EP2209768A1 - In der 2er- und 3er-position substituierte 5,6-diarylpyridine, ihre herstellung und ihre therapeutische verwendung - Google Patents

In der 2er- und 3er-position substituierte 5,6-diarylpyridine, ihre herstellung und ihre therapeutische verwendung

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Publication number
EP2209768A1
EP2209768A1 EP08869799A EP08869799A EP2209768A1 EP 2209768 A1 EP2209768 A1 EP 2209768A1 EP 08869799 A EP08869799 A EP 08869799A EP 08869799 A EP08869799 A EP 08869799A EP 2209768 A1 EP2209768 A1 EP 2209768A1
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European Patent Office
Prior art keywords
group
substituted
alkyl
trifluoromethyl
unsubstituted
Prior art date
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Application number
EP08869799A
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English (en)
French (fr)
Inventor
Lionel Barre
Christian Congy
Philippe Pointeau
Murielle Rinaldi-Carmona
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Sanofi SA
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Sanofi Aventis France
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    • 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
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    • C07D213/40—Acylated substituent nitrogen atom
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6

Definitions

  • the present invention relates to pyridine derivatives, to their preparation and to their therapeutic application.
  • R 1 and R 3 may represent an aryl group and R may represent an alkylcarbonylaminoalkyl group.
  • Patent application WO 2002/055502 describes compounds of formula:
  • Patent application WO2006 / 113704 describes compounds of formula
  • Q represents an oxygen atom, a sulfur atom or a radical -NR 1 - in which R 1 represents a hydrogen atom or a (C 1 -C 4) alkyl group;
  • Z represents a group -NQE ⁇ XR ⁇ -N (R3) COOR5 or -OCON (R3) R5;
  • X represents a group -CO-, -SO2-, -CON (Rg) - or -CSN (Rg) -;
  • R3 represents a hydrogen atom or a (C1-C4) alkyl group;
  • R4 represents:
  • a phenylcyclopropyl group the phenyl group being unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl, (C 1 -C 4) alkoxy group; , (C1-C4) alkylthio, trifluoromethylthio, cyano, nitro, (C1-C4) alkanoyl, phenyl, a group S (O) n AUc, OS (O) n AUc or NR 7 Rg; .
  • R4 may be (C1-C8) alkanoyl or benzoyl or benzylcarbonyl, the phenyl group of said groups being unsubstituted or substituted by one or more identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylthio, trifluoromethylthio, cyano, nitro group, (C1-C4) alkanoyl, phenyl, a group S (O) n Alk, OS (O) n Alk or NR 7 Rg;
  • R 5 represents a phenyl that is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom or a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy, cyano, nitro or (C 1 -C 4) alkoxy group; ,
  • Rg represents a hydrogen atom or a (C 1 -C 4) alkyl group
  • R4 and Rg together with the nitrogen atom to which they are bonded constitute a heterocyclic radical of 3 to 8 atoms, containing or not a second heteroatom selected from an unsubstituted oxygen, sulfur or nitrogen atom; or substituted one or more times with identical or different substituents selected from (C 1 -C 4) alkyl, (C 1 -C 4) alkanoyl, NR 7 R 6 or CONR 7 R 6, phenyl; said phenyl group being unsubstituted or substituted one or more times with identical or different substituents selected from halogen, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, trifluoromethyl, (C 1 -C 4) alkylthio, trifluoromethoxy, trifluoromethylthio or a group OS (O) n Alk, S (O) n Alk or NR 7 Rg;
  • R 7 and R 8 independently of one another represents a hydrogen atom, a (C 1 -C 4) alkyl group or R 7 and R 6 together with the nitrogen atom to which they are bonded, constitute a radical; saturated heterocyclic group of 4 to 8 atoms which may contain another heteroatom selected from nitrogen, oxygen or sulfur;
  • Ar 1 and Ar 2 represent each independently of each other a phenyl which is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 6) alkyl group, C 1 -C 6) alkoxy, (C 1 -C 6) alkylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, cyano, nitro, a group S (O) n Alk, OS (O) n Alk or NRyRg;
  • Y represents a group -Ry t -OR5 '-N (R3') X'R4 ', -N (R 3 OCOOR 5 ', -NRyRg ', -CON (R 3 ') R 5 ', -CSN (R 3 ') R 5', -C (O) R 2 ', -C (O) -OR 2 ', -SO 2 R 2 ', -SO 2 N (R 3 OR 5 ' or -OCON (R 3 ') R 5 ';
  • - R ⁇ represents a radical -CN or a heterocyclic radical of 3 to 8 atoms oxygen, sulfur or nitrogen, saturated or unsaturated, containing or not a second heteroatom selected from nitrogen, oxygen or sulfur, unsubstituted or substituted by one or more identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, hydroxyl, trifluoromethyl, (C 1 -C 4) alkoxy, trifluoromethoxy, trifluoromethylthio, (C 1 -C 4) alkylthio, cyano group, nitro or with an oxo group;
  • X ' represents a group -CO-, -SO 2 -, -CON (Rg') - or -CSN (RO ') - Î
  • R 2 represents:
  • a (C 1 -C 10) alkyl group unsubstituted or substituted by a substituent selected from CF 3 , (C 1 -C 4) alkoxy or hydroxy; . a nonaromatic carbocyclic (C 3 -C 2) unsubstituted or substituted one or more times by identical or different substituents selected from a halogen atom, a (Ci-C4) alkyl, hydroxyl, trifluoromethyl or ( This-
  • a phenyl which is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a group
  • a benzyl which is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (C 1 -C 4) alkoxy group,
  • R 3 ' represents a hydrogen atom or a (C 1 -C 4) alkyl group
  • R4 represents:
  • a (C 1 -C 10) alkyl group unsubstituted or substituted with a CF 3 group; . a nonaromatic carbocyclic (C 3 -C 2) unsubstituted or substituted one or more times by identical or different substituents chosen from a (Ci-C4) alkyl, hydroxyl, halogen, trifluoromethyl, (C 1 -C 4) alkoxy, (C 1-4) alkylthio or cyano; .
