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    BENZISOXAZOLE DERIVATIVES HAVING D4-ANTAGONISTIC ACTIVITY
    71.
    发明公开
    BENZISOXAZOLE DERIVATIVES HAVING D4-ANTAGONISTIC ACTIVITY 有权
    具有D4-拮抗活性的苯并恶唑衍生物

    公开(公告)号：EP1054885A2

    公开(公告)日：2000-11-29

    申请号：EP99914450.4

    申请日：1999-02-05

    申请人： DUPHAR INTERNATIONAL RESEARCH B.V

    发明人： DEN HARTOG, Jacobus A., J. ,  VISSER, Gerben, M. ,  VAN STEEN, Bartholomeus, J. ,  TULP, Martinus, T., M. ,  RONKEN, Eric ,  KRUSE, Cornelis, G. ,  LANGE, Josephus H., M.

    IPC分类号： C07D413/14 ,  A61K31/445

    CPC分类号： C07D413/14

    摘要： The present invention relates to a group of novel benzisoxazole derivatives which are potent and selective antagonists of the dopamine D4-receptor. The compounds have general formula (I) wherein (R1)n represents 0, 1, or 2 substituents, which can be the same or different, from the group C1-3-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino mono- or dialkyl (C1-2)-amino, sulfonyl-(C1-3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1-2)-amino, X is O, S, NH or NCH3, Y represents CH2 or (CH2)2, (R2)m represents 0, 1, or 2 substituents, which can be the same or different, from the group methyl and ethyl, or (R2)m is a methylene bridge or ethylene bridge, A is a group -CH2-(CRH)p- wherein R is hydrogen or methyl and p is 0 or 1, and B represents 2- or 3-indolyl or 2-benzimidazolyl, which groups may be substituted at carbon with 1 or 2 substituents from the group C-1-3-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino, mono- or dialkyl (C1-2)amino, sulfonyl-(C1-3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1-2)-amino.

    摘要翻译： 本发明涉及一组新颖的苯并异恶唑衍生物，它们是多巴胺D4-受体的有效和选择性拮抗剂。 所述化合物具有通式（I）：其中（R 1）n表示0,1或2个取代基，所述取代基可以相同或不同，选自C 1-3烷基或烷氧基，卤素，三氟甲基，硝基， （C1-2） - 氨基，磺酰基 - （C1-3）烷基或 - 烷氧基，磺酰基三氟甲基，磺酰基氨基和磺酰基单或二烷基（C1-2） - 氨基，X是O，S，NH或 NCH 3，Y代表CH 2或（CH 2）2，（R 2）m代表0,1或2个可与甲基和乙基相同或不同的取代基，或（R 2）m是亚甲基桥或亚乙基 桥基，A是基团-CH 2 - （CRH）p - ，其中R是氢或甲基，p是0或1，B代表2-或3-吲哚基或2-苯并咪唑基，这些基团可以在碳上被1 或C1-C3-烷基或烷氧基，卤素，三氟甲基，硝基，氨基，单或二烷基（C1-2）氨基，磺酰基 - （C1-3）烷基或 - 烷氧基，磺酰基三氟甲基， 磺酰基氨基和磺酰基单或二烷基（C1-2） - 氨基。

    Substantially pure hetero-bicyclic alcohol enantiomers
    72.
    发明公开
    Substantially pure hetero-bicyclic alcohol enantiomers 失效
    Wesentlich saubere异双环Alkohol-Enantiomeren

    公开(公告)号：EP0939135A1

    公开(公告)日：1999-09-01

    申请号：EP98204281.4

    申请日：1993-12-09

    申请人： DUPHAR INTERNATIONAL RESEARCH B.V

    发明人： The designation of the inventor has not yet been filed

    IPC分类号： C12P41/00 ,  C12P17/06 ,  C12P17/14 ,  C07D319/20 ,  C07D311/04 ,  C07D265/36 ,  C07D327/06

    CPC分类号： C07D265/36 ,  C07D311/04 ,  C07D319/20 ,  C07D327/06 ,  C12P17/06 ,  C12P17/14 ,  C12P41/004 ,  Y02P20/55 ,  Y02P20/582

