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    Substituted 4-phenyl-4-(1H-imidazol-2-yl)-piperidine derivatives and their use as selective non-peptide delta opioid agonists
    3.
    发明授权
    Substituted 4-phenyl-4-(1H-imidazol-2-yl)-piperidine derivatives and their use as selective non-peptide delta opioid agonists 有权
    取代的4-苯基-4-（1H-咪唑-2-基） - 哌啶衍生物及其作为选择性非肽δ阿片激动剂的用途

    公开(公告)号：US07282508B2

    公开(公告)日：2007-10-16

    申请号：US10491379

    申请日：2002-10-10

    申请人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Francisco Javier Fernández-Gadea ,  Antonio Gómez-Sánchez ,  Theo Frans Meert

    发明人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Francisco Javier Fernández-Gadea ,  Antonio Gómez-Sánchez ,  Theo Frans Meert

    IPC分类号： A61K31/445 ,  C07D401/00

    CPC分类号： C07D401/04 ,  C07D401/14 ,  C07D413/14 ,  C07D417/14

    摘要： The present invention relates to novel 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives according to Formula (I) the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the N-oxide forms thereof. In particular are claimed compounds according to Formula (I) in which A═B is C═O or SO2, X is a covalent bond, R1 is alkyloxy, alkyloxyalkyl, Ar or NR9R10, wherein R9 and R10 each independently are hydrogen or Ar; or A═B and R1 together form a benzoxazolyl radical; p is zero, R3 is benzyl optionally substituted with hydroxy, alkyl or alkyloxycarbonyl and R4 and R5 each are hydrogen. The invention also relates to processes for the preparation of the compounds according to the invention and their use in medicine, in particular as selective non-peptide δ-opioid agonists for use in the treatment of various pain conditions.

    摘要翻译： 本发明涉及式（I）的新的4-苯基-4- [1H-咪唑-2-基] - 哌啶衍生物，其药学上可接受的酸或碱加成盐，其立体化学异构形式，其互变异构体 及其N-氧化物形式。 特别是根据式（I）的化合物，其中AB是CO或SO 2，X是共价键，R 1是烷氧基，烷氧基烷基，Ar或NR 其中R 9和R 10各自独立地是氢或Ar;其中R 9和R 10各自独立地是氢或Ar; 或A-B和R 1一起形成苯并恶唑基; p为0，R 3为任选被羟基，烷基或烷氧基羰基取代的苄基，R 4和R 5各自为氢。 本发明还涉及根据本发明的化合物的制备方法及其在医学中的用途，特别是用于治疗各种疼痛病症的选择性非肽δ-阿片样物质激动剂。

    Substituted 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives for reducing ischaemic damage
    4.
    发明授权
    Substituted 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives for reducing ischaemic damage 有权
    取代的4-苯基-4- [1H-咪唑-2-基] - 哌啶衍生物，用于减少缺血性损伤

    公开(公告)号：US07390822B2

    公开(公告)日：2008-06-24

    申请号：US10492778

    申请日：2002-10-10

    申请人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Francisco Javier Fernández-Gadea ,  Paul Joannes Ludovicus Herijgers ,  Theo Frans Meert ,  Antonio Gómez-Sánchez ,  Willem Flameng ,  Marcel J. M. Borgers

    发明人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Francisco Javier Fernández-Gadea ,  Paul Joannes Ludovicus Herijgers ,  Theo Frans Meert ,  Antonio Gómez-Sánchez ,  Willem Flameng ,  Marcel J. M. Borgers

