represents a substituted or unsubstituted mono- or polycyclic heteroaryl group.
• Alkyl a linear or branched saturated hydrocarbon aliphatic group having from 1 to 5 carbon atoms, preferably from 1 to 2 carbon atoms.
• branched means that at least one lower alkyl group such as methyl or ethyl is carried by a linear alkyl chain.
• lower alkyl refers to alkyl having 1 or 2 carbon atoms; the term “higher alkyl” refers to a linear or branched alkyl group having from 3 to 5 carbon atoms. Examples of alkyl groups that may be mentioned are methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl and n-pentyl.
• Halogen atom means a bromine, chlorine, iodine or fluorine atom; the bromine, chlorine and fluorine designations being preferred;
• Perfluoroalkyl denotes an alkyl group as defined above in which all the hydrogen atoms have been replaced by fluorine atoms.
• the perfluoroalkyl groups the trifluoromethyl and perfluoroethyl groups are preferred;
• Alkoxy denotes an O-alkyl group in which the alkyl group can have the same meaning as that indicated above.
• alkoxy groups there may be mentioned in particular the methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy and pentoxy groups;
• Alkylthio denotes an alkyl-S group in which the alkyl group can have the same meaning as that indicated above.
• alkylthio groups that may be mentioned include methylthio, ethylthio, iso-propylthio, butylthio and pentylthio groups;
• Aryl group denotes any functional group or substituent derived from at least one aromatic ring; an aromatic ring corresponds to any planar mono- or polycyclic group comprising a delocalized ⁇ system in which each atom of the cycle comprises an orbital p, said orbital p overlapping each other; among such aryl groups, mention may be made of phenyl, benzylcyclobutene, pentalene, naphthalene, benzylphenyl and anthracene groups;
• Heteroaryl group means any functional group or substituent derived from at least one aromatic ring as defined above and containing at least one heteroatom selected from P, S, O and N; among the heteroaryl groups, there may be mentioned furan, pyridine, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, pyridine, imidazopyridine, imidazothiazole, pyrazine, pyrimidine, pyridazine, benzofuran, isobenzofuran, indole, isoindole, benzothiophene, benzo [c] thiophene, benzimidazole, indazole, benzoxazole, benzisoxazole, benzothiazole, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, purine, and acridine;
• Saturated or unsaturated mono- or polycyclic hydrocarbon group denotes any functional group or substituent derived from a non-aromatic ring comprising at least 3 carbon atoms optionally optionally comprising one or more heteroatoms chosen from P, S, O and N.
• groups there may be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the cyclohexyl group being preferred.
• the compounds of formula (I) are chosen from those in which:
• R 1, R 2 and R 3 which are identical or different, represent a hydrogen atom or a methyloxy or ethyloxy radical
• X represents a sulfur or oxygen atom
• R 4 and R 5 which are identical or different, are chosen from hydrogen, chlorine, bromine, fluorine, methyl and methoxy;
• Hedgehog protein signaling with a synthetic activator compound of the chlorobenzothiophene type called SAG according to the method described by Chen et al, (Proc Natl Acad Sci USA, 2002, 99 , 14071): N - [[[3- (4-methoxybenzoylamino) phenyl] amino] thioxomethyl] -3,4,5-methoxybenzamide (Ia) (Compound 1); N - [[[3- (2-chloro-benzoylamino) phenyl] amino] thioxomethyl] -3,4,5-methoxybenzamide (I-a) (Compound 2); N - [[[3- (3-methoxybenzoylamino) phenyl] amino]
• the compounds of formula (I) according to the invention can be easily prepared, generally in three or four stages, according to synthetic methods analogous to conventional methods known to those skilled in the art.
• the general synthesis scheme of the compounds of formula (I) according to the invention, in their four variants (Ia) or (I-a '), (Ib) or (Ib 1 ), (Ic) or (Ic 1 ) , (I-d) or (I-d '), can be represented according to the appended FIG.
• a commercial 3-nitroaniline of formula (II) is condensed in which the radicals R 4 and R 5 have the same meanings as those indicated above, with an acid chloride of formula (III) in which R 6 has the same meaning as that indicated above, for example according to the method of Schotten-Baumann, to obtain the amide compound of formula (IV) corresponding.
• Step b) allows a coupling between a commercial 3-nitroaniline of formula (II) in which the radicals R 4 and R 5 have the same meanings as those indicated above, with a commercial isocyanate (IIP), to obtain a nitro-urea of formula (IV) which can lead to compounds (I-b) and (I-b ').
• Step b ') consists in condensing a commercial 3-nitrobenzoic acid of formula (U') with an amine of formula (V), in which R 4 , R 5 and R 4 have the same meanings as those indicated above. to obtain the nitroamide compound of formula (IV ").
