公开(公告)号：US07427615B2

公开(公告)日：2008-09-23

申请号：US10489606

申请日：2002-09-20

申请人： Fumiaki Uehara ,  Keiichi Aritomo ,  Aya Shoda ,  Shinsuke Hiki ,  Masahiro Okuyama ,  Yoshihiro Usui ,  Mitsuru Ooizumi ,  Kazutoshi Watanabe ,  Koichi Yamakoshi

发明人： Fumiaki Uehara ,  Keiichi Aritomo ,  Aya Shoda ,  Shinsuke Hiki ,  Masahiro Okuyama ,  Yoshihiro Usui ,  Mitsuru Ooizumi ,  Kazutoshi Watanabe ,  Koichi Yamakoshi

IPC分类号： C07D401/04 ,  C07D401/14 ,  A61K31/505

CPC分类号： C07D401/04 ,  C07D239/34 ,  C07D239/47 ,  C07D239/56 ,  C07D401/14 ,  C07D413/14

摘要： A pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof having inhibitory activity against tau protein kinase 1: wherein R1 represents a C1-C12 alkyl group which may be substituted; R represents, for example, a group represented by the following formula (II): wherein R2 and R3 independently represent a hydrogen atom or a C1-C8 alkyl group; R4 represents a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms in total.

摘要翻译： 由式（I）表示的嘧啶酮衍生物或其盐，或其溶剂合物或其水合物对tau蛋白激酶1具有抑制活性：其中R 1表示C 1〜 可以被取代的C 1 -C 12烷基; R表示例如由下式（II）表示的基团：其中R 2和R 3独立地表示氢原子或C 1〜 C 1 -C 8烷基; R 4表示可以被取代的苯环，可以被取代的萘环，可以被取代的茚满环，可被取代的四氢萘环，或具有1个的任选取代的杂环 至4个选自氧原子，硫原子和氮原子的杂原子，并且总共具有5至10个环构成原子。

公开(公告)号：US20050090490A1

公开(公告)日：2005-04-28

申请号：US10489606

申请日：2002-09-20

申请人： Fumiaki Uehara ,  Keiichi Aritomo ,  Aya Shoda ,  Shinsuke Hiki ,  Masahiro Okuyama ,  Yoshihiro Usui ,  Mitsuru Ooizumi ,  Kazutoshi Watanabe ,  Koichi Yamakoshi

发明人： Fumiaki Uehara ,  Keiichi Aritomo ,  Aya Shoda ,  Shinsuke Hiki ,  Masahiro Okuyama ,  Yoshihiro Usui ,  Mitsuru Ooizumi ,  Kazutoshi Watanabe ,  Koichi Yamakoshi

IPC分类号： C07D239/40 ,  A61K31/513 ,  A61K31/5377 ,  A61K31/5386 ,  A61P3/04 ,  A61P3/10 ,  A61P9/10 ,  A61P17/14 ,  A61P25/00 ,  A61P25/16 ,  A61P25/18 ,  A61P25/24 ,  A61P25/28 ,  A61P27/02 ,  A61P27/06 ,  A61P35/00 ,  A61P35/02 ,  A61P43/00 ,  C07D239/34 ,  C07D239/46 ,  C07D239/56 ,  C07D401/04 ,  C07D401/14 ,  C07D413/14 ,  C07D417/14 ,  C07D498/10 ,  A61K31/541 ,  C07D43/14

CPC分类号： C07D401/04 ,  C07D239/34 ,  C07D239/47 ,  C07D239/56 ,  C07D401/14 ,  C07D413/14

摘要： a pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof having inhibitory activity against tau protein kinase 1: wherein R1 represents a C1-C12 alkyl group which may be substituted; R represents, for example, a group represented by the following formula (II): wherein R2 and R3 independently represent a hydrogen atom or a C1-C8 alkyl group; R4 represents a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 heteno atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms in total.

