公开(公告)号：US08552060B2

公开(公告)日：2013-10-08

申请号：US11922128

申请日：2006-06-13

申请人： Joseph Palumbo ,  Jonathan Sporn ,  Thomas Steckler ,  Yong Choi ,  James S. Lee

发明人： Joseph Palumbo ,  Jonathan Sporn ,  Thomas Steckler ,  Yong Choi ,  James S. Lee

IPC分类号： A61K31/24

CPC分类号： A61K31/165

摘要： This invention is directed to a method of treating sexual dysfunction in a subject, comprising the step of administering a therapeutically effective amount of a compound of Formula (I): or a pharmaceutically acceptable salt or ester thereof wherein Rx is a member selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, CI, Br and I, alkoxy containing 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, and thioalkoxy containing 1 to 3 carbon atoms; x is an integer of 1 to 3, with the proviso that R may be the same or different when x is 2 or 3; R1 and R2 can be the same or different from each other and are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl of 3 to 7 carbon atoms; R1 and R2 can be joined to form a 5 to 7-membered heterocycle substituted with a member selected from the group consisting of hydrogen, alkyl, and aryl groups, wherein the cyclic compound can comprise 1 to 2 nitrogen atoms and O to 1 oxygen atom, wherein the nitrogen atoms are not directly connected with each other or with the oxygen atom.

摘要翻译： 本发明涉及治疗受试者的性功能障碍的方法，其包括施用治疗有效量的式（I）化合物或其药学上可接受的盐或酯的步骤，其中Rx是选自下组的成员 由氢，1至8个碳原子的低级烷基，选自F，Cl，Br和I的卤素，含有1至3个碳原子的烷氧基，硝基，羟基，三氟甲基和含有1至3个碳原子的硫代烷氧基组成; x为1〜3的整数，条件是当x为2或3时R可以相同或不同; R 1和R 2可以相同或不同，并且独立地选自氢，1至8个碳原子的低级烷基，芳基，芳基烷基，3至7个碳原子的环烷基; R1和R2可以连接形成被选自氢，烷基和芳基的成员所取代的5至7元杂环，其中环状化合物可包含1至2个氮原子和0至1个氧原子 其中氮原子彼此不直接连接或与氧原子直接连接。

公开(公告)号：US20090221553A1

公开(公告)日：2009-09-03

申请号：US11922128

申请日：2006-06-13

申请人： Joseph Palumbo ,  Jonathan Sporn ,  Thomas Steckler ,  Yong Moon Choi ,  James S. Lee

发明人： Joseph Palumbo ,  Jonathan Sporn ,  Thomas Steckler ,  Yong Moon Choi ,  James S. Lee

IPC分类号： A61K31/553 ,  A61K31/27 ,  A61K31/55 ,  A61P15/00

CPC分类号： A61K31/165

摘要： This invention is directed to a method of treating sexual dysfunction in a subject, comprising the step of administering a therapeutically effective amount of a compound of Formula (I): or a pharmaceutically acceptable salt or ester thereof wherein Rx is a member selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, halogen selected from F, CI, Br and I, alkoxy containing 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, and thioalkoxy containing 1 to 3 carbon atoms; x is an integer of 1 to 3, with the proviso that R may be the same or different when x is 2 or 3; R1 and R2 can be the same or different from each other and are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl of 3 to 7 carbon atoms; R1 and R2 can be joined to form a 5 to 7-membered heterocycle substituted with a member selected from the group consisting of hydrogen, alkyl, and aryl groups, wherein the cyclic compound can comprise 1 to 2 nitrogen atoms and O to 1 oxygen atom, wherein the nitrogen atoms are not directly connected with each other or with the oxygen atom.

摘要翻译： 本发明涉及治疗受试者的性功能障碍的方法，其包括施用治疗有效量的式（I）化合物或其药学上可接受的盐或酯的步骤，其中Rx是选自下组的成员 由氢，1至8个碳原子的低级烷基，选自F，Cl，Br和I的卤素，含有1至3个碳原子的烷氧基，硝基，羟基，三氟甲基和含有1至3个碳原子的硫代烷氧基组成; x为1〜3的整数，条件是当x为2或3时R可以相同或不同; R 1和R 2可以相同或不同，并且独立地选自氢，1至8个碳原子的低级烷基，芳基，芳基烷基，3至7个碳原子的环烷基; R1和R2可以连接形成被选自氢，烷基和芳基的成员所取代的5至7元杂环，其中环状化合物可包含1至2个氮原子和0至1个氧原子 其中氮原子彼此不直接连接或与氧原子直接连接。

公开(公告)号：US20060277611A1

公开(公告)日：2006-12-07

申请号：US10557109

申请日：2004-05-13

申请人： Wendy Mia Balemans ,  Diederik Willem Moechars ,  Thomas Steckler ,  Kim Cryns

发明人： Wendy Mia Balemans ,  Diederik Willem Moechars ,  Thomas Steckler ,  Kim Cryns

