公开(公告)号：US06770638B2

公开(公告)日：2004-08-03

申请号：US10209451

申请日：2002-07-30

申请人： David B. Fick ,  Mark M. Foreman ,  Alvin J. Glasky ,  David R. Helton

发明人： David B. Fick ,  Mark M. Foreman ,  Alvin J. Glasky ,  David R. Helton

IPC分类号： A61K3133

CPC分类号： C07D403/12 ,  A61K31/496 ,  A61K31/506 ,  C07D209/08 ,  C07D209/88 ,  C07D403/14 ,  C07D413/12 ,  C07D417/12

摘要： Pharmaceutical composite compositions comprising tetrahydroindolones linked to arylpiperazines and derivatives thereof are disclosed. Specifically, composite compositions useful in treating anti-psychotic disorders are disclosed. The composite compositions disclosed herein can effectively ameliorate symptoms and treat psychotic disorders without causing a decrease in cognitive function. Generally, the composite compounds consist of two moieties, moiety A and B in which a tetrahydroindolone comprises a moiety A linked through a linker L to a moiety B, where B is an arylpiperazinyl moiety. The composite compound provides anti-psychotic actively by interaction with GABA, seratoninne and dopamine receptors. The composite molecules with the combined activities will provide treat psychiatric and neurological diseases without cognitive impairment.

摘要翻译： 公开了包含与芳基哌嗪及其衍生物连接的四氢吲哚酮的药物复合组合物。 具体地，公开了可用于治疗抗精神病药物的复合组合物。 本文公开的复合组合物可以有效地改善症状并治疗精神病，而不引起认知功能的降低。 通常，复合化合物由两个部分A和B组成，其中四氢吲哚酮包含通过连接体L与B部分连接的部分A，其中B是芳基哌嗪基部分。 复合化合物通过与GABA，血清素和多巴胺受体的相互作用积极地提供抗精神病药物。 具有组合活性的复合分子将提供治疗精神和神经疾病而没有认知障碍。

公开(公告)号：US06759427B2

公开(公告)日：2004-07-06

申请号：US09839289

申请日：2001-04-20

申请人： David B. Fick ,  Mark M. Foreman ,  Alvin J. Glasky

发明人： David B. Fick ,  Mark M. Foreman ,  Alvin J. Glasky

IPC分类号： A61K31405

CPC分类号： C07D209/08 ,  C07D209/88

摘要： A tetrahydroindolone derivative or analogue comprises a 9-atom bicyclic moiety, moiety A, linked through a linker L to a moiety B, where B is a carboxylic acid, a carboxylic acid ester, or a moiety of the structure N(Y1)-D, where Y1 can be one of a variety of substituents, including hydrogen or alkyl, and D is a moiety that enhances the pharmacological effects, promotes absorption or blood-brain barrier penetration of the derivative or analogue. The moiety A has a six-membered ring fused to a five-membered ring. The moiety A can have one, two, or three nitrogen atoms in the five membered ring. The moiety A can be a tetrahydroindolone moiety. The moiety B can be one of a variety of moieties, including moieties having nootropic activity or other biological or physiological activity.

摘要翻译： 四氢吲哚酮衍生物或类似物包含通过连接体L与B部分连接的9个双环部分的部分A，其中B是羧酸，羧酸酯或结构N（Y 1）-D 其中Y1可以是各种取代基之一，包括氢或烷基，D是增强药理作用，促进衍生物或类似物的吸收或血脑屏障穿透的部分。 部分A具有与五元环稠合的六元环。 部分A可以在五元环中具有一个，两个或三个氮原子。 部分A可以是四氢吲哚酮部分。 部分B可以是多种部分之一，包括具有向异性活性或其他生物或生理活性的部分。

公开(公告)号：US20120070385A1

公开(公告)日：2012-03-22

申请号：US13246014

申请日：2011-09-27

申请人： Alvin J. Glasky ,  David B. Fick ,  David Helton

发明人： Alvin J. Glasky ,  David B. Fick ,  David Helton

IPC分类号： A61K31/404 ,  A61P25/00 ,  A61K9/12

CPC分类号： C07D209/08 ,  C07D209/88

摘要： The present specification discloses tetrahydroindolone derivatives or analogues and methods for treating cognitive/attention deficit disorders using such tetrahydroindolone derivatives and analogues.