摘要翻译： 由式（I）表示的嘧啶酮衍生物或其盐，或其对tau蛋白激酶1具有抑制活性的溶剂合物或其水合物：其中R 1表示C 1〜 可以被取代的C 1 -C 12烷基; R表示例如由下式（II）表示的基团：其中R 2和R 3独立地表示氢原子或C 1〜 C 1 -C 8烷基; R 4表示可以被取代的苯环，可以被取代的萘环，可以被取代的茚满环，可被取代的四氢萘环，或具有1个的任选取代的杂环 至4个选自氧原子，硫原子和氮原子的Heteno原子，并且总共具有5至10个构成环的原子。

公开(公告)号：US07572793B2

公开(公告)日：2009-08-11

申请号：US10489607

申请日：2002-09-20

申请人： Fumiaki Uehara ,  Keiichi Aritomo ,  Aya Shoda ,  Shinsuke Hiki ,  Masahiro Okuyama ,  Yoshihiro Usui ,  Mitsuru Ooizumi ,  Kazutoshi Watanabe

发明人： Fumiaki Uehara ,  Keiichi Aritomo ,  Aya Shoda ,  Shinsuke Hiki ,  Masahiro Okuyama ,  Yoshihiro Usui ,  Mitsuru Ooizumi ,  Kazutoshi Watanabe

IPC分类号： A61K31/535 ,  A61K31/54 ,  C07D403/00 ,  C07D237/02 ,  C07D265/30 ,  C07D295/00 ,  C07D413/00

CPC分类号： A61K31/535 ,  C07D239/34 ,  C07D239/47 ,  C07D239/56 ,  C07D401/04 ,  C07D401/14 ,  C07D413/14

摘要： A pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof having inhibitory activity against tau protein kinase 1: wherein R1 represents a C1-C12 alkyl group which may be substituted; R represents, for example, a group represented by the following formula (II): wherein R2 and R3 independently represent a hydrogen atom or a C1-C8 alkyl group; R4 represents a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms in total.

摘要翻译： 由式（I）表示的嘧啶酮衍生物或其盐，或其溶剂化物或其水合物对tau蛋白激酶1具有抑制活性：其中R1表示可被取代的C1-C12烷基; R表示例如由下式（II）表示的基团：其中R2和R3独立地表示氢原子或C1-C8烷基; R4表示可被取代的苯环，可被取代的萘环，可被取代的茚满环，可被取代的四氢萘环，或具有1-4个选自下述基团的杂原子的任意取代的杂环 由氧原子，硫原子和氮原子构成，并且总共具有5〜10个构成环的原子。

公开(公告)号：US20050130967A1

公开(公告)日：2005-06-16

申请号：US10489607

申请日：2002-09-20

申请人： Fumiaki Uehara ,  Keiichi Aritomo ,  Aya Shoda ,  Shinsuke Hiki ,  Masahiro Okuyama ,  Yoshihiro Usui ,  Mitsuru Ooizumi ,  Kazutoshi Watanabe

发明人： Fumiaki Uehara ,  Keiichi Aritomo ,  Aya Shoda ,  Shinsuke Hiki ,  Masahiro Okuyama ,  Yoshihiro Usui ,  Mitsuru Ooizumi ,  Kazutoshi Watanabe

IPC分类号： C07D239/36 ,  A61K31/513 ,  A61K31/5377 ,  A61K31/5386 ,  A61P3/04 ,  A61P3/10 ,  A61P17/14 ,  A61P25/02 ,  A61P25/16 ,  A61P25/18 ,  A61P25/28 ,  A61P27/02 ,  A61P27/06 ,  A61P35/00 ,  A61P35/02 ,  A61P43/00 ,  C07D239/34 ,  C07D239/40 ,  C07D239/46 ,  C07D239/56 ,  C07D401/04 ,  C07D401/14 ,  C07D413/04 ,  C07D413/14 ,  C07D417/14 ,  C07D498/10 ,  C07D43/14

CPC分类号： A61K31/535 ,  C07D239/34 ,  C07D239/47 ,  C07D239/56 ,  C07D401/04 ,  C07D401/14 ,  C07D413/14

摘要： A pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof having inhibitory activity against tau protein kinase 1: wherein R1 represents a C1-C12 alkyl group which may be substituted; R represents, for example, a group represented by the following formula (II): wherein R2 and R3 independently represent a hydrogen atom or a C1-C8 alkyl group; R4 represents a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom, and having 5 to 10 ring-constituting atoms in total.

