公开(公告)号：US06756385B2

公开(公告)日：2004-06-29

申请号：US09919630

申请日：2001-07-31

申请人： Mark A. Sanner ,  Chris J. Helal ,  Christoper B. Cooper ,  Frank S. Menniti ,  Michael K. Ahlijanian ,  Annabella Villalobos ,  Lit-Fui Lau ,  Patricia A. Seymour

发明人： Mark A. Sanner ,  Chris J. Helal ,  Christoper B. Cooper ,  Frank S. Menniti ,  Michael K. Ahlijanian ,  Annabella Villalobos ,  Lit-Fui Lau ,  Patricia A. Seymour

IPC分类号： A61K314709

CPC分类号： C07D401/12 ,  C07D233/88 ,  C07D233/90 ,  C07D401/14 ,  C07D403/12 ,  C07D417/14

摘要： The invention provides compounds of formula 1 wherein R1, R2, R3, and R4 are as defined, and their pharmaceutically acceptable salts. Compounds of formula 1 are indicated to have activity inhibiting cdk5, cdk2, and GSK-3. Pharmaceutical compositions and methods comprising compounds of formula 1 for treating and preventing diseases and conditions comprising abnormal cell growth, such as cancer, and neurodegenerative diseases and conditions and those affected by dopamine neurotransmission. Also described are pharmaceutical compositions and methods comprising compounds of formula 1 for treating male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency.

摘要翻译： 本发明提供了式1化合物，其中R 1，R 2，R 3和R 4如上定义，及其药学上可接受的盐。 式1的化合物表示具有抑制cdk5，cdk2和GSK-3的活性。 包含式1化合物的药物组合物和方法，用于治疗和预防包括异常细胞生长（例如癌症）和神经变性疾病和病症以及受多巴胺神经传递影响的疾病和病症。 还描述了包含用于治疗雄性生育力和精子活力的式1化合物的药物组合物和方法; 糖尿病 葡萄糖耐量降低; 代谢综合征或综合征X; 多囊卵巢综合征; 脂肪生成和肥胖; 造血和虚弱，例如年龄相关的身体表现下降; 急性肌肉减少症，例如与烧伤，卧床休息，肢体固定或主要胸部，腹部和/或整形外科手术相关的肌肉萎缩和/或恶病质; 败血症 脱发，脱发，秃头; 和免疫缺陷。

公开(公告)号：US06936638B2

公开(公告)日：2005-08-30

申请号：US10741595

申请日：2003-12-19

申请人： Soumitra S. Ghosh ,  Yazhong Pei ,  Xiao-Qing Tang ,  Spiros J. Liras ,  Michael K. Ahlijanian

发明人： Soumitra S. Ghosh ,  Yazhong Pei ,  Xiao-Qing Tang ,  Spiros J. Liras ,  Michael K. Ahlijanian

IPC分类号： A61K31/185 ,  A61P25/00 ,  C07C65/24 ,  C07C65/30 ,  C07C65/40 ,  C07C69/94 ,  C07D263/56 ,  C07D263/57 ,  C07D277/66 ,  C07D307/80 ,  C07D333/16 ,  C07D333/24 ,  C07D333/56 ,  C07D333/60 ,  A61K31/19 ,  C07D313/04

CPC分类号： C07D263/57 ,  A61K31/185 ,  C07C65/24 ,  C07C65/30 ,  C07C65/40 ,  C07C69/94 ,  C07D277/66 ,  C07D307/80 ,  C07D333/16 ,  C07D333/24 ,  C07D333/56 ,  C07D333/60

摘要： Compounds which have utility in the treatment of conditions associated with altered mitochondrial function. The compounds have the following structure (I): including stereoisomers, prodrugs, and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5 and R6 are as defined herein. Pharmaceutical compositions containing a compound of structure (I), as well as methods relating to the use thereof, are also disclosed.