摘要翻译： 本说明书公开了使用这种四氢吲哚酮衍生物和类似物治疗认知/注意力缺陷障碍的四氢吲哚酮衍生物或类似物和方法。

公开(公告)号：US20090192319A1

公开(公告)日：2009-07-30

申请号：US12414539

申请日：2009-03-30

申请人： Alvin J. Glasky ,  David B. Fick ,  David Helton

发明人： Alvin J. Glasky ,  David B. Fick ,  David Helton

IPC分类号： C07D209/08

CPC分类号： C07D209/08 ,  C07D209/88

摘要： Methods for treating cognitive/attention deficit disorders in general using tetrahydroindolone derivatives and analogues, particularly tetrahydroindolone derivatives or analogues in which the tetrahydroindolone derivative or analogue is covalently linked to another moiety to form a bifunctional conjugate are disclosed. More specifically, methods and compositions for treating attention deficit disorder and attention deficit hyperactivity disorders in adults and children as well as mild cognitive impairment and dementia are provided. The compounds used to treat and/or palliate cognitive/attention deficit disorders in general include a tetrahydroindolone derivative or analogue comprises a 9-atom bicyclic moiety, moiety A, linked through a linker L to a moiety B, where B is a carboxylic acid, a carboxylic acid ester, or a moiety of the structure N(Y1)-D, where Y1 can be one of a variety of substituents, including hydrogen or alkyl, and D is a moiety that enhances the pharmacological effects, promotes absorption or blood-brain barrier penetration of the derivative or analogue. The moiety A has a six-membered ring fused to a five-membered ring. The moiety A can have one, two, or three nitrogen atoms in the five membered ring. The moiety A can be a tetrahydroindolone moiety. The moiety B can be one of a variety of moieties, including moieties having nootropic activity or other biological or physiological activity.

摘要翻译： 公开了通常使用四氢吲哚酮衍生物和类似物，特别是其中四氢吲哚酮衍生物或类似物共价连接到另一部分以形成双功能缀合物的四氢吲哚酮衍生物或类似物的治疗认知/注意力缺陷障碍的方法。 更具体地，提供了用于治疗成人和儿童的注意力缺陷障碍和注意缺陷多动障碍以及轻度认知障碍和痴呆的方法和组合物。 用于治疗和/或缓解认知/注意力缺陷障碍的化合物通常包括四氢吲哚酮衍生物或类似物包含通过连接体L与B部分连接的9位双环部分A部分，其中B是羧酸， 羧酸酯或结构N（Y1）-D的部分，其中Y1可以是各种取代基之一，包括氢或烷基，D是增强药理作用，促进吸收或血液中的部分， 衍生物或类似物的脑屏障穿透。 部分A具有与五元环稠合的六元环。 部分A可以在五元环中具有一个，两个或三个氮原子。 部分A可以是四氢吲哚酮部分。 部分B可以是多种部分之一，包括具有向异性活性或其他生物或生理活性的部分。

公开(公告)号：US08063233B2

公开(公告)日：2011-11-22

申请号：US12414539

申请日：2009-03-30

申请人： Alvin J. Glasky ,  David B. Fick ,  David R. Helton

发明人： Alvin J. Glasky ,  David B. Fick ,  David R. Helton

IPC分类号： C07D209/04

CPC分类号： C07D209/08 ,  C07D209/88

摘要： Methods for treating cognitive/attention deficit disorders in general using tetrahydroindolone derivatives and analogues, particularly tetrahydroindolone derivatives or analogues in which the tetrahydroindolone derivative or analogue is covalently linked to another moiety to form a bifunctional conjugate are disclosed. More specifically, methods and compositions for treating attention deficit disorder and attention deficit hyperactivity disorders in adults and children as well as mild cognitive impairment and dementia are provided. The compounds used to treat and/or palliate cognitive/attention deficit disorders in general include a tetrahydroindolone derivative or analogue comprises a 9-atom bicyclic moiety, moiety A, linked through a linker L to a moiety B, where B is a carboxylic acid, a carboxylic acid ester, or a moiety of the structure N(Y1)-D, where Y1 can be one of a variety of substituents, including hydrogen or alkyl, and D is a moiety that enhances the pharmacological effects, promotes absorption or blood-brain barrier penetration of the derivative or analogue. The moiety A has a six-membered ring fused to a five-membered ring. The moiety A can have one, two, or three nitrogen atoms in the five membered ring. The moiety A can be a tetrahydroindolone moiety. The moiety B can be one of a variety of moieties, including moieties having nootropic activity or other biological or physiological activity.

