3-(6-(二甲基氨基)-4-甲基吡啶-3-基)-2,5-二甲基-N,N-二丙基吡唑并[1,5-a]嘧啶-7-胺 | 195055-03-9

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: 3-(6-(二甲基氨基)-4-甲基吡啶-3-基)-2,5-二甲基-N,N-二丙基吡唑并[1,5-a]嘧啶-7-胺
• 中文别名: 3-(6-(二甲基氨基)-4-甲基吡啶-3-基)-2,5-二甲基-N,N-二丙基吡唑并[1,5-A]嘧啶-7-胺
• 英文名称: 3-[6-(dimethylamino)-4-methyl-3-pyridinyl]-2,5-dimethyl-N,N-dipropylpyrazolo[2,3-a]pyrimidine-7-amine
• 英文别名: 3-[6-(dimethylamino)-4-methyl-3-pyridinyl]-2,5-dimethyl-N,N-dipropyl-pyrazolo[2,3-a]pyrimidine-7-amine；R 121919；(3-(6-(dimethylamino)-4-methylpyridin-3-yl)-2,5-dimethyl-N,N-dipropylpyrazolo[1,5-a]pyrimidin-7-amine)；3-[6-(dimethylamino)-4-methyl-3-pyridinyl]-2,5-dimethyl-N,N-dipropylpyrazolo[1,5-a]pyrimidin-7-amine；5-[7-(dipropylamino)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-3-yl]-N,N,4-trimethylpyridin-2-amine；NBI-30775；3-(6-(Dimethylamino)-4-methylpyridin-3-yl)-2,5-dimethyl-N,N-dipropylpyrazolo[1,5-a]pyrimidin-7-amine；3-[6-(dimethylamino)-4-methylpyridin-3-yl]-2,5-dimethyl-N,N-dipropylpyrazolo[1,5-a]pyrimidin-7-amine
• CAS: 195055-03-9
• 化学式: C₂₂H₃₂N₆
• 分子量: 380.536
• InChiKey: ANNRUWYFVIGKHA-UHFFFAOYSA-N

物化性质

• 密度：
  1.11±0.1 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：6.2 mg/mL（16.29 mM）

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  49.6
• 氢给体数：
  0
• 氢受体数：
  5

安全信息

• 海关编码：
  2933990090
• 储存条件：
  2-8℃

制备方法与用途

生物活性

R121919（NBI30775）是一种高效的小分子CRF1受体拮抗剂，其对CRF1受体的Ki值为2至5 nM。相比之下，它在CRF2受体、CRF结合蛋白或其它70种不同类型的受体上的活性弱于1000倍。

靶点

• Ki: 2 to 5 nM (CRF1)

体外研究

R121919是一种强效的小分子CRF1受体拮抗剂，对CRF1受体具有高亲和力（Ki = 2–5 nM），且在CRF2受体、CRF结合蛋白或其它70种不同类型的受体上的活性弱于1000倍。

体内研究

R121919能够剂量依赖性地减少大鼠应激反应中的促肾上腺皮质激素释放激素和皮质酮水平。在使用10 mg/kg的R121919时，促肾上腺皮质激素释放激素和皮质酮的最大血浆浓度分别减少了9%和25%。此外，该药物还表现出陡峭的剂量-反应曲线，在降低小鼠焦虑方面具有显著效果。研究还发现，如GR、MR、BAG-1和AP-1等分子是其潜在的细胞内靶点。

反应信息

• 作为反应物：
  描述：

  3-(6-(二甲基氨基)-4-甲基吡啶-3-基)-2,5-二甲基-N,N-二丙基吡唑并[1,5-a]嘧啶-7-胺 在 N-氯代丁二酰亚胺 作用下， 以 氯仿 为溶剂， 反应 2.0h， 生成 [6-Chloro-3-(6-dimethylamino-4-methyl-pyridin-3-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-dipropyl-amine
  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：

  N,N,4-三甲基吡啶-2-胺 在 氢溴酸肼 、 potassium tert-butylate 、 溴 、 sodium hydride 、 sodium carbonate 、 magnesium 、 1,2-二溴乙烷 、 三氯氧磷 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙二醇二甲醚 、 乙醇 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 33.67h， 生成 3-(6-(二甲基氨基)-4-甲基吡啶-3-基)-2,5-二甲基-N,N-二丙基吡唑并[1,5-a]嘧啶-7-胺
  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。
• Use of CRF antagonists and related compositions for treating depression and modifying the circadian rhytm
  申请人：Pfizer Products Inc.

  公开号：EP1082960A2

  公开（公告）日：2001-03-14

  A corticotropin releasing factor (CRF) antagonist is administered to treat a condition selected from the group consisting of: c)disorders that can be treated by altering circadian rhythm; and d)depression, further wherein a second compound for treating depression is administered, the second compound for treating depression having an onset of action that is delayed with respect to that of the CRF antagonist.

  一种促肾上腺皮质激素释放因子（CRF）拮抗剂用于治疗选自以下组别的疾病： c)可通过改变昼夜节律来治疗的疾病；以及 d)抑郁症，其中还施用了治疗抑郁症的第二种化合物，治疗抑郁症的第二种化合物的起效时间比CRF拮抗剂的起效时间延迟。
• Use of corticotropin releasing factor antagonists for treating syndrome X
  申请人：Pfizer Products Inc.

  公开号：EP1097709A2

  公开（公告）日：2001-05-09

  The present invention relates to compositions and methods of achieving a thereapeutic effect including, the treatment or prevention of syndrome X in an animal, preferably a mammal including a human subject or a companion animal, using a corticotropin releasing factor (CRF) antagonist alone or together with a glucocorticoid receptor antagonist.

  本发明涉及单独使用促肾上腺皮质激素释放因子（CRF）拮抗剂或与糖皮质激素受体拮抗剂一起使用以达到治疗或预防动物（最好是哺乳动物，包括人类或伴侣动物）X综合征的效果的组合物和方法。