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    Tri-and tetra-substituted guanidines and their use as excitatory amino acid antagonists
    2.
    发明授权
    Tri-and tetra-substituted guanidines and their use as excitatory amino acid antagonists 失效
    三取代和四取代的胍和它们作为兴奋性氨基酸拮抗剂的用途

    公开(公告)号：US06251948B1

    公开(公告)日：2001-06-26

    申请号：US08468028

    申请日：1995-06-06

    申请人： Eckard Weber ,  John F. W. Keana

    发明人： Eckard Weber ,  John F. W. Keana

    IPC分类号： A61K31155

    CPC分类号： B41J2/471 ,  A61K31/155 ,  C07C279/18 ,  C07D311/18 ,  G03G15/1675 ,  G03G15/168 ,  G03G2215/1614 ,  G03G2215/1657

    摘要： Tri- and tetra-substituted guanidines which exhibit a high binding affinity to phencyclidine (PCP) receptors and, more preferably, low affinity to the brain sigma receptors. These guanidine derivatives act as non-competitive inhibitors of glutamate induced responses of the NMDA receptor by acting as blockers for the ion channel of the NMDA receptor-ion channel complex. These compounds thus exert neuroprotective activity and are useful in the therapeutic treatment of neuronal loss in hypoxia, hypoglycemia, brain or spinal cord ischemia, and brain or spinal chord trauma as well as being useful for the treatment of epilepsy, Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, Huntington's disease, Down's Syndrome, Korsakoff's disease and other neurodegenerative disorders.

    摘要翻译： 表现出对苯环利定（PCP）受体的高结合亲和力，更优选对大脑σ受体的低亲和力的三取代和四取代胍基。 这些胍衍生物通过作为NMDA受体 - 离子通道复合物的离子通道的阻断剂，作为NMDA受体的谷氨酸诱导反应的非竞争性抑制剂。 因此，这些化合物发挥神经保护活性，并且可用于治疗缺氧，低血糖，脑或脊髓缺血以及脑或脊髓创伤中的神经元损失，以及用于治疗癫痫，阿尔茨海默病，肌萎缩性侧索硬化症 ，帕金森病，亨廷顿舞蹈病，唐氏综合征，柯萨科夫病和其他神经退行性疾病。

    Glycine receptor antagonists and the use thereof
    6.
    发明授权
    Glycine receptor antagonists and the use thereof 失效
    甘氨酸受体拮抗剂及其用途

    公开(公告)号：US5514680A

    公开(公告)日：1996-05-07

    申请号：US148259

    申请日：1993-11-05

    申请人： Eckard Weber ,  John F. W. Keana

    发明人： Eckard Weber ,  John F. W. Keana

    IPC分类号： C07D241/44 ,  A61K20060101 ,  A61K31/495 ,  A61K31/498 ,  A61K45/00 ,  A61K51/04 ,  A61P9/00 ,  A61P9/10 ,  A61P25/00 ,  A61P25/08 ,  A61P25/18 ,  A61P25/22 ,  A61P25/28 ,  C07D241/38 ,  C07D241/52 ,  C07D241/54 ,  C07D487/04 ,  C07D491/04

    CPC分类号： C07D491/04 ,  A61K31/495 ,  A61K51/0459 ,  C07D241/38 ,  C07D241/44 ,  C07D241/52 ,  C07D241/54 ,  C07D487/04

    摘要： Methods of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome, treating or preventing the adverse consequences of the hyperactivity of the excitatory amino acids, as well as treating anxiety, chronic pain, convulsions, inducing anesthesia and treating psychosis are disclosed by administering to an animal in need of such treatment a compound having high affinity for the glycine binding site, lacking PCP side effects and which crosses the blood brain barrier of the animal.Also disclosed are novel 1,4-dihydroquinoxaline-2,3-diones, and pharmaceutical compositions thereof. Also disclosed are highly soluble ammonium salts of 1,4-dihydroquinoxaline-2,3-diones.

