公开(公告)号：US07501418B2

公开(公告)日：2009-03-10

申请号：US10524123

申请日：2003-08-13

申请人： José Ignacio Andrés-Gil ,  Manuel Jesús Alcázar-Vaca ,  José Manuel Bartolomé -Nebreda ,  Francisco Javier Fernández-Gadea ,  Margaretha Henrica Maria Bakker ,  Antonius Adrianus Hendrikus Megens

发明人： José Ignacio Andrés-Gil ,  Manuel Jesús Alcázar-Vaca ,  José Manuel Bartolomé -Nebreda ,  Francisco Javier Fernández-Gadea ,  Margaretha Henrica Maria Bakker ,  Antonius Adrianus Hendrikus Megens

IPC分类号： A01N43/54 ,  A01N43/40 ,  A61K31/445 ,  A61K31/497 ,  C07D211/32 ,  C07D211/68 ,  C07D211/80 ,  C07D213/02 ,  C07D261/20 ,  C07D239/00 ,  C07D237/26 ,  C07D237/36 ,  C07D413/00 ,  C07D417/00 ,  C07D419/00 ,  C07D471/00 ,  C07D487/00 ,  C07D491/00 ,  C07D495/00 ,  C07D497/00

CPC分类号： C07D498/14

摘要： The invention concerns fused heterocyclic isoxazoline derivatives of Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof and the N-oxide form thereof, more in particular, tetrahydropyranoisoxazole, hexahydroisoxazolopyridine, tetrahydrothiopyrano isoxazole and hexahydrobenzoisoxazole derivatives fused to a heterocyclic ring system via the 6-membered ring of the bicyclic moiety as well as processes for their preparation, pharmaceutical compositions comprising them and their use as a medicine, in particular for treating depression, anxiety, movement disorders, psychosis, Parkinson's disease and body weight disorders including anorexia nervosa and bulimia, wherein the variables are defined as in Claim 1. The compounds have surprisingly been shown to have selective serotonine (5-HT) reuptake inhibitor activity as well as α2-adrenoceptor antagonist activity, compounds according to the invention are also suitable for treatment and/or prophylaxis in diseases where either one of the activities alone or the combination of said activities may be of therapeutic use.

摘要翻译： 本发明涉及式（I）的稠合杂环异恶唑啉衍生物，其药学上可接受的酸或碱加成盐，其立体化学异构体形式及其N-氧化物形式，更特别是四氢吡喃异恶唑，六氢异恶唑并吡啶，四氢噻喃异恶唑和六氢苯并异恶唑衍生物 通过双环部分的6元环以及其制备方法，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 包括神经性厌食症和贪食症的体重紊乱，其中变量如权利要求1中所定义。化合物惊奇地显示具有选择性5-羟色胺（5-HT）再摄取抑制剂活性以及α2-肾上腺素受体拮抗剂活性，根据 发明也适用于f 或治疗和/或预防疾病，其中单独的一种活性或所述活性的组合可能具有治疗用途。

公开(公告)号：US07265103B2

公开(公告)日：2007-09-04

申请号：US10510220

申请日：2003-03-27

申请人： José Ignacio Andrés-Gil ,  Manuel Jesús Alcázar-Vaca ,  Margaretha Henrica Maria Bakker ,  Ana Isabel De Lucas Olivares

发明人： José Ignacio Andrés-Gil ,  Manuel Jesús Alcázar-Vaca ,  Margaretha Henrica Maria Bakker ,  Ana Isabel De Lucas Olivares