    IPC分类号： A61K31/445 ,  A61K31/454

    CPC分类号： A61K31/454

    摘要： The present invention relates to an agent for reducing ischaemic damage to an organ, in particular to a heart and a brain, pharmaceutical compositions comprising said agent and the use of said agent for the treatment of ischaemic diseases to the heart and the brain. The agent comprises a substituted 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivative according to Formula (I) the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof, the N-oxide forms thereof and the prodrugs thereof. In particular are claimed the compounds according to Formula (I) in which A=B is C═O or SO2, X is a covalent bond, R1 is alkyloxy, alkyloxyalkyl, Ar or NR9R10, wherein R9 and R10 each independently are hydrogen or Ar; or A=B and R1 together form a benzoxazolyl radical; p is zero, R3 is benzyl optionally substituted with hydroxy, alkyl or alkyloxycarbonyl and R4 and R5 each are hydrogen. The use of said agents has important clinical ramifications with regard to the reduction of ischaemic damage to an organ in a mammal, in particular to a heart and/or a brain, the prevention of coronary artery diseases in a mammal by inducing a cardioprotective effect and the treatment and prevention of stroke.

    摘要翻译： 本发明涉及用于减轻对器官特别是心脏和脑的缺血性损伤的药剂，包含所述药物的药物组合物和所述药物用于治疗心脏和脑部的缺血性疾病的用途。 该试剂包含根据式（I）的取代的4-苯基-4- [1H-咪唑-2-基] - 哌啶衍生物，其药学上可接受的酸或碱加成盐，其立体化学异构形式，其互变异构形式， 其N-氧化物形式及其前药。 特别要求保护的是根据式（I）的化合物，其中A = B是CO或SO 2，X是共价键，R 1是烷氧基，烷氧基烷基， Ar或NR 9 R 10，其中R 9和R 10各自独立地为氢或Ar; 或A = B和R 1一起形成苯并恶唑基; p为0，R 3为任选被羟基，烷基或烷氧基羰基取代的苄基，R 4和R 5各自为氢。 所述试剂的使用对于减少对哺乳动物，特别是心脏和/或脑的器官的缺血损伤，通过诱导心脏保护作用来预防哺乳动物的冠状动脉疾病，具有重要的临床后果，以及 治疗和预防中风。

    Substituted 1-piperidin-4-yl-4-pyrrolidin-3-yl-piperazine derivatives and their use as neurokinin antagonists
    7.
    发明授权
    Substituted 1-piperidin-4-yl-4-pyrrolidin-3-yl-piperazine derivatives and their use as neurokinin antagonists 有权
    取代的1-哌啶-4-基-4-吡咯烷-3-基 - 哌嗪衍生物及其作为神经激肽拮抗剂的用途

    公开(公告)号：US07795261B2

    公开(公告)日：2010-09-14

    申请号：US10540447

    申请日：2003-12-17

    申请人： Frans Eduard Janssens ,  François Maria Sommen ,  Benoît Christian Albert Ghislain De Boeck ,  Joseph Elisabeth Leenaerts

    发明人： Frans Eduard Janssens ,  François Maria Sommen ,  Benoît Christian Albert Ghislain De Boeck ,  Joseph Elisabeth Leenaerts

    IPC分类号： C07D401/14 ,  C07D405/14 ,  C07D409/14 ,  C07D413/14 ,  C07D417/14 ,  A61K31/496 ,  A61K31/498

    CPC分类号： C07D401/12 ,  C07D401/14 ,  C07D405/14 ,  C07D409/14 ,  C07D413/14 ,  C07D417/14

    摘要： This invention concerns substituted I-piperidin-4-yl-4-pyrrolidin-3-yl-piperazine derivatives having neurokinin antagonistic activity, in particular NK1 antagonistic activity, a combined NK1/NK3 antagonistic activity and a combined NK1/NK2/NK3 antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment of schizophrenia, anxiety, depression, emesis and IBS. 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. In view of their capability to antagonize the actions of tachykinins by blocking the neurokinin receptors, and in particular antagonizing the actions of substance P and Neurokinin B by blocking the NK1, NK2 and NK3 receptors, the compounds according to the invention are useful as a medicine, in particular in the prophylactic and therapeutic treatment of tachykinin-mediated conditions, such as, for instance CNS disorders, in particular schizoaffective disorders, depression, anxiety disorders, stress-related disorders, sleep disorders, cognitive disorders, personality disorders, eating disorders, neurodegenerative diseases, addiction disorders, mood disorders, sexual dysfunction, pain and other CNS-related conditions; inflammation; allergic disorders; emesis; gastrointestinal disorders, in particular irritable bowel syndrome (IBS); skin disorders; vasospastic diseases; fibrosing and collagen diseases; disorders related to immune enhancement or suppression and rheumatic diseases and body weight control.