  • a phenyl which is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl or (C 1 -C 4) alkoxy group, C4) alkylthio, trifluoromethylthio, cyano, nitro, (C1-C4) alkanoyl, phenyl, a group S (O) n AIk, OS (O) n AIk or NRyRg ';
  • a phenylcyclopropyl group the phenyl group being unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl, (C 1 -C 4) alkoxy group; (C1-C4) alkylthio, trifluoromethylthio, cyano, nitro, (C1-C4) alkanoyl, phenyl, a group S (O) n AIk, OS (O) n AIk or NR ⁇ 'Rg '; . a (C1-C2) alkylene substituted with one or two identical or different substituents chosen from:
  • phenyl which is unsubstituted or substituted by one or more substituents, which may be identical or different, chosen from a halogen atom, a group (C 1 -
  • X ' is -CON (R') - or -CSN (R 5 K ⁇ 4 'represent a group C an (Ci-Cg) alkanoyl or benzoyl or benzylcarbonyl, the phenyl group of said groups being not unsubstituted or substituted by identical or different substituents selected from a halogen atom, a (C j ⁇ -C alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl,
  • a non-aromatic (C 3 -C 12) carbocyclic radical which is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, hydroxyl, trifluoromethyl or (C 1 -C 4) group; alkoxy; phenyl which is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy, cyano, nitro, (C 1 -C 4) alkoxy group; (C1-C4) alkylthio, trifluoromethylthio, S (O) n Alk, OS (O) n Alk or NRyRg ',
  • R3 'and R5' together with the nitrogen atom to which they are attached constitute a heterocyclic radical of 3 to 8 atoms, containing or not a second heteroatom chosen from an oxygen, sulfur or nitrogen atom, unsubstituted or substituted one or more times by identical or different substituents selected from a halogen atom, a trifluoromethyl, a (C 1 -C 4) alkyl group, a phenyl group, a NRyRg 'group, a CONRyRg'group; said (C 1 -C 4) alkyl group being substituted or unsubstituted by a trifluoromethyl group; and said phenyl group being unsubstituted or substituted one or more times with halogen, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy trifluoromethyl, (C 1 -C 4) alkylthio, trifluoromethoxy, trifluoromethylthio
  • Rg ' represents a hydrogen atom or a group (C1-C4) alkyl; - or R4 'and Rg> together with the nitrogen atom to which they are attached constitute a heterocyclic radical of 3 to 8 atoms, containing or not a second heteroatom chosen from an oxygen, sulfur or nitrogen atom, unsubstituted or substituted one or more times with identical or different substituents selected from (C 1 -C 4) alkyl group, phenyl group, halogen atom, hydroxyl, trifluoromethyl, (C 1 -C 4) alkoxy, trifluoromethoxy, trifluoromethylthio, (C 1 -C 4) alkylthio, oxo group, (C 1 -C 4) alkanoyl, NRyRg 'or CONR ⁇ 'Rg', said (Ci-C4) alkyl group being substituted or not by a trifluoromethyl group, and said phenyl group being unsub
  • R7 'and Rg' each independently represent a hydrogen atom, a (C1-C4) alkyl group or R ⁇ > and Rg 'together with the nitrogen atom to which they are attached constitute a saturated heterocyclic radical of 4 to 8 atoms which may contain another heteroatom selected from a nitrogen, oxygen or sulfur atom;
  • - Alk represents a linear or branched (Ci-C7) alkyl group
  • - Alk ' represents a linear or branched (Ci-C 5 ) alkyl group
  • n 0, 1 or 2;
  • k 0 or 1
  • n 0 or 1; in the form of base or addition salt, and in the state of hydrate or solvate with an acid.
  • the compounds of formula (I) correspond to the following compounds: compounds of formula (IA4) with Y representing a -C (O) R.2 'group;
  • R2 ', R3', R5 ', R7' and Rg ' preferably have the following definitions: - R.2> represents:
  • (Ci-Cio) has lkyle unsubstituted or substituted by a substituent selected from CF ⁇ , (Cj-C4) alkoxy or hydroxy;
  • non-aromatic carbocyclic radical unsubstituted C3-C12X or substituted one or more times by identical or different substituents selected from a halogen atom, a (Ci-C4) alkyl, (Ci-C4) alkoxy, hydroxyl or trifluoromethyl;
  • - phenyl which is unsubstituted or monosubstituted or polysubstituted by identical or different substituents selected from a halogen atom, a (C I -C 4) alkyl, trifluoromethyl, trifluoromethoxy, (Ci-C4) alkoxy, (Ci-C4 ) alkylthio or trifluoromethylthio;
  • a benzyl which is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy or (C 1 -C 4) alkoxy group, (C 1 -C 4) ) alkylthio or trifluoromethylthio;
  • R 3 ' represents a hydrogen atom or a (C 1 -C 4) alkyl group;
  • R 7 'and R 8' each independently represent a hydrogen atom or a (C 1 -C 4) alkyl group, or R 1 and R 6 'together with the nitrogen atom to which they are attached constitute a saturated heterocyclic radical of 4 to 8 atoms may contain another heteroatom selected from a nitrogen atom, oxygen or sulfur.
  • the compounds of formulas (IA 1 ), (IB 1 ), (IC 1 ) and (IJ 1 ) are particularly preferred.
  • the compounds of formula (I) correspond to the following compounds: the compounds of formula (IB 2) with Y representing a group -SO 2 R 2 '',
  • R2 ' represents:
  • C3-C12X n is unsubstituted or substituted one or more times by identical or different substituents selected from a halogen atom, a (Ci-C4) alkyl, hydroxyl, trifluoromethyl, (C ⁇ -
  • a phenyl that is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a group (C1-C4) alkyl, trifluoromethyl, trifluoromethoxy, (C1-C4) alkoxy, (C1-C4) alkylthio or trifluoromethylthio;
  • R3 ' represents a hydrogen atom or a (C1-C4) alkyl group
  • non-aromatic carbocyclic radical unsubstituted C3-C12X or substituted one or more times by identical or different substituents selected from a halogen atom, a (Ci-C4) alkyl, hydroxyl, trifluoromethyl or (C ⁇ -C4 alkoxy;
  • a phenyl that is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy or (C 1 -C 4) alkoxy group, (C 1 -C 4) alkylthio or trifluoromethylthio;
  • - R3 'and R5' together with the nitrogen atom to which they are attached constitute a heterocyclic radical of 3 to 8 atoms, containing or not a second heteroatom selected from an oxygen atom, sulfur or nitrogen, no substituted or substituted one or more times with identical or different substituents selected from halogen, trifluoromethyl or (C1-C4) alkyl unsubstituted or trifluoromethyl substituted;
  • R7 'and Rg' each independently represent a hydrogen atom, a (C1-C4) alkyl group or R7 'and Rg' together with the nitrogen atom to which they are attached constitute a saturated heterocyclic radical of 4 to 8 atoms may contain another heteroatom selected from a nitrogen atom, oxygen or sulfur.