摘要翻译： 公开了通常使用四氢吲哚酮衍生物和类似物，特别是其中四氢吲哚酮衍生物或类似物共价连接到另一部分以形成双功能缀合物的四氢吲哚酮衍生物或类似物的治疗认知/注意力缺陷障碍的方法。 更具体地，提供了用于治疗成人和儿童的注意力缺陷障碍和注意缺陷多动障碍以及轻度认知障碍和痴呆的方法和组合物。 用于治疗和/或缓解认知/注意力缺陷障碍的化合物通常包括四氢吲哚酮衍生物或类似物包含通过连接体L与B部分连接的9位双环部分A部分，其中B是羧酸， 羧酸酯或结构N（Y1）-D的部分，其中Y1可以是各种取代基之一，包括氢或烷基，D是增强药理作用，促进吸收或血液中的部分， 衍生物或类似物的脑屏障穿透。 部分A具有与五元环稠合的六元环。 部分A可以在五元环中具有一个，两个或三个氮原子。 部分A可以是四氢吲哚酮部分。 部分B可以是多种部分之一，包括具有向异性活性或其他生物或生理活性的部分。

公开(公告)号：US06982269B2

公开(公告)日：2006-01-03

申请号：US10193550

申请日：2002-07-09

申请人： Alvin J. Glasky ,  David B. Fick ,  David Helton

发明人： Alvin J. Glasky ,  David B. Fick ,  David Helton

IPC分类号： A61K31/52 ,  A61K31/495 ,  A61K43/54 ,  A61K31/33

CPC分类号： C07D209/08 ,  C07D209/88

摘要： Methods for treating cognitive/attention deficit disorders in general using tetrahydroindolone derivatives and analogues, particularly tetrahydroindolone derivatives or analogues in which the tetrahydroindolone derivative or analogue is covalently linked to another moiety to form a bifunctional conjugate are disclosed. More specifically, methods and compositions for treating attention deficit disorder and attention deficit hyperactivity disorders in adults and children as well as mild cognitive impairment and dementia are provided. The compounds used to treat and/or palliate cognitive/attention deficit disorders in general include a tetrahydroindolone derivative or analogue comprises a 9-atom bicyclic moiety, moiety A, linked through a linker L to a moiety B, where B is a carboxylic acid, a carboxylic acid ester, or a moiety of the structure N(Y1)-D, where Y1 can be one of a variety of substituents, including hydrogen or alkyl, and D is a moiety that enhances the pharmacological effects, promotes absorption or blood-brain barrier penetration of the derivative or analogue. The moiety A has a six-membered ring fused to a five-membered ring. The moiety A can have one, two, or three nitrogen atoms in the five membered ring. The moiety A can be a tetrahydroindolone moiety. The moiety B can be one of a variety of moieties, including moieties having nootropic activity or other biological or physiological activity.

摘要翻译： 公开了通常使用四氢吲哚酮衍生物和类似物，特别是其中四氢吲哚酮衍生物或类似物共价连接到另一部分以形成双功能缀合物的四氢吲哚酮衍生物或类似物的治疗认知/注意力缺陷障碍的方法。 更具体地，提供了用于治疗成人和儿童的注意力缺陷障碍和注意缺陷多动障碍以及轻度认知障碍和痴呆的方法和组合物。 用于治疗和/或缓解认知/注意力缺陷障碍的化合物通常包括四氢吲哚酮衍生物或类似物包含通过连接体L与B部分连接的9位双环部分A部分，其中B是羧酸， 羧酸酯或结构N（Y 1 H）-D的部分，其中Y 1可以是多种取代基之一，包括氢或烷基， 并且D是增强药理作用，促进衍生物或类似物的吸收或血脑屏障穿透的部分。 部分A具有与五元环稠合的六元环。 部分A可以在五元环中具有一个，两个或三个氮原子。 部分A可以是四氢吲哚酮部分。 部分B可以是多种部分之一，包括具有向异性活性或其他生物或生理活性的部分。

