ethyl 2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate | 667930-76-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: ethyl 2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate
• 英文别名: ethyl 2,7,7-trimethyl-5-phenyl-5,6-dihydro-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylate
• CAS: 667930-76-9
• 化学式: C₁₈H₂₃N₃O₂
• 分子量: 313.4
• InChiKey: KZFHXUDBHRBTQZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  56.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate 在 氯化亚砜 、 potassium hydroxide 作用下， 以 乙醇 、 正己烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 17.0h， 生成
  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：

  苯基(2-甲基-1-丙烯基)甲酮 在 sodium tetrahydroborate 、 sodium hydride 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 、 oil 为溶剂， 反应 3.5h， 生成 ethyl 2,7,7-trimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate
  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：US09447100B2

  公开（公告）日：2016-09-20

  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; X1 is CR1, CR1R2, N or NR13; X2 is N or NR3; Y is C, CR4 or N, Z is CR5, CR5R6, N or NR7; 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; R1, R2, R3, R4, R5, R6, R7 and R13 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, CR5 or N; R8, R9, R10, R11 and R12 are independently, H, an optionally substituted hydrocarbon group, etc., or a salt thereof are also provided. Also specify X1, R3, R1, Y and X3 in formula (II) and (III) as before.

  提供了一种包括式(I)化合物的钙受体调节剂： 其中环A是可选择地取代的5-至7-成员环；环B是可选择地取代的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是可选择地取代的环状基团；R是H、可选择地取代的碳氢基团等；和是单键或双键；R1、R2、R3、R4、R5、R6、R7和R13独立地是H、可选择地取代的碳氢基团；或其盐或前药。还提供了式(II)和(III)的化合物： 其中环A是可选择地取代的5-至7-成员环；Q是C、CR5或N；R8、R9、R10、R11和R12独立地是H、可选择地取代的碳氢基团等，或其盐。 还请在式(II)和(III)中指定X1、R3、R1、Y和X3。
• 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。
• CALCIUM RECEPTOR MODULATING COMPOUND AND USE THEREOF
  申请人：Takeda Pharmaceutical Company Limited

  公开号：EP1572113B1

  公开（公告）日：2017-05-17