  • the compounds of formula (I) correspond to the following compounds:
  • Rp, R2 ', R3', R4 ', R5', R6 ', Ry, Rg' and X ' preferably have the following definitions:
  • R 1 ' represents a heterocyclic radical of 3 to 8 atoms, saturated or unsaturated, oxygenated, sulfurous or nitrogenous, containing or not containing a second heteroatom chosen from nitrogen, oxygen or sulfur, unsubstituted or substituted by one or more identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, hydroxyl, trifluoromethyl, (C 1 -C 4) alkoxy, trifluoromethoxy, trifluoromethylthio, (C 1 -C 4) alkylthio group or an oxo group;
  • X ' represents a group -CO-, -SO2-, -CON (Rg') - or -CSN (Rg ') -; - R2> represents:
  • non-aromatic (C 3 -C 12) carbocyclic radical which is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, hydroxyl or trifluoromethyl group;
  • a phenyl that is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy or (C 1 -C 4) alkoxy group, (C 1 -C 4) alkylthio or trifluoromethylthio;
  • R 3 ' represents a hydrogen atom or a (C 1 -C 4) alkyl group
  • R4 represents:
  • non-aromatic (C 3 -C 12) carbocyclic radical which is unsubstituted or substituted one or more times with identical or different substituents chosen from a (C 1 -C 4) alkyl, hydroxyl, a halogen atom, a trifluoromethyl group or C1-C4) alkoxy;
  • a phenyl that is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl or (C 1 -C 4) alkoxy group;
  • a hydrogen atom a (C 1 -C 10) alkyl group which is unsubstituted or substituted with a CF 3 group;
  • non-aromatic carbocyclic radical (C 3 -C 2) unsubstituted or substituted one or more times by identical or different substituents selected from a halogen atom, a (Ci-C 4) alkyl, hydroxyl, trifluoromethyl or (Ci-C 4) alkoxy;
  • a phenyl that is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4 ) alkyl, trifluoromethyl, trifluoromethoxy or (C 1 -C 4) alkoxy group, (C 1 -C 4) alkylthio, trifluoromethylthio, S (O) n Alk or OS (O) n Alk; - R3 'and R5' together with the nitrogen atom to which they are attached constitute a heterocyclic radical of 3 to 8 atoms, containing or not a second heteroatom selected from an oxygen atom, sulfur or nitrogen, no substituted or substituted one or more times with identical or different substituents selected from a halogen atom, a (C 1 -C 4 ) alkyl group, a NRyRg 'group or CONR ⁇ 'Rg'; - R 'represents a hydrogen atom or a (
  • R4 'and Rg' together with the nitrogen atom to which they are attached constitute a heterocyclic radical of 3 to 8 atoms, containing or not a second heteroatom chosen from an oxygen, sulfur or nitrogen atom, unsubstituted or substituted one or more times with identical or different substituents selected from halogen, hydroxyl, trifluoromethyl, (C 1 -C 4 ) alkoxy, trifluoromethoxy, trifluoromethylthio, (C 1 -C 4 ) alkylthio, an oxo group or a (C 1 -C 4 ) alkyl group, optionally substituted with a trifluoromethyl group;
  • R 7 'and Rg' are each independently of the other a hydrogen atom or a (Ci-C 4) alkyl or R 7 'and R' together with the nitrogen atom to which they are bonded, constitute a saturated heterocyclic radical of 4 to 8 atoms which may contain another heteroatom selected from a nitrogen, oxygen or sulfur atom;
  • Alk represents a linear or branched (Ci-C 7) alkyl group.
  • R 3 represents a hydrogen atom or a (C 1 -C 4 ) alkyl group
  • R 4 represents: . a (C3-C10) alkyl group
  • a non-aromatic carbocyclic radical (C3-C12X unsubstituted or substituted one or more times with a (Ci-C4) alkyl, same or different;
  • a phenyl which is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy or (C 1 -C 4) alkoxy group, (C 1 -C 4) alkylthio, trifluoromethylthio, cyano, (C 1 -C 4) alkanoyl, phenyl, a group S (O) n Alk Or OS (O) n AIk;
  • a benzyl which is unsubstituted or substituted one or more times with identical or different substituents chosen from a halogen atom, a (C 1 -C 4) alkyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, (C 1 -C 4) alkoxy, cyano or phenyl group, a group S (O) n AIk or OS (O) n AIk; R ⁇ represents a hydrogen atom or a (C 1 -C 4) alkyl group;
  • R4 and R5 together with the nitrogen atom to which they are attached constitute a heterocyclic radical of 4 to 8 atoms, containing or not a second heteroatom selected from an oxygen atom, sulfur or nitrogen, unsubstituted or substituted one or more times with identical or different substituents selected from (C1-C4) alkyl, (C1-C4) alkanoyl, NR ⁇ Rg or CONR ⁇ Rg, phenyl; said phenyl group being unsubstituted or substituted one or more times by identical or different substituents selected from a halogen atom, a (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or trifluoromethyl group;
  • R7 and Rg each independently represent a hydrogen atom, a (C1-C4) alkyl group or R7 and Rg together with the nitrogen atom to which they are attached, constitute a chosen heterocyclic radical; from piperidinyl, pyrrolidinyl, piperazinyl, N-methylpiperazinyl, azepinyl or morpholinyl;
  • n 0, 1 or 2;
  • Alk represents a linear or branched (C 1 -C 7) alkyl group.
  • substituent definitions for Z 1 and ⁇ 2 are as follows:
  • R3 represents a hydrogen atom or a methyl, preferably a hydrogen atom
  • R4 represents: . a (C5-Cio) a lkyl e;
  • phenyl substituted one or more times with a halogen atom or groups independently selected from trifluoromethyl, trifluoromethoxy, trifluoromethylthio, (C 1 -C 4) alkoxy, (C 1 -C 4) alkylthio, SO 2 Alk or OSO 2 Alk; and Alk represents a linear or branched (C 1 -C 7) alkyl group.
  • R 4 is 2-propylpentyl, 1-propylbutyl, 5-methylnonyl, 4-methylheptyl, 4-methyl-2,6-dimethylheptyl, cyclopentyl, tetramethylcyclopentyl, cyclohexyl, tetrahydrofuranyl pyrrolidinyl, 1,1,4,4-tetramethylcyclopentyl, 2,2,5,5-tetramethylfuranyl, 2,2,5,5-tetramethylpyrrolidinyl, phenyl unsubstituted or substituted by halogen, trifluoromethyl, a trifluoromethoxy, a trifluoromethylthio or a group SO2Alk or OSO2Alk.
  • Alk represents a linear or branched (Cj-C7) alkyl group.
  • R3 represents a hydrogen atom or a methyl
  • R4 represents:
  • Alk represents a linear or branched (Ci-C7) alkyl group
  • Rg represents a hydrogen atom or a methyl.
