公开(公告)号：US06770676B2

公开(公告)日：2004-08-03

申请号：US10297479

申请日：2002-12-06

申请人： Atsuro Nakazato ,  Toshihito Kumagai ,  Kosuke Kanuma ,  Kazunari Sakagami

发明人： Atsuro Nakazato ,  Toshihito Kumagai ,  Kosuke Kanuma ,  Kazunari Sakagami

IPC分类号： C07C6113

CPC分类号： C07C229/50 ,  C07C2602/18

摘要： The present invention relates to 2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives represented by the formula: the pharmaceutically acceptable salts thereof, or the hydrates thereof. The compounds of the present invention are useful as a medicament, and in particular, are useful as modulators acting on group 2 metabotropic glutamate receptors, having effects for treating and/or preventing psychiatric disorders such as schizophrenia, anxiety and its associated diseases, depression, bipolar disorder, and epilepsy; and/or neurological diseases such as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia associated with muscular stiffness, cerebral ischemia, cerebral failure, myelopathy, and head trauma.

摘要翻译： 本发明涉及由下式表示的2-氨基-6-氟双环[3.1.0]己烷-2,6-二羧酸衍生物或其药学上可接受的盐或其水合物。 本发明的化合物可用作药物，特别是可用作作用于组2代谢型谷氨酸受体的调节剂，具有治疗和/或预防精神病学障碍如精神分裂症，焦虑及其相关疾病，抑郁症， 双相障碍和癫痫; 和/或神经系统疾病如药物依赖性，认知障碍，阿尔茨海默病，亨廷顿氏舞蹈病，帕金森病，与肌肉僵硬相关的运动障碍，脑缺血，脑衰竭，脊髓病和头部创伤。

公开(公告)号：US06500958B2

公开(公告)日：2002-12-31

申请号：US10176528

申请日：2002-06-24

申请人： Atsuro Nakazato ,  Toshihito Kumagai ,  Kazunari Sakagami ,  Kazuyuki Tomisawa

发明人： Atsuro Nakazato ,  Toshihito Kumagai ,  Kazunari Sakagami ,  Kazuyuki Tomisawa

IPC分类号： C07D23500

CPC分类号： C07D235/02 ,  C07C62/26 ,  C07C65/40 ,  C07C69/757 ,  C07C2602/18 ,  C07D339/06 ,  C07D495/10

摘要： The present invention relates to compounds which are useful for efficient synthesis of 2-amino-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acids. The compounds according to the present invention comprise 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid derivatives represented by the formula as follows: [wherein, R1 represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl C1-C6 alkyl group, an aryl group, an aryl C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 alkylthio C1-C6 alkyl group, a C1-C6 mercaptoalkyl group, a tetrahydrofuranyl group, or a tetrahydropyranyl group; R2 and R3 are identical or different, and each represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl C1-C6 alkyl group, an aryl group, or an aryl C1-C6 alkyl group, or alternatively, R2 and R3 together represent —(CH2)n— (wherein n represents 2 or 3); and Y1 and Y2 are identical or different, and each represents a sulfur atom, an oxygen atom, or a nitrogen atom].

摘要翻译： 本发明涉及可用于高效合成2-氨基-4-氧代双环[3.1.0]己烷-2,6-二羧酸的化合物。根据本发明的化合物包含2-氧代双环[3.1.0] 由下式表示的己烷-6-羧酸衍生物：[其中，R1表示氢原子，C1-C6烷基，C3-C6环烷基，C3-C6环烷基C1-C6烷基，芳基 基团，芳基C1-C6烷基，C1-C6烷氧基C1-C6烷基，C1-C6羟基烷基，C1-C6烷硫基C1-C6烷基，C1-C6巯基烷基，四氢呋喃基， 或四氢吡喃基; R2和R3相同或不同，各自表示C1-C6烷基，C3-C6环烷基，C3-C6环烷基C1-C6烷基，芳基或芳基C1-C6烷基，或 或者，R2和R3一起表示 - （CH 2）n - （其中n表示2或3）; Y 1和Y 2相同或不同，各自表示硫原子，氧原子或氮原子]。

公开(公告)号：US06479674B1

公开(公告)日：2002-11-12

申请号：US09937212

申请日：2001-09-24

申请人： Atsuro Nakazato ,  Toshihito Kumagai ,  Kazunari Sakagami ,  Kazuyuki Tomisawa

