公开(公告)号：US08415347B2

公开(公告)日：2013-04-09

申请号：US12850958

申请日：2010-08-05

申请人： José Maria Cid-Núñez ,  Antonius Adrianus Hendrikus Petrus Megens ,  Andrés Avelino Trabanco-Suárez ,  Mohamed Koukni ,  Georges Joseph Cornelius Hoornaert ,  Frans Josef Cornelius Compernolle ,  Tomasz Kozlecki ,  Hua Mao ,  Sushil Chandra Jha ,  Francisco Javier Fernández-Gadea

发明人： José Maria Cid-Núñez ,  Antonius Adrianus Hendrikus Petrus Megens ,  Andrés Avelino Trabanco-Suárez ,  Mohamed Koukni ,  Georges Joseph Cornelius Hoornaert ,  Frans Josef Cornelius Compernolle ,  Tomasz Kozlecki ,  Hua Mao ,  Sushil Chandra Jha ,  Francisco Javier Fernández-Gadea

IPC分类号： A61K31/5377 ,  A61K31/403 ,  A61K31/496 ,  A61K31/381 ,  A61K31/4985 ,  A61K31/352 ,  A61K31/435 ,  C07D491/044 ,  C07D209/58 ,  C07D413/04 ,  C07D333/80 ,  C07D487/04

CPC分类号： C07D333/80 ,  C07D209/70 ,  C07D221/18 ,  C07D307/93 ,  C07D311/94 ,  C07D487/04 ,  C07D491/04

摘要： This invention concerns novel substituted tetracyclic tetrahydrofuran, pyrrolidine and tetrahydrothiophene derivatives with binding affinities towards serotonin receptors, in particular 5-HT2A and 5-HT2C receptors, and towards dopamine receptors, in particular dopamine D2 receptors and with norepinephrine reuptake inhibition properties, pharmaceutical compositions comprising the compounds according to the invention, the use thereof as a medicine, in particular for the prevention and/or treatment of a range of psychiatric and neurological disorders, in particular certain psychotic, cardiovascular and gastrokinetic disorders and processes for their production.The compounds according to the invention can be represented by general Formula (I) and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in Claim 1.

摘要翻译： 本发明涉及对5-羟色胺受体，特别是5-HT2A和5-HT2C受体以及对多巴胺受体，特别是多巴胺D2受体和去甲肾上腺素再摄取抑制性质具有结合亲和力的新型取代四环四氢呋喃，吡咯烷和四氢噻吩衍生物，包含 根据本发明的化合物，其用作药物，特别是用于预防和/或治疗一系列精神和神经障碍，特别是某些精神病性，心血管和胃肠功能障碍及其生产方法。 根据本发明的化合物可以由通式（I）表示，并且还包括其药学上可接受的酸或碱加成盐，其立体化学异构形式，其N-氧化物形式及其前药，其中所有取代基定义为 在权利要求1中。

公开(公告)号：US07799785B2

公开(公告)日：2010-09-21

申请号：US11815726

申请日：2005-12-06

申请人： José Maria Cid-Núñez ,  Antonius Andrianus Hendrikus Petrus Megens ,  Andrés Avelino Trabanco-Suárez ,  Mohamed Koukni ,  Georges Joseph Cornelius Hoornaert ,  Frans Josef Cornelius Compernolle ,  Tomasz Kozlecki ,  Hua Mao ,  Sushil Chandra Jha ,  Francisco Javier Fernández-Gadea

发明人： José Maria Cid-Núñez ,  Antonius Andrianus Hendrikus Petrus Megens ,  Andrés Avelino Trabanco-Suárez ,  Mohamed Koukni ,  Georges Joseph Cornelius Hoornaert ,  Frans Josef Cornelius Compernolle ,  Tomasz Kozlecki ,  Hua Mao ,  Sushil Chandra Jha ,  Francisco Javier Fernández-Gadea

IPC分类号： A61K31/403 ,  A61K31/4985 ,  A61K31/352 ,  A61P3/04 ,  A61P25/00 ,  A61K31/381 ,  A61K31/407 ,  C07D487/04 ,  C07D209/56 ,  C07D491/044

CPC分类号： C07D333/80 ,  C07D209/70 ,  C07D221/18 ,  C07D307/93 ,  C07D311/94 ,  C07D487/04 ,  C07D491/04

摘要： This invention concerns novel substituted tetracyclic tetrahydrofuran, pyrrolidine and tetrahydrothiophene derivatives with binding affinities towards serotonin receptors, in particular 5-HT2A and 5-HT2C receptors, and towards dopamine receptors, in particular dopamine D2 receptors and with norepinephrine reuptake inhibition properties, pharmaceutical compositions comprising the compounds according to the invention, the use thereof as a medicine, in particular for the prevention and/or treatment of a range of psychiatric and neurological disorders, in particular certain psychotic, cardiovascular and gastrokinetic disorders and processes for their production.The compounds according to the invention can be represented by general Formula (I) and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in Claim 1.