摘要翻译： 由式（I）表示的嘧啶酮衍生物或其盐，或其溶剂合物或其水合物对tau蛋白激酶1具有抑制活性：其中R 1表示C 1〜 可以被取代的C 1 -C 12烷基; R表示例如由下式（II）表示的基团：其中R 2和R 3独立地表示氢原子或C 1 -C 3烷基， 8个烷基; R 4表示可以被取代的苯环，可以被取代的萘环，可以被取代的茚满环，可被取代的四氢萘环，或具有1个的任选取代的杂环 至4个选自氧原子，硫原子和氮原子的杂原子，并且总共具有5至10个环构成原子。

公开(公告)号：US20060252768A1

公开(公告)日：2006-11-09

申请号：US10550299

申请日：2004-03-26

申请人： Kazutoshi Watanabe ,  Fumiaki Uehara ,  Shinsuke Hiki ,  Satoshi Yokoshima ,  Yoshihiro Usui ,  Masahiro Okuyama ,  Aya Shoda ,  Keiichi Aritomo ,  Toshiyuki Kohara ,  Kenji Fukunaga

发明人： Kazutoshi Watanabe ,  Fumiaki Uehara ,  Shinsuke Hiki ,  Satoshi Yokoshima ,  Yoshihiro Usui ,  Masahiro Okuyama ,  Aya Shoda ,  Keiichi Aritomo ,  Toshiyuki Kohara ,  Kenji Fukunaga

IPC分类号： A61K31/513 ,  C07D403/14

CPC分类号： C07D401/04 ,  C07D401/14 ,  C07D405/14 ,  C07D409/14 ,  C07D413/14 ,  C07D417/14

摘要： A pyrimidone derivative having tau protein kinase 1 inhibitory activity which is represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof; useful for prventive and/or therapeutic treatment of diseass such as neurodegenerative diseases (e.g. Alzheimer disease); wherein Q represents CH or nitrogen atom; R represents a C1-C12 alkyl group; the ring of Formula (I): represents piperazine ring or piperidine ring; each X independently represents a C1-C8 alkyl group, an optionally partially hydrogenated C6-C10 aryl ring, an indan ring or the like; m represents an integer of 1 to 3; each independently represents a halogen atom, a hydroxy group, a cyano group, a C1-C6 alkyl group or the like; n represents an integer of 0 to 8; when X and Y or two Y groups are attached on the same carbon atom, they may combine to each other to form a C2-C6 alkylene group.

摘要翻译： 具有由式（I）表示的tau蛋白激酶1抑制活性的嘧啶酮衍生物或其盐或其溶剂合物或其水合物; 可用于疾病的预防和/或治疗性治疗，例如神经变性疾病（例如阿尔茨海默病）; 其中Q表示CH或氮原子; R表示C 1 -C 12烷基; 式（I）的环表示哌嗪环或哌啶环; 每个X独立地表示C 1 -C 8烷基，任选部分氢化的C 6 -C 10烷基， 芳环，茚满环等; m表示1〜3的整数， 各自独立地表示卤素原子，羟基，氰基，C 1 -C 6烷基等; n表示0〜8的整数， 当X和Y或两个Y基团连接在同一个碳原子上时，它们可以彼此结合形成C 2 -C 6亚烷基。

公开(公告)号：US07504411B2

公开(公告)日：2009-03-17

申请号：US10550299

申请日：2004-03-26

申请人： Kazutoshi Watanabe ,  Fumiaki Uehara ,  Shinsuke Hiki ,  Satoshi Yokoshima ,  Yoshihiro Usui ,  Masahiro Okuyama ,  Aya Shoda ,  Keiichi Aritomo ,  Toshiyuki Kohara ,  Kenji Fukunaga

发明人： Kazutoshi Watanabe ,  Fumiaki Uehara ,  Shinsuke Hiki ,  Satoshi Yokoshima ,  Yoshihiro Usui ,  Masahiro Okuyama ,  Aya Shoda ,  Keiichi Aritomo ,  Toshiyuki Kohara ,  Kenji Fukunaga

IPC分类号： C07D401/14 ,  C07D403/14 ,  A61K31/496 ,  A61K31/506 ,  A61P3/10 ,  A61P25/28

CPC分类号： C07D401/04 ,  C07D401/14 ,  C07D405/14 ,  C07D409/14 ,  C07D413/14 ,  C07D417/14

摘要： A pyrimidone derivative having tau protein kinase 1 inhibitory activity which is represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof; useful for prventive and/or therapeutic treatment of diseass such as neurodegenerative diseases (e.g. Alzheimer disease); wherein Q represents CH or nitrogen atom; R represents a C1-C12 alkyl group; the ring of Formula (I): represents piperazine ring or piperidine ring; each X independently represents a C1-C8 alkyl group, an optionally partially hydrogenated C6-C10 aryl ring, an indan ring or the like; m represents an integer of 1 to 3; each independently represents a halogen atom, a hydroxy group, a cyano group, a C1-C6 alkyl group or the like; n represents an integer of 0 to 8; when X and Y or two Y groups are attached on the same carbon atom, they may combine to each other to form a C2-C6 alkylene group.

