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    5-fluoro-and 8-fluoro-trimetoquinol compounds and the processes for their preparation
    1.
    发明授权
    5-fluoro-and 8-fluoro-trimetoquinol compounds and the processes for their preparation 失效
    5-氟 - 和8-氟 - 三甲基喹啉化合物及其制备方法

    公开(公告)号：US4737504A

    公开(公告)日：1988-04-12

    申请号：US890490

    申请日：1986-07-25

    申请人： Duane D. Miller ,  Dennis R. Feller ,  Michael T. Clark ,  Adeboye Adejare ,  Karl J. Romstedt ,  Gamal Shams

    发明人： Duane D. Miller ,  Dennis R. Feller ,  Michael T. Clark ,  Adeboye Adejare ,  Karl J. Romstedt ,  Gamal Shams

    IPC分类号： C07D217/20 ,  A61K31/47

    CPC分类号： C07D217/20

    摘要： The present invention relates to novel 5-fluoro- and 8-fluoro-trimetoquinol compounds of the general formula I wherein X.sub.1 =F,X.sub.2 =H or X.sub.1 =H,X.sub.2 =F ##STR1## The present invention also relates to a process for making the 5-fluoro- and 8-fluoro-trimetoquinol compounds by condensation of an appropriately substituted phenethylamine to afford an appropriately substituted phenethylacetamide compound. The amides are cyclized to give appropriately substituted intermediate dihydroisoquinolines. Without isolation, the dihydroisoquinolines are reduced to give appropriately substituted tetrahydroisoqinolines. The hydrochloride salts of tetrahydroisoqinolines are prepared and subjected to hydrogenolysis, to give the fluorine substituted trimetoquinol compounds of the present invention. The present invention also encompasses the preparation of the phenethylamines by reducing appropriately substituted benzylcyanides and to the preparation of an intermediate benzylcyanide compound by converting a fluorine substituted methoxyphenol compound, under aminomethylation conditions into a N, N-dimethyl-4-hydroxy-3-methoxy-5-fluorobenzylamine. The benzylamine is converted to benzylnitrile and a functional group shuffle is carried out which yields the appropriately substituted benzylcyanide compound. In a composition aspect, the present invention encompasses novel pharmaceutical compositions comprising a compound of the formula I, together with a physiologically acceptable carrier or excipient, in an amount sufficient to increase .beta..sub.2 -adrenergic and antithrombotic activities while simultaneously decreasing the .beta..sub.1 -adrenergic activity in mammals, including humans. The compounds of the invention are useful in the treatment of pulmonary, cardiovascular or thromboembolic disorders.

    摘要翻译： 本发明涉及通式I的新的5-氟 - 和8-氟 - 三甲基喹诺酮化合物，其中X1 = F，X2 = H或X1 = H，X2 = F。本发明还涉及一种 通过适当取代的苯乙胺的缩合制备5-氟 - 和8-氟 - 三甲基喹啉化合物，得到适当取代的苯乙基乙酰胺化合物。 使酰胺环化，得到适当取代的中间体二氢异喹啉。 不分离，将二氢异喹啉还原，得到适当取代的四氢异喹啉。 制备四氢异喹啉的盐酸盐并进行氢解，得到本发明的氟取代的三甲基喹诺酮化合物。 本发明还包括通过在氨基甲基化条件下将氟取代的甲氧基苯酚化合物转化成N，N-二甲基-4-羟基-3-甲氧基的方法，通过还原适当取代的苄基氰化物和制备中间体苄基氰化合物来制备苯乙胺 -5-氟苄胺。 将苄胺转化为苄基腈，进行官能团混洗，产生适当取代的苄基氰化合物。 在组合物方面，本发明包括新颖的药物组合物，其包含式I化合物以及生理上可接受的载体或赋形剂，其量足以增加β2-肾上腺素能和抗血栓形成活性，同时降低β1-肾上腺素能 哺乳动物，包括人类的活动。 本发明的化合物可用于治疗肺，心血管或血栓栓塞障碍。

    5-fluoro- and 8-fluoro-trimetoquinol compounds and the processes for their preparation
    2.
    发明授权
    5-fluoro- and 8-fluoro-trimetoquinol compounds and the processes for their preparation 失效
    5-氟 - 和8-氟 - 三甲基喹啉化合物及其制备方法

    公开(公告)号：US4855476A

    公开(公告)日：1989-08-08

    申请号：US167336

    申请日：1988-03-14

    申请人： Duane D. Miller ,  Dennis R. Feller ,  Michael T. Clark ,  Adeboye Adejare ,  Karl J. Romstedt ,  Gamal Shams

    发明人： Duane D. Miller ,  Dennis R. Feller ,  Michael T. Clark ,  Adeboye Adejare ,  Karl J. Romstedt ,  Gamal Shams