    摘要翻译： 本发明涉及具有神经激肽拮抗活性的特异性N-哌啶-4-基-4-吡咯烷-3-基 - 哌嗪衍生物，特别是NK1拮抗活性，组合的NK1 / NK3拮抗活性和组合的NK1 / NK2 / NK3拮抗活性 ，它们的制备，包含它们的组合物及其作为药物的用途，特别是用于治疗精神分裂症，焦虑，抑郁，呕吐和IBS。 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 鉴于其通过阻断神经激肽受体拮抗速激肽的作用的能力，特别是通过阻断NK1，NK2和NK3受体拮抗物质P和神经激肽B的作用，本发明的化合物是 可用作药物，特别是在速激肽介导的病症例如CNS疾病，特别是分裂情感障碍，抑郁症，焦虑障碍，应激相关疾病，睡眠障碍，认知障碍，人格障碍的预防和治疗中的治疗 ，进食障碍，神经变性疾病，成瘾症，情绪障碍，性功能障碍 疼痛等CNS相关病情; 炎; 过敏性疾病; 呕吐 胃肠道疾病，特别是肠易激综合征（IBS）; 皮肤病; 血管痉挛性疾病; 纤维化和胶原病; 与免疫增强或抑制相关的疾病和风湿性疾病和体重控制。

    Substituted 1-piperidin-4-yl-4-azetidin-3-yl-piperazine derivatives and their use as neurokinin antagonists
    8.
    发明授权
    Substituted 1-piperidin-4-yl-4-azetidin-3-yl-piperazine derivatives and their use as neurokinin antagonists 失效

    公开(公告)号：US07435736B2

    公开(公告)日：2008-10-14

    申请号：US10540304

    申请日：2003-12-17

    申请人： Frans Eduard Janssens ,  François Maria Sommen ,  Benoît Christian Albert Ghislain De Boeck ,  Joseph Elisabeth Leenaerts

    发明人： Frans Eduard Janssens ,  François Maria Sommen ,  Benoît Christian Albert Ghislain De Boeck ,  Joseph Elisabeth Leenaerts

    IPC分类号： A61K31/496 ,  A61K31/497 ,  C07D401/12 ,  C07D401/14 ,  C07D409/14 ,  C07D417/14 ,  C07D405/14

    CPC分类号： C07D401/12 ,  C07D401/14 ,  C07D405/14 ,  C07D409/14 ,  C07D417/14

    摘要： The invention concerns substituted 1-piperidin-4-yl-4-azetidin-3-yl-piperazine having neurokinin antagonistic activity, in particular NK1 and NK1/NK3-antagonistic activity, their preparation, compositions comprising them and their use as a medicine, in particular for the treatment of schizophrenia, emesis, anxiety, depression, irritable bowel syndrome (IBS), circadian rhythm disturbances, pain, neurogenic inflammation, asthma, micturition disorders such as urinary incontinence and nociception. 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. In view of their capability to antagonize the actions of tachykinins by blocking the neurokinin receptors, and in particular antagonizing the actions of substance P by blocking the NK receptors, the compounds according to the invention are useful as a medicine, in particular in the prophylactic and therapeutic treatment of tachykinin-mediated conditions, such as, for instance CNS disorders, in particular depression, anxiety disorders, stress-related disorders, sleep disorders, cognitive disorders, personality disorders, schizoaffective disorders, eating disorders, neurodegenerative diseases, addiction disorders, mood disorders, sexual dysfunction, pain and other CNS-related conditions; inflammation; allergic disorders; emesis; gastrointestinal disorders, in particular irritable bowel syndrome (IBS); skin disorders; vasospastic diseases; fibrosing and collagen diseases; disorders related to immune enhancement or suppression and rheumatic diseases and body weight control.