  • R4 is cyclohexyl, phenyl unsubstituted or substituted by halogen, methoxy, trifluoromethyl, trifluoromethoxy or trifluoromethylthio.
  • groups Aq and Ar 2 the latter preferably represent each independently of each other a phenyl which is unsubstituted or substituted one or more times with substituents each independently chosen from a chlorine, bromine or methoxy atom. or methylthio.
  • Aq represents a phenyl substituted by a chlorine or bromine atom
  • Ar2 represents a phenyl substituted by at least 2 halogen atoms; the two identical or different halogen atoms being chosen from chlorine or bromine.
  • the compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.
  • the compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention. These salts can be prepared with pharmaceutically acceptable acids; the salts of other acids which are useful, for example, for the purification or the isolation of the compounds of formula (I) are also part of the invention.
  • halogen atom a fluorine, a chlorine, a bromine or an iodine; Q - (C 1 -C 4 ) alkyl or (C 2 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, (C 2 -
  • a (C1-C4) alkanoyl group an alkyl-carbonyl radical in which the alkyl group is as defined previously.
  • Non-aromatic C 3 -C 12 carbocyclic radicals include mono or polycyclic condensed or bridged radicals.
  • Monocyclic radicals include, for example, cycloalkyls, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; cyclohexyl and cyclopentyl being preferred.
  • the di- or tricyclic radicals condensed, bridged or spiranics include, for example, norbornyl, bomyl, isobornyl, noradamantyl, adamantyl, spiro [5.5] undecanyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl; bicyclo [3.1.1] heptyl.
  • the 3- to 8-membered nitrogen-containing heterocyclic radicals consisting of two substituents together with the nitrogen atom to which they are attached include saturated radicals such as azeridinyl, azetidinyl, pyrrolidinyl, piperidyl, perhydroazepinyl, perhydroazocinyl; the saturated or unsaturated radicals additionally containing a second heteroatom selected from an oxygen, sulfur or nitrogen atom, such as imidazolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, imidazolyl, pyrazolyl isothiazolyl, isoxazolyl, triazolyl, tetrazolyl, oxazolyl; thiazolyl.
  • 8-membered rings further comprising one or more heteroatoms include imidazolyl, pyrrolyl, pyrazolyl isothiazolyl, isoxazolyl.
  • Heterocyclic radicals of 3 to 8 saturated or unsaturated oxygen, sulfur or nitrogen atoms include, in particular, furyl, tetrahydrofuryl, thienyl and pyrrolyl.
  • a compound of general formula (II) is treated in which Z, Aq and Arc are as defined for (I): or with an acid (HI) of general formula R.2 'CC "2H in which R-2' is defined in (I) or by an activated derivative of said acid to obtain a compound of general formula (IAi):
  • a compound (EEl) as defined above can be considered as an intermediate for accessing other compounds (I) according to the invention.
  • (IE1) is treated with an amine (VU) of general formula R3'R5'NH in which R3 'and R5' are as defined in (I) when a compound of general formula (ICI) is to be prepared:
  • step a1 an alcohol of general formula (HIV) is treated with a sulfonyl halide (IX) of general formula Alk-S ⁇ 2-Hal in which Alk represents an alkyl radical, preferably methyl, and Hal, a halogen, chlorine, for example methane sulphonyl chloride in the presence of a base, preferably triethylamine, to give a compound of general formula (X).
  • a sulfonyl halide (IX) of general formula Alk-S ⁇ 2-Hal in which Alk represents an alkyl radical, preferably methyl, and Hal, a halogen, chlorine, for example methane sulphonyl chloride in the presence of a base, preferably triethylamine, to give a compound of general formula (X).
  • This compound (X) comprising a leaving group is treated with a primary amine (XI) of general formula Y- (Alk ') m -NH 2 in which Y, Alk' and m correspond to the definitions given for formulas (IFi), ( (i) or OM1X in the presence of a base such as, for example, potassium carbonate.
  • a primary amine XI
  • Y- (Alk ') m -NH 2 in which Y, Alk' and m correspond to the definitions given for formulas (IFi), ( (i) or OM1X in the presence of a base such as, for example, potassium carbonate.
  • the compound of general formula (X) also gives access to a compound of general formula (IF2) when treated with an alcohol (XII) of general formula R7> Rg'N- (Alk ') wherein R7 'and Rg', Alk 'and m are as defined in (I), in the presence of a base such as potassium tert-butoxide in an aprotic solvent such as dioxane at elevated temperature:
  • step a 2 the compound of general formula (XIIT) carrying a hydroxyl group is engaged in a Mitsunobu reaction in the presence of phthalimide, DEAD and triphenylphosphine to give a compound of general formula (XIV) which, treated with During step b 2, the hydrazine hydrate in refluxing methanol leads to an amine of general formula (XV).
  • This amine of formula (XV) is a key intermediate, and allows access during step C2 to different variations of Z according to the methods described in patent application WO2006 / 042955 A1.
  • the compounds of general formula (XVI) thus obtained are treated during step d2 by a dealkylating agent such as, for example, boron tribromide or hydrobromic acid to give the compound of general formula (VIII).
  • a dealkylating agent such as, for example, boron tribromide or hydrobromic acid
  • step a the compound of general formula (HIV) is engaged in a Mitsunobu reaction in the presence of phthalimide, DEAD and PPI13 to yield an intermediate (XVII) which after treatment with hydrazine hydrate during a step b ⁇ leads to the compound of general formula (II).
  • the compounds of formula (II) can be obtained from a compound of general formula (VIII) according to the following reaction scheme.
  • a leaving group is introduced on the alcohol function, for example an alkyl sulphonate such as methanesulphonate.
  • the compounds of general formula (XVIII) thus obtained may be involved in a substitution reaction in the presence of sodium azide to give azides of general formula (XIX). These can be reduced in the presence, for example, triphenyl phospbine to lead to amines of general formula (II).
  • the alkylating agent (XXI) employed can carry an amino-functional protecting group other than the phthalimido group, for example the BOC group.
  • step bq. of Reaction Scheme 4 when a compound (XXII) is treated with hydrazine hydrate at reflux of methanol there is obtained a compound of general formula (IF3) for which the Ry and Rg 'groups are both hydrogen atoms. hydrogen: SCHEMA 4
  • Such an IF3 compound in addition to being a compound (I) according to the invention, is also an intermediate allowing access for example to various compounds of general formula (IH 3 ):
  • step ag the pyridone (XXIH) is O-alkylated by means of methyl iodide in the presence of a base such as silver carbonate to give the pyridine of general formula (XXIV).
  • the reaction also provides the N-methyl pyridone of general formula (XXIVbis) which is separated from the desired compound of general formula (XXIV) by chromatographic methods or by recrystallization.
