(4aS,5aS)-N-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-1-(pyrazin-2-yl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazole-3-carboxamide | 1268881-17-9

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: (4aS,5aS)-N-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-1-(pyrazin-2-yl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazole-3-carboxamide
• 英文别名: (1aS,5aS)-2-pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diazacyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethylpropyl)amide；AR427412；(1aS,5aS)-2-pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide；(1aS,5aS)-2-pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethylpropyl)amide；(2S,4S)-N-[(2S)-1-hydroxy-3,3-dimethylbutan-2-yl]-9-pyrazin-2-yl-8,9-diazatricyclo[4.3.0.02,4]nona-1(6),7-diene-7-carboxamide
• CAS: 1268881-17-9
• 化学式: C₁₈H₂₃N₅O₂
• 分子量: 341.413
• InChiKey: TVCYLBQVKJBKGA-GMXVVIOVSA-N

物化性质

• 沸点：
  539.3±50.0 °C(Predicted)
• 密度：
  1.45±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  92.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (4aS,5aS)-N-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-1-(pyrazin-2-yl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazole-3-carboxamide 在 间氯过氧苯甲酸 作用下， 以 氯仿 为溶剂， 反应 21.0h， 生成 (1aS,5aS)-2-(4-oxypyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diazacyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethylpropyl)amide
  参考文献：
  名称：

  [EN] CANNABINOID RECEPTOR MODULATORS
  [FR] MODULATEURS DES RÉCEPTEURS DES CANNABINOÏDES

  摘要：

  提供了一些在治疗疼痛方面有用的方法，包括给予化合物Ia的复方及其药物组合物，以调节大麻素CB2受体的活性。

  公开号：

  WO2012116279A1
• 作为产物：
  描述：

  (1S,5R)-bicyclo[3.1.0]hexan-2-one 在 potassium tert-butylate 、 水 、 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.58h， 生成 (4aS,5aS)-N-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-1-(pyrazin-2-yl)-4,4a,5,5a-tetrahydro-1H-cyclopropa[4,5]cyclopenta[1,2-c]pyrazole-3-carboxamide
  参考文献：
  名称：

  [EN] CRYSTALLINE FORMS AND PROCESSES FOR THE PREPARATION OF CONDENSED AZACYCLES ( CANNABINOID RECEPTOR MODULATORS)
  [FR] FORMES CRISTALLINES ET PROCÉDÉS DE PRÉPARATION D'AZACYCLES CONDENSÉS (MODULATEURS DES RÉCEPTEURS DES CANNABINOÏDES)

  摘要：

  本发明涉及（1aS,5aS）-2-(4-氧基吡嗪-2-基)-1a,2,5,5a-四氢-1H-2,3-二氮杂-环丙烯并[α]戊二烯-4-羧酸（(S)-1-羟甲基-2,2-二甲基-丙基）-酰胺（化合物1）的晶型及其调节大麻素CB2受体活性的药物组合物，因此在治疗CB2受体介导的疾病方面具有用处，例如骨关节炎；疼痛；过敏性疼痛；触痛；炎症性过敏性疼痛；神经病性过敏性疼痛；急性疼痛感知；骨质疏松症；多发性硬化相关的痉挛；自身免疫性疾病；过敏反应中枢神经系统炎症，例如；动脉粥样硬化；不良的免疫细胞活性，以及与所选疾病相关的炎症：骨关节炎，过敏反应，贝赫切特氏病，移植排斥反应，血管炎，痛风，脊柱炎，病毒性疾病，细菌性疾病，红斑狼疮，炎症性肠病，自身免疫性肝炎和1型糖尿病；年龄相关性黄斑变性；咳嗽；白血病；淋巴瘤；中枢神经系统肿瘤；前列腺癌；阿尔茨海默病；中风引起的损伤；痴呆症；肌萎缩侧索硬化；和帕金森病。

