6-(3-hydroxy-2-methylpropylamino)isoquinoline-1-carbonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 6-(3-hydroxy-2-methylpropylamino)isoquinoline-1-carbonitrile
• 英文别名: (S)-6-[(3-Hydroxy-2-methylpropyl)amino]isoquinoline-1-carbonitrile；6-[(3-hydroxy-2-methylpropyl)amino]isoquinoline-1-carbonitrile
• 化学式: C₁₄H₁₅N₃O
• 分子量: 241.293
• InChiKey: GFXUJYJYWLBARP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  68.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-(3-hydroxy-2-methylpropylamino)isoquinoline-1-carbonitrile 在 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 17.0h， 生成 [3-[(1-Cyanoisoquinolin-6-yl)-[(2-methylpropan-2-yl)oxycarbonylsulfamoyl]amino]-2-methylpropyl] methanesulfonate
  参考文献：
  名称：

  [EN] CARBONITRILE DERIVATIVES AS SELECTIVE ANDROGEN RECEPTOR MODULATORS
  [FR] DÉRIVÉS CARBONITRILES EN TANT QUE MODULATEURS SÉLECTIFS DU RÉCEPTEUR DES ANDROGÈNES

  摘要：

  公开号：

  WO2015181676A4
• 作为产物：
  描述：

  6-溴异喹啉 在 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 二甲基亚砜 为溶剂， 反应 19.25h， 生成 6-(3-hydroxy-2-methylpropylamino)isoquinoline-1-carbonitrile
  参考文献：
  名称：

  [EN] CARBONITRILE DERIVATIVES AS SELECTIVE ANDROGEN RECEPTOR MODULATORS
  [FR] DÉRIVÉS CARBONITRILES EN TANT QUE MODULATEURS SÉLECTIFS DU RÉCEPTEUR DES ANDROGÈNES

  摘要：

  公开号：

  WO2015181676A4

文献信息

• NOVEL SELECTIVE ANDROGEN RECEPTOR MODULATORS
  申请人：Pfizer Inc.

  公开号：US20140155390A1

  公开（公告）日：2014-06-05

  The present invention relates to a compound of Formula 1, 2 or 3: wherein A is N or —CR 0 —, where R 0 is hydrogen, C 1 -C 6 linear or branched chain alkyl, etc., Z is —CR e —, or, —N—, where R e is hydrogen, C 1 -C 6 linear or branched chain alkyl,etc.; R 1 is hydrogen, C 1 -C 6 linear or branched chain alkyl, etc.; R 2 are independently hydrogen or C 1 -C 6 linear or branched chain alkyl; R 3 and R 4 are independently hydrogen, C 1 -C 6 linear or branched chain alkyl, etc.;. R 5 and R 6 are independently hydrogen or C 1 -C 6 linear or branched chain alkyl, etc.; R 8 is hydrogen, C 1 -C 6 linear or branched chain alkyl, etc.; R 9 and R 10 are independently hydrogen or C 1 -C 6 linear or branched chain alkyl, etc.; Q is —CO—, —(CH 2 ) q —, —(CHR s ) q —, or (CR s R t ) q —, where R s and R t are independently C 1 -C 6 linear or branched chain alkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl; where q is 0, 1, 2, or 3; and, where n is 0, 1, 2, 3, 4 or 5; or, a pharmaceutically acceptable salt thereof, to compositions containing such compounds; and to the uses of such compounds in the treatment of various diseases, particularly, those affected or mediated by the androgen receptor.

  本发明涉及一种具有化学式1、2或3的化合物：其中A为N或—CR0—，其中R0为氢、C1-C6直链或支链烷基等，Z为—CRe—或—N—，其中Re为氢、C1-C6直链或支链烷基等；R1为氢、C1-C6直链或支链烷基等；R2独立地为氢或C1-C6直链或支链烷基；R3和R4独立地为氢、C1-C6直链或支链烷基等；R5和R6独立地为氢或C1-C6直链或支链烷基等；R8为氢、C1-C6直链或支链烷基等；R9和R10独立地为氢或C1-C6直链或支链烷基等；Q为—CO—、—(CH2)q—、—(CHRs)q—或(CRsRt)q—，其中Rs和Rt独立地为C1-C6直链或支链烷基、芳基、烷基芳基、杂芳基或烷基杂芳基；其中q为0、1、2或3；n为0、1、2、3、4或5；或其药学上可接受的盐，以及含有这种化合物的组合物；以及这种化合物在治疗各种疾病中的用途，特别是那些受雄激素受体影响或介导的疾病。
• Methods of use and combinations
  申请人：Pfizer Inc.