  • step b ⁇ the nitrile function present on the compound of general formula (XXIV) is reduced in primary amine function to yield a compound of general formula
  • step dg the compounds of general formula (XXVI) obtained in the preceding step are treated with a dealkylating agent to yield compounds of general formula (XX).
  • dealkylating agents for example, hydrobromic acid or boron tribomide.
  • Y is -NR ⁇ 'Rg'-
  • Q is NH
  • AIk ' is a linear or branched (C 1 -C 5) alkyl group
  • k is zero
  • m is equal to 1.
  • step a ⁇ when the chlorinated derivative of general formula (XXVII) is treated with an excess of primary amine Y- (Alk ') m -NH 2 of general formula (XI) for which Alk', Y and m correspond to for the definitions for (IF), at high temperature in a suitable solvent such as toluene, the compound of general formula (XXVffl) is obtained.
  • step bj the nitrile function carried by the compound of general formula (XXVIII) is reduced in primary amine function by catalytic hydrogenation in the presence of Raney nickel and ammonia to yield compounds of general formula (XXIX).
  • the latter is the direct precursor of the compounds of general formula (IF4) whose different variations of Z are obtained during step C7 according to the processes described in patent application WO2006 / 042955 A1.
  • Y is -NR ⁇ 'Rs '
  • Q is S
  • AIk' is a linear or branched (Cj-C5) alkyl group
  • k is zero
  • m is 1. 5 SCHEME 8
  • step ag the compound of general formula (XXVII) is reacted with a thiol (XXXI) of general formula Y- (Alk ') m-SH for which AIk', Y and m correspond to the definitions given for (IF), in the presence of a suitable base such as potassium or cesium carbonate in a solvent such as toluene at elevated temperature to give the compounds of the general formula (XXXII).
  • a suitable base such as potassium or cesium carbonate
  • solvent such as toluene
  • Step bg is carried out under conditions similar to those of step b ⁇ of Scheme 7.
  • the intermediate compounds of formulas (XX) and (XXV) are new and are used for the preparation of the compounds of formula (I).
  • Z preferably corresponds to -NH-SO 2 -R 4 , -NH-COR 4 , -NH-CO-NHR 4 or -NH-CS-NHR 4 .
  • the subject of the present invention is also the compounds of formula (XXV): wherein Ar i and A12 are as defined for compounds of formula (I).
  • Aq and Ar2 each represent, independently of one another, a phenyl that is unsubstituted or substituted one or more times with substituents each independently selected from a chlorine atom. , bromine, methoxy or methylthio. More preferably, Aq represents a phenyl substituted with a chlorine or bromine atom, and A represents a phenyl substituted by at least 2 halogen atoms; the two identical or different halogen atoms being chosen from chlorine or bromine.
  • Raney Ni Nickel Raney ® pyBOP: benzotriazol-l-yloxytris (pyrrolidino) phosphonium
  • Buffer solution pH 2: solution of 16.66 g of KHSO4 and 32.32 g of K2SO4 in 1 liter of water
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • Nuclear magnetic resonance spectra are recorded at 250 MHz in DMSO-d6.
  • abbreviations are used: s: singlet, d: doublet, t: triplet, q: quadruplet, which: quintuplet, m: massive, si: singlet wide, dd: doublet of doublet.
  • the compounds according to the invention are analyzed by coupling HPLC-UV-MS
  • Agilent and a mass spectrometer that is either: - a ZQ Waters single quadrupole mass spectrometer,
  • the device used consists of a UPLC Waters Acquity chain equipped with a Waters diode bar detector and a SQD Waters mass spectrometer.
  • the eluent is composed as follows:
  • solvent B 0.005% of TFA in acetonitrile.
  • the UV detection is carried out at 220 nm and the chemical ionisation mass detection, called electrospray (ESI) positive, at atmospheric pressure on a ZQ Waters single quadrupole mass spectrometer.
  • ESI electrospray
  • the eluent is composed as follows:
  • solvent B 0.005% of TFA in acetonitrile.
  • Gradient The percentage of solvent B varies from 0 to 90% in 20 minutes with a plateau at 90% of B for 10 minutes.
  • the UV detection is carried out at 220 nm and the chemical ionisation mass detection, called electrospray (ESI) positive, at atmospheric pressure on a ZQ Waters single quadrupole mass spectrometer.
  • ESI electrospray
  • UV detection is carried out at 220 nm and chemical ionization mass detection, known as electrospray (ESI), at atmospheric pressure on a Quattro-Micro Waters triple quadrupole mass spectrometer.
  • ESI electrospray
  • An Acquity BEH C18 column of 2.1 x 50 mm is used; 1.7 ⁇ m, at a temperature of 40 ° C., flow rate 1 ml / minute.
  • the eluent is composed as follows: o -solvent A: 0.005% TFA in water at about pH 3.1 / acetonitrile (97/3)
  • Solvent B 0.035% TFA in acetonitrile.
  • the recording of the mass spectra is carried out in electrospray (ESI) 0 positive mode, in order to observe the ions resulting from the protonation of analyzed compounds (MH + ), or the formation of adducts with other cations such as Na + , K + , etc.
  • ESI electrospray
  • the reaction medium is diluted with 250 ml of ether.
  • the crude product thus obtained is purified on silica eluting with a DCM / methanol mixture of 0 to 1% in 1 hour.
  • the crude residue is treated in the following manner; the residue is redissolved in 200 ml of a v / v 50/50 dioxane / water mixture and the solution is supplemented with 3.5 g of potassium carbonate.
  • the reaction medium is refluxed for 5 hours, filtered and concentrated under reduced pressure.
  • the reaction medium is diluted with 100 ml of ether.
  • the crude product thus obtained is purified on silica eluting with a DCM / methanol mixture of 0 to 1% in 1 hour.
  • fractions containing the purified product are combined and brought to dryness to give 2.2 g of the expected product.
  • the aqueous phase is basified with 100 ml of 10% aqueous sodium hydroxide solution and then extracted with 100 ml of DCM.
  • the organic phase is dried on o
  • fractions containing the purified product are combined and brought to dryness to give 0.25 g of the expected product in base form.
  • the purified product is salified in hydrochloride form according to the standard method (dissolution of the base in a dichloromethane solvent, addition of 2M hydrochloric ether, evaporation to dryness, recovery of the evaporation residue with a dichloromethane solvent, solution poured onto ethyl ether, filtration of the precipitated product, drying). 0.22 g of the expected hydrochloride are obtained.