    摘要翻译： 治疗或预防与中风，缺血，CNS创伤，低血糖和手术相关的神经元损失以及治疗神经变性疾病包括阿尔茨海默病，肌萎缩性侧索硬化，亨廷顿病和唐氏综合征的治疗或预防方法，治疗或预防多动症的不良后果 通过向需要这种治疗的动物施用兴奋性氨基酸以及治疗焦虑症，慢性疼痛，惊厥，诱导麻醉和治疗精神病，通过向甘氨酸结合位点具有高亲和力的化合物，缺乏PCP副作用和哪些 穿过动物的血脑屏障。 还公开了新的1,4-二氢喹喔啉-2,3-二酮及其药物组合物。 还公开了1,4-二氢喹喔啉-2,3-二酮的高度可溶性铵盐。

    Carbocyclic and heterocyclic substituted semicarbazones and thiosemicarbazones and the use thereof
    7.
    发明授权
    Carbocyclic and heterocyclic substituted semicarbazones and thiosemicarbazones and the use thereof 有权
    碳环和杂环取代的缩氨基脲和缩氨基硫脲和其用途

    公开(公告)号：US06458843B1

    公开(公告)日：2002-10-01

    申请号：US09421403

    申请日：1999-10-21

    申请人： Yan Wang ,  Sui Xiong Cai ,  Nancy C. Lan ,  John F. W. Keana ,  Victor I. Ilyin ,  Eckard Weber

    发明人： Yan Wang ,  Sui Xiong Cai ,  Nancy C. Lan ,  John F. W. Keana ,  Victor I. Ilyin ,  Eckard Weber

    IPC分类号： A61K3117

    CPC分类号： C07D213/643 ,  A61K31/17 ,  A61K31/175 ,  A61K31/44 ,  A61K31/445 ,  A61K31/47 ,  A61K31/505 ,  C07C281/12 ,  C07C281/14 ,  C07C2601/14 ,  C07D209/14 ,  C07D211/46 ,  C07D213/68 ,  C07D215/12 ,  C07D307/91 ,  C07D309/12 ,  C07D317/50 ,  C07D317/58 ,  C07D317/62 ,  C07D317/64 ,  C07D319/18

    摘要： This invention is related to carbocyclic and heterocyclic substituted semicarbazones and thiosemicarbazones represented by Formula I: or a pharmaceutically acceptable salt or prodrug thereof, wherein: Y is oxygen or sulfur; R1, R21, R22 and R23 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl; or R22 and R23, together with the N, form a heterocycle; A1 and A2 are independently aryl, heteroaryl, saturated or partially unsaturated carbocycle or saturated or partially unsaturated heterocycle, any of which is optionally substituted; X is one or O, S, NR24, CR25R26, C(O), NR24C(O), C(O)NR24, SO, SO2 or a covalent bond; where R24, R25 and R26 are independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, aryl, aminoalkyl, hydroxyalkyl, alkoxyalkyl or carboxyalkyl. The invention also is directed to the use of carbocycle and heterocycle substituted semicarbazones and thiosemicarbazones for the treatment of neuronal damage following global and focal ischemia, for the treatment or prevention of neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), for the treatment and prevention of otoneurotoxicity and eye diseases involving glutamate toxicity and for the treatment, prevention or amelioration of pain, as anticonvulsants, and as antimanic depressants, as local anesthetics, as antiarrhythmics and for the treatment or prevention of diabetic neuropathy and urinary incontinence.

    摘要翻译： 本发明涉及由式I表示的碳环和杂环取代的缩氨基脲和缩氨基硫脲或其药学上可接受的盐或前药，其中：Y是氧或硫; R1，R21，R22和R23独立地是氢，烷基，环烷基，烯基，炔基，卤代烷基，芳基，氨基烷基，羟基烷基，烷氧基烷基或羧基烷基; 或R 22和R 23与N一起形成杂环; A1和A2独立地是芳基，杂芳基，饱和或部分不饱和的碳环或饱和或部分不饱和的杂环，其中任何一个任选被取代; X是1或O，S，NR 24，CR 25 R 26，C（O），NR 24 C（O），C（O）NR 24，SO，SO 2或共价键; 其中R 24，R 25和R 26独立地是氢，烷基，环烷基，烯基，炔基，卤代烷基，芳基，氨基烷基，羟基烷基，烷氧基烷基或羧基烷基。 本发明还涉及使用碳环和杂环取代的缩氨基脲和缩氨基硫脲来治疗全身和局部缺血后的神经元损伤，用于治疗或预防神经变性疾病如肌萎缩性侧索硬化（ALS），用于治疗和预防 涉及谷氨酸毒性和治疗，预防或改善疼痛，作为抗惊厥药，以及作为局部麻醉剂，作为抗心律失常药物和用于治疗或预防糖尿病性神经病和尿失禁的抗疟药抑制剂。