  公开号：

  WO2012116276A1

文献信息

• [EN] PROCESSES FOR THE PREPARATION OF CANNABINOID RECEPTOR MODULATORS<br/>[FR] PROCÉDÉS DE PRÉPARATION DE MODULATEURS DES RÉCEPTEURS DE CANNABINOÏDES
  申请人：ARENA PHARM INC

  公开号：WO2016085941A1

  公开（公告）日：2016-06-02

  The present invention relates to processes, and process intermediates useful in the preparation of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide (Compound 1) and crystalline forms thereof. The compound (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide has been identified as a modulator of the cannabinoid 2 (CB2) receptor and useful in the treatment of CB2 receptor-mediated disorders, for example, pain, disorders of the immune system (such as, autoimmune disorders, type 1 hypersensitivity and allergic response, conditions associated with CNS inflammation, conditions associated with vascular inflammation, and other disorders associated with aberrant or unwanted immune response), bone and joint diseases (such as, osteoporosis and arthritis), eye disease, cough, cancer, and regenerative medicine. The present invention further provides pharmaceutical compositions comprising Compound 1 and the use of the pharmaceutical compositions for the treatment of CB2 receptor-mediated disorders.

  本发明涉及用于制备(1aS,5aS)-2-(4-氧基吡嗪-2-基)-1a,2,5,5a-四氢-1H-2,3-二氮杂-环丙[a]戊二烯-4-羧酸((S)-1-羟甲基-2,2-二甲基-丙基)-酰胺(化合物1)及其结晶形式的过程和过程中间体。已确定该化合物(1aS,5aS)-2-(4-氧基吡嗪-2-基)-1a,2,5,5a-四氢-1H-2,3-二氮杂-环丙[a]戊二烯-4-羧酸((S)-1-羟甲基-2,2-二甲基-丙基)-酰胺为大麻素2(CB2)受体调节剂，并在治疗CB2受体介导的疾病中有用，例如疼痛、免疫系统疾病(如自身免疫疾病、1型超敏反应和过敏反应、与中枢神经系统炎症相关的疾病、与血管炎症相关的疾病以及其他与异常或不需要的免疫反应相关的疾病)、骨骼和关节疾病(如骨质疏松和关节炎)、眼疾、咳嗽、癌症和再生医学。本发明还提供包含化合物1的药物组合物以及用于治疗CB2受体介导的疾病的药物组合物的用途。
• [EN] CANNABINOID RECEPTOR MODULATORS<br/>[FR] MODULATEURS DES RÉCEPTEURS DE CANNABINOÏDES
  申请人：ARENA PHARM INC

  公开号：WO2011025541A1

  公开（公告）日：2011-03-03

  The present invention relates to certain compounds of Formula Ia and pharmaceutical compositions thereof that modulate the activity of the cannabinoid CB2 receptor. The present invention further relates to certain compounds of Formula Ia and pharmaceutical compositions thereof that modulate the activities of both the CB1 receptor and the CB2 receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of: pain, for example bone and joint pain, muscle pain, dental pain, migraine and other headache pain, inflammatory pain, neuropathic pain, pain that occurs as an adverse effect of therapeutics and pain associated with osteoarthritis; hyperalgesia; allodynia; inflammatory hyperalgesia; neuropathic hyperalgesia; acute nociception; osteoporosis; multiple sclerosis-associated spasticity; autoimmune disorders; allergic reactions; CNS inflammation; atherosclerosis; undesired immune cell activity and inflammation; age-related macular degeneration; cough; leukemia; lymphoma; CNS tumors; prostate cancer; Alzheimer's disease; stroke-induced damage; dementia; amyotrophic lateral sclerosis, and Parkinson's disease.

