公开(公告)号：US08664214B2

公开(公告)日：2014-03-04

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： C07D231/12 ,  C07D409/04 ,  A61K31/4164

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 and variables defined herein.

摘要翻译： 本发明涉及代谢型受体特别是mGlu2受体的小分子增效剂。 本发明还涉及这些化合物用于预防或治疗与谷氨酸功能障碍相关的神经和精神疾病以及涉及代谢型谷氨酸受体的疾病的用途。 因此，本发明提供式I化合物和本文定义的变量。

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.

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.

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.

公开(公告)号：US09938269B2

公开(公告)日：2018-04-10

申请号：US13534127

申请日：2012-06-27

申请人： Hervé Geneste ,  Michael Ochse ,  Karla Drescher ,  Berthold Behl ,  Loic Laplanche ,  Jürgen Dinges ,  Clarissa Jakob ,  Katja Jantos

发明人： Hervé Geneste ,  Michael Ochse ,  Karla Drescher ,  Berthold Behl ,  Loic Laplanche ,  Jürgen Dinges ,  Clarissa Jakob ,  Katja Jantos

IPC分类号： C07D471/04 ,  C07D403/14 ,  C07D405/14 ,  C07D409/14 ,  C07D413/14

CPC分类号： C07D471/04 ,  C07D403/14 ,  C07D405/14 ,  C07D409/14 ,  C07D413/14

摘要： The present invention relates to novel carboxamide compounds, pharmaceutical compositions containing them, and their use in therapy. The compounds possess valuable therapeutic properties and are particularly suitable for treating or controlling medical disorders selected from neurological disorders and psychiatric disorders, for ameliorating the symptoms associated with such disorders and for reducing the risk of such disorders.

公开(公告)号：US08334289B2

公开(公告)日：2012-12-18

申请号：US13103734

申请日：2011-05-09

申请人： Hervé Geneste ,  Wilfried Braje ,  Andreas Haupt

发明人： Hervé Geneste ,  Wilfried Braje ,  Andreas Haupt

IPC分类号： A61K31/506

CPC分类号： C07D401/12

摘要： The invention relates to novel pyridin-2-one compounds of general formula (I), in which A represents a 4- to 6-membered hydrocarbon chain that can have 1 or 2 methyl groups as substituents, wherein 1 or 2 carbon atoms can be replaced by oxygen, a carbonyl group or sulfur, and the hydrocarbon chain can have a double bond or a triple bond; R1, R2, R3 and R4 have the meanings as cited in the claims and in the description. The invention also relates to the tautomers of compounds I, the physiologically acceptable salts of compounds I, and to the physiologically acceptable salts of the tautomers of compounds I. The invention also relates to the use of compounds of general formula (I) and of the tautomers, and to the use of the physiologically acceptable salts of compounds I and of the tautomers for producing a pharmaceutical agent for treating diseases that respond to the influence of dopamine D3 receptor antagonists or agonists.

摘要翻译： 本发明涉及通式（I）的新型吡啶-2-酮化合物，其中A表示可具有1或2个甲基作为取代基的4至6元烃链，其中1或2个碳原子可以是 由氧，羰基或硫取代，烃链可以具有双键或三键; R1，R2，R3和R4具有权利要求书和说明书中引用的含义。 本发明还涉及化合物I的互变异构体，化合物I的生理上可接受的盐，以及化合物I的互变异构体的生理上可接受的盐。本发明还涉及通式（I）的化合物和 互变异构体，以及化合物I和互变异构体的生理上可接受的盐的用途，用于制备用于治疗对多巴胺D3受体拮抗剂或激动剂的影响作出反应的疾病的药剂。

公开(公告)号：US20110245266A1

公开(公告)日：2011-10-06

申请号：US13103734

申请日：2011-05-09

申请人： Hervé Geneste ,  Wilfried Braje ,  Andreas Haupt

发明人： Hervé Geneste ,  Wilfried Braje ,  Andreas Haupt

IPC分类号： A61K31/497 ,  C07D403/14 ,  A61P25/18 ,  A61P25/24

CPC分类号： C07D401/12

摘要： The invention relates to novel pyridin-2-one compounds of general formula (I), in which A represents a 4- to 6-membered hydrocarbon chain that can have 1 or 2 methyl groups as substituents, wherein 1 or 2 carbon atoms can be replaced by oxygen, a carbonyl group or sulfur, and the hydrocarbon chain can have a double bond or a triple bond; R1, R2, R3 and R4 have the meanings as cited in the claims and in the description. The invention also relates to the tautomers of compounds I, the physiologically acceptable salts of compounds I, and to the physiologically acceptable salts of the tautomers of compounds I. The invention also relates to the use of compounds of general formula (I) and of the tautomers, and to the use of the physiologically acceptable salts of compounds I and of the tautomers for producing a pharmaceutical agent for treating diseases that respond to the influence of dopamine D3 receptor antagonists or agonists.