    Tri-and tetra-substituted guanidines and their use as excitatory amino acid antagonists
    9.
    发明授权
    Tri-and tetra-substituted guanidines and their use as excitatory amino acid antagonists 失效
    三取代和四取代的胍和它们作为兴奋性氨基酸拮抗剂的用途

    公开(公告)号：US5767162A

    公开(公告)日：1998-06-16

    申请号：US470345

    申请日：1995-06-06

    申请人： Eckard Weber ,  John F. W. Keana

    发明人： Eckard Weber ,  John F. W. Keana

    IPC分类号： A61K31/155 ,  C07C279/18 ,  C07D311/18 ,  A61K31/37 ,  A61K31/655

    CPC分类号： A61K31/155 ,  C07C279/18 ,  C07D311/18

    摘要： Tri- and tetra-substituted guanidines which exhibit a high binding affinity to phencyclidine (PCP) receptors and, more preferably, low affinity to the brain sigma receptors. These guanidine derivatives act as non-competitive inhibitors of glutamate induced responses of the NMDA receptor by acting as blockers for the ion channel of the NMDA receptor-ion channel complex. These compounds thus exert neuroprotective activity and are useful in the therapeutic treatment of neuronal loss in hypoxia, hypoglycemia, brain or spinal cord ischemia, and brain or spinal chord trauma as well as being useful for the treatment of epilepsy, Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, Huntington's disease, Down's Syndrome, Korsakoff's disease and other neurodegenerative disorders.

    摘要翻译： 表现出对苯环利定（PCP）受体的高结合亲和力，更优选对大脑σ受体的低亲和力的三取代和四取代胍基。 这些胍衍生物通过作为NMDA受体 - 离子通道复合物的离子通道的阻断剂，作为NMDA受体的谷氨酸诱导反应的非竞争性抑制剂。 因此，这些化合物发挥神经保护活性，并且可用于治疗缺氧，低血糖，脑或脊髓缺血以及脑或脊髓创伤中的神经元损失，以及用于治疗癫痫，阿尔茨海默病，肌萎缩性侧索硬化症 ，帕金森病，亨廷顿舞蹈病，唐氏综合征，柯萨科夫病和其他神经退行性疾病。

    4-hydroxy-3-nitro-1,2-dihydroquinolin-2-ones and the use thereof as excitatory amino acid and glycine receptor antagonists
    10.
    发明授权
    4-hydroxy-3-nitro-1,2-dihydroquinolin-2-ones and the use thereof as excitatory amino acid and glycine receptor antagonists 失效
    4-羟基-3-硝基-1,2-二氢喹啉-2-酮及其作为兴奋性氨基酸和甘氨酸受体拮抗剂的用途

    公开(公告)号：US5622965A

    公开(公告)日：1997-04-22

    申请号：US101244

    申请日：1993-08-02

    申请人： Sui X. Cai ,  Eckard Weber ,  John F. W. Keana

    发明人： Sui X. Cai ,  Eckard Weber ,  John F. W. Keana

    IPC分类号： A61K31/47 ,  A61P9/10 ,  A61P25/00 ,  A61P25/28 ,  C07D215/22 ,  C07D215/38

    CPC分类号： C07D215/22 ,  A61K31/47

    摘要： Methods of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome, treating or preventing the adverse consequences of the hyperactivity of the excitatory amino acids, as well as treating anxiety, chronic pain, convulsions and inducing anesthesia are disclosed by administering to an animal in need of such treatment a substituted or unsubstituted 4-hydroxy-3-nitro-1,2-dihydroquinolin-2-one or pharmaceutically acceptable salts thereof which have high binding to the glycine receptor.

    摘要翻译： 治疗或预防与中风，局部缺血，CNS创伤，低血糖和手术相关的神经元损失以及治疗神经变性疾病包括阿尔茨海默病，肌萎缩性侧索硬化，亨廷顿病和唐氏综合征的治疗或预防方法，治疗或预防多动症的不良后果 通过向需要这种治疗的动物施用取代或未取代的4-羟基-3-硝基-1,2-二氢喹啉-2-酮，通过给予兴奋性氨基酸以及治疗焦虑症，慢性疼痛，抽搐和诱导麻醉， 其与甘氨酸受体具有高结合性的一种或其药学上可接受的盐。