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    Substituted 1-piperidin-4-yl-4-pyrrolidin-3-yl-piperazine derivatives and their use as neurokinin antagonists
    3.
    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
    4.
    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
    6.
    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-substituted piperidine derivatives
    7.
    发明授权
    1-(1,2-Disubstituted piperidinyl)-4-substituted piperidine derivatives 失效
    1-（1,2-二取代哌啶基）-4-取代的哌啶衍生物

    公开(公告)号：US06169097A

    公开(公告)日：2001-01-02

    申请号：US09102295

    申请日：1998-06-22

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

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

    IPC分类号： A61K31445

    CPC分类号： C07D401/06 ,  C07D211/44 ,  C07D211/46 ,  C07D211/52 ,  C07D211/58 ,  C07D401/14 ,  C07D405/14 ,  C07D409/14 ,  C07D417/14 ,  C07D471/10 ,  C07D491/10

    摘要： The present invention concerns compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and 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; p is 0, 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 of formula —O—CH2—CH2—O— or —O—CH2—CH2—CH2—O—; R2 is Ar2; Ar2C1-6alkyl; Het or HetC1-6alkyl; R3 is hydrogen or C1-6alkyl; R4 is hydrogen; C1-4alkyl; C1-4aklyloxyC1-4alkyl; hydroxyC1-4alkyl; carboxyl; C1-4aklyloxycarbonyl or Ar3; R5 is hydrogen; hydroxy; Ar3; Ar3C1-6alkyloxy; di(Ar3)C1-6alkyloxy; Ar3C1-6alkylthio; di(Ar3)C1-6alkylthio; Ar3C1-6alkylsulfoxy; di(Ar3)C1-6alkylsulfoxy; Ar3C1-6alkylsulfonyl; di(Ar3)C1-6alkylsulfonyl; —NR7R8; C1-6alkyl substituted with —NR7R8; or a radical of formula (a-1) or (a-2); R4 and R5 may also be taken together; R6 is hydrogen; hydroxy; C1-6alkyloxy; C1-6alkyl or Ar3C1-6alkyl; Ar1, Ar2 and Ar3 are phenyl or substituted phenyl; Ar2 is also naphtalenyl; and Het is an optionally substituted monocyclic or bicyclic heterocycle; 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; p为0,1或2; = Q是= O或= NR3; X是共价键或式-O-，-S-，-NR 3 - 的二价基团; R1是Ar1; 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，氧代或式-O-CH 2 -CH 2 -O-或-O-CH 2 -CH2-CH2-O-; R2是Ar2; Ar2C1-6烷基; Het或HetC 1-6烷基; R3是氢或C1-6烷基; R4是氢; C 1-4烷基; C 1-4烷氧基C 1-4烷基; 羟基C 1-4烷基; 羧基; C 1-4烷氧基羰基或Ar 3; R5是氢; 羟基; Ar3; Ar 3 C 1-6烷氧基; 二（Ar 3）C 1-6烷氧基; Ar 3 C 1-6烷硫基; 二（Ar 3）C 1-6烷硫基; Ar3C1-6烷基磺酰基; 二（Ar 3）C 1-6烷基亚磺酰基; Ar 3 C 1-6烷基磺酰基; 二（Ar 3）C 1-6烷基磺酰基; -NR7R8; 被-NR 7 R 8取代的C 1-6烷基; 或式（a-1）或（a-2）的基团; R4和R5也可以一起使用; R6是氢; 羟基; C 1-6烷氧基; C 1-6烷基或Ar 3 C 1-6烷基; Ar1，Ar2和Ar3是苯基或

    1-(1,2-disubstituted pipeidinyl)-4-substituted piperidine derivatives
    8.
    发明授权
    1-(1,2-disubstituted pipeidinyl)-4-substituted piperidine derivatives 有权
    1-（1,2-二取代的管基）-4-取代的哌啶衍生物

    公开(公告)号：US06346540B1

    公开(公告)日：2002-02-12

    申请号：US09615523

    申请日：2000-07-13

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

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

    IPC分类号： A61K31454

    CPC分类号： C07D401/06 ,  C07D211/44 ,  C07D211/46 ,  C07D211/52 ,  C07D211/58 ,  C07D401/14 ,  C07D405/14 ,  C07D409/14 ,  C07D417/14 ,  C07D471/10 ,  C07D491/10

    摘要： The present invention concerns compounds of formula the N-oxide forms, the pharmaceutically acceptable addition salts and 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; p is 0, 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 of formula —O—CH2—CH2—O— or —O—CH2—CH2—CH2—O—; R2 is Ar2; Ar2C1-6alkyl; Het or HetC1-6alkyl; R3 is hydrogen or C1-6alkyl; R4 is hydrogen; C1-4alkyl; C1-4alkyloxyC1-4alkyl; hydroxyC1-4alkyl; carboxyl; C1-4alkyloxycarbonyl or Ar3; R5 is hydrogen; hydroxy; Ar3; Ar3C1-6alkyloxy; di(Ar3)C1-6alkyloxy; Ar3C1-6alkylthio; di(Ar3)C1-6alkylthio; Ar3C1-6alkylsulfoxy; di(Ar3)C1-6alkylsulfoxy; Ar3C1-6alkylsulfonyl; di(Ar3)C1-6alkylsulfonyl; —NR7R8; C1-6alkyl substituted with —NR7R8; or a radical of formula (a-1) or (a-2); R4 and R5 may also be taken together; R6 is hydroxy; C1-6alkyloxy; C1-6alkyl or Ar3C1-6alkyl; Ar1, Ar2 and Ar3 are phenyl or substituted phenyl; Ar2 is also naphtalenyl; and Het is an optionally substituted monocyclic or bicyclic heterocycle; 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; p为0,1或2; = Q是= O或= NR3; X是共价键或式-O-，-S-，-NR 3 - 的二价基团; R1是Ar1; 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，氧代或式-O-CH 2 -CH 2 -O-或-O-CH 2 -CH2-CH2-O-; R2是Ar2; Ar2C1-6烷基; Het或HetC 1-6烷基; R3是氢或C1-6烷基; R4是氢; C 1-4烷基; C 1-4烷氧基C 1-4烷基; 羟基C 1-4烷基; 羧基; C 1-4烷氧基羰基或Ar 3; R5是氢; 羟基; Ar3; Ar 3 C 1-6烷氧基; 二（Ar 3）C 1-6烷氧基; Ar 3 C 1-6烷硫基; 二（Ar 3）C 1-6烷硫基; Ar3C1-6烷基磺酰基; 二（Ar 3）C 1-6烷基亚磺酰基; Ar 3 C 1-6烷基磺酰基; 二（Ar 3）C 1-6烷基磺酰基; -NR7R8; 被-NR 7 R 8取代的C 1-6烷基; 或式（a-1）或（a-2）的基团; R4和R5也可以一起使用; R6是羟基; C 1-6烷氧基; C 1-6烷基或Ar 3 C 1-6烷基; Ar1，Ar2和Ar3是苯基或取代基

    Fused imidazole derivatives as multidrug resistance modulators
    9.
    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。