• step d) having a mono- or polycyclic heteroaryl Z group, substituted or unsubstituted, and R 4 and R 5 radicals having the same meanings as those indicated above, are obtained according to methods known to those skilled in the art (Yang et al, Angew Chem Int.
• This reduction step can be carried out in a reducing medium, for example by the action of a reducing agent such as lead dichloride or tin dichloride, or alternatively by hydrogenation, for example using activation by microwaves, other hydrogenation methods can also be used depending on the nature of the substituents R 4 and R 5 may be present on the phenyl ring.
• a reducing agent such as lead dichloride or tin dichloride
• hydrogenation for example using activation by microwaves
• other hydrogenation methods can also be used depending on the nature of the substituents R 4 and R 5 may be present on the phenyl ring.
• R 4 and / or R 5 represent a halogen atom such as chlorine, bromine or iodine
• the reduction step is preferably carried out by the action of tin dichloride. In all other cases, it is preferred to carry out a catalytic hydrogenation in the presence of Pd / C or Raney nickel.
• an acylisothiocyanate of formula (VIII) is prepared in which the radicals R 1 to R 3 have the same meaning as that indicated above for the compounds of formula (I), starting from a benzoic acid of formula (VII) or a benzoic acid chloride of formula (VII ') corresponding, for example in a refluxing solvent medium (acetonitrile or acetone) in the presence for example of phosgene and ammonium thiocyanate .
• the compounds of formulas (Ia) and (Ib) are obtained as solids which are then purified in a conventional manner by recrystallization from an alcohol (Rasmussen, CR et al., Synthesis, 1988, 456-459).
• an alcohol Rosmussen, CR et al., Synthesis, 1988, 456-459.
• X O, then in a step h), h '), h ") or h'") are respectively carried out on the oxidation of a compound of formula (Ia), (Ib), (Ic) or ( Id), to obtain a compound of formula of formula (I-a '), (I-b'), (I-c ') or (I-d').
• This oxidation step can be carried out according to methods well known to those skilled in the art, for example using, as copper (Cu (I)) oxidizing agent in an alkaline medium (Narasimhamurthy, K.
• Another subject of the invention relates to novel acylthiourea or acyl-urea derivatives, as such, covered by the formula (I) defined above, corresponding to the following formula (P) (the compounds of formula (I ') having a subfamily of the compounds of formula (I):
• R 1, R 2 and R 3 which are identical or different and independently of each other, represent a hydrogen or halogen atom, a hydroxyl radical, an alkyl, perfluoroalkyl, alkoxy, alkylthio or nitrile group, a substituted alkoxy, or a fused heterocycle obtained from two adjacent radicals R 1 , R 2 and R 3 which can form, together with the carbon atoms of the phenyl ring to which they are bonded, a fused heterocycle;
• X represents a sulfur or oxygen atom
• the compounds of formula (I ') according to the invention have the property of inhibiting the signaling pathway of hedgehog proteins and can therefore be used, as active ingredient, for the preparation of a pharmaceutical composition intended for the treatment of pathologies associated with hyperactivation of the signaling pathway of hedgehog proteins or in which inhibition of this pathway is of therapeutic interest.
• the subject of the present invention is also the compounds of formula (I ') as defined above, for use as a medicament, in particular: i) as a medicament intended for the treatment of tumors associated with hyperactivation of the signaling pathway of Hedgehog proteins; such tumors include nerve tissue tumors (medulloblastomas, primary neuroectodermal tumors, glioblastomas, meningiomas and oligodendrogliomas), cutaneous tumors (basal cell carcinomas, trichoepitheliomas), muscle and bone tissue tumors (rhabdomyosarcomas, osteosarcomas), and tumors. other tissues (kidney, bladder).
• nerve tissue tumors medulloblastomas, primary neuroectodermal tumors, glioblastomas, meningiomas and oligodendrogliomas
• cutaneous tumors basal cell carcinomas, trichoepitheliomas
• muscle and bone tissue tumors rhabdomyosarcomas, osteosarcom
• Another object of the present invention is a pharmaceutical composition, characterized in that it comprises, as active principle, at least one compound of formula (P) as defined above, and at least one pharmaceutically acceptable excipient.
• the compound or compounds of formula (P) are preferably used in an amount for administering unit doses of between 1 mg and 2 g approximately.
• the form of the drug or pharmaceutical composition eg, solution, suspension, emulsion, tablets, capsules, suppositories, etc.
• the form of the drug or pharmaceutical composition eg, solution, suspension, emulsion, tablets, capsules, suppositories, etc.
• the form of the drug or pharmaceutical composition will depend on the chosen route of administration.
