3-(6-dimethylaminopyridin-3-yl)-2,5-dimethyl-7-dipropylaminopyrazolo[1,5-a]pyrimidine | 764651-93-6

• 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: 3-(6-dimethylaminopyridin-3-yl)-2,5-dimethyl-7-dipropylaminopyrazolo[1,5-a]pyrimidine
• 英文别名: 3-[2-(dimethylamino)-5-pyridinyl]-2,5-dimethyl-7-hydroxypyrazolo[2,3-a]pyrimidine
• CAS: 764651-93-6
• 化学式: C₁₅H₁₇N₅O
• 分子量: 283.333
• InChiKey: VZDDWKRIAOIHKX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.18
• 重原子数：
  21.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  66.55
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  3-(6-dimethylaminopyridin-3-yl)-2,5-dimethyl-7-dipropylaminopyrazolo[1,5-a]pyrimidine 在 三氯氧磷 作用下， 以 乙腈 为溶剂， 反应 1.0h， 生成 2,5-dimethyl-3-(6-dimethylaminopyridin-3-yl)-7-chloropyrazolo[1,5-a]pyrimidine
  参考文献：
  名称：

  Design of 2,5-Dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[1,5-a]pyrimidine (NBI 30775/R121919) and Structure−Activity Relationships of a Series of Potent and Orally Active Corticotropin-Releasing Factor Receptor Antagonists

  摘要：

  We have previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series of 3-pyridylpyrazolo[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at the 3-position of the bicyclic nucleus was designed to reduce lipophilicity from the initial leads such as 7. Here, we showed that these 3-pyridyl compounds exhibited potent antagonists at the human CRF1, receptor. Moreover, the hydrophilic and weakly basic pyridine moiety increased the water solubility of some analogues. Compound 26h exhibited good binding affinity at the human CRF1 receptor with a K-i value of 3.5 nM. As a functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing the CRF1 receptor [IC50 = 50 nM), and CRF-stimulated ACTH release from cultured rat pituitary cells [IC50 = 20 nM). 26h had a log P value of 4.9 and water solubility of greater than 10 mg/mL. Pharmacokinetic studies in rats showed that 26h was orally bioavailable and able to penetrate into the brain. 26h has been demonstrated in vivo efficacy in animal behavioral models that measure anxiolytic activity. These results suggest that analogues from this series were potent CRF1, receptor antagonists with proper physicochemical properties and good pharmacokinetic profiles. 26h was developed into a clinical compound and exhibited efficacy in patients with major depression.

  DOI：

  10.1021/jm040058e
• 作为产物：
  描述：

  6-(二甲基氨基)-3-吡啶羧醛 在 氢溴酸肼 、 potassium tert-butylate 、 sodium hydride 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙二醇二甲醚 、 乙醇 、 水 、 乙酸乙酯 为溶剂， 生成 3-(6-dimethylaminopyridin-3-yl)-2,5-dimethyl-7-dipropylaminopyrazolo[1,5-a]pyrimidine
  参考文献：
  名称：

  Design of 2,5-Dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[1,5-a]pyrimidine (NBI 30775/R121919) and Structure−Activity Relationships of a Series of Potent and Orally Active Corticotropin-Releasing Factor Receptor Antagonists

  摘要：

  We have previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series of 3-pyridylpyrazolo[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at the 3-position of the bicyclic nucleus was designed to reduce lipophilicity from the initial leads such as 7. Here, we showed that these 3-pyridyl compounds exhibited potent antagonists at the human CRF1, receptor. Moreover, the hydrophilic and weakly basic pyridine moiety increased the water solubility of some analogues. Compound 26h exhibited good binding affinity at the human CRF1 receptor with a K-i value of 3.5 nM. As a functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing the CRF1 receptor [IC50 = 50 nM), and CRF-stimulated ACTH release from cultured rat pituitary cells [IC50 = 20 nM). 26h had a log P value of 4.9 and water solubility of greater than 10 mg/mL. Pharmacokinetic studies in rats showed that 26h was orally bioavailable and able to penetrate into the brain. 26h has been demonstrated in vivo efficacy in animal behavioral models that measure anxiolytic activity. These results suggest that analogues from this series were potent CRF1, receptor antagonists with proper physicochemical properties and good pharmacokinetic profiles. 26h was developed into a clinical compound and exhibited efficacy in patients with major depression.

