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    Substituted 1-piperidin-4-yl-4-pyrrolidin-3-yl-piperazine derivatives and their use as neurokinin antagonists
    2.
    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
    3.
    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.

    Novel Formulations For Opioid-Based Treatments Of Pain Comprising 1-(1,2-Disubstituted Piperidinyl)-4-Substituted Piperazine Derivatives
    6.
    发明申请
    Novel Formulations For Opioid-Based Treatments Of Pain Comprising 1-(1,2-Disubstituted Piperidinyl)-4-Substituted Piperazine Derivatives 审中-公开
    用于基于阿片样物质治疗包含1-（1,2-二取代的哌啶基）-4-取代的哌嗪衍生物的疼痛的新型制剂

    公开(公告)号：US20080070924A1

    公开(公告)日：2008-03-20

    申请号：US10560482

    申请日：2004-06-07

    申请人： Frans Eduard Janssens ,  Francois Maria Sommen ,  Joseph Elisabeth Leenaerts ,  Yves Emiel Maria Van Roosbroeck ,  Theo Frans Meert

    发明人： Frans Eduard Janssens ,  Francois Maria Sommen ,  Joseph Elisabeth Leenaerts ,  Yves Emiel Maria Van Roosbroeck ,  Theo Frans Meert

    IPC分类号： A61K31/496 ,  A61P25/04

    CPC分类号： A61K31/4468 ,  A61K31/485 ,  A61K31/496 ,  A61K2300/00

    摘要： This invention concerns novel formulations for opioid-based treatments of pain and/or nociception comprising opioid analgesics and 1-(1,2-disubstituted piperidinyl)-4-substituted piperazine derivatives having neurokinin antagonistic activity, in particular NK1 antagonistic activity the use of said formulation for the manufacture of a medicament for the prevention and/or treatment of emesis, pain and/or nociception, in particular in acute and chronic pain treatments, more in particular in inflammatory, post-operative, emergency room (ER), breakthrough, neuropathic and cancer pain treatments and the use of an NK1-receptor antagonist for the manufacture of a medicament for the prevention and/or treatment of respiratory depression and tolerance in opioid-based treatments of pain.The pharmaceutical formulations according to the invention comprise NK1-antagonists according to the general Formula (I) 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.The pharmaceutical composition according to the invention reduces to a large extent a number of unwanted side-effects associated with opioid analgesics, in particular respiratory depression and tolerance, thereby increasing the total tolerability of said opioids in pain treatment.

    摘要翻译： 本发明涉及用于基于阿片样物质治疗疼痛和/或伤害感受的新型制剂，其包含阿片样镇痛药和具有神经激肽拮抗活性的1-（1,2-二取代哌啶基）-4-取代的哌嗪衍生物，特别是NK < 所述制剂用于制备用于预防和/或治疗呕吐，疼痛和/或伤害感受的药物，特别是在急性和慢性疼痛治疗中，特别是在炎性，术后， 急诊室（ER），突破性，神经病理性和癌症疼痛治疗，以及使用NK1受体拮抗剂制备用于预防和/或治疗阿片样物质的呼吸抑制和耐受性的药物 的治疗疼痛。 根据本发明的药物制剂包含根据通式（I）的NK 1 - 拮抗剂，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-氧化物形式和 其中所有取代基如权利要求1中所定义。根据本发明的药物组合物在很大程度上降低了与阿片类镇痛药相关的许多不想要的副作用，特别是呼吸抑制和耐受性，从而增加了 所述阿片类药物在疼痛治疗中。

    Fused imidazole derivatives as multidrug resistance modulators
    7.
    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。