[rac]-2-(2-hydroxy-propylamino)-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 英文名称: [rac]-2-(2-hydroxy-propylamino)-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile
• 英文别名: 2-(2-Hydroxypropylamino)-4-(1,2,4,5-tetrahydro-3-benzazepin-3-yl)-6-(2,2,2-trifluoroethoxy)pyrimidine-5-carbonitrile
• 化学式: C₂₀H₂₂F₃N₅O₂
• 分子量: 421.422
• InChiKey: MUOMJWLJOMXJQH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  94.3
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  2-methanesulfonyl-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile 、 异丙醇胺 以 1,4-二氧六环 为溶剂， 生成 [rac]-2-(2-hydroxy-propylamino)-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile
  参考文献：
  名称：

  1,2,4,5-Tetrahydro-benzo[D]azepin derivatives

  摘要：

  本发明涉及1,2,4,5-四氢苯并[d]氮杂环己烷衍生物，以及它们的药用盐，无论是它们的外消旋形式还是光学活性形式，这些化合物是代谢型谷氨酸受体拮抗剂，因此对于治疗与这些受体相关的疾病是有用的。

  公开号：

  US06218385B1

文献信息

• Tetrahydro-benzo(d)azepines and their use as antagonists at metabotropic glutamate receptors
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP1074549A2