  • Example 2 (Compound 1 of Table I). N - ⁇ [6- (4-bromophenyl) -2 - [(butyrylamino) ethyl] -5- (2,4-dichlorophenyl) pyridin-3-yl] methyl ⁇ -4 - [(trifluoromethyl) thio] benzamide
  • the residue is redissolved in 150 ml of a v / v 50/50 dioxane / water mixture and the solution is supplemented with 2.0 g of potassium carbonate.
  • the reaction medium is refluxed for 5 hours, filtered and concentrated under reduced pressure.
  • the reaction medium is stirred for 1 hour at room temperature, diluted with 50 ml of DCM and then washed with 50 ml of distilled water followed by 50 ml of 10% HCl, 50 ml of a 10% aqueous solution of NaHCO 3, then again 50 ml of distilled water.
  • the organic phase is dried over Na 2 SC 4, filtered and concentrated under reduced pressure to give the crude product.
  • the latter is purified by chromatography on silica eluting with a DCM / MeOH gradient of 0 to 2% MeOH in Ih 30 min.
  • the fractions containing the purified product are combined and brought to dryness to give the expected product in base form.
  • the purified product is salified in the form of hydrochloride according to the standard method.
  • the organic phase is dried over Na 2 SO 4, filtered and then concentrated under reduced pressure to give the crude product.
  • the latter is redissolved in 20 ml of a 50/50 (v / v) dioxane / water mixture to which 0.200 g of potassium carbonate is added. This suspension is refluxed with stirring for 5 hours. This last operation makes it possible to transform into expected alcohol the traces of brominated product which may form during the demethylation reaction with BBrc. After returning to ambient temperature, the medium is filtered and the filtrate is then brought to dryness and taken up in 150 ml of DCM.
  • the latter is purified by chromatography on silica eluting with a DCM / MeOH gradient of 0 to 3% MeOH.
  • the fractions containing the purified product are combined and brought to dryness to give the expected product in free base form.
  • This is salified in the form of hydrochloride according to the standard method.
  • Example 7 (Compound 17 of Table I) N - ⁇ [6- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3 - ( ⁇ [(2-fluorobenzyl) carbamoyl] ammo ⁇ methyl) pyridin-2 yl] methyl ⁇ -2-hydroxyacetamide
  • step A) of example 6 0.5 g of the compound obtained in the previous step is treated according to the procedure employed in step A) of example 6 using 0.105 g of methanesulphonyl chloride, 0.15 ml of triethylamine in solution in 30 ml. ml of DCM. After treatment and evaporation, 0.57 g of expected product is obtained.
  • 0.15 g of the amine obtained in the preceding step is acylated using methoxyacetyl chloride according to the procedure employed in step E) of Example 2. To this end, 0.033 g of dichloride are used. acid and 88 ⁇ l of triethylamine dissolved in 20 ml of DCM. After treatment and evaporation of the solvents, 0.1 g of expected product is recovered.
  • 0.1 g of the compound obtained in the preceding step is treated according to the procedure employed in Example 5 using 0.18 ml of boron tribromide. After treatment, the product is purified by chromatography on silica eluting with a DCM / MeOH gradient of 0 to 6% MeOH. The fractions containing the purified product are combined and concentrated to dryness. The free base is salified in hydrochloride form according to the standard method to give 0.025 g of the expected product.
  • ⁇ [(methoxyacetyl) amino] methyl ⁇ pyridin-3-yl] methyl ⁇ -4- (trifluoromethyl) benzamide is prepared from 0.40 g of N - ⁇ [2- (aminomethyl) -6- (4-chlorophenyl) ) -5- (2,4-dichlorophenyl) pyridin-3-yl] methyl ⁇ -4- (trifluoromethyl) benzamide and 0.084 g of methoxyacetyl chloride using a procedure similar to that of step
  • 0.35 g of the compound obtained in the preceding step is placed in solution in 50 ml of DCM. Under a nitrogen atmosphere and at -30 ° C., 0.6 ml of boron tribromide are slowly added and the reaction medium is then stirred for 12 hours at room temperature. 100 ml of distilled water and 100 ml of DCM are added. The organic phase is dried over Na 2 SC 4, filtered and concentrated under reduced pressure to give the expected product.
  • the evaporation residue is taken up in 150 ml of DCM and 150 ml of distilled water.
  • the organic phase is dried over dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give the product in crude form.
  • the latter is purified by chromatography on silica eluting with a DCM / MeOH gradient of 0 to 4% MeOH.
  • Example 10 (Compound 20 of Table ET) ⁇ L ⁇ [6- (4-bromophenyl) -5- (2,4-dichlorophenyl) -2 - ⁇ [2- (dimétliylamino) ethoxy] methyl ⁇ pyridiii-3-yl] inéthyl ⁇ -4 - [(trifluoromethyl) thio] benzamide 0.10 g of N 5 N dimethyl ethanolamine and 0.11 g of potassium tert-butoxide are placed in 19 ml of dioxane and the mixture is stirred for 20 minutes at room temperature.
  • fractions containing the purified product are combined and brought to dryness to give the expected product in base form.
  • the purified product is salified in the form of hydrochloride according to the standard method. 0.170 g of the expected hydrochloride is obtained.
  • Example 1 0.300 g of the compound obtained in step D) of Example 1 are dissolved in 10 ml of DCM and 0.046 g of n-propylisocyanate is added thereto. The reaction medium is stirred at room temperature for 2 hours and then added with 100 ml of distilled water and 100 ml of DCM. The organic phase is washed with 100 ml of distilled water, dried over Na.sub.2SO.sub.4, filtered and then concentrated under reduced pressure to give 0.400 g of crude product. The latter is purified by chromatography on silica eluting with a DCM / MeOH gradient of 0 to 2% MeOH in Ih 30 min. The fractions containing the purified product are combined and brought to dryness to give
  • 6- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -2-methoxynicotinonitrile 12.6 g of 6- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -2-oxo-1,2-dihydropyridine-3-carbonitrile obtained are obtained according to a procedure similar to that of the WO application. / 2003 082191 A1 (step B of example 1) in solution in 48 ml of chloroform. 37.5 g of silver carbonate and then 21 ml of methyl iodide are added and the mixture is refluxed and protected from light for 12 hours. After returning to ambient temperature, the reaction medium is filtered. The filtrate is washed with water, dried over Na 2 SO 4, filtered and brought to dryness to give the crude product.
  • the expected product is separated from 6- (4-chloro-phenyl) -5- (2,4-dichloro-phenyl) -1-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile by chromatography on silica eluting with DCM // MeOH 0 to 1% in 1 hour. The fractions of purified product are combined and concentrated to dryness. 4.33 g of expected product are obtained.
  • the reaction medium is diluted with 100 ml of DCM and then washed with 100 ml of distilled water.