• the drug or the pharmaceutical composition can be administered by any suitable route, for example by oral, anal, local, systemic, intravenous, intramuscular or mucosal route, or by using a patch, or in encapsulated form, or immobilized on liposomes, microparticles, microcapsules, and the like.
• excipients suitable for oral administration talc, lactose, starch and its derivatives, cellulose and its derivatives, polyethylene glycols, acid polymers acrylic, gelatin, magnesium stearate, animal, vegetable or synthetic fats, paraffin derivatives, glycols, stabilizers, preservatives, anti-oxidants, wetting agents, anti-caking agents, dispersants , emulsifiers, taste modifying agents, penetration agents, solubilization agents, etc.
• excipients suitable for oral administration talc, lactose, starch and its derivatives, cellulose and its derivatives, polyethylene glycols, acid polymers acrylic, gelatin, magnesium stearate, animal, vegetable or synthetic fats, paraffin derivatives, glycols, stabilizers, preservatives, anti-oxidants, wetting agents, anti-caking agents, dispersants , emulsifiers, taste modifying agents, penetration agents, solubilization agents, etc.
• FIG. 2 illustrates, by fluorescence microscopy photographs (DMRXA2, Leica, openlab3.1.2 software, improvision), the inhibition of the Bodipycyclopamine liason by the compounds 31 and 38 of the invention, as well as by the Cyclopamine (Cy), a Smoothened receptor reference antagonist, and
• FIG. 3 represents the dose response curves obtained for compounds 31 and 38 of the invention, and for Cyclopamine (Cy), on the binding of Bodipycyclopamine.
• reaction medium was mixed at room temperature for 150 minutes; the reaction was followed by thin layer chromatography (TLC) using a 1/2 (v / v) mixture of petroleum ether / ethyl acetate (AcOEt) as eluent. After the disappearance of 3-nitroaniline, the solution was poured into 5 ml of 1N hydrochloric acid (HCl). The resulting precipitate was washed with water and crystallized from methanol. There was thus obtained 1.45 g of the expected compound of formula (IV-I) as a brown solid (74% yield).
• the tube was then placed in a microwave oven and subjected to two successive cycles of irradiation according to the following regime:
• the effect of the compounds of formula (I) according to the invention on the inhibition of the hedgehog protein signaling pathway was determined by analysis of the differentiation of the pluripotent fibroblastic cell line.
• ATCC ATCC
• SAG SAG
• Activation by SAG causes differentiation of the cell line and allows them to express alkaline phosphatase. It was thus possible to measure the activity of the Hedgehog protein signaling pathway by measuring the alkaline phosphatase activity.
• the C3H10T1 / 2 cells were inoculated on 96-well plates at a density of 5.10 5 cells per well, 24 hours before the addition of the test compounds at a concentration ranging from 1 nM to 30 ⁇ M and in the presence of 0, 1 ⁇ M SAG using as culture medium DMEM supplemented with 10% fetal calf serum. The tests were carried out in quadruplate. Plates were then incubated for 5-6 days at 37 ° C under 5% CO 2 . The cells were then washed in cold phosphate buffer ("Phosphate Buffer Serum":
• Table 1 shows the inhibition of the alkaline phosphatase activity induced by 10 ⁇ M of each of the compounds tested. These results are expressed as a percentage of the alkaline phosphatase activity induced by the action of SAG.
• the letter A corresponds to an inhibition greater than 80%
• the letter B corresponds to an inhibition of between 20 and 80%
• the letter C corresponds to an inhibition of between 5 and 20%.
• Table 2 shows the concentration tested for each of the compounds which makes it possible to inhibit 50% of the alkaline phosphatase activity (IC 5 o) after induction with SAG at 0.1 ⁇ M.
• the letter A corresponds to an IC 50 of between 0.01 and 1 ⁇ M and the letter B corresponds to an IC 50 of between 1 and 3 ⁇ M.
• HEK293 cells are seeded at 70,000 cells per well on glass slides treated with poly-D-lysine in a 24-well plate, and transfected the next day with 0.25 ⁇ g of plasmid encoding the Smoothened mouse protein (Masdeu C, Faure H., Coulombe J., Schoenfelder A., Mann A., Brabet L, JP Pin., Traiffort E. and Ruât M., Identification and characterization of Hedgehog modulator properties after functional coupling of Smoothened to G 15, Biochem Biophys Res Commun., 2006, 349: 471-479), using 0.7 ⁇ l of fugene ⁇ (Roche biochemicals).
• the culture medium is removed, the cells rinsed once with 1 ml of a PBS (Phosphate Buffered Saline) phosphate buffer solution, and then fixed for 20 minutes in the presence of an ice-cold solution of paraformaldehyde (PFA) at 4 ° C. % glucose 0.12 M in phosphate buffer solution PBS.
• PFA paraformaldehyde
• the cells are then rinsed once and washed twice for 5 minutes with 1 ml of a phosphate buffer solution PBS, 0.5% fetal calf serum (PBS-FCS).
• IC 50 inhibitory concentrations obtained for the compounds 31 and 38 of the invention, and for Cyclopamine (Cy), are the following:
• IC 50 0.12 ⁇ M
• IC 50 0.5 ⁇ M
• IC 50 0.05 ⁇ M.