摘要翻译： 本发明涉及通式（I）的新型吡啶-2-酮化合物，其中A表示可具有1或2个甲基作为取代基的4至6元烃链，其中1或2个碳原子可以是 由氧，羰基或硫取代，烃链可以具有双键或三键; R1，R2，R3和R4具有权利要求书和说明书中引用的含义。 本发明还涉及化合物I的互变异构体，化合物I的生理上可接受的盐，以及化合物I的互变异构体的生理上可接受的盐。本发明还涉及通式（I）的化合物和 互变异构体，以及化合物I和互变异构体的生理上可接受的盐的用途，用于制备用于治疗对多巴胺D3受体拮抗剂或激动剂的影响作出反应的疾病的药剂。

公开(公告)号：US08492540B2

公开(公告)日：2013-07-23

申请号：US12740714

申请日：2008-10-31

申请人： Wilfried Braje ,  Sean Colm Turner ,  Andreas Haupt ,  Udo Lange ,  Hervé Geneste ,  Karla Drescher ,  Liliane Unger ,  Ana Lucia Relo ,  Anton Bespalov

发明人： Wilfried Braje ,  Sean Colm Turner ,  Andreas Haupt ,  Udo Lange ,  Hervé Geneste ,  Karla Drescher ,  Liliane Unger ,  Ana Lucia Relo ,  Anton Bespalov

IPC分类号： C07D253/075 ,  C07D403/14 ,  A61K31/53 ,  A61P25/18 ,  A61P25/30 ,  A61P25/00

CPC分类号： C07D403/12

摘要： The invention relates to compounds of the formula I: wherein A is a saturated or unsaturated hydrocarbon chain having a chain length of 4 to 6 carbon atoms, the hydrocarbon chain being unsubstituted or substituted by 1, 2 or 3 methyl groups; R1 is selected from the group consisting of hydrogen, C1-C3 alkyl and fluorinated C1-C3 alkyl; R2 is hydrogen, halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, fluorinated C1-C3 alkyl or fluorinated C1-C3 alkoxy; R3 is selected from the group consisting of branched C4-C6 alkyl and C3-C6 cycloalkyl, and R4 is C1-C6 alkyl, C3-C6 cycloalkyl, fluorinated C1-C3-alkyl and fluorinated C3-C6 cycloalkyl. and the physiologically tolerated salts of these compounds and the N-oxides thereof. The invention also relates to a pharmaceutical composition that comprises at least one compound of the formula I and/or at least one physiologically tolerated acid addition salt thereof, and further to a method for treating disorders that respond beneficially to dopamine D3 receptor antagonists or dopamine D3 agonists, said method comprising administering an effective amount of at least one compound or physiologically tolerated acid addition salt of the formula I to a subject in need thereof.

摘要翻译： 本发明涉及式I化合物：其中A是链长为4-6个碳原子的饱和或不饱和烃链，烃链未被取代或被1,2或3个甲基取代; R1选自氢，C1-C3烷基和氟化C1-C3烷基; R2是氢，卤素，氰基，C1-C3烷基，C1-C3烷氧基，氟化C1-C3烷基或氟化C1-C3烷氧基; R3选自支链C4-C6烷基和C3-C6环烷基，R4为C1-C6烷基，C3-C6环烷基，氟化C1-C3-烷基和氟化C3-C6环烷基。 以及这些化合物的生理上耐受的盐及其N-氧化物。 本发明还涉及包含至少一种式I化合物和/或其至少一种生理上耐受的酸加成盐的药物组合物，还涉及治疗有益于多巴胺D3受体拮抗剂或多巴胺D3的病症的方法 所述方法包括向有需要的受试者施用有效量的至少一种式I化合物或生理学上耐受的酸加成盐。

