(5R)-N-(1-ethyl-1-(4-ethylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide | 667931-25-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 英文名称: (5R)-N-(1-ethyl-1-(4-ethylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
• 英文别名: TAK-075 free base；(5R)-N-[3-(4-ethylphenyl)pentan-3-yl]-2,7,7-trimethyl-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide
• CAS: 667931-25-1
• 化学式: C₂₉H₃₈N₄O
• 分子量: 458.647
• InChiKey: UEEHORXWFOHMHK-XMMPIXPASA-N

物化性质

• 沸点：
  619.6±55.0 °C(Predicted)
• 密度：
  1.11±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  59
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  1-甲基-5-氨基吡唑-4-羧酸乙酯 在 sodium tetrahydroborate 、 sodium hydride 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 potassium hydroxide 作用下， 以 乙醇 、 正己烷 、 水 、 N,N-二甲基甲酰胺 、 oil 为溶剂， 反应 19.5h， 生成 (5R)-N-(1-ethyl-1-(4-ethylphenyl)propyl)-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
  参考文献：
  名称：

  Novel and potent calcium-sensing receptor antagonists: Discovery of (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide monotosylate (TAK-075) as an orally active bone anabolic agent

  摘要：

  The calcium-sensing receptor antagonist (CaSR) has been recognized as a promising target of anabolic agents for treating osteoporosis. In the course of developing a new drug candidate for osteoporosis, we found tetrahydropyrazolopyrimidine derivative 1 to be an orally active CaSR antagonist that stimulated transient PTH secretion in rats. However, compound 1 showed poor physical and chemical stability. In order to work out this compound's chemical stability and further understand its in vivo efficacy, we focused on modifying the 2-position of the tetrahydropyrazolopyrimidine. As a result of chemical modification, we discovered (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide monotosylate 10m (TAK-075), which showed improved solubility, chemical stability, and in vivo efficacy. Furthermore, we describe that evaluating the active metabolite is important during repeated treatment with short-acting CaSR antagonists. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.02.001

文献信息

• HETEROCYCLIC COMPOUND
  申请人：TAKEDA PHARMACEUTICAL COMPANY LIMITED

  公开号：US20200131174A1

  公开（公告）日：2020-04-30

  The present invention provides a compound or a salt thereof having a calcium-sensing receptor antagonistic activity, and being expected to be useful as an agent for preventing or treating heart failure, pulmonary hypertension, or the like. The compounds represented by formula (I) or a salt thereof has a calcium-sensing receptor antagonistic activity, and is expected to be useful as an agent for preventing or treating heart failure, pulmonary hypertension, or the like, wherein each symbol is as described in the specification.

  本发明提供一种具有钙感受受体拮抗活性的化合物或其盐，预计可用作预防或治疗心力衰竭、肺动脉高压等疾病的药物。由式（I）表示的化合物或其盐具有钙感受受体拮抗活性，并预计可用作预防或治疗心力衰竭、肺动脉高压等疾病的药物，其中每个符号如规范中所述。
• Calcium receptor modulating compound and use thereof
  申请人：Yasuma Tsuneo

  公开号：US20060079536A1

  公开（公告）日：2006-04-13

  There is provided a calcium receptor modulator comprising a compound of the formula (I): wherein ring A is an optionally substituted 5- to 7-membered ring; ring B is an optionally substituted 5- to 7-membered heterocyclic ring; X 1 is CR 1 , CR 1 R 2 , N or NR 13 ; X 2 is N or NR 3 ; Y is C, CR 4 or N, Z is CR 5 , CR 5 R 6 , N or NR 7 ; Ar is an optionally substituted cyclic group; R is H, an optionally substituted hydrocarbon group, etc.; and is a single bond or a double bond; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 13 are independently H, an optionally substituted hydrocarbon group; or a salt thereof or a prodrug thereof. Compounds of the formula (II) and (III): wherein ring A is an optionally substituted 5- to 7-membered ring; Q is C, CR 5 or N; R 8 , R 9 , R 10 , R 11 and R 12 are independently, H, an optionally substituted hydrocarbon group, etc., or a salt thereof are also provided. Also specify X 1 , R 3 , R 1 , Y and X 3 in formula (II) and (III) as before.

  提供了一种含有式(I)化合物的钙受体调节剂：其中，环A是可选取代的5-至7-成员环；环B是可选取代的5-至7-成员杂环；X1是CR1、CR1R2、N或NR13；X2是N或NR3；Y是C、CR4或N；Z是CR5、CR5R6、N或NR7；Ar是可选取代的环状基团；R是H、可选取代的碳氢基团等；是单键或双键；R1、R2、R3、R4、R5、R6、R7和R13独立地是H、可选取代的碳氢基团；或其盐或前药。还提供了式(II)和(III)化合物：其中，环A是可选取代的5-至7-成员环；Q是C、CR5或N；R8、R9、R10、R11和R12独立地是H、可选取代的碳氢基团等；或其盐。在式(II)和(III)中，X1、R3、R1、Y和X3的指定与之前相同。
• SUBSTITUTED PYRAZOLO[1,5-A] PYRIMIDINES AS CALCIUM RECEPTOR MODULATING AGENTS
  申请人：Takeda Pharmaceutical Company Limited

