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    (1-INDANONE)-(1,2,3,6-TETRAHYDROPYRIDINE) DERIVATIVE
    1.
    发明公开
    (1-INDANONE)-(1,2,3,6-TETRAHYDROPYRIDINE) DERIVATIVE 有权
    （1-茚满酮） - （1,2,3,6-四氢）衍生金融

    公开(公告)号：EP1491531A1

    公开(公告)日：2004-12-29

    申请号：EP03712926.9

    申请日：2003-03-25

    申请人： Eisai Co., Ltd.

    发明人： IIMURA, Yoichi ,  KOSASA, Takashi ,  YAMANISHI, Yoshiharu

    IPC分类号： C07D211/70 ,  A61K31/44 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P43/00 ,  A61P27/06 ,  A61P21/04 ,  A61P25/06

    CPC分类号： A61K31/44 ,  C07D211/70

    摘要： The present invention provides an excellent sigma receptor binding agent and/or acetylcholinesterase inhibitor containing an (1-indanone)-(1,2,3,6-tetrahydropyridine) compound. More specifically, it provides an (1-indanone)-(1,2,3,6-tetrahydropyridine) compound represented by the following formula, a pharmacologically acceptable salt thereof or a hydrate of them.

    In the formula (I), R 1 , R 2 , R 3 and R 4 are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, nitrile group, an,alkyl group having one to six carbon atoms which may be substituted, a cycloalkyl group having three to eight carbon atoms which may be substituted, an alkoxy group having one to six carbon atoms which may be substituted, a cycloalkoxy group having three to eight carbon atoms which may be substituted, an acyl group having one to six carbon atoms which may be substituted, an C 1 -C 6 alkoxy-carbonyl group which may be substituted, an C 1 -C 6 alkyl-aminocarbonyloxy group which may be substituted, a di-(C 1 -C 6 alkyl)-aminocarbonyloxy group which may be substituted, nitro group, an amino group which may be substituted, an amide group which may be substituted, mercapto group or a C 1 -C 6 thioalkoxy group which may be substituted, where R 1 and R 2 , or R 2 and R 3 , or R 3 and R 4 may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring; the partial structure:
    is a group represented by >C=CH-(CH 2 ) m - or >C(R 6 )-(CH 2 ) m - (wherein m is 0 or an integer from 1 to 5; and R 6 is hydrogen atom, a halogen atom, hydroxyl group, an alkyl group having one to six carbon atoms, an alkoxy group having one to six carbon atoms, nitrile group, a halo-C 1 -C 6 alkyl group, a hydroxy-C 1 -C 6 alkyl group, a cyano-C 1 -C 6 alkyl group, an amino-C 1 -C 6 alkyl group, nitro group, azide group, an amino group which may be substituted, carbamoyl group which may be substituted, carboxyl group which may be substituted, mercapto group or a C 1 -C 6 thioalkoxy group); and R 5 is hydrogen atom, an alkyl group having one to six carbon atoms which may be substituted, an alkenyl group having two to six carbon atoms which may be substituted, an alkynyl group having two to six carbon atoms which may be substituted, a cycloalkyl group having three to eight carbon atoms which may be substituted, an 2,2-(alkylenedioxy)ethyl group or a group represented by the formula:
    (wherein the ring C is benzene ring, an aliphatic ring or a heterocyclic ring; R 7 s are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, nitrile group, an alkyl group having one to six carbon atoms which may be substituted, an alkenyl group having two to six carbon atoms which may be substituted, an alkynyl group having two to six carbon atoms which may be substituted, a cycloalkyl group having three to eight carbon atoms which may be substituted, an alkoxy group having one to six carbon atoms which may be substituted, an C 1 -C 6 alkoxy-alkoxy group which may be substituted, an aryloxy group which may be substituted, an aralkyloxy group which may be substituted or the like, where two of R 7 s may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring; and n is an integer from 1 to 5).