摘要翻译： 可用于治疗与改变的线粒体功能相关的病症的化合物。 所述化合物具有以下结构（I）：包括其立体异构体，前药和药学上可接受的盐，其中R 1，R 2，R 3， >，R 4，R 5和R 6如本文所定义。 还公开了含有结构（I）化合物的药物组合物以及与其用途有关的方法。

公开(公告)号：US06693226B1

公开(公告)日：2004-02-17

申请号：US09496445

申请日：2000-02-02

申请人： John D. McNeish ,  Michael K. Ahlijanian

发明人： John D. McNeish ,  Michael K. Ahlijanian

IPC分类号： A01K6700

CPC分类号： A01K67/0275 ,  A01K67/0278 ,  A01K2207/15 ,  A01K2217/00 ,  A01K2217/05 ,  A01K2227/105 ,  A01K2267/0312 ,  A01K2267/0318 ,  C07K14/4738 ,  C12N15/8509 ,  C12N2830/008

摘要： The invention provides transgenic, non-human animals and transgenic non-human mammalian cells harboring a transgene encoding a p25 (activator of the protein kinase cdk 5) polypeptide. The two neuropathological lesions associated with Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles (NFTs), composed predominantly of amyloid &bgr; peptides and hyperphosphorylated tau, respectvely. While animal models for plaque formation exist, there is no animal model that recapitulates the formation of NFTs. This invention provides transgenic mice that overexpress human p25, an activator of cdk5, resulting in tau that is hyperphosphorylated at AD-relevant epitopes. Deposition of tau is detected in the amygdala, thalamus and cortex. Increased phosphorylated neurofilament, silver-positive neurons and neuronal death are also observed in these regions. We conclude that the overexpression of p25, an activator of cdk5, is sufficient to produce hyperphosphorylation of tau and neuronal death. The p25 transgenic mouse represents the first model for tau pathology in AD.

摘要翻译： 本发明提供具有编码p25（蛋白激酶cdk 5的活化剂）多肽的转基因的转基因非人动物和转基因非人哺乳动物细胞。 与阿尔茨海默病（AD）相关的两种神经病理学病变是淀粉样斑块和神经原纤维缠结（NFTs），主要由淀粉样β肽组成，超磷酸化tau。 虽然存在斑块形成的动物模型，但没有重现NFT形成的动物模型。 本发明提供过表达人p25的转基因小鼠，其是cdk5的激活剂，导致在AD相关表位处被过度磷酸化的tau。 在杏仁核，丘脑和皮质中检测到tau的沉积。 在这些区域也观察到增加的磷酸化神经丝，银阳性神经元和神经元死亡。 我们得出结论，cd25的激活剂p25的过度表达足以产生tau和神经元死亡的高度磷酸化。 p25转基因小鼠代表AD中tau病理学的第一个模型。

公开(公告)号：US07078529B2

公开(公告)日：2006-07-18

申请号：US10818855

申请日：2004-04-05

申请人： Mark A. Sanner ,  Chris J. Helal ,  Christoper B. Cooper ,  Frank S. Menniti ,  Patricia A. Seymour ,  Michael K. Ahlijanian ,  Anabella Villalobos ,  Lit-Fui Lau

发明人： Mark A. Sanner ,  Chris J. Helal ,  Christoper B. Cooper ,  Frank S. Menniti ,  Patricia A. Seymour ,  Michael K. Ahlijanian ,  Anabella Villalobos ,  Lit-Fui Lau

IPC分类号： C07D233/88

CPC分类号： C07D401/12 ,  C07D233/88 ,  C07D233/90 ,  C07D401/14 ,  C07D403/12 ,  C07D417/14

摘要： The invention provides compounds of formula 1 wherein R1, R2, R3, and R4 are as defined, and their pharmaceutically acceptable salts. Compounds of formula 1 are indicated to have activity inhibiting cdk5, cdk2, and GSK-3. Pharmaceutical compositions and methods comprising compounds of formula 1 for treating and preventing diseases and conditions comprising abnormal cell growth, such as cancer, and neurodegenerative diseases and conditions and those affected by dopamine neurotransmission. Also described are pharmaceutical compositions and methods comprising compounds of formula 1 for treating male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency.

摘要翻译： 本发明提供式1化合物，其中R 1，R 2，R 3，R 4和R 4均为 并且其药学上可接受的盐。 式1的化合物表示具有抑制cdk5，cdk2和GSK-3的活性。 包含式1化合物的药物组合物和方法，用于治疗和预防包括异常细胞生长（例如癌症）和神经变性疾病和病症以及受多巴胺神经传递影响的疾病和病症。 还描述了包含用于治疗雄性生育力和精子活力的式1化合物的药物组合物和方法; 糖尿病 葡萄糖耐量降低; 代谢综合征或综合征X; 多囊卵巢综合征; 脂肪生成和肥胖; 造血和虚弱，例如年龄相关的身体表现下降; 急性肌肉减少症，例如与烧伤，卧床休息，肢体固定或主要胸部，腹部和/或整形外科手术相关的肌肉萎缩和/或恶病质; 败血症 脱发，脱发，秃头; 和免疫缺陷。