发明人： Atsuro Nakazato ,  Toshihito Kumagai ,  Kazunari Sakagami ,  Kazuyuki Tomisawa

IPC分类号： C07D31500

CPC分类号： C07D235/02 ,  C07C62/26 ,  C07C65/40 ,  C07C69/757 ,  C07C2602/18 ,  C07D339/06 ,  C07D495/10

摘要： The present invention relates to compounds which are useful for efficient synthesis of 2-amino-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acids. The compounds according to the present invention comprise 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid derivatives represented by the formula as follows: [wherein, R1 represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl C1-C6 alkyl group, an aryl group, an aryl C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 alkylthio C1-C6 alkyl group, a C1-C6 mercaptoalkyl group, a tetrahydrofuranyl group, or a tetrahydropyranyl group; R2 and R3 are identical or different, and each represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl C1-C6 alkyl group, an aryl group, or an aryl C1-C6 alkyl group, or alternatively, R2 and R3 together represent —(CH2)n— (wherein n represents 2 or 3); and Y1 and Y2 are identical or different, and each represents a sulfur atom, an oxygen atom, or a nitrogen atom].

摘要翻译： 本发明涉及可用于高效合成2-氨基-4-氧代双环[3.1.0]己烷-2,6-二羧酸的化合物。根据本发明的化合物包含2-氧代双环[3.1.0] 由下式表示的己烷-6-羧酸衍生物：[其中，R1表示氢原子，C1-C6烷基，C3-C6环烷基，C3-C6环烷基C1-C6烷基，芳基 基团，芳基C1-C6烷基，C1-C6烷氧基C1-C6烷基，C1-C6羟基烷基，C1-C6烷硫基C1-C6烷基，C1-C6巯基烷基，四氢呋喃基， 或四氢吡喃基; R2和R3相同或不同，各自表示C1-C6烷基，C3-C6环烷基，C3-C6环烷基C1-C6烷基，芳基或芳基C1-C6烷基，或 或者，R2和R3一起表示 - （CH 2）n - （其中n表示2或3）; Y 1和Y 2相同或不同，各自表示硫原子，氧原子或氮原子]。

公开(公告)号：US06333428B1

公开(公告)日：2001-12-25

申请号：US09763408

申请日：2001-02-22

申请人： Atsuro Nakazato ,  Toshihito Kumagai ,  Kazunari Sakagami ,  Kazuyuki Tomisawa

发明人： Atsuro Nakazato ,  Toshihito Kumagai ,  Kazunari Sakagami ,  Kazuyuki Tomisawa

IPC分类号： C07C6974

CPC分类号： C07D317/72 ,  C07C229/50 ,  C07C2602/18 ,  C07D339/06

摘要： The present invention provides fluorobicyclo[3.1.0]hexane derivatives represented by the formula [wherein R1 and R2 are the same or different and each represents a hydrogen atom, a C1-10 alkyl group, a C3-8 cycloalkyl group or a C3-8 cycloalkyl-C1-5 alkyl group: Y1 and Y2 are the same or different and each represents a hydrogen atom, a C1-10 alkylthio group, a C3-8 cycloalkylthio group, a C3-8 cycloalkyl-C1-5 alkylthio group, a C1-5 alkoxy group, a C3-8 cycloalkoxy group or a C3-8 cycloalkyl-C1-5 alkoxy group; or one represents a hydrogen atom and the other represents a hydroxyl group, a C1-5 alkoxy group, a C3-8 cycloalkoxy group or a C3-8 cycloalkyl-C1-5 alkoxy group; or Y1 and Y2 together represent an oxygen atom or —X(CH2)nX— (X represents an oxygen atom or a sulfur atom: N is 2 or 3)], pharmaceutically acceptable salts thereof, or hydrates thereof. The compounds of the present invention are useful as drugs, in particular group 2 metabotropic glutamate receptor agonists, and useful for treatment or prevention of psychiatric disorders such as, for example, schizophrenia, anxiety and associated diseases, depression, bipolar disorder, and epilepsy, as well as neurological diseases such as, for example, drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia associated with muscular stiffness, cerebral ischemia, cerebral failure, myelopathy, and head trauma.