    摘要翻译： （1-茚满酮） - 四氢吡啶衍生物（I）是新的。 式（I）的（1-茚满酮） - 四氢吡啶衍生物及其盐和水合物是新的。 R 1 -R 3，卤素，OH，CN，NO 2，SH或任选取代的Alk，Cyc，OAlk，OCyc，1-6C酰基，COOAlk，OCONHAlk，OCON（Alk）2，NH 2，酰氨基， 或SAlk; 或R 1 + R 2，R 2 + R 3或R 3 + R 4脂族，芳族，杂环或亚烷基二氧基环; A + B：CH = CH（CH 2）mor CR 6（CH 2）m; Alk：1-6C烷基; 环：3-8C环烷基; m：0-5; R 6，卤素，OH，Alk（任选被卤素，OH，CN或NH 2取代），OAlk，CN，NO 2，N 3，SH，SAlk或任选取代的氨基，氨基甲酰基或羧基; R 2,5，（亚烷基二氧基）乙基，CH 2D或任选取代的Alk，2-6C烯基，2-6C炔基或环; D：被1-5R 7取代的苯基，脂环基或杂环基; R 7，卤素，OH，CN或任选取代的Alk，2-6C烯基，2-6C炔基，Cyc，OAlk，OAlkOAlk，芳氧基或芳烷氧基; 或2个R 7脂环基，芳族，杂环基或亚烷基二氧基。 活动：神经保护; 脑保护; 精神药物; 降血糖; 抗抑郁药; 安神; 偏头痛; 眼科。 药物作用机制：抗胆碱酯酶; 西格玛拮抗剂。 在测定中，1-苄基-4 - [（5,6-二乙氧基-2-氟-1-茚满酮）-2-基]甲基-1,2,3,6-四氢吡啶（Ia）抑制[3 H] -DTG与σ50受体结合，IC50值为4.7nM。 （Ia）大鼠脑匀浆中抑制的乙酰胆碱酯酶活性，其IC50为0.4nM。 盐酸多奈哌齐的相应值分别为18.7和3.9nM。

    PROCESS FOR PRODUCTION OF DONEPEZIL DERIVATIVES
    2.
    发明授权
    PROCESS FOR PRODUCTION OF DONEPEZIL DERIVATIVES 有权
    生产DONEPZZIL衍生物的方法

    公开(公告)号：EP1047674B1

    公开(公告)日：2005-03-30

    申请号：EP99900320.5

    申请日：1999-01-14

    申请人： Eisai Co., Ltd.

    发明人： IIMURA, Yoichi

    IPC分类号： C07D213/50 ,  C07D211/32

    CPC分类号： C07D213/50 ,  C07D211/32

    摘要： The present invention provides a novel industrially or economically preferable process for production of a hydrogen halogenide salt of a Donepezil derivative having an excellent pharmacological action as medicament, namely, reaction of 1-indanone derivative with carbonate ester to obtain 2-alkoxycarbonyl-1-indanone derivative, followed by reaction with halogenated (4-pyridyl)methyl or a salt thereof and decarboxylation successively to obtain 2-(4-pyridyl)methyl-1-indanone derivative, then reaction with halogenated benzyl to obtain quaternary ammonium salt, then reduction, and synthetic intermediate thereof. In the formulae step 1, step 2, step 3 and step 5 R1 represents a hydrogen atom or lower alkoxy; n represents an integer of 1 to 4; R2 represents lower alkyl group; and X represents a halogen atom.

    摘要翻译： 本发明提供了一种工业上或经济上优选的制备作为药物的药理学作用优异的多奈哌齐衍生物的氢卤化物盐的方法，即1-茚满酮衍生物与碳酸酯反应得到2-烷氧基羰基-1-二氢茚酮 然后与卤代（4-吡啶基）甲基或其盐反应，依次脱羧得到2-（4-吡啶基）甲基-1-二氢茚酮衍生物，然后与卤代苄基反应得到季铵盐，然后还原， 及其合成中间体。 在式1步骤2，步骤3和步骤5中，R1代表氢原子或低级烷氧基; n表示1至4的整数; R2代表低级烷基; X代表卤素原子。

    SIGMA RECEPTOR BINDER CONTAINING INDANONE DERIVATIVE
    3.
    发明公开
    SIGMA RECEPTOR BINDER CONTAINING INDANONE DERIVATIVE 审中-公开
    SIGMA-REZEPTOR-BINDUNGSMOLEKÜLMIT INDANONDERIVAT

    公开(公告)号：EP1468684A1

    公开(公告)日：2004-10-20

    申请号：EP03701147.5

    申请日：2003-01-22

    申请人： Eisai Co., Ltd.