    摘要： The invention relates to substantially pure hetero-bicyclic alcohol enantiomers of the formula I, III, and IV


    wherein X is O, S, NH, N-(C 1 -C 4 )alkyl or CH 2 ;
    Y 1 , Y 2 and Y 3 are each independently hydrogen or substituents selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 -haloalkyl, nitro and cyano;
    the NO 2 substituent is attached to the bicyclic ring system in
    the 5- or 7-position; and
    the C*-atom has either the R configuration.

    The invention also relates to the use of said enantiomers for the preparation of a pharmacologically active piperazine derivative.

    摘要翻译： 本发明涉及式I，III和IV（CHEM）的基本上纯的异双环醇对映异构体，其中X是O，S，NH，N-（C 1 -C 4）烷基或CH 2; Y 1，Y 2和Y 3各自独立地为氢或选自卤素，C 1 -C 4烷基，C 1 -C 4烷氧基，C 1 -C 4卤代烷基，硝基和氰基的取代基; NO 2取代基连接到5-或7-位的双环体系; 并且C * -atom具有R配置。 本发明还涉及所述对映异构体用于制备药理学活性哌嗪衍生物的用途。

    Substituted pyridylmethylpiperazine and -piperidine derivatives, their preparation and their use for treating central nervous system (CNS) disorders
    73.
    发明公开
    Substituted pyridylmethylpiperazine and -piperidine derivatives, their preparation and their use for treating central nervous system (CNS) disorders 有权
    取代Pyridylmethylpiperazin-和哌啶衍生物，它们的制备和它们在中枢神经系统病症的治疗中的用途（CNS）

    公开(公告)号：EP0908458A1

    公开(公告)日：1999-04-14

    申请号：EP98203154.4

    申请日：1998-09-21

    申请人： DUPHAR INTERNATIONAL RESEARCH B.V

    发明人： Feenstra, R.W. ,  den Hartog, J.A.J. ,  Kruse, C.G. ,  Tulp, M.T.M. ,  Long, S.K.

    IPC分类号： C07D413/12 ,  A61K31/44 ,  C07D405/12 ,  C07D405/14 ,  C07D409/14

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

    摘要： The invention relates to a group of new piperazine and piperidine compounds having interesting pharmacological properties.
    It has been found that compounds of the formula (a)
    wherein

    A represents a heterocyclic group of 5-7 ring atoms wherein 1 - 3 heteroatoms from the group O, N and S are present,
    R 1 is hydrogen or fluoro,
    R 2 is C 1-4 -alkyl, C 1-4 -alkoxy or an oxo group, and p is 0, 1 or 2,
    Z represents carbon or nitrogen, and the dotted line is a single bond when Z is nitrogen, and a single or double bond when Zis carbon,
    R 3 and R 4 independently are hydrogen or C 1-4 -alkyl,
    n has the value 1 or 2,
    R 5 is 2-pyridyl, 3-pyridyl or 4-pyridyl substituted at the meta-position with respect to the methylene bridge with a group Y, and optionally substituted with (R 6 )q,
    Y is phenyl, furanyl or thienyl, which groups may be substituted with 1-3 substituents of the group hydroxy, halogen, CF 3 , C 1-4 -alkoxy, C 1-4 -alkyl, cyano, aminocarbonyl, mono- or di-C 1-4 -alkylaminocarbonyl,
    R 6 is halogen, hydroxy, C 1-4 -alkoxy or C 1-4 -alkyl, and q is 0, 1, 2 or 3
    and salts thereof, show affinities for both the dopamine D 2 -, D 3 -, D 4 - receptors and the serotonin 5-HT 1A receptor.