  DOI：

  10.1021/jm040058e

文献信息

• PYRAZOLOPYRIMIDINES AS CRF RECEPTOR ANTAGONISTS
  申请人：——

  公开号：US20030125341A1

  公开（公告）日：2003-07-03

  This invention concerns compounds of formula 1 including the stereoisomers and the pharmaceutically acceptable acid addition salt forms thereof, wherein R 1 is NR 4 R 5 or OR 5 ; R 2 is C 1-6 alkyl, C 1-6 alkyloxy or C 1-6 alkylthio; R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfoxy or C 1-6 alkylthio; R 4 is hydrogen, C 1-6 alkyl, mono- or di(C 3-6 cycloalkyl)methyl, C 3-6 cycloalkyl, C 3-6 alkenyl, hydroxyC 1-6 alkyl, C 1-6 alkylcarbonyloxyC 1-6 alkyl or C 1-6 alkyloxyC 1-6 alkyl; R 5 is C 1-8 alkyl, mono- or di(C 3-6 cycloalkyl)methyl, Ar 1 CH 2 , C 1-6 alkyloxyC 1-6 alkyl, hydroxyC 1-6 alkyl, C 3-6 alkenyl, thienylmethyl, furanylmethyl, C 1-6 alkylthioC 1-6 alkyl, morpholinyl, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyl, di(C 1-6 alkyl)amino, C 1-6 alkylcarbonylC 1-6 alkyl, C 1-6 alkyl substituted with imidazolyl; or a radical of formula —Alk-O—CO—Ar 1 ; or R 4 and R 5 taken together with the nitrogen atom to which they are attached may form an optionally substituted pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl group; having CRF receptor antagonistic properties; pharmaceutical compositions containing such compounds as active ingredients; methods of treating disorders related to hypersecretion of CRF such as depression, anxiety, substance abuse, by administering an effective amount of a compound of formula (I).

  本发明涉及公式1的化合物，包括其立体异构体和药学上可接受的酸加成盐形式，其中R1是NR4R5或OR5；R2是C1-6烷基，C1-6烷氧基或C1-6烷硫基；R3是氢，C1-6烷基，C1-6烷基磺酰基，C1-6烷基磺酸氧基或C1-6烷基硫基；R4是氢，C1-6烷基，单或双（C3-6环烷基）甲基，C3-6环烷基，C3-6烯基，羟基C1-6烷基，C1-6烷基羰酸酯氧基C1-6烷基或C1-6烷氧基C1-6烷基；R5是C1-8烷基，单或双（C3-6环烷基）甲基，Ar1CH2，C1-6烷氧基C1-6烷基，羟基C1-6烷基，C3-6烯基，噻吩甲基，呋喃甲基，C1-6烷硫基C1-6烷基，吗啉基，单或双（C1-6烷基）氨基C1-6烷基，双（C1-6烷基）氨基，C1-6烷基羰基C1-6烷基，C1-6烷基取代的咪唑基；或公式—Alk-O—CO—Ar1的基团；或R4和R5与它们连接的氮原子一起可以形成可选取代的吡咯烷基，哌啶基，同源哌啶基或吗啉基；具有CRF受体拮抗性质；含有此类化合物作为活性成分的药物组合物；通过给予公式（I）的化合物的有效量治疗与CRF过度分泌相关的紊乱，如抑郁症，焦虑症，物质滥用等的方法。
• [EN] PYRAZOLOPYRIMIDINES AS CRF RECEPTOR ANTAGONISTS<br/>[FR] PYRAZOLOPYRIMIDINES EN TANT QU'ANTAGONISTES DU RECEPTEUR DE CRF
  申请人：JANSSEN PHARMACEUTICA N.V.