  公开（公告）日：2001-02-07

  The present invention is concerned with 1,2,4,5-tetrahydro-benzo[d]azepin derivatives of the general formula wherein R1signifies hydrogen, lower alkyl, oxygen, halogen, or -OR, -O(C3-C6)cycloalkyl, -O(CHR)n-(C3-C6)cycloalkyl, -O(CHR)nCN, -O(CHR)nCF3, -O(CHR)(CHR)nNR2, -O(CHR)(CHR)nOR, -O(CHR)n-lower alkenyl, -OCF3, -OCF2-R, -OCF2-lower alkenyl, -OCHRF, -OCHF-lower alkenyl, -OCF2CRF2, -OCF2Br, -O(CHR)nCF2Br, -O(CHR)n-phenyl, wherein the phenyl group may be optionally substituted independently from each other by one to three lower alkyl, lower alkoxy, halogen, nitro or cyano groups, -O(CHR)(CHR)n-morpholino, -O(CHR)(CHR)n-pyrrolidino, -O(CHR)(CHR)n-piperidino, -O(CHR)(CHR)n-imidazolo, -O(CHR)(CHR)n-triazolo, -O(CHR)n-pyridino, -O(CHR)(CHR)n-OSi-lower alkyl, -O(CHR)(CHR)nOS(O)2-lower alkyl, -O(CH2)nCH=CF2, -O(CHR)n-2,2-dimethyl-[1.3]dioxolane, -O(CHR)n-CHOR-CH2OR, -O(CHR)n-CHOR-(CHR)n-CH2OR or -SR or -S(CHR)nCOOR, or -NR2, -N(R)(CHR)(CHR)nOR, -N(R)(CHR)nCF3, -N(R)(CHR)(CHR)n-morpholino, -N(R)(CHR)(CHR)n-imidazolo, -N(R)(CHR)(CHR)n-pyrrolidino, -N(R)(CHR)(CHR)n-pyrrolidin-2-one, -N(R)(CHR)(CHR)n-piperidino, -N(R)(CHR)(CHR)n-triazolo, -N(R)(CHR)n-pyridino, or nis 1-6; Rsignifies hydrogen, lower alkyl or lower alkenyl, independently from each other, if more than one R is present; R2signifies nitro or cyano; R3signifies hydrogen, lower alkyl, =O, =S, -SR, -S(O)2-lower alkyl, -(C3-C6)cycloalky or piperazino, optionally substituted by lower alkyl, or -CONR2, -(CHR)nCONR2, -(CHR)nOR, -(CH2)n-CF3, -CF3, -(CHR)nOC(O)CF3, -(CHR)nCOOR, -(CHR)nSC6H5, wherein the phenyl group may be optionally substituted independently from each other by one to three lower alkyl, lower alkoxy, halogen, nitro or cyano groups, -(CHR)n-1,3-dioxo-1,3-dihydro-isoindol, -(CHR)n-tetrahydro-pyran-2-yloxy or -(CHR)n-S-lower alkyl, or -NR2, -NRCO-lower alkyl, -NRCHO, -N(R)(CHR)nCN, -N(R)(CHR)nCF3, -N(R)(CHR)(CHR)n-OR, -N(R)C(O)(CHR)nO-lower alkyl, -NR(CHR)n-lower alkyl, -NR(CHR)(CHR)n-OR, -N(R)(CHR)(CHR)n-O-phenyl, wherein the phenyl group may be optionally substituted independently from each other by one to three lower alkyl, lower alkoxy, halogen, nitro or cyano groups, -N(R)(CHR)n-lower alkenyl, -N(R)(CHR)(CHR)n-O-(CHR)nOR, -N(R)(CHR)nC(O)O-lower alkyl, -N(R)(CHR)nC(O)NR-lower alkyl, -N(R)(CH2)n-2,2-dimethyl-[1.3]dioxolane, -N(R)(CHR)(CHR)nmorpholino, -N(R)(CHR)n-pyridino, -N(R)(CHR)(CHR)n-piperidino, -N(R)(CHR)(CHR)n-pyrrolidino, -N(R)(CHR)(CHR)n-O-pyridino, -N(R)(CHR)(CHR)nimidazolo, -N(R)(CHR)n-CR2-(CHR)n-OR, -N(R)(CHR)n-CR2-OR, -N(R)(CHR)n-CHOR-CH2OR, -N(R)(CHR)n-CHOR-(CHR)n-CH2OR, or -OR, -O(CHR)nCF3, -OCF3, -O(CHR)(CHR)n-O-phenyl, wherein the phenyl group may be optionally substituted independently from each other by one to three lower alkyl, lower alkoxy, halogen, nitro or cyano groups, -O(CHR)(CHR)n-O-lower alkyl, -O(CHR)n-pyridino or -O(CHR)(CHR)n-morpholino; and R4signifies hydrogen, lower alkyl, lower alkenyl or nitro, or -OR, -OCF3, -OCF2-R, -OCF2-lower alkenyl, -OCHRF, -OCHF-lower alkenyl, -O(CHR)nCF3, or -(CHR)nCHRF, -(CHR)nCF2R, -(CHR)nCF3, -(C3-C6)cycloalkyl, -(CHR)n(C3-C6)cycloalkyl, -(CHR)nCN, -(CHR)n-phenyl, wherein the phenyl group may be optionally substituted independently from each other by one to three lower alkyl, lower alkoxy, halogen, nitro or cyano groups, -(CHR)(CHR)nOR, -(CHR)nCHORCH2OR, -(CHR)(CHR)nNR2, -(CHR)nCOOR, -(CHR)(CHR)nOSi-lower alkyl, -(CHR)(CHR)n-OS(O)2-lower alkyl, -(CH2)n-CH=CF2, -CF3, -CF2-R, -CF2-lower alkenyl, -CHRF, -CHF-lower alkenyl, -(CHR)n-2,2-dimethyl-[1.3]dioxolane, -(CH2)n-2-oxo-azepan-1-yl, -(CHR)(CHR)n-morpholino, -(CHR)n-pyridino, -(CHR)(CHR)n-imidazolo, -(CHR)(CHR)n-triazolo, -(CHR)(CHR)n-pyrrolidino, optionally substituted by -(CH2)nOH, -(CHR)(CHR)n-3-hydroxy-pyrrolidino or -(CHR)(CHR)n-piperidino, or -NR2, -N(R)(CHR)n-pyridino, -N(R)C(O)O-lower alkyl, -N(CH2CF3)C(O)O-lower alkyl, -N[C(O)O-lower alkyl]2, -NR-NR-C(O)O-lower alkyl or -N(R)(CHR)nCF3, -NRCF3, -NRCF2-R, -NRCF2-lower alkenyl, -NRCHRF, -NRCHF-lower alkenyl; or is absent, if X is -N= or =N-; or R4 and R1 or R3 and R4 are interconnected to the groups -(CH2)3-5-, -(CH2)2-N=, -CH=N-N=-, -CH=CH-N=, -NH-CH=CH- or -NR-CH2-CH2- and form together with the N and C atoms to which they are attached an additional ring; R5, R6signify hydrogen, lower alkyl, lower alkoxy, amino, nitro, -SO2NH2 or halogen; or R5 and R6are interconnected to the group -O-CH2-O- and form together with the C atoms to which they are attached an additional 5-membered ring; R7, R8signify hydrogen, lower alkyl, lower alkoxy, amino, nitro or halogen; R9, R10signify hydrogen or lower alkyl; R11, R12signifies hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkoxycarbonyloxy or lower alkanoyloxy; R13, R14signify hydrogen, tritium or lower alkyl; R15, R16signifies hydrogen, tritium, lower alkyl, hydroxy, lower alkoxy, lower alkoxycarbonyloxy or lower alkanoyloxy or are together an oxo group; or Xsignifies -N=, =N-, -N<, >C= or =C<; Ysignifies -N=, =N-, -NH-, -CH= or =CH-; and the dotted line may be a bond, as well as with their pharmaceutically acceptable salts in their racemic and optically active form. It has surprisingly been found that the compounds of general formula I are antagonists at metabotropic glutamate receptors and therefore useful for the treatment of diseases related to these receptors.