    发明人： IIMURA, Yoichi ,  KOSASA, Takashi ,  YAMANISHI, Yoshiharu

    IPC分类号： A61K31/445 ,  A61P25/00 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P25/06 ,  A61P27/06 ,  A61P43/00 ,  A61P21/04 ,  C07D211/32

    CPC分类号： C07D405/06 ,  A61K31/445 ,  C07D211/32

    摘要： The present invention provides an indanone derivative and an excellent sigma receptor binding agent comprising an indanone derivative. More specifically, it provides a sigma receptor binding agent comprising an indanone derivative represented by the following formula, a pharmacologically acceptable salt thereof or a hydrate of them.
    In the formula (I), R 1 , R 2 , R 3 and R 4 are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, nitrile group, a C 1-6 alkyl group which may be substituted, a cycloalkyl group having three to eight carbon atoms which may be substituted, a C 1-6 alkoxy group which may be substituted, a cycloalkoxy group having three to eight carbon atoms which may be substituted, an acyl group having one to six carbon atoms which may be substituted, a C 1-6 alkoxycarbonyl group which may be substituted, a C 1-6 alkylaminocarbonyloxy group which may be substituted, a di(C 1-6 alkyl)aminocarbonyloxy group which may be substituted, nitro group, an amino group which may be substituted, an amido group which may be substituted, mercapto group or a thio-C 1-6 alkoxy group which may be substituted, and further R 1 with R 2 , R 2 with R 3 , or R 3 with R 4 may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring; the partial structure:
    represents a group represented by >CH-CH 2 -, >C=CH- or >C(-R 7 )-CH 2 -; m represents an integer of 0 or 1 to 5; and R 5 represents hydrogen atom, a C 1-6 alkyl group which may be substituted, a C 2-6 alkenyl group which may be substituted, a C 2-6 alkynyl group which may be substituted, a cycloalkyl group having three to eight carbon atoms which may be substituted, a 2,2-(alkylenedioxy)ethyl group or a group represented by the formula:
    (wherein the ring C represents benzene ring, an aliphatic ring or a heterocyclic ring; R 6 s are the same as or different from each other and each represents hydrogen atom, a halogen atom, hydroxyl group, nitrile group, a C 1-6 alkyl group which may be substituted, a C 2-6 alkenyl group which may be substituted, a C 2-6 alkynyl group which may be substituted, a cycloalkyl group having three to eight carbon atoms which may be substituted, a C 1-6 alkoxy group which may be substituted, a C 1-6 alkoxyalkoxy group which may be substituted, an aryloxy group which may be substituted or an aralkyloxy group which may be substituted, and further two of R 6 s may together form an aliphatic ring, an aromatic ring, a heterocyclic ring or an alkylenedioxy ring; R 7 represents a halogen atom, hydroxyl group, a C 1-6 alkyl group which may be substituted, a C 1-6 alkoxy group, nitrile group, a halogeno-C 1-6 alkyl group, a hydroxyl-C 1-6 alkyl group, a cyano-C 1-6 alkyl group, an amino-C 1-6 alkyl group, nitro group, azide group, an amino group which may be substituted, a carbamoyl group which may be substituted, a carboxyl group which may be substituted, mercapto group or a thio-C 1-6 alkoxy group; and n represents an integer of 1 to 5), provided that 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine, a pharmacologically acceptable salt thereof or a hydrate of them are excluded.

    摘要翻译： 本发明提供茚酮衍生物和包含茚酮衍生物的优异的σ受体结合剂。 更具体地说，它提供了包含由下式表示的茚满酮衍生物，其药理学上可接受的盐或它们的水合物的σ受体结合剂。 在式（I）中，R 1，R 2，R 3和R 4彼此相同或不同，表示氢原子，卤素原子，羟基 腈基，可以被取代的C 1-6烷基，可以被取代的碳原子数为3〜8的环烷基，可以被取代的C 1-6烷氧基，碳原子数为3〜8的环烷氧基， 可被取代的可具有1-6个碳原子的酰基，可被取代的C1-6烷氧基羰基，可被取代的C1-6烷基氨基羰基氧基，二（C1-6烷基）氨基羰基氧基 可以被取代的硝基，可以被取代的氨基，可被取代的酰胺基，巯基或可被取代的硫代C 1-6烷氧基，还有R 1与R 2 > R 2，R 3或R 3与R 4一起形成脂族环，芳香环，杂环或亚烷基二 氧环 部分结构：表示由CH-CH 2 - ，> C = CH-或> C（-R 7）-CH 2 - 表示的基团。 m表示0或1〜5的整数; R 5表示氢原子，可被取代的C 1-6烷基，可被取代的C 2-6烯基，可被取代的C 2-6炔基，具有3〜8个碳原子的环烷基 可以被取代的原子，2,2-（亚烷基二氧基）乙基或由下式表示的基团：其中环C表示苯环，脂族环或杂环; R 6是 相同或不同，各自表示氢原子，卤素原子，羟基，腈基，可被取代的C1-6烷基，可被取代的C2-6烯基，C2-6 可以被取代的炔基，可以被取代的具有3-8个碳原子的环烷基，可以被取代的C1-6烷氧基，可被取代的C1-6烷氧基烷氧基，可以被取代的芳氧基 或可以被取代的芳烷氧基，另外两个R 6可以一起f 脂族环，芳环，杂环或亚烷基二氧基环; R 7表示卤素原子，羟基，可被取代的C 1-6烷基，C 1-6烷氧基，腈基，卤代-C 1-6烷基，羟基-C 1-6烷基 氰基-C 1-6烷基，氨基-C 1-6烷基，硝基，叠氮基，可被取代的氨基，可被取代的氨基甲酰基，可被取代的羧基，巯基 基或硫代C 1-6烷氧基; 并且n表示1至5的整数），条件是不包括1-苄基-4-⑤（5,6-二甲氧基-1-茚满酮）-2-基甲基哌啶，其药理学上可接受的盐或它们的水合物。

