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    NOVEL SMALL MOLECULE POTENTIATORS OF METABOTROPIC GLUTAMATE RECEPTORS I
    2.
    发明申请
    NOVEL SMALL MOLECULE POTENTIATORS OF METABOTROPIC GLUTAMATE RECEPTORS I 有权

    公开(公告)号：US20110245232A1

    公开(公告)日：2011-10-06

    申请号：US13071753

    申请日：2011-03-25

    申请人： Wilfried Braje ,  Katja Jantos ,  Hervé Geneste ,  Mario Mezler ,  Margaretha Henrica Maria Bakker ,  Jayne Froggett

    发明人： Wilfried Braje ,  Katja Jantos ,  Hervé Geneste ,  Mario Mezler ,  Margaretha Henrica Maria Bakker ,  Jayne Froggett

    IPC分类号： A61K31/553 ,  C07D401/12 ,  A61K31/4439 ,  C07D413/14 ,  A61K31/5377 ,  C07D401/14 ,  A61K31/496 ,  A61P25/00 ,  A61P25/18 ,  A61P25/24 ,  A61P25/08 ,  A61P25/06

    CPC分类号： C07D401/12 ,  C07D401/14 ,  C07D403/12 ,  C07D403/14 ,  C07D405/14 ,  C07D413/14

    摘要： The present invention relates to small molecule potentiators of metabotropic receptors, in particular of the mGlu2 receptor. The present invention also relates to the use of these compounds for the prevention or treatment of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The present invention thus provides compounds of formula I wherein X2 is N or C—R2, X3 is N or C—R3, X4 is N or C—R4 provided that none or one of X2, X3 or X4 is N; Y1 is N, C or C—R5, Y2 is N, C or C—R6, Y3 is N, C or C—R7, Y4 is N, C or C—R8 provided that only the moiety Y1, Y2, Y3 or Y4 to which Z is bound is C and further provided at most one of Y1, Y2, Y3 or Y4 is N; Z is O, S, S(O), S(O)2 or NRZ; Q is CH2 or CH2CH2, where one or two of the hydrogen atoms in CH2 or CH2CH2 may be replaced by halogen, C1-C4-alkyl or C1-C4-haloalkyl; R1 is inter alia hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C4-haloalkoxy, C3-C8-cycloalkyl, a radical NR1aR1b, C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, aryl, aryl-CH2, aryloxy, hetaryl, hetaryloxy or hetaryl-CH2, wherein the heterocyclyl, aryl and hetaryl rings ring in the last six radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R1c; R2, R3 and R4 are, inter alia, selected from hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, phenyl, C1-C4-haloalkoxy, a radical (CH2)nNR′R″; R5, R6, R7, R8 are, independently of each other, selected from hydrogen, halogen, etc.; Ra is C3-C6-cycloalkyl, C1-C6-haloalkyl or C1-C6-alkyl, which is unsubstituted or carries one radical selected from C1-C4-alkoxy, C1-C4-haloalkoxy and a radical NRa1Ra2, Rb is hydrogen, halogen or C1-C4-alkyl; and the N-oxides and the pharmaceutically acceptable salts thereof.

    NOVEL SMALL MOLECULE POTENTIATORS OF METABOTROPIC GLUTAMATE RECEPTORS
    3.
    发明申请
    NOVEL SMALL MOLECULE POTENTIATORS OF METABOTROPIC GLUTAMATE RECEPTORS 有权

    公开(公告)号：US20110245247A1

    公开(公告)日：2011-10-06

    申请号：US13073087

    申请日：2011-03-28

    申请人： Wilfried Braje ,  Katja Jantos ,  Hervé Geneste ,  Mario Mezler ,  Margaretha Henrica Maria Bakker

    发明人： Wilfried Braje ,  Katja Jantos ,  Hervé Geneste ,  Mario Mezler ,  Margaretha Henrica Maria Bakker

    IPC分类号： A61K31/5377 ,  C07D401/12 ,  C07D401/14 ,  C07D413/14 ,  C07D403/12 ,  A61K31/4439 ,  A61K31/496 ,  A61K31/4725 ,  A61K31/497 ,  A61K31/4709 ,  A61K31/498 ,  A61P25/00 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  A61P25/08 ,  A61P25/06