    IPC分类号： C07D217/20

    CPC分类号： C07D217/20

    摘要： The present invention relates to novel 5-fluoro- and 8-fluoro-trimetoquinol compounds of the general formula I wherein X.sub.1 =F, X.sub.2 =H or X.sub.1 =H, X.sub.2 =F ##STR1## The present invention also relates to a process for making the 5-fluoro- and 8-fluoro-trimetoquinol compounds by condensation of an appropriately substituted phenethylamine to afford an appropriately substituted phenlethylacetamide compound. The amides are cyclized to give appropriately substituted intermediate dihydroisoquinolines. Without isolation, the dihydroisoquinolines are reduced to give appropriately substituted tetrahydroisoquinolines. The hydrochloride salts of tetrahydroisoquinolines are prepared and subjected to hydrogenolysis, to give the fluorine substituted trimetoquinol compounds of the present invention. The present invention also encompasses the preparation of the phenethylamines by reducing appropriately substituted benzylcyanides and to the preparation of an intermediate benzylcyanide compound by converting a fluorine substituted methoxyphenol compound, under aminomethylation conditions into a N-N-dimethyl-4-hydroxy-3-methoxy-5-fluorobenzylamine. The benzylamine is converted to benzylnitrile and a functional group shuffle is carried out which yields the appropriately substituted benzylcyanide compound. In a composition aspect, the present invention encompasses novel pharmaceutical compositions comprising a compound of the formula I, together with a physiologically acceptable carrier or excipient, in an amount sufficient to increase .beta..sub.2 -adrenergic and antithrombotic activities while simultaneously decreasing the .beta..sub.1 -adrenergic activity in mammals, including humans. The compounds of the invention are useful in the treatment of pulmonary, cardiovascular or thromboembolic disorders.

    摘要翻译： 本发明涉及通式I的新的5-氟 - 和8-氟 - 三甲基喹诺酮化合物，其中X1 = F，X2 = H或X1 = H，X2 = F。本发明还涉及一种 通过适当取代的苯乙胺的缩合制备5-氟 - 和8-氟 - 三甲基喹啉化合物，得到适当取代的苯乙酰基乙酰胺化合物。 使酰胺环化，得到适当取代的中间体二氢异喹啉。 不分离，将二氢异喹啉还原，得到适当取代的四氢异喹啉。 制备四氢异喹啉的盐酸盐并进行氢解，得到本发明的氟取代的三甲基喹诺酮化合物。 本发明还包括通过将氨基甲基化条件下的氟取代的甲氧基苯酚化合物转化成N-二甲基-4-羟基-3-甲氧基-5 - 氟苄胺。 将苄胺转化为苄基腈，进行官能团混洗，产生适当取代的苄基氰化合物。 在组合物方面，本发明包括新颖的药物组合物，其包含式I化合物以及生理上可接受的载体或赋形剂，其量足以增加β2-肾上腺素能和抗血栓形成活性，同时降低β1-肾上腺素能 哺乳动物，包括人类的活动。 本发明的化合物可用于治疗肺，心血管或血栓栓塞障碍。

    Non-competitive NMDA receptor antagonists
    3.
    发明授权
    Non-competitive NMDA receptor antagonists 有权
    非竞争性NMDA受体拮抗剂

    公开(公告)号：US08129414B2

    公开(公告)日：2012-03-06

    申请号：US11820524

    申请日：2007-06-19

    申请人： Adeboye Adejare

    发明人： Adeboye Adejare

    IPC分类号： A61K31/445

    CPC分类号： C07D295/073 ,  A61K31/445 ,  C07D295/033

    摘要： Disclosed herein are non-competitive NMDA receptor antagonists having chemical structures similar to that of phencyclidine (PCP). These antagonists contain a polycyclic ring structure in place of the cycloalkyl ring of PCP. The antagonists also differ from PCP in that they include an electron withdrawing group, a hydroxyl group, or an amine group at the para position of the phenyl ring. The antagonists disclosed herein are useful for treating or ameliorating a symptom of ailments associated with over excitation of cells (e.g., neurons) that express NMDA receptors. Examples of ailments that can be treated and for which symptoms can be ameliorated include epilepsy, neurodegenerative disease (e.g., Alzheimer's and Parkinson's diseases), drug addiction, neuropathic pain, and neuronal and glutamate-dependent tumors.

    摘要翻译： 本文公开了具有与苯环利定（PCP）类似的化学结构的非竞争性NMDA受体拮抗剂。 这些拮抗剂含有多环环结构代替PCP的环烷基环。 拮抗剂也不同于PCP，因为它们在苯环的对位包括吸电子基团，羟基基团或胺基团。 本文公开的拮抗剂可用于治疗或改善与表达NMDA受体的细胞（例如神经元）的过度激发相关的疾病的症状。 可以治疗和可以改善症状的疾病的实例包括癫痫，神经变性疾病（例如阿尔茨海默病和帕金森病），药物成瘾，神经性疼痛和神经元和谷氨酸依赖性肿瘤。

    Non-competitive NMDA receptor antagonists
    4.
    发明授权
    Non-competitive NMDA receptor antagonists 有权
    非竞争性NMDA受体拮抗剂