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

CPC分类号： C07D498/04 ,  C07D498/14

摘要： The invention concerns substituted amino isoxazoline derivatives, more in particular tricyclic dihydrobenzopyranoisoxazoline, dihydroquinolinoisozazoline, dihydronaphthalenoisoxazoline and dihydrobenzothiopyranoisoxazoline derivatives substituted on the phenylpart of the tricyclic moiety with primary, secondary and/or tertiary amino groups, according to Formula (I) wherein X=CH2, N—R7, S or O, R1, R2 and R3 are certain specific substituents, with the proviso that at least one of R1 and R2 is an amino radical of formula N—R10R11 wherein R10 and R11 are each a variety of radicals, Pir is an optionally substituted piperidyl or piperazyl 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 and/of anxiety and disorders of body weight. The compounds according to the invention have surprisingly been shown to have a serotonin (5-HT) reuptake inhibitor activity in combination with additional α2-adrenoceptor antagonist activity and show a strong anti-depressant activity without being sedative. Compounds according to the invention are also suitable for treating depression, anxiety and body weight disorders. The invention also relates to novel combination of substituted amino isoxazoline derivatives according to the invention with antidepressants, anxiolytics and/or antipsychotics to improve efficacy and/or onset of action.

公开(公告)号：US07169786B2

公开(公告)日：2007-01-30

申请号：US10468555

申请日：2002-02-13

申请人： José Ignacio Andrés-Gil ,  Francisco Javier Fernández-Gadea ,  Manuel Jesús Alcázar-Vaca ,  José Maria Cid-Nuñez ,  Joaquin Pastor-Fernandez ,  Antonius Adrianus Hendrikus Petrus Megens ,  Godelieve Irma Christine Maria Heylen ,  Xavier Jean Michel Langlois ,  Margaretha Henrica Maria Bakker ,  Thomas Horst Wolfgang Steckler

发明人： José Ignacio Andrés-Gil ,  Francisco Javier Fernández-Gadea ,  Manuel Jesús Alcázar-Vaca ,  José Maria Cid-Nuñez ,  Joaquin Pastor-Fernandez ,  Antonius Adrianus Hendrikus Petrus Megens ,  Godelieve Irma Christine Maria Heylen ,  Xavier Jean Michel Langlois ,  Margaretha Henrica Maria Bakker ,  Thomas Horst Wolfgang Steckler

IPC分类号： A61K31/496 ,  A61K31/454 ,  C07D498/04 ,  C07D498/14

CPC分类号： A61K31/495 ,  C07D261/20

摘要： The invention concerns substituted isoxazolines derivatives according to Formula (I): wherein X=CH?2#191, N—R7, S or O, R1, R2 and R3 are certain specific substituents, Pir is an optionally substituted piperidyl or piperazyl 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 and/of anxiety and disorders of body weight. 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. Compounds according to the invention arc also suitable for treating patients with anxiety disorders and disorders of body weight. The invention also relates to novel combination of substituted isoxazolines derivatives having anti-depressant activity and/or anxiolytic activity and/or body weight control activity with antidepressants, anxiolytics and/or antipsychotics to improve efficacy and/or onset of action

摘要翻译： 本发明涉及根据式（I）的取代的异恶唑啉衍生物：其中X = CH 2＃191，NR 7，S或O，R 1，R 2， 2和R 3是某些特定取代基，Pir是任选取代的哌啶基或哌嗪基，R 3表示任选取代的芳族碳环或杂环系统，其包括部分或完全氢化的烃链 最大6个原子长，其中环体系连接到Pir基团并且其可以含有一个或多个选自O，N和S的杂原子; 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和/或焦虑和体重紊乱。 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。 根据本发明的化合物也适用于治疗患有焦虑症和体重紊乱的患者。 本发明还涉及具有抗抑郁活性和/或抗焦虑活性和/或体重控制活性的抗抑郁药，抗焦虑药和/或抗精神病药的取代的异恶唑啉衍生物的新组合，以改善作用和/或起效作用

公开(公告)号：US07081453B2

公开(公告)日：2006-07-25

申请号：US10311612

申请日：2001-06-13

申请人： Kristof Van Emelen ,  Marcel Frans Leopold De Bruyn ,  Manuel Jesús Alcázar-Vaca ,  José Ignacio Andrés-Gil ,  Francisco Javier Fernández-Gadea ,  Maria Encarnacion Matesanz-Ballesteros ,  José Manuel Bartolomé-Nebreda