  • the organic phase is dried over Na 2 SC 4, filtered and concentrated under reduced pressure to give 0.411 g of crude product.
  • the latter is purified by flash chromatography on reverse phase cartridge Cl 8 eluting with a methanol / water mixture of 75/25 to 85/15 in 1 hour. The fractions containing the purified product are combined and concentrated under reduced pressure to give 0.275 g of the purified expected product.
  • Example 14 (Compound No. 27 of Table HT) N - ⁇ [6- (4-chlorophenyl) -2- ⁇ 2 - [(cyclopropylcarbonyl) amino] ethoxy ⁇ -5- (2,4-dichlorophenyl) pyridin-3 yl] methyl ⁇ -4- (trifluoromethyl) benzamide
  • Example 12 0.300 g of the compound obtained in F) of Example 12 are placed in solution in 13 ml of DCM. 0.053 g of cyclopropane carboxylic acid, 0.25 ml of triethylamine and 0.318 g of PyBOP are successively added to this solution. The reaction medium is stirred at ambient temperature for 3 hours and then 100 ml of distilled water and 100 ml of DCM are added. The organic phase is washed with 100 ml of distilled water, dried over Na 2 SO 4, filtered and then concentrated under reduced pressure to give 0.500 g of crude product.
  • the latter is purified by flash chromatography on a reverse phase cartridge Cl 8 eluting with a solvent gradient methanol / water of 60/40 to 80/20 in 1 hour then a plateau at 80/20 for an additional hour.
  • the fractions containing the purified product are combined and concentrated under reduced pressure to give 0.231 g of the purified expected product.
  • nC ⁇ H ⁇ and iC ⁇ H ⁇ respectively represent a propyl and isopropyl group.
  • the compounds of formula (I) have a very good in vitro affinity (IC50 ⁇ 5.10 " M) for cannabinoid CB 1 receptors, under the experimental conditions described by M. Rinaldi-Carmona et al (FEBS Letters, 1994, 350
  • the antagonistic nature of the compounds of formula (I) has been demonstrated by the results obtained in the models of adenylate cyclase inhibition as described in M. Bouaboula et al., J. Biol. Chem., 1995, 270, 13973-13980, M. Rinaldi-Carmona et al., J. Pharmacol Exp, Ther., 1996, 278, 871-878 and M. Bouaboula et al., J. Biol Chem.
  • the compounds of formula (I) are compatible with their use as a medicament.
  • the invention relates to medicaments for human or veterinary medicine which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid.
  • the compounds according to the invention can be used in humans or animals (in particular in mammals including, but not limited to, dogs, cats, horses, cattle, sheep) in the treatment or prevention of diseases involving CB cannabinoid receptors
  • the compounds of formula (I) are useful as psychotropic drugs, especially for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders , obsessive-compulsive disorder, psychosis in general, schizophrenia, attention deficit hyperactivity disorder (ADHD) in hyperkinetic children, and the treatment of disorders related to the use of psychotropic substances, including in the case of substance abuse and / or substance dependence, including alcohol dependence and nicotine addiction.
  • psychiatric disorders including anxiety, depression, mood disorders, insomnia, delusional disorders , obsessive-compulsive disorder, psychosis in general, schizophrenia, attention deficit hyperactivity disorder (ADHD) in hyperkinetic children
  • ADHD attention deficit hyperactivity disorder
  • disorders related to the use of psychotropic substances including in the case of substance abuse and / or substance dependence, including alcohol dependence and nicotine addiction.
  • the compounds of formula (I) according to the invention can be used as medicaments for the treatment of migraine, stress, psychosomatic diseases, panic attacks, epilepsy, movement disorders , especially dyskinesias or Parkinson's disease, tremors and dystonia.
  • the compounds of formula (I) according to the invention can also be used as medicaments in the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementias, of Alzheimer's disease, as well as in the treatment of disturbances of attention or alertness.
  • the compounds of formula (I) may be useful as neuroprotective agents, in the treatment of ischemia, head trauma and the treatment of acute or chronic neurodegenerative diseases: including chorea, Huntington's chorea, Tourrette's syndrome. .
  • the compounds of formula (I) according to the invention can be used as medicaments in the treatment of pain: neuropathic pain, peripheral acute pain, chronic pain of inflammatory origin, pain induced by anticancer treatment.
  • the compounds of formula (I) according to the invention can be used as medicaments in human or veterinary medicine in the prevention and treatment of appetite disorders, palatability (for sugars, carbohydrates, drugs, alcohols or any appetizing substance) and / or eating behaviors, especially for the treatment of obesity or bulimia as well as for the treatment of type II diabetes or non-insulin-dependent diabetes and for the treatment of dyslipidemia, metabolic syndrome.
  • the compounds of formula (I) according to the invention are useful in the treatment of obesity and the risks associated with obesity, in particular cardiovascular risks.
  • the compounds of formula (I) according to the invention can be used as medicaments in the treatment and prevention of gastrointestinal disorders, diarrheal disorders, ulcers, vomiting, bladder and urinary disorders, liver diseases of alcoholic or non-alcoholic origin such as chronic cirrhosis, fibrosis, hepatic steatosis, steatohepatitis; as well as endocrine disorders, cardiovascular disorders, hypotension, atherosclerosis, hemorrhagic shock, septic shock, asthma, chronic bronchitis, chronic obstructive pulmonary disease, Raynaud's syndrome, glaucoma, fertility disorders, premature delivery, termination of pregnancy, inflammatory phenomena, diseases of the immune system, particularly autoimmune and neuroinflammatory such as rheumatoid arthritis, reactive arthritis, diseases leading to demyelination, multiple sclerosis, infectious and viral diseases such as encephalitis, stroke and as drugs for cancer chemotherapy, for the treatment of Guillain-Barré syndrome and for the treatment of bone diseases and osteoporosis
  • the compounds of formula (I) are particularly useful for the preparation of medicaments useful for the prevention and treatment of psychiatric disorders, in particular schizophrenia, attention and alertness disorders, disorders attention deficit hyperactivity disorder (ADHD) in hyperkinetic children; for the prevention and treatment of memory deficits and cognitive disorders; substance dependence and withdrawal, particularly alcohol dependence, nicotine addiction, alcohol withdrawal and smoking cessation; acute or chronic neurodegenerative diseases.
  • psychiatric disorders in particular schizophrenia, attention and alertness disorders, disorders attention deficit hyperactivity disorder (ADHD) in hyperkinetic children
  • ADHD attention deficit hyperactivity disorder
  • substance dependence and withdrawal particularly alcohol dependence, nicotine addiction, alcohol withdrawal and smoking cessation
  • acute or chronic neurodegenerative diseases acute or chronic neurodegenerative diseases.