  本发明涉及某些化合物Ia的配方和调节大麻素CB2受体活性的药物组合物。本发明还涉及某些化合物Ia的配方和药物组合物，其调节CB1受体和CB2受体的活性。本发明的化合物和药物组合物用于治疗以下疾病的方法：疼痛，例如骨骼和关节疼痛，肌肉疼痛，牙痛，偏头痛和其他头痛，炎症性疼痛，神经痛，作为治疗的不良反应而发生的疼痛以及与骨关节炎相关的疼痛；痛觉过敏；触觉过敏；炎症性痛觉过敏；神经痛觉过敏；急性疼痛感；骨质疏松症；多发性硬化症相关的痉挛；自身免疫性疾病；过敏反应；中枢神经系统炎症；动脉粥样硬化；不良的免疫细胞活性和炎症；年龄相关的黄斑变性；咳嗽；白血病；淋巴瘤；中枢神经系统肿瘤；前列腺癌；阿尔茨海默病；中风引起的损伤；痴呆症；肌萎缩侧索硬化和帕金森病。
• CANNABINOID RECEPTOR MODULATORS
  申请人：Jones Robert M.

  公开号：US20120214766A1

  公开（公告）日：2012-08-23

  The present invention relates to certain compounds of Formula Ia and pharmaceutical compositions thereof that modulate the activity of the cannabinoid CB2 receptor. The present invention further relates to certain compounds of Formula Ia and pharmaceutical compositions thereof that modulate the activities of both the CB1 receptor and the CB2 receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of: pain, for example bone and joint pain, muscle pain, dental pain, migraine and other headache pain, inflammatory pain, neuropathic pain, pain that occurs as an adverse effect of therapeutics and pain associated with osteoarthritis; hyperalgesia; allodynia; inflammatory hyperalgesia; neuropathic hyperalgesia; acute nociception; osteoporosis; multiple sclerosis-associated spasticity; autoimmune disorders; allergic reactions; CNS inflammation; atherosclerosis; undesired immune cell activity and inflammation; age-related macular degeneration; cough; leukemia; lymphoma; CNS tumors; prostate cancer; Alzheimer's disease; stroke-induced damage; dementia; amyotrophic lateral sclerosis, and Parkinson's disease.

  本发明涉及公式Ia的某些化合物及其制药组合物，其调节大麻素CB2受体的活性。本发明还涉及公式Ia的某些化合物及其制药组合物，其调节CB1受体和CB2受体的活性。本发明的化合物和制药组合物适用于治疗以下疾病的方法：疼痛，例如骨骼和关节疼痛，肌肉疼痛，牙痛，偏头痛和其他头痛，炎性疼痛，神经痛，由治疗副作用引起的疼痛和与骨关节炎相关的疼痛；过敏症；炎性过敏症；神经病性过敏症；急性疼痛感受；骨质疏松症；多发性硬化症相关痉挛；自身免疫疾病；过敏反应；中枢神经系统炎症；动脉粥样硬化；不良的免疫细胞活动和炎症；年龄相关的黄斑变性；咳嗽；白血病；淋巴瘤；中枢神经系统肿瘤；前列腺癌；阿尔茨海默病；中风引起的损伤；痴呆症；肌萎缩性侧索硬化症和帕金森病。
• Cannabinoid receptor modulators
  申请人：Jones Robert M.

  公开号：US08778950B2

  公开（公告）日：2014-07-15

  The present invention relates to certain compounds of Formula Ia and pharmaceutical compositions thereof that modulate the activity of the cannabinoid CB2 receptor. The present invention further relates to certain compounds of Formula Ia and pharmaceutical compositions thereof that modulate the activities of both the CB1 receptor and the CB2 receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of: pain, for example bone and joint pain, muscle pain, dental pain, migraine and other headache pain, inflammatory pain, neuropathic pain, pain that occurs as an adverse effect of therapeutics and pain associated with osteoarthritis; hyperalgesia; allodynia; inflammatory hyperalgesia; neuropathic hyperalgesia; acute nociception; osteoporosis; multiple sclerosis-associated spasticity; autoimmune disorders; allergic reactions; CNS inflammation; atherosclerosis; undesired immune cell activity and inflammation; age-related macular degeneration; cough; leukemia; lymphoma; CNS tumors; prostate cancer; Alzheimer's disease; stroke-induced damage; dementia; amyotrophic lateral sclerosis, and Parkinson's disease.

