公开(公告)号：US06849735B1

公开(公告)日：2005-02-01

申请号：US09602048

申请日：2000-06-23

申请人： Alvin J. Glasky ,  Heinrich Bollinger ,  Hans Rudolf Müller

发明人： Alvin J. Glasky ,  Heinrich Bollinger ,  Hans Rudolf Müller

IPC分类号： A61P25/28 ,  C07D233/88 ,  C07D233/90 ,  C07D473/30

CPC分类号： C07D233/90 ,  C07D473/30

摘要： An improved method of synthesis of a 9-substituted hypoxanthine derivative comprises the steps of: (1) reacting aminocyanacetamide with triethyl orthoformate to form an imidoester derivative of aminocyanacetamide; (2) forming a compound having a reactive amino group on a hydrocarbyl moiety, the hydrocarbyl moiety being linked through an amide group to a physiologically active moiety or an esterified derivative of a physiologically active moiety including therein an esterified benzoyl group; (3) reacting the imidoester with the compound having the reactive amino group on the hydrocarbyl moiety to form a derivative of aminoimidazole-4-carboxamide substituted at the 1-position with a hydrocarbyl moiety linked through an amide group to a physiologically active moiety including therein an optionally esterified benzoyl group; (4) forming the six-membered heterocyclic ring of the purine moiety of the hypoxanthine by reacting the derivative of 5-aminoimidazole-4-carboxamide formed in step (3) with triethyl orthoformate to form a 9-substituted hypoxanthine compound substituted at the 9-position with a hydrocarbyl moiety linked through an amide group to a physiologically active moiety including therein an optionally esterified benzoyl group; and (5) hydrolyzing the ester of the optionally esterified benzoyl group if present.

摘要翻译： 合成9-取代的次黄嘌呤衍生物的改进方法包括以下步骤：（1）使氨基异氰酸乙酰胺与原甲酸三乙酯反应，形成氨基异氰酸乙酰胺的酰亚胺酯衍生物; （2）在烃基部分上形成具有反应性氨基的化合物，烃基部分通过酰胺基与生理活性部分或生理活性部分的酯化衍生物连接，其中包括酯化苯甲酰基; （3）使酰亚胺酯与在烃基部分上具有反应性氨基的化合物反应，以形成在1-位取代的氨基咪唑-4-甲酰胺的衍生物，其中烃基部分通过酰胺基团连接到包括其中的生理活性部分 任选酯化的苯甲酰基; （4）通过使步骤（3）中形成的5-氨基咪唑-4-甲酰胺的衍生物与原甲酸三乙酯反应形成在9位被取代的9-取代的次黄嘌呤化合物，形成次黄嘌呤嘌呤部分的六元杂环 - 具有通过酰胺基团连接到生理活性部分的烃基部分，其中包括任选酯化的苯甲酰基; 和（5）水解任意酯化的苯甲酰基的酯（如果存在）。

公开(公告)号：US06407237B1

公开(公告)日：2002-06-18

申请号：US09505984

申请日：2000-02-16

申请人： Alvin J. Glasky ,  Heinrich Bollinger ,  Hans Rudolf Müller

发明人： Alvin J. Glasky ,  Heinrich Bollinger ,  Hans Rudolf Müller

IPC分类号： C07D47330

CPC分类号： C07D473/30

摘要： The bifunctional compound N-4-carboxyphenyl-3-(6-oxohydropurin-9-yl) propanamide monopotassium salt occurs in a number of crystal forms which differ in their stability. Of these forms, the most stable is designated Type I, which is a monopotassium salt monohydrate in which the water is held as water of crystallization. Other crystalline forms, designated Type II and Type III, convert to Type I. Methods are disclosed for the synthesis of Type I and for the conversion of Type II or Type III to Type I.