摘要翻译： 具有由式（I）表示的tau蛋白激酶1抑制活性的嘧啶酮衍生物或其盐或其溶剂合物或其水合物; 可用于疾病的预防和/或治疗性治疗，例如神经变性疾病（例如阿尔茨海默病）; 其中Q表示CH或氮原子; R代表C1-C12烷基; 式（I）的环表示哌嗪环或哌啶环; 每个X独立地表示C1-C8烷基，任选部分氢化的C 6 -C 10芳基环，茚满环等; m表示1〜3的整数， 各自独立地表示卤素原子，羟基，氰基，C1-C6烷基等; n表示0〜8的整数， 当X和Y或两个Y基团连接在同一个碳原子上时，它们可以彼此结合形成C 2 -C 6亚烷基。

公开(公告)号：US07994315B2

公开(公告)日：2011-08-09

申请号：US11996205

申请日：2006-07-21

申请人： Masahiro Okuyama ,  Fumiaki Uehara ,  Hiroshi Iwamura ,  Kazutoshi Watanabe

发明人： Masahiro Okuyama ,  Fumiaki Uehara ,  Hiroshi Iwamura ,  Kazutoshi Watanabe

IPC分类号： C07D265/30

CPC分类号： C07D265/30 ,  C07D265/32

摘要： Production method of an optically active morpholine compound represented by the formula 10, or a compound represented by the formula 55, which includes the following steps: or wherein each symbol is as defined in the specification. An optically active 2-aryl-substituted morpholine compound and 3-oxo-3-(pyrimidin-4-yl)propionate, which are important as starting materials for synthesizing 2-(2-arylmorpholin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one having a tau protein kinase 1 inhibitory activity and useful as a therapeutic drug for Alzheimer's disease and the like, can be produced in a high yield by an industrially advantageous method.

摘要翻译： 由式10表示的光学活性吗啉化合物的制备方法或由式55表示的化合物，其包括以下步骤：或其中每个符号如说明书中所定义。 光学活性的2-芳基取代的吗啉化合物和3-氧代-3-（嘧啶-4-基）丙酸酯，其作为合成2-（2-芳基吗啉-4-基）-1-甲基 - 可以通过工业上有利的方法以高产率制备具有tau蛋白激酶1抑制活性并且可用作阿尔茨海默氏病等的治疗药物的1H- [4,4']联嘧啶基-6-酮。

公开(公告)号：US20090156804A1

公开(公告)日：2009-06-18

申请号：US11996205

申请日：2006-07-21

申请人： Masahiro Okuyama ,  Fumiaki Uehara ,  Hiroshi Iwamura ,  Kazutoshi Watanabe

发明人： Masahiro Okuyama ,  Fumiaki Uehara ,  Hiroshi Iwamura ,  Kazutoshi Watanabe

IPC分类号： C07D413/14 ,  C07C211/43 ,  C07D265/30 ,  C07D265/32 ,  C07D239/24

CPC分类号： C07D265/30 ,  C07D265/32

摘要： The present invention relates to a production method of an optically active morpholine compound represented by the formula 10, which includes the following steps: wherein each symbol is as defined in the specification.The present invention also relates to a production method of an compound represented by the formula 55, which includes the following steps: wherein each symbol is as defined in the specification.According to the production method of the present invention, an optically active 2-aryl-substituted morpholine compound and 3-oxo-3-(pyrimidin-4-yl)propionate, which are important as starting materials for synthesizing 2-(2-arylmorpholin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one having a tau protein kinase 1 inhibitory activity and useful as a therapeutic drug for Alzheimer's disease and the like, can be produced in a high yield by an industrially advantageous method.