  本发明涉及通式如下的 1，2，4，5-四氢苯并[d]氮杂卓衍生物 其中 R1表示氢、低级烷基、氧、卤素或 -OR、-O(C3-C6)环烷基、-O(CHR)n-(C3-C6)环烷基、-O(CHR)nCN、-O(CHR)nCF3、-O(CHR)(CHR)nNR2、-O(CHR)(CHR)nOR、-O(CHR)n-低级烯基、-OCF3、-OCF2-R、-OCF2-低级烯基、-OCHRF、-OCHRF、-OCHF-低级烯基、-OCF2CRF2、-OCF2Br、-O(CHR)nCF2Br、-O(CHR)n-苯基，其中苯基可任选地被一至三个低级烷基相互独立地取代、低级烷氧基、卤素、硝基或氰基、-O(CHR)(CHR)n-吗啉基、-O(CHR)(CHR)n-吡咯烷基、-O(CHR)(CHR)n-哌啶基、-O(CHR)(CHR)n-咪唑基、-O(CHR)(CHR)n-三唑、-O(CHR)n-吡啶、-O(CHR)(CHR)n-OSi-低级烷基、-O(CHR)(CHR)nOS(O)2-低级烷基、-O(CH2)nCH=CF2、-O(CHR)n-2,2-二甲基-[1.3]二氧戊环，-O(CHR)n-CHOR-CH2OR，-O(CHR)n-CHOR-(CHR)n-CH2OR 或 -SR或-S(CHR)nCOOR，或 -NR2、-N(R)(CHR)(CHR)nOR、-N(R)(CHR)nCF3、-N(R)(CHR)(CHR)n-吗啉基、-N(R)(CHR)(CHR)n-咪唑基、-N(R)(CHR)(CHR)n-吡咯烷基、-N(R)(CHR)(CHR)正-吡咯烷-2-酮，-N(R)(CHR)(CHR)正-哌啶，-N(R)(CHR)(CHR)正-三唑，-N(R)(CHR)正-吡啶，或 n 为 1-6； Rs 表示氢、低级烷基或低级烯基，彼此独立，如果存在一个以上的 R； R2 表示硝基或氰基； R3 指氢、低级烷基、=O、=S、-SR、-S(O)2-低级烷基、-(C3-C6)环烷基或哌嗪基，任选被低级烷基取代，或 -CONR2、-(CHR)nCONR2、-(CHR)nOR、-(CH2)n-CF3、-CF3、-(CHR)nOC(O)CF3、-(CHR)nCOOR、-(CHR)nSC6H5，其中苯基可任选被一至三个低级烷基相互独立地取代、低级烷氧基、卤素、硝基或氰基、-(CHR)n-1,3-二氧代-1,3-二氢-异吲哚、-(CHR)n-四氢吡喃-2-氧基或-(CHR)n-S-低级烷基，或 -NR2、-NRCO-低级烷基、-NRCHO、-N(R)(CHR)nCN、-N(R)(CHR)nCF3、-N(R)(CHR)(CHR)n-OR、-N(R)C(O)(CHR)nO-低级烷基、-NR(CHR)n-低级烷基、-NR(CHR)(CHR)n-OR、-N(R)(CHR)(CHR)n-O-苯基，其中苯基可任选被一至三个低级烷基相互独立取代、低级烷氧基、卤素、硝基或氰基、-N(R)(CHR)n-低级烯基、-N(R)(CHR)(CHR)n-O-(CHR)nOR、-N(R)(CHR)nC(O)O-低级烷基、-N(R)(CHR)nC(O)NR-低级烷基、-N(R)(CH2)n-2,2-二甲基-[1.3]二氧戊环、-N(R)(CHR)(CHR)nmorpholino、-N(R)(CHR)n-吡啶、-N(R)(CHR)(CHR)n-哌啶、-N(R)(CHR)(CHR)n-吡咯烷、-N(R)(CHR)(CHR)n-O-吡啶、-N(R)(CHR)(CHR)n-咪唑，-N(R)(CHR)n-CR2-(CHR)n-OR，-N(R)(CHR)n-CR2-OR，-N(R)(CHR)n-CHOR-CH2OR，-N(R)(CHR)n-CHOR-(CHR)n-CH2OR，或 -OR、-O(CHR)nCF3、-OCF3、-O(CHR)(CHR)n-O-苯基，其中苯基可任选被一至三个彼此独立的低级烷基、低级烷氧基、卤素、硝基或氰基、-O(CHR)(CHR)n-O-低级烷基、-O(CHR)n-吡啶基或-O(CHR)(CHR)n-吗啉基取代；以及 R4 表示氢、低级烷基、低级烯基或硝基，或 -OR、-OCF3、-OCF2-R、-OCF2-低级烯基、-OCHRF、-OCHF-低级烯基、-O(CHR)nCF3 或 -(CHR)nCHRF、-(CHR)nCF2R、-(CHR)nCF3、-(C3-C6)环烷基、-(CHR)n(C3-C6)环烷基、-(CHR)nCN、-(CHR)n-苯基，其中苯基可任选被一至三个低级烷基、低级烷氧基、卤素、硝基或氰基相互独立地取代、硝基或氰基、-(CHR)(CHR)nOR、-(CHR)nCHORCH2OR、-(CHR)(CHR)nNR2、-(CHR)nCOOR、-(CHR)(CHR)nOSi-低级烷基、-(CHR)(CHR)n-OS(O)2-低级烷基、-(CH2)n-CH=CF2、-CF3、-CF2-R、-CF2-低级烯基、-CHRF、-CHF-低级烯基、-(CHR)n-2,2-二甲基-[1.3]二氧戊环，-(CH2)n-2-氧代-氮杂卓-1-基，-(CHR)(CHR)n-吗啉基，-(CHR)n-吡啶基，-(CHR)(CHR)n-咪唑基，-(CHR)(CHR)n-三唑基、-(CHR)(CHR)n-吡咯烷，任选被-(CH2)nOH、-(CHR)(CHR)n-3-羟基吡咯烷或-(CHR)(CHR)n-哌啶取代，或 -NR2、-N(R)(CHR)n-吡啶基、-N(R)C(O)O-低级烷基、-N(CH2CF3)C(O)O-低级烷基、-N[C(O)O-低级烷基]2、-NR-NR-C(O)O-低级烷基或-N(R)(CHR)nCF3、-NRCF3、-NRCF2-R、-NRCF2-低级烯基、-NRCHRF、-NRCHF-低级烯基； 如果 X 是 -N= 或 =N-，则不存在； 或 R4 和 R1 或 R3 和 R4 与基团-(CH2)3-5-、-(CH2)2-N=、-CH=N-N=-、-CH=CH-N=、-NH-CH=CH-或-NR-CH2-CH2-相互连接，并与所连接的 N 原子和 C 原子一起形成一个额外的环； R5、R6 表示氢、低级烷基、低级烷氧基、氨基、硝基、-SO2NH2 或卤素；或 R5 和 R6 与基团 -O-CH2-O- 相互连接，并与所连接的 C 原子一起形成另一个 5 元环； R7、R8 表示氢、低级烷基、低级烷氧基、氨基、硝基或卤素； R9、R10 表示氢或低级烷基； R11、R12 表示氢、低级烷基、羟基、低级烷氧基、低级烷氧基羰氧基或低级烷酰氧基； R13、R14表示氢、氚或低级烷基； R15、R16 表示氢、氚、低级烷基、羟基、低级烷氧基、低级烷氧基羰氧基或低级烷酰氧基，或合在一起表示一个氧代基团；或 X表示-N=、=N-、-NC=或=C<； Y表示-N=、=N-、-NH-、-CH= 或 =CH-；以及 虚线可以是键、 以及外消旋和光学活性形式的药学上可接受的盐类。 令人惊讶的是，通式 I 的化合物是代谢型谷氨酸受体的拮抗剂，因此可用于治疗与这些受体有关的疾病。
• US6218385B1
  申请人：——

  公开号：US6218385B1

  公开（公告）日：2001-04-17
• 1,2,4,5-Tetrahydro-benzo&lsqb;D&rsqb;azepin derivatives
  申请人：Hoffmann-La Roche Inc.

  公开号：US06218385B1

  公开（公告）日：2001-04-17

  The present invention is concerned with 1,2,4,5-tetrahydro-benzo[d]azepin derivatives as well as with their pharmaceutically acceptable salts in their racemic and optically active form, which compounds are antagonists at metabotropic glutamate receptors and therefore useful for the treatment of diseases related to these receptors.

  本发明涉及1,2,4,5-四氢苯并[d]氮杂环己烷衍生物，以及它们的药用盐，无论是它们的外消旋形式还是光学活性形式，这些化合物是代谢型谷氨酸受体拮抗剂，因此对于治疗与这些受体相关的疾病是有用的。