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    Substituted 4-phenyl-4-(1H-imidazol-2-yl)-piperidine derivatives and their use as selective non-peptide delta opioid agonists
    11.
    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。

    1-(1,2-disubstituted piperidinyl)-4-substituted piperazine derivatives
    12.
    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
    13.
    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：US06218381B1

    公开(公告)日：2001-04-17

    申请号：US09142932

    申请日：1998-09-17

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

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

    IPC分类号： A61K31435

    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。

    Substituted 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives for reducing ischaemic damage
    15.
    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。

    1-(1,2-disubstituted piperidinyl)-4 (fused imidazole)-piperidine derivatives
    19.
    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。

    Antiallergic imidazoazepines
    20.
    发明授权
    Antiallergic imidazoazepines 失效
    抗过敏咪唑并吖嗪

    公开(公告)号：US5674866A

    公开(公告)日：1997-10-07

    申请号：US557131

    申请日：1995-12-13

    申请人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts

    发明人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts

    IPC分类号： A61K31/4184 ,  A61K31/55 ,  A61P11/06 ,  A61P17/00 ,  A61P27/14 ,  A61P27/16 ,  A61P37/08 ,  C07D401/04 ,  C07D401/06 ,  C07D401/14 ,  C07D405/14 ,  C07D409/14 ,  C07D471/04 ,  C07D487/04 ,  C07D487/14 ,  C07D491/14 ,  C07D491/147 ,  C07D495/14 ,  C07D513/04 ,  C07D519/00

    CPC分类号： C07D401/04 ,  C07D401/14 ,  C07D405/14 ,  C07D409/14 ,  C07D471/04 ,  C07D487/04 ,  C07D487/14 ,  C07D491/14 ,  C07D495/14 ,  C07D513/04

    摘要： The present invention is concerned with novel imidazoazepines of formula ##STR1## the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein each of the dotted lines independently represents an optional bond; --A--B-- is a radical of formula --X--CH.dbd.CH-- (a-1); --CH.dbd.CH--X-- (a-2); or --CH.dbd.CH-- CH.dbd.CH-- (a-3); X represents O, S or NR.sup.1 ; R.sup.1 represents hydrogen or C.sub.1-6 alkyl; -----Y is a radical of formula .dbd.O (b-1); --OH (b-2); or .dbd.N--OH (b-3); and L represents hydrogen, C.sub.1-4 alkylcarbonyl, C.sub.1-4 alkyloxycarbonyl, phenylcarbonyl, C.sub.1-6 alkyl or C.sub.1-6 alkyl substituted with C.sub.1-4 alkyloxycarbonyl, hydroxycarbonyl, aryl, aryloxy or a radical of formula ##STR2## --D--Z-- is --S--CH.dbd.CH--, --S--CH.sub.2 --CH.sub.2 --, --S--CH.sub.2 --CH.sub.2 --CH.sub.2 --, --CH.dbd.CH--CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --; and aryl is phenyl or phenyl substituted with halo, hydroxy or C.sub.1-4 alkyloxy. Compositions comprising said compounds, processes for preparing the same and the use of these compounds for treating allergic diseases.

    摘要翻译： PCT No.PCT / EP94 / 02287第 371 1995年12月13日第 102（e）日期1995年12月13日PCT 1994年7月6日PCT公布。 公开号WO95 / 02600 日期1995年1月26日本发明涉及式（I）的药学上可接受的加成盐和立体化学异构形式的新型咪唑并吖庚因，其中每条虚线独立地表示任选的键; -A-B-是式-X-CH = CH-（a-1）的基团; -CH = CH-X-（a-2）; 或-CH = CH-CH = CH-（a-3）; X表示O，S或NR1; R1表示氢或C1-6烷基; + E，ovs ----- + EE Y是式= O（b-1）的基团; -OH（b-2）; 或= N-OH（b-3）; （C）-DZ-是-S-的基团，其中L表示氢，C1-4烷基羰基，C1-4烷氧基羰基，苯基羰基，C1-6烷基或被C1-4烷氧基羰基，羟基羰基，芳基，芳氧基或式 -CH = CH-，-S-CH2-CH2-，-S-CH2-CH2-CH2-，-CH = CH-CH = CH-或-CH2-CH2-CH2-CH2-; 并且芳基是苯基或被卤素，羟基或C 1-4烷氧基取代的苯基。 包含所述化合物的组合物，其制备方法以及这些化合物用于治疗过敏性疾病的用途。