摘要翻译： 双官能化合物N-4-羧基苯基-3-（6-氧代氢嘌呤-9-基）丙酰胺单钾盐以稳定性不同的多种晶体形式存在。 在这些形式中，最稳定的是指定为I型的单钾盐一水合物，其中水被保持为结晶水。 其他指定为II型和III型的结晶形式转化为I型。公开了合成I型和II型或III型转化为I型的方法。

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：US06297226B1

公开(公告)日：2001-10-02

申请号：US09419153

申请日：1999-10-15

申请人： Alvin J. Glasky

发明人： Alvin J. Glasky

IPC分类号： C07D47318

CPC分类号： C07D473/18

摘要： The present invention is directed to 9-substituted guanine derivatives in which the guanine moiety is linked to another moiety with physiological or pharmacological activity through a carboxamide linkage. The number of carbon atoms between the guanine moiety and the carboxamide linking group is typically from 1 to 6. In some cases, the chemical moieties can have carbon chains of different lengths within the moiety linked to guanine through the carboxamide linker. A large number of different chemical moieties can be linked to the guanine moiety. The invention also includes pharmaceutical compositions including the 9-substituted guanine derivatives and methods of use of the 9-substituted guanine derivatives.

摘要翻译： 本发明涉及9-取代的鸟嘌呤衍生物，其中鸟嘌呤部分通过羧酰胺键与具有生理或药理活性的另一部分连接。 鸟嘌呤部分和羧酰胺连接基团之间的碳原子数通常为1至6.在一些情况下，化学部分可以通过羧酰胺接头与鸟嘌呤连接的部分内具有不同长度的碳链。 大量不同的化学部分可以连接到鸟嘌呤部分。 本发明还包括药物组合物，其包括9-取代的鸟嘌呤衍生物和使用9-取代的鸟嘌呤衍生物的方法。

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：US06350752B1

公开(公告)日：2002-02-26

申请号：US08878656

申请日：1997-06-19

申请人： Alvin J. Glasky ,  Michel P. Rathbone

发明人： Alvin J. Glasky ,  Michel P. Rathbone

IPC分类号： A61K3152

CPC分类号： A61K31/7076 ,  A61K31/52 ,  A61K31/522 ,  A61K31/708

摘要： Disclosed herein are methods and associated compositions and medicaments directed generally to the control of cellular and neural activity and for selectively and controllably inducing the in vivo genetic expression of one or more naturally occurring genetically encoded molecules in mammals. More particularly, the present invention selectively activates or derepresses genes encoding for specific naturally occurring molecules such as proteins or neurotrophic factors and induces the endogenous production of such naturally occurring compounds through the administration of carbon monoxide dependent guanylyl cyclase modulating purine derivatives. The methods of the present invention may be used to affect a variety of cellular and neurological functions and activities and to therapeutically or prophylactically treat a wide variety of neurodegenerative, neurological, cellular, and physiological disorders.

公开(公告)号：US5801184A

公开(公告)日：1998-09-01

申请号：US488976

申请日：1995-06-08

申请人： Alvin J. Glasky ,  Michel P. Rathbone

发明人： Alvin J. Glasky ,  Michel P. Rathbone

IPC分类号： A61K31/52 ,  A01N43/42 ,  A01N43/90 ,  C07D473/00

CPC分类号： A61K31/7076 ,  A61K31/52 ,  A61K31/522 ,  A61K31/708

摘要： Disclosed herein are methods directed generally to the control of neural activity and for selectively and controllably inducing the in vivo genetic expression of one or more naturally occurring genetically encoded molecules in mammals. More particularly, the present invention selectively activates or derepresses genes encoding for specific naturally occurring molecules such as neurotrophic factors through the administration of carbon monoxide dependent guanylyl cyclase modulating purine derivatives. The methods of the present invention may be used to affect a variety of cellular and neurological activities and to therapeutically or prophylactically treat a wide variety of neurodegenerative, neurological, and cellular disorders.

摘要翻译： 本文公开的方法一般涉及神经活性的控制以及选择性和可控地诱导哺乳动物中一种或多种天然存在的遗传编码分子的体内遗传表达的方法。 更具体地，本发明通过施用一氧化碳依赖性鸟苷酸环化酶调节嘌呤衍生物选择性地激活或去抑制编码特定天然存在的分子如神经营养因子的基因。 本发明的方法可用于影响多种细胞和神经活性，并且可用于治疗或预防性治疗各种各样的神经变性，神经系统和细胞疾病。