(1r,1'R,4R)-4-methoxy-5''-methyl-6'-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3'H-dispiro[cyclohexane-1,2'-inden-1',2'-imidazole]-4''-amine | 1383982-64-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 茚满类
• 英文名称: (1r,1'R,4R)-4-methoxy-5''-methyl-6'-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3'H-dispiro[cyclohexane-1,2'-inden-1',2'-imidazole]-4''-amine
• 英文别名: (1r,1’R,4R)-4-methoxy-5”-methyl-6’-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3’H-dispiro[cyclohexane-1,2’-indene-1’2”-imidazol]-4”-amine；(1r,1'R,4R)- 4-methoxy-5''-methyl-6'-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4''-amine；lanabecestat；AZD-3293；AZD3293；(1r,1'R,4R)-4-methoxy-5''-methyl-6'-(5-prop-1-yn-1-ylpyridin-3-yl)-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4''-amine
• CAS: 1383982-64-6
• 化学式: C₂₆H₂₈N₄O
• 分子量: 412.535
• InChiKey: WKDNQONLGXOZRG-HRNNMHKYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.24
• 重原子数：
  31.0
• 可旋转键数：
  2.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  72.86
• 氢给体数：
  1.0
• 氢受体数：
  5.0

安全信息

• 储存条件：
  -20℃

制备方法与用途

Lanabecestat (AZD3293)是一种高效、高渗透性、具有口服活性并能穿过血脑屏障的抑制剂，其半数有效浓度为0.4 nM。

反应信息

• 作为反应物：
  描述：

  (1r,1'R,4R)-4-methoxy-5''-methyl-6'-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3'H-dispiro[cyclohexane-1,2'-inden-1',2'-imidazole]-4''-amine 在 三甲基甲硫基硅烷 、 四丁基碘化铵 、 zinc(II) iodide 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 48.0h， 以20%的产率得到(1r,1'R,4R)-4''-amino-5''-methyl-6'-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4-ol
  参考文献：
  名称：

  Compounds and their use as BACE Inhibitors

  摘要：

  本发明涉及式(I)的化合物及其药物组合物。此外，本发明涉及治疗方法，用于治疗和/或预防与Aβ相关的病理，如唐氏综合症，β-淀粉样蛋白血管病，如但不限于脑淀粉样蛋白血管病或遗传性脑出血，与认知损害相关的疾病，如但不限于MCI（“轻度认知损害”），阿尔茨海默病，记忆丧失，与阿尔茨海默病相关的注意力缺陷症状，与疾病如阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，早老性痴呆，老年性痴呆和与帕金森病、进行性上核性麻痹或皮层基底节变性相关的痴呆。

  公开号：

  US20120165347A1
• 作为产物：
  描述：

  在 sodium hydroxide 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 0.25h， 生成 (1r,1'R,4R)-4-methoxy-5''-methyl-6'-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3'H-dispiro[cyclohexane-1,2'-inden-1',2'-imidazole]-4''-amine
  参考文献：
  名称：

  Compounds and their use as BACE Inhibitors

  摘要：

  本发明涉及式(I)的化合物及其药物组合物。此外，本发明涉及治疗方法，用于治疗和/或预防与Aβ相关的病理，如唐氏综合症，β-淀粉样蛋白血管病，如但不限于脑淀粉样蛋白血管病或遗传性脑出血，与认知损害相关的疾病，如但不限于MCI（“轻度认知损害”），阿尔茨海默病，记忆丧失，与阿尔茨海默病相关的注意力缺陷症状，与疾病如阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，早老性痴呆，老年性痴呆和与帕金森病、进行性上核性麻痹或皮层基底节变性相关的痴呆。

  公开号：

  US20120165347A1

文献信息

• [EN] COMBINATION OF A BACE INHIBITOR AND AN ANTIBODY OR ANTIGEN-BINDING FRAGMENT FOR THE TREATMENT OF A DISORDER ASSOCIATED WITH THE ACCUMULATION OF AMYLOID BETA<br/>[FR] COMBINAISON D'UN INHIBITEUR DE BACE ET D'UN ANTICORPS OU D'UN FRAGMENT DE LIAISON À UN ANTIGÈNE POUR LE TRAITEMENT D'UN TROUBLE ASSOCIÉ À L'ACCUMULATION DE BÊTA-AMYLOÏDE
  申请人：ASTRAZENECA AB

  公开号：WO2017158064A1

  公开（公告）日：2017-09-21

  The present disclosure provides for methods for treating a subject having a disease or disorder associated with the accumulation of amyloid beta, comprising administering to the subject a BACE inhibitor and an antibody or antigen-binding fragment that binds to amyloid beta n-42. In some embodiments, the disease or disorder is Alzheimer's Disease.