  本发明涉及化合物Ia的某些化合物及其制药组合物，该化合物调节大麻素CB2受体的活性。本发明还涉及化合物Ia的某些化合物及其制药组合物，该化合物调节CB1受体和CB2受体的活性。本发明的化合物及其制药组合物适用于治疗以下疾病的方法：疼痛，例如骨骼和关节疼痛，肌肉疼痛，牙痛，偏头痛和其他头痛，炎症性疼痛，神经痛，作为治疗副作用发生的疼痛和与骨关节炎有关的疼痛；高痛觉性；触痛；炎症性高痛觉性；神经病性高痛觉性；急性伤害感受；骨质疏松症；多发性硬化相关痉挛；自身免疫性疾病；过敏反应；中枢神经系统炎症；动脉硬化；不良的免疫细胞活性和炎症；年龄相关的黄斑变性；咳嗽；白血病；淋巴瘤；中枢神经系统肿瘤；前列腺癌；阿尔茨海默病；中风引起的损伤；痴呆症；肌萎缩性侧索硬化症和帕金森病。
• CRYSTALLINE FORMS AND PROCESSES FOR THE PREPARATION OF CANNABINOID RECEPTOR MODULATORS
  申请人：Blackburn Anthony C.

  公开号：US20140135345A1

  公开（公告）日：2014-05-15

  The present invention relates to crystalline forms of (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide (Compound 1) and pharmaceutical compositions thereof that modulate the activity of the cannabinoid CB 2 receptor and are therefore useful in the treatment of CB 2 receptor-mediated disorders, for example, osteoarthritis; pain; hyperalgesia; allodynia; inflammatory hyperalgesia; neuropathic hyperalgesia; acute nociception; osteoporosis; multiple sclerosis-associated spasticity; autoimmune disorders; allergic reactions; CNS inflammation for example; atherosclerosis; undesired immune cell activity, and inflammation associated with a disorder selected from: osteoarthritis, anaphylaxis, Behcet's disease, graft rejection, vasculitis, gout, spondylitis, viral disease, bacterial disease, lupus, inflammatory bowel disease, autoimmune hepatitis, and type 1 diabetes mellitus; age-related macular degeneration; cough; leukemia; lymphoma; CNS tumors; prostate cancer; Alzheimer's disease; stroke-induced damage; dementia; amyotrophic lateral sclerosis; and Parkinson's disease.

  本发明涉及(1aS,5aS)-2-(4-氧基吡嗪-2-基)-1a,2,5,5a-四氢-1H-2,3-二氮杂环丙烷[a]五环-4-羧酸((S)-1-羟甲基-2,2-二甲基-丙基)-酰胺(化合物1)的晶体形式及其药物组成物，这些药物组成物调节大麻素CB2受体的活性，因此在治疗CB2受体介导的疾病方面非常有用，例如骨关节炎、疼痛、过敏症、炎症性疼痛、神经病性疼痛、急性疼痛、骨质疏松症、多发性硬化症相关痉挛、自身免疫性疾病、过敏反应、中枢神经系统炎症、动脉硬化、不良的免疫细胞活性以及与以下疾病相关的炎症：骨关节炎、过敏反应、Behcet氏病、移植排斥、血管炎、痛风、脊柱炎、病毒性疾病、细菌性疾病、狼疮、炎症性肠病、自身免疫性肝炎和1型糖尿病；年龄相关性黄斑变性；咳嗽；白血病；淋巴瘤；中枢神经系统肿瘤；前列腺癌；阿尔茨海默病；中风引起的损伤；痴呆；肌萎缩性侧索硬化症和帕金森病。