    CPC分类号： C07D401/12 ,  C07D401/14 ,  C07D403/12 ,  C07D413/12 ,  C07D413/14

    摘要： The present invention relates to small molecule potentiators of metabotropic receptors, in particular of the mGlu2 receptor. The present invention also relates to the use of these compounds for the prevention or treatment of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The present invention thus provides compounds of formula I wherein X1 is N or C—R1, X2 is N or C—R2, X3 is N or C—R3, X4 is N or C—R4 provided that none or one of X1, X2, X3 or X4 is N; Y1 is N, C or C—R5, Y2 is N, C or C—R6, Y3 is Y1, Y2, N, C or C—R7, Y4 is N, C or C—R8 provided that only the moiety Y1, Y2, Y3 or Y4 to which Z is bound is C and further provided at most one of Y1, Y2, Y3 or Y4 is N; Z is O, S, S(O), S(O)2 or NRZ; Q is CH2 or CH2CH2, where one or two of the hydrogen atoms in CH2 or CH2CH2 may be replaced by halogen, C1-C4-alkyl or C1-C4-haloalkyl; R1 is inter alia hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C4-haloalkoxy, C3-C8-cycloalkyl, a radical NR1aR1b, C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, aryl, aryl-CH2, aryloxy, hetaryl, hetaryloxy or hetaryl-CH2, wherein the heterocyclyl, aryl and hetaryl rings ring in the last six radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R1c; R2 has one of the meanings given for R1; R3 and R4 are, inter alia, selected from hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, phenyl, C1-C4-haloalkoxy, a radical (CH2)nNR′R″; R5, R6, R7, R8 are, independently of each other, selected from hydrogen, halogen, etc.; Ra is C3-C6-cycloalkyl, C1-C6-haloalkyl or C1-C6-alkyl, which is unsubstituted or carries one radical selected from C1-C4-alkoxy, C1-C4-haloalkoxy and a radical NRa1Ra2; and the N-oxides and the pharmaceutically acceptable salts thereof.

    Small molecule potentiators of metabotropic glutamate receptors
    4.
    发明授权
    Small molecule potentiators of metabotropic glutamate receptors 有权

    公开(公告)号：US08314120B2

    公开(公告)日：2012-11-20

    申请号：US13073087

    申请日：2011-03-28

    申请人： Wilfried Braje ,  Katja Jantos ,  Hervé Geneste ,  Mario Mezler ,  Margaretha Henrica Maria Bakker

    发明人： Wilfried Braje ,  Katja Jantos ,  Hervé Geneste ,  Mario Mezler ,  Margaretha Henrica Maria Bakker

    IPC分类号： A61K31/4375 ,  A61K31/4725 ,  A61K31/403 ,  C07D471/04 ,  C07D217/22 ,  C07D487/04 ,  C07D209/46

    CPC分类号： C07D401/12 ,  C07D401/14 ,  C07D403/12 ,  C07D413/12 ,  C07D413/14

    摘要： The present invention relates to small molecule potentiators of metabotropic receptors, in particular of the mGlu2 receptor. The present invention also relates to the use of these compounds for the prevention or treatment of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The present invention thus provides compounds of formula I wherein X1 is N or C—R1, X2 is N or C—R2, X3 is N or C—R3, X4 is N or C—R4 provided that none or one of X1, X2, X3 or X4 is N; Y1 is N, C or C—R5, Y2 is N, C or C—R6, Y3 is Y1, Y2, N, C or C—R7, Y4 is N, C or C—R8 provided that only the moiety Y1, Y2, Y3 or Y4 to which Z is bound is C and further provided at most one of Y1, Y2, Y3 or Y4 is N; Z is O, S, S(O), S(O)2 or NRZ; Q is CH2 or CH2CH2, where one or two of the hydrogen atoms in CH2 or CH2CH2 may be replaced by halogen, C1-C4-alkyl or C1-C4-haloalkyl; R1 is inter alia hydrogen, halogen, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C1-C4-haloalkoxy, C3-C8-cycloalkyl, a radical NR1aR1b, C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, aryl, aryl-CH2, aryloxy, hetaryl, hetaryloxy or hetaryl-CH2, wherein the heterocyclyl, aryl and hetaryl rings ring in the last six radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R1c; R2 has one of the meanings given for R1; R3 and R4 are, inter alia, selected from hydrogen, halogen, C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, phenyl, C1-C4-haloalkoxy, a radical (CH2)nNR′R″; R5, R6, R7, R8 are, independently of each other, selected from hydrogen, halogen, etc.; Ra is C3-C6-cycloalkyl, C1-C6-haloalkyl or C1-C6-alkyl, which is unsubstituted or carries one radical selected from C1-C4-alkoxy, C1-C4-haloalkoxy and a radical NRa1Ra2; and the N-oxides and the pharmaceutically acceptable salts thereof.