    1-(1,2-disubstituted piperidinyl)-4-substituted piperazine derivatives
    9.
    发明授权
    1-(1,2-disubstituted piperidinyl)-4-substituted piperazine derivatives 有权
    1-（1,2-二取代的哌啶基）-4-取代的哌嗪衍生物

    公开(公告)号：US06521621B1

    公开(公告)日：2003-02-18

    申请号：US09745513

    申请日：2000-12-22

    申请人： Frans Eduard Janssens ,  François Maria Sommen ,  Dominique Louis Nestor Ghislaine Surleraux ,  Joseph Elisabeth Leenaerts ,  Yves Emiel Maria Van Roosbroeck

    发明人： Frans Eduard Janssens ,  François Maria Sommen ,  Dominique Louis Nestor Ghislaine Surleraux ,  Joseph Elisabeth Leenaerts ,  Yves Emiel Maria Van Roosbroeck

    IPC分类号： A61K31496

    CPC分类号： C07D401/12 ,  C07D211/58 ,  C07D405/12 ,  C07D413/14 ,  C07D417/12 ,  C07D471/04 ,  Y02P20/55

    摘要： This invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereoisomeric forms thereof, wherein n is 0, 1 or 2; m is 1 or 2, provided that if m is 2, then n is 1; p is 1 or 2; ═Q is ═O or ═NR3; X is a covalent bond or a bivalent radical of formula —O—, —S—, —NR3—; R1 is Ar1, Ar1C1-6alkyl or di(Ar1)C1-6alkyl, wherein each C1-6alkyl group is optionally substituted with hydroxy, C1-4alkyloxy, oxo or a ketalized oxo substituent; R2 is Ar2, Ar2C1-6alkyl, Het1 or Het1C1-6alkyl; R3 is hydrogen or C1-6alkyl; L is hydrogen; Ar3; C1-6alkyl; C1-6alkyl substituted with 1 or 2 substituents selected from hydroxy, C1-6alkyloxy, Ar3, Ar3C1-6alkyloxy and Het2; C3-6alkenyl; Ar3C3-6alkenyl; di(Ar3)C3-6alkenyl or a radical of formula (a-1), (a-2), (a-3), (a-4) or (a-5); Ar1, Ar2 and Ar3 are each phenyl or substituted phenyl; Het1 and Het2 are each monocyclic or a bicyclic heterocycles; as substance-P antagonists; their preparation, compositions containing them and their use as a medicine.

    摘要翻译： 本发明涉及配制N-氧化物形式的化合物，其药学上可接受的加成盐和立体异构形式，其中n为0,1或2; m为1或2，条件是如果m为2，则n为1; p为1或2; = Q是= O或= NR3; X是共价键或式-O-，-S-，-NR 3 - 的二价基团; R 1是Ar 1，Ar 1 C 1-6烷基或二（Ar 1）C 1-6烷基，其中每个C 1-6烷基任选被羟基，C 1-4烷氧基，氧代或缩酮化的取代基取代; R2是Ar2，Ar2C1-6烷基，Het1或Het1C1-6烷基; R3是氢或C1-6烷基; L是氢; Ar3; C 1-6烷基; 被1或2个选自羟基，C 1-6烷氧基，Ar 3，Ar 3 C 1-6烷氧基和Het 2的取代基取代的C 1-6烷基; C 3-6烯基; Ar3C3-6烯基; 二（Ar 3）C 3-6烯基或式（a-1），（a-2），（a-3），（a-4）或（a-5）的基团。 Ar 1，Ar 2和Ar 3分别为苯基或取代的苯基; Het1和Het2分别是单环或双环杂环; 作为物质-P拮抗剂; 其制剂，含有它们的组合物及其作为药物的用途。