发明人： Kristof Van Emelen ,  Marcel Frans Leopold De Bruyn ,  Manuel Jesús Alcázar-Vaca ,  José Ignacio Andrés-Gil ,  Francisco Javier Fernández-Gadea ,  Maria Encarnacion Matesanz-Ballesteros ,  José Manuel Bartolomé-Nebreda

IPC分类号： A61K31/397

CPC分类号： C07D411/04 ,  C07D491/04

摘要： The present invention concerns compounds of formula (I) a stereochemically isomeric form thereof, an N-oxide form thereof or a pharma-ceutically acceptable acid addition salt thereof, wherein —a1═a2—a3═a4— is a bivalent radical wherein one or two of a1 to a4 are nitrogen and the remaining a1 to a4 are —CH═; —Z1—Z2— is a bivalent radical; —A— is a bivalent radical of formula —N(R6)—Alk2— or a 5, 6 or 7-membered saturated heterocycle containing one or two nitrogen atoms; R1, R2 and R3 are each independently selected from hydrogen, C1-6alkyl, hydroxy, halo and the like; Alk1 and Alk2 are optionally substituted C1-6alkanediyl; R5 is a radical of formula (d-1), (d-2), (d-3), (d-4), (d-5) wherein n is 1 or 2; p1 is 0, and p2 is 1 or 2; or p1 is 1 or 2, and p2 is 0; X is oxygen, sulfur or ═NR9; Y2 is oxygen or sulfur; R7 is hydrogen, C1-6alkyl, C3-6cycloalkyl, phenyl or phenylmethyl; R8 is C1-6alkyl, C3-6cycloalkyl phenyl or phenylmethyl; R9 is cyano, C1-6alkyl, C3-6cyclo-alkyl, C1-6alkyloxycarbonyl or aminocarbonyl; R10 is hydrogen or C1-6alkyl; and Q is a bivalent radical. Processes for preparing said products, formulations comprising said products and their use as a medicine are disclosed, in particular for treating conditions which are related to disturbed fundic accomodation

公开(公告)号：US07732437B2

公开(公告)日：2010-06-08

申请号：US10494006

申请日：2002-11-22

申请人： Frank Tegtmeier ,  Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Koenraad Arthur van Rossem ,  Manuel Jesús Alcázar-Vaca ,  Pedro Martínez-Jiménez ,  José Manuel Bartolomé-Nebreda ,  Antonio Gómez-Sánchez ,  Francisco Javier Fernández-Gadea ,  Jozef Leo Henri Van Reempts

发明人： Frank Tegtmeier ,  Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Koenraad Arthur van Rossem ,  Manuel Jesús Alcázar-Vaca ,  Pedro Martínez-Jiménez ,  José Manuel Bartolomé-Nebreda ,  Antonio Gómez-Sánchez ,  Francisco Javier Fernández-Gadea ,  Jozef Leo Henri Van Reempts

IPC分类号： A61P9/10 ,  A61P37/02 ,  A61P37/08 ,  A61K31/415 ,  A61K31/425 ,  C07D519/00 ,  C07D487/04 ,  C07D471/04

CPC分类号： C07D471/00 ,  C07D487/00 ,  C07D519/00

摘要： The invention concerns a novel histamine receptor antagonist and the use of an histamine receptor antagonist for the reduction of intracranial pressure (ICP), in particular for the prevention and treatment of elevated intracranial pressure and/or secondary ischaemida, in particular caused by brain injury, more in particular caused by traumatic (TBI) and non-traumatic brain injury. The novel compounds comprise compounds according to the general Formula (I) the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof and the N-oxide form thereof. In particular, the preferred compound is 3-[2-[4-(11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepin-6-yl)-2-(phenyl-methyl)-1-piperidinyl]ethyl]-2,10-dimethyl pyrimido[1,2-α]benzimidazol-4(10H)-one, the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof and the N-oxide form thereof. Also claimed is the novel use of commercially available histamine H1-and H2-receptor antagonists for the reduction of intracranial pressure (ICP).

