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    Novel Formulations For Opioid-Based Treatments Of Pain Comprising 1-(1,2-Disubstituted Piperidinyl)-4-Substituted Piperazine Derivatives
    1.
    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。

    Novel formulations of opioid-based treatments of pain comprising substituted 1,4-di-piperidin-4-yl-piperazine derivatives
    2.
    发明申请
    Novel formulations of opioid-based treatments of pain comprising substituted 1,4-di-piperidin-4-yl-piperazine derivatives 审中-公开
    基于阿片样物质治疗疼痛的新型制剂包括取代的1,4-二哌啶-4-基 - 哌嗪衍生物

    公开(公告)号：US20060128721A1

    公开(公告)日：2006-06-15

    申请号：US10560476

    申请日：2004-06-07

    申请人： Frans Janssens ,  Francois Sommen ,  Benoit Christian Albert Ghislain De Boeck ,  Joseph Elisabeth Leenaerts ,  Yves Emiel, Maria Van Roosbroeck ,  Theo Frans Meert

    发明人： Frans Janssens ,  Francois Sommen ,  Benoit Christian Albert Ghislain De Boeck ,  Joseph Elisabeth Leenaerts ,  Yves Emiel, Maria Van Roosbroeck ,  Theo Frans Meert

    IPC分类号： A61K31/496

    CPC分类号： A61K45/06 ,  A61K31/496 ,  A61K31/551 ,  A61K2300/00

    摘要： This invention concerns novel formulations for opioid-based treatments of pain and/or nociception comprising opioid analgesics and 1,4-di-piperidin-4-yl-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 opioid-based 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 in opioid-based treatments of pain. The pharmaceutical formulations according to the invention comprise a pharmaceutically acceptable carrier and, as active ingredients, a therapeutically effective amount of an opioid analgesic and 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 emesis, 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/或伤害感受的新制剂，其包含具有神经激肽拮抗活性的阿片类镇痛药和1,4-二哌啶-4-基 - 哌嗪衍生物，特别是NK1 拮抗活性，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，特别是基于阿片样物质的急性和慢性疼痛治疗的药物的用途，特别是在炎性， 手术，急诊室（ER），突破性，神经病理性和癌症疼痛治疗，以及使用NK 1受体拮抗剂制备用于预防和/或治疗阿片样物质中呼吸抑制的药物 的治疗疼痛。 根据本发明的药物制剂包含药学上可接受的载体，并且作为活性成分，具有治疗有效量的根据通式（I）的药学上可接受的酸的阿片样物质止痛剂和NK 1拮抗剂 或其碱加成盐，其立体化学异构形式，其N-氧化物形式和其前药，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多个不需要的副产物， 与阿片类止痛药相关的作用，特别是呕吐，呼吸抑制和耐受性，从而增加所述阿片类药物在疼痛治疗中的总耐受性。

    1-(1,2-disubstituted piperidinyl)-4-substituted piperazine derivatives
    4.
    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。

    1-(1,2-disubstituted piperidinyl)-4 (fused imidazole)-piperidine derivatives
    6.
    发明授权
    1-(1,2-disubstituted piperidinyl)-4 (fused imidazole)-piperidine derivatives 失效
    1-（1,2-二取代的哌啶基）-4（稠合咪唑） - 哌啶衍生物

    公开(公告)号：US06251894B1

    公开(公告)日：2001-06-26

    申请号：US09102136

    申请日：1998-06-22

    申请人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Yves Emiel Maria Van Roosbroeck

    发明人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Yves Emiel Maria Van Roosbroeck

    IPC分类号： A01N4346

    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 n is 0, 1 or 2; m is 1 or 2, provided that if m is 2, then n is 1; ═Q is ═O or ═NR3; X is a covalent bond or —O—, —S—, —NR3—; R1 is Ar1, Ar1C1-6alkyl or di(Ar1)C1-6alkyl, wherein each C1-6alkyl group is optionally substituted; R2 is Ar2, Ar2C1-6alkyl, Het or HetC1-6alkyl; R3 is hydrogen or C1-6alkyl; L is a piperidine derivative of formula (a-1) or a spiro piperidine derivative of formula (a-2); Ar1 is phenyl or substituted phenyl; Ar2 is naphtalenyl; phenyl or substituted phenyl; and Het is a monocyclic or bicyclic heterocycle; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom; 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及其立体化学异构形式，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; = Q是= O或= NR3; X是共价键或-O - ， - S - ， - NR 3 - ; 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烷基任选被取代; R2是Ar2，Ar2C1-6烷基，Het或HetC1-6烷基; R3是氢或C1-6烷基; L是式（a-1）的哌啶衍生物或式（a-2）的螺哌啶衍生物; Ar 1是苯基或取代的苯基; Ar2是萘基; 苯基或取代的苯基; Het是单环或双环杂环; 每个单环和双环杂环可任选地在碳原子上取代; 作为P物质拮抗剂; 其制剂，含有它们的组合物及其作为药物的用途。

    Substituted 4-phenyl-4-(1H-imidazol-2-yl)-piperidine derivatives and their use as selective non-peptide delta opioid agonists
    7.
    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
    8.
    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。

    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。