  公开号：US20140155416A1

  公开（公告）日：2014-06-05

  There is provided a calcium receptor modulator comprising a compound of the formula (I): wherein ring A is an optionally substituted 5- to 7-membered ring; ring B is an optionally substituted 5- to 7-membered heterocyclic ring; X 1 is CR 1 , CR 1 R 2 , N or NR 13 ; X 2 is N or NR 3 ; Y is C, CR 4 or N, Z is CR 5 , CR 5 R 6 , N or NR 7 ; Ar is an optionally substituted cyclic group; R is H, an optionally substituted hydrocarbon group, etc.; and is a single bond or a double bond; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 13 are independently H, an optionally substituted hydrocarbon group; or a salt thereof or a prodrug thereof. Compounds of the formula (II) and (III): wherein ring A is an optionally substituted 5- to 7-membered ring; Q is C, CR 5 or N; R 8 , R 9 , R 10 , R 11 and R 12 are independently, H, an optionally substituted hydrocarbon group, etc., or a salt thereof are also provided. Also specify X 1 , R 3 , R 1 , Y and X 3 in formula (II) and (III) as before.

  提供了一种含有式(I)化合物的钙受体调节剂，其中环A是可选取代的5-至7元环；环B是可选取代的5-至7元杂环；X1是CR1，CR1R2，N或NR13；X2是N或NR3；Y是C，CR4或N，Z是CR5，CR5R6，N或NR7；Ar是可选取代的环状基团；R是H，可选取代的烃基团等；表示单键或双键；R1、R2、R3、R4、R5、R6、R7和R13独立地是H，可选取代的烃基团；或其盐或前药。还提供了式(II)和(III)的化合物：其中环A是可选取代的5-至7元环；Q是C，CR5或N；R8、R9、R10、R11和R12独立地是H，可选取代的烃基团等，或其盐。同样指定式(II)和(III)中的X1、R3、R1、Y和X3如前。
• SUBSTITUTED PYRAZOLO[1,5-A]PYRIMIDINES AS CALCIUM RECEPTOR MODULATING AGENTS
  申请人：Yasuma Tsuneo

  公开号：US20090215746A1

  公开（公告）日：2009-08-27

  There is provided a calcium receptor modulator comprising a compound of the formula (I): wherein ring A is an optionally substituted 5- to 7-membered ring; ring B is an optionally substituted 5- to 7-membered heterocyclic ring; X 1 is CR 1 , CR 1 R 2 , N or NR 13 ; X 2 is N or NR 3 ; Y is C, CR 4 or N, Z is CR 5 , CR 5 R 6 , N or NR 7 ; Ar is an optionally substituted cyclic group; R is H, an optionally substituted hydrocarbon group, etc.; and is a single bond or a double bond; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 13 are independently H, an optionally substituted hydrocarbon group; or a salt thereof or a prodrug thereof. Compounds of the formula (II) and (III): wherein ring A is an optionally substituted 5- to 7-membered ring; Q is C, CR 5 or N; R 8 , R 9 , R 10 , R 11 and R 12 are independently, H, an optionally substituted hydrocarbon group, etc., or a salt thereof are also provided. Also specify X 1 , R 3 , R 1 , Y and X 3 in formula (II) and (III) as before.

  提供了一种包含式(I)化合物的钙受体调节剂，其中环A是可选取代的5-至7-成员环；环B是可选取代的5-至7-成员杂环；X1是CR1、CR1R2、N或NR13；X2是N或NR3；Y是C、CR4或N，Z是CR5、CR5R6、N或NR7；Ar是可选取代的环状基团；R是H、可选取代的碳氢基团等；和是单键或双键；R1、R2、R3、R4、R5、R6、R7和R13独立地是H、可选取代的碳氢基团；或其盐或前药。还提供了式(II)和(III)化合物：其中环A是可选取代的5-至7-成员环；Q是C、CR5或N；R8、R9、R10、R11和R12独立地是H、可选取代的碳氢基团等，或其盐。同时，如前所述，还指定式(II)和(III)中的X1、R3、R1、Y和X3。
• MEDICINE
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP3395344A1

  公开（公告）日：2018-10-31

  The present invention provides a medicament for preventing or treating heart failure. More specifically, the present invention provides a medicament for preventing or treating heart failure, comprising a compound selected from the group consisting of (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, (5R)-N-[1-ethyl-1-(4-methoxyphenyl)propyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide, (5R)-N-[1-ethyl-1-(4-ethylphenyl)propyl]-5-(2-fluorophenyl)-2,7,7-trimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide and salts thereof.

  本发明提供了一种用于预防或治疗心力衰竭的药物。更具体地说，本发明提供了一种用于预防或治疗心力衰竭的药物，其中包含一种选自以下组别的化合物：(5R)-N-[1-乙基-1-(4-乙基苯基)丙基]-2,7,7-三甲基-5-苯基-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺、(5R)-N-[1-乙基-1-(4-甲氧基苯基)丙基]-2,7,7-三甲基-5-苯基-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺、(5R)-N-[1-乙基-1-(4-乙基苯基)丙基]-5-(2-氟苯基)-2,7,7-三甲基-4,5,6,7-四氢吡唑并[1,5-a]嘧啶-3-甲酰胺及其盐类。