4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoic acid | 1417742-86-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoic acid
• 英文别名: Cr-6086；4-[1-[[6-[[4-(trifluoromethyl)phenyl]methyl]-6-azaspiro[2.5]octane-7-carbonyl]amino]cyclopropyl]benzoic acid
• CAS: 1417742-86-9
• 化学式: C₂₆H₂₇F₃N₂O₃
• 分子量: 472.507
• InChiKey: CADWTPLFEZSAHM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  69.6
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-(1-氨基环丙基)-苯甲酸盐酸盐 在 caesium carbonate 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 72.5h， 生成 4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoic acid
  参考文献：
  名称：

  CYCLIC AMINE DERIVATIVES AS EP4 RECEPTOR ANTAGONISTS

  摘要：

  本发明描述了一组新型的环胺衍生物化合物，具有EP4受体拮抗活性，特别是用于治疗或缓解前列腺素E介导的疾病的药物化合物。因此，本发明涉及的是新型化合物，它们是PGE2受体的EP4亚型的选择性拮抗剂，具有镇痛和抗炎活性，其制备过程，包含它们的药物组合物以及它们作为药物的使用，例如用于治疗或缓解急性疼痛、慢性疼痛、骨关节炎、与炎症相关的疾病如关节炎、类风湿性关节炎、癌症、偏头痛和子宫内膜异位症的前列腺素E介导的疾病。

  公开号：

  US20150087626A1

文献信息

• [EN] CYCLIC AMINE DERIVATIVES AS EP4 RECEPTOR ANTAGONISTS<br/>[FR] DÉRIVÉS AMINÉS CYCLIQUES EN TANT QU'ANTAGONISTES DU RÉCEPTEUR EP4
  申请人：ROTTAPHARM SPA

  公开号：WO2013004290A1

  公开（公告）日：2013-01-10

  There is described a novel group of cyclic amine derivative compounds, having an EP4 receptor antagonistic activity and specifically pharmaceutical compounds which are useful for the treatment or alleviation of Prostaglandin E mediated diseases. The present invention therefore relates to novel compounds which are selective antagonists of the EP4 subtype of PGE2 receptors with analgesic and antinflammatory activity, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments, inter alia for the treatment or alleviation of Prostaglandin E mediated diseases such as acute and chronic pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid arthritis, cancer, migraine and endometriosis.

  本发明描述了一组新型的环状胺衍生物化合物，具有EP4受体拮抗活性，特别是用于治疗或减轻前列腺素E介导的疾病的药物化合物。因此，本发明涉及的是新型化合物，它们是PGE2受体的EP4亚型的选择性拮抗剂，具有镇痛和抗炎活性，其制备过程，包含它们的药物组合物以及它们作为药物的使用，包括用于治疗或减轻前列腺素E介导的疾病，如急性疼痛、慢性疼痛、骨关节炎、与炎症相关的疾病如关节炎、类风湿性关节炎、癌症、偏头痛和子宫内膜异位症。
• [EN] PHARMACEUTICAL COMBINATION OF AN EP4 ANTAGONIST AND IMMUNE CHECKPOINT INHIBITORS FOR THE TREATMENT OF TUMOURS<br/>[FR] COMBINAISON PHARMACEUTIQUE D'UN ANTAGONISTE D'EP4 ET D'INHIBITEURS DE POINTS DE CONTRÔLE IMMUNITAIRES POUR LE TRAITEMENT DE TUMEURS
  申请人：ROTTAPHARM BIOTECH SRL

  公开号：WO2020208088A1

  公开（公告）日：2020-10-15

  The present invention provides a pharmaceutical combination comprising the EP4 antagonist of Formula (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5- carboxamido)cyclopropyl)-benzoic acid or a pharmaceutically acceptable salt thereof and at least one immune checkpoint inhibitor, preferably the sodium salt of (R)-4-(1- (6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl) benzoic acid. A polymorphic form A of sodium salt of (R)-4-(1-(6-(4-(trifluoromethyl) benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate characterized by a powder XRD spectrum with peaks at values of the angle 2θ ±0.2° of 4.3, 5.0, 5.8, 6.4, 7.1, 8.3, 8.7, 12.8, 15.3, 15.9 is also described. The combination and the polymorphic form A are described for use in the treatment of tumours.

  本发明提供了一种药物组合，包括化学式为(R)-4-(1-(6-(4-(三氟甲基)苯基)-6-氮杂螺[2.5]辛烷-5-羧胺基)环丙基)-苯甲酸的EP4拮抗剂或其药用可接受的盐，以及至少一种免疫检查点抑制剂，最好是(R)-4-(1-(6-(4-(三氟甲基)苯基)-6-氮杂螺[2.5]辛烷-5-羧胺基)环丙基)苯甲酸的钠盐。还描述了一种(R)-4-(1-(6-(4-(三氟甲基)苯基)-6-氮杂螺[2.5]辛烷-5-羧胺基)环丙基)苯甲酸钠盐的多形态A，其特征是具有在角度2θ±0.2°处的峰值的粉末XRD谱，分别为4.3、5.0、5.8、6.4、7.1、8.3、8.7、12.8、15.3、15.9。该组合物和多形态A用于肿瘤治疗。
• (R)-4-(1-(6-(4-(TRIFLUOROMETHYL)BENZYL)-6-AZASPIRO[2.5]OCTANE-5-CARBOXAMIDO)-CYCLOPROPYL) BENZOIC ACID OR ITS SALT ALSO IN POLYMORPHIC FORM A FOR USE IN THE PREVENTION OF HETEROTOPIC OSSIFICATION
  申请人：Rottapharm Biotech S.r.l.