    摘要翻译： 本发明涉及一组具有有趣的药理性质的新的哌嗪和哌啶化合物。 已经发现做了式（a） worin甲darstellt 5-7环原子的杂环基worin选自O，N和S的存在1-3杂原子，R 1是氢或氟，R 2中的化合物 是C 1-4烷基，C 1-4烷氧基或氧代基团，且p是0，1或2，Z darstellt碳或氮，且虚线为单键当Z是氮，和单或双 当键Z是碳，R3和R4是unabhängig氢或C 1-4烷基，n的值为1或2，R 5是2-吡啶基，3-吡啶基或4-吡啶基substituiertem在间位相对于亚甲基 与基团Y桥接，并用（R 6）●OPTIONALLY substituiertem，Y是可以被与该组羟基的1-3个取代基取代的苯基，呋喃基或噻吩基，基团，卤素，CF 3，C 1-4 - 烷氧基，C 1 -C 4 - 烷基，氰基，氨基羰基，单 - 或二-C 1-4 - 烷基氨基羰基，R 6是卤素，羟基，C 1-4 - 烷氧基或C 1-4 - 烷基，和q为0，1，2或3以及它们的盐 ，显示亲和力多巴胺无论是D2，D3， D4受体和血清素5-HT1A受体。

    Piperazine and piperidine derivatives as 5-HT1 receptor agonists
    74.
    发明公开
    Piperazine and piperidine derivatives as 5-HT1 receptor agonists 有权
    Piperidin-和Piperazin Derivate als 5-HT1-Rezeptor-Agonisten

    公开(公告)号：EP0900792A1

    公开(公告)日：1999-03-10

    申请号：EP98202832.6

    申请日：1998-08-24

    申请人： DUPHAR INTERNATIONAL RESEARCH B.V

    发明人： Feenstra, R.W. ,  Visser, G.M. ,  Kruse, C.G. ,  Tulp, M.T.M. ,  Long, S.K.

    IPC分类号： C07D263/58 ,  C07D209/34 ,  A61K31/42 ,  A61K31/38 ,  A61K31/47 ,  C07D209/08 ,  C07D265/36 ,  C07D215/227 ,  C07D279/16 ,  C07D401/12 ,  C07D409/12

    CPC分类号： C07D263/58 ,  C07D215/38 ,  C07D265/36 ,  C07D401/12 ,  C07D409/12

    摘要： The invention relates to a group of novel piperazine and piperidine derivatives having interesting pharmacological properties.
    The compounds have the general formula (a)
    wherein

    R 1 is hydrogen or fluoro,
    R' is H or C 1-4 -alkyl,
    R 2 is H, C 1-4 -alkyl or an oxo group, or R' and R 2 together represent a bond,
    R'' is H or C 1-4 -alkyl , and the dotted lines can represent a single or double bond,
    p has the value 0-2,
    Y represents C, O, N or S,
    T represent N or C,
    R 3 and R 4 independently are hydrogen or C 1-4 -alkyl,
    n has the value 1 or 2,
    Q is a group of the formula -CH 2 -C(R 5 R 6 )-Z-R 7 wherein R 5 and R 6 represent H or C 1-7 -alkyl, C 1-3 -alkylphenyl, Z represents -C(R 8 R 9 )-O-, -C(R 8 R 9 )-C(=O)-, -C(R 8 R 9 )-C (=NOR 10 )-, -NH-C(=O)- or -O-CH 2 -, wherein R 8 - R 10 represent H or C 1-4 -alkyl, and R 7 is a 5- or 6-membered cyclic group, aromatic group or hetero-aromatic group, or the 1- or 2-adamantyl group, which group R 7 can be substituted with O-C 1-4 -alkyl, CN, halogen or C- 1-4 -alkyl,
    with the proviso that R 7 cannot be 1-alkylcycloalkyl, and that compounds wherein Z is the group-NH-C(=0)- and R 5 =R 6 =H, T is nitrogen, and the bicylic group is 1,4-benzoxazin-8-yl, quinoxalin-5-yl, quinolin-5-yl, indol-4-yl, benzoxazol-7-yl, benzimidazol-4-yl, benzothiazol-7-yl are not included, and salts thereof.
    These compounds have high affinity for both the dopamine D 2 receptors and serotonine 5-HT 1A receptors.