摘要翻译： 本发明提供由式[其中R 1和R 2相同或不同，表示氢原子，C 1-10烷基，C 3-8环烷基或C 3-8环烷基]表示的氟双环[3.1.0] 8环烷基-C 1-5烷基：Y1和Y2相同或不同，各自表示氢原子，C1-10烷硫基，C3-8环硫基，C3-8环烷基-C1-5烷硫基， C 1-5烷氧基，C 3-8环烷氧基或C 3-8环烷基-C 1-5烷氧基; 或者一个表示氢原子，另一个表示羟基，C 1-5烷氧基，C 3-8环烷氧基或C 3-8环烷基-C 1-5烷氧基; 或Y1和Y2一起表示氧原子或-X（CH 2）n X-（X表示氧原子或硫原子：N为2或3）]，其药学上可接受的盐或其水合物。本发明化合物 本发明可用作药物，特别是组2代谢型谷氨酸受体激动剂，并且可用于治疗或预防精神病学障碍，例如精神分裂症，焦虑和相关疾病，抑郁症，双相性精神障碍和癫痫以及神经系统疾病 例如药物依赖，认知障碍，阿尔茨海默病，亨廷顿氏舞蹈病，帕金森病，与肌肉僵硬相关的运动障碍，脑缺血，脑衰竭，脊髓损伤和头部创伤。

公开(公告)号：US06825375B2

公开(公告)日：2004-11-30

申请号：US10311230

申请日：2002-12-17

申请人： Atsuro Nakazato ,  Toshihito Kumagai ,  Kazunari Sakagami ,  Takeo Taguchi

发明人： Atsuro Nakazato ,  Toshihito Kumagai ,  Kazunari Sakagami ,  Takeo Taguchi

IPC分类号： C07C6974

CPC分类号： C07C69/716 ,  C07C67/317 ,  C07C2601/08 ,  C07C2602/18 ,  C07C69/757

摘要： The present invention relates to a 2-fluoro-2-(3-oxobicyclopentyl)acetate derivative represented by the formula (1): The compound according to the present invention is useful for efficient syntheses of 2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acids.

摘要翻译： 本发明涉及由式（1）表示的2-氟-2-（3-氧代环戊基）乙酸酯衍生物：本发明化合物可用于2-氨基-6-氟双环[3.1。 0]己烷-2,6-二羧酸。

公开(公告)号：US06392086B1

公开(公告)日：2002-05-21

申请号：US09857631

申请日：2001-06-07

申请人： Atsuro Nakazato ,  Toshihito Kumagai ,  Kazunari Sakagami ,  Kazuyuki Tomisawa ,  Hisanako Ito ,  Takeo Taguchi

发明人： Atsuro Nakazato ,  Toshihito Kumagai ,  Kazunari Sakagami ,  Kazuyuki Tomisawa ,  Hisanako Ito ,  Takeo Taguchi

IPC分类号： C07C6974

CPC分类号： C07D235/02 ,  C07B2200/07 ,  C07C51/363 ,  C07C62/38 ,  C07C69/757 ,  C07C227/18 ,  C07C229/50 ,  C07C235/82 ,  C07C255/47 ,  C07C2602/18 ,  C07C2602/40 ,  C07D303/42 ,  C07D303/46

摘要： The present inventions relate to a (1S,5R,6S)- or (1SR, 5RS, 6SR)-3-fluoro-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylic acid derivative represented by Formula (1): [in the formula, R represents OR1 or NR1R2, wherein R1 and R2 are identical or different, and each represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a (C3-C6 cycloalkyl) (C1-C6 alkyl) group, an aryl group, an aryl (C1-C6 alkyl) group, a (C1-C6 alkoxy) (C1-C6 alkyl) group, a C1-C6 hydroxyalkyl group, a (C1-C6 alkylthio) (C1-C6 alkyl) group, or a C1-C6 mercaptoalkyl group], and a process for producing the same, and a process for efficiently producing a fluorine-containing amino acid compound acting on group 2 metabotropic glutamate receptors, which has treatment effects or prevention effects on psychiatric diseases or neurological diseases, characterized by hydrogenating the derivative, and subsequently, subjecting it to hydantoination or aminocyanidation, followed by hydrolysis.