    Fused imidazole derivatives as multidrug resistance modulators
    10.
    发明授权
    Fused imidazole derivatives as multidrug resistance modulators 失效
    熔融咪唑衍生物作为多药耐药调节剂

    公开(公告)号：US06476018B1

    公开(公告)日：2002-11-05

    申请号：US09775524

    申请日：2001-02-02

    申请人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Francois Maria Sommen ,  Dominique Louis Nestor Ghislaine Surleraux

    发明人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Francois Maria Sommen ,  Dominique Louis Nestor Ghislaine Surleraux

    IPC分类号： A61K31437

    CPC分类号： C07D487/14 ,  C07D471/04 ,  C07D487/04 ,  C07D495/14

    摘要： This invention concerns the compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein the dotted line is an optional bond; n is 1 or 2; R1 is hydrogen; halo; formyl; C1-4alkyl optionally substituted with hydroxy, C1-4alkyloxy, C1-4alkylcarbonyloxy, imidazolyl, thiazolyl or oxazolyl; or a radical of formula —X—COOR5, —X—CONR6R7 or —X—COR10 wherein —X— is a direct bond, C1-4alkanediyl or C2-6alkenediyl; R5 is hydrogen, C1-12alkyl, Ar, Het, C1-6alkyl substituted with C1-4alkyloxy, aryl or heteroaryl; R6 and R7 each independently are hydrogen or C1-4alkyl; R2 is hydrogen, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkyloxycarbonyl, carboxyl, formyl or phenyl; R3 is hydrogen, C1-4alkyl or C1-4alkyloxy; R4 is hydrogen, halo, C1-4alkyl, C1-4alkyloxy or haloC1-4alkyl; Z is —CH2—, —CH2—CH2—, —CH═CH—, —CHOH—CH2—, —O—CH2—, —C(═O)—CH2— or —C(═NOH)—CH2—; —A—B— is a bivalent radical; A1 is a direct bond, optionally substituted C1-6alkanediyl, C1-6alkanediyl-oxy-C1-6alkanediyl, carbonyl, C1-6alkanediylcarbonyl, optionally substituted C1-6alkanediyloxy; A2 is a direct bond or C1-6alkanediyl; and Q is aryl. Processes for preparing said products, formulations comprising said products and their use as a medicine are disclosed, in particular for inhibiting or reversing the effects of multidrug resistance.

    摘要翻译： 本发明涉及配制N-氧化物形式的化合物，其药学上可接受的加成盐及其立体化学异构形式，其中虚线是任选的键; n为1或2; R1是氢; 光环; 甲酰基 任选被羟基，C 1-4烷氧基，C 1-4烷基羰基氧基，咪唑基，噻唑基或恶唑基取代的C 1-4烷基; 或式-X-COOR5，-X-CONR6R7或-X-COR10基团，其中-X-是直接键，C1-4烷二基或C2-6亚烯基; R 5是氢，C 1-12烷基，Ar，Het，被C 1-4烷氧基，芳基或杂芳基取代的C 1-6烷基; R6和R7各自独立地为氢或C1-4烷基; R 2是氢，卤素，C 1-4烷基，羟基C 1-4烷基，C 1-4烷氧基羰基，羧基，甲酰基或苯基; R3是氢，C1-4烷基或C1-4烷氧基; R 4是氢，卤素，C 1-4烷基，C 1-4烷氧基或卤代C 1-4烷基; Z是-CH 2 - ， - CH 2 -CH 2 - ， - CH = CH-，-CHOH-CH 2 - ， - O-CH 2 - ， - C（= O）-CH 2 - 或-C（= NOH） -A-B-是二价基团; A1是直接键，任选取代的C 1-6烷二基，C 1-6烷二基 - 氧基-C 1-6烷二基，羰基，C 1-6烷二基羰基，任选取代的C 1-6烷二基氧基; A2是直接键或C1-6烷二基; Q为芳基。 公开了用于制备所述产品的方法，包含所述产品的制剂及其作为药物的用途，特别是用于抑制或逆转多药耐药性的作用。