1-isopropyl-4,6-dihydrospiro[indazole-5,4'-piperidin]-7(1H)-one | 1268521-75-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-isopropyl-4,6-dihydrospiro[indazole-5,4'-piperidin]-7(1H)-one
• 英文别名: 1-Isopropyl-1,4-dihydrospiro[indazole-5,4'-piperidin]-7(6H)-one；1-propan-2-ylspiro[4,6-dihydroindazole-5,4'-piperidine]-7-one
• CAS: 1268521-75-0
• 化学式: C₁₄H₂₁N₃O
• 分子量: 247.34
• InChiKey: ZFXCIWPVPUPDMF-UHFFFAOYSA-N

物化性质

• 沸点：
  409.5±45.0 °C(Predicted)
• 密度：
  1.27±0.1 g/cm3(Predicted)
• pKa：
  10.66±0.20 (Predicted,Most Basic Temp: 25 °C)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  46.9
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-isopropyl-4,6-dihydrospiro[indazole-5,4'-piperidin]-7(1H)-one 在 盐酸 作用下， 以 乙醚 为溶剂， 以293 mg的产率得到1-isopropyl-4,6-dihydrospiro[indazole-5,4'-piperidin]-7(1H)-one hydrochloride
  参考文献：
  名称：

  Synthesis of 7-Oxo-dihydrospiro[indazole-5,4′-piperidine] Acetyl-CoA Carboxylase Inhibitors

  摘要：

  Synthesis of oxo-dihydrospiroindazole-based acetyl-CoA carboxylase (ACC) inhibitors is reported. The dihydrospiroindazoles were assembled in a regioselective manner in six steps from substituted hydrazines and protected 4-formylpiperidine. Enhanced regioselectivity in the condensation between a keto enamine and substituted hydrazines was observed when using toluene as the solvent, leading to selective formation of 1-substituted spiroindazoles. The 2-substituted spiroindazoles were formed selectively from alkyl hydrazones by ring closure with Vilsmeier reagent. The key step in the elaboration to the final products is the conversion of an intermediate olefin to the desired ketone through elimination of HBr from an O-methyl bromohydrin. This methodology enabled the synthesis of each desired regioisomer on 50-75 g scale with minimal purification. Acylation of the resultant spirocyclic amines provided potent ACC inhibitors.

  DOI：

  10.1021/jo202377g
• 作为产物：
  描述：

  1-isopropylspiro[4H-indazole-5,4'-piperidine]-1'-formic acid benzyl ester 在 N-溴代丁二酰亚胺(NBS) 、 Jones reagent 、 1-甲基-1,4-环己二烯 、 palladium 10% on activated carbon 、 水 、 氯化铵 、 锌 作用下， 以 四氢呋喃 、 水 、 乙酸乙酯 、 丙酮 为溶剂， 反应 5.5h， 生成 1-isopropyl-4,6-dihydrospiro[indazole-5,4'-piperidin]-7(1H)-one
  参考文献：
  名称：

  Synthesis of 7-Oxo-dihydrospiro[indazole-5,4′-piperidine] Acetyl-CoA Carboxylase Inhibitors

  摘要：

  Synthesis of oxo-dihydrospiroindazole-based acetyl-CoA carboxylase (ACC) inhibitors is reported. The dihydrospiroindazoles were assembled in a regioselective manner in six steps from substituted hydrazines and protected 4-formylpiperidine. Enhanced regioselectivity in the condensation between a keto enamine and substituted hydrazines was observed when using toluene as the solvent, leading to selective formation of 1-substituted spiroindazoles. The 2-substituted spiroindazoles were formed selectively from alkyl hydrazones by ring closure with Vilsmeier reagent. The key step in the elaboration to the final products is the conversion of an intermediate olefin to the desired ketone through elimination of HBr from an O-methyl bromohydrin. This methodology enabled the synthesis of each desired regioisomer on 50-75 g scale with minimal purification. Acylation of the resultant spirocyclic amines provided potent ACC inhibitors.

  DOI：

  10.1021/jo202377g

文献信息

• N1-Pyrazolospiroketone Acetyl-CoA Carboxylase Inhibitors
  申请人：BAGLEY SCOTT WILLIAM

  公开号：US20110111046A1

  公开（公告）日：2011-05-12

  The invention provides a compound of Formula (I) or a pharmaceutically acceptable salt of the compound, wherein R 1 , R 2 , R 3 and R 4 are as described herein; pharmaceutical compositions thereof; and the use thereof in treating diseases, conditions or disorders modulated by the inhibition of an acetyl-CoA carboxylase enzyme(s) in an animal.