IPC分类号： A01K67/027 ,  C12Q1/68 ,  G01N33/567

CPC分类号： A01K67/0276 ,  A01K2217/075 ,  A01K2227/105 ,  A01K2267/0356 ,  C12N9/16 ,  G01N33/573

摘要： This invention relates to the functional characterization of myo-inositol monophosphatase 2 (IMPA2), one of the enzymes acting in the phosphatidyl inositol signaling pathway. In particular, the present invention provides evidence that IMPA2 is associated with depression- and anxiety inducing conditions, in particular anxiety and affective disorders. In a first aspect the present invention provides the use of an IMPA2 enzyme in an assay to identify anti-anxiety or an anti-depression compounds. In particular to the use of an isolated polynucleotide encoding said IMPA2 protein, wherein said IMPA2 protein is preferably being selected from polynucleotides encoding the mouse, rat or human IMPA2 enzyme. It is thus an object of the present invention to provide a method for identifying anti-anxiety or anti-depression compounds wherein said compounds are capable of enhancing neuronal plasticity, said method comprising the steps of: a) providing a composition comprising an IMPA2 protein; b) contacting the IMPA2 protein with the test compound; and c) measuring the activity of the IMPA2 protein wherein a decrease in the IMPA2 activity in the presence of the test compound is an indicator of an anti-anxiety or anti-depression compound. In these assays the activity of the IMPA2 protein is assessed by measuring the hydrolysis of myo-inositol 1-phosphate to generate inositol and inorganic phosphate, in particular by measuring the accumulation of either myo-inositol monophosphate product in the form of radiolabeled inositol or inorganic phosphate (Pi) in the form of radiolabeled 32Pi or in a colorimetric assay. The compositions comprising the IMPA2 protein could either be cellular extracts, whole cells or organisms expressing the IMPA2 proteins according to the invention.

摘要翻译： 本发明涉及作用于磷脂酰肌醇信号通路的酶之一的肌醇单磷酸酶2（IMPA2）的功能表征。 特别地，本发明提供证据表明IMPA2与抑郁和焦虑诱发病症特别是焦虑和情感障碍有关。 在第一方面，本发明提供了IMPA2酶在测定中用于鉴定抗焦虑或抗抑郁化合物的用途。 具体涉及使用编码所述IMPA2蛋白质的分离的多核苷酸，其中所述IMPA2蛋白质优选选自编码小鼠，大鼠或人IMPA2酶的多核苷酸。 因此，本发明的目的是提供一种用于鉴定抗焦虑或抗抑郁化合物的方法，其中所述化合物能够增强神经元的可塑性，所述方法包括以下步骤：a）提供包含IMPA2蛋白质的组合物; b）使IMPA2蛋白质与测试化合物接触; 和c）测量IMPA2蛋白的活性，其中在测试化合物存在下IMPA2活性的降低是抗焦虑或抗抑郁化合物的指标。 在这些测定中，通过测量肌醇-1-磷酸肌酸水解产生肌醇和无机磷酸酯来评估IMPA2蛋白的活性，特别是通过测量放射性标记的肌醇或无机形式的肌醇单磷酸酯产物的积累 磷酸盐（Pi）以放射性标记的32 PIP的形式或在比色测定中。 包含IMPA2蛋白质的组合物可以是表达本发明的IMPA2蛋白质的细胞提取物，全细胞或生物体。

公开(公告)号：US20060287345A1

公开(公告)日：2006-12-21

申请号：US10552527

申请日：2004-04-08

申请人： Thomas Steckler ,  Frans Janssens ,  Joseph Leenaerts ,  Francisco Fernandez-Gadea ,  Antonio Gomez-Sanchez ,  Theo Meert

发明人： Thomas Steckler ,  Frans Janssens ,  Joseph Leenaerts ,  Francisco Fernandez-Gadea ,  Antonio Gomez-Sanchez ,  Theo Meert

IPC分类号： A61K31/513 ,  A61K31/454

CPC分类号： A61K31/506 ,  A61K31/454

摘要： The present invention relates to the use of 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives according to Formula (I) the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the N-oxide forms thereof as selective non-peptide δ-opioid agonists for use in the prevention and/or treatment of various central nervous system disorders, in particular as selective antidepressant and anxiolytic non-peptide δ-opioid agonists. In particular are claimed compounds according to Formula (I) in which A=B is C═O or SO2, X is a covalent bond, R1 is allyloxy, alkyloxyalkyl, Ar or NR9R10, wherein R9 and R10 each independently are hydrogen or Ar; or A=B and R1 together form a benzoxazolyl radical; p is zero, R3 is benzyl optionally substituted with hydroxy, alkyl or alkyloxycarbonyl and R4 and R5 each are hydrogen.

摘要翻译： 本发明涉及式（I）的4-苯基-4- [1H-咪唑-2-基] - 哌啶衍生物，其药学上可接受的酸或碱加成盐，其立体化学异构形式，互变异构体 形式和其N-氧化物形式作为用于预防和/或治疗各种中枢神经系统疾病的选择性非肽δ-阿片样物质激动剂，特别是作为选择性抗抑郁药和抗焦虑性非肽δ-阿片样物质激动剂。 特别是根据式（I）所述的化合物，其中A = B是CO或SO 2，X是共价键，R 1是烯丙氧基，烷氧基烷基，Ar 或其中R 9和R 10各自独立地是氢或Ar; R 9和R 10各自独立地是氢或Ar; 或A = B和R 1一起形成苯并恶唑基; p为0，R 3为任选被羟基，烷基或烷氧基羰基取代的苄基，R 4和R 5各自为氢。