公开(公告)号：US08377456B2

公开(公告)日：2013-02-19

申请号：US13246014

申请日：2011-09-27

申请人： Alvin J. Glasky ,  David B. Fick ,  David R. Helton

发明人： Alvin J. Glasky ,  David B. Fick ,  David R. Helton

IPC分类号： A61K47/00 ,  C07D209/14

CPC分类号： C07D209/08 ,  C07D209/88

摘要： The present specification discloses tetrahydroindolone derivatives or analogues and methods for treating cognitive/attention deficit disorders using such tetrahydroindolone derivatives and analogues.

摘要翻译： 本说明书公开了使用这种四氢吲哚酮衍生物和类似物治疗认知/注意力缺陷障碍的四氢吲哚酮衍生物或类似物和方法。

公开(公告)号：US06780853B1

公开(公告)日：2004-08-24

申请号：US09321882

申请日：1999-05-28

申请人： Ravindra B. Upasani ,  David B. Fick ,  Derk J. Hogenkamp ,  Nancy C. Lan

发明人： Ravindra B. Upasani ,  David B. Fick ,  Derk J. Hogenkamp ,  Nancy C. Lan

IPC分类号： A61K3158

CPC分类号： C07J1/0029 ,  C07J1/0007 ,  C07J1/0055 ,  C07J1/0077 ,  C07J17/00 ,  C07J21/00 ,  C07J31/006 ,  C07J41/0005 ,  C07J41/005 ,  C07J43/003

摘要： The invention relates to 3&agr;-hydroxy, 17-(un)substituted derivatives of the androstane series and 3&agr;-hydroxy, 21-substituted derivatives of the pregnane series. These derivatives are capable of acting at a recently identified site on the GRC, thereby modulating brain excitability in a manner that will alleviate stress, anxiety, insomnia, mood disorders that are amenable to GRC-active agents (such as depression) and seizure activity. The steroid derivatives of this invention are those having the general structural Formula: wherein R, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are farther defined herein and the dotted lines are single or double bonds. The structure includes androstanes, pregnanes (R4=methyl), 19-norandrostanes, and norpregnanes (R4=H).

摘要翻译： 本发明涉及雄甾烷基系列的3α-羟基，17-（未）取代的衍生物和孕烷系列的3α-羟基，21-取代的衍生物。 这些衍生物能够在最近确定的GRC位点起作用，从而以减轻压力，焦虑，失眠，舒适于GRC活性剂（如抑郁症）和癫痫发作活动的情绪障碍的方式调节脑兴奋性。 本发明的类固醇衍生物是具有以下结构式的化合物：其中R，R 1，R 2，R 3，R 4，R 5，R 6，R 7，R 8，R 9和R 10在本文中进一步定义，虚线是单键或双键。 该结构包括雄甾烷，孕烷（R4 =甲基），19-去雄孕烷和诺孕烷（R4 = H）。

公开(公告)号：US06465472B1

公开(公告)日：2002-10-15

申请号：US09654839

申请日：2000-09-01

申请人： Ravi Upasani ,  Sui X. Cai ,  Nancy C. Lan ,  Yan Wang ,  George Field ,  David B. Fick

发明人： Ravi Upasani ,  Sui X. Cai ,  Nancy C. Lan ,  Yan Wang ,  George Field ,  David B. Fick

IPC分类号： C07D23726

CPC分类号： C07D231/12 ,  C07D233/56 ,  C07D239/82 ,  C07D249/08 ,  C07D491/04

摘要： The invention relates to novel quinazolines and heterocycles which are antagonists or positive modulators of AMPA receptors, and the use thereof for treating, preventing or ameliorating neuronal loss associated with stroke, global and focal ischemia, CNS trauma, hypoglycemia and surgery, as well as treating or ameliorating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease and Down's syndrome, treating, preventing or ameliorating the adverse consequences of the overstimulation of the excitatory amino acids, treating, preventing or ameliorating anxiety, psychosis, convulsions, chronic pain, glaucoma, retinitis, urinary incontinence, muscular spasm and inducing anesthesia, as well as for treating or ameliorating the adverse consequences of excitatory amino acid deficiency such as schizophrenia, myoclonus. Alzheimer's disease and malnutrition and neural maldevelopment, and as cognition and learning enhancers.