  公开号：US10328082B2

  公开（公告）日：2019-06-25

  The present invention relates to a compound of Formula 1, 2 or 3: wherein A is N or —CR0—, where R0 is hydrogen, C1-C6 linear or branched chain alkyl, etc., Z is —CRe—, or, —N—, where Re is hydrogen, C1-C6 linear or branched chain alkyl, etc.; R1 is hydrogen, C1-C6 linear or branched chain alkyl, etc.; R2 are independently hydrogen or C1-C6 linear or branched chain alkyl; R3 and R4 are independently hydrogen, C1-C6 linear or branched chain alkyl, etc.; R5 and R6 are independently hydrogen or C1-C6 linear or branched chain alkyl, etc.; R8 is hydrogen, C1-C6 linear or branched chain alkyl, etc.; R9 and R10 are independently hydrogen or C1-C6 linear or branched chain alkyl, etc.; Q is —CO—, —(CH2)q—, —(CHRs)q—, or —(CRsRt)q—, where Rs and Rt are independently C1-C6 linear or branched chain alkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl; where q is 0, 1, 2, or 3; and, where n is 0, 1, 2, 3, 4 or 5; or, a pharmaceutically acceptable salt thereof, for the treatment of certain diseases, particularly those affected or mediated by the androgen receptor; to combinations comprising such compounds with a second pharmaceutically active ingredient; to compositions containing such combinations; and to such combinations for the treatment of various diseases, particularly, those affected or mediated by the androgen receptor.

  本发明涉及式 1、2 或 3 的化合物： 其中 A 是 N 或 -CR0-，其中 R0 是氢、C1-C6 直链或支链烷基等、Z 是-CRe-，或，-N-，其中 Re 是氢、C1-C6 直链或支链烷基等；R1 是氢、C1-C6 直链或支链烷基等；R2 独立地是氢、C1-C6 直链或支链烷基等；R3 和 R4 独立地是氢、C1-C6 直链或支链烷基等；R5 和 R6 独立地是氢、C1-C6 直链或支链烷基等；R8 是氢、C1-C6 直链或支链烷基等；R9 和 R10 独立地是氢、C1-C6 直链或支链烷基等。Q为-CO-、-(CH2)q-、-(CHRs)q-或-(CRsRt)q-，其中 Rs 和 Rt 独立为 C1-C6 直链或支链烷基、芳基、烷芳基、杂芳基或烷基杂芳基；q 为 0、1、2 或 3；n 为 0、1、2、3、4 或 5；或其药学上可接受的盐，用于治疗某些疾病，特别是受雄激素受体影响或介导的疾病；包含此类化合物与第二种药学活性成分的组合物；包含此类组合物的组合物；以及用于治疗各种疾病，特别是受雄激素受体影响或介导的疾病的此类组合物。
• Kiloscale Buchwald–Hartwig Amination: Optimized Coupling of Base-Sensitive 6-Bromoisoquinoline-1-carbonitrile with (<i>S</i>)-3-Amino-2-methylpropan-1-ol
  作者：Jeffrey B. Sperry、Kristin E. Price Wiglesworth、Ian Edmonds、Phillip Fiore、David C. Boyles、David B. Damon、Roberta L. Dorow、Eugene L. Piatnitski Chekler、Jonathan Langille、Jotham W. Coe

  DOI：10.1021/op5002319

  日期：2014.12.19

  This work describes the optimization and scale-up of a Buchwald-Hartwig amination reaction for the preparation of a pharmaceutical intermediate. This C-N bond formation is challenged by the use of a chiral primary amine, which both adds cost and favors formation of biaryl byproducts. In order to develop a scalable process, a number of factors had to be investigated including catalyst selection and stoichiometry of the chiral amine. These all needed to be optimized while maintaining low palladium levels in the isolated product. The reaction was found to be most effective using Pd(dba)2 with BINAP and Cs2CO3 in THF. When executed on 2.5 kg scale, these conditions provided 2.06 kg of the desired product in 80% yield with only 73 ppm residual palladium. To date, this process has been successfully executed to produce more than 12 kg of compound (S)-3.
• CARBONITRILE DERIVATIVES AS SELECTIVE ANDROGEN RECEPTOR MODULATORS
  申请人：Pfizer Inc.

  公开号：EP3148587B1

  公开（公告）日：2021-02-24
• METHODS OF USE AND COMBINATIONS
  申请人：Pfizer Inc.

  公开号：US20170252352A1

  公开（公告）日：2017-09-07

  The present invention relates to a compound of Formula 1, 2 or 3: I II III wherein A is N or —CR 0 —, where R 0 is hydrogen, C 1 -C 6 linear or branched chain alkyl, etc., Z is —CR e —, or, —N—, where R e is hydrogen, C 1 -C 6 linear or branched chain alkyl, etc.; R 1 is hydrogen, C 1 -C 6 linear or branched chain alkyl, etc.; R 2 are independently hydrogen or C 1 -C 6 linear or branched chain alkyl; R 3 and R 4 are independently hydrogen, C 1 C 6 linear or branched chain alkyl, etc.; R 5 and R 6 are independently hydrogen or C 1 -C 6 linear or branched chain alkyl, etc.; R 8 is hydrogen, C 1 -C 6 linear or branched chain alkyl, etc.; R 9 and R 10 are independently hydrogen or C 1 -C 6 linear or branched chain alkyl, etc.; Q is —CO—, —(CH 2 ) q —, —(CHR s ) q —, or —(CR s R t ) q —, where R s and R t are independently C 1 -C 6 linear or branched chain alkyl, aryl, alkylaryl, heteroaryl or alkylheteroaryl; where q is 0, 1, 2, or 3; and, where n is 0, 1, 2, 3, 4 or 5; or, a pharmaceutically acceptable salt thereof, for the treatment of certain diseases, particularly those affected or mediated by the androgen receptor; to combinations comprising such compounds with a second pharmaceutically active ingredient; to compositions containing such combinations; and to such combinations for the treatment of various diseases, particularly, those affected or mediated by the androgen receptor.