  公开号：EP3827828A1

  公开（公告）日：2021-06-02

  There is described a compound of formula (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)- cyclopropyl)benzoic acid or a pharmaceutically acceptable salt thereof or the form A of its sodium salt for use in the prevention of heterotopic ossification. Preferably such a compound is effective in a specific dose range.

  描述了一种化合物，其化学式为(R)-4-(1-(6-(4-(三氟甲基)苯基甲基)-6-氮杂螺[2.5]辛烷-5-羧胺基)-环丙基)苯甲酸或其药用可接受盐或其钠盐的A型形式，用于预防异位骨化。最好这种化合物在特定剂量范围内有效。
• [EN] PROCESS FOR THE PREPARATION OF (R)-4-(1-(6-(4-(TRIFLUOROMETHYL)BENZYL)-6-AZASPIRO[2.5]OCTANE-5-CARBOXAMIDO)-CYCLOPROPYL) BENZOIC ACID OR A SALT THEREOF<br/>[FR] PROCÉDÉ DE PRÉPARATION DE L'ACIDE (R)-4-(1-(6-(4-(TRIFLUOROMÉTHYL)BENZYL)-6-AZASPIRO[2.5]OCTANE-5-CARBOXAMIDO)-CYCLOPROPYL)BENZOÏQUE OU DE SON SEL
  申请人：ROTTAPHARM BIOTECH SRL

  公开号：WO2021191062A1

  公开（公告）日：2021-09-30

  The present invention provides a process for preparing (R)-6-(tert-butoxycarbonyl)-6- azaspiro[2.5]octane-5-carboxylic acid (SM1), said process comprising the step of: iv) converting a compound of formula (VII) into a compound of formula (VIII) using a Wittig reagent in a suitable solvent; v) reacting through the Makosza reaction the compound of Formula (VIII) using bromoform and a suitable base to obtain cyclopropane compound of Formula (IX); and vi) removing bromine atoms in the presence of a reducing agent and a base in an alcoholic solvent thus obtaining (SM1). The invention relates also to a process for the conversion of the compound (SM1) for preparing (R)- 4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl) benzoic acid (IV) or a salt thereof. The salt is preferably the sodium salt, more preferably the polymorphic form A of sodium (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6- azaspiro[2.5]octane-5-carboxamido)-cyclopropyl) benzoate characterized by a powder XRD spectrum with peaks at values of the angle 2θ ±0.2° of 4.3, 5.0, 5.8, 6.4, 7.1, 8.3, 8.7, 12.8, 15.3, 15.9.

  本发明提供了一种制备(R)-6-(叔丁氧羰基)-6-氮杂螺[2.5]辛烷-5-羧酸（SM1）的方法，该方法包括以下步骤：iv）在适当的溶剂中使用威替试剂将化合物（VII）转化为化合物（VIII）；v）通过Makosza反应，使用溴仿和适当的碱反应化合物（VIII）以获得环丙烷化合物（IX）；vi）在醇溶剂中存在还原剂和碱的情况下去除溴原子，从而获得（SM1）。该发明还涉及一种将化合物（SM1）转化为制备(R)-4-(1-(6-(4-(三氟甲基)苯基)-6-氮杂螺[2.5]辛烷-5-羧氨基)环丙基)苯甲酸（IV）或其盐的方法。该盐优选为钠盐，更优选为钠的多形式A（R)-4-(1-(6-(4-(三氟甲基)苯基)-6-氮杂螺[2.5]辛烷-5-羧氨基)-环丙基)苯酸盐，其具有在角度2θ ±0.2°处的峰值的粉末XRD谱特征为4.3、5.0、5.8、6.4、7.1、8.3、8.7、12.8、15.3、15.9。
• PHARMACEUTICAL COMBINATION OF AN EP4 ANTAGONIST AND IMMUNE CHECKPOINT INHIBITORS FOR THE TREATMENT OF TUMOURS
  申请人：Rottapharm Biotech S.r.l.

  公开号：EP3722319A1

  公开（公告）日：2020-10-14

  The present invention provides a pharmaceutical combination comprising the EP4 antagonist of Formula (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)-benzoic acid or a pharmaceutically acceptable salt thereof and at least one immune checkpoint inhibitor, preferably the sodium salt of (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl) benzoic acid. A polymorphic form A of sodium salt of (R)-4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate characterized by a powder XRD spectrum with peaks at values of the angle 2θ ±0.2° of 4.3, 5.0, 5.8, 6.4, 7.1, 8.3, 8.7, 12.8, 15.3, 15.9 is also described. The combination and the polymorphic form A are described for use in the treatment of tumours.

  本发明提供了一种药物组合，包含式(R)-4-(1-(6-(4-(三氟甲基)苄基)-6-氮杂螺[2.5]辛烷-5-甲酰胺基)环丙基)-苯甲酸或其药学上可接受的盐和至少一种免疫检查点抑制剂，优选(R)-4-(1-(6-(4-(三氟甲基)苄基)-6-氮杂螺[2.5]辛烷-5-甲酰胺基)环丙基)苯甲酸的钠盐。(R)-4-(1-(6-(4-(三氟甲基)苄基)-6-氮杂螺[2.5]辛烷-5-甲酰胺基)环丙基)苯甲酸的钠盐的多晶型 A。5]octane-5-carboxamido)cyclopropyl)benzoate 的粉末 XRD 光谱，其峰值角 2θ ±0.2° 为 4.3、5.0、5.8、6.4、7.1、8.3、8.7、12.8、15.3、15.9。描述了用于治疗肿瘤的组合物和多态形式 A。