  公开号：WO1997029109A1

  公开（公告）日：1997-08-14

  (EN) This invention concerns compounds of formula (I), including the stereoisomers and the pharmaceutically acceptable acid addition salt forms thereof, wherein R1 is NR4R5 or OR5; R2 is C1-6alkyl, C1-6alkyloxy or C1-6alkylthio; R3 is hydrogen, C1-6alkyl, C1-6alkylsulfonyl, C1-6alkylsulfoxy or C1-6alkylthio; R4 is hydrogen, C1-6alkyl, mono- or di(C3-6cycloalkyl)methyl, C3-6cycloalkyl, C3-6alkenyl, hydroxyC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl or C1-6alkyloxyC1-6alkyl; R5 is C1-8alkyl, mono- or di(C3-6cycloalkyl)methyl, Ar1CH2, C1-6alkyloxyC1-6alkyl, hydroxyC1-6alkyl, C3-6alkenyl, thienylmethyl, furanylmethyl, C1-6alkylthioC1-6alkyl, morpholinyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, di(C1-6alkyl)amino, C1-6alkylcarbonylC1-6alkyl, C1-6alkyl substituted with imidazolyl; or a radical of the formula -Alk-O-CO-Ar1; or R4 and R5 taken together with the nitrogen atom to which they are attached may form an optionally substituted pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl group; having CRF receptor antagonistic properties; pharmaceutical compositions containing such compounds as active ingredients; methods of treating disorders related to hypersecretion of CRF such as depression, anxiety, substance abuse, by administering an effective amount of a compound of formula (I).(FR) L'invention concerne des composés représentés par la formule (I) comprenant les stéréo-isomères, ainsi que leurs sels d'addition d'acide acceptables sur le plan pharmaceutique, dans laquelle R1 représente NR4R5 ou OR5; R2 représente alkyle C1-6, alkyloxy C1-6 ou alkylthio C1-6; R3 représente hydrogène, alkyle C1-6, alkylsulfonyle C1-6, alkylsulfoxy C1-6 ou alkylthio C1-6; R4 représente hydrogène, alkyle C1-6, mono- ou di(C3-6 cycloalkyle)méthyle, cycloalkyle C3-6, alkényle C3-6, hydroxyalkyle C1-6, alkylcarbonyloxy C1-6 alkyle C1-6 ou alkyloxy C1-6 alkyle C1-6; R5 représente alkyle C1-8, mono- ou di(cycloalkyle C3-6)méthyle, Ar1CH2, alkyloxy C1-6 alkyle C1-6, hydroxyalkyle C1-6, alkényle C3-6, thienylméthyle, furanylméthyle, alkylthio C1-6 alkyle C1-6, morpholinyle, mono- ou di(alkyle C1-6)aminoalkyle C1-6, di(alkyle C1-6)amino, alkylcarbonyle C1-6 alkyle C1-6; alkyle C1-6 substitué par imidazolyle; ou un radical représenté par la formule -Alk-O-CO-Ar1; ou R4 et R5, pris ensemble avec l'atome d'azote auquel ils sont fixés, peuvent constituer un groupe éventuellement substitué pyrrolidinyle, pipéridinyle, homopipéridinyle ou morpholinyle; possédant des propriétés d'antagonistes du récepteur de CRF; des compositions pharmaceutiques contenant ces composés en tant qu'ingrédients actifs; des procédés servant à traiter des maladies provoquées par l'hypersécrétion de CRF, telles que la dépression, l'anxiété, la toxicomanie, au moyen de l'administration d'une quantité efficace d'un composé représenté par la formule (I).

  该发明涉及式(I)的化合物，包括其立体异构体和药学上可接受的酸加成盐形式，其中R1为NR4R5或OR5；R2为C1-6烷基，C1-6烷氧基或C1-6烷硫基；R3为氢，C1-6烷基，C1-6烷基磺酰基，C1-6烷基亚磺酸基或C1-6烷基硫基；R4为氢，C1-6烷基，单或双(C3-6环烷基)甲基，C3-6环烷基，C3-6烯基，羟基C1-6烷基，C1-6烷基羧酸酯氧基C1-6烷基或C1-6烷氧基C1-6烷基；R5为C1-8烷基，单或双(C3-6环烷基)甲基，Ar1CH2，C1-6烷氧基C1-6烷基，羟基C1-6烷基，C3-6烯基，噻吩基甲基，呋喃基甲基，C1-6烷硫基C1-6烷基，吗啡啉基，单或双(C1-6烷基)氨基C1-6烷基，双(C1-6烷基)氨基，C1-6烷基羧酰基C1-6烷基，C1-6烷基取代咪唑基；或式-Alk-O-CO-Ar1的基团；或R4和R5与它们连接的氮原子一起可以形成一个可选的取代的吡咯烷基，哌啶基，同型哌啶基或吗啡啉基；具有CRF受体拮抗作用；含有这种化合物作为活性成分的制药组合物；通过给予式(I)化合物的有效量来治疗与CRF过度分泌有关的疾病，例如抑郁症、焦虑症、物质滥用的方法。
• Pyrazolopyrimidines as CRF receptor antagonists
  申请人：Neurocrine Biosciences, Inc.