摘要翻译： 本发明涉及对5-羟色胺受体，特别是5-HT2A和5-HT2C受体以及对多巴胺受体，特别是多巴胺D2受体和去甲肾上腺素再摄取抑制性质具有结合亲和力的新型取代四环四氢呋喃，吡咯烷和四氢噻吩衍生物，包含 根据本发明的化合物，其用作药物，特别是用于预防和/或治疗一系列精神和神经障碍，特别是某些精神病性，心血管和胃肠功能障碍及其生产方法。 根据本发明的化合物可以由通式（I）表示，并且还包括其药学上可接受的酸或碱加成盐，其立体化学异构形式，其N-氧化物形式及其前药，其中所有取代基定义为 在权利要求1中。

公开(公告)号：US20080287450A1

公开(公告)日：2008-11-20

申请号：US11815726

申请日：2005-12-06

申请人： Jose Maria Cid-Nunez ,  Antonius Adrianus Hendrikus Petrus Megens ,  Andres Avelino Trabanco-Suarez ,  Mohamed Koukni ,  Georges Joseph Cornelius Hoornaert ,  Frans Josef Cornelius Compernolle ,  Tomasz Kozlecki ,  Hua Mao ,  Sushil Chandra Jha ,  Francisco Javier Fernandez-Gadea

发明人： Jose Maria Cid-Nunez ,  Antonius Adrianus Hendrikus Petrus Megens ,  Andres Avelino Trabanco-Suarez ,  Mohamed Koukni ,  Georges Joseph Cornelius Hoornaert ,  Frans Josef Cornelius Compernolle ,  Tomasz Kozlecki ,  Hua Mao ,  Sushil Chandra Jha ,  Francisco Javier Fernandez-Gadea

IPC分类号： A61K31/403 ,  C07D487/04 ,  C07D209/56 ,  C07D491/044 ,  A61K31/4985 ,  A61K31/352 ,  A61P3/04 ,  A61P25/00 ,  A61K31/381 ,  A61K31/407 ,  C07D333/50 ,  C07D311/94

CPC分类号： C07D333/80 ,  C07D209/70 ,  C07D221/18 ,  C07D307/93 ,  C07D311/94 ,  C07D487/04 ,  C07D491/04

摘要： This invention concerns novel substituted tetracyclic tetrahydrofuran, pyrrolidine and tetrahydrothiophene derivatives with binding affinities towards serotonin receptors, in particular 5-HT2A and 5-HT2C receptors, and towards dopamine receptors, in particular dopamine D2 receptors and with norepinephrine reuptake inhibition properties, pharmaceutical compositions comprising the compounds according to the invention, the use thereof as a medicine, in particular for the prevention and/or treatment of a range of psychiatric and neurological disorders, in particular certain psychotic, cardiovascular and gastrokinetic disorders and processes for their production.The compounds according to the invention can be represented by general Formula (I) and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in Claim 1.

摘要翻译： 本发明涉及对5-羟色胺受体，特别是5-HT 2A和5-HT 2C受体具有结合亲和力的新型取代四环四氢呋喃，吡咯烷和四氢噻吩衍生物，并且涉及多巴胺受体 ，特别是多巴胺D2受体和去甲肾上腺素再摄取抑制性质，包含根据本发明的化合物的药物组合物，其作为药物的用途，特别是用于预防和/或治疗一系列精神和神经障碍，特别是 某些精神病，心血管和胃肠功能障碍及其生产过程。 根据本发明的化合物可以由通式（I）表示，并且还包括其药学上可接受的酸或碱加成盐，其立体化学异构形式，其N-氧化物形式及其前药，其中所有取代基定义为 在权利要求1中。