    公开(公告)号：US08703799B2

    公开(公告)日：2014-04-22

    申请号：US13361974

    申请日：2012-01-31

    申请人： Adeboye Adejare

    发明人： Adeboye Adejare

    IPC分类号： A61K31/445

    CPC分类号： C07D295/073 ,  A61K31/445 ,  C07D295/033

    摘要： Disclosed herein are non-competitive NMDA receptor antagonists having chemical structures similar to that of phencyclidine (PCP). These antagonists contain a polycyclic ring structure in place of the cycloalkyl ring of PCP. The antagonists also differ from PCP in that they include an electron withdrawing group, a hydroxyl group, or an amine group at the para position of the phenyl ring. The antagonists disclosed herein are useful for treating or ameliorating a symptom of ailments associated with over excitation of cells (e.g., neurons) that express NMDA receptors. Examples of ailments that can be treated and for which symptoms can be ameliorated include epilepsy, neurodegenerative disease (e.g., Alzheimer's and Parkinson's diseases), drug addiction, neuropathic pain, and neuronal and glutamate-dependent tumors.

    摘要翻译： 本文公开了具有与苯环利定（PCP）类似的化学结构的非竞争性NMDA受体拮抗剂。 这些拮抗剂含有多环环结构代替PCP的环烷基环。 拮抗剂也不同于PCP，因为它们在苯环的对位包括吸电子基团，羟基基团或胺基团。 本文公开的拮抗剂可用于治疗或改善与表达NMDA受体的细胞（例如神经元）的过度激发相关的疾病的症状。 可以治疗和可以改善症状的疾病的实例包括癫痫，神经变性疾病（例如阿尔茨海默病和帕金森病），药物成瘾，神经性疼痛和神经元和谷氨酸依赖性肿瘤。

    Non-competitive NMDA receptor antagonists
    5.
    发明申请
    Non-competitive NMDA receptor antagonists 有权

    公开(公告)号：US20120129889A1

    公开(公告)日：2012-05-24

    申请号：US13361974

    申请日：2012-01-31

    申请人： Adeboye Adejare

    发明人： Adeboye Adejare

    IPC分类号： A61K31/445 ,  A61P25/00 ,  A61P35/00 ,  A61P27/02

    CPC分类号： C07D295/073 ,  A61K31/445 ,  C07D295/033

    摘要： Disclosed herein are non-competitive NMDA receptor antagonists having chemical structures similar to that of phencyclidine (PCP). These antagonists contain a polycyclic ring structure in place of the cycloalkyl ring of PCP. The antagonists also differ from PCP in that they include an electron withdrawing group, a hydroxyl group, or an amine group at the para position of the phenyl ring. The antagonists disclosed herein are useful for treating or ameliorating a symptom of ailments associated with over excitation of cells (e.g., neurons) that express NMDA receptors. Examples of ailments that can be treated and for which symptoms can be ameliorated include epilepsy, neurodegenerative disease (e.g., Alzheimer's and Parkinson's diseases), drug addiction, neuropathic pain, and neuronal and glutamate-dependent tumors.

    Non-competitive NMDA receptor antagonists
    10.
    发明申请
    Non-competitive NMDA receptor antagonists 有权
    非竞争性NMDA受体拮抗剂

    公开(公告)号：US20080039498A1

    公开(公告)日：2008-02-14

    申请号：US11820524

    申请日：2007-06-19

    申请人： Adeboye Adejare

    发明人： Adeboye Adejare

    IPC分类号： A61K31/445 ,  A61P25/00 ,  C07D211/06

    CPC分类号： C07D295/073 ,  A61K31/445 ,  C07D295/033

    摘要： Disclosed herein are non-competitive NMDA receptor antagonists having chemical structures similar to that of phencyclidine (PCP). These antagonists contain a polycyclic ring structure in place of the cycloalkyl ring of PCP. The antagonists also differ from PCP in that they include an electron withdrawing group, a hydroxyl group, or an amine group at the para position of the phenyl ring. The antagonists disclosed herein are useful for treating or ameliorating a symptom of ailments associated with over excitation of cells (e.g., neurons) that express NMDA receptors. Examples of ailments that can be treated and for which symptoms can be ameliorated include epilepsy, neurodegenerative disease (e.g., Alzheimer's and Parkinson's diseases), drug addiction, neuropathic pain, and neuronal and glutamate-dependent tumors.

    摘要翻译： 本文公开了具有与苯环利定（PCP）类似的化学结构的非竞争性NMDA受体拮抗剂。 这些拮抗剂含有多环环结构代替PCP的环烷基环。 拮抗剂也不同于PCP，因为它们在苯环的对位包括吸电子基团，羟基基团或胺基团。 本文公开的拮抗剂可用于治疗或改善与表达NMDA受体的细胞（例如神经元）的过度激发相关的疾病的症状。 可以治疗和可以改善症状的疾病的实例包括癫痫，神经变性疾病（例如阿尔茨海默病和帕金森病），药物成瘾，神经性疼痛和神经元和谷氨酸依赖性肿瘤。