  公开号：US20040127483A1

  公开（公告）日：2004-07-01

  This invention concerns compounds of formula 1 including the stereoisomers and the pharmaceutically acceptable acid addition salt forms thereof, wherein R 1 is NR 4 R 5 or OR 5 ; R 2 is C 1-6 alkyl, C 1-6 alkyloxy or C 1-6 alkylthio; R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfoxy or C 1-6 alkylthio; R 4 is hydrogen, C 1-6 alkyl, mono- or di(C 3-6 cycloalkyl)methyl, C 3-6 cycloalkyl, C 3-6 alkenyl, hydroxyC 1-6 alkyl, C 1-6 alkylcarbonyloxyC 1-6 alkyl or C 1-6 alkyloxyC 1-6 alkyl; R 5 is C 1-8 alkyl, mono- or di(C 3-6 cycloalkyl)methyl, A 1 CH 2 , C 1-6 alkyloxyC 1-6 alkyl, hydroxyC 1-6 alkyl, C 3-6 alkenyl, thienylmethyl, furanylmethyl, C 1-6 alkylthioC 1-6 alkyl, morpholinyl, mono- or di(C 1-6 alkyl)aminoC 1-6 alkyl, di(C 1-6 alkyl)amino, C 1-6 alkylcarbonylC 1-6 alkyl, C 1-6 alkyl substituted with imidazolyl; or a radical of formula —Alk—O—CO—Ar 1 ; or R 4 and R 5 taken together with the nitrogen atom to which they are attached may form an optionally substituted pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl group; having CRF receptor antagonistic properties; pharmaceutical compositions containing such compounds as active ingredients; methods of treating disorders related to hypersecretion of CRF such as depression, anxiety, substance abuse, by administering an effective amount of a compound of formula (I).

  本发明涉及式1的化合物，包括其立体异构体和药物可接受的酸盐形式，其中R1是NR4R5或OR5; R2是C1-6烷基，C1-6烷氧基或C1-6烷硫基; R3是氢，C1-6烷基，C1-6烷基磺酰基，C1-6烷基磺酸氧基或C1-6烷基硫基; R4是氢，C1-6烷基，单或双（C3-6环烷基）甲基，C3-6环烷基，C3-6烯基，羟基C1-6烷基，C1-6烷基羰酰氧基C1-6烷基或C1-6烷氧基C1-6烷基; R5是C1-8烷基，单或双（C3-6环烷基）甲基，A1CH2，C1-6烷氧基C1-6烷基，羟基C1-6烷基，C3-6烯基，噻吩基甲基，呋喃基甲基，C1-6烷硫基C1-6烷基，吗啉基，单或双（C1-6烷基）氨基C1-6烷基，二（C1-6烷基）氨基，C1-6烷基羰基C1-6烷基，C1-6烷基取代咪唑基; 或式—Alk—O—CO—Ar1的基团; 或R4和R5与它们连接的氮原子一起可以形成可选取代的吡咯烷基，哌啶基，同型哌啶基或吗啡基; 具有CRF受体拮抗性质; 包含此类化合物作为活性成分的制药组合物; 通过给予式（I）化合物的有效量来治疗与CRF高分泌相关的疾病，例如抑郁症，焦虑症，物质滥用等的方法。
• US6664261B2
  申请人：——

  公开号：US6664261B2

  公开（公告）日：2003-12-16
• US7074797B2
  申请人：——

  公开号：US7074797B2

  公开（公告）日：2006-07-11