Landscapes

• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Neurosurgery (AREA)
• Immunology (AREA)
• Diabetes (AREA)
• Psychology (AREA)
• Physical Education & Sports Medicine (AREA)
• Obesity (AREA)
• Hospice & Palliative Care (AREA)
• Endocrinology (AREA)
• Emergency Medicine (AREA)
• Psychiatry (AREA)
• Transplantation (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Hematology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Heterocyclic Compounds Containing Sulfur Atoms (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
• Furan Compounds (AREA)
• Indole Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pyridine Compounds (AREA)

Priority Applications (5)

Applications Claiming Priority (2)

Publications (2)

Family

ID=40085488

Family Applications (1)

Country Status (7)

Cited By (4)

Families Citing this family (5)

Family Cites Families (19)

• 2008
  • 2008-04-24 FR FR0802302A patent/FR2930552B1/fr not_active Expired - Fee Related
• 2009
  • 2009-04-16 JP JP2011505549A patent/JP5819188B2/ja not_active Expired - Fee Related
  • 2009-04-16 US US12/988,975 patent/US9073835B2/en not_active Expired - Fee Related
  • 2009-04-16 EP EP09733789.3A patent/EP2291352B1/fr not_active Not-in-force
  • 2009-04-16 WO PCT/FR2009/000442 patent/WO2009130422A2/fr not_active Ceased
  • 2009-04-16 CA CA2722258A patent/CA2722258C/fr not_active Expired - Fee Related
  • 2009-04-16 ES ES09733789.3T patent/ES2651272T3/es active Active

Also Published As

Similar Documents

Legal Events