公开(公告)号：US20090023721A1

公开(公告)日：2009-01-22

申请号：US11915202

申请日：2006-05-24

申请人： Antonius Adrianus Hendrikus Petrus Megens ,  Andres Avelino Trabanco-Suarez ,  Jose Maria Cid-Nunez ,  Hua Mao ,  Sushil Chandra Jha ,  Francisco Javier Fernandez-Gadea ,  Mohamed Koukni ,  Georges Joseph Cornelius Hoornaert ,  Frans Josef Cornelius Compernolle ,  Tomasz Kozlecki

发明人： Antonius Adrianus Hendrikus Petrus Megens ,  Andres Avelino Trabanco-Suarez ,  Jose Maria Cid-Nunez ,  Hua Mao ,  Sushil Chandra Jha ,  Francisco Javier Fernandez-Gadea ,  Mohamed Koukni ,  Georges Joseph Cornelius Hoornaert ,  Frans Josef Cornelius Compernolle ,  Tomasz Kozlecki

IPC分类号： A61K31/4184 ,  C07D235/02 ,  C07D241/36 ,  C07D333/50 ,  A61K31/498 ,  A61K31/35 ,  A61K31/5377 ,  A61P25/00 ,  A61K31/403 ,  A61K31/381 ,  C07D311/02 ,  C07D209/56 ,  C07D413/12

CPC分类号： C07D209/94 ,  C07D221/18 ,  C07D307/93 ,  C07D311/94 ,  C07D333/80 ,  C07D487/04 ,  C07D491/04

摘要： This invention concerns novel substituted tetracyclic tetrahydrofuran, pyrrolidine and tetrahydrothiophene derivatives with binding affinities towards serotonin receptors, in particular 5-HT2A and 5-HT2C receptors, and towards dopamine receptors, in particular dopamine D2 receptors and with norepinephrine reuptake inhibition properties, pharmaceutical compositions comprising the compounds according to the invention, the use thereof as a medicine, in particular for the prevention and/or treatment of a range of psychiatric and neurological disorders, in particular certain psychotic, cardiovascular and gastrokinetic disorders and processes for their production.The compounds according to the invention can be represented by general Formula (I) and comprises also the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in Claim 1.

摘要翻译： 本发明涉及对5-羟色胺受体，特别是5-HT2A和5-HT2C受体以及对多巴胺受体，特别是多巴胺D2受体和去甲肾上腺素再摄取抑制性质具有结合亲和力的新型取代四环四氢呋喃，吡咯烷和四氢噻吩衍生物，包含 根据本发明的化合物，其用作药物，特别是用于预防和/或治疗一系列精神和神经障碍，特别是某些精神病性，心血管和胃肠功能障碍及其生产方法。 根据本发明的化合物可以由通式（I）表示，并且还包括其药学上可接受的酸或碱加成盐，其立体化学异构形式，其N-氧化物形式及其前药，其中所有取代基定义为 在权利要求1中。

公开(公告)号：US06998494B2

公开(公告)日：2006-02-14

申请号：US10496279

申请日：2002-12-02

申请人： Yolande Lydia Lang ,  Bart Petrus Anna Maria Jozef Medaer ,  Georges Joseph Cornelius Hoornaert ,  Thierry Brossette ,  Frans Josef Cornelius Compernolle ,  Michel Joseph Maurice André Guillaume ,  Hua Mao ,  Tomasz Kozlecki

发明人： Yolande Lydia Lang ,  Bart Petrus Anna Maria Jozef Medaer ,  Georges Joseph Cornelius Hoornaert ,  Thierry Brossette ,  Frans Josef Cornelius Compernolle ,  Michel Joseph Maurice André Guillaume ,  Hua Mao ,  Tomasz Kozlecki

IPC分类号： C07D307/93

CPC分类号： C07D307/93

摘要： The present invention concerns processes for the preparation of each of the 4 diastereomers of formula (I) in stereochemically pure form from either of two enantiomerically pure precursors. The tetracyclic ringsystem having trans-fused five and seven membered rings is formed in an acid-catalysed cyclization reaction. The invention further relates to the thus obtained cis-fused tetracyclic alcohol intermediates, the methanamine end-products, the methanamine end-products for use as a medicine, in particular as CNS active medicines.