摘要翻译： 本发明涉及式（1S，5R，6S） - 或（1SR，5RS，6SR）-3-氟-2-氧代双环[3.1.0]己-3-烯-6-羧酸衍生物 1）：[式中，R表示OR 1或NR 1 R 2，其中R 1和R 2相同或不同，表示氢原子，C1-C6烷基，C3-C6环烷基，（C3-C6环烷基） ）（C1-C6烷基），芳基（C1-C6烷基），（C1-C6烷氧基）（C1-C6烷基），C1-C6羟基烷基，（C1-C6烷基） 烷基硫基）（C1-C6烷基）或C1-C6巯基烷基]及其制备方法，以及有效地制备作用于第2族代谢型谷氨酸受体的含氟氨基酸化合物的方法，其具有 治疗效果或预防对精神疾病或神经系统疾病的影响，其特征在于使该衍生物氢化，然后使其进行乙烯基化或氨基化，然后进行水解。

公开(公告)号：US06316498B1

公开(公告)日：2001-11-13

申请号：US09601131

申请日：2000-07-27

申请人： Atsuro Nakazato ,  Toshihito Kumagai ,  Kazunari Sakagami ,  Kazuyuki Tomisawa

发明人： Atsuro Nakazato ,  Toshihito Kumagai ,  Kazunari Sakagami ,  Kazuyuki Tomisawa

IPC分类号： C07C6974

CPC分类号： C07C229/50 ,  C07C2602/18

摘要： Fluorine-containing amino acid derivatives represented general formula (I), pharmaceutically acceptable salts thereof or hydrates of the same, wherein X1 represents hydrogen or fluorine; and R1 and R2 are the same or different and each represents hydrogen or lower C1-10 alkyl. These compounds are useful as drugs, in particular, group 2 metabotropic glutamate receptor agonists for treating and preventing psychiatric disorders such as schizophrenia, anxiety and associated diseases, depression, bipolar disturbance and epilepsy, and neurological diseases such as drug addiction, cognition disorder, Alzheimer's disease, Huntington's chorea, Parkinson's disease, motility disturbance associating muscular stiffness, cerebral ischemia, cerebral insufficiency, spinal cord lesion and head disturbance.

摘要翻译： 含氟氨基酸衍生物表示通式（I），其药学上可接受的盐或其水合物，其中X1表示氢或氟; 并且R 1和R 2相同或不同，各自表示氢或低级C 1-10烷基。 这些化合物可用作药物，特别是用于治疗和预防精神疾病如精神分裂症，焦虑和相关疾病，抑郁症，双相障碍和癫痫以及神经系统疾病如药物成瘾，认知障碍，阿尔茨海默氏症的药物，特别是第2代代谢型谷氨酸受体激动剂 疾病，亨廷顿氏舞蹈病，帕金森病，运动障碍，肌肉僵硬，脑缺血，脑功能不全，脊髓损伤和头部干扰。

公开(公告)号：US06407121B1

公开(公告)日：2002-06-18

申请号：US09646080

申请日：2000-09-13

申请人： Masashi Nagamine ,  Makoto Gotoh ,  Masanori Yoshida ,  Atsuro Nakazato ,  Toshihito Kumagai ,  Shigeyuki Chaki ,  Kazuyuki Tomisawa

发明人： Masashi Nagamine ,  Makoto Gotoh ,  Masanori Yoshida ,  Atsuro Nakazato ,  Toshihito Kumagai ,  Shigeyuki Chaki ,  Kazuyuki Tomisawa

IPC分类号： A61K31445

CPC分类号： C07D401/14 ,  C07D405/14 ,  C07D417/14

摘要： The present invention provides an arylpiperidine derivative of the formula (I) or a pharmaceutically acceptable salt thereof, which has antipsychotic effect: wherein D is a carbon atom or a nitrogen atom, E is a CH group or a nitrogen atom, G is an oxygen atom, a sulfur atom, a nitrogen atom or an NH group, Y1 is a hydrogen atom or a halogen atom, n is an integer of 1 to 4, and R1 is a group represented by any of the formulas (i) to (iv) defined in the specification.

摘要翻译： 本发明提供具有抗精神病作用的式（I）的芳基哌啶衍生物或其药学上可接受的盐，其中D为碳原子或氮原子，E为CH基或氮原子，G为氧 原子，硫原子，氮原子或NH基，Y1是氢原子或卤素原子，n是1〜4的整数，R1是由式（i）〜（iv）中的任一个表示的基团 ）。

公开(公告)号：US06329525B1

公开(公告)日：2001-12-11

申请号：US09555568

申请日：2000-06-01

申请人： Atsuro Nakazato ,  Taketoshi Okubo ,  Toshihito Kumagai ,  Shigeyuki Chaki ,  Kazuyuki Tomisawa ,  Masashi Nagamine ,  Makoto Gotoh ,  Masanori Yoshida

发明人： Atsuro Nakazato ,  Taketoshi Okubo ,  Toshihito Kumagai ,  Shigeyuki Chaki ,  Kazuyuki Tomisawa ,  Masashi Nagamine ,  Makoto Gotoh ,  Masanori Yoshida