  该发明提供了化合物I的化合物或其药用可接受的盐，其中R1、R2、R3和R4如本文所述；以及其药物组合物；以及在治疗受乙酰辅酶A羧化酶抑制调节的动物疾病、症状或紊乱中的使用。
• [EN] CRYSTALLINE 2-AMINO-2-(HYDROXYMETHYL)PROPANE-1,3-DIOL SALT OF 4-(4-(1-ISOPROPYL-7-OXO-1,4,6,7-TETRAHYDROSPIRO[INDAZOLE-5,4'-PIPERIDINE]-1'-CARBONYL)-6-METHOXYPYRIDIN-2-YL)BENZOIC ACID<br/>[FR] SEL DE 2-AMINO-2-(HYDROXYMÉTHYL)PROPANE-1,3-DIOL CRISTALLIN DE L'ACIDE 4-(4-(1 -ISOPROPYL-7-OXO-1,4,6,7-TÉTRAHYDROSPIRO[INDAZOLE-5,4'-PIPÉRIDINE]-1 '-CAR BONYL)-6-MÉTHOXYPYRIDIN-2-YL)BENZOÏQUE
  申请人：PFIZER

  公开号：WO2019102311A1

  公开（公告）日：2019-05-31

  The invention provides the tris salt of 4-(4-(1-isopropyl-7-oxo-1,4,6,7- tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzoic acid as a crystalline anhydrous or tri-hydrate; as well as polymorphs, pharmaceutical compositions, dosage forms, and the use thereof in treating diseases, conditions or disorders modulated by the inhibition of an acetyl-CoA carboxylase (ACC) enzyme(s) in an animal.

  该发明提供了4-(4-(1-异丙基-7-氧代-1,4,6,7-四氢螺[吲唑-5,4'-哌啶]-1'-羰基)-6-甲氧基吡啶-2-基)苯甲酸的三盐，作为结晶的无水物或三水合物；以及其多晶形态、药物组合物、剂型，以及在治疗受乙酰辅酶A羧化酶(ACC)抑制调节的动物疾病、症状或疾病中的使用。
• Combinations For Treatment Of NASH/NAFLD And Related Diseases
  申请人：Pfizer Inc.

  公开号：US20200071306A1

  公开（公告）日：2020-03-05

  The combination of (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide or pharmaceutically acceptable salt thereof, and 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoic acid or pharmaceutically acceptable salt thereof, for treatment of diseases, including non-alcoholic steatohepatitis (NASH), in mammals are described herein.

  本文描述了(S)-2-(5-((3-乙氧基吡啶-2-基)氧基)吡啶-3-基)-N-(四氢呋喃-3-基)嘧啶-5-羧酰胺或其药学上可接受的盐，以及4-(4-(1-异丙基-7-氧代-1,4,6,7-四氢螺[吲唑-5,4'-哌啶]-1'-羰基)-6-甲氧基吡啶-2-基)苯甲酸或其药学上可接受的盐的组合物，用于哺乳动物的疾病治疗，包括非酒精性脂肪性肝炎（NASH）。
• [EN] COMBINATIONS COMPRISING BENZODIOXOL AS GLP-1R AGONISTS FOR USE IN THE TREATMENT OF NASH/NAFLD AND RELATED DISEASES<br/>[FR] COMBINAISONS COMPRENANT DU BENZODIOXOL EN TANT QU'AGONISTES DE GLP-1R DESTINÉES À ÊTRE UTILISÉES DANS LE TRAITEMENT DE LA NASH/NAFLD ET DE MALADIES ASSOCIÉES
  申请人：PFIZER

  公开号：WO2020234726A1

  公开（公告）日：2020-11-26

  In part, the invention provides a new combination comprising (1) a GLP-1R agonist and (2) an ACC inhibitor or a DGAT2 inhibitor, or a KHK inhibitor or FXR agonist. The invention further provides new methods for treating diseases and disorders, for example, fatty liver, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepotitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or with a metabolic-related disease, obesity, and type 2 diabetes, for example, using the new combination described herein.

  部分地，该发明提供了一种新的组合，包括（1）GLP-1R激动剂和（2）ACC抑制剂或DGAT2抑制剂，或KHK抑制剂或FXR激动剂。该发明还提供了治疗疾病和疾病的新方法，例如脂肪肝，非酒精性脂肪肝病，非酒精性脂肪性肝炎，伴有肝纤维化的非酒精性脂肪性肝炎，伴有肝硬化的非酒精性脂肪性肝炎，以及伴有肝细胞癌或代谢相关疾病的非酒精性脂肪性肝炎，肥胖和2型糖尿病等，例如，使用本文所述的新组合。
• SUBSTITUTED ACETYL-COA CARBOXYLASE INHIBITORS
  申请人：Dow Robert Lee

  公开号：US20120270893A1

  公开（公告）日：2012-10-25

  The invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof; wherein G is R 1 , R 2 and R 3 are as described herein; pharmaceutical compositions thereof; and the use thereof in treating diseases, conditions or disorders modulated by the inhibition of an acetyl-CoA carboxylase enzyme(s) in an animal.

  该发明提供了公式（I）的化合物或其药用可接受的盐；其中G为R1，R2和R3如本文所述；其药用组合物；以及其在治疗由于抑制动物中乙酰辅酶A羧化酶而调节的疾病、症状或疾病中的用途。