公开(公告)号：US08008488B2

公开(公告)日：2011-08-30

申请号：US10548931

申请日：2004-03-12

申请人： Hervé Geneste ,  Andreas Kling ,  Wilfried Braje ,  Andreas Haupt ,  Liliane Unger

发明人： Hervé Geneste ,  Andreas Kling ,  Wilfried Braje ,  Andreas Haupt ,  Liliane Unger

IPC分类号： C07D403/06 ,  C07D403/14 ,  C07D401/06 ,  C07D401/14 ,  A61K31/505 ,  A61K31/506 ,  A61P25/16 ,  A61P25/18 ,  A61P25/24 ,  A61P25/22 ,  A61P25/30

CPC分类号： C07D239/36 ,  C07D239/52 ,  C07D239/54 ,  C07D239/553 ,  C07D239/56 ,  C07D401/12 ,  C07D403/14 ,  C07D405/14 ,  C07D409/14

摘要： The invention relates to pyrimidin 2-one compounds of general formula (I), in addition to the derivatives and tautomers of (I) and the physiologically acceptable salts of said compounds. In said formula, A represents linear or branched C3-C6 alkene, which can have a double bond or triple bond and/or a group Z, which is not adjacent to the nitrogen atom of the pyrimidinone ring and is selected from O, S, C(O), NR3, C(O)NR3, NR3C(O), OC(O) and C(O)O; B represents a group of the formula (II), in which X stands for CH2 or N and Y stands for CH2 or CH2CH2, or X—Y can also jointly represent C═CH, C═CH—CH2 or CH—CH═CH; R1 and R2 are defined as cited in the description and the claims; and Ar represents an optionally substituted aromatic group. The invention also relates to a pharmaceutical agent, containing at least one compound (I) and the tautomers, derivatives and/or acid addition salts of said compound, optionally together with physiologically acceptable carriers and/or auxiliary agents. The invention also relates to the use of compounds of formula (I), and their tautomers, derivatives and pharmacologically acceptable acid addition salts for producing a pharmaceutical agent for treating diseases which respond to the influence of dopamine D3 receptor ligands.

摘要翻译： 除了（I）的衍生物和互变异构体以及所述化合物的生理学上可接受的盐之外，本发明涉及通式（I）的嘧啶-2-酮化合物。 在所述式中，A表示可以具有双键或三键的直链或支链C 3 -C 6烯基和/或不与嘧啶酮环的氮原子相邻并且选自O，S， C（O），NR 3，C（O）NR 3，NR 3 C（O），OC（O）和C（O）O; B表示式（II）的基团，其中X表示CH2或N，Y表示CH2或CH2CH2，或X-Y也可共同表示C = CH，C = CH-CH 2或CH-CH = CH ; R1和R2定义为在说明书和权利要求书中引用的; 并且Ar表示任选取代的芳族基团。 本发明还涉及含有至少一种化合物（I）和所述化合物的互变异构体，衍生物和/或酸加成盐，任选地与生理上可接受的载体和/或辅助剂一起的药剂。 本发明还涉及式（I）化合物及其互变异构体，衍生物和药理学上可接受的酸加成盐的用途，用于制备用于治疗对多巴胺D3受体配体的影响作出反应的疾病的药剂。

公开(公告)号：US20110077253A1

公开(公告)日：2011-03-31

申请号：US12746700

申请日：2008-12-05

申请人： Thorsten Oost ,  Astrid Netz ,  Hervé Geneste ,  Wilfried Braje ,  Wolfgang Wernet ,  Andrea Hager-Wernet ,  Liliane Unger ,  Wilfried Hornberger ,  Wilfried Lubisch

发明人： Thorsten Oost ,  Astrid Netz ,  Hervé Geneste ,  Wilfried Braje ,  Wolfgang Wernet ,  Andrea Hager-Wernet ,  Liliane Unger ,  Wilfried Hornberger ,  Wilfried Lubisch

IPC分类号： A61K31/496 ,  C07D401/14 ,  A61K31/4545 ,  A61P25/00

CPC分类号： C07D401/14

摘要： The present invention relates to novel amidomethyl-substituted oxindole derivatives, pharmaceutical compositions comprising them, and their use for the treatment of vasopressin-dependent disorders.

摘要翻译： 本发明涉及新的酰胺甲基取代的羟基吲哚衍生物，包含它们的药物组合物及其用于治疗加压素依赖性病症的用途。