1,1,5,5-tetramethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine | 24782-74-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 1,1,5,5-tetramethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine
• 英文别名: 1,1,5,5-tetramethyl-3,4-dihydro-2H-3-benzazepine
• CAS: 24782-74-9
• 化学式: C₁₄H₂₁N
• 分子量: 203.327
• InChiKey: QPEJHYYABLMLIC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  15
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  12
• 氢给体数：
  1
• 氢受体数：
  1

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)n 、-O(CHR)(CHR)nNR2、-O(CHR)(CHR)nOR、-O(CHR)n-低级烯基、-O 、-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- OR，-O(CHR)n-CHOR-(CHR)n- OR 或 -SR或-S(CHR)nCOOR，或 -NR2、-N(R)(CHR)(CHR)nOR、-N(R)(CHR)n 、-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、-( )n-CF3、- 、-(CHR)nOC(O) 、-(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)n 、-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)( )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- OR，-N(R)(CHR)n-CHOR-(CHR)n- OR，或 -OR、-O(CHR)n 、-O 、-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、-O 、-OCF2-R、-OCF2-低级烯基、-OCHRF、-OCHF-低级烯基、-O(CHR)n 或 -(CHR)nCHRF、-(CHR)nCF2R、-(CHR)n 、-(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)nCHOR OR、-(CHR)(CHR)nNR2、-(CHR)nCOOR、-(CHR)(CHR)nOSi-低级烷基、-(CHR)(CHR)n-OS(O)2-低级烷基、-( )n-CH=CF2、- 、-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，-( )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-( )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( )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)n 、-NR 、-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-( )3-5-、-( )2-N=、-CH=N-N=-、-CH=CH-N=、-NH-CH=CH-或-NR- - -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- -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