IPC分类号： C07D215227

CPC分类号： C07D401/06 ,  C07D215/54 ,  C07D241/44

摘要： A 1,2-dihydro-2-oxoquinoline derivative represented by the formula: wherein Ar is a pyridyl group or a group represented by the formula: (wherein X3 and X4 are the same or different, and are each a hydrogen atom, a halogen atom, a C1-5 alkyl group, a C1-5 alkoxy group, a hydroxyl group or a trifluoromethyl group), Y is a nitrogen atom, CH or C(OH), R1 and R2 are the same or different, and are each a hydrogen atom, a C1-10 alkyl group, a C3-15 alkoxyalkyl group or a C3-15 alkylaminoalkyl group, or R1 and R2 taken together with the nitrogen atom to which they are attached form a cyclic amino group, X1 and X2 are the same or different, and are each a hydrogen atom, a C1-5 alkyl group, a C1-5 alkoxy group or a halogen atom, or X1 and X2 taken together form an alkylenedioxy group, and n is an integer of 1 to 3; or a pharmaceutically acceptable salt thereof.

摘要翻译： 由下式表示的1,2-二氢-2-氧代喹啉衍生物：其中Ar是吡啶基或由下式表示的基团：（其中X 3和X 4相同或不同，并且各自为氢原子，卤素 原子，C 1-5烷基，C 1-5烷氧基，羟基或三氟甲基），Y是氮原子，CH或C（OH），R 1和R 2相同或不同，各自相同或不同 氢原子，C 1-10烷基，C 3-15烷氧基烷基或C 3-15烷基氨基烷基，或者R 1和R 2与它们所连接的氮原子一起形成环状氨基，X 1和X 2是 相同或不同，各自为氢原子，C1-5烷基，C1-5烷氧基或卤素原子，或X1和X2一起形成亚烷基二氧基，n为1〜3的整数 ; 或其药学上可接受的盐。

公开(公告)号：US06281355B1

公开(公告)日：2001-08-28

申请号：US09555570

申请日：2000-06-01

申请人： Atsuro Nakazato ,  Taketoshi Okubo ,  Toshihito Kumagai ,  Shigeyuki Chaki ,  Kazuyuki Tomisawa ,  Masashi Nagamine ,  Makoto Gotoh ,  Kuniaki Kondoh ,  Masanori Yoshida

发明人： Atsuro Nakazato ,  Taketoshi Okubo ,  Toshihito Kumagai ,  Shigeyuki Chaki ,  Kazuyuki Tomisawa ,  Masashi Nagamine ,  Makoto Gotoh ,  Kuniaki Kondoh ,  Masanori Yoshida

IPC分类号： A61K31403

CPC分类号： C07D471/04 ,  C07D495/04

摘要： A nitrogen-containing tetracyclic compound represented by the formula: wherein Y1—Y2—Y3 is N—C═N or a group represented by the formula: C═C—NR3 (wherein R3 is a hydrogen atom, a C1-5 alkyl group or a nitrogen-containing C2-10 alkyl group), Y4 is S, SO, SO2, CH2 or a group represented by the formula: NR4 (wherein R4 is a C1-5 alkanoyl group or a C1-5 alkyl group), R1 and R2 are the same or different, and are each a hydrogen atom, a C1-10 alkyl group, a C3-15 alkoxyalkyl group or a C3-15 alkylaminoalkyl group, or R1 and R2 taken together with the nitrogen atom to which they are attached form a cyclic amino group, X1 and X2 are the same or different, and are each a hydrogen atom, a C1-5 alkyl group, a C1-5 alkoxy group or a halogen atom, and n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

摘要翻译： 一种由下式表示的含氮四环化合物：其中Y1-Y2-Y3为NC = N或由下式表示的基团：C = C-NR3（其中R3为氢原子，C1-5烷基或 含氮的C2-10烷基），Y4是S，SO，SO2，CH2或由下式表示的基团：NR4（其中R4是C1-5烷酰基或C1-5烷基），R1和R2 各自为氢原子，C 1-10烷基，C 3-15烷氧基烷基或C 3-15烷基氨基烷基，或者R 1和R 2与它们所连接的氮原子一起形成 环状氨基，X1和X2相同或不同，分别为氢原子，C1-5烷基，C1-5烷氧基或卤素原子，n为0,1或2; 或其药学上可接受的盐。