    ACETYLCHOLINESTERASE INHIBITORS CONTAINING 1-BENZYL- PYRIDINIUM SALTS
    7.
    发明公开
    ACETYLCHOLINESTERASE INHIBITORS CONTAINING 1-BENZYL- PYRIDINIUM SALTS 审中-公开
    医药维生素VE乙酰胆碱酯酶HEMMERN DIE 1-BENZYLPYRIDINIUMSALZE ENTHALTEN

    公开(公告)号：EP1285656A1

    公开(公告)日：2003-02-26

    申请号：EP01919838.1

    申请日：2001-04-09

    申请人： Eisai Co., Ltd.

    发明人： IIMURA, Yoichi ,  KOSASA, Takashi

    IPC分类号： A61K31/4425 ,  A61P43/00 ,  A61P25/22

    CPC分类号： A61K31/4425

    摘要： The present invention provides an excellent acetylcholinesterase inhibitor. That is, it provides an acetylcholinesterase inhibitor comprising a 1-benzylpyridinium salt represented by the following formula:
    wherein R 1 , R 2 , R 3 and R 4 are the same as or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitrile group, a C 1-6 alkyl group, a C 1-6 alkoxy group etc.; R 5 represents a hydrogen atom, a halogen atom etc.; the partial structure:
    is a group represented by the formula >C(R 6 )-CH 2 - (wherein R 6 is a hydrogen atom or a halogen atom) or >C=CH-; X - represents a halide ion or organic sulfonic acid ion; and m is 0 or an integer from 1 to 5.

    摘要翻译： 本发明提供优异的乙酰胆碱酯酶抑制剂。 也就是说，它提供了包含由下式表示的1-苄基吡啶鎓盐的乙酰胆碱酯酶抑制剂：其中R 1，R 2，R 3和R 4相同或不同 彼此各自表示氢原子，卤素原子，羟基，腈基，C 1-6烷基，C 1-6烷氧基等; R 5表示氢原子，卤素原子等; 部分结构：是由式> C（R 6）-CH 2 - （其中R 6是氢原子或卤素原子）或> C = CH-表示的基团。 X“表示卤离子或有机磺酸离子; m为0或1〜5的整数。

    PROCESS FOR PRODUCTION OF DONEPEZIL DERIVATIVES
    10.
    发明公开
    PROCESS FOR PRODUCTION OF DONEPEZIL DERIVATIVES 有权
    用于生产DONEPEZILDERIVATEN

    公开(公告)号：EP1047674A1

    公开(公告)日：2000-11-02

    申请号：EP99900320.5

    申请日：1999-01-14

    申请人： Eisai Co., Ltd.

    发明人： IIMURA, Yoichi

    IPC分类号： C07D213/50 ,  C07D211/32

    CPC分类号： C07D213/50 ,  C07D211/32

    摘要： The present invention provides a novel industrially or economically preferable process for production of a hydrogen halogenide salt of a Donepezil derivative having an excellent pharmacological action as medicament, namely, reaction of 1-indanone derivative with carbonate ester to obtain 2-alkoxycarbonyl-1-indanone derivative, followed by reaction with halogenated (4-pyridyl)methyl or a salt thereof and decarboxylation successively to obtain 2-(4-pyridyl)methyl-1-indanone derivative, then reaction with halogenated benzyl to obtain quaternary ammonium salt, then reduction, and synthetic intermediate thereof. In the formulae step 1, step 2, step 3 and step 5 R1 represents a hydrogen atom or lower alkoxy; n represents an integer of 1 to 4; R2 represents lower alkyl group; and X represents a halogen atom.