    C6-and C9-substituted chromeno[4,3-c]isoxazoline derivatives and their use as anti-depressants
    8.
    发明授权
    C6-and C9-substituted chromeno[4,3-c]isoxazoline derivatives and their use as anti-depressants 有权
    C6-和C9-取代的色烯并[4,3-c]异恶唑啉衍生物及其作为抗抑郁剂的用途

    公开(公告)号：US07462717B2

    公开(公告)日：2008-12-09

    申请号：US10524989

    申请日：2003-08-19

    申请人： José Ignacio Andrés-Gil ,  Manuel Jesús Alcázar-Vaca ,  Maria Encarnacion Matesanz-Ballesteros ,  Margaretha Henrica Maria Bakker ,  Antonius Adrianus Hendrikus Petrus Megens

    发明人： José Ignacio Andrés-Gil ,  Manuel Jesús Alcázar-Vaca ,  Maria Encarnacion Matesanz-Ballesteros ,  Margaretha Henrica Maria Bakker ,  Antonius Adrianus Hendrikus Petrus Megens

    IPC分类号： A61K31/55 ,  A61K31/5377 ,  A61K31/496 ,  C07D498/04 ,  C07D413/00

    CPC分类号： C07D498/04

    摘要： The invention concerns substituted tricyclic isoxazoline derivatives, more in particular tricyclic dihydrobenzopyranoisoxazoline, dihydroquinolinoisoxazoline, dihydronaphthalenoisoxazoline and dihydrobenzothiopyranoisoxazoline derivatives substituted on at least one of the C6- and C9-positions of the phenylpart of the tricyclic moiety with a selected radical, according to Formula (I) wherein X=CH2, N—R7, S or O, R1, R2, R14 and R15 are certain specific substituents, with the proviso that at least one of R14 and R15 is not hydrogen, Pir is preferably an optionally substituted piperidinyl or piperazinyl radical and R3 represents an optionally substituted aromatic homocyclic or heterocyclic ring system including a partially or completely hydrogenated hydrocarbon chain of maximum 6 atoms long with which the ring system is attached to the Pir radical and which may contain one or more heteroatoms selected from the group of O, N and S; a process for their preparation, pharmaceutical compositions comprising them and their use as a medicine, in particular for the treatment of depression, anxiety, movement disorders, psychosis, Parkinson's disease and body weight disorders. The compounds according to the invention have surprisingly been shown to have a serotonine (5-HT) reuptake inhibitor activity in combination with additional α2-adrenoceptor antagonist activity and show a strong anti-depressant activity without being sedative. The invention also relates to novel combination of isoxazoline derivatives according to the invention with one or more other compounds selected from the group of antidepressants, anxiolytics, anti-psychotics and anti-Parkinson's disease drugs to improve efficacy and/or onset of action.

    摘要翻译： 本发明涉及取代的三环异恶唑啉衍生物，更具体地是三环二氢苯并吡喃恶唑啉，二氢喹诺酮异恶唑啉，二氢萘硫基异恶唑啉和二氢苯并噻唑并恶唑啉衍生物，其被三选择基团的苯基部分的C 6 - 和C 9位中的至少一个与选定的基团取代， ）其中X = CH 2，N-R 7，S或O，R 1，R 2，R 14和R 15是某些具体取代基，条件是R14和R15中的至少一个不是氢，Pir优选为任选取代的哌啶基或哌嗪基 基团和R 3表示任选取代的芳族双环或杂环系统，其包括最多6个原子长的部分或完全氢化的烃链，其中环系统连接到Pir基团，并且其可以含有一个或多个选自以下的杂原子： O，N和S; 其制备方法，包含它们的药物组合物及其作为药物的用途，特别是用于治疗抑郁症，焦虑症，运动障碍，精神病，帕金森病和体重障碍。 根据本发明的化合物令人惊奇地显示具有与另外的α2-肾上腺素受体拮抗剂活性组合的5-羟色胺（5-HT）再摄取抑制剂活性，并且在没有镇静作用的情况下表现出强烈的抗抑郁活性。 本发明还涉及根据本发明的异恶唑啉衍生物与一种或多种选自抗抑郁药，抗焦虑药，抗精神病药和抗帕金森病药物的其它化合物的新组合，以改善疗效和/或起效。