  • the compounds of formula (I) according to the present invention are useful in the preparation of medicaments useful in the treatment and the prevention of appetite disorders, appetite disorders, metabolic disorders, obesity, type H diabetes, metabolic syndrome, dyslipidemia, gastrointestinal disorders, inflammatory phenomena, diseases of the immune system, psychotic disorders, alcohol addiction, nicotine addiction.
  • the present invention relates to the use of a compound of formula (I), of its pharmaceutically acceptable salts for the treatment of the disorders and diseases indicated above.
  • the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
  • compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt of said compound, as well as at least one pharmaceutically acceptable excipient.
  • Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known to those skilled in the art.
  • compositions according to the present invention may contain, besides a compound of formula (I), one (or more) other active ingredient useful in the treatment of the disorders and diseases indicated above.
  • the subject of the present invention is also pharmaceutical compositions containing a compound of formula (I) according to the present invention combined with one (or more) active principle chosen from one of the following therapeutic classes:
  • an antihyperlipidemic agent or an antihypercholesterolemic agent an antihyperlipidemic agent or an antihypercholesterolemic agent
  • a nicotinic agonist another anti-obesity agent or acting on metabolic disorders; a nicotinic agonist, a partial nicotinic agonist;
  • an antidepressant an antispychotic, an anxiolytic
  • an anticancer agent or an antiproliferative agent an anticancer agent or an antiproliferative agent
  • a useful agent for treating osteoporosis a useful agent for treating osteoporosis; a nonsteroidal or steroidal anti-inflammatory drug;
  • the compound of formula (I), one of its pharmaceutically acceptable salts or one of their solvates and the other associated active ingredient may be administered simultaneously, separately or spread over time.
  • Extended use means the sequential administration of the first compound of the composition of the invention, included in a pharmaceutical form, then the second compound of the composition according to the invention, included in a separate pharmaceutical form. .
  • the lapse of time elapsing between the administration of the first compound of the composition according to the invention and the administration of the second compound of the same composition according to the invention generally does not exceed 24 hours.
  • the active ingredient of formula (I) above, or its possible salt may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.
  • Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration. by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
  • the compounds according to the invention can be used in creams, gels, ointments or lotions.
  • a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg Mannitol 223.75 mg
  • the dose of active ingredient administered per day can reach 0.01 to 100 mg / kg, in one or more doses, preferably 0.02 to 50 mg / kg.
  • the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
  • the present invention also relates to a method for treating the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP08869799A 2007-10-12 2008-10-10 In der 2er- und 3er-position substituierte 5,6-diarylpyridine, ihre herstellung und ihre therapeutische verwendung Withdrawn EP2209768A1 (de)

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FR0707186A FR2922209B1 (fr) 2007-10-12 2007-10-12 5,6-DIARYLES PYRIDINES SUBSTITUES EN POSITION 2 et 3, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE.
PCT/FR2008/001421 WO2009087285A1 (fr) 2007-10-12 2008-10-10 5,6-diaryles pyridines substitues en position 2 et 3, leur preparation et leur application en therapeutique

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GB201103419D0 (de) 2011-02-28 2011-04-13 Univ Aberdeen
EP2780013A4 (de) * 2011-11-18 2015-07-01 Constellation Pharmaceuticals Inc Modulatoren methylmodifizierender enzyme, zusammensetzungen und verwendungen davon
EP2780014A4 (de) 2011-11-18 2015-07-01 Constellation Pharmaceuticals Inc Modulatoren methylmodifizierender enzyme, zusammensetzungen und verwendungen davon
NZ628762A (en) 2012-02-10 2016-07-29 Constellation Pharmaceuticals Inc Modulators of methyl modifying enzymes, compositions and uses thereof
WO2014151142A1 (en) 2013-03-15 2014-09-25 Constellation Pharmaceuticals, Inc. Modulators of methyl modifying enzymes, compositions and uses thereof
EP3033334A1 (de) 2013-08-15 2016-06-22 Constellation Pharmaceuticals, Inc. Indolderivate als modulatoren methylmodifizierender enzyme, zusammensetzungen daraus und verwendungen davon
US10577350B2 (en) 2015-08-28 2020-03-03 Constellation Pharmaceuticals, Inc. Crystalline forms of (R)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide
US10457640B2 (en) 2016-10-19 2019-10-29 Constellation Pharmaceuticals, Inc. Synthesis of inhibitors of EZH2
EP3575286B1 (de) * 2017-01-26 2022-05-11 Mitsui Chemicals Agro, Inc. Pyridonverbindung und bakterizid für landwirtschaft und gartenbau mit dieser verbindung als wirkstoff

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US5686470A (en) * 1995-02-10 1997-11-11 Weier; Richard M. 2, 3-substituted pyridines for the treatment of inflammation
WO2002055502A1 (en) 2001-01-02 2002-07-18 Fujisawa Pharmaceutical Co., Ltd. Pyridine derivatives useful as cyclooxygenase inhibitor
WO2003082191A2 (en) * 2002-03-28 2003-10-09 Merck & Co., Inc. Substituted 2,3-diphenyl pyridines
GB0314057D0 (en) 2003-06-18 2003-07-23 Astrazeneca Ab Therapeutic agents
FR2876691B1 (fr) * 2004-10-18 2006-12-29 Sanofi Aventis Sa Derives de pyridine, leur preparation, leur application en therapeutique
CA2606288A1 (en) 2005-04-18 2006-10-26 Neurogen Corporation Subtituted heteroaryl cb1 antagonists

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US20100256202A1 (en) 2010-10-07
WO2009087285A1 (fr) 2009-07-16
WO2009087285A4 (fr) 2009-09-24
AU2008346293A1 (en) 2009-07-16
IL205016A0 (en) 2010-11-30
PA8798201A1 (es) 2009-05-15
US8362045B2 (en) 2013-01-29
JP5465179B2 (ja) 2014-04-09
FR2922209A1 (fr) 2009-04-17
PE20091034A1 (es) 2009-08-19
JP2011500543A (ja) 2011-01-06
MA31839B1 (fr) 2010-11-01
UY31387A1 (es) 2009-05-29
CA2702012A1 (fr) 2009-07-16
CN101855208A (zh) 2010-10-06
TW200922567A (en) 2009-06-01
MX2010003983A (es) 2010-05-27
FR2922209B1 (fr) 2010-06-11
CL2008003027A1 (es) 2009-10-16
EA201070460A1 (ru) 2010-10-29
BRPI0818061A2 (pt) 2015-03-31
KR20100065377A (ko) 2010-06-16

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