(5R)-N-[1-(4-acetylphenyl)-1-ethylpropyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide | 1292827-38-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (5R)-N-[1-(4-acetylphenyl)-1-ethylpropyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide
• 英文别名: (5R)-N-[3-(4-acetylphenyl)pentan-3-yl]-2,7,7-trimethyl-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide
• CAS: 1292827-38-3
• 化学式: C₂₉H₃₆N₄O₂
• 分子量: 472.63
• InChiKey: RSIFWSLPLFKXMS-XMMPIXPASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  76
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (5R)-N-[1-(4-acetylphenyl)-1-ethylpropyl]-2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide 在 sodium tetrahydroborate 作用下， 以 乙醇 为溶剂， 反应 4.0h， 生成 (5R)-N-{1-ethyl-1-[4-(1-hydroxyethyl)phenyl]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
• 作为产物：
  描述：

  1-甲基-5-氨基吡唑-4-羧酸乙酯 在 1,1'-双(二苯基膦)二茂铁 、 sodium tetrahydroborate 、 氯化亚砜 、 palladium diacetate 、 sodium hydride 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 potassium hydroxide 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 正己烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 oil 为溶剂， 反应 62.5h， 生成 (5R)-N-[1-(4-acetylphenyl)-1-ethylpropyl]-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

• 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。
• US9447100B2
  申请人：——

  公开号：US9447100B2

  公开（公告）日：2016-09-20
• 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
  作者：Masato Yoshida、Akira Mori、Shinji Morimoto、Etsuo Kotani、Masahiro Oka、Kohei Notoya、Haruhiko Makino、Midori Ono、Mikio Shirasaki、Norio Tada、Hisashi Fujita、Junko Ban、Yukihiro Ikeda、Tomohiro Kawamoto、Mika Goto、Hiroyuki Kimura、Atsuo Baba、Tsuneo Yasuma

  DOI：10.1016/j.bmc.2011.02.001

  日期：2011.3

  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.