  本披露提供了一种治疗患有与淀粉样蛋白β积累相关的疾病或障碍的方法，包括向受试者施用BACE抑制剂和结合到淀粉样蛋白β n-42的抗体或抗原结合片段。在某些实施例中，该疾病或障碍是阿尔茨海默病。
• [EN] CAMSYLATE SALT<br/>[FR] SEL DE CAMSYLATE
  申请人：ASTRAZENECA AB

  公开号：WO2013190302A1

  公开（公告）日：2013-12-27

  A camsylate salt of (1r,1 'R,4R)- 4-methoxy-5"-methyl-6'-[5-(prop-1-yn-1-yl)pyridin-3-yl]-3'H-dispiro[cyclohexane-1,2'-inden-1'2'-imidazole]-4"-amine, pharmaceutical compositions containing the salt and therapeutic uses of the salt for treating Αβ-related pathologies such as Alzheimer's Disease, Down's syndrome, β-amyloid angiopathy and conditions such as dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

  (1r,1 'R,4R)- 4-甲氧基-5"-甲基-6'-[5-(丙炔基)吡啶-3-基]-3'H-双螺[环己烷-1,2'-茚-1'2'-咪唑]-4"-胺的氨基甲磺酸盐，含有该盐的药物组合物以及该盐用于治疗阿尔茨海默病、唐氏综合征、β-淀粉样蛋白血管病和痴呆症等Αβ相关病理的治疗用途，包括混合性血管性和变性起源的痴呆症、早老性痴呆症、老年性痴呆症以及与帕金森病、进行性上核性麻痹或皮质基底节变性相关的痴呆症。
• Process Development of a Suzuki Reaction Used in the Manufacture of Lanabecestat
  作者：Ian W. Ashworth、Andrew D. Campbell、Janette H. Cherryman、Jemma Clark、Alex Crampton、Edward G. B. Eden-Rump、Matthew Evans、Martin F. Jones、Sahar McKeever-Abbas、Rebecca E. Meadows、Kathryn Skilling、David T. E. Whittaker、Robert L. Woodward、Phillip A. Inglesby

  DOI：10.1021/acs.oprd.8b00312

  日期：2018.12.21

  hydrolyses under the reaction conditions. Herein, we report that the liberated diethanolamine plays an important role in the catalytic process, with supporting evidence for an equilibrium between an unbound and bound palladium complex. Additionally, the diethanolamine acts as an internal scavenger during the crystallization of lanabecestat by increasing the solubility of the palladium species, obviating the

  我们开发了可扩展的Suzuki工艺来合成lanabecestat（+）-camsylate，这是一种活性药物成分，最近在治疗早期阿尔茨海默氏病的III期临床计划中进行了研究。该方法的发展最终通过使用稳定的结晶二乙醇胺硼酸酯在反应条件下迅速水解而达到。在此，我们报道释放的二乙醇胺在催化过程中起着重要作用，并为未结合和结合的钯配合物之间的平衡提供了支持证据。另外，二乙醇胺在拉贝司他的结晶过程中通过增加钯物质的溶解度而起内部清除剂的作用，从而消除了不连续的清除步骤的需要。
• COMPOUNDS AND THEIR USE AS BACE INHIBITORS
  申请人：ASTRAZENECA AB

  公开号：US20160184303A1

  公开（公告）日：2016-06-30

  The present invention relates to compounds of formula (I) and their pharmaceutical compositions. In addition, the present invention relates to therapeutic methods for the treatment and/or prevention of Aβ-related pathologies such as Down's syndrome, β-amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI (“mild cognitive impairment”), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

  本发明涉及式（I）化合物及其制药组合物。此外，本发明还涉及用于治疗和/或预防与Aβ相关的病理学，例如唐氏综合症、β淀粉样蛋白病变（如但不限于脑淀粉样血管病变或遗传性脑出血）、与认知障碍相关的疾病（如但不限于轻度认知障碍）、阿尔茨海默病、记忆丧失、与阿尔茨海默病相关的注意力缺陷症状、与疾病相关的神经退行性疾病（如阿尔茨海默病或痴呆症，包括混合血管性和退行性起源的痴呆、早老性痴呆、老年性痴呆和与帕金森病、进行性核上性麻痹或皮质基底节变性相关的痴呆）。
• Compounds and Their Use as BACE Inhibitors
  申请人：Csjernyik Gabor

  公开号：US20130210837A1

  公开（公告）日：2013-08-15

  The present invention relates to compounds of formula (I) and their pharmaceutical compositions. In addition, the present invention relates to therapeutic methods for the treatment and/or prevention of Aβ-related pathologies such as Down's syndrome, β-amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI (“mild cognitive impairment”), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.

  本发明涉及式（I）的化合物及其制药组合物。此外，本发明涉及治疗和/或预防与Aβ相关的病理学，例如唐氏综合症，β-淀粉样蛋白血管病（例如脑淀粉样血管病或遗传性脑出血），与认知损害相关的疾病（例如轻度认知障碍），阿尔茨海默病，记忆力丧失，与阿尔茨海默病相关的注意力缺陷症状，与阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，老年前期痴呆，老年痴呆和与帕金森病，进行性核上性麻痹或皮质基底节变性相关的痴呆。