    摘要翻译： 本发明涉及具有感兴趣的药理学性质的一组新的哌嗪和哌啶衍生物。 化合物具有通式（a）其中R 1是氢或氟，R'是H或C 1-4 - 烷基，R 2是H，C 1-4 - 烷基或氧代基，或者R'和R 2一起 代表键，R“为H或C 1-4 - 烷基，虚线表示单键或双键，p表示0-2，Y表示C，O，N或S，T表示N或 C，R 3和R 4独立地为氢或C 1-4 - 烷基，n为1或2，Q为式-CH 2 -C（R5R6）-Z-R7的基团，其中R5和R6代表H或C1- （C8R9）-O-，-C（R8R9）-C（= O） - ， - C（R8R9）-C（= NOR10） - ，-NH- C（= O） - 或-O-CH 2 - ，其中R 8 -R 10表示H或C 1-4 - 烷基，R 7为5-或6-元环状基团，芳族基团或杂芳族基团， - 或2-金刚烷基，该基团R7可以被O-C 1-4 - 烷基，CN，卤素或C 1-4 - 烷基取代，条件是R 7不能是1-烷基环烷基，其中化合物其中 Z是基团-NH-C（= O） - ，R5 = R6 = H，T是氮，双 c基团是1,4-苯并恶嗪-8-基，喹喔啉-5-基，喹啉-5-基，吲哚基-4-基，苯并恶唑基，苯并咪唑-4-基，苯并噻唑-7-基不是 包括，及其盐。 这些化合物对多巴胺D2受体和5-羟色胺5-HT 1A受体具有高亲和力。

    3,4-Dehydropiperidine derivatives
    78.
    发明公开
    3,4-Dehydropiperidine derivatives 失效
    3,4-脱氢哌啶衍生物

    公开(公告)号：EP0535722A1

    公开(公告)日：1993-04-07

    申请号：EP92202082.1

    申请日：1992-07-08

    申请人： DUPHAR INTERNATIONAL RESEARCH B.V

    发明人： Hulkenberg, Antonius ,  van Charldorp, Karin J. ,  van Hes, Rolf ,  van Wijngaarden, Ineke

    IPC分类号： C07D409/04 ,  C07D405/04 ,  C07D401/04 ,  A61K31/33 ,  A61K31/44

    CPC分类号： C07D409/04

    摘要： The invention relates to a group of new 3,4-dehydropiperidine derivatives of the formula

    wherein

    R₁ is a hydrogen atom or an alkyl group having 1-3 carbon atoms;
    Y is a group of the general formula 2


    wherein

    R₂ is a group of the formula -(CH₂) n -C(=X)-NR₃R₄, -(CH₂) n -SO₂-NR₃R₄, -(CH₂) n -NR₅-C(=X)-R₆ or -(CH₂) n -NR₅-SO₂-R₆, wherein R₃, R₄ and R₅ independent of each other represent hydrogen or alkyl (1-3C), R₆ is alkyl (1-3C), X represents O or S; n is 0-4, and
    R is hydrogen or alkyl (1-3C).

    These compounds have interesting serotonin-1-like (partial) agonistic activity and can be used for the treatment of migraine.

    摘要翻译： 本发明涉及下式的一组新的3,4-脱氢哌啶衍生物，其中R 1是氢原子或具有1-3个碳原子的烷基; Y是通式2的基团，其中R 2是式 - （CH 2）nC（= X）-NR 3 R 4， - （CH 2）n -SO 2 -NR 3 R 4， - （CH 2）n -NR 5 -C 其中R 3，R 4和R 5彼此独立代表氢或烷基（1-3C），R 6是烷基（1-3C），X代表O或-OR 6或 - （CH 2）n -NR 5 -SO 2 -R 6， S; n是0-4，R是氢或烷基（1-3C）。 这些化合物具有令人感兴趣的血清素-1样（部分）激动活性，可用于治疗偏头痛。