摘要翻译： 本发明涉及一种新的组胺受体拮抗剂和组胺受体拮抗剂用于降低颅内压（ICP）的用途，特别是用于预防和治疗颅内压升高和/或继发性白斑，特别是由脑损伤引起的， 更特别是由创伤性（TBI）和非创伤性脑损伤引起的。 新化合物包括根据通式（I）的药学上可接受的酸或碱加成盐，其立体化学异构形式和其N-氧化物形式的化合物。 特别地，优选的化合物是3- [2- [4-（11,12-二氢-6H-苯并咪唑并[2,1-b] [3]苯并氮杂-6-基）-2-（苯基 - 甲基） - 1-哌啶基]乙基] -2,10-二甲基嘧啶并[1,2-a]苯并咪唑-4（10H） - 酮，其药学上可接受的酸或碱加成盐，其立体化学异构形式和N-氧化物形式 其中。 还要求的是市售的组胺H1和H2受体拮抗剂用于降低颅内压（ICP）的新颖用途。

公开(公告)号：US07476662B2

公开(公告)日：2009-01-13

申请号：US10479839

申请日：2002-06-11

申请人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Koenraad Arthur Van Rossem ,  Manuel Jesús Alcázar-Vaca ,  Pedro Martínez-Jiménez ,  José Manuel Bartolomé-Nebreda ,  Antonio Gómez-Sánchez ,  Francisco Javier Fernández-Gadea ,  Jos Van Reempts

发明人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Koenraad Arthur Van Rossem ,  Manuel Jesús Alcázar-Vaca ,  Pedro Martínez-Jiménez ,  José Manuel Bartolomé-Nebreda ,  Antonio Gómez-Sánchez ,  Francisco Javier Fernández-Gadea ,  Jos Van Reempts

IPC分类号： A61K31/00 ,  A61P43/00 ,  C07D487/04 ,  C07D519/00 ,  C07D495/04 ,  C07D487/14

CPC分类号： C07D487/04 ,  C07D471/04

摘要： The invention concerns novel substituted tetracyclic imidazole derivatives useful for the treatment of elevated intracranial pressure (ICP) and/or secondary ischaemia, in particular caused by brain injury, more in particular caused by traumatic (TBI) and non-traumatic brain injury, processes for their preparation, pharmaceutical compositions comprising them and their use as a medicine. The novel compounds comprise compounds according to the general Formula (I), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof and the N-oxide form thereof. In particular, the preferred compound is 3-[2-[4-(11,12-dihydro-6H-benzimidazo[2,1-b][3]benzazepin-6-yl)-2-(phenyl-l-methyl)-1-piperidinyl]ethyl]-2,10-dimethyl pyrimido[1,2-α]benzimidazol-4(10H)-one, the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof and the N-oxide form thereof.

摘要翻译： 本发明涉及可用于治疗升高的颅内压（ICP）和/或继发性缺血的新型取代的四环咪唑衍生物，特别是由脑损伤引起的，特别是由创伤性（TBI）和非创伤性脑损伤引起的 其制备方法，包含它们的药物组合物及其作为药物的用途。 新化合物包括根据通式（I）的化合物，其药学上可接受的酸或碱加成盐，其立体化学异构形式及其N-氧化物形式。 特别地，优选的化合物是3- [2- [4-（11,12-二氢-6H-苯并咪唑并[2,1-b] [3]苯并氮杂-6-基）-2-（苯基-1-甲基 ）-1-哌啶基]乙基] -2,10-二甲基嘧啶并[1,2-a]苯并咪唑-4（10H） - 酮，其药学上可接受的酸或碱加成盐，其立体化学异构形式和N- 氧化物形式。