摘要翻译： 本发明涉及制备式（I）的四种非对映异构体中的每一种的方法，化学式id =“CHEM-US-00001”num =“000

公开(公告)号：US07205335B2

公开(公告)日：2007-04-17

申请号：US10496277

申请日：2002-12-02

申请人： Mao Hua ,  Tomasz Kozlecki ,  Frans Josef Cornelius Compernolle ,  Georges Joseph Cornelius Hoornaert

发明人： Mao Hua ,  Tomasz Kozlecki ,  Frans Josef Cornelius Compernolle ,  Georges Joseph Cornelius Hoornaert

IPC分类号： A61K31/343 ,  C07D307/93

CPC分类号： C07D307/93

摘要： The present invention concerns a process for preparing each of the 4 individual diastereomers of formula (I) in stereochemically pure form from a single enantiomerically pure precursor. The tetracyclic ringsystem having cis-fused five and seven membered rings is formed in a base-catalysed cyclization reaction. The invention further relates to the thus obtained cis-fused tetracyclic alcohol intermediates and methanamine end-products, and the methanamine end-products for use as a medicine, in particular as CNS active medicines

摘要翻译： 本发明涉及从单一对映异构体纯的前体以立体化学纯的形式制备式（I）的4种单独的非对映异构体的方法。 在碱催化的环化反应中形成具有顺式稠合的五元和七元环的四环环系。 本发明还涉及由此获得的顺式稠合四环醇中间体和甲胺终产物，以及用作药物的甲胺最终产物，特别是CNS活性药物

公开(公告)号：US07105522B2

公开(公告)日：2006-09-12

申请号：US10468447

申请日：2002-03-13

申请人： Paul Adriaan Jan Janssen ,  Koen Jeanne Alfons Van Aken ,  Paulus Joannes Lewi ,  Lucien Maria Henricus Koymans ,  Marc René de Jonge ,  Jan Heeres ,  Frederik Frans Desire Daeyaert ,  Georges Joseph Cornelius Hoornaert ,  Frans Josef Cornelius Compernolle ,  Amuri Kilonda

发明人： Paul Adriaan Jan Janssen ,  Koen Jeanne Alfons Van Aken ,  Paulus Joannes Lewi ,  Lucien Maria Henricus Koymans ,  Marc René de Jonge ,  Jan Heeres ,  Frederik Frans Desire Daeyaert ,  Georges Joseph Cornelius Hoornaert ,  Frans Josef Cornelius Compernolle ,  Amuri Kilonda

IPC分类号： A61K31/4965 ,  C07D401/00 ,  C07D403/00 ,  C07D405/00 ,  C07D241/02

CPC分类号： C07D241/20

摘要： This invention concerns a compound of formula a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein R1 is hydrogen, hydroxy, cyano, amino, mono-or di(C1-4alkyl)amino, formyl, carboxyl, C1-6alkyl, hydroxyC1-6alkyl, polyhaloC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C1-6alkyloxy, C1-6alkylcarbonyl, aminocarbonyl, —S(═O)m—NH2, mono-or di(C1-4alkyl)aminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, aryl, arylC1-6alkyl or aryloxy; R2 is hydrogen; halo; mercapto; formyl; cyano; carboxy; azido; hydroxy; oxiranyl; amino; mono- or di(C1-4alkyl)amino; formylamino; R5R6N—C(═O)—; R7—N═C(R8)—; C1-6alkyl-S(═O)m; aryl-S(═O)m; optionally substituted C2-6alkenyl; optionally substituted C2-6alkynyl; C1-6alkyloxy; hydroxyC1-6alkyloxy; aminoC1-6alkyloxy; mono- or di(C1-4alkyl)amino-C1-6alkyloxy; C1-6alkylcarbonyl; arylcarbonyl; Het1carbonyl; C1-6alkyloxycarbonyl; C1-6alkylcarbonyloxy; aryl; aryloxy; arylC1-6alkyloxy; arylthio; arylC1-6alkylthio; mono- or di(aryl)amino; Het1; Het1oxy; Het1thio; Het1C1-6alkyloxy; Het1C1-6alkylthio; mono- or di(Het1)amino; C3-7cycloalkyl; C3-7cycloalkyloxy; C3-7cycloalkylthio; C1-6alkylthio; hydroxyC1-6alkylthio; aminoC1-6alkylthio; mono- or di(C1-4alkyl)aminoC1-6alkylthio; optionally substituted C1-6alkyl; R3 or R4 each independently represent optionally be substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; —X— is a bivalent radical selected from —NR14—, —NH—NH—, —N═N—, —O—, —C1-6alkanediyl-, —C(═O)—, —CHOH—, —S—, —S(═O)m—; aryl is optionally substituted phenyl; Het1, Het2 or Het3 represent an optionally substituted monocyclic or bicyclic heterocycle; their use as a medicine, their processes for preparation and pharmaceutical compositions comprising them.