摘要翻译： 本发明涉及由式10表示的光学活性吗啉化合物的制备方法，其包括以下步骤：其中每个符号如说明书中所定义。 本发明还涉及由式55表示的化合物的制备方法，其包括以下步骤：其中每个符号如说明书中所定义。 根据本发明的制备方法，光学活性2-芳基取代的吗啉化合物和3-氧代-3-（嘧啶-4-基）丙酸酯作为合成2-（2-芳基吗啉） -4-基）-1-甲基-1H- [4,4']二嘧啶基-6-酮，其具有tau蛋白激酶1抑制活性，可用作阿尔茨海默氏病等的治疗药物，可以以高 通过工业上有利的方法得到。

公开(公告)号：US07166617B2

公开(公告)日：2007-01-23

申请号：US10220359

申请日：2001-02-26

申请人： Haruko Yamabe ,  Masahiro Okuyama ,  Akira Nakao ,  Mitsuru Ooizumi ,  Ken-ichi Saito

发明人： Haruko Yamabe ,  Masahiro Okuyama ,  Akira Nakao ,  Mitsuru Ooizumi ,  Ken-ichi Saito

IPC分类号： A61K31/445 ,  C07D401/06

CPC分类号： C07D401/06 ,  C07D401/14 ,  C07D405/14 ,  C07D413/14 ,  C07D471/04 ,  C07D491/04 ,  C07D495/04

摘要： Novel compounds represented by the following formula (I) that act as a ligand to sigma receptor/binding cite and a medicament comprising the same as an active ingredient: wherein X represents an alkyl group, an aryl group, a heterocyclic group or the like; Q represents a group represented by —CH2—, —CO—, —O—, —CH(OR7)— or the like wherein R7 represents a hydrogen atom, an alkyl group or the like; n represents an integer of from 0 to 5; R1 and R2 each represent a hydrogen atom, an alkyl group or the like; B represents either of the following groups: wherein R3, R4, R5, and R6 each represent a hydrogen atom, a halogen atom, an alkoxyl group or the like; m represents 1 or 2; and the ring of: represents an aromatic heterocyclic ring.

摘要翻译： 作为σ受体/结合物的配体的下述式（I）表示的新型化合物和含有该活性成分的药物，其中X表示烷基，芳基，杂环基等; Q表示由-CH 2 - ， - CO - ， - O - ， - CH（OR 7） - 表示的基团，其中R 7， / SUB表示氢原子，烷基等; n表示0〜5的整数， R 1和R 2各自表示氢原子，烷基等; B表示以下基团中的任一个：其中R 3，R 4，R 5和R 6各自 表示氢原子，卤素原子，烷氧基等; m表示1或2; 且环：表示芳族杂环。

公开(公告)号：US07683069B2

公开(公告)日：2010-03-23

申请号：US10538766

申请日：2003-12-12

申请人： Yoshihiro Usui ,  Masahiro Okuyama ,  Tokushi Hanano

发明人： Yoshihiro Usui ,  Masahiro Okuyama ,  Tokushi Hanano

IPC分类号： C07D401/14 ,  A61K31/505

CPC分类号： C07D401/14 ,  C07D409/14 ,  C07D413/14

摘要： A pyrimidone derivative represented by formula (I) or a salt thereof, or a solvate thereof or a hydrate thereof useful as a tau protein kinase 1 inhibitor: wherein X represents CH or nitrogen atom; R1 represents a C?1#191-C?12#191 alkyl group which may be substituted; R2 represents a C?1#191-C?8#191 alkyl group which may be substituted, a benzene ring which may be substituted, a naphthalene ring which may be substituted, an indan ring which may be substituted, a tetrahydronaphthalene ring which may be substituted, or an optionally substituted heterocyclic ring having 1 to 4 hetero atoms selected from the group consisting of oxygen atom, sulfur atom, and nitrogen atom, and having 5 to 10 ring-constituting atoms in total.

摘要翻译： 用作tau蛋白激酶1抑制剂的由式（I）表示的嘧啶酮衍生物或其盐或其溶剂合物或其水合物：其中X表示CH或氮原子; R1表示可被取代的C 1〜191-C 12〜191烷基; R2表示可被取代的C 1〜191-C 18〜191烷基，可被取代的苯环，可被取代的萘环，可被取代的茚满环，可以被取代的四氢萘环， 或具有1〜4个选自氧原子，硫原子和氮原子的杂原子的任意取代的杂环，并且总共具有5〜10个构成环的原子。