摘要翻译： 本发明涉及作为AMPA受体的拮抗剂或阳性调节剂的新型喹唑啉和杂环，以及其用于治疗，预防或改善与中风，全身和局灶性缺血，CNS创伤，低血糖和手术相关的神经元损失以及治疗 或改善神经变性疾病，包括阿尔茨海默病，肌萎缩性侧索硬化，亨廷顿病，帕金森病和唐氏综合征，治疗，预防或改善兴奋性氨基酸过度刺激的不良后果，治疗，预防或改善焦虑，精神病，惊厥，慢性 疼痛，青光眼，视网膜炎，尿失禁，肌肉痉挛和诱导麻醉，以及治疗或改善兴奋性氨基酸缺乏症如精神分裂症，肌阵挛的不良后果。 阿尔茨海默病和营养不良和神经发育不良，以及认知和学习增强剂。

公开(公告)号：US07531670B2

公开(公告)日：2009-05-12

申请号：US11002329

申请日：2004-12-01

申请人： Alvin Jerald Glasky ,  David B. Fick ,  David R. Helton

发明人： Alvin Jerald Glasky ,  David B. Fick ,  David R. Helton

IPC分类号： C07D209/04

CPC分类号： C07D209/08 ,  C07D209/88

摘要： Methods for treating cognitive/attention deficit disorders in general using tetrahydroindolone derivatives and analogues, particularly tetrahydroindolone derivatives or analogues in which the tetrahydroindolone derivative or analogue is covalently linked to another moiety to form a bifunctional conjugate are disclosed. More specifically, methods and compositions for treating attention deficit disorder and attention deficit hyperactivity disorders in adults and children as well as mild cognitive impairment and dementia are provided. The compounds used to treat and/or palliate cognitive/attention deficit disorders in general include a tetrahydroindolone derivative or analogue comprises a 9-atom bicyclic moiety, moiety A, linked through a linker L to a moiety B, where B is a carboxylic acid, a carboxylic acid ester, or a moiety of the structure N(Y1)-D, where Y1 can be one of a variety of substituents, including hydrogen or alkyl, and D is a moiety that enhances the pharmacological effects, promotes absorption or blood-brain barrier penetration of the derivative or analogue. The moiety A has a six-membered ring fused to a five-membered ring. The moiety A can have one, two, or three nitrogen atoms in the five membered ring. The moiety A can be a tetrahydroindolone moiety. The moiety B can be one of a variety of moieties, including moieties having nootropic activity or other biological or physiological activity.

摘要翻译： 公开了通常使用四氢吲哚酮衍生物和类似物，特别是其中四氢吲哚酮衍生物或类似物共价连接到另一部分以形成双功能缀合物的四氢吲哚酮衍生物或类似物的治疗认知/注意力缺陷障碍的方法。 更具体地，提供了用于治疗成人和儿童的注意力缺陷障碍和注意缺陷多动障碍以及轻度认知障碍和痴呆的方法和组合物。 用于治疗和/或缓解认知/注意力缺陷障碍的化合物通常包括四氢吲哚酮衍生物或类似物包含通过连接体L与B部分连接的9位双环部分A部分，其中B是羧酸， 羧酸酯或结构N（Y1）-D的部分，其中Y1可以是各种取代基之一，包括氢或烷基，D是增强药理作用，促进吸收或血液中的部分， 衍生物或类似物的脑屏障穿透。 部分A具有与五元环稠合的六元环。 部分A可以在五元环中具有一个，两个或三个氮原子。 部分A可以是四氢吲哚酮部分。 部分B可以是多种部分之一，包括具有向异性活性或其他生物或生理活性的部分。